Advances in Psoriasis

Advances in Psoriasis
A Multisystemic Guide
Jeffrey M. Weinberg
Mark Lebwohl
Editors
Second Edition
123
Jeffrey M. Weinberg • Mark Lebwohl
Editors
A Multisystemic Guide
Second Edition
Editors
Jeffrey M. Weinberg Mark Lebwohl
Department of Dermatology, Suite 11D Icahn School of Medicine
Icahn School of Medicine at Mount Sinai
at Mount Sinai New York, NY
New York, NY USA
USA
ISBN 978-3-030-54858-2 ISBN 978-3-030-54859-9 (eBook)

https://doi.org/10.1007/978-3-030-54859-9
© Springer Nature Switzerland AG 2014, 2021

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Contents
1 Introduction to and History of Psoriasis and

Psoriasis Therapy�� 1
John B. Cameron and Abby S. Van Voorhees
2 Pathophysiology of Psoriasis/Novel Pathways�� 9
Jeremy M. Hugh and Jeffrey M. Weinberg
3 Psoriasis: Clinical Review and Update�� 19
Ivan Grozdev and Neil J. Korman
4 Psoriasis: Epidemiology, Potential Triggers,
Disease Course�� 27
5 Topical Therapy I: Corticosteroids and
Vitamin D Analogues �� 39
Eric J. Yang and Shari R. Lipner
6 Topical Therapy II: Retinoids, Immunomodulators,
and Others�� 51
Lyn C. Guenther
7 Topical Therapy II: Retinoids, Immunomuodulators,
and Others/Ultraviolet Therapy for Psoriasis �� 71
Kristen M. Beck and John Koo
8 Laser Therapy in Psoriasis�� 93
Quinn Thibodeaux and John Koo
9 Traditional Systemic Therapy I: Methotrexate
and Cyclosporine�� 103
Erin Boh, Andrew Joselow, and Brittany Stumpf
10 Traditional Systemic Therapy II:
Retinoids and Others �� 119
Vignesh Ramachandran, Ted Rosen, Misha Koshelev,
and Fareesa Shuja Sandoval
11 Apremilast�� 141
Jerry Bagel and Elise Nelson
12 Etanercept�� 145
Andrew F. Alexis and Charlotte M. Clark
v
vi Contents
13 Adalimumab for Psoriasis �� 153

Cooper B. Tye and Jennifer C. Cather
14 Infliximab, Golimumab, and Certolizumab Pegol�� 173
Jacob A. Mojeski and Robert E. Kalb
15 Ustekinumab�� 201
George Han, Caitriona Ryan, and Craig L. Leonardi
16 Guselkumab�� 213
Deep Joshipura, Brooke Rothstein, and David Rosmarin
17 Tidrakizumab �� 225
George Han
18 Risankizumab�� 235
Erica B. Lee, Deeti J. Pithadia, Kelly A. Reynolds,
and Jashin J. Wu
19 Secukinumab for the Treatment of Inflammatory
Skin and Joint Disease �� 243
Jason E. Hawkes and Avishan Vishi Hawkes
20 Ixekizumab �� 253
Caitriona Ryan and Roisin O’Connor
21 Brodalumab�� 263
Annika S. Silfvast-Kaiser, Dario Kivelevitch, So Yeon Paek,
and Alan Menter
22 Biosimilars for Psoriasis�� 279
Sarah Lonowski, Nirali Patel, Nika Cyrus,
and Paul S. Yamauchi
23 Research Pipeline I: Oral Therapeutics for Psoriasis�� 291
D. Grand, K. Navrazhina, J. W. Frew, and J. E. Hawkes
24 Research Pipeline II: Upcoming Biologic Therapies�� 303
Ahuva D. Cices and Jeffrey M. Weinberg
25 Pediatric Psoriasis�� 311
Starling Tolliver, Amber N. Pepper, Salma Pothiawala,
and Nanette B. Silverberg
26 Challenges in Psoriasis Treatment: Nail, Scalp,
and Palmoplantar Involvement�� 343
Jeffrey J. Crowley
27 Psoriasis and Comorbidities�� 363
Philip M. Laws and Richard B. Warren
28 Summary of Published Treatment Guidelines�� 399
Vignesh Ramachandran, Abigail Cline,
and Steven R. Feldman
Index�� 415
Introduction to and History
of Psoriasis and Psoriasis Therapy 1
John B. Cameron and Abby S. Van Voorhees
Abstract icity. The use of tar and anthralin, while still in

use today by some, were some of the first
The history of psoriasis has had a long and
modalities to provide care. Early observations
complicated path. With initial challenges in
by Goeckerman and Ingram demonstrated the
recognizing this disease, psoriasis was misun-
benefit of combining these topical treatments
derstood in ancient times as documented in the
with ultraviolet B light to allow for enhanced
Bible as well as in other ancient texts. At first
efficacy. In the 1970s both methotrexate and
mistakenly thought to be leprosy or other infec-
PUVA photochemotherapy were developed,
tious processes such as impetigo, those with
allowing for the outpatient care of psoriasis.
psoriasis were ostracized from their communi-
Systemic and topical retinoids followed, as
ties. It was only in the mid 1800s that Camille
did narrowband UVB. It was however, the ser-
Gibert clarified psoriasis as a papulosquamous
endipitous discovery of the benefit of cyclo-
disease. Remarkable progress in our under-
sporine that truly allowed us to understand the
standing has occurred over the millennium,
importance of the immune system in this dis-
some a result of scientific investigation while
ease. Drugs first targeting T cells were then
other has come as a consequence of serendipity.
followed by those targeting TNF, and now
Even in the just the past decade we continue to
more recently those targeting IL17 and IL23.
refine our understanding of the immune dys-
With each new achievement in the understand-
regulation that causes this condition.
ing of psoriasis, the ability to more finely tar-
Given the poor characterization of this dis-
get the abnormalities of the immune system
ease, those with psoriasis also suffered from a
has improved, and with that, the efficacy of
lack of effective treatments. We review the
our newest agents has greatly expanded.
history of the treatments that have been
employed. Starting with Fowler’s solution,
sometimes the treatments had significant tox-
Key Learning Objectives
1. To understand the evolution of the under-
J. B. Cameron standing of the pathogenesis of psoriasis
Department of History, Old Dominion University, 2. To understand the evolution of the treat-
Norfolk, VA, USA ment paradigm for psoriasis
A. S. Van Voorhees (*) 3. To describe the evolving understanding
Department of Dermatology, Eastern Virginia of the diagnosis of psoriasis over time
Medical School, Norfolk, VA, USA
e-mail: [email protected]
© Springer Nature Switzerland AG 2021 1

J. M. Weinberg, M. Lebwohl (eds.), Advances in Psoriasis,
https://doi.org/10.1007/978-3-030-54859-9_1
2 J. B. Cameron and A. S. Van Voorhees
History of Psoriasis MOIST
An understanding of disease overall and, skin dis-

air water
ease in particular, has been a unique part of modern G
WI
IN od old N
times. Previously those with psoriasis were often ho a
TE e
ch R
SP
PH
mislabeled, poorly regarded, and suffered as a con-
R
OD
ild
g
L
EG
BL
sequence. Symptoms were often considered the dis-
Sanguine Phlegmatic
ease itself, and consequent progress in treatment HOT choleric Melancholic COLD
R bille)
MELA
was limited by this lack of understanding of the dis-
(bla NC
LEellow
ma UM
k c
ease and its cause. The history of psoriasis therefore
AU
y
bil
r e
tur
wo O
(yello CH HO )
T
LY ty
i
requires an appreciation of how the understanding
th
ER
You M N
of disease has progressed over time and the often SU
M
Fire earth
serendipitous findings of treatment options.
Pre-scientific societies often viewed disease
as resulting from a violation of the sacred order, DRY
the malignant influence of magic or the breaking DIAGRAM OF HUMOURS, ELEMENTS,
QUALITIES, AND SEASONS
of a taboo. For example the entire thirteenth
chapter of the Book of Leviticus concerns how
the priests may determine if an outbreak on the
skin is leprosy and the fourteenth chapter con- I dentification of Psoriasis as a Unique
cerns which animals (lambs and birds) shall be Disease
sacrificed to purify the victim.1
The first cultures that developed notions of It is extremely difficult to tease out the history of
rational science were China and Greece. Western psoriasis and its treatment in the ancient world
medicine finds its roots in the Greek belief that dis- because of confusion between psoriasis and
ease results from natural causes, that in some way many other diseases. Furthermore in the past the
the balance or integrity of the body has been dis- names assigned to diseases and symptoms were
rupted. Treatment, therefore, consisted in restoring arbitrary and inconsistent. Identification of pso-
that balance or integrity. Hippocrates may be the riasis in Egypt is especially difficult because of
father of western medicine but the most influential confusion between the disease and leprosy in
founder was more likely Galen of Pergamon (130– later times.3 However, since extensive examina-
200 CE) To Galen the human body was a very tion of Egyptians mummies would indicate that
complex organism made up not just of the four leprosy was not present in Egypt before the com-
humors but also of gradations of dry and moist and mon era, it is possible that psoriasis was misla-
hot and cool.2 Treatment of disease was not limited beled as leprosy.
to bleedings and purges but also included the use of We face similar problems of terminology in
lotions designed to restore health. Galen’s system Greek medicine. The Corpus Hippocraticum
was so completely accepted that only in the nine- contains precise descriptions and treatments for
teenth century would the humors and miasma dis- many recognizable diseases of the skin.4 Again, it
appear from medical belief to be replaced by the is likely that much of what was referred to as lep-
germ theory of disease. rosy was in fact psoriasis. The appearance of true
leprosy early in the common era compounded the
confusion and sometimes lead to harsh treat-
The Bible Book of Leviticus, chapters 13 and 14.
1
Arikha, N (2007) Passions and Tempers. Harper

2
Perennial, New York. Also Crissey, JT, Parish, LC, Stelley,

3
Pusey WA (1933) History of Dermatology. Charles
WB (1981) The Dermatology and Syphilology of the C. Thomas, Baltimore, pp 11–17.
Nineteenth Century. Praeger Scientific, New York, 4
pp. 4–5. C. Thomas, Baltimore, pp 19–25.
1 Introduction to and History of Psoriasis and Psoriasis Therapy 3
ments for those with psoriasis since lepers were he delivered an address entitled, “The Etiology
often isolated and forbidden to associate with of Psoriasis” pointing out the tendency of
non-leprosy population. prior trauma to produce psoriasis lesions. The
The first indisputable reference to psoriasis “Koebner Phenomenon” is still viewed as an
comes from the fifth and sixth books of Aulus important indication of psoriasis.9 In 1898
Cornelius Celsus, De Re Medica (circa 25 BCE- Munro described the micro abscesses of pso-
circa 50 CE) a Roman who compiled an exten- riasis now called Munro’s abscesses. With the
sive list of diseases and treatment for use by addition in the early twentieth century of Leo
estate owners.5 Celsus did not use the term pso- van Zumbusch of generalized pustular psoriasis
riasis but rather describes it under the heading and Waranoff’s description of the pale halo now
impetigo. called “woranoff ring,” accurate diagnosis of
After the collapse of Roman culture, the prac- psoriasis became commonplace.
tice of scientific medicine in the west disappeared
and only returned as a part of the Renaissance.
Geronimo Mercurialis penned a summary of History of the Treatment of Psoriasis
what was known of skin diseases in 1572.6
Mercuralis lumped psoriasis in with other dis- The history of the treatment of psoriasis has
eases as Lepra. He mentions several treatments been largely driven by serendipitous findings.
including wolf dung rubbed in with vinegar, The late 1700s and 1800s included treatments
blood of a mountain goat as well as the rubbing such as arsenic, chrysarobin and ammoniated
of psoriasis with cantharides. mercury. Anthralin and tar came into widespread
Robert Willan (1757–1812) set out clear use in the first half of the twentieth century.
and uniform nomenclature of skin diseases in Starting in the 1950s topical steroids were devel-
1809. However, his terminology unfortunately oped followed by the arrival of methotrexate,
perpetuated some confusion in that he called retinoids, and immunosuppressive medications
psoriasis lepra vulgaris.7 That confusion would in the 1970s, 1980s and 1990s respectively. An
end by mid-century when Camille Melchoir enhanced understanding of the pathogenesis of
Gibert (1792–1866) dropped lepra vulgaris psoriasis has allowed for more targeted drug
and used only psoriasis as the sole term for development in the twenty-first century. Our
the disease and his work made clear important therapeutic armamentarium now includes medi-
distinctions among papulosquamous diseases.8 cations known as the biologics which target vari-
Gibert’s successors improved the distinctions. ous aspects of the immune system allowing for
Hebra fully distinguished the clinical practice its regulation.
of leprosy from psoriasis; Heinrich Auspitz
(1835–1886) noted bleeding points after remov-
ing scales (Auspitz sign); Heinrich Köebner rsenic, Ammoniated Mercury
A
made an important contribution in 1872 when and Chrysarobin
During the eighteenth and nineteenth centuries

5
C. Thomas, Baltimore, p. 28. three topical agents are known to have been used
6
Sixteenth Century Physician and his Methods: in the treatment of psoriasis. While probably first
Mercurialis on Diseases of the Skin. Translated from De developed by the ancient Greeks, arsenic solu-
Morbis Cutaneis et Omnibus Corporis Humani tion was first utilized in dermatology in 1786.10
Excrementis Tractatus, by Sutton RL Jr (1986) The Lowel
Press,Kansas City, Missouri.
7
Pusey WA (1933) History of Dermatology. Charles Crissey JT, Parish LC, Shelley WB (1981) The dermatol-
9
C. Thomas, Baltimore, pp62ff. ogy and syphilology of the nineteenth century. Praiger
8
Pusey WA (1933) History of Dermatology. Charles Publishers, New York, pp 367–369.
C. Thomas, Baltimore, pp 81–82. 10
Farber M, “History of the treatment of psoriasis,” J
The first report of its use in psoriasis though was acid, zinc oxide and ultraviolet light. For many
attributed to Girdlestone in 1806. He is credited decades this combination was the mainstay of
with noting the efficacy of Fowler’s solution for psoriasis treatment in Europe.
improving the lesions of psoriasis.11 Ammoniated Coal tar was also pioneered in the early 1900s.
mercury, another topical agent was also used at In 1925 Goeckerman noted the beneficial effect
this same time.12 The use of this mercury in the of the combination of coal tar with ultraviolet
topical treatment of psoriasis has been attrib- light B radiation in the treatment of psoriasis.15
uted to Dr. Fox in 1880. It was championed as While the beneficial effect of sunlight on psoria-
well by Duhring. The use of both of these topi- sis had been long known, Goeckerman realized
cal agents continued until the 1950s and 1960s that this effect might be enhanced if combined
when concerns about their possible toxicity risks with a topical photosensitizer. The success of this
and accidental poisonings caused their prohibi- approach was demonstrated by its widespread
tion. The third topical agent that was identified use for many decades. While both the Goeckerman
was chrysarobin. A serendipitous finding, it was protocol and the Ingram protocol were often
noted to be of benefit in the treatment of psoriasis effective, the main limitation of these approaches
by Balmonno Squire in 1876. His patient, who was that they were very time-intensive, requiring
was using Goa powder to treat a presumed fungal patients to remain hospitalized for weeks each
infection, was noted to have improvement of his year to control their disease.
psoriasis. Kaposi in 1878 also published his expe-
rience with this topical approach to psoriasis.
Corticosteroids
Anthralin and Tar The development of steroids both for systemic

and topical use revolutionized the treatments of
After the first identification of the potential ben- many diseases including psoriasis. First discov-
efit of chrysarobin, the 1900s were a time of its ered in 1950, it was only two years later that the
further exploration. During the early part of this potential role of this agent in a topical form was
century scientists learned how to convert chrysa- demonstrated in psoriasis.16 Known as compound
robin to anthralin. The active agent was identified F, hydrocortisone was beneficial in treating pso-
as 2-methyl dithranol. During World War 1 when riasis. From this time to the present, topical ste-
natural supplies were interrupted the process of roids have continued to play a significant role in
synthesizing anthralin was discovered. It was reducing the inflammation in various cutaneous
then in 1916 that Unna came to understand the conditions. Topical steroids continue to be the
potential of this compound in the treatment of most frequently prescribed medication in the
psoriasis.13 In 1953, Ingram further refined the treatment of psoriasis today.
treatment of psoriasis with anthralin.14 He dem-
onstrated that treatment could be enhanced by
utilizing the combination of anthralin, salicylic Methotrexate and PUVA
Amer Acad Dermaol 1992; 27: 640–5. Methotrexate was developed in the 1950s for the
Bechet PE, “History of the use of arsenic in dermatol-
11 treatment of malignancies. As seen with treat-
ogy,” Arch Dermatol 1931; 23: 110–7. ments before, it was only a short while before its
Farber EM, “History of the treatment of psoriasis,” J
12
Amer Acad Dermatol 1992; 27: 640–5.

Unna PG” Cignolin als Heilmittel der psoriasis,”
13 15
Goeckerman WH, “Treatment of Psoriasis,” Northwest
Dermatol Wochenschr 1916; 62: 116–86. Fry L,” Med 1925; 24: 229.
Psoriasis,” 1988; 119: 445–561. 16
Sulzberger MB, Witten VH, “The Effect of topically
Ingram JT, “The Approach to Psoriasis,” Br Med J 1953;
14
applied coumpound F in select dermatoses,” J Invest
2: 591–594. Dermatol 1952; 19: 101.
potential in the treatment of psoriasis was identi- However, in the late 1970s the first reports sur-
fied. In 1946 Farber developed aminopterin for faced of cutaneous malignancies.22 Longitudinal
the treatment of leukemia. Five years later studies of the original cohort of patients in subse-
Gubner noted its role in the treatment of psoria- quent years confirmed this finding.23 Stern noted
sis.17 While using this agent in the treatment of the increase risk of SCC, BCC and potentially
Rheumatoid arthritis, he noted that his patient, melanoma skin cancer in those treated with high-
who concurrently had psoriasis, also had dose exposures and long-term therapy. Concerns
improvement of his skin. A more stable deriva- about the potential risk of cutaneous malignancy
tive of aminopterin with less toxicity, methotrex- has limited the utilization of this modality over
ate, was introduced in 1958 for the treatment of the past decades.
psoriasis.18 This agent was subsequently approved
by the FDA for the treatment of psoriasis in 1972
after the first guidelines for its use were pub- arrowband UVB, Retinoids,
N
lished.19 It continues to be an important agent in Vitamin D
the treatment of psoriasis today.
The efficacy of PUVA in the treatment of pso- As the potential risk of non-melanoma skin can-
riasis was also demonstrated during the 1970s. cers associated with long-term use of PUVA
While the combination of ultraviolet light and a became increasingly apparent, discoveries con-
photosensitizing compound had been used in the tinued and additional new approaches to treat
treatment of vilitigo for hundreds of years in psoriasis came into prominence in the 1980s and
Egypt and in India,20 the demonstration of its role the 1990s. Parrish and Jaenicke identified what
in psoriasis was novel. Ancient healers had those has come to be known as narrowband UVB.24
with vitiligo ingest psoralen-rich foods such as They identified that the most therapeutically
figs and limes and then exposed their skin to nat- effective wavelengths of UVB were those
ural sunlight. It took however until 197421 to between 300–313 nm, while the remaining wave-
demonstrate the effectiveness of the combination lengths of UVB light contributed primarily to the
of psoralen and artificial UVA light exposure development of erythema. Subsequently, 311 nm
(320–400 nm) in psoriasis. Known as PUVA, this was identified as the most efficacious wavelength
therapeutic approach was a highly efficacious for the clearance of psoriasis lesions.25 This
approach for many patients with chronic psoria- modality therefore allowed for clearance of the
sis. PUVA was widely utilized since it allowed skin with more limited risk of erythema; narrow-
patients to achieve control of their disease with- band UVB has come to replace the broad-band
out incurring long inpatient hospitalizations. UVB phototherapy upon which it was based.
In the 1980s systemic retinoids previously
Guber R, August S, Ginsbergerg V,” Therapeutic sup-
17 developed for acne and hyperkeratosis were also
pression of tissue reactivity; effect of aminopterin in
Rheumatoid arthritis and psoriasis,” Am J Med Sci 1951; 22
Stern RS, Thibodeau LA, Kleinerman RA, Parrish JA,
221: 176–182. Fitzpatrick TB, et al, “Risk of Cutaneous Carcinoma in
Edmondson W, Guy WB, “Treatment of psoriasis with
18
patients treated with oral methoxsalen photochemother-
folic acid antagonist,” Arch Dermatol 1958; 78(2) apy for psoriasis,” New Engl J Med 1979; 300: 809–813.
200–203. 23
Stern RS, Lange R, et al, “Non-melanoma Skin Cancer
Roenigk HH Jr, Maibach HI, Weinstein G, “Guidelines
19
Occurring in patients treated with PUVA Five to Ten Years
in methotrexate therapy for psoriasis,” Arch Dermatol after First Treatment, J Invest Dermatol 1988; 91:
1972; 105: 363–365. 120–124.
Gupta AK, Anderson TF, “Psoralen photochemother-
20 24
Parrish JA, Jacnicke KF, “Action Sprectrum for photo-
apy,” 1987; 17: 703–34. therapy of Psoriasis,” J Invest Dermatol 1981; 76(5):
Parrish Jam Fitzpatrick TB, Tanenbaum L, Pathak M,
21 359–62.
“Photochemotherapy of psoriasis with oral methoxsalen 25
Green C, Ferguson J, Lakshmipathi T, Johnson BE,”
and longwave ultraviolet light,” New Engl J Med 1974; 311 nm UVB phototherapy-an effective treatment for pso-
291: 1207–1211. riasis,” Br J Dermatol 1988; 119: 691–6.
explored for their possible benefit in the treat- approval was delayed until the 1990s because of
ment of psoriasis. The second-generation retinoid concerns of possible risks associated with this
etretinate, followed by the development of its medication.29
metabolite acitretin, were both shown to be ben- The knowledge gained in the twenty first cen-
eficial.26 Etretinate was eventually removed from tury from cyclosporine in the understanding of
the market given its lipophilic nature and conse- psoriasis opened the door for the development of
quent persistence in the subcutaneous fat. medications that more specifically targeted the
Acitretin however, remains a systemic treatment immune system. A number of biologic agents
of psoriasis today. A third generation retinoid, were initially developed which included those
tazarotene was also developed as a topical agent targeting T cells as well as those targeting tumor
that continues to be utilized in the treatment of necrosis factor and IL 12/23. While heralded with
psoriasis. great promise, the T cell targeting compounds
Vitamin D and its derivatives were investi- alefacept30 and efulizumab31 have subsequently
gated in the 1980s as well. Based on a chance been removed from the market because of poten-
observation of a patient’s psoriasis skin improv- tial side effects and/or lack of efficacy. However
ing with the administration of systemic Vitamin the TNF inhibitors—adalimumab,32 etanercept,33
D, the development of topically applied Vitamin and infliximab34 and the IL-12/23 compound
D derivatives began. While still not fully under- ustekinumab35 have revolutionized the care of
stood, these topical agents remain important in patients with psoriasis. They have become main-
the armamentarium of dermatologists when treat- stays in the treatment of this disease. The initial
ing patients with psoriasis.27 assumption about ustekinumab was that the IL12
portion was the key blockade. Instead research
has now established that the IL23 inhibition is
Systemic Immunosuppressive most important in psoriasis. This has opened our
Medications eyes to an ever-greater understanding of the
Understanding the importance of immunosup- 29

Griffiths CEM, DUBrtret L, Ellis CN, et al, “CIclosporin
pression in the treatment of psoriasis was another in psoriasis clinical practice: an international consensus
statement,” Br J Dermatol 2004; 150 (Suppl 67): 11–23.
example of gains achieved by serendipitous find- 30
Ellis CN, Krueger GG, “Alefacept Study Group.
ings. When cyclosporine was initially developed Treatment of CHorinc Plaque Psoriasis by selective tar-
in the 1970s the critical role of the immune sys- geting of memory effector T lymphocytes,” New Engl J
tem in the pathogenesis of psoriasis was not yet Med 2001; 345(4): 248–25.
appreciated. When transplant patients who coin- 31
Gordon KB, Papp KA, Hamilton TK, et al, “Efalizumab
cidentally had psoriasis were placed on cyclospo- for patients with moderate to severe plaque psoriasis: a
randomized controlled trial“JAMA 2003; 290 (23):
rine to prevent graft rejection they were noted to 3073–80.
have improvement of their skin lesions.28 The 32
Menter A, Tyring SK, Gordon K, et al, “Adalimumab
efficacy of this treatment on the psoriasis helped therapy for moderate to severe psoriasis: a randomized,
to identify the importance of T cells, and the controlled phase 3 trial,” J Amer Acad Dermatol 2007; 58:
immune system more generally, in this disease. 106–15.
Despite its demonstrated effectiveness FDA
33
Leonardi CL, Powers JL, Matheson RT, et al, “Etanercept
Psoriasis Study group: Etanercept as monotherapy in
patients with psoriasis,” New Engl J Med 2003; 349 (21):
Ellis CN, Voorhees JJ, “Etretinate therapy,” J Amer Acad
26
2014–22.
Dermatol, 1987; 16: 267–91. 34
Chaudri U, Romano P, Mulcahy LD, et al,” Efficacy and
Kragballe K, Beck HI, Sogaard H, “Improvement of
27
safety of infliximab monotherapy for plaque-type psoria-
psoriasis by a topical Vitamin D3 analogue (MC 903) in a sis: a randomized trial,” Lancet 2001; 357 (9271):
double-blind study,” Br J Dermatol 1988; 119(2): 1842–7.
223–230. 35
Krueger GG, Langley RG, Leonardi C, et al, “A Human
Mueller W, Hermann B, “Cyclosporin A for psoriasis,”
28
interleukin-12/23 monoclonal antibody for the treatment
New Engl J Med 1979; 301 (10): 555. of psoriasis,” New Engl J Med 2007; 356: 580–92.
immune system and the key role of IL17 cells in associated with psoriatic arthritis, we have
the immunologic cascade in psoriasis. With each become more aware of the frequency with which
new class of medication developed, the role of psoriasis patients suffer from other concurrent
the immune system in psoriasis has become illnesses such as inflammatory bowel disease,
increasingly apparent. This knowledge has diabetes and obesity. Patients with psoriasis have
allowed for the development of IL17 inhibitors also been shown to have an increased risk of car-
including secukinumab36 and Ixekizumab,37 IL17 diovascular disease including cardiovascular
receptor blocker brodalumab,38 and IL23 inhibi- death, and more frequently suffer from the meta-
tors guselkumab39 and rizukizumab.40 New agents bolic syndrome, sleep apnea, renal disease and
targeting different sites of the inflammatory cas- others.
cade are currently under development and may Thus, our understanding of psoriasis as well
further add to both our understanding of psoriasis as the knowledge of how to treat this disease has
and our therapeutic armamentarium. become inextricably linked over time. With each
In addition to understanding the pathogenesis step forward therapeutically, more and more is
of psoriasis we have also come to understand that learned so that we enhance our understanding
psoriasis is truly a disease of systemic inflamma- this disease process. This new knowledge has
tion. While long known that psoriasis can be facilitated the development of medications with
which to treat psoriasis, thereby allowing patients
to achieve control of their disease. The expecta-
LangleyRG, Elewski BE, Lebwohl M, et al,
36
tion for treatment response has increased to lev-
“Secukinumab in plaque psoriasis-results of two phase 3
els unimaginable only ten years ago. Each step in
trials,” NEJM 2014; 371(4): 326–338.
Gordon KB, Blauvelt A, Papp KA, et al, “Phase 3 trials
37 the understanding of the disease as well as its
of Ixekizumab in Moderate to Severe Psoriasis,” NEJM possible treatments has been built upon the les-
2016; 375(4): 345–356. sons learned previously. The National Psoriasis
Lebwohl M, Strober B, Menter A, et al, “Phase 3 studies
38
Foundation has set target goals for those with
comparing Brodalumab with Ustekinumab in psoriasis of having a body surface area of 1 or
Psoriasis“NEJM 2015; 373: 1318–1328.
less while on treatment. With the vast array of
Reich K, Armstrong AW, Foley P, et al, “Efficacy and
39
Safety of guselkumab, an anti-interleukin-23 monoclonal medications at our disposal and their ability to
antibody compared with adalimumab for the treatment of allow for clearance of the skin, achieving clear or
patients with moderate to severe psoriasis with random- almost clear skin has become an obtainable goal.
ized withdrawal and retreatment: results from the phase 3, We may soon be entering an era where “the heart-
double-blind, placebo- and active comparator-controlled
Voyage 2 trial,” J Amer Acad Dermatol 2017; 76(3): break of psoriasis” reigns no more.
418–431.
Gordon KB, Strober B, Lebwohl M, “Efficacy and
40 Disclosures John B. Cameron Ph.D.—none
Safety of Risankizumab in Moderate to Severe plaque Abby S. Van Voorhees, MD—She has served as a con-
psoriasis (UltiMMa-1 and UltiMMa-2): results from two sultant for the following companies:
double-blind, randomized, placebo-controlled and Derm Tech, WebMD, Novartis, Lilly, UCB, Celgene.
ustekinumab-controlled phase 3 trials,” Lancet 2018; 39: —She has served as an investigator for Celgene, Lilly,
650–661. AbbVie.
Pathophysiology of Psoriasis/
Novel Pathways 2
Jeremy M. Hugh and Jeffrey M. Weinberg
Abstract and IL-23 secreted by antigen-presenting cells

(APCs) in the skin. Through various cytokines,
1 . Psoriasis is a systemic inflammatory disease.
such as tumor necrosis factor (TNF) α, these
2. We now have an increased understanding of
cells cause a chronic inflammatory state and
the specific cytokines involved in the disease.
alter epidermal hyperproliferation, differentia-
3. Therapies have been developed to target these
tion, apoptosis, and neoangiogenesis that pro-
cytokines.
duce the cutaneous findings seen in this disease.
The newer biologic therapies target the immu-
nologic signaling pathways and cytokines identi-
fied in the pathogenesis of psoriasis and provide
1. To learn the underlying pathophysiol-
notable clinical improvement. Further study in
ogy of psoriasis
the pathogenesis of psoriasis can help identify
2. To learn how treatments were developed
targets for future therapies.
with the increased understanding of
The last 30 years of research and clinical
psoriatic pathways
practice have revolutionized our understanding
3. To understand novel pathways eluci-

of the pathogenesis of psoriasis as the dysregula-
dated for psoriasis
tion of immunity triggered by environmental and
genetic stimuli. Psoriasis was originally regarded
as a primary disorder of epidermal hyperprolif-
Psoriasis is a genetically programmed pathologic eration. However, experimental models and clini-
interaction among skin cells, immunocytes, and cal results from immunomodulating therapies
numerous biologic signaling molecules that is have refined this perspective in conceptualizing
triggered by environmental stimuli. The immune psoriasis as a genetically programmed pathologic
response is a cellular one; type 1 (TH1) and interaction among resident skin cells; infiltrating
type 17 (TH17) T cells are activated by IL-12 immunocytes; and a host of proinflammatory
cytokines, chemokines, and growth factors pro-
J. M. Hugh duced by these immunocytes. Two populations of
Department of Dermatology, University of Colorado, immunocytes and their respective signaling mol-
Aurora, CO, USA ecules collaborate in the pathogenesis: (1) innate
J. M. Weinberg (*) immunocytes, mediated by antigen-presenting
Department of Dermatology, Icahn School of cells (APCs)(including natural killer (NK) T
Medicine at Mount Sinai, New York, NY, USA lymphocytes, Langerhans cells, and neutrophils),

https://doi.org/10.1007/978-3-030-54859-9_2
10 J. M. Hugh and J. M. Weinberg
and (2) acquired or adaptive immunocytes, medi- the innate and the acquired (or adaptive) immune
ated by mature CD4+ and CD8+ T lymphocytes responses—both of which contribute to the
in the skin. Such dysregulation of immunity and pathophysiology of psoriasis [2]. Innate immu-
subsequent inflammation is responsible for the nity responses occur within minutes to hours of
development and perpetuation of the clinical antigen exposure but fail to develop memory for
plaques and histological inflammatory infiltrate when the antigen is encountered again. However,
characteristic of psoriasis. adaptive immunity responses take days to weeks
Although psoriasis is considered to be an to respond after challenged with an antigen.
immune-mediated disease in which intralesional The adaptive immune cells have the capacity to
T lymphocytes and their proinflammatory sig- respond to a greater range of antigens and develop
nals trigger primed basal layer keratinocytes to immunologic memory via rearrangement of anti-
rapidly proliferate, debate and research focus on gen receptors on B and T cells. These specialized
the stimulus that incites this inflammatory pro- B and T cells can then be promptly mobilized and
cess. Our current understanding considers psoria- differentiated into mature effector cells that pro-
sis to be triggered by exogenous or endogenous tect the host from a foreign pathogen.
environmental stimuli in genetically susceptible Innate and adaptive immune responses are
individuals. Such stimuli include group A strep- highly intertwined; they can initiate, perpetuate,
tococcal pharyngitis, viremia, allergic drug reac- and terminate the immune mechanisms respon-
tions, antimalarial drugs, lithium, beta-blockers, sible for inflammation. They can modify the
IFN-α withdrawal of systemic corticosteroids, nature of the immune response by altering the
local trauma (Köebner phenomenon), and emo- relative proportions of type 1 (TH1), type 2 (TH2),
tional stress. These stimuli correlate with the and the more recently discovered type 17 (TH17)
onset or flares of psoriatic lesions. Psoriasis subset of helper T cells and their respective sig-
genetics centers on susceptibility loci and corre- naling molecules. A TH1 response is essential
sponding candidate genes, particularly the psori- for a cellular immunologic reaction to intracel-
asis susceptibility (PSORS) 1 locus on the major lular bacteria and viruses or cellular immunity.
histocompatibility complex (MHC) class I region. A TH2 response promotes IgE synthesis, eosino-
Current research on the pathogenesis of psoriasis philia, and mast cell maturation for extracellu-
examines the complex interactions among immu- lar parasites and helminthes as well as humoral
nologic mechanisms, environmental stimuli, and immunity, while a TH17 response is important for
genetic susceptibility. After discussing the clini- cell-mediated immunity to extracellular bacteria
cal presentation and histopathologic features of and plays a role in autoimmunity [3]. The innate
psoriasis, we will review the pathophysiology and adaptive immune responses employ com-
of psoriasis through noteworthy developments, mon effector molecules such as chemokines and
including serendipitous observations, reactions cytokines, which are essential in mediating an
to therapies, clinical trials, and animal model immune response.
systems that have shaped our view of the disease
process. In addition to the classic skin lesions,
approximately 23% of psoriasis patients develop Implicating Dysregulation
psoriatic arthritis, with a 10-year latency after of Immunity
diagnosis of psoriasis [1].
Our present appreciation of the pathogenesis of
psoriasis is based on the history of trial-and-error
Principles of Immunity therapies; serendipitous discoveries; and the cur-
rent immune targeting drugs used in a variety
The immune system, intended to protect its of chronic inflammatory conditions, including
host from foreign invaders and unregulated cell rheumatoid arthritis, ankylosing spondylitis, and
growth, employs two main effector pathways— inflammatory bowel disease. Before the mid-
2 Pathophysiology of Psoriasis/Novel Pathways 11
1980s, research focused on the hyperproliferative They were injected into prepsoriatic skin grafted
epidermal cells as the primary pathology because on immunodeficient mice, creating a psoriatic
a markedly thickened epidermis was indeed plaque with an immune response showing cyto-
demonstrated on histologic specimens. Altered kines from TH1 cells rather than TH2 cells [12].
cell-cycle kinetics were thought to be the culprit When psoriatic plaques were treated topically
behind the hyperkeratotic plaques. Thus, initial with the toll-like receptor 7 agonist imiquimod,
treatments centered on oncologic and antimitotic aggravation and spreading of the plaques were
therapies used to arrest keratinocyte proliferation noted. The exacerbation of psoriasis was accom-
with agents such as arsenic, ammoniated mer- panied by an induction of lesional TH1-type
cury, and methotrexate [4]. interferon produced by plasmacytoid dendritic
However, a paradigm shift from targeting epi- cell (DC) precursors. Plasmacytoid DCs were
dermal keratinocytes to immunocyte populations observed to compose up to 16% of the total der-
was recognized when a patient receiving cyclospo- mal infiltrate in psoriatic skin lesions based on
rine to prevent transplant rejection noted clearing their coexpression of BDCA2 and CD123 [13].
of psoriatic lesions in the 1980s [5]. Cyclosporine Additionally, cancer patients being treated with
was observed to inhibit messenger RNA tran- interferon alfa experienced induction of psoriasis
scription of T-cell cytokines, thereby implicating [14]. Moreover, patients being treated for warts
immunologic dysregulation, specifically T-cell with intralesional interferon alfa developed pso-
hyperactivity, in the pathogenesis of psoriasis [6]. riatic plaques in neighboring prior asymptom-
However, the concentrations of oral cyclosporine atic skin [15]. Patients with psoriasis who were
reached in the epidermis exerted direct effects treated with interferon gamma, a TH1 cytokine
on keratinocyte proliferation and lymphocyte type, also developed new plaques correlating
function in these patients [7]. Thus, the question with the sites of injection [16].
was raised as to whether the keratinocytes or the
lymphocytes drove the psoriatic plaques. The use
of an IL-2 diphtheria toxin-fusion protein, deni- Intralesional T Lymphocytes
leukin diftitox, specific for activated T cells with
high-affinity IL-2 receptors and nonreactive with Psoriatic lesions contain a host of innate immu-
keratinocytes, distinguished which cell type was nocytes, such as APCs, NK cells, and neutrophils,
responsible. This targeted T-cell toxin provided as well as adaptive T cells and an inflammatory
clinical and histological clearing of psoriatic infiltrate. These cells include CD4 and CD8
plaques. Thus, T lymphocytes rather than kerati- subtypes in which the CD8+ cells predominate
nocytes were recognized as the definitive driver in the epidermis, while CD4+ cells show prefer-
behind the psoriatic plaques [8]. ence for the dermis [17]. There are two groups of
Additional studies have demonstrated that CD8+ cells: one group migrates to the epidermis,
treatments that induce prolonged clearing of pso- expressing the integrin CD103, while the other
riatic lesions without continuous therapy, such group is found in the dermis but may be headed
as psoralen plus UVA irradiation, decreased the to or from the epidermis. The CD8+ cells residing
numbers of T cells in plaques by at least 90% in the epidermis that express the integrin CD103
[9]. However, treatments that require continual are capable of interacting with E-cadherin, which
therapy for satisfactory clinical results, such as enables these cells to travel to the epidermis and
cyclosporine and etretinate, simply suppress bind resident cells. Immunophenotyping reveals
T-cell activity and proliferation [10, 11]. that these mature T cells represent chiefly acti-
Further evidence has linked cellular immu- vated memory cells, including CD2+, CD3+,
nity with the pathogenesis of psoriasis, defining CD5+, CLA, CD28, and CD45RO+ [18]. Many
it as a TH1-type disease. Natural killer T cells of these cells express activation markers such as
were shown to be involved through the use of a HLA-DR, CD25, and CD27, in addition to the
severe combined immunodeficient mouse model. T-cell receptor (TCR).
T-Lymphocyte Stimulation psoriasis [20]. Furthermore, the cytokines pro-

duced from the immunologic response, such as
Both mature CD4+ and CD8+ T cells can respond tumor necrosis factor (TNF) α, IFN-γ, and IL-2,
to the peptides presented by APCs. Although correspond to cytokines that are upregulated in
the specific antigen that these T cells are react- psoriatic plaques [21].
ing to has not yet been elucidated, several anti- Integral components of the immunologic syn-
genic stimuli have been proposed, including apse complex include co-stimulatory signals,
self-proteins, microbial pathogens, and micro- such as CD28, CD40, CD80, and CD86, and adhe-
bial superantigens. The premise that self-reactive sion molecules such as cytotoxic T-lymphocyte
T lymphocytes may contribute to the disease antigen 4 and lymphocyte function- associated
process is derived from the molecular mimicry antigen (LFA) 1, which possess corresponding
theory in which an exuberant immune response receptors on the T cell. These molecules play a
to a pathogen produces cross-reactivity with self- key role in T-cell signaling, as their disruption
antigens. Considering that infections have been has been shown to decrease T-cell responsive-
associated with the onset of psoriasis, this theory ness and associated inflammation. The B7 fam-
merits consideration. However, it also has been ily of molecules routinely interacts with CD28 T
observed that T cells can be activated without cells to co-stimulate T-cell activation. Cytotoxic
antigens or superantigens but rather with direct T-lymphocyte antigen 4 immunoglobulin, an
contact with accessory cells [19]. No single the- antibody on the T-cell surface, targets B7 and
ory has clearly emerged. Researchers continue to interferes with signaling between B7 and CD28.
search for the inciting stimulus that triggers the In psoriatic patients, this blockade was demon-
T lymphocyte and attempt to determine whether strated to attenuate the T-cell response and cor-
T cells are reacting to a self-derived or non–self- related with a clinical and histologic decrease in
derived antigen. psoriasiform hyperplasia [22]. Biologic therapies
that disrupt the LFA-1 component of the immu-
nologic synapse also have demonstrated efficacy
T-Lymphocyte Signaling in the treatment of psoriasis. Alefacept is a human
LFA-3 fusion protein that binds CD2 on T cells
T-cell signaling is a highly coordinated process and blocks the interaction between LFA-3 on
in which T lymphocytes recognize antigens via APCs and CD2 on memory CD45RO+ T cells and
presentation by mature APCs in the skin rather induces apoptosis of such T cells. Efalizumab is
than the lymphoid tissues. Such APCs expose a human monoclonal antibody to the CD11 chain
antigenic peptides via MHC I or II molecules for of LFA-1 that blocks the interaction between
which receptors are present on the T-cell surface. LFA-1 on the T cell and intercellular adhesion
The antigen recognition complex at the T-cell and molecule 1 on an APC or endothelial cell. Both
APC interface, in concert with a host of antigen- alefacept and efalizumab, 2 formerly marketed
independent co-stimulatory signals, regulates biologic therapies, demonstrated remarkable
T-cell signaling and is referred to as the immu- clinical reduction of psoriatic lesions, and alefa-
nologic synapse. The antigen presentation and cept has been shown to produce disease remis-
network of co-stimulatory and adhesion mole- sion for up to 18 months after discontinuation of
cules optimize T-cell activation, and dermal DCs therapy [23–25].
release IL-12 and IL-23 to promote a TH1 and
TH17 response, respectively. The growth factors
released by these helper T cells sustain neoan- NK T Cellss
giogenesis, stimulate epidermal hyperprolifera-
tion, alter epidermal differentiation, and decrease Natural killer T cells represent a subset of CD3+
susceptibility to apoptosis that characterizes the T cells present in psoriatic plaques. Although NK
erythematous hypertrophic scaling lesions of T cells possess a TCR, they differ from T cells
by displaying NK receptors comprised of lectin migrate to local lymph nodes where they pres-
and immunoglobulin families. These cells exhibit ent their native antigens to T cells. This process
remarkable specificity and are activated upon rec- allows the T-cell response to be tailored to the
ognition of glycolipids presented by CD1d mol- appropriate antigens in the corresponding tissues.
ecules. This process occurs in contrast to CD4+ Immature DCs that capture antigens mature by
and CD8+ T cells, which, due to their TCR diver- migrating to the T-cell center of the lymph node
sity, respond to peptides processed by APCs and where they present their antigens to either MHC
displayed on MHC molecules. Natural killer T molecules or the CD1 family. This presentation
cells can be classified into two subsets: (1) one results in T-cell proliferation and differentiation
group that expresses CD4 and preferentially pro- that correlates with the required type of T-cell
duces TH1- versus TH2-type cytokines, and (2) response. Multiple subsets of APCs, including
another group that lacks CD4 and CD8 that only myeloid and plasmacytoid DCs, are highly rep-
produces TH1-type cytokines. The innate immune resented in the epidermis and dermis of psori-
system employs NK T cells early in the immune atic plaques as compared with normal skin [30].
response because of their direct cytotoxicity and Dermal DCs are thought to be responsible for
rapid production of cytokines such as IFN-γ, activating both the TH1 and TH17 infiltrate by
which promotes a TH1 inflammatory response, secreting IL-12 and IL-23, respectively. This
and IL-4, which promotes the development of TH2 mixed cellular response secretes cytokines and
cells. Excessive or dysfunctional NK T cells have leads to a cascade of events involving keratino-
been associated with autoimmune diseases such cytes, fibroblasts, endothelial cells, and neutro-
as multiple sclerosis and inflammatory bowel dis- phils that create the cutaneous lesions seen in
ease as well as allergic contact dermatitis [26–28]. psoriasis [3].
In psoriasis, NK T cells are located in the Although DCs play a pivotal role in eliciting
epidermis, closely situated to epidermal kera- an immune response against a foreign invader,
tinocytes, which suggests a role for direct they also contribute to the establishment of tol-
antigen presentation. Furthermore, CD1d is over- erance. Throughout their maturation, DCs are
expressed throughout the epidermis of psoriatic continuously sensing their environment, which
plaques, whereas normally, CD1d expression is shapes their production of TH1- versus TH2-type
confined to terminally differentiated keratino- cytokines and subsequently the nature of the
cytes. An in vitro study examining cytokine-based T-cell response. When challenged with a virus,
inflammation demonstrative of psoriasis treated bacteria, or unchecked cell growth, DCs mature
cultured CD1d-positive keratinocytes with IFN-γ into APCs. However, in the absence of a strong
in the presence of alpha- galactosylceramide stimulus, DCs fail to mature into APCs and pres-
of the lectin family [29]. IFN-γ was observed ent self-peptides with MHC molecules, thereby
to enhance keratinocyte CD1d expression, and creating regulatory T cells involved in peripheral
subsequently, CD1d-positive keratinocytes were tolerance [31]. If this balance between immuno-
found to activate NK T cells to produce high lev- genic APCs and housekeeping T cells is upset,
els IFN-γ, while levels of IL-4 remained unde- inflammatory conditions such as psoriasis can
tectable. The preferential production of IFN-γ result.
supports a TH1-mediated mechanism regulated
by NK T cells in the immunopathogenesis of
psoriasis. Cytokines
Cytokines are low-molecular-weight glycopro-

Dendritic Cells teins that function as signals to produce inflam-
mation, defense, tissue repair and remodeling,
Dendritic cells are APCs that process antigens in fibrosis, angiogenesis, and restriction of neo-
the tissues in which they reside after which they plastic growth [32]. Cytokines are produced by
immunocytes such as lymphocytes and macro- E-selectin), angiogenesis via vascular endothelial
phages as well as nonimmunocytes such as endo- growth factor, the synthesis of proinflammatory
thelial cells and keratinocytes. Proinflammatory molecules (IL-1, IL-6, IL-8, and nuclear fac-
cytokines include IL-1, IL-2, the IL-17 family, tor κβ), and keratinocyte hyperproliferation via
IFN-γ, and TNF-α, while anti-inflammatory vasoactive intestinal peptide [34].
cytokines include IL-4 and IL-10. A relative A role for TNF-α in psoriasis treatment was
preponderance of TH1 proinflammatory cyto- serendipitously discovered in a trial for Crohn
kines or an insufficiency of TH2 anti-inflamma- disease in which infliximab, a mouse-human
tory cytokines induces local inflammation and IgG1 anti–TNF-α monoclonal antibody, was
recruitment of additional immunocyte popula- observed to clear psoriatic plaques in a patient
tions, which produce added cytokines [33]. A with both Crohn disease and psoriasis [35].
vicious cycle of inflammation occurs that results Immunotherapies that target TNF-α, including
in cutaneous manifestations such as a plaque. infliximab, etanercept, and adalimumab, demon-
Psoriatic lesions are characterized by a relative strate notable efficacy in the treatment of psoria-
increase of TH1-type (eg, IL-2, IFN-γ, TNF-α, sis [36–38]. Tumor necrosis factor α is regarded
TNF-β) to TH2-type (eg, IL-4, IL-5, IL-6, IL-9, as the driver of the inflammatory cycle of pso-
IL-10, IL-13) cytokines and an increase in TH17- riasis due to its numerous modes of production,
type cytokines. Natural killer T cells stimulated capability to amplify other proinflammatory sig-
by CD1d-overexpressing keratinocytes increase nals, and the efficacy and rapidity with which it
production of proinflammatory IFN-γ without produces clinical improvements in psoriasis.
effect on the anti-inflammatory IL-4. In addi-
tion to the cytokines produced by T cells, APCs
produce IL-18, IL-23, and TNF-α found in the IL-23/TH17 Axis
inflammatory infiltrate of psoriatic plaques. Both
IL-18 and IL-23 stimulate TH1 cells to produce A new distinct population of helper T cells has
IFN-γ, and IL-23 stimulates TH17 cells. Clearly, a been shown to play an important role in psoria-
TH1- and TH17-type pattern governs the immune sis. These cells develop with the help of IL-23
effector cells and their respective cytokines pres- (secreted by dermal DCs) and subsequently
ent in psoriatic skin. secrete cytokines such as IL-17; they are, there-
fore, named TH17 cells. CD161 is considered a
surface marker for these cells [39]. Strong evi-
Tumor Necrosis Factor α dence for this IL-23/TH17 axis has been shown
in mouse and human models as well as in genetic
Although a network of cytokines is responsible studies.
for the inflammation of psoriasis, TNF-α has been IL-23 is a cytokine that shares the p40 sub-
implicated as a master proinflammatory cytokine unit with IL-12 and has been linked to autoim-
of the innate immune response due to its wide- mune diseases in both mice and humans [3]. It is
spread targets and sources. Tumor necrosis factor required for optimal development of TH17 cells
α is produced by activated T cells, keratinocytes, [40] from a committed CD4+ T-cell population
NK cells, macrophages, monocytes, Langerhans after exposure to transforming growth factor
APCs, and endothelial cells. Psoriatic lesions β1 in combination with other proinflammatory
demonstrate high concentrations of TNF-α, while cytokines [41, 42]. IL-23 messenger RNA is
the synovial fluid of psoriatic arthritis patients produced at higher levels in inflammatory pso-
demonstrates elevated concentrations of TNF-α, riatic skin lesions versus uninvolved skin [43],
IL-1, IL-6, and IL-8 [33]. In psoriasis, TNF-α and intradermal IL-23 injections in mice pro-
supports the expression of adhesion molecules duced lesions resembling psoriasis macroscopi-
(intercellular adhesion molecule 1 and P- and cally and microscopically [44]. Furthermore,
several systemic therapies have been shown to drugs targeting the IL-23/TH17 axis include
modulate IL-23 levels and correlate with clini- secukinumab, ixekizumab, brodalumab, gusel-
cal benefit [3]. Alterations in the gene for the kumab, and tildrakizumab.
IL-23 receptor have been shown to be protec-
tive for psoriasis [45–47], and the gene coding
for the p40 subunit is associated with psoriasis Genetic Basis of Psoriasis
[45, 46].
Type 17 helper T cells produce a number of Psoriasis is a disease of overactive immunity
cytokines, such as IL-22, IL-17A, IL-17F, and in genetically susceptible individuals. Because
IL-26; the latter 3 are considered to be specific patients exhibit varying skin phenotypes, extra-
to this lineage [41]. IL-22 acts on outer body cutaneous manifestations, and disease courses,
barrier tissues, such as the skin, and has anti- multiple genes resulting from linkage disequi-
microbial activity. Blocking the activity of librium are believed to be involved in the patho-
IL-22 in mice prevented the development of genesis of psoriasis. A decade of genome-wide
skin lesions [48], and psoriasis patients have linkage scans have established that PSORS1 is
elevated levels of IL-22 in the skin and blood the strongest susceptibility locus demonstrable
[49, 50]. The IL-17 cytokines induce the expres- through family linkage studies; PSORS1 is
sion of proinflammatory cytokines, colony- responsible for up to 50% of the genetic compo-
stimulating factors, and chemokines, and they nent of psoriasis [60]. More recently, HLA-Cw6
recruit, mobilize, and activate neutrophils [51]. has received the most attention as a candidate
IL-17 messenger RNA was found in lesional gene of the PSORS1 susceptibility locus on the
psoriatic skin but not unaffected skin [52], and MHC I region on chromosome 6p21.3 [61].
cells isolated from the dermis of psoriatic skin This gene may function in antigen presenta-
have been shown to produce IL-17 [53]. IL-17A tion via MHC I, which aids in the activation of
is not elevated in the serum of psoriatic patients the overactive T cells characteristic of psoriatic
(unlike other autoimmune diseases) [54], and it inflammation.
is, therefore, thought that TH17 cells and IL-17A Studies involving the IL-23/TH17 axis have
production are localized to the affected psoriatic shown genetics to play a role. Individuals may be
skin. Consistent with this concept is the finding protected from psoriasis with a nonsynonymous
that treatments such as cyclosporin A and anti- nucleotide substitution in the IL23R gene [46–
TNF agents decrease proinflammatory cyto- 48], and certain haplotypes of the IL23R gene are
kines in lesional skin but not in the periphery associated with the disease [46, 48] in addition to
[55–57]. These cytokines released by TH17 cells other autoimmune conditions.
in addition to those released by TH1 cells act on Genomic scans have shown additional suscep-
keratinocytes and produce epidermal hyperpro- tibility loci for psoriasis on chromosomes 1q21,
liferation, acanthosis, and hyperparakeratosis 3q21, 4q32–35, 16q12, and 17q25. Two regions
characteristic of psoriasis [3]. on chromosome 17q were recently localized via
New therapies have been developed to target mapping, which demonstrated a 6 Mb separa-
the IL-23/TH17 axis. Ustekinumab is approved tion, thereby indicating independent linkage
for moderate to severe plaque psoriasis. This factors. Genes SLC9A3R1 and NAT9 are pres-
treatment’s effect may be sustained for up to ent in the first region, while RAPTOR is dem-
3 years, it is generally well tolerated, and it may onstrated in the second region [62]. SLC9A3R1
be useful for patients refractory to anti-TNF and NAT9 are players that regulate signal trans-
therapy such as etanercept [58]. Briakinumab, duction, the immunologic synapse, and T-cell
another blocker of IL-12 and IL-23, was studied growth. RAPTOR is involved in T-cell function
in phase 3 clinical trials, but its development was and growth pathways. Using these genes as an
discontinued due to safety concerns [59]. Newer example, we can predict that the alterations of
regulatory genes, even those yet undetermined, 9. Vallat V, Gilleaudeau P, Battat L, et al. PUVA bath
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Identification of cellular pathways of “type 1,” Th17
Psoriasis: Clinical Review
and Update 3
Abstract consensus each subtype of pustular psoriasis is

subclassified on the basis of the presence/
Plaque psoriasis is the most common and well-
absence of associated features. Erythrodermic
recognized disease type. It affects more than
psoriasis is a severe form of psoriasis charac-
80% of patients. Sebopsoriasis is a term used
terized by generalized inflammatory erythema
when lesions predominate on seborrhoeic
and scaling involving at least 75% of the body
areas. Guttate psoriasis is characterized by an
surface area. Precipitating factors may include
acute generalized eruption of small, usually
inappropriate use of potent topical and sys-
less than 1 cm in diameter, erythematous scaly
temic corticosteroids. Other clinical variants of
papules, distributed as “droplets” over the
psoriasis are nail and inverse (flexural) psoria-
body. It is common in children and young
sis. In pediatric population, psoriasis presents
adults with a family history of psoriasis and
the same clinical types. However, lesions may
typically follows streptococcal infection of the
differ in distribution and morphology. In the
upper respiratory tract. Guttate psoriasis and
future, a more clearly defined clinical classifi-
chronic plaque psoriasis are genetically similar
cation of psoriasis is needed to provide more
conditions with a strong association to the
specific management of each psoriasis type.
PSORS1 genetic locus. Pustular psoriasis is a
group of inflammatory skin conditions charac-
terized by infiltration of neutrophil granulo-
cytes in the epidermis clinically manifested
1. To understand the clinical features of
with sterile pustules. The three typical pustular
psoriasis
forms are generalized pustular psoriasis, pal-
2. To understand the different variants of
moplantar pustulosis, and acrodermatitis con-
psoriasis
tinua of Hallopeau. According to the European
3. To understand the differential diagnosis
Rare and Severe Psoriasis Expert Network
of psoriasis
I. Grozdev (*)
Department of Dermatology, Brugmann University Psoriasis can present in various patterns and
Hospital, Brussels, Belgium forms. Different classifications of the disease
N. J. Korman have been proposed based on either its epide-
Department of Dermatology, University Hospitals miology, age of onset, clinical morphology, or
Case Medical Center, Cleveland, OH, USA severity [1, 2]. However, the diagnosis is typi-

https://doi.org/10.1007/978-3-030-54859-9_3
20 I. Grozdev and N. J. Korman
cally made by the recognition of the classic and clearing of the lesions with an active border is
distinctive lesions—well-demarcated erythema- present. Psoriatic leukoderma defines the post-
tous plaques with adherent silvery scales. These inflammatory hypopigmentation as the psoriatic
correlate to the inflammation, vascular dilatation, plaques regress. Pruritusis present is as many as
and altered epidermal proliferation and differen- 60–90% of psoriasis patients [10].
tiation seen histopathologically. The most com-
mon sites include symmetric involvement of the
elbows, knees, lower back, and buttocks, but the Guttate Psoriasis
disease can involve any cutaneous surface. The
disease varies widely in severity and extent of Guttate psoriasis is characterized by an acute gen-
involvement. There are multiple types of psoria- eralized eruption of small, usually less than 1 cm
sis that have been classified based upon a combi- in diameter, erythematous scaly papules, distrib-
nation of morphology, distribution, and pattern. uted as “droplets” over the whole body surface.
This section will review the clinical forms of the Usually, lesions occur over the trunk as the palms
disease along with some updates on its particular and soles are spared. Guttate psoriasis is com-
subtypes. mon in children and young adults with a family
history of psoriasis and typically follows strep-
tococcal infection of the upper respiratory tract
Plaque Psoriasis or acute stressful life events [11]. It can appear
either de novo or as an acute exacerbation of pre-
This is the most common and well-recognized existing psoriasis. This form of psoriasis may
form of psoriasis, also known as psoriasis vul- resemble other cutaneous conditions like pityria-
garis. It affects more than 80% of patients. It is sis rosea or secondary syphilis. The prognosis is
characterized by sharply defined erythematous excellent in children as spontaneous remissions
scaly plaques, usually distributed symmetrically are known to occur within weeks or months.
over the extensor surfaces of the upper and lower The risk of developing chronic plaque psoriasis
extremities, lower back and scalp [3]. There can after a first episode of guttate psoriasis has been
be variation in the intensity of erythema and estimated to be 25–40% [12, 13]. Guttate psoria-
amount of scale. The size of the lesions varies sis and chronic plaque psoriasis are genetically
from coin-sized to palm-sized and larger. The similar conditions with a strong association to
term nummular psoriasis is used if coin-sized the PSORS1 genetic locus [14]. Although guttate
lesions predominate [4]. Additional features of psoriasis is highly associated with streptococcal
psoriatic plaques include the Auspitz sign as the infections, there is little evidence-based data to
presence of pinpoint bleeding when the tightly support treatment of these patients with antibiot-
adherent scales are removed from the surface of ics or tonsillectomy [15, 16].
the plaque, and Woronoff ring as the presence
of a white ring around erythematous plaques
undergoing topical treatment or phototherapy [5, Pustular Psoriasis
6]. Psoriasis is well known to develop at sites of
physical trauma (scratching, sunburn or surgery), Pustular psoriasis is a group of inflammatory skin
which is the isomorphic or Koebner’s phenom- conditions characterized by infiltration of neu-
enon [7] and occurs in 11 to 75% of patients trophil granulocytes in the epidermis clinically
[8]. The term sebopsoriasis is used if lesions manifested with sterile pustules. Historically,
predominate on seborrhoeic areas, occasionally the three typical pustular forms (generalized
causing difficulties separating the disease from pustular psoriasis, palmoplantar pustulosis,
seborrheic dermatitis [9]. Lesions of plaque acrodermatitis continua of Hallopeau) have
psoriasis are quite stable over time. The term been integrated in the large spectrum of pustu-
annular or polycyclic psoriasis is used if central loses. (Table 3.1).
3 Psoriasis: Clinical Review and Update 21
Table 3.1 Generalized and localized pustuloses (from a woman without prior history of psoriasis [20].
Camisa C, 2004, modified) [17]
Resolution occurs with delivery. Recurrences
Generalized variants Localized variants might be associated with menstruation and oral
Von Zumbusch-type One or more plaques contraceptives [21]. Some cases have been found
with pustules
to have IL-36RN mutations, suggesting that
Impetigo herpetiformis Palmoplantar pustulosis
Acute generalized Annular (Subcorneal impetigo herpetiformis and generalized pustular
exanthematous pustulosis pustular dermatosis of psoriasos are the same disease [22].
Sneddon and Wilkinson)
Acrodermatitis continua
of Hallopeau
cute Generalized Exanthematous
A
Keratoderma
blenorrhagicum Pustulosis
(Previously known as
Reiter’s syndrome) AGEP is a drug-triggered severe cutaneous reac-
SAPHO syndrome tion characterized by rapid development of non-
(synovitis, acne, pustulosis,
follicular, sterile pustules on an erythematous
hyperostosis, osteitis)
base. A wide variety of drugs has been associ-
ated with thecondition, antibiotics being the most
common cause. Typically, within 48 h of ingest-
Generalized Pustular Psoriasis ing the causative medication, there is acute onset
of fever and pustulosis with leukocytosis. In
This condition was described by Leopold von severe cases, there can be mucous membrane and
Zumbusch. It is a severe form of psoriasis and can systemic organ involvement [23]. In some AGEP
be life-threatening. It may be preceded either by cases, the same IL-36RN mutations were found
plaque psoriasis or arise de novo. Withdrawal of as in generalized pustular psoriasis [24].
systemic steroids may trigger the disease. This form
of psoriasis is characterized by sterile pustules aris-
ing from the surface of large erythematous patches Localized Pustular Forms
of skin distributed over the trunk and extremities.
The pustules eventually dry and peel. In some Palmoplantar pustulosis is the most common
cases, these pustules may form confluent large lakes variant of pustular psoriasis. It is characterized
of pus. Oral lesions may be present with pustules by pruritic or burning erythematous patches on
or acute geographic tongue. The eruption is usu- the palms and soles, within which multiple pus-
ally accompanied by systemic symptoms including tules develop. Initially, the pustules are yellow.
fever, chills, diarrhea, and arthralgias. Leukocytosis Later they turn dark brown, dry up and form
and an elevated erythrocyte sedimentation rate are crusts that subsequently exfoliate leaving tender
commonly encountered. Generalized pustular pso- and diffusely eroded surfaces [25]. Those patients
riasis may be associated with polyarthritis and cho- experience great impairment of their quality of
lestasis from neutrophilic cholangitis [18]. It has life with difficulty in walking and using their
been reported that pustular psoriasis occurs in 9% hands. Some authors consider palmoplantar pus-
of psoriasis patients without psoriatic arthritis and tulosis to be a separate dermatologic disorder as
in 41% of patients with psoriatic arthritis [19]. it affects predominantly female patients, has a
higher age of onset, is associated with cigarette
smoking (up to 100% of cases at onset), and
Impetigo Herpetiformis consistently responds poorly to topical therapy.
Palmoplantar pustulosis does not share the asso-
Originally described in 1872 by von Herba, ciation of PSORS1 gene locus with plaque psori-
impetigo herpetiformis refers to a generalized asis, supporting the concept that these are distinct
pustular eruption anytime during pregnancy in entities.
Acrodermatitis continua of Hallopeau is a least 75% of the body surface area [28]. It may
rare, chronic, and recalcitrant pustular eruption develop gradually or acutely during the course of
of the fingers and toes that is widely considered chronic psoriasis, but it may also be the initial
to be a localized variant of pustular psoriasis. The manifestation of psoriasis. Important precipi-
pustules are located on the fingertips or toes and tating factors for erythrodermic psoriasis may
are very painful and disabling, often leading to include inappropriate use of potent topical and
loss of function in the affected digits and substan- systemic corticosteroids. Psoriatic erythroderma
tial morbidity. Nail dystrophy and paronychial is not substantially clinically different from
erythema are typically seen [26]. erythroderma caused by eczematous dermatitis,
seborrhoeic dermatitis, pityriasisrubra pilaris,
drug induced erythroderma, lymphoma, or leuke-
Consensus Statement mia. Associated findings may include lymphade-
of Phenotypes of Pustular Psoriasis nopathy, hypothermia, tachycardia, peripheral
edema, elevated erythrocyte sedimentation rate,
For clinical use, pustular psoriasis is still grouped hypoalbuminemia, anemia, leukocytosis or leu-
with psoriasis vulgaris. However, accumulating copenia, elevations of lactate dehydrogenase,
data reveal that the two conditions are genetically liver transaminases, uric acid, and calcium [29].
and phenotypically different, respond differently to Severe medical complications can develop due to
treatment. The European Rare and Severe Psoriasis dehydration from extensive fluid and electrolyte
Expert Network was founded to define consensus disturbances, protein losses, high-output cardiac
criteria for diagnosis and phenotypes of pustular failure, and infection.
psoriasis, to analyze the genetics and pathophysiol-
ogy, to prepare for prospective clinical trials [27].
According to the consensus of this expert group, Manifestations of Psoriasis
each subtype of pustular psoriasis is subclassified in Specific Locations
on the basis of the presence or absence of associ-
ated features. Generalized pustular psoriasis is Scalp Psoriasis
defined as primary, sterile, macroscopically visible
pustules on non-acral skin, excluding cases where The scalp is a very common location for psoria-
pustules are restricted to psoriatic plaques. It can sis. Plaques typically form on the scalp and along
occur with or without systemic inflammation, with the hair margin. Many patients discover they
or without psoriasis vulgaris, and can be either a have psoriasis because of a dandruff-like desqua-
relapsing (> 1 episode) or persistent (> 3 months) mation. When the scalp is the only location of
condition. Palmoplantar pustulosis is defined as pri- psoriasis, it may be difficult to distinguish from
mary, persistent (> 3 months), sterile, macroscopi- seborrheic dermatitis. The term sebopsoriasis is
cally visible pustules on the palms and/or soles used in such cases [9]. The scales can firmly be
and can occur with or without psoriasis vulgaris. attached to the scalp hair. This particular variety
Acrodermatitis continua of Hallopeau is defined as is called pseudotinea amiantacea and is more
primary, persistent (> 3 months), macroscopically frequent in children [30]. Scarring alopecia may
visible pustules affecting the nail apparatus, with or develop in some patients [31].
without psoriasis vulgaris.
Nail Psoriasis
ErythrodermicPsoriasis
The nails are commonly affected in patients with
Erythrodermic psoriasis is a severe form of pso- psoriasis. In cases where skin lesions are absent
riasis characterized by generalized inflammatory or equivocal, nail changes may be of assistance in
erythema and widespread scaling involving at making the diagnosis of psoriasis. Two patterns
of nail disorders have been shown to be caused cum can develop psoriasiform skin lesions 1–2
by psoriasis [32]. Nail matrix involvement can months after the onset of arthritis. with involve-
result in features such as leukonychia, pitting, red ment of the palms, soles, and the scalp [37]. The
spots in the lunula and crumbling. Onycholysis, psoriasiform patch has distinctive circular scaly
salmon or oil-drop patches, subungual hyper- borders that develop from fusion of papulovesic-
keratosis and splinter hemorrhages are classic ular plaques with thickened yellow scale.
features of psoriasis nailbed involvement. Nail
psoriasis causes aesthetic and functional impair-
ment, and is considered as an indicative of pso- Pediatric Psoriasis
riasis joint involvement.
Approximately 30–50% of adults with pso-
riasis developed psoriasis before the age of 20.
Inverse (Flexural, Intertiginous) The prevalence of childhood psoriasis has been
Psoriasis reported to be up to 2% [38].
Although children present with the same clini-
Inverse psoriasis affects the skin fold areas cal types of psoriasis seen in adults, lesions may
including the axillae, submammary regions, glu- differ in distribution and morphology. Plaque
teal cleft, retroauricular, and inguinal folds [33]. psoriasis is the most common type of psoriasis in
Obese patients often have this form of psoriasis children. Typical erythematous plaques with
involving their excess skin folds [34]. Thin well- overlying white scales are often thinner and
demarcated erythematous patches without des- smaller. Lesions tend to develop more often on
quamation are the typical skin lesions. Usually the scalp, face, and flexural areas. Young children
the patches are superficially eroded with fissur- usually present with a diaper rash that is irrespon-
ing in the body folds. Inverse psoriasis may occur sive to irritant diaper dermatitis treatment [39].
alone but is more frequently accompanied by Guttate psoriasis is the second most common
plaque psoriasis elsewhere. In cases where it is type of psoriasis in childhood. It could be trig-
the only location of psoriasis, inverse psoriasis gered by a beta-hemolytic streptococcal or viral
may be confused with bacterial, fungal, or can- infection, and tends to resolve spontaneously
didal intertrigo. Scrapings or cultures are then within 3–4 months of onset. It has been reported
needed to exclude infection. that a proportion of children with guttate psoria-
sis eventually develop plaque psoriasis [40].
Pustular psoriasis is seen in 1.0–5.4% of chil-
Rare Forms and Some Specific dren with psoriasis. Other less common types of
Locations psoriasis in children are inverse psoriasis, palmo-
plantar psoriasis, isolated facial psoriasis, linear
Geographic tongue also known as benign migra- psoriasis, erythrodermic psoriasis. Nail changes
tory glossitis may be seen in psoriatic patients, have been reported in up to 40% of children with
especially in patients with generalized pustular psoriasis. Approximately 7% of all patients with
psoriasis. It is characterized by erythematous juvenile idiopathic arthritis appear to have juve-
patches surrounded by a white line and loss of nile psoriatic arthritis [41].
filiform papillae on the dorsum of the tongue Children suffering from psoriasis have higher
[35]. The lips can be affected in psoriasis but prevalence of comorbidities, including obesity,
this should be differentiated from discoid lupus diabetes, hypertension, rheumatoid arthritis,
erythematosus and desquamative cheilitis [36]. Crohn’s disease and psychiatric disorders, com-
If psoriasis only affects the glans, the most compared to children without psoriasis [42].
mon site of involvement is the proximal part [30]. Overall, 13% to 27% of children have moder-
It should be differentiated from erythroplasia of ate to severe disease, with a 10% body surface
Queyrat. Patients with Keratoderma blenorrhagi- area affected, and may warrant the use of systemic
Table 3.2 Differential diagnosis of variants of psoriasis References

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Psoriasis: Epidemiology, Potential
Triggers, Disease Course 4
Abstract
Worldwide prevalence rates of psoriasis range 1. To understand the epidemiology of

from 0.6 to 4.8%. The disease tends to have a psoriasis
bimodal distribution of onset with the major 2. To examine the triggers of psoriasis
peak occurring at age of 20–30, and a later 3. To understand the clinical course of the
smaller peak occurring at age of 50–60. While disease
there are many potential triggers of psoriasis,
infections are an important trigger and up to
half of children with psoriasis have an exacer-
bation within 2 weeks following an upper
Epidemiology
respiratory infection. Psychological distress is
a causative or maintaining factor in disease
Worldwide prevalence rates of psoriasis range
expression for many patients with psoriasis.
from 0.6 to 4.8% [1, 2]. Women and men are
Other well-documented triggers for flares
equally affected. The prevalence of the disease
include trauma, alcohol and smoking, as well
varies depending on the climate and ethnicity,
as obesity. Plaque psoriasis is usually chronic
although these relationships are complicated.
with intermittent remissions. Plaques may
The Caucasian population of Europe and the US
persist for months to years at the same loca-
are affected equally by psoriasis [3, 4]. The dis-
tions; however, periods of complete remission
ease is uncommon in the Mongoloid race. Asian
may occur.
Americans have a prevalence of between 0.4%
[5] and 0.7% [6]. African-Americans have a
prevalence of 1.3% [7], while American-Indians
have prevalence of 0.2% or less [6]. Psoriasis
is absent in certain populations such as South
American Indians and Australian Aborigines
I. Grozdev (*) [8], while in the Arctic Kasah’ye its prevalence
Department of Dermatology, Sofia Medical Faculty, is 11.8% [9]. A positive correlation between lati-
Sofia, Bulgaria tude and psoriasis prevalence would be expected
N. J. Korman given the efficacy of ultraviolet light as a treat-
Department of Dermatology, University Hospitals ment [10]. However, Jacobson et al. identified 22
Case Medical Center, Cleveland, OH, USA population-based surveys, case-control studies,

https://doi.org/10.1007/978-3-030-54859-9_4
and reviews on psoriasis prevalence rates from described by Heinrich Koebner in 1872). Trauma
numerous regions around the globe and found no as a trigger is more commonly seen in patients
correlation between absolute latitude and psoria- who develop psoriasis at an early age and those
sis prevalence [11]. These findings suggest that who require multiple therapies to control their
other factors or a combination of factors may disease [20]. In clinical studies the prevalence
play a role in the frequency of psoriasis rather of the Koebner phenomenon may range from
than latitude alone. Differences in the prevalence 24–51% of patients while in experimental stud-
rates of psoriasis between two areas of the same ies among selected patients with severe psoriasis
continent (West Africa prevalence rates of 0.05– and a history of the Koebner phenomenon, it was
0.9% compared to South Africa prevalence rates observed in up to 92% of patients [21]. Factors
of 2.8–3.5% [12]) suggest that genetic factors that may lead to the Koebner phenomenon include
play an important role [13]. acupuncture, vaccinations, scratches, removal of
Although new onset psoriasis occurs in all adhesive bandages, insect and animal bites, burns
age groups from newborns to age 108 [14], the (thermal, chemical, electrosurgical), radiation,
disease tends to have a bimodal distribution of incisions, cuttings, abrasions, tattoos, irritant and
onset with the major peak occurring at age of allergic contact dermatitis, phototoxic dermatitis,
20–30, and a later smaller peak occurring at age as well as skin diseases including acne, furuncles,
of 50–60. Patients with early age onset of pso- herpes zoster, and lichen planus. The “reverse”
riasis are more likely to have a family history Koebner phenomenon which occurs when
of psoriasis, the course of the disease tends to trauma within a psoriatic lesion causes clearing
be more unstable with frequent remissions and of that psoriatic lesion has also been observed
relapses, the disease tends to be more resistant [22]. Some treatment modalities for psoriasis are
to treatment and more severe disease tends to be based on the reverse Koebner phenomenon such
more common. Late age onset psoriasis tends to as electrodissecation, dermabrasion, cryotherapy,
have a more stable chronic clinical course, and is and CO2-laser therapy.
more likely to be associated with psoriatic arthri-
tis, nail involvement and palmoplantar pustular
involvement [15, 16]. The mean age of onset of Infections
psoriasis varies from study to study, but nearly
75% of patients with psoriasis have an onset Infections have long been recognized as impor-
before the age of 40, and 12% of patients have tant triggers for psoriasis exacerbations. Up to
the onset of psoriasis at age of 50–60 [17]. More half of children with psoriasis have an exacerba-
recent studies have indicated an increasing prev- tion of their disease within 2 weeks following
alence of childhood psoriasis [18]. The known an upper respiratory infection [23, 24]. Infection
familial concentration of psoriasis indicates an with streptococcus pyogenes has a well-known
important role of hereditary factors; however a association with guttate psoriasis [25]. Up to
67%-concordance in monozygotic twins sug- 85% of patients with an episode of acute guttate
gests that environmental factors may also be an psoriasis show evidence of a preceding strep-
important component of psoriasis [19]. tococcal infection as demonstrated by positive
anti-streptolysin-O titers [24]. In another study,
84% of patients with guttate psoriasis had a
Potential Triggers history of infection prior to occurrence of skin
lesions, and the majority of these patients (63%)
Trauma had a verified streptococcal pharyngitis [26].
Although pharyngeal origin of the infection is
Trauma can trigger the exacerbation of psoriatic most common, skin infection with streptococ-
lesions or the development of new lesions (this cus pyogenes can also lead to guttate psoriasis.
is known as the Koebner phenomenon, originally Streptococcal infections can elicit exacerbations
4 Psoriasis: Epidemiology, Potential Triggers, Disease Course 29
of other types of psoriasis and psoriatic arthri- plaque psoriasis may go on to develop guttate or
tis as well. Patients with psoriasis develop sore pustular lesions. Psoriasis may occur at any time
throats much more frequently than non-psoriatic in the course of an HIV infection and exacerba-
individuals and it is well documented that strep- tions tend to be longer and more frequent than
tococcal throat infections can trigger the onset those in otherwise healthy psoriasis patients [46].
of psoriasis, and such infections cause exacerba- There is no observed relationship between pso-
tion of chronic psoriasis [27]. The study of 111 riasis and the CD4 count. There is one report of
patients isolated streptococcus pyogenes in 13% psoriasis remission in the terminal stages of the
of patients with a guttate flare of chronic plaque acquired immunodeficiency syndrome [47] and
psoriasis, in 14% of patients with chronic plaque another report on complete resolution of eryth-
psoriasis, and in 26% of patients with acute gut- rodermic psoriasis in an HIV and HCV patient,
tate psoriasis, while 7% of the patients in the unresponsive to anti-psoriatic treatments after
control group had streptococcus pyogenes iso- highly active antiretroviral therapy [48]. Rapid
lated [28]. Although many reports suggest a pos- onset of acute eruptive psoriasis, frequent exac-
sible role for antibiotics or tonsillectomy in the erbations or resistance to conventional and bio-
treatment of guttate psoriasis [27, 29–33], the logic treatments should raise the possibility of
data is controversial about the beneficial effect underlying HIV disease [48, 49]. It has been sug-
of either intervention [34]. gested that inflammation within psoriatic lesions
Superantigens such as streptococcal pyogenic develops against unknown antigens and super
exotoxin [35–38] as well as peptidoglycan derived antigens of viral origin such as human papilloma
from various different bacterial sources [39, 40] virus 5 (HPV5), human endogenous retroviruses,
can lead to the development of psoriasis due to Coxsackie adenoviruses, Arboviruses and others
an abnormal response of the innate immune sys- [43, 50, 51].
tem towards the super antigen. Development and
use of experimental vaccines to treat psoriasis are
based on this hypothesis [41, 42]. Other microor- Stress
ganisms reported to be potential triggers for pso-
riasis include Staphylococci, Candida, H pylori Psychological distress is a causative or maintain-
and Malassezia spp [25, 43] while infections with ing factor in disease expression for many patients
Yersinia spp have been reported to induce psori- with psoriasis. In one study, over 60% of psoria-
atic arthritis [25]. sis patients believed that stress was the principal
Another important potential triggering factor factor in the cause of their psoriasis [52]. Farber
for psoriasis is infection with the human immu- and colleagues surveyed over 5000 patients with
nodeficiency virus (HIV). The link between HIV psoriasis and 40% reported that their psoriasis
infection and psoriasis onset seems paradoxical occurred at times of worry and 37% experienced
as the immunosuppression should lead to psoria- worsening of psoriasis with worry [5]. In a more
sis improvement [44]. It is suggested that either recent study of 400 patients with newly developed
HIV could function as a super antigen or other psoriasis, 46% of the patients with plaque psoria-
microorganisms, including opportunistic ones, sis and 12% of the patients with guttate psoriasis
could develop in the host because of the immune linked the onset of their disease with a life crisis,
dysregulation [44]. The prevalence of psoriasis in including divorce, severe or life-threatening dis-
patients with HIV infection is nearly 5%, about ease of the patient or a family member, death in
twice that seen in the general population. The clin- the family, financial burden, dismissal, or harass-
ical manifestations of psoriasis in HIV-infected ment in school [53]. In another study among 50
patients are similar to those in non-HIV-infected psoriasis patients, stressful life events were seen
patients. However, lesions of more than one sub- in 26% of the patients within 1 year preceding
set of psoriasis are often found in the same HIV onset or exacerbation of psoriasis, suggesting
patient [45]. For example, a patient with chronic the potential value of relaxation therapies and
stress management programs in the management psoriasis include lithium, beta-blockers, non-ste-
of patients with psoriasis [54]. Stress-induced roidal anti-inflammatory drugs, tetracyclines, and
relapse rates of up to 90% have been reported in antimalarials [65, 67]. Several other medications
children [23]. In an epidemiological study of 784 that have reported to worsen psoriasis include
Greek psoriasis patients, stress was self-reported angiotensin converting enzyme (ACE) inhibi-
as the main cause for psoriasis exacerbations by tors, terbinafine, clonidine, iodine, amiodarone,
60% of patients [55]. It was demonstrated that penicillin, digoxin, interferon-alpha, and inter-
“low level worriers” achieved clearing of their leukin-2. The abrupt discontinuation of systemic
skin with PUVA (psoralen plus ultraviolet-A) a or superpotent topical corticosteroids can serve
median of 19 days earlier than “high level wor- as triggers of psoriasis although the frequency of
riers” undergoing the same treatment [56]. Other this association has not been studied. While these
studies reveal that cognitive-behavioral therapy observations suggest the possibility that certain
in conjunction with medical therapy can lead to medications may trigger psoriasis worsening, no
a significantly greater reduction in the severity controlled trials have proven an association.
of psoriasis than medical therapy alone [57, 58]. Newly developed psoriasis has been reported
The role that acute psychosocial stressors play in in patients taking TNF-alpha blockers for indica-
altering hypothalamic-pituitary-adrenal (HPA) tions other than psoriasis, including Crohn’s dis-
responses in patients with psoriasis is an area of ease and rheumatoid arthritis [68, 69].
controversy. Some data shows that stress-exacer- Interferons play an important role in the
bated psoriasis flares lead to decreased levels of pathogenesis of psoriasis. Their use as medica-
cortisol [59], while other fails to show such a cor- tions such as IFN (α, β, γ) and imiquimod may
relation [60, 61]. The epidemiologic data linking induce or worsen psoriasis [43, 70]. Additionally,
psychological stress and onset or exacerbation of withdrawal of interferon use in hepatitis C com-
psoriasis is also controversial with some studies monly leads to improvement in psoriasis [71].
supporting this association [62], while others do
not [63, 64].
Alcohol and Smoking
Medications Alcohol and smoking have both been implicated

as triggering factors for psoriasis exacerbations.
Various medications used for concomitant dis- It is well documented that the prevalence of pso-
eases may influence psoriasis in terms of precipi- riasis is increased among patients who abuse
tating or worsening it. Drug-induced psoriasis alcohol [72]. However, conflicting evidence
is defined as the development of psoriasis after exists as to whether increased alcohol intake in
treatment with a medication that remits when that psoriasis patients is a factor in the pathogenesis
medication is withdrawn, while drug-triggered or whether having a chronic disorder like psoria-
or drug-exacerbated psoriasis is defined as the sis leads to greater intake of alcohol in an attempt
development of psoriasis after treatment with to self-medicate. A study of 144 Finnish patients
a medication whose withdrawal does not influ- with psoriasis demonstrated that alcohol con-
ence the clinical course [65]. The time between sumption in the previous 12 months was linked
the start of the drug intake and the outbreak of to the onset of psoriasis. This study suggests that
psoriatic eruption may vary and depends on the psoriasis may lead to sustained alcohol abuse and
drug and is classified as follows: short (<4 weeks that this alcohol intake may perpetuate the dis-
between the start of the drug and the onset of pso- ease [73]. Qureshi et al. prospectively evaluated
riatic eruption), medium (>4 and <12 weeks), and the association between total alcohol consump-
long (>12 weeks) [66]. Several medications may tion and risk of incident psoriasis in a cohort of
trigger or worsen psoriasis. The most common 82,869 nurses [74]. Compared with women who
medications that have been reported to trigger did not drink alcohol, the multivariate relative
risk of psoriasis was significantly higher for an pared to 25% smokers in the general population
alcohol consumption of 2.3 drinks per week or [79]. Although the Finnish study of 144 psoria-
more. Moreover, examining the type of alcoholic sis patients, mentioned above, found no associa-
beverage, non-light beer intake was associated tion between smoking and the onset of psoriasis
with an increased risk of developing psoriasis [73], another study of 55 women demonstrated
among women, while other alcoholic bever- an increased smoking rate of psoriasis patients
ages did not increase this risk. Recently, a meta- compared to controls [80]. Naldi et al. examined
analysis of case-control studies showed that the 560 patients and showed that the risk for develop-
overall odds ratio of psoriasis for drinking per- ing psoriasis was the greater in former smokers
sons compared to those with non-drinking habits and current smokers than in those who had never
was 1.531 (P = 0.002), suggesting that alcohol smoked [81]. A hospital-based Chinese study
consumption is associated with an increased evaluated 178 psoriasis patients and 178 controls
risk of psoriasis [75]. Further support of increas- and found a graded positive association between
ing alcohol abuse as a post-diagnosis condition the risk of psoriasis and the intensity or duration
was seen in a case-control study of 60 Australian of smoking [82]. Moreover, they showed that the
twins who were discordant for psoriasis [76]. In risk of psoriasis in smokers with the HLA-Cw6
this study, no difference in alcohol consumption haplotype was increased by 11-fold over non-
between discordant twins, either monozygotic smokers without the HLA-Cw6 haplotype dem-
or dizygotic, was discovered. The influence of onstrating an additive effect of genetics on that
increasing alcohol consumption on the severity of smoking in inducing psoriasis. Gene-smoking
of psoriasis has also been investigated and there interaction was found also by Yin et al. [83]. In
appears to be a tendency for heavy drinkers to a larger Italian study of 818 patients, those that
develop more extensive and severe psoriasis that smoked greater than 20 cigarettes per day were at
lighter drinkers [77]. a twofold increased risk for more severe psoria-
Mortality related to alcohol use in psoriasis has sis than those who smoked less than 10 cigarettes
also been evaluated. A population-based study of per day [84]. The largest and most definitive
over 5000 patients followed for 22 years demon- study investigating the association of smoking
strated that psoriatic patients have an increased with psoriasis was the Nurses’ Health Study II
mortality rate when compared to a control group which prospectively followed a cohort of over
[78]. However, this study did not account for 78,000 US nurses over a 14 year time period.
previous hepatotoxic psoriasis therapies or other They demonstrated a “dose-response” relation-
medical conditions, and used the most severe ship for smoking and the risk of developing inci-
psoriasis patients (those who required hospital dent psoriasis [85] and that the risk of incident
admission for their psoriasis), suggesting that psoriasis decreases nearly back to that of never
the elevated mortality rates attributed to these smokers 20 years after stopping smoking. In
patients may have been overstated. In summary, addition, they also found that prenatal and child-
alcohol consumption is more prevalent in psoria- hood exposure to passive smoke was associated
sis patients, and it may also increase the severity with an increased risk of psoriasis.
of psoriasis. The association of alcohol with the
pathogenesis and exacerbation of p soriasis is less
clear. Prolonged alcohol abuse may lead to alco- Obesity
holic liver disease, and in that way may decrease
treatment responsiveness and options, which may Numerous studies demonstrate an increased prev-
prolong exacerbations. alence of obesity, defined as a body mass index
Patients with psoriasis are more likely than (BMI) ≥30 kg/m2, among patients with psoriasis
those without psoriasis to smoke. In a large [79, 86–90]. The findings of a systematic review
cross-sectional study from Utah, 37% of psoriatic and meta-analysis of multiple observational stud-
patients acknowledged they were smokers com- ies support an increased prevalence of obesity
in patients with psoriasis [90]. The pooled odds BMI of 21.0–22.9 kg/m2 at age 18, the multivari-
ratio [OR] for obesity for patients with psoriasis ate relative risk for the development of psoriasis
compared with a control group without psoriasis for subjects with a BMI ≥30 kg/m2 at the same
was 1.66 (95% CI 1.46–1.89). Further support for age was 1.73 (95% CI, 1.24–2.41), and only 0.76
this link between psoriasis and obesity derives (95% CI, 0.65–0.90) for women with a BMI
from a review of over 10,000 patients with mod- <21 kg/m2.
erate to severe psoriasis enrolled in clinical tri- Data on the effects of weight loss on disease
als of biologic therapies [86] where the average severity in psoriasis are limited. The first ran-
BMI for all patients in the trials was 30.6 kg/ domized trial designed to explore the effect of
m2. There is also a correlation between obesity weight loss on the severity of psoriasis found
and the severity of psoriasis [79, 87, 91]. In the a statistically non-significant trend towards
systematic review and meta-analysis described greater improvement in psoriasis (as assessed
above, the risk for obesity was more pronounced by Psoriasis Area Severity Index [PASI] score)
in patients with severe psoriasis (pooled OR in overweight or obese psoriasis patients who
2.23, 95% CI 1.63–3.05) than patients with mild were placed on a low-energy diet compared
psoriasis (pooled OR 1.46, 95% CI 1.17–1.82) with a similar group of patients who continued
[91]. One study of 4065 individuals with pso- to eat ordinary healthy foods [94]. The median
riasis and 40,650 controls that was included in baseline PASI score for all patients (5.4) corre-
the meta-analysis illustrated a progressive rela- lated with mild to moderate psoriasis, and during
tionship between disease severity and obesity. the 16-week trial, patients allocated to the low-
Among patients with mild (≤2% body surface energy diet lost a mean of 15.8 kg compared with
area [BSA]), moderate (3–10% BSA), and severe a mean loss of 0.4 kg in the control group. By
psoriasis (>10% BSA), the prevalence of obesity study end, PASI scores were reduced by a mean
compared to controls increased by 14, 34, and of 2.3 in the low-energy diet group compared
66%, respectively [91]. with only 0.3 in the control group. In addition,
Children with psoriasis also have an increased improvement in the Dermatology Quality of Life
risk for obesity. In an international cross-sectional Index (a secondary outcome measure aimed at
study of 409 children with psoriasis, children assessing the change in the impact of psoriasis on
with psoriasis were significantly more likely to patient quality of life) was significantly greater in
be obese (BMI ≥95th percentile) than controls the low-energy diet group.
(OR 4.29, 95% CI 1.96–9.39) [92]. Similar to the Improvement in psoriasis following gastric
general population of patients with psoriasis, a bypass surgery has been previously documented
correlation between disease severity and obesity [95–97]. The mechanism of this is unclear, but
was observed. Children with severe psoriasis had may be related to alterations in the production of
a greater increase in risk for obesity than children pro-inflammatory and anti-inflammatory adipo-
with mild disease (OR 4.92, 95% CI 2.20–10.99 kines, or weight-loss related changes in cutane-
versus 3.60, 95% CI 1.56–8.30). ous microflora that result in the elimination of
More than one factor may contribute to an antigenic stimulant [98]. However, worsening
the association between obesity and psoriasis. of psoriasis has also occurred after weight loss
Although the negative psychosocial impact of and weight loss surgery [99–101]. Further study
psoriasis was initially considered the sole rea- is therefore necessary to better understand the
son for excess weight in patients with psoriasis effect of weight loss on psoriasis.
[79], more recent data suggest that obesity may Obesity may impact the efficacy of some
increase risk for psoriasis. In an analysis of data psoriasis treatments [102]. A cohort study of
collected from almost 80,000 women in the approximately 2400 patients receiving systemic
Nurses’ Health Study II, increased adiposity and therapy for psoriasis (including conventional
weight gain were identified as strong risk factors and biologic agents) found that compared to
for psoriasis [93]. Compared to women with a individuals with a BMI of 20–24 kg/m2, obese
subjects (BMI ≥30 kg/m2) were less likely to disease, some patients may develop other vari-
achieve 75% improvement in disease severity ants including guttate, pustular, inverse or eryth-
(odds ratio 0.62, 95% CI 0.49–0.79 at 16 weeks) rodermic variants.
regardless of the type of therapy [103]. In addi- Plaque psoriasis is usually chronic with inter-
tion, in a randomized trial of 61 obese patients mittent remissions. Plaques may persist for
with moderate to severe psoriasis, weight loss months to years at the same locations; however,
improved the response to cyclosporine (2.5 mg/ periods of complete remission do occur. Psoriatic
kg per day) [104]. The weight-based dosing regi- plaques usually develop slowly over time. During
men for ustekinumab, a newer treatment option exacerbations, however, plaques tend to enlarge
for psoriasis, is used to mitigate the reduction in more rapidly with an active peripheral edge of
drug efficacy observed when the standard dose is increasingly intense erythema and scale along with
utilized in obese patients [102]. increases in plaque thickness. New psoriatic pap-
ules may arise in areas of normal skin surrounding
the established plaques and coalesce with these to
Estrogen form increasingly larger plaques. Resolution of a
plaque typically begins at its center. The end result
Elevated estrogen levels may serve as a trigger of plaque clearance may be post-inflammatory
for psoriasis in some patients. Reports of new hypo- or hyper-pigmentation that gradually fades
onset psoriasis at puberty, psoriasis worsened giving way to normal-appearing skin. Complete
by estrogen therapy, and psoriasis that may be remission of psoriasis for several years followed
cyclical and related to menses, all suggest an by reoccurrence of disease can occur.
etiologic role for elevated estrogen levels [105]. Traditionally, chronic plaque psoriasis has
However, there have also been reports of psoria- been considered a single entity; however, recent
sis occurring or being exacerbated at the onset of evidence demonstrates that patients with thin and
menopause, which supports the opposite inter- thick plaque psoriasis have differing clinical fea-
pretation. These findings demonstrate that the tures [109]. In addition to cutaneous involvement,
potential role of estrogen as a triggering factor plaque psoriasis may be associated with internal
for psoriasis is not entirely clear. Additionally, involvement, including joints and extra-articular
while some patients report a worsening of psoria- sites such as the eyes. Concomitant psoriatic
sis during pregnancy, nearly twice as many report arthritis occurs in up to 30% of patients with cuta-
improvement of their psoriasis during pregnancy neous psoriasis [110]. In a minority of patients,
[106–108]. Relapse during the early postpartum the symptoms of psoriatic arthritis appear before
period is common. The mechanism by which skin involvement. The prevalence of ophthalmic
psoriasis tends to improve during pregnancy is involvement in patients with cutaneous disease
not well understood. However, there is now data is not known; however, it is thought to occur in
to suggest that the up regulation of Th2 cytokines approximately 10% of patients [111]. Psoriasis
during pregnancy counteracts the effects of pro- may affect almost any part of the eye, leading to
inflammatory Th1 cytokines which are key play- blepharitis, peripheral keratopathy, acute anterior
ers in the pathogenesis of psoriasis [77]. uveitis, posterior synechiae, conjunctivitis, and
cataract formation.
Guttate psoriasis may clear spontaneously
Disease Course over weeks to months. There is a tendency
toward younger age of onset with elevated anti-
Psoriasis encompasses a spectrum of cutaneous streptolysin O (ASO) titer in patients with invo-
manifestations that varies from patient to patient luting course. Guttate psoriasis may become
and even in the same patient over time. While the chronic and progress to plaque psoriasis, par-
majority of patients have chronic plaque psoriasis ticularly in patients with a family history of pso-
throughout the typically lifelong course of their riasis [112].
Palmoplantar pustulosis, which is now con- 9. Eckes L, Ananthakrishnan R, Walter H. The geo-
graphic distribution of psoriasis [in German].
sidered a single entity distinct from pustular pso- Hautarzt. 1975;26:563–7.
riasis, is a chronic disease which tends to remain 10. Okada S, Weatherhead E, Targoff IN, Wesley R,
localized to the palms and soles. It is significantly Miller FW. International Myositis Collaborative
aggravated by extrinsic factors, such as stress, Study Group. Global surface ultraviolet radiation
intensity may modulate the clinical and immuno-
smoking, and infections. It is less responsive to logical expression of autoimmune muscle disease.
standard treatment and is commonly associated Arthritis Rheum. 2003;48(8):2285–93.
with sterile inflammatory bone lesions, such as 11. Jacobson CC, Kumar S, Kimball A. Latitude and
the SAPHO syndrome (synovitis, acne, pustulo- psoriasis prevalence (research letter). J Am Acad
Dermatol. 2011;65(4):870–3.
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Localized palmoplantar psoriasis presents Saharan Africa. Joint Bone Spine. 2012;79(1):17–9.
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and soles that may be also seen with or with- RJ, Chimenti S, Krueger GG, Leonarid C, Menter
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Topical Therapy I: Corticosteroids
and Vitamin D Analogues 5
Eric J. Yang and Shari R. Lipner
Abstract
Psoriasis is a common disease affecting 1. To understand the mechanism of action
approximately 2% of the population world- of topical steroids and vitamin D
wide. Topical therapies play an integral role in analogues
the treatment of patients with mild-to- 2. To understand the appropriate use and
moderate disease. The mainstays of treatment efficacy of topical steroids and vitamin
are topical corticosteroids, vitamin D ana- D analogues
logues, or a combination of the two. This 3. To understand the safety issues of topi-
chapter will discuss the pharmacokinetics and cal steroids and vitamin D analogues
mechanism of action of topical corticosteroids
and vitamin D analogues for the treatment of
psoriasis. Additionally, long-term adverse
effects of these medications, vehicle selection,
Topical Corticosteroids
potency, and combination use with other treat-
ment modalities will also be discussed.
Topical corticosteroids (TCS) are a mainstay in
treatment of a wide range of inflammatory der-
matoses. There are seven classes of topical ste-
roids ranging from superpotent (class 1) to very
low-potency topical steroids (class 7). These
classes have been developed based on vasocon-
strictor assays [1]. These vasoconstrictor assays
involve preparing the test corticosteroid in 95%
alcohol and then applying it to the volar surface
of a normal volunteer’s forearm. The alcohol is
left to evaporate and then the test area is covered
E. J. Yang with an occlusive dressing for 16 h. Afterwards,
Chicago Medical School, Rosalind Franklin the area is washed off and vasoconstriction is
University, North Chicago, IL, USA assessed. The vasoconstrictive assay is reproduc-
S. R. Lipner (*) ible and correlates well with the clinical efficacy
Department of Dermatology, Weill Cornell Medical of TCS (Fig. 5.1).
College, New York, NY, USA

https://doi.org/10.1007/978-3-030-54859-9_5
40 E. J. Yang and S. R. Lipner
Fig. 5.1 Topical CH2OH

corticosteroid 21
20 O
18
HO 12
17
11 OH
13
19
16
1 9
14
2 8 15
3
7
5
O
4 6
Pharmacokinetics/Mechanism dexamethasone, betamethasone and triamcino-

of Action lone, is accomplished by the addition of a 16-α
methyl, 16-β methyl, or 16-α hydroxyl group.
Three factors determine the pharmacokinetics Finally, epidermal enzymes cause de-
and potency of a topical corticosteroid: the struc- esterification of topical corticosteroids into inac-
ture of the corticosteroid molecule, the vehicle, tive metabolites. Increased potency can be
and the skin onto which the corticosteroid is accomplished by inhibiting de-esterification
applied [2]. Hydrocortisone is the central struc- through halogenation at the 21 position.
ture of most topical corticosteroids. Variations
are formed by placing hydroxyl groups onto the
11-β, 17-α, and 21 positions. Additionally, ketone Vehicle
groups at the 3 and 20 positions and a double
bond into the 4 position of the glucocorticoid The vehicle of a topical corticosteroid can influ-
nucleus distinguish between classes. Adding or ence percutaneous absorption and therapeutic
altering functional groups such as hydroxyl, efficacy. When choosing a topical steroid, one
hydrocarbon, ester, fluoro, chloro, acetonide or must first decide on the desired potency based on
ketone groups at certain positions can vastly the severity and the location of the skin disease.
impact the molecule’s pharmacokinetics [2]. The Then, one must decide on the vehicle based on
alteration of hydroxyl groups modifies the mole- the type of lesion to be treated, need for hydration
cule’s lipophilicity, solubility, percutaneous or drying effect, location and potential for irrita-
absorption and glucocorticoid receptor binding tion by components of the vehicle, and patient
ability [2]. preference. Lotions are often preferred for the
Glucocorticoid potency is increased by adding face, ointments work well for dry lesions, and
a double-bond at position one, or with additional gels are more useful in hairy areas or for a drying
fluorination or chlorination [2]. Additionally, effect for wet lesions. Patients typically prefer
halogenation at the 6-α or 9-α position increases vehicles that are quickly absorbed, non-greasy,
glucocorticoid receptor binding activity [2]. and easy to apply [3], such as lotions and foams,
Decreased mineralocorticoid activity, as in but patient preferences may vary greatly [4].
5 Topical Therapy I: Corticosteroids and Vitamin D Analogues 41
Potent and superpotent topical steroids should be Immunologic Mechanisms

avoided on the thin skin of the face and intertrigi-
nous areas due to an increased risk of skin Topical corticosteroids are closely involved with
atrophy. all aspects of inflammation in the body, affecting
The vehicle may alter the pharmacokinetics of both adaptive and innate immunity. TCS have
a topical steroid molecule, thereby affecting its been shown to decrease the number and function
potency. A novel formulation for halobetasol proof Langerhans’ cells, which are antigen present-
pionate 0.01% lotion has demonstrated similar ing cells found in the skin important in initiating
efficacy for psoriasis as compared to halobetasol immune responses. Neutrophils are decreased,
0.05% cream despite a lower drug concentration less adherent to vascular endothelium and have
[5], due to increased drug delivery of the active decreased phagocytic function with corticoste-
ingredient by the vehicle [6]. Propylene glycol roid use [9–11]. Similarly, leukocytes show
and alcohol, which are common solvents, can decreased antibody-dependent cellular toxicity
affect percutaneous absorption by altering the and natural killer cell function [12, 13]. In addi-
topical corticosteroid molecule’s solubility in the tion, the production of many cytokines is
vehicle. Propylene glycol enhances potency decreased including interleukin (IL)-1, IL-2,
through increasing penetration through the stra- interferon (IFN)-γ, tumor necrosis factor and
tum corneum (Fig. 5.2). granulocyte-monocyte-stimulating factor [2].
For some agents, brand-name preparations are Topical steroids decrease the mitotic rate of
not always equivalent to generics and may have the epidermis, thereby causing thinning of the
higher or lower potency. For example, Valisone stratum corneum and granulosum and flattening
0.1% cream (Schering) and Kenalog 0.1% cream of the basal layer [14]. TCS also cause atrophy of
(Westwood-Squibb) have both demonstrated the dermis through inhibition of fibroblast prolif-
increased vasoconstriction over generics [2]. In eration, migration, chemotaxis and protein syn-
addition, Synalar 0.025% cream is also more thesis. They have also been shown to cause
potent than generic fluocinolone acetonide inhibition of fibroblast synthesis of both glycos-
0.025% cream (Fougera and Company) [2]. aminoglycans and collagen [15–17].
However, Aristocort 0.025% cream and Aristocort
0.05% cream (Lederle Laboratories) are signifi-
cantly less potent than generic triamcinolone Use in Psoriasis
0.025 and 0.05% cream (Fougera and Company)
[2]. In general, generic vs. brand-name ointments The antiproliferative and atrophogenic character-
tend to be closer in vasoconstrictive assays than istics of TCS are useful in treating psoriasis.
creams. Additionally, there are differences Topical corticosteroids are the mainstay of treat-
between different generic preparations as well as ment and often first-line for the management of
different brand-name preparations of the same mild to moderate psoriasis, as well as for inter-
topical corticosteroids [7]. triginous areas and genitalia, as these areas can
Bioavailability and penetration of the topical become irritated with the use of other topical
corticosteroid increase with inflamed or diseased agents [18]. In general, for the treatment of local-
skin, as well as with increased hydration of the ized plaque-type psoriasis, high potency or super-
stratum corneum. The thickness of the stratum potent TCS are prescribed twice daily. Optimal
corneum is inversely proportional to the degree improvement with high potency TCS is often
of penetration of the topical corticosteroid. Very achieved after 2 weeks. Superpotent TCS are rec-
occlusive agents, such as ointments, increase the ommended for the treatment of nail psoriasis [19],
absorption of topical corticosteroids through whereas low-to-mid-potency TCS are typically
increased hydration of the stratum corneum [8]. used for intertriginous and genital psoriasis [18].
Fig. 5.2 Diagram of Calcitriol chemical structure

steroid molecule. (Top) 22
Clacitriol chemical 21 24
27
structure, (Bottom)
Calcipotrience chemical OH
18 20 23 25
structure 26
12 17
11 16
13
9
14 15
8
5 19
4
10
3 1
HO OH
2
Calcipotriene chemical structure

OH
•H2O
H
HO OH
Katz and colleagues in several studies indi- Adverse Effects

cated the efficacy of clobetasol ointment or beta-
methasone dipropionate ointment in clearing Systemic adverse effects from topical corticoste-
plaque type psoriasis and found that remission roids are uncommon and are increased with young
could be maintained by applying 3.5 g three times age, liver disease, renal disease, the potency of the
a week [20, 21].In a placebo-controlled trial, Katz drug, amount of skin surface involvement, the use
et al. demonstrated that with maintenance therapy of occlusion, frequency of application and the
consisting of 12 weeks of weekend-only use of duration of treatment [2]. The liver metabolizes
betamethasone dipropionate ointment, 74% of corticosteroids and the kidneys excrete both
patients remained in remission as compared to metabolized and unmetabolized corticosteroid
21% of the patients receiving placebo [22]. [36]. Infants and young children are particularly
Occlusion can greatly increase penetration predisposed to systemic adverse effects from TCS
and efficacy of TCS. Studies have demonstrated due to a higher skin surface-to- body ratio,
that triamcinolone acetonide 0.1% ointment increased cutaneous permeability, and immature
under occlusion is more effective than clobetasol renal function [37]. Catch-up growth is expected
propionate 0.05% cream twice daily or triamcin- when topical corticosteroids are discontinued in
olone acetonide 0.1% ointment alone [23, 24]. this population. Cushing’s syndrome and hypotha-
Flurandrenolide (Cordran) tape is frequently pre- lamic-pituitary-adrenal (HPA) axis suppression
scribed due to its occlusive nature and has been has been noted in patients applying high quantities
shown to be superior to twice-daily diflorasone of topical corticosteroids for prolonged periods of
diacetate ointment in a randomized bilateral time [38–40]. Screening for HPA axis suppression
comparison study of plaque-type psoriasis [25]. is done using the 8 AM plasma cortisol level and
Clobetasol propionate lotion applied under occlu- definitive diagnosis requires the cosyntropin test.
sion with a hydrocolloid dressing (Duoderm ET) Local adverse effects are also rare but occur
once weekly also showed faster remission of pso- more frequently than systemic adverse effects.
riasis than unoccluded clobetasol propionate Cutaneous atrophy is the most commonly
ointment applied twice daily [26, 27]. Foams observed side effect, and is characterized by tel-
have been found to have increased efficacy over angiectasias, striae, hypopigmented, wrinkled or
lotions of the same class of TCS when treating shiny skin [41]. Striae are typically seen after
the scalp [28, 29]. many weeks to months of topical steroid use; risk
factors include the potency of corticosteroid,
location of application, occlusion, and use in
Combination with Other Therapies infancy/childhood. “Corticosteroid phobia” is an
exaggerated and often irrational fear of using
In patients with psoriasis, vitamin D analogues topical steroids, and is common amongst patients
are frequently added at the onset, as there is a [42], often resulting in treatment nonadherence
synergistic effect with TCS. Topical corticoste- [43]. Patients’ primary concerns often stem from
roids work synergistically with light therapy as TCS “thinning the skin,” but a 2011 study by
well as many systemic agents. Psoriasis clears Hong et al. demonstrated that appropriate long-
faster when using psoralen plus ultraviolet A term use of topical corticosteroids in children
(PUVA) with TCS versus PUVA alone. The addi- with dermatitis does not cause skin atrophy [44].
tion of topical corticosteroids to cyclosporine Application of TCS may also result in perioral
therapy also leads to more rapid clearance of pso- dermatitis, characterized by erythematous pap-
riasis [30]. Topical steroids may also be com- ules in a periorificial distribution. Treatment for
bined with other topical agents, such as tazarotene perioral dermatitis consists of an oral tetracycline
[31, 32], salicylic acid [33, 34], or anthralin [35], in addition to a long taper with a non-fluorinated
providing increased efficacy due to increased topical corticosteroid, such as hydrocortisone
penetration. acetate cream.
Prolonged use of topical glucocorticoids on market: calcipotriene, calcitriol, tacalcitol and

the eyelids can lead to glaucoma and cataracts, maxacalcitol.
and thus is not recommended [45]. These compli- The skin both synthesizes vitamin D (where
cations may also occur in patients who apply 7-dehydrocholesterol is converted to vitamin
TCS peripherally on their body, if inadvertent eye D3 in the presence of ultraviolet (UV) radiation)
contact occurs. and is a target organ for vitamin D activity.
Allergic contact dermatitis to topical steroids Vitamin D receptors transduce the effects of 1,
may occur and can be suspected when a patient 25-dihydroxyvitamin D3 and have been identified
fails to respond to topical steroid therapy or flares in keratinocytes, Langerhans’ cells, melanocytes,
with topical steroid therapy [46, 47]. This allergy fibroblasts and endothelial cells [52]. The vita-
may be to the vehicle or the actual corticosteroid min D receptor (VDR) is activated by binding to
molecule, which can be confirmed with patch its ligand (1,25-dihydroxyvitamin D3) or a syn-
testing. Topical corticosteroids often have a thetic analogue such as calcipotriene or calcitriol.
delayed reaction and persist for at least 96 h, thus This vitamin D receptor complex, in association
requiring a delayed check [48]. with the retinoid X receptor-α (RXR-α), then
Loss of clinical effect may occur with repeated binds to specific DNA binding sites called
application of topical corticosteroids—known as Vitamin D Response Elements (VDREs), result-
tachyphylaxis. This phenomenon occurs more ing in induction or repression of their target gene.
commonly with higher strength topical cortico- In addition to inhibiting the proliferation of kera-
steroids, but often subsides after a rest period of a tinocytes and promoting epidermal differentia-
few days. There is no established regimen to pre- tion, vitamin D promotes the formation of the
vent tachyphylaxis. A commonly recommended cornified envelope by increasing gene expression
regimen is twice daily application of TCS for and thereby increasing levels of involucrin and
2 weeks followed by a 1 week rest period or transglutaminase [53].
weekend-only application [49]. Vitamin D also possesses anti-inflammatory
benefits. It has been shown to increase levels of
anti-inflammatory cytokine interleukin (IL)-10
Vitamin d Analogues and decrease levels of pro-inflammatory cytokine
IL-8in psoriatic plaques [54]. In addition, it has
Structure, Biosynthesis been shown to inhibit the production IL-2 and
and Mechanism of Action IL-6 by T cells, blocks transcription of interferon
(IFN)-γ and inhibits cytotoxic T cell and natural
Vitamin D as a treatment for psoriasis was first killer cell activity [55].
discovered after a patient receiving oral vitamin
D for osteoporosis was cured of psoriasis [50].
Calcitriol, the active form of vitamin D3, was Calcitriol
found to inhibit the keratinocyte proliferation and
modulate the keratinocyte differentiation [51]. Calcitriol is the natural active form of vitamin D3.
However, the therapeutic doses of oral vitamin Calcium metabolism is affected by calcitriol
D3 for osteoporosis produce hypercalcemia and through release of calcium from bone, decreasing
hypercalciuria, thus limiting its practicality for parathyroid hormone, increasing tubular resorption
use in dermatology. As a result, topical vitamin D of calcium in the kidney, and stimulating calcium
analogues were developed to minimize the risk of transport in the intestines. Thus, if applied exces-
hypercalcemia, while maintaining the other ben- sively, calcitriol may result in hypercalcemia and
eficial cellular effects of vitamin D. There are hypercalciuria. Calcitriol is available in an oint-
currently four vitamin D3 analogues out in the ment form as Vectical (USA) and Silkis (Europe).
Calcipotriene (Calcipotriol) roids in the treatment of psoriasis [57–59].

