REVIEW

From Empirical to Pathogenesis-Based

Treatments for Psoriasis
Peter CM. van de Kerkhof1
Since the foundation of the European Society for epidermal differentiation. Genetic factors predispose for
Dermatological Research, pathogenesis of psoriasis psoriasis, and triggering factors may aggravate the disease.
has been studied by many research groups, focusing The European Society of Dermatological Research (ESDR)
on various compartments of the skin. Understanding celebrated its 50th anniversary during the annual meeting on
of the pathogenesis of psoriasis has evolved into a 23e25 September 2021. In this review, we will overview 50
branching model of innate and acquired immunity. years of research on the pathogenesis of psoriasis. During the
Insights in the genetics of psoriasis proved to be first 25 years of the ESDR, research groups focused on various
compatible with this model. fields of interest: epidermal growth and differentiation,
Inspired by these insights, pathogenesis-based treat- inflammation, and immune mechanisms. The evidence in
favor of immunopathogenesis and a central role for the T
ments have emerged with unprecedented efficacy
cells have been accumulating during these years. Subse-
and sustainability. In particular, the cytokine network
quently, during the next 25 years, immunopathogenesis has
harbors major treatment targets for biologics with
been the unifying principle in the research and treatment
TNF-a, the IL-17 family, IL-23 and, in the case of
development of psoriasis.
generalized pustular psoriasis, IL-36. Furthermore, the The innovations in psoriasis are a showcase for trans-
Jak TYK2, PDE-4, and AHR are targets for new small lational medicine: the transition from empirical innovations
molecules in the treatment of psoriasis. Psoriasis to drug discovery on the basis of insights into the pathogen-
research is a showcase par excellence of translational esis of the disease.
medicine, resulting in pathogenesis-based
treatments. PSORIASIS, A T CELL DRIVEN DISEASE
Journal of Investigative Dermatology (2022) 142, 1778e1785; doi:10.1016/ Several observations have convinced researchers that T cells
j.jid.2022.01.014 are crucial in the pathogenesis of psoriasis. The first obser-
vation is that T cells accumulate in early psoriatic lesions
(Braun-Falco and Christophers, 1974). Furthermore, clusters
of activated HLA-DRþ immunocompetent cells have been
Editor’s Note observed in the psoriatic lesion, suggesting an ongoing im-
mune response (Baker et al., 1984; de Boer et al., 1994).
This Review is part of a series of articles invited from HLA-DR molecules are present on keratinocytes (KCs), sug-
lectures presented at the 2021 Meeting of the European gesting that KCs may activate T cells (Gottlieb et al., 1986).
Society for Dermatological Research, in celebration of its Further support for the hypothesis that psoriasis is a T-cell
50th Anniversary. driven disease is the increased numbers and activation of
non-Langerhans antigen-presenting cells (APCs) in the pso-
riatic lesion (Baadsgaard et al., 1989) and the expression of
ICAM-1 and interferon-gamma inducible protein-10 on KCs
INTRODUCTION TO THE HISTORY OF DRUG
(Gottlieb, 1990). Finally, injection of CD4 cells into pre-
DISCOVERY IN PSORIASIS
psoriatic skin engrafted onto severe combined immunodefi-
Psoriasis is an inflammatory disease involving the skin, joints,
ciency (SCID) mice induces psoriasis (Nickoloff and Wrone-
cardiovascular system, and CNS. Psoriasis of the skin is
Smith, 1999).