Calcipotriene applied twice daily has been shown
Calcipotriene is a synthetic form of calcitriol. It to be more effective than once daily applications,
was the only vitamin D analogue that was avail- without increased skin irritation [60, 61].
able in the U.S. for many years. Its molecular Calcipotriene is associated with slightly more
structure differs slightly from calcitriol, as it con- skin irritation than topical steroids, which rarely
tains a double bond and ring structure in its side leads to withdrawal of therapy [59].
chain which enables it to be metabolized much In a study of 114 patients by Bruce et al., cal-
more rapidly. As a result, it is less likely to cause cipotriene ointment was superior to fluocinonide
hypercalcemia than calcitriol. It is available ointment in the treatment of plaque psoriasis
under ointment, cream, solution, and foam forms through 6 weeks [62]. A 2003 study of 258 pso-
under the trade names Dovonex (USA), Sorilux riasis patients by Camarasa et al. in 2003 found
(USA), Daivonex (Europe, Asia), Psorcutan that though betamethasone dipropionate 0.05%
(Europe) and Dermocal (South America). ointment was associated with slightly higher
global improvement than calcitriol ointment, a
statistically significantly higher proportion of
Tacalcitol patients remained in remission following cal-
citriol therapy (48%) than betamethasone therapy
Tacalcitol’s (1,24(OH)2D3) structure is slightly (25%) [63].
different from calcitriol, as it contains a hydroxyl Calcipotriene may be used for intertriginous
group at the 24-position rather than the psoriasis, though burning and irritation are com-
25-position. Nevertheless, it has a similar affinity monly encountered [18, 60]. Less frequent appli-
for vitamin D receptors and similar therapeutic cation and alternation with low-potency topical
effects. Tacalcitol is less selective than calcipotri- steroids in these areas may be less irritating.
ene in its effect on calcium metabolism and has Calcipotriene is an effective and well-tolerated
been shown to induce hypercalcemia at equiva- modality for treating scalp psoriasis, and in com-
lent doses to calcitriol. It is available under oint- bination with other topical agents, may lead to
ment, cream, lotion and solution forms in Japan improved response to treatment. In long-term
and under lotion and ointment forms in Europe as studies, calcipotriene has been shown to be a safe
Curatoderm. and effective therapy for the chronic manage-
ment of psoriasis. Sustained disease improve-
ment has been documented with twice daily use
Maxacalcitol for 1 year without elevation of serum calcium
levels [64].
Maxacalcitol (1α,25-dihydroxy-22-oxacalcitriol) Vitamin D analogues have been shown to be
is available as Oxarol in Japan and has been effective and well-tolerated in children. In an
shown to be 10 times more potent than calcitriol uncontrolled pilot study of 12 children under the
and tacalcitol in inhibiting keratinocyte age of 15 with long-term follow-up of 106 weeks
proliferation and 60 times less calcemic than cal- by Park et al., patients showed significant
cipotriene [56]. It has shown benefit in the treat- improvement in PASI scores compared to base-
ment of psoriasis and has not posed a significant line, with no detected serious adverse effects or
risk of hypercalcemia. hypercalcemia [65].
Indication for Psoriasis Use with Other Treatment Modalities
Vitamin D analogues perform as well as midpo- Topical steroids are commonly used in conjunc-
tency steroids, but less well than superpotent ste- tion with vitamin D analogues, as these therapies
have a synergistic effect when used in combina- demonstrated that the combination betametha-
tion. Combination therapy of TCS with vitamin sone dipropionate 0.064% with calcipotriene
D analogues improves the clinical response rate 0.005% maintains the efficacy of etanercept after
and minimizes the side effects of both treatments a step down dose to 50 mg weekly from 50 mg
[60, 66, 67]. Topical steroids reduce or eliminate twice weekly [81]. Patients with inadequate
the irritation associated with calcipotriene use. response to etanercept also demonstrated
Additionally, a study by Lebwohl demonstrated improved efficacy with combination calcipotriol
that patients using superpotent topical steroids on and etanercept treatment [82].
weekends and calcipotriene during the week
maintained a longer remission than patients using
superpotent topical steroids alone [68]. Adverse Effects
Formulations of a combination of calcipotri-
ene and betamethasone dipropionate ointment Vitamin D analogues are typically well tolerated,
have demonstrated greater efficacy and a more with the main side effects being application-site
rapid onset of action compared to either medica- burning and irritation. These symptoms are more
tion alone [69]. This combination is highly effec- common on the thin skin of the face and in the
tive for scalp psoriasis and is associated with intertriginous areas, with irritation developing in
significantly fewer side effects than with calci- about 20% of patients treating those areas [83].
potriol alone [70, 71]. The foam formulation has Irritation is self-limited and resolves quickly
demonstrated superior efficacy for psoriasis as once the drug is discontinued.
compared to the gel formulation in previous stud- Patients are recommended to use less than
ies [72]. The calcipotriol/betamethasone propio- 100 g of topical calcipotriene weekly [84], as
nate combination is available in the ointment topical calcipotriene demonstrates a dose-
(Daivobet, Taclonex), topical suspension dependent suppression of serum parathyroid hor-
(Taclonex), and foam (Enstilar) forms. mone production and 1,25 dihydroxyvitamin D3
Combining vitamin D analogues and photo- levels [65, 85]. Patients undergoing long-term
therapy has also been shown to clear lesions more treatment exceeding 100 g of topical vitamin D
rapidly than either entity alone and produces a analogues weekly should have their serum para-
greater reduction in Psoriasis Area and Severity thyroid hormone and vitamin D levels checked.
Index (PASI) [73, 74]. Studies combining PUVA Patients with renal disease are at increased risk of
with calcipotriene have also demonstrated developing hypercalcemia with topical vitamin D
increased efficacy than when using PUVA alone analogue therapy, and thus may benefit from reg-
[75]. Total cumulative UVA exposure required ular monitoring, even when applying less than
for clearance of psoriasis with vitamin D ana- 100 g per week.
logues is reduced, thus decreasing the risk of
developing skin cancer. Vitamin D analogues
should be applied following phototherapy, as the
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Topical Therapy II: Retinoids,
Immunomodulators, and Others 6
Lyn C. Guenther
Abstract well tolerated in the treatment of intertrigi-

nous, facial and genital psoriasis. The use of
Tazarotene is the only topical retinoid
tar and anthralin has declined with the devel-
approved for treatment of psoriasis. Although
opment of cosmetically elegant, efficacious
it is used primarily for plaque psoriasis, it may
treatments that do not stain the skin or cloth-
be beneficial for palmoplantar and nail psoria-
ing. Although coal tar contains many known
sis. Use in combination with a mid- to super-
carcinogens, use in psoriasis has not been
potency topical steroid enhances efficacy and
associated with an increase in skin cancer.
reduces irritancy and the atrophogenic poten-
Addition of tar to erythemogenic UVB does
tial of steroids. Thrice a week use with a twice
not enhance efficacy.
weekly superpotent topical steroid may main-
tain improvement long-term. The once daily
fixed combination lotion containing the super-
potent steroid halobetasol propionate and taz- Key Learning Objectives
arotene 0.045% (Duobrii™) is convenient, 1. To understand the mechanism of action
providing synergistic efficacy and unrestricted of topical retinoids, immunomodula-
duration of use until clearance occurs. Use of tors, and other topicals.
tazarotene with broad band and narrow band 2. To understand the appropriate use and
UVB can enhance efficacy and decrease the efficacy of topical retinoids, immuno-
cumulative dose of UV. Addition of tazarotene modulators, and other topicals.
to broadband or narrowband UVB, or PUVA 3. To understand the safety issues of topi-
phototherapy enhances efficacy and decreases cal retinoids, immunomodulators, and
the total dose of ultraviolet radiation. The cal- other topicals.
cineurin inhibitors pimecrolimus and tacroli-
mus and phosphodiesterase-4 inhibitor
crisaborole are not approved for treatment of
In addition to the commonly used topical corti-
psoriasis, although they are efficacious and
costeroids and vitamin D analogues, there are
several other topical therapies which are used
L. C. Guenther (*) in the management of psoriasis. Tazarotene, a
Division of Dermatology, Western University, The receptor-selective topical retinoid, is the first
Guenther Dermatology Research Centre, and only topical retinoid to be approved to
London, ON, Canada treat psoriasis. Topical tretinoin and isotreti-

https://doi.org/10.1007/978-3-030-54859-9_6
52 L. C. Guenther
noin, two other retinoids, have been abandoned Mechanism of Action

due to the variable efficacy and irritancy of
tretinoin [1–5], and failure to show superior Tazarotene is a synthetic acetylenic retinoid
efficacy of isotretinoin compared to placebo which is a prodrug. Its free-acid active metabolite
[6]. The calcineurin inhibitors pimecrolimus tazarotenic acid, binds to the nuclear retinoic acid
and tacrolimus are commonly used off-label receptor (RAR) β and γ, weakly to RARα, but not
for intertriginous, facial, and genital psoriasis to retinoid X receptors (RXRs) [10]. RARγ is the
[7]. Coal tar and anthralin were once in com- predominant subtype in the epidermis [11].
mon use, however their use has declined with RARs affect gene transcription after forming het-
the development of more cosmetically elegant, erodimers with RXRs [12]. Tazarotenic acid can-
efficacious agents [8]. not be converted to other retinoids since it does
not contain isomerizable double bonds [10].
Tazarotene decreases inflammation and nor-
Tazarotene malizes the abnormal keratinocyte hyperprolif-
eration and differentiation seen in psoriasis [10].
Tazarotene is available as a 0.05 and 0.1% gel The lymphocytic infiltrate in the dermis, number
and cream [9] (Fig. 6.1). of HLA-DR and intracellular adhesion molecule
Figure 6.1 also known as; Tazorac, Zorac, (ICAM-1) positive cells in the epidermis and der-
Avage, 118292-40-3, tazaroteno, tazarotenum, mis, expression of epidermal growth-factor
Suretin, Tazoral, AGN-190168. It is also avail- receptor (EGFR), the hyperproliferative keratins
able in a fixed combination lotion with halobeta- K16 and K6, skin-derived antileukoproteinase
sol (Duobrii). (SKALP) and macrophage migration inhibitory
Tazarotene (marketed as Tazorac, Avage and factor-related-protein-8 (MRP-8), keratinocyte
Zorac) is a prescription topical retinoid sold as a transglutaminase type 1 (TGase K), and involu-
cream or gel. Halobetasol propionate/tazarotene crin, are reduced, and filaggrin expression in the
lotion is a topical prescription superpotent ste- upper stratum spinosum and stratum granulosum
roid/retinoid combination. Tazarotene is approved increased [10, 13]. SKALP is an elastase inhibi-
for treatment of psoriasis, acne and sun damaged tor [14] in the suprabasal layers of psoriatic epi-
skin, while halobetasol/tazarotene is approved dermis, which is not present in normal epidermis
for treatment of plaque psoriasis in adults. Unlike [15]. The enzyme TGase K and protein involu-
other products that contain topical steroids, this crin are involved in formation of the cross-linked
combination product does not have a limitation envelope and are prematurely expressed in pso-
on how long the product can be used. riasis [16]. Tazarotene can also induce expression
of tazarotene-induced genes (TIG). TIG1 is a cell
adhesion molecule which promotes cell to-cell
S contact and reduces keratinocyte proliferation
[17]. TIG2 is not anti-proliferative, but is involved
in keratinocyte differentiation [18, 19]. TIG3
C
C N regulates keratinocyte terminal differentiation
and cornified envelope formation through the
O activation of type 1transglutaminase (TG1) [20].
O
Pharmacokinetics
Fig. 6.1 Also known as; Tazorac, Zorac, Avage, 118292-
40-
3, tazaroteno, tazarotenum, Suretin, Tazoral, AGN-
190168 (Molecular Formula: C12H21NO2S. Molecular The half life of tazarotene is 2–18 min [10].
Weight: 351.46194) Tazarotene is converted via esterase metabolism
6 Topical Therapy II: Retinoids, Immunomodulators, and Others 53
to its active metabolite tazarotenic acid which has Tazarotene 0.05% and 0.1% gels did not exhibit
linear pharmacokinetics and a 1–2 h elimination phototoxic or photoallergic potential in healthy
half-life [10]. Tazarotenic acid is then metabo- adult Caucasians [29]. In common with other
lized into inactive sulphoxide and sulphone retinoids, systemic tazarotene is teratogenic [10].
metabolites and more polar conjugate metabo- Topical tazarotene is contraindicated in preg-
lites [10]. Fecal elimination peaks approximately nancy [30], although in clinical trials, healthy
2.5 days after dosing and is for all intensive pur- babies were reported in all eight women who
poses complete by 1 week [21]. Urinary excre- inadvertently became pregnant [31].
tion is virtually complete by 2–3 days [21].
Tazarotene and tazarotenic acid do not accumu-
late in tissues [10]. In a study of 6 patients with Clinical Studies in Plaque Psoriasis
psoriasis, 4.54% of a 2 mg dose administered at a
concentration of 2.5 μg/cm2 was absorbed into Clinical trials of tazarotene and other topicals are
the stratum corneum, 1.38% into the epidermis, summarized in Table 6.1. In the two phase 2 tri-
and 0.97% into the dermis; 0.43% was recovered als, 0.01% tazarotene aqueous gel was not found
in the feces and 0.33% in the urine [21]. The sys- to be efficacious, while 0.05 and 0.1% tazarotene
temic absorption after an occluded 10 h 2 mg gels once and twice daily showed similar efficacy
application (2.5 μg/cm2) of tazarotene 0.1% gel with significant improvement in elevation, scal-
to the backs of 6 healthy males was 5.3% and ing, erythema and overall clinical severity of
drug half life in blood and urine, 17–18 h [22]. plaques as early as 1 week [32]. Treatment-
Application of the 0.1% gel to 20% body surface related adverse effects (primarily burning, pruri-
area (BSA) of healthy volunteers for 7 days tus, stinging, and erythema) occurred in 30% in
resulted in a mean Cmax +/− SD of tazarotenic the first trial and 22.2% in the second trial. In the
acid of 0.72 ± 0.58 ng/ml [23]. Low plasma con- second trial, up to 50% of plaques had erythema
centrations of tazarotene (<0.15 ng/ml) and taz- of the surrounding skin.
arotenic acid (0.05–6.1 ng/ml) were noted in In a phase 3, placebo-controlled study, once
2.8% (2/72) and 47.2% (34/72) of patients treated daily tazarotene 0.05 and 0.1% gel for 12 weeks
with 0.05% or 0.1% gel [24, 25]. In a similar had similar efficacy and were superior to vehicle
study, after 12 weeks of therapy only 1 psoriasis (p < 0.05) in all efficacy measures [24]. At the
patient had a low concentration (0.069 ng/ml) of end of treatment, 59% on 0.05% tazarotene gel
tazarotene, while 69.4% had detectable tazaro- and 70% on the 0.1% gel had at least 50%
tenic acid [26]. In two phase 3 cream studies, taz- improvement. Twelve weeks after treatment dis-
arotenic acid was found in approximately ½ of continuation, 52% in the 0.05% group and 41%
the samples, with a highest concentration of in the 0.1% group continued to have at least 50%
0.874 ng/ml [27]. improvement. Treatment related adverse effects
(AEs) consisted primarily of mild to moderate
local irritation. A small uncontrolled study
Toxicology (n = 43) suggested that these AEs could be mini-
mized without compromising efficacy, by short-
In contrast to tretinoin, tazarotene and tazaro- contact application for 20 min followed by
tenic acid are not cytotoxic to Chinese hamster washing with water [33]. Two phase 3 placebo-
ovary cells [28]. In addition, tazarotene is not controlled cream studies involving 1303 patients
mutagenic [10]. In a 21-month mouse study, it showed that tazarotene 0.05 and 0.1% creams
was not carcinogenic, however, in the hairless were significantly better than vehicle with regards
mouse photocarcinogenicity study, similar to to overall assessment, global response to treat-
other retinoids, it enhanced the photocarcinoge- ment, and reduction in plaque elevation and scal-
nicity associated with ultraviolet irradiation [21]. ing [27]. One of the studies included a 12-week
54 L. C. Guenther
Table 6.1 Clinical trials of tazarotene in psoriasis

Study # Patients Treatment Efficacy Safety
Krueger 45 (with 90 2 of: 0.01 or 0.05% 0.01% taz: Minimal 33% of plaques had Rx
et al. bilateral tazarotene (taz) gel, or efficacy. 45% on 0.05% gel related adverse effects
(1998) symmetrical vehicle gel BID × 6 weeks had ≥75% improvement (AEs), especially
[32] plaques) vs. 13% on vehicle. erythema and pruritus
(p < 0.05)
Krueger 108 (with 2 of the following: 0.05% No significant differences Rx-related AEs in 22.2%
et al. 216 bilateral taz gel OD or BID, 0.1% in ≥75% improvement (burning, pruritus,
(1998) symmetrical taz gel OD or with Rx (range: 48% with stinging, erythema; 13%
[32] plaques) [31] BID × 8 weeks then 0.05% taz OD to 63% with with 0.05% OD vs. 30%
8 weeks follow-up 0.05% taz BID) or 8 weeks with 0.1% BID).
follow-up Perilesional erythema in
½. Rx withdrawal due to
AEs in 5.1%.
Weinstein 324 with 318 Taz 0.05, 0.1% gel or Taz 0.05 and 0.01% similar Mild to moderate
(1997) evaluable vehicle gel OD × 12 weeks and better than placebo in irritation: Pruritus (8%
[24] [24] then 12 weeks follow-up all efficacy measures on vehicle, 17% on
(p < 0.05).59% on 0.05 and 0.05% taz, 23% on 0.1%
70% on 0.1% had ≥50% taz), burning (6, 15, 19%
improvement. At respectively), erythema
follow-up, 52 and 41% (1, 7, 8% respectively).
respectively maintained Withdrawal due to AEs:
improvement. 3, 10 and 12%
respectively
Weinstein 1303 in 2 Taz 0.05 or 0.1% cream Taz 0.05 and 0.1% more In the 2 studies, pruritus
et al. studies (cr) or vehicle × 12 weeks efficacious than vehicle. on vehicle: 12.2 and
(2003) (with 12 weeks follow-up 12 weeks pooled data: 8.9%, vs. 16.1 and 7.1%
[27] in 1 study) 25.3% on vehicle, 41.1% on taz 0.05%, and 29.4
on taz 0.05 and 44.9% on and 15.6% on taz 0.1%.
0.1% taz had an overall Taz: More burning,
lesional assessment ≤mild. stinging, desquamation,
skin irritation, erythema
Lebwohl 348 with 340 Taz 0.05, or 0.1% gel OD At week 12, no significant Taz: Mild to moderate
et al. evaluable for OR fluocinonide 0.05% cr difference between taz pruritus, burning,
(1998) efficacy BID × 12 weeks with &fluocinonide. More rapid erythema. Fluocinonide:
[26] 12 weeks follow-up period. relapse with fluocinonide Minimal irritation.
after treatment Withdrawal due to AEs:
discontinuation 12% on taz 0.05,18% on
0.1% taz, 2% on steroid.
Tzung 23, but 19 Taz 0.1% gel Comparable efficacy at Irritation in 35% on taz
et al. evaluable OD + petrolatum, or, week 12 Taz: Greater and 0% on calcipotriene
(2005) with 44 calcipotriene 0.005% ung maintenance of
[34] lesion pairs BID × 12 weeks with improvement
4 weeks follow-up
Kaur et al. 20 Left side: Taz 0.05% or Comparable efficacy of OD No discontinuation due
(2008) 0.1% gel OD × 8 weeks taz 0.1% & BID to AEs. No statistically
[35] right side: Calcipotriene calcipotriene. Greater significant difference in
0.005% BID efficacy of calcipotriene AEs between the 2 sides
than OD taz 0.05%
Kumar 30, with 27 Taz 0.1% gel OD right side No significant difference AEs in 48.1% on taz, but
et al. evaluable for 5% crude coal tar (CCT) between 2 sides (74.15% none on CCT
(2010) per protocol ung OD left ESI reduction with taz;
[36] side × 12 weeks. 8 weeks 77.37% with CCT,
follow-up p > 0.05)
Table 6.1 (continued)
Lebwohl 300 with 284 Taz 0.1% gel OD + Taz + mometasone furoate Burning peaked at week
et al. evaluable for (fluocinolone acetonide 0.1% or fluocinonide 4 and was seen in 19%
(1998) efficacy and 0.01% cr or mometasone 0.05% was superior to taz in the taz + placebo
[37] 299 for safety furoate 0.1% cr or 0.1% + placebo after 2, 8 group compared to
fluocinonide 0.05% cr or and 12 weeks. Similar 7–15% in the
placebo [Glaxal® efficacy of fluocinolone & taz + steroid groups
base]) × 12 weeks placebo groups
+4 weeks follow-up
Dubertret 398 Taz 0.1% gel alternate Greater reduction in Fewer treatment-related
et al. evenings with: 1% elevation, scaling and AEs with steroids (36%
(1998) hydrocortisone, 0.05% erythema with with hydrocortisone,
[39] aclometasone dipropionate, taz + betamethasone 32% with aclometasone,
betamethasone valerate valerate. Median time to 31% with
0.1%, or placebo 50% improvement was betamethasone) vs. 42%
2 weeks vs. 4 weeks in the with placebo
other groups
Dhawan 10 Taz 0.1% cr OD + 0.12% 2 clear at week 4. No AEs No AEs
et al. betamethasone valerate 4 clear at week 8.1 patient
(2005) foam OD × 12 weeks (open did not have any
[41] label) improvement
Green and 259 with 229 Taz 0.1% gel hs +/− am The greatest efficacy was The mometasone furoate
Sadoff evaluable steroid (fluocinonide 0.05% seen with betamethasone ung regime was best
(2002) ung, 0.1% mometasone dipropionate cr (50% mean tolerated (17% incidence
[42] furoate ung, 0.05% reduction vs. 20% with of drug-related AEs vs.
diflorasone diacetate ung, monotherapy, p ≤ 0.001), 40% with taz
0.05% betamethasone followed by mometasone monotherapy). There
dipropionate cr, 0.005% furoate ung (41% were no treatment-
fluticasone propionate ung, reduction, p ≤ 0.05) and related withdrawals due
or 0.05% diflorasone diflorasone to AEs in the
diacetate cr) × 12 weeks Diacetate ung (38% mometasone furoate ung
reduction, p ≤ 0.05). regimen vs. 18% on taz
Maximal improvement at monotherapy
8 weeks
Koo and 73 Taz 0.1% gel Greater, more rapid global 1 dermatitis on
Martin OD + mometasone furoate improvement, plaque mometasone.
(2001) 0.1% cr OD, or, elevation and scaling with Taz + steroid: 19% Rx
[43] mometasone furoate 0.1% taz + steroid vs. steroid related AEs at week 4,
cr BID × up to 12 weeks monotherapy (p ≤ 0.05 by 17% at week 8 and 0%
With 12 weeks follow-up if week 4 or 8) at week 12. Burning
clear by week 4 or ≥ 50% 11%, pruritus 11%,
better by week 12 irritation 9%, eruption
6%, new psoriasis or
exacerbation 6%
Guenther 120 Taz 0.1% + 0.1% At week 2, ≥75% Greater AEs with
et al. mometasone furoate OD or, improvement in 45% on taz + steroid. [42% vs.
(2000) calcipotriene 0.005% taz + steroid vs. 26% on 8% burning, 32% vs.
[44] BID × 8 weeks +12 weeks calcipotriene (p ≤ 0.05). 13% pruritus, 28% vs.
follow-up if clear at week 2 Also greater reduction in 12% irritation, 25% vs.
or 4, or week 8 ≥ 50% BSA, elevation, scaling and 7% erythema (p ≤ 0.05)
better erythema for each AE]
(continued)
56 L. C. Guenther
Tanghetti 1393 Taz 0.05% or 0.1% gel OD Increased efficacy with Increased tolerability
et al. for up to 12 weeks either as adjunctive emollient and/or with adjunctive steroid
(2000) monotherapy or in corticosteroid more AEs with
[45] combination with other Adjunctive mid- or high monotherapy (22% at
topicals (open label) potency steroid is at least week 4) vs. 13% with
as efficacious and often mid- or high potency
superior to super potent steroid or 12% with
steroid super-potent steroid
Bowman 15 with 28 Taz 0.1% gel Marked reduction in No Rx withdrawal due
et al. lesion pairs OD + calcipotriene 0.005% scaling, elevation and to AEs no Rx-related
(2002) gel BID, or, clobetasol ung overall lesional severity on AEs with Clobetasol
[48] BID × 2 weeks, then both sides (p < 0.0001) Taz/calcipotriene:
4 weeks follow-up (open with no difference between Asymptomatic erythema
label) the 2 sides. More in 53%, peeling in 33%,
improvement of erythema pruritus in 7 and
with clobetasol (p < 0.01) irritation in 7%
Sugarman 212 Phase 2. Halobetasol At week 8, 52.5%, 33.3%, Application site pain,
JL et al. propionate (HP) 0.01%/taz 18.6% and 9.7% pruritus, and erythema
(2017) 0.045% lotion vs. HP vs. respectively had treatment most frequent with taz
[50] taz vs. vehicle OD x success (IGA clear/almost (22.4%) and 0.2%HP/taz
8 weeks clear + at least a 2-grade (10.2%)
improvement from Comparable number of
baseline) patients on HP/taz
(3.4%) and vehicle
(3.2%) reporting ≥1AE
leading to
discontinuation vs.
12.2% on taz
monotherapy
Stein Gold 418 2 phase 3 studies HP/taz At week 8, 35.8% (study 1) Contact dermatitis
L et al. lotion or vehicle od X and 45.3% (study 2) had (6.3%), pruritus (2.2%)
(2018) 8 weeks treatment success (IGA and pain at the
[51] clear/almost clear + at least application site (2.6%)
a 2-grade improvement were the most common
from baseline) treatment-related AEs
Lebowohl 555 HP/taz lotion daily x At week 24, 20.9% 7.5% discontinued due
MG et al. 8 weeks, then as needed in discontinued treatment due to treatment-emergent
(2019) 4 week intervals up to 24 to lack of efficacy AEs: Dermatitis (7
[52] continuous weeks. people), pruritus (7
people) and pain (6
people), being the most
common
Koo 54 patients Broad band UVB 3×/week Time to 50% improvement Taz + UVB: No
(2000) with 108 ½ body with +2/3: No reduced by ½ (25 days vs. photosensitivity or
[53] target lesions topical, vehicle, or taz 0.1% 53 days) cumulative UVB phototoxicity 16.7% had
gel OD × 2 weeks pre-UV, reduced by 76% Rx-related AEs
then 3×/week (irritation, burning and
pruritus)
Behrens 10 ½ body hs taz 0.05% gel or After 4 weeks, 64% PASI Mild irritation with taz,
et al. emollient +311 nb UVB reduction taz vs. 48% but no phototoxicity
(2000) 5×/week
[54]
Stege 20 0.1% taz gel or 5% Significantly faster and
et al. salicylic acid 1 week before greater efficacy in ½ body
(1998) & during 3 weeks narrow treated with taz
[55] band (nb) UVB
Dayal 30 2 target plaques on right At week 12, target plaque Lesional irritation
et al. and left sides of body. score reduced by 99.64% 6.67%, burning 3.33%,
(2018) Right side treated with taz and 84.92% respectively pruritus 6.67% with taz
[56] 0.05% gel + nbUVB BIW; Complete clearance in No statistically
left side with nb UVB BIW 96.7% and 6.7% significant difference
respectively between the 2 sides
16.4 +/− 2.8 and 23.33 (p = 0.352)
+/− 1.2 sessions
respectively for clearance
Behrens 12 ½ body taz 0.05% gel or Faster and greater efficacy No photo-toxicity. With
et al. vehicle + bath PUVA 4×/ with taz. At 3 weeks, taz, mild irritation
(1999) week 76.5% median PASI (transient burning and
[58] reduction vs. 58.5%. erythema)
(p < 0.05)
Tzaneva 31 Oral PUVA 4 × weeks Similar efficacy with taz Tacalcitol: 1 mild irritant
et al. +0.1% taz gel (0.05% if not and tacalcitol. Compared to dermatitis, 1
(2002) tolerated) 1 lesion 1 side, PUVA mono-therapy, the hypertrichosis Taz: 7
[59] tacalcitol ung 1 lesion cumulative UVA was less had AEs (dryness,
opposite side with taz or tacalcitol irritant dermatitis,
(p < 0.01) pruritus, burning);
resolved after changed
to 0.05%
follow-up phase; treatment response was gener- tazarotene 0.1% gel and fluocinonide). A small
ally maintained after the drug was discontinued. right/left study showed similar efficacy of tazaro-
In this study, an overall lesional score of mild or tene 0.1% gel once daily + emollient once daily
better was noted at the end of the 12 weeks treat- and calcipotriene BID, and however tazarotene
ment period and 12 weeks follow-up period in was more irritating, but had a better maintenance
24.4 and 21.8% respectively on vehicle, 41.7 and effect after treatment discontinuation (overall
33.4% respectively on 0.05% tazarotene, and severity p = 0.007, erythema p = 0.01, scaling
39.4 and 30.3% respectively on tazarotene 0.1% p < 0.001, elevation p < 0.001) [34]. In a small
cream. The skin-associated treatment-related open label right/left pilot study of 20 patients,
AEs including pruritus, burning, erythema, skin twice daily calcipotriene was also found to be
irritation, stinging and desquamation were more comparable to once daily 0.1% tazarotene, but
common in the tazarotene arms, particularly the was more efficacious than once daily 0.05% taz-
0.1% arm. In a steroid comparison study, after arotene [35]. A small (n = 30) open-label right/
12 weeks of therapy, tazarotene 0.05 and 0.1% left study showed that tazarotene and 5% crude
gels had comparable efficacy to fluocinonide coal tar ointment had similar efficacy as mea-
0.05% cream [26]. However, the psoriasis sured by erythema, scaling and induration (ESI)
returned faster in the steroid group. In those [36].
patients who achieved an overall lesional score of Addition of a mid-potency corticosteroid
mild or better at the end of treatment, relapse to a (mometasone furoate 0.1% cream) or high
score of moderate or worse was noted at the end potency cream (fluocinonide 0.05% cream)
of the 12 weeks follow up period in 18% in the improved efficacy and reduced adverse effects
0.1% arm, 37% in the 0.05% tazarotene arm, and [37]. At least 50% improvement was noted in
55% in the fluocinonide arm (p < 0.05% between 91% and 95% in the mid- and high-potency ste-
58 L. C. Guenther
roid arms respectively compared to 80% in the severity [46]. In another similar subset study
placebo arm. The cumulative rates of burning involving 246 patients switched from calcipotri-
were only 61% as frequent in the mid-potency ene + steroid at baseline to tazarotene + steroid,
steroid arm (14%), and 52% as frequent in the 75% achieved at least 50% global improvement
high-potency steroid arm (12%) compared to the at the final visit (up to 12 weeks) [47]. A small
placebo arm (23% rate). Addition of a low- open-label right/left comparison pilot study
potency steroid (fluocinolone acetonide 0.01%) (n = 15) showed similar efficacy of tazarotene +
had minimal additive benefit. Tazarotene can also calcipotriene ointment, and the superpotent ste-
reduce the development of steroid induced epi- roid clobetasol ointment [48].
dermal atrophy. In a 4-week long study of healthy Tazarotene can be used to maintain improve-
volunteers, epidermal thickness was reduced by ment. After a 6 weeks open-label treatment phase
43% with diflorasone diacetate ointment mono- with tazarotene 0.1% gel + clobetasol propionate
therapy vs. 28% when used in combination with 0.05% ointment, a double-blind 5 months main-
tazarotene 0.1% gel (p ≤ 0.003) [38]. Another tenance phase showed that those on tazarotene
study showed that combination therapy with taz- Monday, Wednesday, Friday + clobetasol
arotene 0.1% gel used alternate evenings with Tuesday, Thursday maintained 75% global
betamethasone valerate 0.1% enhanced efficacy improvement (p ≤ 0.001 vs. vehicle group,
and tolerance [39, 40]. The foam formulation of p ≤ 0.05% vs. tazarotene/vehicle), those on taz-
betamethasone valerate (0.12%) was studied in a arotene Monday, Wednesday, Friday + vehicle
small open-label study involving 10 patients; all Tuesday, Thursday 50% improvement, and those
but 1 had improvement and 4 were clear at week on vehicle Monday, Wednesday, Friday + white
8 [41]. In an effort to determine the optimal ste- petrolatum Tuesday, Thursday, 25% improve-
roid to use with tazarotene, tazarotene monother- ment [49].
apy was compared to combination therapy with 3 A fixed combination of halobetasol propio-
different high-potency and 3 different mid-to- nate (HP) 0.01% and tazarotene (taz) 0.045%
high-potency steroids [42]. Greatest efficacy was lotion had greater treatment success (i.e.
seen when tazarotene 0.1% gel was used in com- Investigator Global Assesssment (IGA) of clear/
bination with betamethasone dipropionate 0.05% almost clear with at least a 2-grade improvement
cream, followed by mometasone furoate 0.1% from baseline) at week 8 (52.5%) vs. HP (33.3%,
ung and diflorasone diacetate 0.05% ung. The p = 0.033), taz (18.6%, p < 0.001), and Vehicle
best tolerated regimen was the tazarotene + (9.7%, p < 0.001) in a phase 2, multicenter,
mometasone furoate 0.1% ung, making this regi- double-blind study [50]. In two phase 3 trials, by
men the one with the optimal balance of efficacy week 8, treatment success occurred in 35.8%
and tolerability. Tazarotene 0.1% gel in combina- (study 1) and 45.3% (study 2) compared with
tion with mometasone furoate 0.1% cream once 7.0% and 12.5% on Vehicle (p < 0.001) [51]. A
daily was shown to be more efficacious than rapid onset of action was noted in both studies;
twice daily mometasone furoate cream [43] and by 2 weeks, HP/Taz lotion was statistically sig-
twice daily calcipotriene 0.005% ointment [44]. nificantly superior to vehicle [50, 51]. In a 1-year
A large (n = 1393) open-label effectiveness open label study (n = 555) with a focus on safety,
study also showed that mid- to high potency ste- HP/taz lotion was applied daily for 8 weeks, then
roids were optimal potencies to be used in combi- as needed [52]. Those without an IgA of clear/
nation with tazarotene, and that superpotent almost clear at week 8 were treated for additional
steroids were not superior [45]. A subset of 166 4 weeks. At week 12, those with no improvement
patients were switched from calcipotriene +/− a in IGA from baseline were discontinued (4.7%).
steroid to tazarotene + a steroid. There was a sub- For the remainder of the study, patients were
stantial improvement in efficacy and patient sat- treated for 4 weeks with HP/taz if they had an
isfaction of these patients with 71% having at IGA of 2 or more at a visit, to a maximum of
least a 1 grade improvement in overall psoriasis 24 weeks continuous treatment. At week 24,
20.9% discontinued treatment due to lack of effi- Psoralen ultraviolet A (PUVA) studies have
cacy. The rate of adverse events was similar to also shown added benefit with topical tazarotene.
that in the pivotal trials, peaked at day 60 and In a ½ body bath PUVA study (n = 12), the side
remained stable from day 90 until the end of the treated with tazarotene improved faster and to a
study. Treatment-emergent AEs resulted in dis- greater extent [58]. After 3 weeks, the median
continuation of 7.5% of study participants. PASI reduction was 76.5% (95% confidence
Addition of tazarotene to phototherapy can interval (CI) 65–86) compared to 58.5% (95% CI
enhance efficacy and decrease he total dose of 50–69). No phototoxic effects were seen. In an
ultraviolet (UV) radiation. Daily pre-treatment oral PUVA study (n = 31) addition of tazarotene
with 0.1% tazarotene gel for 2 weeks, then three gel or tacalcitol ointment resulted in faster clear-
times a week immediately after broad band UVB ing and 14 rather than 16 PUVA exposures [59].
treatment, increased the rapidity of improvement
and overall efficacy [53]. The time to reach 50%
improvement decreased from 53 days to 25 days linical Studies in Other Types
C
with an associated 76% reduction in median of Psoriasis (Palmoplantar, Nail)
cumulative UVB exposure (390 vs. 1644 mJ/
cm2). The time to reach 75% improvement was Tazarotene is efficacious in the treatment of pal-
28 days earlier. By day 81, 75% improvement or moplantar and nail psoriasis. In a 12-week ran-
better occurred in 50% on UVB monotherapy domized trial with 30 patients with palmoplantar
versus 82% on UVB + tazarotene 0.1% gel. No psoriasis randomized to once daily 0.1% tazaro-
treatment related photosensitivity or phototoxic- tene cream or 0.05% clobetasol propionate
ity were noted. Similar results were seen with cream, there was no significant difference in the
narrow-band (nb) UVB. In a small study (n = 10), reduction in the erythema scaling fissures and
after 4 weeks of 5×/week nb UVB, the psoriasis induration (ESFI) score between the two groups
area and severity index (PASI) score decreased (83.2 and 89.1% respectively) and complete
from 18.3 to 6.5 (95% confidence interval (CI) clearance (52.9 and 61.5% respectively) [60].
5.29–7.91) with the addition of tazarotene 0.05% A double-blind, vehicle-controlled 24-week
gel hs, compared to 9.5 (95% CI 7.70–11.70) study (n = 31) showed greater reduction in ony-
with emollient (p < 0.05) [54]. In a half body cholysis (p ≤ 0.05% weeks 4 and 12) and pitting
study involving 20 patients, tazarotene in combi- (p ≤ 0.05 at week 24) in occluded and nonoc-
nation with nb UVB was more efficacious than cluded tazarotene 0.1% gel treated nails [61]. An
5% salicylic acid with nb UVB [55]. In an open- open-label study (n = 35) showed fingernail
label trial (n = 30), a target plaque was picked improvement after only 4 weeks with nonoc-
from similar sites on each side of the body [56]. cluded tazarotene 0.1% gel applied to the nail
Both sides were treated with nb UVB, but the plates, nail folds and periungual skin [62].
right side was also treated with topical tazarotene Hyperkeratosis and oil drop changes responded
0.05% gel. After 12 weeks of therapy, the mean faster; pitting was the most persistent. After
target plaque was reduced by 99.64% in the 12 weeks of treatment of fingernails and toenails,
taz + nb UVB side vs. 84.92 on the nb UVB the mean visual assessment score for onycholysis
monotherapy side. Complete clearance was decreased from 26 to 2, hyperkeratosis 25 to 2,
achieved at the end of 12 weeks in 96.67% vs. oil spots 18 to 3, and pitting 13 to 1 (p < 0.0001
6.67%. Fewer treatment sessions were required for each change). A case report in a 6-year-old
for clearance on the tazarotene side (16.40 child showed that 8 weeks treatment with nonoc-
=/−2.799 vs. 23. 33 =/−1.212. Tazarotene nb cluded 0.05% tazarotene gel improved nail pso-
UVB combination therapy was found to be simi- riasis, especially hyperkeratosis [63]. Occluded
lar to calcipotriene nb UVB combination therapy tazarotene 0.1% cream and clobetasol propionate
in a study of 10 patients [57]. 0.05% cream had similar efficacy in a double-
60 L. C. Guenther
blind study of 46 patients with nail psoriasis [64]. A macrolide isolated from the culture broth of
Both treatments showed significant improvement a strain of Streptomyces tsukabaensis that has
in onycholysis, hyperkeratosis, salmon patches strong immunosuppressive activity in vivo and
and pitting. prevents the activation of T-lymphocytes in
response to antigenic or mitogenic stimulation
in vitro.
Application Tips
Since tazarotene is photostable, it can be applied Mechanism of Action

at any time of day [65]. When used in combina-
tion with a topical steroid, both compounds can After binding to macrophilin-12, topical calci-
be used at the same time of day without adversely neurin inhibitors inhibit the calcium dependent
affecting each other’s stability [66]. The gel and phosphatase calcineurin, which in turn results in
cream formulations rub in well and do not stain. inhibition of translocation of nuclear factor of
Only a small quantity is needed; larger amounts activated T cells (NFAT) and down regulation of
can increase the risk of irritation [67]. A cotton- cytokine synthesis [7].
tipped applicator to apply tazarotene and applica-
tion of moisturizer around psoriatic lesions can
minimize perilesional irritation from inadvertent Toxicity
application to unaffected skin. The gel and cream
should be dry before clothes are worn to mini- Application site burning is the most frequent
mize spread onto unaffected skin. The 0.05% for- adverse drug reaction [7]. The FDA issued a con-
mulation should be considered for individuals troversial lymphoma “black box” warning in
with sensitive skin [67]. If irritation should occur, March 2006 [68]. This warning noted that,
use of the 0.05% cream formulation rather than although a causal relationship has not been
the gel, alternate day treatment, and short contact established, rare cases of malignancy (e.g., skin
treatment for as little as 5 min followed by a cor- and lymphoma) have been reported in patients
ticosteroid or emollient immediately after the treated with topical calcineurin inhibitors. A
tazarotene has been washed off, should be con- study of 293,253 patients with atopic dermatitis,
sidered [67]. did not find an increased risk of lymphoma asso-
ciated with use of calcineurin inhibitors [70]. The
main factor associated with an increase risk of
opical Calcineurin Inhibitors
T lymphoma was disease severity [70]. A 2015
(Immunomodulators) Pimecrolimus Cochrane review of tacrolimus found no evi-
and Tacrolimus dence to support a possible increased risk of can-
cer [71].
Topical pimecrolimus is available as a 1% cream In contrast to topical steroids, calcineurin
and tacrolimus as a 0.03 and 0.1% ointment. inhibitors are not atrophogenic [72]. Tacrolimus
They were approved by the FDA in 2001 and has been shown to increase collagen synthesis
2000 respectively [68]. Pimecrolimus is a deriva- [73] and pimecrolimus to reverse skin atrophy
tive of the ascomycin macrolactam while tacroli- [74].
mus was isolated from the bacterial strain
Streptomyces tsukubaensis [68]. They are indi-
cated to treat atopic dermatitis. Although they are Clinical Studies in Psoriasis
not FDA approved for the treatment of psoriasis,
they are efficacious in the treatment of intertrigi- In the treatment of plaque psoriasis, non-occluded
nous, facial and genital psoriasis [69]. (Fig. 6.2). tacrolimus was effective in two small studies
Fig. 6.2 Also known H H

as: TACROLIMUS O
MONOHYDRATE,
Protopic (TN),
H
109581-93-3, FK-506 O
monohydrate,
Tacrolimus (USAN/ O
INN), Tacrolimus
hydrate (JP16), F4679_
SIGMA (Molecular
Formula: C44H71NO13;
Molecular Weight:
822.03344)
H O
H
O
H N
H
O O
O
O O
O
H O
(one monotherapy [75] and one with concurrent ment. Two patients experienced a warm sensation
6% salicylic acid gel [76]) but not in another in facial lesions after application. In an 8-week
[77], while occluded tacrolimus [75, 78] and open label study of 21 patients with intertrigi-
pimecrolimus [79] were. Studies in inverse pso- nous and/or facial psoriasis treated with 0.1%
riasis are summarized in Table 6.2. In one study tacrolimus, all patients had at least 75% improve-
(n = 57), after 2 weeks of 1% pimecrolimus, ment and 81% were clear [82]. In a study of 167
71.4% were clear/almost clear vs. 20.7% on vehi- patients with intertriginous and/or facial psoria-
cle (p < 0.0001) [80]. Only 1 patient on pimecro- sis, by day eight 24.8% treated with 0.1% tacroli-
limus had a treatment-related AE (paresthesia). mus vs. 6% on vehicle were at least 90% better
However a 4-week study did not show superiority (p = 0.004); by 8 weeks, the numbers had risen to
of pimecrolimus over vehicle [81]. In a small 66.7 and 36.8% respectively (p < 0.0001) [83].
study (n = 15), the mean total score for erythema, The face and intertriginous areas showed similar
scaling and thickness on the face, genitalia and improvement (42% with facial and 48% with
intertriginous area decreased from 6.88 at base- intertriginous lesions were clear) [84]. Similar
line to 0.37 after 60 days of tacrolimus 0.1% oint- efficacy (47.6% clear) was seen in an open label
62 L. C. Guenther
Table 6.2 Studies of calcineurin inhibitors in inverse psoriasis

Gribetz 57 Pimecrolimus (P) Clear/almost clear: Day 3: 1 mild application site
et al. 1% cream or 14.3% on P, 0% on V, paresthesia with P 1
(2004) vehicle (V) p = 0.0477 moderate tenderness
[80] BID × 8 weeks Week 8: 71.4% on P, 20.7% with V. no withdrawal
on V, p < 0.0001 due to AEs
Kreuter 80 P 1% cream or Mean M-PASI score P: 5/20 mild itching
et al. calcipotriene (C) reduction: B: 86.4%, C: and burning
(2006) 0.005% or 0.1% 62.4%, P: 39.7%, V: 21.1%. C: 2/20 increased
[81] betamethasone No significant difference erythema, warmth,
valerate (B) or between B and C, P and C, irritation
vehicle and P and V. B better than P, B: No AEs
(V) × 4 weeks p < 0.05 and V, p < 0.01. C V: 1/20 herpes
better than V, p < 0.01. genitalis
Matyin 15 0.1% tac Erythema decreased from 2.9 2 had a transient
Rzquerra ung × 60 days at baseline to 0.19, infiltration warm sensation
et al. (open label) from 2.1 to 0.11 and
(2006) desquamation from 1.8 to 0.07.
[75] (for each, p < 0.001) N.B.
includes face + genital psoriasis
Freeman 21 intertriginous 0.1% tac Complete clearing in 81% 2 had itching and a
et al. and/or facial (tac) × 8 weeks and 75–99% clearing in 19% feeling of warmth
(2003) psoriasis (2/21 face (open label) (N.B. includes 2 pts. with
[82] only) only facial lesions)
Lebwohl 104 intertriginous 0.1% tac ung or V 48% with intertriginous Burning in 8% on tac,
et al. 167 with BID × 8 weeks psoriasis on tac were clear vs. 7.3% on V,
(2004, intertriginous and/or 14% on V (p < 0.001) hyperesthesia in 4.5%
2005) [83, facial psoriasis on tac and 0% on V,
84] itching in 7.1% on tac
and 1.8% on V. all NS
Steele 13 children 12 with 0.1% tac 1 12/12 on 0.1% tac had 1 on 0.03% had
et al. with 0.03% tac complete clearance within burning and irritation
(2005) (retrospective 2 weeks
[86] review) No improvement in 1 patient
on 0.03% but difficulty with
adherence
Brune 8 children with 0.1% tac Reduction in overall severity Pruritus in 1
et al. intertriginous/11 BID × 180 days incl. Face (1.63 to 0.71,
(2007) with face and/or (open label) p < 0.0001) in the 8 who
[87] intertriginous completed
psoriasis
facial study (n = 21), although 5/10 with com- ital PASI decreased from 15.8 to 1.2 (p < 0.001)
plete clearing had recurrences during 1 month of after 8 weeks of twice daily tacrolimus 0.1%
follow-up [85]. Adverse effects of tacrolimus. ointment [89]. Success in male genital psoriasis
were not significantly different than in the pla- has also been reported with pimecrolimus [90]
cebo arm [83]. Studies in children have also
shown efficacy of tacrolimus in facial and inter-
triginous psoriasis [86, 87]. In one open label Crisaborole 2% Ointment
study, marked improvement was noted in all 10
patients with long-standing genital and facial Crisaborole 2% ointment is a phosphodiesterase-
psoriasis after 1 week of 0.1% tacrolimus oint- 4 inhibitor approved for the treatment of mild-to-
ment [88], and in another one (n = 12), male gen- moderate atopic dermatitis. It is not approved for
treatment of psoriasis. In a double-blind vehicle- liculitis, acneiform eruptions, irritation, allergic

controlled study involving 21 individuals with contact dermatitis, erythroderma, tar keratoses
intertriginous, anogenital, or facial psoriasis, and keratoacanthomas [92]. Acute tar intoxica-
after 4 weeks of therapy, the crisaborole arm had tion may occur if tar is ingested, or if large
66% improvement in the Target Lesion Severity amounts of tar are absorbed after topical applica-
Scale (TLSS) compared to 9% improvement with tion; erythrodermic psoriasis patients and young
vehicle [91]. There were no application site reac- children are at a higher risk [92]. Carcinogenicity
tions, atrophy or telangiectasia [91]. concerns arose after Sir Percival Pott, a London
surgeon, linked the increased risk of scrotal can-
cer in chimney sweeps to soot [96], however
Tar there was no increase in the expected rate of skin
cancer a study of 719 patients with psoriasis [97]
Although the German Guidelines [7] do not rec- and a 25-year follow-up study of 280 patients
ommend tar for psoriasis treatment and describe treated with crude coal tar and UVB [98].
it as “obsolete,” tar is still widely used in many
parts of the world [92]. Tar has been used for
more than 2000 years and became standard treat- Clinical Studies in Psoriasis
ment with ultraviolet B phototherapy after
Goeckerman’s report in 1925 [92]. There are 3 Tar extract in oil was superior to the oil base in
types of tar, coal tar, wood tar (pine, beech, birch, 5 subjects [99], however coal tar was signifi-
juniper), and shale (ichthammols, bituminous cantly less effective than betamethasone valer-
tars) [93]. Coal tar comes from coal distillation in ate (38% mean PASI reduction vs. 69%) in
the manufacture of coke and contains approxi- another study [100]. Concentrations of 1 and
mately 10,000 compounds including polycyclic 6% crude coal tar have similar efficacy when
aromatic hydrocarbons such as benzenes, naph- used with UVB [101]. Daily UVB and tar oint-
thalenes, creosoles and phenols [94]. The tem- ment three times a day for an average of 20 days
perature of the distillation and type of coal used yielded good to excellent improvement in 95%
affect the final composition [95]. Liquor Carbonis of 123 patients with remission rates of 2 months
Detergens (LCD) is an alcoholic extract of coal to 8 years (average 1.7 years) [102]. In a similar
tar that can be mixed in cream, ointment or study, 60% of patients were still in remission
lotions bases, usually in a concentration of 2 years after treatment [103]. With erythemo-
5–15% [94]. genic doses of UVB, a number of studies failed
to show increased efficacy with tar compared to
petrolatum [104–108]. Studies with suberythe-
Mechanism of Action mogenic UVB showed less UVB energy and
fewer side effects with tar oil vs. emollients in
Tar inhibits DNA synthesis which in turn results one study [109], faster improvement with 1%
in decreased epidermal proliferation [92]. It is crude coal tar in petrolatum vs. petrolatum
also said to be vasoconstrictive, antifungal, anti- (22%/week vs. 14.7%/week, p < 0.0005) and
parasitic, and antipruritic [92]. 5% tar extract in oil vs. oil base (19.6%/week
vs. 11.4%/week, p < 0.0005) in another [107],
and no benefit in another [110]. Menkes et al.
Toxicity showed similar efficacy of suberythemogenic
UVB with tar oil, and maximally erythemogenic
Coal tar is malodorous, can stain hair and fabric UVB with emollients in a study of 49 patients
and unlike wood and shale tars, is photosensitiz- with psoriasis, however the total UVB dose to
ing at wavelengths of 330–550 nm [892. It can clearing was 44% less in the suberythemogenic
also cause burning, stinging (“tar smarts”), fol- UVB with tar group [111].
64 L. C. Guenther
Anthralin in 1961; 95% were clear in a mean time of

15.2 days as inpatients and 19.5 days as outpa-
Anthralin (1,8-dihydroxyanthrone) was first syn- tients [120]. Average clearance times in other
thesized in 1916 by Galewsky in Germany, after inpatient series have varied from 11.0 to 20 days
chysarobine, a related compound from Goa pow- [112]. Short contact anthralin ointment with a
der produced from the araroba tree in Brazil, was 10 min to 1 h contact time was tried in an effort
noted to be an effective treatment for psoriasis to minimize staining and irritation [121]. It was
[112]. In the 1930s Ingram used anthralin in as effective as conventional treatment with
Lassar’s paste (petrolatum, salicylic acid, zinc anthralin ointment [122], difluorosone acetate
oxide, starch) with tar baths and UVB to treat [122], and twice daily calcipotriene [123]. If
psoriasis [112]. The Ingram regimen was in com- anthralin is considered in the outpatient setting,
mon use for several decades, but is now rarely short contact application (20–30 min) with an
used. Anthralin has also been formulated as an initial 1% concentration, increasing the concen-
ointment [112], gel [113] and in a cream base tration as tolerated, has been recommended [69].
which washes off easily and has minimal staining
[114]. Commercial formulations are no longer
available in Canada due to the development of Moisturizers and Keratolytics
efficacious, convenient, more cosmetically
acceptable alternatives. Moisturizers and keratolytics such as salicylic
acid and urea are considered ‘Basic Therapy’ of
psoriasis [7], although there are no placebo-
Mechanism of Action controlled studies supporting their use.
Moisturizers decrease scaling, limit painful fis-
In vitro, anthralin has been shown to inhibit DNA suring and are anti-pruritic. Salicylic acid
replication and DNA repair synthesis [115], should be not used to large areas since systemic
interfere with mitochondria [116], decrease kera- toxicity might occur, especially if applied to
tinocyte transforming growth factor-α expression >20% of the body surface, or to patients with
and epidermal growth factor (EGF) receptor impaired renal or hepatic f unction [69].
binding [117], inhibit leukotriene production by
neutrophils [118], and inhibit monocyte secretion
of interleukin (IL)-6, IL-8 and tumour necrosis Conclusions
factor (TNF)-α [119].
Although tazarotene is efficacious as monother-
apy, it is more commonly used in combination
Toxicity with a topical steroid to enhance tazarotene’s tol-
erance, increase efficacy and decrease steroids’
Adverse effects include staining of skin, nails and atrophogenic potential [50, 124]. The once daily
clothing due to oxidation of anthralin, burning, lotion containing the superpotent steroid halo-
and irritant and allergic contact dermatitis [112]. betasol propionate 0.01% and tazarotene 0.045%
In order to minimize irritation, care should be (Duobrii™) is convenient with greater efficacy
taken to avoid application to uninvolved skin and and fewer AEs than tazarotene monotherapy.
intertriginous areas should not be treated. There is no duration limitation in the U.S. label-
ing, although treatment should be stopped when
the skin is clear. Use of tazarotene with broad
Clinical Studies band and narrow band UVB can enhance efficacy
and decrease the cumulative dose of UV. Although
The benefits of the Ingram regime in 2120 phototoxicity was not noted in clinical studies, if
patients were reported by Maclennan and Hellier tazarotene is added to ongoing phototherapy, it
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monocytes to secrete IL-6, IL-8 and TNF-alpha, but between tazarotene and ultraviolet light. J Am Acad
not IL-1. Br J Dermatol. 1997;136:542–7. Dermatol. 1999;41:927–30.
120. Maclennan A, Hellier FF. Treatment time in psoria-
sis. Br J Dermatol. 1961;73:439–44.
Topical Therapy II: Retinoids,
Immunomuodulators, and Others/ 7
Ultraviolet Therapy for Psoriasis
Kristen M. Beck and John Koo
Abstract
Total-body ultraviolet therapy (UV) for 1. To understand the mechanism of action
moderate-to-severe psoriasis consists of nar- and types of phototherapy for psoriasis.
rowband and broadband-UVB, psoralen plus 2. To understand the appropriate use and
UVA (PUVA—where psoralen can be ingested efficacy of phototherapy for psoriasis.
orally or applied topically), inpatient photo- 3. To understand the safety concerns of

therapy (i.e. Goeckerman Therapy, Ingram utilizing phototherapy for psoriasis.
therapy), non-office-based phototherapy (i.e.
use of commercial sunlamps/sunbeds or home
UVB for psoriasis treatment, heliotherapy, cli-
matotherapy), and combined UVB/PUVA
UVB Phototherapy
with retinoid or biologic agents. For each type
of UV therapy discussed in this chapter, essen-
UVB phototherapy has been used worldwide
tial information regarding dosage and admin-
since the early 1900s. It consists of narrowband
istration, efficacy (including comparator data
UVB (NB-UVB) and broadband UVB
if available), short-term side effects, and long-
(BB-UVB), which are still the most commonly
term photocarcinogenic risks are discussed. A
chosen phototherapeutic options for patients with
well-balanced understanding of the advan-
psoriasis.
tages and drawbacks of each photo-therapeutic
option can help phototherapy practitioners
optimize clinical outcomes as well as enhance
Dosage and Administration
the quality of life for patients affected by this
chronic skin condition.
The calculation of the initial UVB dose can be
done after assessment of the MED (the minimal
erythema dose that induces barely perceptible ery-
thema on non-involved skin) or the Fitzpatrick
skin type of each patient [1]. Skin testing to deter-
mine MED can add significant time to the first
phototherapy visit. Therefore, dosimetry is often
K. M. Beck (*) · J. Koo based on estimation of Fitzpatrick skin types.
Department of Dermatology, University of California, Subsequent dosing depends on response of psoriasis
San Francisco, CA, USA

https://doi.org/10.1007/978-3-030-54859-9_7
72 K. M. Beck and J. Koo
and phototoxic reactions to previous doses. For Table 7.2 Dosing guidelines for narrowband ultraviolet B
example, if a patient experiences mild-to-moderate According to skin type
pruritus or discomfort (but no skin burns), he or Initial UVB UVB
she should be treated with the same light dose until dose, mJ/cm2 increase
after each Maximum
these reactions resolve [1]. If skin burns or intense
treatment, dose, mJ/
skin inflammation (i.e. “beefy red” erythema, Skin type mJ/cm2 cm2
severe pruritus, etc.) develops, light treatment I 130 15 2000
should be withheld from patients until the ery- II 220 25 2000
thema completely resolves. In the latter case, pho- III 260 40 3000
totherapists might consider the use of “cooling IV 330 45 3000
procedures” to calm intense skin inflammation, for V 350 60 5000
example, with very potent topical steroids, before VI 400 65 5000
According to MED
cautiously re-instituting phototherapy. Skin that
Initial 50% of
recently experienced phototoxicity reactions is UVB MED
often extra-sensitive to re-exposure to UVB. Please Treatments Increase by
see Tables 7.1 and 7.2 [2]. 1–20 10% of
The optimal number of UVB exposures per initial MED
week is three, since less than three treatments per Treatments Increase as
≥21 ordered by
week may result in lower efficacy, and more than physician
three treatments per week have not been consis- If subsequent treatments are missed for
tently shown to be more effective [3]. Once 4–7 day Keep dose
same
Table 7.1 Dosing guidelines for broadband ultraviolet B 1–2 week Decrease
dose by 25%
According to skin type 2–3 week Decrease
Initial UVB UVB increase after dose by 50%
dose, mJ/cm2 each treatment, mJ/ or start over
Skin type cm2 3–4 week Start over
I 20 5 Maintenance therapy for NB-UVB after >95%
II 25 10 clearance
III 30 15 1 ×/ week NB-UVB for Keep dose
IV 40 20 4 week same
V 50 25 1 ×/ 2 week NB-UVB for Decrease
VI 60 30 4 week dose by 25%
According to MED 1 ×/ 4 week NB-UVB 50% of
Initial UVB 50% of MED highest dose
Treatments Increase by 25% MED Minimal erythema dose, NB narrowband, UV ultra-
1–10 of initial MED violet. Administered 3–5 ×/ week. Because there is broad
Treatments Increase by 10% range of MED for NB-UVB by skin type, MED testing is
11–20 of initial MED generally recommended. It is critically important to meter
Treatments As ordered by UVB machine once weekly. UVB lamps steadily lose
≥21 physician power. If UV output is not periodically measured and actual
output calibrated into machine, clinician may have false
If subsequent treatments are missed for
impression that patient can be treated with higher doses
4–7 day Keep dose same
when machine is actually delivering much lower dose than
1–2 week Decrease dose number entered. Minimum frequency of phototherapy ses-
by 50% sions required per week for successful maintenance as well
2–3 week Decrease dose as length of maintenance period varies tremendously
by 75% between individuals. Above table represents most ideal sit-
3–4 week Start over uation where patient can taper off phototherapy. In reality,
MED Minimal erythema dose, UV ultraviolet. many patients require 1 ×/ week. NB-UVB phototherapy
Administered 3–5×/week. Reproduced with permission indefinitely for successful long- term maintenance.
from Menter et al. [2] Reproduced with permission from Menter et al. [2]
7 Topical Therapy II: Retinoids, Immunomuodulators, and Others/Ultraviolet Therapy for Psoriasis 73
patients achieve marked improvement in their follow-up, 38% of the NB-UVB cohort retained
psoriasis, then the therapeutic regimen can be clearance, compared with 5% of the BB-UVB
tapered slowly to once weekly. Since this mainte- cohort. Such magnitude of efficacy difference
nance therapy is less intensive and well tolerated, has not yet been replicated by other studies or in
it may be continued for as long as possible in the usual practice settings.
order to prevent recurrence of psoriasis [1, 3]. More moderate results are be found in another
Figures 7.1, 7.2, and 7.3 are intended to study involving 22 patients with psoriasis who
illustrate the office-based practice of UVB
received half-body exposure to BB- or
phototherapy. NB-UVB. After 3 weeks of treatment, clinical
resolution occurred in 86% of NB-UVB-treated
plaques and 73% of the BB-UVB-treated plaques
Efficacy [5]. Long-term efficacy of NB-UVB was reported
by Karawaka et al., who reported that 56% of
Rare comparator studies have documented a their 52-patient cohort retained PASI 50 response
much larger difference in efficacy between broad- for at least 1 year after a 4-week course of
band and narrowband UVB than what is typically NB-UVB phototherapy [6].
observed in practice. In a study by Green et al., The difference in efficacy between BB-UVB
52 patients with plaque psoriasis treated with and NB-UVB—where the latter is, to some extent,
NB-UVB achieved clearance in 6.6 weeks, superior as a treatment for psoriasis—deserves
whereas 25 patients treated with BB-UVB explanation. Some of the UV rays emitted by
achieved clearance in 22 weeks [4]. At 1-year BB-UVB lamps (i.e. 254, 280, or 294 nm rays) are
Fig. 7.1 Nurse stations and light boxes for office-based UVB phototherapy
less effective than UV rays with longer wave-

lengths (i.e. 311 or 312 nm rays) at clearing psoria-
sis [7]. The 311 nm rays emitted by NB-UVB
lamps are capable of clearing psoriatic plaques
with a little as 0.4 times the MED. Furthermore,
NB-UVB therapy confers the benefit of causing
fewer phototoxic reactions for patients than
BB-UVB therapy at the same doses.
Side Effects and Safety
Side effects of UVB phototherapy include visible

erythema, burning, blistering, discomfort, and
post-inflammatory hyperpigmentation [1, 5, 8].
In addition, “over-exposure” to UVB has been
associated with precipitation of erythrodermic
psoriasis in two reported cases [9]. Do not per-
form UVB if the patient is erythrodermic or
near-erythrodermic.
Fig. 7.2 Eye protection for whole-body UVB irradiation

Photocarcinogenicity of UVB
Phototherapy
Studies with mice have often not mirrored human

exposure to UVB. They should not be extrapo-
lated at face value to determine the carcinogenic
risk of UVB phototherapy in humans. For
instance, UVB irradiation of 30 hairless, lightly
pigmented mice who are not cancer-prone for
30 weeks was linked with an 83% rate of SCC
development [10]. This study lacked a control
mice group. Moreover, the mice received UVB 5
days per week, while humans with psoriasis are
usually treated three times weekly.
In another study using hairless, lightly pig-
mented mice, all mice developed skin tumors,
while mice receiving 311 nm UVB developed
skin tumors earlier than mice treated with
BB-UVB [11]. Of note, some of the mice had
total-body exposure to UVB at doses that were
multitudes of the MED (also known as “supra-
erythemogenic” doses). In humans, total body
use of supraerythemogenic doses not done since
intense UVB irradiation of non-involved skin is
Fig. 7.3 Whole-body UVB irradiation using a stool to likely to result in frequent, severe skin burns,
increase lower-body exposure which can increase the risk of skin cancer.
Meanwhile, review of the worldwide literature PUVA (Psoralen Plus PUVA)

on human experience revealed no convincing data
of an increased photocarcinogenic risk of long- Dosage and Administration
term UVB phototherapy for psoriasis. In a publi-
cation by Lee et al., no increased carcinogenic risk PUVA is the combination of the plant-originated
associated with UVB phototherapy was appreci- compound psoralen and UVA (320–400 nm) irra-
ated in 10 out of the 11 studies that were reviewed diation for the treatment of psoriasis. Available as
in the medical literature [12]. One exception is the Oxsoralen Ultra® 10 mg capsules in the US, pso-
report featuring a 30-case/137-control sub-cohort ralen can be taken orally or diluted in a bath solu-
from a large-scale Finnish study in psoriasis tion for topical administration within the hour
patients, where the relative risk ratio of developing before UVA irradiation. In the beginning of their
SCC in patients with a history of UVB treatments treatment course, patients are encouraged to
was 1.6. This risk is slightly elevated but turned undergo PUVA treatment thrice weekly. For the
out to be not statistically significant. purpose of maintaining marked improvement or
In addition, there was no increased risk of skin clearance of psoriasis, the number of weekly
cancer in 484 Northern Irish patients who had at office visits for PUVA can be tapered slowly to
least 18 NB-UVB exposures individually [13]. A once weekly, once every other week, or even a
larger retrospective study involving 3886 patients less frequent schedule. Dosimetry of PUVA is
treated with UVB at a Scottish hospital found 27 described in Tables 7.3 and 7.4 [2]. Information
BCC, 7 SCC, and 6 melanomas, which were about dosage following missed PUVA exposures
comparable to expected incidences for the 3 can be found in Table 7.5.
types of skin cancer, respectively, in the matched Please refer to Fig. 7.4 for an illustration of
populations [14]. In this study, only patients who “hands” PUVA (PUVA just for the hands) and to
received both NB-UVB and PUVA had a higher Figs. 7.5, 7.6, 7.7, and 7.8 for an illustration of
incidence of BCC [15] than the expected inci- bath PUVA.
dence [14] in the general Scottish population, but
not among those who received UVB alone [14].
In a follow-up study of 195 patients who Efficacy
received either BB- or NB-UVB treatment for
psoriasis, only one patient developed melanoma Following activation by UVA irradiation, pso-
in situ. This patient’s tumor was diagnosed in the ralen cross-links with DNA of various cell types
same year phototherapy was instituted; hence, its in psoriatic skin (i.e. keratinocytes, T cells, etc.)
development may have been unrelated to the lim- to inhibit inflammation and cell proliferation. A
ited UVB exposure [16]. Another study followed randomized, double-blind, placebo-controlled
1908 Scottish patients who had long-term UVB trial involving 40 psoriasis patients revealed an
treatment for an average of 4 years. Remarkably, 86% PASI 75 response rate in the PUVA arm ver-
the study found no incidence of melanoma or sus 0% PASI 75 response rate in the UVA arm
squamous cell carcinoma (SCC) [17]. Ten after 12 weeks of therapy [18]. In another study,
patients developed basal cell carcinoma (BCC)
mostly on the face compared with the expected
Table 7.3 Dosing of 8-methoxypsoralen for oral pso-
incidence of 4.7 in the matched population [17]. ralen plus ultraviolet A
The predilection of BCC for the face attested to Patient weight
the possible increase in solar exposure as an lb kg Drug dose, mg
uncontrolled variable, since patients with psoria- <66 <30 10
sis often engage in this practice to augment 66–143 30–65 20
office-based phototherapy. In contrast, the face’s 144–200 66–91 30
patient is usually covered during whole-body UV > 200 >91 40
irradiation. Reproduced with permission from Menter et al. [2]
Table 7.4 Dosing of ultraviolet A radiation for oral pso-

ralen plus ultraviolet A
Skin Initial dose, Increments, J/ Maximum dose,
type J/cm2 cm2 J/cm2
I 0.5 0.5 8
II 1.0 0.5 8
III 1.5 1.0 12
IV 2.0 1.0 12
V 2.5 1.5 20
VI 3.0 1.5 20
Reproduced with permission from Menter et al. [2]
Table 7.5 Subsequent dosing protocol for PUVA

Number of missed
days Subsequent dosing
Fig. 7.5 Oxsoralen Ultra® 10 mg capsules for bath PUVA
3–5 Continue routine dosing increase
6–14 Hold dose
15–21 Decreased dose by 25%
22–28 Decreased dose by 50%
>28 Re-institute phototherapy and
dosimetry
Adapted from UCSF Psoriasis Center with permission of
the author (JK)
Fig. 7.6 Boiled water to dissolve Oxsoralen Ultra***

10 mg capsules
study, both PUVA and NB-UVB irradiation were

done thrice weekly for a maximum of 30 expo-
Fig. 7.4 PUVA for the hands/feet psoriasis or eczema
sures or clearance, whichever came first. In
another study of 28 patients with psoriasis, 54%
88.8% of 3175 patients with psoriasis achieved of the PUVA-treated cohort versus 78% of the
95–100% clearance after an average of 20 PUVA NB-UVB-treated cohort achieved clearance after
exposures [19]. a maximum of 30 exposures [21]. Interestingly,
When compared against NB-UVB photother- in this study PUVA was administered twice
apy, PUVA demonstrates inferior efficacy in weekly, which is not the optimal regimen to
small-scale studies but superior efficacy in large- achieve rapid clearance of psoriasis.
scale studies. A comparator trial involving only In terms of a larger “head to head” comparison
17 patients reported a PASI score reduction of study, Gordon et al. treated 100 patients thrice
45% in the PUVA-treated cohort compared with weekly with either PUVA or NB-UVB photo-
77% in the NB-UVB-treated cohort [20]. In this therapy. Eighty-four percent of the PUVA-treated
et al. involving 93 patients showed an 84% clear-

ance rate in the PUVA arm after 17.0 exposures
compared with 65% in the NB-UVB arm after
28.5 exposures [23]. Sixty-eight percent of the
PUVA-treated subjects versus thirty-five percent
of the NB-UVB-treated subjects remained in
remission for 6 months after treatments had
ended. Evidence from these large, randomized
trials seem to support superior efficacy of PUVA
over NB-UVB, especially with regard to duration
of therapeutic effects.
Side Effects
Dose-dependent effects of PUVA include skin

irritation, skin burns, and tanning. In addition,
ingestion of psoralen has been associated with
nausea, headaches, dizziness, and extremely rare
instances of psychiatric disturbance (i.e. insom-
nia, depression) [8]. To minimize nausea, patients
can try decreasing the dose of psoralen and/or
Fig. 7.7 Concentrated solution made by dissolving
Oxsoralen Ultra 10 mg capsules in hot water ingesting psoralen with food later in the day [8].
After decades of use, the association of PUVA
with an increased risk of cataracts has not been
substantiated in an evidence-based fashion [24].
The author (JK) feels that an ophthalmic exami-
nation is mainly useful for documenting the pres-
ence or absence of pre-existing cataracts.
Therefore, for the author (JK), even the presence
of pre-PUVA cataracts does not necessarily con-
stitute an absolute contraindication for initiating
PUVA therapy. There is no convincing human
data after decades of worldwide use to prove that
PUVA increases the risk of cataracts, provided
that the patient is compliant with UVA eye pro-
tection measures for 24 hours after psoralen
Fig. 7.8 Measuring water level for bath PUVA. The ingestion.
water level corresponding to 100 L is indicated on the Long-term exposure to PUVA is associated
ruler with photoaging marked by premature cutaneous
degeneration and pigmentation [25].
cohort achieved clearance of psoriasis after 16.7
exposures compared with sixty-three percent of
NB-UVB-treated cohort after 25.3 exposures Photocarcinogenicity of PUVA
[22]. Moreover, the number of PUVA-treated
patients who retained clearance 6 months after Long-term UVA irradiation exposure has been
therapy was almost double that of NB-UVB- associated with melanocytic atypia (i.e. large,
treated patients [22]. A similar study by Yones angular hyperchromatic nuclei and binucleated
melanocytes) called “PUVA lentigines”, suggest- However, one study published by Stern et al.
ing aberrant cellular kinetics [26]. A list of 25 recorded an increased risk of cutaneous mela-
PUVA follow-up studies conducted worldwide noma associated with PUVA. In this study, 1380
can be found in Table 7.6. Out of 25 published patients across the USA were monitored for up to
studies, 24 did not show an elevated risk of mela- 21 years during and after photochemotherapy.
noma associated with long-term PUVA exposure. During the first 15 years of follow-up, the relative
Table 7.6 Risk of melanoma associated with PUVA treatment

Number of Follow-up Mean or Relative risk of
Number of melanoma periods median invasive
Authors (Year) Country subjects cases (years) follow-up melanoma
Honigsmann et al. Austria 418 0 1–5 a a
(1980) [27]
Lobel et al. (1981) Australia 489 0 a a a
[28]
Lassus et al. (1981) Finland 525 0 1–3.6 2.2 a
[29]
Lindskov (1983) [30] Denmark 198 0 1–6 3.5 a
Ros et al. (1983) [31] Sweden 250 0 0–7 4.1 a
Reshad et al. (1984) United 216 0 0–7 4.8 a
[32] Kingdom
Eskelinen et al. Finland 1047 0 0–8 a a
(1985) [33]
Tanew et al. (1986) Austria 297 0 3.4–8.0 5.3 a
[34]
Henseler et al. (1987) Europe 1643 1 invasive 0–11 8.0 a
[35]
Barth et al. (1987) Germany 6820 0 0–10 a a
[36]
Cox et al. (1987) [37] United 95 0 0–8 a a
Kingdom
Torinuki & Tagami Japan 151 0 0–10 a a
(1988) [38]
Abdullah & Keczkes United 198 1 in situ 0–10 a a
(1989) [39] Kingdom

Forman et al. (1989) United 551 1 invasive 0–10 4.8 a
[40] States
Bryunzeel et al. Netherlands 260 0 0–12.8 8.7 a
(1991) [41]
Chuang et al. (1992) United 492 0 0–14 5.4 a
[42] States
Lever & Farr (1994) United 54 0 6–15 11.2 a
[43] Kingdom
Gritiyarangsan et al. Thailand 113 0 2–14 6.2 a
(1995) [44]
Maier et al. (1996) Austria 496 0 0.4–17.2 6.2 a
[45]
McKenna et al. Northern 245 0 2–15 9.5 a
(1996) [46] Ireland

Hannuksela et al. Finland 527 0 0–16 11 a
(1996) [47]b
Cockayne & August United 150 0 5–17 a a
(1997) [48] Kingdom

Number of Follow-up Mean or Relative risk of
Number of melanoma periods median invasive
Authors (Year) Country subjects cases (years) follow-up melanoma
Stern et al. (1997) United 1380 18 invasive 0–24 19 [49] 1975–1990:
[49] & Stern (2001) States 7 in situ 1.0
[50] 1 ocular 1991–1996:
4.7 (1.4–16.1)
1996–1999:
7.4 (2.2–25.1)
Lindelof et al. (1999) Sweden 4799 0–21 16 M: 1.1
[51] (0.4–2.3)
F: 1.0
(0.5–2.2)
Hannuksela-Svahn Sweden, 944 0 0–18 14.7 M: 0.7
et al. (1999) [52]b Finland (0.0–3.8)
F: 1.3
(0.0–7.2)
Information not provided or not able to be calculated from data
a
Bath PUVA only

b
incidence of melanoma was not different than ing variables such as a history of sunburns, fam-
expected in the general US population, based on ily history of skin neoplasm, other UV light
cancer statistics from the SEER (Surveillance, treatments, or medications that possess carcino-
Epidemiology, and End Results) Program [49]. genic risk, etc.
In the next 5 years of follow-up, seven new cases An extension of the original study by five
of melanoma were diagnosed, giving a relative more years followed the same cohort of 1380
risk ratio of 5.4 [49]. The authors thus hypothe- PUVA-treated patients. The relative risk ratio
sized that a period of latency exists before the within this latest five-year period is 7.4, once
risk of melanoma related to long-term PUVA again based on cancer statistics from SEER [50].
treatment becomes recognizable. In contrast, the largest PUVA study that has been
Comprehensive knowledge of how SEER published to date was conducted in Sweden by
derives its cancer statistics can influence how one Lindelof et al., who examined a cohort of 4799
interprets Stern et al.’s results and the implications PUVA-treated psoriasis patients. The data pub-
of their study. SEER approximates melanoma lished by Lindelof et al. revealed no increased
prevalence in the general US population based on risk of melanoma compared to the general
chart reviews of hospitals and “search of private Swedish population during an average
laboratory records” in designated regions, which, 15–16 years of follow-up [51]. There was not
as of 1990, comprised 9.6% of the total US popu- even an increased risk of melanoma in a sub-
lation. Unlike systemic cancers for which SEER cohort of 1867 patients who were followed up for
database was primarily intended, many cases of longer than 15 years [51]—this is where Stern
melanoma in situ and early-stage invasive mela- et al. claimed to have observed an increased car-
noma are excised on an outpatient basis by prac- cinogenic risk of PUVA. The prevalence of mela-
ticing dermatologists without being registered noma used to calculate relative risk ratio of
into any of the above databases [15, 53]. As a melanoma in Lindelof et al.’ study comes from
result, data generated by SEER may underesti- the Swedish Cancer Registry. It is likely to reflect
mate the actual prevalence of melanoma in the the actual prevalence in the Swedish population,
general US population. This could inflate the since reporting of melanoma diagnoses in
melanoma risk for PUVA that was calculated in Sweden is compulsory, unlike the situation in the
Stern et al.’s study. Additionally, the study lacked USA where no melanoma-reporting requirement
a matched control group to account for confound- exists.
Concerning the risk of NMSC, the results of enjoyed widespread use in the USA until the
Lindelof et al.’s study supported an increased risk Diagnostically Related Groups (DRG) made
of SCC associated with long-term PUVA use: prolonged hospitalization for dermatologic con-
relative risk ratios were 3.6 for women and 5.6 ditions impossible. It is still considered by many
for men [51]. Furthermore, analysis of the dermatologists as the gold standard treatment
1380-patient US PUVA cohort by Nijsten and based on high efficacy, safety of not requiring
Stern revealed higher than expected incidences of any internal agents, and induction of prolonged
SCC and BCC compared to the general US popu- remission times. Furthermore, Goeckerman
lation (based on SEER statistics). This NMSC therapy can be used to treat patients who have
risk is particularly notable in patients with more failed a number of therapeutic modalities beyond
than 200 lifetime PUVA treatments [54]. topical steroids, such as PUVA, UVB, and bio-
Conversely, a follow-up study in 944 Swedish logics [57].
and Finnish psoriasis patients treated only with
bath PUVA, not systemic PUVA, did not show Dosage and Administration
any increased risk of SCC or malignant mela- Goeckerman therapy is an intensive therapy
noma after a mean follow-up period of 14.7 years requiring all-day, everyday continuous participa-
[52]. Whether different cellular mechanisms are tion for typically 4–6 weeks in a hospital unit or
involved or the total UVA dose is lower, bath psoriasis day care center (Figs. 7.9 and 7.10)
PUVA appears to have less photocarcinogenic [58]. The treatment regimen begins each day with
risk than oral PUVA. UVB irradiation, since UV light will not pene-
It is important to recognize that available data trate after application of crude coal tar (CCT)
about long-term safety of PUVA therapy mostly [59]. The second step is to lather the patient’s
come from studies involving Caucasians. Murase skin with CCT in petroleum (Fig. 7.11), which
et al. conducted the only review of PUVA-related comes in 2%, 5%, and 10% preparations, and to
skin cancer incidence in non-Caucasian patients soak the patient’s scalp in 20% liquor carbonis
with various photosensitive dermatoses. Their detergens (LCD) in Neutraderm lotion (Fig. 7.12)
analysis included 4294 long-term PUVA patients [58]. Twenty percent LCD in Aquaphor ointment
who had at least 5 years of follow-up in studies is applied to the total body of each patient before
conducted in Japan, Korea, Thailand, Egypt, and he/she leaves the facility. It is also sent home with
Tunisia. The relative risk of developing skin neo- the patient to be done once more at bedtime. If
plasm in these patients compared to the general the patient’s condition is so severe that tar plus
dermatology oupatient population in each respec- UVB do not provide adequate control, then com-
tive country where the PUVA follow up data pounded anthralin and even topical PUVA can be
originated was 0.86 (with a confidence interval of added [1]. Infrequently, truly recalcitrant psoria-
0.36–1.35). This means that the increased risk of sis might necessitate the concomitant use of reti-
skin cancer related to long-term PUVA in Asian noids and topical vitamin D derivatives in order
and North African patients has yet to be demon- to achieve clearance [1].
strated [55]. Further investigation into the protec-
tive nature of darker skin phototypes is needed. Efficacy
Goeckerman therapy has high efficacy for recal-
citrant psoriasis, even when single or multiple
Inpatient Photothearpy biological agents have failed to show improve-
ments [57]. In a prospective study, 95% and
Goeckerman Therapy 100% of 25 psoriasis patients who were treated
with Goeckerman therapy reached PASI 75 by
Formulated in 1925, Goeckerman’s eponymous week 8 and week 12, respectively [60]. In another
therapy is one of the oldest forms of photother- study, clearance of psoriasis has been docu-
apy for the treatment of psoriasis [56] and mented in 90% of 300 patients after only 18 days
Fig. 7.9 The common area for Goeckerman therapy patients at a psoriasis day care center, which often turns into a
therapeutic milieu (i.e. where the ambient supportive atmosphere is experienced by the patients as therapeutic)
Fig. 7.10 Physicians performing rounds on a patient undergoing Goeckerman therapy

Fig. 7.11 Nursing staff

applying crude coal tar
with occlusion to
psoriatic skin
of treatment. Eight-month remission was r emission duration of 5.1 months was calculated

recorded in 90% of these subjects [58]. It should based on 185 patients who experienced relapse
be noted that the second study featured a more during the observation period [61]. However,
intensive treatment regimen than the commonly there were 15 patients in the study who did not
encountered Goeckerman therapy: UVB and tar relapse during the entire observation period. Had
therapy were administered twice daily, and these 15 patients been included, the calculated
patients attended the program six instead of 5 mean remission duration would have been longer
days a week [58]. This may explain their signifi- than 5.1 months.
cantly rapid clearance rate.
In 1979 DesGroseilliers et al. implemented a ide Effects and Long-term Safety
S
modified design to render Goeckerman therapy Side effects of Goeckerman therapy include fol-
less time-intensive and more cost-effective. 200 liculitis and phototoxic reactions, which are can
patients were treated with coal tar application at be managed by dose adjustment of tar and
home plus office-based UVB irradiation the fol- UVB. The pustules associated with Goeckerman
lowing day 5 days a week. After 1 month of treat- therapy can develop on non-involved skin and are
ment, 86% of patients in this cohort achieved therefore distinct from pustular psoriatic lesions
clearance of their psoriasis [61]. The mean [62]. Rarely, precipitation of erythrodermic
consists of a succession of tar bath, light treat-

ment, and application of anthralin paste or oint-
ment to involved skin. Adding crude coal tar to
anthralin has been shown to reduce skin irritation
without compromising antipsoriatic efficacy
[66]. In a retrospective study by De Bersaques,
275 psoriasis patients who were treated in a hos-
pital with Ingram therapy achieved clearance
after an average of 25 days [65]. Patients did not
need another treatment or hospitalization for 8 to
11 months after therapy [65]. However, being a
single center study, these results might have been
influenced by loss to follow-up of patients who
sought care from other practitioners due to early
relapse.
Non-office-based Phototherapy
Commercial Tanning Therapy
In commercial tanning facilities, phototherapy

for psoriasis can be conducted using “tanning
beds” that emit high-intensity UVA rays mixed
with small quantities of contaminant UVB. This
is different from office-based, outpatient UVB
phototherapy, where healthcare professionals fre-
Fig. 7.12 Nursing staff applying 20% liquor carbonis
detergens in Neutraderm lotion to a psoriasis patient’s
quently perform clinical assessments and light
scalp dose adjustments. For 16 out of 20 psoriasis
patients treated with tanning beds, the initial
mean PASI score of 7.96 (+/− 1.77) was dimin-
p soriasis has been documented in patients aller- ished to 5.04 (+/− 2.5) after 6 weeks of treatment
gic to crude coal tar [63]. To investigate long- [67]. Even those who did not complete the entire
term safety, a 25-year follow-up study was treatment course had a 23.5% improvement of
conducted in 280 psoriasis patients treated with their PASI score [67]. Furthermore, most patients
Goeckerman therapy over a 5-year period. The reported significant improvements in health-
results consisted of 1 melanoma, 22 BCC, 7 SCC, related quality of life, while mild burning and
and 3 tumors of unknown type [64]. Based on transient pruritus were infrequent and well toler-
cancer statistics from a matched population, there ated [67].
was no increase in the risk of skin cancer in these There is controversy surrounding the exis-
patients [64]. tence of an association between exposure to com-
mercial UV tanning devices (i.e. sunlamps,
sunbeds) and an increased risk of melanoma. In
Ingram Therapy 2006 the International Agency for Research on
Cancer issued a detailed report on the photocar-
Ingram therapy is the inpatient treatment of pso- cinogenic risk of artificial UV exposure, which
riasis with UV irradiation and anthralin, which addressed 23 case-control studies related to
was introduced to dermatology in 1916 [65]. It indoor tanning and melanoma. The risks for
Table 7.7 Meta-analysis of all studies included Table 7.8 Meta-analysis of the cohort and population-
based case–control studies included
Number Summary Heterogeneity a
of relative risk P-value Number Summary Heterogeneitya

Exposure studies (95% CI) χ2 H of relative risk P-value
Ever use 19 1.15 0.013 1.37 Exposure studies (95% CI) χ2 H
of indoor (1.00–1.31) Ever use 10 1.17 0.011 1.540
tanning of indoor (0.96–
facility tanning 1.42)
First 7 1.75 0.55 0.91 facility
exposure (1.35–2.26) First 5 1.71 0.435 0.973
in youth exposure (1.25–
Exposure 5 1.49 0.018 1.65 in youth 2.33)
distant in (0.93–2.38) Exposure 2 1.58 0.502 0.830
time distant in (0.25–
Exposure 5 1.10 0.81 0.67 time 9.98)a
recent in (0.76–1.60) Exposure 2 1.24 0.762 0.521
time recent in (0.52–
Reproduced with permission from the IARC (2005) [68] time 2.94)
a
The degrees of freedom for the Chi-square are given by Reproduced with permission from the IARC (2005) [68]
the number of databases included minus one, not by the a
The confidence interval is very wide because this analysis
number of studies includes only 2 studies, one of which has two estimates
elanoma associated with “ever use” (any expo-

m p rofound in Caucasian female users with more
sure to sunlamps/sunbeds in one’s lifetime), “first than 10 lifetime tanning sessions compared with
use in youth” (exposure to sunlamps/sunbeds those having less than 10 sessions [71]. The
starting at 35 years old or younger), “distant use” results of this study do not apply to Caucasian
(5 years or more from the time of the interview), male users, possibly due to the fact that they visit
and “recent use” (less than 5 years from the time tanning facilities less frequently than their female
of the interview) of indoor tanning devices were counterparts [71]. In addition, this cut-off of 10
compared and contrasted using reported relative tanning sessions is an arbitrary proposal based on
risk ratios. Meta-analysis of 19 of these 23 stud- the results of one study. More convincing data is
ies (Table 7.7) revealed a calculated summative needed to establish a photocarcinogenic thresh-
relative risk of 1.15 (95% confidence interval: old for UV exposure through tanning devices.
1.00–1.31) for “ever use” of indoor tanning facil-
ity [68]. The same relative risk becomes slightly
elevated to 1.17 (0.96–1.42) when data only from Home UVB Therapy
cohort and population-based case-control studies
were employed for calculation (Table 7.8) [68]. Most devices employed in home phototherapy
In both meta-analyses the summative relative risk emit UVB. This form of phototherapy is tailored
is higher for first exposure in youth than for “ever to patients with stable psoriasis and logistical dif-
use” of indoor tanning facility and also higher for ficulty, such as lack of time to do office photo-
“distant” exposure versus “recent” exposure [68]. therapy or no access to transportation to
In a systematic review of case-control studies, dermatology practices with UVB capacity. In a
6 out of 19 studies reported a dose-response rela- randomized trial involving 196 psoriasis patients,
tionship between tanning lamp/bed exposure and 70% of patients receiving home UVB therapy
melanoma risk [69]. Another review of 10 case- reached PASI 50 compared to 73% in the outpa-
control studies reported that the odds ratios tient group [72]. Short-term safety profiles were
spanned anywhere from 0.7 (0.5–1.0) to 2.9 (1.3– not notably different between the groups [72].
6.4) for “ever use” versus “never use” (no expo- Moreover, the burden of therapy (a function of
sure at all during one’s lifetime) of sunlamps/ method and time commitment) was significantly
sunbeds [70]. Of note, the dose-dependent risk lower for home phototherapy patients than for
for invasive melanoma is likely to be more office-based outpatients [73].
Heliotherapy UVB and Retinoid Therapy
Heliotherapy is the therapeutic use of sunlight to Acitretin, an oral retinoid agent, has been shown
treat psoriasis and other photosensitive dermato- to enhance the efficacy of UVB phototherapy. In
ses. There are not many large, randomized, con- an 8-week, randomized, comparator study involv-
trolled studies to determine the efficacy of ing 82 psoriasis patients, 60% of the combined
heliotherapy, let alone comparator studies involv- BB-UVB and acitretin cohort (re-UVB) versus
ing other forms of phototherapy. In a study with 24% of the BB-UVB cohort reached PASI 75
373 subjects, the rate of clearance of psoriasis [78]. Phototherapy was administered 3–5 times
was 22% and that of PASI 75 response was 84% weekly, and acitretin was available as 25 mg tab-
after 1 month of treatment [74]. The median lets taken once daily [78]. Treatment with acitre-
remission time was 2.6 months (80 days) [74]. tin 25 mg plus thrice weekly NB-UVB resulted in
Short-term side effects are similar to other photo- 75% improvement of psoriasis in 30 out of 40
therapeutic modalities: skin burns, irritation, pru- patients from another study [79].
ritus, erythema, heat, etc. Skin cancer risks The phenomenon “delayed retinoid burn” was
associated with long-term heliotherapy in patients described in 2011 after a psoriasis patient experi-
with psoriasis have not been studied. enced a severe phototoxic reaction as a result of
adding acitretin 25 mg daily to a previously toler-
ated UVB dose [80]. Since acitretin induces cell
Climatotherapy at the Dead Sea differentiation and leads to sloughing of keratin
layers from psoriatic plaques, the introduction of
Climatotherapy is the exposure of skin to a spe- acitretin in the middle of already ongoing photo-
cial kind of climate for the treatment of psoriasis. therapy can lead to too much light penetration
Its efficacy was established in a study involving causing phototoxicity to previously tolerated
64 patients: PASI 75 response after 1 month of dosimetry. Therefore, phototherapy providers
climatotherapy at the Dead Sea was 75.9%, and should consider reducing UV dose when starting
median duration of remission was 5.8 months concomitant retinoid therapy. The authors recom-
(23.1 weeks) [75]. Analysis of skin cancer data mended cutting UVB dose by 50% as soon as
from a cohort of 1738 Danish patients who were acitretin is added, and gradually going back
followed up for an average of 6.1 years revealed toward the pre-acitretin UVB dose level if no
no association between climatotherapy and an phototoxicity occurs [80]. How this is conducted
increased risk of melanoma [76]. There were, in each phototherapy provider’s office is a judg-
however, 8 SCC and 28 BCC compared with 0.8 ment call.
expected SCC and 6.6 expected BCC [76]. It was
later discovered that the subjects in this follow-
up study had received more than three times the PUVA and Retinoid Therapy
necessary amount of UVB to achieve therapeutic
results [77]. This important information might Similarly, rapid improvement of recalcitrant pso-
partially explain the significant difference riasis might be achieved by adding oral retinoid
between observed and expected incidence of agents to PUVA. In a study comparing the
non-melanoma skin cancer. efficacies of combined PUVA plus acitretin one
mg/kg body weight/day (re-PUVA) versus PUVA
alone, clearance was achieved in 96% of the
Combination Therapy combination cohort and 80% of the PUVA cohort
after 11 weeks of treatment [81]. Had the 48 sub-
For patients with severe psoriasis based on large jects of this study undergone PUVA treatment
BSA coverage and/or resistance to traditional three instead of four times weekly, the clearance
single therapies, combinations of therapies are rates in both arms might not have been as high
available as treatment options. and their difference easier to appreciate.
Furthermore, another head-to-head compari- severe psoriasis were promising: after 12 weeks
son study between re-PUVA and re-UVB showed of combined adalimumab 40 mg every other
100% clearance rate in the re-PUVA cohort com- week and NB-UVB three times weekly, 95% and
pared with 93% in the re-UVB cohort after a 85% of the patients reached PASI 75 and clear-
6-week treatment course [82]. Etretinate one mg/ ance, respectively [86]. Moreover, 65% of
kg body weight/day was used instead of acitretin. patients retained PASI 75 response 12 weeks fol-
Duration of therapeutic effects was longer for re- lowing the end of treatment [86]. A similar but
PUVA patients versus re-UVB patients [82]. larger trial (known by the acronym “UNITE”)
However, this study was limited in its small size with NB-UVB thrice weekly plus etanercept
(each cohort consisted of 15 patients) and by the 50 mg twice weekly also showcased high effi-
fact that PUVA or UVB was done twice weekly cacy of combination therapy: at week 12, 84.9%
for each combination therapy. of 86 psoriasis patients reached PASI 75 [87].
When photo(chemo)therapy was instituted at There was also an equally important and signifi-
the optimal treatment regimen (thrice weekly) in cant improvement in health-related quality of life
60 psoriasis patients, clearance was achieved in in almost all the UNITE study subjects [87].
63.3% of the re-PUVA cohort versus 56.6% of
the re-UVB cohort [83]. The reported clearance
rates were lower in this study than in the previous Photocarcinogenicity of Combination
studies because acitretin was dosed at 0.3–0.5 mg Therapy
instead of 1 mg/kg body weight/day. In spite of
the dosing differences between these comparison Oral retinoid agents can lower the skin cancer
studies, all consistently proved that re-PUVA is risk associated with phototherapy through pro-
more effective at reducing clinical severity of motion of keratinocyte differentiation. There is a
psoriasis than re-UVB combination therapy. case report of one patient on once daily acitretin
25 mg whose number of squamous cell carcino-
mas decreased while on acitretin and increased
UVB and Biologics when taken off acitretin [88]. In addition, the
results of a 15-year follow-up study in 135 pso-
UVB therapy can be added to biological agents to riasis patients who received PUVA and acitretin/
expedite clearance of moderate-to-severe psoria- etretinate for more than 6 months seemed con-
sis. A six-week study involving 14 patients vincing: the numbers of SCC diagnosed during
showed that combined UVB and etanercept the time of using and not using acitretin/etreti-
helped patients achieve a 64 +/− 28.8% reduction nate were 196 and 302, respectively [89]. The
of their modified PASI scores compared with the adjusted incidence rate ratio of SCC was calcu-
53.7 +/− 36.9% PASI score reduction in patients lated to be 0.79, which implicates the potential of
treated with etanercept alone [84]. UVB was oral retinoid agents to decrease non-melanoma
given thrice weekly, and etanercept was dosed at skin cancer risk in phototherapy patients [89].
25 mg twice weekly. De Simone et al. performed Whether or not these agents have any effect on
a single-arm, open label study in which 33 melanoma risk is a question that has not yet been
patients with moderate-to-severe psoriasis were addressed in the literature.
treated for 8 weeks with etanercept 50 mg once The carcinogenicity of combined photother-
weekly plus NB-UVB thrice weekly, after which apy plus biological agents is an on-going con-
only etanercept was continued for another cern. In 2011, Gamblicher et al. compared
4 weeks. At Week 4, 8, and 12 of treatment, PASI psoriatic plaques that were treated with either
75 was reached in 24.2%, 66.7%, and 81.8% of BB-UVB at two MED or combined BB-UVB at
the study participants [85]. two MED plus etanercept 50 mg one time in 11
The results of a single-arm, single-center, study subjects. Punch biopsies of the treated
open-label study involving 20 patients with areas were taken at 1, 24, and 72 hours after
Fig. 7.13 Excimer laser

therapy requires the
most powerful excimer
laser machine to
adequately treat
moderate-to-severe
psoriasis
BB-UVB treatment [90]. Immunohistochemical therapy can confer some skin cancer chemo-
analysis revealed increased expression of sur- protective effects limited to the periods of reti-
vivin (a tumor marker) and decreased activity of noid use [92].
cyclin D and p53 (regulators of tumor develop- In terms of efficacy, both forms of UVB ther-
ment) in BB-UVB-plus-etanercept-treated sites apy are not as effective as Goeckerman or PUVA
compared with BB-UVB-monotherapy-treated but fare better than heliotherapy [91, 92, 94]. The
sites [90]. Large randomized controlled trials are combination of UVB and oral retinoid or biologi-
needed to determine if an increased risk of mela- cal agents can lead to more successful therapy for
noma or NMSC exists in psoriasis patients treated patients than any of these modalities alone.
with combined photo(chemo)therapy and Short-term side effects of UVB phototherapy are
biologics. well tolerated, and no studies so far have con-
vincingly demonstrated any relationships
between long-term UVB treatment and an
Conclusion increased risk of skin cancer. If office UVB is not
feasible, climatotherapy, commercial and home
All day, every day Goeckerman therapy is one of UV therapies should still be considered as useful
the most effective regimens for moderate-to- alternatives in the care of patients with psoriasis.
severe psoriasis, and it still maintains an appeal- Finally, excimer laser therapy, to which
ing safety profile [91, 92]. PUVA has been shown another chapter of this book is dedicated, has
to result in high clearance rates, but the associa- been conducted worldwide for more than 10 years
tion of PUVA with an increased risk of NMSC in to target recalcitrant plaque psoriasis (Fig. 7.13).
fair-skinned Caucasian patients has rendered it Current data on its efficacy revealed that fewer
less popular nowadays than narrowband UVB exposures to light are needed to induce remission
[92]. Until this date whether or not PUVA causes [95–98]. No signal regarding an increased risk of
an increase in melanoma risk is a controversial skin cancer from therapeutic use of excimer laser
topic due to contradictory results between a has been reported. Furthermore, excimer laser
United States 16-center study and numerous spares non-involved skin, so there is a possibility,
other studies primarily from Europe [49, 93]. in terms of cutaneous malignancy safety, that this
Fortunately, adding oral retinoid agents to PUVA targeted phototherapy may even be better than
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content under my authorship has been published in narrow-band ultraviolet B and broad-spectrum
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Laser Therapy in Psoriasis
8
Quinn Thibodeaux and John Koo
Abstract
Treatment options for psoriasis are numerous 1. To understand the mechanism of action
and span a wide array of modalities. For mild- and types of laser therapy for psoriasis
to-moderate disease, topical therapy may be 2. To understand the appropriate use and
adequate for complete control; however, efficacy of laser therapy for psoriasis
moderate-to-severe disease often requires sys- 3. To understand the safety concerns of

temic agents or phototherapy. Laser therapy is utilizing laser therapy for psoriasis
also a helpful tool in the armamentarium
against psoriasis. For localized disease that is
not adequately controlled with topicals or for
lesions in difficult-to-treat areas, laser therapy
Introduction
may be an ideal treatment option. Lasers
enable the delivery of therapeutic radiation to
Psoriasis is a chronic inflammatory disorder of
lesional skin only, thus sparing non-lesional
the skin and nails that affects over 3% of adults in
skin from any possible adverse events. Over
the United States [1]. The most common form of
the past few decades, various lasing devices
the disease is plaque psoriasis, which presents as
have been demonstrated to be safe and effec-
scaly, erythematous lesions frequently involving
tive treatment options for psoriasis. The most
the scalp, elbows, knees, umbilicus, and lower
commonly used devices include the 308-nm
back. First line therapies for mild to moderate
excimer laser and the 585 or 595-nm pulsed
psoriasis include topical agents such as cortico-
dye laser. Despite recent advances in targeted
steroids, vitamin D analogues, coal tar, and topi-
biologic therapy, lasers continue to play an
cal retinoids. For more severe disease, oral
important role in the management of psoriatic
systemic agents, injectable biologics, or photo-
disease.
therapy may be required for adequate control.
For localized disease or when limited plaques
are recalcitrant to other therapies, laser therapy
may be beneficial. When compared to non-
lesional skin, psoriatic plaques are able to with-
Q. Thibodeaux (*) · J. Koo stand greater doses of radiation without burning
Department of Dermatology, University of California or blistering. Treatment with lasers allows the
San Francisco, San Francisco, CA, USA targeting of lesional skin with supraerythemo-

https://doi.org/10.1007/978-3-030-54859-9_8
94 Q. Thibodeaux and J. Koo
genic doses (i.e. beyond the minimal erythema tinocytes and T lymphocytes, promoting local
dose) of radiation leading to increased efficacy. immunosuppression, and inducing cell-cycle
Sparing of non-lesional skin helps to reduced arrest [3]. p53, a promotor of cell-cycle arrest and
treatment-related adverse effects such as burning, apoptosis has been found to be elevated in
blistering, and hyperpigmentation. Laser therapy lesional skin following irradiation with excimer
is also ideal for difficult-to-treat areas such as the laser [4].
scalp, lower legs, palms, soles, and intertriginous
regions.
Multiple lasers have been evaluated for their Efficacy
efficacy and safety in the treatment of psoriasis.
In the following chapter, the literature regarding A pair of early efficacy studies evaluated the dif-
excimer, pulsed dye, Nd:YAG, and carbon diox- ferences between medium and high-dose treat-
ide lasers will be reviewed. ment regimens. In the medium-dose study, 20
subjects received thrice weekly treatments for up
to 8 weeks. The treatment regimen allowed pos-
Excimer Laser sible dose increments of 25–30% per treatment.
Of the 15 subjects who completed the protocol,
Background >95% clearance was seen in an average of 10.6
treatments with a mean remission time (<25%
The excimer laser is the most widely-used tar- disease recurrence) of 3.5 months [5]. The high-
geted phototherapy device for psoriasis and is dose study treated 32 plaques in 16 patients with
also used in the treatment of other dermatologic doses of 8 and 16 times their MED (minimal ery-
conditions including vitiligo, alopecia areata, and thema dose). Following this single high-dose
cutaneous T-cell lymphoma. The device was treatment, mean modified PASI scores decreased
invented in 1970 and produces a monochromatic from 6.31 at baseline to 3.875 at follow-up
wavelength upon the dissociation of “excited 2 months later (P = 0.002) with partial clearing
dimers”, which gives the technology its name. A noted in 11 of the 16 after only 1 month [6].
xenon dimer was used initially; however, further The earliest large-scale study evaluating
development resulted in a xenon-chloride (XeCl) excimer laser in plaque psoriasis recruited 124
dimer that produced a 308 nm wavelength within patients from multiple centers. Subjects were
the ultraviolet B (UVB) spectrum (290–320 nm). initially treated with an average of 3 MED and
In 1997, Bónis et al. were the first to report the then twice weekly with dose adjustments in
use of excimer laser in the treatment of psoriasis. response to treatment. Seventy-two percent of
They found that in comparison to treatment with patients who completed the protocol experi-
narrowband UVB (311 nm), the excimer laser enced at least 75% improvement of their lesions
was able to clear plaques of psoriasis in less time in an average of 6.2 treatments. In all, 84% of
and with lower cumulative doses of radiation [2]. patients achieved 75% improvement in less than
10 treatments, with 50% reaching clearance of
90% or higher [7].
Mechanism of Action In another large, open-label study, 120 patients
received an initial 3 MED dose followed by
The mechanism of action of excimer laser in pso- increases of 1 MED per session. Treatments were
riasis is thought to be multifactorial and is drawn administered twice weekly for 3 weeks and then
from studies analyzing other forms of UVB pho- weekly until clearance was attained. Within 10
totherapy. Numerous mechanistic theories have treatment sessions, 65.7% of subjects had
been proposed and include shifting of lesional achieved 90% improvement, with 85.3% reach-
cytokine profiles away from the Th1/Th17 axis, ing PASI90 after 13 sessions. The average length
inducing apoptosis in epidermal and dermal kera- of treatment was 7.2 weeks [8].
8 Laser Therapy in Psoriasis 95
A smaller study evaluated 26 patients with altered in response to changes in induration [11].
macular-type and 14 patients with chronic plaque In general, doses are increased or decreased
psoriasis. After an average of 13.7 treatment ses- based on response to therapy or the development
sions, PASI improvements of 90.12 +/− 10.12% of adverse events. Treatments should be sepa-
and 77.34 +/− 17.04% were noted in the macular rated by at least 48 h, and generally occur two to
and plaque groups, respectively [9]. three times per week in most protocols.
While the above protocols are most commonly
used, other, more aggressive treatment algo-
Safety rithms have also been implemented successfully.
Reports include a patient who achieved PASI 79
Judicious use of the excimer laser has proven to after only two treatments using a plaque-based
be a safe treatment option for psoriasis with no sub-blistering dosimetry [12] and a cohort of 13
serious or long-term side effects reported. patients whose global PASI scores decreased by
Common adverse events are similar to those of 42% 8 weeks after a single “TURBO” dose of 10
more generalized phototherapy but are limited to times their MED [13]. Higher fluences were
the areas receiving radiation. These common noted to be more efficacious early in the develop-
reactions include pain, burning, erythema, blis- ment of the excimer laser, and Asawanonda et al.
ters, erosions, and hyperpigmentation and are were the first to report quicker clearance and lon-
typically mild and self-resolving [7, 8]. Although ger remission of psoriasis with high dose (8 and
no studies exist on the relationship between the 16 times MED) versus medium (2, 3, 4, and 6
treatment of psoriasis with excimer laser and skin times MED) and low (0.5 and 1 times MED) dose
carcinogenesis, a retrospective cohort study of treatments [14].
over 5000 Korean patients with vitiligo found no Few maintenance strategies have been evalu-
increased risk of actinic keratosis, non-melanoma ated. One protocol involved reducing the fre-
skin cancers, or melanoma [10]. This relationship quency of treatments after achieving PASI 75 to
is likely to hold true for the treatment of psoriasis once per week for 4 weeks, then once every
as well, as no reports have surfaced of an other week for 4 weeks, and then to one final
increased risk of skin cancer, even anecdotally, treatment 4 weeks later. With this regimen, none
despite over 20 years of use. of the five patients treated experienced >50%
PASI worsening during the 3-month taper [15].
In general, remission times of 3–4 months have
Dosing/Protocols been reported following discontinuation of ther-
apy [5, 6, 14].
To the authors’ knowledge, little data exists com-
paring the efficacies of various treatment
regimens. In general, initial dosages are based on ther Morphologies and Special
O
either a predetermined MED or by the induration Populations
of individual plaques. The MED is determined by
applying increasing dosages of radiation to In addition to chronic plaque psoriasis, treatment
healthy, non-psoriatic skin and observing the first with excimer laser has also shown efficacy in
dose that creates a well-demarcated, minimally other forms of psoriasis as well, including palmo-
erythematous macule. In the earliest large, open- plantar pustulosis [16, 17], TNF-alpha inhibitor-
label study, initial dosages were one to three induced palmoplantar pustular psoriasis [18],
times the MED, regardless of plaque characteris- inverse psoriasis [19, 20], scalp psoriasis [21,
tics [7]. Other studies have utilized the induration 22], and palmoplantar psoriasis [21, 23–25]. A
component of the mPASI score to determine the side-by-side study with 10 patients compared the
initial dose for specific plaques independent of efficacy of excimer laser to topical PUVA for the
the patient’s skin type. Subsequent doses are then treatment of palmoplantar psoriasis and found
near equivalent reductions in PASI after 5 weeks Pulsed Dye Laser

(−63.57% for excimer; −64.64% for topical
PUVA) [26]. Background
The safety and efficacy of excimer laser has
also been demonstrated in a pediatric popula- The pulsed dye laser (PDL) is a lasing device that
tion [27]. is comprised of various combinations of organic
dyes mixed in solvents. These combinations are
“pumped” by an external high-energy source that
Adjuvant Therapies excites the dye molecules, leading to the pulsed
emission of radiation at a wavelength of 585 or
The safety and efficacy of excimer laser has been 595 nm. At this wavelength, oxyhemoglobin acts
shown to increase with the concomitant use of as the main target within the skin. The pulsed dye
various topical medications. One right-versus- laser is mainly used in the treatment of vascular
left study compared twice weekly excimer treat- lesions such as port wine stains, hemangiomas,
ment to twice weekly excimer plus twice daily and telangiectasias; however, its efficacy in the
calcipotriene ointment. By week 6 the average treatment of psoriasis has also been evaluated.
PASI of the combination group (1.82 +/− 0.74)
was significantly lower than that of the mono-
therapy group (5.08 +/− 1.65). In addition to bet- Mechanism of Action
ter efficacy, the combination group also required
significantly less cumulative radiation [28]. The pulsed dye laser exerts its biological effects
Another study comparing excimer laser with based on selective photothermolysis, whereby a
concomitant flumetasone/salicylic acid oint- specific targeted tissue is preferentially destroyed
ment to excimer laser alone had similar results, leaving the surrounding tissues undamaged [32].
with the laser plus topical group experiencing In the case of PDL, the absorption of energy by
greater improvement in PASI scores with lower oxyhemoglobin leads to the destruction of the
average cumulative doses of phototherapy [29]. microvasculature. Because one of the defining
Combinations of various topicals in addition to histologic features of psoriasis is dilated and tor-
excimer have also been evaluated. One study tuous capillaries in the dermal papillae, PDL is
treated patients for 12 weeks with twice weekly able to treat psoriatic disease by ablating the ves-
excimer laser in addition to alternating months of sels that supply blood, oxygen, and nutrients to
twice daily clobetasol spray and calcitriol oint- skin lesions.
ment. Of the 30 patients enrolled, 83% achieved Reductions in plaque severity scores have
PASI75 by week 12 [30]. been correlated to decreases in plaque microves-
Excimer laser has also been evaluated as an sel area following PDL treatment, with more
adjuvant therapy to PUVA treatment. One study clinically significant improvement seen in
evaluated 272 patients who were treated with plaques with larger pre-to-post treatment area
either PUVA four times weekly monotherapy or reductions [33, 34]. One early histologic study
PUVA four times weekly plus up to four suggested that a more tortuous or horizontal vas-
excimer treatments within the first 2 weeks. cular pattern was associated with poorer response
Overall efficacy between the two treatments to treatment in comparison to more vertically ori-
was equivalent, with 67.3% of the monotherapy ented vessels [35]. Another immunohistochemi-
group and 63.6% of the PUVA plus excimer cal evaluation found that the thermolytic effect of
group achieving PASI 90; however, the PUVA PDL treatment was limited to the superficial cap-
plus excimer group achieved PASI 90 in almost illary bed and did not affect the deeper vessels in
half the treatment time (15 +/− 6 vs. 27 +/− the upper reticular dermis. In a similar pattern, a
7 days) and with significantly less cumulative reduction of CD4+ and CD8+ T cells was seen in
UVA exposure [31]. the papillary dermis but not in the epidermis or
upper reticular dermis [36]. Although thermoly- Another study compared the efficacy of PDL,
sis of superficial capillaries occurs as a result of NB-UVB, and the combination of PDL plus
plaque treatment with PDL, overall blood flow NB-UVB versus no treatment. It found that while
continues to be significantly elevated when com- both modalities led to significant improvement
pared to uninvolved skin, suggesting that deeper by week 13, there was no significant difference
vessels are also involved in the pathogenesis of between the two and the benefits of both modali-
psoriasis [37]. ties were not synergistic [44].
Efficacy Safety
Hacker and Rasmussen were the first to report the Side effects of PDL are similar to those of other
efficacy of PDL in chronic plaque psoriasis. They light-based therapies; however, because the
treated a single plaque in 20 patients with flu- modality directly targets and destroys the vascu-
ences of 5.0, 7.0, and 9.0 J/cm2, leaving one lature, more specific effects from the extravasa-
quadrant as an untreated control. Eleven (57%) of tion of red blood cells have been noted. The most
19 patients experienced positive effects after a common adverse events seen with PDL include
single dose of the 9.0 J/cm2 fluence, with negli- petechia, purpura, pain, erosions, hyperpigmen-
gible improvement in quadrants treated with the tation, hypopigmentation, and atrophic scarring
5.0 and 7.0 J/cm2 doses and no improvement in [39, 40, 44]. Aside from rarely reported events
the control quadrant [38]. Following this proof- of scarring, side effects are typically mild and
of-concept, Katugampola et al. recruited eight short-lived.
patients with symmetric chronic plaque psoriasis
and treated one plaque with PDL every 2 weeks
for three sessions, leaving the corresponding con- Other Morphologies
trol plaque untreated. At week 16, five of the
eight patients showed improvement of >/= 50% de Leeuw et al. demonstrated that PDL may
of the treated plaque. One patient remained clear be effective for palmoplantar psoriasis. Their
after 10 months of follow-up [39]. Another early study involving 41 patients treated once every
study by Ros et al. found noticeable improve- 4–6 weeks found that 76% of participants
ment in 6 of 10 treated patients after 1–3 sessions achieved >70% improvement in their lesions after
[40]. Zelickson et al. treated 36 patients across an average of 4.2 treatments with over 50% expe-
two treatment groups and found that PDL signifi- riencing greater than 90% improvement [45].
cantly improved plaque psoriasis in two to five Much of the research into PDL and psoriasis
sessions. No significant difference was noted has focused on the treatment of nail disease. A
between treatment with short (450 μs) and long study comparing the efficacy of PDL and PDT
(1500 μs) pulse-widths [35]. (methyl-aminnolaevulinic acid occlusion for
Two studies have compared PDL to topical 3 hours followed by PDL as a light source) in
active comparators. Each found that PDL signifi- the treatment of nail psoriasis found significant
cantly improved the targeted psoriatic plaques; improvement in both nail matrix and nail bed
however, one study found the active comparator disease for both modalities, with no significant
to be superior (clobetasol propionate + salicylic difference noted between the two [46]. Another
acid) while the other found the active comparator small study of 5 patients treated with monthly
to be inferior (calcipotriol/betamethasone) [41, PDL for 3 months found improvements in both
42]. One case series compared PDL to dermabra- nail matrix (mean NAPSI from 7.0 +/− 1.4 to 2.2
sion. Of the 11 patients treated with PDL, three +/− 0.7) and nail bed (mean NAPSI from 14.6
experienced complete remission in comparison +/− 2.5 to 0.5 +/− 0.5) lesions [47]. A larger study
to five of six treated with dermabrasion [43]. involving 20 patients and 79 nails also showed
significant improvement in both nail bed and nail different spot sizes significantly improved lesions
matrix NAPSI scores with no significant differ- at week 4, but these improvements were not
ence noted between longer (6 ms) and shorter maintained through the remainder of the study.
(0.45 ms) pulse durations [48]. In a randomized, They concluded that the laser was not “of addi-
single-blind study involving 20 patients and 192 tional value in the array of treatment modalities
diseased nails, treatment with monthly PDL for for chronic localized plaque psoriasis.” [51]
6 months resulted in significant improvement Nd:YAG laser has also been evaluated for the
in both nail matrix and nail bed disease. In the treatment of psoriatic nail disease. Kartal et al.
treatment group, mean NAPSI scores decreased treated 16 patients with three monthly sessions of
from 25.45 +/− 5.38 at baseline to 4.95 +/− 4.03 Nd:YAG and assessed for changes in NAPSI
1 month after the last treatment session [49]. scores. Patients’ mean NAPSI score decreased
from 26 +/− 7.2 at baseline to 22 +/− 6.6, 13 +/−
6, and 5.7 +/− 4.3 after treatment sessions one,
Nd:YAG Laser two, and three, respectively. NAPSI scores at all
timepoints were significantly improved from
Background baseline [52].
The Nd:YAG laser is a solid-state device that uti-

lizes a crystal of neodymium-doped yttrium alu- Carbon Dioxide Laser
minum garnet as a lasing medium. The laser
emits infrared radiation at a wavelength of Background
1064 nm and is used as an ablative device in mul-
tiple specialties including ophthalmology, oncol- The carbon dioxide (CO2) laser is a high-powered
ogy, urology, and dermatology; however, little lasing device that operates in the infrared spec-
evidence exists for its use in the treatment of pso- trum with wavelengths generally ranging from
riasis. Because the laser is able to penetrate up to 9.4 to 10.6 micrometers. At this wavelength,
7 mm into the skin, it was postulated that water absorbs and converts the energy to heat,
improvement in psoriatic lesions could result leading to local tissue destruction. The device is
from the destruction of deeper vasculature used in soft-tissue surgery in multiple medical
structures. specialties and has rarely been utilized for psoria-
sis due to the high likelihood of adverse events
and plaque recurrence.
Efficacy
Ruiz-Esparza was the first to report the use of Efficacy

Nd:YAG laser in psoriasis in a 1999 case series.
Using a 1320 nm Nd:YAG laser, he treated three Békássy and Astedt were the first to report the
patients with four sessions each and noted use of CO2 laser in the treatment of psoriasis.
improvement in all irradiated lesions. No quanti- Their case series included three patients who
tative measurements or validated scales were underwent vaporization to approximately 1 mm
used in this report [50]. van Lingen et al. com- of multiple plaques after the administration of
pared monthly treatment with 1064 nm Nd:YAG local anesthesia. The lesions were allowed to heal
to daily calcipotriol/betamethasone dipropionate over 4–6 weeks, and remission times of 3–5 years
(CBD) ointment for 3 months in four patients were reported; however, their recovery was com-
using an intrapatient left-to-right study design. plicated by two instances of bacterial superinfec-
Application of CBD ointment was found to sig- tion that required systemic antibiotics [53]. Alora
nificantly improve plaques at weeks 4, 8, and 12 et al. compared the effects of varying the depth of
of the study. Nd:YAG laser treatment using two ablation by using curettage, debridement, and
increasing numbers of CO2 laser passes in sepa- patient left-to-right study comparing PDL and
rate quadrants of individual plaques. In one Nd:YAG laser for the treatment of nail psoriasis
cohort, five of six patients noted recurrence of found no statistical difference between reduc-
their entire plaque within 8 weeks, while the final tions in NAPSI scores between the two modali-
patient noted recurrence after 12 weeks. In the ties when each was combined with calcipotriol/
second cohort, four of six patients experienced betamethasone gel [58].
relapse by 8 weeks, but two subjects experienced
no recurrence 4 months after treatment [54].
Another study compared the effects of CO2 laser References
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Traditional Systemic Therapy I:
Methotrexate and Cyclosporine 9
Erin Boh, Andrew Joselow, and Brittany Stumpf
Abstract Introduction
This chapter will review the traditional sys-
temic drugs, methotrexate and cyclosporine, Psoriasis is a chronic inflammatory disease
both of which are used in treating patients affecting over seven million individuals. It can be
with moderate to severe or recalcitrant psoria- debilitating and associated with systemic co-
sis. The pharmacology and use of these drugs morbidities such as arthritis, hypertension, hyper-
in the treatment of patients with psoriasis will lipidemia and insulin resistance [1–3]. Recently,
be covered as well as the parameters to screen it has been suggested that psoriasis may be asso-
patients, monitoring guidelines and adverse ciated with or part of metabolic syndrome [4–6].
effects associated with each. In addition to topical therapy and phototherapy,
systemic agents, including a newly developed
class referred to as biologics, have been used for
Key Learning Objectives its treatment. Systemic therapies are often
1. To understand the mechanism of action reserved for patients with moderate to severe
of methotrexate and cyclosporine. psoriasis. The goals of treatment are to quickly
2. To understand the appropriate use and effi- clear or reduce psoriatic lesions, to make the
cacy of methotrexate and cyclosporine. patient comfortable by alleviating symptoms and
3. To understand the safety concerns and to provide long-term maintenance with minimal
appropriate monitoring for methotrex- toxicity for the patient.
ate and cyclosporine. In the past, systemic therapy has been used for
those individuals with moderate to severe psoria-
sis as defined by greater than 10% body surface
area or debilitating disease. With the develop-
ment of biologic agents, the treatment algorithm
has changed tremendously, giving us additional
therapeutic options that are potentially less toxic
to the liver, kidneys, and bone marrow and are
not teratogenic. There still remains a place for
E. Boh (*) · A. Joselow · B. Stumpf traditional agents for some patients with moder-
Department Dermatology, Tulane University School ate to severe disease. While the biologics have a
of Medicine, New Orleans, LA, USA very good safety and efficacy profile, they have
e-mail: [email protected]; [email protected]; not totally replaced traditional agents for the
[email protected]

https://doi.org/10.1007/978-3-030-54859-9_9
104 E. Boh et al.
treatment of psoriasis. Traditional systemic ther- being treated with aminopterin, a precursor to
apies continue to play an important role in the methotrexate, Edmunson and Guy first reported
treatment of psoriasis with their oral route of methotrexate’s efficacy in treating psoriasis in
administration and low cost (compared with bio- 1958 [10]. The FDA approved methotrexate in
logics) making them an important treatment 1972 for the indication of psoriasis [11].
option in the appropriate patient. Interestingly, it was not until the early 1980s
Contraindications due to comorbid conditions, that methotrexate was approved for rheumatoid
insurance restrictions as well as cost may be limit- arthritis. Since these early years, methotrexate
ing factors for the use of these biologic agents. has become the “gold standard” for treating
This chapter will review the traditional sys- moderate to severe psoriasis and psoriatic arthri-
temic drugs, methotrexate and cyclosporine, and tis [12]. Over the years, dosing has been modi-
how they can be used as monotherapy or even fied to minimize the toxicity associated with
adjunctive therapy (combination therapy) in methotrexate [7, 8].
treating patients with moderate to severe or recal-
citrant psoriasis.
Mechanism of Action
Methotrexate Methotrexate has anti-proliferative, anti-

inflammatory and immunosuppressive actions.
Introduction As a synthetic analogue of folic acid, methotrex-
ate competitively inhibits dihydrofolate reduc-
Methotrexate is the most widely used systemic tase, an enzyme responsible for conversion of
treatment for moderate to severe psoriasis. The folic acid to reduced folate (tetrahydrofolate)
National Psoriasis Foundation and American (Fig. 9.1). Tetrahydrofolate is required for the
Academy of Dermatology recently published transfer of 1-carbon units in the thymidylate and
detailed dosing and monitoring guidelines [7, purine synthesis pathway [13]. This inhibition
8]. Methotrexate is a synthetic analogue of folic blocks synthesis of deoxythymidylic acid, which
acid, which exhibits immunosuppressive as well is required for DNA synthesis. As a consequence,
as anti-inflammatory properties. It has been methotrexate causes the arrest of cell division in
used successfully to treat psoriasis for over the S phase.
50 years. While Gubner et al. in 1951 [9] first Studies have shown that the anti-proliferative
reported clearance of psoriasis in cancer patients effects of high-dose methotrexate can be reversed
Fig. 9.1 Structure of H

methotrexate (Methotrex N N N
ate|C20H22N8O5 https:// H
pubchem.ncbi.nlm.nih.
gov/compound/
N N
Methotrexate. Accessed
N O
June 14, 2019. Source: H
U.S. National Library of
Medicine) N N
H H H
O
O O
H
9 Traditional Systemic Therapy I: Methotrexate and Cyclosporine 105
by high doses of folic acid, thus supporting the standing, methotrexate appears to have multiple
mechanism of inhibition of DNA synthesis [13, mechanisms of action at play. Methotrexate has
14]. Low-dose methotrexate may exhibit other been shown to help restore a typical immune bal-
mechanisms of action, including anti-inflammatory ance of T-cells by lowering the level of Th1 and
and immunomodulatory effects. This observation Th17 cells and increasing Th2 and T-reg cells –
is supported by the widespread practice by derma- essentially shifting from a pro-inflammatory to
tologists and rheumatologists of administering low an anti-inflammatory T-cell phenotype [19].
doses of folic acid (i.e. 1 mg per day) to patients on
methotrexate to minimize adverse effects without
compromising efficacy [15]. Absorption and Bioavailability
While high-dose methotrexate inhibits DNA
synthesis, primarily through the inhibition of Methotrexate may be given orally, intramuscu-
dihydrofolate reductase, lower doses as used in larly, subcutaneously or intravenously. Food
treatment of psoriasis have more anti-intake does not influence absorption in adults but
inflammatory and immunomodulatory effects. may in children [14]. Once absorbed, methotrex-
These anti-inflammatory effects seem to involve ate is actively transported into cells where it is
the formation of intracellular metabolites of metabolized into polyglutamate imidazole prod-
methotrexate [13, 16]. ucts, which appear to be the more active drug.
Once absorbed, methotrexate is metabolized These products accumulate, resulting in increased
intracellularly to polyglutamate derivatives, adenosine contributing both to toxicity and effi-
potent inhibitors of a number of folate-dependent cacy [16]. Current data suggests that methotrex-
enzymes leading to the accumulation of intracel- ate is metabolized intracellularly, including in the
lular imidazole products. These inhibit adenosine liver, to form polyglutamate metabolites that
deaminase, ultimately resulting in accumulation exert effects on various tissues.
of adenosine [16]. Adenosine suppresses the Peak levels are attained fairly rapidly, approxi-
secretion of inflammatory cytokines by macro- mately one hour after oral administration, slower
phages and neutrophils, as well as diminishes the relative to other modes of administration.
expression of adhesion molecules. Additionally, Absorption after ingestion may be affected by
adenosine, through binding to the A2 receptor, dosing: higher doses having incomplete or vari-
exhibits potent anti-inflammatory effects by able absorption. Steady-state levels of methotrex-
inhibiting neutrophil leukotriene synthesis [13]. ate may be more reliable in smaller doses over the
Activated T cells play a pivotal role in psoriasis, course of 12–24 h one day per week. Plasma lev-
and it appears that methotrexate not only inhibits els have a triphasic response. Once the drug is
DNA replication of these T-cells but also dimin- absorbed, plasma levels decrease rapidly within
ishes antigen-stimulated T-cell proliferation. By the first hour, reflecting distribution throughout
inhibiting mitogen-activated T-cells, these cells body tissues. The second phase of reduction
become more susceptible to apoptosis [17]. reflects renal excretion over the next 2–4 h.
Johnston et al. recently refuted this notion of Importantly, renal function such as glomerular fil-
increased susceptibility to apoptosis [18]. These tration and tubular secretion can significantly
authors propose that methotrexate exerts its affect blood levels. The final phase occurs through
effects through both folate-dependent (decreased slow release from the tissues over 10–27 h after
synthesis of antigen stimulated T-cells) and ingestion reflecting its half-life (T ½).
folate-independent mechanisms (altered adhe- Approximately 50% of methotrexate is trans-
sion molecule expression through alterations in ported bound to plasma proteins. The free or
adenosine). Most likely, the benefits seen involve unbound portion is the active form of the drug.
both processes, and methotrexate should be Plasma levels can be affected by the binding of
viewed as an immunosuppressing and immuno- other drugs to these plasma proteins either
modulating agent. At this point in our under- displacing or blocking methotrexate, resulting in
106 E. Boh et al.
elevated blood levels. Drug interactions will be psoriasis including specific guidance on dosing,
discussed below. route of administration, risk and monitoring of
Orally administered MTX has been found to liver toxicity [8, 24].
have a saturable intestinal absorption and nonlin- There are several important parameters to
ear pharmacokinetics, with significant conse- consider when choosing methotrexate as a form
quences on drug bioavailability and clinical of therapy. These include the severity of the dis-
efficacy. The current evidence shows that paren- ease, the patient’s co-morbidities such as associ-
terally administered MTX results in rapid and ated arthritis, socioeconomic factors, and the
complete absorption, higher serum levels, and ability of the patient to participate in treatment.
less variable exposure than oral dosing. The use As a general rule, methotrexate is suggested for
of parenteral MTX, particularly when adminis- patients with at least 10% body surface area
tered as a subcutaneous (SC) injection, has (BSA) affected, who have failed or can no longer
recently raised great interest in order to overcome perform topical therapy, or who have failed or
the limitations of oral MTX. have contraindications to phototherapy. Absolute
Various clinical experiences have suggested and relative contraindications to methotrexate
that SC MTX is more effective than oral MTX and therapy, listed in Table 9.1, should be reviewed
may provide significant benefit even in patients in carefully and discussed with the patient prior to
whom oral MTX proved to be inadequate. The initiation of the drug. Considerations for patient
increased efficacy of SC MTX resulting from selection should be based on patient history, lab-
higher drug exposure compared with oral MTX oratory findings and co-morbidities. Absolute
has been associated with a similar safety profile contraindications mandate an alternative form of
and in various reports even with a lower frequency therapy. Methotrexate is a teratogen, and women
of gastrointestinal complaints [20]. of childbearing potential should use birth control.
In the future, novel colloidal drug delivery It is contraindicated in pregnancy as well as dur-
systems may provide advantages over prior for- ing breastfeeding. Men should also be counseled
mulations with improved skin permeability and on not impregnating a woman until 3 months off
targeted delivery systems may improve efficacy, therapy. Relative contraindications include Type
and decrease toxicity in psoriasis patients [21].
Table 9.1 Contraindications to methotrexate therapy
Relative
Use in Psoriasis
Absolute contraindications contraindications
Excessive alcohol consumption Renal insufficiency
Methotrexate is FDA-approved for the treatment resulting in liver damage
of moderate and moderate-to-severe psoriasis in Alcoholic liver disease or other Advanced age
adults and psoriatic arthritis [13]. The first treat- chronic liver diseases,
ment guidelines on the use of MTX in psoriasis including hepatitis B or C
Bone marrow abnormalities: Alcohol
were published by Roenigk et al. in 1973 [22]; Anemia, thrombocytopenia, consumption:
and, since that time, many newer treatment leukopenia History of or current
guidelines for the use of methotrexate and other alcohol consumption
systemic agents in psoriasis have been published Immunodeficiency Peptic ulcer disease
[7, 8, 14, 23]. The most recent guidelines for the Nursing mothers Concomitant use of
hepatotoxic drugs
treatment of psoriasis with methotrexate were
Pregnancy Family history of
published by the National Psoriasis Foundation inheritable liver
and by the American Academy of Dermatology disease
in 2019 [7, 8]. Methotrexate hypersensitivity Diabetes mellitus
These guidelines, as well as a systematic Active infection Hyperlipidemia
review of the literature, has led to evidence-based Morbid obesity
recommendations on the use of methotrexate in Active infection
2 diabetes, insulin resistance, alcohol consump- 2.5–5 mg every 2–4 weeks until a response is
tion, obesity and hypertriglyceridemia. As a gen- seen, up to approximately 25 mg weekly, the
eral rule, these patients should be evaluated for maximum recommended dose.
other treatments. Patients with relative contrain- There are published reports suggesting that
dications can use methotrexate with appropriate folic acid protects against gastric upset, nausea,
precautions. For instance, patients with peptic oral ulcerations and may even impact bone mar-
ulcer disease may be treated with concomitant row toxicity, especially in rheumatoid arthritis
proton pump inhibitor therapy. The decision to patients [15].
treat should be based on the patient’s individual A recent study found drug-survival, the time
situation. period of treatment with a specific drug before its
While used to treat psoriatic arthritis for years, cessation, was significantly higher in those
the SEAM-PsA trial is only one of a few studies patients whose methotrexate therapy was supple-
that suggest methotrexate (20 mg/week) is bene- mented with folic acid compared to those who
ficial as a monotherapy in treatment-naïve psori- received methotrexate alone (27.6 months vs
atic arthritis patients or in combination with a 18.5 months, respectively) [27].
biologic [25]. Therefore, a 1 mg per day folic acid supple-
Similarly, Appani et al., found methotrexate ment is recommended based on expert evaluation
initiation (>15 mg/week) resulted in significant [15]. Some practitioners recommend not taking
improvement in dactylitis along with other psori- folic acid on the day patients dose with metho-
atic arthritis symptoms [26]. trexate, but the significance of this has not been
studied.
All dosing schedules should be adjusted to the
Dosing individual patient to obtain or maintain adequate
disease control with minimal side effects. In
Methotrexate is generally given as a single order to ensure some degree of safety, monitoring
weekly oral dose administered over a 12 h period. should be done on a continuous basis.
It is available as a 2.5 mg, 7.5 mg, 10 mg, 15 mg Vena et al. reviewed the current literature on
tablets and an injectable 25 mg/ml solution. use of subcutaneous vs oral methotrexate for
Intramuscular or subcutaneous administration is patients with inflammatory arthritis and psoriasis
helpful when there is gastrointestinal intolerance [20] .These authors concluded that current evi-
to oral dosing or if there are concerns regarding dence indicates that SQ administration of MTX
patient compliance. Subcutaneous injection is is characterized by linear and predictable phar-
equally effective and can be self-administered at macokinetics resulting in higher bioavailability
home. as compared with oral methotrexate, especially
Dosing is equivalent whether the oral or with weekly doses of 15 mg. Subcutaneous MTX
injectable form is used. Many practitioners give a is useful for those with GI intolerability or for
single test dose of 2.5 or 5 mg to evaluate for sig- those individuals who have not gotten maximal
nificant bone marrow suppression or acute response from orally dosed levels of MTX.
hepatic injury in susceptible patients. Although
there are no established maximum or minimum
dosages of methotrexate, weekly dosages usually Monitoring Guidelines
range from 7.5 to 25 mg.
After the test dose of 5 mg of methotrexate, Prior to initiation of methotrexate treatment, the
blood tests (complete blood count with platelets patient should have pretreatment blood tests,
and renal and liver function tests) are obtained including liver function tests, creatinine, hepatitis
5–6 days later. If blood work is within normal B and C screening, tuberculosis screening, a
limits, treatment doses are started at 10–15 mg complete medical history with emphasis on med-
once weekly. Methotrexate can be increased by ications and co-morbidities, and a complete
108 E. Boh et al.
Table 9.2 Monitoring methotrexate guidelines Table 9.3 High risk factors for hepatic toxicity from
methotrexate
Baseline
History and physical Risk factors
Careful review of drug history and evaluation of low History of or current alcohol consumption
risk versus high-risk patients Persistent abnormal liver chemistry studies
Laboratory History of liver disease, including chronic hepatitis B
Complete blood count with differential and platelet or C
counts (CBC) Family history of inheritable liver disease
Comprehensive metabolic panel- renal and hepatic Diabetes mellitus
(CMP) Obesity
Hepatitis B and C screening History of significant exposure to hepatotoxic drugs or
Tuberculosis screening with PPD or blood test chemicals
Serum or urine pregnancy screening Potential significant drug interactions
On-going monitoring Lack of folate supplementation
Periodic review of drug history Hyperlipidemia
Physical exam
Laboratory
CBC with differential and platelets q month for should be drawn at a 5-day interval from the last
3 months then every 3 months dose since values may be elevated 1 to 2 days
CMP q month for 3 months, then every 3 months after ingestion of methotrexate. If a significant
Tuberculosis screening every year persistent abnormality in liver chemistry devel-
ops, methotrexate therapy should be withheld for
1 to 2 weeks and repeat blood work should be
physical examination performed. Patients should performed. Discuss with the patient if any new
be counseled on methotrexate and its potential medications were prescribed or other situations
side effects. Documentation should include the have developed.
type of psoriasis, past treatments, patient’s qual-
ity of life measures, the body surface affected, Liver Biopsy
risk factors for hepatotoxicity and other potential Guidelines for liver biopsy in psoriasis patients
toxicities. Patients taking methotrexate should be were published in 1998 and updated in the
monitored regularly for potential organ toxicity. American Academy of Dermatology (AAD)
Baseline and ongoing monitoring guidelines are guidelines for treatment of psoriasis in 2009 [23,
listed in Table 9.2. 24, 28]. Initially, guidelines suggested liver
Monitoring of the blood parameters should be biopsy at the start of therapy and after every 1.5
done approximately 2–4 weeks after adjusting gram cumulative dose thereafter [28]. The AAD
the dose. It is important to remain at the minimal and National Psoriasis Foundation guidelines for
effective dose and to record the total cumulative monitoring have been updated to differentiate
dose of methotrexate while maintaining disease patients at low risk for hepatotoxicity from those
control and medication tolerance. It is also impor- at high risk [7, 8]. Table 9.3 outlines those patients
tant to consider a liver biopsy in those patients on at high risk for hepatotoxicity. For low-risk
long-term therapy, or those with significant risk patients, methotrexate can be initiated without
for hepatotoxicity. performing a baseline liver biopsy. A liver biopsy
While practitioners have their individual should be performed after approximately a 3.5–
styles of practice, it is advisable to perform a 4.0 gram cumulative dose. High-risk patients
periodic history and physical exam on patients on should obtain a liver biopsy after approximately a
methotrexate therapy to ensure the highest qual- 300–600 mg cumulative dose to ensure a response
ity of care and to minimize potential adverse to therapy before subjecting the patient to the
events. If laboratory abnormalities occur, blood risks of a biopsy. Table 9.4 summarizes the grad-
tests may be repeated and more frequent moni- ing system proposed by Roenigk et al. for inter-
toring may be necessary. Liver function tests pretation of liver biopsy histologic results [28].
Table 9.4 Evaluation of liver biopsy findings [25] FibroSure test uses 10 biochemical markers in
Grade Findings Disposition combination with age, sex, height, and weight.
I Fatty infiltration; mild; Normal The NASH FibroSure test is reported to have a
nuclear variability; mild; Continue sensitivity of 83% and a specificity of 78% in
portal inflammation methotrexate
detecting risk of significant fibrosis and a sensi-
II Moderate to severe fatty Continue
infiltration; moderate to methotrexate tivity of 71% and a specificity of 72% in identify-
severe nuclear variability; ing risk of significant steatosis in patients with
portal tract expansion; NAFLD [29].
portal tract inflammation
Bauer et al. postulate that a liver biopsy can-
and necrosis
IIIA Mild fibrosis; slight Fibrosis not be entirely replaced by the NASH FibroSure
enlargement of portal tracts Discontinue test; they do, however, support the idea that the
without disruption methotrexate number of liver biopsies can be significantly
Repeat biopsy reduced by the use of noninvasive tests such as
sooner
the NASH FibroSure [30].
IIIB Moderate to severe fibrosis; Fibrosis
cirrhosis Discontinue
methotrexate
IV Cirrhosis Cirrhosis Adverse Effects
Discontinue
methotrexate
There are a number of common and uncommon
adverse effects reported with methotrexate usage.
As a general rule, patients with grade I and II can Common minor complaints by patients include
continue methotrexate. Those with grade IIIA fatigue, nausea, vomiting, headache and stomati-
may cautiously continue therapy with more strin- tis. Many of these adverse effects are eliminated
gent monitoring if better alternatives are not by administration of folic acid. If gastrointestinal
available. Only those patients without other symptoms persist, methotrexate can be adminis-
options should continue methotrexate. Patients tered by injection, subcutaneously or intramuscu-
with grade IIIB and IV should discontinue the larly. Dosing may also be administered in divided
drug regardless. It is important to closely work doses over a 24-h period. The three primary areas
with a hepatologist who is also up to date with the of potential major toxicity include hepatotoxic-
current published guidelines. ity, myelopsuppression and pulmonary fibrosis.
Although noninvasive tests for monitoring
MTX-induced hepatic fibrosis have been studied Hepatotoxicity
and shown to be useful in reducing the number of There are both acute and chronic hepatotoxic
liver biopsies, no single test has emerged as a adverse effects. Acute hepatocellular damage, as
replacement for liver biopsy. A family of related manifested by elevated liver enzymes, may result
noninvasive tests for hepatic fibrosis is available; from high blood levels of methotrexate. High
these tests consist of panels of serum biomarkers blood levels occur when the dose exceeds 25 mg
and patient biometrics that are put into patented per week or when levels are increased by a sig-
mathematical models that generate scores predic- nificant drug interaction or displacement of
tive of hepatic fibrosis. bound methotrexate by another medication.
The nonalcoholic steatohepatitis (NASH) Acute hepatocellular damage almost always
FibroSure test (LabCorp) is similar to the results in abnormal liver enzyme studies.
FibroTest used for assessing fibrosis in Hepatitis However, chronic damage to the liver may occur
C infection but was specifically developed for even when liver blood studies remain normal.
patients with NAFLD. With a computational Chronic hepatotoxicity results from the cumula-
algorithm to provide a quantitative surrogate tive effects of methotrexate on the portal system
marker of liver fibrosis, steatosis, and nonalco- resulting in fibrosis. The histologic damage and
holic steatohepatitis (NASH), the NASH subsequent fibrosis can only be assessed by liver
110 E. Boh et al.
biopsy. As discussed above, biopsy of the liver methotrexate therapy as well as monitor while on
can be delayed in those patients who are at low therapy to minimize these risks. If anemia,
risk of hepatotoxicity but should be done at an thrombocytopenia or leucopenia occurs acutely,
earlier interval if the patient is at high risk. The it can be reversed with folic acid administration
histopathologic features of methotrexate-induced or in severe cases, folinic acid (leucovorin) res-
liver toxicity resemble nonalcoholic steatohepati- cue. High dose folic or folinic acid can be given
tis (NASH), a similar pattern observed in patients by mouth or intravenously at doses of 15 mg
who are obese, hyperlipidemic or diabetic. every 6 h for 1 to 2 days or until the methotrexate
Methotrexate likely aggravates preexisting levels approach zero. Administration of daily
steatohepatitis. folic acid while on methotrexate may minimize
As stated, the risk of methotrexate-associated gastrointestinal and liver toxicity, but its impact
liver damage is increased in patients with preex- on the bone marrow toxicity remains controver-
isting risk factors such as obesity and hypercho- sial [15].
lesterolemia. While older studies estimate the
risk of elevated transaminases and elevations Pulmonary Fibrosis
twice the upper limit of normal as nearly 50% Pulmonary fibrosis and interstitial pneumonitis
and 17% respectively, recent studies suggest, may uncommonly occur in patients with psoriasis
with appropriate monitoring and dosing, the risk being treated with methotrexate, but is more com-
may be significantly lower [31]. mon in patients being treated for rheumatoid
In their recent review, Conway et al. [31] arthritis. Pulmonary fibrosis is more commonly
noted a more accurate level of risk for elevated associated with high dose methotrexate therapy.
transaminases and those elevated beyond twice Patients should be monitored for signs and symp-
the upper limit of normal is likely closer to 20% toms such as dry cough, dyspnea at rest and low-
and 1% respectively. grade fever. Other very uncommon pulmonary
Serum assays for assessing liver fibrosis, such complications include cryptogenic organizing
as the measurement of the amino-terminal pep- pneumonia (COP), pleuritis and pleural effusions.
tide of procollagen III, have been used in Europe
as an alternative to liver biopsy but are not cur-
rently available in the United States [32]. Drug Interactions
Currently, there are no blood assays or diagnostic
tests adequate to monitor for chronic liver toxic- Methotrexate has many reported and presumptive
ity other than biopsy or FibroSure testing. drug interactions that may result in decreased or
increased levels of methotrexate and potentiate
Myelosuppression end-organ toxicity. Therefore, it is very important
Myelosuppression is potentially a very signifi- to take a complete medication history as part of
cant toxicity associated with methotrexate admin- pre-methotrexate screening. It is also important
istration. Methotrexate can cause leukopenia, to counsel patients regarding possible drug inter-
thrombocytopenia and anemia. It is usually dose- actions, especially with regards to over-the-
dependent and due to direct toxic action on the counter and commonly prescribed drugs.
bone marrow. Rarely, there is an idiosyncratic Table 9.5 has some of the common potential drug
myelosuppression, which occurs early in treat-
ment. Idiosyncratic reactions may be more likely Table 9.5 Common drug Interactions with methotrexate
in patients with advanced age, renal insufficiency, Trimethoprim Phenothiazines
underlying bone marrow disease, hypoalbumin- Sulfonamides Salicylates
emia, concomitant medications or folate defi- Chloramphenicol NSAIDs
ciency. For this reason, physicians administer the Tetracyclines Systemic Retinoids
test dose of methotrexate. It is imperative to Dapsone Probenacid
screen patients appropriately before starting Phenytoin Triamterene
interactions. There are numerous medications and originally used as an immunosuppressive

that increase or decrease blood methotrexate lev- agent in organ transplantation, it was first shown
els either by displacing it from protein binding to be effective for psoriasis in 1979 [33].
sties, blocking its binding, and altering the Cyclosporine primarily acts by inhibiting T-cell
metabolism of it through the cytochrome P-450 function and interleukin IL-2 via binding to
system. Other medications may also have an cyclophyllin.
additive effect on end-organ damage. The original formulation (Sandimmune) had
considerable variations in absorption and bio-
availability. Newer microemulsion formulations
Cyclosporine (Neoral/ cyclosporine modified) have better and
more predictable bioavailability and are more
Introduction cost effective. Neoral was FDA approved in 1997
for psoriasis and rheumatoid arthritis.
Cyclosporine, a cyclic peptide of 11 amino acids, Cyclosporine is considered safe and effective for
was isolated from the soil fungus Tolypocladium psoriasis. However, there is still reticence about
inflatum Gams in 1970 (Fig. 9.2). CSA is a highly its use in psoriasis. It has a particularly useful
effective and rapidly acting systemic agent for role in managing psoriatic crises due to its rapid
the treatment of psoriasis. Discovered in 1970 onset and its efficacy in treating psoriasis unre-
Fig. 9.2 Structure of

cyclosporine (Cyclospor
ine|C62H111N11O12 https://
pubchem.ncbi.nlm.nih. O
gov/compound/5280754. O H
Accessed June 14, 2019. N N O
Source: U.S. National
Library of Medicine)
H H
N N
O
N N
O
N N
N N O
H
N
O
O
O
H
H
112 E. Boh et al.
sponsive to other modalities, bridging to other transcription of proinflammatory genes, most

therapies, and treating psoriasis within a rota- notably IL-2, and the up-regulation of the IL-2
tional scheme of other medications [34]. receptor [38]. As a consequence, T-cell activation
Appropriate patient selection and monitoring will and production of inflammatory cytokines is
significantly decrease the risks of side effects. impaired. It is now widely accepted that psoriasis
Despite published guidelines for use in psoria- is mediated by these activated T cells and their
sis, there still remains controversy and disagree- cytokine products. Cyclosporine appears to also
ment over treatment strategy and monitoring dampen expression of intercellular adhesion mol-
[34]. In contrast to other traditional agents such ecule (ICAM)-1 on keratinocytes and endothelial
as methotrexate and hydroxyurea, cyclosporine is cells. Cyclosporine also decreases tumor necrosis
not remarkably cytotoxic, does not suppress the factor, a key cytokine in psoriasis pathogenesis,
bone marrow and is not teratogenic. It does have and suppresses the Th17 genes, IL-17, IL-22 and
potential significant renal side effects, including the IL-23p19 subunit, all of which are overex-
hypertension. pressed in psoriatic skin [39].
Numerous clinical trials have demonstrated
the efficacy of CSA in psoriasis. The original
studies evaluating CSA’s efficacy in psoriasis Absorption and Bioavailability
provided evidence that psoriasis is a T-cell driven
immunologic disorder rather than a disorder of Cyclosporine is lipophilic and exhibits very poor
altered keratinocyte growth and differentiation. solubility in water. As a consequence, suspension
CSA given at 2.5 to 5 mg/kg/d for 12 to 16 weeks and microemulsion forms of the drug have been
leads to rapid and dramatic improvement in pso- developed for oral administration and for injec-
riasis in up to 80% to 90% of patients [35]. When tion. The first formulation, Sandimmune, was
dosed at 3 mg/kg/d, CSA leads to a PASI 75 produced in 1983. It had variable and unpredict-
response in 50% to 70% of patients and a PASI able bioavailability among patients secondary to
90 response in 30% to 50% of patients [36]. its high dependence on bile solubility. This was
A large, well-conducted systematic review improved by the introduction of a microemulsion
published in 2016 found no significant difference formulation, Neoral, in July 1995. Several other
in efficacy between CSA and MTX in PASI or cyclosporine modified formulations have subse-
PGA in the treatment of psoriasis [37]. quently been brought to market. The bioavailabil-
ity of generic cyclosporine is approximately 30%
that may be slightly increased with some branded
Mechanism of Action versions. Cyclosporine capsules and liquid oral
formulations are considered bioequivalent. There
Cyclosporine primarily acts by inhibiting T-cell are few published reports comparing bioavail-
function and interleukin (IL-2) [38]. After an ability and efficacy among different generic for-
antigen-presenting cell binds to a T cell, intracy- mulations although the perception that differences
toplasmic levels of calcium increase leading to in these agents exists is prevalent [40]. Since
calmodulin activation of calcineurin phospha- cyclosporine has a narrow therapeutic window,
tase. Calcineurin phosphatase dephosphorylates careful monitoring and consistency in generic
cytoplasmic nuclear factor of activated T cells formulations is required.
allowing translocation into the nucleus and Cyclosporine is absorbed in the small intes-
enabling transcription of proinflammatory genes, tine with peak concentrations occurring from
including IL-2, IL-4, interferon gamma and 1–8 h. The absorption is dependent on bile salts,
transforming growth factor beta. increased with fatty foods. Metabolism is affected
Calcineurin inhibition by a cyclosporine- with concurrent grapefruit juice ingestion [41].
cyclophilin complex prevents activation of calci- Cyclosporine distributes through multiple organ
neurin phosphatase, thus preventing downstream systems, including the skin, and can be found in
breast milk. It crosses the placenta but not the the more severe cases [34]. For reasons not totally
blood brain barrier. understood, dermatologists do not use cyclospo-
Cyclosporine is metabolized by the hepatic rine often for recalcitrant psoriasis and view it
cytochrome P-450 3A4 (CYP3A4) enzyme sys- only as a rescue drug treatment. The drug is very
tem, and almost completely excreted in bile safe to use if proper patient selection is done,
through the feces. The dose may need to be with knowledge of the patient’s co-morbidities
reduced in patients with hepatic insufficiency but and medications and with proper clinical moni-
not in renal insufficiency or with hemodialysis. toring. Since the drug is very effective with rapid
The elimination half-life of cyclosporine is about onset of action, offering dramatic clearance in as
19 h, and its metabolism is age-dependent with a little as 2–4 weeks, it can be used to clear patients
two-fold increase in half-life in adults compared quickly allowing time to plan and transition to a
to children. long-term maintenance regimen. It has also been
used successfully for erythrodermic and pustular
psoriasis. While cyclosporine’s beneficial effects
Use in Psoriasis on psoriasis were first observed during trials for
rheumatoid arthritis, it is not as useful for arthri-
Cyclosporine is FDA approved for severe psoriatis as for psoriasis lesions.
sis, resistant/recalcitrant psoriasis and disabling While not approved for children or pregnant
psoriasis. It has several advantages over other tra- women, cyclosporine has been used with good
ditional oral agents- it has rapid onset of action results in these patient populations. It is consid-
and it is weight based dosing. These features ered category C and should be used with caution
allow for rapid control of flaring psoriasis. in pregnancy and during lactation [45].
Numerous studies have been published on cyclo- Cyclosporine has been associated with low birth
sporine evaluating its efficacy, its comparison to weight (<2500 gm) and prematurity (< 37 weeks)
methotrexate and etretinate, and its long-term when used in renal transplant patients. Limited
maintenance/remission data. In a randomized information is known about the effect of cyclo-
study comparing methotrexate and cyclosporine sporine in pregnant women with psoriasis, who
after 16 weeks, cyclosporine and methotrexate typically are prescribed lower doses. Cyclosporine
appeared to be equally effective, with PASI 75 does not appear to be a teratogen and has been
improvement being 71% and 60%, respectively used in pregnant women with successful out-
[37, 42]. In a study comparing the oral retinoid comes. Overall, it is the authors’ opinion that
etretinate with cyclosporine, PASI 75 improvement cyclosporine is safe to use in high risk psoriasis
was seen in only 47% of patients on etretinate patients during pregnancy if the benefits far out-
compared to 71% on cyclosporine [43]. weigh the risks in severely debilitating disease.
Cyclosporine rapidly controls psoriasis, but rapid However, at this point in time, there are biologics
withdrawal may result in rebound. Open label which appear to be safe to use in pregnancy [46].
studies evaluating discontinuation of cyclosporine If cyclosporine is used in a pregnant patient, the
after one year of therapy with a gradual (1 mg/kg/ mother and fetus should be carefully followed by
wk) taper or abrupt cessation were published in high-risk obstetrician. Cyclosporine has been
1999 and 2001 [35, 44]. No significant rebound used in children and appears to be safe and effica-
was noted in either group, and the median time to cious [47]. Doses are similar to that used in the
relapse was not significantly different. Since more adult population, 2.5–3.0 mg/kg per day in
than 50% of patients will relapse after 4 months, divided doses. Treatment courses should be lim-
new treatments should be added at the time of ited to 6-month intervals [34, 44]. Risks of malig-
taper or once psoriasis returns. nancy and lymphoproliferative disorders seem to
According to recently published recommen- be minimal in children treated for skin diseases
dations by the National Psoriasis Foundation, due to limited courses of therapy and dosages
cyclosporine should be used with caution and for that are below 5 mg/kg/day.
114 E. Boh et al.
Cyclosporine is contraindicated in patients tuberculosis screening, a complete medical his-

with uncontrolled or difficult to control hyperten- tory with emphasis on medications and co-
sion and in those individuals with significant morbidities, complete physical exam and baseline
renal disease or frequent infections. Careful blood pressure measurements. Patients should be
attention should be paid to individuals with a per- counseled on adverse effects and the need for
sonal history of cutaneous malignancies as cyclo- careful monitoring. Baseline and ongoing moni-
sporine can increase the numbers of skin cancers toring guidelines are listed in Table 9.6.
over time. Particular caution should be given Frequent monitoring, especially for iatrogenic
with patients who have had extensive PUVA ther- hypertension and signs of renal insufficiency, is
apy (greater than 200 treatments) as the risk of required [34]. Usually office visits with repeated
nonmelanoma skin cancers, particularly squa- counseling and education parallel the blood eval-
mous cell carcinoma, and melanoma may be uation schedule. If warranted, patients can also
increased [48]. As with methotrexate, the deci- monitor blood pressure at home. The package
sion to use cyclosporine should be made based on insert recommends stopping cyclosporine if the
a patient’s individual situation. blood pressure remains elevated after an attempt
to lower the cyclosporine dose on several occa-
sions. Many practitioners initiate low dose amlo-
Dosing dipine or other calcium channel blocker in
normotensive adult patients for renal protection
Generally, patients are treated with 2.5–3 mg/kg/ [49]. Because of possible permanent damage to
day, usually in divided doses. The package insert the kidney and loss of renal function in patients
suggests dosing at ideal body weight; but, in the on long-term therapy, cyclosporine is a drug that
authors’ experience, dosing is subtherapeutic at requires careful patient selection and subsequent
ideal weights in significantly obese patients. monitoring to be used safely. Therefore, a careful
Dosing may need to be adjusted, especially in the assessment of psoriasis disease severity is critical
first few weeks as bioavailability is variable and when assessing the risk-benefit ratio of treatment
may vary with different generics. Cyclosporine is
best absorbed on an empty stomach in children. Table 9.6 Monitoring guidelines for cyclosporine
However, adult patients can take it with food but Baseline
should be consistent with dosing regimens, same History and physical
time and amount of food ingested. Absorption Careful review of drug history
may even be improved slightly with food in Blood pressure evaluation
adults. Levels may be decreased with grapefruit Laboratory screening
juice [41] in both populations. Unlike transplan- Complete blood count with differential and platelet
counts (CBC)
tation patients, peak and trough levels do not
Comprehensive metabolic panel- renal and hepatic (CMP)
need to be routinely done to ensure adequate
Hepatitis B and C screening
blood levels in psoriasis patients. Levels may be Tuberculosis screening with PPD or blood test
checked if there is a question of compliance or Serum or urine pregnancy screening
issues with absorption. Cyclosporine therapy is On going monitoring at q 2 weeks x 1 then q
generally used on a short-term basis to control 4-weeks x 3 months then q 2 months
severe flares, rarely more than 6–12 months. Periodic review of drug history
Physical exam
BP at every visit and home monitoring if warranted
Laboratory
Monitoring Guidelines
CBC with differential and platelets at 2 weeks then q
month for 3 months then every 2 months
Prior to initiating cyclosporine therapy, the CMP at 2 weeks then q month for 3 months then every
patient should have pretreatment blood tests, 2 months
including creatinine, urinalysis, magnesium, Tuberculosis screening every year
with cyclosporine. With the wide availability of logic complaints, including lowering the seizure
other useful agents for psoriasis, it is reasonable threshold, transient gastrointestinal complaints
to consider an alternative if the blood pressure or and respiratory complaints of cough and rhinitis.
kidney function remains elevated after two read-
ings. Patients on cyclosporine are also immuno- Nephrotoxicity
suppressed and are more susceptible to infections, Nephrotoxicity is the most common and clini-
bacterial, viral and fungal. Patients should be cally significant adverse effect and can present as
examined and screened for these types of infec- acute azotemia or as a chronic, slowly progres-
tion before as well as during treatment. sive renal insufficiency or failure. Although
reversible changes in the kidney may be related
to the vascular effect, long-term therapy may lead
Adverse Effects to permanent scarring with loss of renal function.
Therefore, it is very important to routinely moni-
While the frequency and severity of side effects tor the renal function with a serum creatinine and
is reduced when used at doses for psoriasis, the a urinalysis as well as the blood pressure in
major toxicities associated with cyclosporine patients on cyclosporine. It is important to
remain renal insufficiency and hypertension remember that elderly patients may have a
Table 9.7. The most common side effects associ- decrease in the glomerular filtration rate (GFR)
ated with cyclosporine administration include without a decrease in creatinine. Patients who are
headaches (15%), hypertrichosis (6%), and gin- on cyclosporine for a year are suggested to get an
gival hyperplasia, which is seen more frequently annual GFR. This is not routinely done, since
in transplant patients but can uncommonly occur patients do not usually remain on cyclosporine
in psoriasis patients. Other side effects include for greater than a year at a time. Patients with
hirsurtism, tremor, diarrhea, hypertriglyceride- elevations of serum creatinine greater than 25%
mia, hypomagnesemia, nausea/vomiting, pares- from baseline on two occasions (separated by
thesias and influenza-like symptoms. Blood 2 weeks) should have a 25% to 50% decrease in
abnormalities include hypomagnesemia, hyper- their dosage. If the creatinine level remains ele-
lipidemia and hyperuricemia. As a consequence vated, the cyclosporine dose should once again
of these potential abnormalities, magnesium and be decreased by 25% to 50%. If after these
uric acid levels should be obtained regularly. changes, the creatinine does not return close to
Lipid monitoring is less frequently needed but baseline, cyclosporine should be discontinued.
should be considered in patients on longer treat-
ment periods. Rare side effects include neuro- Hypertension
Hypertension is caused by renal vasoconstriction
and sodium retention, and usually presents early
Table 9.7 Side effects of cyclosporine
in the course of treatment. Dose reduction or
Increased risk of Nausea/vomiting/ addition of an anti-hypertensive such as amlodip-
malignancies diarrhea
Increased risk of infections Flu-like symptoms
ine can ameliorate this adverse effect. Caution
Renal impairment Myalgias the patient that they may experience dependent
Hypertension Lethargy edema, a side effect common to both cyclospo-
Malignancies Hypertriglyceridemia rine and amlodipine. Since amlodipine has been
Headache, tremor, Hypomagnesemia reported to be renal protective in the transplant
paresthesia population on cyclosporine, the addition of amlo-
Cutaneous Hyperkalemia dipine at this juncture is reasonable. In fact, many
Hypertrichosis
Gingival hyperplasia clinicians familiar with using the drug will start
Hyperbilirubinemia amlodipine at low doses such as 5 mg q day even
Worsening acne in normotensive individuals as a prophylactic
Increased risk of infection measure at onset of therapy [49].
116 E. Boh et al.
Table 9.8 Potential cyclosporine (CyA) drug-drug interactions

Drug class Increases CyA Decreases CyA Drug levels increased by CyA
Antiarythmics Amiodarone
CCBa Diltiazem;verapamil Verapamil;diltiazem
Diuretics Thiazodes;furosemide
Antifungals Azoles Griseofulvin
Antibiotics Quinolones;cephalosporins Beta-lactams;
doxycycline nafcillin;rifampin
Anti-HIV Protease inhibitors Efivarenz
Anti-malarials Hydroxychloroquine
SSRIb Fluoxetine;sertraline
Foods Grapefruit
Anti-neoplastic Imatinib;
Steroids Dexamethasone;methylpredniso
lone
Anti-convulsants Phenytoin;phenobarbitol;
valproic acid
Others OCPc Statins
Retinoids Bexarotene
Calcium channel blockers; bSelective Serotonin Reuptake Inhibitors; coral contraceptive pills
a
Drug Interactions statin have been described [50]. Medications that

may potentiate renal toxicity such as aminogly-
Since cyclosporine is metabolized by the hepatic cosides or nonsteroidal anti-inflammatory drugs
CYP3A4 system, a variety of drug interactions as well as medications that may elevate potas-
can occur. Table 9.8 has a list of some common sium levels should be restricted. Given the long
drug interactions seen with cyclosporine admin- list of possible drug interactions, a thorough
istration. Concomitant use of medications metab- medication history must be obtained for all
olized by the CYP3A4 system compete as patients before initiating treatment, and patients
substrates and may increase serum levels and should be educated regarding the introduction of
potentiate toxicity. Induction or inhibition of the new drugs with continued therapy.
enzyme may decrease or increase serum levels, As a general rule, drugs that alter the cyto-
respectively. Foods usually do not affect cyclo- chrome P450 system should be introduced cau-
sporine levels but grapefruit juice increases lev- tiously and potentially nephrotoxic drugs, such
els of cyclosporine by CYP3A4 inhibition. as nonsteroidal anti-inflammatory drugs, amino-
Interactions may also occur with over the counter glycosides, ciprofloxacin, clotrimazole, and
nutraceuticals, herbal and vitamin preparations. fibrates that can impair renal function during
For instance, St John’s wort may decrease cyclo- cyclosporine treatment should be avoided if
sporine concentrations. In patients who have possible.
severe liver disease, metabolism may be
decreased, leading to higher drug levels. Although
heavy alcohol intake increase cyclosporine lev- Summary
els, mild to moderate alcohol consumption has
little effect. Both methotrexate and cyclosporine improve
Cyclosporine is an inhibitor of CYP3A4 psoriasis by decreasing inflammation and sup-
affecting other drugs such as calcium channel pression of T-cell mediated production of inflam-
blockers, erectile dysfunction drugs, and statins. matory cytokines that are known to be pivotal in
Reports of serious rhabdomyolysis occurring in the pathogenesis of psoriasis. While methotrex-
patients who are concurrently treated with a ate and cyclosporine are safe and reliable treat-
ments for psoriasis with proper patient selection 12. Weinstein GD. Methotrexate. Ann Intern Med.