characterized by erythema, induration and scaling, reflecting
The potent efficacy of ciclosporin in psoriasis (Ellis et al.,
inflammation, epidermal hyperproliferation, and abnormal
1986; Griffiths et al., 1986) has lent important support for
the actual relevance of targeting T cells as pathogenesis-
1
Department of Dermatology, Radboud University Nijmegen Medical based treatment of psoriasis. Ciclosporin binds to cyclo-
Centre, Nijmegen, The Netherlands
philin and inhibits calcineurin, resulting in inhibition of NFAT
Correspondence: Peter CM van de Kerkhof, Department of Dermatology,
transcription factor for the IL2 gene in T cells. The efficacy of
Radboud University Nijmegen Medical Centre, PO box 9100, 6500 HB
Nijmegen, The Netherlands. E-mail: [email protected] blockade of activated T cells by IL-2 conjugated to diphtheria
Abbreviations: APC, antigen-presenting cell; DC, dendritic cell; ESDR, Eu- toxin fragments in psoriasis shows that specific inhibition of
ropean Society for Dermatological Research; GPP, generalized pustular this pathway improves psoriasis (Gottlieb et al., 1995), which
psoriasis; KC, keratinocyte; MHC, major histocompatibility complex; mDC, is compelling evidence for the relevance of this pathway to
myeloid dendritic cell; SCID, severe combined immunodeficiency; Th, T
helper; TLR, toll-like receptor; Treg, regulatory T cell; TRM, tissue-resident
the pathogenesis of psoriasis. Furthermore, the antipsoriatic
memory T cell efficacy of anti-CD4 and CTLA-4eIg (Abrams et al., 2000;
Received 24 September 2021; revised 23 January 2022; accepted 25 January Nicolas et al., 1991) provide robust evidence for T-cell tar-
2022; corrected proof published online 3 March 2022 geting as a pathogenesis-based treatment principle.

ª 2022 The Author. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology. This is
1778 Journal of Investigative Dermatology (2022), Volume 142 an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
 PCM van de Kerkhof
Pathogenesis and Treatment of Psoriasis

EPIDERMAL CHALLENGES STIMULATE DENDRITIC CELLS, 2. Innate lymphocytes, NK cells, and NKT cells have been
RESULTING IN ACTIVATION OF T HELPER 1 AND 17 shown to produce IL-17 (Coquet et al., 2008; Polese et al.,
CELLS 2020; Villanova et al., 2014).
An injury or friction of the skin may trigger a psoriatic lesion. 3. Neutrophils have been shown to contain IL-17, although
Virus or autologous DNA binds to the cathelicidin-derived transcription of IL17 by these cells has not been shown
antimicrobial peptide LL-37 (Lande et al., 2007). LL-37 was convincingly (Keijsers et al., 2014; Lin et al., 2011).
shown to enhance DNA-induced IFN-a responses in a toll-
like receptor (TLR) 7- and TLR8-dependent manner in plas- IL-17 is a crucial cytokine in psoriasis (Krueger et al., 2012;
macytoid DCs (DCs) (Ganguly et al., 2009; Lande et al., Lowes et al., 2008, 2007). IL-17 can be produced by several
2007). In clinical practice, IFN-a is a well-known trigger for immunocytes in psoriasis. Both IL-17A and IL-17-F are
psoriasis. The TLR7 agonist imiquimod proved to trigger considered to be relevant in psoriasis. The robust efficacy of
psoriasis and represents an animal model for psoriasis (van antieIL-17 treatments confirms the relevance of this pathway
der Fits et al., 2009). IFN-a stimulates myeloid DCs to psoriasis and psoriasis treatment. IL-22 is produced by
(mDCs), which release IL-12 and IL-23 upon stimulation Th17 and Th22 cells. In contrast to antieIL-17 treatments,
(Lowes et al., 2014, 2007). IL-12, in the context of other antieIL-22 treatment was not successful in psoriasis but was
cytokines, stimulates activation and proliferation of T helper effective in atopic dermatitis (Guttman-Yassky et al., 2018).