1977;86:199–204.
and monitoring, the risk of serious potential com- 13. Warren RB, Griffiths EM. Systemic therapies for pso-
plications remains. Patients and physicians riasis: methotrexate, retinoids, and cyclosporine. Clin
should be aware of these side effects and discuss Dermatol. 2008;26:438–47.
risks and benefits prior to starting therapy. From 14. Carrerero G, Puig L, Dehesa L, Carrascosa J, et al.
Guidelines on the use of methotrexate in psoriasis.
the physician’s perspective, careful selection of Actas Dermosifiliogr. 2010;101:600–13.
the patient is paramount to eliminate potential 15. Strober B, Menon B. Folate supplemantation during
complications. From the patient’s perspective, methotrexate therapy for patients with psoriasis. J
the importance of follow-up appointments and Amer Acad Dermatol. 2005;53:652–9.
16. Cronstein BN, Naime D, Ostad E. The anti-

appropriate, timely blood monitoring needs to be inflammatory mechanism of methotrexate. Increased
understood. These agents may serve a useful role adenosine release at inflamed sites diminishes leuko-
in bridging patients onto biologics, in those cyte accumulation in an vivo and in vitro model of
patients with a recent history of malignancy or in inflammation. J Clin Invest. 1993;92:2675–82.
17. Genestier L, Paillot R, Fournel S, Ferraro C, Miossec P,
those patients where biologics are contraindi- Revillard JP. Immunosuppressive properties of meth-
cated or not available (Table 9.8). otrexate: apoptosis and clonal deletion of activated
peripheral T cells. J Clin Invest. 1998;102:322–8.
18. Johnston A, Gudjonsson JF, Sigmundsdottir H, et al.
The anti-inflammatory action of methotrexate is not
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Traditional Systemic Therapy II:
Retinoids and Others 10
Vignesh Ramachandran, Ted Rosen,
Misha Koshelev, and Fareesa Shuja Sandoval
Abstract mended for long-term maintenance due to pos-

sible hepatotoxicity. Systemic tacrolimus is
Some patients with psoriasis either do not
best used to treat severe, recalcitrant plaque
respond to or develop significant toxicities
psoriasis; nephrotoxicity limits long-term use.
fromwell-recognized first-line systemic thera-
Though usually used for rheumatoid arthritis,
pies. However, a number of second-line sys-
leflunomide can also be considered in
temic agents may be considered. For example,
treatment-resistant chronic plaque psoriasis or
acitretin is particularly effective in erythroder-
psoriatic arthritis. Penicillin V or erythromycin
mic psoriasis, palmoplantar pustulosis, and gen-
are options for guttate psoriasis when the latter
eralized pustular psoriasis. Since acitretin does
is associated bacterial infection (usually of the
not induce immunocompromise, it can be used
upper respiratory system). Apremilast, a newly
to manage psoriasis associated with HIV infec-
approved treatment for psoriasis and psoriatic
tion. Concomitant ultraviolet B (UVB) or pso-
arthritis, does not induce immunosuppression,
ralen plus ultraviolet A (PUVA) is synergistic
has a good safety profile, does not require lab-
with acitretin. Although not FDA-approved to
oratory monitoring, and is available in a conve-
treat psoriasis, hydroxyurea has demonstrated
nient oral formulation. Nevertheless, its lower
efficacy for chronic plaque psoriasis and, in
efficacy may limit utility.
short bursts, for flares of pustular psoriasis.
Mycophenolate mofetil is used to treat
moderate-to-severe chronic plaque psoriasis,
most often as a maintenance therapy. Key Learning Objectives
6-thioguanine is used to treat plaque psoriasis 1. To understand the mechanism of action
and palmoplantar pustulosis which is resistant of retinoids and other oral agents used
to other systemic agents, but is not recom- in the treatment of psoriasis.
2. To understand the appropriate use and
efficacy of retinoids and other oral agents
V. Ramachandran · T. Rosen (*)
used in the treatment of psoriasis.
Department of Dermatology, Baylor College of
Medicine, Houston, TX, USA 3. To understand the safety issues and

appropriate monitoring for retinoids and
M. Koshelev
University of Texas, McGovern Medical School at other oral agents used in the treatment
Houston, Houston, TX, USA of psoriasis.
F. S. Sandoval
Westlake Dermatology, Austin, TX, USA

https://doi.org/10.1007/978-3-030-54859-9_10
120 V. Ramachandran et al.
Psoriasis affects 1 in 50 individuals with mani- factors within cells. However, beyond this, thehe
festations appearing in the skin, nails, and joints exact mechanism of action of acitretin in psoria-
[1]. Patients with psoriasis are most commonly sis is unknown though it is likely related to its
treated with topical agents, which is effective in ability to decrease epidermal proliferation and
70–80% of patients [2]. Systemic treatments tend induce differentiation [4].
to be reserved for patients with more than 10%
body surface area (BSA) involvement or severe
psoriasis of the scalp, palms and soles, genitalia, When Best to Use
or intertriginous sites. Even in this era of biolog-
ics, traditional systemic therapies remain both Acitretin is one of the suggestedtreatments for
useful and appropriate.These drugs offer compar- relatively stable generalized pustular psoriasis
atively inexpensive, oral alternatives with well- and is an effective treatment for less acute patients
known short and long-term risks [3]. Although with exfoliative erythrodermic psoriasis [11]. It
methotrexate and cyclosporine are recognized is also a suggested traditional systemic for pso-
first-line treatments for psoriasis, patients who do riasis in the setting of human immunodeficiency
not respond or who develop toxicities are candi- virus (HIV) infection due to its lack of immu-
dates for alternative second-line systemic agents. nosuppression [12]. In palmoplantar pustulosis,
In this chapter, we provide a clinically-oriented acitretin is commonly used to ameliorate hyper-
summary of several second-line systemic agents keratosis and decreases pustulation. In acitretin-
used in the treatment of psoriasis. Specifically, the responsive patients with chronic plaque psoriasis,
medications discussed herein are: acitretin, hydroxy- it can be an effective maintenance therapy [11].
urea, mycophenolate mofetil (MMF), thioguanine Acitretin can safely be combined with pho-
(6TG), systemic tacrolimus, leflunomide, penicillin totherapy to potentiate its efficacy. Additionally,
V, erythromycin, and apremilast (Fig. 10.1, 10.2, and it may be used in combination with biologic
10.3). In doing so, we hope to aid clinicians navigate therapies, including etanercept (resulting in
the myriad of alternative tradiational systemic treat- reduced etanercept dosing) and adalimumab.
ment options within the patients’ clinical contexts Randomized, controlled trial evidence is lacking
with an evidence-based understanding of best use for its use in combination with other biologics
practices, side effects, monitoring, and efficacy. [13]. Although seemingly contraindicated by the
acitretin prescribing information which warns of
the risk of hepatotoxicity, acitretin and metho-
Acitretin trexate have been combined when monotherapy
was inadequate, particularly in cases of general-
FDA-Approved Indication(s) ized pustular psoriasis. It is crucial to monitor
liver function closely with this combination [4,
Acitretin is FDA-approved for the treatment of 14]. Acitretin has been used with cyclosporine
severe psoriasis in adults [4]. In women of child- for short-term treatment albeit with frequent
bearing potential, acitretin is only advised for non- monitoring of lipids. Acitretin has also been
pregnant individuals who do not respond to other combined with hydroxyurea to treat recalcitrant
psoriasis medications or have c ontraindications palmoplantar pustulosis.
to their use. The FDA recommends its prescrip-
tion by physicians knowledgeable in the use of
systemic retinoids [4]. Dosage
The general acitretin dose ranges from 10 to

Mechanism of Action 50 mg daily, administered with meals [4, 15].
Generalized pustular psoriasis typically requires
Acitretin interacts with with cytosolic proteins an acitretin dose of 25–50 mg [8]. After clinical
and nuclear factors, which act as transcription response, the dose is tapered to 10–25 mg daily.
10 Traditional Systemic Therapy II: Retinoids and Others 121
OH
O
Acitretin
S
O
H
N
N
HO
N
H NH2
N
H2N N
Hydroxyurea H
6-Thioguanine
HO
OH
N O
O
O
O O
HO
Tacrolimus
Fig. 10.1 Chemical structures of acitretin, hydroxyurea, 6-thioguanine, and tacrolimus; adapted from the package
inserts for the corresponding medications [4–7]
O
S
NH O
H
N
O
+ – NH
O
N K
O
F O
O
F F
Leflunomide
Penicillin V
Potassium
OH
HO
O
HO
O
O O
OH
O O O
O N
OH
Erythromycin
Fig. 10.2 Chemical structures of leflunomide, penicillin V potassium, and erythromycin; adapted from the package
inserts for the corresponding medications [7–10]
Exfoliative erythrodermic psoriasis requires an [4, 15]. Maximal response is usually seen after
acitretin dose of 25–50 mg daily [15]. 3–6 months of treatment [15].
Clinical trials have employed varying acitre- Two randomized, controlled trials (8-week and
tin doses to treat chronic plaque psoriasis. A 16-week) assessed the efficacy acitretin (10 mg,
daily dose of 25 mg or less minimizes adverse 25 mg, 50 mg, 75 mg) compared to placebo in the
events. Initiation of therapy should begin with treatment of moderate-to-severe plaque psoriasis
a low dose with progressive uptitration to avoid [13]. Low-dose treatment was defined as approx-
an initial disease flare and to improve tolerability imately 25 mg/day, whereas high-dose treatment
O Table 10.1 Frequency of selected adverse events

reported in clinical trials of acitretin [4, 15]
Percent of patients
O O reporting event(s) Adverse event(s) reported
More than 75% Cheilitis
50–75% Alopecia
N O Skin peeling
O 25–50% Rhinitis
S Xerosis
O Nail disorder
O NH
Pruritus
10–25% Rigors
Xerophthalmia
Xerostomia
Fig. 10.3 Chemical structure of apremilast (OTEZLA®) Epistaxis
Arthralgia
Spinal hyperostosis
was defined as approximately 50 mg/day. The Erythematous rash
studies showed that, overall, low-dose acitretin is Hyperesthesia
not only safer than high-dose acitretin, but may Paresthesia
also be more efficacious in treating psoriasis. Paronychia
Skin atrophy
Sticky skin
Adverse Events Less than 10% Nausea
Abdominal pain
Decreased night vision
Acitretin is associated with a number of adverse
Headache
effects (Table 10.1). Many of the common events Myalgia
are related to increased epidermis turnover, dry-
ing of the skin, and their related sequelae.
The average half-life of acitretin is 49 hours
and that of its isomer cis-acitretin is 63 hours;
Recommended Monitoring however, in the presence of alcohol, etretinate,
whose average half-life is 120 days, can form.
Obtain a history and physical examination, CBC Etretinate has been detected 2.1–2.9 years after
with platelets, BUN/Cr, LFTs, lipid profile, and a stopping therapy, most likely due to storage in
pregnancy test if indicated before starting acitre- fatty tissue. This is why acitretin is contraindi-
tin [14, 15]. The clinician should perform a phys- cated in women who plan to become pregnant
ical examination and obtain a CBC with platelets, within 3 years of stopping the medication and is
BUN/Cr, LFTs, and lipid profile monthly for the given with extreme caution (if at all) in women of
first 3–6 months, then every 3 months [14]. BUN/ child-bearing potential. Patients are also advised
Cr and CBC with platelets may be ordered every against donating blood from the initiation of
other monitoring period if desired. Pregnancy treatment to 3 years after discontinuation. Fetal
tests may be done monthly, if indicated. abnormalities reported with retinoid use include
meningomyelocele, meningoencephalocele,
decreased cranial volume, and cardiovascular
Perils and Pitfalls malformations [4, 15].
Acitretin may interact with a number of medi-
Acitretin is contraindicated in patients with cations. It interferes with the contraceptive effects
hypersensitivity to retinoids, chronically elevated of the microdose progestin minipill [4, 15]. When
lipids, severely impaired kidney or liver func- given with tetracyclines, the combination raises
tion, nursing mothers, and pregnant women [4]. the risk of increased intracranial pressure and
manifest pseudotumor cerebri [4]. Acitretin can after 1 month depending on clinical response; the
potentiate the glucose-lowering effects of gliben- mean dose was 0.4 mg/kg/day. After 4 months,
clamide and may reduce phenytoin protein bind- the mean PASI reduction was 59.4% [18].
ing. Acitretin should not be given with other oral There are no head-to-head trials comparing
retinoids nor with excessive vitamin A supple- the effectiveness of acitretin to methotrexate or
mentation to avoid hypervitaminosis A [4, 15]. cyclosporine in the treatment of chronic plaque
Hepatobiliary abnormalities such as elevated psoriasis, but it is the American Academy of
serum bilirubin and transaminases, toxic hepati- Dermatology’s general consensus acitretin is
tis, acute reversible hepatic injury, and cirrhosis a less effective monotherapy [15]. However, a
have been associated with acitretin [1]. In clini- head-to-head comparison between cyclosporine
cal trials, 66% of patients treated with acitre- and etretinate, the pro-drug of acitretin which is
tin had triglyceride elevations; of note, these unavailable in the United States, demonstrated
patients were likely to have increased alcohol cyclosporine was more efficacious in the treat-
intake, diabetes mellitus, obesity, pre-existing ment of severe plaque psoriasis [19].
disturbances of lipid metabolism, or a family Acitretin has been studied in the treatment of
history of these conditions. Acitretin-induced palmoplantar pustulosis [11, 20]. A randomized,
serum triglyceride levels above 800 mg/dL have open-label study of67 patients with palmoplan-
been associated with fatal fulminant pancreati- tar pustulosis assessed the efficacy of acitretin.
tis. Acitretin-induced pancreatitis without an Patients received 10 mg/day for 4 weeks followed
increase in serum triglycerides has also been by dosage adjustment based on clinical response
reported. Forty percent of patients treated with for 8 weeks. After the 12 weeks, patients had an
acitretin in clinical trials had decreased HDL average of 3.9 pustules compared to their average
levels and one-third had serum cholesterol ele- of 57.8 at baseline [20].
vations. Changes in lipid levels resolved after Acitretin is more efficacious when com-
stopping acitretin. Thromboembolic events, bined with phototherapy [15]. A randomized,
acute myocardial infarction, and pseudotumor controlledstudy of patients with moderate-to-
cerebri have been reported, as have depression, severe psoriasis (20–80% BSA) assessed the
thoughts of self-harm, aggressive feelings, and efficacy of broadband-UVB (bb-UVB) with
other psychiatric symptoms. Adults receiv- acitretin or placebo. Overall, combinational
ing acitretin have rarely experienced abnormal therapy led to 74% reduction in psoriasis sever-
ossification. ity scores after 12 weeks comparedto 42% reduc-
tion in patients treatedwith acitretin alone and
35% reduction with UVB alone [21]. Another
Strength of Evidence multicenter, randomized, controlled trial of 82
patients with severe psoriasis (chronic plaque or
Acitretin can be an effective short and long- examthematic-type pustular variant) investigated
term therapy for chronic plaque psoriasis [16]. A the efficacy of acitretin plus UVB compared to
multicenter trial of 37 adults treated with acitre- placebo plus UVB. Treatment-group patients
tin for psoriasis was conducted for 12 months took 35 mg acitretin daily for 4 weeks followed
with 10 mg dose adjustments (up or down, range by 25 mg acitretin daily plus BB-UVB [22].].
10–70 mg daily) occurring monthly. Seventy- PASI decreased on average by 79% with acitretin
nine percent of patients achieved PASI 75 [17]. and UVB compared to 35% in the control group
A prospective study enrolled 17 patients with (placebo and UVB). Median cumulative UVB
plaque psoriasis who had failed treatment with dose needed to reach 75% improvement was
methotrexate, cyclosporine, or PUVA, or had at 41% lower for the acitretin and UVB group than
least 10% BSA involvement to assess the efficacy for the placebo and UVB group [22]. It is impor-
of acitretin [18]. Acitretin was started at 0.3 mg/ tant to note these older studies utilize BB-UVB
kg/day and could be increased to 0.5 mg/kg/day in lieu of narrow-band (nb-UVB), which is the
more readily available and commonly used UVB Hydroxyurea

regimen in most practices.
Combination therapy with biologics are lim- FDA-Approved Indication(s)
ited. However, a randomized, controlled, double-
blinded study investigated acitretin alone versus Hydroxyurea (HYDREA®) is FDA-approved as a
etanercept alone versus acitretin with etanercept treatment for resistant chronic myeloid leukemia
for patients with moderate-to-severe plaque pso- and locally advanced squamous cell carcinomas
riasis. Over six months, twenty patients received of the head and neck (excluding lip) in combina-
0.4 mg/kg oral acitretin daily, 22 patients received tion with concurrent chemoradiation [5]. Another
25 mg etanercept subcutaneously twice perweek, formulation of hydroxyurea (DROXIA®) is FDA-
and 18 patients received 0.4 mg/kg oral acitretin approved for reduce the frequency of painful cri-
daily with etanercept 25 mg subcutaneously once ses and to reduce the need for blood transfusions
a week. Thirty percent of patients in the acitrein adult patients with sickle cell [26].
tin group achieved PASI 75, compared to 45% of
patients treated with etanercept alone and 44% of
patients treated with both etanercept and acitre- Mechanism of Action
tin. Overall, it appears acitretin is less effective
than etanercept. Adding acitretin to etanercept The precise mechanism of action of hydroxy-
achieves an efficacy rate similar to that of etan- urea in psoriasis is unknown [5, 15, 27, 28].
ercept alone. The results, however, may bedrug- Hydroxyurea inhibits ribonucleotide reductase
dose-dependent [23]. and suppresses DNA synthesis, which is thought
There are limited other clinical trial studies to contribute to an anti-proliferative role in
assessing acitretin in psoriasis. A multicenter, psoriasis.
randomize, controlled, double-blinded trial of
108 moderate-to-severe plaque psoriasis patients
assessed the efficacy of acitretin alone (with pla- When Best to Use
cebo) or in combination with “total glucosides
of paeony” (TGP), a Chinese traditional herbal Hydroxyurea has been given to patients with
medication. After 12 weeks, the treatment group moderate-to-severe chronic plaque psoriasis who
treated with added TPG achieved PASI 50 in have received the recommended cumulative dose
90% of patients compared to 70.5% in the con- of methotrexate or who cannot tolerate adverse
trol group (P < 0.05 [24]. Similarly, in another events related to methotrexate [29]. Hydroxyurea
randomized, controlled, double-blinded trial of has also been used with low-dose cyclosporine in
15 patients with moderate-to-severe plaque pso- short-course therapy to treat recalcitrant, severe
riasis were treated with acitretin with or with- psoriasis and with acitretin to treat recalcitrant
out curcumin (main active constituent of the palmoplantar pustulosis [30]. Hydroxyurea
rhizome of turmeric with various anti-inflam- may also be beneficial in generalized pustular
matory, anti-
proliferative, and anti-angiogenic psoriasis [27].
effects) nanoparticles. At the end of the study
period (12 weeks), higher percentages of patients
treated with the adjuctive curcumin nanoparticles Dosage
achieved PASI 50 (93% versus 66%), PASI 75
(43% versus 20%), and PASI 90 (36% versus Hydroxyurea is initiated at a dose of 500 mg
13%) compared to the control arm (all P < 0.001) twice daily, and increased to 3 g daily (total) as
[25]. These results must be reproduced with tolerated. Dosing at 3–4.5 g weekly has also been
larger cohorts and assessed for possible unac- used [15, 27, 29]. The senior author has utilized
counted confounding factors to establish the hydroxyurea as a short-term “rescue” drug dur-
strength of this data. ing flares of von Zumbusch pustular psoriasis,
starting at 3 g as a daily dose and decreasing by Perils and Pitfalls

500 mg daily, for a 1 week total course.
Hydroxyurea is contraindicated in patients with
known hypersensitivity to hydroxyurea and
Adverse Events in patients with leukopenia, severe anemia, or
thrombocytopenia. Additionally, it is also con-
Hydroxyurea is associated with a number of traindicated during pregnancy and in nursing
adverse events, most of which are related to cell mothers [5, 15]. Hydroxyurea may raise uric
turnover/production of highly proliferative cell acid levels and require changes in the doses of
types including the bone marrow and gastrointes- uricosuric medications to prevent gout flares [5].
tinal tract (Table 10.2). Severe peripheral neuropathy, fatal and nonfatal
pancreatitis, hepatotoxicity and fatal hepatic fail-
ure have been described in HIV patients given
Recommended Monitoring hydroxyurea and didanosine with or without
stavudine [31]. These adverse events are rare in
Before starting hydroxyurea, the clinician should normal hosts.
obtain a good history,perform a general physical Patients given long-term hydroxyurea have
examination, and obtain laboratories (CBC and reportedly developed both lymphoma and non-
pregnancy test) (if indicated) [9]. Weekly CBCs melanoma skin cancer. In patients treated with
are obtained until a stable dose is achieved. hydroxyurea for myeloproliferative disorders,
Thereafter CBCs are obtainedmonthly as long secondary leukemia has developed. These
as treatment with this agent is continued. Repeat patients have also developed gangrene and vas-
physical examination, focusing on skin cancer culitic ulcerations, but most were simultaneously
and checking for enlarged lymph nodes, should receiving interferon. Self-limiting megaloblastic
be done biannually. Periodic pregnancy testing is erythropoiesis may occur early in the course of
performed if indicated. hydroxyurea therapy.
Myelosuppression may occur in patients
treated with hydroxyurea. Leukopenia generally
Table 10.2 Selected adverse events reported with the use occurs first, followed by anemia or thrombocy-
of hydroxyurea; events reported in psoriasis patients are
topenia. Bone marrow recovery is rapid when
marked with an asterisk [9, 19, 20, 22, 23]
treatment is stopped. Increased myelosuppres-
Myelosuppression, including anemia*, leukopenia*,
and thrombocytopenia*
sion may be seen when hydroxyurea is used con-
Gastrointestinal symptoms, including diarrhea*, currently with radiotherapy or myelosuppressive
aphthous ulcers*, nausea, vomiting, constipation, drugs [15].
anorexia, and stomatitis
Dermatological symptoms, including nail
pigmentation*, alopecia*, pruritus*, dermatomyositis-
like skin changes, rash, and ulceration
Strength of Evidence
Systemic symptoms, including edema*, asthenia,
chills, malaise, and fever A comparative study of methotrexate to
Neurologic symptoms, including hallucinations, hydroxyurea in 30 patients (15 in each treatment
dizziness, headache, disorientation, and convulsions group) assessed the efficacy of these treatments
Serum creatinine, BUN, and uric acid elevations with for moderate- to-severe plaque psoriasis [29].
temporary impairment of renal tubular function
Patients had ≥20% BSA involvement and a PASI
LFT elevations
Rare pulmonary fibrosis of ≥10. In the methotrexate group, patients given
Rare dysuria 15 mg of the medication weekly for 4 weeks; the
Nonfatal and fatal pancreatitis and hepatotoxicity, dose was then increased up to 20 mg weekly
severe peripheral neuropathy in HIV patients given in patients with less than 25% PASI reduction.
hydroxyurea with other antiretrovirals Patients receiving hydroxyurea were given
500 mg twice a day on two consecutive days for Mycophenolate Mofetil (MMF)
1 week, then 500 mg three times a day on two
consecutive days for 3 weeks. After 4 weeks, FDA-Approved Indication(s)
patients with ≤25% PASI reduction were given
500 mg three times a day on three consecutive MMF is FDA-approved in combination with cor-
days. Overall, 10/15 patients (66.7%) treated ticosteroids and cyclosporine to prevent organ
with methotrexate and 2/15 patients (13.3%) rejection in liver, heart, and kidney transplant
treated with hydroxyurea achieved PASI 75 patients [34].
at 12 weeks (P < 0.05). Though most patients
treated with hydroxyurea did not achieve PASI
75, they did have a mean PASI reduction of Mechanism of Action
48.47% while experiencing fewer adverse events
than the methotrexate group [29]. However, a MMF is hydrolyzed to its active metabolite,
short-term (8-week) comparative study of meth- mycophenolic acid, which inhibits de novo gua-
otrexate (control) and hydroxyurea treatment nosine nucleotide synthesis and selectively sup-
in 24 patients with moderate-to-severe plaque presses lymphocyte growth and division [34]. As
psoriasis [28]. The results of this study dem- a result, psoriasis, a T-cell mediated inflamma-
onstrated that although the PASI scores before tory disorder, is thought to be responsie to MMF
and after treatment in each group significantly for this reason.
decreased (P < 0.05), there was no difference in
mean percentage change of PASI scores between
the groups (P > 0.05) [32]. When Best to Use
A prospective study of 34 patients with
moderate-to-severe plaque psoriasis, erythroder- MMF is utilized to treat moderate-to-severe
mic, or generalized pustular psoriasis refractory chronic plaque psoriasis in patients who cannot
to topical treatments and methotrexate under- tolerate any of the various first-line agents [35].
went a regimen of hydroxyurea to assess its MMF can be given with cyclosporine, making it
efficacy in treating their condition [27]. Patients useful as both a bridge and maintenance therapy
were initiated on 500 mg hydroxyurea twice for patients needing cyclosporine for acute dis-
daily. If hydroxyurea was tolerated and PASI ease control [36].
reduction was less than 25% after 2 weeks, it
was increased to 1.0 and 1.5 g on alternate days,
and then to 1.5 g daily as tolerated. If greater Dosage
than 95% clearance was achieved, treatment was
tapered over 4–8 weeks. Mean PASI reduction MMF can be given as 1.0–2.0 g twice daily [35].
was 76% at 10–12 weeks. Three patients devel-
oped leukopenia which recovered after discon-
tinuing treatment. Five patients relapsed within Adverse Events
12 months [27]
A prospective, non-randomized sries of 31 Psoriasis patients given MMF reported abdomi-
patients (including 26 with history of systemic nal cramping, diarrhea, nausea, elevated LFTs,
psoriasis therapy) were given hydroxyurea 1.0– severe hyperbilirubinemia, severe hypertension,
1.5 g per day for mean follow-up of 36.1 weeks life-threatening hyperuricemia, life-threatening
(+/− 13.8). At or before 8 weeks, nearly 75% hypokalemia, periorbital edema, urticaria, furun-
of the cohort demonstrated adequate response culosis, and pruritus [35, 37, 38]. Transplant
(defined ≥35% PASI reduction), and over50% of patients given MMF reported vomiting, geni-
patients showed >70% PASI reduction [33]. tourinary urgency, genitourinary frequency,
dysuria, sterile pyuria, headaches, insomnia, disease [34]. Adults given prolonged courses of
peripheral edema, hypercholesterolemia, hypo- MMF haveincreased risk of skin cancer, espe-
phosphatemia, and hyperkalemia [15, 34]. cially squamous cell carcinomas Fatal cases of
progressive multifocal leukoencephalopathy
(PML) with the use of MMF were reported in
Recommended Monitoring patients with risk factors such as pre-existing
immune function impairment and treatment with
The clinician should obtain a history andphysical other immunosuppressants [39].
examination. Baseline labs should includeCBC
with differential, serum chemistry panel, LFTs,
and pregnancy test (if indicated) before starting Strength of Evidence
MMF [15, 34]. After initiation of therapy, com-
plete blood and platelet counts should be checked A randomized, open-label clinical trial evaluated
weekly for 1 month, then every 2 weeks for the efficacy and safety of MMF versus metho-
2 months, then monthly thereafter. It is wise to trexate in patients with chronic plaque psoria-
also obtain serum chemistries and LFTs monthly, sis (PASI score of at least 10) and a history of
a physical examination focusing on skin cancer inadequate response to topical therapies [35].
and lymph nodes biannually, and ongoing preg- Seventeen patients received MMF 1 g twice daily
nancy tests (if indicated) [39]. for 12 weeks. Fifteen patients received methotrex-
ate 7.5 mg/week for 1 week, then 15 mg/week for
3 weeks, and then 20 mg/week for 8 weeks. Ten
Perils and Pitfalls of 17 patients (58.8%) in the MMF group and 11
of 15 patients (73.3%) in the methotrexate group
MMF is contraindicated in patients with hyper- achieved PASI 75 (P > 0.05) [35].
sensitivity to MMF or mycophenolic acid, during Another randomized open-label clinical trial
pregnancy, and in nursing mothers [34]. MMF evaluated the efficacy of MMF versus cyclospo-
can cause first trimester spontaneous abortions rine in chronic plaque psoriasis patients with a
and fetal malformations [25]. It can interact PASI score of at least 10 [28]. Sixteen patients
with acyclovir, ganciclovir, valganciclovir, pro- received MMF 1 g twice daily for 6 weeks. Then
benecid, xanthine bronchodilators, high-dose they received 500 mg MMF twice daily if they
salicylates, cholestyramine, phenytoin, antibiot- had 60% or greater PASI reduction, 1 g MMF
ics, calcium, iron, and aluminum or magnesium- twice daily if they had 25–60% PASI reduc-
containing antacids [15]. Since the effects of tion, and 1.5 g MMF twice daily if they had
these other medications on MMF are varied, it 25% or less PASI reduction. Twenty-one patients
is recommended to consult the FDA-approval received 1.25 mg/kg cyclosporine twice daily for
documentation to assess impact on bioavailabil- the first 6 weeks, and then either 1.25 mg/kg once
ity and subsequent efficacy [34]. daily, 1.25 mg/kg twice daily, or 2.5 mg/kg twice
Patients given MMF have developed severe daily based on PASI reduction thresholds identi-
neutropenia. Two percent of kidney and heart cal to those in the MMF group. After 12 weeks,
transplant patients and 5% of liver transplant mean PASI decreased from 22.4 to 10.6 in the
patients given MMF in clinical trials developed MMF group and from 24.6 to 6.6 in the cyclo-
fatal infection/sepsis. Live attenuated vaccines sporine group [37].
should not be given to patients taking MMF [15, Use of concomitant MMF and cyclosporine to
34]. Pure red cell aplasia, anemia, leukopenia, treat severe recalcitrant psoriasis was described
and thrombocytopenia have also been reported. in nine patients who failed to clear on cyclospo-
Between 0.4% and 1% of transplant patients rine alone or could not tolerate higher cyclo-
given MMF with other immunosuppressive drugs sporine doses [36]. Three patients showed good
developed lymphoma or lymphoproliferative clinical improvement and four patients showed
moderate disease control after a follow-up period When Best to Use

of 3–11 months. No additional toxicity was
seen after starting MMF in patients already tak- 6TG can be used to treat plaque psoriasis and
ing cyclosporine. Notably, this study included a palmoplantar pustulosis resistant to more com-
patient with erythrodermic psoriasis and another monly utilized systemic agents or when these
with generalized pustular psoriasis [36]. other agents are contraindicated [39]. It may be
An open-label pilot study involving 20 patients considered a third-line systemic traditional sys-
with psoriasis (PASI >10) assessed the efficacy temic treatment [39].
of enteric-coated mycophenolate sodium 720 mg
twice daily for 6 weeks followed by 360 mg twice
daily for another 6 weeks. By week six, none of Dosage
the patients achieved PASI 75. However, 8/20
(40%) of patients achieved PASI 50. By week 12, 6TG is given two to three times per week to
2/8 (25%) of patients achieved PASI 75. Some reduce the risk of myelosuppression [42, 43]. The
patients in the cohort did relapse (4/13 by week starting dose is 80 mg twice per week; the dose
12). Twenty-five percent (2/8) achieved a PASI is increased by 20 mg every 2–4 weeks [15]. The
75% in week 24 [40]. maximum dose is 160 mg given up to three times
Another study compared the efficacy of MMF per week.
to cyclosporine in 80 patients with chronic plaque
psoriasis via a prospective, sequential, cross-
over, non-randomized, two-phase, open-label Adverse Events
study. Both treatments were efficacious, result-
ing in decreased in PASI scores from baseline. According to various reports, 22–68% of psoria-
However, cyclosporine was faster to produce sis patients given 6TG develop myelosuppression
results and produced more significant decreases [43, 44]. Up to 12% of patients given the drug
in PASI scores (45.7%, 60.2% and 60.5% at 3, reported gastrointestinal adverse events, includ-
8 and 16 weeks respectively for mycophenolate ing nausea, vomiting, aphthous ulcers, gastric
mofetil compared to 89.7%, 95.3% and 95.3%, ulcers, gastroesophageal reflux, and dysgeusia
respectively, for cyclosporin) [41]. [15, 43, 44]. One quarter of patients treated with
6TG for psoriasis experienced LFT elevations
[15, 43]. Patients treated with this agent also
6-Thioguanine (6TG) developed headaches, fatigue, photodermatitis,
herpes zoster, multiple warts, hyperuricemia,
FDA-Approved Indication(S) hepatic veno-occlusive disease, portal hyperten-
sion, and non-melanoma skin cancer [15, 43, 44].
6-thioguanine (6TG) is FDA-approved to induce Psoriasis patients treated with 6TG have rarely
and sustain remission in patients with acute non- developed hepatotoxicity; in the event that this
lymphocytic leukemia, most commonly in com- adverse event does occur, stopping treatment
bination with other chemotherapeutic agents [6]. leads to resolution [6, 15, 42, 43].
It is not recommended for long-term treatment
due to a significant risk of hepatotoxicity.
Recommended Monitoring
Mechanism of Action The clinician should obtain a history and physical

examination.Laboratory evaluation entails CBC
6TG is a purine nucleotide analogue that inter- with differential, serum chemistry panel, LFTs,
feres with nucleic acid synthesis, curtailing cel- hepatitis B and C tests, tuberculosis screening,
lular proliferation [6]. and pregnancy test (if indicated) before initiating
6TG therapy [6, 15]. After starting treatment, a An open-label study of 14 patients with severe,
CBC with differentialshould be checked every recalcitrant plaque psoriasis investigated the effi-
2–4 weeks, serum chemistries every 3 months, cacy of pulse-dosing 6TG. Two-to-threetimes per
and a physical examination focusing on lymph week (120 mg twice a week to 160 mg 3 times a
nodes and skin cancer biannually; periodic preg- week) resulted in marked improvement in 10 of
nancy tests should be performed, if indicated [15]. 14 (71%) patients [43].
A retrospestive study of 81 patients (76 plaque
psoriasis, 6 palmoplantar pustulosis) treated with
Perils and Pitfalls 6TG was reported on to assess this medication’s
efficacy [45]. Overall, 78% of patients had com-
6-thioguanine is contraindicated in patients with plete or almost complete clearing, 11% had some
known hypersensitivity to the drug. It is also improvement, and 11% had little or no change in
contraindicated in patients with liver disease, their psoriatic lesions. Four out of five patients
immunosuppression, anemia, leukopenia, and/ with palmoplantar pustulosis had complete or
or thrombocytopenia. Pregnant patients and nurs- almost complete clearing. Patients maintained
ing mothers are also contraindicated from taking their response for 3–145 months (mean = 33).
6TG [6, 12]. The most commonside effect was myelosuppres-
The cytoplasmic enzyme thiopurine meth- sion [45].
yltransferase (TPMT) metabolizes 6TG and Case reports corroborate these findings, albeit
other thiopurines [6, 44]. TPMT activity in with limited strength of evidence [42, 46].
Caucasians varies based on genetic polymor-
phisms. Specifically, 10% of Caucasians have
intermediate TPMT activity and one in approxi- Systemic Tacrolimus
mately 300 Caucasian individuals has no TPMT
activity [44]. Lower TPMT activity increases FDA-Approved Indication(s)
the risk of myelosuppression in patients taking
6TG. Aminosalicylate derivatives, such as olsala- Oral tacrolimus is FDA-approved, in conjunc-
zine, mesalazine, and sulfasalazine, may inhibit tion with corticosteroids, to prevent organ
TPMT [6, 15]. Life-threatening infections due rejection in patients with kidney, liver, or heart
to 6TG-induced granulocytopenia have been transplants [7].
reported [3]. It has been recommended that phy-
sicians measure TPMT activity in all psoriasis
patients before starting 6-thioguanine to deter- Mechanism of Action
mine initial dosage and assess the risk of myelo-
suppression [37]. Tacrolimus inhibits the phosphatase activity of
calcineurin and thereby suppresses T cell activa-
tion and proliferation via DNA replication [7].
A retrospective 4-year review of the treatment of When Best to Use

18 patients with moderate-to-severe plaque pso-
riasis treated with 6-thioguanine. Overall, 14/18 Systemic tacrolimus is best used to treat severe,
(78%) patients had more than 90% improve- recalcitrant, chronic plaque psoriasis [47].
ment; 3 patients (17%) had 50–90% improve- Evidence also exists for its use in lieu of cyclo-
ment while only 1 patient had less than 50% sporine in patients with increased cardiovascular
improvement [44]. risk [47, 48].
Dosage s ymptoms of hypertension alongside repeat mea-

surements [15].
Systemic tacrolimus is started at a dose of
0.05 mg/kg/day [7, 15, 47]. The dose can be
increased to 0.10 mg/kg/day after 3 weeks and to Perils and Pitfalls
0.15 mg/kg/day after 6 weeks [47, 48].
Systemic tacrolimus is contraindicated in patients
with known hypersensitivity to tacrolimus or to
Adverse Events its metabolites and in nursing mothers [7, 15].
It causes fetal harm in pregnant animals [7, 15].
The adverse effects associated with oral or intra- Transplant patients treated with tacrolimus have
venous (i.e. systemic) tacrolimus include: insom- an increased risk of developing lymphoma and
nia, tremors, headaches, altered sensory function, skin malignancies and an increased susceptibility
muscle pains, pruritus, malaise or fatigue, pho- to infection [7]. Since psoriasis patients already
tophobia, nausea, and diarrhea [47]. Tremor, have an increased baseline risk of lymphoma,
nausea, and abnormal renal function tests are this particular potential problem needs to be fol-
commonly reported in transplant patients whereas lowed closely. The clinician must advise patients
hyperglycemia (and diabetes mellitus), hyperka- to take oral tacrolimus consistently either with
lemia, hypertension, myocardial hypertrophy, or without food, as the presence of food affects
elevated LFTs, leukocytosis, dyspnea, anemia the drug’s bioavailability. The cytochrome P450
(including red cell aplasia), edema, fever, neph- system metabolizes systemic tacrolimus, and it
rotoxicity, neurotoxicity and arthralgias were less therefore interacts with many drugs [15]. One
commonly reported in these patients when given should not give systemic tacrolimus concurrently
systemic tacrolimus [7, 15, 47]. with cyclosporine; discontinue one drug at least
24 hours before starting the other.
At baseline, the provide should obtain a detailed
medical history and perform a physical examina- A randomized, controlled trial evaluated the
tion. Baseline and repeat serum creatinine, potas- safety and efficacy of systemic tacrolimus
sium, and fasting glucose should be obtained and (0.1 mg/kg/d titrated to response and side effects)
evaluated regularly. Monitoring of metabolic and rcompared to placebo in 50 patients with severe
blood components should be clinically guided recalcitrant plaque psoriasis over the course of
[47]. Since tacrolimus can increase blood sugar nine weeks [48]. At the conclusion of the study
levels when administered systemically, repeat period, PASI scores decreased by 83% on aver-
blood sugars (serum concentration and hemo- age in the tacrolimus group compared to 47% in
globin A1c must be obtained periodically. A the placebo group (P < 0.02) [48]. The most com-
CBC count with differential, serum BUN and mon side effects were diarrhea and paresthesias.
creatinine levels, LFTs, and pregnancy test (if An open-label pilot study of 26 patients with
indicated) should all be obtained before starting severe refractory plaque psoriasis investigated
systemic tacrolimus [9]. After starting treatment, the efficacy of oral tacrolimus (0.1 mg/kg/day
serial evaluations should be done of the patient’s divided equally into two doses per day). Overall,
blood pressure, serum chemistries, BUN and 21/26 (80.37%) of participants hadimprovement
creatinine, LFTs, and pregnancy test (if indi- in mean PASI scores at the end of the trial. Of
cated) [7, 15, 47]. A monitoring frequency has these 21 patients with improvement, 19 achieved
not been firmly established. Even if asymptom- at least PASI 75 and, of those, 11 scored PASI 90.
atic, patients should be monitored for signs and The most common adverse events experienced
were: diarrhea, abdominal pain, acral paraesthe- elevated liver enzymes [39]. Rarely, patients
sia, and myalgia [49]. taking leflunomide have rarely developed pan-
The combination of systemic evirolimus and cytopenia, agranulocytosis, thrombocytopenia,
tacrolimus was shown to be effective in com- Stevens-Johnson syndrome, and toxic epidermal
pletely clearing refractory chronic plaque psoria- necrolysis [8].
sis in one post-transplant patient [50].
Leflunomide
The clinician should obtain history and perform
FDA-Approved Indication(s) a physical examination. Additionally, at baseline,
providers should obtain CBC with differential
Leflunomide is FDA-approved to treat active and LFTs. Pregnancy test (if indicated) may also
rheumatoid arthritis in adults [8]. be obtained before starting leflunomide [39] After
starting treatment, a CBC with differential and
LFTs should be checked monthly for 6 months,
Mechanism of Action then every 6–8 weeks [8]. If indicated, ongoing
pregnancy tests should be checked [8].
Leflunomide inhibits de novo pyrimidine synthe-
sis and thereby suppresses cell proliferation and
inflammation [8]. Perils and Pitfalls
Leflunomide is contraindicated in patients with

When Best to Use hypersensitivity to leflunomide and in pregnant
or nursing mothers [8]. Hepatotoxicity and fatal
Leflunomide can be considered for patients with liver failure have been reported in patients treated
treatment-resistant, widespread, chronic plaque with leflunomide, and it is well worth noting that
psoriasis as a second-line systemic therapy or concurrent methotrexate therapy increases the
psoriatic arthritis as a disease modifying anti- risk of hepatotoxicity. Concurrent rifampin use
rheumatic agent [15, 51]. leads to increased and potentially toxic peak lev-
els of leflunomide’s active metabolite [8].
Dosage
Leflunomide should be started at 100 mg/day for
3 days, and then maintained at a dose of 20 mg/ A randomized, placebo-controlled trial evalu-
day [8, 15, 51]. ated the safety and efficacy of leflunomide
compared to placebo in 109 patients with
active psoriatic arthritis and psoriasis with
Adverse Events ≥3% BSA involvement … Seventeen percent
of the leflunomide- treated group achieved
The most common adverse events in patients tak- PASI 75 compared to 8% in the placebo group
ing leflunomide are diarrhea, nausea, upper respi- (P = 0.048). Additionally, 59% of leflunomide-
ratory tract infection, headache, hypertension, treated patients achieved 20% in Psoriatic
and alopecia. Baseline LFTs arer recommended Arthritis Response Criteria compared to 30% in
as some patients may uncommonly experience the placebo group (P < 0.0001) [51].
Penicillin V and Erythromycin Recommended Monitoring
FDA-Approved Indication(S) No specific hematologic or biochemical monitor-

ing is recommended for short-term therapy with
Among other indications, penicillin V and eryth- penicillin V or erythromycin [9, 10]. These medi-
romycin are both approved to treat mild to moder- cations have good safety profiles.
ate Streptococcus pyogenes-associated infections
[9, 10].
Perils and Pitfalls
Mechanism of Action Penicillin is contraindicated in patients with

hypersensitivity to the drug; reported hyper-
Penicillin V inhibits biosynthesis of cell-wall sensitivity reactions have been fatal [10].
mucopeptides during cellular multiplication Patients receiving penicillin V have developed
in penicillin-sensitive microorganisms [10]. Clostridium difficile associated diarrhea. High-
Erythromycin inhibits protein synthesis in sus- dose penicillin is rarely associated with leukope-
ceptible microorganisms by binding to the 23S nia, anemia, thrombocytopenia, nephropathy, and
ribosomal RNA molecule within the 50S subunit, neuropathy [10].
preventing elongation of peptide chains [9]. Erythromycin is contraindicated in patients
taking terfenadine, astemizole, pimozide, or
cisapride due to increased risk of fatal ventricu-
When Best to Use lar arrhythmia and also in patients with hyper-
sensitivity to erythromycin [9]. Patients taking
Penicillin V or erythromycin can be used to treat erythromycin have developed LFT abnormali-
guttate psoriasis when the condition appears ties, hepatitis, pseudomembranous colitis, Q-T
related to or associated with a bacterial infection, interval, ventricular arrhythmias, erythema mul-
usually of an upper respiratory nature (classically tiforme, Stevens-Johnson syndrome, toxic epi-
Streptococcal pharyngitis) [52–54]. If patients dermal necrolysis, pancreatitis, convulsions, and
present well after the episode of possible infec- reversible hearing loss [9].
tion preceding guttate psoriasis antibiotic treat- While the association of Streptococcal infec-
ment may not be appropriate. tion of the pharynx is a well-known, forgotten in
examination may be perianal source of infection
which may lead to withheld antibiotics [55].
Dosage
Both antibiotics (penicillin V or erythromycin) Strength of Evidence

are given orally in a dosage of 250 mg four times
daily, for 14 days [54]. A few antibiotic regimens have been studied in
the contex of guttate psoriasis, including pencil-
lin V, erythromycin, rifampin (proposed to act
Adverse Events via anti-inflammatory effects), or combination of
these treatments (erythromycin plus rifampin).
Patients given penicillin V sometimes report These studies are largely limited to small and
nausea, vomiting, abdominal pain, diarrhea, and uncontrolled investigations [52–59].
black hairy tongue [10]. Patients taking erythro- In 2019, a Cochrane Database systematic
mycin often develop nausea, vomiting, abdomi- review sought to assess the effects of antistrep-
nal pain, diarrhea, and anorexia [9]. tococcal interventions for guttate and chronic
plaque psoriasis. The conclusion of this study immunodeficiency virus, acquired immune defi-
was that there was a major lack of well-designed ciency syndrome, malignancy) or iatrogenic
studies, limiting evidence to low-quality studies immunocompromised states (e.g. chemother-
with potential for various biases. Overall, the apy), apremilast is a valuable treatment [12].
efficacy and safety of antistreptococcal therapy in Furthermore, apremilast may be a consideration
the manangement of guttate and chronic plaque in patients for whom the side effects or con-
psoriasis are uncertain and cannot be strongly traindications of other biologic regimens (e.g.
recommended at present [60]. infection, heart failure, demyelinating disorders)
exclude them from consideration [64].
Patients with psoriasis may have various
Apremilast comorbidities necessitating numerous daily
medications [65]. In such patients, apremilast
FDA-Approved Indication(s) may be beneficial due to its minimal interac-
tions with cytochrome P450. Serum levels are
Apremilast (OTEZLA®) is FDA-approved to not increased inpatients taking medications that
treat adults with active psoriatic arthritis and inhibit cytochrome P450 [66, 67]. Additionally,
patients with moderate-to-severe plaque psoriasis unlike other disease-modifying agents antirheu-
who are candidates for phototherapy or systemic matic drugs, aprelimast does not exclude patients
therapy [61]. with hepatic impairment [68]. In obese patients,
the side effect of weight loss may be beneficial in
treatment [61].
Mechanism of Action Apremilast’s oral formulation may also
improve adherence in patients with needle phobia
Apremilast is a selective inhibitor of phospho- (or “needle-fatigue”), elderly patients, or those
diesterase (PDE) 4, the predominant PDE in facing impediments to social life or work activity
inflammatory and immune cells, resulting in secondary to injections [69].
increased intracellular levels of cyclic adenosine
monophosphate (cAMP) [62]. The increased lev-
els of cAMP modulate the expression of inflam- Dosage
matory cytokines involved in the pathogenesis of
psoriasis. Inducible nitric oxide synthase, tumor Regardless of use, the FDA-approved daily dos-
necrosis factor alpha (TNF-α), interferon gamma age of apremilast is 30 mg twice daily [39].
(IFN-γ), interleukin (IL)-17A/F, IL-22, and This final recommended dosage is supported
IL-23 are all decreased whereas IL-10, an anti- by clinical phase II trials, which assessed clini-
inflammatory cytokine, is increased [62, 63]. cal response to differing doses and frequency of
apremilast, showing that 30 mg twice daily was
the optimal regimen [70–72]. To improve the tol-
When Best to Use erability, gradual uptitration is advised in achiev-
ing the final recommended dose. The following
There are several benefits to apremilast for regimen is suggested [73]:
plaque psoriasis, manifesting in some general
principles for its best use. Since apremilast is • Day 1: 10 mg in the morning
not immunosuppressive, it is useful in patients • Day 2: 10 mg in morning and 10 mg in evening
with underlying/active infectious diseases • Day 3: 10 mg in morning and 20 mg in evening
(e.g. viral hepatitis, tuberculosis) or those at • Day 4: 20 mg in morning and 20 mg in evening
increased risk for infection (e.g. liver cirrhosis, • Day 5: 20 mg in morning and 30 mg in evening
diabetes, intravenous drug users). In patients • Day 6 and thereafter: 30 mg in morning and
with pre-existing disease-associated (e.g. human 30 mg in evening
Adults with severe renal impairment (end- not differ from the extremely low rates observed
stage renal disease stage 3b and above) are rec- in the ESTEEM 1 and 2 studies [77]. These
ommended to take 30 mg once daily. During the short- and long-term findings were corroborated
titration stage at the start of therapy, only the and validated by the LIBERATE studies [78, 79].
morning dose should be given [74]. Real-world investigation outside of clinical trials
also validate the strong safety profile found in
phase 3 trial data [80] (Table 10.4).
Adverse Events Overall, the safety data does not seem to show
significant increase in serious infections, oppor-
Since apremilast functions as an anti-inflammatory tunistic infections, major cardiac events, organ
rather than an immunosuppressant, no increased damage, or malignancies. Additionally, there was
risk of opportunistic infections has been observed no change in laboratory abnormalities [75–79].
[68]. In the Efficacy and Safety Trial Evaluating
the Effects of Apremilast in Psoriasis (ESTEEM)
phase III trials (ESTEEM 1 and 2), adverse Recommended Monitoring
effects were compared in the 0–16-week period
(placebo-controlled) and assessed in the solely Apremilast has the added benefit of no required
apremilast exposure period (0–52 weeks) laboratory monitoring, such as liver and kid-
(Table 10.3) [75, 76]. ney function test, due to lack of organ-specific
The most common adverse events were diar- or cumulative toxicities with this medication
rhea, nausea, upper respiratory tract infection, [47]. However, monitoring patients for adverse
nasopharyngitis, and headaches (Table 10.2). sequelae of adverse effects is warranted.
Of these, the adverse events most different from Although the risk is low, patients with a history
the placebo group were: diarrhea and nausea. of depression, suicidal ideation, or history of sui-
Long-term (0 to ≥156 weeks) investigation of cide should be closely monitoring for worsen-
pooled data from ESTEEM 1 and 2 showed no ing symptoms during therapy [69, 81]. Advising
new adverse events affecting ≥5% of the cohort patients, family members, and caregivers of these
were observed [77]. Overall, adverse events, seri- side effects is recommended. Additionally, the
ous adverse events, and adverse events leading to risk of weight loss warrants periodic body weight
drug discontinuation did not increase with long- checks, especially in underweight patients.
term drug use. Furthermore, the rates of major Clinically significant weight loss should prompt
cardiac events, depression, and malignancy did medication discontinuation [68, 81].
Table 10.3 Pooled adverse event data from the ESTEEM 1 and 2 phase III clinical trials for apremilast. AE = adverse
events
Apremilast-exposure period
Placebo-controlled period (0–16 week) (0–52 weeks)
Placebo Placebo Apremilast Apremilast Apremilast Apremilast
ESTEEM 1 ESTEEM 2 ESTEEM 1 ESTEEM 2 ESTEEM 1 ESTEEM 2
(n = 282) (n = 136) (n = 560) (n = 272) (n = 804) (n = 380)
≥1 AE 157 82 (60.3%) 388 (69.3%) 185 (68.0%) 633 (78.7%) 296 (77.9%)
(55.7%)
≥1 severe AE 9 (3.2%) 6 (4.4%) 20 (3.6%) 12 (4.4%) 48 (6.0%) 33 (8.7%)
≥1 serious AE 8 (2.8%) 3 (2.2%) 12 (2.1%) 5 (1.8%) 34 (4.2%) 18 (4.7%)
≥1 AE leading 9 (3.2%) 7 (5.1%) 29 (5.2%) 15 (5.5%) 59 (7.3%) 27 (7.1%)
to drug
withdrawal
≥1 AE leading 1 (0.4%) 0 (0.0%) 1 (0.2%) 0 (0.0%) 1 (0.1%) 0 (0.0%)
to death
Table 10.4 Pooled side effect data from the ESTEEM 1 and 2 phase III clinical trials for apremilast
Apremilast-exposure period
Placebo-controlled period (0–16 week) (0–52 weeks)
Placebo Placebo Apremilast Apremilast Apremilast Apremilast
ESTEEM 1 ESTEEM 2 ESTEEM 1 ESTEEM 2 ESTEEM 1 ESTEEM 2
(n = 282) (n = 136) (n = 560) (n = 272) (n = 804) (n = 380)
Diarrhea 20 (7.1%) 8 (5.9%) 105 (18.8%) 43 (15.8%) 150 (18.7%) 55 (14.5%)
Upper respiratory 21 (7.4%) 6 (4.4%) 57 (10.2%) 13 (4.8%) 143 (17.8%) 35 (9.2%)
tract infection
Nausea 19 (6.7%) 9 (6.6%) 88 (15.7%) 50 (18.4%) 123 (15.3%) 63 (16.6%)
Nasopharyngitis 23 (8.2%) 6 (4.4%) 41 (7.3%) 20 (7.4%) 108 (13.4%) 55 (14.5%)
Headache 13 (4.6%) 1 (0.7%) 31 (5.5%) 17 (6.3%) 52 (6.5%) 22 (5.8%)
Tension headaches 12 (4.3%) 2 (1.5%) 31 (5.5%) 14 (5.1%) 52 (6.5%) 29 (7.6%)
Perils and Pitfalls mean change (−6.6%), and pruritus visual ana-

logue scale (VAS) score decrease (−31.5%)
Patients with known hypersensitivity to apre- were significantly different in apremilast-treated
milast or any excipients in its formulation are patients compared to placebo-treated patients
contraindicated from this medication [82]. (5.3%, 17.0%, 3.9%, −2.1%, and − 7.3%, respec-

Concurrent use of cytochrome P450 activators tively) (all P < 0.0001) [75].
(e.g. rifampin) can lead to loss of efficacy [82]. Similarly, another phase III, multicenter,
The effects of apremilast on pregnancy, labor, double-blind, placebo-controlled study (ESTEEM
delivery, and lactation in humans is unknown. 2) randomized 274 adults (2:1) to apremilast of
Although cases reports exist regarding its use in placebo. By week 16, the percentage of patients
pediatric patients, apremilast has not been stud- apremilast-treated patients achieving PASI-75
ied in this population and is off-label in this pop- (28.8%), PASI-50 (55.5%), sPGA score of 0 or
ulation [82]. 1 (20.4%), DLQI mean change (−6.7%), and
Dose titration is important as the gastroin- pruritus VAS score decrease (−33.5%) were sig-
testinal side effects are much prevalent when nificantly different in apremilast-treated patients
not performed, leading to higher rates of drug compared to placebo- treated patients (5.8%,
withdrawal [73]. Xanthines, which are found in 19.7%, 4.4%, −2.8%, and − 12.2%, respectively)
caffeine, can increase cAMP through PDE inhi- (all P < 0.0001) [55]. The LIBERATE studies
bition. This can lead to increased risk of diarrhea validate these prior two studies’ findings over the
or other side effects [83]. long-term (104 weeks) [78, 79].
There is some evidence that apremilast is Apremilast does not appear to be as efficacious
more effect in biologic-naïve patients reflected as other biologics as demonstrated by its lower
by a higher efficacy in this group of patients in PASI-75 scores compared to other biologics
the ESTEEM trials [75, 76]. [84, 85]. The German Society of Dermatology’s
consensus psoriasis treatment guidelines noting
the drug as the least efficacious biologic [86].
Strength of Evidence Nevertheless, real-world multi-center studies
cite apremilast as a valuable part of the derma-
A phase III, multicenter, double-blind, placebo- tologists’ armamentarium against psoriasis. One
controlled study (ESTEEM 1) randomized 844 such retrospective study of 148 patients noted a
adults (2:1) to apremilast or placebo. By week greater proportion of apremilast monotherapy
16, Psoriasis Area and Severity Index (PASI)- patients achieving response (PASI-75) (26/59,
75 (33.1%), PASI-50 (58.7%), static Physician’s 44.1%) compared to patients undergoing com-
Global Assessment (sPGA) score of 0 or 1 binational therapy (apremilast plus one of: pho-
(21.7%), dermatology life quality index (DLQI) totherapy, systemic therapy, biologic therapy)
(33/89, 37.1%) (P = 0.396). However, the authors 4. Soriatane [package insert]. Coral Gables: Stiefel
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2017 Mar;31(3):507–17. ment patterns and healthcare costs among biologic-
80.
Papadavid E, Rompoti N, Theodoropoulos K, naive patients initiating apremilast or biologics
Kokkalis G, Rigopoulos D. Real-world data on the for the treatment of psoriasis. J Med Econ. 2019
efficacy and safety of apremilast in patients with Apr;22(4):365–71.
moderate- to-severe plaque psoriasis. J Eur Acad 88. Feldman SR. Disease burden and treatment adherence
Dermatol Venereol. 2018 Jul;32(7):1173–9. in psoriasis patients. Cutis. 2013;92(5):258–63.
81. Vangipuram R, Alikhan A. Apremilast for the
89. Feldman SR, Horn EJ, Balkrishnan R, et al. Psoriasis:
management of moderate to severe plaque improving adherence to topical therapy. J Am Acad
psoriasis. Expert Rev Clin Pharmacol. 2017 Dermatol. 2008;59(6):1009–16.
Apr;10(4):349–60. 90. Carroll CL, Feldman SR, Camacho FT, et al. Better
82. Smith RL. Pediatric psoriasis treated with apremilast. medication adherence results in greater improve-
JAAD Case Rep. 2016;2(1):89–91. ment in severity of psoriasis. Br J Dermatol.
83. Chi CC, Wang SH. Efficacy and cost-efficacy of
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the intention-to-treat principle. Biomed Res Int. ated with biologics in Medicaid enrolled patients with
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84. Egeberg A, Ottosen MB, Gniadecki R, Broesby-

Olsen S, Dam TN, Bryld LE, Rasmussen MK, Skov
L. Safety, efficacy and drug survival of biologics and Recommended Reading
biosimilars for moderate-to-severe plaque psoriasis.
Br J Dermatol. 2018 Feb;178(2):509–19.
Hsu S, Papp KA, Lebwohl MG, et al. Consensus guide-
85. Schmitt J, Rosumeck S, Thomaschewski G, Sporbeck
lines for the management of plaque psoriasis. Arch
B, Haufe E, Nast A. Efficacy and safety of sys-
Dermatol. 2012;148:95–102.
temic treatments for moderate-to-severe psoriasis:
Apremilast
11
Jerry Bagel and Elise Nelson
Abstract
In 2014 apremilast was the first oral FDA 1. To understand the mechanism of action
approved therapy in almost 20 years. Although of apremilast
the efficacy of apremilast, PASI 75—33% 2. To understand the appropriate use and
@ week 16 was inferior to the biologic efficacy of the apremilast
agents approved in its era, i.e. ustekinumab, 3. To understand the safety issues of

Adalimumab, PASI 75—71%, the safety of apremilast
apremilast resulted in many dermatologists
prescribing apremilast to their patients with
psoriasis. The reason for the expansive use of
In 2014 the FDA approved apremilast for the
apremilast is at least partially due to the fol-
treatment of psoriasis and psoriatic arthritis.
lowing factors, no risks of malignancy, seri-
Acetretin and cyclosporine were FDA approved
ous infections, no opportunistic infections, no
in 1996 and 1997 respectively. In this time frame
laboratory monitoring required.
there were six biologic therapies approved, how-
Many psoriatics, in part to direct to con-
ever, apremilast was the first new oral therapy in
sumer marketing, have been fearful of the side
almost 20 years.
effects of biologic agents, yet since topical
As opposed to biologic agents which bind
therapy was not providing adequate efficacy
extracellular targets i.e. TNF-alpha, IL-12, IL-23,
they wanted a different option. In addition to
IL-17, apremilast is a small molecule which acts
showing efficacy for plaque psoriasis, apremi-
intracellularly. The mechanism by which apremi-
last has also been studied and revealed effi-
last acts is by inhibiting the activity of phospho-
cacy in psoriatic arthritis (FDA approved),
diesterase 4 (PDE4). In inflammatory cells,
psoriatic onychodystrophy, scalp psoriasis,
PDE4 catalyzes the conversion of cAMP to
and palmar plantar psoriasis.
AMP. The ratio of cAMP to AMP regulates the
transcription of either anti-inflammatory media-
tors or pro-inflammatory mediators. Higher intra-
J. Bagel (*) · E. Nelson cellular concentrations of AMP result in a greater
Psoriasis Treatment Center of Central New Jersey,
East Windsor, NJ, USA transcription of pro-inflammatory mediators i.e.
IL-17, IL-22, TNF alpha and accordingly, less
The Mount Sinai School of Medicine,
New York, NY, USA transcription of anti-inflammatory mediators.
More specifically, an increase in intracellular
The University of Pisa, Pisa, Italy

https://doi.org/10.1007/978-3-030-54859-9_11
142 J. Bagel and E. Nelson
cAMP activates Protein Kinase A (PKA). PKA tinued through week 104 without any increase
activates certain transcription factors, but inhibits in adverse events noted.
NF-KB which is thought to decrease the amount There have been reports of weight loss associ-
of pro-inflammatory mediators. Hence, by inhib- ated with apremilast. In view of the fact that over
iting PDE4, apremilast increases intracellular 35% of patients have a BMI > 30, weight loss is
cAMP and promotes anti-inflammatory tran- generally not a concern. However, for those thin-
scription via the activation of the cAMP-response ner individuals and elderly, weight loss may be
element binding protein. an issue. In addition diarrhea and/or vomiting
The FDA approval of apremilast was based on may result in electrolyte imbalance especially in
two phase III clinical trials, ESTEEM 1 and 2. those taking diuretics. Diarrhea is listed as a
The ESTEEM 1 and 2 randomized, placebo- warning, it tends to occur in the first two weeks
controlled studies evaluated apremilast 30 mg and resolve over time with continued dosing. It
BID in adult patients with chronic moderate-to- can be severe, reduce dose/discontinue, if needed.
severe plaque psoriasis, PASI ≥ 12, BSA ≥ 10, Many of the nuisance side effects i.e. head-
PGA ≥ 3. Patients with a history of prior photo- aches, diarrhea, nausea, and vomiting may be
therapy, systemic, and biologic therapy were eli- ameliorated by prolonging the tapering period of
gible to participate in the trial. The primary apremilast at the initiation of therapy i.e. instead
endpoint was PASI-75 response at week 16. of a 5 day taper starting at 10 mg on day 1,
In ESTEEM 1, 844 patients participated (562 advancing to 30 mg bid on day 6, a 10 or 15 day
apremilast, 282 placebo), with a mean age of 46 taper significantly decreases the incidence of
who had psoriasis for approximately 20 years. these nuisance side effects. There is a warning
The mean PASI = 19, BMI = 31, and over half related to depression, so it is important to exclude
had prior systemic or biologic therapy. At week patients with a history of major depressive
16, PASI-75 was achieved by 33.1% in the apre- episodes.
milast cohort vs placebo which was 5.3%. In Based on the phase 3 Palace 1–3 clinical trials
addition, the PASI-50, PASI change from base- apremilast was FDA approved for psoriatic
line, Scalp PGA = 0–1, NAPSI-50, and DLQI % arthritis. At week 16 apremilast yielded ACR
response was 59, 52, 47, 33, 70 in the apremilast 20 = 32%–41%, placebo = 19%. At week 260,
cohort vs 17, 17, 18, 15, 34 for placebo. the ACR 20, 50, 70 for apremilast was 67%, 44%,
Evaluating psoriatic onychodystrophy there was and 27% respectively. A significant number of
a 22% improvement in NAPSI scores within 16 these subjects had been biologically experienced
weeks. and biologic-failures. ACR 20 = 23% response
PASI-75 response was maintained through rates in biologic failures was lower than biologi-
week 32. In those patients who obtained a PASI- cally naive = 43% at week 16. Overall swollen
75 at week 32, there was an 80% improvement in joint counts and tender joint counts decreased by
PASI through Week 52. 87% and 80% respectively over 260 weeks. In
The most common adverse events reported in addition 80% and 54% of subjects obtained dac-
>5% of patients in the apremilast cohorts were tylitis count = 0 and enthesitis score = 0 at 260
diarrhea, nausea, upper respiratory tract infec- weeks of treatment.
tions, and headaches. There were no serious While apremilast is not the most efficacious
opportunistic infections, the rates of malignancy treatment for psoriasis, it is popular due to its
and laboratory abnormalities were comparable safety profile. Based on its mechanism of action,
between the apremilast cohort and placebo. apremilast does not suppress any of the extracel-
The LIBERATE study compared apremilast lular pro-inflammatory molecules as much as
to placebo and had an active control in etaner- monoclonal antibodies. By not suppressing as
cept. At week 16, PASI-75 for placebo, apremi- much, there is no increase in serious infections,
last, and etanercept was 12%, 40%, and 48% hence, apremilast acts as an immunomodulating
respectively. In this study apremilast was con- agent not as an immunosupressive. There were
11 Apremilast 143
no serious opportunistic infections, no increase in C, Cather JC. Long-term safety and tolerability of
apremilast in patients with psoriasis: pooled safety
malignancy with cumulative experience, labora- analysis for ≥156 weeks from 2 phase 3, random-
tory anomalies were infrequent and transient, and ized, controlled trials (ESTEEM 1 and 2). J Am Acad
in fact no laboratory monitoring is required. Dermatol. 2017 Aug;77(2):310-7.e1. https://doi.
In addition, a phase IV study evaluated apre- org/10.1016/j.jaad.2017.01.052. Epub 2017 Apr 14.
3. Danesh MJ, Beroukhim K, Nguyen C, Levin E, Koo
milast 30 mg bid in adults with moderate-to- J. Apremilast and adalimumab: a novel combination
severe palmoplantar psoriasis. At week 32, 24% therapy for recalcitrant psoriasis. Dermatol Online J.
patients randomized to apremilast were clear or 2015 Jun 16;21(6). pii: 13030/qt5gf406zs.
almost clear. In a post-hoc analysis of ESTEEM 4. Duffin KC, Papp KA, Bagel J, Levi E, Chen R,
Gottlieb AB. Evaluation of the physician global
1 and 2 and a phase II study approximately 48% assessment and body surface area composite tool for
(n = 92) were clear or almost clear at week 16, assessing psoriasis response to apremilast therapy:
however the placebo rate was rather high with an results from ESTEEM 1 and ESTEEM 2. J Drugs
average of 27% (n = 52). Baseline PPPGA ≥ 3. Dermatol. 2017 Feb 1;16(2):147–53.
5. Kavanaugh A, Mease PJ, Gomez-Reino JJ, Adebajo
In a Phase III study in patients with moderate AO, Wollenhaupt J, Gladman DD, Hochfeld M, Teng
to severe scalp psoriasis (SSA ≥ 20%) 43% of LL, Schett G, Lespessailles E, Hall S. Longterm (52-
patients treated with apremilast at week 16 were week) results of a phase III randomized, controlled
clear or almost clear compared to placebo = 14%. trial of apremilast in patients with psoriatic arthritis.
J Rheumatol. 2015 Mar;42(3):479–88. https://doi.
Scalp itch and whole body itch response was seen org/10.3899/jrheum.140647. Epub 2015 Jan 15.
in 47% and 45% of patients respectively. 6. Kavanaugh A, Gladman DD, Edwards CJ, Schett
In my experience, many patients who opt for G, Guerette B, Delev N, Teng L, Paris M, Mease
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patients with psoriatic arthritis: 5-year results from
much less commonly needle phobic. However, a PALACE 1-3 pooled analysis. Arthritis Res Ther.
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Apremilast has not been evaluated in combi- 8. Nguyen CM, Leon A, Danesh M, Beroukhim K, Wu JJ,
Koo J. Improvement of nail and scalp psoriasis using
nation with biologics. Ustekinumab may clear apremilast in patients with chronic psoriasis: Phase
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9. Papp K, Reich K, Leonardi CL, Kircik L, Chimenti
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Etanercept
12
Andrew F. Alexis and Charlotte M. Clark
Abstract
Etanercept is a soluble dimeric fusion protein 1. To understand the mechanism of action
that was the first anti-tumor necrosis factor of Etanercept
(TNF-α(alpha)) drug to be approved for the 2. To understand the appropriate use and
treatment of psoriasis and psoriatic arthritis. It efficacy of the Etanercept
is administered subcutaneously by self- 3. To understand the safety issues of
injection. As with other biologic drugs for Etanercept
psoriasis, etanercept offers a targeted approach
to treatment that lacks end organ side effects
of traditional systemic therapies such as meth-
otrexate, cyclosporine, or acitretin. With over
Introduction
8 years of postmarketing experience in psoria-
sis (and over 14 years since approval for mod-
Etanercept was the first anti-tumor necrosis fac-
erate to severe RA in 1998), a large body of
tor (TNF-α(alpha)) drug to be approved for the
safety data exists for etanercept. Here, we
treatment of psoriasis and psoriatic arthritis.
review the safety and efficacy of etanercept in
As a TNF-α(alpha) blocking agent, etanercept
the treatment of plaque psoriasis and psoriatic
modulates inflammatory processes of innate and
arthritis, with emphasis on published Phase 3
extrinsic immune responses, cell trafficking, and
and Phase 4 clinical trial data. Safety consid-
acute and chronic inflammation that are aber-
erations, recommended monitoring, and stud-
rant in psoriasis. In this chapter, the safety and
ies of combination therapy are also discussed.
efficacy of etanercept in the treatment of plaque
psoriasis and psoriatic arthritis will be reviewed,
with emphasis on published Phase 3 and Phase 4
clinical trial data.
A. F. Alexis (*)
Department of Dermatology, Icahn School of Background
Medicine at Mount Sinai, New York, NY, USA
e-mail: [email protected] Psoriasis is a chronic inflammatory disease, char-
C. M. Clark acterized by hyperkeratotic epidermal lesions
Department of Dermatology, Columbia University formed in response to T cell activation and the
Medical Center, New York, NY, USA

https://doi.org/10.1007/978-3-030-54859-9_12
146 A. F. Alexis and C. M. Clark
associated release of proinflammatory cytokines to osteoarthritis controls [2]. Psoriatic arthritis

[1]. Although the exact pathogenesis of psoria- patients treated with etanercept have shown to
sis remains to be fully elucidated, TNF appears have significant reductions in cutaneous psoriasis
to play a key role in the inflammatory cascade lesions as well as improvement of their arthritis
associated with psoriasis and psoriatic arthritis. [1, 6]. Etanercept (25 mg SC twice-weekly) has
When compared to uninvolved skin, greater con- been shown to be efficacious in the treatment
centrations of TNF-α are expressed in the stratum of psoriatic arthritis as evidenced by signifi-
corneum of psoriatic lesions [2]. cantly greater percentages of subjects achieving
Etanercept is a TNF-α inhibitor and FDA a 20% or greater reduction in American College
approved drug for the treatment of adult patients of Rheumatology criteria (ACR20) scores [6].
with chronic moderate to severe plaque psoria- Significant inhibition of radiographic disease
sis who are candidates for systemic therapy or progression (measured by mean change in modi-
phototherapy. Etanercept is also approved for the fied total Sharp score) has also been shown in
treatment of other TNF mediated inflammatory controlled clinical trials of etanercept in the treat-
diseases such as rheumatoid arthritis, psoriatic ment of psoriatic arthritis [6, 7].
arthritis, ankylosing spondylitis, and polyarticu-
lar juvenile idiopathic arthritis.
Etanercept in the Treatment
of Psoriasis
Structure and Mechanism of Action
The safety and efficacy of etanercept has been
Etanercept is a soluble dimeric fusion protein shown in large double blinded placebo-controlled
that includes two TNF-α receptors fused to the trials [8–10]. Based on US and Global phase III
constant region (Fc) of human IgG1, allowing trial data the dosage approved by the US FDA for
it to bind specifically with non-membranous the treatment of plaque psoriasis is 50 mg SC twice
bound TNF-α [1, 3, 4]. Etanercept binds to and weekly for 12 weeks followed by 50 mg SC there-
inactivates TNF [3]. Furthermore, etanercept after. Statistically significant proportions of etan-
modifies responses induced by TNF activity, ercept treated subjects achieved a 75% or greater
such as adhesion molecule expression (needed reduction in Psoriasis Area and Severity Index
for leukocyte migration) and blood cytokine (PASI 75) scores compared to placebo (Table 12.1)
levels [5]. Therapy is administered as a subcu- [6, 7]. Clinically meaningful improvements in the
taneous injection by patients at home. The peak quality of life have also been demonstrated in pso-
absorption of etanercept is at 51 h, with a mean riasis patients treated with etanercept [6].
half-life of 68 h [4]. After discontinuation of therapy, a gradual onset
of disease recurrence is observed. In one study,
median time to disease relapse (measured as ≥50%
Etanercept in the Treatment loss of PASI improvement achieved from baseline
of Psoriatic Arthritis after 24 weeks of therapy) was 3 and 2 months, in
PASI 50 and PASI 75 responders, respectively [8].
Psoriatic skin lesions typically precede the onset Successful discontinuation and re-treatment with
of joint symptoms and therefore, dermatologists etanercept has also been shown [8, 9].
can potentially diagnose psoriatic arthritis in Therapeutic efficacy after dosage reduction
early stages through careful history and exami- at 12 weeks from 50 mg SC twice weekly to
nation. Elevated TNF-α levels have been found 50 mg once weekly is maintained by a majority of
in psoriatic arthritis joint fluid in comparison patients as demonstrated by the percentage of sub-
12 Etanercept 147
Table 12.1 The US and Global Phase III psoriasis clinical trials; study design, baseline characteristics, and clinical
outcomes [6, 7]
US Phase III clinical trial [6] Global Phase III clinical trial [7]
Study design Multicenter (47 sites), randomized, Multicenter (50 sites), randomized,
double-blinded, placebo-controlled, double-blinded, placebo-controlled,
parallel-group parallel-group
Number of patients 672 patients were randomized, 652 611 patients were randomized, 583
participated in study treatment participated in study treatment
Duration 24 weeks 24 weeks
Drug regimen 1. Placebo (n = 166) for 12 weeks, then 1. Placebo (n = 193) for 12 weeks, then
etanercept 25 mg BIW for 12 more etanercept 25 mg BIW for 12 more
weeks weeks
2. Low dose (25 mg QIW) (n = 160) 2. Etanercept 25 mg BIW (n = 196) for
24 weeks
3. Medium dose (25 mg BIW) (n = 162) 3. Etanercept 50 mg BIW (n = 194) for
4. High dose (50 mg BIW) (n = 164) 12 weeks, then etanercept 25 mg
BIW for 12 more weeks
Efficacy endpoints Primary endpoint: PASI 75 at week 12 Primary endpoint: PASI 75 at 12 weeks
Secondary endpoints: Secondary endpoints:
1. PASI 50 and 90 at week 12 1. PASI 50 and 90 at 12 weeks
2. Physician global assessment 2. Patient global assessment
3. Patient global assessment
4. Dermatology life quality index
Demographics Placebo Low dose Medium High dose Placebo Etanercept Etanercept
and baseline group group dose group group group 25 mg BIW 50 mg BIW
clinical (mean) (mean) (mean) (mean) (median) group group
characteristics (median) (median)
Duration of 18.4 ± 0.9 19.3 ± 0.9 18.5 ± 0.9 18.6 ± 0.9 17.5 (range 21.5 (range 18.1 (range
psoriasis 1.4–51.2) 0.8–64.6) 0.8–60.5)
(years)
PASI score 18.3 ± 0.6 18.2 ± 0.7 18.5 ± 0.7 18.4 ± 0.7 16.0 (range 16.9 (range 16.1 (range
7.0–62.4) 4.0–51.2) 7.0–57.3)
Affected body 28.8 ± 1.4 27.7 ± 1.5 28.5 ± 1.6 29.9 ± 1.6 20.0 (range 23.0 (range 25.0 (range
surface area 10.0–95.0) 7.8–95.0) 10.0–80.0)
(%)
Efficacy Placebo Low dose Medium High dose Placebo Etanercept Etanercept
group group dose group group group 25 mg BIW 50 mg BIW
group group
Results 12 weeks 12 weeks
PASI 50 14% 41%a 58%a 74%a 9% 64%b 77%b
PASI 75 4% 14%a 34%a 49%a 3% 34%b 49%b
PASI 90 1% 3%a 12%a 22%a 1% 11%b 21%b
Mean PASI 14.0 ± 2.6 40.9 ± 2.4a 52.6 ± 2.7a 64.2 ± 2.4a NA NA NA
improvement
Results 24 weeks 24 weeks
PASI 50 NA 58% 70% 77% NA NA NA
PASI 75 33% 25% 44% 59% 28% 45% 54%
PASI 90 NA 6% 20% 30% NA NA NA
Mean PASI NA 50.3 ± 2.5 62.1 ± 2.5 71.1 ± 2.2 NA NA NA
improvement
a
P < 0.001 for comparison with placebo at week 12
b
P < 0.0001 for comparison with placebo at week 12
jects maintaining a PASI 50 or greater after “step- Table 12.2 Recommended risk assessment prior to
introduction etanercept therapy (a) and recommended
down” therapy [8]. In addition, approximately
symptom and laboratory monitoring prior to initiating and
30% of the non-responders (those not achieving a while maintaining etanercept therapy (b) [4, 5, 18, 19]
PASI 75) after 12 weeks of dose- reduction were (a)
shown to achieve a PASI 75 by week 24, despite Contraindications
continued reduced-dose therapy [8]. Concurrent live vaccination
The long-term safety and efficacy of etaner- History of etanercept-induced hypersensitivity
cept 50 mg twice weekly in patients with psoria- reactions
sis has been investigated in a 96 week open-label Use in those with Wegener’s granulomatosis receiving
immunotherapy (associated with higher incidence of
extension trial [11].
solid malignancies and does not improve clinical
Significant improvement in psoriasis associ- outcome if compared to standard therapy alone)
ated depression in patients treated with etaner- Septicemia, or active infection
cept (compared to placebo) was demonstrated Relative contraindications/cautions
in a study that included assessment of the Beck Pregnancy (pregnancy category B), inadequate data
depression inventory (BDI) and Hamilton rating for risk assessment for breast feeding, caution advised
Caution if CHF, especially CHF grade III–IV new
scale for depression (HAM-D) [12].
York heart association (NYHA)
A recent retrospective study investigating Caution in patients with or at risk for demyelinating
potential racial and ethnic differences found no disorders
differences in safety and efficacy variables (includ- Caution if HBV carrier
ing adverse event rates and improvements in body Personal history of frequent or recurrent infections,
surface area of involvement) between Caucasians, including history of chronic open wounds. Caution if
TB risk, history of latent TB, or if patient travels or
African-Americans, and Hispanics [13]. resides to regions with endemic TB or mycoses
Caution if moderate to severe alcoholic hepatitis
Personal history of uncontrolled diabetes mellitus
Combination Therapy History of malignancy within the past 5 years or in
patients with increased malignancy risk
Etanercept has been used safely in combination History of blood disorders or myelosuppression
with other agents to enhance or maintain efficacy. Caution in patient >65 years of age
Caution use in patients with concurrent
Adjunctive topical calcipotriene 0.005% and immunosuppressants- anakinra or abatacept is not
betamethasone dipropionate 0.064% ointment recommended with etanercept therapy
[14], narrow-band UVB phototherapy [15], or In patients with a significant exposure to varicella
methotrexate [16, 17], has been reported in pub- virus, etanercept therapy should be temporarily
lished trials. The above adjunctive therapies can discontinued and considered for prophylactic
treatment with varicella zoster immune globulin
be considered in cases of waning or insufficient
Caution in patients with latex allergy- the needle cover
efficacy with etancercept monotherapy. However, of prefilled syringes and needle cover within needle
potential risks and benefits must be considered cap contain latex-derived components
and appropriate monitoring is advised when com- (b)
bining therapies (especially those with potential Baseline monitoring
immunosuppressive and/or malignancy risks). PPD (baseline and annually) or Quantiferon gold (for
latent TB) is required, along with CXR for exclusion
of active TB
Liver function test (baseline and every 2–6 months),
Safety hepatitis B and C testing, complete blood count
(baseline and every 2–6 months), basic chemistry
(baseline and every 2–6 months), and optional
A general outline recommending risk assess-
baseline antinuclear antibodies (ANA)
ment prior to commencing etanercept therapy, as Monitoring of signs and symptoms
well as recommendations for specific monitoring Discontinue etanercept therapy during active infection.
of symptoms and routine laboratory tests when Consider empiric anti-fungal treatment for those at risk
initiating and maintaining etanercept therapy, is for invasive fungal infections or for patients residing or
travelling to regions where mycoses are endemic
provided (Table 12.2) [4, 5, 18, 19].
12 Etanercept 149
Table 12.2 (continued) Malignancies

Discontinue etanercept 1–2 weeks prior to surgery,
and reinitiation of etanercept therapy 2 weeks after Malignancies have been reported in patients using
uncomplicated surgical procedures
etanercept and other anti-TNF agents. Rates of
Discontinue etanercept therapy 4 weeks prior to and
reinitiate 4 weeks after vaccination (to prevent malignancies among patients with anti-TNF ther-
decreased vaccination efficacy) apy have been analyzed using clinical trial data
Discontinue etanercept therapy if malignancy and large rheumatologic disease and biologic
detected, with the exception of cutaneous basal cell therapy databases [21–25]. Reported malignan-
carcinoma
cies include lymphomas, non- melanoma skin
Periodic evaluation of signs and symptoms of
opportunistic infections cancers (NMSC), leukemia, and rare cases of
Yearly examination for skin cancer detection Merkel Cell carcinoma [26].
If pregnancy occurs, discuss risks versus benefits Among adult psoriasis patients treated with etan-
(pregnancy category B drug) ercept in clinical trials (n = 4410) up to 36 months,
Consider risks versus benefits in patients with the observed rate of lymphoma was comparable to
cardiovascular co-morbidities
that in the general population [5]. No cases were
Provide annual inactivated influenza vaccination,
preferably prior to biologic therapy initiation observed in the etanercept- or placebo- treated
Monitor hepatitis B carriers for reactivation during and patients during the controlled portions of these
several months after initiating etanercept therapy. If trials. However, in the controlled portions of etan-
reactivation occurs, consider discontinuing etanercept ercept trials in adult rheumatology patients - with
and beginning anti-viral therapy
rheumatoid arthritis (RA), ankylosing spondyli-
CHF congestive heart failure, PPD purified protein deri- tis (AS), and psoriatic arthritis (PsA)—two lym-
vation, CXR chest X-ray
phomas were observed among etanercept treated
patients versus 0 among control patients [5]. In
As with other anti-TNF therapies, serious combined data of controlled and uncontrolled
and opportunistic infections, (including bacte- portions of clinical trials of etanercept for adult
rial, mycobacterial, fungal, viral, parasitic) have rheumatology patients (RA, AS, and PsA) repre-
been observed in patients receiving etanercept. senting 12,845 patient years of therapy, the rate of
Reactivation of latent tuberculosis (TB) is a risk lymphoma observed (0.10 per 100 patient-years)
for this class of biologics and therefore screening was threefold higher than that expected in the
for TB is required at baseline and annually [4, general US population based on the Surveillance,
5, 18, 19]. Fatal cases of reactivation of hepati- Epidemiology, and End Results (SEER) Database
tis B virus have also been reported and as such, [5]. However, higher rates of lymphoma (up to
baseline screening for viral hepatitis is required several-fold) have been reported in the RA patient
before initiation of treatment with etanercept [4, population compared to the general population [5].
5, 18, 19]. Higher rates of non-melanoma skin cancer
Other non-infectious considerations include have been observed among psoriasis patients
congestive heart failure (CHF) and demyelin- treated with etanercept. In controlled clinical
ating disorders. Worsening of CHF and rare trials of adult psoriasis patients (n = 1245), the
new onset cases of CHF have been reported in rate of NMSC observed was 3.54 cases per 100
patients taking etanercept [3–5, 19, 20]. In addi- patient-years among those treated with etan-
tion, there are rare reports of exacerbation or new ercept versus 1.28 cases per 100 patient-years
onset of demyelinating disorders among etaner- among control patients [5]. Rare cases of Merkel
cept patients [4, 5, 19]. Therefore, TNF inhibi- cell carcinoma have been reported in the post-
tors, including etanercept should be considered marketing period [5]. For all etanercept patients
with caution in patients with pre-existing CHF or at risk for skin cancer, full body skin examina-
demyelinating disorders [4, 5, 19]. tions are recommended [5].
Excluding lymphoma and NMSC, no differ- 12. Tyring S, Gottlieb A, Papp K, et al. Etanercept and
clinical outcomes, fatigue, and depression in pso-
ence in exposure-adjusted rates of malignancies riasis: double-blind placebo-controlled randomised
between etanercept and placebo-treated patients phase III trial. Lancet. 2006;367(9504):29–35.
have been observed in the controlled portions of 13. Shah SK, Arthur A, Yang YC, Stevens S, Alexis

etanercept clinical trials (across all indications) AF. A retrospective study to investigate racial
and ethnic variations in the treatment of psoria-
[5, 27]. sis with etanercept. J Drugs Dermatol. 2011;10(8):
In the pediatric population, malignancies 866–72.
including lymphoma and leukemia have been 14. Kircik LH. Topical calcipotriene 0.005% and beta-
reported, particularly among children or adoles- methasone dipropionate 0.064% maintains efficacy
of etanercept after step-down dose in patients with
cents taking concomitant immunosuppressive moderate- to-severe plaque psoriasis: results of an
agents [5]. open label trial. J Drugs Dermatol. 2011;10(8):
878–82.
15. Gambichler T, Tigges C, Scola N, et al. Etanercept
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Adalimumab for Psoriasis
13
Cooper B. Tye and Jennifer C. Cather
arthritis, a painful and potentially debilitating

Key Learning Objectives inflammatory arthritis (6–42% depending on the
1. To understand the mechanism of action population studied) [4]. Psoriasis is also associ-
of Adalimumab ated with a number of comorbidities including
2. To understand the appropriate use and obesity, cardiovascular disease, diabetes (Type
efficacy of the Adalimumab II), psychiatric disorders, and metabolic syn-
3. To understand the safety issues of drome [5–7]. Individuals with psoriasis may also
Adalimumab be at risk for other inflammatory diseases, such as
Crohn’s disease and Hidradenitis Suppurativa [8,
9]. A variety of treatment options are available
and patients with moderate to severe psoriasis are
Introduction
candidates for systemic therapy [10, 11]. A num-
ber of biologic agents have been approved for
Psoriasis is an immune-mediated inflammatory
psoriasis and additional molecules are currently
disease that affects 2–3% of the population world-
being studied in clinical trials [12]. Here we
wide [1]. Psoriasis patients experience episodic
review adalimumab (brand name Humira), a fully
flares with few spontaneous remissions. Psoriasis
human monoclonal IgG1 antibody that blocks
is characterized by scaling, erythema, and thick-
tumor necrosis factor alpha (TNF-a), a cytokine
ened plaques on the skin. In addition to physical
elevated in inflammation [13]. Adalimumab binds
symptoms, psoriasis patients often experience
both soluble and membrane-bound TNF-a and
psychosocial issues and have poor health related
blocks TNF-a interactions at the p55 and p75 TNF
quality of life (HRQoL) [2]. Psoriasis is a com-
cell surface receptors with high affinity.
plex disease, and onset results from a combination
of genes and the environment [3]. Additionally,
some patients with psoriasis develop psoriatic
Adalimumab
C. B. Tye Adalimumab was first approved in 2002 for rheu-

UT Health San Antonio School of Medicine, matoid arthritis. Today, it is approved for 10 indi-
San Antonio, TX, USA cations which include ankylosing spondylitis,
Crohn’s disease, fingernail psoriasis, hidradenitis
J. C. Cather (*) suppurativa (HS), juvenile idiopathic arthritis,
Mindful Dermatology, Modern Dermatology and
plaque psoriasis, psoriatic arthritis, rheumatoid
Modern Research Associates, Dallas, TX, USA

https://doi.org/10.1007/978-3-030-54859-9_13
154 C. B. Tye and J. C. Cather
arthritis, ulcerative colitis, and uveitis [14, 15]. umab every other week dosing in moderate to
Adalimumab is given by subcutaneous injection, severe psoriasis trial), CHAMPION (Comparative
with dosing dependent on indication. Adalimumab study of adalimumab versus methotrexate versus
is available as a single-use prefilled pen placebo in psoriasis patients), and ADEPT
(40 mg/0.8 mL) or a single-use prefilled syringe (Adalimumab efficacy and safety in psoriatic
(40 mg/0.8 mL or 20 mg/0.4 mL). Recently, a arthritis). Additionally, a number of biologic
citrate free formulation was approved which pro- comparator trials have been performed which we
vides for a better patient injection experience. will briefly describe; however, full details are
Adalimumab was the third TNF-inhibitor provided in separate chapters in this book.
approved for psoriatic arthritis and psoriasis and
other approved TNF-inhibitors for these indica-
tions include etanercept (brand name Enbrel), REVEAL
infliximab (brand name Remicade), and certoli-
zumab (brand name Cimzia). Golimumab (brand The pivotal phase III psoriasis trial, REVEAL,
name Simponi), is a TNF-inhibitor only approved was a 52-week, prospective multicenter, random-
for psoriatic arthritis. ized, double-blind placebo-controlled trial of
A number of guidelines of care for psoriasis 1212 moderate to severe psoriasis patients,
have been published, including American designed to examine efficacy, safety, and tolera-
Academy of Dermatology guidelines, [16–18] bility of adalimumab [13]. The criteria for enroll-
German guidelines, [19, 20] Canadian guide- ment was similar to many biologics trials, where
lines, [21] European guidelines, [22, 23], Italian individuals were at least 18 years old, had been
guidelines, [24] and British guidelines [25]. diagnosed with moderate to severe psoriasis for
Consensus statements have also explored moni- at least 6 months, and had stable psoriasis for at
toring and vaccinations with biologics [26] and least the past 2 months. Here, moderate to severe
monitoring comorbidities, [27] while others have psoriasis was defined as 10% or more body sur-
examined psoriasis treatment in a case-based face area affected, a psoriasis area severity index
manner [28, 29]. A chapter in this textbook is (PASI) of 12 or greater, or a physician’s global
dedicated to exploring the guidelines of care. assessment (PGA) of at least moderate severity at
Here we provide an overview of adalimumab the baseline visit. Treatment washout periods
in psoriasis and psoriatic arthritis, as well as in were required and similar to other biologic trials:
comorbidities including fingernail psoriasis, topical therapy (2 weeks), phototherapy (2 weeks
hidradenitis suppurativa, and include a very brief for UVB phototherapy and 4 weeks for PUVA),
mention of inflammatory bowel disease. We systemic therapies (4 weeks), and biologic thera-
review the pivotal phase III clinical trials for pso- pies (12 weeks, or 6 weeks for efalizumab). Low
riasis, psoriatic arthritis, fingernail psoriasis, and to mid-potency topical corticosteroids were per-
hidradenitis suppurativa, and ongoing safety and mitted on the palms, soles, face, and intertrigi-
monitoring considerations. We also provide nous areas. All potential participants were
insight into treatment of special populations as screened for latent tuberculosis, and if latent dis-
well as biologic comparator studies. Biosimilar ease was present, individuals could enroll as soon
data is included elsewhere in this text. as appropriate chemoprophylaxis for tuberculo-
sis was started. Patients with a history of chronic
recurrent infections, demyelinating disease, can-
Adalimumab in Clinical Trials cer, or lymphoproliferative disease were
for Psoriasis and Psoriatic Arthritis excluded.
The 52-week study trial design included 3 dif-
A number of clinical trials have been conducted ferent treatment periods. During the first
for psoriasis and psoriatic arthritis. REVEAL 16 weeks (Period A), patients were randomized
(Randomized controlled evaluation of adalim- 2:1, adalimumab to placebo. The adalimumab
13 Adalimumab for Psoriasis 155
group received 80 mg adalimumab at week 0 fol- Additionally, when looking at PASI scores, 79%
lowed by 40 mg adalimumab at week 1 and then of adalimumab treated patients achieved PASI75
40 mg every other week thereafter for 15 weeks, at 52 weeks, 54% achieved PASI90, and 32%
while the other group received placebo. Period B achieved PASI100. In the control group, 43% of
was defined as weeks 16–32 and at week 16, individuals achieved PASI75, 18% achieved
patients in the placebo arm received 80 mg adali- PASI90, and 8% achieved PASI100.
mumab, followed by 40 mg adalimumab every The REVEAL trial had an open label exten-
other week beginning in week 17. Also, at week sion (OLE) period that enabled participants to
16, all patients achieving a 75% or greater receive adalimumab therapy for approximately
response rate were entered into a 17-week open 3 years [30]. For those who achieved PASI75,
label extension, receiving 40-mg adalimumab efficacy was well maintained over the 3-year
every other week. Those who did not achieve period, using a last observation carried forward
PASI 75 were entered into a different open label (LOCF) analysis. A subanalysis examined con-
extension, receiving 40 mg every other week. sequences of when therapy was stopped and
Period C, weeks 33–52, was FDA mandated to restarted with adalimumab [30]. Efficacy was
examine loss of adequate response in patients slightly higher for those who received continu-
who had achieved PASI 75 at weeks 16 and 33. In ous adalimumab therapy compared to the
Period C this set of PASI75 responders were re- retreatment group (75% compared to 73% at
randomized 1:1 to adalimumab or placebo. Time week 108 using LOCF). Retreatment response
to loss of response and retreatment data were was greatest in patients who had experienced
obtained with this patient population. PASI50 or greater at the time retreatment was
At week 16, the primary efficacy endpoint of started.
at least a 75% improvement in PASI score Additionally, individuals who were part of the
(PASI75) was reported as 71% of patients in the REVEAL clinical trial, along with 3 other clini-
adalimumab group compared to 7% of placebo cal trials, who achieved PASI <75 by 16 weeks,
using intent to treat (ITT) analysis. In ITT, those achieved PASI50 to PASI <75 by 33 weeks, and
lost to follow-up are considered non-responders lost response at the end of the trial were eligible
in the analysis. PASI 90 and PASI 100 were to enroll in a long term OLE study. Patients who
achieved by 45% and 20%, respectively, in the completed 52 weeks of REVEAL were also eli-
adalimumab group at 16 weeks, compared to gible for this study. During the REVEAL OLE
only 2% and 1% in the placebo group. At week study, patients received adalimumab 40 mg twice
24, 70% of all patients had achieved PASI 75. At a month for at least 108 weeks, and their responses
week 33, the loss of adequate response phase was were analyzed relative to the REVEAL baseline.
initiated. Patients randomized to placebo lost At the end of the REVEAL OLE study, 88% of
response more frequently (28% compared to 5% treated patients achieved a PASI75, 57% achieved
in the adalimumab group), and the time to loss of a PASI90, and 38% achieved PASI 100. Also,
adequate response was shorter in the placebo 71% of these treated patients achieved a PGA of
group. clear or minimal.
At 33 weeks in the REVEAL study, patients Adalimumab was well-tolerated in the
who maintained a PASI75 while randomized to REVEAL trail. The majority of adverse effects
adalimumab treatment (n = 290) at the primary (AEs) were mild to moderate. Less than 2% of
endpoint were further randomized to treatment patients discontinued use due to adverse events
with adalimumab (n = 250) or placebo (n = 240). and there were no deaths. Infections included
At the end of the secondary endpoint of 52 weeks, upper respiratory tract infections, nasopharyngi-
68% of individuals randomized to the adalim- tis, and sinusitis. Injection site reactions were
umab treatment group maintained clear or mini- more common in the adalimumab group, occur-
mal diseased based on PGA, as opposed to 28% ring in 3.2% of the adalimumab group compared
of individuals in the placebo group [13]. to 1.8% of the placebo group. Serious adverse
events (SAEs) were comparable in both groups at of overweight individuals (BMI ≥25 but <30),
16 weeks. and 79% of individuals with a normal BMI (BMI
Because 16 weeks is not sufficient for identi- 18.5 < 25). There were no significant differences
fying AEs, a 3-year extension provides more in SAEs between adalimumab and placebo across
insight into potential safety concerns. During the subgroups. Subgroups examined included age,
3-year open label extension, adalimumab was sex, race, baseline weight intervals, baseline
well tolerated [30]. There were 2 cases of tuber- body mass index, disease duration, baseline
culosis, 5 candidiasis infections, and 2 deaths severity, prior treatments and comorbidities.
(coronary artery disease in a 75-year old man and Another subanalysis explored the effects of
unknown cause of death in a 47-year old man). comorbidities (e.g. hypertension, psoriatic arthri-
There were no cases of lymphoma, lupus-like tis, hyperlipidemia, obesity, depression, arthritis,
syndrome, or demyelinating disorders during this diabetes mellitus, and cardiovascular disease) on
period. One of the limitations of the open label patient reported outcomes [35]. Comorbidities
extension is that individuals whose dose esca- were associated with greater impairment in
lated to 40- mg every week were considered off HRQoL and work productivity, measured by the
protocol, and LOCF prior to dose escalation was Dermatology Life Quality Index (DLQI), Short
used in the analysis, although they were still Form 36 (SF-36) health survey, and WPAI ques-
receiving adalimumab. tionnaire. There were consistent improvements in
In addition to the physical symptoms of pso- DLQI, SF-36 physical component summary
riasis, psoriasis can also impact an individual’s score, SF-36 mental components summary score,
ability to work [31]. The effect of adalimumab on and WPAI in the group receiving adalimumab at
work productivity was examined using the Work 16 weeks. In an analysis of a phase II study,
Productivity and Activity Impairment (WPAI) patients receiving adalimumab also experienced
questionnaire during the REVEAL trial [32]. At a reduction of symptoms of depression compared
16 weeks, adalimumab decreased psoriasis to the placebo group, measured by the Zung Self-
related work productivity and activity impair- rating Depression score [36].
ment, and improvements in WPAI were seen in
the adalimumab treated group compared to the
placebo group, 15.5% and 11.1%, respectively. Champion
Individuals who were unemployed and had high
scores of total work productivity impairment and Another psoriasis trial of interest, CHAMPION,
total activity impairment also had measurably was conducted in Europe and Canada and
more severe psoriasis. When psoriasis symptoms included a comparator arm of methotrexate as
worsened, patients described increases in pain, well as a traditional placebo arm [37]. Patient
increased WPAI scores, and greater impairment inclusion criteria and washout periods were simi-
in mental and physical component summaries, lar to the REVEAL trial (described in detail
respectively [33]. above) except patients were required to be meth-
A number of subanalyses were also conducted otrexate and TNF-inhibitor naïve. CHAMPION
from the REVEAL trial. One analysis examined was a randomized, double blind, double dummy
if there were any differences in adalimumab effi- placebo-controlled trial, and 217 patients were
cacy or safety between different patient sub- randomized 2:2:1 to adalimumab (40 mg every
groups during the initial 16 weeks of the trial other week after an 80 mg loading dose), metho-
[34]. While improvement in psoriasis was seen trexate (7.5–25 mg weekly), or placebo.
consistently across most subgroups, decreased The primary endpoint was patients achieving
response to adalimumab occurred in patients a 75% improvement in PASI score at 16 weeks.
with greater weight or body mass index. This was At week 16, 79.6% of the adalimumab group
most apparent in obese individuals (BMI ≥ 30), achieved PASI75, compared to 35.5% of the
where 65% achieved PASI75, compared to 75% methotrexate group and 18.9% of the placebo
group. In addition, 16.7% of the adalimumab ADEPT

group, 7.3% of the methotrexate group, and 2%
of the placebo group achieved PASI100. This Adalimumab has also been studied in psoriatic
study has been acknowledged for using the tradi- arthritis. ADEPT was a phase III randomized,
tional systemic therapy methotrexate as an active double-blind, parallel-group, placebo controlled
comparator. It has also been criticized, because trial examining adalimumab efficacy and safety
the methotrexate arm was conducted for such a in psoriatic arthritis patients [40]. Like other pso-
short time period, and a successful methotrexate riatic arthritis trials, patients who had moderately
regimen typically takes a longer period of time to severely active psoriatic arthritis and a history
and has additional dose modifications. of inadequate response to non-steroidal anti-
Many patients reported adverse events, inflammatory drugs (NSAIDS) were eligible to
including 73.8% of the adalimumab group, participate. Patients were stratified by methotrex-
80.9% of the methotrexate group and 79.2% of ate use and psoriasis skin involvement (≥ 3%
the placebo group. Most adverse events were BSA or < 3%). Approximately half of patients
mild. Some (5% or 15 patients) withdrew from were taking methotrexate at baseline. Patients in
the study, and 8 of the withdrawals were for the adalimumab arm received 40 mg adalimumab
adverse events, including 1 from the adalim- subcutaneously every other week for 48 weeks. If
umab group, 6 from the methotrexate group, and improvement was not seen at week 12 (defined as
one from the placebo group. Elevated liver at least a 20% decrease in both swollen and ten-
enzymes were more common in the methotrex- der joint counts on 2 consecutive visits), partici-
ate group compared to the adalimumab or pla- pants could receive corticosteroids or disease
cebo groups, 9.1%, 1.9%, and 7.5% respectively. modifying anti-rheumatic drugs (DMARDS).
An additional analysis of the CHAMPION trial Primary endpoints were the American College of
examined adverse event free days during the Rheumatology 20% improvement (ACR20)
comparator arm of the trial [38]. Those in the response at week 12 and changes in modified
adalimumab group experienced more adverse- total Sharp score (mTSS) of structural damage at
event free days (36.9 days) compared to those in week 24. In addition, HRQoL was measured in
the methotrexate (8.3 days) or placebo (6.7) all patients. For those patients who also had 3%
groups over the 16-week period. While these or more body surface area of psoriasis, skin
data are encouraging, a limitation is the short improvement was also measured.
duration of the comparator arm, allowing only At 12 weeks, 58% of the adalimumab group
those adverse events occurring within the first achieved ACR20, compared to 14% of the pla-
16 weeks to be captured. cebo group. Patients in the adalimumab group
An analysis of the week 16 efficacy scores of had a modified Psoriatic Arthritis Response
adalimumab compared to methotrexate and pla- Criteria (PsARC) response rate of 62% at week
cebo stratified by baseline body mass index has 12, and 60% at week 24, compared to placebo
been published. At week 16, normal weight rates of 26% at week 12 and 23% at week 24.
(<25 kg/m2), overweight (25 to <30 kg/m2), and Adalimumab also inhibited joint destruction,
obese (> = 30 kg/m2) patients on adalimumab as is seen with the TNF-inhibitors etanercept and
had PASI75 responses of 85%, 85.7%, and 61.3% infliximab [41]. Radiographs were taken at base-
compared to 43.4%, 29.3%, and 26.1% with line, 24, and 48 weeks. The mean change in
methotrexate and 28.6%, 16.7%, and 0% for pla- mTSS at 24 weeks was −0.1 for patient receiving
cebo. Additionally, at week 16, the PASI90 adalimumab compared to 0.9 for those receiving
results were 70%, 53.6%, and 35.5% with adali- placebo. At 48 weeks, patients on adalimumab
mumab; 26.7%, 7.3%, and 8.7% with methotrex- showed a mean change in mTSS of −0.2. Erosion
ate, and 9.5%, 16.7%, and 0% for placebo. The scores were examined, and there was improve-
greatest DLQI improvements were seen in the ment in those receiving adalimumab (mean
adalimumab treatment arms [39]. change 0) compared to placebo (mean change
0.6). When joint space narrowing scores were ACR scores were obtained using an ITT analysis
examined, there was a mean change of −2 in the in the open label extension. Skin improvement
adalimumab group compared to 0.4 in those was also maintained at 48 weeks in the adalim-
receiving placebo. umab group, with response rates of 67%, 58%,
Skin symptoms also improved in those 46%, and 33% for PASI50, PASI75, PASI90, and
patients who also had psoriasis. Improvements in PASI100, respectively. In the group receiving
health-related quality of life, fatigue, and disabil- placebo until week 24, improvement was seen at
ity, measured using the DLQI, SF-36, Functional week 48, with response rates of 61%, 54%, 33%,
Assessment of Chronic Illness Therapy - Fatigue and 31% achieving PASI50, PASI75, PASI90,
(FACIT-Fatigue) Scale and HAQ DI were also and PASI100.
seen [42]. HAQ DI scores improved significantly Improvements in disability measurements
in patients receiving adalimumab compared to were also maintained at 48 weeks. When consid-
the control group. At 24 weeks, patients with pso- ering joint progression, patients receiving adali-
riatic arthritis treated with adalimumab saw mumab the entire time had a mean mTSS of −0.1
improvement of their HAQ DI score to 0.4, as at week 24, and − 0.1 at week 48, indicating sus-
opposed to a score of 0.9 in the placebo group. In tained control of progression. For those in the
addition, patients treated with 40 mg of adalim- placebo group until week 24 that then received
umab every other week showed a reduction rate adalimumab until week 48, mTSS were 0.9 and
in their HAQ DI burden of 47% and 49% respec- 1.0, respectively, indicating potential halting of
tively at 12 and 24 weeks, while those in the pla- progression at week 48. Improvements were also
cebo group had rates of 1% and 3% during the seen in joint erosion scores and joint progression
same time frame. scores through 48 weeks.
Regarding safety data from the ADEPT trial, Adalimumab was well tolerated during weeks
adverse events were similar between the adalim- 24–48, with the most common adverse events
umab and placebo groups at 24 weeks [40]. There being upper respiratory tract infections, naso-
were 12 serious adverse events, 7 in the adalim- pharyngitis, and injection site reactions. One
umab group and 5 in the placebo group. Treatment serious infection was reported (gastroenteritis)
was discontinued by 4 individuals because of and 10 other SAEs were reported. Elevated serum
adverse events, 3 in the adalimumab group and transaminase levels were also reported in 9
1 in the placebo group. Alanine aminotransferase patients. During the first 48 weeks there were no
levels (ALT) were elevated more frequently in deaths and no reports of tuberculosis or granulo-
patients in receiving adalimumab, and in most matous infections, demyelination, lymphoma or
cases ALT elevations were transient, resolving carcinoma, new antinuclear antibody formation,
without discontinuing adalimumab. Elevated drug-induced lupus, or congestive heart failure.
ALT levels were observed in individuals taking 2-year data has also been published from the
concomitant methotrexate, isoniazid, or alcohol. ADEPT trial, providing a better understanding of
At the end of the 24-week trial, participants efficacy and safety in patients with psoriatic
could continue into a 24-week open-label exten- arthritis [42]. The open-label extension of the
sion [43]. Adalimumab was given 40 mg subcuta- ADEPT trial was continued for 120 weeks, and
neously every other week after week 24 for data were available for 144 weeks after the begin-
24 weeks. Radiographs were taken at week 48, ning of the ADEPT trial. ACR20, ACR50, and
and safety data was collected. Many (n = 285) ACR70 scores at week 104 were 57.3%, 27.8%,
enrolled in the open-label extension, including and 29.9% respectively. PsARC response rates
138 from the adalimumab arm and 147 from the were 65.9% at week 48 and 63.5% at week 104.
placebo arm. ACR responses were maintained at All analyses used LOCF. Improvements in
48 weeks. Those on continuous adalimumab HRQoL and disability were also maintained.
therapy had ACR20, ACR50, and ACR 0 rates of Inhibition of radiographic progression was also
48%, 24%, and 20%, respectively at week 48. seen throughout the 144 weeks.
From baseline to week 48, 87% of adalim- one-third experience worsening of disease, and
umab treated patients had no progression, and the remaining third see no change in their pso-
79% of patients had no radiographic progression riasis [45]. Experts recommend using adalim-
at week 144, as evaluated with mTSS. At week umab with caution during pregnancy [46]. The
24, the mean change from baseline of mTSS was benefit/risk ratio is acceptable in first and sec-
−0.1 for the adalimumab treated group compared ond trimester for moderate to severe plaque
to 0.8 of the placebo group. The adalimumab patients and must be re-evaluated in the third
treated group also had mean changes of mTSS of trimester. Infants exposed to adalimumab in
0.1 and 0.5 at 48 and 144 weeks respectively. A utero should avoid live vaccines for 6 months.
subanalysis of the ADEPT trial examined risk Women who become pregnant while on adalim-
factors that predict radiographic progression umab, or any biologic, are encouraged to enroll
[44]. Elevated baseline C-reactive protein (CRP) in a pregnancy registry. Additionally, TNF-
(> = 1.0 mg/dl: odds ratio = 3.28) was a strong inhibitors are not typically used during lactation
independent risk factor for joint progression, and [47]. Interestingly, adalimumab has been stud-
treatment with adalimumab reduced the risk of ied during in vitro fertilization (IVF). Women
progression five-fold. Individuals taking adalim- with lower levels of TNF-a had better success
umab also experienced lowering of CRP levels rates with IVF, and there were no increases in
compared to controls. birth defects due to adalimumab treatment,
Over the 2 years, adalimumab was well toler- although the study was small (100 pregnant
ated, and adverse events were similar to what is women, 136 babies) [48, 49].
expected in rheumatoid arthritis patients.
Throughout 2 years of exposure, there were 5
opportunistic infections, 1 patient had peritoneal Pediatric
tuberculosis and 4 patients experienced oral can-
didiasis. Additionally, there was one case of non- Psoriasis in children can be challenging to treat,
Hodgkin’s B-cell lymphoma, 2 basal cell as few treatments have been studied in children.
carcinomas, and 1 neuroendocrine carcinoma of Etanercept has been studied in a pediatric psoria-
the skin. There were no reports of central nervous sis population and is reviewed in this textbook
system demyelinating disease, lupus-like syn- [50]. Adalimumab is approved in Europe for
drome, congestive heart failure, or adalimumab- pediatric psoriasis in ages 4 and older; however,
related allergic reactions. in the US, it is only approved for four pediatric
indications (Crohn’s Disease, Hidradenitis
Suppurativa, Uveitis and Juvenile Idiopathic
Adalimumab for Special Arthritis) [15, 51]. A phase 3 double-blind, mul-
Populations tiperiod trial was performed to evaluate the safety
and efficacy of adalimumab compared to weekly
Most clinical trials are conducted in adults, and methotrexate in children aged 4 up to 18 years of
there is limited data about TNF-inhibitor use in age with severe psoriasis unresponsive to topical
women of childbearing potential during preg- therapies. Children received adalimumab based
nancy, in children, in the elderly, and in rare situ- on their weight with significant improvement in
ations. Use of adalimumab in these special PASI75 [52]. A real-life retrospective multicenter
populations is reviewed below. analysis of children treated with adalimumab
over a 52-week period found that at week 16,
29.6% of patients achieved a PASI90, 55.5%
Pregnancy and Lactation achieved a PASI75. Results were sustained over
24 weeks and did not differ between biologic
Pregnancy can affect the severity of psoriasis, as naïve and biologic exposed patients. No serious
one-third of women experience improvement, infections were observed [53].
Elderly The main endpoint for the study was the num-
ber of patients achieving a PGA-F score of ≤1
Geriatric psoriasis patients pose additional man- with a ≥ 2 grade improvement from their base-
agement challenges. In the elderly, adalimumab line [56]. Another secondary endpoint was the
can be used as a first line therapy in patients with amount of patients achieving a mNAPSI 75 [56].
more extensive disease [54]. It is important that Also, beginning at week 16, patients whose base-
elderly patients are properly monitored, due to line BSA increased ≥25 were taken out of the
the higher general incidence of comorbidities study to an escape period [56]. At 26 weeks in the
which include cardiovascular disease, metabolic trial, patients’ mNAPSI and PGA-F scores were
syndrome, nonalcoholic fatty liver disease, infec- evaluated. The study found that 49% of patients
tions and malignancies. Lymphoma rates in receiving adalimumab achieved a PGA-F score
patients with psoriasis 65 years of age or older of clear or minimal, as compared to 7% of the
appear to be 3x higher than in age matched con- placebo group. 47% of adalimumab patients also
trols without psoriasis [55]. Additionally, achieved a mNAPSI75 compared to only 3% of
nonmelanoma skin cancers are more common in the placebo group [15, 57]. A decrease in nail
this demographic so skin cancer screening is pain in adalimumab treated patients was also
important. demonstrated in this study [15].
Fingernail Psoriasis Hidradenitis Suppurativa
Adalimumab was studied for its effectiveness Hidradenitis Suppurativa is a chronic inflamma-
in treating fingernail psoriasis using a phase 3, tory disease characterized by recurrent, painful
multicenter, double-blinded, randomized, sinus tracts, abscesses, and nodules [58]. Similar
placebo-controlled trial with parallel-arm. To to chronic psoriasis, HS is associated with
be eligible for the study, patients must have had increased levels of inflammatory cytokines,
moderate or worse severity plaque psoriasis, including TNF alpha [59], a delay in diagnosis,
ranked on the PGA scale, as well as moderate and significant psychological and physiological
or worse severity fingernail psoriasis, which comorbidities [60]. Individuals with psoriasis
was graded on a 5-point Physician’s Global have also been shown to be more likely to also be
Assessment of Fingernail Psoriasis (PGA-F) affected with HS [8].
scale. Eligible patients also had to have a Adalimumab has been studied for HS in the
Modified Nail Psoriasis Severity Index PIONEER 1 and 2 studies which were the first
(mNAPSI), a scale that judges patients’ finger- completed Phase 3 trials for HS [15, 61]. Briefly,
nail psoriasis based on the presence and sever- the induction dosing for patients with HS is the
ity of pitting, onycholysis, oil-drop dyschromia, same as inflammatory bowel disease patients and
splinter hemorrhages, and hyperkeratosis, ≥8 the maintenance dosing, which starts on day 29,
with a BSA involvement of ≥10%, or else have is a weekly 40 mg subcutaneous injection.
a mNAPSI of ≥20 with a BSA involvement of Adalimumab is the only FDA approved therapy
≥5% [56]. for HS. The safety profile of adalimumab in the
During the trial, 217 patients were random- PIONEER trials were consistent with other trials
ized to receive either adalimumab (n = 109) or [15, 61].
to a placebo group (n = 108). At week 0, patients
in the adalimumab group were given a loading
dose of 80 mg adalimumab, and then from week Generalized Pustular Psoriasis
1 on all patients in this group received 40 mg of
adalimumab subcutaneously every other week In Japan, an open-label 52-week study examined
[15, 56]. the safety and efficacy of adalimumab in 10
patients with generalized pustular psoriasis. Biologic Comparator Trials

Induction was similar to current psoriasis dosing;
however, if needed the patients could increase to Briefly, we will discuss some of the important
80 mg every other week. Seven of the patients plaque psoriasis trials in which a newer biologic
(including 3 who dose escalated to 80 mg) has been compared to adalimumab. More com-
achieved clinical response at week 16 and 5 plete details of these trials can be found in the
achieved clinical response at week 52 [62]. chapters that focus on the comparator drug.
1. Guselkumab
Inflammatory Bowel Disease (IBD) Voyage 1 and 2 Trials compared the safety
and efficacy of guselkumab (an anti-IL23
Psoriasis and inflammatory bowel disease, espe- monoclonal antibody) to adalimumab.
cially Chron’s disease share several epidemio- Additionally, data on withdrawal, retreatment,
logic factors, genetic similarities, and adalimumab non-responders treated with
inflammatory cytokine profiles [63–65]. A guselkumab, and maintenance data out to 1
retrospective US claims based study involving year was obtained. Guselkumab demonstrated
5492 pairs of patients with moderate to severe superior efficacy compared to adalimumab
psoriasis and their age, gender, and geographic [71, 72]. A secondary analysis of the trial
based matched controls found that psoriasis results has been published for the difficult to
patients had approximately 3.5 fold increase treat body regions, such as scalp, hands, feet,
prevalence of IBD [66]. Additionally, a prospec- and nails. Guselkumab was not superior to
tive study of women in the Nurses’ Health Study adalimumab when looking at efficacy in nails;
1 and 2 (n = 174,476) evaluated the incidence of however, it was superior for other difficult to
psoriasis and IBD. There were 2752 women in treat areas examined [73].
these two studies and in a pooled analysis the 2. Ixekizumab
women were found to have a four-fold increase in Two trials evaluated the efficacy of ixeki-
Crohn’s disease but no increase incidence of zumab versus adalimumab for the treatment
ulcerative colitis [67]. Patients with severe psori- of psoriatic arthritis: SPIRIT-P1 and SPIRIT-
asis and psoriatic arthritis have the highest risk H2H. Full details are described in the
for Crohn’s disease and ulcerative colitis [68]. Ixekizumab chapter in this text.
There are no known trials dedicated to the treat- In the SPIRIT-P1 trial, adult biologic naïve
ment of psoriasis patients who have concomitant patients with psoriatic arthritis achieved com-
IBD. However, both adalimumab and infliximab parable ACR results at week 24 with ixeki-
have demonstrated efficacy in psoriasis, psoriatic zumab or adalimumab. There was no added
arthritis, Crohn’s disease and ulcerative colitis value when methotrexate was used in combi-
[69]. nation with ixekizumab; however, adalim-
umab patients did better on combination
therapy [74].
Hemodialysis SPIRIT-H2H directly compared ixeki-
zumab and adalimumab with endpoint mea-
A case report involving a patient with psoriasis sures of ACR50 and PASI100 at week 24.
being treated with infliximab required transition Again, ixekizumab scores for ACR50 and
to adalimumab due to pulmonary edema thought PASI100 were not improved with concurrent
secondary to intravenous fluids at time of inflix- methotrexate use. However, adalimumab
imab infusion [70]. again demonstrated improved efficacy in
these measures when combined with metho- cination history, as well as personal or family
trexate [75]. history of inflammatory bowel disease history
3. Risankizumab and arthritis. A total body skin examination
IMMvent, a phase 3, randomized, double- should also be performed. Clinicians should also
blind, active-comparator-controlled trial inquire about social and lifestyle history, and
investigated adalimumab vs risankizumab for family planning if relevant. A number of labs can
the treatement of moderate-severe plaque pso- also be requested, including a complete blood
riasis [76]. Risankizumab showed signifi- count (CBC) and comprehensive metabolic panel
cantly greater efficacy in providing skin (CMP), Hepatitis screen (B and C), a human
clearance compared to adalimumab. immunodeficiency virus (HIV) screen if war-
ranted, and a tuberculosis test upon initiation and
yearly. Once systemic therapy is initiated, moni-
Practical Considerations toring patients on therapy is vital. Patients should
for TNF-Inhibitors have periodic total body skin examinations as
well as a yearly evaluation for tuberculosis [10].
There are a number of safety and practical consid-
erations for all TNF-inhibitors, including adalim-
umab [10]. TNF-inhibitors are contraindicated in Safety Update
patients with active, serious infections. Testing for
tuberculosis should be performed on all patients Leonardi et al. analyzed the long-term safety of
who will be treated with TNF- inhibitors. The adalimumab from 18 clinical trials involving
Centers for Disease Control (CDC) has released 3727 adults with plaque psoriasis. The cumula-
guidelines regarding testing for tuberculosis [77]. tive exposure was 5429.7 patient years. The
Additionally, live vaccines should not be used in adverse events remained stable with no new
patients receiving TNF-inhibitors. Demyelinating safety signals [78].
events, new onset or exacerbation of symptoms, In a recent review of safety registries involv-
may also occur under TNF-blockade. Anti-TNF ing adults with psoriasis, Strober et al. found that
therapy should not be used in patients with a his- across multiple registries the adalimumab safety
tory of demyelinating disease (e.g. multiple scle- data was consistent with the long-term safety
rosis, optic neuritis, and peripheral demyelinating data reported from the clinical trial experience
disease such as Guillain-Barre syndrome). Caution [79].
should be used in patients with congestive heart An analysis explored adalimumab safety in
failure. Patients should also be screened for hepa- 23,457 participants across 71 global trials, rheu-
titis B prior to receiving therapy, as TNF-blockers matoid arthritis (36 trials, n = 14,109), juvenile
may reactivate hepatitis B in patients who are car- idiopathic arthritis (3 trials, n = 212) ankylosing
riers of the disease. Many individuals experience spondylitis (4 trials, n = 1684), psoriatic arthritis
injection site reactions, although most are minor (4 trials, n = 837), psoriasis (13 trials, n = 3010),
and the citrate free formula has improved patients’ and Crohn’s disease (11 trials, n = 3606) [80].
injection experience. Malignancies, hepatotoxic- This analysis represented 12 years of adalim-
ity, and new onset psoriasis with anti-TNF therapy umab exposure, with 52.5% and 48.7% of
are also considerations. patients receiving concomitant immunosuppres-
Prior to initiating systemic therapy, including sant agents or concomitant systemic steroids,
adalimumab, a physical examination should be respectively. The majority of patients (60%) were
performed and a full medical history taken. It is rheumatoid arthritis patients, and approximately
important to ask about age appropriate cancer two-thirds received concomitant therapy. The
screening (pap smears, mammograms and colo- most frequently reported serious adverse events
noscopies), cancer history, infection history, vac- were infections, and these were most often seen
in the rheumatoid arthritis and Crohn’s disease In the controlled portions of adalimumab tri-
trials. Malignancy rates were as expected in als across all indications, adalimumab treated
adalimumab-treated patients compared with the patients had a rate of serious infections of 4.3 per
general population. There was an increase in 100 patient years (n = 7973) compared to a rate of
lymphoma incidence in patients with rheumatoid 2.9 per 100 patient years in placebo-treated
arthritis, but this increase was in the expected patients (n = 4848) [15]. These same trials
range of rheumatoid arthritis patients not on anti- showed a reported active TB rate of 0.2 per 100
TNF-therapy. Non-melanoma skin cancer rates patient years. The rate of positive purified protein
were elevated in rheumatoid arthritis patients, derivative conversion in this same study was 0.09
psoriasis patients, and Crohn’s disease patients. per 100 patient years [15]. Through 16 weeks of
While there may be some distinct differences in the REVEAL RCT trial, a rate of serious infec-
patient populations, no new safety signals were tions of 2.8% was observed in adalimumab
revealed. treated patients (n = 814) vs. a rate of 3.3% in the
placebo group (n = 398). From weeks 33–52, the
rates of infection among adalimumab treated
lack Box Warnings: Infection
B patients and the placebo group were 1.1%
and Malignancy (n = 250) and 2.4% (n = 240) respectively [13].
Tuberculosis rates for this study were 0.0% for
A series of warnings are detailed on the prescrib- both groups at the 16-week mark, and 0.0% and
ing information of adalimumab, including black 1.2% for the adalimumab and placebo treated
box warnings for serious infections and malig- groups, respectively, from 33–52 weeks [13]. In
nancies [81]. Patients taking adalimumab are at 30 psoriasis clinical trials, there was a rate of
increased risk of serious infection, and many who serious infection of 1.37% across 1403 adalim-
developed serious infections while taking adali- umab patients, as well as a rate of active tubercu-
mumab were also taking concomitant immuno- losis of 0.18% [82]. The ESPIRIT rate of serious
suppressants (e.g. methotrexate or infection per 100 patient years was 1.0 (n = 6045)
corticosteroids). Tuberculosis is a concern, and the rate of active tuberculosis was <0.1 [83].
including active tuberculosis and reactivation of Malignancies have been reported in patients
latent tuberculosis. All patients should be taking TNF-inhibitors, including hepatosplenic
screened for latent tuberculosis prior to initiating T-cell lymphoma (HSTCL), a rare and usually
therapy. If latent tuberculosis is present, anti-TB fatal T-cell lymphoma almost exclusively
therapy should be initiated prior to beginning reported in adalimumab-treated males with
adalimumab or any TNF-inhibitor. Because anti- Crohn’s disease taking concomitant azathioprine
TB therapy can increase liver function tests, and or 6-mercaptopurine. In the controlled phase of
in rare cases adalimumab can too, we wait a adalimumab trials across all indications, an equal
month after beginning anti-TB therapy before number of malignancies, including lymphomas,
starting adalimumab. Compliance with tubercu- were seen in the adalimumab group compared to
losis prophylaxis is key. Consultation with an the control group. These trials showed 0.7 malig-
infectious disease clinician for managing patients nancies per 100 patient years among 7973 adali-
with latent tuberculosis is recommended. Invasive mumab treated patients and 4848 placebo treated
fungal infections (e.g. histoplasmosis, coccidioi- patients. Lymphoma rates in these trials were
domycosis, candidiasis, aspergillosis, blastomy- 0.11 per 100 patient years [15]. In the REVEAL
cosis, and pneumocystosis) and opportunistic RCT, both adalimumab and placebo treated
bacterial (e.g. legionella, listeria) or viral infec- patients showed similar incidences of malignan-
tions have been reported. Patients presenting cies, with an incidence of 0.8 through 16 weeks
with a serious infection should discontinue and 0.0 from weeks 33–52. No lymphoma was
adalimumab. seen in this RCT [13]. The ESPIRIT 8-year post
marketing malignancy incidence was 1.1 in adali- Post-Marketing Safety Information

mumab treated patients (n = 6405) and the lym-
phoma rate was <0.1 [83]. A publication A number of additional safety signals have been
evaluating 13 adalimumab clinical trials for treat- observed in post-marketing surveillance of adali-
ment of moderate to severe plaque psoriasis with mumab [81]. Hypersensitivity reactions may
treatment for up to 5 years did not show cumula- occur, and anaphylaxis or angioneurotic edema
tive toxicity and adverse event rates were stable may be rare events. Allergic reactions were seen
or decreased over time [82]. in ~1% of patients taking adalimumab. There
There was an increased rate of non-melanoma have also been rare reports of hematologic reac-
skin cancer in adalimumab trials and it was more tions, including cytopenia, with TNF-therapy.
prevalent in those patients with previous immu- Adalimumab treatment may result in autoanti-
nosuppressant therapy and psoriasis patients pre- body formation, and in rare cases, the develop-
viously treated with PUVA. When considering ment of a lupus-like syndrome [89]. Demyelinating
lymphoma, more cases of lymphoma were disease [90], reactivation of hepatitis B infections,
observed in the TNF-blocker patients compared and worsening of congestive heart failure have
to controls. In adalimumab trials, 3 lymphomas been reported, underscoring the importance of
occurred in 6693 adalimumab treated patients appropriate screening. Elevations in liver enzymes
compared to 1 in 3749 patients in the control were also reported. TNF-inhibitors are acceptable
group, across 32 global trials. In 45 trials, the rate for patients with Hepatitis B and C as long as
of lymphoma was 0.11 per 100 patient years, appropriate monitoring and/or antiviral therapy is
approximately three-fold higher than that of the in place with hepatology and/or infectious disease
general population. Patients with chronic inflam- consultation [91, 92].
matory disease states such as rheumatoid arthri- A number of adverse events have also been
tis, psoriasis, psoriatic arthritis, hidradenitis and reported in post-marketing surveillance [81].
inflammatory bowel disease may be at a higher These include gastrointestinal disorders (diver-
risk for lymphomas than the general population, ticulitis, large bowel perforations including per-
even in the absence of therapies. In fact, several forations associated with diverticulitis and
studies have suggested that there is no increased appendiceal perforations associated with appen-
risk for lymphoma when using TNF inhibitors to dicitis, pancreatitis, ulcerative colitis [93], liver
treat these disease states [84–87]. More data is failure, sarcoidosis, nervous system disorders
needed at this time as post-marketing cases of (demyelinating disorders and cerebrovascular
acute and chronic leukemia have also been accident), respiratory disorders (interstitial lung
observed. Most patients who developed malig- disease, including pulmonary fibrosis, pulmo-
nancies were also receiving concomitant nary embolism), skin reactions (Stevens Johnson
immunosuppressants. Syndrome, cutaneous vasculitis, erythema multi-
It has been challenging to determine the rela- forme, new or worsening psoriasis (all sub-types
tionship between infection and malignancy and including pustular and palmoplantar) [94, 95],
TNF-inhibitors. A meta-analysis examined 20 alopecia [96], and vascular disorders (systemic
randomized, placebo-controlled psoriasis trials vasculitis and deep vein thrombosis).
of TNF-inhibitors, etanercept, infliximab, adali-
mumab, golimumab and certolizumab, with 6810
patients total [88]. There was a small increased Adalimumab Pearls
risk of infection (odds ratio 1.18) but no increased
risk of serious infection (odds ratio 0.7). There 1. Dose adjustments may be required.
was an increased risk of malignancy in the TNF- There are 10 different indications for adali-
inhibitor group compared to the control group mumab and multiple different dosing regi-
(odds ratio 1.48 for all malignancies and 1.26 mens. Ryan et al. evaluated in patients with
when nonmelanoma skin cancer was excluded). psoriasis or hidradenitis the safety of weekly
versus every other week dosing and found PASI 50, (of these 4 achieved PASI 75 and 1
similar adverse event rates [97]. Additionally, achieved PASI 90). No serious adverse events
optimizing therapy with temporary dose esca- were reported.
lation followed by de-escalation permitted the A sub-analysis of BELIEVE was also con-
achievement of long-term disease control in ducted to examine efficacy of adalimumab in
patients treated out to 252 weeks [98]. Dose patients treated previously with anti-TNF
escalation was not associated with additional agents [105]. BELIEVE was a double-blind,
safety concerns. Individualization of therapy randomized, controlled trial where patients
with adalimumab has been attempted by eval- received 80 mg at week 0 and 40 mg every
uating serum trough levels in 51 patients over other week of adalimumab with topical vehi-
time. Excellent responses were seen with cle or topical calcipotriol/betamethasone
serum trough levels at 6.46 micrograms per dipropionate once daily for 4 weeks and then
mL [99]. as needed [106]. The trial enrolled 703
2. Adalimumab is the market leader for the patients, with 38.6% having prior anti-TNF
treatment of psoriasis with concomitant pso- therapy compared to 61.4% who were naïve
riatic arthritis but newer agents are also to anti-TNF therapy. Nearly two-thirds
effective. (61.7%) of patients with prior anti-TNF ther-
Historically, TNF-inhibitors have been the apy achieved PASI 75 at week 16 compared to
treatment of choice for individuals with both 71.17% of anti-TNF naïve patients.
psoriasis and psoriatic arthritis [4]. An indi- Adalimumab was well tolerated, and adverse
rect comparison using individual patient data events were similar between those with previ-
from randomized clinical trials involving ous anti-TNF therapy and those without.
adalimumab (REVEAL and CHAMPION) as Another open-label phase IIIb trial, PRIDE
well as trials comparing etanercept to placebo (an open-label access program to evaluate the
found adalimumab significantly outperformed safety and effectiveness of adalimumab when
etanercept in PASI, DLQI, Patient global added to inadequate therapy for the treatment
assessment, symptom and lesion resolution, of psoriasis), was conducted in Canada, and
and adverse event [100]. examined adalimumab response in patients
TNF-inhibitors show synergy with metho- who had not responded previously to other
trexate, and patients with higher BMIs tend to psoriasis therapies [107]. The trial enrolled
do better on the monoclonal TNF inhibitors, 203 patients in the 24-week trial. Patients
including adalimumab [101, 102]. received 80 mg loading dose at week 0 and
Rotation within the TNF-inhibitor class is 40 mg every other week beginning at week 1,
possible, but there may be diminishing returns for 23 weeks. At week 16, 70.9% achieved
after trying two different TNF- inhibitors. A PASI 75. Adalimumab was generally well tol-
number of small studies have examined rota- erated with 9 patients reporting serious
tion within the TNF-inhibitor class. In one adverse events.
study, 30 patients who failed etanercept were As more experience and data is accumu-
transitioned to adalimumab [103]. Efficacy lated with the IL-17 inhibitors, there will be
was examined at weeks 12, 24, and 48, and erosion of the TNF-inhibitor market share
27%, 36%, and 54% achieved PASI75. since they also address both psoriasis and pso-
Adalimumab was well tolerated, and there riatic arthritis. Biomarkers are being evalu-
was no increase in adverse events for patients ated as predictors for response to both
receiving adalimumab who had previously TNF-inhibitors and IL-17 antagonists [108,
received etanercept. Another study examined 109].
14 patients with inadequate responses to etan- 3. Adalimumab is my treatment of choice for
ercept who were transitioned to adalimumab psoriasis patients or psoriatic arthritis patients
[104]. At 16 weeks, 9/14 (64%) achieved with hidradenitis suppurativa
Case series report success using adalimumab Complications of Not Treating

for patients with psoriasis and concomitant Psoriasis
HS [110]. Remember, HS requires a much
higher dose of adalimumab so even if HS is The majority of moderate to severe psoriasis
mild and psoriasis is the major reason for patients are not being treated as suggested by
therapy, consider the dosing regimen for HS guidelines. A National Psoriasis Foundation sur-
to ensure adequate disease control for both vey showed that nearly 40% of patients surveyed
diseases. were not in treatment for their psoriasis [113]. Of
4. Adalimumab is my treatment of choice for those who were in treatment, 57% of patients
psoriasis and or psoriatic arthritis patients with severe psoriasis were on topical therapy
with concomitant inflammatory bowel alone, and only 3% of these patients had ever
disease tried phototherapy, a systemic therapy, or a bio-
As described above, TNF-inhibitors are the logic. In a chart review of dermatologists treating
treatment of choice for patients with psoriasis 10 or more psoriasis patients per month, 40% of
and concomitant psoriatic arthritis and inflam- patients with severe disease received topical ther-
matory bowel disease. apy alone [114]. Additionally, individuals with
5. Pediatric data is available for plaque psoriasis psoriatic arthritis are also undertreated, with 59%
and adalimumab is approved in the EU; how- of patients diagnosed receiving no medication,
ever, it is not approved for psoriasis in the US biologic or topical, for their psoriatic arthritis
at this time. [115].
6. Clinic experience with biologics are different There are complications of not treating psoria-
than clinical trial experience. sis. Extensive psoriasis leaves an unresolved
As with all psoriasis therapies, it is impor- inflammatory burden in skin. In addition, there is
tant to understand real-world patient experi- an elevated systemic inflammatory burden that
ences. A real-world drug survival impacts comorbidities. New data suggests that
meta-analysis has been published (cut off for treatment with TNF-inhibitors can reduce the
study inclusion was Oct 2017). Thirty-seven risk of myocardial infarction [116]. Gkalpakiotis
studies with 32,631 subjects were included et al. have reported the results of their pilot study
and drug survival for all biologics decreased looking at the beneficial effects adalimumab has
over time dropping from 66% at year 1 to on biomarkers connected to cardiovascular dis-
41% at year 4 for etanercept, from 69% to ease [117]. A decrease in both E-Selectin and
47% for adalimumab, from 61% to 42% for IL-22 were seen after 3 months on adalimumab—
infliximab and from 82% to 56% for both are linked with cardiovascular disease and
ustekinumab [111]. A recent study examined more studies are needed to elucidate the impor-
patient reported reasons for discontinuing tance of this affect.
treatment [112]. Patients (n = 1095) with In addition to physical complications, there
moderate to severe psoriasis who received are also psychosocial implications. Untreated or
systemic treatment were interviewed. Of inadequately controlled psoriasis can impact
these, 200 patients received adalimumab in quality of life and physical functioning. Finally,
the past and were asked why they discontin- untreated psoriasis may have an economic impact
ued it. The top three reasons for discontinuing through time lost from work and reduced produc-
adalimumab were because it did not work tivity while at work. There are a number of appro-
well enough (34%), worked well at first but priate treatments for individuals with moderate to
stopped working well (22%), or non-life- severe psoriasis. Adalimumab is one of these
threatening side effects (14.5%). treatments and is a viable option for some.
Conclusion 8. Kridin K, Shani M, Schonmann Y, Fisher S, Shalom

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Lebwohl M. Psoriasis treatment patterns: results of a
Infliximab, Golimumab,
and Certolizumab Pegol 14
Jacob A. Mojeski and Robert E. Kalb
Abstract
1. To understand the mechanism of action
Psoriasis and psoriatic arthritis are common
of Infliximab, Golimumab, and
chronic inflammatory disorders that cause
Certolizumab Pegol
substantial physical, financial, and psychoso-
cial burdens for patients. Biologic therapy for
efficacy of the Infliximab, Golimumab,
these diseases has led to a major improvement
and Certolizumab Pegol
in the therapeutic armamentarium, and subse-
3. To understand the safety issues of
quently, patient quality of life. The tumor
Infliximab, Golimumab, and
necrosis factor alpha (TNFα) blocking class is
Certolizumab Pegol
one family of biologic therapy that has pro-
vided significant relief for patients. Infliximab
was the first TNFα inhibitor approved for use
in the United States in 1998 while golimumab
and certolizumab pegol are more recent addi- Introduction
tions. With over 20 years of clinical experi-
ence using TNFα inhibitors, physicians may The treatment of psoriasis and psoriatic arthritis
employ these agents in a manner that maxi- has undergone a revolution with the advent of
mizes efficacy while decreasing risks of biologic therapy providing patients with more
potential side effects. This chapter will pro- treatment choices and greater hope for sustained
vide a comprehensive review of the published symptomatic relief [1, 2]. Infliximab, golimumab
data on the safety and efficacy of infliximab, and certolizumab are all part of the Anti-TNF
golimumab, and certolizumab. class of drugs. Although these drugs have similar
profiles, each have specific therapeutic qualities
that can be taken advantage of in the clinical set-
ting. Infliximab and golimumab are known for
their rapid-onset of clinical efficacy while cer-
tolizumab has the added benefit of use during
pregnancy as minimal to no drug crosses the pla-
J. A. Mojeski · R. E. Kalb (*)
Department of Dermatology, School of Medicine centa or into breast milk.
and Biomedical Sciences, State University at of
New York at Buffalo, Buffalo, NY, USA
e-mail: [email protected]; [email protected]

https://doi.org/10.1007/978-3-030-54859-9_14
174 J. A. Mojeski and R. E. Kalb
Infliximab (Remicade) is one of the more nent of the typical IgG antibody structure, cer-
widely used tumor necrosis factor (TNF)-alpha tolizumab contains only a monovalent Fab
inhibitors, and has extensive clinical experience fragment of humanized anti-TNFa antibody [15].
in various immunologic conditions. It is a chime- Additionally, situated on the hinge region of the
ric human-murine monoclonal antibody, consist- drug are two polyethylene glycol chains, which
ing of human constant and murine variable confer its pegylated component (PEG) [16, 17].
regions and binds to both soluble and membra- Similar to other anti-TNF agents, Certolizumab
nous forms of TNF-alpha, thereby neutralizing has been FDA approved for multiple indications
the cytokine’s effect [3–6]. It was first approved in the treatment of various inflammatory dis-
by the U.S. Food and Drug Administration (FDA) eases. The current list of approved conditions
for the treatment of moderate to severe Crohn’s includes moderate-severe rheumatoid arthritis,
disease in August of 1998. Its use was later axial spondyloarthritis, psoriatic arthritis, psoria-
expanded to include the following indications: sis, and Crohn’s disease [18]. Dosing is via sub-
rheumatoid arthritis (11/1999), ankylosing spon- cutaneous injection and is typically standard
dylitis (12/2004), psoriatic arthritis (05/2005), throughout its indications. For psoriasis, it is
ulcerative colitis (09/2005), pediatric Crohn’s administered 400 mg Q2W and for psoriatic
disease (05/2006), psoriasis (09/2006), and pedi- arthritis dosing varies between 200 mg Q2W or
atric ulcerative colitis (09/2011) [7, 8]. For the 400 mg Q4W.
treatment of psoriasis and psoriatic arthritis the
drug is usually administered intravenously over 2
h, at a dosage of 5 mg/kg on weeks 0, 2, and 6, Mechanism of Action
followed by maintenance infusions every 8 weeks
thereafter [3, 9]. While the intravenous adminis- The specific mechanisms of immune-mediated
tration can be inconvenient, it is administered inflammatory diseases have yet to be fully eluci-
infrequently and has the benefit of rapidly achiev- dated, however, the over-expression of tumor
ing high serum concentrations, therefore offering necrosis factor (TNF) is believed to play a pivotal
the potential for rapid and sustained improve- role. This is documented by extensive investiga-
ment [4, 6, 10, 11]. tion and confirmed by the efficacy of anti-TNF
Golimumab (Simponi, Simponi Aria) is biologics in treating these disorders [14, 19, 20].
another member of the TNF antagonist family Numerous in vitro and in vivo studies have con-
and available in subcutaneous injection (Simponi) tributed to the knowledge base behind TNF-alpha
or IV formulation (Simponi Aria). It is a fully inhibitors, and it has been proposed that apopto-
human IgG1k monoclonal antibody that targets sis, reduction of pro-inflammatory cytokines,
both transmembrane and soluble forms of TNF- down-regulation of adhesion molecules, and
alpha with high affinity and specificity [12, 13]. increases in circulating T regulatory cells are the
As of 2017, both formulations of golimumab main mechanisms of action behind the efficacy of
have been FDA approved for use in numerous TNF-alpha inhibition [3, 13]. Infliximab, golim-
inflammatory diseases, including moderate- umab and certolizumab exert their anti-
severe rheumatoid arthritis, ankylosing inflammatory effects by binding to the soluble
spondylitis, and psoriatic arthritis either alone or and transmembrane forms of TNF-alpha. This
in combination with conventional agents. leads to inhibition of the induction of the inflam-
Subcutaneous golimumab has an additional indi- matory cascade and ultimately results in the rapid
cation for the treatment of ulcerative colitis [13, reduction in the number of cells at the site of
14]. Golimumab is self-administered as a 50 mg inflammation. Infliximab and golimumab have
or 100 mg subcutaneous injection once each the additional function of being able to induce
month or intravenously at 2 mg/kg for at weeks 0 complement-dependent cytotoxicity and
and 4 then every 8 weeks thereafter. antibody-
dependent cell-mediated cytotoxicity
Certolizumab Pegol (Cimzia) is a biologically through their Fc portions [20, 21]. Current devel-
unique anti-TNF agent. Lacking the Fc compo- opments in the biology of the TNF receptor path-
14 Infliximab, Golimumab, and Certolizumab Pegol 175
way have suggested pleotropic effects. There are neonatal FcRn-mediated transfer across the pla-
two antagonizing TNF receptor pathways includ- centa. Subsequently, minimal to no drug is deliv-
ing the TNF receptor 1 (TNFR1) and TNF recep- ered to the fetus of mothers being treated with a
tor 2 (TNFR2) pathways. The TNFR1 pathway certolizumab regimen [24–28]. This is a signifi-
signals most of TNF’s effects including inflam- cant advantage if anti-TNF therapy is required in
mation and cell death and is expressed ubiqui- a woman of child bearing potential.
tously whereas the TNFR2 pathway is only
expressed through immune cells, endothelial
cells, and multiple CNS cells and provides fficacy for Psoriasis and Psoriatic
E
homeostatic function [22, 23]. Recently, alterna- Arthritis
tive strategies in blocking TNF receptors are
being developed that target the TNF receptor-1 Infliximab
(TNFR1) pathway and augment the TNF recep-
tor-2 (TNFR2) pathway [22]. The first documented treatment response with
Importantly, the Fc region of an antibody, infliximab was published in a case report of a
which infliximab and golimumab contain, pro- patient with a long-standing history of Crohn’s
longs half-life and prevents premature degrada- disease with concomitant severe psoriasis [29].
tion of biologic drugs. Certolizumab does not The patient received a single infusion of inflix-
contain this Fc portion. The covalent linking of imab (5 mg/kg) and 4 weeks later there was a dra-
its PEG moiety to the hinge region of the anti- matic improvement in the severity of the
body increases the half-life of the drug and psoriasis.
decreases protease sensitivity [24]. Subsequently, a double-blind, randomized
Certolizumab’s safety profile during pregnancy trial was conducted in 2001 by Dr. Alice
and breastfeeding is thought to be due to its dis- Gottlieb’s research group (Fig. 14.1) [30]. The
tinctive lack of an Fc component. Because there trial enrolled 33 patients with clinically-defined
is no Fc region, the drug is unable to bind the moderate-severe plaque psoriasis who were ran-
Infliximab Therapy
Week 0 Week 10
PASI 42 PASI 1.8
Fig. 14.1 Before and after 10 weeks of intravenous infliximab therapy. A significant reduction in plaques is demon-
strated providing promising data of the benefits of infliximab in decreasing disease burden
domized to receive either intravenous placebo or 5 mg/kg, or placebo administered at weeks 0, 2,

intravenous infliximab in either 5 mg/kg or and 6 [31]. At week 10, 72% and 88% of the
10 mg/kg dosages at weeks 0, 2, and 6. Three patients treated with 3 mg/kg and 5 mg/kg of inf-
patients withdrew from the study, one from each liximab, respectively, achieved a 75% or greater
treatment group. At week 10, 9 of the 11 (82%) improvement using the PASI evaluating system
patients in the infliximab 5 mg/kg group and 10 in comparison to only 6% of patients in the pla-
of the 11 (91%) patients in the infliximab 10 mg/ cebo group (p < 0.001). Furthermore, 46% of
kg group were considered responders (clear or patients treated with 3 mg/kg and 58% treated
almost clear rating according to the PGA) com- with 5 mg/kg reached a 90% improvement in
pared to only 2 of 11 (18%) receiving placebo PASI score compared to only 2% of the patients
(p < 0.01). Additionally, nine of 11 (82%) in the in the placebo group (p < 0.001). Quality of life
infliximab 5 mg/kg group and 8 of 11 (73%) in scores were also improved with the use of inflix-
the infliximab 10 mg/kg group achieved at least a imab. This study was notable for rapid clinical
PASI 75 compared with only 2 of 11 (18%) in the improvement after only 2 weeks in each treat-
placebo group (p < 0.05). In both infliximab- ment group [31].
treated groups, the median time to response was In 2005 and 2007, data from two large phase
only 4 weeks. This trial provided promising data III multicenter, randomized, double-blind
for the high degree of clinical benefit and rapid placebo-controlled studies emerged -- EXPRESS
time to response in the treatment of moderate- I and EXPRESS II (Fig. 14.2) [32, 33]. These
severe plaque psoriasis with infliximab. studies further demonstrated the dramatic effec-
Numerous randomized controlled trials followed tiveness of infliximab in patients suffering from
to confirm this initial success. moderate-severe plaque psoriasis. In EXPRESS
In the multicenter, double-blind phase II I, patients were allocated to receive infusions of
SPIRIT trial by Gottlieb et al. in 2004, patients either 5 mg/kg of infliximab or placebo at weeks
with severe plaque psoriasis were randomly 0, 2, and 6, and then every 8 weeks thereafter to
assigned to receive infusions of either 3 mg/kg, week 46 [33]. Beginning at week 24, the patients
Infliximab phase III study efficacy
EXPRESS EXPRESS II
80 82
78 78
61
57 58 56 55
% of Patients
45 43
34
n=301 n=276 n=281 n=150 n=141 n=134
PASI 75 PASI 90
Fig. 14.2 PASI response to IV infliximab therapy at weeks 10, 24, and 50. At week 10, approximately 80% of patients
in the EXPRESS and EXPRESS II trials achieved PASI 75. This response was largely maintained through week 24 with
82% of patients in the EXPRESS trial achieving PASI 75 and 78% achieving PASI 75 in the EXPRESS II trial
in the placebo group crossed over to receive inf- group, and this response was also maintained
liximab treatments. Although remarkable clinical through week 50 (p < 0.0001 for week 24)
improvements were noted at week 6 (after only (Fig. 14.5) [32].
two infusions), by the end of the induction period The EXPRESS II trial also documented the
(week 10) 80% of patients treated with inflix- efficacy of infliximab in a placebo-controlled
imab achieved PASI 75, with 57% reaching at protocol (Fig. 14.2) [33]. This trial compared the
least a 90% improvement (PASI 90), and 26% of efficacy of continuous therapy (every 8 weeks)
patients achieving complete clearing of the skin versus intermittent (as needed) maintenance regi-
(a score of 0 in PASI). This is in comparison to mens. Patients were randomized to induction
3%, 1%, and 0% in the placebo group, respec- therapy at weeks 0, 2, and 6 with infliximab
tively (p < 0.0001). These responses were main- 3 mg/kg, 5 mg/kg, or placebo. At week 14, the
tained through week 50, with 82% and 61% of infliximab group was then further randomized to
patients attaining a PASI 75 at weeks 24 and 50 continuous or maintenance regimens at their
(Figs. 14.3 and 14.4) [32]. Additionally, inflix- originally designated dose. Through week 50,
imab therapy was noted to have a significant this study demonstrated that the clinical response
effect on nail manifestations of psoriasis, a to treatment was best maintained using continu-
traditionally treatment-resistant disease. Nail
ous infliximab therapy compared to an as-needed
Psoriasis Severity Index (NAPSI) improvements basis in both dosage groups. The median of the
were noted as early as week 10 in infliximab- average percent improvement in PASI from week
treated patients. At week 24, there was a 56% 16 through week 50 was 89.6% in the 5 mg/kg
mean decrease of the NAPSI in the infliximab every 8-week group compared to 76.4% in the
Median Serum concentration of infliximab

through week 50 in week 10 responders
Infliximab 5 mg/kg
100
Median Serum Infliximab
Concentration (µg/mL)
10
< 0.1
Week 0 2 6 10 14 22 30 38 46 50
Infusion
Responders at Week 10 and

Maintain Response at Week 50 (n = 56)
Responders at Week 10 and
Do Not Maintain Response at Week 50 (n = 19)
Fig. 14.3 Difference in median serum infliximab concentration between responders and non-responders in EXPRESS
and EXPRESS II trials. As an independent predictor of treatment response, patients that responded to infliximab therapy
had a significantly higher median serum concentration of infliximab than nonresponders
Infliximab therapy
Baseline Week 24
Fig. 14.4 Clinical response to Infliximab. Another example of disease improvement on IV infliximab therapy during
the EXPRESS trials. A patient with significant baseline disease burden achieves almost a complete response after 24
weeks of infusions
as-needed group (p < 0.001). Similar results were assigned to receive infusions of either 5 mg/kg
obtained for the 3 mg/kg group as well, with of infliximab or placebo at weeks 0, 2, 6, and 14.
80.6% improvement in the continuous group ver- After week 16, patients initially assigned to
sus 72.4% in the as-needed group (p < 0.001). receive placebo were crossed over to receive inf-
Furthermore, the authors showed that a 5 mg/kg liximab, and all groups received 5 mg/kg of inf-
dosage regimen achieved superior induction and liximab every 8 weeks through week 50. At week
maintenance scores compared to the lower dos- 16, 65% of patients treated with infliximab
age. Patient assessments across treatment groups attained an ACR20 response, compared to only
were consistent with the PASI scores, as the con- 10% of placebo-treated patients (p < 0.001). In
tinuous infusion of 5 mg/kg group reported the addition, 46% of the infliximab group produced
greatest improvements in their DLQI quality of an ACR 50 response and 29% an ACR 70
life scores. response, where no placebo-treated patients
Also in 2005 and 2007, the IMPACT I and II achieved either of these end points (p < 0.001).
trials were conducted as randomized, Furthermore, at the 16-week evaluation 75% of
double-blind placebo-controlled studies enroll- infliximab-treated patients were improved
ing patients with psoriatic arthritis in whom according to the PsARC, compared to only 21%
prior therapy with at least one disease-modifying of placebo-controlled patients (p < 0.001).
anti-rheumatic drug (DMARD) had previously Additionally, although secondary endpoints the
failed [34, 35]. In IMPACT I, patients were infliximab group showed substantial improve-
Infliximab therapy
Baseline Week 24
Fig. 14.5 Infliximab in patients with nail disease. Nail Psoriasis Severity Index (NAPSI) improvements were noted
during the EXPRESS and EXPRESS II trials. By week 24, a 56% mean decrease in NAPSI was achieved in the inflix-
imab treatment group
ments in in psoriatic skin disease as well as the ficient dose for a majority of patients. Dose esca-
percentages of patients suffering from the com- lation from 5 mg/kg to 10 mg/kg was assessed in
mon complications of psoriatic arthritis, namely 15 non-responders (patients who did not achieve
dactylitis and enthesitis [34, 35]. ACR 20). Interestingly, in the patients requiring
The IMPACT II trial was a 54-week multi- dose escalation, patients who had not achieved an
center study designed to expand the published ACR 20 score before escalation did not achieve
clinical response data from the initial, 24-week, ACR 20 despite doubling of the drug dosage.
double blind placebo-controlled period [36] with Furthermore, dose escalation did not appear to
an expansion of the number of enrolled patients significantly improve PASI responses. Out of the
[35]. As previously reported, these results dem- 15 patients who receive dose escalations, only 12
onstrated significant improvements in the signs had a baseline BSA of 3% or greater and were
and symptoms of psoriasis and psoriatic arthritis, therefore included in the PASI analysis. Five of
as well as quality of life and physical functioning these patients achieved a PASI 75 at week 38 and
in patients through 1 year of treatment. Another maintained that response through week 54.
outcome assessed was attainment of a “major Conversely, the seven patients who did not
clinical response,” which is defined as ACR 70 achieve a PASI 75 response at week 38 were
improvement for 24 consecutive weeks. At week unable to achieve the response after dose escala-
54, major clinical response was achieved by tion. Overall, these studies show that infliximab
12.1% of the infliximab-treated group. The therapy significantly reduces the signs and symp-
authors also demonstrated that 5 mg/kg is a suf- toms of psoriatic arthritis in patients that were
resistant to other treatment modalities and these PsARC) and skin (PASI) outcomes from
benefits were sustained through 1 year of 12–14 weeks [38]. Etanercept appears to be
therapy. slightly less efficacious than its counterparts,
In August 2011, the first documented head-to- demonstrating 50% of patients attaining a PASI
head, randomized trial (RESTORE 1) comparing of 75 at 12 weeks. Authors of a recent network
the efficacy and safety of infliximab versus meth- meta-analysis concluded that, anti-TNF agents
otrexate was published [37]. 868 methotrexate- may be slightly less efficacious compared to anti-
naïve patients were randomized to receive 5 mg/ IL17 and anti-IL12/23 inhibitors, but are more
kg of infliximab at weeks 0, 2, 6, 14, and 22 or effective than anti-metabolites such as metho-
15 mg weekly methotrexate with a dose increase trexate [39]. Anti-TNF agents have the advantage
to 20 mg weekly at week 6 if the PASI response in terms of a well-known long term side effect
was <25%. Patients with less than a PASI 50 based on over 20 years of experience.
response were allowed to switch treatment groups Promising data was recently published in The
at week 16. At week 16, a PASI 75 response was Lancet pertaining to the efficacy of a biosimilar
achieved by 508/653 (78%) of infliximab-treated to infliximab known as CT-P13 which was
patients compared to 90/215 (42%) of patients approved by the FDA in 2016 for all indications
receiving methotrexate, and this response was of infliximab after its patent expired in 2015. A
maintained throughout the 26-week study treatment switch was performed in a Norwegian
(p < 0.001). Key secondary endpoints, including 52-week randomized, double-blind study known
PGA, DLQI, and PASI 90 were likewise achieved as NOR-SWITCH. Patients were enrolled from
by a greater proportion of infliximab-treated each inflammatory condition that infliximab is
patients. More impressively, 46/63 (73%) patients currently indicated for including plaque psoria-
who switched from methotrexate to infliximab at sis, psoriatic arthritis, Crohn’s disease, ulcerative
week 16 demonstrated a PASI 75 at week 26. colitis, rheumatoid arthritis, and ankylosing
Although the incidence of severe adverse events spondylitis. In a 1:1 ratio, patients were either
was slightly higher in the infliximab group (7% continued on infliximab or switched to CT-P13
vs. 3%), a majority of the serious adverse events treatment with unchanged dosing regimen. The
were infusion-related reactions, and the overall study showed that switching therapy to this bio-
adverse event incidence was comparable between similar was not inferior to continued treatment
groups. The study demonstrated that infliximab with infliximab. However, the study was not pow-
was both well tolerated and more efficacious than ered sufficiently to suggest non-inferiority in
methotrexate in patients with moderate-severe individual disease processes. With a cost-saving
plaque psoriasis. Moreover, infliximab was of up to 69% when compared to infliximab, the
proven to be a successful alternative agent in use of this drug and introduction of other biosim-
patients who had previously failed methotrexate ilars can significantly improve access to biologic
therapy. therapies and lessen the financial burden of these
While all biologics have performed well in medications [40].
short-term clinical trials, very limited direct com- One of the major advantages of infliximab is
parisons between agents are available, particu- that it has a weight-based dosing on a milligram
larly for psoriasis. However, since most studies per kilogram basis unlike a majority of the TNF
used similar designs and end points, limited com- antagonists used to treat psoriasis [41, 42]. This
parisons from randomized controlled trials are allows for a more individualized patient-tailored
possible. Adalimumab and infliximab appear to therapy, which is particularly important as
have similar efficacy, with 70–80% of patients patients with psoriasis are typically above aver-
achieving a PASI 75 score at 12 weeks [9]. age weight [41, 42]. Additionally, a few studies
According to a systematic review by Rodgers have demonstrated the continued efficacy of inf-
et al., infliximab is associated with the highest liximab regardless of body mass index, whereas
probability of response on joint (ACR and the efficacy of fixed-dose TNF antagonists may
Infliximab: BMI and efficacy
100
77.5 78.3
80 74.4
Percent of Patients
60
40
20
5.0
1.7 2.6
0 n=60 n=231 n=121 n=373 n=155 n=519
Normal (<25) Overweight (25-30) Obese (≥30)
Body Mass Index
Placebo Combined Infliximab Groups
Fig. 14.6 Infliximab and BMI. There is no significant difference between normal weight patients and obese patients in
achieving an efficacious response with fixeddose infliximab suggesting that there may be no need for weight-based
dosing
be compromised [41–43]. In one study in JAAD cellular infiltration at 4 weeks of therapy [49].
(Fig. 14.6), there was no significant difference Additionally, an open-label study (RESPOND
between the number of patients who achieved an study) was conducted comparing the efficacy and
efficacious response with a BMI greater than or safety of methotrexate alone versus methotrexate
equal to 30 (74.4%) compared to those of normal in combination with infliximab in patients suffer-
body weight (77.5%) [43]. ing from psoriatic arthritis [50]. 115 methotrexate-
naïve patients were randomly assigned to receive
either 15 mg/week of methotrexate plus inflix-
Combination Therapy imab 5 mg/kg at weeks 0, 2, 6, and 14, or metho-
trexate therapy alone (15 mg/week). At week 16,
Currently, there is some evidence to suggest that 86.3%, 72.5%, and 49.0% of patients receiving
patients with psoriasis may obtain an improved combination therapy compared to 66.7%, 39.6%,
response from combination therapy with inflix- and 18.8% of patients receiving methotrexate
imab and another therapeutic agent such as meth- alone achieved ACR 20 (p = 0.021), 50
otrexate, cyclosporine, acitretin, narrow-band (p = 0.0009), and 70 (p = 0.0015) responses,
UVB (nb-UVB) phototherapy, azathioprine, and respectively. With regards to skin disease, patients
apremilast [44–49]. A retrospective analysis of whose baseline PASI was 2.5 or greater, 97.1% of
23 patients receiving infliximab in combination those on combination therapy and 54.3% of those
with methotrexate or azathioprine showed PASI on methotrexate alone experienced a 75% or
50 improvements by 91.3% of patients. A pro- greater improvement in PASI scores (p < 0.0001).
spective study performed by Goedkoop et al. Importantly, combination therapy was deter-
showed that infliximab plus methotrexate therapy mined to be generally well-tolerated by the
decreased PASI score and biopsy findings from patient population. In the infliximab plus metho-
the patients showed decreased angiogenesis and trexate group, 46% had treatment-related adverse
events (2 serious AEs) while the methotrexate ate combination therapy [52]. Whether combina-
alone group experienced 24% AEs (no serious tion therapy with all TNF antagonists, including
AEs). While the overall incidence of adverse infliximab, will be more effective in improving or
events was higher in the combination therapy maintaining response are important questions to
group, a majority of the events were mild to mod- be answered for patients with psoriasis.
erate. Overall, this study suggested potential ben- As previously mentioned, maintaining the
efit of combination therapy for patients with high initial response with infliximab therapy for
psoriatic arthritis. a chronic disease such as psoriasis remains a
In 2010, the New England Journal of Medicine challenge. The mechanisms for loss of response
published a randomized, double-blind trial com- include antibodies to infliximab, tolerance to the
paring the efficacy of infliximab monotherapy, drug, and drug metabolism for individual
azathioprine monotherapy, and the combination patients [7, 53–58]. Predictors of continued
of the two drugs in patients with Crohn’s disease response include serum levels of infliximab at
[51]. 508 patients with moderate to severe the time of infusion (Fig. 14.3) [32], as well as
Crohn’s disease were randomized to receive effective trough plasma concentrations [57].
either 5 mg/kg infliximab at weeks 0, 2, 6, and Approximately 10% of patients with Crohn’s
then every 8 weeks thereafter, 2.5 mg/kg oral disease and rheumatoid disease in clinical trials
azathioprine daily, or combination therapy with have developed antibodies [59], and reports of
the two medications (with the monotherapy up to one-third of patients with psoriatic disease
groups also receiving either oral or infusion pla- [33, 60]. Studies have established relationships
cebos). At week 26, 56.8% of the patients receiv- among antibody formation and low serum drug
ing combination therapy were in steroid-free levels or failure and loss of response in patients
clinical remission compared to 44.4% of those with rheumatic and inflammatory bowel disease
receiving infliximab alone (p = 0.02) and 30.0% [61–65]. In psoriasis, elevated levels of antibod-
receiving azathioprine alone (p = 0.006 for com- ies were discovered in non-responders, and
parison with infliximab and p < 0.001 for com- authors concluded that they appeared to play a
parison with combination therapy). At week 50, a role in the lack or regression of response [33,
similar trend was obtained with 46.2% of patients 66, 67]. In one trial in particular, patients with
on combination therapy, 34.9% on infliximab an initial response to infliximab positive for
alone (p = 0.04), and 24.1% on azathioprine antibodies to the drug at week 10 were less
alone (p = 0.03 for comparison with infliximab likely to maintain a good response at 1 year than
and p < 0.001 for comparison with combination their antibody-negative counterparts [33].
therapy) maintaining clinical remission status. Recently, a retrospective cohort study of 93
Safety data was generally similar among groups patients receiving infliximab therapy for psoria-
with serious infections occurring in 3.9% of the sis was performed to assess dosing techniques
combination group compared to 4.9% in the inf- for prolonged infliximab response. The authors
liximab group and 5.6% in the azathioprine confirmed that concomitant methotrexate use
group. While this study documented the incre- was associated with increased time to discon-
mental benefit of combination therapy for tinuation or dose escalation, likely due to its
Crohn’s disease, controlled data are lacking in ability to decrease the formation of anti-inflix-
psoriasis. Only two randomized control trials imab antibodies. Additionally, increased dosing
have been performed to date assessing efficacy of frequency, as compared to increasing the size of
combination therapy in plaque psoriasis with the dose, lead to statistically significant increase
both involving etanercept with methotrexate. in time to discontinuation or dose escalation
Each showed superior efficacy compared to etan- [58]. Thus, in order to maintain response, physi-
ercept monotherapy. Another trial known as cians may either start with methotrexate in com-
OPTIMAP is underway currently that will assess bination with infliximab or add methotrexate
the performance of adalimumab and methotrex- during therapy.
Golimumab week 14 [68]. This was compared to only a 3%

PASI 75 response in placebo-treated patients
Subcutaneous and intravenous golimumab have (p < 0.001). This beneficial response was main-
shown impressive efficacy results in patients with tained through week 24 in both golimumab
psoriatic arthritis. Although one may expect that groups (56% and 66% for 50 mg and 100 mg)
the effects of golimumab in the treatment of whereas only 1% of patients in the placebo
plaque psoriasis are comparable to other TNF group reached a PASI 75 at this time marker
antagonists with a similar benefit in psoriatic (p < 0.001). At week 104, data revealed a PASI
arthritis, there are no published trials directly 75 of 68.8% of patients in the 50 mg group and
assessing the effects of this medication in plaque 76% in the 100 mg golimumab group [12, 68,
psoriasis to date. Therefore, it is not known how 69]. However, the trial failed to show consistent
golimumab compares to other TNF inhibitors in difference in PASI score in patients treated with
the treatment of moderate to severe plaque a golimumab regimen compared to patients with
psoriasis. baseline methotrexate use [69]. This study gave
With regards to psoriatic arthritis, In a ran- significant evidence that subcutaneous golim-
domized, placebo-controlled, multicenter clini- umab improved the clinical signs and symptoms
cal study (GO-REVEAL), 405 patients with of psoriatic arthritis, along with associated skin
active psoriatic arthritis were enrolled and ran- and nail disease, as well as physical functioning
domly assigned to receive subcutaneous injec- and quality of life [12, 68, 69].
tions of placebo, golimumab 50 mg, or Intravenous golimumab has had similar effi-
golimumab 100 mg every 4 weeks [68]. At week cacy results as evidenced by the GO-VIBRANT
14, 51% and 45% of patients receiving golim- trial. In the phase III, randomized, double-blind,
umab 50 mg and 100 mg respectively, achieved placebo-controlled trial, patients with psoriatic
an ACR 20 response, compared with only 9% of arthritis were assigned to IV placebo or golim-
patients receiving placebo therapy (p < 0.001). umab at 2 mg/kg at weeks 0, 4, 12, and 20. A
At week 24, an ACR 20 response was observed primary endpoint of ACR20 response was
in 52% of patients in the 50 mg group and 61% assessed and was achieved by 75.1% of patients
in the 100 mg group, versus 12% of patients in the golimumab group compared to 21.8% of
receiving placebo (p < 0.001). The trial contin- patients in the placebo group (p < 0.001).
ued and an impressive 279 patients completed Additionally, greater mean changes were
five total years of therapy. At the five-year con- observed in each of the secondary endpoints of
clusion of the study, ACR20, 50, and 70 scores the study. ACR50 and ACR70 responses were
were 62.8–69.9%, 43.4–50.7%, and 30.8– found in 43.6% and 24.5% of golimumab-
35.6%, respectively. This showed that golim- treated patients compared to only 6.3% and
umab not only made significant clinical 2.1% in placebo group, respectively.
improvements for patients, but the therapy also Additionally, 59.2% of golimumab-treated
had significant longevity. Improvement in dac- patients enrolled in the study achieved PASI75
tylitis and enthesitis scores, as well as nail pso- response compared to only 13.6% of placebo
riasis severity was evident. Patient’s PASI scores patients. This study suggests comparable effi-
were determined as a secondary endpoint and cacy of both formulations of golimumab in the
showed improvement against placebo. In treatment of psoriatic arthritis. Again, although
patients who were suffering from at least 3% this gives some evidence toward the use of goli-
BSA involvement of skin psoriatic disease, 40% mumab for the treatment of plaque psoriasis, a
in the 50 mg golimumab group and 58% in the randomized control study would be more effec-
100 mg golimumab group had at least 75% tive to determine golimumab’s place in the man-
improvement in their skin disease (PASI 75) by agement of the condition [70].
Certolizumab tions every 2 weeks and patients were assessed at

16 weeks and 48 weeks. At week 16, patients
Certolizumab has significant promise in the man- enrolled in CIMPASI I and II achieved PASI 75
agement of both moderate-severe plaque psoria- responder rates of 75.8% and 82.6%, respectively
sis and psoriatic arthritis. With regards to plaque in the certolizumab 400 mg group and 66.5% and
psoriasis, there have been three phase 3 trials 81.4%, respectively in the certolizumab 200 mg
(CIMPACT I, CIMPASI I, and CIMPASI II). The group. When compared to patients receiving only
CIMPACT trial compared certolizumab against placebo therapy, 6.5% of patients in CIMPASI-I
etanercept and placebo while CIMPASI I and II and 11.6% of patients in CIMPASI-II receiving
were solely placebo-controlled studies. The placebo achieved PASI 75 (P < 0.001). These
CIMPACT trial results showed that the use of results were largely maintained throughout the
certolizumab for patients with chronic plaque 48-week trial (Fig. 14.8). Additionally, pooled
psoriasis was associated with a significant differ- analysis of both trials showed impressive PASI
ence in PASI 75 scores compared to placebo. 100 response rates of 34.5% for certolizumab
Additionally, when directly compared to its anti- 400 mg and 28.5% for certolizumab 200 mg.
TNF counterpart etanercept, certolizumab End-points of Dermatology Life Quality Index
400 mg was superior to and 200 mg was non- and Physician Global Assessment also showed
inferior to etanercept (Fig. 14.7) [28]. significant improvement [71].
In the randomized-control CIMPASI I and II Certolizumab’s use in the management of pso-
trials patients were enrolled and assigned to 2:2:1 riatic arthritis was studied in a 4-year trial
treatment groups consisting of certolizumab (RAPID-PsA) performed in patients treated with
400 mg, certolizumab 200 mg (with loading and without concomitant DMARD therapy. The
doses of 400 mg at 0, 2, and 4 weeks) and pla- study was a double-blind and placebo-controlled
cebo. Each group received subcutaneous injec- study through 24 weeks, dose-blind to 48 weeks
100
Placebo (N = 57)
CZP 200 mg Q2W (N = 165)
CZP 400 mg Q2W (N = 167)
80
ETN (N = 170) †
74.7%
66.7% †‡ †
68.2%
Responder rate (%)
60 61.3% †§
†
53.3%
40 †
20 *
* 5.0%
3.8%
0
0 2 4 8 12 16
Week
Fig. 14.7 Percentage of responders (PASI 75) in placebo, certolizumab and etanercept groups within the CIMPACT
trial. Certolizumab displays superiority to etanercept at 400mg Q2W dosing and non-inferiority at 200mg Q2W dosing
100
87.1%
75.8%†
Responder rate (%)

80
†
CIMPASI-1
60 66.5%† 67.2%
*
†
Placebo (N=51)
40
* *
CZP 200 mg Q2W
(N=95) 20
CZP 400 mg Q2W 6.5%
(N=88) 0 *
0 2 4 8 12 16 20 24 28 32 40 48
100
82.6%† 81.3%
†
Responder rate (%)
80
† †
CIMPASI-2 † 81.4% 78.7%
60 †
Placebo (N=49)
40 *
CZP 200 mg Q2W
(N=91) 20 *
CZP 400 mg Q2W * 11.6%
(N=87) 0
0 2 4 8 12 16 20 24 28 32 40 48
Week
100
82.0% † 83.6%
Responder rate (%)
80 †
Pooled † † 76.7%†
60 70.7%
†
Placebo (N=100) 40
†
CZP 200 mg Q2W 20

(N=186) * 9.9%
CZP 400 mg Q2W 0
(N=175) 0 2 4 8 12 16 20 24 28 32 40 48
Week
Fig. 14.8 CIMPASI-I and CIMPASI-II randomized control trail results. Patients randomized to both the certolizumab
200mg Q2W and certolizumab 400mg Q2W achieve significant benefit compared to patients in placebo group. Results
were maintained throughout 48-week trial period
and then open label until 216 weeks [72–76] In an increase to 66.3% at 216 weeks. Additionally,
the trial, 409 patients were randomized to com- at four-years, resolution rates for enthesitis, dac-
plete 24 weeks of treatment with either certoli- tylitis, and nail psoriasis were 71%, 81%, and
zumab 200 mg every 2 weeks, 400 mg every 65% respectively [73, 74, 76].
4 weeks, or placebo. ACR 20 response was sig-
nificantly greater at 12 weeks (58.0% and 51.9%
vs. 24.3%, respectively (p < 0.001)) and PsARC Safety Considerations
achievement was also significant against placebo
group at 24 weeks (78.3% and 77.0% vs. 33.1% Throughout their nearly two decades of clinical
(p < 0.001) [72]. The study was continued over 4 use, the safety profile of TNF-inhibitors is well
years with exciting results. Of the 67% of patients characterized [2]. In clinical trials, infliximab,
who completed 216 weeks of therapy, 60.4% golimumab, and certolizumab have been proven
achieved a Disease Activity Index for Psoriatic to be generally well tolerated, however, due to
Arthritis low disease activity or remission with their down-regulatory effects on the immune sys-
tem, all TNF antagonists have labeled warnings among patients involved in psoriasis trials (393
about the potential development of bacterial, patients with psoriatic arthritis and 1112 patients
viral, and fungal infections during treatment with psoriasis) were the lowest of all inflamma-
(9,77–79). While the most common adverse tory conditions examined. When examining these
events are mild, consisting of nausea, headache, data it is also important to note that inflammatory
upper respiratory tract infections, abdominal conditions have been associated with adverse
pain, fatigue, and fever, serious and sometimes reactions regardless of the effect of anti-TNF
fatal events have been reported [7, 77–79]. agents such as psoriasis and cardiovascular risk
Kavanaugh et al. reported that only 8.6% of [75].
patients treated with golimumab experienced a
serious adverse event up to 104 weeks [12].
Infusion-related reactions are also possible and Infusion-Reactions
were reported in about 20% of patients receiving
infliximab compared to only 10% in placebo Infusion-related reactions are unique to inflix-
groups [31, 59]. These reactions included hyper- imab and golimumab as these are currently the
tension, hypotension, bronchospasm, chest pain, only TNF antagonists that are administered intra-
dyspnea, pruritis, and fever [80, 81]. Infusion- venously. Infliximab infusions can be adminis-
related reactions may occur with all intravenously- tered within a hospital or a community setting
administered biologic agents, but because [82]. Typically, infliximab is administered over a
infliximab is a human-mouse antibody, anaphy- 2 hour time span, however, a prospective cohort
laxis is possible, although uncommon [2]. For study demonstrated that infliximab infusion can
golimumab, injection site reactions occurred in be safely administered over 1 hour in patients
8.9% of golimumab treated patients, but only with no past history of significant infusion reac-
with 0.7% of all golimumab injections over tion [84]. IV Golimumab is administered over a
104 weeks of treatment [12]. Malignancy, auto- 30-minute period [70, 85]. A majority of the
immune disease, demyelinating disease, and con- infusion-reactions are mild, consisting of flush-
gestive heart failure [13] serve as additional ing, dizziness, nausea, sweating, and increase in
concerns with the use of these agents, however temperature, typically occurring within the first
with appropriate screening and selection of 2 hours after treatment [31, 86–88]. However,
patients, the potential for development of these patients may develop antibodies to golimumab
more serious conditions declines. Also of impor- and infliximab which may lead to more serious
tant note, the adverse event data of many of the reactions, although rare, including shortness of
biologics are derived primarily from patients breath, hypo/hypertension, chest tightness, symp-
with rheumatoid arthritis (RA) or inflammatory toms of anaphylaxis such as urticaria, and bron-
bowel disease (IBD) as they have the most chospasms. Additional reactions of arthralgias,
long-term and extensive data available [1, 38]. myalgias, headache, fatigue, and influenza-like
The generalizability of these findings in patients symptoms may occur as well ([32, 85, 86, 89,
suffering from psoriasis and psoriatic arthritis 90]). It has been estimated that infusion reactions
remains unclear. More recent data suggests the occur in 3–22% of patients receiving treatment
side effect profile may be more favorable in with infliximab for psoriasis [87]. Golimumab
patients with psoriatic diseases [1, 77, 82, 83]. appears to have a lower incidence of infusion-
For certolizumab specifically, a study performed related reactions with 0.8% of patients experienc-
by Curtis et al. analyzed the side-effect profile of ing a reaction through 24 weeks of the
the drug used on 11,317 patients across a multi- GO-VIBRANT study and 1.1% of patients
tude of inflammatory conditions including psori- treated with a combination of methotrexate and
asis, psoriatic arthritis, axial spondyloarthritis, golimumab in the GO-FURTHER study [85, 90]
rheumatoid arthritis, and Crohn’s disease [77]. Typically, symptoms can be monitored and will
These data show that the rates of adverse events resolve with minor analgesics or antihistamines.
If a severe reaction develops, infliximab should patients with psoriasis receive monotherapy in
be discontinued immediately with commence- clinical trials [104–108]. Although the overall
ment of appropriate treatment [88]. Generally, risk for infection reached statistical significance,
infliximab and golimumab treatment can be con- it may have limited clinical implications as 97.6%
tinued after a mild or moderate reaction. Attempts of the reported infections were non-serious, with
have been made to reduce the probability of a large majority represented by upper respiratory
infusion-related reactions. Various agents have infections [1]. More surprisingly, Dommasch
been administered as pre-medications, including et al. found a marginally statistically significant
intravenous steroids, acetaminophen, and antihis- decreased risk of serious infection [1]. There
tamines, however, most trials have failed to dem- were three reported cases of cellulitis in the pla-
onstrate a protective effect of premedications and cebo group, versus only one in the treatment
lead to doubt on whether their risk of potential group. It is postulated that an improvement in
side effects is justifiable [84, 90–93]. skin disease and a decreased amount of excoria-
Co-medication with disease-modifying therapies tions and breaks in the skin barrier are possible
[84, 94–96] and ensuring a reliable maintenance explanations for this unexpected finding.
schedule (opposed to an as-needed schedule) A significant concern of health practitioners is
[88] have been shown to reduce the risk. the potential for the reactivation of tuberculosis
[7, 59, 60]. The risk of reactivation of latent TB
is, of course, dependent on the incidence of latent
Infection infection [4]. From January 1998 to September
2002, the reported cumulative incidence for
Infections are serious complications that can patients in the USA was estimated at 54/100,000
result from the use of TNF antagonists. While the for infliximab [109]. However, the reality of this
most common types reported are upper respira- serious risk has lead to the introduction of pre-
tory tract infections and urinary tract infections, treatment screening procedures, which have suc-
more serious infections such as cellulitis, pneu- cessfully reduced the number of cases [99, 110].
monia, abscesses, skin ulceration, pyelonephritis, It has been reported that reactivation occurs at the
cholecystitis, and sepsis have occurred [12, 59, greatest frequency within the first 12 weeks of
68, 79]. Although observational studies and treatment [111, 112]. The mechanism by which
meta-analyses of rheumatoid arthritis and inflam- TB reactivation occurs is not fully understood.
matory bowel disease randomized controlled tri- Anti-TNF agents likely lead to apoptosis of active
als have indicated an increased risk of serious CD8+ T cells. These cells, along with the cyto-
and non-serious infections [97–103], clinical kine TNF-alpha, are crucial for the maintenance
safety data specific for psoriasis and psoriatic of granulomas and the lysis of host cells harbor-
arthritis demonstrated only a very small increased ing intracellular invaders, such as Mycobacterium
risk of overall infection with the short-term use tuberculosis. The anti-TNF agent etanercept is
of biologics, without an increased risk in the associated with a lower risk of TB reactivation in
development of more serious infections [1]. comparison to other anti-TNF agents. This may
Furthermore, the authors even suggested that the be due to less inhibition of TNF-a as etanercept
increased risk of overall infection may be attrib- binds solely soluble TNF-a whereas other anti-
utable to variations in follow-up time between TNF agents bind tmTNF [3, 19]. There is also
the treatment and placebo groups. Rheumatoid some data to suggest that psoriasis itself is a risk
arthritis and IBD patient populations are typi- factor for the risk of TB infection [113]. Screening
cally treated with the concomitant use of addi- for TB infection should include a full history and
tional immunosuppressants and have a higher physical exam. Additionally, patients require a
background incidence of infection. These factors tuberculin skin test (TST), and/or interferon-
are the likely explanations for an increased infec- gamma release assay (IGRA) with chest radiog-
tion rate in these groups [97, 98]. By design, raphy occurring after positive screen [13,
113–115]. The CDC guidelines suggest that 3 and assessment of risk factors [117]. In the case
months of isoniazid/rifapentine is the treatment of a positive result, anti-TNF therapy should be
of choice in countries such as the USA with low initiated only in combination with hepatitis treat-
to moderate levels of latent infection. As of 2018, ment and close monitoring of liver enzymes and
this recommendation has been expanded from viral DNA levels under the supervision of a spe-
only adults to patients aged 2–17 years and cialist [118–121]. There is currently limited evi-
patients with HIV infection and taking antiretro- dence on the safety of infliximab treatment in
viral medications [116]. In the setting of active HIV positive individuals as most of these patients
TB, anti-TNF agents should be discontinued are excluded from trials with biologic agents [13,
immediately. There is still no conclusive evi- 117]. Caution is therefore advised when consid-
dence on when to re-start or initiate anti-TNF ering anti-TNF therapy in these high-risk indi-
therapy after treatment of active or latent TB viduals [122].
infection. A multi-disciplinary panel, the Italian In addition to the aforementioned screening
multidisciplinary task force for screening of measures, no live vaccinations should be admin-
tuberculosis before and during biologic therapy istered to a patient undergoing TNF antagonist
(SAFEBIO) reviewed the available evidence therapy, and these agents should be withheld if
from phase III randomized control trials in which patients are given antibiotics and completely dis-
anti-TNF agents were studied. The panel evalu- continued in the presence of severe infections, as
ated latent TB infection, identification of indi- these patients have a higher propensity to develop
vidualized level of risk of TB reactivation, and serious bacterial complications [123–125].
management of patients when TB reactivation Despite the risk of infectious complications,
occurred. The panel recommended that biologic the overwhelming majority of these infections
agents could be initiated or resumed 1 month are minor, consisting mainly of upper respiratory
after the treatment of latent or active TB. Since infections [1]. JAMA published a multi-center,
the TST and IGRA will not be helpful for the retrospective study examining whether the use of
diagnosis of TB reactivation in these patients, biologic agents was associated with an increased
they need consistent clinical monitoring for signs risk of serious infections requiring hospitaliza-
and symptoms of active TB [113]. tion in comparison to non-biologic agents [126].
Additional rare severe, opportunistic infec- They determined that TNF-antagonists were not
tions have also been reported, such as listeriosis, associated with an increased risk of hospitaliza-
coccidioidomycosis, and histoplasmosis along tion for serious infections across multiple auto-
with infections caused by Cryptococcus, immune diseases, including psoriasis and
Aspergillus, and Pneumocystis [2, 79]. Although psoriatic arthritis. However, it was noted that for
the incidence of fungal infections were not sig- rheumatoid arthritis patients, infliximab was
nificantly increased in clinical trials, based on associated with a higher rate of serious infection
case reports and post-marketing surveillance when compared alone to non-biologics (adjusted
data, a fungal infection should be suspected if a hazard ratio: 1.25, 95% confidence interval:
patient on biologic therapy develops a fever [13]. 1.07–1.48) and when compared to the other TNF
Viral infections are an additional concern, as agents, etanercept (aHR: 1.26; 95% CI: 1.07–
there have been reports of reactivated hepatitis B, 1.47) and adalimumab (aHR: 1.23; 95% CI:
and worsening of hepatitis C [2]. All anti-TNF 1.02–1.48). Subgrouping of the TNF antagonists
agents carry a boxed warning regarding the reac- was not performed for psoriasis specifically,
tivation of hepatitis B. Although these complica- however the rate of serious infections for the bio-
tions exist, a recent recommendation from a logics as a group compared to the non-biologics
JAAD literature review concluded grade C evi- was not significantly different. Baseline use of
dence for the use of hepatitis B and C screening. glucocorticoids, however, was associated with a
Therefore, this can be left to clinical judgement significantly increased risk of serious infection
and hospitalization compared to no baseline use gistic effect resulting in an increased risk of
of steroids. infection and malignancy that may not be appli-
An additional concern surrounding the cable to the psoriatic patient population [104–
increased risk of infections is whether or not this 108]. In fact, in a meta-analysis the authors
risk will further increase perioperatively, and concluded that there was no statistically signifi-
whether or not infliximab infusions should be cant increased risk of malignancy in patients with
held for a certain period of time before a major or psoriatic disease on short-term biologic therapy
minor surgery. Current recommendations from [1].
many professional societies recommend with- Overall, in the malignancies observed, 70.6%
holding therapy prior to surgery. The therapy were non-melanoma skin cancers [1]. Whether
may be withheld for 3–5 half-lives of the drug or this was an artifact of increased recognition as
individualized to patient characteristics and sur- the psoriatic lesions healed is uncertain.
gery type. However, this is not without risk and Additionally, it has been proposed that a patient’s
disease flares can lead to adverse functional out- psoriasis may inherently increase their risk for
comes and impair rehabilitation [127]. A retro- developing lymphoma, further complicating the
spective study was conducted to assess the safety analysis of biological agents [144, 145]. In the
of preoperative infliximab use before restorative golimumab trials, non-melanoma skin cancers
proctocolectomy and ileal pouch-anal anastomo- were also the most common, however colon can-
sis (IPAA) in patients suffering from ulcerative cer, prostate cancer, and small cell lung carci-
colitis (UC) [128]. Although controversy exists noma were also observed, although infrequently
surrounding the risks of preoperative infliximab [12]. Furthermore, the results of randomized con-
[129–132], it was determined that short-term trolled trials show that 26% of malignancies
postoperative and infectious complications were occur within 12 weeks from enrollment in
similar between the group that had received inf- patients receiving TNF inhibitors, suggesting
liximab within 12 weeks of the surgery (44.8%), pre-existence of the cancers before initiation of
and those who had not (44.2%) [133]. In fact, a biologic therapy [146]. Therefore, it is prudent
trend toward lower rates of wound infection was that patients undergo age and risk adequate
observed for the infliximab group (3.5%) com- screening before initiation of treatment.
pared to controls (19.2%). Another recent retro- Another meta-analysis was performed on
spective cohort performed on patients receiving patients enrolled on certolizumab therapy regi-
infliximab within 4 weeks of elective hip or knee mens for all approved indications. This study
arthroplasty were not at an increased risk within determined a standardized incidence ratio (SIR)
1 year compared to patients withholding therapy of malignancy to be 1.03 (95% CI 0.87 to 1.20)
[134]. While these results are promising, there is using the SEER database and an SIR of 1.45
still a need for prospective studies. (95% CI 1.23 to 1.69) when using the worldwide
GLOBOCAN healthy population data set for
patients taking certolizumab. The authors suggest
Malignancy that, although the SEER data base is typically
used in biologic safety studies, GLOBOCAN
Similar to infections, meta-analyses and observa- data may be more representative of the popula-
tional studies with TNF antagonists in the RA tion and caution should be exercised when deal-
population demonstrated an increased risk of ing with biologics and malignancy risk [18].
malignancy [97, 98, 135, 136], although there is Overall, the short-term risk-benefit profile of
conflicting evidence [137–144]. Again, the same biologics in patients with psoriatic disease is
argument holds true as above where the different favorable. However, continued long-term studies
disease states and the combination of immuno- with larger patient populations are necessary in
suppressants in this population may have a syner- order to adequately assess the risk of cancer and
serious infection with chronic use of infliximab, use of TNF antagonists [9, 13]. Because of this
golimumab, and certolizumab. increased risk, patients with MS along with their
first-degree relatives have been cautioned against
the use of the drugs [123, 124].
Laboratory Data/Autoimmune
Disease
Dermatologic
Some studies have reported abnormalities in lab-
oratory data associated with the use of infliximab. Various skin complications have been reported
In a randomized study by Reich et al., a signifi- with the use of anti-TNF agents, some of which
cant increase in liver enzymes, aspartate and ala- include, delayed hypersensitivity type reactions,
nine aminotransferases was observed [32]. lupus-like syndrome, bullous skin lesions,
Anti-TNF agents have been associated with a eczematous-like purpura, annular lichenoid erup-
number of cases of liver injury, such as choles- tion, and leucocytoclastic vasculitis [79]. In addi-
tatic disease and hepatitis, with some life- tion, several eczematous eruptions have occurred
threatening cases reported [147–149]. with the use of infliximab, however most reac-
Additionally, an association has been made tions resolve with discontinuation of the offend-
between anti-TNF agents and the development of ing agent [155].
autoimmune hepatitis type 1 reactions. After dis- Interestingly, there are an increasing number
continuation of the anti-TNF agent, liver enzymes of cases documenting the paradoxical formation
return to normal values and harmful reactions of psoriasis during treatment with TNF inhibitors
such as hepatitis typically regress. Interestingly, [3, 134, 156–160], primarily in patients treated
anti-TNF agents have also been anecdotally used for other autoimmune diseases, such as Crohn’s
as rescue therapy in treatment-resistant primary disease and rheumatoid arthritis [133, 161]. It is
biliary cholangitis and autoimmune hepatitis likely that the pathophysiology involves the dis-
[147]. Other laboratory abnormalities including equilibrium of cytokines caused by the inhibition
hematological disturbances have also been noted, of TNF-alpha. It has been suggested that TNF-a
such as rare cases of aplastic anemia and pancy- normally inhibits plasmacytoid dendritic cell
topenia, which can further predispose the patient secretion of interferon-alpha (IFN-a), a known
to serious infections [2]. inducer of psoriasiform lesions. The upregulation
Additionally, due to its chimeric nature, inflix- of IFN-a that occurs in patients on anti-TNF-a
imab has been shown to result in the formation of therapy may result in the formation of skin dis-
antibodies [79]. Most commonly, antinuclear ease in predisposed individuals [160, 162].
antibodies (ANA), antibodies to double-stranded Various treatments have been reported to be use-
DNA, and anti-cardiolipin antibodies have been ful in this situation, such as aggressive topical
reported [150–152]. Studies of Crohn’s disease therapy, the addition of methotrexate, acitretin,
show that 44% develop ANAs at some point dur- cyclosporine, phototherapy, or switching the
ing the course of their treatment with infliximab TNF agent [160, 163]. Most frequently used
[7, 59]. While the development of systemic lupus agents have been glucocorticoids and vitamin D
erythematosus (SLE) in patients undergoing bio- analogs for topical therapy and methotrexate,
logic treatment is rare, it is postulated that the glucocorticoids, and phototherapy for systemic
important role TNF plays in autoregulation may treatment. Complete discontinuation of all bio-
be linked with new signs of autoimmune disease logics is often unnecessary, and a change in the
in patients receiving anti-TNF agents [13, 153, TNF antagonist used should be considered if con-
154]. It is also noted that withdrawal of therapy ventional treatment fails. Ultimately, 30.7–100%
typically results in resolution of symptoms. of patients were able to continue on anti-TNF-a
Several demyelinating and neurologic events, therapy with adjuvant topical or systemic treat-
including exacerbations of pre-existing multiple ment [160, 162].
sclerosis (MS), have also been reported with the
Treatment Switches As an important aside, treatment switches

from anti-TNF therapy for non-medical reasons,
There is evidence that a gradual decline in thera- such as job loss or change of insurance, has been
peutic efficacy occurs in some patients with TNF associated with deteriorating clinical outcomes.
antagonists, whether through decreased bioavail- In a 2017 study, disease flares, disease control,
ability of the drug or as a biological adaptation to and health care utilization was compared between
chronic blockade, such as the development of patients who were switched/discontinued and
anti-drug antibodies [7, 56, 164]. However, those that continued their anti-TNF agent.
switching to a different biologic agent has proven Switchers were further classified by those that
effective in treatment-refractory patients. In switched to another biologic therapy and those
2007, JAAD published a retrospective study that switched to conventional therapy. The data
involving the efficacy of infliximab in patients included patients with inflammatory conditions
who previously failed treatment with etanercept including plaque psoriasis, psoriatic arthritis,
[164]. Infliximab was initiated at 5 mg/kg and spondylarthritis, IBD, and rheumatoid arthritis.
administered on weeks 0, 2, 6, 14, and every Importantly, the authors found that switchers/dis-
8 weeks thereafter. After only 12 to 14 weeks of continuers had worse clinical outcomes, even if
infliximab therapy, 17 of 19 (89%) patients the agent that was switched to was another bio-
showed improvements in their PGA and logic agent (165). This study suggests that physi-
BSA. Fifteen (79%) still maintained adequate cians need to be careful in the management of
control on infliximab at the time of study publica- their patients with inflammatory conditions and
tion, although 10 patients required infliximab have considerable knowledge about the insurance
dose escalation, with a majority of patients formularies and compliance of their respective
requiring infusions every 6 weeks to maintain patients.
continued response. In addition, safety data was
obtained and compared between the two TNF-
antagonists. The use of infliximab was associated Conclusion
with a possible increased incidence in adverse
events compared to etanercept (16 versus 5 Infliximab has been clinically available for over
events, respectively). However, a majority of two decades and a large body of data exists prov-
these events were considered minor. ing its generally increased efficacy and fewer
A multicenter, open-label prospective study adverse events over traditional agents in numer-
(PSUNRISE) was conducted to evaluate the clin- ous inflammatory disorders, including psoriasis
ical response of an etanercept-to-infliximab and psoriatic arthritis. Although newer anti-IL17
switch in patients with psoriasis unresponsive to, and anti-IL12/IL23 agents may have similar or
or with a loss of response to, etanercept therapy slightly superior efficacy in the treatment of pso-
[55]. Patients were included who had a PGA riasis, research has proven the effectiveness of
score of at least 2 despite 4 or more months of infliximab, golimumab, and certolizumab in
treatment with etanercept. Patients received intra- treating signs and symptoms of psoriasis, and
venous infusions of infliximab 5 mg/kg at weeks demonstrated their rapid and prolonged suppres-
0, 2, 6, 14, and 22. At week 10, 65.4% of patients sion of inflammation preventing long-term dis-
achieved a PGA score of 0 (clear) or 1 (minimal) ease progression, especially in debilitating
and 61.3% of patients maintained this response disease such as psoriatic arthritis. Infliximab and
throughout the 26 weeks. Moreover, there were golimumab are unique in the IV formulations
no unexpected side effects or safety concerns providing a rapid onset of action. Certolizumab
experienced during this study. This trial demon- has a unique treatment niche in women of child
strates that patients with an inadequate response bearing potential. No new or unexpected safety
to etanercept may achieve substantial benefit issues have emerged over the years, and inflix-
after switching to infliximab. imab, golimumab, and certolizumab have been
shown to be well-tolerated when clinicians
appropriately select patients and adhere to ade- 10. Scallon B, Cai A, Solowski N, et al. Binding and
quate screening and monitoring guidelines. As functional comparisons of two types of tumor
necrosis factor antagonists. J Pharmacol Exp
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is needed in order to fully characterize the role of necrosis factor alpha blockade reduces the synovial
cell infiltrate early after initiation of treatment, but
neutralizing anti-drug antibodies. Overall, the apparently not by induction of apoptosis in synovial
risk-benefit profile of these medications is favor- tissue. Arthritis Rheum. 2003;48:2155–62. https://
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Battafarano DF. Psoriatic skin lesions induced by
Ustekinumab
15
George Han, Caitriona Ryan, and Craig L. Leonardi
Abstract ical practice has borne out that ustekinumab

remains a safe and effective treatment for pso-
Ustekinumab is a fully human IgG antibody to
riasis and psoriatic arthritis.
the common p40 subunit of interleukin-12 (IL-
12) and IL-23, which has shown considerable
efficacy in the treatment of psoriasis and psori-
atic arthritis. This review examines the efficacy Key Learning Objectives
and safety of ustekinumab for the treatment of 1. To understand the mechanism of action
psoriasis in clinical studies to date. of ustekinumab.
Ustekinumab was shown to be highly effective 2. To understand the appropriate use and
in the treatment of moderate-to-severe psoria- efficacy of the ustekinumab.
sis with sustained response for up to 5 years in 3. To understand the safety issues of

the majority of patients. Adverse events in ustekinumab.
clinical studies to date have been for the most
part, mild and similar to that in placebo-treated
patients. Similarly, ustekinumab has shown
Introduction
efficacy in psoriatic arthritis and in adolescent
psoriasis in patients ages 12 and up. While
Ustekinumab (Janssen Biotech, Philadelphia,
early questions about major adverse cardiovas-
PA) is a fully human immunoglobulin G1/kappa
cular events existed in relation to this class of
(IgG1/κ) monoclonal antibody to the p40 subunit
medication, the burden of evidence over the
common to interleukin-12 (IL-12) and IL-23,
clinical trial program and over a decade in clin-
which has shown efficacy in the treatment of
moderate-to-severe psoriasis and psoriatic arthiri-
tis [1]. It was first approved for treatment of
G. Han (*)
Department of Derrmatology, Icahn School of plaque psoriasis in adults in the United States in
Medicine at Mount Sinai, New York, NY, USA 2009 and subsequently received approval to treat
e-mail: [email protected] psoriatic arthritis in 2013 and psoriasis in adoles-
C. Ryan cents in 2017. It is also approved in Europe and
Department of Dermatology, Baylor University multiple other countries for psoriasis and psori-
Medical Center, Dallas, TX, USA atic arthritis; and for use in psoriasis for ages 6
C. L. Leonardi and up by the European Medicines Agency [2].
Department of Dermatology, Saint Louis University IL-12 and IL-23 are heterodimeric cytokines
School of Medicine, St. Louis, MO, USA

https://doi.org/10.1007/978-3-030-54859-9_15
202 G. Han et al.
which possess a common p40 subunit linked by a absolute bioavailability (F) of ustekinumab was
disulfide bond to a unique chain, IL-12p35 and estimated to be 57.2% after a single subcutane-
IL-23p19, respectively [3, 4]. The p40 subunit ous dose, with an apparent volume of distribution
binds to the IL-12 receptor-beta1 (IL-12Rb1) on of 79-161 ml/kg at the terminal phase [17].
the surface of T lymphocytes and natural killer Steady-state concentrations were achieved by
cells. Interleukin-12 is a potent inducer of week 28 in phase III studies in psoriasis, with
interferon-gamma (IFN-g), which promotes trough steady-state serum concentrations (ctrough)
T-cell differentiation toward a Th1 lineage, while showing dose proportionality. The median ctrough
interleukin-23 is the major regulator of Th17 in those taking 90 mg every 12 weeks was twice
CD4 cells, a subset of T helper cells distinct from that of those taking 45 mg in two phase III psoria-
Th1 and Th2 cells, defined by their ability to pro- sis studies (0.47 vs 0.21ug/ml in PHOENIX 1
duce IL-17 [5]. Interleukin-23 stimulates IL-17A, and 0.49 vs 0.26ug/ml in PHOENIX 2), with no
IL-17F and IL-22 production from Th17 cells evidence of accumulation with either dosage reg-
and mediates its effects through Janus kinase-2 imen. The metabolic pathway of ustekinumab
(JAK2) and STAT3, leading to hyperproliferation has not yet been fully elucidated. As a human IgG
of keratinocytes and production of chemokines, monoclonal antibody, ustekinumab is most likely
angiogenic factors (VEGF) and pro-inflammatory degraded into small peptides and amino acids by
mediators such as tumor necrosis factor-alpha the reticuloendothelial system in the same man-
(TNF-a), nitric oxide and IL-1b [6, 7]. As psoria- ner as endogenous IgG. A combined analysis of
sis was originally thought to predominately be a phase III studies in psoriasis calculated the mean
Th1-cell mediated disease, ustekinumab was spe- half-life to be 21.6 days [18]. A population based
cifically developed to target IL-12; indeed, IL-23 approach was used to further characterize the
was not even identified until after ustekinumab pharmacokinetic profile of ustekinumab based on
was submitted to the FDA for approval. The two phase III studies [1, 18, 19]. Mean values for
dichotomy of these two cytokines lies in their apparent clearance, apparent volume of distribu-
upregulation of Th1 cells (for IL-12) and Th17 tion and absorption rate constant were 0.465 L/
cells (for IL-23) [6, 8]. Interestingly, it has since day, 15.7 L and 0.354/day, respectively. Based on
been shown that IL-12 may have little to do with the known bioavailability of ustekinumab, the
the pathogenesis of psoriasis [9, 10] and actually volume of distribution of ustekinumab was calcu-
inhibits IL-23 itself [11]. The concomitant inhibi- lated to be approximately 8.9 L in a 90 kg psoria-
tion of IL-23 was thus, a fortuitous result of tar- sis patient, suggesting that ustekinumab is
geting the p40 subunit [12, 13]. It is worthwhile confined to the intravascular system, with limited
to note that a similar monoclonal antibody target- tissue distribution. Factors influencing variation
ing the p40 subunit, briakinumab, was under in apparent clearance and apparent volume of
development but was withdrawn from clinical tri- distribution included body weight, diabetes mel-
als due to safety concerns relating primarily to litus (independent of weight) and anti-drug anti-
adverse cardiovascular risk [14]. bodies to ustekinumab [18]. The most significant
effect was caused by body weight, with an appar-
ent clearance and apparent volume of distribution
Pharmacokinetics approximately 55% and 37% higher, respec-
tively, in those with a bodyweight of greater than
In phase I studies in psoriasis, ustekinumab 100 kg compared with those of 100 kg or less.
showed linear pharmacokinetics with both This emphasizes the importance of dose adjust-
ascending single intravenous doses and ascend- ment in those who have a higher bodyweight to
ing single subcutaneous doses of the drug [15]. achieve a similar efficacy. None of the 28 con-
After a single subcutaneous dose, ustekinumab comitant medications analyzed had a significant
was slowly absorbed, reaching maximum con- effect on the pharmacokinetic profile. 3.2% of
centration (tmax) between 7 and 14 days [16]. The patients developed antibodies to ustekinumab,
15 Ustekinumab 203
which was associated with a mean increase in of these cytokines at week 1 compared to base-
apparent clearance of 35.5% in these patients. line, the mRNA expression of IL-8, IL-18 and
In the US, the current licensed dosage regimen IFN-γ was significantly decreased in the lesional
is 45 mg of ustekinumab at baseline, 4 weeks and skin of those who had a sustained response of at
every 12 weeks in those less than 100 kg in least 70% improvement in PASI at 3 separate
weight, and 90 mg of ustekinumab at the same time-points (week 8, 12 and 16), compared with
intervals for those heavier than 100 kg. These those without sustained PASI improvement.
dosage recommendations were made based on The effects of ustekinumab on lesional skin
analyses of 10-Kg increments with a presumed and peripheral blood in a subset of psoriasis
ideal cutoff point to separate response between patients were examined in a phase II psoriasis
the lower and higher dose regimens [20]. study [22]. At week 12, a significant decrease in
median epidermal thickness correlated with a
reduction in cellular proliferation (Ki67) and
Pharmacodynamics T-cell infiltration (CD3) by 84.3% and 70.7%,
respectively, in the combined ustekinumab group.
Two phase I studies have examined the pharma- Surprisingly, the level of IL-12p40, the target of
codynamics of ustekinumab in lesional psoriatic ustekinumab, increased 13-fold from baseline to
skin. The first examined the effect of intravenous week 12, before slowly decreasing to near base-
ustekinumab in 18 patients. There was a signifi- line levels by week 32. This was postulated to be
cant reduction in the expression of IFN-g, TNF- due to decreased clearance of non-functional cir-
α, IL-8, IL-10, IFN-γ-inducible protein-10 and culating complexes of ustekinumab-bound
monocyte chemotactic protein-1 (MCP-1) within IL-12p40. The expression of cutaneous lympho-
2 weeks of administration of the drug before clin- cyte antigen (CLA), which facilitates homing of
ical response and histological changes were evi- activated T cells to the skin, significantly
dent [21]. A significant reduction in total CD3+ T decreased from baseline in ustekinumab-treated
cells was observed in responders (those achiev- patients compared with placebo, while there was
ing a PASI-75 response) but not in non-responders no change in expression of CD45RA, CD45RO,
by week 2. Levels of TNF-α were significantly CXCR3, CD25 or HLA-DR on T cells. The sys-
reduced in responders but not in poor responders, temic effects of ustekinumab were also investi-
while levels of IL-12p40 and IL-23p19 were gated in vitro in healthy donors using isolated
reduced in both populations, particularly in peripheral blood mononuclear cells in the absence
responders. When baseline genetic expression of or presence of recombinant IL-12 or IL-23 [22].
responders was compared to that of non- Ustekinumab inhibited up-regulation of IL-12R,
responders, mRNA expression of TNF-α was sig- IL-2Rα (CD25) and the co-stimulatory receptor
nificantly higher in responders and correlated CD40L, while reducing IL-12 and IL-23-induced
with the percentage improvement in PASI, sug- secretion of the pro-inflammatory cytokines IFN-
gesting that this may be a predictor of treatment γ, TNF-α, IL-2 and IL-17A.
response. The second phase I study examined the
effect of subcutaneous ustekinumab in 21
patients. Punch biopsies were obtained from Clinical Efficacy
lesional skin 24 hours before, and 1 week after
IL-12/23 antibody administration, and the mRNA Two large scale phase 3, multicenter, random-
expression of various cytokines, including TNF- ized, double-blind, placebo-controlled, parallel
α, IFN-γ, IL-8, IL-18, IL-12/23p40 subunit, studies (PHOENIX 1 and PHOENIX 2) were
IL-23p19 subunit, IL-12p35 subunit, IL-10, performed to evaluate the subcutaneous adminis-
IP-10, RANTES and CCL-2 was measured using tration of ustekinumab in patients with moderate-
real-time polymerase chain reaction. Although to-severe psoriasis [1, 19]. In PHOENIX 1, 766
there was no significant change in the expression patients were randomized to receive 45 mg or
204 G. Han et al.
90 mg of ustekinumab at baseline, week 4, fol- patients randomized to receive 45 mg or 90 mg
lowed by every 12 weeks, or to receive placebo at of ustekinumab or placebo at baseline, week 4,
week 0 and 4, with crossover to receive either and then every 12 weeks or placebo at baseline
45 mg of ustekinumab or 90 mg of ustekinumab and week 4, followed by a placebo crossover to
at week 12 [1]. Those in the initial ustekinumab receive 45 mg or 90 mg of ustekinumab (week
group who achieved a sustained PASI-75 at both 12–28) [19]. At week 28, partial responders
week 28 and 40 were re-randomized at week 40 (those who had achieved greater than PASI-
to ongoing treatment or withdrawal from treat- 50 but less than PASI-75), were randomized to
ment for another 36 weeks until loss of response escalate dosing to every 8 weeks at their origi-
(weeks 40–76). These patients were retreated nally assigned dose, or to continue receiving
when they lost at least 50% of PASI improve- ustekinumab every 12 weeks (week 28–52). At
ment. At week 12, PASI-75 was achieved in week 12, 66.7% of patients receiving 45 mg
67.1% of those receiving 45 mg, and 66.4% of ustekinumab, and 75.7% receiving 90 mg
those receiving 90 mg of ustekinumab compared ustekinumab achieved PASI-75, compared
with 3.1% of those taking placebo, while PASI- with 3.7% receiving placebo, while PASI-90
90 was achieved in 41.6%, 36.7% and 2% of was achieved in 42.3%, 50.9% and 0.7% of
these groups, respectively. Those receiving pla- these groups, respectively. There was also a
cebo, achieved similar response rates after cross- highly significant improvement in DLQI in the
over to active treatment. Maximum efficacy was ustekinumab treated patients compared with
achieved at week 24, with PASI-75 responses of the placebo group at week 12 (p < 0.0001).
76.1% and 85% for the 45 mg and 90 mg Maximum PASI-75 response rates were
ustekinumab groups, respectively. A significantly attained at week 20 (74.9% of the 45 mg group
higher proportion of those receiving maintenance and 83.5% of the 90 mg group). At week 28,
treatment maintained a PASI-75 response com- 22.7% of patients in the 45 mg ustekinumab
pared to those from whom treatment was with- group were partial responders compared with
drawn (p < 0.0001). Response rates stayed stable 15.8% in the 90 mg group. Independent pre-
up to 76 weeks in the maintenance group, with a dictors of partial response included increased
median time to loss of PASI-75 of 15 weeks. No bodyweight, a history of non- response to
rebound flare was observed on discontinuation of biologic agents, longer duration of psoriasis
ustekinumab (defined as a PASI greater than and the presence of psoriatic arthritis. Partial
125% of baseline). Of the 195 patients who responders had a significantly higher incidence
recommenced ustekinumab after losing response, of antibodies to ustekinumab (12.7%) com-
85.6% reestablished a PASI-75 response within pared to responders (2%), and serum trough
12 weeks. Patient-determined quality of life, as drug levels were two to three times lower than
determined by DLQI, showed a similar improve- those of responders. Escalation from a 12
ment to objective assessments of disease severity, weekly to an 8 weekly dosing regime resulted
with median changes in ustekinumab-treated in a four to five times increase in the mean
patients significantly greater than placebo-treated trough serum concentrations in partial respond-
patients at week 12. A subsequent analysis ers between week 28 and week 52. In partial
showed that at 3 years, 79.8% of patients (601 of responders who received dosing intensifica-
753 patients) who received one or more dose of tion of ustekinumab 90 mg every 12 weeks to
ustekinumab remained in the study and that ustekinumab 90 mg every 8 weeks, there was
80.9% (45 mg) and 82.7% (90 mg) of week 40 a significant increase in those achieving PASI-
responders continuing treatment every 12 weeks 75, compared to those who remained at a dose
achieved a PASI-75 response [23]. of ustekinumab 90 mg every 12 weeks, with
In PHOENIX 2, a similar schedule was response rates of 68.8% and 33.3%, respec-
followed over 52 weeks, with a total of 1230 tively. There was no significant difference in
15 Ustekinumab 205
response, however, in those randomized to of patients on ustekinumab 45 mg and 90 mg,
receive 45 mg of ustekinumab every 8 weeks, respectively. About half of the patients took
compared to those who continued to receive methotrexate during the study, which did not
45 mg every 12 weeks. Further data were gath- influence the likelihood of attainment of ACR20
ered out to 5 years of follow-up, with patients for ustekinumab vs. placebo, though the benefit
randomized to either 45 mg or 90 mg groups was likely to be slightly greater in patients who
where dosage and interval adjustments (from were not using concomitant methotrexate.
q12 weeks to q8 weeks; from 45 mg to 90 mg) A later trial was conducted (PSUMMIT-2)
were allowed at the discretion of the investiga- which was a randomized, double-blind, placebo-
tor. At week 244, the proportions of patients controlled, Phase III study of ustekinumab in
achieving PASI 75 were 76.5% and 78.6% psoriatic arthritis, with the notable difference
for those who started in the 45 mg and 90 mg from PSUMMIT-1 that patients who had used
groups, respectively; PASI 90 was achieved in TNF-α inhibitors previously were now allowed
50.0% and 55.5% of patients in the 45 mg and into the study [27]. A total of 312 patients were
90 mg groups, respectively [24]. studied, including 180 with prior exposure to
The first study to directly compare the efficacy TNF-α inhibitors. For TNF-α-naïve patients,
of two biologic agents in psoriasis was the ACR20 rates were similar to PSUMMIT-1—with
ACCEPT study, a single-blind randomized, par- 43.7% and 43.8% of patients achieving this
allel phase III study of 903 psoriasis patients threshold for ustekinumab 45 mg and 90 mg,
comparing the safety and efficacy of ustekinumab respectively. However, the response rates for
with etanercept [25]. Patients were randomized patients who had previously been on TNF-α
to receive ustekinumab 45 mg or 90 mg at base- inhibitors was somewhat lower—36.7% and
line and at week 4 or etanercept 50 g twice 34.5% for ustekinumab 45 mg and 90 mg, respec-
weekly for 12 weeks. There was no placebo arm tively. Notably, the study was not powered to
in this study. At week 12 PASI-75 was achieved assess for a statistically significant difference in
in 67.5% of those receiving 45 mg ustekinumab, response rates between the two groups (TNF-α
73.8% of those receiving 90 mg of ustekinumab experienced or naïve). Also interestingly, the
and 56.8% of those receiving etanercept, while patients’ skin disease seemed to track along with
PASI-90 was achieved in 36%, 45% and 23% of the psoriatic arthritis response, where patients
these groups, respectively. A PGA of cleared or previously exposed to TNF-α inhibitors experi-
minimal was achieved in 65.1%, 70.6% and 49% enced a little over 10% lower achievement of
of the groups. PASI-75 than patients who had never been on
that class of biologic.
Psoriatic Arthritis
Adolescent Patients
A randomized, double-blind, placebo-controlled,
Phase III study of ustekinumab was performed A randomized, double-blind, placebo-controlled
in 615 patients with active psoriatic arthritis Phase III study was completed in adolescent
(PSUMMIT-1) [26]. Patients who previously used patients from 12–17 years of age [28]. The study
methotrexate and those who were using disease- was conducted with a primary endpoint of PGA
modifying antirheumatic drugs (DMARDs) or 0/1 and PASI 75 at week 12, with a long-term
NSAIDs were allowed in the study but patients extension to 1 year. A total of 110 patients were
with a history of TNF-α inhibitor use were not. studied and assigned to different dosing regi-
The primary endpoint was ACR20 at week 24. At mens, including a half-dose cohort. Patients
the end of 24 weeks, 22.8% patients on placebo under 60Kg received 0.75 mg/Kg in the standard
achieved ACR20 compared to 42.4% and 49.5% dose (SD) group or 0.375 mg/Kg in the half-
206 G. Han et al.
standard dose (HSD) group. Patients from greater Serious Infections

than 60 Kg to 100 Kg received 45 mg (SD) or
22.5 mg (HSD) and patients greater than 100 Kg Based on animal models of cytokine deficiency
received 90 mg (SD) or 45 mg (HSD). Overall, and patients with genetic mutations encoding
78.4% of patients in the HSD and 80.6% in the IL-12 and IL-23 or their receptors, there was par-
SD group achieved PASI 75 compared to 10.8% ticular concern about a theoretical increase in the
for placebo. 54.1% of patients in the HSD group risk of serious infections or malignancy with the
achieved PASI 90 compared to 61.1% of patients advent of these agents. In animal models, IL-12
in the SD group and 5.4% of patients in the pla- has been shown to be important in prevention
cebo group. In the placebo-controlled period against mycobacteria, salmonellosis and toxo-
(through 12 weeks), 56.8% of placebo, 51.4% of plasmosis and patients with a genetic deficiency
HSD, and 44.4% of SD patients reported adverse of the IL-12 receptor or the IL-12p40 subunit
events. No major safety issues were observed dif- have an increased risk of severe infections with
ferent from the side effects seen from ustekinumab intracellular pathogens such as mycobacteria and
in adults. Based on this data, the FDA approved salmonella [32–36]. Experimental animal mod-
ustekinumab for patients above 12 years of age at els of herpes viral infection, viral encephalitis,
the standard dosing regimen. viral hepatitis and aquired immunodeficiency
syndrome (AIDS), have also demonstrated a
central role for IL-12 in protecting against viral
Adverse Effects infection [37–40]. Interleukin-12 also appears
to be important in defense against opportunistic
There is a good deal of safety data for fungal infections, with increased susceptibility
ustekinumab available from a pooled longitu- to Cryptococcus neoformans infection observed
dinal analysis of phase II and phase III clinical in p35−/− or p40−/−knockout mice and preven-
trials in moderate-to-severe psoriasis [29–31] as tion of infection following the administration of
well as longer term registry databases, including IL-12 [41, 42]. Similarly, IL-12p40−/− knock-
the Psoriasis Longitudinal Assessment Registry out mice did not control fungal proliferation and
(PSOLAR). Initial safety data was based on all dissemination and succumbed to infection fol-
safety data available from the Phase 2 study, lowing intravenous inoculation of yeast cells of
PHOENIX 1 and 2 and the ACCEPT study, with paracoccidioidomycosis.
a total of 5 years’ of safety data. A total of 3117 Interleukin-23 is also believed to contribute to
patients had been followed for up to 4 years immune protection in the skin, lung and gut.
(6791 patient- years). During the combined Interleukin-23 and IL-17, however, have been
12 week placebo-controlled period of these stud- shown to be only marginally involved in primary
ies, 50.4%, 57.6% and 51.6% of patients treated infections with pathogens that require TH1 immu-
with placebo, 45 mg of ustekinumab and 90 mg nity [43–47]. One study showed that blocking
of ustekinumab, respectively, experienced at least IL-23 alone does not increase bacterial burden in
one adverse event, while 1.4%, 1.6% and 1.4% immunocompetent mice after BCG infection but
of patients in these groups experienced a seri- that blocking TNF-α or the p40 subunit results in
ous side effect and 1.9%, 1.1% and 1.4% were increased infectious burden [48, 49]. Interleukin-
withdrawn from the study due to adverse effects. 23p19 deficient mice showed significant mortal-
The most common side effects were nasopharyn- ity following a sub-lethal dose of intrapulmonary
gitis, upper respiratory tract infections, headache Klebsiella pneumoniae, however, while
and arthralgias. Rates of adverse events, seri- IL-12p40-deficient, IL-12p35- deficient and
ous adverse events, infections or adverse events IL-17R-deficient mice also show increased sus-
requiring discontinuation of treatment did not ceptibility to infection following inoculation
increase with increased duration of treatment and [50]. Administration of IL-17 restored the normal
were comparable between ustekinumab doses. infectious response in IL-23p19-deficient mice,
15 Ustekinumab 207
but not completely in p40-deficient mice, sug- 55]. Patients with congenital deficiencies of
gesting the additional role of IL-12-induced IL-12p40 or IL-12R, however, do not appear to
IFN-g production in the immune defense to have an increased incidence of malignancy [35].
Klebsiella infection. Another experimental study Interleukin-23, in contrast, appears to promote
showed that IL-23 plays a critical role in the host tumor growth, suggesting that inhibition of this
defense to Pneumocystis Carinii [51]. Individuals cytokine may inhibit carcinogenesis [56].
with abnormalities of Th17 cell function, such as There were no differences in the incidence
patients with hyper-IgE (Job’s) syndrome and of non-melanoma skin cancer (NMSC) or other
chronic mucocutaneous candidiasis, are more malignancies during the placebo-controlled
prone to infection with Staphylococcus aureus phases of usekinumab studies [31]. The rate of
and candida albicans. NMSC was 0.7/100PY in the 45 mg group and
However, clinical studies to date have not 0.53/100PY in the 90 mg group (34 BCC and
shown an increase in serious infections with the 10 SCC) and higher among patients previously
use of ustekinumab [31]. In the pooled analysis, treated with psoralen-UVA [31, 57]. Long-term
the frequency of infection during the placebo- follow-up data showed rates of malignancies
controlled period of the studies in patients receiv- other than NMSC of 0.63/100PY in the 45 mg
ing placebo, 45 mg of ustekinumab or 90 mg group and 0.61/100PY in the 90 mg group, with
of ustekinumab, was 23.2%, 27% and 24.1%, a total of 42 malignancies over the course of the
respectively, while the rates of serious infection studies [31]. These rates were consistent with
were similar between the placebo (1.70/100PY) age-, race- and gender-matched rates expected in
and 90 mg (1.97/100PY) groups but lower in the the normal United States population according to
in the 45 mg group (0.49/100PY) [31]. The rates the Surveillance, Epidemiology, and End Results
of overall infection, serious infection and infec- (SEER) database. Furthermore, analysis of the
tions requiring antibiotic treatment remained PSOLAR database showed no increased malig-
stable or decreased over the 4 years, with rates nancy risk for ustekinumab in matched-control
serious infection of 0.8/100 patient years (PY) cohort.
and 1.32/100PY for patients treated with 45 mg
and 90 mg of ustekinumab respectively and were
consistent with expected rates in psoriasis patients Major Adverse Cardiovascular Events
using the Marketscan Database. No cases of
tuberculosis were reported in the pooled analysis, The withdrawal of a similar biologic treatment
but one man who had a previously negative puri- mechanistically, briakinumab, from clinical stud-
fied protein derivative and QuantiFERON-TB ies generated some interest and concern regard-
Gold screening tests, had a tuberculosis reactiva- ing the potential adverse cardiovascular effects of
tion after two doses of ustekinumab in a RCT of anti-IL-12p40 agents. A total of five MACE
Asian psoriasis patients [52]. (0.3%), including one cardiovascular death, were
reported in 1582 ustekinumab-treated patients
compared with no events in 732 placebo recipi-
Malignancy ents (0%) during the placebo-controlled phases
of the pooled analysis [31]. All of these events
Animal studies have also suggested increased occurred in patients with three or more cardio-
tumorigenicity following inhibition of IL-12 vascular risk factors. All cardiovascular events
[53–55]. Interleukin-12 has shown anti-tumor were re-adjudicated externally at the four-year
and anti-metastatic activity in murine tumor follow-up safety analysis and a total of 34 MACE
models of melanoma, renal cell carcinoma and were identified, with four cardiovascular deaths
breast cancer, while IL-12 deficient mice have an [31]. The rate of MACE was 0.56/100PY and
increased incidence of UVB-induced skin tumors 0.46/100PY in the 45 mg and 90 mg groups,
and malignant transformation of papillomas [53– respectively. This was reported to be within the
208 G. Han et al.
expected range of such events for both the gen- showed a significantly higher risk of MACE in
eral US population and the psoriatic population, patients treated with anti-IL-12/23 agents com-
leading the sponsoring company to conclude that pared with placebo (odds ratio = 4.23, p = 0.04).
there was no apparent change in cardiac risk with The discrepancy between these meta-analyses
this agent. However, it is clear that numerically, a results from the use of different statistical meth-
higher number of MACE were observed in the ods to compare MACE rates. Risk difference is
placebo-controlled period in the ustekinumab- considered to be a more conservative measure
treated cohort compared to control. in comparing rare events but has the potential to
Two subsequent meta-analyses have been introduce false negative results. This was chosen
performed to evaluate the effect of anti-IL-12/23 over the Peto odds ratio method by the authors
agents on cardiovascular risk [14, 58]. The first of the first study because 16 of the 22 studies
was an independent meta-analysis of 22 random- had zero events and would have been excluded
ized controlled trials (RCTs) comprising 10,183 from the analysis if the odds ratio was used,
patients to evaluate the effect of biologic agents possibly leading to selection bias [59]. A later
on cardiovascular risk in psoriasis patients [14]. meta-analysis of a number of biologics including
Double-blind, placebo-controlled RCTs of anti- ustekinumab also used the Peto odds ratios, and
IL12p40 agents (ustekinumab and briakinumab) concluded that there was not a significant risk of
and TNF-a inhibitors (infliximab, etanercept and MACE with ustekinumab [60]. Somewhat reas-
adalimumab) were compared and absolute risk suringly, further studies of ustekinumab use in the
differences were used as an effect measure, mea- real world have not shown a significant increase
suring the excess probability of major adverse in MACE; a cohort study of over 60,000 patients
cardiovascular events (MACE, a composite end- from multiple databases was studied and no sig-
point of myocardial infarction, cerebrovascular nificant difference was found in the risk of devel-
accident, or cardiovascular death) in those receiv- oping atrial fibrillation or MACE after initiation
ing active treatment compared to those receiving of therapy with ustekinumab vs. a TNF-α inhibi-
placebo. During the placebo-controlled phases tor [61]. While there is some disagreement in the
of the anti-IL-12p40 studies, 10 of the 3179 literature, the majority of currently-available evi-
patients treated with anti-IL-12p40 therapies dence—after over a decade on the market—sup-
had a MACE compared with zero events in 1474 ports that there is no significant safety signal with
patients treated with placebo (risk difference 1.2 MACE for ustekinumab.
events/100PY, p = 0·12). In anti-TNF-a trials,
only one of 3858 patients treated with anti-TNF-
a treatments had a MACE compared with one of Other Adverse Events
1812 treated with placebo (risk difference 0.05
events/100PY, p = 0.94). Although the apparent Although there was initial concern that IL-12
increase in MACE observed with patients receiv- blockade could result in skewing towards a Th2
ing anti-IL-12p40 antibodies was not statistically type cytokine profile, there was no evidence of
significant, the findings did raise questions about exacerbation of any atopic disease in these stud-
the cardiovascular safety of the anti-IL-12p40 ies. No cases of demyelination were reported
agents and the authors recommended heightened apart from a possible case in a patient who was
vigilance when commencing patients with car- retrospectively diagnosed with human immuno-
diovascular risk factors on ustekinumab. The sec- deficiency virus and profoundly lymphopenic at
ond meta-analysis examined the rate of MACE the time. Two cases of reversible posterior leuke-
in patients in randomized, placebo-controlled, ncephalopathy syndrome were reported as well;
monotherapy studies of IL-12/23 antibodies one in a 65 year old with a history of alcohol
using the Peto one-step odds-ratio, an alterna- abuse who recovered fully from the episode and a
tive statistical method, as an effect measure. This 58 year old with a positive urine drug screen for
15 Ustekinumab 209
MDMA, benzodiazepenes, barbiturates, and of ustekinumab to nursing mothers, where the

marijuana who also recovered fully [62, 63]. unknown risks to the infant from gastrointesti-
nal exposure to ustekinumab should be weighed
against the known benefits of breast-feeding [65].
Laboratory Abnormalities Ustekinumab is excreted in the milk of lactating
monkeys, and as endogenous IgG is excreted in
In phase I studies of ustekinumab in psoria- human milk, it is expected that ustekinumab will
sis, transient asymptomatic decreases in CD4+ be also be present. It is not known if ustekinumab
T cells and CD16+/CD56+ natural killer cells would be absorbed systemically through the
were observed in some patients but this was not immature neonatal gastrointestinal tract after
seen in phase II or III studies [15, 16]. In phase ingestion.
II and III studies in psoriasis and in psoriatic
arthritis, the incidence of haematological and
biochemical abnormalities was low and simi- Cautions for Patients Treated
lar between ustekinumab-treated and placebo- with Anti-IL-12p40 Agents
treated patients. In the phase II study of psoriasis,
however, there was a non-significant trend of ele- There are no absolute contraindications to treat-
vated non-fasting glucose levels in ustekinumab- ment with ustekinumab [65]. Treatment should
treated patients (10%) compared with controls be deferred in patients with clinically important
(4%) (p = 0.23) [64]. This was not observed in active infections until the infection resolves or is
subsequent phase III studies in psoriasis and appropriately treated [65]. No increase in seri-
ustekinumab was shown to have no effect on hae- ous infections has been observed with the use of
moglobin A1c levels. ustekinumab, however, despite initial concerns
regarding longer half-life of the drug [31]. Patients
with evidence of active or latent tuberculosis
Pregnancy and Lactation should be treated with anti-tuberculosis treat-
ment prior to initiating treatment [65]. Current
Ustekinumab is pregnancy category B. The evidence does not support use or avoidance of
product prescribing information states that ustekiniumab within populations at risk for major
ustekinumab should be used during pregnancy adverse cardiovascular events. Ustekinumab has
only if the potential benefit justifies the poten- no currently known drug interactions. Patients
tial risk to the fetus [65]. Toxicology studies should receive all age- appropriate immuniza-
on cynomolgus monkeys revealed no maternal tions recommended by current guidelines prior
or fetal abnormalities following administration to commencing ustekinumab and live vaccines
of intravenous and subcutaneous doses of up should not be administered during treatment. The
to 50 mg/kg during the period of organogen- Bacillus Calmette-Guérin (BCG) vaccine should
esis [65]. Post-marketing data is an important not be administered for 1 year prior to or after
source of information for pregnancy risks and discontinuation of treatment [65].
outcomes. A publication from 2019 reported the
outcomes of 478 maternal pregnancies across all
indications of ustekinumab (including Crohn’s Conclusions
disease and ulcerative colitis)—the majority
resulted in live births and the rates of live births, The field of psoriasis research has been revolution-
spontaneous abortion, and congenital anoma- ized by the increased understanding of the pivotal
lies were consistent with the general population role of the Th-17/IL-23 axis in disease pathogen-
[66]. The product prescribing information for esis. As the first non-TNF-α inhibiting biologic for
ustekinumab advises caution in administration the treatment of psoriasis, ustekinumab signaled
210 G. Han et al.
the arrival of new therapeutic options for psoria- References

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Guselkumab
16
Deep Joshipura, Brooke Rothstein,
and David Rosmarin
Abstract Introduction
Guselkumab is a fully human IgG antibody to Guselkumab (Janssen Pharmaceuticals, Inc.,

the p19 subunit of interleukin-23 (IL-23). Philadelphia, PA) is a fully human monoclonal
Guselkumab has potent efficacy in the treat- IgG1λ antibody that selectively binds to the p19
ment of plaque psoriasis with a favorable subunit of interleukin 23 (IL-23) [1] (Fig. 16.1).
safety profile, providing patients with a sus- It is currently FDA approved for the treatment of
tained response for 3 years in long term stud- moderate-to-severe plaque psoriasis. IL-23 is a
ies. In addition, there is growing evidence that heterodimeric cytokine composed of subunits
guselkumab is effective at treating psoriatic p40 and p19 and found at high levels in the serum
arthritis. This review discusses the efficacy and plaques of patients with psoriasis.
and safety of guselkumab in the treatment of Ustekinumab (Janssen Pharmaceuticals, Inc.,
plaque psoriasis and provides an update on the Philadelphia, PA) binds to the p40 subunit which
published data available from clinical trials. is common to both IL-12 and IL-23. In contrast,
guselkumab binds to the p19 subunit only, and
therefore IL-12 is not suppressed. IL-12 is a pro-
Key Learning Objectives moter of T-cell differentiation to Th1 cells
1. To understand the mechanism of action whereas IL-23 promotes the development of
of Guselkumab Th17 cells which produce IL-17A, IL-17F, and
2. To understand the appropriate use and IL-22 [1]. These cytokines are crucial in the
efficacy of the Guselkumab pathogenesis of psoriasis and signal through the
3. To understand the safety issues of Janus kinase (JAK) and signal transducers and
Guselkumab activators of transcription (STAT) pathway.
Structure and Mechanism
Pharmacodynamics
D. Joshipura · B. Rothstein · D. Rosmarin (*) and Pharmacokinetics
Tufts Medical Center, Boston, USA
e-mail: [email protected]; Structurally guselkumab is a human monoclonal
[email protected]; drosmarin@ IgG1λ antibody that selectively binds to the p19
tuftsmedicalcenter.org

https://doi.org/10.1007/978-3-030-54859-9_16
214 D. Joshipura et al.
Guselkumab IL-23
IL-17A
p19 T17 cell IL-17F Keratinocyte
p40 proliferation
Dendritic cells a b
T22 cell
IL-22
IL-23
Receptor
Macrophages Naive T cell

membrane
When guselkumab binds to the p19 subunit of IL-23, and blocks its interaction with its receptor, the IL-23- mediated signaling pathway
and release of pro-inflammatory cytokines are consequently blocked.
Fig. 16.1 The mechanism of action of guselkumab in survival of T cells subsets. T17 cells include Th17, Tc17,
plaque psoriasis. Release of IL-23 by activated dendritic ILC3 and γδ T cells (reprinted with permission from
cells and macrophages. Once IL-23 binds to its cell sur- Springer nature)
face receptor, it triggers differentiation, proliferation and
subunit which is shared by the cytokines interleu- psoriasis. Mean terminal half-life (t1/2) was
kin 23 (IL-23), and IL-39 [2]. IL-23 is a heterodi- 15–17 days in patients with psoriasis and
meric cytokine composed of p19 and p40 secreted 12–19 days in healthy controls. Both the intrave-
by activated dendritic cells and macrophages. nous and subcutaneous forms of administration
Once activated through interaction with its IL-23 were well tolerated in this study.
receptor on T-lymphocytes, it induces differentia- Following subcutaneous administration of
tion of Th-17 and Th-22 cells (Fig. 16.1). guselkumab 100 mg at 0, 4 and every 8 weeks,
Activation of Th-17 cells leads to secretion of the mean guselkumab steady-state trough serum
IL-17 and IL-22 causing epidermal hyperplasia concentration was approximately 1.2 mcg/mL
and inflammation in psoriasis [3]. In patients [2]. After a single 100 mg subcutaneous injec-
with psoriasis, administration of guselkumab tion, the absolute bioavailability was estimated to
reduced serum levels of IL-17A, IL-17F and be approximately 49% in healthy subjects. The
IL-22 relative to pre-treatment levels on explor- exact pathway through which guselkumab is
atory analysis of the pharmacodynamic markers metabolized is not well characterized. As a
[2]. The role of IL-39 in psoriasis, if any, is human IgG monoclonal antibody, guselkumab is
unclear. expected to be degraded similar to endogenous
The pharmacokinetics, pharmacodynamics, IgG into small peptides and amino acids [2].
safety, and tolerability of guselkumab were ana- Development of anti-drug antibodies occur
lyzed in a phase I clinical trial of 24 patients with due to normal immune response to a foreign pro-
moderate-to-severe plaque psoriasis and 47 tein. Formation of anti-drug antibodies can affect
healthy controls [4]. The healthy participants half-life, increase elimination of the drug, and
were administered a single intravenous (0.03– decrease efficacy. A study done by Zhu et al.,
10 mg/kg) or subcutaneous (10–300 mg) dose of evaluated anti-drug antibodies (ADA) through
guselkumab, and the subjects with psoriasis were 100 weeks of drug exposure from the pivotal
administered a single subcutaneous dose of pla- VOYAGE 1 and VOYAGE 2 trials. It was deter-
cebo or guselkumab (10, 30, 100, 300 mg). mined that 8.5% of subjects in these trials had
Guselkumab exhibited linear pharmacokinetics anti-drug antibodies [5]. Most of these patients
for both intravenous and subcutaneous doses had low titers and the anti-drug antibodies were
tested in healthy participants and subjects with often transient, with serum guselkumab concen-
16 Guselkumab 215
trations being comparable between ADA+ and week 16 was 34%, 34%, 45%, 62%, and 57% in
ADA- patients. Anti-drug antibodies did not the guselkumab groups, respectively, 2% in the
affect the efficacy of guselkumab. The incidence placebo group, and 44% in the adalimumab
of injection site reactions was low in patients group. Guselkumab was effective through week
with and without anti-drug antibodies. 40; however, there was some loss of efficacy right
before the scheduled dose of guselkumab when
the injection was dosed every 12 weeks.
Clinical Efficacy Guselkumab was well-tolerated and adverse
events were similar among the treatment groups.
Guselkumab has been FDA approved since 2017 This successful phase II study showed promising
for the treatment of moderate-to-severe plaque evidence of the clinical efficacy of IL-23 inhibi-
psoriasis in patients who are candidates for sys- tors for the treatment of plaque psoriasis leading
temic therapy or phototherapy. This approval was to further studies in a phase 3 program.
based on efficacy demonstrated in three large piv-
otal phase III clinical trials VOYAGE 1 [6],
VOYAGE 2 [7], and NAVIGATE [8]. The find- VOYAGE 1
ings above were also supported by other trials
such as a phase I pilot study of guselkumab by VOYAGE 1 was a phase III, randomized, double-
Sofen H et al. [9], a phase II (X-PLORE) [10] blind, placebo- and active comparator- controlled
trial, and a phase III trial conducted in Japan [11]. multinational trial (n = 837) conducted to con-
In a phase I trial of 24 plaque psoriasis patients firm the efficacy and safety of guselkumab com-
who were randomized to placebo or guselkumab pared to adalimumab and placebo for the
10, 30, 100 or 300 mg, PASI75 was achieved at treatment of plaque psoriasis [6]. Patients
week 12 in 50% of patients on guselkumab ≥18 years old who were candidates for systemic
10 mg, 60% on 30 mg, 60% on 100 mg, and therapy or phototherapy with moderate-to-severe
100% on 300 mg. On skin immunohistochemis- plaque psoriasis (characterized by Investigator
try, there was a reduction in epidermal thickness Global Assessment (IGA) score ≥ 3, Psoriasis
as well as T-cell and dendritic cell infiltration. Area and Severity Index (PASI) score ≥ 12, and
There were also serum reductions in IL-17A lev- body surface area (BSA) ≥ 10) for at least
els in responsive patients [12]. 6 months were included. Excluded patients were
In the phase II trial [10] of 293 moderate-to- those with severe progressive medical conditions
severe psoriasis patients randomized to receive or cancers (except nonmelanoma skin cancer)
guselkumab (5 mg at weeks 0 and 4 and every diagnosed within 5 years, history of active tuber-
12 weeks thereafter, 15 mg every 8 weeks, 50 mg culosis, and those who had received guselkumab
at weeks 0 and 4 and every 12 weeks thereafter, or adalimumab at any time.
100 mg every 8 weeks, or 200 mg at weeks 0, 4 Patients were randomized to receive gusel-
and every 12 weeks thereafter), placebo, or adali- kumab, adalimumab, or placebo for 16 weeks; at
mumab, significant improvement was observed week 16 the patients on placebo were crossed-
with guselkumab. At week 16, the proportion of over to receive guselkumab through week 48.
patients with a PGA score of 0 or 1 was 34%, Co-primary endpoints were the proportions of
61%, 79%, 86%, and 83% in the guselkumab patients achieving an IGA score of clear/minimal
groups, respectively, 7% in the placebo group, disease (IGA 0/1) and 90% or greater improve-
and 58% in the adalimumab group. The propor- ment in PASI score from baseline (PASI90) at
tion of patients achieving a PASI75 at week 16 week 16 [6].
was 44%, 76%, 81%, 79%, and 81% in the gusel- Clinical response of guselkumab was demon-
kumab groups, respectively, 5% in the placebo strated against placebo for all the co-primary
group, and 70% in the adalimumab group. The and major secondary endpoints (all p < 0.001).
proportion of patients achieving a PASI90 at At week 16, 85.1% of patients in the gusel-
kumab group achieved an IGA score of 0/1 and then guselkumab was re-initiated in the pla-
compared to 6.9% for placebo. Additionally, at cebo group once 50% clinical response was lost.
this same timepoint, 73.3% of patients in the Adalimumab responders were switched to pla-
guselkumab group achieved PASI90 compared cebo at week 28 and guselkumab was initiated
to 2.9% in the placebo group. At week 16, gusel- once 50% clinical response was lost, whereas
kumab was superior to adalimumab in IGA 0/1 adalimumab non-responders stopped treatment at
scoring (85.1% versus 65.9%), PASI 90 scoring the end of week 23 and guselkumab was initiated
(73.3% versus 49.7%), and achievement of at week 28 [7] (Table 16.1).
PASI 75 (91.2% versus 73.1%) [6]. Guselkumab The co-primary end points were the propor-
was also superior to adalimumab at week 24 in tions of patients on guselkumab achieving IGA
IGA 0/1 (84.2% versus 61.7%) and PASI90 0/1 and PASI90 at week 16 as compared to
(80.2% versus 53.0%) scoring. The superior placebo. At week 16, guselkumab was superior to
efficacy of guselkumab was also observed at placebo with higher IGA 0/1 scoring (84.1% ver-
week 48 with a significantly higher proportion sus 8.5%) and PASI90 scoring (70.0% versus
of guselkumab patients achieving scores of IGA 2.4%) (Table 16.2). Similar to VOYAGE I, gusel-
0/1 (80.5% versus 55.4%) and PASI90 (76.3% kumab was superior to adalimumab at week 16
versus 47.9%). Patients randomized to placebo both in IGA 0/1 (84% versus 68%) and PASI90
achieved similar results to the guselkumab scoring (70.0% versus 46.8%). From weeks 28 to
group once they were crossed over [6]. 48, better persistence of response was observed
in the guselkumab maintenance versus with-
drawal group, with 88.6% of patients in the main-
VOYAGE 2 tenance group sustaining a PASI90 response
compared to 36.8% of those in the withdrawal
VOYAGE 2, a phase III, multicentered, random- group (p < 0.001). The median time to loss of
ized, double-blind, placebo- and adalimumab PASI90 response was 23 weeks after the last
comparator-controlled study (n = 992), evaluated guselkumab dose. Of adalimumab non-
the efficacy and safety of interrupted guselkumab responders who switched to guselkumab, 66.1%
treatment, as treatment gaps frequently occur in achieved PASI90 by the end of the study [7].
clinical practice [7]. In addition, VOYAGE 2 In a pooled analysis of VOYAGE 1 and
assessed the transition from adalimumab to VOYAGE 2, guselkumab was effective at treating
guselkumab, providing clinically relevant infor- disease-specific areas such as the scalp, hands,
mation about patients who switch biologics. The and fingernails [15].
inclusion/exclusion criteria were similar to At week 16, significantly more patients on
VOYAGE 1 as stated above. The study consisted guselkumab compared to placebo achieved a
of a placebo-controlled period (weeks 0–16), an scalp-specific Investigator Global Assessment
active comparator-controlled period (weeks (ss-IGA) score of 0 or 1 (81.8% versus 12.4%).
0–28), and a randomized withdrawal and re- At week 16, 75.5% of patients on guselkumab
treatment period (weeks 28–72). Patients were achieved a Physician Global Assessment of hands
initially randomized to guselkumab 100 mg at and/or feet (hf-PGA) score of 0 or 1 compared to
weeks 0, 4, 12, and 20; placebo at weeks 0, 4, and 14.2% of placebo patients. Guselkumab was
12, then guselkumab at weeks 16 and 20; or superior to adalimumab at week 24 in achieving
adalimumab 80 mg at week 0, 40 mg at week 1, a score of 0 or 1 in both ss-IGA (85% versus
and every 2 weeks thereafter through week 23 68.5%) and hf-PGA (80.4% versus 60.3%). At
(Fig. 16.2 and Table 16.1). At week 28, patients week 16, more patients on guselkumab than pla-
who achieved PASI90 on guselkumab were re- cebo achieved a fingernail Physician Global
randomized to continue guselkumab or start pla- Assessment (f-PGA) score of 0 or 1 (46.7% ver-
cebo (to simulate an interruption in treatment) sus 15.2%). Similar proportions of patients
16 Guselkumab 217
Active-comparator period Randomized withdrawal and

Placebo-controlled period Placebo-crossover period retreatment period
Placebo → retreatment
R
Continue guselkumab 100 mg q8w
Guselkumab 100 mg weeks 0, 4. then q8w NR

Continue guselkumab 100 mg q8w
R
Placebo → retreatment
R
Placebo Guselkumab
NR
100 mg Continue guselkumab 100 mg q8w
R
Placebo → guselkumab 100 mg 0, 4, then q8w*
Adalimumab 80 mg at week 0 → 40 mg at
NR
week 1, then q2w Initiate guselkumab 100 mg 0, 4, then q8w*
Week 0 16 24 28 48
PE SE SE
SE
R = Randomization PE = Primary endpoint SE = Secondary endpoint

q2w = every 2 weeks q8w = every 8 weeks
Responders R = 90% or greater improvement in Psoriasis Area and Severity Index (PASI 90)
Nonresponders NR = < PASI 90 response
Fig. 16.2 Schema showing randomization of patients at baseline in VOYAGE II (reprinted with permission from
K. Reich et al)
achieved an f-PGA of 0 or 1 on guselkumab and consistent clinical response across all weight
adalimumab (60.0% and 64.3% p = 0.11). quartiles compared to adalimumab. In patients in
Improvement in difficult-to-treat areas such as the highest weight quartile of >100 kg, 78.3% of
the scalp, palms, and soles, with about 70% guselkumab patients achieved an IGA of 0 or 1
achieving complete clearance, led to significant compared to only 45.2% of adalimumab patients.
improvement in health-related quality of life. Improvements in the Dermatology Life
In a pooled analysis of the 1829 patients from Quality Index (DLQI) were greater for gusel-
VOYAGE 1 and VOYAGE 2, guselkumab was kumab versus placebo at week 16 and for gusel-
superior to placebo and adalimumab in almost all kumab versus adalimumab at week 24 [13]. The
subpopulations of patients who were stratified proportion of patients who achieved a DLQI of 0
based on age, gender, weight, body mass index, or 1, indicating no impact on quality of life, at
ethnicity, baseline disease features, and previous week 24 was higher with guselkumab compared
treatments [16]. Guselkumab showed a more to adalimumab (58.9% versus 40.2%).
Table 16.1 Dosing regimens from phase 3 VOYAGE 1 Maintenance and Recapture

and VOYAGE 2 trials permission (reprinted with permis-
sion from Springer nature)
Based on VOYAGE 1, clinical responses were
Randomized
Active WD and
maintained through 100 and 156 weeks for
comparator re-TX perioda patients on guselkumab, with 82.1% and 82.8%
Trial (ADA) period (wks 28–72) of patients achieving a PASI90 at these time
PL-controlled PL points, respectively. Similarly, IGA 0/1 was
period (wks crossover maintained by 83.3% and 82.1% of guselkumab
0–16) periodb
patients at week 100 and 156, respectively.
VOYAGE GUS wks 0 GUS q8w NA
1 [13] and 4 → q8w continued Patients did have improvement in DLQI and
to wk 44 Psoriasis Symptoms and Signs diary scores at the
PL wks 0, 4 GUS wks NA same time points [14]. In VOYAGE 2, patients
and 12 16 and 20 with ≥90% PASI scores were re-randomized to
→ q8w to
wk 44 continue guselkumab versus withdrawal and pla-
ADA 80 mg ADA NA cebo. The treatment with guselkumab was
wk 0, 40mg 40 mg restarted upon losing ≥50% of PASI at week 28
wk 1 → q2w or at week 72. Loss of PASI75 response was
40 mg q2w continued
associated with increased serum levels of IL-17A
to wk 47
VOYAGE GUS wks 0 GUS at R: PLc or from week 40, IL-17F from week 36, and IL-22
2 [14] and 4 → q8w wk 20 GUS q8w from week 44 onwards. Maintenance of response
NR: GUS was associated with suppression of serum levels
q8w of IL-17A, IL-17F, and IL-22. If there is an inter-
PL wks 0, 4 GUS at R: PLc ruption in treatment with guselkumab, there is a
and 12 wks 16
and 20
slow relapse of psoriasis and restarting gusel-
NR: GUS kumab can recapture the initial response in most
q8w patients [17].
ADA 80 mg ADA R: PLc
wk 0, 40mg 40 mg
wk 1 → q2w to wk
40 mg q2w 23; no TX
NAVIGATE
wks 24–28
NR: GUS In the NAVIGATE phase III trial, the efficacy of
study-wks guselkumab was analyzed in patients who did not
28 and 32 adequately respond to ustekinumab [8]. Inclusion/
→ q8w
exclusion criteria were similar to VOYAGE 1
ADA adalimumab, GUS guselkumah 100 mg, NA not
applicable, NR PASI 90 non-responder, PASI 90 ≥ 90% except patients who had received ustekinumab
improvement in Psoriasis Area and Severity Index, PL (as opposed to adalimumab) within 3 months of
placebo, pts patients, qxw every x weeks, R PASI 90 study onset were excluded. The study started
responder, re(TX) re(treatment), WD withdrawal, wk/s with a 16-week open-label period where all the
week/s, → indicates thereafter
a
VOYAGE 1 wks 16–48; VOYAGE 2 wks 16–28, prior to randomized patients received on-label dosing of
randomized withdrawal and re-Tx through to wk 72 ustekinumab (weight based dosing of either
b
GUS-treated pts were re-randomized based on PASI 45 mg or 90 mg) at week 0 and 4. At week 16,
response at wk 28; NR = PASI < 90 and R ≥ PASI 90 inadequate responders (IGA ≥ 2) were random-
c
Upon loss of ≥ 50% of the 28-wk PASI response, pts
were switched to GUS (100 mg at wk 0 and 4 → GUS ized to guselkumab 100 mg at weeks 16, 20 and
100 mg q8w) every 8 weeks thereafter, or to continue
16 Guselkumab 219
Table 16.2 Efficacy of guselkumab along with HR-QOL outcomes at week-16 in pivotal VOYAGE 1 and VOYAGE 2
trials (reprinted with permission from Springer nature)
Regimen (no. of PASI (% IGA 0/1 (% ssIGA 0/1 (% HR-QOL outcomes mean change
Trial pts) pts) pts)b pts)a from BL [BL]
75b 90c PSSD symptomd DLQId
VOYAGE 1 [5, GUS (329) 91*† 73*† 85*† 83* –42 [54]
*
–11*
13] [14]
ADA (334) 73 50 66 70 –35 [54] –9 [14]
PL (174) 6 3 7 15 –3 [48] < – 1
[13]
VOYAGE 2 [5, GUS (496) 86*† 70*† 84*† 81* –40* [54] –11*
14] [15]
ADA (248) 69 47 68 67 –33 [54] –10
[15]
PL (248) 8 2 9 11 –8 [59] –3
[15]
ADA adalimumab, BL baseline value, DLQI Dermatology Life Quality Index, GUS guselkumab, HR-QOL health-
related quality of life, IGA Investigator Global Assessment (0 = cleared; 1 = minimal), PASI Psoriasis Area and Severity
Index, PASI x improvement of ≥ x% from BL in PASI score, PL placebo, PSSD Psoriasis Symptoms and Signs Diary,
pts patients, qxw every x weeks, ssIGA scalp-specific IGA (0 = absence; 1 = very mild), UST ustekinumab
*
p ≤ 0.001 vs. PL; †p < 0.001 vs. ADA
a
Major secondary outcome GUS vs. PL. Assessed in pts with BL ss-IGA score of ≥2 who had a ≥ 2-grade improve-
ment; included 277, 286 and 145 pts in the GUS, ADA and PL groups, respectively, in VOYAGE 1 and 408, 194 and
202 pts in VOYAGE 2. No statistical comparisons performed for GUS vs. ADA
b
Major secondary outcome for GUS vs. ADA
c
Co-primary endpoint for GUS vs. PL at wk 16 in the VOYAGE trials; major secondary endpoint for GUS vs. ADA
d
Major secondary outcome for GUS vs. PL: mean change from BL in PSSD symptom score assessed in 249, 274 and
129 pts in the GUS, ADA and PL groups, respectively, in VOYAGE 1 and 411, 201 and 198 pts in VOYAGE 2; mean
change from BL in DLQI score assessed in 322, 328 and 170 pts in the GUS, ADA and PL groups, respectively, in
VOYAGE 1 and 496, 248 and pts in VOYAGE 2
ustekinumab at week 16 and every 12 weeks ECLIPSE

thereafter, while responders with IGA 0/1 contin-
ued to receive ustekinumab. The primary end A phase III, multicenter, randomized, double-
point of the trial was the number of visits at blind, active comparator controlled study named
which patients achieved an IGA score of 0 or 1 ECLIPSE compared the efficacy and safety of
and at least a two-grade improvement relative to guselkumab and the anti-IL17a inhibitor,
week 16 from week 28 through week 40 [8]. secukinumab, in adult patients with moderate-to-
Among randomized patients, the guselkumab severe plaque psoriasis [18]. 1048 adult patients
group had a significantly higher mean number of with moderate-to-severe plaque psoriasis were
visits at which patients had an IGA score of 0 or randomized to receive guselkumab or
1 and at least a two-grade improvement relative secukinumab in a 1:1 ratio for 44 weeks.
to week 16 from week 28 through week 40 (pri- The primary endpoint was the proportion of
mary end point) compared with the ustekinumab patients who achieved a ≥ 90% improvement in
group (1.5 versus. 0.7; p < 0.001). Furthermore, Psoriasis Area Severity Index score (PASI90) at
at week 52, 51.1% of guselkumab patients com- week 48. At week 48, guselkumab was superior
pared to 24.1% of ustekinumab patients reached to secukinumab in achieving PASI90 (84.5% ver-
a PASI90 [8]. sus 70.0%; p < 0.001). Major secondary end-
points were not met such as the superiority in Placebo Guselkumab Adalimumab
proportion of patients achieving a PASI75 in the Patients treated, n 422 823 581
guselkumab group compared to the secukinumab Average weeks 15.9 16.2 16.1
group at both week 12 and 48 (84.6% versus of follow-up