(Th) 1 cells. This pathway will be explored later under acti-
vation and trafficking of Th1 cells. HOW KCs ARE AFFECTED BY T CELLS AND CYTOKINES
Increased expression of IL-23 has been shown in the pso- Activated T cells affect KCs in various ways. Lesion-derived T-
riatic lesion (Lee et al., 2004). IL-23 induces proliferation and cell clones can induce growth of KCs in culture; IFN-g,
activation of Th17 cells in a concerted action with other although a growth inhibitor on its own, acts cooperatively
cytokines, including TNF-a. TNF-a activates mDCs, which with other T-cell GFs to cause KC growth induction (Bata-
synthesize IL-23. One can conclude from the suppression of Csorgo et al., 1995). It is intriguing that IFN-g is not a treat-
IL-23 signaling by the TNF-a inhibitor etanercept that TNF-a ment target in psoriasis.
signaling is relevant to the IL-23/IL-17 cascade (Zaba et al., T-cellederived cytokines, including IL-17 and IL-22, acti-
2009, 2007). Ustekinumab, targeted against the p40 chain, vate KCs to produce host defense proteins, cytokines, and
which IL-12 and IL-23 have in common, is a biologic with a chemokines. IL-17 and IFN-g synergize in the enhancement
well-appreciated efficacy in psoriasis. Biologics that selec- of proinflammatory cytokine production by human KCs
tively target the p19 chain of IL-23 have an even higher (Teunissen et al., 1998), in particular CXC, CXCL, and CCL20
clinical efficacy. chemokines, which enhances tracking of neutrophils, T cells,
After stimulation by LL-37eDNA complexes, DCs from and DCs (Harper et al., 2009). IL-22 upregulates the
psoriatic plaques are potent stimulators of T-cell proliferation. expression of host defense proteins in KCs, downregulates the
The important role of DCs in the pathogenesis of psoriasis expression of at least seven genes associated with differenti-
and the efficacy of antieIL-23 treatments converge to the ation of KCs, and induces epidermal hyperproliferation
conclusion that IL-23 is a master cytokine in psoriasis and a (Boniface et al., 2005; Wolk et al., 2004).
relevant therapeutic target. IL-6 is expressed in high levels in the psoriatic lesion. It is a
pleiotropic proinflammatory cytokine that is produced by a
variety of cells such as fibroblasts, macrophages, endothelial
IL-17e AND IL-22eProducing CELLS cells, and KCs in response to a variety of stimuli, which
Th17 cells differentiate from naive CD4 cells in a milieu of include other cytokines such as IL-1, TNF-a, and PDGF
IL-6 and TGFb with IL-23 as a critical stimulator (Grossman et al., 1989). IL-6 stimulates the proliferation of
(Morishima et al., 2009). Th17 cells release IL-17A, IL-17F, human KCs. AntieIL-6 therapies, which are effective for
and IL-22 on stimulation (Liang et al., 2006). In addition to rheumatoid arthritis, are either ineffective for psoriasis or can
Th17 cells, IL-17eproducing CD8 cells (Tc17) have been induce new-onset psoriasis-like disease (Fritz et al., 2017).
shown in the psoriatic epidermis (Ortega et al., 2009). KCs in allergic contact dermatitis and in psoriasis have
After successful treatment, IL-17eproducing ab T-cell been shown to express both TNF-a and IL-17 receptors
clones are still present in the apparently symptomless (Albanesi et al., 1999; Boniface et al., 2007). The synergism
psoriatic skin, which suggests that these cells belong to the of TNF-a and IL-17 signaling has been studied by Chiricozzi
most persistent T cells of the psoriatic lesion (Matos et al., et al. (2011). This synergism revealed a much larger set of
2017). Th22 cells also differentiate from naive CD4 cells, significant disease-signature genes in the psoriasis tran-
and these cells are stimulated by IL-23, TNF-a, and IL-6 to scriptome than that in TNF-a and IL-17 in isolation.
release IL-22 (Fujita, 2013). Th22 cells release IL-22 on In the psoriatic lesion, IL-17A, IL-17F, IL-22, TNF-a, IFN-g,
activation. and IL-6 are integrated into a cytokine network. These cyto-
In addition to the Th/Tc17 lineage, several other cell types kines induce epidermal proliferation, premature keratiniza-
may produce IL-17: tion, expression of host defense proteins, and chemokines.