Total patient-years 128 255 179
80.2%; p = 0.062) [18]. of follow-up
At least on 198 (46.9) 407 (49.5) 291 (50.1)
adverse events
Common advers eventsa
Other Studies Nasopharyngitis 33 (7.8) 65 (7.9) 54 (9.3)
Upper respiratory 19 (4.5) 41 (5.0) 20 (3.4)
tract infection
Guselkumab was evaluated in a phase III ran- Headache 14 (3.3) 38 (4.6) 18 (3.1)
domized, double-blind, placebo-controlled study Arthralgia 9 (2.1) 22 (2.7) 10 (1.7)
in Japanese patients with moderate-to-severe Hypertension 8 (1.9) 20 (2.4) 12 (2.1)
Injecton site 3 (0.7) 16 (1.9) 26(4.5)
plaque psoriasis. Results were similar to erythema
VOYAGE 1 and VOYAGE 2 in which approxi- Diarrhoea 4 (0.9) 13 (1.4) 13 (1.4)
mately 70% of patients on guselkumab achieved Pruritus 17 (4.0) 13 (1.6) 13 (1.6)
Injection site bruising 4 (0.9) 11 (1.3) 11 (1.3)
a PASI90 at week 16 [11]. Guselkumab was also Back pain 8 (1.9) 10 (1.2) 10 (1.2)
evaluated in 159 Japanese patients with palmo- Cough 5 (1.2) 10 (1.2) 10 (1.2)
plantar pustulosis and showed superiority over Fatigue 6 (1.4) 9 (1.1) 9 (1.1)
Gastroehteritis 3 (0.7) 9 (1.1) 9 (1.1)
placebo [19]. Adverse events leading 5 (1.2) 10 (1.2) 10 (1.2)
to discontinuation
Infections 90 (21.3) 193 (23.5) 145 (25.0)
Safety/Adverse Events Infections requiring

treatment
30 (7.1) 56 (6.8) 43 (7.4)
Serious adverse events 6 (1.4) 16 (1.9) 12 (2.1)

Overall guselkumab is well tolerated, and side Data are presented as n (%). aCommon adverse event are defined
effects are usually mild. In a pooled analysis of as those occurring in at least 1% of patients in the guselkumab
VOYAGE 1 and VOYAGE 2 through 100 weeks, group.
safety of guselkumab was assessed [20]. The
Fig. 16.3 Common adverse events noted in the pooled
most common adverse events (AE) reported were analysis of VOYAGE 1 and VOYAGE 2 phase 3 clinical
nasopharyngitis, upper respiratory tract infec- trials on guselkumab (Reprinted with permission from
tion, and headache. Arthralgias were reported in Reich et al.)
2.7% of patients on guselkumab compared with
2.0% and 2.1% of patients on adalimumab and tively. The proportion of patients with injection
placebo, respectively [20]. There were no differ- site reactions was higher in the adalimumab
ences in serious AEs between the groups group before the crossover to guselkumab (8.8%
(Fig. 16.3). versus 0.8%). No events of Crohn’s disease were
Through week 52, guselkumab and adalim- reported and the rates of vulvovaginal (0.4%) and
umab treated patients had few adverse events and skin (0.2%) candidiasis and neutropenia (0.1%)
serious adverse events (262.45/100 PYs versus were low [20].
328.28/100 PYs and 6.2/100 PYs versus 7.77/100
PYs) (Fig. 16.4) Serious infections, non-
melanoma skin cancers (NMSC), malignancy Pediatrics and Breastfeeding
excluding NMSC, and major adverse cardiovas-
cular events (MACEs) were low for patients There have been reports of pediatric patients
treated with guselkumab and no increased signal treated with guselkumab [21, 22], though there
was seen with treatment from weeks 0 to 100 are no large studies evaluating safety in this
compared to just weeks 0 to 52 [20]. patient population. There is a lack of safety data
Injection site reactions were noted in 2.8% for patients who are pregnant receiving gusel-
and 2.8% of patients at week 52 and 100, respec- kumab. Guselkumab was not detected in the milk
16 Guselkumab 221
Guselkumaba Adalimumab
Through Week 52 Through Week 100 Before crossover b After crossover c
Treated patients. n 1221 1221 581 500

Average weeks of follow-up 45.4 89.0 45.1 51.7
Total PYs of follow-up 1065 2084 502 496
Adverse events
2795 4384 1647 794
Observed number of events
Incidence per 100 PYs 262.45 210.41 328.28 160.15
95% confidence interval 252.81–272.37 204.23–216.73 312.62–344.23 149.20–171.69
Adverse events leading to discontinuation
Observed number of patients 26 38 23 8
95% confiedence interval 1.60–3.60 1.30–2.51 2.93–6.94 0.70–3.19
Infections
Observed number of events 1070 1703 540 353
Infections requiring treatment
300 495 145 95
Observed number of events
28.17 23.76 28.90 19.16
Incidence per 100 PYs
Serious adverse events
Observed number of events 66 131 39 22
aIncludes patients randomized to guselkumab at baseline (n = 825) and those initially randomized to placebo who crossed over to receive
guselkumab at week 16 (n = 398) in VOYAGE 1 and VOYAGE 2. bInclude patents randomized at baseline to adalimumab before crossover
to guselkumab at the end of the active-comparator perod (week 52) in VOYAGE 1 and before crossover to guselkumab during the random-
ized withdrawal and retreatmet period (starting at week 28) (28-08.20) in VOYAGE 2. cIncludes patients randomized at baseline to
adalimumabafter crossover to guselkumab at the end of the active-comparator perod (week 52) in VOYAGE 1 and after crossover
to guselkumab during the randomized withdrawal and retreatmet period (starting at week 28) in VOYAGE 2.
Fig. 16.4 Summary of adverse events per 100 patient years through 100 weeks of follow up. Data from the pooled
analysis from VOYAGE 1 and 2 (reprinted with permission from Reich et al.)
of lactating monkeys, though IgG is known to be Malignancy

present in human milk [2]. It is not known if
guselkumab would be absorbed systemically Guselkumab does not target the activity of IL-12/
through an immature neonatal gastrointestinal Th-1 helper cells. Furthermore, in certain situa-
tract after breastfeeding. tions IL-23 may promote tumor growth [24], so
in theory, use of guselkumab may be safe in
patients with cancer as guselkumab inhibits the
Tuberculosis, HIV, and Live Vaccines activity of IL-23; however there is an absence of
evidence in the literature on the use of gusel-
Patients should be screened for tuberculosis kumab in patients with malignancy. Therefore,
(TB) prior to starting guselkumab. For patients guselkumab should be used with caution in this
being treated for latent TB, they can be safely patient population pending more data.
started on guselkumab at the same time as the
patient receives the first dose of antitubercular
treatment. There is one case report of a patient Inflammatory Bowel Disease
who is HIV positive who received guselkumab
with stable CD4 counts at 12 months [23]. As Guselkumab treatment is not associated with
for all psoriasis biologics, live vaccines are new-onset or exacerbations of inflammatory
contraindicated since there is an absence of bowel disease (IBD) and may serve as a future
safety data. treatment modality [25]. The anti-IL12/IL23
inhibitor ustekinumab [26] and anti-IL23 blocker Hidradenitis Suppurativa

risankizumab have both been shown to improve
inflammatory bowel disease [27]. Hidradenitis suppurativa (HS) is a chronic
inflammatory debilitating skin condition charac-
terized by development of painful abscess, cysts
Psoriatic Arthritis followed by development of sinus tracts and scar-
ring. An overactivity of IL-23/Th-17 pathway has
The efficacy of Guselkumab was studied in a been hypothesized to play a role in the pathogen-
phase 2 clinical trial done in patients with active esis of HS [29]. Two case series evaluating the
psoriatic arthritis [28]. 149 patients were use of guselkumab in patients with HS reported
included with ≥3 tender and swollen joints, benefit in some of the patients [22, 30].
with C-reactive protein levels ≥3 mg/L Guselkumab and other IL-23 inhibitors are cur-
and ≥ 3% BSA of plaque psoriasis. Patients rently under further investigation as a treatment
were randomized to 2:1 to receive either gusel- option for patients with HS.
kumab 100 mg at week 0, 4 and every 8 weeks
through week 44 or placebo. Patients receiving
placebo were subsequently crossed over to Patient Controlled Injector
receive guselkumab at week 24, 28 then every
8 weeks through week 44. An early escape to In the placebo-controlled double-blind phase III
open label ustekinumab was enabled in patients ORION study which evaluated guselkumab
with <5% improvement from baseline in both administered through a patient-controlled injec-
swollen and tender joints. Primary endpoint was tor (One-Press), the primary endpoints were
ACR20 response at week 24 which was achieved PASI90 and IGA of 0 or 1 at week 16 [31].
in 58% of patients on guselkumab versus 18.4% Patients also filled out the self-injection assess-
of placebo. 34% of patients on guselkumab ment questionnaire (SIAQ) and patient-controlled
achieved ACR50 versus placebo at week 24 injection device questionnaire. Guselkumab was
compared to 10.2% of placebo patients, and superior to placebo in terms of PASI90 (75.8%
14% of patients had ACR70 response at week 24 versus 0.0%) and IGA of 0 or 1 (80.6% versus
compared to 2.0% of placebo patients. 60% of 0.0%). Injection site reactions were similar for
patients with prior anti-TNF-alpha exposure both placebo and guselkumab treated subjects.
achieved ACR20 versus 57.8% of anti-TNF- SIAQ post-dose scores were also favorable with
alpha naive patients at week 24.56.6% of patients rating the one-press device as easy/very
patients on guselkumab had complete resolution easy to use from weeks 0 to 28 (87%–100%) and
of enthesitis at week 24 versus 29% in the pla- were satisfied/very satisfied with the device
cebo group. Similarly, 55.2% of patients in the (81%–100%).
guselkumab group had complete resolution of
dactylitis at week 24 versus 17.4% in the pla-
cebo group. 23% of patients had achieved mini- Conclusion
mal disease activity at week 24 compared to
2.0% of patients on placebo [28]. While there is The IL-23 inhibitor guselkumab offers a targeted
some promising early data on the use of gusel- therapy for patients with moderate-to-severe
kumab for patients with psoriatic arthritis, there plaque psoriasis. The ability to achieve high effi-
is no evidence that guselkumab reduces radio- cacy with minimal safety risk and infrequent
graphic progression of disease. Furthermore, injections are major advantages of guselkumab.
more data is needed to determine the relative Therefore, the development of anti-p19 agents is
efficacy of guselkumab against first line FDA a significant advancement in the treatment of
approved agents for psoriatic arthritis which tar- psoriasis. The ability of guselkumab to treat pso-
get TNF-alpha and IL-17. riatic arthritis and other comorbidities of psoria-
16 Guselkumab 223
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[Internet]. 2017;76(3):405–17. Available from:
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tion on the maintenance of therapeutic response Randazzo B, et al. Efficacy and safety of guselkumab,
and rare adverse events that may be associated an anti-interleukin-23 monoclonal antibody, com-
pared with adalimumab for the treatment of patients
with guselkumab use. with moderate to severe psoriasis with randomized
withdrawal and retreatment: Results from the phase
Conflict of Interest III, double-blind, p. J Am Acad Dermatol [Internet].
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Regeneron Pharmaceuticals Inc., and Sanofi. severe psoriasis. J Allergy Clin Immunol [Internet].
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Tidrakizumab
17
George Han
Abstract
Tildrakizumab is a monoclonal antibody tar- 1. To understand the mechanism of action
geting the p19 subunit unique to the cytokine of Tidrakizumab
IL-23 that is FDA-approved in the treatment 2. To understand the appropriate use and
of plaque psoriasis. IL-23 is a central regula- efficacy of the Tidrakizumab
tory cytokine in the pathogenesis of psoriasis. 3. To understand the safety issues of

Tildrakizumab was shown to have superior Tidrakizumab
efficacy in treating psoriasis as compared to
both placebo and an active comparator (etan-
ercept) in two parallel pivotal phase III trials.
This biologic medication has demonstrated
Introduction
efficacy, combined with strong evidence of
durability and an excellent safety profile.
Tildrakizumab (Tildrakizumab-asmn, SUN
Additionally, the fact that it is dosed every
Pharmaceuticals US, Cranbury, NJ) is a high-
12 weeks is an attractive feature to many
affinity IgG1/κ monoclonal antibody targeting
patients. Early results for treatment of psori-
the p19 subunit of the cytokine IL-23. It rep-
atic arthritis are promising, and treatment
resents the first biologic that was studied tar-
seems to be consistent across patient weight
geting IL-23 specifically, with phase II trials
categories and previous treatment characteris-
starting in 2010 and phase III trials starting in
tics. Numerous nuances exist in the approach
2012 [1]. Initially developed by Schering-Plough
to systemic therapy for psoriasis patients, and
(Kenilworth, NJ) and then Merck (Kenilworth,
tildrakizumab is able to navigate many comor-
NJ), the rights to market this medication were
bidities to deliver a reasonable first-line bio-
bought by SUN Pharmaceuticals in 2014.
logic medication for patients with psoriasis.
Subsequently, a licensing agreement was made
with Almirall (Barcelona, Spain) for market-
ing of the medication in Europe. Results from
phase III trials were reported in 2017, with active
comparator (Etanercept) and placebo controls.
G. Han (*) It is FDA approved in the US for the treatment
Icahn School of Medicine at Mount Sinai, of plaque psoriasis with studies currently under
New York, NY, USA way for treatment of psoriatic arthritis. The dos-

https://doi.org/10.1007/978-3-030-54859-9_17
226 G. Han
ing of this medication is an injection of 100 mg agents (Mendelian susceptibility to mycobacte-

at 0 weeks and 4 weeks, followed by injections rial disease) often caused by an autosomal reces-
every 12 weeks. It is indicated in the US for sive deficiency in IL-12. Furthermore, these
administration by a health care provider. patients are susceptible to Candida and Klebsiella
infections [5]. With regards to tumor immunity, it
is becoming clear that there are numerous roles
Rationale of Targeting IL-23 of IL-12 in tumor immunity, with a role of
IL-12 in both promoting cytotoxic Natural Killer
IL-23 is a proinflammatory cytokine that func- (NK) cell function and in activating Interferon-
tions via upregulation of the Th17 axis in inflam- gamma (IFN-γ) producing Th1 cells via the
mation, with downstream effects carried out STAT4 pathway [6–8]. Furthermore, IL-12 can
primarily via IL-17. Specifically, IL-23 induces effectively reprogram immune cells to act against
differentiation of naïve CD4+ T cells into patho- tumor cells in certain environments [9]. Thus,
genic Th17 cells, which then produces IL-17, there may be a role of IL-12 in protecting the host
IL-6, and TNF-α [2]. Prior to the study of til- against the emergence of spontaneous tumors
drakizumab, numerous medications had been [10] and it would be preferable to not block this
developed targeting the IL-12/IL-23 pathway in cytokine in this context. On the contrary, IL-23
psoriasis. Ustekinumab and briakinumab are has been proposed as a disease marker in cancer,
both monoclonal antibodies targeting the shared with numerous pro-tumor and metastasis func-
p40 subunit of IL-12 and IL-23 [3]. While early tions that are appearing in varied malignancies
studies focusing on examining the role of the p40 such as breast cancer, hepatocellular carcinoma,
subunit seemed to show a role of this pathway in colorectal cancer, oral squamous cell carcinoma,
psoriasis, subsequently, it was determined that and non-small cell lung cancer [11–16], among
these medications are able to treat psoriasis pri- others [10]. Thus, it seems rather consistent that
marily by blocking IL-23. A study with human blocking this pro-tumor molecule (IL-23) should
skin biopsy samples showed that while the p40 not lead to any concerns about malignancy;
subunit (shared by IL-12 and IL-23) and the p19 indeed, utilization of anti-IL-23 treatment in
subunit (unique to IL-23) are elevated in lesional oncology has been proposed as a potential treat-
psoriasis skin, the p35 subunit (unique to IL-12) ment in combination with other immunotherapies
is not. On the contrary, levels of all three subunits [17]. It should be noted that in long-term registry
are the same in non-lesional skin from psoriasis data, no evidence was found that blocking IL-12
patients. In normal skin, expression of all three and IL-23 with ustekinumab increased the risk
subunits are the same or lower than in non- for cancer [18].
lesional skin from psoriasis patients [4]. Taken Previously, there was some concern that tar-
together, these data were important in determining geting p40 (IL-12 and IL-23) was associated with
that the inflammation underlying psoriasis pri- the development of major adverse cardiovascular
marily hinges upon increased levels of IL-23 and events (MACE). One drug, briakinumab, was
has little reliance on IL-12. withdrawn from clinical development due to the
Aside from the theoretical rationale that sup- emergence of multiple MACE during Phase II
ports targeting IL-23 rather than IL-12 in treating and III trials. While a statistically significant
psoriasis, there are specific considerations that increase in risk of MACE is under debate and
make targeting IL-23 much more attractive than multiple analyses have shown both risk and no
IL-12. In terms of immunosuppression, it appears risk in this regard [19–22], the data does seem to
that there are numerous functions of IL-12 in host support at least a trend towards MACE among
defense. It has been shown that IL-12 appears to these studies. On the contrary, there seems to be
be important in the immune response to no signal or trend towards MACE in any of the
Mycobacterium and Salmonella infections, with medications targeting IL-23 [22]. The mecha-
a condition that causes susceptibility to these nisms whereby blockade of these interleukins
17 Tidrakizumab 227
can result in a cardiac event are unclear, but what- III parallel trials across sites in North America,
ever minimal trend there seems to be with medi- Europe, Asia, and Australia (reSURFACE 1 and
cations targeting both IL-12 and IL-23 together reSURFACE 2) [29]. The study was conducted
seems to disappear with IL-23 blockade alone. with two doses of tildrakizumab (100 mg q12wk
As compared to IL-17 blocking agents, one and 200 mg q12wk), which was likely a result
notable difference among these agents is with of the dose-ranging phase IIb studies showing a
regard to their roles in intestinal immunoregula- difference of about 10% in achievement of the
tion. IL-17 inhibition exacerbates colitis, likely primary endpoint (PASI75 achievement, both at
due to weakening intestinal epithelial barrier week 12 and week 16) [1]. While many medica-
function (subsequently allowing for microbial tions proceed with one tested dose in Phase III
penetration and increased inflammation) while trials, the sponsor likely thought that there was
IL-23 inhibition seems to promote an anti- enough of a benefit in the higher dose group to
inflammatory milieu in the gut [23]. While IL-17 proceed with testing it in larger phase III trials.
has been shown to exacerbate inflammatory bowel For one of the the Phase III trials (reSURFACE
disease (IBD) [24], IL-23 blockade appears to be 2), an active comparator group treated with etan-
a promising candidate in treatment of Crohn’s dis- ercept in addition to the control group was also
ease [25]. Notably, the actual incidence of IBD in included.
large analyses of IL-17 inhibitors is low [26, 27], Baseline characteristics of this trial were simi-
but it is a true, predictable result of the mechanism lar to most psoriasis trials [29]. The vast majority
of action of this class of medication. of patients were white (65–92%, percentages
given as proportion of patients in each arm) and
male (65–72%). Average weight was close to 90
Pharmacokinetics/ Kg and average body surface area was slightly
Pharmacodynamics over 30%. The mean PASI at baseline was
roughly 20. In reSURFACE 1, percent treated
Subcutaneous dosing of tildrakizumab results in previously with biologics was 23% across all
slow systemic clearance, limited volume of dis- groups whereas in reSURFACE 2, that number
tribution, and a long half-life in pharmacokinetic was between 12–13%.
studies [28]. After a single subcutaneous injec- The co-primary endpoints of reSURFACE 1
tion of tildrakizumab, a dose-related increase in and 2 were achievement of PASI 75 and PGA or 0
serum concentration was observed, peaking at or 1 with at least a 2-point reduction in PGA from
roughly 1 week and exhibiting a slow, linear baseline. Importantly, the primary endpoint out-
decrease over time. The volume of distribution come measures were taken at week 12. At the
was fairly low and the half-life was roughly time of these trials, there were only three approved
23–25 days for the doses studied. Bioavailability injectable biologics for psoriasis: etanercept,
of tildrakizumab was estimated to approach 80% adalimumab, and ustekinumab. Likely due to the
[28]. There is no weight-based dosing for til- rate of efficacy for TNF-α inhibitors, the para-
drakizumab; although multiple doses were stud- digm at the time was to measure primary end-
ied in Phase III trials, there was not enough of a points at week 12, even for ustekinumab [30].
difference in efficacy between doses to allow for Additionally, in the Phase II trials of tildraki-
approval of the higher dose. zumab, the rise in achievement of PASI 75
between weeks 12 and 16 was rather modest [1].
However, it has since become more clear that tar-
Clinical Efficacy geting IL-12/23 and specifically IL-23 as well,
leads to a somewhat slower rise towards peak effi-
The efficacy of tildrakizumab in treating psoriasis cacy [31]. While tildrakizumab treatment was sig-
was demonstrated in two large, multicenter, ran- nificantly better than placebo at week 12 in both
domized, double-blind placebo-controlled phase co-primary endpoints, the numbers were perhaps
228 G. Han
somewhat disappointing as they were found to be achieve PASI75 early on in treatment are more
only comparable to previously reported numbers likely than not to progress to a PASI90 response.
with ustekinumab. The percent achieving PASI 75
for tildrakizumab 200 mg was 62% and 66% for
reSURFACE 1 and 2, respectively; for tildraki- Psoriatic Arthritis
zumab 100 mg, 64% and 61%; for etanercept
48% (reSURFACE 2 only); and for placebo, 6% While psoriatic arthritis trials are ongoing for til-
and 6%. The achievement of PGA 0 or 1, a some- drakizumab and phase III trials have not been
what more stringent criteria, for tildrakizumab completed at the time of writing, the Phase IIb
200 mg was 59% and 59% for reSURFACE 1 and study of tildrakizumab for treating psoriatic
2, respectively; for tildrakizumab 100 mg, 58% arthritis has been conducted and the results have
and 55%; for etanercept 48%; and for placebo, been reported. The results of this smaller study
7% and 4% [29]. Thus, it appeared from the pri- are quite interesting and represent a departure
mary endpoint outcomes that there was not much from the perceived weakness of the IL-23 inhibi-
of a difference between the two doses of tildraki- tor class, namely treating psoriatic arthritis. From
zumab. Notably, the week 28 data was much bet- a conceptual standpoint, it has been shown that
ter for tildrakizumab, with PASI 75 achieved by there seems to be a different gene signature
79% of patients on tildrakizumab 200 mg and between psoriatic skin and synovium—the for-
77% of patients on tildrakizumab 100 mg. Clear mer is IL-17 dominant, while the latter tends to
or minimal PGA was attained by 67% of tildraki- have a stronger TNF signature [35]. Furthermore,
zumab 200 mg treated patients and 63% of til- a report of a different IL-23 inhibitor, risanki-
drakizumab 100 mg treated patients at week 28. zumab, revealed that not only were primary end-
PASI 100 was achieved by 31% of patients on points for treating ankylosing spondylitis (AS)
tildrakizumab 200 mg and 22% of patients on til- not met, there was no evidence of clinically
drakizumab 100 mg. As IL-23 serves as more of a meaningful improvements compared to placebo
regulatory cytokine in the pathogenesis of psoria- [36]. But the same does not seem to hold true for
sis than an effector molecule (such as IL-17), it is psoriatic arthritis in general, where it is expected
perhaps not surprising that it takes longer for that targeting IL-23 should offer efficacy in treat-
these medications to reach peak efficacy, but it ing psoriatic arthritis. This was supported by a
should be noted that durability does seem to be a Phase II trial of another IL-23 inhibitor, gusel-
strength of this drug (see below). kumab, where 58% of patients achieved ACR20
At this point, 3-year data has been presented at week 24 [37]. This result was similar to the
for tildrakizumab showing strong durability of ACR20 response to adalimumab in the corre-
effect [32]. At week 148, 91.2% of the observed sponding Phase III trial (ADEPT) [38].
cohort of responders (i.e. those who achieved However, when the psoriatic arthritis treatment
PASI75 and entered long-term extension) main- data for tildrakizumab were released, it was an
tained PASI75. It should be noted that while NRI unexpected surprise. The ACR20 for tildraki-
data were presented (72.6% of responders main- zumab 100 mg (at the same dosing as for psoria-
tained PASI75 response), the reporting of NRI sis, every 12 weeks) was reported to be 71.4%. In
data at 3 years or longer is abnormal owing to the fact, ACR50 for this dose was 45.5% and ACR70
likelihood that life events may necessitate some- was achieved in 22.1% of patients [39]. Of course,
one’s withdrawal from a clinical trial. Other these numbers have to be taken with a grain of salt
reports have generally used as observed data or as they are Phase II trials with only about 80
other imputation methods for data points signifi- patients in each group, but the numbers are strik-
cantly longer than 100 weeks [33, 34]. ingly higher than reported Phase II trial data of a
Interestingly, over half of the NRI cohort (53.8%) medication targeting the same pathway. It remains
and over 2/3 of the observed population (67.6%) to be seen how these different medications in the
achieved PASI90, implying that patients who same class end up distinguishing themselves, but
17 Tidrakizumab 229
efficacy in psoriatic arthritis could potentially be a through 52–64 weeks, with about 2.5% of
significant differentiator for tildrakizumab if the patients developing treatment-emergent, neutral-
results hold up in Phase III trials. izing antibodies, which are generally associated
with reduced serum concentrations of the active
drug and thus modestly reduced efficacy [40].
Safety/Adverse Events This was found to be true in a sub-analysis of the
tildrakizumab trials, where treatment-emergent,
From a safety standpoint, the effects of tildraki- neutralizing antibodies were associated with a
zumab do not seem to be associated with any modest decrease in PK of tildrakizumab and a
major safety concerns that stand out; in fact, the mean PASI reduction of about 10–15%. It should
specific safety data profile appears to be one of be noted that comparatively, these are still low
the cleanest among all biologics. In the parallel rates of immunogenicity and neutralizing anti-
trials, the rates of adverse events (one or more) bodies were not found to be associated with any
were 42% and 49% for tildrakizumab 200 mg, drug-related or serious adverse events [41].
47% and 44% for tildrakizumab 100 mg, 48%
and 55% for placebo, and 54% for etanercept.
The rates of serious adverse reactions were low Considerations in Treatment
across all groups; ranging from 1–3% for all Approach
groups in the placebo-controlled period (with no
consistent trend observed). The most common When considering treatment options for psoria-
adverse events were nasopharyngitis and upper sis, there are numerous factors to consider. First,
respiratory infection. The percentages of patients there is of course efficacy. However, it should be
experiencing nasopharyngitis were 6% and 11% noted that the actual improvements in gross effi-
for tildrakizumab 200 mg, 8% and 13% for til- cacy have started to cluster within a relatively
drakizumab 100 mg, 5% and 8% for placebo, and narrow range for the majority of patients. Thus,
12% for etanercept. Respiratory tract infection other considerations may take a more prominent
was only reported in reSURFACE 1 (likely an role in the selection of an appropriate medication
issue with coding the adverse events) and this for patients with psoriasis.
was seen in 5% of patients on tildrakizumab
200 mg, 3% of patients on tildrakizumab 100 mg,
and 6% of patients on placebo. Importantly, in Speed of Onset
part 2 of both trials, the rates of these infections
remained stably low. There were very low rates It should be noted that in general, the function of
and no signal for serious adverse events of inter- IL-12/23 and IL-23 inhibitors is on the slower
est, including severe infections, malignancies, side, especially as compared to IL-17 inhibitors.
non-melanoma skin cancer, major adverse car- Patients may drift upwards slowly with any class
diovascular events, and drug-related hypersensi- of medication, but the rapid onset of action (i.e.
tivity reactions. Overall, the rates of adverse time to achieve 50% reduction in baseline PASI)
events with tildrakizumab are among the lowest is the fastest for brodalumab, followed by ixeki-
reported with any biologic and must be consid- zumab and then secukinumab [42]. IL-23 inhibi-
ered as a significant strength of the medication. tors lag behind by a few weeks but the difference
is not on the order of months. Similarly, all bio-
logics take a little more time to cross successive
Immunogenicity PASI thresholds with plateauing of PASI 75 com-
ing before that of PASI 90 and PASI 100 across
Immunogenicity is a possibility as with any bio- the board, even with IL-17 inhibitors. When con-
logic. The specific rates of anti-drug antibody sidering an important life event or other extenuat-
formation for tildrakizumab was about 6.5% ing circumstances, if one wishes to optimize for
230 G. Han
rapidity of onset of action, an IL-23 inhibitor 82.9 Kg without metabolic syndrome). The
would likely yield to an IL-17 inhibitor. responses of both groups of patients (with meta-
bolic syndrome and without), notwithstanding
the stark difference in body weight among other
Prior Treatment with Biologics factors, was very similar in all outcome measures
studied—PASI75, PASI90, PASI100, and mean
One useful consideration is to evaluate whether PASI improvement [44]. Further data are needed
patients who have previously been on other bio- about disease-specific modifying factors, as there
logics will respond to a given treatment. For til- is a logical argument that reducing levels of pro-
drakizumab, the percent achieving PASI 75 was inflammatory cytokines in the bloodstream by
very similar whether or not a patient was on a treating psoriasis with a biologic could reduce
biologic previously. The number achieving PGA atherosclerosis and cardiovascular risk, which
0/1 was slightly lower in biologic-experienced has been shown to hinge on similar cytokines and
individuals (46.2% vs. placebo for tildrakizumab specifically IL-23 [44].
100 mg) than for biologic-naïve patients (52.5%
vs. placebo for tildrakizumab 100 mg) [43].
Withdrawal and Retreatment
Inflammatory Bowel Disease Tildrakizumab has been shown to have a rela-

tively long duration of effect even after medica-
For patients with concerns about inflammatory tion withdrawal, possibly due to the upstream/
bowel disease (either a personal history or a regulatory function of IL-23 in psoriasis. In part
strong family history), a clear choice in this realm 3 of the phase II trial, some patients were fol-
would be either a TNF-α inhibitor, an IL-12/23, lowed for 20 additional weeks off treatment after
or an IL-23 inhibitor. The former two classes of the 52-week treatment period—less than 10%
medications are approved for treatment of relapsed in the tildrakizumab 100 mg group
Crohn’s disease/IBD while IL-23 inhibitors have (maximum PASI improvement reduced by 50%
already reported promising Phase II data in the or more) [1]. In a separate Phase III trial, 49% of
treatment of IBD. Conversely, IL-17 inhibitors patients on tildrakizumab 100 mg treatment
have been found to exacerbate IBD, as previously maintained their PASI75 response 36 weeks after
outlined [24]. cessation of treatment [45]—this is a different
measure and a higher bar than the previously
defined relapse metric. Average time to relapse
Metabolic Syndrome for tildrakizumab 100 mg treated patients was
226 days. In the same study, it was shown that
Given that metabolic syndrome is a common retreatment with tildrakizumab 100 mg for at
comorbidity afflicting patients with psoriasis, it least 12 weeks was able to achieve PASI75 in
should be noted that some reports dealing with 85.7% of patients.
tildrakizumab treatment have specifically looked
at this subject. One report showed that patients
with metabolic syndrome in the reSURFACE tri- Pregnancy
als had a higher incidence of cardiovascular dis-
orders (50.6% for patients with metabolic With regards to pregnancy, animal studies showed
syndrome vs. 16.9% without) and psoriatic no evidence of embryotoxicity or teratogenicity,
arthritis (21.5% for patients with metabolic syn- per the FDA label for tildrakizumab. The only
drome vs. 14.8% without). Patients with meta- data available for human pregnancy thus far
bolic syndrome were also heavier on average, comes from a total of 13 patients who became
with a mean weight at baseline of 106.9 Kg (vs. pregnant in the clinical trials who were then
17 Tidrakizumab 231
removed from the study drug. Out of these one should not think of tildrakizumab as a rea-
patients, all pregnancies carried to full term sonable first-line option in treating psoriasis
resulted in normal live births and the rates of given its efficacy, safety, durability, and potential
spontaneous abortion were similar to the general to treat psoriatic arthritis.
population (2 out of 13) [46]. Interestingly, given
the above duration of effect for tildrakizumab
where about half of patients maintain PASI75 References
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A, Boisson-Dupuis S, Feinberg J, Al-Muhsen S,
Tildrakizumab is an effective treatment for Janniere L, Rose Y, de Suremain M, Kong XF, Filipe-
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Risankizumab
18
Erica B. Lee, Deeti J. Pithadia, Kelly A. Reynolds,
and Jashin J. Wu
Abstract
Risankizumab is a humanized IgG1 monoclo- 1. To understand the mechanism of action
nal antibody that targets the p19 subunit of of Risankizumab
interleukin-23 (IL-23). It has demonstrated 2. To understand the appropriate use and
substantial clinical efficacy in the treatment of efficacy of the Risankizumab
psoriasis. This chapter reviews the efficacy 3. To understand the safety issues of

and safety of risankizumab for the treatment Risankizumab
of psoriasis as evidenced by the clinical trials
to date. Four phase III trials have shown
risankizumab to be more effective than
ustekinumab and adalimumab in terms of
Introduction
PASI and sPGA scores with similar safety
profiles to placebo. Thus far, no significant
Interleukin-23 (IL-23) is a heterodimer of a p40 sub-
safety concerns have emerged for this drug,
unit shared by IL-12 and IL-23 and a p19 subunit
though further long-term studies will be criti-
that is exclusive to IL-23 [1, 2]. Since its discovery
cal in confirming this.
in 2000, it has been identified as a key inflamma-
tory cytokine involved the pathogenesis of psoria-
sis [2, 3]. Ustekinumab, an IL-12/23 inhibitor, has
demonstrated effectiveness in treating psoriasis and
other autoimmune diseases [4–7]. However, more
E. B. Lee recent evidence has shown that psoriatic skin lesions
Department of Dermatology, University of Nebraska
Medical Center, Omaha, NE, USA have elevated levels of the IL-23 p40 and p19 sub-
units but normal levels of the IL-12 specific subunit,
D. J. Pithadia
Department of Pediatrics, Massachusetts General p35 [8]. In a phase I study, Kopp et al. later con-
Hospital, Boston, MA, USA firmed that specific inhibition of IL-23 by tildraki-
K. A. Reynolds zumab improves psoriatic symptoms [9]. Moreover,
Department of Internal Medicine, Kettering Hospital molecular and histopathologic profiles of skin from
Network, Kettering, OH, USA patients treated with an IL-23 inhibitor were shown
e-mail: [email protected] to have “excellent improvement” in global histo-
J. J. Wu (*) pathologic scores at significantly higher rates than
Dermatology Research and Education Foundation, patients treated with ustekinumab [10].
Irvine, CA, USA

https://doi.org/10.1007/978-3-030-54859-9_18
236 E. B. Lee et al.
Risankizumab (AbbVie Pharmaceuticals, Inc., respectively. Bioavailability when given subcuta-

Chicago, IL) is a humanized IgG1 monoclonal neously was markedly higher than previous find-
antibody that specifically targets and inhibits the ings at 89%. Steady-state plasma exposure was
p19 subunit of interleukin (IL)-23 [11]. It is the attained by week 16 of dosing.
third IL-23 inhibitor to be approved for the treat-
ment of moderate-to-severe plaque psoriasis (fol-
lowing guselkumab and tildrakizumab) [12]. It Dosing and Monitoring
is also being investigated for use in Crohn’s dis-
ease, ankylosing spondylitis, atopic dermatitis, The standard dosing of risankizumab is 150 mg
ulcerative colitis, asthma, and hidradenitis sup- (two 75 mg injections) administered subcutane-
purativa [13–20]. ously at week 0, week 4, then every 12 weeks.
Prescribing information recommends that all
patients undergo evaluation for tuberculosis
Pharmacology infection prior to beginning risankizumab [24].
The guidelines for treatment with biologics pub-
A phase I, single-rising-dose, placebo-controlled lished by the American Academy of Dermatology
trial of patients with moderate-to-severe plaque (AAD) and the National Psoriasis Foundation
psoriasis investigated the safety, efficacy, phar- (NPF) also suggest that patients be screened with
macokinetics, and biomarker results of risanki- a complete blood count, complete metabolic pro-
zumab [21]. Eighteen patients received a single file, serologic tests for tuberculosis, hepatitis B
intravenous (IV) dose of 0.01, 0.05, 0.25, 1, 3, and C, and possibly HIV testing at the discretion
or 5 mg/kg and 13 patients received a single of the prescriber [25].
dose of 0.24 or 1 mg/kg subcutaneously. In this With regard to ongoing monitoring, the
study, risankizumab showed linear pharmacoki- AAD/NPF guidelines suggest yearly tubercu-
netics with mean clearance of 0.33 L/day and a losis screening in high-risk patients (patients in
mean terminal phase volume of distribution of contact with individuals with active TB and in
10.8 L. Risankizumab’s half-life ranged between patients with an underlying medical condition).
20 and 28 days. Maximal exposure ranged from All other patients may be screened annually at
4 to 10 days in patients receiving risankizumab the discretion of the provider. Patients should
subcutaneously. Bioavailability was 59% for also have regular follow-up visits with their der-
both subcutaneous and IV administration. matologists, which should include screening for
These findings were confirmed by phase I and nonmelanoma skin cancer, hepatitis B and C,
II trials in subjects with psoriasis and Crohn’s dis- adverse effects, and infections [25].
ease [22]. Based on the results of these analyses,
clearance was estimated to be 0.35 L/day. Steady-
state volume of distribution was estimated to be Clinical Efficacy
11.7 L, and terminal-phase elimination half-life
was calculated as 27 days. In patients receiving Phase I and II trials have demonstrated the effi-
risankizumab subcutaneously, bioavailability was cacy of risankizumab in treating patients with
72%. It was also found that higher body weight moderate-to-severe psoriasis. In the previously
may have modest effect on risankizumab levels, mentioned phase I trial, 87% of patients treated
particularly in patients greater than 100 kg. with a single dose of risankizumab achieved at
Upon incorporation of data from phase III least a 75% decrease in the Psoriasis Area and
clinical trials, clearance was found to be rela- Severity Index (PASI), with 58 and 16% achiev-
tively similar to previous estimates at 0.31 L/ ing PASI 90 and PASI 100, respectively, by week
day [23]. Calculated steady-state volume of dis- 12 [21]. The phase II trial directly compared
tribution and terminal-phase elimination half- risankizumab to ustekinumab in 166 patients ran-
life were also consistent at 11.2 L and 28 days, domized to receive either risankizumab 18, 90,
18 Risankizumab 237
or 180 mg (weeks 0, 4, and 16) or ustekinumab The results of UltiMMa-2 also demonstrated
45 or 90 mg (based on body weight, weeks 0, superior efficacy of risankizumab compared to
4, and 16) [11]. At week 12, the proportion of placebo and ustekinumab. At week 16, 74.8%
patients achieving PASI 90 was 77% in those (220 of 294) of patients in the risankizumab
treated with risankizumab, compared to 40% of group achieved PASI 90, versus 2.0% (2 of
ustekinumab patients (P < 0.001). Moreover, 98) and 47.5% (47 of 99) in the placebo and
98% of the patients in the 90-mg risankizumab ustekinumab groups, respectively (P < 0.0001 vs.
group achieved PASI 75, with 80% of patients both placebo and ustekinumab). In addition, an
reaching this endpoint as early as week 8. sPGA 0/1 score was attained by 83.7% of risanki-
Four phase III trials have formally evalu- zumab patients, 5.1% of placebo patients, and
ated the safety and efficacy of risankizumab: 61.6% of ustekinumab patients (P < 0.0001 vs.
UltIMMa-1, UltIMMa-2, IMMvent, and placebo and ustekinumab). In this trial, 50.7% of
IMMhance. UltIMMa-1 and UltIMMa-2 were patients treated with risankizumab experienced
replicate, randomized, double-blind, placebo- and complete clearance of psoriatic lesions at week
active-comparator-controlled trials [26]. Patients 16; this increased to 59.5% in patients on con-
were randomized to receive either 150 mg risanki- tinuous risankizumab by week 52.
zumab (week 0, 4, then every 12 weeks), 45 or The IMMvent trial was a double-blind, active-
90 mg ustekinumab (based on weight per label), comparator trial that assessed the safety and
or placebo for the first 16 weeks of the study. From efficacy of risankizumab compared to the TNF
weeks 16 to 52, patients initially treated with inhibitor adalimumab [27]. In the first phase of
placebo received risankizumab, while all others the trial, patients were randomly assigned to ther-
maintained their original treatment. Co-primary apy with either risankizumab 150 mg (subcutane-
endpoints included the percentage of patients ous injection at weeks 0, 4, then every 12 weeks)
achieving PASI 90 and a static Physician’s Global or adalimumab (80 mg at week 0, 40 mg at week
Assessment (sPGA) of 0 or 1 at week 16. 1, then 40 mg every other week thereafter).
In UltiMMa-1, risankizumab outperformed During weeks 16–52, those who were originally
both placebo and ustekinumab in terms of the pri- assigned to adalimumab were regrouped based
mary endpoints. PASI 90 was achieved by 229 of on their response at 16 weeks: those with less
304 patients receiving risankizumab (75.3%) com- than PASI 50 response switched to risankizumab,
pared to 5 of 102 (4.9%) receiving placebo and 42 those with PASI 90 remained on adalimumab,
of 100 (42.0%) treated with ustekinumab at week and those with response between PASI 50 and
16 (P < 0.0001 vs. placebo and ustekinumab). By PASI 90 were re-randomized to either initiate
the first measured time point (week 4), the propor- risankizumab or continue adalimumab. Patients
tion of patients on risankizumab attaining PASI 90 originally assigned to risankizumab continued
was significantly higher than those treated with their treatment with dosing every 12 weeks.
placebo, and by week 8, significantly higher than Although the data has not yet been formally pub-
ustekinumab (P = 0.0001). Findings were similar in lished, it has been reported that risankizumab
terms of sPGA scores, with 87.8% of patients reach- performs significantly better than adalimumab
ing sPGA 0 or 1 versus 7.8 and 79.9% of patients both in terms of the primary endpoints at week 16
receiving placebo and ustekinumab, respectively (PASI 90 and sPGA 0/1), and the secondary end-
(P < 0.0001). Moreover, 35.9% of patients receiv- point, PASI 100 at week 44 [27]. Of 301 patients
ing risankizumab achieved PASI 100, or complete in the risankizumab group, 72% achieved PASI
clearance of psoriatic lesions, by week 16, com- 90, compared to 47% of 304 patients in the adali-
pared to 12% of patients receiving ustekinumab mumab group at week 16. Eighty-four percent of
and 0% receiving placebo. At the end of the study risankizumab patients attained sPGA 0/1 at this
period, 81.9% of patients on continuous risanki- time point, versus 60% of adalimumab patients.
zumab and 78.4% of patients who were switched In addition, of those who switched to risanki-
from placebo at week 16 achieved PASI 90. zumab at week 16, 40% achieved PASI 100 at
week 44. Preliminary results were not reported apy. These included alcoholic pancreatitis, isch-
for patients who had been on risankizumab for emic thalamic stroke, transient ischemic attack,
duration of the entire trial. and polymyositis; investigators considered each
The fourth phase III clinical trial, IMMhance, of these independent of the study medication.
was a placebo-controlled study comparing the Injection-site reactions were reported in 2 of 24
safety and efficacy of continuous treatment and patients receiving risankizumab intravenously,
randomized withdrawal of risankizumab over while no reactions were reported in the subcuta-
the course of 104 weeks [28, 29]. In the ini- neous administration group.
tial phase, subjects were randomized to receive The UltIMMa phase III trials demonstrated
either risankizumab 150 mg or placebo for the similar frequency of AEs among individu-
first 28 weeks. The primary endpoints were PASI als treated with risankizumab and those treated
90 and sPGA 0/1. In the second phase, risanki- with ustekinumab [26]. At the end of week
zumab patients who achieved sPGA 0/1 were 16 in UltIMMa-1, 49.7% of patients receiving
re-randomized to continue risankizumab (main- risankizumab and 50.0% of patients receiving
tenance) or placebo (withdrawal). Starting at ustekinumab reported adverse events. Seven
week 32, any patient who experienced a relapse, risankizumab patients reported SAEs in this
defined as sPGA score of 3 or greater, was reini- time period, including one serious infection
tiated on risankizumab (injection given immedi- and one squamous cell carcinoma. Findings
ately, 4 weeks later, then every 12 weeks). The were similar in UltIMMa-2; 45.6 and 53.5% of
primary endpoint for the second phase of the patients reported any AE in the risankizumab
study was sPGA 0/1 at week 52. At week 16, 73% and ustekinumab groups, respectively, by the
of patients assigned to risankizumab achieved end of week 16. Six SAEs were reported among
PASI 90, and 84% attained sPGA 0/1, compared risankizumab- treated patients, including three
2 and 7%, respectively, in the placebo group. At serious infections and one basal cell carcinoma.
week 52, the proportion of patients in the contin- Across both trials, the most commonly reported
uous risankizumab group maintaining sPGA 0/1 adverse events were upper respiratory infection,
was 87%, versus 71% in the withdrawal group psoriasis, and diarrhea. No tuberculosis, oppor-
(P < 0.001). These findings suggest that like tunistic infections, major adverse cardiovascular
other biologics, the efficacy of risankizumab is events (MACEs) or serious hypersensitivity reac-
maximized with continuous treatment rather than tions were reported.
periods of discontinuation and re-initiation. Overall rates of AEs per patient-years
(PY) across the entire 52-week durations of
UltIMMa-1 and UltIMMa-2 were 245.6 and
Safety 281.0 for risankizumab and ustekinumab, respec-
tively [27]. Serious AEs occurred at a rate of 9.8
As risankizumab is one of the newest biologics per 100 PY on risankizumab, compared to 1.9
to be approved, safety data is limited to what per 100 PY on ustekinumab. Of these, serious
has been reported in clinical trials. Adverse infections occurred slightly less frequently in the
events (AEs) were reported in 65% (20 of 31) of risankizumab group (1.6 per 100 PY vs. 2.5 per
patients followed for 24 weeks after a single dose 100 PY with ustekinumab), though MACE (0.5
of risankizumab in the phase I trial, though sever- per 100 PY vs. 0.0 per 100 PY), malignancy of
ity of adverse events did not appear to correlate any kind (1.5 per 100 PY vs. 0.5 per 100 PY),
with the dose received [21]. The most common and death (0.3 per 100 PY vs. 0.0 per 100 PY)
adverse events reported were mild-to-moderate occurred with higher frequency in patients on
upper respiratory tract infections (10%), mild risankizumab. One risankizumab patient died
nasopharyngitis (13%), and mild-to-moderate from sudden cardiac arrest 101 days after the
headache (10%). Four serious AEs (SAEs) were last dose of risankizumab, and a second died
reported concurrently with risankizumab ther- of an unknown cause 161 days after the last
18 Risankizumab 239
dose. Moreover, an additional risankizumab- biologic therapies. The advent of IL-23 inhibi-
treated patient in the IMMvent trial died of an tors has provided psoriasis patients with novel
acute myocardial infarction on study day 73. options with exceptional clinical efficacy seen in
The IMMhance trial also reported death of one the phase III clinical trials. However, it is impor-
patient on risankizumab; this occurred on study tant to consider the paucity of long-term efficacy
day 263 and was ruled to be due to a MACE [29]. and safety data. Further studies are undoubtedly
All of these patients had cardiovascular risk fac- necessary to specify the role of IL-23 inhibitors in
tors prior to initiation of the drug. It is impor- the treatment of psoriasis.Conflicts of InterestDr.
tant to consider that the sample sizes of the trials Wu is an investigator for AbbVie, Amgen, Eli
conducted so far are still relatively small; further Lilly, Janssen, Novartis; a consultant for AbbVie,
research and larger population sizes are needed to Almirall, Amgen, Bristol-Myers Squibb, Celgene,
determine whether risankizumab may have any Dermira, Dr. Reddy’s Laboratories, Eli Lilly,
serious long-term adverse effects. Janssen, LEO Pharma, Novartis, Promius Pharma,
Pooled data from all phase III clinical tri- Regeneron, Sun Pharmaceutical, and UCB,
als found that 24% (263 of 1079) of patients Valeant Pharmaceuticals North America LLC;
treated with risankizumab were positive for and a speaker for AbbVie, Celgene, Novartis,
anti-risankizumab antibodies by week 52 [24]. Regeneron, Sanofi Genzyme, Sun Pharmaceutical,
Of these, about 57% (14% of all risankizumab- UCB, Valeant Pharmaceuticals North America
treated patients) were deemed to have neutraliz- LLC. The rest of the authors have no conflicts to
ing antibodies. However, higher antibody levels disclose.
were associated with lower risankizumab con-
centrations and reduced clinical efficacy in only
1% of patients. References
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Secukinumab for the Treatment
of Inflammatory Skin and Joint 19
Disease
Jason E. Hawkes and Avishan Vishi Hawkes
Abstract and rheumatology. While the exact roles of

interleukin-17 in the development of inflam-
Psoriasis is a chronic inflammatory skin con-
matory diseases is not entirely clear, ongoing
dition characterized by thick, erythematous,
research and clinical studies are expanding
scaly plaques commonly found on the exten-
our knowledge base and leading to the devel-
sor surfaces, scalp, and trunk. While the etiol-
opment of new treatments that can improve
ogy of this skin condition has not been fully
clinical outcomes for patients affected by
elucidated, research has unequivocally shown
these conditions.
that psoriasis represents a bona fide T cell-
mediated disease that involves the skin, joints,
and a myriad of other organs/tissues. The
Abbreviations
recent discovery of a set of pathogenic T cells
that produce high levels of interleukin-17 in
ACR 20 American College of Rheumatol-
response to interleukin-23 led to a major para-
ogy 20 score
digm shift in the pathogenic model for this
AS Ankylosing spondylitis
condition resulting in numerous novel targeted
ASAS 20 Assessment of Spondyloarthritis
immune therapies. The robust phase 3 clinical
International Society 20 (ASAS
trial program for anti-interleukin-17A via
20) response
secukinumab (sold under the brand
axSpA Axial spondyloarthritis
Cosentyx®) for the treatment of moderate-to-
DLQI Dermatology Life Quality Index
severe plaque psoriasis, psoriatic arthritis, and
FDA US Food and Drug Administration
ankylosing spondylitis provides a solid foun-
IBD Inflammatory bowel disease
dation supporting the high clinical efficacy
Ig Immunoglobulin
and safety of this medication in dermatology
IL-17 Interleukin-17
IL-23 Interleukin-23
NAPSI NAil Psoriasis Severity Index
J. E. Hawkes (*)
Department of Dermatology, University of California nr-axSpA Nonradiographic axSpA
Davis and PCN-Rocklin, Sacramento, CA, USA PASI Psoriasis Area and Severity Index
e-mail: [email protected] PK Pharmacokinetic
A. V. Hawkes PPP Palmoplantar psoriasis
Regeneron Pharmaceuticals, Inc., ppPASI Palmoplantar Psoriasis Area and
Tarrytown, NY, USA Severity Index

https://doi.org/10.1007/978-3-030-54859-9_19
244 J. E. Hawkes and A. V. Hawkes
PsA Psoriatic arthritis selective blockade of IL-17A and IL-23p19. This

PSSI Psoriasis Scalp Severity Index book chapter will focus on secukinumab, the first
TNF Tumor necrosis factor FDA-approved monoclonal antibody to selec-
tively target IL-17A for the treatment of psoriatic
disease.
of Secukinumab Secukinumab: Background
2. To understand the appropriate use and and Pivotal Clinical Trial Data
efficacy of the Secukinumab
3. To understand the safety issues of
The rapid onset, clinical efficacy, and safety
Secukinumab profile of secukinumab underscores the impor-
tance of the IL-23/IL-17 signaling pathway in
the pathogenesis of psoriasis and inflammatory
joint diseases. Originally developed in 1996
Introduction from HuMab® mice (Medarex, Inc.) using a por-
tion of the human immunoglobulin repertoire,
Psoriasis is a chronic, inflammatory skin dis- secukinumab (previously known as AIN457) is
ease that is estimated to affect approximately a fully human immunoglobulin (Ig)G1/κ mono-
3% of the US population [1]. Plaque psoriasis, clonal antibody that was subsequently tested
the most common disease subtype, is typified in clinical trials by Novartis Pharmaceuticals
by well- demarcated, scaly, thickened plaques Corporation for the treatment of psoriasis,
on the scalp, trunk, and extensor surfaces of the rheumatoid arthritis, and uveitis [4]. The FDA
extremities. Inflammatory involvement of the approved secukinumab for the treatment of
joints, known as psoriatic arthritis (PsA), occurs moderate- to-severe plaque psoriasis in adults
in approximately one-third of patients with pre- on January 21, 2015. Secukinumab is currently
existing skin disease or can be the presenting sold under the trade name Cosentyx® and selec-
symptoms of psoriasis. Other less common pso- tively targets the IL-17A isoform. It was the first-
riasis variants include erythrodermic, pustular, in- class FDA-approved monoclonal antibody
palmoplantar, guttate, and inverse subtypes. that directly inhibits the IL-17 immune axis [5].
The pathogenesis of psoriasis is a complex, Secukinumab was subsequently approved for the
T-cell mediated skin and joint disease primar- treatment of ankylosing spondylitis (AS) and PsA
ily driven by upregulation of the interleukin-23 in adults on January 15, 2016. Below is a sum-
(IL-23)/IL-17 signaling pathway [2, 3]. While mary of pivotal clinical trials for secukinumab
the exact cause of psoriasis is still unknown, for each approved clinical indication.
the onset of disease is clearly modified by sev-
eral factors including psoriasis-associated genes
or susceptibility loci, environmental exposures, Plaque Psoriasis
diet, medications, and infections. In the last two
decades, science and clinical trials have rapidly For plaque psoriasis, secukinumab is admin-
expanded our knowledge of psoriatic disease, istered subcutaneously with a loading dose of
leading to the development and US Food and 300 mg (two 150 mg injections) at weeks 0, 1,
Drug Administration (FDA) approval of a broad 2, 3, and 4, then monthly thereafter. The 150 mg
array of topicals, oral immunosuppressants, and dose at the same dosing interval is available and
injectable immunotherapies. This therapeutic may be sufficient for some patients. Key phase
armamentarium includes 11 monoclonal anti- 3 clinical trials provide evidence demonstrating
bodies (or biologics) whose targets range from the efficacy of secukinumab in the treatment of
inhibition of tumor necrosis factor (TNF) to moderate-to-severe plaque psoriasis: ERASURE,
19 Secukinumab for the Treatment of Inflammatory Skin and Joint Disease 245
FIXTURE, and CLEAR trials. Additional, sub- compared to only 58% from the ustekinumab
sequent phase 3 trials built upon and bolster the group. The distinct superiority of secukinumab
clinical data obtained from these three major compared to ustekinumab was still evident fol-
trials. lowing 1 year of treatment [8], and secukinumab
ERASURE was a double-blind, 52-week, was strongly associated with a significantly
placebo- controlled trial with 738 patients higher Dermatology Life Quality Index. The
enrolled into secukinumab (300 or 150 mg SCULPTURE trial reported a similar, sustained
weekly for 5 weeks, then monthly) versus pla- clinical efficacy and safety for secukinumab
cebo [6]. 75% improvement in the Psoriasis Area through 5 years [9]. Finally, the JUNCTURE [10]
and Severity Index (PASI 75) for patients in the and FEATURE [11] trials also demonstrated the
secukinumab treatment groups (300 or 150 mg) efficacy and safety of secukinumab administered
were 82 and 72%, respectively. Less than 5% of for auto-injector/pen and pre-filled syringes, and
patients achieved a PASI 75 in the placebo arm. clinical results were comparable with previous
The FIXTURE trial was also a double-blind, studies.
52-week, placebo-controlled with 1306 patients
randomized to treatment with secukinumab (300
and 150 mg as above) or etanercept (50 mg twice ifficult to Treat Psoriasis Subtypes:
D
weekly for 12 weeks, then weekly) versus pla- Palmoplantar, Nail, and Scalp
cebo [6]. In this trial, a PASI 75 was achieved Psoriasis
in 77 and 67% of patients by week 12 in the
300 and 150 mg treatment arms, respectively. Most psoriasis clinical trials to date have been
In comparison, only 44% of patients achieved a designed for plaque psoriasis or PsA, excluding
PASI 75 with etanercept versus 5% in the pla- less common disease subtypes and patients with
cebo treatment arm. Importantly, a pooled analy- disease that predominantly involves the scalp,
sis of the data from ERASURE and FIXTURE palmoplantar, intertriginous, or genital skin.
also showed ~95% of patients who had achieved Scalp psoriasis, palmoplantar psoriasis (PPP),
a PASI 75 in the core clinical trials were able and nail abnormalities have historically been
to achieve this same response by 12 weeks fol- classified as more difficult to treat psoriasis areas.
lowing secukinumab treatment interruption The exact reasons for the patterned expression or
(data presented at the 2017 American Academy recalcitrant nature of disease in these specific skin
of Dermatology Annual Meeting in Orlando, areas is not currently known. However, dispro-
Florida). portionate environmental triggers (e.g. increased
The CLEAR study was a subsequent trauma) and/or differences in resident immune
52-week, double-blind, randomized controlled cells in these areas of skin represent a possible
trial that enrolled 676 patients to treatment with explanation for these observations. Secukinumab
secukinumab (300 mg weekly for 5 weeks, then was one of the first psoriasis biologics evaluated
monthly) versus ustekinumab (45 or 90 mg at in trials specifically designed for patients with
weeks 0, 4, then every 12 weeks based on body these difficult to treat subtypes in the GESTURE,
weight) [7]. Due to the high efficacy shown for TRANSFIGURE, and scalp psoriasis trials.
both treatments from previous studies, a more GESTURE was a phase 3, randomized,
stringent primary study endpoint of PASI 90 double- blind, placebo-controlled, multicenter,
instead of PASI 75 was used in the ERASURE trial conducted across 15 countries and consisted
and FIXTURE studies. The benchmark of PASI of 132 weeks of treatment for PPP patients [12].
90 as a primary study endpoint would continue to 205 subjects were randomized to secukinumab
be used in subsequent studies for newer, highly 300 or 150 mg versus placebo. The primary end-
effective biologic agents tested for the treatment point was Palmoplantar Investigator’s Global
of psoriasis. At week 16, 79% of psoriasis patients Assessment (ppIGA) 0 (clear) or 1 (almost clear/
achieved a PASI 90 in the secukinumab group minimal) after 16 weeks of treatment. At week
16, 33 and 22% of patients achieved clear or Psoriatic Arthritis

almost clear in the 300 and 150 mg treatments
groups, respectively, compared to only 1.5% in For PsA patients with coexistent skin disease,
the placebo treatment arm. This clinical response secukinumab is dosed and administered as above
was accompanied by significant reductions in for moderate-to-severe plaque psoriasis. For PsA
Palmoplantar Psoriasis Area and Severity Index with no skin disease, 150 mg of secukinumab can
(ppPASI) and higher Dermatology Life Quality be administered with a loading dose (150 mg at
Index (DLQI) 0/1 responses. Continued clini- weeks 0, 1, 2, 3, and 4, then monthly) or without a
cal improvement and a sustained efficacy was loading dosage (150 mg every 4 weeks). 300 mg
observed in moderate-to-severe PPP patients dosing should be considered for PsA patients
on continuous secukinumab treatment for up to with persistent or recalcitrant clinical disease and
2.5 years [13]. symptoms despite receiving the 150 mg dosing
In a very similar design as the GESTURE of secukinumab for an adequate period of time to
trial, TRANSFIGURE was conducted across allow symptoms to resolve (usually 3–4 months).
39 study locations and consisted of 132 weeks Two initial phase 3 clinical trials (FUTURE 1
of secukinumab treatment for psoriatic nail and 2) evaluated the efficacy of secukinumab for
involvement [14]. The primary study endpoint the treatment of PsA. FUTURE 1 was a 52-week,
was improvement in the NAil Psoriasis Severity double-blind, placebo-controlled trial that ran-
Index (NAPSI) after 16 weeks of secukinumab domized 606 patients with PsA to treatment with
treatment. The primary endpoint was met dem- secukinumab (10 mg/kg dose at weeks 0, 2, and 4,
onstrating mean nail improvement in 73 and then 150 or 75 mg subcutaneously every 4 weeks)
64% of patients treated with secukinumab 300 versus placebo [16]. Approximately 50% of
and 150 mg, respectively. Improved NAPSI patients achieved at least a 20% improvement in
scores were sustained with continuous treatment the American College of Rheumatology 20 score
over 2.5 years and was associated with multiple (ACR 20) for both treatment arms compared to
improved patient reported outcomes and Quality only 17% in the placebo arm. This response was
of Life indices. observed and sustained through 1 year after ini-
Finally, secukinumab was studied for the tiation of secukinumab treatment. FUTURE 2
treatment of scalp psoriasis in a phase 3, double- was a 4-year study that enrolled and randomized
blind, randomized trial of 102 psoriasis patients 397 PsA to secukinumab (300, 150, or 75 mg
across 17 study locations [15]. In this 24-week monthly after weekly injections at weeks 0, 1,
study, patients were randomized to secukinumab 2, 3, and 4) versus placebo [17]. After 24 weeks
300 mg at weeks 0, 1, 2, 3, and 4 followed by of secukinumab treatment, 54% (300 mg), 51%
monthly injections for 20 weeks versus placebo. (150 mg), and 29% (75 mg) of patients treated with
The primary study measure was 90% improve- secukinumab achieved an ACR 20 versus 15% of
ment of Psoriasis Scalp Severity Index (PSSI patients in the placebo arm. At week 128, patients
90) score from baseline to week 12. The propor- with inadequate response to 150 or 75 mg dosing
tion of patients achieving a PSSI 90 response at were escalated to 300 mg based on the judgment
week 12 was 53% for the secukinumab 300 mg of the trial investigators. The ACR 20 and ACR 50
treatment group compared to only 2% of response rates were maintained around 70–75%
patients receiving placebo. More than one-third and 40–50%, respectively, between weeks 26
of patients receiving secukinumab achieved through 208. PASI 75/90 scores were slightly
complete clearance of the scalp at week 12,
lower for patients with PsA compared to plaque
whereas 0% of patients receiving placebo had psoriasis, but similar to those observed in the piv-
complete scalp clearance. otal phase 3 trials for plaque psoriasis.
FUTURE 5 was another randomized, double- Ankylosing Spondylitis

blind, placebo-controlled clinical trial and the
largest ever conducted for PsA patients receiving Axial spondyloarthritis (axSpA) is an inflam-
treatment with any biologic [18]. In this study, 996 matory, spinal arthritis which can be severely
patients were randomized to 52 weeks of treat- disabling for patients due to chronic back pain
ment in four different groups: secukinumab 300 that often manifests before the age of 45. Patients
or 150 mg monthly after loading doses at weeks with axSpA are characterized as having either AS
0, 1, 2, 3, and 4; secukinumab 150 mg monthly (also known as radiographic axSpA) or nonradio-
with no loading dose; or placebo. The primary graphic axSpA (nr-axSpA). This condition is also
endpoint was ACR 20 response at week 16 and associated with psoriasis and shares overlapping
was achieved in 63, 56, and 60% of patients in the clinical features with PsA, such as sacroiliitis,
secukinumab 300 mg + loading, 150 mg + load- synovitis, enthesitis, dactylitis, and the HLA-
ing, and 150 mg with no loading treatments B27 gene [19, 20]. It is not surprising, therefore,
groups, respectively. 27% of patients receiving that a significant proportion of patients with AS
placebo achieved an ACR 20 response at week and PsA respond to treatment with secukinumab.
16. The ACR 20 response was sustained through Secukinumab for the treatment of AS is adminis-
week 52 in all treatments arms with superiority tered as 150 mg with or without a loading dose:
observed in the secukinumab 300 mg + loading 150 mg every 4 weeks or 150 mg at weeks 0, 1, 2,
dose group. Importantly, the study also evaluated 3, and 4 followed by monthly injections.
multiple secondary endpoints including radio- The efficacy of secukinumab for the treatment
graphic progression of joint disease at week 52, of active AS was studied in four pivotal phase 3,
complete response of enthesitis, and complete double-blind, randomized, placebo-controlled
response of dactylitis, which were achieved in trials: MEASURE 1-4. MEASURE 1 enrolled
roughly half of patients for all treatment groups. and randomized 371 AS patients for treatment
To date, most clinical trials have not discrimi- with intravenous secukinumab (10 mg/kg dose)
nated between subtypes of PsA (e.g. axial PsA). at weeks 0, 2, and 4 followed by 150 or 75 mg
This may be due in part to our evolving under- every 4 weeks versus placebo [21]. The primary
standing and terminology around inflammatory endpoint for MEASURE 1 and 2 was the propor-
arthropathies. Regardless, knowing whether these tion of patients with at least 20% improvement in
subtypes have differential responses to specific the Assessment of Spondyloarthritis International
treatments is an important question to address. Society (ASAS 20) response criteria at week 16.
Novartis will attempt to address this via an ongo- At week 16, ASAS 20 response rates were 61 and
ing phase 3b clinical trial (ClinicalTrials.gov 60% for the 150 and 75 mg doses, respectively,
Identifier: NCT02721966) evaluating the safety compared to only 29% in the placebo group. In
and efficacy of secukinumab 150 or 300 mg in MEASURE 2, a total of 219 AS patients were
the treatment of axial PsA patients who have enrolled and randomized to treatment for 3 years
failed at least 2 non-steroidal anti-inflammatory with subcutaneous secukinumab (150 or 75 mg)
drugs for at least 1 month. ASAS 20 response at weeks 0, 1, 2, 3, and 4 followed by monthly
with secukinumab 300 mg versus placebo at injections versus placebo [21]. Patients in the
Week 12 is the listed primary study end point of placebo group were then randomly switched to
this trial. This and other studies designed to tease subcutaneous secukinumab (150 or 75 mg) at
out PsA subtypes prior to the trial design will week 16. ASAS 20 response rates at week 16
be of interest to clinicians treating this group of were 61 and 41% for subcutaneous secukinumab
patients with complex disease. (150 and 75 mg), respectively, compared to only
28% of patients in the placebo group. ASAS 40 erties for this medication have been established
response rates at week 16 for the 150 mg treat- across three major multiple clinical indications
ment group were 36% and gradually improved and in a highly diverse demographic of patients.
to 49% through week 52. It is important to note Secukinumab has also been used safely in
that significant improvement in AS symptoms plaque psoriasis, PsA, and AS patients for more
were observed for patients treated with 150 mg than 5 years. Therefore, the above referenced phase
of secukinumab in all dosing groups, whereas 3 clinical trials have provided a robust data set that
75 mg of secukinumab was only significant with establishes the high efficacy and excellent safety
a higher loading dose. of secukinumab across multiple indications. The
MEASURE 3 was a 52-week trial that evalu- adverse events reported in clinical trials for these
ated the safety and efficacy of subcutaneous three indications have been remarkably similar
secukinumab 300 and 150 mg monthly main- and are summarized in Table 19.1. The most com-
tenance dosing for AS following intravenous monly reported adverse events in approximately
loading (10 mg/kg at weeks 0, 2, and 4) versus 10% of patients was headache and nasopharyngi-
placebo [22]. 61 and 58% of patients achieved tis or upper respiratory infections. Less common
the ASAS 20 response rate target at week 16 adverse events included non-serious infections or
for the 300 and 150 mg treatment arms, respec- infestations, diarrhea, arthralgias, mucocutaneous
tively, compared to 36.8% in the placebo group. candidiasis, hypertension, and hypercholesterol-
As with prior studies, improvements in clini- emia. Rare adverse events (occurring in less than
cal disease were maintained from week 16 1% of patients) included transient neutropenia,
through week 52. The clinical improvements and major adverse cardiac event, inflammatory bowel
ASAS20 response rates observed in MEASURE disease (IBD), serious infections, uveitis, and
3 were essentially reproduced in MEASURE 4 malignancy or unspecific tumor formation.
[23], which evaluated the efficacy and safety of Mucocutaneous candidiasis and IBD are
secukinumab 150 mg via a self-administered pre- two particular adverse events of interest for this
filled syringe (with or without a loading regimen) particular class of medication. The develop-
in AS patients for 104 weeks. However, due to ment of candida and other viral infections as a
a high placebo response rate, the results in the result of IL-17 inhibition reflects the importance
study were not statistically significant.
Table 19.1 Summary of adverse events for secukinumab
observed in phase 3 clinical trials for the treatment of
plaque psoriasis, psoriatic arthritis (PsA), and ankylosing
Pharmacologic Properties spondylitis (AS)
and Safety
Common Adverse Events: >10% of patients
• Nasopharyngitis or upper respiratory infections
The pharmacologic and biochemical properties • Headache
of secukinumab and its mode of administration Less Common Adverse Events: 9–1% of patients
determine its observed clinical efficacy and safety • Diarrhea
in treated patients. As a human IgG1-based anti- • Mucocutaneous candidiasis
body targeting IL-17A, secukinumab shares the • Non-serious infection/infestation
• Hypertension
stability and long half-life of other IgG1 antibod- • Hypercholesterolemia
ies in humans [24]. These properties, as well as • Arthralgias
its abundance in the human body, were factors Rare Adverse Events: <1% of patients
that certainly influenced the decision underlying • Inflammatory bowel disease
the design of secukinumab. The pharmacokinetic • Serious infections
• Injection site reactions
(PK) properties of secukinumab have also been • Major adverse cardiac event
established with a known half-life of ~25 days, • Uveitis
high absolute bioavailability, and no dose- • Neutropenia
dependent clearance [25]. The favorable PK prop- • Malignancy or unspecified tumors
of this specific cytokine in providing humans psoriasis is treated. Nevertheless, patients

and the skin with protection against this infec- with psoriatic disease who are unresponsive to
tion. Humans with inborn errors of IL-17RA or secukinumab or other agents in this drug class
IL-17F are also associated with recurrent candida underscore the complexity of this disease, espe-
infections, upper respiratory infections, and mild cially since many of these patients are responsive
skin infections that provides a natural experiment to broader-acting agents such as TNF inhibi-
in human nature that reflects complete blockade tors, methotrexate, or cyclosporine. The rapid
of IL-17 signaling in the skin [26]. progress in the treatment of skin manifestations
The potential association between IL-17 of psoriasis with IL-17 antagonists compared to
blockade with secukinumab and the subsequent first- and second-generation biologic treatments
development of IBD is complicated for several (TNF inhibitors or ustekinumab) is astonishing
reasons. First, the families and individuals with in comparison to the minimal progress we have
inborn errors in IL-17 signaling (i.e. no produc- made in the treatment of inflammatory arthropa-
tion of IL-17 in the body) do not go on to develop thies with these same agents. A side-by-side com-
any major sequela, such as IBD or malignancy. parison of the PASI and ACR scores from phase
This observation argues against the suggested link 3 clinical trials for biologics used for psoriasis
between suppression of IL-17 by secukinumab and accentuates the treatment gap for the treatment
the development of IBD. Second, secukinumab of skin versus joint disease [2]. This has raised
and brodalumab (an IL-17 receptor inhibitor) some experts in the field to suggest a future treat-
were tested for clinical efficacy in patients with ment strategy that includes the concomitant use
IBD and no prior history of psoriatic disease. of IL-17 inhibitors with a TNF inhibitor or the
Some of the patients in these trials reported wors- use or novel molecules that simultaneously target
ening of their gastrointestinal symptoms [27, 28]. two cytokines (e.g. TNF and IL-17A) via bispe-
This has led some clinicians to exercise caution cific antibodies [30].
with IL-17 inhibitors when treating patients with Recent phase 2 clinical data in plaque psoria-
IBD and a concomitant inflammatory condition, sis for bimekizumab, which targets both IL-17A
such as psoriasis or PsA. However, patients with and IL-17F, is very encouraging and provides an
psoriatic disease already have an increased risk excellent proof of concept for this novel thera-
for developing IBD compared to the general pop- peutic strategy [31]. Additional data about the
ulation, which suggests a potential genetic rather testing of bispecific antibodies is also avail-
than treatment-associated link [29]. Attempts to able for review [32, 33]. The anticipated high
prove a causative association between IL-17 inhi- cost and/or increased adverse events associated
bition and the development of new-onset IBD with two simultaneously administered biologics
in humans or mice are ongoing, but have thus are the most likely deterrents for this treatment
far been inconclusive. Understanding the role of approach. Preclinical or early phase 1 clinical
IL-17 in the mucosa and gastrointestinal system trial data for bispecific antibodies in the treat-
are critically important as we are just beginning to ment of inflammatory conditions are just starting
understand the role of the IL-23/IL-17 signaling to emerge. As technology continues to advance,
in tissues beyond the skin. the promise of dual cytokine inhibition for the
treatment of chronic inflammatory diseases is
strong and worth ongoing investigative efforts.
uture Direction of IL-17 Blockade
F The continued development of novel bispecific
for Chronic Inflammatory molecules in conjunction with translational
Conditions research projects that investigate the role of IL-17
on the immune cells unique to specific tissues
The development of secukinumab and other will help advance our ability to better manage
IL-17 inhibitors (e.g. ixekizumab, brodalumab, these complex inflammatory conditions. The role
and bimekizumab) have transformed the way of secukinumab and other IL-17 antagonists for
the treatment of neutrophilic dermatosis, such as ment of psoriasis. J Immunol. 2018;201(6):1605–13.

https://doi.org/10.4049/jimmunol.1800013.
pyoderma gangrenosum or Sweet syndrome, will 3. Martin DA, Towne JE, Kricorian G, Klekotka P,
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especially those with comorbidities or reserva- in clearing skin of subjects with moderate to severe
plaque psoriasis: CLEAR, a randomized controlled
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Acknowledgements None. years of treatment (SCULPTURE Extension Study).
J Eur Acad Dermatol Venereol. 2018;32(9):1507–14.
https://doi.org/10.1111/jdv.14878.
Conflict of Interest JEH currently serves on the medical
10. Paul C, Lacour JP, Tedremets L, Kreutzer K, Jazayeri
board of the National Psoriasis Foundation and has been a
S, Adams S, et al. Efficacy, safety and usability of
consultant for AbbVie, Janssen, LearnSkin, Novartis,
secukinumab administration by autoinjector/pen in
Pfizer, Regeneron-Sanofi, VisualDx, and UpToDate. AVH
psoriasis: a randomized, controlled trial (JUNCTURE).
is a current employee of Regeneron Pharmaceuticals, Inc.
J Eur Acad Dermatol Venereol. 2015;29(6):1082–90.
and receives stock in the company as part of her
https://doi.org/10.1111/jdv.12751.
employment.
11. Blauvelt A, Prinz JC, Gottlieb AB, Kingo K, Sofen H,
Ruer-Mulard M, et al. Secukinumab administration
by pre-filled syringe: efficacy, safety and usability
results from a randomized controlled trial in psoria-
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Ixekizumab
20
Caitriona Ryan and Roisin O’Connor
Abstract
Ixekizumab is a fully human monoclonal anti- 1. To understand the mechanism of action
body that selectively targets IL-17A which has of Ixekizumab
shown to be highly effective in the treatment 2. To understand the appropriate use and
of psoriasis and psoriatic arthritis. This chap- efficacy of the Ixekizumab
ter reviews the efficacy and safety profile of 3. To understand the safety issues of

ixekizumab for the treatment of psoriasis Ixekizumab
based on clinical studies to date. Studies dem-
onstrate that ixekizumab is highly effective in
the treatment of moderate-to-severe psoriasis
and the majority of patients achieve high
Introduction
clearance rates. Uncommon adverse events
reported during ixekizumab therapy, included
Ixekizumab (Taltz, Eli. Lilly) is a humanised
neutropenia, candida infections, and inflam-
IgG4 monoclonal antibody that selectively binds
matory bowel disease, however long-term
to IL-17A and inhibits its interaction with the
safety data beyond 5 years is not yet
IL-17 receptor [1, 2]. It has been consistently
available.
shown to be effective in the treatment of
moderate-to-severe psoriasis [3]. Ixekizumab has
been approved in adults for the treatment of
moderate- to-severe plaque psoriasis and also
psoriatic arthritis [4].
Ixekizumab is composed of two light chain
polypeptides of 219 amino acids each, and two
heavy chain polypeptides of 445 amino acids
C. Ryan (*) each [5]. Ixekizumab selectively blocks IL-17A
Institute of Dermatologists Ireland, Dublin, Ireland which is a member of the IL-17 family of cyto-
Charles Institute of Dermatology, University College kines along with IL-17B, IL-17C, IL-17D,
Dublin, Dublin, Ireland IL-17E and IL-17F [1]. Il-17A is produced by
e-mail: [email protected] CD4+ T-cells called Th17 cells which represent
R. O’Connor a subset of CD4+ helper lymphocytes [6]. The
Department of Dermatology, Children’s Health family of IL-17 homodimeric proteins differ in
Ireland (CHI) at Crumlin, Dublin, Ireland

https://doi.org/10.1007/978-3-030-54859-9_20
254 C. Ryan and R. O’Connor
amino acid sequence and consequently in spa- ule. Estimated mean (SD) of Cmax,ss is 21.5 (9.16)
tial structure [1]. Ixekizumab binds specifically μg/ml, and Ctrough,ss is 5.23 (3.19) μg/ml. After
to IL-17A [1]. The active form of IL-17A occurs swapping from the 80 mg Q2W dosing schedule
as a homodimer (A/A) or a heterodimer (A/F) to the 80 mg Q4W dosing regimen at Week 12,
with IL-17F [1]. The physiological response to steady state is reached after approximately
IL-17A involves the release of cytokines and 10 weeks. Estimated mean (SD) of Cmax,ss, is 14.6
chemokines which are responsible for recruiting (6.04) μg/ml and Ctrough,ss is 1.87 (1.30) μg/ml [10].
and activating neutrophils and memory T-cells
to the site of inflammation, and maintaining a
pro-inflammatory state [1]. Il-17A has a key role Clinical Efficacy
in chronic inflammation and autoimmunity [1].
Current data suggests that IL-17A has three main Three pivotal phase III trials, UNCOVER-1,
functions including host defence, neutrophil UNCOVER-2 and UNCOVER-3 have evaluated
homeostasis, and chronic pathogenic inflamma- the efficacy and safety of various dosing regi-
tion [1, 7, 8]. mens of ixekizumab compared to placebo in
The discovery of IL-17, which plays a criti- patients with moderate to severe psoriasis [3].
cal role in the development of psoriasis, has UNCOVER-2 and UNCOVER-3 trials also com-
opened many new treatment options. The class pared ixekizumab to etanercept [11].
of IL-17 inhibitors includes secukinumab, ixeki- In UNCOVER-1 1296 patients were randomly
zumab, brodalumab, bimekizumab, netakimab assigned in a 1:1:1 ratio to receive 80 mg ixeki-
and M1095 [9]. zumab every 2 weeks (Q2W), 80 mg ixekizumab
every 4 weeks (Q4W), or placebo. Patients
assigned to the ixekizumab cohort received
Pharmacodynamics 160 mg starting dose followed by 80 mg Q2W or
Q4W. The co-primary endpoints were Psoriasis
Ixekizumab targets the IL-17 cytokine pathway Area and Severity Index (PASI) 75 and static
which plays a key role in the pathogenesis of pso- Physician Global Assessment (sPGA) 0 or 1 at
riasis. Phase 1 data based on psoriatic skin biop- week 12. Patients who responded to ixekizumab
sies demonstrate a dose-dependent reduction of treatment at 12 weeks (sPGA 0-1) were re-
epidermal thickness, a reduction in proliferating randomised to receive placebo, ixekizumab
keratinocytes, T cells, dendritic cells and reduc- 80 mg Q4W, or ixekizumab 80 mg every
tions in inflammatory markers including 12 weeks with 48 weeks of follow up [3, 12].
C-reactive protein from baseline to day 43 [9, 10]. By week 12, a significant superior response
was reported to both ixekizumab regimens com-
pared to placebo. The percentage of patients
Pharmacokinetics achieving PASI 75 was 89.1 and 82.6% for ixeki-
zumab Q2W and Q4W compared to 3.9% in the
Mean peak concentrations occur between 4 and placebo group (p < 0.001 compared to placebo)
7 days following the administration of one subcu- [12]. 81.8% achieved an sPGA of 0 or 1 with
taneous dose of ixekizumab in patients with pso- ixekizumab Q2W and 76.4% with ixekizumab
riasis, with doses ranging from 5 to 160 mg [10]. Q4W compared to 3.2% in the placebo group
Analyses suggest the average bioavailability of (P < 0.001) [12]. Of the patients in the 2-week
ixekizumab following subcutaneous injection is dosing cohort, 70.9% had a PASI 90 response,
54–0%. After the 160 mg starting dose, the mean and 35.3% had a PASI 100 response at week 12
(SD) maximum plasma concentration (Cmax) of [12]. UNCOVER-1 demonstrated that this
ixekizumab is 19.9 (8.15) μg/ml. Steady state is response was sustained through 60 weeks.
achieved by week 8 following the initial starting 72.9% of ixekizumab-treated responders
dose of 160 mg and the 80 mg Q2W dosing sched- maintained sPGA of 0 or 1, 77.7% maintained or
20 Ixekizumab 255
achieved PASI 75, and 52% maintained or 4 or more points in both ixekizumab-treated
achieved PASI 100 [11, 12]. groups compared to placebo and etanercept.
In UNCOVER-2, 1224 patients were ran- Improvements were reported as early as week 1
domly assigned in a 2:2:2:1 ratio to receive 80 mg for each ixekizumab dose versus placebo or etan-
ixekizumab Q2W, 80 mg ixekizumab Q4W, etanercept (p < 0.0001) [11].
ercept 50 mg twice weekly or placebo [12]. The Pooled data from 2570 patients in
UNCOVER-1 and UNCOVER-2 trials shared UNCOVER-2 and UNCOVER-3 trials showed
similar induction designs. Patients in the ixeki- that ixekizumab treated patients achieved more
zumab groups received 160 mg starting dose fol- rapid improvements both in health-related qual-
lowed by 80 mg Q2W or Q4W. At 12 weeks, the ity of life (HRQol) and itch compared to those
study showed ixekizumab was statistically supe- receiving etanercept or placebo [2].
rior compared to placebo [12]. The percentage of Ixekizumab-treated patients (both dosing
patients achieving PASI 75 was 89.7 and 77.5% groups) achieved the minimally clinical impor-
for ixekizumab Q2W and Q4W respectively, tant difference (MCID) for the dermatology life
compared to 2.4% in the placebo group quality index (DLQI) and itch numeric rating
(P < 0.0001) [12]. 83.2% of the Q2W group and scale (NRS) scores at 2.1 weeks, while the
72.9% of the Q4W group achieved sPGA of 0 or median times for MCID in etanercept-treated
1, compared to 2.4% in the placebo group patients were 4 weeks for DLQI and 8.1 weeks
(P < 0.0001 compared to placebo) [12]. Both dos- for NRS. The majority of patients in the placebo
ing schedules of ixekizumab were superior to group did not achieve the MCID during the
placebo in achieving PASI 90, PASI 100, and 12-week induction period [2].
improvement in DLQI score (P < 0.0001 com-
pared to placebo) [12]. Ixekizumab 80 mg Q2W
and Q4W regimens were also more efficacious in Bodyweight
terms of number of patients reaching PASI 75
and sPGA 0 or 1 at week 12 when compared to Pooled data from three Phase 3 studies
etanercept (P < 0.001) [11, 12]. (UNCOVER-1, UNOCVER-2, UNCOVER-3)
In UNCOVER-3 1346 patients were randomly were used to evaluate the effect of bodyweight on
assigned in a 2:2:2:1 ratio to receive 80 mg ixeki- the efficacy of ixekizumab treatment in patients
zumab Q2W, 80 mg ixekizumab Q4W, etanercept with moderate-to-severe psoriasis [13]. 3855
50 mg twice weekly, or placebo [12]. patients were included in the analysis and patients
Patients in the ixekizumab groups received were stratified into three bodyweight groups
160 mg starting dose followed by 80 mg dosing (<80 kg, 80 to <100 kg, ≥100 kg) [13]. A higher
Q2W or Q4W [12]. UNCOVER-3 showed statis- proportion of patients across all body weight
tically better results for ixekizumab 80 mg Q2W groups treated with ixekizumab achieved PASI
and ixekizumab 80 mg Q4W than placebo [12]. 75, PASI 90, or PASI 100 at week 12 compared to
87.3% of the Q2W group and 84.2% of the Q4W placebo or etanercept [13]. There was no signifi-
group achieved PASI 75, compared to 7.3% in cant difference in PASI 75 response rates across
the placebo group (P < 0.0001) [12]. 80.5% of the the different bodyweight groups [13].
Q2W and 75.4% of the Q4W group achieved an
sPGA of 0 or 1, compared to 6.7% in the placebo
group (P < 0.0001) [12]. Both ixekizumab dosing Psoriatic Arthritis
regimens were superior to placebo in achieving
PASI 90, PASI 100 and improvements in DLQI Two phase III clinical trials, SPIRIT-P1 and
(p < 0.0001) [11, 12]. SPIRIT-P2, demonstrated the superiority of
Significantly more patients who had an itch ixekizumab (80 mg Q2W and Q4W) over pla-
numeric rating scale (NRS) score of 4 or more cebo in moderate-to-severe psoriatic arthritis
at baseline experienced an improvement of (PsA) in patients who failed treatment with either
NSAIDs, conventional disease-modifying anti- twice weekly), or 80 mg ixekizumab Q2W or

rheumatic drugs (csDMARDs), or tumour necro- Q4W after a starting dose of 160 mg [17]. At
sis factor-α inhibitors (TNFi) for multiple joint week 12, all ixekizumab-treated patients were
and cutaneous indices [14]. assigned to open-label to receive ixekizumab
In SPIRIT-P1, 417 patients naive to biologic Q4W through to week 60 [17]. At week 12, the
therapy with active psoriatic arthritis PsA were placebo group received a 160 mg starting dose
randomised to receive subcutaneous injections of of ixekizumab, followed by IXE Q4W thereaf-
placebo, adalimumab 40 mg once every 2 weeks, ter [17]. A week 12, the etanercept group
ixekizumab 80 mg Q2W, or ixekizumab 80 mg received placebo washout, then IXE Q4W at
Q4W [15]. Both ixekizumab dosing regimens week 16 and thereafter [17].
included a 160-mg starting dose. The primary Of 1346 patients in this study, 796 had finger-
endpoint was an American College of nail psoriasis at baseline and were included in
Rheumatology (ACR) 20 response at week 24 this subgroup analysis [17]. The Nail Psoriasis
compared to placebo [15]. More patients achieved Severity Index (NAPSI) was the assessment tool
an ACR20 response with ixekizumab Q2W used to evaluate the severity of fingernail psoria-
(62.1%) and ixekizumab Q4W (57.9%) than pla- sis. A modified version of NAPSI was used and
cebo (30.2%) (p ≤ 0.001) [15]. Significantly less toenail involvement was not assessed [17]. Each
disease activity and functional disability was fingernail was divided into four quadrants and
reported with both ixekizumab Q2W and Q4W NAPSI was used to assign a score to each nail for
when compared to placebo at week 12 and 24 nail bed and nail matrix psoriasis [17]. The total
[15]. Significantly less progression of structural NAPSI fingernail score ranged from 0 (no nail
damage was reported at week 24 (p ≤ 0.01) with psoriasis) to 80 (severe nail psoriasis) [17].
ixekizumab treatment [15]. Ixekizumab was also Ixekizumab showed significant improvement
superior in achieving PASI 75, 90 and 100 com- in fingernail psoriasis with promising results evi-
pared to placebo in this study (p ≤ 0.001) [15]. dent as early as week 2, with greater NAPSI
363 patients with psoriatic arthritis for a min- improvement in the ixekizumab Q4W (5.1%)
imum of 6 months who had an incomplete arm of the study compared to etanercept (−7.9%,
response to, or were intolerant of, tumour necro- p = 0.024) [18]. By week 12, both ixekizumab
sis factor inhibitors were recruited to SPIRIT-P2 groups exhibited greater NAPSI improvements
[16]. 363 patients were randomly assigned from baseline in contrast to placebo and etaner-
(1:1:1) to receive 80 mg of ixekizumab Q2W or cept [17].This effect was maintained through
Q4W after 160 mg starting dose, or placebo [16]. 60 weeks of treatment [17].
The primary endpoint was ACR-20 response at Patients that were switched to ixekizumab
week 24 [16]. The percentage of patients who from placebo or etanercept at week 12 or 16
achieved ACR-20 response by week 24 was 53 respectively, demonstrated comparable improve-
and 48% for ixekizumab Q4W and Q2W, respec- ments to patients who received continuous ixeki-
tively, compared to 20% of placebo-treated zumab treatment [17]. A higher proportion of
patients [16]. patients in the ixekizumab Q4W (19.7%) and
Q2W (17.5%) group achieved complete resolu-
tion of fingernail psoriasis compared to placebo
Nail Psoriasis (4.3%) or etanercept (10.2%) at week 12 [17].
Irrespective of the initial stratification, more than
Subgroup analysis in UNCOVER-3 evaluated 50% of patients achieved complete resolution by
the efficacy of ixekizumab compared to placebo week 60 IXE Q4W treatment [17]. Complete
or etanercept in patients with baseline finger- resolution rates in this study are significantly
nail psoriasis [17]. Patients were randomized higher when compared to reports of clearance
1:2:2:2 to receive placebo, etanercept (50 mg rates with other biologics [17, 19–21].
20 Ixekizumab 257
Scalp psoriasis on the palms and soles. PPASI is calculated

as the sum of results for erythema, induration and
The scalp is very often affected in psoriasis and is desquamation multiplied by a score for the degree of
a particularly challenging area to treat [22]. There palm and sole involvement (range 0–72) [26].
is limited information available on the efficacy of 28.3% of patients from UNCOVER-1,
biologic therapy for scalp psoriasis [22]. A sub- UNCOVER-2 and UNCOVER-3 had evidence of
group analysis was performed in a subset of palmoplantar psoriasis at baseline (PPASI ≥ 0).
patients with scalp psoriasis from UNCOVER-1, Of these, 9.1% of patients had moderate-to-
UNCOVER-2 and UNCOVER-3 trials to evaluate severe palmoplantar psoriasis at baseline
the efficacy of ixekizumab over 60 weeks [22]. (PPASI ≥ 8) [26]. Among patients with palmo-
The Psoriasis Scalp Severity Index (PSSI) was plantar psoriasis, 85.9, 73.9 and 48.9% treated
the assessment tool used to evaluate the severity with ixekizumab Q4W and 79.8, 69.3 and 51.8%
of scalp psoriasis. PSSI is calculated as the sum treated with ixekizumab Q2W achieved PPASI
of results for erythema, induration and desqua- 50, 75 and 100 respectively, at week 12, which is
mation multiplied by a score for the degree of significantly more than placebo (32.9, 18.8 and
scalp involvement [22]. 8.2%; p < 0.001) and etanercept (67.8, 44.1, and
Among patients with scalp psoriasis at base- 32.2%; p < 0.05) [26].This response was main-
line, (PSSI) 75, 90 and 100 were achieved at week tained or improved in patients continuing on
12 in a higher proportion of patients treated with ixekizumab Q4W through week 60 [26].
ixekizumab Q2W (89.9, 81.7 and 74.6%) or Q4W
(83.6, 75.6 and 68.9%) compared to placebo (12.7,
7.6 and 6.7%) or etanercept (67.6, 55.5 and 48.1%) Genital Psoriasis
[22]. These responses were sustained through
week 60 of the maintenance (UNCOVER-1 Genital psoriasis is a common, distressing and
and UNCOVER-2) and LTE arm of the study in difficult-to-treat form of plaque psoriasis with a
patients who remained on ixekizumab Q4W [22]. detrimental impact on quality of life and psycho-
Improvements occurred in patients with base- sexual functioning [27].
line scalp psoriasis in the UNCOVER-3 trial. The Ixora-Q was a phase IIIb, randomised, double-
median time to PSSI 75, 90 and 100 were 2.1, 4.1 blind, placebo-controlled trial which appraised
and 4.3 weeks, respectively in the ixekizumab the efficacy of ixekizumab in patients with
Q2W group compared to 8.1, 8.3 and 12 weeks, moderate-to-severe genital psoriasis with ≥1%
respectively in etanercept group [22]. body surface area involved [27]. The static
Physician’s Global Assessment of Genitalia
(sPGA-G) was developed to assess the severity of
Palmoplantar Psoriasis genital psoriasis [27]. 149 patients with moderate-
to-severe genital psoriasis (sPGA-G) score ≥ 3),
Palmoplantar psoriasis is not only associated with with BSA ≥ 1% were randomised 1:1 to receive
considerable discomfort, and pain it also affects placebo or ixekizumab (160 mg at week 0, then
dexterity and mobility with significant quality of 80 mg every 2 weeks) [27]. The primary endpoint
life implications [23–26]. Using pooled data from was to establish if ixekizumab was superior to
UNCOVER-1, UNCOVER-2 and UNCOVER-3 placebo at week 12. This was measured by the
trials, the efficacy of ixekizumab was evaluated in percentage of patients achieving 0 or 1 (clear or
a subpopulation of patients with moderate-to- minimal) on the sPGA-G [27].
severe plaque psoriasis and moderate- to-severe At week 12, 73% of patients in the ixekizumab
non pustular palmoplantar involvement [26]. group achieved clear or almost clear genital skin
The Palmoplantar Psoriasis Area and Severity (sPGA-G 0 or 1) compared to 8% in the placebo
Index (PPASI) was used to assess the severity of group. Fifty-six percent of patients achieved com-
plete clearance of genital psoriasis compared to Japanese patients with plaque psoriasis (n = 78),
placebo 5% (p < 0.001) [27]. In keeping with previ- erythrodermic psoriasis (n = 8) and generalized
ous clinical studies of ixekizumab, 73% of patients pustular psoriasis (n = 5) [31]. 160 mg of ixeki-
achieved an overall sPGA 0 or 1 compared to pla- zumab was administered at week 0, followed by
cebo (3%, p < 0.001) [27]. Significant clinical 80 mg every 2 weeks from weeks 2 to 12, and
improvement was reported as early as week 1 for every 4 weeks from weeks 16 to 52 [31]. At week
sPGA-G 0 or 1, sPGA-G 0 and overall sPGA 0 or 52, PASI 75, PASI 90 and PASI 100 was achieved
1, and as early as week 4 for overall sPGA 0 [27]. in 92.3, 80.8 and 48.7% of patients [31]. Patients
Ixekizumab resulted in significant improve- with erythrodermic psoriasis or generalised pus-
ments in genital itch and HRQoL. 60% of patients tular psoriasis responded favourably to ixeki-
treated with ixekizumab achieved a clinically zumab therapy and 75 and 60% of patients
meaningful (≥3-point) improvement from base- achieved a sPGA 0 or 1 at week 52 [31].
line in the genital itch numeric rating scale (NRS) Improvements in PASI, PSSI, DLQI and itch
compared to placebo (8%) at week 12 [27]. NRS were reported at week 12 and maintained
Almost 80% of patients treated with ixeki- through week 52 [31].
zumab reported that the frequency of sexual
activity was rarely affected by genital psoriasis
by week 12 of treatment and significant improve- Adverse Effects
ment was already observed within the first week
of treatment. Additionally, 45% of patients receiv- Comprehensive ixekizumab safety data comes
ing ixekizumab reported no clinically significant from the cumulative safety analysis covering up
impact on HRQoL at week 12 [27]. There are to 319 weeks of ixekizumab exposure combined
limited number of published open-label studies from 11 controlled and uncontrolled ixekizumab
that have investigated the efficacy of therapeutic studies on psoriasis, including three Phase 3 stud-
interventions for genital psoriasis [28–30]. ies (UNCOVER-1, -2, and -3) [32]. Ixekizumab
exhibited an acceptable safety profile and no
novel safety findings compared to previous
Body Regions reports [3, 11, 32, 33].
5689 patients treated with ixekizumab from
Pooled data from 3 trials (UNCOVER-1, 11 studies were included in the analysis, which
UNCOVER-2, UNCOVER-3) through week 12 accounted for 12 061.5 PY of exposure [32].
was used to assess the efficacy of ixekizumab on Treatment-emergent adverse events (TEAE)
moderate-to-severe psoriasis affecting various were reported by 83.9% of patients. 71% of
body sites (head/neck, arms, trunk, legs) [18]. patients reported mild-to-moderate TEAEs and
Ixekizumab Q2W was associated with signifi- 12.9% reported severe TEAEs [32]. A TEAE was
cantly greater mean percent improvements in an event that first occurred or increased in sever-
PASI from baseline compared to placebo for each ity after baseline, on or prior to the final day,
body region. Improvements increased through within the treatment time [32]. The most com-
week 12 with the highest on the trunk (92.8%), monly (>6%) reported TEAE after 12 061.5 PY
followed by the head/neck (91.4%), arms (89.9%) of ixekizumab therapy was: nasopharyngitis
and legs (88.7%) (p < 0.001 vs. placebo) [18]. (22.9%), upper respiratory tract infection
(13.5%), injection-site reaction (9.5%), head-
aches (7.8%) and arthralgia (7.1%) [32]. These
Erythrodermic and Pustular results are similar to those previously reported
Psoriasis with 6480 PY exposure [33]. Serious adverse
events AEs were reported in 11.8% of patients
A phase 3, multicentre, single-arm, open-label, and death occurred in 0.4% of patients (cardiac
long-term study was carried out to evaluate the disorder (n = 11), neoplasm (n = 2), unknown
long term efficacy and safety of ixekizumab in cause (n = 5), respiratory failure (n = 2), severe
20 Ixekizumab 259
cerebrovascular event (n = 1), severe dementia ous infection affecting 0.5% of ixekizumab
(n = 1) and injury (n = 1) [32]. treated patients [32]. In keeping with IL-17A
6.7% of patients reported TEAEs resulting in blockade and its role in mucosal immunity,
discontinuation from the study. There was no mucocutaneous candidiasis was the most com-
cases of confirmed tuberculosis (TB) or reactiva- monly observed opportunistic infection. This
tion. However, 0.5 and 0.2% of patients reported integrated analysis of 11 clinical studies showed
a positive Mycobacterium tuberculosis complex no reports of endemic mycoses, systemic candi-
test and a positive tuberculin test. These were the diasis, invasive aspergillus or other invasive fun-
most commonly reported AE that lead to discon- gal infections [32].
tinuation from the study [32].
Research suggests a high rate of false-positive
TB test results are commonly found in popula- IBD
tions with a low risk of Mycobacterium tubercu-
losis infection which reflects the cohorts in these Research has shown that the prevalence of
studies [34–36]. Crohn’s disease and ulcerative colitis is
While there were no serious injection-site increased in patients with psoriasis [37–40].
reactions reported, 0.2% of patients discontinued Pooled data from seven ixekizumab psoriasis
the study due to injection site reaction [36]. trials reported that the incidence of Crohn’s dis-
ease and ulcerative colitis cases were uncom-
mon (<1%) in ixekizumab treated patients [41].
Adverse Events of Special Interest The results are similar with those observed in
the analysis of combined data of 11 ixekizumab
Ixekizumab exposure over 156 weeks showed psoriasis trials. Following 3 years of ixekizumab
no increase in incidence rates (IR) of adverse treatment the IRs of Crohn’s disease and ulcer-
events of special interest (AESI) [32]. Infections, ative colitis were 0.0 and 0.1 per 100 PYs,
injection site reactions and allergic reactions/ respectively [32].
hypersensitivities were the most commonly
reported AESI [32]. Contact dermatitis, eczema,
urticaria, dermatitis, rash and allergic rhinitis Malignancy
were the most common allergic events. Most of
the injection-site reactions were mild or moder- Based on the combined data of 11 ixekizumab
ate [32]. psoriasis trials, ixekizumab exposure up to
156 weeks was not associated with in increased
risk malignancy [32].
Infections
In keeping with published literature to date infec- Depression

tions are the most frequently AEs associated
ixekizumab therapy [11, 33]. 60.8% of patients Depression is common in patients with pso-
reported an infection while on ixekizumab ther- riasis. The efficacy of ixekizumab was evalu-
apy, however 25.4% were mild and 32.4% were ated in patients with moderate-to-severe plaque
moderate [32]. Only 3% were reported as severe psoriasis and moderately severe depressive
infections [32]. Nasopharyngitis (22.9%), upper symptoms [42]. Data were pooled from 3 ran-
respiratory tract infection (13.5%), bronchitis domised, double- blind, controlled phase 3 tri-
(5.2%) and sinusitis (5.4%) are among the most als. Depressive symptoms and inflammation
commonly reported infections [32]. Serious were evaluated at baseline and week 12 using
infections were reported in 2.6% of patients, a self-report questionnaire to quantify depres-
however none of these resulted in death [32]. sive symptoms (QIDS-SR16) and by measuring
Cellulitis was the most frequently reported seri- serum C-reactive protein (hs CRP) [42]. A sub-
group analysis was performed on patients with 3. Gordon KB, Blauvelt A, Papp KA, Langley RG,
Luger T, Ohtsuki M, et al. Phase 3 trials of ixeki-
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better responses in their QIDS-SR16 total score label/2018/125521s009lbl.pdf
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was associated with higher rates of remission of 7. Stark MA, Huo Y, Burcin TL, Morris MA, Olson TS,
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with placebo (17.8%; p ≤ 0.01) [42]. Ixekizumab lates granulopoiesis via IL-23 and IL-17. Immunity.
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kines. Numerous clinical trials (UNCOVER-1, zumab with etanercept or placebo in moderate-to-
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shown Ixekizumab to be efficacious in treat- results from two phase 3 randomised trials. Lancet.
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Brodalumab
21
Annika S. Silfvast-Kaiser, Dario Kivelevitch,
So Yeon Paek, and Alan Menter
Abstract
Brodalumab is a recombinant, fully human 1. To understand the mechanism of action
monoclonal receptor IgG2 antibody approved of brodalumab
for the treatment of moderate-to-severe plaque 2. To understand the appropriate use and
psoriasis. It inhibits the IL-17 receptor A efficacy of brodalumab
(IL-17RA), differing from other biologics in 3. To understand the safety issues of

the IL-17 class which target the IL-17A cyto- brodalumab
kine itself. It is a highly effective medication,
with a rapid onset of action. Its superiority to
placebo and to ustekinumab has been shown
in clinical trials, reducing both the severity
Introduction
and the extent of psoriasis, with efficacy
sustained up to 52 weeks. It has also shown
Psoriasis affects approximately 2–3% of the
superiority to placebo in patients with diffi-
worldwide population [1]. It is characterized by
cult-to-treat nail and scalp psoriasis and early
an extensive inflammatory infiltrate in the der-
evidence of efficacy in patients with psoriatic
mis with excessive growth of the epidermal skin
arthritis. Brodalumab is generally well-
layer, presenting as well-demarcated, erythema-
tolerated with a safety profile similar to that of
tous plaques with overlying silvery scale [2]. In
other biologics, with the addition of a label
addition to skin manifestations, 30–35% of pso-
warning relating to suicidal ideation. Herein,
riasis patients are affected by psoriatic arthritis
we review the data behind the use of broda-
(PsA), usually presenting 10–15 years after the
lumab for the treatment of psoriasis and psori-
onset of skin lesions [3]. Psoriasis is now largely
atic arthritis.
considered a systemic disease which can affect a
multitude of organ systems including the cardio-
vascular system in addition to psychosocial
health issues. Psoriasis is thought to result from
initial antigenic or environmental stimuli in
A. S. Silfvast-Kaiser · D. Kivelevitch · S. Y. Paek combination with predisposing genetic factors
A. Menter (*) and dysregulation of the innate and adaptive
Division of Dermatology, Baylor Scott & White, immune systems [4]. These antigenic stimuli
Dallas, TX, USA activate native immune cells including T-helper

https://doi.org/10.1007/978-3-030-54859-9_21
264 A. S. Silfvast-Kaiser et al.
cells (Th1 and Th17), dendritic cells, and kerati- Brodalumab

nocytes which then produce multiple pro-inflam-
matory cytokines including tumor necrosis Brodalumab (Siliq™, Ortho-Dermatologics,
factor (TNF)-alpha, interferon-alpha, IL-12, United States; Kyntheum®, Leo Pharma, Europe)
IL-17, and IL-23 [5, 6]. A complex interplay is a fully human IgG2 monoclonal antibody that
between immune cells and proinflammatory differs from other anti-IL-17 agents (secukinumab
cytokines exists in this T-cell mediated chronic and ixekizumab) by binding the subunit A of the
inflammatory skin disease. Ultimately, the cyto- IL-17 receptor rather than the IL-17 cytokine
kines released by Th1 and Th17 cells result in itself [18] (Fig. 21.1). By blocking IL-17RA,
the characteristic inflammatory environment brodalumab manages to inhibit the downstream
seen in psoriasis. Among others, Th17 cells inflammatory activity of several interleukins
release the full spectrum of cytokines IL-17A (IL-17A, IL-17C, IL-17F, IL-17E [IL-25], as
through IL-17F. IL-17A is the most influential, well as the IL17A/F heterodimer, preventing pso-
having been established as a factor in the devel- riatic inflammation [19, 20]. Brodalumab is the
opment of psoriasis, multiple sclerosis, rheuma- only biologic currently approved for the treat-
toid arthritis, and inflammatory bowel disease ment of psoriasis with activity against IL-17C, a
[7]. IL-17 is involved in neutrophil chemotaxis cytokine critical in the development of psoriasis,
and stimulates fibroblast production of vascular and the most abundant IL-17 cytokine found in
endothelial growth factor, leading to endothelial psoriatic lesional skin [21–28]. Brodalumab was
cell proliferation and angiogenesis [8]. IL-17A approved in February 2017 for the treatment of
also plays a role in the innate immune defense moderate-to-severe plaque psoriasis. Its superior-
against fungal and bacterial pathogens [9]. ity to placebo as well as to ustekinumab has been
shown at 12 weeks for both PASI 75 and PASI 90
[29, 30]. It is not currently approved for the treat-
Role of IL-17 in Psoriasis ment of psoriatic arthritis, but is under investiga-
tion in clinical trials for this indication.
IL-17 and its related cytokines play an important
role in the immunopathogenesis of psoriasis [10–
12]. This family of cytokines (IL-17A, IL-17B, osing, Storage, Administration,
D
IL-17C, IL-17D, IL-17E [IL-25], and IL-17F) and Pharmacokinetics
has been shown to induce expression of psoriatic
pro-inflammatory molecules in keratinocytes [9, Brodalumab is a subcutaneous, self-injectable
13]. IL-17 receptors are found on the surface of medication dosed initially as one 210 mg/1.5 mL
keratinocyte cells and promote signaling within prefilled syringe at weeks 0, 1, and 2, and subse-
the cell by receiving IL-17 cytokines. Elevated quently every 2 weeks [28, 31]. Storage of the
IL-17A, 17C, and 17F messenger RNA (mRNA) syringe should occur at 2–8 °C or can be stored at
have been shown in the serum and plaques of room temperature (for up to 2 weeks, then it
psoriasis patients [14–16]. The success of IL-17 should be discarded). No re-refrigeration should
and IL-23 biologic targeting agents in the treat- occur. The medication should be allowed to reach
ment of psoriasis has established the IL-17 cyto- room temperature for approximately 30 minutes,
kines as key players in psoriasis disease if the syringe has been refrigerated before injec-
development [16, 17]. As our understanding of tion [32]. If no or inadequate improvement is
psoriasis continues to develop, an increasing seen at 16 weeks, discontinuation of brodalumab
number of systemic biologic agents that target should be considered as the likelihood of reach-
these cytokines have been developed and are ing greater disease improvement after this time
available to patients. Brodalumab is one such point is unlikely [32].
agent, targeting the IL-17 cytokines via blockage Brodalumab reached maximum plasma con-
of the IL-17 receptor A. centration 2–4 days after one brodalumab 210 mg
21 Brodalumab 265
Fig. 21.1 Mechanism
of action of brodalumab.
The heterodimeric
IL-17RA is blocked by Th17 cell
brodalumab, decreasing IL-17A - IL-17F
the downstream release
of psoriasis-related
inflammatory cytokines
IL-17F
IL-17A
Brodalumab
IL-17RA
Brodalumab Brodalumab
Target cell
subcutaneous dose, with steady-state achieved early response (seen as early as 4 weeks), mainte-
after 10–12 weeks. After 20 weeks of administra- nance of response (up to 52 weeks), as well as no
tion the estimated accumulation ratio was 2.5- loss of efficacy in patients with prior biologic
fold [33]. After subcutaneous injection, the exposure.
estimated bioavailability was 57.6% [34]. The The most common methods for clinical assess-
estimated half-life of brodalumab is 10.9 days ment in psoriasis clinical trials are the Psoriasis
[33]. Age, sex and race had no effect on the phar- Assessment and Severity Index (PASI) and the
macokinetics of brodalumab. The effect of renal Physicians Global Assessment (PGA). The PASI
or hepatic impairment on its pharmacokinetics score is based on the quality of psoriatic lesions
has not been studied. Hepatic impairment and (i.e. erythema, induration, and scale) weighted by
renal elimination are not expected to be clinically body surface area, on a scale of 0–72, with higher
relevant as brodalumab is mainly eliminated via scores indicating more severe disease. Trial end-
catabolism [33]. Although the area under the points commonly assess the percentage of
serum concentration-time curve at steady state patients who achieve a certain reduction in PASI
was predicted to be two-fold higher in patients score compared to baseline (i.e. a 75% reduction
weighing less than 75 kg, no dosage adjustments in PASI score is termed PASI 75 with a 90%
for body weight are recommended [33]. reduction termed as PASI 90). The PGA score is
graded on a scale of 0–5 with 0 representing
“clear” and 5 representing “severe” disease
Clinical Efficacy in Plaque Psoriasis involvement.
Brodalumab is indicated for the treatment of
Overall, brodalumab has shown similar efficacy moderate-to-severe plaque psoriasis in adult
to the other two IL-17 inhibitors. It exhibits an patients who are candidates for systemic therapy
or phototherapy, having either had inadequate safety profiles of both the brodalumab and pla-
response to, or lost response to, other systemic cebo cohorts were similar. Two patients (one
therapies [28]. Below, we discuss the results of from the 350 mg cohort and another from the
the phase I, II, and III clinical trials that led to 700 mg cohort) receiving brodalumab exhibited
brodalumab’s eventual approval. formation of non-neutralizing antibodies.
Another phase I clinical trial in Japan evalu-
Phase I Clinical Trials ated the safety, tolerability, pharmacokinetics,
Brodalumab’s safety and efficacy was initially and pharmacodynamics of brodalumab in 40
investigated in a double-blind, randomized, healthy volunteers and in 8 subjects with
placebo-controlled, ascending single-dose trial of moderate-to-severe psoriasis [37]. Subjects with
25 healthy controls and patients with moderate- psoriasis had to meet inclusion criteria of
to-
severe psoriasis with a Psoriasis Area and PASI ≥ 10, BSA ≥ 10%, and have undergone at
Severity Index (PASI) score ≥ 10 and Body least one previous phototherapy or systemic ther-
Surface Area (BSA) ≥ 10%. Patients were fol- apy. In the healthy group, 8 subjects were ran-
lowed for 85 days with 20 of 25 patients receiv- domized in a 2:6 ratio to receive either placebo or
ing a single dose of brodalumab (4 patients a single dose of brodalumab at 70 mg, 140 mg,
received 140 mg subcutaneously (SC), 8 received 210 mg, or 420 mg SC or 210 mg IV. Psoriasis
350 mg SC, and 8 received 700 mg intravenously patients either received one dose of 140 mg SC
(IV)). The 5 other patients received placebo. The brodalumab or 350 mg SC. Rapid, dose-
majority of patients were men (76%) with a dependent improvement was seen in all psoriasis
median age of 43 years and mean baseline PASI patients receiving brodalumab treatment. All 7
score of 14.1 [35, 36]. Rapid, dose-dependent patients in the 350 mg cohort reached PASI 50; 6
improvement in both PASI and static Physician of these patients achieved PASI ≥ 75; 3 of 6
Global Assessment (sPGA) scores within patients in the 140 mg cohort also achieved
2 weeks of dosing with either 350 mg SC or PASI ≥ 75. Safety profiles were similar between
700 mg IV brodalumab was seen. Two of four both the healthy patients and those with psoriasis.
patients who received 140 mg SC achieved PASI Injection site erythema was the most commonly
50. All patients on 700 mg IV achieved PASI 50 reported AE for both placebo and brodalumab.
by 4 weeks, with all but one achieving PASI 75 or Brodalumab antibodies were not detected in any
greater by week 6. Three patients achieved PASI group up to 9 weeks.
90 by week 6. Six of eight patients who received
350 mg SC achieved PASI 50 and 3 of 8 patients Phase II Clinical Trials
receiving the same dose reached PASI 75. None A total of 188 patients with moderate-to-severe
of the 5 patients receiving placebo achieved PASI psoriasis with BSA ≥ 10% and PASI ≥ 12 were
50 [35]. enrolled and completed a phase II, randomized,
Lesional and non-lesional skin biopsies were double-blind, placebo-controlled, dose-ranging
performed on all subjects prior to treatment and study to evaluate the short term efficacy and
then twice after dosing. The patients in the two safety of brodalumab. Sixty-six percent of the
highest dose cohorts (300 and 700 mg) showed patients were male with a mean age of 43, and a
significant reductions in epidermal thickness, mean PASI and BSA of 19 and 24%, respectively
keratin 16, and Ki67-expresssing cells (as early [18]. Patients were randomly assigned to one of
as week 1 after dosing of the two highest doses), five treatment groups (70 mg, 140 mg, or 210 mg
along with lesional IL-17A, F and C mRNA lev- SC on day 1, week 1, 2, 4, 6, 8, and 10; or 280 mg
els which returned to non-lesional levels over SC at day 1, week 4, and week 8; or placebo).
6 weeks [20, 35]. The most common adverse The percentage of improvement in PASI score at
events (AEs) experienced by those receiving bro- week 12 compared to baseline was the primary
dalumab were headache, gastroenteritis, and the endpoint. Secondary endpoints were attaining
Koebner phenomenon at the biopsy site. The PASI 50, 75, 90, 100, as well as BSA and sPGA
21 Brodalumab 267
scores at week 12. Compared to placebo, all bro- to increase their dose back to 210 mg (n = 19).
dalumab groups achieved significantly greater Ninety percent of patients achieved sPGA 0/1
mean PASI improvement at week 12 (p < 0.001), (clear to almost clear) at 12 weeks, 85% at
with the earliest clinical improvement seen at 48 weeks, 76% at 96 weeks, and 72% at 144 weeks.
week 2. In the various brodalumab dosing arms At weeks 12 and 48, the mean BSA improvement
receiving 70, 140, 210, or 280 mg the mean PASI from the baseline BSA of the parent study was 95
improvement was 45, 85.9, 86.3, and 76% respec- and 96%, respectively. The most frequently
tively. The placebo arm had 16% mean PASI reported AEs occurring during open-label exten-
improvement. At week 12, PASI 75 or greater sion were mild to moderate in severity and included
was achieved by 77% in the 140 mg brodalumab nasopharyngitis, upper respiratory tract infection,
group and 82% in the 210 mg brodalumab group. arthralgia, back pain, and influenza. 14 patients
In these two groups, PASI 90 or greater was seen reported AEs of grade 3 (severe) or greater and 9%
in 72 and 75%, respectively. 38.3% of patients in of patients reported SAEs including cholecystitis,
the 140 mg arm and 80% of patients in the constipation (likely related), pyelonephritis, and
210 mg arm reached PASI 100. A sub-analysis of benign parathyroid tumor. One death occurred due
this phase II data also showed that patients to rupture of an aortic aneurysm [38, 39].
achieved clinical improvement and similar rates In Japan, a phase II study randomized 151
of AEs irrespective of whether self-reported pso- moderate-to-severe plaque psoriasis patients to
riatic arthritis was present or not [38]. doses of 70, 140, 210 mg, or placebo at day 1,
Compared to placebo, the brodalumab groups weeks 1, 2, 4, 6, 8 and 10 [40]. Efficacy and
also showed significantly greater improvements safety outcomes were similar to the phase II trial
in BSA, sPGA, Dermatology Quality of Life discussed above with the most common AEs in
Index (DLQI) and SF-36 at week 12 [18]. brodalumab patients being nasopharyngitis, diar-
Inflammatory markers and epidermal thickness rhea, upper respiratory tract inflammation, and
also significantly improved in the brodalumab folliculitis. At week 12, the mean improvement in
groups compared to placebo. The most com- PASI scores for the 70 mg, 140 mg, 210 mg, and
monly reported AEs in the brodalumab group placebo arms were 37.7, 82.2, 96.8, and 9.4%,
were nasopharyngitis, upper respiratory i nfection, respectively. PASI 75 was achieved at week 12 by
arthralgia, and injection site erythema. Three 26, 78, and 95% of patients in the 70, 140, and
serious adverse events occurred with broda- 210 mg groups, respectively. PASI 90 or greater
lumab: renal colic and two cases of grade 3 and PASI 100 was achieved by 15, 65, 92% and
asymptomatic neutropenia (resolving after bro- 2.6, 35, and 59% of these patients, respectively.
dalumab withdrawal). Secondary analyses have DLQI scores of 0 or 1 were also significantly
also shown that at week 12, the brodalumab treat- more common in patients in the 140 mg and
ment groups demonstrated significant improve- 210 mg groups at week 12 (54.1 and 56.8%)
ment in patient reported outcome measures compared to those on placebo (8.8%). Long-term
including DLQI and Psoriasis Symptom brodalumab treatment also showed sustained
Inventory (PSI) compared to placebo. Patients clinical response and favorable safety profile in
with prior biologic exposure and those naïve to an open-label extension (OLE) of this study [41].
prior biologic therapies showed no difference in 133 of 145 patients (92%) completed the study
the mean improvements in PASI scores [18, 38]. with 94.4, 87.5, and 55.6% of patients in the
A 5-year open-label extension of this phase II 210 mg cohort achieving PASI 75, 90, and 100 by
trial enrolled 181 of the original 198 patients to week 52 and 78.1, 71.2, and 43.8% of patients in
evaluate the long-term safety and efficacy of broda- the 140 mg group achieving PASI 75, 90, and
lumab 210 mg every 2 weeks [39]. At 52 weeks, a 100, respectively. Nasopharyngitis (35.2%),
dose reduction to 140 mg for patients ≤100 kg upper respiratory tract inflammation (10.3%),
(n = 119) was implemented. Patients with inade- and contact dermatitis (9.7%) were the most
quate response to this lower dose were then allowed commonly reported AEs.
hase III Clinical Trials

P or almost clear. Between 37 and 44% of patients
Three phase III clinical trials (AMAGINE-1, in all AMAGINE trials achieved a PASI 100
AMAGINE-2, and AMAGINE-3) have been response by week 12 and approximately 70% of
completed to assess the efficacy, safety, and patients achieved PASI 90 by week 12.81% of
withdrawal- retreatment effect of brodalumab patients who had failed prior biologic therapy
versus placebo in moderate-to-severe plaque pso- were able to attain PASI 75 response with 32% of
riasis. AMAGINE-1 compared brodalumab only them achieving PASI 100. Of the PASI 100
to placebo. AMAGINE-2 and AMAGINE-3 com- responders from week 12 in the AMAGINE 2 and
pared brodalumab’s efficacy and safety to that of 3 trials, 72% maintained PASI 100 response at
ustekinumab in addition to placebo. Both of these week 52.
studies were multicenter, randomized, double-
blind, placebo-controlled, active comparator- AMAGINE-1
controlled, parallel group trials with a 12-week In AMAGINE-1, 661 patients with moderate-to-
induction period, followed by maintenance with severe psoriasis were followed through a 12-week
brodalumab up to week 52 (Table 21.1) [29, 30]. induction phase and then a withdrawal and treat-
All phase III studies required a diagnosis of ment phase through 52 weeks [29]. Ninety six
plaque psoriasis for ≥6 months, BSA ≥ 10%, percent of patients completed the induction phase
PASI ≥ 12 and sPGA ≥ 3. The primary endpoint and 84.4% of patients continued through treat-
for all three AMAGINE trials was PASI 75 and ment withdrawal and re-treatment through week
sPGA 0/1 at week 12 as compared to placebo. 52. During the induction phase, patients received
For AMAGINE-2 and AMAGINE-3, PASI 100 either brodalumab 140 mg, 210 mg, or placebo,
for brodalumab versus ustekinumab was also a every 2 weeks for 12 weeks. After 12 weeks,
primary endpoint. Between 76 and 80% of patients with sPGA score of 0/1 were re-
patients in all three trials achieved sPGA of clear randomized to either continue with their current
Table 21.1 Brodalumab phase III clinical trial outcomes [29, 30]
Brodalumab Phase III trial results
Phase III trial Study arms Week 12 Week 12 Week 52 Outcomes
Primary & Secondary sPGA 0/1 & sPGA 0 (PASI 75/90/100)
Outcomes (PASI
75/90/100)
AMAGINE-1 Placebo 2.7/0.9/0.5% 1.4 & 0.5% –
(n = 661) Brodalumab 60.3a/42.5 a/23.3a% 53.9 & 23.3% –/66.7/43.9%
140 mg 83.3a/70.3a/41.9a% 75.7 & 41.9% –/78.3/67.5%
Brodalumab
210 mg
AMAGINE-2 Placebo 8.1/1.9/0.6% 3.9 & 0.6% –
(n = 1831) Ustekinumab 70/47/21.7% 61 & 21.7% –
Brodalumab 66.6a,b/49a,b/25.7a,b% 58 & 25.7% –
140 mg 86.3a,b/69.9a,c/44.4a,c% 78.6 & 44.8% 80/75/56%
Brodalumab
210 mg
AMAGINE-3 Placebo 6/2.9/0.3% 4.1 & 0.3% –
(n = 1881) Ustekinumab 69.3/47.9/18.5% 57.2 & 18.5% –
Brodalumab 69.2a,b/52a,b/27a,c% 59.9 & 27% –
140 mg 85.1a,c/68.9a,c/36.7a,c% 79.6 & 36.7% 80/73/53%
Brodalumab
210 mg
a
p < 0.001 for the comparison with placebo
b
p > 0.05 for the comparison with ustekinumab
c
p < 0.01 for the comparison with ustekinumab
21 Brodalumab 269
treatment or to switch to placebo. Patients who pared to 3.2% in the placebo group [46]. At week
experienced disease return with sPGA ≥ 3 after 12, the most frequently reported adverse events
re-randomization to placebo were then re-started in the brodalumab cohorts were nasopharyngitis,
on their induction dose of brodalumab up to week upper respiratory tract infection, and headache.
52. If patients had originally been randomized to SAEs while on brodalumab 210 mg, 140 mg, and
the placebo group, or if they had sPGA ≥ 1 after placebo occurred in 1.8, 2.7, and 1.4% of patients,
week 12, they were started on brodalumab respectively.
210 mg every 2 weeks. The impact of brodalumab treatment on qual-
By week 12, PASI 75 was achieved by 83.3% ity of life outcomes was also investigated in
of the brodalumab 210 mg group, 60.3% of bro- AMAGINE-1. At 12 weeks, in those receiving
dalumab 140 mg group, and in 2.7% of those brodalumab, a significant proportion of patients
receiving placebo [29]. In the 210 and 140 mg reported PSI of 0, DLQI of 0, and satisfaction
brodalumab arms, PASI 90 response was seen in with treatment compared to placebo patients.
70.3 and 42.5% of patients respectively, com- Health-related quality-of-life measures also
pared to 0.9% in the placebo group. 41.9 and showed significantly greater improvement in
23.3% of patients in the 210 and 140 mg arms patients treated with brodalumab compared with
achieved PASI 100 respectively, compared to placebo. Over 60% of patients with moderate and
0.5% in the placebo group [29, 38, 42]. These severe anxiety or depression at baseline exhibited
significant differences in clinical response were improvement to mild, moderate, or normal sever-
sustained until week 52. sPGA scores of 0/1 were ity by week 12 on brodalumab [29].
achieved by 75.7 and 53.9% of patients on broda- In addition, psoriasis biomarkers such as
lumab 210 mg and 140 mg, respectively, com- mRNA expression of IL-17 cytokines, IL-23, and
pared to placebo at 1.4%. Significant cell counts of epidermal Ki-67, dermal CD3, epi-
improvements on the Psoriasis Symptom dermal CD3, dermal CD8, and epidermal CD8,
Inventory (PSI) (which evaluates 8 psoriasis were all significantly reduced in psoriatic lesional
signs and symptoms; see Table 21.2) were also skin at 12 and 52 weeks, compared to baseline in
seen compared to placebo [43, 44]. the patients treated with brodalumab [3].
Those who lost control of their psoriasis with
withdrawal of brodalumab were able to recover AMAGINE-2 and AMAGINE-3
their previous treatment sPGA score within AMAGINE-2 and AMAGINE-3 were both large,
12 weeks of resuming therapy with brodalumab double-blind, placebo-controlled, multinational
[45]. One hundred percent improvement in the studies in moderate-to-severe plaque psoriasis
Psoriasis Scalp Severity Index (PSSI) was with identical designs [30]. The efficacy and
achieved by 63.4 and 41% of patients in the safety of brodalumab 140 and 210 mg every
140 mg and 210 mg brodalumab groups, as com- 2 weeks was evaluated in comparison to both
ustekinumab and placebo (in a 2:2:1:1 ratio).
Ustekinumab is a human monoclonal antibody
Table 21.2 Psoriasis symptom inventory items [44] which acts against the p40 subunit common to
Psoriasis Symptom Inventory (PSI)a,b IL-12 and IL-23. Ustekinumab works upstream
• Itch compared to brodalumab which works by driving
• Redness
• Scaling downstream signaling. Ustekinumab was
• Burning approved for the treatment of moderate-to-severe
• Stinging plaque psoriasis in 2009 and for PsA in 2013.
• Cracking During the first 12 weeks the treatment arms of
• Flaking
• Pain both AMAGINE-2 and -3 included: 140 or
210 mg brodalumab every 2 weeks; ustekinumab
a
Each item is scored on a scale of 0 (not at all severe) to 4
(very severe), with a total score from 0 to 32 (45 mg if ≤100 kg, 90 mg if >100 kg), on day 1
b
Response of PSI is defined as attaining a total score of ≤8 and week 4; or placebo. Patients who were
receiving brodalumab were randomly reassigned defense, Candida infections occurred more com-
to 1 of 4 maintenance schedules: 140 mg or monly with brodalumab (1.2%) than with
210 mg every 2 weeks, 140 mg every 4 weeks, or ustekinumab (0.5%) or placebo (0.5%) in the
140 mg every 8 weeks after the initial 12-week induction phase [47–49].
period. Those who were assigned to the Over the 52-week trial periods, 6 deaths
ustekinumab arm from the beginning continued occurred in both the brodalumab and ustekinumab
receiving ustekinumab every 12 weeks. Those groups due to: stroke (1), cardiac arrest (3), pan-
who commenced on placebo were switched to creatic carcinoma (1), and accidental death after
brodalumab 210 mg every 2 weeks. After week motor vehicle collision (1). In AMAGINE-2, one
52 and completion of the maintenance phase, patient committed suicide 19 days after the last
patients who were still continuing to receive dose of brodalumab 210 mg. After the comple-
ustekinumab were eligible to switch to broda- tion of the studies, an additional 3 deaths
lumab 210 mg every 2 weeks as part of the OLE. occurred: one due to suicide, another from hemo-
Two co-primary endpoints assessed the effi- phagocytic histiocytosis syndrome, and the third
cacy of both brodalumab arms in both studies from cardiomyopathy. One additional suicide
compared to placebo: the percentage of patients occurred during the OLE, after week 52 [30].
who reached PASI 75 and sPGA 0/1 at week 12. A pooled secondary data analysis of
The efficacy of 210 mg brodalumab was also AMAGINE-1, -2, and -3, compared patients who
compared to ustekinumab in both studies with achieved PASI 100 or sPGA 0 to those who
PASI 100 as the primary endpoint at 12 weeks. achieved PASI 75 to <100 or an sPGA of 1, in
Both AMAGINE-2 and -3 showed superiority of order to evaluate the clinical meaningfulness of
210 mg brodalumab over ustekinumab and pla- complete skin clearance based on PSI scores and
cebo. However, the patients in the brodalumab DLQI. When comparing PASI groups, a signifi-
140 mg arm had response rates significantly supe- cantly greater proportion of patients achieving
rior to ustekinumab only in AMAGINE-3 [30]. PASI 100 reported a PSI score of 0 (45%) com-
A pooled analysis of both trials showed simi- pared to those achieving PASI 75 to <100 (8%).
lar efficacy of brodalumab in patients with prior A similarly significant trend was seen in these
biologic exposure, as well as those who were two groups as related to DLQI scores of 0/1 (80%
naïve. Non-neutralizing antibodies against broda- of PASI 100 and 55% of PASI 75 to <100
lumab were found in AMAGINE-2 and patients). When comparisons were based on
AMAGINE-3 (in 1.8 and 2.3% of patients, sPGA 0/1, similar results were also seen [50].
respectively). No loss of efficacy or adverse
events were associated with these antibodies. AMAGINE-2
Neutralizing antibodies were not found in any In AMAGINE-2, brodalumab was superior to
patients [30]. ustekinumab in achieving PASI 100 at both the
The most common AEs included nasopharyn- 140 mg and 210 mg doses at week 12, but only sig-
gitis, upper respiratory tract infection, headache, nificantly superior with the 210 mg group.
and arthralgia, with the proportion of patients on Response rates for PASI 75/90/100 in the broda-
brodalumab or ustekinumab reporting at least lumab 140 mg, brodalumab 210 mg, and
one AE greater than that of placebo patients. ustekinumab groups were 67%/49.0%/25.7%,
Transient, reversible, mostly mild cases of neu- 86%/69.9%/44.4%, and 70%/47.0%/21.7%,
tropenia also occurred more frequently in the respectively. Placebo response rates for PASI
brodalumab and ustekinumab groups as com- 75/90/100 were: 8.1%/1.9%/0.6%, respectively
pared to placebo, but were not associated with [30]. Rates of sPGA scores of 0/1 were also signifi-
serious infections. No clinically apparent differ- cantly higher with both doses of brodalumab (58
ences were seen in the types of serious AEs and 79%) as compared to placebo (4%). The most
among the study groups. Consistent with the role common AEs were the common cold, upper respi-
that IL-17A plays in mucocutaneous host ratory tract infection, headache, and joint pain [51].
21 Brodalumab 271
AMAGINE-3 Clinical Efficacy in Psoriatic Arthritis

In AMAGINE-3, brodalumab was also shown to be
superior to ustekinumab and placebo with a pri- Brodalumab has also been investigated as a
mary endpoint of PASI 100. Week 12 response potential treatment for psoriatic arthritis.
rates for PASI 75/90/100 in the brodalumab 140 mg Although early results from PsA trials showed
and 210 mg arms were: 69%/52.0%/27.0% and some promise, further investigations are needed
85%/68.9%/36.7%, respectively. Ustekinumab and to evaluate its potential to benefit patients with
placebo exhibited response rates of PASI 75/90/100 PsA, as brodalumab does not yet carry an indi-
at 69%/47.9%/18.5% and 6%/2.9%/0.3%, respec- cation for the treatment of PsA. A phase II ran-
tively [30]. The secondary endpoints of PSI, PASI domized, placebo-controlled trial showed that
100 and sPGA at week 12 were greater for broda- approximately 40% of 159 patients treated with
lumab compared to ustekinumab and placebo; brodalumab 140 or 280 mg every 2 weeks were
however, statistically significant results were not able to achieve ACR20 (American College of
achieved against ustekinumab. Rates of sPGA Rheumatology response criteria) compared to
scores of 0/1 were significantly higher with both 18% of placebo patients at week 12. At week 12,
doses of brodalumab (60 and 80%) when com- rates of ACR50 for brodalumab versus placebo
pared to placebo (4%) [30]. The most commonly were 14 and 4%, respectively. By 24 weeks,
reported AEs in the brodalumab groups were naso- 51% patients in the 140 mg group and 64% in
pharyngitis, upper respiratory tract infection, the 280 mg group achieved ACR20 response
arthralgia, and headache [52]. versus 44% for those who switched from pla-
At 52 weeks, PASI 75/90/100 was achieved by cebo to open-label brodalumab. Response was
80%/73%/53% of patients on 210 mg broda- sustained through week 52 [55]. It is important
lumab, respectively, outperforming both the to recognize that in clinical trials for PsA, up to
ustekinumab (69%/57%/19%) and placebo 50% of patients are maintained on their pre-
cohorts [42]. Significant clinical efficacy of bro- existing systemic therapies when commencing a
dalumab was maintained through 120 weeks in biologic clinical trial. The most commonly
an OLE study [53]. A systematic review of the reported AEs were similar to those of the plaque
long-term efficacy of brodalumab compared to psoriasis trials. Rates of serious adverse events
other novel biologic agents for psoriasis con- were similar as well (3 vs. 2% in brodalumab vs.
cluded that brodalumab showed superiority com- placebo groups, respectively). No statistical dif-
pared to secukinumab, ustekinumab, and ference in response was seen in non-naïve bio-
etanercept in sustaining PASI response as well as logic patients [32].
52-week complete clearance [54]. In a Japanese phase II trial for moderate-to-
The majority of patients rescued with broda- severe plaque psoriasis, 20% improvement in
lumab after initial ustekinumab treatment achieved ACR20 was seen in patients receiving broda-
PASI 75 and sPGA 0/1 responses by week 12 [30]. lumab 70 mg (1 patient), 140 mg (2 patients), and
By week 52, a significant number of these patients 210 mg (4 patients) and none receiving placebo
had also achieved PASI 100. Brodalumab showed [40]. At week 52, 75% of the patients with PsA in
greater effectiveness when compared to the 210 mg group achieved ACR20 compared to
ustekinumab in non-naïve biologic patients, with 38% in the 140 mg group [41].
40% of brodalumab patients achieving PASI 100 Brodalumab completed phase 3 testing for
compared to 17% of those on ustekinumab. psoriatic arthritis in 2017 (AMVISION-2).
Brodalumab exhibited more rapid onset of action Results have not been published. One phase 3
as well, achieving PASI 75 at a median of trial (AMVISION-1) was terminated in 2015,
4.2 weeks versus 9.4 weeks with ustekinumab. with a cited reason of “sponsor decision.”
linical Efficacy in Difficult-to-Treat

C be an effective therapeutic option for pustular
Psoriasis forms of psoriasis [60, 61].
Subgroup analyses in psoriasis patients treated

with brodalumab with nail and scalp involvement Improvements in Quality of Life
(both considered difficult-to-treat areas) showed
improvement in nail psoriasis severity index Health-related quality of life assessed by the
(NAPSI) score as well as psoriasis scalp severity Psoriasis Symptom Inventory (PSI) and the
index (PSSI) from a baseline score of ≥6, and Dermatology Life Quality Index (DLQI) in all
≥15 with scalp surface area involvement of clinical trials with brodalumab exhibited signifi-
≥30%, respectively. In patients with either of cantly higher numbers of patients with improve-
these two subtypes of psoriasis, significant ment on both doses of brodalumab compared to
improvements from baseline to week 12 were placebo [29, 30]. At week 12 of a pooled analysis
seen in both NAPSI and PSSI scores (p < 0.001). of AMAGINE-1, -2, and -3, significantly more
For the brodalumab 140 mg and 210 mg groups, brodalumab patients in the 210 mg every 2 weeks
37.5 and 46.3% improvement of NAPSI was group had a DLQI score of 0/1 versus those on
shown, respectively, compared to 11.6% for pla- placebo (59 vs. 6% respectively, p < 0.001) [62].
cebo patients at week 12. Of 661 patients enrolled A majority of patients (68–84%) receiving bro-
in the AMAGINE-1 study, 9.5, 61.8, and 89% of dalumab also reported that psoriasis had no
the placebo, brodalumab 140 mg, and 210 mg impact on their daily activities, leisure activities,
groups, achieved PSSI 75 response at the end of personal relationships, and work/school as a
the 12-week induction phase, respectively. PSSI result of their treatment [62]. In AMAGINE-2
90 and 100 responses of 4.2%, 52.4%, 76.8% and and -3, brodalumab also improved productivity
3.2%, 41%, and 63.4%, were seen in the same loss as indicated by the self-reported Work
treatment groups, respectively. Significant Limitations Questionnaire [63]. Depression and
improvement in both brodalumab groups was anxiety as assessed by the Hospital Anxiety and
seen as early as week 2 and maintained until Depression Scale (HADS) were also improved.
week 12 [46, 56]. Among those patients with baseline moderate
Palmoplantar pustular psoriasis (PPPP), also and severe anxiety or depression (n = 139), a
known as palmoplantar pustulosis (PPP), is a majority improved to normal, mild, or moderate
form of psoriasis characterized by sterile yellow at week 12 [64].
pustules of the palms and/or soles, sometimes in
addition to the characteristic indurated, erythem-
atous, scaly lesions of plaque psoriasis. Largely Safety and Tolerability
because of the location of involvement, this con-
dition can be extremely debilitating due to pain Common Adverse Events
and disease-related functional limitation. Recent
studies have shown that the IL-17 cytokine plays The most common adverse events relating to bro-
an important role in the pustular forms of psoria- dalumab therapy, reported through week 120 of
sis, with detectable levels of IL-17A, -C, and -F an open label extension (OLE) study in patients
in palmoplantar pustular lesions [57–59]. There receiving treatment with brodalumab can be
are limited data available regarding the effective- found in Table 21.3 [32].
ness of biologic treatment for this psoriatic vari- Most adverse events regarding brodalumab
ant. The few case reports regarding PPPP/PPP are related to its potential to increase the risk of
patients treated with brodalumab show inconsis- infection due to its role as an immune modulator.
tent results. Formal clinical trials need to be per- Similar to other IL-17 inhibitors, brodalumab has
formed to determine whether brodalumab could demonstrated a small increased risk of neutrope-
21 Brodalumab 273
Table 21.3 Most commonly reported adverse events of dence of new-onset Crohn’s disease in clinical
brodalumab through week 120 of open-label extension
trials with brodalumab was approximately less
Most common adverse events with brodalumab than 1:1000, with one patient on treatment with
therapy through 120 weeks
brodalumab experiencing new-onset Crohn’s dis-
• Nasopharyngitis (27%)
• Upper respiratory tract infections (20%) ease during the maintenance phase. In general,
• Arthralgia (16%) providers should use caution when considering
• Back pain (11%) the use of IL-17 inhibitors in patients with IBD
• Gastroenteritis (10%) [28, 30, 56].
• Influenza (9%)
• Oropharyngeal pain (9%)
• Sinusitis (9%)
Serious Infections
nia and Candida infections, as well as potential In the pivotal phase 3 clinical trials, serious infec-
exacerbation of inflammatory bowel disease [6, tions and fungal infections were observed at a
32, 33]. In addition to the most common adverse higher rate in patients on brodalumab as com-
events (seen in Table 21.2), mild to moderate oral pared to placebo [30]. One patient had to discon-
candidiasis, injection site reactions, and serious tinue therapy due to cryptococcal meningitis [31].
adverse events occurred in 3, 8, and 15% of
patients, respectively. Transient grade 2 absolute
neutrophil abnormalities were seen in 2% of Immunizations
patients. All resolved on their own without treat-
ment modification. Several cases of grade 3 neu- The use of live vaccines in patients on broda-
tropenias were also reported [32]. SAEs lumab should be avoided [28]. If necessary, treat-
throughout the entirety of the study occurred at a ment may be interrupted for administration [65].
rate of 8.3 in subjects treated with brodalumab,
and at a rate of 13 with those on ustekinumab.
Within AMAGINE-2 and AMAGINE-3 the rates Pregnancy
were 7.9 and 4.0, respectively.
Patients should be counseled to seek medical No specific contraindication exists for the use of
care should signs or symptoms of infection occur brodalumab in pregnancy. However, risks and
while on biologic therapies, including brodalumab. benefits should be carefully assessed prior to ini-
tiation of therapy as efficacy and safety of broda-
lumab use in pregnancy has not been investigated.
Inflammatory Bowel Disease It is unknown whether brodalumab is excreted in
human milk.
There is a known association between psoriasis
and inflammatory bowel disease (IBD). Patients
with Crohn’s disease and ulcerative colitis (UC) Elderly
have shown higher prevalence rates of psoriasis.
Similarly, psoriasis patients have also shown Brodalumab has not been associated with higher
higher rates of IBD. Crohn’s disease is geneti- rates of adverse reactions in the elderly [66].
cally linked to psoriasis [28].
Brodalumab is contraindicated in patients
with Crohn’s disease [28]. Clinical trials for bro- Suicidal Behavior
dalumab excluded patients with an established
diagnosis of IBD as potential risk of exacerbation During the phase III brodalumab clinical trials, 4
had already been observed in patients in the completed suicides (one case was ruled as inde-
ixekizumab and secukinumab trials. The inci- terminate) were seen. These all occurred after the
first 12 weeks of the trials (after the placebo- Table 21.4 Screening guidelines prior to initiation of
therapy with brodalumab
controlled portion), with 3 of 4 suicides occur-
ring in patients who had previously attained PASI Screening guidelines for brodalumab initiation
100 on brodalumab. All patients who completed – Complete blood count
– Comprehensive metabolic panel
suicide had underlying psychiatric disorders or – Hepatitis B/C
stressors and had received brodalumab therapy at – HIV
210 mg every 2 weeks; however, none of the sui- – TB
cides occurred during active treatment with bro- – Personal or family history of IBD or
symptomatology consistent with IBD
dalumab [67]. The suicides occurred 58, 27, and – Psychiatric history
19 days after each subject’s last dose [16, 68].
The FDA concluded there was no established
drug-related risk of suicide or suicidal ideation; Contraindications and Cautions
they also found no causal or temporal relation-
ship. Although a causal or temporal relationship Brodalumab is contraindicated in patients with
is lacking, brodalumab carries a black box warn- Crohn’s disease due to observed worsening. It
ing for increased risk of suicidal ideation and should be used with caution in patients with
behavior [69, 70]. As a result, it is only available IBD. Careful attention should also be paid to
to registered providers to prescribe through the patients who present with chronic or recurrent
Siliq® Risk Evaluation and Mitigation Strategy infections. Should a patient experience a non-
(REMS) Program which requires providers to be resolving active infection, the medication should
certified with the program in addition to having be discontinued.
patients sign an agreement and receive a pocket-
size guide explaining suicidal behavior and what
behaviors would warrant immediate medical Initiation of Therapy
evaluation [32, 68].
Oftentimes, the burden of psoriasis extends In addition to screening for any of the above con-
past the skin’s surface. This includes significant traindications, most providers recommend estab-
effects on patient quality of life and disease- lishing baseline health before initiating therapy
related morbidity. Studies have shown that with biologics, including brodalumab. In general,
patients with psoriasis are overall more prone to a patient’s health history, existence of comorbidi-
experience psychological burden and to attempt ties, and baseline status prior to the initiation of
suicide than patients without psoriasis [71–74]. biologic therapies such as IL-17 agents should be
Patients with psoriasis experience higher rates of established by performing a thorough history and
depression, anxiety, self-harm, and suicidality physical, along with the appropriate laboratory
compared to the general population. assessments (Table 21.4). This includes recom-
Unsurprisingly then, most of the patients who mended tuberculosis (TB) testing [32].
completed suicide during the brodalumab clinical
trials had a history of predisposing risk factors
such as depression and/or suicidal behavior [67]. Conclusion
Prior to prescribing brodalumab, providers
should weigh the risks and benefits of therapy with Psoriasis is a complex and debilitating disease
brodalumab in patients with a history of depres- which can impact both the physical and emo-
sion, suicidal ideation, and/or behavior. Patients tional health of a patient. The scope of psoriasis
and their caregivers should also be instructed to treatments has widened considerably within the
seek medical attention immediately should the last decade. As the understanding of psoriasis and
patient begin experiencing worsening or new its pathogenesis deepens, psoriasis therapies are
depression, manifestations of suicidal ideation or becoming increasingly more effective and spe-
behavior, or other significant mood changes. cific. For many years, PASI 50 and later PASI 75,
21 Brodalumab 275
were used as the standard end point in clinical the duration to clinical improvement compared to
trials for the evaluation of treatment efficacy. other biologic agents available for the treatment
With newer biologic agents such as brodalumab, of psoriasis. The efficacy and rapidity of improve-
PASI 90 and PASI 100 are increasingly becoming ment with brodalumab treatment speaks volumes
the new standard as these are now realistic, regarding the exciting future of biologics for
achievable endpoints [18, 37, 75]. Brodalumab’s moderate-to-severe psoriasis.
efficacy, rapid onset of action, and role in
difficult-to-treat psoriasis help distinguish it from
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Biosimilars for Psoriasis
22
Sarah Lonowski, Nirali Patel, Nika Cyrus,
and Paul S. Yamauchi
Abstract tive, regulatory, and scientific framework for

the development and approval of biosimilars.
Biologics have revolutionized the treatment of
We also review the current state of the biosim-
numerous conditions. While the therapeutic
ilars market as it relates to psoriasis, and
benefit of biologics has been dramatic, the
examine current barriers to widespread utili-
development of these agents has been accom-
zation of biosimilar agents in clinical
panied by significant increases in healthcare
practice.
costs. Recently there has been growing inter-
est in the development of biosimilar agents,
which have the potential to decrease costs and
improve access to this powerful class of medi-
cations. In this chapter, we discuss the legisla- 1. To understand the development path-

way for biosimilars
2. To understand the approval process for
biosimilars
S. Lonowski 3. To review the use of biosimilars for

Department of Medicine, Division of Dermatology, process
David Geffen School of Medicine, University of
California Los Angeles, Los Angeles, CA, USA
N. Patel Background
e-mail: [email protected] Biologics are highly complex pharmaceuti-
N. Cyrus cal agents isolated or synthesized from natural
Division of Dermatology, Kaiser Permanente Orange sources. These may take the form of antibodies,
County, Irvine, CA, USA recombinant proteins, vaccines, blood, and plasma
P. S. Yamauchi (*) products [1–3]. Biologics are distinguished from
Department of Medicine, Division of Dermatology, chemically-synthesized drugs by their much larger
size (100–1000×) and complex molecular struc-
tures [4]. Biologics have revolutionized the treat-
ment of numerous dermatologic diseases, chronic
inflammatory diseases, and certain malignancies.
Dermatology Institute & Skin Care Center, Inc.,
Biologics are the fastest-growing segment of the
Clinical Science Institute, Santa Monica, CA, USA

https://doi.org/10.1007/978-3-030-54859-9_22
280 S. Lonowski et al.
Table 22.1 Available patent expiration dates for psoriasis biologics in the US and EU [2, 6]
Brand name Generic name Expiration year (US) Expiration year (EU)
Humira Adalimumab 2016 2018
Remicade Infliximab 2018 2015
Stelara Ustekinumab 2023 2024
Cimzia Certolizumab 2024 2021
Enbrel Etanercept 2028 2015
Cosentyx Secukinumab 2028 2030
Taltz Ixekizumab 2036 Unavailable
pharmaceutical industry, accounting for 22% of States (US) in 2017 [3]. Tumor necrosis factor-
the drugs approved by the United States Food alpha inhibitors adalimumab, etanercept, and inf-
and Drug Administration (FDA) between 2008 liximab were 3 of the top 5 most expensive drugs
and 2017 [5]. Within the field of dermatology, the in terms of overall expenditures in 2016 [13]. The
wave of biologics has undoubtedly had the great- economic burden of psoriasis alone in the US is
est impact on the treatment of psoriasis, with 11 substantial, with estimates ranging from $35.2 to
biologic agents currently FDA-approved for this $112 billion [14, 15].
indication and 5 new agents since 2017. The Biologics Price Competition and
As many biologics reach the end of their Innovation Act (BCPI) of 2009 was approved as
patent protection (Table 22.1), there has been part of the Patient Protection and Affordable Care
growing interest in the development of biosimi- Act and provided a legislative framework for an
lar agents [7]. Biosimilars are reproductions of abbreviated process for the approval of biosimi-
biologics which are highly similar to the original lars. The stated goal of the BPCI was to improve
biologic agent (called the reference product) in patient access to biologic therapies by decreasing
terms of structure, mechanism of action, safety, costs [2]. In addition to lowering drug develop-
and efficacy and must be given in the same form ment costs, the BCPI was expected to lead to
and dosage as the reference product [2, 8–10]. increased competition among manufacturers [16].
The FDA defines a biosimilar as a biologic prod- The BPCI enabled the FDA to approve biosimilar
uct that is “highly similar to a US licensed refer- medications following a review of the “totality of
ence biological product notwithstanding minor evidence” from extensive analytical, nonclinical,
differences in clinically inactive components, and clinical studies for these agents [4, 11, 17].
and for which there are no clinically meaning- The first biosimilar agent was not approved in
ful differences between the biological product the US until 2015, however the speed of develop-
and the reference product in terms of the safety, ment has increased dramatically in the past few
purity, and potency of the product” [11]. The years. As of June 27, 2019 there are 21 biosimi-
European Medicines Agency (EMA) defines a lars approved by the FDA, though not all of these
biosimilar as “a biological medicinal product that are commercially available [18]. The potential
contains a version of the active substance of an for future growth is substantial, with over 1000
already authorized original biological medicinal agents currently in the biosimilar pipeline [19].
product” [10]. The global biosimilars market size is expected to
While the therapeutic benefit of biologics has reach a value of USD $61.47 billion by 2025 [20].
been dramatic, the development of these com-
plex agents has been accompanied by significant
increases in healthcare costs. Biologics are expen- Generics Versus Biosimilars
sive, with an average cost of $10,000–30,000 per
year [12]. Biologics accounted for nearly a quar- While conceptually similar to generic small mol-
ter (24%) of worldwide pharmaceutical spending ecule medications, biosimilars differ from gener-
in 2015 and 40% of drug spending in the United ics in several important ways. Generic drugs are,
22 Biosimilars for Psoriasis 281
by definition, identical to their brand name equiv- ner similar to the labeling of generic medica-
alents, whereas biosimilars are not exact copies tions [2]. Notably, these labels may not include
of their reference products [17]. Biosimilars information on clinical data demonstrating no
are much larger products and have complex, clinically meaningful differences between the
dynamic structures that are highly vulnerable to biosimilar and its reference product [2, 17].
alterations in the manufacturing process. Even
slight changes in temperature, purification, and
storage can lead to chemical modifications, such Development of Biosimilars
as misfolding or glycosylation, which affect the
ultimate form and potentially the functionality The process of biosimilar development centers
of the drug [3, 17, 21]. For this reason, biolog- on reproduction of the essential aspects of the
ics cannot be exactly reproduced. Biosimilars are reference product following a thorough exami-
therefore considered “unique but related” to their nation of its structure and function. Biosimilar
reference product [22]. It is important to note that manufacturers must first study the reference
manufacturing of reference biologic products is product based on publicly available information,
also intricate, and changes in manufacturing pro- then use “reverse engineering” to independently
cesses, handling, and storage have the potential design a process that will reproduce a highly
to cause slight modifications in the end-product, similar biological agent [3, 4]. Because of the
a phenomenon known as batch variability [23]. large and dynamic structure of these agents, the
Biosimilars take longer and are more expen- goal of this undertaking is not to create an exact
sive to produce than generics. Biosimilars take on copy of the originator biologic, but to create a
average 5–10 years and cost $100–250 million to bioequivalent product, with only minor varia-
develop, compared with 2 years and $1–10 mil- tions in clinically insignificant components of
lion for most generics [3]. Another important the structure. Initially, detailed characterization
distinction between generics and biosimilars studies are performed in order to identify the
is the potential for immunogenicity. Biologics, critical quality attributes (CQAs) of the refer-
and therefore biosimilars, have the potential to ence biologic agent [11]. These CQAs determine
elicit an immune response resulting in the pro- the biologic function and therefore the resulting
duction of anti-drug antibodies. Therefore, the clinical effect [11]. Once a biosimilar manufac-
development of biosimilars requires a thorough turer has produced a product that is highly simi-
assessment of immunogenic potential and immu- lar to the reference product in terms of structure,
nologic adverse events, which is not required for mechanism of action, and CQAs, the product can
generic agents [24]. undergo approval through appropriate regulatory
bodies.
Naming of Biosimilars
Approval Process
In January 2017 the FDA released guidelines
which require a four-letter suffix to be appended The approval process for biosimilars focuses on
to the original nonproprietary biologic name. For establishing biosimilarity between the proposed
instance, Amjevita, a biosimilar to adalimumab, product and the reference biologic agent rather
is designated as adalimumab-atto. The stated than demonstrating independent safety and effi-
purpose of the guideline is to prevent confusion cacy, as is the case for most novel pharmaceutical
between products and to facilitate ongoing phar- agents. The manufacturer of the biosimilar prod-
macovigilance monitoring [25]. uct submits comparative data to the reference
FDA requires that biosimilar package inserts agent, which is subsequently analyzed by the
contain the same information as the reference regulatory bodies to determine whether the pro-
biologic regarding safety and efficacy, in a man- posed product will be approved as a biosimilar.
Nonclinical Clinical
Characterization Comparative
studies pharmacologic
studies clinical study
(Animal) studies
• Analysis of structure • Animal PK, PD, and • Pharmacokinetic (PK) • Confirmatory safety
and function toxicity profile assays and efficacy studies
• Pharmacodynamic • Phase III clinical trial
(PD) assays for at least one
• Immunogenicity specific indication
assessment
Fig. 22.1 Totality of evidence approach in approval of biosimilars by regulatory agencies
The FDA has an abbreviated pathway for the any potential differences that could impact clini-
approval of biosimilars which was established cal performance [27]. Minor differences in areas
through the BCPI in 2009 [26]. Initially, manu- of the compound that are not clinically active,
facturers submit a biologics license application. such as N- or C- terminal truncations, are
In this 351(k) application, the biosimilar is tested acceptable [1].
across an array of different analytical assays, Next, functional assays are performed to assess
which must demonstrate by standard criteria that the pharmacologic activity of the biosimilar. In
the activity of the new product is equivalent to vitro functional assays must demonstrate simi-
the original agent, utilizes the same mechanism larity between the biosimilar and the reference
of action for the proposed condition(s) of use, product in terms of mechanism of action, receptor
and has the same route of administration, dosage binding, effector cell response, chemokine pro-
form, and strength [26]. In addition, they must duction, cytotoxicity, and other measures [8]. In
present data showing absence of clinically mean- other words, these studies must prove the biosimi-
ingful differences. lar replicates the effect of the originator product.
The approval of biosimilars through the
FDA and the EMA uses a “totality of evidence”
approach. This involves a stepwise investigational Nonclinical (Animal) Studies
process which includes analytical studies, ani-
mal studies, clinical pharmacokinetic (PK) and In vivo (i.e. animal) studies are not required for
pharmacodynamic (PD) studies, immunogenicity biosimilar approval, but may be undertaken in
assessments, and, in some cases, additional clinical some instances. Animal studies can provide more
studies (Fig. 22.1) [11]. data in support of biosimilarity; in particular,
animal toxicity studies may be utilized to dem-
onstrate a similar safety profile compared to the
Analysis of Structure and Function reference product. Animal studies may be con-
sidered unnecessary if available structural and
First, comparative analytical characterization of functional data already strongly support a high
the structure and function of the biosimilar is degree of similarity between the biosimilar and
performed in order to demonstrate that the bio- the originator biologic [2].
logical product is “highly similar” to the refer-
ence agent. Structural analyses ensure that the
biosimilar encodes the same primary amino acid Clinical Studies
sequence as the original biologic agent [1]. The
primary structure of the protein, its arrangement, After completion of the analytical/functional and
size variants, level of glycosylation, and molecu- nonclinical studies, clinical pharmacologic studies
lar charge are evaluated to characterize the quality are designed as the ultimate comparative assess-
attributes of the proposed biosimilar and to identify ment to establish bioequivalence. These studies
are typically conducted in healthy subjects, and to the approval of a given biosimilar medica-
must be statistically powered to determine differ- tion for additional clinical indications, outside
ences between the biosimilar agent and the refer- of those tested in a clinical trial. According to
ence product. The purpose of pharmacokinetic the FDA, this is allowable if there is “sufficient
(PK) assays is to determine how the human body scientific justification for extrapolating clinical
affects the drug in terms of absorption, distribution, data to support a determination of biosimilarity
metabolism, and elimination [7]. Phase I human for each condition of use for which licensure is
PK studies are required for all biosimilar candi- sought” [11]. For example the biosimilar Inflectra
dates, and must demonstrate pharmacologic bio- (infliximab-dyyb) underwent clinical trials in
equivalence in certain parameters such as serum patients with rheumatoid arthritis and ankylosing
concentration of drug over time [17]. Human spondylitis, but has now been FDA-approved for
pharmacodynamic (PD) studies are not always all the same indications as the reference product,
required, but may be conducted to supplement including plaque psoriasis and psoriatic arthritis
PK data. For a human or humanized monoclonal [28, 29]. In fact, all infliximab and some adalim-
antibody drug it can be difficult to determine how umab and etanercept biosimilars were approved
much of the drug is present in the serum at any for psoriasis via extrapolation [4].
given time. Through an assessment of the PK and Manufacturers must provide justification
PD data available for the biosimilar and the ref- for extrapolation via explanation of the drug’s
erence product, exposure response profiles can be mechanism of action, pharmacokinetics, biodis-
compared. tribution, and immunogenicity [24]. Biosimilars
Clinical immunogenicity assessments are also may not be approved for indications that are pro-
undertaken to evaluate for any differences in tected by regulatory exclusivity, such as adali-
the incidence and severity of immune responses mumab’s exclusive indication for adults with
between the reference product and the biosimilar. moderate to severe hidradenitis suppurativa [2,
Such studies are important because alterations 24]. Extrapolation decreases biosimilar develop-
in immune response elicited by the biosimilar ment costs by decreasing the extent of clinical
agent may promote the development of anti-drug trials that must be performed. However, the lack
antibodies and/or lead to acute clinical responses of clear clinical trial data may be a point of hesi-
such as anaphylaxis [11, 17]. At least one clini- tation for some clinicians considering prescribing
cal study comparing the immunogenicity of the biosimilars for extrapolated indications.
proposed biosimilar to the reference product
is required by the FDA [11]. The formation of
anti-drug antibodies is compared through titer Pharmacovigilance Studies
changes, time to development of antibodies, and
impact on pharmacokinetics [27]. The clinical studies required for FDA approval
Following PK, PD, and immunogenicity stud- are of limited duration and are conducted in a
ies, biosimilar candidates must undergo at least limited population, and therefore may not iden-
one phase III clinical trial for a specific indication tify all potential adverse effects. Post-approval
per FDA guidelines. Typically designed as an safety monitoring is recommended by the WHO,
equivalence trial, the objective is not to establish FDA, and the EMA, but the specific require-
efficacy of the biosimilar agent per se but rather ments for this monitoring varies by agency [4].
to demonstrate non-inferiority to its reference The EMA requires pharmacovigilance plans
product in terms of efficacy and safety [2, 11]. as part of the initial biosimilar approval pro-
The biosimilar sponsor may choose which indi- cess, however the FDA does not [30]. The FDA
cation is tested. instead recommends that manufacturers “consult
Importantly, biosimilar agents may eventually with appropriate FDA divisions to discuss the
be approved for non-tested indications based on sponsor’s proposed approach to post-marketing
the concept of extrapolation. Extrapolation refers safety monitoring” on a case-by-case basis [11].
In response to concerns regarding lack of safety biosimilar does not have any impact on safety,
data, the International Psoriasis Council has immunogenicity, or effectiveness.
suggested the establishment of registries of all A biosimilar with an interchangeable designa-
patients treated with biosimilars to enable moni- tion may be substituted for an originator biologic
toring of adverse treatment events over time [25]. without active intervention (such as a change in
prescription) by a prescribing provider, though
individual state substitution laws will impact this
Interchangeability practice [33]. In some states, a product that is
designated as interchangeable may be exchanged
Biosimilars can obtain a special classification as for the reference product by a pharmacist without
an “interchangeable biosimilar” through an addi- notifying the ordering physician [33]. The NPF
tional approval process by the FDA, which was has issued a position statement on interchange-
finalized in May 2019 [31]. Interchangeability is able biosimilar substitution, detailing the mini-
a specific designation given to biosimilars that are mum requirements that should be met in order
expected to achieve the same clinical outcome as for biosimilar substitution to occur [34].
the biologic product in any given patient, with- At the time of this publication there are no
out any change in the safety or efficacy profile FDA-approved interchangeable biosimilars in
between the new product and original agent [32]. the US. This may not be true for long, however.
The approval process for these agents requires Boehringer Ingelheim is currently pursuing an
additional information from the manufacturer interchangeability designation for BI 695501, its
to ensure that the biologic agent can be effec- adalimumab biosimilar [35]. It is likely that other
tively deemed interchangeable. Importantly, the pharmaceutical companies will follow suit in the
application for interchangeability must include coming months and years as the market continues
“switching studies,” which demonstrate that to grow and additional agents obtain regulatory
switching between the reference product and the approval (Fig. 22.2).
Payment for Payment for

product product
Biologic manufacturer Drug wholesaler Dispensing pharmacy
Drug
m ent
Formulary reimburse
r iption Drug
rebate Presc
Payer reimbursement Payer/ Insurance premiums

Pharmacy benefits
manager (PBM) Health Plan
% Pass through of rebate
Premium payment Patient

Legend
Payments andProduct
cash flow Employer
Fig. 22.2 US Pharmaceutical Distribution and Reimbursement System (for self-administered drugs)—simple
version [36]
Of note, several interchangeable biosimilars adalimumab. Erelzi (etanercept-szzs) and Eticovo

have been approved outside the US. Other coun- (Etanercept- ykro) are biosimilar medicines to
tries have been studying the interchangeability etanercept. Inflectra (infliximab-dyyb), Renflexis
of biosimilars in their respective markets. The (infliximab-abda), and Ixifi (infliximab-qbtx) are
NOR-SWITCH study was a randomized con- biosimilar medicines to infliximab. While these
trolled study initiated by the Norwegian govern- biologic agents have all been approved for use
ment to study the safety and viability of switching in patients with moderate to severe psoriasis,
and interchanging infliximab and its biosimilar only three (Amjevita, Erelzi, and Hyrimoz) have
agents in several diseases including psoriasis, undergone clinical trials specifically for the indi-
RA, spondyloarthritis, psoriatic arthritis, ulcer- cation of psoriasis [4]. The remaining biosimilars
ative colitis, and Crohn’s disease [37]. The study were approved via extrapolation.
found that there were no differences or clini- There are several other biosimilars in phase
cal worsening in any of these conditions when III clinical trials for the treatment of moderate
patients were switched between original products to severe plaque psoriasis. These include BCD-
and their biosimilars. They also found no differ- 457, CHS-1420, GP2017, M923, MSB11022,
ence in the development of anti-drug antibod- and Myl-1401A, which are all biosimilars of
ies [37]. Additional studies regarding multiple adalimumab. Biosimilars of etanercept ONS-
switch designs, including VOLTAIRE-X, will 3010 and CHS-0214 are also undergoing clinical
provide additional information about the effect trials for psoriasis [4]. There are also several bio-
of switching between biosimilars and innovator similars currently being studied for rheumatoid
products [38]. arthritis that may be approved for psoriasis via
extrapolation if approved by the regulatory agen-
cies their respective countries. These include
Biosimilars in Dermatology FKB327 and LBALM (adalimumab biosimi-
lars), PF-06410293 and LBEC0101 (etaner-
Current FDA-approved biosimilars for the treat- cept biosimilars), and ABP 710, BCD-055, and
ment of moderate to severe psoriasis are shown N1-071 (infliximab biosimilars), all currently in
in Table 22.2. Amjevita (adalimumab-atto), phase III clinical trials [4].
Cyltezo (adalimumab-adbm), and Hyrimoz Data regarding biosimilar use among derma-
(adalimumab-adaz) are biosimilar medicines to tologists in the United States is limited, due to
multiple factors including limited access to bio-
Table 22.2 Currently approved biosimilars for psoriasis similars in the current market and prescriber unfa-
[18] miliarity with these medications [38]. Biosimilars
Phase III are more widely used in Europe resulting in
Brand FDA trial for accumulation of significant data supporting the
name Generic name approval date psoriasis
use of biosimilars for psoriasis. A 10-year study
Erelzi Etanercept-szzs August Yes
2016 from Danish registries, for example, found no
Eticovo Etanercept-ykro April 2019 No significant differences in safety or drug survival
Amjevita Adalimumab- September Yes between reference and biosimilar versions of
atto 2016 etanercept and infliximab [39]. In some European
Cyltezo Adalimumab- August No countries, national legislation has influenced the
adbm 2017
use of biosimilars as part of efforts to decrease
Hyrimoz Adalimumab- October Yes
adaz 2018 costs and increase the availability of these drugs.
Inflectra Infliximab-dyyb April 2016 No In May 2015, for instance, Denmark instituted
Renflexis Infliximab-abda April 2017 No a national policy that patients should be started
Ixifi Infliximab-qbtx December No on or switched to the cheapest version of a given
2017 biologic (i.e. the biosimilar version) [39].
Economic Advantage of Biosimilars available [46]. Most have been withheld from the
market due to ongoing patent disputes between
In general, cost savings with biosimilars are less the reference product manufacturer and the bio-
than those seen with generic small molecule similar manufacturer [12]. Additionally, while
agents. While cost reductions associated with many original drug patents for biologics are
small molecule generics can be 80% or higher, approaching their expiration dates, some have
estimated biosimilar acquisition cost savings in additional patents related to manufacturing pro-
the US have ranged from 10 to 40% [5, 40–43]. cesses which provide ongoing protection; for
According to a 2017 estimate, the average cost for example two additional patents for etanercept
an 8-week supply of an infliximab biosimilar was (Enbrel) can extend patent protection until 2029
18% less than its reference product [5]. Outside [3, 21]. In many instances, patent litigation has
the US, cost savings on biosimilars are variable, had the effect of postponing market entry for
ranging from as high as 70% in Norway (due to biosimilar products. Recent litigation settlements
discounted government pricing) to 30% in India involving Amgen and Sandoz, for instance, have
[25]. Europe has approved 23 biosimilars, with an resulted in delayed introduction of adalimumab
average price reduction of 20–30% [40]. biosimilars until 2023 [5].
While estimated US cost savings may seem
modest, they remain significant when viewed in
the context of the overall market size for biologic Prescriber Considerations
agents. In 2014, the Rand Corporation estimated
a direct cost savings potential of $44.2 billion Physician awareness and comfort level with pre-
between 2014 and 2024, accounting for about scribing biosimilars is another barrier to wide-
4% of total biologic spending over that period spread use of these medications. Incomplete
[17, 44]. As the biosimilar market expands, com- understanding of what biosimilars are, apprehen-
petition grows, and regulatory changes allow for sion about the significance of “minor differences”
streamlining of the developmental process for between reference products and biosimilars, and
biosimilars, greater cost decreases may be seen. lack of long-term safety data are factors that may
limit physician willingness to prescribe biosimi-
lars. According to a recent online survey of US
arriers to Use and Future
B dermatologists, only 25% stated they “will defi-
Directions nitely or are highly likely to prescribe biosimi-
lars” [47]. Frequently cited concerns included
Despite the passage of the BCPI nearly a decade safety (66%), efficacy (71%), immunogenic-
ago, market uptake of biosimilars in the US has ity (63%) and the potential for patients to be
been slow. Reports from 2017 indicated that less switched from a biologic to a biosimilar without
than 10% of total biologic spending ($11.5 bil- clinician awareness [47]. Since no biosimilars
lion) was subject to competition from biosimi- have yet been given an interchangeable designa-
lars [45]. There are several factors at play which tion in the US, some clinicians remain wary of
continue to limit access to and acceptance of bio- the potential for adverse immunologic effects if
similars, some of which will be reviewed here. patients switch between originator biologics and
biosimilars. It is worthy of note, however, that
switching studies completed to date suggest that
atent Disputes and Extended
P immunologic risk is low [5, 48] (Fig. 22.3).
Patents for Branded Drugs Prescriber acceptance of biosimilars hinges on
knowledge and comfort level with these agents.
As of July 2019, 20 biosimilars have received A 2017 cross-sectional survey of dermatologists
FDA approval but only 7 are commercially found that physicians who were “fairly to very
familiar” with biosimilars were more comfort- Conclusion

able prescribing biosimilars for psoriasis, even
if they had not been clinically studied for this In summary, biosimilars are a rapidly growing
indication [49]. sector of the pharmaceutical industry, both in
the US and globally. Despite the slow adoption
of biosimilars in the US to date, there is potential
Patient Factors for greater use of biosimilars in the future; the
adoption of generic agents in the United States
While the economic benefits of biosimilars are was similarly slow, but now generics account
easy to appreciate from a systems level perspec- for the vast majority of prescribed medications
tive, this benefit may not be immediately appar- [50]. At present, legal, regulatory, and finan-
ent to the end user, i.e. the patient. The decreased cial constructs, lack of commercial availability,
acquisition cost of a biosimilar is most relevant to and low provider comfort level with the use of
patients who have high deductible plans or who these agents remain barriers to large-scale adop-
have co-insurance plans with expenses calculated tion of biosimilars. Numerous biosimilar agents
as a percentage of a given drug’s list price [24]. are currently in the pipeline as multiple com-
Patients with fixed copays are not incentivized monly prescribed biologics are approaching
to seek out medications with a lower acquisi- their patent expiration dates. In the future, as
tion cost, since this cost is not directly passed on utilization of these novel agents becomes more
to them. In fact, such patients may be likely to widespread, biosimilars have the potential to
prefer brand name reference products over bio- decrease healthcare costs globally and increase
similars in these instances, given greater name patient access to additional valuable disease-
recognition and overall familiarity. modifying therapies.
Premium Payment
Legend
Patient Employer
Contracts and Services
Insurance Coverage
Prescriptions
Payments and Cash Flow

Coinsurance
Dispenses
Premium
Payment
Medication Purchase Prescription Reimbursement
(Contracted Price) (Contracted Rate)
Dispensing Health Plan/
Pharmacy Medical Benefit
Wholesale Agreement Network Agreement
Prescription
Benefit
Pharmacy
Pharmaceutical
Benefit Manager
Wholesaler
(PBM)
Management Fees
Distribution Agreement
Rebate
Pharmaceutical
Medication Purchase Manufacturer
(Contracted Price) Formulary Placement
Fig. 22.3 US Pharmaceutical Distribution and Reimbursement System (for self-administered drugs)—complex
version [36]
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Research Pipeline I: Oral
Therapeutics for Psoriasis 23
D. Grand, K. Navrazhina, J. W. Frew,
and J. E. Hawkes
Abstract antagonists, adenosine A3 receptor agonists,

H4 receptor antagonists, PRINS inhibitors,
Over the last two decades, tremendous
and spleen tyrosine kinase inhibitors.
advances have been made in the treatment of
psoriatic disease. Our understanding of the
complex immunopathogenesis of this chronic
inflammatory condition has led to the devel-
opment of highly effective, safe, targeted
monoclonal antibodies that result in clearance
of novel oral agents in development for
in the vast majority of treated patients.
the treatment of psoriasis
However, these recently approved therapies
have multiple drawbacks and limitations that
efficacy of novel oral agents in develop-
necessitate the development and testing of
ment for the treatment of psoriasis
additional treatment modalities. To address
3. To understand the safety issues and

this need, scientists and the pharmaceutical
appropriate monitoring of novel oral
industry have pursued the identification and
agents in development for the treatment
testing of several oral small molecules as
of psoriasis
novel treatments for plaque and psoriatic arthri-
tis. These molecules in testing include JAK/
TYK2 inhibitors, phosphodiesterase inhibitors,
RORγt inhibitors, fumarate esters, sphingosine
Introduction
1 phosphate antagonists, neurokinin-1 receptor
Psoriasis is chronic inflammatory skin dis-
D. Grand · K. Navrazhina · J. W. Frew ease with a complex etiology. Current research
Laboratory for Investigative Dermatology,
The Rockefeller University, New York, NY, USA demonstrates that interleukin-23 (IL-23) and
e-mail: [email protected]; IL-17-producing T (T17) cells are central to the
[email protected]; [email protected] pathogenesis of this condition [1]. The effective-
J. E. Hawkes (*) ness of current anti-psoriatic therapies is largely
Laboratory for Investigative Dermatology, correlated with the ability of the treatment to dis-
The Rockefeller University, New York, NY, USA rupt the dysregulated IL-23/T17 signaling axis
Department of Dermatology, Icahn School of in the skin. With the recent approval of multiple
Medicine at Mount Sinai, New York, NY, USA selective monoclonal antibodies against IL-23

https://doi.org/10.1007/978-3-030-54859-9_23
292 D. Grand et al.
Table 23.1 List of novel therapies currently in clinical trials for the treatment of psoriasis
Drug name Drug class Phase Company Clinical trials
Baricitinib JAK1/2 inhibitor 2b Eli Lilly NCT01490632
Upadacitinib JAK1 inhibitor 3 AbbVie NCT03104374
NCT03104400
Filgotinib JAK1 inhibitor 2 Galapagos NCT03320876
NCT03101670
NCT03926195
ASP015K JAK3 inhibitor 2 Janssen NCT01096862
BMS-986165 Tyk2 inhibitor 3 BMS NCT04036435
NCT03624127
LEO32731 PDE4 inhibitor 2 LEO NCT02888236
NCT03231124
VTP-43742 RORγt inhibitor 2 Vitae Pharma NCT03724292
NCT02555709
LAS41008 Dimethyl fumarate 3 Almirall NCT02955693
NCT01726933
FP187 Fumaric acid 2/3 Forward Pharma NCT01230138
NCT01815723
NCT02475304
XP23829 Fumaric acid 2 Xenoport NCT02173301
Ponesimod S1P receptor antagonist 2 Actelion NCT01208090
(ACT-128800) NCT00852670
Amiselimod S1P receptor antagonist 2 Mitsubishi Tanabe Pharma NCT01987843
(MT-1303)
Serlopitant Neurokinin-1 receptor 3 Menlo Therapeutics NCT03343639
(VPD-737) antagonist
CF101 Adenosine A3 receptor 3 Can-Fite Biopharma NCT03168256
agonist
ZPL-389 H4 receptor antagonist 2 Ziarco Pharma NCT02618616
Prurisol IL-20 and PRINS inhibitor 2 CellCeutix NCT02101216
NCT02494479
NCT02949388
and IL-17, we are witnessing unprecedented therapeutics being studied for the potential treat-
advances in the treatment of patients with pso- ment of psoriatic disease (Table 23.1).
riasis. Nevertheless, monoclonal antibodies
have limitations including their high cost, insur-
ance accessibility, loss of efficacy over time JAK Inhibitors
potentially due to anti-drug antibodies, and the
need for intravenous or subcutaneous admin- The Janus kinase (JAK) family is composed of
istration. The potential advantage of novel oral four tyrosine kinases (JAK1, JAK2, JAK3, and
small molecules for the treatment of psoriasis TYK2) that have essential roles as signal trans-
include a decreased cost, avoidance of protein- ducers downstream of activated cytokine recep-
related immune mechanisms leading to loss of tors. In contrast to c-KIT and insulin, cytokine
efficacy with time, and ease of administration. receptors lack intrinsic protein kinase domains
Accordingly, many companies are testing the and, therefore, rely upon constitutively active JAK
efficacy of a variety of small molecules for the tyrosine kinases (TYK) to convey immune sig-
potential treatment of plaque and psoriatic pso- nals [2]. Following JAK activation, one of the six
riasis. The purpose of this chapter is to provide an STAT family members are consequently activated
overview of the research pipeline for novel, oral (STAT1–6) leading to its function as a transcrip-
23 Research Pipeline I: Oral Therapeutics for Psoriasis 293
H4 Receptor GPCR Pathway JAK-STAT

SYK NF-kB
Pathway Pathway (S1P, A3AR, NK1) Pathway
Pathway
CF101
ponesimod
ZPL-399
amiselimod
JAK/
TYK2
SYK cAMP baricitinib

apremilast upadacitinib
MyD88 filgotinib
fostamatinib LEO32731
ASP015k
Protein
Kinase C BMS-986165
Protein
Kinase A NF-kB
STAT
JNK/ERK LAS41008
FP187
MEK/ERK XP23829
CYTOPLASM
VTP-43742
RORy
abacavir hydroxyacetate
PRINS
NUCLEUS
Fig. 23.1 Schematic of a T lymphocyte and the proposed mechanisms of action for several small molecules being
tested in clinical trials for the treatment of psoriatic disease
tion factor. Significant overlap between the various does not directly suppress IL-17, it works indi-
JAK and STAT isoforms have been demonstrated rectly through other STAT-dependent cytokines
in mouse knockout models, thus highlighting the acting upstream (e.g. IL-23) [6, 7]. Novel thera-
need to carefully study the impact of combination pies targeting the JAK-STAT pathway must bal-
versus more selective JAK blockade [3]. ance suppression of pro-inflammatory signaling
Novel small molecules target one or more versus the over-suppression and disruption of
JAK isoforms (Fig. 23.1). JAK1 and JAK2 are vital developmental functions, such as neuronal
involved in interferon-gamma signaling, whereas development, protection against infections, and
JAK3 is involved in signaling from type I cyto- hematopoiesis [8].
kine receptors that use the common gamma chain Some of the differences between JAK iso-
(γc) including IL-2, IL-4, IL-7, IL-9, IL-15 and forms can be inferred from the effects observed
IL-21 [4, 5]. Although the JAK-STAT pathway in individuals living with JAK deficiencies as
294 D. Grand et al.
well as the clinical results from human studies. [13, 14]. SELECT-PsA 1 is an active phase III
JAK3 deficiency (severe combined immunodefi- study with 640 participants who have had an
ciency or SCID) is associated with decreased T inadequate response to at least one non-biologic
and NK cell numbers, but unaffected B cells [9]. disease-modifying anti-rheumatic medication
TYK2 deficiency is associated with susceptibility (e.g. methotrexate). SELECT-PsA 2 is currently
to viral, fungal, and mycobacterial infection [10]. recruiting participants who have had an inad-
Activating somatic mutations in JAK1, JAK2, equate response to at least one biologic disease-
and JAK3 have also been identified in myelopro- modifying anti-rheumatic drug with estimated
liferative disease, leukemia, and lymphoma [11] enrollment of 1640 participants. Both trials
raising the concern for a potential increase in wills compare two daily doses of upadacitinib
malignancy risk with long-term treatment. versus placebo and adalimumab and will mea-
In May 2012, the FDA approved tofacitinib, an sure ACR20 at week 12 as the primary endpoint
oral pan-JAK inhibitor, for the treatment of rheu- [13, 14]. No clinical trials testing this compound
matoid arthritis. This was the first approval of a for the treatment of plaque psoriasis have been
medication in this specific drug class. Subsequent reported.
FDA approval of tofacitinib for the treatment of The EQUATOR trial evaluated the efficacy
psoriatic arthritis occurred in December 2017. and safety of JAK1-selective inhibitor, filgotinib,
Other first-generation JAK Inhibitors include in patients with psoriatic arthritis [15]. 131 sub-
ruxolitinib, baricitinib, and oclacitinib. jects were randomly assigned to daily filgotinib
A phase 2b trial for a JAK1/2-selective inhibi- 200 mg versus placebo. 80% of the filgotinib
tor, baricitinib, randomized 271 participants to group achieved ACR20 at week 16 compared to
placebo and four daily doses of baricitinib (2, 4, 33% of the placebo group (P value < 0.0001).
8, or 10 mg) for 12 weeks [12]. Based on treat- A greater percentage of participations in the fil-
ment response at week 12, doses were either con- gotinib group achieved PASI75 than the placebo
tinued or increased for the next 12 weeks. 75% group (45.2 vs. 15%, P value = 0.0034). The
improvement in the Psoriasis Area and Severity incidence of adverse events was similar between
Index (PASI75) at week 12 was achieved in filgotinib and placebo with nasopharyngitis
42.9% of the 8 mg group and 54.1% of the and headache being the most common reported
10 mg group. Both proportions were statisti- adverse events [15]. An open-label extension
cally significant compared to the placebo group study is ongoing and will provide long-term data
(17%). Greater than 81% of treatment respond- on filgotinib therapy [16]. No clinical trials test-
ers at week 12 maintained a PASI75 at week ing this compound for the treatment of plaque
24. With dose escalation, 48% of those who had psoriasis have been reported.
not achieved PASI75 at week 12 achieved it by A phase 2a trial evaluating the efficacy and
week 24. The most common adverse events of the safety of JAK3-selective inhibitor, ASP015K,
placebo and baricitinib groups were infection- randomized 124 participants to four twice-daily
related (e.g. nasopharyngitis). Cytopenia was doses (10, 25, 60, or 100 mg) or one daily dose
observed in 4.6% of patients receiving baricitinib (50 mg) versus placebo for 6 weeks [17]. A
compared to 0% in placebo; higher cytopenia greater change in PASI score was observed in a
rates were documented in the 8 and 10 mg treat- dose-dependent manner in those receiving active
ment groups. Rates of drug discontinuation due treatment with ASP015K compared to control
to adverse events was highest in the 8 mg (6.3%) (P value < 0.001). Histological studies of biop-
and 10 mg (5.8%) treatment groups [12]. Phase sied lesional skin demonstrated active treatment
III clinical trials for baricitinib in the treatment of dose-dependent decreases in epidermal thick-
plaque psoriasis are currently underway. ness, number of proliferating epidermal cells
There are two ongoing phase 3 trials study- (measured by Ki67 staining), number of dermal
ing the efficacy of a JAK1-selective compound, CD3+ T cells, and number of CD11c+ dendritic
upadacitinib, in participants with psoriatic arthritis cells. A greater percentage of ASP015K subjects
(46.3%) experienced treatment-related adverse PDE4 Inhibitors

events compared to the placebo group (37.9%),
but the number of drug-related adverse events Phosphodiesterases (PDEs) are comprised of 11
were similar among the two groups. No serious families of molecules responsible for the deg-
adverse events were reported [17]. No clinical radation of cyclic nucleotides on adenosine and
trials testing this compound for the treatment of guanine monophosphates (cAMP and cGMP,
psoriatic arthritis have been reported. respectively). PDE4 is a specific isoform found
to be highly expressed in keratinocytes and
inflammatory leukocytes (T cells, monocytes,
Tyk2 Inhibitor dendritic cells, and neutrophils), as well as brain,
cardiovascular, and smooth muscle tissues [21].
BMS-986165 is a selective Tyk2 inhibitor. A Suppression of PDE4 leads to elevation in cAMP
phase 2 trial randomized 267 participants to five and activation of protein kinase A (Fig. 23.1),
doses of BMS-986165 (3 mg every other day, as well as other downstream mediators such as
3 mg daily, 3 mg twice daily, 6 mg twice daily, Epac1/2. Several PDE4 inhibitors have been
or 12 mg daily) versus placebo for 12 weeks fol- developed based upon the subtypes of PDE4 ele-
lowed by a 30-day follow-up period [18]. PASI75 vated in the primary tissues involved in specific
at 12 weeks was observed in 9, 39, 69, 67, and inflammatory diseases. In psoriasis and psoriatic
75% of the treatment doses, respectively, versus arthritis, PDE4B and PDE4D were identified as
7% of the placebo group. PASI100 was observed differentially expressed in psoriasis peripheral
in 18% of the 6 mg twice daily group and 25% blood mononuclear cells. Accordingly, apremi-
of the 12 mg daily group compared to 0% of the last, which has high specificity for PDE4, was
placebo group. Treatment effects were evident developed as an oral therapy for the treatment
as early as day 15 and persisted after the 30-day of psoriasis and psoriatic arthritis [22, 23]. The
follow-up period. Nasopharyngitis, headache, downstream effects of apremilast in psoriasis
diarrhea, nausea, and upper respiratory infections include the downregulation of interferon-γ and
were the most common reported adverse effects. TNF-α with resultant Th17 pathway suppression
A greater proportion of patients in the active and skin clearance [24]. Apremilast was approved
treatment group experienced mild-to-moderate by the FDA for the treatment of moderate-to-
acne, possibly due to a change in the microbiome severe plaque psoriasis in September 2014. It
in response to the altered cytokine profile follow- is also approved for the treatment of psoriatic
ing treatment. However, no cases of pathologic arthritis and Behcet’s disease.
agents such as herpes zoster, tuberculosis, or Since the FDA’s approval of apremilast,
opportunistic infections, were documented [18]. another PDE4 inhibitor, LEO32731, is currently
Two phase 3 trials (POETYK-PSO-1 and 2) being studied in human trials. A phase 2 single-
further testing BMS-986165 are currently under- center study of 36 participants with moderate-
way and recruiting participants for a multicenter to-severe psoriasis compared twice-daily 30 mg
study in subjects with moderate-to-severe plaque LEO32731 to placebo. Endpoints included PASI
psoriasis [19, 20]. An estimated 600 and 1000 score and the Itch Numeric Rating Scale score
participants will be randomized to BMS-986165 between baseline and week 16 of treatment. The
versus apremilast or placebo. The proportion of study was completed in June 2017, but results
patients who achieved a Static Physicians Global have not yet been published [25]. No clinical
Assessment (sPGA) score of 0/1 and PASI75 at trials testing this compound for the treatment of
week 16 of treatment will be the primary measure psoriatic arthritis have been reported. However,
of treatment efficacy [19, 20]. No clinical trials several other topical PDE4 inhibitors are cur-
testing this compound for the treatment of psori- rently under development, including pefcalcitol
atic arthritis have been reported. and HFP034.
296 D. Grand et al.
RORγt Inhibitors New oral formulations of fumarates with

greater gastrointestinal tolerability are being
RAR-related orphan receptor gamma t (RORγt developed, including FP187 and XP23829. A
or RORγ2) is a DNA-binding transcription factor dose-ranging phase 2 clinical trial at two study
(Fig. 23.1) expressed in CD4+ T cells leading to locations in Germany investigated the efficacy
for Th17 differentiation. It is essential for IL-17 of FP187 on moderate-to-severe psoriasis [33].
production and is, therefore, an attractive target Participants were randomized to three-times daily
for small molecule inhibition in psoriatic disease FP187 (250 mg), twice-daily FP187 (375 mg),
[26]. Murine models have shown that RORγt twice-daily and FP187 (250 mg) versus pla-
knockdown suppressed the Th17 response cebo. The primary endpoint was the proportion
induced by intradermal IL-23 injection. IL-17A/ of patients achieving PASI75 at 20 weeks. This
C/F, CCL20, and CCR6 are relevant genes known study was completed in January 2012, but results
to be regulated by RORγt and RORα [27]. have not yet been published [33]. Additional
A phase 1 single ascending dose study ran- phase 2 and 3 clinical trials involving FP187 for
domized 53 healthy volunteers to a single dose of the treatment of psoriatic arthritis and plaque
VTP-43742 (ranging from 30 to 2000 mg) versus psoriasis, respectively, were initiated but subse-
placebo [28]. A phase 1 multiple ascending dose quently withdrawn. A multicenter, dose-ranging,
study randomized 40 healthy volunteers to VTP- phase 2 clinical trial randomized plaque psoria-
43742 (ranging from 100 to 1400 mg/dL) versus sis participants to three XP23829 doses (400 mg
placebo [29]. In both studies, VTP-43742 was daily, 800 mg daily, or 400 mg twice daily) ver-
shown to be safe and well-tolerated at all doses, sus placebo [34]. Efficacy was assessed as the
and ex vivo whole blood assays showed a dose- percent change in PASI score at 12 weeks. This
dependent decrease in IL-17A secretion following study was completed in May 2015, but results
treatment. In the multiple ascending dose study, all have not yet been published [34]. No clinical
but the lowest dose resulted in a >90% inhibition of trials testing this compound for the treatment of
RORγt-dependent IL-17A secretion for 24 h [28– psoriatic arthritis have been reported.
30]. No clinical trials testing this compound for the The BRIDGE trial was a phase 3 noninferiority
treatment of psoriatic arthritis have been reported. trial where participants were randomly assigned
into three groups: LAS41008 (dimethyl fuma-
rate), fumaderm (dimethyl fumarate combined
Fumarate Esters with monomethyl fumarate salts), or placebo
[35]. Doses of each were escalated based upon
Oral fumarates are a longstanding treatment clinical response with a maximum daily dimethyl
for moderate-to-severe psoriasis, particularly fumarate dose limited to 720 mg. 37.5% of sub-
in Europe. However, the exact mechanism of jects receiving LAS41008 at week 16 achieved
action by which this class of drugs act is incom- PASI75 making it superior to placebo (15.3%,
pletely understood. The esters of fumaric acid, p < 0.001) and noninferior to fumaderm (40.3%,
monomethyl fumarate and dimethyl fumarate, p < 0.001). LAS41008 demonstrated superior-
are the active fumarates responsible for the anti- ity to placebo upon assessment with sPGA 0/1
inflammatory properties of this therapeutic class at week 16 (33 vs. 13%, p < 0.001). Rebound
[31]. Multiple mechanisms of action have been was observed in 1.1% of LAS41008 subjects at
proposed, including lowering glutathione levels, 2 months off treatment compared to 9.3% of pla-
activation of Nrf2 antioxidant pathways, inhibi- cebo subjects. Lymphopenia is a known adverse
tion of NF-κB activity (Fig. 23.1), shifting Th1/ effect of dimethyl fumarate- containing com-
Th17 to a Th2 dominant phenotype, binding of pounds. In this study, lymphocyte counts lower
monomethyl fumarate to GPR109A (implicated than 0.7 × 109 cells/L were observed in a greater
in the flushing response of patients on fuma- percentage of LAS41008 (7.9%) and fumaderm
rates), and modulation of hypoxia inducible fac- (7.4%) subjects compared to placebo (0.7%).
tor and JAK-STAT signaling pathways [32]. However, the lymphopenia resolved upon treatment
discontinuation. Most adverse effects were mild ease, macular degeneration, ulcerative colitis,
in severity and included gastrointestinal disorders pyoderma gangrenosum, and uveitis. Two S1P
and flushing [35]. No clinical trials testing this modulators, amiselimod and ponesimod, have
compound for the treatment of psoriatic arthritis undergone Phase 2 trials for chronic plaque psori-
have been reported. asis. A phase 2a study of ponesimod randomized
66 participants with moderate-to-severe chronic
plaque psoriasis to either ponesimod 20 mg daily
S1P Receptor Antagonists or placebo [40]. The primary endpoint was per-
centage change in PASI score at week 6. Results
Sphingosine 1 phosphate (S1P) is a bioac- have not yet been published. In 2012, a phase 2
tive lipid molecule first identified as a stimula- trial randomized 326 participants to two daily
tor of fibroblast proliferation. It was originally doses of ponesimod (20 or 40 mg) versus pla-
described as an intracellular second messenger of cebo [41]. A greater proportion of participants in
G protein coupled receptors (GPCR) mediating the 20 and 40 mg groups (46 and 48.1%, respec-
intracellular calcium levels secondary to platelet- tively) achieved PASI75 at week 16 compared
derived growth factor (PDGF) and IgE signaling to placebo (13.4%, P value < 0.0001 for both
(Fig. 23.1). However, the discovery of high affin- groups). Additionally, sPGA 0/1 was noted in
ity cell surface receptors (S1P1–5) and the role 27.8 and 32.3% of the ponesimod 20 and 40 mg
of these receptors in angiogenesis, tissue remod- groups, respectively, compared to only 4.5% of
eling, and inflammatory mediator synthesis have the placebo group. At week 16, those who had
accelerated the development of target molecules received ponesimod and achieved a greater than
to modulate these pathways [36]. The fungus 50% decrease in PASI score either continued pon-
Isaria sinclairii, used in traditional Chinese med- esimod at the same dose or switched to placebo.
icine, contains Myriocin from which synthetic At week 28, a greater proportion of those who
S1P modulators have subsequently been devel- remained on ponesimod achieved PASI75 com-
oped for clinical use and testing [37]. pared to those who switched to placebo. In addi-
Fingolimod is a non-selective S1P agonist and tion, those that switched to placebo had a greater
functional antagonist of S1P receptors 1, 3, 4 and likelihood of disease relapse. Laboratory analy-
5 [38]. The binding of phosphorylated fingoli- sis revealed dose-dependent lymphopenia in the
mod results in intracellular signaling via GPCRs ponesimod groups (56 and 65% mean decrease in
(Fig. 23.1). The overall effect of fingolimod is lymphocyte count, respectively) compared to 2%
immune modulation via trapping of lymphocytes of the control group. The incidence of infection
in secondary lymphoid tissues, thus causing T was similar across all groups. The most common
and B cells to accumulate rather than migrate into reported adverse events associated with ponesi-
the blood stream. Sustained lymphopenia is the mod were dyspnea, elevated liver enzymes, and
suspected mechanism of action responsible for dizziness [41].
the efficacy of this drug in the treatment of relaps- A phase 2a dose-ranging study of amiselimod
ing-remitting multiple sclerosis. Lymphopenia recruited 142 subjects with moderate-to-severe
associated with fingolimod resolves in approxi- psoriasis and randomized them to low, medium,
mately 7 days after cessation of the drug [39]. and high doses of amiselimod versus placebo
The mechanism of action of fingolimod and [42]. The proportion of participants achieving
other S1P modulators makes this class of drug an a PASI75 at week 16 was the primary measure
attractive potential therapy for multiple autoim- of treatment efficacy. This study was completed
mune or inflammatory conditions. in September 2014, but study results have not
Other S1P modulators are in various stages yet been published. No clinical trials testing
of development for the treatment of psoriasis, ponesimod or amiselimod for the treatment of
SLE, dermatomyositis, graft versus host dis- psoriatic arthritis have been reported.
298 D. Grand et al.
Neurokinin-1 Receptor Antagonists identification of this receptor as a potential thera-

peutic target [50]. The binding of adenosine to
Neurokinin-1 (NK1) is the preferred receptor A3AR constitutively inhibits adenylyl cyclase
for substance P, the binding of which results in and mitogen-activated protein kinase pathways.
rapid downstream activation of NF-κB, ERK, Chronic elevation of adenosine in the setting of
and p21 associated pathways (Fig. 23.1) [43, 44]. pro-inflammatory cytokines leads to increased
Substance P has a vital role in the stimulation levels of membrane bound A3AR, which has been
of pro-inflammatory leukocytes, as well as the identified in malignancy and chronic inflamma-
innate response to viral, parasitic, and bacterial tory disorders [51]. This chronic elevation of
infections through enhanced production of IL-1, adenosine results in delayed internalization of
IL-6, TNF-α, MIP-1B and IFN-γ [45]. NK1 path- A3AR and upregulation of downstream NF-κB
ways are also implicated in the modulation of itch, (Fig. 23.1), and β-catenin signaling resulting
stress, sleep, anxiety, and nausea via the central in transcriptional alterations leading to a pro-
nervous system. This has led to the development inflammatory environment. Therefore, A3AR
of NK1 receptor (NK1R) antagonists for pruritus agonists are being evaluated for the treatment of
as well as chemotherapy-associated nausea and rheumatoid arthritis, inflammatory bowel disease,
vomiting [46]. NK1R antagonists have also been and uveitis, as well as melanoma, prostate, colon,
tested in psoriasis given the associated pruritus breast, and hepatocellular carcinomas [52].
and the contribution of pro-inflammatory cyto- A phase 2 dose-ranging clinical trial ran-
kines to the keratinocyte mediated feed-forward domized 75 participants to twice-daily doses of
pathway in psoriasis [47]. Additionally, localized CF101 (1 mg, 2 mg, or 4 mg) versus placebo [53].
TGFβ elevation in psoriatic skin is associated Efficacy, as measured by percent change in PASI
with delayed internalization of the NK1R com- score, showed a bell-shaped response in which
plex, which leads to increased elevation of IL-1, the 2 mg group had the greatest change in PASI
IL-6, and TNFα levels [43]. score at weeks 4, 8, and 12. Adverse events were
A phase 2 study randomized participants to a similar among the treatment and placebo groups.
serlopitant 5 mg daily group or placebo group. The However, the results of this study are limited due to
primary endpoint WI-NRS 4-point responder rate its small sample size [53]. Another phase 2/3 clini-
at 8 weeks was achieved in 33.29% of the serlo- cal trial randomized 293 patients with moderate-to-
pitant group versus 21.07% of the placebo group severe plaque psoriasis to either twice daily 2 mg
[48]. Serlopitant was not associated with any seri- CF101 versus placebo [54]. 8.5% of participants
ous adverse events. Diarrhea, nasopharyngitis, and in the CF101 group achieved the primary endpoint
headache were the most common adverse events (PASI75) at week 16 compared to 6.9% of placebo
reported. An open-label extension study is ongo- group. 31% of the CF101 group achieved the sec-
ing and will provide long-term data on serlopitant ondary endpoint (PASI50 or 75) at week 16 com-
therapy for the treatment of psoriasis [49]. No clin- pared to 17% in the placebo group [54].
ical trials testing this compound for the treatment An ongoing phase 3 clinical trial will assess
of psoriatic arthritis have been reported. CF101 therapy in those with moderate-to-
severe plaque psoriasis [55]. An estimated 407
participants will be randomized to twice daily
Adenosine A3 Receptor Agonists regimens of CF101 2 mg, CF101 3 mg, or apre-
milast 30 mg versus placebo. The primary end-
Adenosine A3 receptors (A3AR) are GPCRs point will be the proportion of subjects who
(Fig. 23.1) associated with regulation of local tis- achieve PASI75. This trial is currently recruiting
sue function in the absence of an adequate energy participants [55]. No clinical trials testing this
supply. They are specifically overexpressed in compound for the treatment of psoriatic arthritis
inflamed and malignant tissues leading to the have been reported.
H4 Receptor Antagonists Abacavir hydroxyacetate, also known as

Prurisol, is a chemical known to inhibit PRINS
Histamine, as a ligand for the H1-H4 receptors, is (Fig. 23.1). Two phase 2 trials investigating the
classically released by mast cells in response to efficacy of prurisol in chronic plaque psoriasis
immunological and non-immunological stimuli. have been completed. One trial randomized 115
The localization of histamine receptor subtypes participants with mild-to-moderate psoriasis into
differs between tissues with H4 receptors pre- four daily treatment arms: prurisol 50 mg, pru-
dominately expressed on the surface of hema- risol 100 mg, and prurisol 200 mg versus pla-
topoietic cells, including eosinophils, T cells, cebo [62]. The primary endpoint was percentage
neutrophils, and other leukocytes (Fig. 23.1) of participants with a ≥2-point improvement in
[56]. Aside from its well-documented effect on IGA rating at day 84. Another trial randomized
eosinophils migration, H4 receptor antagonists 199 participants with moderate-to-severe psoria-
also inhibit CD4+ T cell activation. While the pri- sis to twice daily prurisol 150 or 200 mg versus
mary T cell population affected by H4 receptor placebo [63]. The primary endpoint was the pro-
blockade are Th2 lymphocytes, modulation of the portion of participants achieving PASI75 at week
Th17 cell population with a subsequent decrease 12. These studies were completed in April 2016
in the production of IL-17 production has also and June 2017, respectively, but results of these
been noted [57–59]. This suggests that blockade studies have not yet been published. No clinical
of the H4 receptor in psoriasis may represent a trials testing this compound for the treatment of
novel therapeutic strategy in psoriatic disease. psoriatic arthritis have been reported.
A phase 2 trial for ZPL389, a novel H4 recep-
tor antagonist, involving 129 participants with
moderate-to-severe plaque psoriasis was com- SYK Inhibitors
pleted in December 2016 [60]. Participants were
randomized to either ZPL389 (30 mg daily) or Spleen tyrosine kinase (SYK) is a cytoplasmic
placebo, and the primary endpoint was change in tyrosine kinase (Fig. 23.1) mainly expressed in
PASI score at week 12. Results have not yet been hematopoietic cells. It has crucial T cell, macro-
published for this trial. No clinical trials test- phage, neutrophil, and mast cell functions via the
ing this compound for the treatment of psoriatic IgG and IgE receptors, as well as involvement in
arthritis have been reported. the TLR9-mediated B cell response [64]. It also
demonstrates other diverse functions including
cell adhesion, innate immune recognition, osteo-
IL-20/PRINS Inhibitor clast maturation, and vascular remodeling [65].
Zap70 is a SYK tyrosine kinase essential to T
Psoriasis-associated non-protein coding RNA cell development, the absence of which results in
induced by stress (PRINS) are cytosolic RNA SCID [66].
found in non-lesional psoriatic skin and are pur- SYK inhibition using fostamatinib (a prodrug
ported to oppose chronic inflammation caused by of tamatinib) has been demonstrated as effective
cytosolic DNA fragments [61]. PRINS expres- in rheumatoid arthritis as well as in murine mod-
sion is modified by UVB irradiation, hypoxia, els of psoriasis [67, 68]. Interestingly, tamatinib
and microbial stimulation and interacts with the demonstrates inadequate SYK specificity com-
innate immune response of keratinocytes via pared to fostamatinib. The effect of fostamatinib
IL-6 and CCL-5/RANTES [61]. Compounds that is mediated through suppression of SYK expres-
directly inhibit PRINS are attractive as potential sion in dendritic cells leading to downstream
novel therapies in inflammatory conditions like Th17 pathway downregulation [69]. SYK inhibi-
psoriasis due to their modulation of the inflam- tion has been suggested as a potential therapeutic
matory and immune response. option for lupus, autoimmune thrombocytopenic
300 D. Grand et al.
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required for IL-2-mediated STAT activation. Mol Cell
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est to the field and those studying this class of titis by inhibiting IL-22 and the IL-23/IL-17 axis. J
molecules. Immunol. 2014;193(7):3278–87.
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Research Pipeline II: Upcoming
Biologic Therapies 24
Ahuva D. Cices and Jeffrey M. Weinberg
Abstract
2. To understand the appropriate use

Psoriasis is a chronic inflammatory condition and efficacy of novel biologic agents
mediated by activated T-cells. Cutaneous in development for the treatment of
manifestations of psoriasis have been shown psoriasis
to have a tremendous impact on quality of life, 3. To understand the safety issues and

particularly in patients with moderate to appropriate monitoring of novel bio-
severe disease. Given the high morbidity asso- logic agents in development for the
ciated with psoriasis, disease control is para- treatment of psoriasis
mount. Systemic treatments are indicated for
effective management of cutaneous disease
and the comorbidities that result from chronic
inflammation. Prior systemic treatments were
Introduction
non-specific and associated with significant
side effect profiles. With the development of
Psoriasis is a chronic, inflammatory, multisystem
biologics, treatments have become increas-
disease mediated by activated T-cells with an
ingly targeted and efficacious. This chapter
estimated prevalence of 3.2% of the adult US
will review biologic drugs currently in devel-
population [1, 2]. Comorbidities of psoriasis
opment that may eventually add to the grow-
include psoriatic arthritis, metabolic syndrome,
ing armamentarium of psoriasis treatments.
cardiovascular disease, depression, and impaired
quality of life. While mild to moderate disease
can typically be controlled with topical medica-
tions or phototherapy, traditional treatments are
often insufficient for moderate to severe disease.
of novel biologic agents in development
Topical treatments and phototherapy are limited
for the treatment of psoriasis
by logistic issues related to application and do
not target systemic disease manifestations. In
patients with psoriatic arthritis, systemic treat-
ment preventing irreversible joint destruction is
A. D. Cices · J. M. Weinberg (*) critical.
Department of Dermatology, Icahn School of Prior to the advent of biologics, systemic ther-
Medicine at Mount Sinai, New York, NY, USA apies were non-specific immunosuppressive

https://doi.org/10.1007/978-3-030-54859-9_24
304 A. D. Cices and J. M. Weinberg
agents with toxic side effects. Cyclosporine, p40 in psoriatic lesions, and elevated levels of
methotrexate, and acitretin were the cornerstones serum IL-17 and TNFα in patients with psoriasis
of treatment until our understanding of the under- [6, 7].
lying aberrant pathways allowed for development Granulocyte-macrophage colony-stimulating
of targeted therapies. factor (GM-CSF) has been implicated in main-
Biologics are complex protein based mole- taining positive feedback loops involved in acti-
cules produced by living organisms that are uti- vated T-cell populations in patients with
lized for their ability to target specific genes or autoimmune disease, particularly related to
proteins [3]. The relevant proteins in psoriasis are Il-17A [8]. Programmed cell death- protein 1
interleukins, cytokines involved in cell-to-cell (PD-1) or CD279 is an immune checkpoint that
signaling related to immune cell differentiation, promotes self-tolerance and has been hypothe-
or their receptors. Binding of biologics to these sized to play a role in autoimmune disease includ-
targets allows for specific modulation of the ing psoriasis as demonstrated in a study showing
immune response. decreased levels of PD-1 expression on T-cells of
psoriasis patients compared with healthy controls
as well as case series describing psoriasis flares
Overview of Pathogenesis in patients treated with PD-1 inhibitors [9, 10].
Advances in our understanding of psoriasis at the

molecular level have paved the way for the devel- Overview of Biologic Treatments
opment of targeted and safe biologic therapies.
Studying the complex interactions and signaling TNFα antagonists are the first generation of bio-
between T-cells, dendritic cells, and neutrophils logics widely used in the treatment of psoriasis.
with keratinocytes has been integral to the devel- While anti-TNFα therapies are effective treat-
opment of novel effective psoriasis therapies. ments for psoriasis, they are not without risk.
Psoriatic disease is initiated by the interaction Due to the broad activity of TNFα throughout the
of self-nucleotides and innate antimicrobial pep- immune system, TNFα inhibitors have signifi-
tides with toll-like receptors of plasmacytoid cant side effects including increased risk for TB
dendritic cells resulting in production of type I reactivation, infections, and certain malignancies
interferons, which then stimulate myeloid den- [4]. Meta analysis of rheumatoid arthritis patients
dritic cells to secrete cytokines including tumor treated with anti-TNFα therapies showed
necrosis factor alpha (TNFα), interleukin 12 (IL- increased risk of serious infections and a dose-
12), and interleukin 23 (IL-23) [4, 5]. Dendritic depended increase in malignancy; however, meta
cells bridge the innate and adaptive immune sys- analysis of psoriasis patients treated with anti-
tem by promoting T-helper 1-cell and T-helper TNFα therapies showed a small increased risk of
17-cell (Th17) differentiation through activation infection without increased risk of serious infec-
of innate pathways. TNFα, IL-23, and interleukin tions or malignancy, suggesting that some of the
17 (IL-17) promote inflammatory pathways and risks associated with TNFα antagonists may be
amplification of these responses. IL-23 stimu- specific to rheumatoid arthritis populations [11,
lates hyperproliferation that is a hallmark of pso- 12]. Second generation biologics for psoriasis
riasis by inducing differentiation and survival of that target IL-17 and IL-23 have improved effi-
Th17 cells, maintaining a favorable cytokine cacy and safety profiles with increased risk of
milieu. Clinical studies supporting the integral some non-serious infections, but importantly
role of these inflammatory mediators include without increased risk of malignancy or serious
increased expression of IL-23 subunits p19 and infections [1].
24 Research Pipeline II: Upcoming Biologic Therapies 305
Clinical Trial Background a fixed variable correlated to the BSA of the rep-
resentative region. The sum of these scores from
Clinical trials consist of organized, prospective, each region yields the PASI score, which can
exposures of patients to interventions [13]. In range from 0 (no active disease) to 72. Clinical
order for a new drug to be marketed in the United trials for biologics tested in moderate to severe
States, the U.S. Food and Drug Administration populations typically include inclusion criteria of
(FDA) must approve the drug after careful review BSA ≥10% and PASI ≥12. In clinical trials per-
of pre-clinical and clinical tests, including Phase cent of improvement in PASI score is used to
I-III studies. assess efficacy, with many of the newer drugs
Phase I studies are initial human studies achieving high rates of PASI 90 (90% improve-
designed to document initial safety data. In these ment in PASI score at a given time point from
studies, investigational drug is given to a small baseline) and even PASI 100 (no residual
number of people, typically 20–80 patients or disease).
healthy volunteers, to evaluate preliminary safety Physician’s global assessment (PGA) or inves-
and dosing. tigator’s global assessment (IGA) is a useful tool
Phase II studies evaluate the effectiveness of a for measuring cutaneous psoriatic disease activ-
drug for a specific medical indication. Typically ity in clinical trials. It allows for a quick, but sub-
these studies consist of several hundred patients jective method of stratification based on overall
and look at the effect of treatment on clinical out- severity without taking into account the affected
comes as well as side effects. Ideally, phase II BSA. There are multiple versions of the scale
studies are double blind and placebo controlled. which utilize variations in the criteria for each
Phase III studies are conducted for experimen- score [14]. The IGA mod 2011 scale is a 5 point
tal drugs with evidence of efficacy in previously scale commonly used in psoriasis clinical trials,
completed phase II trials in order to gather addi- the scores are designated as follows: 0 (clear), 1
tional evidence of efficacy and safety. These are (almost clear), 2 (mild), 3 (moderate), and 4
randomized clinical trials conducted in large (severe). Inclusion criteria for psoriasis studies
populations (often >1000 patients) to further evaluating patients with moderate to severe pso-
evaluate efficacy and safety. Typically, at least riasis require a PGA/IGA score of 3 or 4 and
two successful phase III clinical trials demon- treatment success is defined by the FDA as a
strating adequate efficacy and safety are required PGA/IGA score of 0 or 1 with at least 2 grade
by the FDA prior to approval. improvement from baseline.
Standardized measurements are utilized in American College of Rheumatology (ACR)
clinical trials to allow for consistent comparison score is an instrument specifically developed for
of data across studies. The Psoriasis Area and rheumatoid arthritis and extended for use in pso-
Severity Index (PASI) serves as the gold standard riatic arthritis, which is utilized in rheumatologic
for measuring disease activity. PASI score takes clinical trials as a measure of disease activity in
into account the affected body surface area (BSA) inflammatory arthritis. ACR measurement incor-
as well as severity of lesions. Lesions are assessed porates number of tender or swollen joints, phy-
separately over four body regions: the head and sician global assessment of disease severity,
neck, upper extremities, trunk, and lower extrem- patient global assessment of disease severity,
ities. Average intensity of erythema, thickness, patient reported functional ability, patient
and scale is graded in each of the four locations reported visual analogue pain scale, and acute
from 0 (none) to 4 (very severe). Within each phase reactants, namely erythrocyte sedimenta-
region, the severity sum is multiplied by an area tion rate (ESR) and C-reactive protein (CRP).
score based on the affected BSA and adjusted by Improvement is measured by the percent
improvement in number of tender or swollen cebo dosed every 4 weeks [17]. Primary endpoint
joints as well as at least 3 out of 5 of the above of PASI 90 at week 12 was achieved in signifi-
criteria. Previous biologics were considered suc- cantly more patients in all bimekizumab treated
cessful with achievement of ACR 20, while many groups (46.2–79.1%) compared with placebo
newer medications are evaluating treatment suc- (0%) (p < 0.0001) [17]. Also seen across all doses,
cess with ACR 50. were significant improvements (p ≤ 0.0003) in all
secondary endpoints compared to placebo, which
included PASI 90 at week 8, PASI 75 at week 12,
Psoriasis Biologics Pipeline PASI 100 at week 12, and IGA 0/1 at weeks 8
and 12. Three serious TEAEs were reported in 2
IL-17 patients, however they were not considered related
to study treatment (viral meningitis in a patient on
Bimekizumab/UCB4940 is a humanized mono- placebo and a large intestinal polyp/colon cancer
clonal IgG1 antibody targeting IL-17A and in a subject 15 days after initiating treatment with
IL-17F being studied as a treatment for chronic bimekizumab 480 mg). There were no unexpected
plaque psoriasis, psoriatic arthritis, ankylosing safety signals: common TEAEs occurring in >5%
spondylitis, non-radiographic axial spondyloar- of bimekizumab treated subjects included naso-
thritis, hidradenitis suppurativa, and rheumatoid pharyngitis, upper respiratory infections, arthral-
arthritis. A phase I placebo-controlled, dose- gia, elevated GGT, tonsillitis, oral candidiasis,
escalating study (NCT02529956) in 39 subjects headache, leukopenia, vomiting, and neutropenia.
with mild to moderate psoriasis showed efficacy No subjects in the placebo group had neutropenia,
of bimekizumab compared to placebo in treat- while five subjects receiving bimekizumab had
ment of mild to moderate psoriasis with dose- transient, non-serious neutropenia that resolved
dependent improvements in PASI and PGA spontaneously and did not interrupt treatment.
following a single dose of intravenous bimeki- Maintenance of response through week 60 was
zumab at doses ranging from 8 to 640 mg [15]. seen in the phase II extension study BE ABLE 2
Statistically significant clinical improvement was (NCT03010527) with PASI 90 in 80–100% and
seen as early as week 2, with maintenance of near PASI 100 in 70–83% of study subjects [18]. No new
maximal response through weeks 12–20 (depend- safety signals were identified, and consistent with
ing on endpoint) following a single IV dose previous data oral candidiasis and nasopharyngi-
≥160 mg. No unexpected safety signals and simi- tis were the most commonly occurring treatment
lar numbers of treatment emergent adverse events emergent adverse events. The phase II psoriatic
(TEAE) were observed in bimekizumab and pla- arthritis BE ACTIVE study (NCT02969525) ran-
cebo treated groups. PA007, a phase I placebo- domized 206 adults with active psoriatic arthri-
controlled study (NCT02141763) in 53 subjects tis 1:1:1:1:1 to one of four bimekizumab doses
with psoriatic arthritis, that compared five dos- (16 mg, 160 mg, 160 mg with 320 mg loading, or
ages of bimekizumab (240 mg/160 mg/160 mg; 320 mg) or placebo administered every 4 weeks.
80 mg/40 mg/40 mg; 160 mg/80 mg/80 mg and After week 12, subjects administered placebo and
560 mg/320 mg/320 mg) administered at weeks 0, the lowest bimekizumab dose were re-randomized
3 and 6 demonstrated efficacy in treatment of and maintained through week 48. The primary
arthritis and skin lesions with an ACR 20 in 80% outcome of ACR 50 at week 12 was achieved in
and PASI 100 in 86.7% of subjects in the top 3 significantly more subjects treated with 16 mg
doses at week 8 compared to 16.7 and 0% respec- bimekizumab (OR 4.2, p = 0.032), 160 mg bime-
tively in placebo treated subjects [16]. kizumab (OR 8.1, p = 0.012), and 160 mg bime-
In the 12 week, phase II BE ABLE 1 trial kizumab with loading dose (OR 9.7, p = 0.0004)
(NCT02905006) subjects were randomized compared to placebo.
1:1:1:1:1:1 to 64 mg, 160 mg, 160 mg with Multiple phase III studies for bimekizumab in
320 mg loading dose, 320 mg, 480 mg, or pla- the treatment of moderate to severe chronic
plaque psoriasis are underway and have shown bimekizumab to adalimumab with placebo con-
promising preliminary results with all three stud- trol though week 16.
ies achieving the co-primary endpoints of PASI Netakimab/BCD-085 is a humanized mono-
90 and IGA 0/1 with at least two-grade improve- clonal antibody to IL-17 developed and approved
ment and with a safety prolife similar to that in Russia for treatment of moderate to severe
demonstrated in the BE ABLE studies [19]. The plaque psoriasis based on favorable results in the
BE VIVID 52 week study (NCT03370133) ran- phase II BCD-085-2 study (NCT02762994) with
domized 570 subjects to bimekizumab, low dose long-term extension and phase III BCD-085-7/
ustekinumab if weight ≤100 kg, high dose PLANETA study (NCT03390101) conducted in
ustekinumab if weight >100 kg, or placebo, with Russia. Results have not been published, but a
subjects randomized to placebo crossed over to press release from the company show PASI
bimekizumab after week 16. Bimekizumab was 75/90/100 in 83%/92%/59% of subjects at week
superior to ustekinumab and placebo in achiev- 12 respectively [20, 21]. Netakimab is also being
ing PASI 90, PASI 100, IGA 0, and IGA 1. The evaluated for the treatment of ankylosing spon-
56-week BE READY study (NCT03410992) ran- dylitis, psoriatic arthritis, and primary biliary
domized 435 subjects to bimekizumab or placebo cholangitis.
for an initial 16-week treatment period followed Vunakizumab/SHR-1314 is a humanized
by a randomized withdrawal period through IL-17A inhibitor under development for psoriasis
week 56. All ranked secondary endpoints were and axial spondyloarthritis. Preliminary safety
met notably PASI 100 at week 16, patient reported was established in healthy adults in a phase I study
itch, pain and scaling, and scalp IGA 0/1 superior (NCT02934412) with doses ranging from 20 to
to placebo. The BE SURE 56-week study 240 mg. A second phase I study (NCT03710681)
(NCT03412747) randomized 480 subjects to one is underway, comparing 160 and 240 mg admin-
of two bimekizumab regimens or adalimumab istered every 2 weeks for 168 days in subjects
for 24 weeks, followed by a dose-blind mainte- with moderate to severe plaque psoriasis. A mul-
nance through week 56. All ranked secondary tiple dose, escalating design, combined phase I
endpoints were achieved, including statistically and phase II study (NCT03463187) is ongoing
significant superior PASI 75 at week 4 and PASI for moderate to severe plaque psoriasis and an
100 at weeks 16 and 24 compared to adalim- upcoming phase II study (NCT04121143) will
umab. Given the positive results from these phase compare low dose short interval, high dose long
III studies, plans are underway for bimekizumab interval, high dose short interval, and placebo
to be submitted for FDA approval in mid-2020. for 16 weeks in subjects with moderate to severe
Additional continuing studies evaluating psoriasis.
bimekizumab for the treatment of moderate M1095/ALX-0761/MSB0010841 is a triva-
to severe psoriasis include the following: BE lent monomeric nanobody specific for IL-17A,
RADIANT (NCT03536884), comparing two IL-17F, and human serum albumin allowing for
bimekizumab doses and secukinumab with a pri- increased circulation time in the bloodstream
mary endpoint of PASI 100 at week 16, a phase [22]. Data from a recently completed phase I
III long-term extension study (NCT03598790) placebo-controlled, dose escalation 6 week study
comparing two bimekizumab doses through week (NCT02156466) showed promising results [22].
160, and a phase III study (NCT03766685) com- 44 subjects with moderate to severe psoriasis
paring bimekizumab administered by auto injec- were randomized 4:1 to 30 mg, 60 mg, 120 mg or
tor or syringe. Ongoing studies for bimekizumab 240 mg M1095 or placebo administered subcuta-
in the treatment of psoriatic arthritis include the neously bi-weekly. A dose response relationship
phase II long term extension study BE ACTIVE 2 was observed. In the 240 mg cohort, all subjects
(NCT03347110), a phase III, placebo-controlled achieved PASI 90 and 56% of subjects achieved
study BE VITAL (NCT03896581), and another PASI 100 at day 85. The most common TEAEs
phase III study (NCT03895203) comparing were pruritus and headaches. 2 patients withdrew
due to adverse events, one due to an injection site with results expected in the near future. OASIS-3
reaction and another due to transaminitis. An (NCT03556202) is an open label extension study
upcoming placebo-controlled, active comparator currently underway comparing two different
(secukinumab) phase II study (NCT03384745) mirikizumab doses for 208 weeks.
will compare 30 mg every 4 weeks, 60 mg every
4 weeks, 120 mg every 8 weeks, and 120 mg
every 4 weeks subsequent to a loading dose. Miscellaneous
ABY-035/AFO2 is a novel multivalent and
specific molecule targeting both IL-17A subunits CC-90006 is a PD-1 agonist antibody in the ini-
as well as albumin. Favorable safety and tolera- tial stages of development. A phase I study
bility was established across multiple doses and (NCT03337022) for treatment of mild to moder-
dosing regimens in healthy volunteers and psori- ate plaque psoriasis was recently completed. The
asis subjects in an initial phase I/II study study consists of 40 subjects divided into 4
(NCT02690142) [23]. A two cohort phase I trial cohorts of 10 patients with escalating doses
(NCT03580278) evaluating 75 mg daily for administered at weeks 0, 2, and 4. Data has not
14 days or 150 mg daily for up to 28 days in pso- yet been released, but continued development is
riasis subjects is ongoing. Encouraging interim underway [25].
results have been reported in the AFFIRM-35 Namilumab/MT203/AMG203 is an IgG1 kappa
phase II trial (NCT03591887), in which subjects monoclonal antibody targeting GM-CSF being pur-
with moderate to severe psoriasis were random- sued as a novel treatment for psoriasis, rheumatoid
ized 1:1:1:1:1 to 2 mg, 20 mg, 80 mg, 160 mg or arthritis, and axial spondyloarthritis. Safety was
placebo administered subcutaneously every established in a phase I, placebo controlled study
2 weeks for 12 weeks followed by dose adjust- (NCT02354599) in healthy Japanese and Caucasian
ments and re-randomization after week 12 [23]. adult men. The NEPTUNE phase II placebo con-
trolled, proof of concept study (NCT02129777)
randomized 122 subjects with moderate to severe
IL-12/23 psoriasis to 20, 50, 80, or 150 mg subcutaneous
namilumab [26]. The number of subjects in all
Promising results have been shown with miriki- groups achieving the primary endpoint of PASI 75
zumab, a humanized IgG4 monoclonal antibody at week 12 was low in all cohorts, with no clinical
to the p19 subunit of IL-23, which is being tested significance between groups and similar results for
for treatment of moderate to severe psoriasis as other assessments. Given the results of the phase II
well as inflammatory bowel disease. In AMAF, a study, which suggest that namilumab inhibition
placebo controlled phase II trial (NCT02899988) does not inhibit pathogenic inflammatory processes
evaluating single doses of subcutaneous miriki- of psoriasis Namilumab is no longer being studied
zumab in subjects with moderate to severe psori- in psoriasis.
asis at weeks 0 and 8, the percentage of patients
meeting the primary objective of PASI 90 at week
16 compared to placebo was clinically significant Summary
in all tested doses with rates of 0, 29, 59 and 67%
for subjects treated with placebo, 30, 100, and Psoriasis is a multi-system disorder that is not
300 mg respectively [24]. Risk of adverse events skin-limited and often has significant effects on
was not elevated in subjects treated with miriki- patient quality of life. Recent advances in immu-
zumab compared to placebo. Pivotal phase III nology have vastly expanded our comprehension
studies OASIS-1/AMAK (NCT03482011) and of psoriasis. Identifying key mediators of cell
OASIS-2/AMAJ (NCT03535194), which com- signaling pathways associated with pathogenic
pared mirikizumab to placebo and secukinumab subsets of T-cells paved the way for the develop-
or placebo respectively, have been completed, ment of novel therapies, namely biologics. These
medications are remarkably effective and safe infections and malignancies: systematic review and
meta-analysis of rare harmful effects in randomized
due to their specificity. New therapeutic targets controlled trials. JAMA. 2006;295(19):2275–85.
will continue to emerge as our understanding of 12. The safety of tumor necrosis factor antagonists in
psoriasis continues to increase, and may include patients with psoriatic disease: a systematic review
innate immune pathways or genetic predisposi- and metaanalysis of randomized controlled trials. J
Am Acad Dermatol. 2011;64(2):AB8.
tions. The development of novel psoriasis treat- 13. Junod SW. FDA and clinical drug trials: a short his-
ments will continue to produce highly effective tory FDA. Available from https://www.fda.gov/
and safe medications. media/110437/download.
14. Langley RG, Feldman SR, Nyirady J, van de Kerkhof
P, Papavassilis C. The 5-point Investigator’s Global
Assessment (IGA) Scale: a modified tool for evalu-
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Pediatric Psoriasis
25
Starling Tolliver, Amber N. Pepper,
Salma Pothiawala, and Nanette B. Silverberg
Abstract erally requires a global approach including

identifying infectious triggers, addressing
Psoriasis is a chronic multi-system inflamma-
health risks including obesity, and psychologi-
tory condition with an autoimmune compo-
cal support. Prescription care includes appli-
nent. One-third to one-half of cases have onset
cation of mid-potency topical corticosteroids
in childhood. There are a variety of pediatric
and/or calcipotriene, phototherapy with
variant types of psoriasis, including general-
Narrowband UVB or excimer laser. In severe
ized disease, that is similar to adult psoriasis,
cases, cyclic prescribing of systemic agents
and types distinctive to childhood, including
for 6–12 months including methotrexate,
diaper involvement and pityriasis amiantacea.
cyclosporine, etanercept, adalimumab, and
Pediatric psoriasis is associated with infec-
recently approved agents ixekizumab and
tious triggers and exacerbation by the Koebner
ustekinumab can aid in disease clearance with
phenomenon. Children with psoriasis may
minimization of side effects. Emerging stud-
have more of a tendency toward obesity as
ies for the efficacious and safe use of biologics
reflected by a large waist circumference. More
in children broaden treatment options for
extensive disease in childhood is associated
managing severe psoriatic disease early.
with a poor quality of life, anxiety, and depres-
sion. Therapeutics of pediatric psoriasis gen-
1. To understand the clinical presentation
of psoriasis in the pediatric population
S. Tolliver · N. B. Silverberg (*)
Department of Dermatology, Icahn School of 2. To understand the therapeutic manage-
Medicine at Mount Sinai, New York, NY, USA ment of psoriasis in the pediatric
e-mail: [email protected]; population
[email protected] 3. To understand the specific safety con-
A. N. Pepper cerns in the management of psoriasis in
Department of Internal Medicine, USF Health the pediatric population
Morsani College of Medicine, Tampa, FL, USA
S. Pothiawala
Department of Dermatology and Cutaneous Surgery,
University of South Florida, Tampa, FL, USA

https://doi.org/10.1007/978-3-030-54859-9_25
312 S. Tolliver et al.
Introduction cal problem in the pediatric population. These

data likely represent under reported incidences
Psoriasis is a chronic inflammatory disorder, secondary to potential disparities in access to
believed to have an autoimmune basis. It is char- care, mild undertreated disease, misdiagnoses,
acterized by aberrant T cell activity causing and racial disparities in patient reporting [17].
hyperproliferation of epidermal keratinocytes, The peak age of onset varies in the literature,
with development of erythematous skin plaques but usually ranges anywhere between 2 and
covered by a silvery or micaceous scale [1, 2]. 11 years of age [1, 3, 8, 9]. The mean age at diag-
Pediatric psoriasis differs from adult onset psori- nosis has been reported to be between 10 and
asis in types of environmental triggers, with 11 years of age by a recent large population-
trauma, stress, and bacterial infection being the based study [10]. Onset may occur slightly ear-
most common pediatric disease triggers [1, 3], lier for females [18], although studies have shown
while drug-reactions, smoking, alcohol use, and nearly equal male to female prevalence ratios [8,
underlying HIV infection are triggers more com- 9, 11]. Onset may also occur earlier in those with
mon in adulthood [4]. Recently, obesity and the a positive family history of psoriasis [18].
metabolic syndrome have been linked to both Table 25.1 shows a review of worldwide presen-
pediatric and adult psoriasis [5]. Treatment tation of pediatric psoriasis.
options are similar for adult and pediatric psoria- The annual incidence of psoriasis has been
sis patients, although therapy selection for pedi- shown to be increasing, nearly doubling (from
atric psoriasis varies according to patient age and 29.6 cases per 100,000 to 62.7 cases per 100,000)
is limited by the fact that systemic treatments for from 1970 to 2000 in both pediatric and adult
pediatric psoriasis are off-label. patients [10, 19]. Recent studies in the United
In the United States, high-potency topical cor- States have reported a prevalence of mild and
ticosteroids were the most frequently prescribed moderate-to-severe pediatric psoriasis to be 128
outpatient treatment for pediatric patients overall per 100,000 and 16 per 100,000 respectively
from 1979 to 2007 [6]. Few therapies for psoria- [20]. Plaque psoriasis (Figs. 25.1 and 25.2) is the
sis are approved by the FDA for the pediatric age most common variant, occurring in 34–74% of
group, and drug dosages must be altered based on children, with the majority of lesions localized to
weight and/or age in children. However, with the extensor surfaces of elbows and knees, scalp,
emerging data on the safety and efficacy of these face (Fig. 25.3), trunk, and posterior auricular
therapies for pediatric patients, this is changing. region (Table 25.1) [8–11, 22]. Guttate psoriasis
This chapter will explore the epidemiology, is more common in pediatric patients, occurring
pathogenesis, diagnosis, and therapeutic man- in approximately 6–33% of cases of pediatric
agement options of pediatric psoriasis, with a psoriasis (Fig. 25.4) [1, 18]. Pustular disease, is a
special focus on aspects of the disease specific to relatively uncommon presentation in children,
the pediatric patient. however, a Turkish group reported 13% of their
pediatric patients had pustular lesions [1, 8].
A single study from Greece sited 8% of chil-
Epidemiology (Table 25.1) dren as having erythroderma [24] however, most
studies demonstrate that <1% of children pres-
Psoriasis vulgaris is a common dermatologic dis- ent this way [3, 8, 16, 18]. Glossitis and mucosal
order, affecting 3.15% of the United States popu- diseases are uncommon in childhood [1, 3, 8,
lation and 1.5% of the population in the United 16, 18].
Kingdom [14, 15]. Onset occurs before 16 years In infants and toddlers (less than 2 years old),
of age in approximately one third of all cases [7, psoriatic diaper rash is the most common presen-
16], making psoriasis a significant dermatologi- tation sometimes involving the intertriginous
Table 25.1 Worldwide demographics of pediatric psoriasis
Sex
distribution Ages of kids
Number of (M:F and Race and or (range, median, Areas of
Author, year Country kids %M; %F) ethnicity mean) Types of psoriasis (%) involvement Triggers Family history
Seyhan et al. Turkey 61 1:1.7 Not discussed Onset mean Plaque 54% (At onset) URTI 15% 23%
2006 [1] 38; 62 (Turkish) 6.9 ± 4.1 Guttate 33% Trunk 44% +Group B
25 Pediatric Psoriasis
At time of Pustular 13% Scalp 36% strep culture

study Inverse 7% Extremities 21%
10.0 ± 4.1 Erythrodermic 3% 54%
Palmoplantar 2% Diaper rash
5%
Nails 21%
Kumar et al. India 419 1.1:1 Not discussed Onset mean Plaque 61% (At onset) Only recalled 4.5%
2004 [3] 52; 48 (Indian) 9.1 overall Guttate 10% Trunk 8% by 7% of
(M) 8.1 ± 2.1 Pustular <1% Extremities participants
(F) 9.3 ± 2.3 Inverse <1% 35% Trauma 14 pts
Range 4–14 Erythrodermic 1% Scalp 21% Throat
Palmoplantar 6% Soles 19% infection ten
Plantar 13% Palms 3% patients
Nails 3% Psych 3 pts
Drug rxn 1 pt
Raychaudhuri USA 223 1:1.3 Not discussed Not discussed Not discussed (At onset) Trauma 50% 68%
and Gross 2000 44; 56 Scalp 57% Stress 50%
[7] Trunk 14% Pharyngitis
Extremities 28%
52%
Face 9%
Nails 13%
Fan 2007 [8] China 277 1:1.1 Not discussed Median age of Plaque 69% (At onset) Not discussed 8% (7 1st, 1
47; 53 (Chinese) onset 10 Guttate 29% Scalp 47% 2nd)
Range: Pustular 1% Face 20%
9 months to Erythroderma 1% Trunk 43%
15 years Arms 51%
Legs 66%
Nail 6%
Palmoplantar
37%
313
(continued)
314
Sex
distribution Ages of kids
Number of (M:F and Race and or (range, median, Areas of
Author, year Country kids %M; %F) ethnicity mean) Types of psoriasis (%) involvement Triggers Family history
Kwon 2011 [9] Korea 358 1.1:1 Not discussed Mean age Plaque 67% Trunk 70% Not discussed 32%
51; 49 onset: Guttate 18% Legs 65%
10.5 ± 4.3 Generalized pustular Arms 48%
pustulosis 7% Face 46%
Palmoplantar 4% Palms/soles
Erythroderma 1% 22%
Tollefson 2010 USA 357 1:1.1 Mostly Median age of Plaque 74% Scalp 47% Not discussed Not
[10] 48;52 Caucasian but onset 10.6 Guttate 14% Extremities discussed
not specified Range Sebo-psoriasis 8% 60%
6.8–14.4 Pustular 1% Palms/soles
5%
Trunk 35%
Face 18%
Genital/groin
9%
Nails 17%
Morris 2001 Australia 1262 1:1.1 Not discussed No median or Plaque 34% Face 38% Not discussed 71% (based
[11] 47;53 mean Scalp 12% Otherwise not on 61% who
described Diaper rash 13% discussed responded)
Range: Guttate 6%
1 month to Face only 4%
15 years Pustular <1%
Nail <1%
Erythrodermic <1%
S. Tolliver et al.
Vogel 2012 [6] USA 3.8 million 1:1 Race Mean age at Not discussed (NB: Not discussed Not discussed Not
outpt 50;50 White 93% visit 11.3 article discusses discussed
VISITS for Black 3% outpatient visits and
ped Asian/ treatment choices, not
psoriasis Pacific individual patients)
Islander 3%
American
Indian/
Eskimo/
Aleut 0.5%
Ethnicity
85%
non-
Hispanic
8% Hispanic
7% other
Wu 2011 [12] USA 1361 1:1.2 Non-Hispanic 11.8 ± 4.4 in Not discussed Not discussed Not discussed Not
45; 55 white 38% M discussed
Hispanic white 12.5 ± 4.4 in F
38%
Black 3%
Asian or
Pacific Islander
7%
Others 3%
Stefanaki 2011 Greece 125 1.4:1 81% Greek Peak age of Plaque 57% Extremities Not discussed 16%
[13] 59; 41 onset 9–10 grp Scalp? 34% 56%
Range: Guttate 12% Scalp 48%
<1–13 years Flexural 10% Trunk 47%
No mean or Erythrodermic 8% Nails 10%
median given Nails only 5%
315
Fig. 25.3 Facial psoriasis can be a challenging condition

due to the combination of disfigurement, psychological
distress and limitations of therapy on the thin-skinned
face
Fig. 25.1 Untreated plaque psoriasis affecting the trunk

with large circinate plaques with overlying micaceous
scale (Reprinted with permission from Silverberg [21])
Fig. 25.2 Close-up of plaque with micaceous scale dem-

onstrates areas of Auspitz sign, pinpoint bleeding due to
manual removal of scale
neck and axillary areas (Fig. 25.5) [11, 22].

Psoriasis presenting in infancy has a better prog-
nosis for long-term remission than childhood
psoriasis [24]. Involvement of the folds, i.e. Fig. 25.4 Guttate psoriasis of the trunk in a child with
inverse psoriasis, is an uncommon appearance in psoriasis flared by an upper respiratory infection (Taken
older children. Inverse psoriasis in any age group from Silverberg [23] with permission)
can be exacerbated by concurrent cutaneous
overgrowth of streptococcal, staphylococcal and Nail psoriasis can arise in the setting of
candidal species. plaque-type psoriasis, psoriatic arthritis, or with
25 Pediatric Psoriasis 317
point toward a psoriatic etiology of arthritis in

affected children [30]. As many as 25% of
patients with psoriatic arthritis have joint damage
by 5 years after symptoms begin, thus early
screening and treatment is important [31].
Pediatric psoriasis has been shown to nega-
tively affect quality of life. The psychological
impact of skin disease is becoming an important
area of research with some studies reporting
prevalence rates as much as 70% [32]. Studies
have shown that cutaneous diseases such as,
Fig. 25.5 Inverse psoriasis in an infant (Taken from atopic dermatitis, psoriasis and urticaria have a
Silverberg [23] with permission) direct impact on psychological well-being [33].
Pediatric patients with psoriasis are increasingly
isolated nail disease. This manifestation can be being found with higher rates of depression, anx-
found in as many 16–32% of pediatric patients iety, and even bipolar disorder in some studies
[25, 26]. It is associated with male sex and higher [34]. One study showed a 9- and 6-fold risk for
disease burden at onset as well as follow-up [25, anxiety and depression respectively verses
26]. Nail disease may also suggest a more morbid healthy controls [32]. The psychological stress
disease course for patients [25]. Common fea- caused by psoriasis may even be significantly
tures include nail pitting on the fingernails while higher than other chronic cutaneous diseases.
onycholysis and pachyonychia were found on the Multiple studies have determined depression to
toenails [25]. Psoriatic arthritis with active joint be higher in patients with psoriasis compared to
involvement is less common in childhood than atopic dermatitis [33, 35]. This may be more pro-
adulthood, but should remain in the differential nounced in younger children who have less
for children with arthritis [3]. In the majority of developed coping mechanisms [36]. Mounting
children, dermatologic manifestations precede pressures within their social circles and decreased
the onset of psoriatic arthritis [27]. levels of maturity may increase the risk of lower
There is a bimodal age of psoriatic arthritis quality of life [32]. Children with moderate-to-
onset with peaks during the first few years of life severe psoriasis have similar health-related qual-
and in early adolescence [28]. Skin manifesta- ity of life as compared to children with arthritis
tions are often established before joint involve- or asthma, but worse than children with diabetes
ment [22]. The early onset form of psoriatic [37]. Adult females with psoriatic arthritis suffer
arthritis is most likely to be polyarticular, ANA greater disability than their male counterparts,
(antinuclear antibody) positive, and favors the but no gender differences have been reported in
female sex [29, 30]. The adolescent-onset form children thus far [32, 38]. Impairment in quality
of psoriatic arthritis has a higher incidence of of life is also described in families with children
axial joint involvement and favors the male sex. who have psoriasis [39]. This phenomenom is
The proximal and distal interphalangeal joints of likely multifactorial with emotional well-being
the hand, knees, and ankles are most commonly and burden of care being the factors with the
involved initially. Children often present with oli- most impact [39, 40].
goarthritis, which may progress to polyarthritis; There is current debate on the role psychiatric
dactylitis can be associated. Psoriatic arthritis can disorders play in the development of psoriasis.
be differentiated from idiopathic juvenile rheu- Some studies have shown distress as an impor-
matoid arthritis by the presence of blue discolor- tant trigger in the onset as well as exacerbating
ation of the joints, nail pitting and/ or nail factor in leading to psoriatic lesions [32, 41]. One
dystrophy [27]. Predominant involvement of the paper described an association between other
wrists and small joints of the hands and feet also autoimmune diseases and schizophrenia suggest-
ing potential shared genetic risk factors in the interact with the susceptibility alleles, cyclindro-
development of both diseases [42]. The gene matosis gene, CYLD; and transglutaminase 5,
implicated in this pathogenesis is EPHB4, a TGM5 [48]. Other genes that have been impli-
transmembrane receptor that has activity in regu- cated include IL12-B9 (1p31.3); IL-13 (5q31.1);
lating cell migration with multiple roles in IL-23R (1p31.3); HLABW6; PSORS6, signal
immune cells and neuronal pathways [42]. transducer and activator of transcription gene 2
Lower psoriatic incidence has been noted in STAT2 and IL-23A (12q13.2); tumor necrosis
Inuit people; the single most prominent ethnic factor α-induced protein 3, TNFAIP3 (6q23.3);
variation that has been noted. This information and TNFAIP3 interacting protein 1, TNIP1
suggests that diets high in omega-3 fatty acids (5q33.1) [46]. The gene PSORS1 within HLA-C
may be protective against the development of and PSORS2 (17q24-q25) have also been impli-
psoriasis [43]. New studies on ethnic variations cated as increasing the risk for psoriasis develop-
have suggested Asians and Hispanics are more ment [49, 50]. Yet another gene, PSORS6
likely to have pustular and erythrodermic psoria- (19p13), has been shown to interact with PSORS1
sis as compared to their Caucasian counter parts [49]. SCL12A8, which belongs to the solute car-
[44]. The authors suggested these differences are rier gene family, has also been named as a sus-
associated with socioeconomic disparities ceptibility gene [48]. The role of these genes is
between these ethnic groups which may allow for regulation of Th2 and Th17 lymphocyte activity
more severe presentations of disease [44]. One as well as the NF-κB signaling pathway, which
study of children in southern California found the indicates both Th2 and Th17 cells may play a role
highest prevalence of pediatric psoriasis to be in in the pathogenesis of psoriatic disease.
non-Hispanic whites and the lowest but not neg- Collections of Th17, Th2 and Th1 cells have been
ligible incidence in blacks. Also, of note, a lower found in psoriatic skin lesions [46, 51]. It is theo-
overall prevalence was noted than historically rized interactions among these cells, along with
would be seen in other areas of the country. The dendritic cells and neutrophils lead to the release
authors speculated that increased sunlight expo- of cytokines, like IL-17 and IL-23, which causes
sure and a lower population-based proportion of hyperproliferation of keratinocytes and the
non-Hispanic whites may have led to this obser- release of proinflammatory factors within the
vation [12]. skin [52].
New susceptibility genes are continually
being discovered. Additionally, it appears that
Pathogenesis susceptibility genes for psoriasis may overlap
with other autoimmune disorders. For example,
Although the exact pathogenesis of psoriasis has the genes IL-12B and IL-23R are shared with
not yet been revealed, it is clear that both genetic Crohn’s disease and IL-23R is shared with ulcer-
and environmental factors play a role in the ative colitis. Patients with Crohn’s disease are
development of psoriasis. A positive family his- five times more likely to develop psoriasis as
tory is present in 23–71% of pediatric psoriatic compared to the general population, a fact that
cases [1, 11, 45]. There is a higher rate of con- may be explained, as least in part, by shared sus-
cordant psoriasis in identical as compared to fra- ceptibility genes [46]. Decreased expression of
ternal twins (65–72 vs. 15–30% respectively) the CD18 gene, mutations in which result in leu-
[46, 47]. kocyte adhesion deficiency type I, may also be
Psoriasis vulgaris cannot be linked to a single low in certain patients with psoriasis [53].
gene. It appears that several genes may play a Another example includes the gene CARD14
role in the genetic susceptibility of psoriasis, which involves the NF-κB signaling pathway.
most notably HLA-Cw6 [46]. HLA-Cw6 may This aberrant gene is evident in chronic condi-
tions such as psoriasis vulgaris, pityriasis rubra Table 25.2 Suggested work-up for children with psoria-
pilaris, and pustular psoriasis [54, 55]. These dis- sis (Wolverton [62])
eases, especially pityrisiasis rubra pilaris and At onset:
psoriasis vulgarius, share similar clinical mani- Throat culture or ASO (especially in guttate psoriasis)
festations that are distinguishable histologically Biopsy in atypical cases
Annually:
[54]. Conversely, a gain of function mutation in
Joint evaluation (referral to rheumatology for specific
CARD14 is associated with developing psoriasis symptoms)
while a loss of function mutation in the same Cardiac markers: weight, height, body mass index,
gene is associated with developing atopic derma- blood pressure, lipid profile (cholesterol, triglyceride)
titis [56]. Although no studies have shown a dif- Optional evaluations:
ference in the genetics of pediatric-onset psoriasis Cultures of macerated or crusted lesions for diagnosis
as compared to adult-onset psoriasis, preliminary of superinfection (bacterial culture, fungal culture)
Celiac panel for children with stomach symptoms,
studies have shown differences in inflammatory difficulty with clearance or severe disease
composition in adults and pediatric patients [57]. Thyroid screen for co-morbid arthritis or vitiligo and
Additional genes such as IL36RN in generalized in symptomatic cases
pustular psoriasis is a growing area of research. Screening for medications (co-manage with
This gene is an inhibitor of IL-36a, IL-35B, and rheumatology when arthritis suspected):
IL-36y via competitive binding to the IL1RL2 Cyclosporine: blood pressure, complete blood count,
complete metabolic profile, urinalysis, magnesium,
receptor which leads to downstream inhibitor fasting lipid profile (q1–2 weeks for 2 months or for
effects in the NF-KB and MAPK signaling path- dosage elevations then monthly); urine pregnancy
ways [58]. screening at baseline in girls of child bearing age
New pathogenic mechanisms are being con- Methotrexate: PPD (baseline and annually), complete
blood count with platelets, liver function testing and
sidered in the literature. Emerging studies on
renal function testing (every few weeks for dosage
serum levels of IL-22 in adult patients suggest escalations and at initiation of therapy, then monthly),
other potential pathogenic mechanisms for future Hepatitis A, B and C screening, HIV testing for
therapeutic use. Some studies report higher levels individuals at risk (at baseline); urine pregnancy
screening at baseline in girls of child bearing age
of IL-22 in psoriatic patients compared to con-
Liver biopsies are rarely performed in children at this
trols and increase with disease burden [59]. Other time. Co-management with rheumatology and/or
studies have linked an IL-22 variant that was gastroenterology may be helpful in prolonged usage
associated with disease manifestation at an ear- Acitretin. Isotretinoin: complete blood count, liver
lier age [59]. Psoriasis is increasingly linked to function tests, cholesterol, triglycerides, urine
pregnancy in girls of child bearing age (monthly for
several autoimmune diseases. Diseases like
isotretinoin due to the iPLEDGE program for the
celiac disease, IBD, uveitis and non-alcoholic duration of therapy; for acitretin after 6 months can
fatty liver diseases, which involve the gastroin- change to quarterly labs); spiral x-rays for suspected
testinal tract, may share a pathogenic link [60]. DISH; ophthalmology with prolonged usage
Some studies are researching the differences in Etanercept/adalimumab/infliximab/ixekizumab/
ustekinumab: PPD at baseline and annually; screening
composition of the gut microbiome in psoriasis for prior hepatitis; periodic evaluation for lymph node
patients [61]. Conflicting studies demonstrate enlargement; periodic laboratory re-evaluation
both increased and decreased bacterial diversity Referrals:
in their participants necessitating further studies Endocrinology for comorbid endocrinopathy, obesity
in this area [61]. management, work-up for HPA axis suppression in
chronic steroid users
Table 25.2 gives a list of potential laboratory
Rheumatology for joint pains, limited mobility,
or diagnostic evaluations for children with pso- co-management of methotrexate or biologics
riasis. The most common precipitating environ- (optional, but suggested for cases with arthritis or
mental factors in pediatric psoriasis appear to suspicion of)
be stress and upper respiratory infections (continued)
Table 25.2 (continued) atric patients, meriting celiac disease screening in

Gastroenterology for management/work-up of children with severe psoriasis [71]. An uncertain
suspected comorbid inflammatory bowel disease, relationship remains between psoriasis and auto-
celiac disease; co-management of methotrexate immune thyroid diseases. In adults, psoriatic
(optional)
arthritis has been linked to a higher incidence of
Nutritionists/weight down programs
Ophthalmology screening for issues arising from oral autoimmune thyroiditis than the general popula-
retinoids tion, especially in patients with concomitant
rheumatoid arthritis [72]. However no such cor-
(Table 25.1), especially with group A relation has been shown with psoriasis localized
β-hemolytic Streptococcus (Streptococcus pyo- to the skin and without associated arthritis, as
genes). Upper respiratory tract infections have thyroiditis markers are statistically similar
been reported to be an inciting factor in 14.8– between psoriatic adults and age-matched con-
28% of pediatric psoriasis cases, while 21.3% trols [73]. Pediatric studies investigating a link
of asymptomatic children have tested positive between psoriasis and autoimmune thyroid dis-
for group A ß-hemolytic streptococcus on eases have yet to be reported. Since the data in
throat culture prior to developing psoriasis [1]. the adult population is inconsistent and no stud-
Streptococcal pharyngitis may trigger up to 2/3 ies with children participants exist to be used as
of all cases of guttate psoriasis [63] as well as guidelines, routine annual screening for thyroid
exacerbate existing plaque psoriasis [2]. disorders is not recommended in pediatric
Children with psoriasis induced by patients with psoriasis. Screening for thyroid dis-
Streptococcal infections frequently experience orders may be warranted in children with psori-
remission [17, 22]. It appears that patients with atic arthritis or in psoriatic pediatric patients with
psoriasis have a unique host-specific response concomitant vitiligo, or another autoimmune dis-
to the streptococcal antigens [63, 64]. eases that are more closely associated with thy-
Enterotoxin-producing Staphylococcus roid abnormalities [74]. A suggested work-up for
aureus, Candida albicans, and Human papillo- children with psoriasis is included in Table 25.2.
mavirus DNA has also been isolated from patients
with psoriasis, suggesting that these entities and
the corresponding immune response to them may Obesity and Metabolic Syndrome
also play a role in the pathogenesis of psoriasis
[65–67]. Environmental factors, such as exposure Recently, an association between psoriasis and
to cigarette smoke, as well as obesity, have also the various characteristics of the metabolic syn-
recently been associated with the development of drome has surfaced in the literature. A growing
pediatric psoriasis [45]. body of evidence points to an increased risk of
Psoriasis is an autoimmune disease which, by cardiovascular mortality in adult patients with
definition, means it is characterized by the severe psoriatic disease. New research is showing
immune system mounting a response against similar cardiac risk factors present even pediatric
self-antigens. Thus, it is of no surprise that pso- patients [22, 34, 75, 76]. Increased rates of hyper-
riasis is associated with other autoimmune condi- tension, hyperlipidemia, diabetes mellitus, and
tions, most frequently of the skin. Patients with obesity are seen in children and adolescents with
morphea have been found to have a higher preva- psoriasis, with the former three comorbidities
lence of psoriasis than the general population occurring twice as often in pediatric psoriatic
[68]. There have also been case reports of famil- patients as compared to healthy controls [77].
ial associations between psoriasis and vitiligo Furthermore, there is an association with increas-
[69, 70]. Individuals with celiac disease are at ing weight and psoriasis severity with some stud-
increased risk for the development of psoriasis ies showing that adiposity may precede psoriatic
and this association is most pronounced in pedi- lesions by 2 years in a majority of patients [17,
22]. Waist to height ratio, a tool commonly used programs are advisable interventions in obese
to determine central adiposity, was found to be adolescents with psoriasis.
more common in patients with moderate to severe
psoriasis, suggesting increased risk for cardio-
vascular disease [78]. Even in patients with both Diagnosis and Clinical
normal and overweight, central adiposity was Characteristics (Tables 25.1 and 25.3)
associated with psoriasis which also suggest that
this chronic condition effects the body even The various clinical variants of psoriasis are
before lesions are seen [79]. Newly established listed in Tables 25.1 and 25.3. The most common
screening protocol guidelines for comorbidities presentation in children is plaque type, with ery-
associated with pediatric psoriasis have been cre- thematous plaques with overlying silvery scale
ated to aid clinicians in early management and localized to the extensor surfaces and scalp
prevention strategies [80]. Adolescents with pso- (Table 25.3). In children, psoriatic lesions are
riasis have been found to elevated plasma lipids generally thinner, possess less scale and are more
irrespective of body mass index, suggesting pso- pruritic as compared to adults [22, 89]. Certain
riasis itself may lead to metabolic abnormalities physical findings are characteristic of psoriasis,
[5, 81]. Some studies have suggested an associa- including pediatric cases. These findings include:
tion with higher blood pressures in patients with (1) The Koebner phenomenon, (2) post-inflam-
psoriasis irregardless of weight [82, 83] while matory pigmentary alteration, especially in chil-
others have found no association with hyperten- dren of color, (3) the presence of punctate
sion and psoriasis [34]. Regardless, this evidence bleeding spots when scales are removed or the
suggests a need for early screening and manage- Auspitz sign, and (4) nail pitting [90].
ment of these co-morbidities in children [75, 84]. The scalp is the leading site of psoriatic lesions
Recent studies suggest obesity may even be an in all age groups with koebnerization as a com-
independent risk factor in the development of mon initial insult in some studies [22, 91]. Scalp
psoriasis [85]. Pubescent females (aged 12–13) psoriasis was found to be associated with more
with an elevated BMI appear to be at an increased extensive disease process and suggests that it
risk for the development of severe psoriasis later may indicate scalp involvement as an early clini-
in adolescence [86]. As for obesity in psoriatic cal marker for more aggressive treatment [91].
arthritis, no meaningful differences in weight Typical presentation include thick erythematous
were found in patients with psoriasis and patients plaques of the scalp, extending onto the forehead,
with psoriatic arthritis [87]. Interestingly, this over the ears and onto the nape of the neck. The
study did not show an increased prevalence of forehead is an especially important site in child-
obesity in psoriatic arthritis compared to healthy hood psoriasis due to the fact that facial disease is
controls. Whether this was secondary to unmea- more prevalent in childhood (Fig. 25.2). It is
sured confounding factors or accounting for a important to differentiate scalp psoriasis from
patients BMI only at the time of the study remains tinea capitis [92]. A specific scalp finding that is
unclear. Nevertheless, future studies are needed associated with psoriasis, but may be noted even
to understand the association between obesity in the absence of psoriasis, is pityriasis amianta-
and psoriatic arthritis in pediatric patients [87]. In ceia, presenting as thick hyperkeratotic concre-
adults with psoriasis, unhealthy lifestyle habits tions attached to the hairs accompanied by scalp
such as cigarette smoking, excess alcohol intake, erythema. Children in Scandinavia with pityria-
and poor dietary choices have been linked to an sis amiantaceia have a stronger family history
increased risk of cardiovascular comorbidities and personal tendency towards psoriasis than
[88]. This highlights the need for prevention children in the general population [93]. Some
through the early development of healthy habits authors believe pityriasis amiantaceia is de facto
in pediatric patients with psoriasis. Referrals to psoriasis, often scalp limited, and usually of
nutritionists, endocrinology, and weight-down childhood. Staphylococcal overgrowth is noted in
Table 25.3 Clinical variants of pediatric psoriasis [22, 30]
322
Type of
psoriasis Clinical appearance Diagnostic features and tests Co-morbidities Differential diagnosis Treatment
Plaque-type Erythematous plaques with Usually a clinical diagnosis Check for recent Nummular dermatitis Treatments must be tailored based upon:
micaceous scale Nail pitting can be noted as a pharyngitis, (Group A Seborrheic dermatitis (1) the age of the patient, (2) quality of
Typical areas: Scalp extending clue to the diagnosis of beta hemolytic Tinea capitis life issues, (3) surface area and (4) sites
to forehead, nuchal, psoriasis in children Streptococcus) ID reaction affected
postauricular, elbows, knees, Biopsy (when needed) Rule out secondary Pityriasis rubra pilaris Topical therapeutic regimens are
umbilical and buttocks features infection with S. Lichen planopilaris prescribed including keratolytic agents,
Thickened epidermis, aureus Tinea corporis topical anti-inflammatory compounds
neutrophils in the horny layer, Consider comorbid Atopic dermatitis (overlap (e.g. corticosteroids and calcineurin
the spongiform pustules of autoimmunity (e.g. can rarely be seen) inhibitors) and topical vitamin A and D
Kogoj and the subcorneal thyroid disease, celiac analogues
microabscess of Munro disease) Systemic agents and phototherapy may
(collections of neutrophils in In the setting of be needed in moderate to severe disease
the epidermis) obesity, disease
Pharyngeal bacterial culture or severity can be a
ASO testing marker of
cardiovascular risk
Guttate Small, annular localized Clinical diagnosis is often Recent pharyngitis, Nummular dermatitis Topical therapy similar to plaque-type
erythematous to salmon colored possible (Group A beta Lichen planus psoriasis
plaques with mild Biopsy is similar to that of hemolytic Secondary syphilis Oral antibiotics are often used initially
hyperkeratosis, sometimes plaque-type psoriasis Streptococcus) Pityriasis rosea due to presumptive infectious
micacous Check for recent pharyngitis, ID reaction precipitating factors and for anti-
Commonly noted on the trunk, (Group A beta hemolytic Tinea corporis inflammatory capabilities
abdomen and back Streptococcus), by Pharyngeal Pityriasis rubra pilaris (erythromycin, azithromycin
bacterial culture or ASO Pityriasis lichenoides cephalosporins)
testing Systemic agents and phototherapy may
be needed in moderate to severe disease
unresponsive to oral antibiotics
Inverse Erythematous, sometimes Although clinical diagnosis is Secondary infection Intertrigo Topical medications should be
macerated thick plaques of the often possible, similarity to with Candida and/or Erythrasma non-steroidal or low-potency topical
intertriginous skin, including other diseases may require Streptococcus may Tinea corporis corticosteroids to avoid atrophy of the
axillae and groin biopsy for differentiation require cutaneous Langerhans cell occluded skin
Can be associated with plaque culture for diagnosis histiocytosis Oral or topical anti-infectives should be
type psoriasis in other sites and prescription of Candidiasis added where appropriate
topical anti-infectives Darier’s/Hailey-Hailey
disease
Contact dermatitis
S. Tolliver et al.
Nail Pitting, onycholysis, 1. Fungal culture and nail Secondary infection Onychomycosis 1. After treatment of any fungal
onychodystrophy, splinter plate biopsy to rule out tinea with Alopecia areata super-infection, topical corticosteroids
hemorrhages oil spots, infection or secondary Candida and/or Lichen planus with tazarotene or calcipotriene can be
subungual hyperkeratosis candidal infection of the nail Streptococcus Pityriasis rubra pilaris applied to the paronychial skin.
trachyonychia: (i.e. Extensive bed is needed when subungual And/or dermatophytes Trauma Intralesional kenalog can also be used in
pitting and subungual hyperkeratosis is present the same region to reduce the subungual
hyperkeratosis) 2. Avoid trauma orexcess inflammation
manipulation (e.g. aggressive 2. May require usage of topical

manicures) anti-infectives
Napkin or Macerated, well-demarcated Biopsy may need to be Secondary infections Irritant contact dermatitis Mild topical corticosteroids with or
diaper shiny erythema of the groin performed or perianal strep Diaper dermatitis without topical anti-candidal agents can
Psoriasis region including the folds and Bacterial and fungal cultures Candidal diaper dermatitis be helpful
(“nappy”) the genital skin may be needed for suspected Allergic contact dermatitis Barrier therapy with zinc oxide pastes
secondary infections or reduces secondary irritant reactions
perianal strep
Erythroderma Generalized erythema and Two biopsies are generally Fever, chills and Atopic dermatitis Topical anti-inflammatory agents can be
thickening of the skin, required from separate sites to malaise can Congenital nonbullous used similar to the therapy of extensive
sometimes with hyperkeratosis differentiate psoriatic accompany ichthyosiform plaque-type psoriasis; however, control
erythroderma from other erythroderma, making Atopic dermatitis of extensive disease is difficult with
causes of erythroderma in bacteremia a possible Lichen planus topical agents and systemic anti-
childhood co-morbidity which Pityriasis rubra pilaris inflammatory agents and/ or
should be ruled out Seborrheic dermatitis phototherapy are often required to
conclusively ivia blood Langerhans cell control severe and extensive disease
cultures histiocytosis NB: Special care must be taken to acoid
Pityriasis rubra pilaris systemic corticosteroids which can
Mycosis fungoides precipitate a pustular flare
Staph scalded skin
syndrome
(continued)
323
324
Type of
psoriasis Clinical appearance Diagnostic features and tests Co-morbidities Differential diagnosis Treatment
Pustular Erythroderma accompanied by 1. Biopsy is often needed Bacterial or fungal Blistering distal dactylitis Topical therapy (see plaque-type
sterile pustule formation, 2. Bacterial culture of the infections should be Acute generalized psoriasis) are often ineffective and
sometimes localized to the distal pustules ruled out through exanthamatous pustulosis systemic agents (especially
extremities, sometimes 3. Fungal culture of the culture Staphylococcal scalded cyclosporine, acitretin) or topical PUVA
generalized. Prior history of oral pustules skin syndrome may be needed
steroid usage may be noted 4. ASO titers can be drawn to Subcorneal pustular
rule out streptococcal dermatosis
precipitant Sweets syndrome Infected
dyshidrotic dermatitis
Tinea infection with Tinea
mentagrophytes
Herpetic whitlow
Hand foot mouth disease
Mucosal/oral Annular plaques on the tongue Generally, a clinical diagnosis, Rarely has any Aphthosis No therapy is usually needed, however
may be noted in patients with however, biopsy is similar to morbidity Lichen planus topical medicaments in an oral base can
psoriasis that of pustular psoriasis White sponge nevus be used when needed
Lichen sclerosis
Lichen simplex
Acrodermatitis
enteropathica
Contact dermatitis
Source: Modified from Silverberg [24]
S. Tolliver et al.
a majority of cases of pityriasis amiantaceia and tongue and psoriatic skin lesions may be two
may play a causative role in disease [92]. manifestations of the same disease process [98].
Several case studies in the literature have Although this manifestation has been difficult to
reported oral mucosal changes in adult patients confirm it as a discrete clinical entity, it is now
with psoriasis and there is debate over whether commonly accepted in the community [94, 95].
these changes are part of the spectrum of psori- Other potential causes such as candidiasis, lichen
atic disease. Due to the transient nature of these planus, leukoplakia, and other autoimmune
lesions clinical detection maybe difficult and mucosal manifestations must be ruled out before
may be underdiagnosed [94]. Lesions of all areas the diagnosis can be confirmed [94].
of the oral cavity, including the tongue, lips, buc- The PASI score was devised to give objective
cal mucosa, gingivae and palate have been measurement to the severity of psoriasis, espe-
reported. However, the overall incidence among cially in regard to clinical research, however the
patients with psoriasis is low [95]. One study score has not been validated in childhood and
found a 7.7% prevalence of this manifestation in may not adequately reflect severity of childhood
their cohort [94]. Fissured tongue and geographic disease especially as it lacks a pruritus or quality
tongue (also called benign migratory glossitis) of life component. It is a calculation based upon
are the most commonly reported oral lesions [95, the severity of psoriatic lesions (determined by
96], and the incidence of geographic tongue erythema, induration, and scale), location of
increases as the severity (as measured by the lesions, and total body surface area involved.
PASI score) of psoriasis increases [96]. Cases of This calculation is outlined in Table 25.4, ranges
geographic tongue in children with psoriasis have from 0 to 72, and can be used in older children
been also reported [97]. In a systematic review of and adults [4]. A website is also available to sim-
the literature the authors found no clear associa- plify the PASI calculation [99].
tion with of tongue psoriasis with plaque psoria- Other methods of psoriasis scoring base the
sis [94]. The histopathology of geographic tongue overall severity of psoriasis on total body surface
resembles that of pustular psoriasis, leading some area involved, quality of life impairment, and the
experts in the field to believe that geographic presence or absence of psoriatic arthritis. Still
Table 25.4 Psoriasis area severity index (PASI) calculation [4]