1. Regulatory T cells (Tregs) may differentiate to IL- TRAFFICKING AND ACTIVATION OF TH1 CELLS
17eproducing cells. In the psoriatic lesion, IL-17þ As explained earlier, activation and proliferation of Th1 cells
CD4þCD25highFoxP3þ Tregs have been identified result from IL-12eproducing mDCs, which have been stim-
(Bovenschen et al., 2011). ulated by an epidermal challenge. Injection of CD4 cells into

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 PCM van de Kerkhof
Pathogenesis and Treatment of Psoriasis

prepsoriatic skin engrafted onto SCID mice induces psoriasis (Asadullah et al., 2000). It remains intriguing that IFN-g, a
(Nickoloff and Wrone-Smith, 1999). Injection of these cells Th1 cytokine, is not a target for antipsoriatic treatments.
seems to be essential in the elicitation of early psoriasis. Th1 cells and not Th2 cells contribute to the pathogenesis
These accumulations of CD4 cells in the dermis are followed of psoriasis. Immunodeviation from Th1 to Th2 dominance
by CD8 cell activation and recruitment, accumulating in the proved to be a therapeutic principle for psoriasis.
epidermis. The Th1 cells are likely to participate in an earlier
stage of psoriasis pathogenesis by inducing CCL20 and IL-23 T CELL TRAFFICKING INTO THE EPIDERMIS IS
production in mDCs, thus playing a role upstream of the MANDATORY FOR THE PSORIATIC LESION
proinflammatory cascade controlled by the IL-23/IL-17 axis Activated T cells invading the epidermis of patients with
(Diani et al., 2016). psoriasis express heterodimeric integrin a1b1, the receptor
The uncommitted T cell may differentiate into a Th1 cell for collagen I, which is a component of the basement
in a milieu of IL-12 and IL-18 or into a Th2 cell in a milieu membrane. Blocking a1b1, using a neutralizing mAb, pre-
of IL-4. Th1 cells release Th1 cytokines such as TNF-a, vented both the accumulation of epidermal T cells and the
IFN-g, and IL-2. Th2 cells release Th2 cytokines such as IL- development of psoriatic lesions in a xenotransplantation
4, IL-5, IL-10, and IL-13. Psoriasis is a disease with Th1 mouse model (Conrad et al., 2007). These studies strongly
cytokine dominance (Austin et al., 1999; Schlaak et al., suggest that interaction between T cells and KCs is required
1994). In addition to the Th1 cell dominance, cytotoxic for the development of the disease. New strategies in psori-
T-cell dominance has been observed as well by Austin asis treatment focusing on T-celleextracellular matrix in-
et al. (1999). In contrast, atopic dermatitis is a disease teractions seem to be promising. T cells residing in the
with Th2 cytokine dominance. Studies on T-cell pop- epidermis have a highly relevant role in the pathogenesis of
ulations in biopsies taken from psoriatic lesions and atopic psoriasis.
dermatitis lesions in the same patient revealed distinct T- In particular, in the chronic psoriatic lesion and during
cell infiltrates compatible with the Th1/Th2 paradigm the resolution of the psoriatic lesion, intraepidermal entry
(Eyerich et al., 2011). Th1 cytokines dominance implies a and activation of CD8 cells have been observed (Baker
strong cell-mediated immunity, whereas Th2 cell domi- et al., 1984). When peripheral bloodederived mixtures
nance is associated with attenuated cell-mediated immu- of CD4/CD8 cells are injected into symptomless psoriatic
nity. This explains why bacterial infections of the skin are skin engrafted onto SCID mice, psoriatic lesional skin is
seldom seen in patients with psoriasis and are frequent in characterized by preferential migration of CD8 cells into
patients with atopic dermatitis. Although psoriasis and the hyperplastic epidermis (Wrone-Smith and Nickoloff,
atopic dermatitis were supposed to be mutually exclusive 1996). In the epidermis of the psoriatic plaque, CD8
(Christophers and Henseler, 1987), atopic dermatitis and cells prevail, whereas CD4 cells are the predominant cells
psoriasis may present in the same individual, both simul- in the dermis. Psoriatic epidermis exhibits a pronounced
taneously and consecutively, and coexistence of disease CD8 cell epidermotropism with accompanying epidermal
may occur at a level equal to or lower than expected hyperproliferation and abnormal keratinization, and the
(Cunliffe et al., 2021). changes are only minimally expressed in atopic dermatitis
The relevance of Th1 cells to the pathogenesis of psoriasis and lichen planus (Bovenschen et al., 2005).
has been confirmed by the efficacy of antieIL-2 blockade of Epidermal T cells are highly activated in psoriasis, and a
activated T cells by IL-2 conjugated to diphtheria toxin high proportion of CD8 cells belong to the tissue-resident
fragments in the treatment of psoriasis (Gottlieb et al., 1995). memory T (TRM) cells. CD8þ TRM cells have been ascribed
However, later studies showed that IL-2 can be produced by a role in immunity after resolved viral skin infections, and
CD8þ cells as well. these cells may express TRM markers, including CD69,
AntieTNF-a molecules have revolutionized the treatment CD103, and CD49a. CD8þCD49aþ TRM cells produce IFN-g,
of psoriasis between 2000 and 2010, resulting in a long- and CD8þCD49ae TRM cells produce IL-17. Selective reten-
term improvement of psoriasis in at least half of the pa- tion of CD8þ TRM cells in resolved psoriatic lesions explains
tients. As a result, the number of hospital beds for psoriasis why psoriatic lesions often recur at the same sites. TRM cells
was substantially reduced in Europe. Although originally are a potential biomarker for residual disease activity versus
antieTNF-a was considered to be a treatment targeted at deep remission (Cheuk et al., 2014; Benezeder and Wolf,
Th1 cells, TNF-a signaling is involved in various compo- 2019).
nents of the pathogenesis of psoriasis, and antieTNF-a is by Intraepidermal accumulation of CD8 cells is mandatory for
no means a treatment targeted specifically against Th1 cells the development of the psoriatic lesion. In particular, the
(Gottlieb et al., 2005). Cytokine, GF, and chemokine pro- CD8þ TRM cells persist after clinical resolution of the lesion
duction by lymphocytes, neutrophils, DCs, and KCs are all and may be a biomarker to differentiate between partial
affected by TNF-a. TNF-a activates mDCs that synthesize versus deep remission.
IL-23 and other regulators of T-cell development (Zaba
et al., 2009, 2007). The TNF-a inhibitor etanercept has AUTOANTIGEN PRESENTATION AND COSTIMULATORY
been shown to suppress the IL-23/IL-17 axis (Zaba et al., PATHWAYS
2009, 2007). Not an epidermal challenge but the presentation of auto-
On the basis of the Th1/Th2 paradigm, IL-10 treatment has antigens may initiate and maintain the psoriatic lesions. In
been investigated and a significant but modest clinical antigen presentation, the primary interaction is between the
improvement has been shown in patients with psoriasis major histocompatibility complex (MHC) of DCs and TCRs.

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Pathogenesis and Treatment of Psoriasis

DCs and T cells interact in an antigen-specific manner. In Autoantigens may be initiators of psoriasis. The interaction
addition, other cells of the epidermis, including KC and between APCs and T cells represent treatment targets.