Body locations Head Trunk Upper extremity Lower extremity
Severity of psoriatic lesions
0 = none; 1 = slight; 2 = moderate; 3 = severe; 4 = very severe
Erythema 0–4 0–4 0–4 0–4
Induration 0–4 0–4 0–4 0–4
Scaling 0–4 0–4 0–4 0–4
Totals Head severity Trunk severity UE severity LE severity
total total total total
Surface area (SA) of psoriatic involvement
0 = none; 1 = 10% or less; 2 = 10–29%; 3 = 30–49%; 4 = 50–69%; 5 = 70–89%; 6 = 90–100%
Degree of involvement 0–6 0–6 0–6 0–6
Totals Head SA total Trunk SA total UE SA total LE SA total
Multiply severity total × SA total Head combined Trunk combined UE combined LE combined
total total total total
Correction factor (based on area of 0.10 0.30 0.20 0.40
involvement)
Multiply combined totals × correction Head corrected Trunk corrected UE corrected LE corrected
factor total total total total
Add together Corrected Totals for each Body Location to obtain final PASI score
Source: Van de Kerkhof and Schalkwijk [4]
others are based solely upon the total body sur- Table 25.5 (continued)
face area involved, with <3% being mild disease, Differential diagnosis of psoriasis
3–10% being moderate disease, and >10% being Differential of
severe disease. However, the latter method may generalized psoriasis Clues to diagnosis
be oversimplified, as quality of life may be sig- Cutaneous lupus Does not typically involve
erythematosus extensor surfaces
nificantly impaired with minimal total body sur-
Discoid lupus with follicular
face area involvement [100, 101]. One such hyperkeratosis, including ear
example is psoriatic lesions localized to the face, comedones and scarring
which is much more common in children (affect- SCLE usually more annular and
ing 38%) than their adult counterparts [11]. in sun-exposed areas
Alterations of PASI with extra weighting for Photoexacerbation noted
Nasal bridge and cheeks more
head and neck disease in children may more ade- commonly involved than
quately reflect body surface area distribution in forehead/ nuchal
smaller children. Facial disease in our experience Malar rash/ photosensitivity
is the leading cause of patients and parents seek- associated with systemic disease
ing systemic therapy. Pityriasis rosea Herald patch may be present
Disease comes up over 6 weeks
and resolves over 6 weeks
Typically oval lesions with a
Differential Diagnosis (Table 25.5) collarette of scale that follow
skin cleavage lines of Langer
The differential diagnosis of pediatric psoriasis Differential of scalp psoriasis
includes other papulosquamous diseases of child- Seborrheic Greasy and yellowish scale
dermatitis
hood, including psoriaform id reactions, pityria-
Tinea capitis Positive potassium hydroxide
sis rosea, and pityriasis rubra pilaris (PRP), as stain and fungal culture (for
well as lichen planus, dermatomyositis and lupus dermatophyte)
erythematosus; as well, pustular disease and nail Broken-off stumps of hairs,
often with pustules, alopecia and
cervical lymph nodes
Table 25.5 Differential diagnosis of pediatric psoriasis
Differential of guttate psoriasis
Differential diagnosis of psoriasis Small plaque Variably erythematous (but often
Differential of parapsoriasis less intense than psoriasis)
generalized psoriasis Clues to diagnosis Covered with a fine scale
Lichen planus Purple, polygonal, planar Pityriasis Red–brown and finely scaly
papules over the extensor lichenoides papules
surfaces chronica Indolent course and recurrent
Hypertrophic skin lesions in crops
individuals of color
Pityriasis rosea See above
Oral white erosive plaques
Differential of inverse psoriasis
Nail changes include
Tinea Annular appearance with central
longitudinal ridging and
clearing
pterygium formation
Positive potassium hydroxide
Pityriasis rubra Small follicular papules,
prep and fungal culture
pilaris disseminated as well as notably
over anterior shins Candidiasis Beefy red macerated plaques
Disseminated yellowish-pink to Satellite pustules
salmon scaling patches including Erythrasma Coral red fluorescence on
scalp Wood’s lamp evaluation
Palmoplantar hyperkeratosis Contact dermatitis Usually follows the pattern of
Dermatomyositis Poikiloderma, atrophy, contactant exposure
heliotrope sign, nailfold changes Generally spares inguinal folds
Prominent hyperpigmentation in (continued)
patients of color
Table 25.5 (continued) hyperkeratosis is distinguished from psoriasis by

Differential diagnosis of psoriasis the scales, which in psoriasis are silvery, light
Differential of and overlapping as well as by the papules with
generalized psoriasis Clues to diagnosis extend peripherally to form patches in PRP [4].
Langerhans cell Typically also have scalp scaling Only about 1–4% of cases of lichen planus
histiocytosis and crust
are seen in children. Lichen planus mainly
Adenopathy may accompany
lesions affects the flexor surfaces of the wrists and
Differential of palmoplantar psoriasis ankles with purple to violaceous, pruritic pap-
Atopic dermatitis Intensely pruritic vesicles and/or ules Nail changes in lichen planus include longi-
bullae tudinal ridging and pterygium formation. In
May have other classic areas of addition, chronic plaque psoriasis may need to
involvement (flexural surfaces)
be distinguished from mycosis fungoides. As
Juvenile plantar Balls of feet toe pads, and hands
dermatosis symmetrically tender and both can have scaling and fissures, palmoplantar
reddened, dry with shiny plaque psoriasis mimics keratotic eczema of the
appearance, may have scale and palms and soles. Examination of the rest of the
painful cracks and fissures
skin for evidence of psoriasis as well as margin-
Palmoplantar Hereditary vs Acquired thick,
keratoderma yellow hyperkeratosis, involves ation of the lesions, which favors psoriasis, can
the lateral aspects of the hands provide clues to the diagnosis. Further, chronic
and feet transgredient vs lesions of dermatitis may look clinically and his-
non-transgredient tologically similar to partially treated psoriasis.
Reiter’s syndrome Urethritis, arthritis, ocular
Histological examination via biopsy is usually
findings, and oral ulcers in
addition to psoriasis form skin the best method to differentiate these skin disor-
lesions ders from true psoriasis [4].
Lesions on the plantar surface In the case of guttate psoriasis, the differential
with thick yellow scale and often diagnosis includes small plaque parapsoriasis,
pustular (keratoderma
blennorrhagicum)
pityriasis lichenoides chronica (PLC), and pity-
riasis rosea. Small plaque parapsoriasis typically
occurs in the middle aged and elderly, but can
changes can be mimicked by cutaneous infec- occur in childhood. However, the lesions of gut-
tions. Like psoriasis, the distribution of dermato- tate psoriasis do not typically affect the palms or
myositis can include extensor surfaces especially soles and are often more erythematous than those
elbows and knees. However, patients with derma- of parapsoriasis. In PLC, the papules are ery-
tomyositis have skin changes that show poikilo- thematous to red–brown and scaly. There is no
derma, atrophy, a heliotrope sign, and nailfold Auspitz sign when the scale is lifted off. The
changes (on dermoscopy or capillaroscopy), lesions of PLC come up in successive crops every
none of which are typically seen in psoriasis [4]. 6–8 weeks and regress over weeks to months,
Lupus erythematosus, however, usually lacks often with post-inflammatory hypopigmentation
involvement of extensor surfaces. Furthermore, in individuals of color. Tinea corporis is also on
psoriasis is generally improved by, not exacer- the differential of guttate psoriasis, when the
bated by UV exposure [4]. The eruption of pity- lesions are more limited number or are annular.
riasis rosea is typically located on the upper arms, Psoriasis of the flexures (inverse psoriasis) is
trunk, and thighs with a duration of a few weeks. one cause of intertrigo. Other etiologies include
A herald patch is frequently noted, and lesions tinea corporis, cutaneous candidiasis, erythrasma,
are typically oval and follow skin cleavage lines. and contact dermatitis. Candidiasis will usually
Individual lesions only have a collarette of scale present with a beefy red color and satellite pus-
and have crinkling of the epidermis [4]. PRP with tules. Contact dermatitis (usually irritant in
its small follicular papules, disseminated yellow- infants) typically spares the inguinal folds, unlike
ish-pink scaling patches, and palmoplantar psoriasis. Erythrasma can be differentiated by
using a Wood’s lamp, demonstrating coral red logically. In pustular psoriasis, there are more
fluorescence. Tinea corporis typically shows an marked accumulations of neutrophils in the epi-
annular border. In infants especially, the possibil- dermis, similar to the spongiform pustules of
ity of Langerhans cell histiocytosis needs to be Kogoj and microabscesses of Munro [4]. Lesser
considered. In these patients, there may also be known pathognomonic findings such as sand-
scalp involvement with scaling and crust, lymph wich sign depict neutrophils and parakeratosis
node enlargement and internal organ alternating in the statum corneaum [102].
involvement.
On the scalp, tinea capitis, and seborrheic der-
matitis often mimic psoriasis. Distinguishing fea- Therapeutic Management
ture of tinea capitis are broken-off stumps of (Table 25.2 and Fig. 25.6) [62]
hairs, often in patches in which there are crusts
and pustule. When examined, the broken-off
hairs are loose and found to be surrounded by or
contain the fungus. Seborrheic dermatitis often Topical Therapies
co-exists with psoriasis, although it’s uncommon
past infancy and prior to puberty. Although typi- Topical therapies are the initial treatment of
cally the scales in psoriasis are dry, shiny and choice for pediatric patients with limited psoria-
white, versus those of seborrheic dermatitis sis of the skin (i.e. in the absence of joint dis-
which are greasy and yellowish, distinguishing ease). In general, thicker vehicles, such as
the two requires fungal culture. ointments, are more effective, but the location of
[62] involvement and patient preference will ulti-
mately affect the decision of which vehicle will
Biopsy and Histology be used. Thinner preparations are commonly
used on the scalp and face while thicker ones are
Psoriatic lesions contain characteristic histologic used on the extremities [103].
features when biopsied that can help differentiate Keratolytics, such as urea, salicylic acid, and
psoriasis from other skin diseases if the clinical α-hydroxy acids, are the most simplified of the
picture is unclear. A mixed inflammatory perivas- topical therapies. The mechanism of action of
cular infiltrate is commonly seen in the dermis. these agents is through removal of the character-
The epidermis appears acanthotic with focal istic superficial hyperkeratosis of psoriatic
areas of spongiosis containing inflammatory lesions, allowing for better penetration of other
cells. There is thinning of the suprapapillary topical therapies [21, 103]. Salicylic acid appli-
plate, and the stratum granulosum may be absent. cation can lead to percutaneous salicylism in
Parakeratosis, the persistence of nucleated kerati- infants and is therefore avoided in this age group
nocytes in the stratum corneum, is common [22]. [103].
Psoriatic plaques with dotted vessels can be seen One of the earliest topical therapies devel-
on dermoscopy [22]. oped, and still in use today in some areas of the
There are two possible pathognomonic find- world, is the Goeckermann regimen. It involves
ings in psoriasis histology. The first is the spongi- topical application of coal tar, or a modified ver-
form pustule of Kogoj, characterized by a sion with addition of a cream called liquor car-
spongiotic pustule filled with neutrophils in the bons detergents, followed by exposure to UV
stratum spinosum. The second is the microab- light. It is proven to be effective in children, with
scess of Munro, characterized by the presence of 85% achieving >80% clearance in psoriatic skin
neutrophils in the stratum corneum. As the lesion lesions [104]. The mechanism of action remains
progresses, the rete ridges elongate and become unclear, but antimitotic effects, inhibition of
blunted, and the hyperproliferation of the epider- DNA synthesis, and enzyme inactivation may
mal keratinocytes becomes more apparent histo- play a role [103]. Despite its effectiveness, the
Evidence of Oral antibiotic therapy +

streptococcal infection topical agents;
Diagnosis of
or rapid-onset tonsillectomy in
psoriasis in a child
cutaneous disease with recurrent streptococcal
Small BSA pharyngitis pharyngitis induced
involved flares
Larger BSA involved;
decreased quality of life
Adjuncts
Topical agents
Topical
Corticosteroids exfoliants Perform screening tests before
prescribing systemic agents
Goeckermann Omega-3 fatty
regimen acids (oral)
Anthalin Prior TB or HBV infection, CBC, liver function
Vitamin D3 prior tests, lipid panel,
derivatives malignancy/lymphoma, blood pressure, UA,
immunosuppressed state pregnancy test
Calcineurin
inhibitors Prior TB, HBV, cancer risk,
None
or immunosuppressed
Localized Rotational
phototherapy therapy
TNF-a Inhibitors to (6–12 mo alternating)
PUVA or Biologic Agents Topical agents
narrowband UVB Methotrexate
Enteracept Generalized
Excimer laser phototherapy Cyclosporin A
Adalimumab
PUVA or Acitretin
infliximab narrowband UVB
Ixekizumab
Ustekinumab
BSA = body surface area, TB = tuberculosis, HBV= hepatitis B virus,

CBC = complete blood count, UA = urinalysis, TNF-α = tumor necrosis factor alpha
PUVA = psoralen plus UVA
Fig. 25.6 Schema of psoriasis therapy in childhood, based on Silverberg [21]
Goeckermann treatment has fallen out of favor in Unfortunately, there are no Food and Drug
industrialized nations due to concern over its Administration (FDA) (United States) topical
long-term consequences. The coal tar contains therapies specifically approved for the treatment
polycyclic hydrocarbons and, when exposed to of psoriasis in children under 12 years of age, but
UV irradiation, this combination has been shown there have been several studies demonstrating
to cause increased chromosomal abnormalities in efficacy of off-label agents, including topical cor-
peripheral lymphocytes and an elevated Heat ticosteroids, vitamin D2 and D3 derivatives, and
Shock protein (specifically Hsp70) response in immunosuppressants (e.g. calcineurin inhibitors)
children [105]. However, there is no concrete evi- [106–108]. The strength and formulation of ther-
dence demonstrating that treatment with coal tar apies should be based on the patient’s age, PASI
or its derivatives leads to an increase in skin can- score, and impact on quality of life. A recent sys-
cer risk as compared to the general population tematic review of 64 studies from The Netherlands
[103] A milder variation on this theme is to use proposed an algorithm of beginning with topical
dilute tar bath additives the night before narrow- synthetic vitamin D3 derivatives with or without
band UVB therapy (1–2 caps tar added to tub and topical corticosteroids, followed by anthralin
soak 10–15 min). cream [106]. However, in the United States, topi-
cal corticosteroids are usually the initial treat- suppressive agent which inhibits T-lymphocytes
ment of choice [103]. through an unclear mechanism of action. Adverse
Topical corticosteroids are frequently effects are minimal due to limited systemic
employed by practitioners for the treatment of absorption and include irritation and staining of
pediatric psoriasis. The choice of which topical clothing or hair [103, 106]. Short contact therapy
steroids to use depends upon the skin areas for several minutes a day minimizes staining and
involved, and parallels the treatment algorithms irritation of the skin [103].
for atopic dermatitis in children. Low potency Vitamin D3 derivatives, such as calcipotriol/
steroids (classes 5–7) are used for more sensitive calcipotriene or calcitriol, have also been proven
areas such as the head, neck, and intertriginous to be effective in children with psoriasis. Side
regions. Moderate potency (classes 2–4) steroids effects include local reactions such as erythema,
are generally used on the scalp and extremities. irritation and pruritis. Mechanistically, they
Higher potency (class 1) steroids are reserved for inhibit keratinocyte proliferation which allows
persistent, thickened lesions that do not respond them to work synergistically with corticosteroids
to lower potency steroids [21, 103]. Two class 1 [22]. There is also a theoretical risk of systemic
corticosteroids, clobetasol and halobetasol, have absorption leading to elevated serum calcium lev-
been studied and found to be effective in chil- els, especially when applied to a large body sur-
dren. Clobetasol (in some specific preparations) face area [106, 110, 111]. Doses of calcipotriene
is approved for children >12 years of age for up to 45 g/m2/week have been shown to have no
2 weeks or less, while halobetasol is not currently significant effect on calcium homeostasis in chil-
FDA-approved for use in children. For scalp pso- dren [103]. A head-to-head comparison of calci-
riasis, the combination of calcipotriene 0.005% potriol and anthralin showed similar efficacy in
and betamethasone dipropionate 0.064%, or psoriatic children [112]. Clinical trials determin-
taclonex, has been FDA-approved for patients ing the long-term safety and efficacy of calcitriol
12 years or older [17]. Treatment duration with ointment, vectical, are underway and may lead to
class 1 steroids is often limited to 2 weeks in chil- the first FDA-approved topical treatment for
dren, as these agents have an extensive side effect pediatric patients under 12 years old.
profile with long-term use, including skin atro- Tazarotene, a topical retinoid, is also effective
phy, striae, and potential hypothalamic-pituitary- for limited psoriatic skin disease and nail psoria-
adrenal (HPA) axis dysfunction [106, 107, 109]. sis [103]. Topical calcineurin inhibitors, such as
All topical corticosteroids if used prolongedly tacrolimus and pimecrolimus, have also been
and especially over large surface areas, including shown to promote the clearance of psoriatic
classes 2–7, are theoretically associated with lesions in children [106, 113]. These agents are
these adverse effects as well. The risk of systemic immunosuppressants that inhibit cytokine pro-
absorption and HPA dysfunction increases with duction (IL-2 in particular) by T lymphocytes
the body surface area to which the steroid is and thus limit their proliferation. Tacrolimus
applied increases. This is of particular concern in (0.03% for children ages 2–15 years and 0.1%
children, as they have usually not yet reached ointment for ages 16 years and over) and pimecro-
their growth potential [21]. A recent systematic limus 1% cream are approved for the treatment of
review of the use of topical corticosteroids atopic dermatitis in children >2 years of age, but
showed no systemic and minimal topical adverse its use is off-label for psoriasis [103, 113]. The
effects in the studies included. The incidence of advantage of these agents is the lack of potential
adverse events can be decreased by rotating the skin atrophy, allowing their use in more sensitive
use of topical corticosteroids with other topical areas such as the face, neck, and intertriginous
treatments listed below [103]. areas [103, 113]. However, use of calcineurin
Anthralin 1% cream, or dithranol, is a topical inhibitors on plaque psoriasis how been shown to
therapy that can be used for localized areas of be less effective likely secondary to poor absorp-
psoriasis. It is an anti-proliferative and immuno- tion rates in the skin [111]. Side effects most fre-
quently noted include local irritation and pruritis adults. Therefore, the use of systemic antibiotics
[106]. This class of topical medication also car- for the treatment of pediatric psoriasis remains
ries a black box warning in the US due to a theo- controversial [106, 116, 119]. Tonsillectomy has
retical increased risk of skin cancer and been recommended by some as a treatment for
lymphoma. Sun protection is therefore advisable recurrent guttate psoriasis [117], but this has also
concurrent with calcineurin inhibitor products not been proven to be effective in an evidence-
[114]. based manner [106, 119].
Methotrexate was the original therapy avail-
able for extensive psoriasis. It is generally safe in
Systemic Therapies (Table 25.2 children and is a well-established treatment for
and Fig. 25.6) moderate to severe psoriatic disease. Methotrexate
is also the drug of choice for patients with psori-
Systemic therapies for the treatment of pediatric atic arthritis in addition to skin disease [120].
psoriasis are usually reserved for those patients Methotrexate is associated with a >75% improve-
who have failed topical treatments, have exten- ment in PASI score [121]. Dosages used range
sive body surface area involvement, have signifi- from 0.2 to 0.7 mg/kg per week [120–122]. The
cant impairment in quality of life and/or most common side effect in children is nausea
psychological health, or have concomitant psori- and vomiting. Although routine monitoring of
atic arthritis. Like all systemic medications, the blood counts and liver function tests are recom-
agents available for use in pediatric psoriasis mended, bone marrow suppression, such as
have side effects. For this reason, many physi- microcytic anemia and pancytopenia, and liver
cians employ a cyclic approach for systemic ther- toxicity are rare adverse drug events.
apy, alternating between different available Liver toxicity appears to be relatively rare in
treatments every 6–12 months to minimize long- children, although obesity and associated fatty
term adverse events. Systemic therapies include liver changes are associated with an increased
oral antibiotics, methotrexate, cyclosporine A, risk of this adverse reaction [106, 120, 122].
retinoids, TNF-α inhibitors, and biologics. Concomitant folic acid supplementation (1 mg/
Oral antibiotics are considered the safest of day) is protective against bone marrow suppres-
the systemic agents due to their superior side sion and liver enzyme abnormalities [123].
effect profile. Benefits with oral antibiotics are Cyclosporine, another immunosuppressant
most impactful in the setting of severe, rapid- which inhibits cytokine signaling by lympho-
onset cutaneous disease following streptococcal cytes, may be effective for psoriatic skin disease
pharyngitis or perianal streptococcal disease, and in children. In doses ranging from 2 to 4 mg/kg/
in pustular and guttate psoriasis [115–117]. A day, cyclosporine can improve the overall sever-
recent controlled trial of 50 patients (ages ity and appearance of skin lesions, but studies
13–63 years) found that a 48-week course of investigating its effectiveness in children are lim-
azithromycin therapy (4 days of azithromycin ited [124, 106, 125, 126]. Recent studies from
500 mg tab once-daily, followed by 10 days off India followed 8 children’s use of cyclosporine
therapy, with repeat of the cycle every 2 weeks) and found the drug to have few side effects,
resulted in a PASI 75 of 80% at 48 weeks in the abdominal pain and increased creatinine, with
treatment group as compared to no significant significant improvement in psoriatic lesions.
difference in the control group. Only 12 patients These patients were treated until achieving a
had a positive ASLO test for streptococcal infec- PASI 75 then subsequently tapered 50 mg every 2
tion [118]. Despite this and other studies demon- weeks [126]. Because of its rapid onset this med-
strating an association between streptococcal ication can be utilized as a “rescue” treatment
infection and the onset of psoriasis, it remains and then switched to a safer drug for maintenance
unclear whether antibiotic therapy improves therapy [126, 127]. In addition, its use is hindered
PASI scores or disease clearance in children or by the side effects of nephrotoxicity, secondary
hypertension, hyperlipidemia, and immunosup- literature determining long term safety data in
pression as well as the requirement for close pediatric patients treated specifically for psoria-
monitoring of blood pressure and renal function- sis, there is much debate on this use of biologics
ing, which is more likely to become permanently in this population. Early studies determining long
impaired in individuals on therapy beyond term safety profiles for these drugs are being con-
6 months (Table 25.2). Cyclosporine is of partic- ducted. One study followed 12 patients over
ular benefit for the therapy of pustular psoriasis 8 years and found similar side effects, infections
(Poster SPD) [127]. Reports of an increased can- and injection-site reactions, previously reported
cer risk secondary to immunosuppression have by other investigations [131]. Furthermore, they
also been reported, but the low doses, diligent found that up to 50% of patients initially treated
monitoring, short courses and rotational thera- with etanercept needed to switch to another bio-
pies used in treatment of skin-limited psoriasis logic. Whether this is due to the changing immu-
decrease these risks [120]. nologic make-up in pediatric patients remains to
Retinoids, such as acitretin or etretinate, are be seen. However, this suggests a potential treat-
other treatment options for children with pustu- ment strategy for failed biologic therapies [124,
lar, erythrodermic, or plaque psoriasis, although 131–134].
they are not as extensively studied or as safe as TNF-α inhibitors have been used to treat rheu-
methotrexate [106, 128]. Adverse effects include matoid arthritis, tumor necrosis factor
teratogenicity, elevation of liver enzymes, 1-associated fever, juvenile idiopathic arthritis,
impaired lipid profile, alterations in blood counts, ulcerative colitis and Crohn’s disease in children
and bony abnormalities. Due to the ability of reti- for more than a decade [21]. The most extensive
noids to cause severe birth defects, oral contra- studies of the safety of TNF-α inhibitors in chil-
ceptives are recommended for 1 month before dren come from research investigating their use
initiating therapy and for 3 years after the cessa- in juvenile rheumatoid arthritis, with up to 8 years
tion of therapy in girls of childbearing age [22]. of published data on this subject. Side effects
Isotretinoin may be a preferred choice for those include reactivation of latent tuberculosis or hep-
at risk of pregnancy. Good pregnancy prevention atitis infections as well as increased risks for
(2 methods of birth control) and monitoring for malignancies including lymphoma, opportunistic
pregnancy are needed in those of child bearing infections, and demyelinating disease. The FDA
age. Close monitoring of liver function tests and has recently placed a black box warning on
lipid profiles during therapy are necessary as Enbrel for pediatric psoriasis stating, “Lymphoma
well. High-dose systemic retinoids used for and other malignancies, some fatal, have been
greater than 2.5 years have been associated with reported in children and adolescent patients
premature epiphyseal closure in children. treated with TNF blockers, including Enbrel.” A
Hyperostosis and osteoporosis are other potential recent retrospective cohort study comparing 9045
bony side effects [129]. However, cyclic short- pediatric psoriasis patients and 77, 206 healthy
term therapy for 6–12 months, as indicated in controls found that there was no overall increased
rotational therapy, decreases the risk for bony cancer risk when taking TNF-a inhibitors.
abnormalities. Longer courses of treatment in However, lymphoma the primary cancer reported
children require periodic skeletal surveys [120]. in these patients [135].
TNF-α inhibitors, such as etanercept, adalim- In one study following pediatric patients with
umab, and infliximab, have been used to treat juvenile rheumatoid arthritis treated with etaner-
pediatric psoriasis, but only entercept is approved cept, no cases of tuberculosis, opportunistic
for this purpose. This recent change comes after a infections, malignancies, lymphomas, lupus,
recent randomized double-blinded, placebo-con- demyelinating disorders, or deaths were reported
trolled study showed promising long-term safety after 8 years [136]. The most commonly reported
data with beneficial effects on quality of life in side effects with etanercept specifically are injec-
pediatric patients [17, 130]. With the paucity of tion site irritation and non-opportunistic infection
[106]. Interestingly, there have studies showing However, the safety profile of these medications
that TNF-α inhibitors are associated with out- are still being elucidated [141].
breaks of psoriasis and other cutaneous manifes- Biologic agents initially approved in adults have
tations in children and adults being treated for been examined and approved in childhood and
other autoimmune disease processes [124, 132, adolescent psoriasis [145]. Etanercept, which is the
133, 137, 138]. One study suggests that this most extensively studied of the TNF-α inhibitors in
potential is a result from the loss of inhibition of children, has recently been approved for use in
TNF-α on dermal plasmacytoid dendritic cells children 6 years and older with ulcerative colitis
which leads to increases in IFN-γ [132, 133]. and Crohn’s disease, and is now approved to treat
Emerging data regarding this phenomenon is psoriatic arthritis and plaque psoriasis in adults and
especially seen in children with IBD with one pediatric patients 4 years and older [130, 146].
study demonstrating 8.8 percent of their patients Etanercept at doses of 0.8 mg/kg weekly has been
treated with TNF-α inhibitors developing psoria- shown to achieve PASI 90 in 27% and PASI 75 in
sis [132]. Another study based on patients with 57% of treated patients as compared to 11 and 7%
JIA found a 5.4% prevalence of psoriasis when of placebo-treated patients after 12 weeks of treat-
using TNF-α inhibitors, with female predomi- ment respectively [147]. This benefit appears to be
nance and low incidence of personal or family maintained in the majority of patients after
history of psoriasis [132]. As for which TNF-α 96 weeks [148]. Etanercept has also been shown to
drug is most likely to cause this adverse effect improve overall and disease-specific quality of life
remains to be seen, some studies showed equal in children with moderate to severe plaque-type
prevalence of psoriasiform lesions when using psoriasis [149]. It has also been shown to improve
both adalimumab, infliximab and etanercept depression in adults, irrespective of disease clear-
while other studies implicate infliximab as the ance. This suggests that the inflammatory response
culprit [132–134, 139, 140]. More studies on this itself, rather than the psychological effects of an
subject are needed to understand this paradoxical undesirable physical appearance, may contribute to
side effect of TNF-α inhibitors. depressed mood in psoriatic patients [150, 151].
The literature as well as clinical practice are Other TNF-α inhibitors have not been extensively
trending toward increased use of biologics with studied in children with psoriasis [106].
as much as 25% of children with psoriasis being Adalimumab is currently not FDA-approved in
treated with these medications [141]. When the USA. However, with increasing understanding
determining which patients will benefit from bio- of the chronicity of psoriasis and associated co-mor-
logic therapy consider children and adolescents bidities, long-term treatment with safe and effective
with greater than 10% BSA, DLQI >10, failed drugs are an important area of research. Recent
standard therapies or other contraindications results from Phase 3 clinical trials comparing the
[142] with special attention to educating patients efficacy and safety of adalimumab and methotrexate
on the risks and benefits of using these medica- are promising [152]. Patients were able to maintain
tions. Some studies suggest using systemic thera- resolution of disease with 0.8 mg/kg every other
pies earlier in mild psoriasis and patients with week in this study for 52 weeks. Furthermore,
lower DLQI scores. Allowing patients to advance patient’s refractory to methotrexate were able to
to systemic treatment may improve quality of life achieve improvement when switched to adalim-
[135]. Vaccinations are another special consider- umab every other week. Patients were found to have
ation for patients starting biologic therapy. Live a similar safety profile as adults with nasopharyngi-
vaccines are absolute contraindications to bio- tis and upper respiratory infections being the most
logic therapy [142, 143]. Biologics, over other common adverse effects [152]. The safety of adali-
systemic treatments like methotrexate and cyclo- mumab in pediatric patients was further studied in
sporine, require less stringent treatment sched- patients who were being evaluated for its use in JIA,
ules, have fewer adverse effects, decreased need pediatric enthesitis-related arthritis, psoriasis, and
for monitoring, and greater efficacy [144]. crohns disease [153]. In 577 patients who partici-
pated in clinical trials dating back to September refractory to high potency topical steroids, photo-
2002 the most common side effects reported were therapy, and systemic treatments such as metho-
infections with no malignancies reported at all. This trexate, adalimumab, and ustekinumab [157]. In
study adds to the amounting evidence that adalim- this patient guselkumab was added to the dosage
umab is safe in pediatric patients with similar of methotrexate and the patient’s psoriatic
adverse events as in adults [153]. plaques thinned by week 4 with full resolution by
Ustekinumab or Stelara, is emerging as safe 5 months. No adverse effects were reported. This
and efficacious treatment modality for improve- case report demonstrates a potential future treat-
ment of moderate to severe psoriasis in adoles- ment modality in which patient’s refractory to
cents. Ustekinumab is an Il-12 and IL-23 inhibitor other biologics and systemic agents can achieve
that is FDA approved for patients 6 years or older remission of their disease [157]. There is one
[140]. Its dosing schedule recommends starter case report in the literature that details the use of
doses at week 0 and week 4 then once every apremilast an oral phosphodiesterase-4 inhibitor,
12 weeks thereafter. This less involved dosing in a 14-year-old boy with guttate psoriasis [102].
schedule is ideal for adolescents with many time Previous therapies used include topical therapies,
sensitive activities [128]. It has been shown to natural light exposure, antibiotics. Apremilast
have a favorable side effect profile and efficacy was prescribed at the adult dosing based on the
comparable to adult populations being treated for patient’s weight. After 6 months of therapy the
psoriasis [140]. The CADMUS Jr trial addressed patient had improved in both his skin disease and
efficacy of ustekinumab in 6-12 year old children quality of life [102]. There have been reports of
with moderate to severe psoriasis, with 84% of psychological distress in adults taking apremi-
children achieving PASI 75 and 64% PASI 90 by last, depression and suicidal ideation, thus war-
12 weeks, with no new safety signals [154]. ranting monitoring [158]. To date there are no
Approval in children 6 years of age and older has case report detailing the use of secukinumab, and
been granted in the United States. IL-17 inhibitor, treating plaque psoriasis in pedi-
The IXORA-PEDS study addressed the high- atric patients. There have been case reports dem-
affinity IL-17a monoclonal antibody ixekizumab onstrating its use in patients with recalcitrant
in pediatric psoriasis. PASI-75 was 89% at week nails disease which suggests other potential indi-
12. Approval in children 6 years of age and older cations for pediatric patients [143]. Several clini-
has been granted in the United States [155]. cal trials are underway to determine the safety
Other potential treatments are being considered profile and efficacy of secukinumab in patients’
for cases refractory to the TNF-a inhibitors, children and adolescents with moderate to severe
ixekizumab and ustekinumab such as gusel- psoriasis as well as dosing strategies.
kumab, apremilast, secukinumab. Guselkumab is
an anti- interleukin-23 monoclonal antibody.
There is a paucity of literature for the use of Phototherapy
guselkumab in even adult patients. However, the
recent NAVIGATE clinical trial demonstrates the UV light therapy is used to treat a variety of skin
efficacy of guselkumab in ustekinumab refrac- diseases in children, including atopic dermatitis,
tory patients [156]. In this study guselkumab was vitiligo, acne vulgaris and psoriasis [159]. When
shown to have a greater efficacy when compared determining what patients are good candidates for
to ustekinumab in patients unable to achieve 0 or phototherapy a thorough assessment of history,
1 investigator assment scores. The safety profile former unsuccessful treatments, availability and
of guselkumab and ustekinumab were similar transportation should be completed [111].
with guselkumab having a slightly higher inci- Indications for use include older pediatric patients
dence of adverse events, infection being reported with extensive disease, contraindications to sys-
most often [156]. As for pediatric patients, there temic treatments, guttate psoriasis, and thinner
is one case report of guselkumab use in a patient plaques. Phototherapy is available in the form of
broadband UVB, narrowband UVB or UVA in as burning, redness, and pain because of the
combination with psoralen (PUVA). Both UVB increased amount of ultraviolet exposure [111].
and UVA have been shown to be efficacious when Therapy is required once or twice per week for a
be used in combination with topical steroids, topi- 1–3 months before psoriatic lesions clear and a
cal retinoids, emollients, coal tar or vitamin D maintenance phase can be reached [21]. This can
analogs [111]. Narrowband UVB (NB UVB) and be difficult for many families with busy sched-
PUVA therapy have shown the most success in ules and varying temperaments in young chil-
treating children with psoriasis [21, 103, 159]. dren. A potential option for this barrier is to
However, NBUVB (311 nm) is the treatment of consider home treatment using either 10–15 min
choice, as PUVA therapy has been associated with of natural sunlight or at home light boxes. As for
an increased risk of carcinogenesis in adult natural sunlight, this option can be considered
patients with psoriasis and development of cata- during the spring and summer months and is cost
racts in pediatric patients with psoriasis [111, effective [111]. Potential barriers include sched-
159]. NB UVB is also highly effective and safe, ules during day light hours that may make it dif-
with a response rate approaching 80% in pediatric ficult to be outside like school in adolescent
patients [111, 160]. Topical PUVA therapy is children. As for home light therapy, this option is
therefore recommended for refractory palmoplan- for children in need of long-term therapy and has
tar psoriasis based on its side effect profile [111]. the benefit of it less intimidating that a doctor’s
If PUVA therapy is used, topical psoralen is pre- office. As a tradeoff, these treatments are usually
ferred, due to the necessity for 24 h of protective longer because of lower fluences and necessitate
eyewear following treatment with oral psoralen. direct parental supervision [111].
For this reason and the increased risk of other sys- Excimer laser, a narrowband UVB 308 nm
temic adverse reactions, oral psoralen should be laser light source has been described to be effec-
avoided children less than 12 years of age. tive for the therapy of localized psoriasis. Scalp,
Absolute contraindications include diseases char- palms and soles and areas on the face and body
acteristically exacerbated by UV light, such as can be treated. Some data on usage in childhood
lupus erythematosus, dermatomyositis, and xero- shows benefit for children with localized psoria-
derma pigmentosum [111]. sis, and children may experience superior benefit
Common adverse events of phototherapy with excimer usage. Therapy has some ultraviolet
include local irritation and erythema. There is light induced side effects, but is generally well
also the possibility of reactivation of a latent her- tolerated [163].
pesvirus infection, photoaging, and the long-term
risk of carcinogenesis [106, 159–162].
Phototherapy maybe administered in the form of Natural Supplements
a handheld laser, phototherapy booth, or hand/
foot units. If a phototherapy booth is employed, Various natural supplements have been investi-
the child must be old enough to remain still for gated in the treatment of pediatric psoriasis and this
the length of each therapeutic session [21]. is a common topic of inquiry among parents. No
Compliance issues in younger children may natural remedies have found to be curative, but a
restrict treatment, thus phototherapy is often few may help alter the disease progress. Omega-3
more useful in adolescents [21, 159]. Although fatty acids, such as those found in salmon and other
there are no strict guidelines on the age in which fatty fish, may lead to slight improvements in PASI
phototherapy can be initiated, school age chil- score. As previously mentioned, this finding is sup-
dren are a reasonable starting point, however ported by the observation that Inuit populations,
younger patients, if able, can still receive therapy which consume diets high in omega-3 fatty acids,
[111]. Special considerations for teenagers using have a low incidence of psoriasis. The benefits of
phototherapy include tanning bed use. This pres- omega-3 fatty acid supplementation are superior to
ents an increased risk for adverse reactions such omega-6 fatty acid supplementation. The mecha-
nism of action appears to be alterations in the level may exacerbate psoriatic lesions [84]. Thus, the
of eicosapentanoic acid and arachidonic acid, lead- benefits of a healthy balanced diet remains an
ing to decreased production of pro-inflammatory important factor in overall management of psori-
metabolites [43]. The benefits of omega-3 fatty atic patients. Furthermore, adiposity has been
acids are minimal or possibly non-existent, but this noted to precede onset of psoriasis, making diet a
supplement appears to be essentially harmless, and potentially important preventive agent [170, 171]
thus safe for use in children. There may be a more Dietary modifications that eliminate foods and
important role for dietary changes in pediatric the role of large supplements in children are con-
patients with metabolic syndrome and psoriasis, cerning for risk of side effects and potential mal-
due to the recent association between these two dis- nutrition. Recent studies investigating dietary
ease entities. Diets low in fat and high in fiber have recommendations for adults with psoriasis or pso-
been found to beneficial in treating metabolic syn- riatic arthritis have shown that hypocaloric diets
drome in children, and along with exercise, can leading to weight loss in overweight and obese
even cure patients of this condition with lasting adults has a positive impact on patients regarding
benefits into adulthood [164, 165]. psoriasis severity and dermatologic quality of life
Indigo naturalis, a traditional Chinese medi- [169]. Hypocaloric diets refer to ranges from 800
cine, has been reported to aid in clearance of to 1400 kcal per day. Diet alone does not maintain
pediatric psoriatic lesions after 8 weeks of topical psoriasis remission and adjunctive biologic ther-
application in one anecdotal study [166]. Other apy is recommended [169]. Whether the type of
traditional Chinese medicines and natural supple- diet or weight reduction leads to the reduced
ments may ultimately cause more harm than ben- severity needs further investigation. The benefit of
efit and it is important for dermatologists to be calorie restriction in children is unknown and
aware of the potential side effects of these thera- therefore, it is best to work with the parents, chil-
pies [167]. The role of this medication in children dren, nutritionists and the pediatrician to find the
is unknown at this time. best strategy for healthier weight achievement
and maintenance. Gluten-free diets in psoriatic
with celiac disease were highly recommended.
Dietary Recommendations Psoriatic patients with positive serologic markers
for gluten sensitivity were recommended to
The role of diet and supplementation in the man- undergo a 3-month trial of gluten-free diet with
agement of psoriasis is controversial. Anecdotally, adjunctive medical therapy [169]. As for adult
some patients report improvement of symptoms patients with psoriatic arthritis, it was highly rec-
with changes in diet. Healthier food choices lead ommended that they undergo a trial of vitamin D
to reductions in heart disease, diabetes, and obe- supplementation with 0.5 μg alfacalcidol or 0.5–
sity, however, the effect of healthier food choices 2.0 μg of calcitriol daily [169]. Usage of oral vita-
on the disease burden of psoriasis remains min D supplements in children with psoriasis and/
unclear. The National Psoriasis Foundation over- or psoriatic arthritis has not been adequately
all recommends meals nutritionally balanced explored at this time. For other supplements, such
with lean proteins, whole grains, fresh produce, as omega-3 fatty acids, selenium, Vitamin B12,
and healthy fats, and is sometimes referred to as and micronutrients evidence was limited and
the “anti-
inflammatory” or Mediterranean diet therefore no recommendations were made.
[168, 169]. Foods that promote inflammation
include fatty red meats, processed foods, refined
sugars, and dairy products [168]. Although there Conclusions
is limited evidence to justify changing eating
habits there is a well-established linked between Psoriasis of childhood is a common and complex
metabolic syndrome, obesity and psoriasis [169]. disorder that can occur from birth up through
Body fat has pro inflammatory mediators that adolescence. Consideration for the child’s emo-
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Challenges in Psoriasis Treatment:
Nail, Scalp, and Palmoplantar 26
Involvement
Jeffrey J. Crowley
Abstract
Psoriasis can affect many areas of the body 1. To understand the diagnosis and man-
and treatments should target the areas of agement of nail psoriasis
involvement. Nail disease is difficult to treat 2. To understand the diagnosis and man-
with topical therapy as the vehicle must be agement of scalp psoriasis
optimized to penetrate the nail and surround- 3. To understand the diagnosis and man-
ing tissues. Some of the inflammation in nail agement of palmoplantar psoriasis
disease is deep in the nail matrix and thus dif-
ficult for topical therapies to access. Scalp dis-
ease is difficult to treat with topical and
phototherapy due to the presence of hair, bath-
Nail Psoriasis
ing habits, and convenience issues. The palms
and soles often have particularly thick plaques
Psoriasis is a chronic systemic inflammatory dis-
of psoriasis which may prevent absorption of
ease involving the skin, nails, and joints.
topical therapy and resist phototherapy.
Approximately 50% of psoriasis patients have
Patients with primarily palmoplantar disease
some nail involvement and the lifetime incidence
often do not respond to multiple therapies, and
of nail disease is estimated at 80–90%. Nail dis-
many require combination therapy for disease
ease may rarely be the only manifestation of pso-
control. Collectively, nail, scalp, and palmo-
riasis [1]. Nail psoriasis is associated with higher
plantar psoriasis are considered “tough to
overall disease severity and male gender.
treat” and often do not respond as well as
Importantly, nail psoriasis can cause significant
plaque psoriasis elsewhere on the body. This
pain, discomfort, and embarrasment, leading to
chapter will critically address the challenges
impairment in quality of life (QoL) and work
posed by each condition and evaluate avail-
function [2, 3].
able treatment options.
There is a strong correlation of nail psoria-
sis and psoriatic arthritis [4]. Psoriatic arthritis
patients have rates of nail disease as high as 70%
and there is evidence that nail psoriasis may be
a predictor of joint disease developing later in
J. J. Crowley (*) life [5]. Psoriatic arthritis may involve the dis-
Bakersfield Dermatology and Skin Cancer Medical tal interphalangeal joints and the anatomic link
Group, Bakersfield, CA, USA

https://doi.org/10.1007/978-3-030-54859-9_26
344 J. J. Crowley
between these joints and the nail unit may result The methods of reporting changes in nail
in nail changes. In fact, nail disease is one of the disease within clinical trials have not been stan-
components of the CASPAR criteria, which is dardized. The nail psoriasis and severity index
used to aid in the diagnosis of psoriatic arthri- (NAPSI) was developed to measure changes in
tis [6]. Fingernail psoriasis, due to its visibility nail disease over time [11]. When utilizing this
and impacts on function, is more problematic for measure each nail is divided into 4 quadrants and
many patients compared with toenail disease. then assessed for the presence or absence of signs
Additionally, psoriatic toenails are often second- of both nail matrix and nail bed disease. Each
arily infected with dermatophytes which may quadrant of nail with disease present is given a
complicate treatment assessment [7]. Treatment score of “1” for signs of matrix disease and “1” for
with immuosuppressive medications may even signs of nail bed disease. A normal nail is scored
contribute to the development of onychomyco- “0” and the maximum value for each nail is 8, 4
sis in patients with toenail psoriasis. For these for matrix involvemet and 4 for nail bed disease.
reasons, most studies evaluate fingernail psoria- Thus, the maximum NAPSI value for a study
sis alone [8]. measuring fingernail disease is 80 and the maxi-
Clinically, nail disease has many different
presentations which depend on the location of
the infllammatory process. Nail pitting, the most
common finding in nail psoriasis, nail dystrophy,
and leukonychia (white discoloration of nails)
are due to nail matrix involvement [9] (Fig. 26.1).
Nail bed psoriasis is characterized by onycholy-
sis (lifting of the distal nail from the nail bed),
oil drop patches (yellow discolorations below the
nail), subungal hyperkeratosis (thickening of the
nail), and splinter hemorrhages (linear streaks of
dried blood in the nail) [1] (Fig. 26.2a, b). One
recent study demonstrated that nail clippings of
clinically uninvolved nails from patients with Fig. 26.1 Nail matrix psoriasis—note the extensive pit-
ting in this nail. Some of the pits are linear and a splinter
psoriasis may show abnormalities, thus subclini-
hemorrhage is also present. This patient has concomitant
cal nail disease exists [10]. psoriatic arthritis and inflammatory bowel disease
a b
Fig. 26.2 (a) Nail bed psoriasis. Note the hyperkeratosis, the onycholysis, oil droplet formation, and distal
onycholysis, oil droplet formation in the nail bed, and hyperkeratosis
destruction of the distal nail. (b) Nail bed psoriasis. Note
26 Challenges in Psoriasis Treatment: Nail, Scalp, and Palmoplantar Involvement 345
mum for a target nail is 8. NAPSI measures the support the efficacy of topical cyclosporine,
extent of nail disease but not the severity of nail topical tacrolimus, clobetasol nail lacquer,
involvement, so a modified NAPSI (mNAPSI) calcipotriol, calcipotriol plus betamethasone,
has also been used as a clinical endpoint in some tazarotene, and indigo naturalis extract [18–
studies [12]. The mNAPSI has a maximum score 25]. Keratolytics such as urea and salicylic acid
of 13 for each nail. Some studies utilize a single are also used in patients with nail psoriasis and,
target nail or an overall nail severity score. Other in particular, for nail debridement [26]. Topical
scales have been used to measure nail involve- preparations, in particular, take several months
ment but most of the studies reviewed herein uti- to show efficacy and adherence to therapy over
lize some form of the NAPSI. The wide variety months is challenging. In a study comparing cal-
of objective measures used in psoriasis studies cipotriol twice daily with calcipotriol/betametha-
to measure nail disease and the variety of time sone once daily, adherence to the twice daily
points when the measurements are made, make regimen was only 26% [21]. Therefore, topical
comparison of treatment outcomes for various therapy may not only be limited by penetration
interventions difficult. The goal of treating nail into the nail unit but also by adherence to lengthy
psoriasis is total clearance of the nail and given treatment regimens lasting weeks or months. In a
the current highly efficacious therapies, this goal Cochrane review of topical agents for nail psoria-
is attainable for some patients. sis the strongest evidence was for the two com-
pound products (calcipotriol and betamethasone
dipropionate) although this product is only mar-
Treatment of Nail Psoriasis ginally superior to betamethasone dipropionate
alone [27].
An array of treatment options are available for Procedures have also been studied in the treat-
nail psoriasis including topical products, proce- ment of nail psoriasis. Phototherapy, a common
dural interventions, and oral systemic and bio- treatment for skin disease, in the absence of
logic agents. The challenges to treating nail psoralen or a retinoid, is not likely to improve
disease are many; poor penetration of topical nail disease and is therefore not a viable option
therapy into the nail and surrounding tissue, pain for nail psoriasis. There is limited efficacy data
associated with intralesional injections, side showing improvement of NAPSI scores with
effects and monitoring of systemic therapies and psoralen plus UVA (PUVA), acitretin plus UVA
patient adherence to therapy [13]. A Cochrane (Re-PUVA) and acitretin plus UVB (Re-UVB)
review has recently been published which [28]. In a 1999 study of Grenz ray therapy (super-
reviewed the published literature on randomized ficial x-ray therapy), 22 patients with nail psoria-
double-blind placebo controlled trials (RDBPCT) sis had one hand treated with weekly radiation
of nail psoriasis [14]. Unfortunately, many of the and the other hand serve as an internal control.
treatments most commonly used to treat psoriasis The treated hand showed significant but mod-
do not have published RDBPCT specifically erate improvement but the effect proved more
addressing nail disease. Others have reviewed limited with hyperkeratotic nails [29]. Limited
nail psoriasis treatments and the results of a access to Grenz ray therapy, a mostly historical
Delphi consensus conference have also been pub- therapy in the United States, may further inhibit
lished [15–17]. the use of this modality. Several studies evalu-
Topical agents are often the first-line option ated pulsed dye laser (PDL) in nail psoriasis.
for treating patients with nail disease. These The studies noted that therapy is limited by pain,
products are readily available, may have cost experienced by all patients, and an incidence of
advantages, and rarely require laboratory moni- both petechiae and hyperpigmentation in one
toring. Although data are limited and pla- third of patients [30, 31]. A combination of PDL
cebo controlled trials rare, there are data to and tazarotene cream was studied in two groups
346 J. J. Crowley
of nail psoriasis patients; those on stable doses (10 mg/ml) versus methotrexate (25 mg/ml)
of systemic medication and those on no systemic versus cyclosporine (50 mg/ml) showed ≥75%
medication. The study showed efficacy in both improvement in over half of the nails injected
groups but did not show any difference between with triamcinolone and methotrexate but a low
the groups [31]. Another study evaluated PDL response to cyclosporine [35].
both with and without the addition of methyl- The systemic agents acitretin, methotrex-
aminolevulinic acid (photodynamic therapy, ate and cyclosporine, which are effective in
PDT) and found no additional benefit of PDT plaque psoriasis, are also effective in nail dis-
over PDL [32]. Intralesional injection of corti- ease. Apremilast, a newer oral agent for psoriasis
costeroid is an accepted clinical treatment for which targets phosphodiesterase 4, also has data
localized nail psoriasis. Even though this tech- showing efficacy in nail disease. Additionally,
nique has been used for many decades, pub- tofacitinib, approved for psoriatic arthritis but
lished data to support the safety or efficacy of not for psoriasis, shows efficacy in nail disease.
intralesional injections is extremely limited. Appropriate monitoring of both the patient and
Injection techniques vary but generally involve the laboratory values pertinent to the systemic
injection of 0.1–0.2 ml of 5–10 mg/ml triamcin- therapy should be performed.
olone acetonide suspension into the lateral nail Supporting evidence for the efficacy of oral
folds [33]. Nerve blocks and/or topical anesthet- systemic therapies is detailed in Table 26.1.
ics, to ease the pain associated with injection, Cyclosporine and methotrexate, in a compara-
may be performed prior to steroid injection [34]. tor trial, showed a 43.3 and 37.2% mean reduc-
Injections are repeated at various intervals. Side tion in NAPSI, respectively, over a 24 week
effects from intralesional steroids include pain on period [38]. The most robust efficacy data with
injection, skin atrophy, depigmentation, second- methotrexate is from a randomized double blind
ary infection, cyst formation, subungual hemor- trial of methotrexate and the experimental anti-
rhage, and tendon rupture [34]. Nonetheless, for interleukin-12/23 antibody briakinumab (a drug
a patient with one or two isolated psoriatic nails, no longer being studied). Methotrexate showed a
intralesional injection after ring block anesthe- 48% improvement in target nail NAPSI at 1 year
sia has been a useful method in the author’s prac- [36]. In a 6 month open label trial of acitretin for
tice. A trial comparing intra-matrix triamcinolone nail psoriasis there was a 41% mean reduction
Table 26.1 Efficacy of systemic therapies in nail psoriasis

Patients NAPSI
Agent Dose Length (n) Trial type improvement References
Methotrexate 15–20 mg/ 52 weeks 317 Randomized, double 48% [36]
weeks blind, controlled trial (no
placebo)
Acitretin 0.2–0.3 mg/ 24 weeks 36 Open-label 41% [37]
kg/day
Cyclosporine 5.0 mg/kg/day 24 weeks 37 Comparator (vs. 43.3% [38]
methotrexate)
Apremilast 30 mg bid 52 weeks 558 Randomized, double 60.2% [39]
blind, placebo controlled (ESTEEM 1)
phase III trials, 59.7%
subanalysis of patients (ESTEEM 2)
with baseline nail disease
Tofacitinib 5 mg bid 16 weeks 487 Randomized, double 16.9% [40]
10 mg bid 476 blind, placebo controlled (NAPSI-75)
phase III trials, 28.1%
subanalysis of patients (NAPSI-75)
with baseline nail disease
in NAPSI [37]. Apremilast, FDA approved for 58.1 and 82.3% of patients in the twice weekly/
psoriasis and psoriatic arthritis, has been studied weekly group and 50.5 and 80.7% in the weekly
in nail disease. In the phase III ESTEEM 1 and group at 12 and 24 weeks respectively [44]. In
2 studies, 66.1 and 64.7% of patients had nail a RDBPCT patients with psoriatic arthritis were
psoriasis (NAPSI ≥ 1). Mean percent change treated with placebo, golimumab 50 mg every
in target NAPSI score from baseline was −22.5 4 weeks, or golimumab 100 mg every 4 weeks
and −29% at week 16 and −43.6 and −60% at for 24 weeks. Median percent change in NAPSI
week 32 for ESTEEM 1 and 2 respectively [41]. at weeks 14 and 24 was 0%, 25%, 43%, and
In a post-hoc analysis of two phase III clini- 0%, 33%, and 54% for the placebo, golimumab
cal trials of tofacitinib in psoriasis, NAPSI was 50 mg, and golimumab 100 mg groups respec-
evaluated for patients with nail disease. NAPSI- tively. Patients in this trial for psoriatic arthritis
75 was achieved by 16.9, 28.1, and 8.8% at were allowed to use stable doses of methotrexate
16 weeks in the 5 mg bid, 10 mg bid and placebo and prednisone during the study [45]. Currently
groups respectively. Continued tofacitinib use golimumab is FDA approved for psoriatic arthri-
to 52 weeks demonstrated additional improve- tis but not for psoriasis. In a RDBPCT of inflix-
ment in nail disease [40]. These agents may be imab, patients were randomized to either placebo
an excellent option for a patient who is otherwise or infliximab 5 mg/kg at weeks 0, 2, 6, and every
a candidate for systemic therapy for psoriatic 8 weeks through week 46, with placebo cross-
disease. Combination treatment for nail psoria- over at week 24. Mean percentage improvement
sis, though widely used, is little studied. A 2004 in target nail NAPSI at week 10 and 24 was 26.8
study of oral cyclosporine and topical calcipotriol and 57.2%, compared with −7.7 and −4.1% for
showed that at 12 weeks the combination group infliximab and placebo respectively [52]. In a
showed 79% of patients with improvement com- retrospective analysis of patients from this same
pared with 47% of patients on cyclosporine alone infliximab study, mean NAPSI improvement was
[42]. Combination therapy with topical agents 28.3, 61.4, and 67.8%, at weeks 10, 24 and 50
and systemic therapy is frequently employed respectively [46].
in clinical practice and is likely safe and may No controlled comparisons of anti-TNF
be more effective than systemic therapy alone. agents in nail psoriasis have been performed.
Table 26.2 reviews the data on biologics in nail However, an open label prospective study showed
psoriasis. In a rare trial of a biologic, designed that infliximab was superior to adalimumab and
specifically to target patients with nail psoria- etanercept at 14 weeks [53]. A retrospective com-
sis, adalimumab showed a modified NAPSI 75 parison of these agents also showed high efficacy
response at 26 weeks in patients with and with- of all the TNF blocking agents in nail psoriasis
out psoriatic arthritis of 61.5 and 40.9% respec- with some greater improvement with infliximab
tively (placebo 0.5 and 4.6%) [50]. Adalimumab, [54]. The differences in efficacy of these agents
in a RPCDBT of patients with psoriasis involv- in nail psoriasis may parallel the differences
ing the hands and/or feet, demonstrated 50% seen in skin response. Infliximab may also have
improvement in NAPSI at 16 weeks compared an advantage in the speed to which clearance is
with 8% for placebo [43]. In a study evaluating achieved. However, after 4 months or more, all
both fingernails and toenails, open label adali- anti-TNF therapies are successful in improv-
mumab showed improvements at 6 months in ing nail disease by at least 50%, as measured
NAPSI of 85 and 72% in fingernails and toenails by NAPSI.
respectively [51]. An open label study of etaner- Robust data is also available for IL-12/23
cept in nail psoriasis compared patients random- blockade in nail psoriasis. Data from a large
ized to 2 dosing regimens; 50 mg twice weekly phase III trial of ustekinumab showed significant
for 12 weeks followed by 50 mg weekly for improvement in NAPSI compared with placebo at
12 weeks, or 50 mg weekly for 24 weeks. A 50% 12 weeks. Additionally, the ustekinumab 45 and
improvement in NAPSI was demonstrated in 90 mg groups showed 46.5 and 48.7% NAPSI
348 J. J. Crowley
Table 26.2 Efficacy of biologic therapies in nail psoriasis

Outcomes (note different
Patients primary outcome
Agent Dosing (n) Trial type Weeks measures) References
Adalimumab 80 mg/40 mg 72 RPCDBT in hand/ 16 50% reduction in [43]
eow foot psoriasis NAPSI (8% for
placebo)
Etanercept 50 mg biw/50 mg 711 Randomized dose 24 82.3% NAPSI 50 [44]
qw comparison response
Golimumab 100 mg q4 weeks 405 RPCDBT in 24 54% reduction in [45]
psoriatic arthritis NAPSI (0% for
placebo)
Infliximab 5 mg/kg weeks 378 RPCDBT, data from 50 67.8% reduction in [46]
0,2, and 6 then the open label NAPSI (49.2% with
q8 weeks extension complete nail
clearance)
Ustekinumab 45 or 90 mg at 545 RDBPCT 24 46.5% (45 mg), 48.7% [47]
weeks 0, 4, 16 (90 mg) reduction in
NAPSI
Secukinumab 150 or 300 mg at 198 RDBPCT of 32 52.6% (150 mg) and [48]
weeks 1–5 then patients with nail 63.2% (300 mg)
q4 weeks disease, data from reduction in NAPSI
the open label
extension
Ixekizumab 80 mg q2 or q4 1346 RDBPCT, 24 34 and 30% with no [49]
weeks for retrospective nail involvement
12 weeks then analysis of open (NAPSI = 0) on q2 and
80 mg q4 weeks label period q4 doses, respectively
eow every other week, NAPSI nail area psoriasis severity index, RDBPCT randomized double-blind placebo con-
trolled trial
improvement, respectively, at 24 weeks [47]. involvement on ixekizumab q2weeks/q4 weeks,

Long-term data with 68 weeks of ustekinumab and ixekizumab q4 weeks/q4 weeks, respectively.
in a Japanese study showed a 56.6 and 67.8% At 60 weeks, half of the patients with initial nail
improvement from baseline NAPSI in patients disease had a NAPSI = 0 while on continuous
treated with 45 or 90 mg of ustekinumab respec- ixekizumab. Secukinumab, another antibody to
tively [55]. IL-17A, was studied in a clinical trial specifically
Antibodies to interleukin 17-A and an interleu- designed to study patients with nail psoriasis.
kin 17 receptor antagonist are currently approved In the TRANSFIGURE study, mean improve-
for psoriasis. Data from a phase II dose finding ment of NAPSI from baseline was 10.8, 37.9,
trial of the anti-interleukin 17 antibody ixeki- and 45.3 at week 16 for placebo, secukinumab
zumab showed improvement of 57.1 and 49.3% in 150 mg, and secukinumab 300 mg, respectively.
NAPSI scores at the 75 and 150 mg doses respec- At week 32, in the open label period, a 52.6 and
tively at 16 weeks [56]. Further data with ixeki- 63.2% improvement in mean NAPSI was seen
zumab from the UNCOVER 3 phase III clinical for secukinumab 150 and 300 mg respectively
trial has also been published [49]. At week 12, [48]. Currently in development for psoriasis and
patients with baseline nail involvement showed psoriatic arthritis is bimekizumab which targets
reduction in NAPSI of 39, 40, 28, and −4.7% both IL-17A and IL-17F and data on efficacy in
in the ixekizumab every 2 weeks, ixekizumab nail disease will be forthcoming [57]. The rapid
every 4 weeks, etanercept 50 mg twice weekly, onset of action and high levels of efficacy make
and placebo groups, respectively. Additionally, these anti-IL-17 agents particularly attractive
at 24 weeks, 34 and 30% of patients had no nail for patients with extensive nail disease.
Treatment Approach to Nail Disease length of a clinical trial must reflect this delay.
Few studies, with the exception of the anti-IL
A treatment algorithm for nail psoriasis, based on 17 inhibitors and infliximab, demonstrate any
published data for treatment of nail psoriasis and significant improvement before 12 weeks and
expert opinion where data is lacking, has been several studies with adalimumab, etanercept,
previously published by the Medical Board of the infliximab, ustekinumab, ixekizumab, and
National Psoriasis Foundation [58] and is sum- scukinumab demonstrate continued improve-
marized here. All psoriasis patients should be ment up to and even beyond 6 months [44, 46,
evaluated for nail disease and the extent to which 53, 61].
their nail disease contributes to overall disease One of the problems in reviewing data on
burden. Nail disease should be classified as mild nail psoriasis is the lack of consistent outcome
if it has minimal impact on QoL and poses no reporting among the studies. Even when NAPSI
functional impact for the patient. Significant or data is presented, it may be presented in different
extensive nail disease has real impact on daily ways. Target nail NAPSI, mean improvement in
activities, may be disfiguring, and may be associ- NAPSI, percent of patients with no nail disease
ated with significant pain. Patients with signifi- (NAPSI = 0), and modified NAPSI, are some
cant nail disease need therapies to address their of the many outcomes reported. The dermatol-
nail psoriasis. Patients with moderate to severe ogy life quality index (DLQI) contains some
psoriasis and significant nail disease should be questions pertinent to nail signs and symptoms
treated with appropriate therapy which addresses but does not specifically account for the influ-
skin and nail disease. Previous consensus guide- ence of nail disease on QoL. Some researchers
lines for the treatment of moderate to severe pso- have used QoL measures validated in onycho-
riasis also apply to the patient with nail disease mycosis and applied these to psoriasis [62]. A
[59]. Options include cyclosporine, methotrex- validated measure specific to nail psoriasis, the
ate, acitretin, apremilast, and the biologics. NPQ10, has been published but not extensively
Patients with significant nail disease and psori- utilized [63]. Additionally, the Nail Assessment
atic arthritis (PsA) should be treated with an in Psoriasis and Psoriatic Arthritis (NAPPA) may
appropriate systemic treatment for PsA that has prove useful in evaluating response to therapy in
efficacy in nails. Data support the following nail disease [64]. Clearly there is a need for more
options in this patient group; methotrexate, apre- uniform reporting of nail outcomes and adoption
milast, the TNF inhibitors, IL-17 inhibitors and of a valid and easily performed QoL metric that
the IL-12/23 inhibitor. For the rare patient with is specific to nail disease.
nail disease as the primary manifestation of their
psoriatic disease, a 3–6 month trial of topical
therapy and/or intralesional injections may be Scalp Psoriasis
appropriate. For patients with severe nail disease
affecting QoL, systemic and biologic therapies Is scalp psoriasis difficult to treat? Indeed, it may
may be needed. Patients who have their skin and/ respond faster than other body regions to some
or joint disease well controlled but still have sig- biologic therapies but it remains a challenge to
nificant nail involvement may need combination obtain good results with both topical and photo-
topical therapy or intralesional injections. If this therapy. While the head and neck represent about
fails, a change in the systemic or biologic therapy 10% of the body surface area, the impact of pso-
may be warranted. riasis in this region may be disproportionate to
Improvements in nail psoriasis often trail the area, and may have social and emotional
the improvements in skin and joint disease. impacts on affected individuals. Most scalp pso-
Fingernails grow at a rate of 3–4 mm/month, riasis is treated with topical therapies including
thus it takes 5–7 months for a nail to grow from shampoos, oils, foams, liquids, and gels. Over the
matrix to distal fingertip [60]. Therefore, the counter remedies, containing tar, salicylic acid,
350 J. J. Crowley
zinc, and others are relatively inexpensive and ell-defined plaques with silvery scale and an
w
widely available. One of the reasons that scalp erythematous border (Fig. 26.3). Classic scalp
psoriasis has been labeled “tough to treat” is the lesions are asymmetric, sharply demarcated, cov-
difficulty with using and complying with topical ered with silvery-white or gray scale, and may
medications. Prescription topical therapy mainly extend beyond scalp margins to affect the fore-
involves the use of mid to high potency topical head, ear, and neck [76]. Most patients with pso-
steroids and topical vitamin D analogues. Many riasis of the face also have scalp disease [77].
larger trials for the biologics have had measures Multiple surveys have cited itching and scaling as
of scalp psoriasis as secondary endpoints. A few the most disturbing aspects of scalp psoriasis [78,
trials have been designed specifically to assess 79]. This itch may be so severe that it can inter-
scalp disease and these will be highlighted in this fere with sleep and lead to actual hair loss due to
chapter. Indeed, scalp psoriasis provides chal- hair breakage and trauma.
lenges to both practitioner and patient. Scalp psoriasis is usually not associated with
The incidence of scalp psoriasis in patients significant hair loss, however, some patients may
with psoriasis is estimated between 40 and 90 have alopecia due to the trauma of chronic itch-
percent. In up to half of patients, psoriasis may ing leading to hair breakage. In an analysis of
initially present on the scalp [65, 66]. Some 47 patients with psoriatic alopecia followed for
patients only have psoriasis on the scalp. The several years, many patients only had alopecia in
scalp is characterized by the presence of the some of the scalp plaques and indeed, as the pso-
prominent pilosebaceous unit and has a micro- riasis cleared, the hair regrew [80]. In some cases
biome that differs from other skin sites. Both the differentiation of scalp psoriasis and sebor-
yeast and bacteria colonize the scalp [67]. Indeed rheic dermatitis can be difficult. Seborrheic
Malessazia furfur, M. globosa, candida, and dermatitis is characterized by diffuse thin
other commensal organisms are found on the scale that is localized to the hair bearing scalp
scalp in significant numbers and may influence and may involve the central face and chest.
scalp diseases such as seborrheic dermatitis and Psoriasis, on the other hand, may extend
psoriasis [68, 69]. The role of these organisms in beyond the scalp, is sharply marginated, and
psoriasis is not well established but they likely may occur elsewhere on the body [81].
play a role. Treatments targeting these organisms
have shown some efficacy in seborrheic dermati-
tis [70, 71]. Friction and trauma to the scalp from Measuring Scalp Disease
scratching and hair grooming my also contribute
to scalp disease severity [72, 73]. A variety of measures have been developed to
Recent studies have shown that the hair in assess the extent and burden of scalp psoriasis
patients with scalp psoriasis may also be modified
by the presence of psoriatic inflammation. Indeed,
hair shafts evaluated in patients with psoriasis
reveal pits, thought to be analogous to the pit-
ting seen in nails [74]. Additionally, recent stud-
ies evaluating the transcriptome of both scalp and
body psoriasis suggest there may be differences in
gene activation between the scalp and body [75].
linical Presentation of Scalp

C
Psoriasis
Scalp lesions may vary from mild, with minimal

erythema and scaling, to severe with thick Fig. 26.3 Scalp psoriasis
Table 26.3 Measures of scalp psoriasis

Measure Parameters measured Max. score Description References
Psoriasis Scalp Extent of involvement, 72 Sum of 3 parameter scores (0–4) [82]
Severity Index erythema, induration, and multiplied by a score for the area of
(PSSI) desquamation of scalp involvement (1–6)
Scalp-modified Extent of involvement, 7.2 Sum of 3 parameter scores (0–4) [83]
PASI (S-mPASI) erythema, induration, multiplied by a score for the area of
desquamation of scalp involvement (1–6) times a constant
(0.1)
Head and Neck Extent of involvement, 7.2 Sum of 3 parameter scores (0–4) [84]
PASI (HN-PASI) erythema, induration, multiplied by a score for the area of
desquamation of head and involvement (1–6) times a constant
neck (0.1)
Total Severity Score Erythema, induration, 9 Sum of scores (0–3) for erythema, [85]
(TSS) desquamation of scalp induration, and desquamation
Scalp-specific Overall scalp disease, as −2 to +2 Current scalp disease severity [83]
Patient’s Global judged by the patient, as compared with baseline visit on a
Assessment compared to baseline 5-point scale; “much worse” (−2)
(SPaGA) involvement through “much improved” (+2)
Global Severity Overall scalp disease 5 Assessment of scalp disease from [85]
Score (GSS) measured by investigator “none” (0) to “very severe” (5)
Scalpdex Measure of symptoms, 0–100 Measures may be combined to form [78]
functioning, and emotions subscores for symptoms,
on scalp disease (23 items) functioning, and emotions
(Table 26.3). The Psoriasis Scalp Severity Index issue for many scalp psoriasis patients, may be
(PSSI) and the Scalp-modified PASI (S-mPASI) measured by a visual analogue scale [87] of itch.
are modifications of the standard PASI measure- Scalpdex is a validated measure of quality of life
ment of psoriasis [82, 83]. Both the PSSI and the for scalp conditions (not specific to psoriasis)
Sm-PASI measure erythema, induration, and des- that utilizes 23 questions that address symptoms,
quamation of the plaques of psoriasis on the scalp emotions, and functions surrounding the scalp
only in contrast to PASI where the entire body is condition [78].
evaluated. Some studies, including one on the
IL-17 inhibitor secukinumab, have utilized the
head and neck portion of the PASI score anagement of Scalp Psoriasis:
M
(HN-PASI) as a proxy for scalp involvement Topical Therapies
[84]. Other measures have also been used for
evaluation of scalp psoriasis including the Total Topical therapies are the foundation in the man-
Severity Scale (TSS), the Scalp-specific agement of scalp psoriasis and utilized by
Physicians Global Assessment (S-PGA), and the approximately 60% of patients [66]. These thera-
Global Severity Scale (GSS) [85]. A recent study pies have been formulated into shampoos, gels,
of 102 patients with predominately scalp psoria- foams, oils, and solutions. Some of these prod-
sis treated with secukinumab or placebo utilized ucts have been evaluated in large clinical trials.
a 90% improvement of PSSI and a 2 point High costs limit the use of many of these propri-
improvement in Investigators Global Assessment etary products. Calcipotriol is a synthetic deriva-
as the two primary endpoints to the study [86]. tive of calcitriol (Vitamin D3); calcipotriol binds
Patient assessment tools have also been devel- to the vitamin D3 receptor, but unlike calcitriol,
oped to evaluate scalp psoriasis. The Scalp- is a poor regulator of calcium metabolism. The
specific Patient’s Global Assessment (S-PaGA) efficacy and safety of calcipotriol solution sup-
has been utilized to gauge patient assessment of port its use as a first-line therapy as well as its use
disease change from baseline. Pruritus, a major as maintenance therapy [88, 89]. This treatment,
352 J. J. Crowley
however, can be associated with some burning, However, do patients adhere to treatment with
redness, dryness, and itching in some patients. topical therapy? There is some evidence that
The combination of calcipotriol and topical ste- optimizing the vehicle may improve adherence
roids decreases some of the irritation of calcipot- to scalp psoriasis treatments, however adherence
riol and is certainly more efficacious than to topical therapy for psoriasis is low [94]. Even
calcipotriol monotherapy. There may also be an with interventions to assist and remind patients
advantage to this combination due to the poten- to apply topical therapies, adherence is less than
tial protective effect of calcipotriol on corticoste- 50% after several weeks [95]. In clinical practice,
roid induced skin atrophy. the use of anti-dandruff shampoos is generally
Shampoos and foams containing high potency encouraged by dermatologists to help remove the
topical steroids such as clobetasol propionate scale from the plaques of psoriasis. The use of
0.05% have demonstrated improvement in scalp high potency topical steroids is usually limited
psoriasis in as little as 2 weeks. In these short, 2–4 to a few weeks but patients may continue to use
week studies, skin atrophy, folliculitis and telan- these products intermittently for months and even
giectasia were not observed [90, 91]. Clobetasol years. The use of topical vitamin D products,
propionate 0.05% shampoo was superior in effi- when available and when well tolerated, is also
cacy and tolerability compared with calcipotriol a reasonable approach to maintenance therapy.
0.005% solution [85]. In a study comparing 1% Many practitioners will utilize a high potency
tar blend shampoo with clobetasol shampoo, topical steroid 1 or 2 days per week and a topical
the clobetasol product was cosmetically more vitamin D analogue on the other days in an effort
acceptable to patients [91]. Betamethasone val- to minimize potential side effects of long term
erate 0.12% in a mousse (foam) vehicle was topical steroid use [96].
compared to topical corticosteroid solution and
calcipotriol lotion and showed superior efficacy
over 4 weeks. Most of these patients preferred Procedural Therapies for Scalp
the foam formulation [88]. An open label study Psoriasis
of the combination product (betamethasone/cal-
cipotriene) in patients 12–17 years of age showed Intralesional injection of corticosteroids has also
efficacy over 8 weeks with one patient demon- been used by dermatologists to address localized
strating mild adrenal suppression and no patients treatment resistant plaques of psoriasis with some
demonstrating hypercalcemia [92]. The authors success. Triamcinolone acetonide (5–10 mg/ml)
concluded that this treatment was safe and effica- is injected directly into the psoriatic plaques in
cious in adolescents with scalp psoriasis. small (0.1–0.2 ml) aliquots. The aim is to deliver
A 2016 Cochrane review of topical therapies the steroid directly into the area of inflammation
reviewed 59 randomized controlled clinical tri- in the dermis. This technique, however, has not
als in scalp psoriasis [93]. They concluded that been studied in a rigorous fashion [34].
a corticosteroid of high or very high potency Phototherapy for scalp psoriasis is limited
or a combination of a corticosteroid and vita- due to hair blocking the penetration of the light.
min D (calcipotriol) was superior to vitamin D Devices have been designed and are available
alone. The two-compound combination also led to help deliver phototherapy to the scalp. These
to fewer withdrawals from treatment compared devices use fiber-optics that penetrate through
to the other treatments. Further the authors con- the hair and deliver the phototherapy, broad-
cluded “Given the comparable safety profile and band or narrow-band UVB, directly to the scalp
only slim benefit of the two-compound combina- [97]. Additionally, the 308-nM laser can be used
tion over the corticosteroid alone, monotherapy to treat scalp psoriasis. In one study, 17 of 35
with generic topical steroids of high and very patients had >95% clearance after a mean of 21
high potency may be fully acceptable for short treatments [98]. In this study the hair was manu-
term therapy.” ally parted to gain access to the psoriatic plaques.
Notably, all patients demonstrated erythema and Apremilast, an oral phosphodiesterase 4

some blistering to treated sites. In another study, inhibitor, is approved for psoriasis and psoriatic
patients treated with the laser administered with arthritis. Scalp disease was evaluated as a sec-
a blow dryer to part the hair, had significant ondary endpoint in the two phase III psoriasis
improvement after twice weekly treatments for programs for apremilast. Scalp disease was mod-
up to 15 weeks [99]. Grenz ray therapy has also erate or greater in about two thirds of patients
been efficacious in scalp psoriasis. The lack of in these trials. Approximately half of those with
availability of Grenz ray therapy units and the baseline moderate scalp involvement achieved
potential for skin cancer formation in the treated a clear or almost clear PGA at 16 weeks. Most
area significantly limit this modality [100, 101]. patients who continued in trial maintained this
response out to 1 year [39, 41]. Apremilast may
be a reasonable option for patients with signifi-
Systemic Therapy for Scalp Psoriasis cant scalp disease.
There are few studies that specifically address the

efficacy of methotrexate, cyclosporine, and Biologic Therapy for Scalp Psoriasis
acitretin in scalp psoriasis. Nonetheless, these
therapies may be effective in treating scalp dis- The treatment of scalp psoriasis with biologics is
ease. Appropriate monitoring of liver function summarized in Table 26.4. There have been some
(methotrexate, acitretin), creatinine (cyclospo- studies specifically designed to evaluate scalp
rine, methotrexate), complete blood counts psoriasis. Etanercept, a TNF-fusion protein that
(methotrexate), triglycerides (acitretin), and binds TNF-alpha, was used in a study specifically
blood pressure (cyclosporine) should be main- addressing patients with scalp disease [102]. In
tained during treatment with these agents. this placebo-controlled trial, PSSI at week 12
Table 26.4 Efficacy of systemic therapies in scalp psoriasis

Outcomes (note different
Patients primary outcome
Agent Dosing (n) Trial type Weeks measures) References
Apremilast 30 mg biw 558 RPCDBT, 16 Scalp PGA of clear or [41]
subanalysis of almost clear (0 or 1) of
patients with 46.5% (ESTEEM 1)
moderate scalp and 40.9% (ESTEEM
involvement 2)
Etanercept 50 mg biw or 124 Placebo controlled 12 Improvement in PSSI [102]
placebo study in moderate from baseline 86.8%
scalp disease (vs. 20.4% for placebo)
Adalimumab 80 mg weeks. 0, 730 RPCDBT, 16 77.2% improvement in [103]
then 40 mg eow subanalysis of PSSI
patients with
baseline scalp
disease
Secukinumab 300 mg weeks. 102 RPCDBT in 12 52.9% PSSI [86]
0–4, then 300 mg patients with scalp improvement (2% for
q4 weeks psoriasis placebo)
Ixekizumab 80 mg weeks. 0, 3866 RDBPCT with 12 PSSI 100 response of [104]
then 80 mg q2 or etanercept 74.6, 68.8, 48.1, and
q4 weeks, also comparator arm 6.7% in Ixe q2w, Ixe q4
comparator arm wk, etanercept, and
with etanercept biw placebo respectively
biw twice weekly, eow every other week, RPCDBT randomized placebo-controlled double blind clinical trial, PGA
physician’s global assessment, PSSI psoriasis scalp severity index
354 J. J. Crowley
was improved by 86.8 and 20.4% in the etaner- not had a previous history of psoriasis [106, 107].
cept 50 mg biw group and placebo group respec- These cases have been reported with all the anti-
tively. Improvement continued in the open label TNF agents and the patients are often being
period to week 24. In a subanalysis of a larger treated for rheumatoid arthritis and inflammatory
trial of adalimumab in psoriasis, PSSI was bowel disease. The scalp, palms, soles, and other
improved by an median of 100% (mean 77.2%) body areas may be involved. Occasionally, these
at 16 weeks [103]. patients may have lesions consistent with pustu-
Blockade of interleukin-17 has also been stud- lar psoriasis [107]. Some patients can be treated
ied in scalp psoriasis. In a placebo controlled study with topical or phototherapy and remain on the
designed specifically for scalp disease patients, TNF agent while others may require discontinua-
secukinumab 300 mg achieved 90% improve- tion of the TNF inhibitor to control the eruption.
ment in PSSI in 52.9% of patients compared with The incidence of this eruption is between 1 and
2% on placebo at 12 weeks. Investigators global 2% of patients treated with anti-TNF agents
assessment of clear or almost clear was achieved [108]. The cause of this phenomenon is not well
by 56.9% on secukinumab and 5.9% on placebo elucidated but may involve compensatory
at 12 weeks [105]. In a subanalysis of larger phase increases in interferon in patients treated with
III trials for ixekizumab, scalp psoriasis was eval- anti-TNF’s [109].
uated [104]. Of patients with baseline scalp pso-
riasis, PSSI 90 and PSSI 100 at 12 weeks were
obtained by 81.7 and 74.6, 75.6 and 68.8, 55.5 and Palmoplantar Psoriasis
48.1, and 7.6 and 6.7, in the ixekizumab q2 weeks,
ixekizumab q4 weeks, etanercept 50 mg biw, and Psoriasis of the hands and feet may be one of the
placebo groups, respectively. Thus, more than half most difficult therapeutic dilemmas for the der-
of patients on etanercept, and over three quarters matologist. Palmoplantar psoriasis affects up to
of patients on ixekizumab had complete clearance 5% of patients with psoriasis [110]. First, how-
of scalp psoriasis at 12 weeks. ever, we need to define the spectrum of psoriatic
disease that can affect the palms and soles. There
are several distinct presentations of psoriasis on
reatment Algorithm for Scalp
T the palms and soles:
Psoriasis
• Plaque psoriasis of the hands and feet with
For limited scalp disease, treatment with potent significant psoriasis elsewhere (Fig. 26.4)
topical steroids with or without vitamin D deriva- • Plaque psoriasis of the hands and feet with
tives is a reasonable initial treatment. This may be little psoriasis elsewhere (palmoplantar psori-
augmented by OTC shampoos to remove scale. asis, PPP, Fig. 26.5)
For patients who fail to respond to a trial of topi- • Pustular psoriasis of the hands and feet (pal-
cal therapy, phototherapy (if available), and oral moplantar pustulosis, PPPP, Fig. 26.6). This
treatment with methotrexate or apremilast may be may also be called Acrodermatitis Continua of
appropriate. For patients who prove recalcitrant to Hallopeau, particularly when it involves bony
these therapies or for patients with significant resorption of the distal phalanx [111].
psoriasis elsewhere, biologic therapies that target • Psoriasiform dermatitis of the hands and
TNF or interleukin-17 are recommended. feet—with features of hand dermatitis and
psoriasis
TNF Induced Psoriasis These presentations represent distinct patient

populations that may respond differently to vari-
Paradoxically, treatment with anti-TNF agents ous therapies and may have differing genetic and
may induce scalp psoriasis in patients who have environmental factors involved in their disease
Recently, pustular psoriasis (particularly the

generalized form) has been associated with muta-
tions in the IL-36 receptor [112]. There is also
a small clinical trial demonstrating that an anti-
body that targets the IL-36 receptor is effective
in treating generalized pustular psoriasis [113].
Some PPPP patients have mutations in the IL-36
receptor but other genes are also implicated
including CARD14 and AP1S3. Notably, patients
with PPPP do not have mutations in PSORS1
which is common in patients with plaque psoria-
Fig. 26.4 Palm psoriasis in a patient with chronic plaque sis [114]. These genetic associations may provide
psoriasis therapeutic targets to address PPPP in the future.
A key factor in palmoplantar disease is dis-
ability. The use of the hands and feet may be
significantly compromised by disease. The
scale, fissures, cracking, and hyperkeratosis can
lead to pain with movement. Chung et al. evalu-
ated the quality of life (QoL) of patients with
PPP and compared them with plaque psoriasis
[115]. These patients were receiving treatment
with systemic or phototherapy. The palmoplan-
tar psoriasis patients had significantly more
impairment in QoL characterized by limitations
Fig. 26.5 Severe palmoplantar plaque psoriasis in a of mobility, self-care, and pursuing usual activi-
patient with minimal psoriasis on body ties. Additionally, palmoplantar patients were
more likely to be taking multiple topical and oral
therapies for their disease. Others have reported
on physical disability and discomfort associated
with PPP [116]. Smoking appears to play a role
in palmoplantar disease and there is some data
suggesting that pustular disease severity may
improve with smoking cessation [117].
There are few controlled clinical trials
addressing treatments for palmoplantar disease.
Most treatment has been based on case series,
small clinical trials, and anecdotal clinical evi-
dence. If you were to ask 10 dermatologists for
their top five treatments for hand and foot psori-
atic disease, you would get dramatically differ-
Fig. 26.6 Palmar pustular psoriasis. Note resorption of ent answers. Reviews of the literature have also
distal digits and extensive pustules. These are features of yielded differing recommendations for treatment
a variant of pustular psoriasis termed acrodermatitis con-
tinua of Hallopeau of palmoplantar psoriasis. Seravin et al. con-
cluded in 2013 “Phototherapy, cyclosporine and
topical corticosteroids seem to be able to control
development. This review will focus on plaque PPPP. However, the standard of care for PPPP
psoriasis of the hands and feet (PPP) and pustular remains an issue and there is a strong need for reli-
psoriasis of the hands and feet (PPPP). able RCTs to better define treatment strategies for
356 J. J. Crowley
PPPP” [118]. The National Psoriasis Foundation the 16 week placebo controlled period. At week
concluded in a 2012 review of treatments for pus- 16, 46 and 25% of patients showed a PP-PGA
tular psoriasis that “acitretin, cyclosporine, meth- of clear or almost clear for the apremilast and
otrexate, and infliximab are considered to be first placebo groups, respectively [130]. Thus, acitre-
line therapies in generalized pustular disease” tin, cyclosporine, and apremilast all demonstrate
[119]. All sources conclude that better data is some efficacy in PPP and/or PPPP. However,
needed to guide clinical decisions regarding treat- there are no randomized placebo controlled stud-
ment. Topical steroids, Vitamin D analogues, tar ies specifically addressing these systemic agents
and anthralin preparations, either by themselves in PPP or PPPP.
or in combination, and under occlusion have all The biologics have also been studied in PPP
been reported to improve psoriasis and are regu- and PPPP. Adalimumab was studied in patients
larly used in palmoplantar disease. In a compara- with at least moderate plaque psoriasis of the
tive trial, in PPP, of clobetasol plus tar compared hands and feet and moderate to severe plaque pso-
with topical psoralen plus UVA, both treatments riasis elsewhere [43]. In this placebo c ontrolled
were effective [120]. Phototherapy with psoralen trial, 31% of patients in the adalimumab group
plus UVA (PUVA), and narrowband UVB, have were able to achieve a hand/foot PGA of clear or
shown some efficacy in hand and foot disease almost clear at week 16, compared to only 4% in
[121]. Multiple small studies and case series have the placebo group. In a study of 24 palmoplan-
demonstrated the efficacy of the 308 nM laser in tar psoriasis patients randomized to placebo or
the treatment of palmoplantar disease [122–124]. infliximab infusions, more patients reached 75%
A recent comparison of paint PUVA (psoralen improvement in palmoplantar PASI in the inflix-
not ingested but instead painted on the skin) and imab group (33.3 vs. 8.3%), but this did not reach
broad band UVB showed improvement with both statistical significance [131]. Success with treat-
treatments but more complete and longer remis- ing PPP and PPPP has also been demonstrated
sions with paint PUVA [125]. Another study used in case reports with etanercept [132, 133]. The
a split hand design to treat one side with narrow- TNF inhibitors do appear to show some efficacy
band-UVB and the other with topical PUVA. The in treating PPP, but this efficacy is significantly
PUVA side fared better than the hand treated with attenuated compared with overall plaque psoria-
narrowband UVB [126]. Thus, topical therapies sis results.
and phototherapy may be beneficial in treating Ustekinumab, in an open label study of
palmoplantar psoriasis. patients with PPP and PPPP, cleared 35% (7/20),
Systemic treatments for palmoplantar disease however the 90 mg dose was superior to 45 mg
have also been studied. Methotrexate (0.4 mg/ [134]. The interleukin-17 inhibitors have been
kg weekly) and acitretin (0.5 mg/kg daily) were studied in both PPP and PPPP. In a subanaly-
studied in an active comparator trial of 111 PPP sis of the large phase III trials of ixekizumab in
patients [127]. Both treatments showed improve- psoriasis, patients with significant palmoplantar
ment but methotrexate significantly improved disease (PP-PASI of ≥8) at baseline were evalu-
more patients. Wald et al. published a series ated [135]. This analysis involved 105 patients
of 48 hand foot psoriasis patients treated with (total study n = 1224) and revealed PP-PASI
methotrexate, most in combination with other 75 and PP-PASI-100 results of 16.7, 44.1, 81.8,
therapies, and concluded that methotrexate was 74.2 and 5.6, 29.4, 45.5, and 51.6 in the placebo,
effective in PPP [128]. In a study of cyclosporine etanercept 50 mg biw, ixekizumab q2 weeks,
in PPPP, most patients improved on relatively low and ixekizumab q4 weeks, respectively. Thus,
doses (1–2 mg/kg/day) of cyclosporine [129]. In roughly half of the ixekizumab treated patients
a pooled analysis of phase II and two phase III achieved total clearance of their plaque pso-
trials of apremilast, a phosphodiesterase 4 inhibi- riasis of the hands and feet. Secukinumab was
tor, in psoriasis, patients with baseline palmo- studied in a placebo controlled trial of patients
plantar physicians global assessment (PP-PGA) with moderate to severe palmoplantar psoriasis
of moderate or greater were evaluated during [136]. Many of these patients would not have had
enough psoriasis to meet enrollment criteria for 2. de Jong EM, Seegers BA, Gulinck MK, Boezeman
JB, van de Kerkhof PC. Psoriasis of the nails asso-
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1998;139(6):997–1004. Austria, October, 2016
Psoriasis and Comorbidities
27
Philip M. Laws and Richard B. Warren
Abstract evant primary and secondary care prevention

strategies. Additionally, effective control of
Psoriasis is increasingly recognised as one of
the inflammatory burden of psoriasis may
a group of immune-mediated inflammatory
modify the risk of comorbidities associated
diseases (IMIDs) with overlapping pathogen-
with psoriasis and would support earlier use of
esis. The ability to detect diseases associated
immunomodulatory therapies. This chapter
with psoriasis has been complemented through
will cover the comorbidities (including car-
interrogation of large datasets utilising
diovascular disease [CVD], metabolic syn-
genome wide association scans to demonstrate
drome and malignancy) associated with
overlapping genetic risk factors of associated
psoriasis and consider how these factors may
diseases. Many of these associated conditions,
influence or impact on management of the
such as psoriatic arthritis and inflammatory
patient.
bowel disease have a significant impact on
morbidity. In addition the inflammatory bur-
den associated with psoriasis is associated Key Learning Objectives
with a myriad of systemic sequalae including 1. To review systemic comorbidities asso-
higher levels of cardiovascular risk. This pro- ciated with psoriasis
vides the dermatologist with an opportunity to 2. To review the health implications of

holistically treat a patient and to promote rel- these comorbidities
3. To review treatment strategies to address
P. M. Laws these comorbidities
Department of Dermatology, Leeds Teaching 4. To review the published literature on

Hospitals, The University of Leeds, Leeds, UK comorbidities
Dermatological Sciences, Manchester NIHR
Biomedical Research Centre, Salford Royal Hospital,
The University of Manchester, Manchester, UK
e-mail: [email protected] Introduction
R. B. Warren (*)
The Dermatology Centre, Leeds Teaching Hospitals, Psoriasis is increasingly recognised as one of a
The University of Leeds, Leeds, UK group of immune-mediated inflammatory dis-
The Dermatology Centre, Manchester NIHR eases (IMIDs). Recent progress in the under-
Biomedical Research Centre, Salford Royal standing of psoriasis immunopathogenesis has
Hospital,The University of Manchester, Manchester, UK

https://doi.org/10.1007/978-3-030-54859-9_27
364 P. M. Laws and R. B. Warren
identified a number of immune cells, including dyslipidaemia where standardised criteria are
from the innate and adaptive immune system, not universally established.
being important players with the Th17 cell play- 2. Study cohort—May involve hospital (in-patient
ing a pivotal role. Progress in understanding the or out-patient), community or mixed groups.
pathogenesis of psoriasis has also been comple- Access to healthcare in many c ountries is vari-
mented by a greater awareness of psoriasis as a able depending on health insurance. These fac-
disease of chronic inflammation associated with tors can result in selection bias. Additionally
a myriad of systemic sequalae. The identification exposure to health professionals increases for
of psoriatic arthritis as distinct from other rheu- patients attending specialist clinics and may
matological disease heralded the beginning of affect the detection rate of comorbid disease.
this appreciation that psoriasis is more than “skin 3. Confounders—Psoriasis is associated with

deep”. increased prevalence of adverse lifestyle
The ability to detect diseases associated with behaviours which may also be associated with
psoriasis has been enabled through large datasets comorbid conditions and are not easily
including use of genome wide association scans adjusted for, or evaluated.
and interrogation of large populations of patients
with psoriasis. These studies have identified a
wide range of associated diseases which have a Obesity
significant impact on morbidity and mortality
and afford an opportunity to ensure appropriate Obesity, defined by a body mass index (BMI) of
primary and secondary prevention strategies are ≥30 kg/m2, is a growing public health concern glob-
employed. Effective psoriasis therapy may also ally. In the United States in 2015 prevalence data
mitigate, or reduce, the risk of comorbidities indicates that 39.8% of the population (93.3 million
associated with psoriasis. people) are affected [1]. Obesity is associated with
This is perhaps of the greatest relevance with an increased risk of multiple comorbid conditions
respect to cardiovascular disease which is associ- including hypertension, dyslipidaemia, Type II dia-
ated with psoriasis. If effective treatment of pso- betes mellitus, coronary heart disease, stroke, osteo-
riasis moderates risk of cardiovascular disease arthritis, sleep apnoea and certain cancers
one could argue that earlier treatment could (endometrial, breast, ovarian and colon) [2–4].
improve prognosis. Adipose tissue is an active metabolic tissue with
This chapter will cover the comorbidities multiple physiological roles including energy stor-
(including cardiovascular disease [CVD], meta- age, endocrine signalling, thermoregulation, lipid
bolic syndrome and malignancy) associated with and carbohydrate metabolism, coagulation and
psoriasis and consider how these factors may inflammation. Excess adipose tissue consequently
influence or impact on management of the may have profound impact on the physiology
patient. The reader is referred to Chap. 4 for a beyond CVD risk. Increasing adiposity results in
review of psoriatic arthritis. hypertrophy of the adipocyte which results in a rela-
Current evidence for psoriasis and associated tive hypoxic stress, leading to a low grade inflam-
comorbid diseases are subject to numerous limi- matory diathesis [5]. This is most pronounced and
tations including: relevant to visceral adiposity compared with subcu-
taneous adipose tissue [6]. Visceral adipose tissue is
1. Diagnostic criteria—Many studies involving associated with a greater burden of vascular inflam-
large-scale databases utilise either a diagnos- mation, a marker of subclinical CVD [7].
tic code or use of disease specific therapies to The association between body weight and pso-
identify patients. Reliability of this technique riasis was first suggested in 1986 in an observa-
is variable depending on the dataset being tional study of 159,200 Swedish patients with
studied. Diagnostic criteria may also differ by psoriasis [8]. This was later supported by Henseler
geographical location or clinical environment. and Christophers who observed an association
This is particularly true for conditions such as between psoriasis and obesity with an observed/
27 Psoriasis and Comorbidities 365
expected ratio for obesity of 2.05 (p < 0.05) [9]. (BMI ≥ 30 kg/m2) patients respectively [23]. The
More recently a study using the UK General authors calculated the population attributable risk
Practice Research Database (GPRD), a primary- of psoriasis related to elevated BMI was 16% [23].
care records database established for large-scale Additional support for this association has been
epidemiological studies, examined a cohort of published from a Norwegian study (HUNT) of a
127,706 patients with mild psoriasis and 3854 population of 33,734 which reported that an
patients with severe psoriasis and demonstrated a increase in body weight of 10 kg or more conferred
significantly increased obesity prevalence of 15.8 a relative risk of incident psoriasis of 1.72 (95% CI
and 20.7% respectively compared with 13.2% in 1.15–2.58) compared with stable body weight [17].
the control group [10]. For patients with severe This has also been reported in other ethnic group
psoriasis this equates to an odds ratio of 1.79 including a Korean population. Abdominal obesity
(95% CI, 1.55–2.05) when compared with the was reported as conferring a Hazard ratio for inci-
control group [10]. These findings are supported dent psoriasis of 1.31 (95% CI 1.26–1.35) for indi-
by several other studies across a range of cultural viduals with a waist circumference of >105 cm
and ethnic groups (Table 27.1) [12–15, 19, 20]. when compared with a waist circumference of
Large-scale clinical trials investigating the effi- 80 cm. This remained valid even after adjusting for
cacy of biologic agents in the treatment of psoria- confounders including BMI [18].
sis emphasise the prevalence and impact of obesity The relationship between psoriasis and obe-
in psoriasis management. A study of 2897 patients sity is complex and is likely to be multifactorial
with moderate to severe psoriasis (PASI ≥ 12) including immune mediated, genetic and behav-
involved in the PHOENIX 1, PHOENIX 2 and ioural. The pathogenesis of psoriasis and obesity
ACCEPT studies demonstrated that 80.4% of have some features in common and this may pro-
patients were overweight (BMI ≥ 25 kg/m2) and vide a mechanism for co-association of the two
47.9% were obese (BMI ≥ 30 kg/m2) [21]. This conditions. It is well established that psoriasis is
pattern of obesity is repeated across the majority a chronic, inflammatory disease of the skin which
of phase 3 clinical trials for psoriasis. is mediated through immune cells including Th1
Whilst the evidence linking psoriasis and obe- and Th17; activated following interaction with
sity is compelling the relationship is complex. antigen presenting cells including keratinocytes
Herron et al. provided evidence that obesity is [24]. Proinflammatory cytokines (interferon-γ
almost twice as common in psoriasis patients as in (gamma) (IFNγ (gamma)), tumour necrosis
the general population (34% compared with 18%) factor-alpha (TNFα (alpha)), interleukin(IL)-17
[20]. Based on a questionnaire of patient percep- and IL-22) are up regulated in concert with this
tion of body weight and date of psoriasis disease expansion of lymphocytes. This proinflammatory
onset it was concluded that psoriasis predisposed state results in elevated systemic inflammatory
an individual to developing obesity, and that obe- markers and is reversible with the treatment of
sity was not a risk factor for onset of psoriasis. skin disease [25, 26]. Obesity is a disease of
In contrast the Nurses’ Health Study II provided chronic, low grade inflammation associated with
evidence that obesity increases the relative risk of elevated levels of C reactive protein (CRP),
incident psoriasis [22]. In an observational study TNFα (alpha), IL-6, IL-17 and other cytokines
involving 78,626 nurses followed up over 14 years [27]. TNFα correlates with the degree of adipos-
the relative risk of developing psoriasis was 1.40, ity, a cytokine intrinsically linked with the patho-
1.48 and 2.69 for BMI of 25.0–29.9, 30.0–34.9 and genesis of psoriasis [28]. It is well established
≥35 kg/m2 respectively [22]. Additionally, this that Th17 cells play a pivotal role in the patho-
study suggested that the greatest risk of psoriasis genesis of psoriasis. Th17 cells also play a sig-
was in those individuals who gained weight after nificant role in obesity providing another
the age of 18 years [22]. In support of this data an mechanistic overlap underpinning the close rela-
Italian cohort of 560 patients demonstrated the tionship between obesity and psoriasis [29].
odds ratio for incident psoriasis was 1.6 and 1.9 for Weight loss is associated with reduced, or nor-
overweight (BMI 26–29 kg/m2) and obese mal, levels of overlapping proinflammatory cyto-
366
Table 27.1 Summarising large scale studies (n > 1000) reporting risk of psoriasis and obesity
Incidence/
Number Prevalence in cohort Prevalence in controls OR/PR (95% prevalence
References Country Cohort Number patients controls % (n) % (n) CI) psoriasis
Henseler 1995 [9] Germany DO 2941 NA 113 NA OE 2.05 P
Neimann 2006 [10] UK G M 127,706 465,252 15.8 (13,404) 13.1 (36,117) 1.27 P
S 3854 14,065 20.7 (545) 13.0 (1093) (1.14–1.42)
1.79
(1.55–2.05)
Cohen 2008 [11] Israel G 16,851 48,681 24.5 (3060) 15.6 (3790) 1.7 (1.5–1.9) P
Kaye 2008 [12] UK G 44,164 219,784 6.3 (2760) 5.5 (11,996) 1.18 I
(1.14–1.23)
Shapiro 2011 [13] Israel DI 1079 1079 13.3 (143) 8.7 (94) 1.32 P
(0.99–1.75)
Augustin 2010 [14] Germany G 33,981 1,310,090 17.8 10.4 1.72 P
(1.68–1.76)
Huerta 2007 [15] UK G 3994 10,000 11.3 (452) 8.8 (883) 1.33 P
(1.16–1.52)
Langan 2011 [16] UK G 4065 40,650 23.5 (887)a 20.5 (7678)a 1.52 P
17.5 (662)b 13.1 (4907)b (1.37–1.68)a
1.78
(1.59–1.98)b
Snekvik 2017 [17] Norway G 33,734 population assessed for RR psoriasis per 10 kg weight gain 1.72 (1.15–2.58) I
incident psoriasis
Han 2019 [18] Korea G 399,461 22,633,536 BMI > 30 HR 1.118 (1.100–1.137) compared with BMI 18–23 I
M mild psoriasis, S severe psoriasis, G general population, DI dermatology inpatient, DO dermatology outpatient, CI confidence interval, HR hazard ratio, OR odds ratio, OE
observed/expected ration, RR relative risk
a
BMI 30–35
b
BMI > 35
P. M. Laws and R. B. Warren
kines [30]. It is interesting to note that psoriasis response to treatment in some biologic agents
has been reported to improve with weight loss [40–42]. This is particularly true of fixed dose
strategies, including surgical interventions [31, biologic therapies. Response rates with adalim-
32]. In 3 RCTs weight loss did provide a modest umab decrease across weight quartiles such that
benefit in psoriasis severity and supports the in a cohort of 1212 patients after 16 weeks weight
hypothesis of low grade inflammation associated groups 40–78, 78–90, 90–105, and 105–204 kg
with adiposity exacerbates psoriasis severity [33]. achieve PASI 75 in 75, 80, 67 and 62% respec-
Adipose tissue is an active endocrine tissue and tively in comparison to 2.3–13.3% in the placebo
is associated with multiple adipokines which have arm [43]. Treatment with ustekinumab also
been implicated in several pathological processes, appears to be adversely affected by body weight.
perhaps most notably cardiovascular disease. Within the PHOENIX 2 cohort (n = 1230)
Leptin is an adipokine directly related to the vol- patients who were partial responders (PASI
ume of adipose tissue. In addition to control of 50–75) were on average 7.4 kg heavier than pri-
appetite leptin has immunomodulatory activity mary responders (PASI 75) [44]. This has been
[24], influencing the development of a Th1 or Th2 supported by review of clinical experience of
inflammatory profile. Leptin activates macrophage ustekinumab [45, 46]. As such the variable dos-
and potentiates proinflammatory cytokines. ing of ustekinumab offers a valuable dose escala-
Adiponectin is an important adipokine with tion for heavier patients. IL-17 inhibitors do not
anti-inflammatory properties and is inversely cor- appear to be affected by obesity based on clinical
related with obesity, lower levels being associ- trial data to date [47] Apremilast may also be an
ated with CVD. Adiponectin promotes the release appealing option for some patients due to associ-
of IL-10 and IL-1 receptor antagonist and inhib- ated weight loss [48].
its the production of TNF-α, IL-6, and ICAM-1. In summary, obesity and psoriasis are intrinsi-
Adiponectin has been reported to have an inverse cally linked and share several pathogenic fea-
relationship with psoriasis severity [34]. tures. Obesity is more frequently observed in
The role of leptin and other adipokines (adipo- psoriasis, particularly severe psoriasis, and com-
nectin, resistin, visfatin) in relation to psoriasis plicates treatment options. Given this relation-
has been the focus of a review [35]. The relationship, and the reduced efficacy of treating psoriasis
ship between psoriasis and these adipokines, in obese individuals, weight loss strategies are
including leptin, remains to be fully elucidated clearly of great importance in managing over-
but may prove important in understanding the weight patients.
relationship between metabolic dysfunction and
psoriasis [24].
Dyslipidaemia
Treatment Considerations
Treatment of psoriasis remains a significant chal- The relationship between psoriasis and dyslipi-
lenge and is adversely affected by obesity. daemia has been the focus of several recent stud-
Standard systemic therapies are less effective in ies (Table 27.3) [10, 12, 14, 16, 49–52, 54, 57]
overweight patients and more frequently compli- Perhaps the greatest challenge when considering
cated by side effects (Table 27.2) [38]. any potential relationship between psoriasis and
Treatment of psoriasis with biologic therapies dyslipidaemia relates to the lack of a single dis-
can be complicated by increased body weight crete definition of dyslipidaemia, resulting in
and obesity [21]. This is further complicated by challenges when collating population based data.
evidence that weight gain is commonly observed Despite the challenge, multiple studies have sug-
in patients treated with TNFi and may be 2–3 kg gested a potential link with psoriasis and elevated
depending on the TNFi being considered [39]. triglycerides (TG), low density lipoprotein
Body weight, rather than BMI, has been noted to (LDL), very low density lipoprotein (VLDL),
be most influential in determining clinical and reduced high density lipoprotein (HDL). The
368
Table 27.2 Describing contraindications and risk of side effects of psoriasis treatments with respect to comorbid conditions observed in association with psoriasis
Multiple
Diabetes Dyslipidaemia Obesity Hypertension NAFLD CCF IHD sclerosis Malignancy IBD Depression
Methotrexate ± + ± increased + ± + + +b − + +
hepatotoxicity
Cyclosporine – – − increased – + − − + – + +
nephrotoxicity
Acitretin + – − increased + + + + + ++ +a +
dyslipidaemia
Fumaric acid + + + + + + + ++ ?+ − +
esters
Apremilast + + ++ + + + + + + ± ?±
TNF Etanercept + + + May induce + + − Avoid ++b − − ++ +
inhibitors weight gain in
NYHA
Adalimumab + + + ++b ++ +
Class I,
Infliximab + + + II and IV ++b ++ +
IL-12/23 Ustekinumab + + + + + + + + ?+ ++ +
inhibitors
IL17 Secukinumab + + + + + + + + ?+ – +
inhibitors Ixekizumab + + + + + + + + ?+ – +
Brodalumab + + + + + + + + ?+ – ?+
IL-23 Guselkumab + + + + + + + + ?+ ++ +
Inhibitors Risankizumab + + + + + + + + ?+ ++ +
Tildrakizumab + + + + + + + + ?+ ++ +
++ recommended treatment + acceptable/no contraindication to treatment, ± equivocal option (may be increased risks), − relatively contraindicated or caution required, – con-
traindicated NAFLD non-alcoholic fatty liver disease, CCF congestive cardiac failure, NYHA New York Heart Association, IHD ischaemic heart disease, IBD inflammatory bowel
disease
a
Acitretin has been demonstrated effective in reducing progression of actinic keratosis to squamous cell carcinomas in small studies [36]
b
Evidence from limited studies suggest a reduced risk of CVD following effective treatment with methotrexate and TNFα inhibitors [37]
?+ acceptable/no contraindication but lacking longer term evidence/real world data
? prefix implies possible beneficial/adverse association but requires further study
Table 27.3 Summarising large scale studies (n > 1000) reporting associated risk of psoriasis and dyslipidaemia
Number Number Prevalence in cohort Prevalence in controls Incidence/
References Country Cohort patients controls % (n) % (n) OR/RR prevalence
Dreiher 2008 [49] Isr G 10,669 22,996 56.9 (6074) 47.3 (10,882) 1.19 (1.40–1.55) P
Neimann 2006 [10] UK G 127,706 465,252 4.72 (6024) 3.29 (15,297) 1.16 (1.12–1.21) P
27 Psoriasis and Comorbidities
3854 14,065 6.02 (232) 3.56 (501) 1.04 (0.84–1.28)

Kaye 2008 [12] UK G 44,164 219,784 4.3 (1900) 3.7 (8111) 1.17 (1.11–1.23) I
Langan 2011 [16] UK G 4065 40,650 35.7 (1453)a 27.5 (11,181)a 1.49 (1.39–1.60)a P
24.7 (1007)b 20.1 (8180)b 1.32 (1.22–1.43)b
Tsai 2011 [50] Tai G 51,800 997,771 7.7 (3968) 5.4 (11,111) 1.61 (1.54–1.68) P
Yang 2011 [51] Tai G 1685 5055 18.5312 15.1762 1.28 (1.10–1.48) P
Augustin 2010 [14] Ger G 33,981 1,310,090 29.9 17.05 1.75 (1.72–1.78) P
Wu 2008 [52] USA G 1127 1127 – – 1.35 (1.11–1.63) P
Kimball 2008 [53] USA G 20,614 82,456 31.2 (6432) 31.6 (8065) 1.26 (1.22–1.30) P
25,556 101,507 27.8 (22,941) 26.8 (27,239) 1.18 (1.14–1.22)
Gelfand 2006 [54] UK G M 127,139 556,995 4.58 (5822) 3.33 (18,534) 3.08 (2.93–3.23) P
S 3837 5.92 (227) 3.18 (3.02–3.36)
Fernandez-Armenteros Spain G 6868 398,701 28.8 (1979) 17.4 (68,201) 1.92 (1.82–2.03) P
2019 [55]
Al-Mutairi 2009 [56] Kuwait DO 1661 1835 Mild 14.1 (249) 4.96 (91) Mild 3.38 P
Severe 22.48 (29) (2.63–4.34)
Severe 5.56
(3.49–8.83)
Isr Israel, Ger Germany, Tai Taiwan, M mild psoriasis, S severe psoriasis, G general population, DI dermatology inpatient, DO dermatology outpatient, CI confidence interval,
HR hazard ratio, OR odds ratio, OE observed/expected ration
a
Hypertriglyceridaemia
b
Low LDL
369
relationship between psoriasis and lipid abnor- duration) and 285 controls a modest elevation of
malities is complicated by other features of the VLDL cholesterol: triglyceride ratio, HDL-
metabolic syndrome (see Section “Metabolic cholesterol concentration and HDL cholesterol:
Syndrome”) which are themselves associated triglyceride ratio was identified in the psoriasis
with psoriasis. cohort [59].
A recent systematic review of epidemiological Dyslipidaemia has also been reported in psori-
studies found a trend towards dyslipidaemia in atic arthritis patients following analysis of a
psoriatic patients in 7 of 12 studies with an odds cohort of patients (n = 725) in the Consortium of
ratio (OR) of 1.0 (95% CI 1.0–1.3) to 2.09 (95% Rheumatology Researchers of North America
CI 1.23–3.54) [58]. A national database study of (CORRONA) registry. An abnormal total choles-
UK patients registered via general physician terol (TC) (>200 mg/dl) with an odds ratio
records (General Practice Research Database (OR) = 1.58 (95% CI 1.11, 2.24) and abnormal
[GPRD]) demonstrated a statistically significant triglycerides (TG) (>150 mg/dl), OR = 1.64 (95%
increased prevalence of hypertriglyceridaemia CI 1.16, 2.32) was reported [60].
and low HDL cholesterol in a pooled cohort of Despite multiple sources identifying a rela-
4065 psoriasis patients in which 35.7 and 24.7% tionship between psoriasis and dyslipidaemia this
fulfilled criteria for hypertriglyceridemia and low relationship is not universal and other studies
HDL cholesterol respectively compared to 27.5 have failed to identify a relationship [11]. This
and 20.1% in the control group [16]. This has perhaps serves to emphasise the challenge of
been further supported by an observational study studying the relationship between psoriasis and
utilising a healthcare database in Spain which multiple comorbidities which overlap within the
reported a higher prevalence of multiple cardio- context of the metabolic syndrome. Further com-
vascular risk factors in psoriatic patients complicating this relationship, multiple adverse life-
pared to the general population including: style factors are associated with patients with
diabetes mellitus type 2 (13.9 vs. 7.4%, OR 2.01), psoriasis further compounding this issue (e.g.
dyslipidaemia (28.8 vs. 17.4%, OR 1.92), hyper- exercise and diet).
tension (31.2 vs. 19.0%, OR 1.93), obesity (33.7 In addition to an association between psoriasis
vs. 28.1%, OR 1.30), altered fasting basal glycae- and dyslipidaemia evidence from a small clinical
mia (21.4 vs. 15.1%, OR 1.54), low cholesterol study has reported functional activity and com-
HDL (38.1 vs. 32.3%, OR 1.29), hypertriglyceri- position of HDL cholesterol (a cardioprotective
demia (45.7 vs. 35.2%, OR 1.55) and high waist lipoprotein) improves with effective anti-psoriatic
circumference (75.7 vs. 72.3%, OR 1.19) [55]. therapy. This suggests that psoriasis may impact
Al-Mutairi et al. have reported an association on normal lipid metabolism, potentially via low
between psoriasis and dyslipidaemia in a Kuwait grade chronic inflammation [61].
population. In a cohort 1835 patients, 1661
(90.5%) had mild/moderate disease and 129 Treatment Considerations
(7.0%) had severe psoriasis. Despite adjustments Dyslipidaemia does not generally present a sig-
for potential confounders patients with mild or nificant challenge in terms of therapeutic options
moderate disease had an aOR for dyslipidaemia for the dermatologist except in regards to manag-
of 3.4 (95% CI 2.6–4.3). Patients with severe ing cardiovascular disease risk or when consider-
psoriasis had an aOR for dyslipidaemia of 5.55 ing treatment with acitretin or ciclosporin.
supporting a dose response relationship (95% CI Despite the diverse studies and challenges of
3.49–8.83) [56]. interpreting data associated with a variable defi-
Mallbris et al. report that lipid abnormalities nition of dyslipidaemia the evidence of an asso-
may be observed at psoriatic disease onset [59]. ciation with psoriasis is compelling [62]. The
This included elevation of apolipoprotein A-1 causality of this relationship is less clear and
and cholesterol: triglyceride ratios. In a cohort of remains to be elucidated; complicated in part by
200 patients with incident psoriasis (≤12 months other features of metabolic syndrome.
Hypertension use, and sociodemographic factors (HR 1.18

[95% CI 1.08–1.28]).
Hypertension is associated with an increased risk The role of inflammation has been implicated
of cardiovascular (CV) morbidity and mortality. in several previous studies in psoriatic patients as
Several large data sets, across a range of ethnic a potential mechanism linking psoriasis with
groups, have explored the relationship between hypertension [11, 70]. Elevated serum concentra-
psoriasis and hypertension (Table 27.4). Whilst tions of renin, known to increase blood pressure,
the majority of studies indicate an increased rela- have been reported in patients with psoriasis [71,
tive risk of hypertension this is not universal. 72]. Additionally serum levels of endothelin-1, a
Confounder variables undoubtedly account for potent vasoconstrictor, appear to be elevated in
some of this relationship including adverse life- patients with psoriasis [73].
style choices (smoking, alcohol), comorbidity,
and medications (see Table 27.2). Regardless of Treatment Considerations
the aetiology of this association increasing evi- Treatment of psoriasis may be complicated by
dence indicates hypertension is common in psori- hypertension most notably in the context of ciclo-
atic patients; a recent large US based study of sporin where it is a relative contraindication to
469,097 psoriasis patients reported prevalence treatment.
and incidence of hypertension of 45.6 and 30.8% Based on published research to date psoriasis
respectively [65]. Despite this prevalence Gelfand does appear to confer an increased risk of hyper-
et al. were unable to establish an independent tension. Identification of hypertension in a UK
relationship between psoriasis and hypertension based study of psoriasis patients reported approx-
in a UK based database study of 130,976 patients imately 50% affected with over 10% of these
with psoriasis [54, 66] An association has been detected during screening and therefore untreated
reported in an Israeli database study of 12,052 [74]. This highlights the need for primary preven-
patients with psoriasis with an OR of 1.37 (95% tion and detection of CVD risk factors in patients
CI 1.29–1.46) [67]. A subsequent meta analysis with psoriasis.
has identified a risk of hypertension in psoriatic
patients with an odds ratio (OR) of 1.58 (95% CI
1.42–1.76) compared with the controls. This risk on-alcoholic Fatty Liver Disease
N
did appear to be greater in patients with more (NAFLD)
severe psoriasis; mild psoriasis OR 1.30 (95% CI
1.15–1.47) and severe psoriasis OR 1.49 (95% CI Whilst patients with psoriasis may be at increased
1.20–1.86) compared with the controls [68]. risk of liver disease as a complication of alcohol
A study examining the reverse association intake and anti-psoriatic therapies, such as meth-
studied a population of patients with hyperten- otrexate, evidence for an independent link
sion and found an increased risk of psoriasis [69]. between non-alcoholic fatty liver disease
A Korean study of a health insurance database (NAFLD) and psoriasis is compelling. NAFLD
was interrogated between 2003 and 2013 for inci- includes a range of liver diseases including
dent psoriasis in a cohort of 42,726 hypertensive hepatic steatosis and steatohepatitis and confers
patients and 213,630 individuals (control group). an increased risk of hepatic cirrhosis which is not
During the follow up period 5.0% (2, 152) in the related to alcohol consumption (Fig. 27.1) [75].
hypertension group and 3.3% (7, 102) in the con- NAFLD has been described as the hepatic mani-
trol group developed psoriasis. This difference festation of the metabolic syndrome and should
was calculated as a HR of 1.54 (95% CI 1.47– serve to reinforce the association between psoria-
1.61) which was significant even after adjusting sis and the metabolic syndrome [75].
for diabetes, dyslipidaemia, antihypertensive Estimates on prevalence in the general popula-
medication, nonsteroidal anti-inflammatory drug tion for NAFLD vary depending on country but
372
Table 27.4 Summarising large scale studies reporting the associated risk of psoriasis patients (n > 1000) and hypertension
Number Number Prevalence in cohort Prevalence in controls Incidence/
References Country Cohort patients controls % (n) % (n) OR/RR prevalence
Cohen 2010 [63] Isr G 12,502 24,285 38.8 (4851) 29.1 (7057) 1.37 (1.29–1.46) P
Augustin 2010 [14] Ger G 33,981 1,310,090 35.6 20.6 1.73 (1.71–1.76) P
Tsai 2011 [50] Tai G 51,800 997,771 20.1 (10,435) 16.1 (33,353) 1.51 (1.47–1.56) P
Yang 2011 [51] Tai G 1685 5055 29.1 (491) 25.5 (1289) 1.24 (1.07–1.43) P
Shapiro 2012 [13] Isr G 1079 1079 51.5 (556) 42.7 (461) 1.42 (1.20–1.69) P
Henseler 1995 [9] Ger DO 2941 39,520 2.0 (58) 0.01 (279) 1.90 P
Langan 2011 [16] UK G 4065 40,650 31.1 (1265) 27.6 (11,204) 1.2 (1.11–1.29)
Huerta 2007 [15] UK G 3994 10,000 – – NS P
Neimann 2006 [10] UK G M 127,706 465,252 14.7 (18,718) 11.8 (54,840) 1.03 (1.01–1.06) P
S 3854 14,065 20.0 (769) 13.2 (1855) 1.00 (0.87–1.14)
Wu 2008 [52] USA G 1127 1127 – – 1.49 (1.23–1.80) P
Kaye 2008 [12] USA G 44,164 219,784 6.3 (2765) 5.8 (12,754) 1.09 (1.05–1.14) I
Gelfand 2006 [54] UK G M 127,139 556,995 14.57 (18,521) 11.92 (66,366) 1.26 (1.20–1.30) P
S 3837 19.86 (762) 1.25 (1.13–1.39)
Kimball 2008 [57] USA G 20,614 82,456 35.5 (7308) 32.6 (26,886) 1.14 (1.10–1.17) P
25,556 101,507 29.3 (7497) 25.7 (26,037) 1.20 (1.17–1.24)
Quereshi 2009 [64] USA G 1813 76,248 21.3 (3860) 19.6 (15338) RR 1.17 (1.06–1.30) I
Shah 2017 [65] USA DO 469,097 – 42.19 (187,920) – – P
Fernandez-Armenteros Spain G 6868 398,701 31.2 19.0 1.93 (1.83–2.03, P
2018 P < 0.001)
Gelfand 2009 [66] UK G Mild 129,143 496,666 17.7 (22,829) 17.8 (88,397) – P
Severe 3603 14,330 23.8 (858) 21.3 (3049)
Isr Israel, Ger Germany, Tai Taiwan, M mild psoriasis, S severe psoriasis, G general population, DI dermatology inpatient, DO dermatology outpatient, CI confidence interval,
OE observed/expected ration, RR relative risk, HR hazard ratio, OR odds ratio
Fig. 27.1 Schematic
representation of ≥5% steatosis in hepatocytes without evidence
spectrum of Non- HepaticSteatosis of hepatocyte injury
Alcoholic Fatty Liver
Disease (NAFLD).
*—1–2% may progress
to cirrhosis over
15–20 years. $—12%
may progress over
8 years. Adapted
Non-Alcoholic
from [75] * Hepatic steatosis with evidence of hepatocyte
Steatohepatitis
(NASH) inflammation and injury.
Cirrhosis
are typically between 20 and 30% in the developed likely to suffer severe liver disease than the non-
world [75]. The prevalence of NAFLD in psoriatic psoriatic patients with NAFLD [79].
patients has been reported in three small studies. In This emerging evidence of NAFLD in psoria-
a cohort of 130 patients with psoriasis Gisondi sis patients has an adverse impact on prognosis; a
et al. report a prevalence of NAFLD of 47% Dutch study of individuals aged >55 years has
(n = 61) [76], in comparison to 28% in the control reported a prevalence of advanced liver fibrosis
group. The severity of psoriasis was greater in of 8.1% in patients with psoriasis compared with
those individuals with NAFLD compared with 3.6% in the general population (p = 0.05). This
patients without NAFLD (PASI 14.2 ± 12.6 com- was significant even after adjusting for common
pared to 9.6 ± 7.4; p < 0.01) [76]. The same group confounders with an odds ratio of 2.57 (95% CI
reported a second cohort of 124 patients with pso- 1.00–6.63) [80].
riasis and reported prevalence of NAFLD in 44% Despite the challenges of study heterogeneity
compared to 26% in the control group which was a recent meta-analysis has also published a sig-
significant even after adjusting for age, sex, BMI, nificant association between psoriasis and non-
hypertension and diabetes [77]. A similar study in alcoholic fatty liver disease (OR 1.95, 95% CI
Iran of 123 patients compared to controls matched 1.35–2.83, P = 0.0004) [81].
for age, sex and BMI reported rates of NAFLD of Inflammation is a central feature of NAFLD
65.6 vs. 35% (p = 0.01) respectively [78]. pathogenesis. Gisondi et al. have speculated that
An Italian study of 142 unselected psoriasis the inflammatory mediators elevated in psoriasis
patients attending dermatology outpatient clinic contribute to the development of insulin resis-
reported prevalence of NAFLD in 59.2% (n = 84) tance and progression of NAFLD [76]. Given
of patients with psoriasis [79]. This study com- that NAFLD would appear to be linked with an
pared patients with psoriasis to individuals with increased severity of psoriasis researchers have
biopsy proven NAFLD and no psoriasis (n = 125). suggested that inflammation associated with
This comparison indicated that patients with pso- NAFLD precipitates a more severe expression of
riasis had an adverse outcome and were more psoriasis [76, 82].
Treatment Considerations and presents compelling evidence for a link

NAFLD is commonly observed in psoriasis between psoriasis and diabetes. A later meta-
patients and consequently dermatologists need to analysis examining prevalence by Armstrong
be familiar with how this may impact on treat- et al. demonstrated an odds ratio (OR) of 1.59
ment. Abnormal liver function testing may be (95% CI, 1.38–1.83) for diabetes. Sub analysis
observed when prescribing acitretin, methotrex- revealed an OR of 1.53 (95% CI, 1.16–2.04) for
ate and TNF inhibitors. This does not necessarily mild psoriasis and 1.97 (1.48–2.62) for severe
require treatment cessation but may affect moni- psoriasis. Studies assessing incidence have
toring. The risk of hepatotoxicity with metho- reported a relative risk of 1.27 (95% CI, 1.16–
trexate therapy is increased with coexistent 1.40) for diabetes [86].
NAFLD but is not considered a contraindication A German study of a national database com-
to treatment. Acitretin may be associated with pared 33,981 patients with psoriasis to 1,344,071
hepatic dysfunction but typically is more of a control subjects. This demonstrated an increased
concern in individuals with significant impair- prevalence rate of 2.02 (1.96–2.08) with 12% of
ment of synthetic function of the liver. TNF the psoriatic group affected with diabetes com-
inhibitors may be associated with an increase in pared with 6.0% in the control group [14].
transaminases but rarely requires treatment Consistent with this a Kuwait study of 1835
cessation. patients with psoriasis reported similar findings
The relationship between psoriasis and liver with increased type 2 diabetes prevalence in
disease remains to be fully appreciated. Given patients with psoriasis (37.4, 41 and 16% for
that NAFLD is seen as the hepatic manifestation mild-moderate psoriasis, severe psoriasis and
of metabolic syndrome this evidence supports the controls respectively) [56].
large cardiometabolic complications of psoriasis A recent study of UK patients utilising The
and emphasise the need for holistic care of the Health Improvement Network (THIN) compared
patient. The physician should be aware of the patients with psoriasis (n = 8124) and healthy
high prevalence of liver disease in psoriatic controls (n = 76,599) and followed the cohort for
patients and consider this in selecting systemic 4 years. Incident diabetes occurred in 3.4 and
therapies (Table 27.2). 2.4% of the psoriasis and control groups respec-
tively; equating to a hazard ratio of 1.21 (95% CI,
1.01–1.44), 1.01 (95% CI, 0.81–1.26), and 1.64
I nsulin Resistance and Type 2 (95% CI, 1.23–2.18) for individuals with <2%
Diabetes Mellitus BSA affected, 3–10% affected, and >10%
affected compared with controls respectively
Type 2 diabetes, which is characterised by the (P = 0.004) [87]. This supports a dose-response
development of insulin resistance and reduced effect of psoriasis, with more severe psoriasis
secretion of insulin from the pancreas, is a global conferring the greatest risk of comorbid diabetes
epidemic of increasing concern. It is estimated that and supporting the hypothesis that systemic
324 million people will be affected by diabetes inflammatory burden may play an important role
globally by 2025; with a lifetime risk of 1 in 3 indi- in disease association.
viduals who will develop the disease [83]. It is well A small study (n = 39) evaluating insulin sen-
established that the metabolic syndrome is a strong sitivity has reported that psoriasis severity, as
predictor for the development of diabetes [84]. determined by PASI, is positively correlated with
A meta-analysis of 22 eligible studies with a insulin resistance, as measured by homeostasis
total of 3,307,516 participants provided evidence model assessment of insulin resistance (HOMA)
that patients with psoriasis are at modestly [88]. This was supported in a further study by the
increased risk of diabetes when compared to con- same group who demonstrated a correlation
trols (OR 1.42 [95% CI 1.40–1.45]) [85]. This between C-peptide and PASI in patients with a
included data sets from a range of ethnic groups pathological HOMA (>2.5) [89].
Knowledge pertaining to the mechanistic link into glucose metabolism and genetic studies sup-
between psoriasis and diabetes is limited. Th1 port a link between psoriasis and diabetes, most
lymphocytes, and Th1 cytokines, are implicated notably type 2 diabetes. The consequences of
in both diseases. TNFα (alpha) induces insulin diabetes are well recognised and may have a pro-
resistance and is well established as a key cyto- found impact on quality of life and life expec-
kine of psoriasis pathogenesis. In addition, a tancy. It is therefore of the utmost importance
genetic association may increase susceptibility to that diabetes is recognised early and well con-
Type 2 diabetes in patients with psoriasis and trolled. Data suggests that in psoriasis patients
there is emerging evidence of a shared suscepti- recognition of these CVD risk factors, including
bility loci including the CDKAL1 gene [90, 91]. diabetes, is often sub optimal and furthermore
Recent genotyping has further identified a novel psoriatic patients appear to be at a greater risk of
association between IL2/IL21 and Type 1 psoria- microvascular and macrovascular events [99].
sis (onset <40 years of age) which is shared with
a number of autoimmune diseases including Type
1 diabetes [91]. Recent studies have also identi- Metabolic Syndrome
fied additional shared susceptibility genes
(PTPN22, ST6GAL1, JAZF1) in a Chinese popu- The metabolic syndrome describes a clustering
lation [92]. of CV risk factors (including obesity, hyperten-
The link between psoriasis and diabetes has sion, dyslipidaemia and insulin resistance)
gained further interest following studies of observed in association with one another more
improvement in psoriasis after initiation of thera- frequently than would be expected by chance
pies aimed at improving blood glucose control. alone [100]. Insulin resistance is a fundamental
Large-scale observational studies of patients component of the metabolic syndrome and
treated for diabetes with thiazolidinediones have reflects the relative hyperinsulinaemia required
reported improved control of psoriasis in affected in the fasting state to maintain euglycaemia.
patients [93]. This has not been demonstrated for However, the existence of the metabolic syn-
use of statins [94]. Overlap between diabetic drome as a distinct entity continues to generate
therapies and immunomodulatory effects, includ- controversy [101]. Despite this the European
ing glucagon-like peptide-1 receptor agonists Group for Study of Insulin Resistance and the
(liraglutide) and dipeptidyl peptidase-4 inhibitors National Cholesterol Education Program: Adult
(sitagliptin), have generated some interest and Program Treatment Panel III (NCEP:ATP III)
offer pathogenic overlap [95, 96]. Large scale have described defining criteria (Table 27.5)
prospective studies would be required to more [102, 103]. These features are more clinically rel-
comprehensively address any anti-psoriatic effect evant given that the data is extractable from stan-
from standard treatments for diabetes. dard patient assessment and do not require
evaluation of insulin sensitivity. Other features
Treatment Considerations associated with the metabolic syndrome include
Diabetes is associated with a number of compli- Non-Alcoholic Fatty Liver Disease (NAFLD),
cations in the longer term which impact on see Section “Non-alcoholic Fatty Liver Disease
treatment decisions in the context of psoriasis. (NAFLD)” [104].
Ciclosporin is associated with hypertension and Within the background population prevalence
evidence supports that diabetes is an independent of the metabolic syndrome is estimated at
risk factor for renal impairment in such patients 15–25% [105]. However, this prevalence is
[97]. Diabetes may further complicate use of dependent on geographical location, gender, age
methotrexate and increase the risk of hepatotox- and ethnicity [100]. In the United States 7% of
icity [98]. the population aged 20–29 years have a diagnosis
A growing body of evidence including of metabolic syndrome compared with 44% of
population-wide studies, mechanistic insights 60–69 year olds [105].
The metabolic syndrome is clinically relevant CVD mortality in individuals diagnosed with the
as it is predictive of the future development of metabolic syndrome has been estimated as 1.44
diabetes and CV risk and will impact on thera- (95% CI, 1.17–1.84) and 2.26 (95% CI, 1.61–
peutic management of psoriatic disease [106– 3.17) respectively for men and 1.38 (95% CI,
108]. A hazard ratio of all-cause mortality and 1.02–1.87) and 2.78 (95% CI, 1.57–4.94) respec-
tively for women [109].
Table 27.5 Defining criteria for metabolic syndrome for Psoriasis is associated with the metabolic syn-
European Group for Study of Insulin Resistance and drome including many of its constituent compo-
National Cholesterol Education Program: Adult Program nents (Table 27.6). Sommer et al. described an
Treatment Panel III (NCEP:ATP III)
odds ratio for metabolic syndrome of 5.92 (95%
National Cholesterol CI, 2.78–12.8) for a cohort of hospitalised
Education Program: Adult
European Group for Study Program Treatment Panel patients with psoriasis (n = 581) when compared
of Insulin Resistance III (NCEP:ATP III) with controls [111]. A similar study of 338
Insulin resistance or 3 or more of the following patients with psoriasis managed in a dermatology
fasting hyperinsulinaemia Fasting plasma glucose outpatient department demonstrated a prevalence
(the highest 25% of ≥6.1mmol/L
of metabolic syndrome of 30.1% compared with
general population) Central obesity
2 or more of the Waist circumference 20.6% for the control group; odds ratio 1.65
following: ≥102 cm (male) (95% CI, 1.16–2.35) [110]. This report indicated
Fasting plasma glucose ≥88 cm (female) that the prevalence of metabolic syndrome was
≥6.1 mmol/L Hypertension
independent of psoriasis severity. A Kuwaiti
Central obesity Blood pressure
Waist circumference ≥135/85 mmHg study of 1661 dermatology outpatients with pso-
≥94 cm (male) OR antihypertensive riasis demonstrated an odds ratio of metabolic
80cm (female) medication syndrome of 2.62 (95% CI, 2.09–3.20) [56].
Hypertension Dyslipidaemia
Triglycerides
Recent sub analysis of 2899 patients included in
Blood pressure
≥140/90 mmHg >1.7 mmol/L ustekinumab phase III clinical trials (PHOENIX
OR antihypertensive Low HDL cholesterol 1, PHOENIX 2 and ACCEPT) indicated preva-
medication <1.0 mmol/L (male) lence of the metabolic syndrome to be approxi-
Dyslipidaemia <1.3 mmol/L
(female)
mately 36.2%; all of whom were patients with
Triglycerides
>2.0 mmol/L severe psoriasis (PASI ≥ 12) [21].
HDL cholesterol Two large-scale database studies support the
<1.0 mmol/L observation that metabolic syndrome is associ-
Adapted from [102] ated with psoriasis. Cohen et al. demonstrated
Table 27.6 Evidence for association between psoriasis and the metabolic syndrome
Prevalence Prevalence
Number Number in cohort % in controls
References Country Cohort patients controls (n) % (n) OR
Cohen 2008 Israel G 16,851 48,681 – – 1.3 (1.1–1.4)
[11]
Gisondi 2007 Italy DO 338 334 30.1 (102) 20.6 (69) 1.65
[110] (1.16–2.35)
Sommer 2006 Germany DI 625 1044 4.3 (25) 1.1 (11) 5.92
[111] (2.78–12.8)
Al-Mutairi Kuwait DO 1661 1835 16 (265) 6.8 (124) 2.62
2010 [56] (2.09–3.28)
Langan 2011 UK G 4065 40,650 34 24 1.41
[16] (1.31–1.51)
G general population, DO dermatology out-patient, DI dermatology in-patient, OR odds ratio
an increased risk of metabolic syndrome in a Insulin resistance is a key facet of the meta-
cross sectional study of 16,851 patients, bolic syndrome and resistance to insulin is
extracted from the Clalit Health Services (CHS) increased by inflammatory cytokines (e.g. TNFα)
database in Israel, with an adjusted odds ratio of which are also key drivers of psoriasis [100, 116].
1.3 (95% CI, 1.2–1.5) [11]. Langan et al. have A state of relative adipocyte hypoxia through
published data utilising The Health Improvement adipocyte hypertrophy and increased oxygen ten-
Network (THIN) General practice database in sion results in low grade inflammation with acti-
UK patients. A total of 4065 patients were vation of macrophage and T cells and elevation in
included and stratified into mild (BSA < 2%), inflammatory cytokines including: TNF-α, IL-6,
moderate (BSA 3–10%) and severe leptin, resistin, chemerin, vascular endothelial
(BSA > 10%) disease. This revealed 34% of growth factor, and procoagulant factors [100,
patients with psoriasis had features of the meta- 117]. Visceral fat is considered ‘dysfunctional
bolic syndrome compared to 26% of controls in adipose tissue’ and particularly predisposes to
a “dose-response” manner. The odds ratio for this inflammatory state [116, 118].
metabolic syndrome increased with increasing This low-grade inflammatory cascade further
severity of psoriasis [16]. These findings are in exacerbates systemic insulin resistance, dysgly-
contrast to the previous reports by Gisondi et al. cemia, atherogenic dyslipidemia, vascular dys-
who demonstrated an association between meta- function, and NAFLD [119].
bolic syndrome and psoriasis but not in a “dose- The inflammatory milieu of the metabolic
response” relationship [110]. syndrome includes elevated levels of leptin which
A meta-analysis published in 2013 supports is also elevated in obesity. Leptin is a proinflam-
these studies. Analysis of 12 observational studies matory adipokine and known to activate macro-
demonstrated an adjusted OR of 2.26 (95% CI phage and promote the development of a Th1
1.70–3.01) for psoriasis and the metabolic syn- phenotype [120, 121]. Wang et al. suggested that
drome [112]. This has recently been updated by hyperleptinaemia was predictive of development
the same group and demonstrated a pooled odds of metabolic syndrome in patients with psoriasis
ratio of 2.14 (95% CI 1.84–2.48) based on 46,714 [121]. The observation of Langan et al. of a
psoriasis patients and a total 1,450,188 partici- “dose-response” relationship between psoriasis
pants over 35 observational studies [113]. This and metabolic syndrome may indicate that more
study did recognise significant reporting bias in patients will suffer more severe cutaneous dis-
the studies evaluated and should be interpreted ease as the burden of obesity and metabolic syn-
accordingly. drome increase in the background population.
A recent study of a Korean Health insurance
service reported in a cohort of 2,595,878 with Treatment Considerations
metabolic syndrome (total cohort of 9,718,591) The component features of the metabolic syn-
an adjusted hazard ratio for incident psoriasis drome may complicate the management of
over an 8-year follow up period of 1.05 (95% CI patients with psoriasis. This presents two signifi-
1.04–1.06) [114]. This is consistent with the cant challenges to the dermatologist. First, it is
increased incidence of psoriasis observed in important to treat the patient holistically and con-
patients with obesity discussed above. It is note- sider investigation and management of comorbid
worthy that the prevalence of psoriasis in Asian conditions; including use of primary prevention
populations is lower than in other ethnic groups strategies. Secondly, several systemic agents for
and therefore this figure may be higher in other the treatment of psoriasis have the potential to
population groups. exacerbate or precipitate elements of the meta-
An overwhelming body of evidence suggests bolic syndrome (Table 27.2). The metabolic syn-
that inflammation is a central aspect of the patho- drome is an epidemic of the developed world and
genesis of both psoriasis and the metabolic syn- associated with an energy rich diet. Given the
drome [115]. relatively high prevalence of psoriasis in the gen-
eral population it is reasonable to expect that the tion between psoriasis and CVD is complicated
issue of patient management in the context of by the increased prevalence of traditional CV risk
metabolic syndrome will increase in the future. factors including diabetes, obesity, smoking,
The dermatologist must be aware of this associa- hypertension and hyperlipidaemia present in both
tion and should be vigilant for opportunities to conditions. Additional potential confounders
address these comorbidities. which are difficult to quantify include exercise,
In summary metabolic syndrome is strongly alcohol and diet. Despite this, increasing evi-
associated with psoriasis. The nature of the rela- dence from population databases and clinical
tionship between psoriasis and metabolic syn- studies overwhelmingly support an association
drome remains to be fully elucidated but strong between psoriasis and CVD.
genetic, pathogenic and population studies support The key mediators of psoriasis and atheroscle-
overlapping patterns of disease. The role of chronic rosis are similar and provide a mechanism by
low-grade inflammation is again a central theme in which the two may be linked (Fig. 27.2). Th1 and
current understanding of disease progression. Th17 cells and their respective cytokines are
implicated in the pathogenesis of both diseases
[122]. Cytokines common to both diseases
Cardiovascular Disease (CVD) include IL-1, IL-6, IL-10, leptin, and adiponectin
[24]. In addition to the epidemiological evidence
Concern that psoriasis may be associated with this mechanistic overlap provides further support
CVD has been a topic of intense research interest to this hypothesis.
for over 20 years [9]. Understanding the associa-
Trigger Trigger
Psoriatic Antherosclerotic
Keratinocytes Endothelical cells palque
plaque
Cytokines e.g. Cytokines e.g.