melanocyte may interact with CD8 cells through MHC class
IeTCR binding. The oligoclonal T-cell expansion in psori- PSORIASIS, A DISEASE OF BRANCHING INNATE AND
asis, analyzing TCR usage on the infiltrated T cells, provides ACQUIRED IMMUNITY
clear evidence in favor of an antigen-specific T-cell The various components of the immunopathogenesis provide
response in the psoriatic lesion (Chang et al., 1994; an integrated system of innate and acquired immunity. In
Menssen et al., 1995). Figure 1, the segments of research on the pathogenesis of
The following candidate epidermal autoantigens have been psoriasis have been integrated. After an epidermal challenge,
proposed: stimulation of DCs results in IL-12 and IL-23 release, which
activate Th/Tc1 and Th/Tc17 cells. Autoantigens may be
1. KC proteins with similarity to streptococcal antigens presented to T cells, also resulting in IL-17 release. IL-17, in
(Besgen et al., 2010; Valdimarsson et al., 2009); concerted action with other cytokines, including TNF-a, IFN-
2. lipid antigens generated by PA24D: PA24D generated g, IL-22, IL-2, and IL-6, induces epidermal proliferation and
lipid antigen activates CD1a Langerhans cells, and these parakeratosis and releases host defense proteins and che-
bind to CD1a-reactive T cells, which generate IL-17 and mokines, which induce accumulation of neutrophils, T cells,
IL-22 (Cheung et al., 2016); macrophages, and DCs. Persistence and disease memory of
3. melanocyte autoantigen ADAMTSL5 (Prinz, 2017): psoriasis is mediated by CD8þ TRM cells.
through MHC class I, melanocytes bind to the TCR of CD8 In individual patients, some segments of the pathogenesis
cells, and On activation, these T cells release IL-17; and may be more dominant than others, which may explain the
4. host defense protein LL-37 (Fuentes-Duculan et al., 2017; heterogeneity of psoriasis when comparing individual
Lande et al., 2014): LL-37especific T cells belong to both patients.
CD4 and CD8 cells, resulting in Th1 and Th17 secretion
ability.
PSORIASIS SUSCEPTIBILITY GENES ARE ASSOCIATED
The interaction between TCR and MHC may be a future WITH IMMUNE MECHANISMS IN PSORIASIS
target for drug development. CD4 and CD8 molecules bind Psoriasis is a polygenic disease. More than 80 psoriasis risk
to the MHC molecule, stabilizing the TCReMHC interac- loci have been reported (Zhu et al., 2021). Several of these
tion. It has been shown that anti-CD4 treatments have genes are associated with the biological mechanisms as
therapeutic efficacy in psoriasis (Nicolas et al., 1991). explained earlier. Some susceptibility genes are associated
Because the majority of T cells in the epidermis are CD8 with antigen presentation, IL-23/IL-17 axis, type I IFN
cells, therapeutic approaches to reduce CD8 cells seem signaling, NF-kB signaling, and skin barrier (Dand et al.,
promising. 2020). Outcomes of studies on the genetics of psoriasis are
Furthermore, so-called costimulatory pathways are criti- entirely compatible with a key role of the aforementioned
cally required for the process of T-cell activation, comprising signaling pathways. At present, research on the genetics of
antigen-dependent and antigen-independent T-cell activa- psoriasis has identified far more genes, which will be re-
tion. Costimulatory pathways have been identified to be ported in future publications.
relevant to psoriasis because selective inhibitors proved to
improve psoriasis clinically: PATHOGENESIS-BASED BIOLOGICS AND SMALL
MOLECULES
1. Alefacept inhibits the activation of memory effector T The biologics, which are available for the treatment of pso-
cells (CD45RO T cells) by blocking the costimulatory riasis, have been listed in Box 1.
interaction between LFA-3 and CD2 (Krueger, 2002). Long-term effective and safe control of psoriasis can be
LFA-3 is localized on APCs and CD2 on memory achieved with the available biologics. Anti-TNF treatments
effector T cells. CD2eLFA-3 interaction may activate T are realizing a 75% improvement of PASI in the majority of
cells in the absence of TCR triggering. Another mech- patients and antibodies against the IL-17 family, and antieIL-
anism of alefacept in the treatment of psoriasis is 23 biologics are permitting a 100% improvement of disease
inducing apoptosis of memory effector T lymphocytes severity in about half of the patients, illustrating the relevance
and depletion of CD2 cells by binding to NK cells of the IL-23/IL-17 signaling in psoriasis. The efficacy of bi-
through its Fc region. Alefacept has been registered by ologics has been compared and contrasted in network meta-
Food and Drug Administration but not by European analyses (Armstrong et al., 2020).