TNFα, IL-2, IL-17, TNFα, IL-2, IL-17,
IL-23, IFNα IL-23, IFNα
Dermis IL-1β, IL-6, TNFα IL-1β, IL-6, TNFα Intima
Th Th
APC APC
Th Th
Lymph node Lymph node
Fig. 27.2 Overlapping pathogenesis of psoriasis and cardiovascular disease. Th CD4 lymphocyte (Th1 and Th17),
APC antigen presenting cell
Inflammation is a central theme underpinning psoriasis and CVD has been the focus of intense
a theoretical link between psoriasis and scrutiny with the interrogation of large databases
CVD. CRP has been linked with hypertension of patients with psoriasis. Perhaps one of the
[123] an adverse prognostic factor in respect of most influential papers on this topic published
CV events [124, 125]. Inflammation is instru- data on a cohort of psoriasis patients in the UK
mental in the development of vascular disease with mild (n = 127,139) and severe (n = 3837)
and implicated in endothelial dysfunction and disease extracted from the UK GPRD [54].
atheroma development [126, 127]. Activation of Multivariate regression demonstrated a signifi-
T cells and infiltration of the endothelium by cant increase in relative risk of myocardial infarc-
macrophage are early steps in disease progres- tion (MI), which was most marked in young
sion [127]. Development of lipid laden foam cells patients with severe disease [54]. It was calcu-
beneath the endothelium herald the onset of ath- lated that a 30 year old with mild disease has an
erosclerotic plaques. This core region is the focus adjusted relative risk of MI of 1.29 (95% CI,
over which smooth muscle and matrix remodel- 1.14–1.46) compared with 3.10 (95% CI, 1.98–
ling ensues, with the development of the fibrous 4.86) for severe disease [54]. This risk was inde-
cap of the atheroma. Activation of the plaque, and pendent of traditional CV risk factors. Patients
development of a thrombus, is implicated in sub- were classified as having severe disease based on
sequent ischaemic events. Both the plaque for- an appropriate clinical code and exposure to sys-
mation and plaque destabilisation are heavily temic therapies (including psoralen, photother-
driven by inflammatory cytokines, T cells and apy, methotrexate, azathioprine, cyclosporine,
macrophage [127]. etretinate, acitretin, hydroxyurea, or
Oxidation modified lipoproteins have been mycophenolate mofetil). It is noteworthy that

implicated in vascular inflammation and CVD and 16.4% of patients with severe psoriasis had
are elevated in patients with psoriasis [128]. A received azathioprine, a drug not typically used
recent study of 232 psoriasis patients, compared for the treatment of psoriasis. The same group
with 20 healthy controls, reported a significant have subsequently published further evidence
association of oxidized LDL (β = 0.10; P = 0.020) that severe psoriasis confers an increased risk of
and oxidized HDL (β = −0.11; P = 0.007) with major adverse CV events (MACE; including MI,
non-calcified arterial plaque disease burden [129]. stroke or death due to CV event) and CV death
In this study effective treatment of psoriasis [135, 138, 139]. In a cohort of 14,330 UK based
resulted in a reduction in oxidized HDL. patients with severe psoriasis, extracted from the
Inflammation therefore appears to serve as a GPRD, the adjusted hazard ratio for MACE was
mechanistic link between lipid dysfunction, CVD 1.53 (95% CI, 1.26–1.85); equating to an addi-
and psoriasis. Oxidative stress results in reactive tional 6.2% absolute risk of 10-year MACE
oxygen species (ROS) which can have a functional [135]. Mehta et al. have also reported in a cohort
role in the “normal state” [119]. If these ROS of 3603 patients with severe psoriasis that CV
become elevated the homeostatic balance may be mortality was increased when compared with
impaired with cellular damage and the potential controls, independent of traditional factors; the
for a myriad of physical consequences [130]. adjusted hazard ratios for CV mortality was 1.57
(95% CI, 1.26–1.96) [139]. Evidence from other
population groups includes recent work from
Heart Disease Shiba et al. who reported an adjusted odds ratio
(OR) for MI of 1.87 (CI 1.26–2.68; p = 0.0022)
vidence for an Association Between
E for a Japanese hospital population in a cohort of
CVD and Psoriasis 1197 psoriasis patients compared with 111,868
The association with CVD and psoriasis has been control patients [140]. Other similar or overlap-
demonstrated in a large number of studies [8, 9, ping studies have also supported these observa-
56, 131–137]. Recently the association between tions [141–144].
The evidence from population based studies is risk of myocardial infarction. The relative risk for
supported by smaller mechanistic studies including MI for mild and severe psoriasis was 1.29 (CI
a study using PET (Positron Emission Tomography) 1.02–1.63) and 1.70 (CI, 1.32–2.18) respectively.
scanning. This demonstrated that aortic inflamma- The relative risk of stroke for mild and severe
tion, an accepted marker of atherosclerosis, is ele- psoriasis was 1.12 (CI, 1.08–1.16) and 1.56 (CI,
vated in patients with psoriasis with respect to a 1.32–1.84) respectively [149].
control group [145]. In a cohort of 60 psoriasis
patients and 20 controls the authors reported that an vidence Against an Association
E
elevated psoriasis area severity index score (PASI) Between CVD and Psoriasis
was associated with an increase in aortic target-to- In contrast to this Wakkee et al. presented data for
background ratio (β = 0.41, P = 0.001), which a cohort of 15,820 psoriasis patients compared
remained significant even after adjusting for age, with 27,577 controls extracted from a database
sex, and Framingham risk score. Follow up studies utilising Dutch health records which failed to
on this technology have demonstrated that vascular demonstrate a significant increase in CV mortal-
inflammation, and MACE events in a nationwide ity when adjusted for established confounders
registry, appear to be associated with psoriatic dis- [150]. Adjusted hazard ratios of 1.05 (85% CI,
ease duration [146]. This supports the hypothesis 0.95–1.17) and 0.94 (95% CI, 0.80–1.11) were
that psoriasis confers an adverse CVD risk profile reported for ischaemic heart disease and acute MI
which is affected by the amount (psoriasis severity) respectively [150]. The authors selected patients
and duration of inflammation. who were definitely diagnosed with psoriasis
A study in a Danish cohort of 34,371 and 2621 using an algorithm which included a criteria that
patients with mild and severe psoriasis respec- the patient must have been prescribed either pso-
tively followed over a 10 year observation period ralen, calcipotriol, calcitriol, dithranol, fumaric
found supportive evidence of an increased risk of acid or efalizumab. Whilst this is likely to select
CV mortality [147]. For mild psoriasis the inde- the majority of patients with psoriasis the authors
pendent risk ratio for CV mortality was 1.14 acknowledged that patients with severe psoriasis
(95% CI, 1.06–1.22) and for severe psoriasis this managed with other systemic therapies may be
increased to 1.57 (95% CI, 1.27–1.94). An omitted from this analysis (e.g. methotrexate and
increased risk of CVD has also been reported in cyclosporine). The same group have subsequently
two large database studies of US psoriasis also reported an absence of association with pso-
patients extracted from the IMS Health Integrated riasis and CVD as measured by a number of sur-
Claims Database (n = 20,614) and the rogate markers including carotid intima thickness
MarketScan® Commercial Claims and [151]. Further evidence suggesting that psoriasis
Encounters Database (n = 25,556) [57]. The may not be an independent risk factor for CVD
adjusted odds ratio for CVD was reported as 1.13 has been reported in a longitudinal study of 1376
(95% CI, 1.06–1.20) and 1.18 (95% CI, 1.09– patients with severe psoriasis treated with PUVA
1.28) respectively [57]. The Nurses’ Health (psoralens and ultraviolet- A therapy) and fol-
Study II has provided additional support for an lowed up for 30 years. This study indicated an
association between psoriasis and CVD disease increased all-cause mortality but no increased risk
in a study of 96,008 individuals with psoriasis. of CVD [152, 153]. This has proven a contentious
The multivariate-adjusted hazard ratio (HR) of area with multiple discussions in the published
non-fatal CVD and non-fatal MI was 1.55 (95% literature [154–156].
CI, 1.04–2.31) and 1.70 (95% CI, 1.01–2.84) Given the strength of evidence in support of
respectively [148]. an independent risk of CVD in several large pop-
A large meta-analysis of published studies ulation cohort studies two consensus statements
including 9 studies, representing 201,239 patients have been supportive of the position that psoria-
with mild psoriasis and 17,415 patients with sis is an independent risk factor for CVD and are
severe psoriasis, reported a significantly increased now widely accepted [53, 157].
ffect of Treatment of Psoriasis

E risk reduction was observed in patients with pso-
on CVD Risk riasis and psoriatic arthritis (n = 750); hazard
Patients with psoriasis are at an increased risk of ratio for MI 0.957 (95% CI, 0.60–1.53; p = 0.855).
CVD, the aetiology of which is complicated by As with all population-based studies there are
numerous confounder variables. Despite this a multiple limitations to consider including patient
significant outstanding question relates to the selection bias. This is particularly true in coun-
effect of anti-psoriatic therapy on CV risk. tries where health insurance schemes offer vari-
Prodanovich et al. retrospectively examined vas- able access of therapeutic options.
cular disease in a cohort of outpatients with pso- Many smaller studies utilising surrogate mark-
riasis (n = 7615) and rheumatoid arthritis ers of CVD have been undertaken including flow
(n = 6707) [158]. In patients treated with metho- mediated dilatation of vasculature, carotid intima
trexate the relative risk of vascular disease was media thickness and PET scanning. These have
0.73 (95% CI 0.55–0.98) and 0.83 (95% CI 0.71– provided some supportive evidence that effective
0.96) for psoriasis and rheumatoid arthritis suppression of psoriasis inflammation results in an
respectively. Smaller prospective studies have improved marker of CVD morbidity and mortality
demonstrated amelioration of adverse markers of [164, 165]. Use of PET in a cohort of 50 patients
CVD with use of systemic anti-psoriatic thera- treated for 12 months who were scanned at base-
pies [159]. Utilising a private health insurance line and followed for 1 year, demonstrated that
claims register Wu et al. examined MACE events effective treatment of cutaneous disease was asso-
between patients with psoriasis treated with ≥2 ciated with improvement in total coronary plaque
TNFi or methotrexate prescriptions. After burden (β = 0.45, 0.23–0.67; P < 0.001) and non-
12 months CVD events were 1.45% and 4.09% calcified coronary plaque burden (β = 0.53, 0.32–
(p = 0.01) for TNFi patients (n = 9148) and meth- 0.74; P < 0.001) beyond traditional risk factors
otrexate patients (n = 8581) respectively giving a [166]. Further support for reduction in CVD asso-
hazard ratio of 0.55 (p = 0.01) [160]. The same ciated with psoriasis has been published in a
group compared 11,410 patients treated with US-based prospective study of psoriasis patients
TNFi compared to 12,433 patients treated with (n = 290) treated with biologics (adalimumab,
phototherapy. After 6 months a reduced hazard etanercept, ustekinumab, secukinumab and ixeki-
ratio for CV events was noted in the TNFi group zumab) and followed for 1-year, having undergone
compared with the phototherapy group (hazard serial coronary angiography. Biologic therapy was
ratio 0.77, 95% CI 0.60–0.99). This effect was associated with a 6% reduction in non-calcified
cumulative such that the effect was greater with plaque burden (P = 0.005) at follow up [167].
longer treatment with TNFi. The authors esti- Improvement in coronary plaque burden was sig-
mated that a number needed to treat with TNFi nificant when compared with non-biologic ther-
instead of phototherapy was 161 to avoid a single apy. The Vascular Inflammation in Psoriasis (VIP)
CV event [161]. Further evidence supporting this clinical trials are an ongoing series of studies
data has been reported in a Danish registry which which are examining whether vascular inflamma-
demonstrated a reduced risk of cardiovascular tion is impacted by anti-psoriatic therapies includ-
events in a cohort of 6902 patients, with maxi- ing phototherapy, adalimumab, apremilast,
mum 5 year follow up, treated with TNFi (HR secukinumab and ustekinumab. In contrast to the
0.46; CI 0.22–0.98) or methotrexate (HR 0.53; CI studies reported above preliminary data has not
0.34–0.83) [162]. A study of 24,081 patients with established a reduction in vascular inflammation
psoriasis and psoriatic arthritis suggested that in over a 52 week follow up period comparing adali-
the cohort of patients treated with TNFi mumab and phototherapy although other studies
(n = 1877) the hazard ratio for MI in the psoriasis- are yet to be reported [168].
only group (n = 971) was 0.264 (95% CI, 0.12– The need for primary intervention for CVD
0.59; p = 0.0012) compared with those who risk factors has been highlighted in a recent
received oral therapy or phototherapy [163]. No review summarising the comorbidities in patients
Table 27.7 Summary of risk factors undiagnosed or Table 27.8 Adjusted odds ratio for development of atrial
untreated in patients with moderate to severe psoriasis fibrillation and stroke for psoriasis patients with mild and
(PASI≥12) in phase III clinical trials for ustekinumab severe psoriasis, divided by age < or ≥50 years [136]
(n = 2899) [21]
Adjusted rate ratios (95%
Cardiovascular risk Undiagnosed Untreated confidence interval)
factor (%) (%) Atrial
Diabetes 2.3 19.1 Fibrillation Stroke
Hypertension 9.1 21.8 Mild <50 years 1.50 1.97
Hyperlipidaemia 4.9 38.6 psoriasis (1.21–1.86) (1.66–2.34)
≥50 years 1.16 1.13
(1.08–1.24) (1.04–1.21)
Severe <50 years 2.98 2.80
with psoriasis who are participating in phase III psoriasis (1.80–4.92) (1.81–4.34)
clinical trials of ustekinumab (n = 2899) which ≥50 years 1.29 1.34
indicated that participants were frequently undi- (1.01–1.65) (1.04–1.71)
agnosed and untreated for diabetes, hypertension
and hyperlipidaemia (Table 27.7) [21].
that patients with psoriasis are at an increased
Treatment Considerations risk of stroke and atrial fibrillation (AF) [136]. A
Treatment of patients at risk or with CVD may cohort study of the Danish population compared
significantly impact on treatment choice in the 36,765 patients with mild psoriasis, 2793 patients
clinic. Evidence supportive that methotrexate with severe psoriasis and 4,478,926 controls
may reduce CVD, albeit to a lesser extent than between 1997 and 2006 [136]. The rate ratios for
TNFi, make it a good first choice option for pso- AF and stroke are summarised in Table 27.8. It is
riasis treatment. Ciclosporin is relatively contra- interesting to note that this evidence indicates the
indicated due risk of hypertension and renal greatest risk of AF and stroke is in young indi-
impairment compounding risk of CVD. The viduals with the most severe disease, consistent
impact of biologic therapies on CVD risk has with CVD risk reported by Gelfand et al. and
been somewhat mixed and requires further study again supporting a hypothesis that inflammation
to establish a clearer association. Patients with plays a pivotal role [54].
NYHA heart failure stage 3 or 4 should not be An analysis of patients managed with non-
treated with a TNFi due to risk of precipitating valvular AF and assessed for thromboembolism
further deterioration in heart failure. and stroke has also been reported in Denmark
In summary it would appear that psoriasis [170]. This study identified an increased risk of
may be an independent risk factor for CVD and venous thrombosis and stroke in patients with
effective treatment of psoriasis may have a posi- severe psoriasis (n = 549) compared to the back-
tive impact on CVD risk. The need to better ground population (n = 99,357) with median fol-
understand this is reinforced by evidence that all low up of 3.5, 3.1, and 2.8 years for patients with
cause mortality is significantly greater in severe no psoriasis, mild psoriasis and severe psoriasis.
psoriasis equating to 5 years loss of life [138, The study reported a 2.6- to 3.4-fold increased
169]. Given that the prevalence of CVD and tra- risk of venous thrombosis compared to predicted
ditional risk factors are elevated in patients with score using currently accepted modelling. The
psoriasis the dermatologist must be engaged in incidence rate ratios for fatal stroke was 0.97
detection, management and primary prevention (0.80–1.12) and 1.51 (1.12–2.05) for mild and
of these complications. severe psoriasis respectively. The risk of stroke
and atrial fibrillation has been further studied in
the entire Danish population (n = 5,251,888) with
Stroke and Atrial Fibrillation specific cross referencing of depression and pso-
riasis [171]. The study identified that risk of AF
Evidence to support a more generalised impact on and stroke was greater in patients with psoriasis
vascular function has been presented indicating and was further increased by coexistent depression
Table 27.9 Hazard ratios for new onset AF in relation to Treatment Considerations
psoriasis severity and presence or absence of depression
The impact of psoriasis on CVD and the impact
[171]
of effective treatment is of great clinical and
Hazard ratios (95% CI)
research interest but remains to be definitively
New onset
AF Stroke answered. Co-existent CVD may complicate
Mild No co-existent 1.14 0.95 treatment such that ciclosporin is contraindicated
psoriasis depression (1.08–1.33) (0.88–1.03) or may affect choice of other therapies. This is
Co-existent 1.19 1.63 true also of biologic therapies where it is impor-
depression (1.06–1.33) (1.43–1.85) tant to avoid TNFi in patients with NYHA heart
Severe No co-existent 1.32 1.16
failure stage 3 or 4.
psoriasis depression (1.15–1.53) (0.97–1.39)
Co-existent 1.74 2.47 In summary this evidence is supportive of the
depression (1.43–2.11) (2.07–2.95) hypothesis that chronic inflammatory burden
associated with psoriasis has an impact on sys-
temic vascular health in a similar manner as that
(Table 27.9). This indicates that patients with observed in CVD. The reduction in risk observed
severe psoriasis and depression are at the greatest in older patients is likely to reflect concomitant
risk of new onset AF and stroke. Given the well disease and adverse risk factors which cumula-
described psychological consequences of psoria- tively dilute the relative impact of psoriasis.
sis this research serves to emphasise the need for
holistic assessment of the individual. A UK based
cohort study of 48,523 patients with psoriasis and Cancer and Lymphoma
208,187 controls followed for a median 5.2 years
demonstrated a multivariate HR of transient isch- An association between psoriasis and malignancy
emic attack of 2.74 (2.41–3.12) and atrial fibrilla- has been suggested in a number of studies but is
tion HR 1.54 (1.36–1.73) [172]. complicated by the additional influence of photo-
Contrary to the evidence of Ahlehoff et al., therapy and immunosuppressive therapy which
Yang et al. has reported evidence of no increased may affect cumulative risk of malignancy, par-
risk of stroke in a cohort of 1685 patients with ticularly cutaneous malignancy. This is further
psoriasis and 5055 controls following interroga- complicated by confounder variables, such as
tion of Taiwan’s National Health Insurance obesity, which are well recognised risk factors
(NHI) programme. In this study prevalence of for malignancy, or behavioural factors more com-
stroke was 6.5% (n = 109) for patients with pso- mon in psoriatic patients (e.g. sunbed use, exer-
riasis and 6.0% (n = 304) in the control group cise, smoking, alcohol).
(p = 0.728) [51]. However, stroke in Caucasian A recent Taiwan-based health insurance data-
populations typically result from extracranial base of 3686 psoriasis patients, compared with a
large artery atherosclerosis whilst in Chinese control group of 200,000, demonstrated a 7-year
populations intracranial small vessel disease is incidence rate of cancer of 4.8% which provided
more common [51]. The authors acknowledge an adjusted HR of developing cancer in psoriasis
that ischaemic stroke is mechanistically differ- patients of 1.66 (1.38–2.00). Cancers associated
ent in Chinese and Caucasian populations and with psoriasis were skin, lymphoma/leukaemia,
may therefore not be comparable. Interestingly urinary bladder, oropharynx/larynx, liver/gall-
a more recent study in a Korean population bladder, pancreas and lungs in male patients and
13,385 patients with psoriasis did find an asso- colorectal carcinomas in female patients. It is
ciation with psoriasis and stroke and AF. In important to note that this did not adjust for fam-
patients with severe psoriasis adjusted hazard ily history, diet or smoking status [174].
ratio for AF was 1.44 (95% CI 1.14–1.82) and A UK based study of malignancy risk has also
for thromboembolic events was 1.26 (95% CI reported a risk of malignancy based on a cohort
1.07–1.47) [173]. of 186,076 with mild psoriasis and 12,290 with
moderate-to-severe disease observed between Lymphoma

2002 and 2014. This reported an increased risk of
non-melanoma skin cancer with an adjusted HR Using the UK GPRD 153,197 patients with pso-
of 1.06 (95% CI 1.02–1.09), Lymphoma adjusted riasis (149,203 mild, 3994 severe) were studied
HR of 1.34 (95% CI 1.18–1.51), and an increased alongside a control group of 765,950 individuals
risk of lung cancer with an aHR of 1.15 (95% CI [179]. Adjusted odds ratio for lymphoma were
1.03–1.27). Breast, colon, prostate, and leukemic 1.34 (95% CI, 1.16–1.54) and 1.59 (95% CI,
malignancy was not associated with an increased 0.88–2.89) for patients with mild and severe pso-
HR for psoriasis patients. Cofounder variables riasis respectively. This is consistent with the
included age, sex, BMI, smoking, and alcohol work of Brauchli et al. discussed below [180].
intake [175]. Sub analysis of the data reported by Gelfand
A recent meta-analysis has provided support- et al. suggested that the greatest risk of lym-
ive evidence linking psoriasis and malignancy phoma was conferred for Cutaneous T Cell
but was limited by heterogeneity of the publica- Lymphoma (CTCL) [179]. Given the potential
tions. The study reported a possible increase in for clinical mis-diagnosis of CTCL and psoriasis
risk of solid tumours with a standardized inci- one must be cautious in the interpretation of this
dence ratio (SIR) of 1.52 (CI 1.35–1.71), 3.05 evidence but does appear to be significant.
(CI 1.74–5.32), 1.31 (CI 1.11–1.55) and 1.90 (CI
1.48–2.44) for respiratory malignancy, upper
aerodigestive tract malignancy, urinary tract General Cancer Risk
malignancy and liver cancer. The risk of non-
Hodgkin lymphoma was 1.40 (CI 1.06–1.86) and One of the first significant studies adding to this
squamous cell carcinoma 5.3 (CI 2.63–10.71) literature was a large population study of 17,000
and basal cell carcinoma 2.00 (CI 1.83–2.20). patients with psoriasis compared to patients with
Melanoma was not identified to be at an increased hypertension. This study identified an increased
risk. It is perhaps noteworthy that the solid organ risk of malignancy with a risk ratio of 1.78 (CI
tumours are typically associated with alcohol and 1.3–2.40) in severe psoriatic patients. Most
smoking which potentially identifies significant malignancies were lymphoproliferative. It is
confounders to the meta-analysis [176]. important to note that adjustment was only pos-
sible for age and sex but not alcohol, smoking or
obesity [181].
Skin Cancer The risk of malignancy associated with psoria-
sis is likely to be significantly influenced by
Evidence of an association with psoriasis and genetic factors inherent to the background popu-
skin cancer is emerging but remains challenging lation. A large study of 1,773,786 Korean patients,
to fully assess due to the potential confounder 5788 with a diagnosis of psoriasis, were analysed
variables including sun exposure and sun bed use over a 15-year observation period utilising a
in patients with psoriasis. Skin cancer is com- national health insurance database. An adjusted
monly observed in psoriatic patients and should HR of overall malignancy and gastric cancer was
remain part of clinical assessment in affected 1.08 (CI 1.00–1.18) and 1.31 (CI 1.08–1.58)
individuals. This is particularly important given respectively compared to controls [182].
that PUVA has been reported to increase the risk A study of the UK GPRD performed by
of squamous cell carcinoma (SCC) 14-fold [177]. Brauchli et al. in 36,702 patients with psoriasis
Use of any cyclosporine in patients with psoriasis and 36,702 matched controls demonstrated an
previously treated with >200 treatments of PUVA increased overall odds ratio for cancer of 1.50
demonstrated an additional risk of SCC with an (95% CI, 1.30–1.74) for patients with psoriasis
adjusted incidence rate ratio of 3.1 (95% CI, 2.6– ≥4 years [180]. This odds ratio is controlled for
3.7) [178]. age, sex, BMI and smoking status. The relative
risk was greatest for lymphohematopoietic variables relevant to the individual. Ciclosporin
malignancy. For patients who have not received is contraindicated given the increased risk of
systemic therapy the odds ratio for cancer devel- malignancy. Methotrexate should be used cau-
opment was 1.59 (95% CI, 1.01–2.50) for tiously and in discussion with oncologists or rel-
<2 years psoriasis duration and 2.12 (95% CI, evant specialists. Acitretin has been shown to
1.45–3.10) for ≥2 years psoriasis duration. This reduce non-melanoma skin cancer risk in some
study controlled for age, gender and years on the population groups and given that it is not immu-
GPRD but did not control for smoking, alcohol nosuppressive offers a valuable option in treat-
intake or family history of cancer. ment [37]. Evidence around biologic therapies is
Additional support for an association between limited by multiple confounders but has been
psoriasis and cancer has been reported in a reviewed and discussed in multiple papers over
Taiwan based study. Utilising the National Health recent years [184]. In clinical practice patients
Insurance Research Database (NHIRD) between are now more frequently treated with a range of
1996 and 2000 3686 patients with psoriasis were newer therapies despite a past history of cancer.
compared with 200,000 control patients [174]. Biologic registries have a valuable role in adding
Chen et al. calculated an adjusted hazard ratio for to the evidence base and ultimately providing
developing a cancer of 1.66 (95% CI, 1.38–2.00) more definitive answers to how to approach such
with significant associations including urinary, complex scenarios. At this stage a case by case
skin, oropharynx/larynx, liver/gall bladder and approach is needed. Similarly, evidence relating
colon/rectum. A significant limitation of this to the role of apremilast in treating patients with
study was that these ratios were not adjusted for cancer is also uncertain due to the lack of robust
smoking, alcohol intake or family history. evidence but warrants further investigation as it
A study of the Iowa Women’s Health Study may have a useful role in such patients The reader
compared 719 psoriasis patients with 32,191 is further referred to relevant chapters of the book
non-psoriatic patients between 1991 and 2004 regarding considerations of specific biologics in
[183]. An adjusted hazard ratio (adjusted for age, psoriasis.
smoking, BMI, education, physical activity, hor-
mone therapy use) was reported for colon cancer
in patients with psoriasis; HR 1.6 (95% CI, 1.0– Autoimmune Disease
2.4) [183].
In summary it would appear that psoriasis Understanding of the genetics and pathogenesis
may confer an increased risk of malignancy, par- of psoriasis has moved forward dramatically in
ticularly lymphoproliferative disease. Further the past 20 years and afforded a valuable oppor-
studies are required to more clearly evaluate the tunity to further understand associations between
impact of adverse confounder variables observed psoriasis and other diseases affecting the immune
more frequently in patients with psoriasis than system including; inflammatory bowel disease
the background population (such as family his- (Crohns disease and ulcerative colitis), multiple
tory, diet, exercise, smoking and alcohol). sclerosis, coeliac disease, Type 1 diabetes melli-
Primary prevention and risk assessment of all tus, and Graves disease [91, 185, 186]. More
patients with psoriasis is of great importance in recently this has included the identification of an
early detection and management and in reducing association with rheumatoid arthritis, alopecia
risk in patients being considered for immunosup- areata, systemic sclerosis, Sjogren’s syndrome,
pressive systemic therapies. vitiligo, chronic urticaria, systemic lupus erythe-
matosus, giant cell arteritis and chronic glomeru-
Treatment Considerations lonephritis [187]. The apparent clustering of
Treatment choice in individuals with malignancy autoimmune diseases and clinical overlap has led
is fraught with challenge and will be made in to the term IMID (Immune mediated inflamma-
close discussion with the patient considering all tory disease). This has proven useful in delineating
genetic, pathogenic and clinical overlap in the a ssociation has been published from a German
clinical environment. health insurance database of 33,981 patients with
The relationship between psoriasis and inflam- psoriasis and 1,344,071 control patients. The
matory bowel disease has been suggested for prevalence rate for Crohns was 2.06 (1.84–2.31)
over 30 years. Case-control studies suggest that [14]. An Israeli study utilising a national health
7–11% of patients with Crohns disease also have database compared psoriasis (n = 12,502) patients
psoriasis [188–190]. Numerous genetic suscepti- with age and sex matched controls (n = 24,287)
bility loci are common to both psoriasis and and identified an odds ratio for Crohns of 2.49;
Crohns disease and this provides further evidence (CI 1.71–3.62). Additionally a positive associa-
to support this observation [191, 192]. tion was reported between psoriasis and ulcer-
The association between psoriasis and IBD ative colitis; OR was 1.64 (CI 1.15–2.33) [196].
may be due to clinical overlap of the disease, A Dutch study of all psoriasis patients attending
shared genetic factors or a combination of these a general hospital were reviewed between 2009
and other as yet undefined risks. A recent meta and 2014. The group reported a 4 times higher
analysis of 5 GWAS analyses including 6215 prevalence of Crohns disease compared to the
Crohns patients, 8644 psoriasis patients and general population. Interestingly the cohort of
20,560 healthy individuals identified 7 non-HLA patients with psoriasis and Crohns disease
susceptibility loci shared between CD and PS appeared to have a more severe phenotype of
(9p24 near JAK2, 10q22 at ZMIZ1, 11q13 near Crohns disease as classified by fistulating/pene-
PRDX5, 16p13 near SOCS1, 19p13 near FUT2, trating disease with more frequent use of cortico-
17q21 at STAT3, 22q11 at YDJC) [163]. steroids and other systemic agents [197].
The parallels between psoriasis and Crohns A US based study of 25,556 psoriasis patients
are further identified when considering disease matched with controls on a 1:3 basis demon-
pathogenesis. Epithelial barrier dysfunction in strated a prevalence ratio as follows: Crohns dis-
both conditions is impaired with activation of ease 1.6 (1.4–2.0), ulcerative colitis 1.3 (CI
innate and adaptive immunity resulting in an 1.1–1.6), and inflammatory bowel disease 1.4 (CI
inflammatory cascade with activation of the Th17 1.2–1.6) [181, 198].
pathway. The incidence or flaring of IBD in the
context of IL-17 inhibition appears to contradict Treatment Considerations
this but may relate to impaired mucosal barrier Overlapping IMIDs presents an opportunity to
function [193]. rationalise treatment and use fewer immunomod-
A Danish registry of 10,923 patients with pso- ulatory therapies to manage symptomatology.
riasis matched to controls (n = 109,230) demon- This is appealing but is not without challenge;
strated that approximately 20% of patients with evidence above suggests that coexistent disease
psoriasis developed at least 1 IMID compared may be more resistant to treatment or of a more
with 7.4% in the general population. This was severe phenotype (psoriasis and Crohns).
calculated to give an odds ratio of 3.10 (CI 2.94– Treatment options will need to be considered in
3.26) [194]. light of the specific co-existent autoimmune dis-
Analysis of the Nurses Health study (NHS) I ease. With respect to Crohns standard systemic
and II compared 174,476 women observed therapies are generally acceptable options for
between 1996–2008 (NHS I) and 1991–2007 psoriasis therapy although caution may be
(NHS II). Multivariate adjusted RR for develop- required with apremilast and fumaric acid esters
ment of Crohns was 4.00 (95% CI 1.72–9.27) for due to the potential to exacerbate bowel symp-
NHS I and 3.76 (1.82–7.74) for NHS II. There toms. TNFi and IL12/23i are licensed in both
was no significant increased risk of UC. This psoriasis and Crohns and may be a valuable
supports previous work and is consistent with the option with coexistent disease. IL-17 inhibitors
established pathogenic overlap between Crohns are contraindicated in Crohns due to the risk of
and psoriasis [195]. Further support for this exacerbating the disease.
The link between psoriasis and autoimmune A literature review has reported depressive
disease is compelling and suggests both shared symptoms of 28% with prevalence of clinical
genetic factors and potentially overlapping patho- depression in 12% and an OR 1.57 (CI 1.40–
genesis. Increasing access to genetic studies 1.76) for depression [151].
(such as genome wide association scans) and A US based study utilising administrative data
large scale databases offer a number of method- of psoriasis patients (n = 36,214) matched with
ologies to evaluate such associations. This will the general population reported an annual inci-
provide increasingly valuable insight into disease dence rate ratio of 1.14 (CI, 1.11, 1.17) [212]. A
pathogenesis. large Danish study of patients with psoriasis
assessed between 1997 and 2016 were compared
with matched controls for incidence of depres-
Psychiatric Illness sion (n = 247,755 individuals in psoriasis cohort
and control group). Over a maximum 20 year fol-
Psoriasis is highly visible and consequently has a low up 45,641 patients with psoriasis and 36,299
significant social stigma which may result in mal- controls developed depression with a HR of
adaptive coping mechanisms and increased stress. 1.19–1.50 depending on disease severity [213].
This negative impact on quality of life is compa- An international observational study of
rable to many major medical conditions including depression, anxiety and suicidal ideation follow-
heart disease and diabetes [199]. Several studies ing clinical surveys of patients (n = 3635) and
have reported an increased prevalence of depres- controls (n = 1359) has reported an aOR for
sion and mood disorders in association with pso- depression, anxiety and suicidal ideation in pso-
riasis. A questionnaire of 2391 patients by riasis of 3.02 (1.86–4.90), 2.91 (2.01–4.21) and
Esposito et al. reported depressive symptoms in 1.94 (1.33–2.82) respectively. Within the cohort
62% of patients with psoriasis who responded 17.3% of patients had experienced suicidal ide-
[200]. This is consistent with a questionnaire of ation [214]. Interestingly evidence supports that
6194 patients with severe psoriasis which demon- depression increases the risk of psoriatic arthritis
strated that 79% considered that their psoriasis in patients with psoriasis; hazard ratio 1.37 (CI
had a negative impact on their quality of life 1.05–1.80) [215]. This association of depression
[201]. The severity of this negative impact on and psoriasis with psoriatic arthritis, stroke and
quality of life is emphasised by a study of 138 AF (discussed above) provide further support for
patients in which 7.2% reported thoughts of sui- pathogenic overlap between the conditions inten-
cidal ideation [202]. The association with suicidal sifying cumulative disease burden to the
ideation is supported by a recent meta analysis individual.
which reported a pooled odds ratio (OR) of 2.05 The increased rates of depression have also
(CI 1.54–2.74) In patients with psoriasis [203]. been observed in other ethnic and geographical
Depression is thought to be mediated by dys- groups. A recent study in Taiwan utilising a
function in regulation of neurotransmitters health insurance database on 17,086 psoriasis
including serotonin, norepinephrine, dopamine, patients and 1,607,242 controls reported depres-
gamma-aminobutyric acid (GABA), and gluta- sion prevalence of 11.5% in psoriasis patients
mate. Inflammatory cytokines (TNF-α, IL-1, compared to 7.7% in the background population
IL-1b, IL-2, IL-6, IL-8, IL-17, IL-23, and [216]. A previous study using the Taiwan National
C-reactive protein) are implicated in pathogene- Health Insurance (NHI) claims database com-
sis of depression and may provide further mecha- pared 51,800 psoriasis patients with a control
nistic overlap [204–209]. A common pathogenic group of 997,771, reporting a prevalence of
pathway for psoriasis and depression may involve depression in 2.13% (1, 103) of subjects com-
IL-12 which is elevated in depression and is also pared to 1.52% (3, 152) in controls (P < 0.0001)
a key cytokine established in the pathogenesis of [50]. This conferred an adjusted relative risk of
psoriasis [210, 211]. 1.50 (95% CI, 1.39–1.61) [50]. Further support
of an association between psoriasis and psychiat- Psoriasis has a dramatic and negative impact
ric comorbidity is provided from an Israeli popu- on mental health. The routine use of the
lation based study of 10,669 patients with Dermatology Life Quality Index (DLQI) as a
psoriasis compared with 22,996 control patients means to evaluate the impact of psoriasis on qual-
[49]. The prevalence of psychiatric comorbidity ity of life reflects the recognition of this in der-
was 15.8% (1685) for patients with psoriasis and matological practice [223]. The cumulative effect
13.1% (3019) for the control group (p < 0.001). of coexistent disease is profound and it is note-
Despite the above evidence the association worthy that effective treatment of psoriasis helps
between psoriasis and depression is not univer- to mitigate some of the mental health burden of
sal. A further study examining comorbid disease psoriatic disease [224].
in Taiwan failed to demonstrate such an associa-
tion in a population based study of 1685 patients Treatment Considerations
with psoriasis and 5055 control subjects [51]. Treatment options for psoriasis in general do not
Depression was recorded in 3.7% (n = 62) of exacerbate or precipitate psychological disease.
patients with psoriasis and 3.0% (151) of the Some studies have raised concern over apremi-
comparison group (p = 0.188). A large Norwegian last and brodalumab from phase 3 and 4 clinical
study also failed to identify depression in associ- trials. The evidence around this is complicated by
ation with chronic plaque psoriasis, although it the clinical trial design and inclusion/exclusion
did with inverse psoriasis [217]. criteria. Subsequent analyses have questioned
Despite the high prevalence of mental health this risk but should continue to be considered
symptoms and depression less than 50% of patients when selecting a treatment for a given individual
with depression are appropriately identified [218]. [225, 226].
This highlights the large clinical unmet need
and potential opportunity for improved care. It is
also noteworthy that the consequence of mental Conclusions
health symptoms will have a negative impact on
patient engagement and adherence and may Emerging data from large-scale epidemiological
increase risk of other comorbid disease including studies and genome wide association studies are
psoriatic arthritis, stroke and AF. providing evidence that psoriasis is a multisys-
Given the impact of psoriasis on quality of life tem disorder with multiple comorbidities.
an association between psoriasis and depression Patients with psoriasis are at an increased risk
appears intuitive. Whilst depression is a contrain- of CVD and several CVD risk factors (obesity,
dication to inclusion in clinical trials, symptoms dyslipidaemia, hypertension, diabetes, NAFLD
of depression are frequently observed to improve and the metabolic syndrome). The aetiology of
over the period of treatment as measured by qual- this remains to be fully elucidated. It is clear that
ity of life indices [219–221]. patients with psoriasis demonstrate a number of
Support for abnormal cognitive function in adverse lifestyle choices (e.g. smoking, poor
patients with psoriasis has been reported in a diet) which undoubtedly contribute to CVD and
small cohort (n = 13) examined for functional CVD risk factors.
brain activity in response to disgust, measured by In developed societies obesity and the meta-
functional magnetic resonance imaging (fMRI) bolic syndrome are highly prevalent and reflects
[222]. The insular cortex is activated in individu- changes in lifestyle relating to a range of factors
als who experience disgust or see others demon- including diet and physical activity. This epi-
strating facial expressions of disgust. In this demic has enormous implications to delivery of
cohort a significantly reduced response in the healthcare. The acceptance of psoriasis as a mul-
insular cortex was reported in patients with pso- tisystem disease associated with obesity and
riasis when compared with controls. The authors potentially metabolic syndrome raises significant
suggest that this is a coping mechanism related to questions about the future prevalence and sever-
social stigma of disease [222]. ity of psoriasis in the general population and how
the dermatology community should be engaged Patient and physician education are of the
in managing this problem. utmost importance. Psoriasis is a multisystem
Current evidence provides compelling support disease that requires a multimodal approach to
for a central role of inflammation linking psoriasis, holistic patient-centred care. For the patient
CVD and CVD risk factors, particularly obesity. increased awareness of comorbid disease will
Evidence supports that effective control of inflam- allow greater opportunity for lifestyle modifica-
mation associated with psoriasis will result in tion to reduce disease burden and improve mor-
improvement, or stabilisation, of CVD or CVD risk bidity and mortality. For the clinician, recognition
factors. Evidence in support of this has been sug- of psoriasis as a systemic disease should prompt
gested in preliminary work in patients with psoria- a broader approach to clinical practice and utili-
sis, rheumatoid arthritis and systemic lupus sation of primary and secondary prevention strat-
erythematosus and reduced incidence of MI in indi- egies to improve morbidity and mortality in this
viduals treated with methotrexate and biologics patient group. Increasingly clinical experts work
(particularly TNFα inhibitors). This is of significant across clinical specialities to efficiently treat
importance for the clinician as an additional factor patients according to the spectrum of clinical dis-
to consider when evaluating treatment options for a ease. Perhaps most noticeably dermato-
patient with moderate to severe psoriasis. rheumatology services are increasingly common.
Psoriasis appears to confer an additional risk In the era of advanced and personalised medicine
of malignancy. This would appear to be greatest it is appealing to consider that in the future we
for lymphomas. Many of the studies evaluating may be able to diagnose patients with a disease of
this relationship are limited by the inability to a particular cytokine pathway, with multiple
control for significant confounders (e.g. family organ specific manifestations including dermato-
history, smoking). This data should serve to logical, and target treatment accordingly.
inform the clinician of an increased prevalence of
malignancy in this patient cohort. This is particu- Funding Sources None.
larly pertinent when considering systemic immu-
nosuppressive therapies and the need for baseline Conflict of Interest PML has received honoraria and/or
grants as an investigator, speaker, and/or advisory board
evaluations and monitoring (e.g. cervical smear member for AbbVie, Actelion, Almirall, Celgene,
testing, mammography). Janssen, Leo, Lilly, Novartis, UCB and Sanofi.
Evidence in support of an association between
RBW has received Research Grants: AbbVie, Almirall,
psoriasis and a broad range of autoimmune dis- Amgen, Celgene, Janssen, Lilly, Leo, Novartis, Pfizer &
ease is increasingly robust, particularly with UCB and Consulting Fees: AbbVie, Almirall, Amgen,
respect to Crohns disease. Many of these associa- Arena, Avillion, Bristol Myers Squibb, Boehringer
Ingelheim, Celgene, Janssen, Leo, Lilly, Novartis, Pfizer,
tions are linked through shared genetic loci.
Sanofi & UCB
Identification of overlapping diseases provides
an opportunity to rationalise treatment options
for dual pathologies.
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Summary of Published Treatment
Guidelines 28
Vignesh Ramachandran, Abigail Cline,
and Steven R. Feldman
Abstract other guideline focus on systemic treatments

without definitive recommendations in some
Psoriasis is a chronic, remitting disease with no
cases. Limitations of the guidelines include
definitive cure. Treatment can be challenging
lack of recommendations for newer biolog-
with an array of therapeutic modalities from
ics and, in some cases, many years without
which to choose. To address this challenge,
update leading to recommendations based on
organizations across the globe have produced
older research. Psoriasis treatment must be
evidence-based treatment guidelines compiled
individualized to patients’ needs and prefer-
by expert panels to aid clinicians with deci-
ences, and guidelines must be updated to offer
sion-making. In this chapter, we consolidate
optimal clinical utility; given the rapidity with
this information to allow the clinician to make
which the psoriasis treatment landscape is
evidence-based decisions using multiple soci-
evolving, this is a tall order.
eties’ guidelines at once and highlight impor-
tant similarities and differences that may affect
management. These guidelines vary in scope
and depth. Some comprehensively describe Key Learning Objectives
available topical, phototherapy, and system- 1. To review recent published treatment

ics (non-biologics and biologics) with strong guidelines from organizations and soci-
recommendations clearly highlighted, while eties worldwide
2. To understand the treatment consider-
V. Ramachandran (*) · A. Cline ations within these guidelines
Department of Dermatology, Center for Dermatology 3. To review considerations for specific

Research, Medical Center Boulevard, Wake Forest patient populations
School of Medicine, Winston-Salem, NC, USA
S. R. Feldman
Department of Dermatology, Center for Dermatology
Research, Medical Center Boulevard, Wake Forest
School of Medicine, Winston-Salem, NC, USA Introduction
Department of Pathology, Medical Center Boulevard,
Wake Forest School of Medicine, Psoriasis is a chronic, remitting disease with no
Winston-Salem, NC, USA definitive cure. Beyond the multisystemic physi-
Department of Social Sciences & Health Policy, cal manifestations of disease, psoriasis can cause
Wake Forest School of Medicine,
profound emotional, psychosocial, and quality of
Winston-Salem, NC, USA

https://doi.org/10.1007/978-3-030-54859-9_28
life burdens [1, 2]. In 2003, the American treatment guidelines from organizations and
Academy of Dermatology (AAD) issued a con- societies across the globe.
sensus statement declaring the goal of psoriasis
treatment is to create lasting improvement in
symptoms while minimizing adverse effects [3]. Methods
Furthermore, the National Psoriasis Foundation
(NPF) came out with “Target to Treat” in 2017, a Guidelines were reviewed for types of treatments
strategy in which patients and their providers discussed and extracted were evidence-based
determine specific targets/goals for improved recommendations with strength of recommenda-
outcomes [4]. tion Grade A or B or Level of Evidence I or II and
Psoriasis treatment involves a plethora of consensus statements based on expert opinion.
modalities: conservative measures, topical This information was extracted from the follow-
medications, ultraviolet (UV) light regimens, ing societies’ guidelines: Canadian Dermatology
and systemics (non-biologics and biologics) [5]. Association (CDA), American Academy of
To help physicians navigate the complexities of Dermatology (AAD), European Association of
treating this disease, various national organiza- Dermatology and Venereology (EADV), German
tions have established evidence-based treatment Society of Dermatology (DDG), Spanish
guidelines based on clinical research studies and Academy of Dermatology and Venereology
compiled by expert panels (Table 28.1). While (SADV), British Association of Dermatology
patient-
specific factors—including comorbidi- (BAD), National Psoriasis Foundation (NPF),
ties, preferences, and adherence—influence Dermatological Society of South Africa (DSSA),
treatment options, these evidence-based guide- Dermatological Society of Malaysia (PDM),
lines aid in clinical decision-making [6, 7]. This Scottish Intercollegiate Guidelines Network
chapter summarizes the more recent published (SIGN), National Institute for Health and
Table 28.1 Overview of published guidelines reviewed by organization

Evidence- Year of
Organization Therapies discussed based? publication
Canadian Dermatology Topicals, phototherapy and photochemotherapy, Yes 2009
Association non-biologic systemics, biologics
American Academy of Topicals, phototherapy and photochemotherapy, Yes 2008–2010
Dermatology non-biologic systemics, biologics
European Association of Non-biologic systemics, biologics Yes 2009
Dermatology and Venereology
German Society of Dermatology Topicals, phototherapy and photochemotherapy, Yes 2007
non-biologic systemics, biologics
Spanish Academy of Non-biologic systemics, biologics Yes 2016
Dermatology and Venereology
British Association of Non-biologic systemics, biologics Yes 2016–2017
Dermatology
National Psoriasis Foundation Phototherapy, non-biologic systemics, biologics Yes 2012
Dermatological Society of South Topicals, phototherapy and photochemotherapy, Yes 2010
Africa non-biologic systemics, biologics
Dermatological Society of Topicals, phototherapy and photochemotherapy, Yes 2013
Malaysia non-biologic systemics, biologics
Scottish Intercollegiate Topicals, phototherapy and photochemotherapy, Yes 2010
Guidelines Network non-biologic systemics, biologics
National Institute for Health and Topicals, phototherapy and photochemotherapy, Yes 2014
Care Excellence non-biologic systemics, biologics
Swiss Society of Dermatology Non-biologic systemics, biologics Yes 2016
and Venereology
28 Summary of Published Treatment Guidelines 401
Care Excellence (NICE), and Swiss Society of Corticosteroids

Dermatology and Venereology (SSDV).
Topical corticosteroids are considered first-line
in several guidelines and strongly recommended
Overview of Treatment Guidelines in others [18–24]. In guidelines that only discuss
systemic treatments, topical corticosteroids are
General Principles still discussed as part of combination therapy,
especially in the treatment of flares and localized
Psoriasis is a chronic condition associated with lesions [25, 26]. Although very effective and
comorbidities related to disease, lifestyle, and strongly recommended, topical corticosteroids
treatment [8]. Disease-related comorbidities do have potential side effects, including skin
include psoriatic arthritis, psychiatric disorders, atrophy, striae, and purpura [20, 24]. Some guide-
cardiovascular disease, inflammatory bowel dis- lines are more cautious and have explicit recom-
ease, nonalcoholic fatty liver disease, obstruc- mendations for use of topical corticosteroids in
tive sleep apnea, and erectile dysfunction long-term treatment plans. For instance, the PDM
[8–10]. Alternatively, those related to lifestyle guidelines recommend limiting use of super
include smoking, alcoholism, and anxiety; side potent topical corticosteroids to 2 weeks and
effects of treatment can include hypertension potent topical corticosteroids to 4 weeks before a
(e.g. cyclosporine), hepatotoxicity (e.g. metho- break from therapy [22]. Additionally, areas of
trexate), and dyslipidemia (e.g. acitretin) [11– sensitive skin (e.g. face, intertriginous) should be
15]. It may be prudent to screen patients with treated with lower potency steroids [18, 19, 21,
psoriasis for these conditions. Concurrent treat- 24]. Combination treatment with vitamin D
ment of their illness and comorbidities may derivatives are recommended by several guide-
have synergistic effects on quality of life and lines to lower exposure to corticosteroids and
outcomes [8]. improve efficacy [18, 19, 21, 23, 24]. Only the
Body surface area (BSA) involvement often AAD guidelines remark on combinational treat-
determines treatment modality and escalation. ment with salicylic acid, a descaling agent, as an
Those with 5–10% or less BSA affected gener- effective option [19]. Overall, the efficacy of
ally were treated with topical medication (unless topical corticosteroids depends on various fac-
palm/sole involvement or otherwise extenuating tors, including vehicle, potency, occlusion, and
circumstance required more than topical treat- compliance [19].
ment. Only beyond 5–10% BSA was when UV
light and systemic medications were considered
appropriate. However, small areas of psoriatic Vitamin D Derivatives
disease, especially on the scalp and palms, can
profoundly impact quality of life and produce Vitamin D derivatives (calcipotriol and calcitriol)
severe symptoms [16, 17]. As such, treatment is are recommended as first-line therapy in some
always in part dependent on the impact is has on guidelines [18, 20, 24]. Other guidelines recom-
patients and small BSA involvement may warrant mend vitamin D derivatives as first-line therapy
escalation of therapy in select cases. for long-term maintenance treatment with good
efficacy in the short-term but not as efficacious as
topical corticosteroids [19, 21–23]. The combina-
Topicals tion medication calcipotriol-betamethasone dipro-
prionate is recommended by a few guidelines as a
Topical therapies in the treatment of psoriasis more efficacious first-line option than either medi-
include: corticosteroids, vitamin D derivatives, cation alone (corticosteroid or vitamin D deriva-
tazarotene (vitamin A derivative), calcineurin tive) [18, 20, 22–24]. Sites of thin skin are less
inhibits, anthralin, and coal tar (Table 28.2). tolerant of vitamin D derivatives and other options,
Table 28.2 Summary of topical treatment guidelines
402
Guidelines Corticosteroids Vitamin D derivatives Tazarotene Calcineurin inhibitors Anthralin Coal tar
Canadian First line as First line: calcipotriol, Monotherapy or in Use in select patients
Dermatology monotherapy or in calcitriol combination as liquor carbonis
Association combination distillate 15%
American Academy First line as Monotherapy or in Monotherapy or in Use off-label for Not recommended
of Dermatology monotherapy or in combination combination facial and
combination Combination: Combination: topical intertriginous
Combination: topical calcipotriol- corticosteroids psoriasis
vitamin D, tazarotene, or betamethasone Combination:
salicylic acid diproprionate tacrolimus and
salicylic acid
German Society of First line as First line: calcipotriol Monotherapy or in Recommended for Inpatient induction Not recommended
Dermatology monotherapy or in Monotherapy or in combination face, intertriginous, therapy as monotherapy
combination combination Combination: and anogenital or in combination
Combination: systemic Combination: corticosteroid areas Combination:
therapies or topicals corticosteroids, UV, or phototherapy or other
systemics topicals
Dermatological First line as First line: calcipotriol Monotherapy or in Recommended for Short-term induction Monotherapy or in
Society of South monotherapy or in Tacalcitol for sensitive combination intertriginous or therapy combination
Africa combination areas (e.g. face) Combination(s): facial psoriasis Recommended Combination: UV
Combination: systemic Combination: corticosteroid outpatient for
therapies or other corticosteroids, 4–8 weeks
topicals combined formulations, Combination: UV or
UV, or systemic topicals
therapies
Dermatological Monotherapy or in Monotherapy or in Recommended Monotherapy or in First-line
Society of Malaysia combination combination tacrolimus and combination
Potent: 4 weeks Combination: UV pimecrolimus for
Super potent: 2 weeks face/flexure
psoriasis
Scottish Monotherapy or in Monotherapy or in Recommended when Recommended when Recommended when
Intercollegiate combination combination vitamin D analogue is vitamin D analogue is vitamin D analogue
Guidelines Combination: vitamin D ineffective or not ineffective or not is ineffective or not
Network analogue tolerated tolerated tolerated
National Institute First-line Maintenance therapy Recommended for Recommends dithranol Recommended as
for Health and Care Limit very potent to when off corticosteroids face, flexures or for treatment-resistant adjunct if vitamin D
Excellence 4-week course and Combination: genitals psoriasis of the trunk or analogue is
potent to 8 weeks corticosteroids limbs ineffective or not
V. Ramachandran et al.
Combination: vitamin D tolerated

such as topical calcineurin inhibitors, are recom- has restricted utility. For instance, the AAD
mended [19, 20, 22–24]. The DSSA guidelines, guidelines state that it was an important treatment
however, do state that tacalcitol is appropriate for in the past but is not correctly recommended [19].
sensitive areas [20]. Vitamin D and UV light is Guidelines that do have recommendations for
more effective than either alone [20, 22]. anthralin usually limit its use to the in-patient set-
ting as part of short-duration induction therapy
[20, 23, 24]. This is partly because the messy for-
Tazarotene mulation and tedious use limit adherence and
utility in the outpatient setting [27, 28].
Some guidelines recommend the use of tazaro- Nevertheless, some guidelines do suggest its use
tene, a topical retinoid (vitamin A derivative), in in the outpatient setting. The SIGN guidelines
the treatment of mild-to-moderate plaque psoria- state that anthralin can be considered in
sis [18, 19]. However, tazarotene is recommended appropriate patients when vitamin D analogues
less frequently compared to topical corticoste- are ineffective or not tolerated. The PDM guide-
roids or vitamin D derivatives (Table 28.2). SIGN lines give a Grade A recommendation for use
guidelines only recommend tazarotene in appro- without specifying treatment setting [21, 22].
priate patients when vitamin D analogues are not Combination treatment with phototherapy, vita-
effective or tolerated [21]. Some guidelines rec- min D derivatives, or topical corticosteroids are
ommend combination therapy with corticoste- more effective [20, 24].
roids to achieve greater efficacy and limit the side
effects of either drug [19, 20, 24].
Coal Tar
Topical Calcineurin Inhibitors Coal tar is another treatment modality not as

often discussed in guidelines (Table 28.2).
Despite their relatively common use in psoriasis Some guidelines state that coal tar (used as
therapy, calcineurin inhibitors are not approved by topical liquor carbonis distillate) can be used in
the United States Food and Drug Administration select patients, especially in low-income coun-
(FDA) for use in psoriasis [19]. While the AAD tries, as it is relatively inexpensive [18–21].
does not officially recommend the use of topical PDM guidelines states that tar-based prepara-
calcineurin inhibitors, it does report widespread tions may be first-line in mild psoriasis [22].
off-label use for facial and intertriginous psoriasis. Other guidelines, citing lack of efficacy, recom-
Effective combination treatment with salicylic mend against coal tar or only suggest it as a pos-
acid is also described [19]. Similarly, the DDG, sible adjunct treatment [23, 29]. Combination
DSSA, and PDM guidelines state that topical cal- treatment with phototherapy, specifically UVB,
cineurin inhibitors may be used in facial and inter- is suggested in some but refuted in other guide-
triginous psoriasis [20, 22, 24]. In contrast, the lines [20, 24].
NICE guidelines state that topical calcineurin
inhibitors should only be used in the face, flexures
or genitals if the response to short-term moderate Phototherapy
potency topical corticosteroids is unsatisfactory or and Photochemotherapy
if long-term treatment is needed [23].
Phototherapy and photochemotherapy entails
treatment with UV light of different wavelengths
Anthralin with or without psoralen, a deoxyribonucleic acid
cross-linking compound [30] (Table 28.3). UV
Anthralin, also known as dithranol, has varying light can be UVA or UVB, the latter of which is
recommendations in the guidelines. Overall, it further broken down into narrowband (NB) and
Table 28.3 Summary of phototherapy and photochemotherapy guidelines

Excimer
Guidelines UVA or UVA with PUVA UVB laser
Canadian Dermatology Monotherapy or in combination Recommended 3×/week
Association NB-UVB more effective
than BB-UVB
American Academy of Monotherapy or in combination NB-UVB as monotherapy
Dermatology Oral PUVA and combination PUVA with or in combination
topical agents Not recommended:
BB-UVB, UVB + PUVA
combination
European Association of PUVA if UVB not effective NB-UVB as monotherapy
Dermatology and Combination: retinoids, methotrexate or in combination
Venereology Combination: retinoids,
methotrexate
German Society of Monotherapy or in combination Monotherapy or in Focal
Dermatology Combination: topical vitamin D analogues combination lesions
Combination: topical
vitamin D analogues
National Psoriasis Monotherapy or in combination Monotherapy or in Focal
Foundation Combination: acitretin, calcitriol, and combination lesions
tazarotene 3×/week less likely to lead
to clearance
Combination: calcitriol and
tazarotene
Dermatological Society Monotherapy or in combination Monotherapy or in Focal
of South Africa Combination(s): topical vitamin D combination lesions
analogues Combination(s): topical
Not recommended for long-term treatment vitamin D analogues
Not recommended for
long-term treatment
Dermatological Society Oral PUVA is superior to NB-UVB with NB-UVB Focal
of Malaysia better remission rate at 6 months and longer Recommended 2×/week lesions
duration of remission than NB-UVB Combination: acitretin
Combination: acitretin Not recommended for
Not recommended for maintenance or >200 maintenance or >350
sessions for PUVA sessions for UVB
Scottish Intercollegiate PUVA for patients without response to NB-UVB as monotherapy
Guidelines Network NB-UVB or in combination
Recommended 3×/week
Not recommended:
BB-UVB
National Institute for Consider PUVA irradiation to treat NB-UVB as monotherapy
Health and Care palmoplantar pustulosis or in combination
Excellence Not recommended: concomitant acitretin Recommended 3x/week
NB-UVB: Narrow-band UVB; BB-UVB: Broad-band UVB
broadband (BB). NB-UVB is recommended over nation treatment with acitretin in patients without
BB-UVB in various guidelines [17, 18, 20–22, response to NB-UVB monotherapy and topical
31, 32]. Thrice weekly NB-UVB treatment is psoralen in combination with NB-UVB as a
most commonly recommended [18, 21–23, 32]. highly effective dual treatment [22].
Combination treatment, such as with topical vita- Psoralen with UVA (PUVA) recommenda-
min D derivatives or tazarotene, can reduce the tions show more variation. Some of the guide-
dose of UVB exposure needed for clearance [18, lines (most commonly older guidelines) do not
20, 23, 24]. The PDM guidelines suggests combi- make much distinction between PUVA and UVB
[17, 18, 20, 24, 32]. However, others state that combination treatment with retinoids followed
NB-UVB is recommended over PUVA and is by methotrexate [31].
safer [21, 31]. Furthermore, some guidelines sug- Tanning (predominantly UVA) is effective in
gest PUVA use in certain cases (e.g. NICE sug- treating plaque psoriasis [33–36]. Although some
gests PUVA for palmoplantar pustulosis), state guidelines do not make much distinction between
PUVA is superior to NB-UVB without comment UVA and UVB, recommendations for tanning are
on safety or only recommend PUVA after failure not included.
of NB-UVB [17, 20, 22, 31]. Oral PUVA is supe-
rior to topical [17]. Combination with acitretin is
suggested by some guidelines, but contraindi- Systemics
cated in others [22, 23].
Long-term treatment with any form of photo- Non-biologic systemics
therapy/photochemotherapy is not recommended
[18, 20, 22, 31]. Excimer laser can be effective Acitretin, cyclosporine A (cyclosporine), and
for limited plaque psoriasis lesions [20, 22, 24]. methotrexate at the most commonly used of these
The EADV guidelines give the strongest recom- agents although others such as apremilast are
mendation for phototherapy/photochemotherapy also discussed (Table 28.4).
Table 28.4 Summary of non-biologic systemics guidelines

Fumaric Acid
Guidelines Acitretin Cyclosporine Methotrexate Apremilast Esters
Canadian Recommend in Recommended for Recommended
Dermatology combination severe disease and for long-term use
Association Combination: intermittent use with routine lab
topical agents Combination: monitoring
calcipotriol- Recommend
betamethasone folate
supplementation
American Recommend for Recommended for Recommended Not
Academy of intermittent use severe disease and for long-term use recommended
Dermatology Combination: intermittent use with routine lab
UV Taper to prevent monitoring
rapid relapse
European Recommended in Recommended for Recommended Not as strongly Recommended
Association of combination intermittent use for long-term use recommended for induction
Dermatology Combination: Long-term with routine lab as biologics and long-term
and cyclosporine, treatment in select monitoring Suggested after treatment
Venereology etanercept, patients (2 years Combination: failing other Combination(s):
methotrexate maximum with etanercept, therapies infliximab,
nephrology acitretin, methotrexate
consultation) adalimumab,
fumaric acid
esters, infliximab
German Society Induction therapy Induction therapy Induction Recommended Induction
of Dermatology Combination: therapy for induction therapy
topicals therapy
Spanish Recommended Recommended for Recommended
Academy of for long-term use intermittent use for long-term use
Dermatology Combination:
and biologics
Venereology
(continued)
Fumaric Acid
Guidelines Acitretin Cyclosporine Methotrexate Apremilast Esters
National Monotherapy or Recommended for Recommended
Psoriasis in combination intermittent use for long-term use
Foundation Combination: (less than with routine lab
topicals, 12 weeks) monitoring
biologics, UV Recommend
folate
supplementation
Dermatological Recommended as Recommended for Recommended Recommended
Society of combination intermittent use for long-term use for recalcitrant
South Africa therapy with routine lab psoriasis or
Combination: monitoring HIV-affected
UV, topicals Recommend patients
folate
supplementation
Dermatological Monotherapy or Recommended for First-line
Society of in combination intermittent use or systemic
Malaysia in patients who treatment
fail, intolerant or
have
contraindications
to methotrexate
Not recommended
in patients with
prior PUVA or for
longer than
2 years
Scottish Monotherapy or Recommended for Recommended Recommended
Intercollegiate in combination intermittent use for long-term use
Guidelines
Network
National Recommended Recommended for First-line Recommended
Institute for for pustular intermittent use systemic after failing
Health and psoriasis or if and palmoplantar treatment other therapies
Care methotrexate and pustulosis Switch to Discontinue if
Excellence cyclosporine are Switch to cyclosporine inadequate
not appropriate methotrexate when response response at
or have failed when response inadequate 16 weeks
inadequate
Swiss Society Monotherapy or Recommended for Recommended Recommended
of Dermatology in combination intermittent use, for pustular or off-label
and Combination(s): erythrodermic, erythrodermic
Venereology UV, and pustular variants
methotrexate, variants
cyclosporine, Combination:
TNF-inhibitors, topical steroids,
ustekinumab vitamin D
Recommended in analogues
cancer patients
Acitretin drug has limited efficacy [18, 20, 24, 32, 37].
Acitretin, an oral vitamin A derivative, is a sys- Guidelines state that acitretin can be considered
temic treatment for psoriasis. Several guidelines as a viable treatment option. Additionally, some
report that, upon review of the literature, this are reserved in the strength of recommendation,
stating that efficacy is increased when combined treatment of psoriasis [29, 39]. In many guide-
with UV, or recommend its use after failure of lines, it is recommended as a long-term man-
other traditional systemics [21, 23, 25, 38]. On agement option [18, 20–23, 25, 26, 31, 32, 37,
the other hand, there are a few guidelines, such as 38, 40]. However, the DDG guidelines state
those by SSDV and PDM, that more strongly rec- that methotrexate may be also used in induc-
ommend acitretin [22, 26]. The SSDV guidelines tion therapy of moderate-to-severe disease [24].
also go on to say that acitretin can be used for The PDM and NICE guidelines are more defini-
pustular or erythrodermic psoriasis and is a use- tive, recommending methotrexate as a first-line
ful option in patients with malignancies given its systemic treatment for moderate-to-severe
lack of immunosuppression [26]. Combination plaque psoriasis [22, 23]. The BAD guidelines
treatments suggested include: UV phototherapy; recommend it as a steroid-sparing agent rather
methotrexate; cyclosporine; tumor necrosis fac- than monotherapy [40]. The CDA and NPF
tor (TNF)-inhibitors; ustekinumab; topical vita- recommend folic acid supplementation [18,
min D derivatives; etanercept [26, 32, 37, 38]. 32]. However, the DSSA and SSDV guidelines
state that although folate use may reduce side
effects, it may lessen efficacy or that there is no
Cyclosporine A clear consensus on folic acid supplementation,
respectively [20, 26].
Cyclosporine is another systemic immuno-
suppressant used in the treatment of psoriasis.
Discussed in nearly all guidelines, cyclosporine Apremilast
is most often recommended as a short-term treat-
ment for rapid induction therapy for moderate- Apremilast is an oral small molecule inhibitor of
to-severe psoriasis and treatment of flares [18, phosphodiesterase-4 [41]. It is infrequently dis-
20–25, 31, 32, 37, 38]. The NICE guidelines go cussed in the guidelines reviewed. Overall, apre-
as far as to say that cyclosporine is a first-choice milast is recommended in adults with plaque
systemic agent for people who meet criteria for psoriasis for induction and long-term treatment
systemic therapy [23]. It has a significant side [23, 37, 42]. It is the least effective biologic
effect profile, which includes nephrotoxicity and according to DDG guidelines [43]. Apremilast
hypertension, that prevents long-term use. The can be used for patients in whom TNF-inhibitors
EADV guidelines suggest long-term use with are contraindicated [37]. Combination treatments
consultation with a nephrologist [31, 37]. The are not discussed in the already limited recom-
PDM guidelines state that cyclosporine may be mendations for this drug.
used for up to 2 years [22]. The SSDV guidelines
do not comment on duration of treatment [26].
This drug may also be used as rescue therapy Systemic Corticosteroids
for erythrodermic, pustular, and palmoplantar
pustulosis [20, 23, 26]. Combinations suggested Corticosteroids function by binding to vari-
include: vitamin D analogues, calcipotriol- ous signal transduction molecules within the
betamethasone, and other topicals to reduce over- cytoplasm of cells to reduce inflammatory
all dose and possible toxicities [18, 24, 26]. reaction [44]. Almost all guidelines discuss
topical corticosteroids. Systemic use is not
often discussed. PDM guidelines recommend
Methotrexate use in pregnancy- induced pustular psoriasis
[22]. SIGN and AAD guidelines imply use in
Methotrexate, a folate antagonist and potent psoriatic arthritis (intra-articular and systemic
anti-inflammatory via release of adenosine at administration) [21, 38]. Erythrodermic flares
low doses, has been used for decades in the are reported with use [18].
Other Systemic Medications severe disease, long-term use, and induction ther-
apy [18, 20, 21, 23, 32, 37, 42, 47]. SADV and
Other systemic medications are infrequently dis- BAD guidelines state that adalimumab is a first-
cussed in guidelines either because they are not line biologic and that dose interval can be
approved in respective countries’ guidelines or increased when used as maintenance therapy [25,
due to insufficient evidence. The AAD guide- 45, 48]. SIGN guidelines state that adalimumab
lines state that evidence for fumaric acid esters may be more effective than methotrexate and
is very strong from studies performed in other etanercept [21]. DDG guidelines state that adali-
countries. However, it is not FDA-approved mumab is more effective than etanercept and
[38]. Azathioprine, hydroxyurea, leflunomide, apremilast and equally effective as ustekinumab
mycophenolate mofetil, sulfasalazine, and and secukinumab [42]. Combination treatments
6-thioguanine have varying levels of evidence and are suggested with methotrexate (strongest),
recommendation strength [38]. The PDM guide- cyclosporine and ustekinumab (expert opinion;
lines report small evidence for mycophenolate increased risk of immunosuppression) [37].
mofetil, hydroxyurea, sulfasalazine, and lefluno-
mide but do not make formal recommendations
for these medications [22]. In Germany, where Etanercept
fumaric acid esters are approved, they are recom-
mended for induction and long-term treatment Etanercept is a fusion protein that functions as a
[24]. The EADV guidelines also recommend decoy receptor, limiting the effects of TNF and is
fumaric acid ester use and suggest combination administered as a shot [49, 50]. Etanercept is
with infliximab and methotrexate [31]. The SIGN appropriate for long-term use and induction ther-
and SSDV guidelines also support fumaric acid apy in the treatment of moderate-to-severe dis-
ester use, however it is off-label in Switzerland ease [18, 20, 21, 23, 37, 42, 47]. SADV guidelines
[21, 26]. The DSSA guidelines say hydroxy- state that it is also a first-line biologic [25]. As per
urea may have a role in treating HIV-affected DDG guidelines, its efficacy is only higher than
patients and, in contrast to the AAD guidelines, apremilast among all other biologics [42]. Some
that there is little evidence for sulfasalazine [20]. guidelines highlight the combination of metho-
Hydroxycarbamide is only suggested as a treat- trexate and etanercept as being effective, espe-
ment option in the SIGN guidelines [21]. cially in patients without adequate response to
methotrexate alone [18, 37].
Biologics
Infliximab
Adalimumab, etanercept, infliximab, ustekinumab,
and secukinumab are the most often discussed Infliximab a monoclonal antibody against TNF-
biologics in the guidelines examined (Table 28.5). alpha that is administered via intravenous induc-
The BAD guidelines may be the most comprehen- tion [51]. It is highly effective initially even in
sive, providing comparisons between the different severe flares, and is the one of the most effica-
biologics [45]. cious biologics as per the DDG and BAD guide-
lines [18, 20, 32, 42, 45]. SADV guidelines also
state that it may be considered a first-line bio-
Adalimumab logic in patients requiring rapid control of dis-
ease [25]. BAD guidelines recommend infliximab
Adalimumab is a tumor necrosis factor (TNF)- be reserved for people with very severe disease
inhibitor administered subcutaneously [46]. It is when other biologics have failed [45, 48]. Long-
discussed in all guidelines searched. Generally, term treatment may also be possible with inflix-
adalimumab is recommended for moderate-to- imab [21, 23, 37, 42]. DDG guidelines give
Table 28.5 Summary of biologic guidelines

Organization Adalimumab Etanercept Infliximab Ustekinumab Secukinumab
Canadian Recommended Recommended Recommended Recommended
Dermatology for long-term for long-term use for severe, acute for long-term
Association use and for Can add to flares use
patients who regimen in
failed etanercept patients without
adequate
response to
methotrexate
American Recommended Recommended Recommended
Academy of for long-term for long-term use for long-term use
Dermatology use
European Recommended Recommended Recommended Recommended Recommended
Association of after failing after failing after failing other after failing after failing
Dermatology other therapies other therapies therapies other therapies other therapies
and Venereology Combination: Combination: Combination: Combination:
cyclosporine, methotrexate cyclosporine, adalimumab,
methotrexate, fumaric acid cyclosporine,
ustekinumab esters, etanercept,
methotrexate, infliximab
ustekinumab
German Society Recommended Recommended Recommended Recommended Recommended
of Dermatology for induction for induction for induction for induction for induction
therapy therapy therapy therapy therapy
Spanish First-line First-line First-line
Academy of biologic biologic biologic
Dermatology Recommended Recommended Recommended
and Venereology for continuous or for continuous or after failing
intermittent use intermittent use TNF agent
Increase dose Increase dose Not
interval during interval during recommended:
maintenance maintenance intermittent use
British First-line Recommended Recommended First-line First-line
Association of biologic for children for severe disease biologic biologic
Dermatology older than or after failing
6 years old other biologics
Dermatological Recommended Recommended Recommended Awaiting
Society of South for long-term for long-term use for long-term use approval at time
Africa use of this
publication
Dermatological Recommended for patients who fail, have intolerance, or contraindication to conventional
Society of systemic treatment and phototherapy
Malaysia Combination: methotrexate, NB-UVB
Scottish Recommended Recommended Recommended Recommended
Intercollegiate for long-term for long-term use for severe for induction
Guidelines use psoriasis, and maintenance
Network especially when
rapid disease
control is
required
National Recommended Recommended Recommended Recommended Recommended
Institute for after failing after failing after failing other after failing after failing
Health and Care other therapies other therapies therapies other therapies other therapies
Excellence Discontinue if Discontinue if Discontinue if Discontinue if Discontinue if
inadequate inadequate inadequate inadequate inadequate
response at response at response at response at response at
16 weeks 12 weeks 10 weeks 16 weeks 12 weeks
infliximab and secukinumab the highest efficacy Table 28.6 FDA approved biologic medications for
plaque psoriasis not in guidelines
rating of all biologics discussed [42]. However,
there is a risk of antibody formation, which can Medication FDA approval EMA approval
limit utility [20]. Combination treatment with Brodalumab February July 2017
2017
fumaric acid esters, methotrexate, and
Certolizumab May 2018 July 2018
ustekinumab is suggested [37]. Guselkumab July 2017 November 2017
Ixekizumaba March 2016 May 2016
Tildrakizumab March 2018 Not approved by the
Ustekinumab EMA
Briefly discussed in British guidelines
a
Ustekinumab is a monoclonal antibody targeting

the interleukin (IL)-12/23 shared p40 subunit
and is administered subcutaneously and intrave- onsiderations for Less Common
C
nously [52]. It is a safe and effective biologic for Psoriasis Types
long-term use in moderate-to-severe disease [18,
21, 23, 32, 37, 42, 45]. It is considered a first-line Evidence-based treatment guidelines are usually
biologic in SADV and BAD guidelines [25, 45]. lengthy and detailed given the complexities of
Some comparisons are mentioned. DDG guide- treating psoriasis and the vast amount of literature
lines only give infliximab and secukinumab compiled to formulate recommendations. It is, how-
with higher efficacy scores [43]. It is suggested ever, unless specified, guidelines refer to psoriasis
to be more efficacious than etanercept [32]. It vulgaris (also known as plaque psoriasis) treatment
has similar efficacy at 3 and 6 months as adali- recommendation since this type of psoriasis com-
mumab and infliximab, but is superior to etan- prises approximately 80% of all psoriasis cases
ercept as per SIGN guidelines [21]. In general, [29]. We outline available recommendations from
ustekinumab should not be used intermittently the guidelines for the other types of psoriasis.
[25]. Combination treatment with adalimumab,
cyclosporine, etanercept, and infliximab are fea-
sible [37]. Pustular
Cases of pustular psoriasis may necessitate

Secukinumab immediate referral to dermatologist as this condi-
tion can be very severe and life-threatening [18,
Secukinumab is a monoclonal anti-IL-17A anti- 20–22]. Guidelines state that acitretin may be an
body that is administered subcutaneously [53]. effective systemic treatment and is considered
Recommendations are limited in guidelines. first-line [20, 21, 26, 32]. For chronic palmoplan-
EADV guidelines recommend its use as a first- or tar pustulosis, oral PUVA is equally effective as
second-line medication based on patient- per the DSSA guidelines, which recommend both
dependent factors (such as response to other acitretin and PUVA in combination which is
treatments or contraindications) for induction more efficacious than either alone [20, 54].
and long-term treatment of moderate-to-severe Methotrexate and systemic corticosteroids are
disease [37]. Similar recommendations are made two other treatment options, although less fre-
in the DDG and NICE [23, 42]. DDG guidelines quently recommended [18, 22]. However, the
score it as having the highest efficacy (tied with DSSA guidelines state that evidence is insuffi-
infliximab) and the British guidelines recom- cient to warrant methotrexate as a treatment in
mend secukinumab as a first-line biologic in these patients [20]. Anthralin is contraindicated
adults with psoriasis [42, 45]. Combination treat- in these patients [18, 20, 22]. BAD guidelines
ments are not discussed in the already limited recommend infliximab for generalized pustular
recommendations for this drug (Table 28.6). psoriasis [40, 48].
Erythrodermic agents, and anthralin are not recommended given

high systemic absorption [22]. Tazarotene is con-
Treatments for erythrodermic psoriasis share traindicated given theoretical risk of systemic
overlap with pustular type, and both are severe absorption leading to fetal defects [18].
variants. As per SSDV guidelines, acitretin, Several guidelines recommend phototherapy
cyclosporine, and methotrexate are effective in with NB-UVB in pregnant women who are inad-
treating erythrodermic psoriasis [26]. DSSA equately treated with topical medications or have
guidelines also recommend acitretin for this severe disease [18, 22, 25, 32].
variant [20]. Infliximab is another viable treat- Systemic treatment with cyclosporine is
ment for this disease [25]. advised as other common options (acitretin,
methotrexate) are teratogenic [18, 22, 32].
Cyclosporine may cause increased risk of prema-
Flexural/Inverse turity and intrauterine growth restriction [22].
All biologics can be used in pregnancy [55].
Recommendations for treatment of flexural/ CDA guidelines specifically recommend the use
inverse psoriasis are limited. However, the guide- of adalimumab, etanercept, and infliximab in
lines do recommend short-tern moderate potency pregnant patients [18]. No malformations are
corticosteroids [18, 21]. If this treatment fails, seen with etanercept or infliximab. However,
other considerations include topical calcineurin women taking infliximab are recommended to
inhibitors [18, 21]. PDM guidelines discuss use contraception during treatment for at least
pimecrolimus (a calcineurin inhibitor) as a pos- 6 months after discontinuation [18]. Etanercept is
sible first-line options for flexural/inverse psoria- recommended as the biologic of choice in the
sis treatment [22]. SADV guidelines [25]. Alternatively, in the PDM
guidelines state that TNF-inhibitors should be
used with caution. The teratogenic risk of adali-
onsiderations for Specific Patient
C mumab is unknown. There is a lack of pregnancy-
Populations related data on ustekinumab use, and infliximab
is associated with low birthweight and prematu-
Pregnancy rity [22]. NPF simply states that biologics can be
used after careful risk-benefit assessment [32].
While many of the guidelines list pregnancy as a Certolizumab pegol was recently FDA-approved
contraindication for various treatments, few dedi- for use in pregnancy and is considered the safest
cate specific portions of their guidelines to pso- for this use [56]. However, it is not discussed in
riasis management in pregnant patients [18, 22, any guidelines, which are too old to include this
32, 45]. In some guidelines, safe topical agents recommendation.
include corticosteroids, anthralin, and tar-based
preparations in the second and third trimesters
and limited tacrolimus use [18, 22]. SADV Children
guidelines recommend low-to-moderate strength
corticosteroids of short duration as first-line ther- In children, it is important to consider the differ-
apy [25]. However, other guidelines state that ences in affected body surface area compared to
topical corticosteroids are Category C for preg- adult counterparts. Lack of research on systemic
nant patients and their safety in nursing patients treatments in children warrants their use only
is unknown at this time [19]. The NPF recom- after topical treatments have been exhausted [18].
mends topical corticosteroids, calcitriol, or Topical corticosteroids are first-line in children.
anthralin to control mild disease in pregnant However, CDA and NICE guidelines recommend
patients [32]. This is in contrast to PDM guide- avoiding very potent formulations and monitor-
lines, which state that salicylic acid, calcipotriol ing for possible side effects [18, 23]. Calcipotriol
is also effective in children and avoids systemic the guidelines are constructed via committees
side effects [18]. using voting systems, biases may be present.
PUVA is not recommended in children if other
treatment options are available [23]. Similarly,
acitretin should be used in children only in excep- Conclusion
tional cases (e.g. when methotrexate and cyclo-
sporine have failed) [23]. Methotrexate and When deciding on therapeutic options for psoria-
cyclosporine may be used in children with c areful sis patients, guidelines are helpful in navigating
monitoring [18, 45]. In fact, the CDA guidelines the myriad of options. However, several factors
state that acitretin and similar vitamin A deriva- should be considered in selecting a treatment
tive compounds have been used safely and effec- including pre-existing comorbidities, special
tively in children. As per the guidelines, long-term patient populations, resource-limited settings,
exposure may cause premature epiphyseal clo- and adherence. Many treatments, particularly,
sure and result in poor bone growth [18]. systemics have contraindications based on pre-
The three biologics often recommended for existing comorbidities [57]. Specific patient pop-
use in children are: etanercept, adalimumab, and ulations, as prior discussed, must be considered
ustekinumab [18, 20, 23, 45]. Etanercept is best [58, 59]. Treatment options may be restricted in
studied and is FDA-approved for use in children resource-limited settings [60]. Furthermore, an
from age 4 to 17 years [18]. Alternatively, BAD important general principle is that the best treat-
and NICE guidelines state that etanercept may be ment is one the patient will be adherent to [61–
used from age 6 and up, adalimumab from age 64]. This concept may be considered in deciding
4 years and up, and ustekinumab from age 12 and treatments.
up (FDA-approved for use in children 12 and Overall, in this chapter we present guidelines
above) [40, 45, 48]. The DSSA guidelines state that are mostly similar, but there are variations
that etanercept has been used successfully in relating to first-line medications, recommenda-
children between age 4 and 17 with plaque pso- tions for UVA versus UVB, strength of recom-
riasis [20]. mendation in systemic agents, and differences in
suggested combination treatments. Even the most
recent guidelines lack recommendations on many
Limitations of the newer biologics. Many are 5–10 years old.
Intermittent updates have not been thorough.
A major limitation of this chapter is that many Furthermore, most guidelines focus on traditional
guidelines are outdates (Table 28.1). This mani- systemic and biologic treatments, excluding the
fests in recommendations that may be based on vital role topical treatments can play in isolation
outdated studies, combination treatments that fail or in combination with systemic medications.
to consider new treatments, and lack of discus- The utility of guidelines may increase if fre-
sion of newer systemic treatments (especially quently updated given the breakneck pace psoria-
biologics). Some guidelines are updated many sis treatment evolution. Recommendations will
years apart (e.g. DDG 2007 guidelines and 2018 soon be needed for biosimilars.
update), which may highlight the length process
of constructing guidelines [24, 42]. As a result,
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Index
A post-marketing safety information, 164

Acitretin recommended monitoring, 148
adverse events, 123 safety indications, 148–149
BB-UVB, 85 systemic therapy, 146
chemical structures, 121 treatment, 146–148
vs. cyclosporine, 124 Adalimumab effectiveness in psoriatic arthritis trial
dosage, 120–123 (ADEPT)
FDA-approved indications, 120 ACR20, 157, 158
half-life, 123 adverse events, 158
hydroxyurea, 120, 121 alanine aminotransferase, 158
lipids monitoring, 120 C-reactive protein, 159
mechanism of action, 120 DMARDS, 157
multicenter Canadian trial, 124 FACIT-Fatigue Scale, 158
palmoplantar pustulosis, 120 HAQ DI scores, 158
phototherapy, 120 levels, 158
recommended monitoring, 123 mTSS, 157
tetracyclines, 123 NSAIDS, 157
TNF-α, 124 open label extension, 158
treatment, 120 Adenosine A3 receptors (A3AR), 298
triglyceride elevations, 124 AMAGINE-1, 268–269
Adalimumab AMAGINE-2, 269–270
ADEPT, 157–159 AMAGINE-3, 271
BELIEVE, 165 American Academy of Dermatology (AAD), 104, 106,
biologic approvals, 161–162 108, 124, 154, 236, 245
CHAMPION, 156–157 American College of Rheumatology criteria (ACR20)
complications, 166 scores, 147, 156, 158, 178, 183, 205, 228, 271
guidelines, 154 American National Psoriasis Foundation, 104, 106, 108,
indications and dosing, 154 113, 166, 349, 356, 400
PRIDE, 165 Anthralin, 3, 4, 52, 64, 329, 330, 359, 403, 410, 411
REVEAL trial Antigen-presenting cells (APCs), 9, 112
adverse effects, 155 Anti-interleukin 17, 348
body mass index, 156 Antinuclear antibodies (ANA), 148, 158, 190, 317
comorbidities, 156 Apremilast
demographics/disease characteristics, 154 ACR20, 146
intent to treat (ITT) analysis, 155 ankylosing spondylitis, 149
LOCF analysis, 155, 156 biologic agents, 141
open label extension, 155, 156, 158 clinical trials, 142
PASI, 155 Dermatology Life Quality Index scores, 156
PGA, 154, 155 DMARD, 157
WPAI, 156 ESTEEM, 142, 143
special populations, 159 ESTEEM-1, 142
TNF-inhibitors ESTEEM-2, 142
black box warnings, 163–164 mechanism of action, 141, 142
live vaccines, 148 nausea and dizziness, 141, 142

https://doi.org/10.1007/978-3-030-54859-9
416 Index
Apremilast (cont.) safety and tolerability

patient-reported outcomes (PROs), 142 adverse events, 272–273
phosphodiesterase type 4 (PDE4), 141 cautions, 274
placebo-controlled study, 142 contraindications, 274
psoriatic arthritis, 142, 143 elderly, 273
rheumatoid arthritis, 146 IBD, 273
safety issues, 141 immunizations, 273
severe plaque psoriasis, 142 pregnancy, 273
Azathioprine, 163, 181, 182, 379, 408 serious infections, 273
suicidal behavior, 273–274
storage, 264–265
B T-helper cells, 263–264
Beck depression inventory (BDI), 148
Biologics Price Competition and Innovation
Act (BCPI), 280 C
Biologic therapies Cardiovascular disease (CVD)
clinical trial organization, 305–306 CRP and hypertension, 382
interleukin 17, 306–308 Danish cohort, 380
interleukin (IL12/IL 23), 308 Encounters Database, 380
Th17 cell, 304 inflammation, 379
tumor necrosis factor alpha (TNF-α), 304 MarketScan® Commercial Claims, 380
Biosimilars myocardial infarction (MI), 379, 380
animal studies, 282 overlapping pathogenesis, 378
approval process, 281–282 prevalence, 378, 382
barriers to use, 286 stroke and atrial fibrillation, 382–383
BPCI, 280 treatment, 383
chronic inflammatory diseases, 279 CASPAR criteria, 344
clinical studies, 282–283 Centers for disease control (CDC), 162, 188
in dermatology, 285 Certolizumab pegol (CZP), 173–192
development of, 281 Chronic inflammatory skin disease, 291
economic advantage of, 286 Climatotherapy, 85, 87
extended patents for branded drugs, 286 Clinical assessment
generics vs., 280–281 differential diagnosis, 24
interchangeability, 284–285 erythrodermic psoriasis, 22
naming of, 281 guttate psoriasis, 20
patent disputes, 286 locations
patient factors, 287 geographic tongue, 21
pharmacovigilance studies, 283–284 inverse psoriasis, 23
reference product, 280 nail psoriasis, 23
structure and function, 282 psoriasiform patch, 23
US and EU, patent expiration dates, 280 scalp psoriasis, 22, 24
Briakinumab (ABT 874), 15, 202, 207, 208, plaque psoriasis, 20
226, 231, 346 pustular psoriasis
Bristol-Myers Squibb (BMS-582949), 210, 239 generalized, 21
Brodalumab, 7, 15, 263–275 impetigo herpetiformis, 21
administration, 264–265 localized, 21–22
clinical efficacy, plaque Comorbid disease
psoriasis, 265–266 autoimmune disease, 385–387
difficult-to-treat psoriasis, 272 confounders, 364
dosing, 264–265 CVD
IL-17 role, 264 CRP and hypertension, 382
initiation of therapy, 274 Danish cohort, 380
pharmacokinetics, 264–265 Encounters Database, 380
phase I clinical trials, 266 evidence suggesting and association, 377
phase II clinical trials, 266–267 inflammation, 379
phase III clinical trials MarketScan® Commercial Claims, 380
AMAGINE-1, 268–269 myocardial infarction (MI), 379, 380
AMAGINE-2, 269–270 overlapping pathogenesis, 378
AMAGINE-3, 271 prevalence, 378, 382
psoriatic arthritis, 271 stroke and atrial fibrillation, 382–383
quality of life, 272 treatment, 383
Index 417
diagnostic criteria, 364 E

dyslipidaemia, 367–370 Epidemiology, 27–34
hypertension, 371 EQUATOR trial, 294
insulin resistance, 374–375 Erythrodermic psoriasis, 22–24, 29, 63, 74, 120, 122,
Iowa Women’s Health Study, 385 129, 258, 407, 411
Lymphoma, 384 ESTEEM, 142, 143
metabolic syndrome, 375–378 Etanercept
NAFLD, 375 combination therapy, 148
obesity congestive heart failure (CHF), 148, 149
leptin, 367 demyelinating disorders, 149
pathogenesis, 365 malignancy, 148
side effects, 367 opportunistic infections, 149
treatment, 367 PASI, 146–148
psychiatric illness, 387–388 phototherapy/systemic therapy, 148
study cohort, 364 psoriatic arthritis, 146, 148
type 2 diabetes mellitus, 374–375 recommended monitoring, 148
obesity risk assessment, 148
GPRD, 365 safety and efficacy
Nurses’ Health Study II, 365 dose reduction, 148
risk, 365 PASI, 146–148
Congestive heart failure (CHF), 149, 158, 159, patient-reported Dermatology Life Quality
162, 164, 186 Index, 147
Corticosteroids, 4, 10, 22, 30, 34, 39–46, 93, 127, 130, US and Global Phase III psoriasis clinical
157, 311, 330, 352, 355, 401, 410, 411 trials, 146
topical corticosteroids (TCS), 39–44 structure and mechanism, 146
Critical quality attributes (CQAs), 281 treatment, 146–148
Crohn’s disease, 14, 23, 30, 153, 159, 161–163, 174, European Association of Dermatology and Venereology,
175, 180, 182, 186, 190, 227, 230, 236, 259, 400, 404, 405, 409
273, 274, 285, 318, 332, 333, 385, 386 European Medicines Agency (EMA), 280
Cutaneous atrophy, 43 Excimer laser therapy
CVD, see Cardiovascular disease adverse effects, 94
Cyclosporine, 346 factors, 64
absorption and bioavailability, 112–113 minimal erythema dose, 71
adverse effects vs. NB-UVB, 71
hypertension, 115 vs. PDL, 96
nephrotoxicity, 115 size, 86
dosing, 114
drug interactions, 116
hypertension, 115 F
mechanism of action, 112 FDA-approved biosimilars, 285
vs. methotrexate, 104–111 Fingernail psoriasis, 344
monitoring guidelines, 114–115 Fingolimod, 297
pregnant women, 113 Food and Drug Administration (FDA), 174, 244, 280,
structure, 111 305, 329, 403
treatment, 112–116 Fumaric acid esters, 368, 386, 405, 408–410
Functional Assessment of Chronic Illness
Therapy-Fatigue (FACIT-Fatigue)
D scale, 158
Dermatological Society of South Africa, 400, 402,
404, 406, 409
Dermatology Life Quality Index (DLQI), 136, 147, G
156, 184, 217, 219, 245, 246, 255, German Society of Dermatology, 136, 400,
272, 349, 388 402, 404, 405
Dermatology Quality of Life Index (DLQI), 267 Goeckerman therapy
Disease course crude coal tar, 80
guttate psoriasis, 20 efficacy, 83
palmoplantar pustulosis, 21 gold standard treatment, 80
plaque psoriasis, 20 hospital unit/psoriasis day care center, 80, 81
Disease modifying anti-rheumatic drug (DMARD), 157, ingram therapy, 83
178, 256, 294 Neutraderm lotion, 80, 83
Dyslipidaemia, 364, 367–370, 375, 376 side effects and long-term safety, 82–83
418 Index
Golimumab lymphoma and non-melanoma skin cancer, 126

GO-REVEAL trial, 183 mechanism of action, 125
IgG1k monoclonal antibody, 174 vs. methotrexate, 124
malignancy, 186, 189–190 myelosuppression, 126
mechanism of action, 174–175 recommended monitoring, 126
NAPSI, 177, 179 treatment, 126, 127
psoriatic arthritis, 175–181 Hypertension, 23, 103, 114–116, 131, 132, 186, 248,
safety and efficacy, 185–186 320, 321, 368, 371, 376, 382, 384, 388, 407
safety considerations, 175–181
G protein coupled receptors (GPCR), 297
Grenz ray therapy, 345 I
Guselkumab Ileal pouch-anal anastomosis (IPAA), 189
clinical efficacy IL-20/PRINS inhibitor, 299
ECLIPSE, 219–220 Immunomodulators
NAVIGATE, 218–219 clinical study, 53–60
recapture, 218 mechanism of action, 60
VOYAGE 1, 215–216 toxicity, 60
VOYAGE 2, 216–218 Indigo naturalis, 336, 345
hidradenitis suppurativa, 222 Inflammatory bowel disease, 221–222
inflammatory bowel disease, 221–222 Inflammatory bowel disease (IBD), 273
malignancy, 221 Infliximab
mechanism, 213–215 autoimmune antibodies, 186
pediatrics, 220–221 BMI and efficacy, 181
psoriatic arthritis, 222 clinical trials, 180, 182
safety/adverse events, 220 combination therapy, 181–182
structure, 213–215 Crohn’s disease, 174, 180
tuberculosis, 221 DLQI, 180
EXPRESS I and II trials, 176–179
IMPACT I and II trials, 176–179
H infection
Hamilton rating scale for depression (HAM-D), 148 glucocorticoids, 188
Health related quality of life (HRQOL), 153, 156–158, opportunistic, 188
167, 255, 258 tuberculosis (TB), 187
Heliotherapy, 85, 87 upper respiratory tract, 187
Hepatotoxicity, 108–110, 119, 120, 126, 129, 132, 162, urinary tract, 187
374, 375, 401 viral infection, 188
Hidradenitis suppurativa (HS), 222 infusion-reactions, 186–187
History malignancy, 189–190
anthralin, 4 mechanism of action, 174–175
arsenic and ammoniated mercury, 3–4 vs. methotrexate, 186, 190
chrysarobin, 3–4 NAPSI, 177, 179
corticosteroids, 4 PASI, 175–177
germ theory, 2 patient tailored therapy, 180
identification, 2–3 retrospective study, 188, 189
methotrexate, 4–5 SPIRIT trial, 176
narrowband UVB, 5–6 TNF-alpha inhibitors, 174
PUVA, 4–5 treatment, 191
retinoids, 5–6 Ingram therapy, 83
systemic immunosuppression, 6–7 Intercellular adhesion molecule (ICAM)-1, 112, 367
tar, 4 Interleukin-17, 354
treatment, 3 IPAA, see Ileal pouch-anal anastomosis
vitamin D, 5–6 Ixekizumab
Hospital anxiety and depression scale (HADS), 272 adverse effects, 258–259
H4 receptor antagonists, 299 body regions, 258
Hydroxyurea bodyweight, 255
adverse events, 126 clinical efficacy, 254–255
contraindications, 126 depression, 259–260
dosage, 125–126 erythrodermic, 258
FDA-approved indications, 125 genital psoriasisis, 257–258
generalized pustular psoriasis, 129 IBD, 259
Index 419
infections, 259 myelosuppression, 110

malignancy, 259 pulmonary fibrosis, 110
nail psoriasis, 256 contraindications, 106
palmoplantar psoriasis, 257 disease severity, 106
pharmacodynamics, 254 dosing, 107
pharmacokinetics, 254 drug interactions, 110–111
psoriatic arthritis, 255–256 folate-dependent, 105
scalp, 257 high-dose, 104, 105
low-dose, 105
monitoring guidelines
J blood parameters, 108
Janus kinase (JAK), 292–295 liver biopsy, 108–109
Janus kinase inhibitor, 292–295 periodic history and physical examination, 108
structure, 104
treatment, 105
K treatment guidelines, 106
Keratolytics, 345 MMF, see Mycophenolate mofetil
Koebner phenomenon, 266 Modified NAPSI (mNAPSI), 345
Modified total sharp score (mTSS), 157–159
Mycophenolate mofetil (MMF)
L adverse events, 127–128
Laser therapy contraindications, 134
excimer laser vs. cyclosporine, 127, 128
adverse effects, 94 dosage, 127
depleting T cells, 94 FDA-approved indications, 127
factors, 94 mechanism of action, 127
minimal erythema dose, 94 vs. methotrexate, 128
vs. NB-UVB, 97 neutropenia, 128
vs. PDL, 97 plaque psoriasis, 127, 128
size, 98 recommended monitoring, 128
lesional and non-lesional skin, 93–94 Myelosuppression, 110, 126, 129, 130, 148
Nd:YAG, 94
PDL, 96
plaque clearance, 93, 94 N
Last observation carried forward (LOCF) Nail bed psoriasis, 344
analysis, 155, 156, 158 Nail matrix psoriasis, 344
Leflunomide Nail psoriasis, 23–24, 41, 99, 153, 154, 160, 177, 179,
adverse events, 132 183, 185, 246, 256, 330, 343–349
contraindications, 134 anti-IL-17 agents, 348
dosage, 132 anti-TNF therapies, 347
FDA-approved indications, 132 CASPAR criteria, 344
mechanism of action, 132 combination therapy, 347
plaque psoriasis/psoriatic arthritis, 134 efficacy of biologic therapies, 348
recommended monitoring, 132 efficacy of systemic therapies, 346
treatment, 132 fingernail psoriasis, 344
Lesional and non-lesional skin biopsies, 266 grenz ray therapy, 345
Liquor carbonis detergens (LCD), 63, 80, 83 intralesional steroids, 346
mNAPSI, 345
nail bed psoriasis, 344
M nail matrix psoriasis, 344
Major Adverse Cardiovascular Events (MACE), 207, psoriatic arthritis, 343
208, 220, 226, 236, 238, 379, 381 RDBPCT, 345
Malignancy, 221 treatment algorithm, 349
Maxacalcitol, 44, 45 Nail Psoriasis Severity Index (NAPSI), 160, 177,
Metabolic syndrome, 7, 103, 153, 160, 230, 303, 312, 179, 246, 256
320, 336, 364, 370, 371, 374–378, 388 National Psoriasis Foundation Medical Board, 7, 104,
Methotrexate, 346 106, 108, 113, 166, 349, 356, 400, 404, 406
absorption and bioavailability, 105–106 NAVIGATE, 218–219
adverse effects Neodymium-doped yttrium aluminum garnet laser
hepatotoxicity, 109–110 (Nd:YAG), 94, 98, 99
420 Index
Nephrotoxicity, 115, 131, 331, 368, 407 type 1 and type 2 responses, 10
Neurokinin-1 (NK1), 298 natural killer (NK) T cells, 12–13
Non-alcoholic fatty liver disease (NAFLD), 109, 368, T lymphocytes
371–375, 377, 388 intralesional, 11
Non-office-based phototherapy signaling, 12
climatotherapy, 85 stimulation, 12
heliotherapy, 85 TNF-alpha, 24, 30
home UVB therapy, 84 PDE4 inhibitors, 295
tanning therapy, 83–84 Pediatric psoriasis
Auspitz sign, 321, 327
biopsy and histology, 328
O clinical variants, 321–324
Obesity diagnosis and clinical characteristics, 321–324
GPRD, 365 differential diagnosis
leptin, 367 cutaneous lupus erythematosus, 326
Nurses’ Health Study II, 365 dermatomyositis, 326
pathogenesis, 365 guttate psoriasis, 326
risk, 365 herald patch, 326
side effects, 367 inverse psoriasis, 326–327
treatment, 367 lichen planus, 326
Oral fumarates, 296–297 lupus erythematosus, 326
Oral therapeutics papulosquamous diseases, 326
anti-psoriatic therapies, 291 pitryiasis rubra pilaris (PRP), 326
A3AR, 298 pityriasis rosea, 326
clinical trials, 292 seborrheic dermatitis, 326
H1-H4 receptors, 299 tinea capitis, 326
IL-20/PRINS inhibitor, 299 epidemiology
JAK inhibitors, 292–295 Crohn’s disease, 318
NK1 receptor, 298 elbows and knees, scalp, 312
oral fumarates, 296–297 enterotoxin-producing Staphylococcus aureus, 320
PDE4 inhibitors, 295 guttate psoriasis, 320
receptor antagonists, 297 HLA-Cw6, 318
RORγ2 inhibitors, 296 Human papillomavirus DNA, 320
SYK inhibitors, 299–300 incidence, 312
Tyk2 inhibitor, 295 intertriginous neck and axillary areas, 312, 316
Oxarol, 45 obesity and metabolic syndrome, 320–321
Oxsoralen Ultra®, 75–77 plaque psoriasis, 312
potential laboratory/diagnostic evaluations, 319
psoriatic arthritis, 320
P upper respiratory tract infections, 320
Palmoplantar psoriasis worldwide demographics, 313
controlled clinical trials, 355 Koebner phenomenon, 21
plaque psoriasis, 354, 355 nail pitting, 317
PPP and PPPP, 356–357 natural supplements, 335–336
psoriasiform dermatitis, 354 PASI score, 325, 329
pustular psoriasis, 354 phototherapy, 334–335
Palmoplantar pustulosis (PPP), 19–22, 24, 34, 95, 120, postinflammatory pigmentary alteration, 321
124, 129, 130, 220, 357, 405, 407 scalp psoriasis, 321, 330
Pathophysiology systemic therapies, 331
clinical presentations, 10 cyclosporine, 331–333
cytokines, 13–14 etanercept, 319, 332, 333
dendritic cells, 13 juvenile rheumatoid arthritis, 317, 332
genetics, 15–16 methotrexate, 331, 333
histopathology, 325 oral antibiotics, 331
IL-23/TH 17 axis, 14–15 retinoids, 331
immunity TNF-α inhibitors, 331
innate and adaptive immune responses, 10 topical corticosteroids, 312, 330
NKT cells, 12–13 topical therapies
PUVA, 4–5 coal tar, 328, 329
T cell hyperactivity, 11 immunosuppressants, 329–330
T H 17 response, 10, 12 keratolytics, 328
Index 421
tazarotene, 330 TNF-α inhibitors, 342

topical corticosteroids, 329 ustekinumab, 348
vitamin D2 and D3 derivatives, 329 cardiovascular and metabolic risk, 295
Penicillin V and erythromycin CASPAR
adverse events, 133 vs. arthropathies, 247
contraindications, 133 clinical research-oriented diagnostic tool, 344
dosage, 133 radiologic study, 345
FDA-approved indications, 133 rheumatologists, 105
guttate psoriasis, 133 clinical history, 154, 271
mechanism of action, 133 diagnosis, 205, 209, 228
vs. phenoxymethyl penicillin, 133 indication, 45
recommended monitoring, 133 joint assessment tools
Pharmacodynamics, 213–214 ACR20, 158, 205, 222, 228
Pharmacokinetics, 213–214 ACR50, 158
Phosphodiesterase 4 (PDE4), 141 ACR70, 158, 222, 228
Phosphodiesterases (PDEs), 295 PsARC, 178, 180
Physician’s global assessment (PGA), 136, 154, 160, joint progression, 158
237, 257, 265, 305, 353 mortality, 31, 364
Pimecrolimus, 52, 60–62, 330, 411 treatment
Pityriasis lichenoides chronica (PLC), 326, 327 AAD guidelines, 401, 403
Plaque psoriasis, 6, 7, 15, 20, 29, 33, 45, 94, 124, 132, leflunomide, 408
215, 244–245, 327, 354 methotrexate, 407, 408
clinical efficacy, 265–266 NSAIDs, 110, 157
Potential triggers prednisone, 347
alcohol and smoking, 30–31 sulfasalazine, 408
estrogen, 33 Psoriatic Arthritis Response Criteria (PsARC), 132, 157
medications, 30 Pulmonary fibrosis, 109, 110, 126, 164
microbial infection, 28–29 Pulsed dye laser (PDL), 96–99, 345
obesity, 31–33 Pustular psoriasis, 354
stress, 29–30 generalized, 21
trauma, 28 impetigo herpetiformis, 21
Progressive multifocal leukoencephalopathy (PML), 128 localized, 21
Psoralen plus puva (PUVA) Tazarotene, 52
bath, 75–77, 80
dosimetry, 75
dosing protocol, 95 R
efficacy, 94–95 Randomized double-blind placebo controlled trials
hands/feet psoriasis, 76 (RDBPCT), 345
photocarcinogenicity RAR-related orphan receptor gammat (RORγt)
cellular mechanisms, 80 inhibitors, 296
long-term safety, 80, 82–83 Recalcitrant plaques, 87, 130, 131
melanoma, risk of, 79 Retinoids, 3, 5, 51–65, 71–88, 123, 124, 127
NMSC risk, 80 Ruxolitinib, 294
SEER program, 79, 80
side effects, 82–83
Psoriasiform dermatitis, 354 S
Psoriasis Area and Severity Index (PASI), 46, 59, 136, Scalp psoriasis, 22, 24, 45, 46, 95, 143, 245, 246, 257,
146, 215, 217, 236, 245, 246, 254, 266, 294 330, 349–354
Psoriasis Assessment and Severity Index (PASI), 265 biologic therapy for, 353–354
Psoriasis Process of Care Consensus Panel, 22 management of, 351–352
Psoriasis Symptom Inventory (PSI), 267, 272 measures of, 350–351
Psoriatic arthritis, 222, 343 procedural therapies for, 352–353
Psoriatic arthritis (PsA) significant hair loss, 350
axial assessment, 247 systemic therapy for, 353
biologic therapy TNF induced psoriasis, 354
adalimumab, 348 topical therapies, 349
CZP, 184–185 tough to treat, 350
etanercept, 347, 348 treatment algorithm for, 354
golimumab, 347 Scalp-specific Physicians Global Assessment
IL-12/23 inhibitors, 308 (S-PGA), 351
infliximab, 348 Seborrheic dermatitis, 350
422 Index
Secukinumab (AIN457), 7, 15, 219, 244–250, 264, 348, Topical medications

354, 357 anthralin, 64
Serious adverse events (SAE), 135, 138, 152, 165, 180, coal tar, 63
186, 206, 220, 221, 229, 258, 267, 271, 295 corticosteroids, 39–46, 329, 330, 355, 401
Spanish Academy of Dermatology and Venereology, 400, immunomodulators
405, 409 clinical study, 53, 57–59
Sphingosine 1 phosphate (S1P), 297 mechanism of action, 52
Sphingosine 1 phosphate (S1P) receptor antagonists, 297 toxicity, 60
Spleen tyrosine kinase (SYK), 299–300 keratolytic agents, 322
Sulfasalazine, 130, 408 moisturizers and keratolytics, 64
Surveillance, Epidemiology, and End Results (SEER) non-medicated emollients, 59
program, 79, 149, 207 phototherapy/systemic medications, 59
SYK inhibitors, 299–300 pimecrolimus, 60
tacrolimus, 60–62
tar
T clinical study, 63
Tacrolimus mechanism of action, 63
adverse events, 131 toxicity, 63
chronic plaque psoriasis, 131 types, 63
contraindications, 131 tazarotene
dosage, 131 clinical trials, 54, 57–59
FDA-approved indications, 130 gel and cream formulations, 60
mechanism of action, 130 mechanism, 52
recommended monitoring, 131 open-label study, 59
safety and efficacy of, 131 palmoplantar and nail psoriasis, 59–60
Tazarotene pharmacokinetics, 52–53
clinical trials, 53 placebo-controlled study, 53
gel and cream formulations, 60 PUVA study, 59
mechanism, 52 steroid study, 57, 58, 60
open-label study, 58 toxicology, 53
palmoplantar and nail psoriasis, 59 UVB monotherapy, 59
pharmacokinetics, 53 TCS
placebo-controlled study, 53 immunologic mechanisms, 41
PUVA study, 59 pharmacokinetics/mechanism, 40
steroid study, 58 potential side effect, 43
toxicology, 53 vs. PUVA, 43
UVB monotherapy, 59 systemic and local adverse effects, 43
6-Thioguanine (6TG) tachyphylaxis, 44
adverse events, 129 topical glucocorticoids, 44
dosage, 129 uses, 41, 44
FDA-approved indications, 129 vehicle, 41, 44
mechanism of action, 129 vitamin D analogues
plaque psoriasis and palmoplantar pustulosis, 130 anti-inflammator, 44
recommended monitoring, 130 betamethasone valerate, 58
TPMT, 130 calcipotriene, 45
Thiopurine methyltransferase (TPMT), 130 calcitriol, 44
TNF-fusion protein, 353 indication, 45
TNF induced psoriasis, 354 tacalcitol, 44
Tofacitinib, 294, 346, 347 Taclonex®, 46
Topical calcineurin inhibitors, 60, 65, 330, 403, 411 VDR, 44
immunomodulators, 60 Total Severity Scale (TSS), 351
Topical corticosteroids (TCS) Traditional systemic therapy
immunologic mechanisms, 41 cyclosporine, 114–116
pharmacokinetics/mechanism, 40 methotrexate, 104–111
potential side effect, 43 see also Cyclosporine; Methotrexate
vs. PUVA, 43 Treatment guidelines
systemic and local adverse effects, 43 acitretin, 401
tachyphylaxis, 44 American Academy of Dermatology, 404
topical glucocorticoids, 44 American National Psoriasis Foundation, 404
uses, 41, 44 azathioprine, 408
vehicle, 41, 44 biologics
Index 423
adalimumab, 408 US pharmaceutical distribution and reimbursement

efalizumab, 380 system, 287
etanercept, 408 Ustekinumab, 356
infliximab, 408, 410 adverse effects
ustekinumab, 408 malignancy, 207–208
Canadian guidelines, 154 phase II and phase III clinical trials, 206
cyclosporine, 408 serious infections, 206–207
Dermatological Society of South Africa, side effects, 206
400, 408, 409 anti-IL-12p40 agents, 209
European Association of Dermatology and clinical efficacy
Venereology, 400, 404, 409 ACCEPT study, 205, 206
fumaric acid esters, 405, 408 PHOENIX 1, 206
German Society of Dermatology, 402, 404, 405 PHOENIX 2, 203, 204
hydroxyurea, 408 psoriatic arthritis, 205
leflunomide, 408 definition, 201–202
methotrexate, 408 efficacy, 203–205
mycophenolate mofetil, 408 interleukin (IL12/IL 23), 201
National Psoriasis Foundation Medical Board, 400, laboratory abnormalities, 209
404, 406 MACE, 207–208
PASI, 376, 380 mechanism, 201
phototherapy, 403–405 pharmacodynamics, 203
Spanish Academy of Dermatology and Venereology, pharmacokinetics, 202–203
400, 405, 409 pregnancy and lactation, 209
sulfasalazine, 408 safety, 205, 206
tacrolimus, 402, 411 treatment, 204, 206, 208
6-Thioguanine (6TG), 408 UVB and biologics, 86
topical medications UVB phototherapy
anthralin, 64 BB-UVB and NB-UVB efficacy, 71, 73
coal tar, 63 cooling procedures, 72
corticosteroids, 39–46, 329, 330, 355, 401 dosing guidelines, 72
keratolytic agents, 322 eye protection, 74
non-medicated emollients, 59 lower-body exposure, 74
pimecrolimus, 60 MED, 71, 72, 74
tacrolimus, 60–62 nurse stations and light boxes, 73
vitamin D analogues, 44 photocarcinogenicity, 74–75
transplant rejection prophylaxis, 11 side effects and safety, 74
Tumor necrosis, 280
Tyk2 inhibitor, 295
Tyrosine kinase inhibitor, 292, 299 V
Vitamin D analogues
anti-inflammatory
U betamethasone valerate, 58
UK General Practice Research Database (GPRD), 365 calcipotriene, 45
Ultraviolet therapy (UV) calcitriol, 45
excimer laser therapy, 87 indication, 45
inpatient phototherapy (see Goeckerman therapy) tacalcitol, 45
non-office-based phototherapy Taclonex®, 46
climatotherapy, 85 VDR, 44
heliotherapy, 85 VOYAGE 1, 215–216
home UVB therapy, 84 VOYAGE 2, 216–218
tanning therapy, 83
photocarcinogenicity, 53, 74–75
Psoralen plus puva (see PUVA) W
PUVA, 75–80 Work productivity and activity impairment
retinoid therapy, 85 (WPAI), 156

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Advances in Psoriasis

ISBN 978-3-030-54858-2 ISBN 978-3-030-54859-9 (eBook)

© Springer Nature Switzerland AG 2014, 2021

1 Introduction to and History of Psoriasis and

13 Adalimumab for Psoriasis �������������������������������������������������������������� 153

Abstract icity. The use of tar and anthralin, while still in

© Springer Nature Switzerland AG 2021 1

History of Psoriasis MOIST

An understanding of disease overall and, skin dis-

Arikha, N (2007) Passions and Tempers. Harper

Perennial, New York. Also Crissey, JT, Parish, LC, Stelley,

During the eighteenth and nineteenth centuries

Anthralin and Tar The development of steroids both for systemic

Amer Acad Dermatol 1992; 27: 640–5.

Understanding the importance of immunosup- 29

Abstract and IL-23 secreted by antigen-presenting cells

© Springer Nature Switzerland AG 2021 9

T-Lymphocyte Stimulation psoriasis [20]. Furthermore, the cytokines pro-

Cytokines are low-molecular-weight glycopro-

53. Lowes MA, Kikuchi T, Fuentes-Duculan J, et al.

Abstract consensus each subtype of pustular psoriasis is

© Springer Nature Switzerland AG 2021 19

Table 3.2 Differential diagnosis of variants of psoriasis References

© Springer Nature Switzerland AG 2021 27

Medications Alcohol and smoking have both been implicated

© Springer Nature Switzerland AG 2021 39

Fig. 5.1 Topical CH2OH

Pharmacokinetics/Mechanism d­examethasone, betamethasone and triamcino-

Potent and superpotent topical steroids should be Immunologic Mechanisms

Fig. 5.2 Diagram of Calcitriol chemical structure

Calcipotriene chemical structure

Katz and colleagues in several studies indi- Adverse Effects

Prolonged use of topical glucocorticoids on market: calcipotriene, calcitriol, tacalcitol and

Calcipotriene (Calcipotriol) roids in the treatment of psoriasis [57–59].

Indication for Psoriasis Use with Other Treatment Modalities

Abstract well tolerated in the treatment of intertrigi-

© Springer Nature Switzerland AG 2021 51

noin, two other ­retinoids, have been abandoned Mechanism of Action

Table 6.1 Clinical trials of tazarotene in psoriasis

Since tazarotene is photostable, it can be applied Mechanism of Action

Fig. 6.2 Also known H H

Table 6.2 Studies of calcineurin inhibitors in inverse psoriasis

treatment of psoriasis. In a double-blind vehicle-­ liculitis, acneiform eruptions, irritation, allergic

Anthralin in 1961; 95% were clear in a mean time of

© Springer Nature Switzerland AG 2021 71

less effective than UV rays with longer wave-

Side Effects and Safety

Side effects of UVB phototherapy include visible

Fig. 7.2 Eye protection for whole-body UVB irradiation

Studies with mice have often not mirrored human

Meanwhile, review of the worldwide literature PUVA (Psoralen Plus PUVA)

Table 7.4 Dosing of ultraviolet A radiation for oral pso-

Table 7.5 Subsequent dosing protocol for PUVA

Fig. 7.6 Boiled water to dissolve Oxsoralen Ultra***

study, both PUVA and NB-UVB irradiation were

et al. involving 93 patients showed an 84% clear-

Dose-dependent effects of PUVA include skin

Table 7.6 Risk of melanoma associated with PUVA treatment

Ros et al. (1983) [31] Sweden 250 0 0–7 4.1 a

Reshad et al. (1984) United 216 0 0–7 4.8 a

1 Introduction to and History of Psoriasis and

13 Adalimumab for Psoriasis �� 153

History of Psoriasis MOIST

Anthralin and Tar The development of steroids both for systemic

T-Lymphocyte Stimulation psoriasis [20]. Furthermore, the cytokines pro-

Medications Alcohol and smoking have both been implicated

Pharmacokinetics/Mechanism dexamethasone, betamethasone and triamcino-

Potent and superpotent topical steroids should be Immunologic Mechanisms

Katz and colleagues in several studies indi- Adverse Effects

Calcipotriene (Calcipotriol) roids in the treatment of psoriasis [57–59].

Indication for Psoriasis Use with Other Treatment Modalities

noin, two other retinoids, have been abandoned Mechanism of Action

Since tazarotene is photostable, it can be applied Mechanism of Action

treatment of psoriasis. In a double-blind vehicle- liculitis, acneiform eruptions, irritation, allergic

Anthralin in 1961; 95% were clear in a mean time of

Side Effects and Safety

Meanwhile, review of the worldwide literature PUVA (Psoralen Plus PUVA)

of treatment. Eight-month remission was r emission duration of 5.1 months was calculated

Commercial Tanning Therapy

elanoma associated with “ever use” (any expo-

Heliotherapy UVB and Retinoid Therapy

near equivalent reductions in PASI after 5 weeks Pulsed Dye Laser

Ruiz-Esparza was the first to report the use of Efficacy

Methotrexate Methotrexate has anti-proliferative, anti-

Drug Interactions statin have been described [50]. Medications that

more readily available and commonly used UVB Hydroxyurea

starting at 3 g as a daily dose and decreasing by Perils and Pitfalls

moderate disease control after a follow-up period When Best to Use

Mechanism of Action The clinician should obtain a history and physical

A retrospective 4-year review of the treatment of When Best to Use

Dosage s ymptoms of hypertension alongside repeat mea-

Penicillin V and Erythromycin Recommended Monitoring

FDA-Approved Indication(S) No specific hematologic or biochemical monitor-

Mechanism of Action Penicillin is contraindicated in patients with

Both antibiotics (penicillin V or erythromycin) Strength of Evidence

Perils and Pitfalls mean change (−6.6%), and pruritus visual ana-

Table 12.2 (continued) Malignancies

group. In addition, 16.7% of the adalimumab ADEPT

Fingernail Psoriasis Hidradenitis Suppurativa

patients with generalized pustular psoriasis. Biologic Comparator Trials

marketing malignancy incidence was 1.1 in adali- Post-Marketing Safety Information

Case series report success using adalimumab Complications of Not Treating

Conclusion 8. Kridin K, Shani M, Schonmann Y, Fisher S, Shalom

Golimumab week 14 [68]. This was compared to only a 3%

Certolizumab tions every 2 weeks and patients were assessed at