Medicines Agency. In addition to the revolutionary development of new bi-
2. Efalizumab is an IgG1 antibody against the CD11a sub- ologics in psoriasis, several small molecules are in various
unit of LFA-1 and blocks LFA-1/ICAM-1 interaction stages of development (Box 2):
(Leonardi, 2004). Efalizumab reversibly blocks LFA-1/
ICAM-1 interaction, resulting in reduced T-cell activa- 1. The gene for the Jak TYK2 proved to be a susceptibility
tion and impaired T-cell trafficking. Efalizumab was gene for psoriasis (Dand et al., 2017). This Jak is associated
withdrawn from the market because of reported cases of with IFN-a, IL-12, and IL-23 signaling. Deucravacitinib, a
progressive multifocal leukoencephalopathy in patients TYK2 inhibitor, proved to be effective in psoriasis; PASI 90
on efalizumab treatment. was reached by 44% of the patients (Papp et al., 2018).

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Pathogenesis and Treatment of Psoriasis

Figure 1. An integrated concept of innate and acquired immunity. After an epidermal challenge, self-DNA is complexed with the host defense protein LL-37. LL-
37 was shown to enhance DNA-induced IFN-a responses in a TLR7- and TLR8-dependent manner in pDCs. As a result, mDCs are activated, and this activation is
reinforced by an autocrine TNF-a loop. mDCs migrate to lymph nodules and release IL-12 and IL-23, which promote the differentiation and proliferation of Th/Tc1,
Th/Tc17, and Th/Tc22 cells from naive T cells. These T cells migrate to the skin and remain stimulated by mDCs. Th1 cells release IL-2, TNF-a, and IFN-g; Th/Tc17
cells release IL-17A, IL-17F, IL-22, and TNF-a; and Th22 cells IL-22. Autoantigens may be presented to T cells. The melanocyte autoantigen ADAMTSL5 binds to
TCR of CD8 cells through MHC class I. On activation, these T cells release IL-17. PLA2G4DAg activates CD1a Langerhans cells, and these bind to CD1a-reactive T
cells, which generate IL-17 and IL-22. IL-17A and IL-17F, in concerted action with other cytokines, including TNF-a, IFN-g, IL-22, and IL-2, induce epidermal
proliferation and parakeratosis and release host defense proteins and chemokines, which results in accumulation of neutrophils, T cells, macrophages, and
dendritic cells in the established lesion. Several of these inflammatory cells such as neutrophils contribute to IL-17 production. Epidermal cells release IL-37, which
activates IL-8. IL-8 is a potent chemoattractant for neutrophils. Enhanced IL-36 signaling is a crucial pathway in pustular psoriasis. The established psoriatic lesion
continues to release self-DNA which binds LL-37 and again stimulates the pDCs. The cytokine IL-36, released by the epidermis of the psoriatic lesion, also activates
pDCs. The pathogenesis of psoriasis is an activation loop. In the chronic lesion, CD8 cells prevail and may differentiate to CD8þ TRM cells, which mediate
persistence and disease memory of psoriasis. MHC, major histocompatibility complex; mDC, myeloid dendritic cell; pDC, plasmacytoid dendritic cell; T1, type 1 T
cell, T17, type 17 T cell; T22, type 22 T cell; TLR, toll-like receptor; TRM, tissue-resident memory T cells. Illustration assistance provided by Heather McDonald,
BioSerendipity, LLC, Elkridge, MD.

2. PDE-4 inhibits the breakdown of the second messenger inhibitors restore this distorted balance: apremilast is
cAMP in immunocytes, resulting in protein kinase A acti- available as a systemic treatment (Forchhammer and
vation, resulting in activation of NF-kB and inhibition of Ghoreschi, 2015; Papp et al., 2015) and roflumilast is in
CRE-binding protein and ATF-1. This modulation of tran- development as a topical treatment (Lebwohl et al., 2020).
scription factors results in a dominancy of IFN-g, IL-12, IL- 3. The AHR is activated by several exogenous ligands such as
17, IL-22, and IL-23 in comparison to IL-6 and IL-10. PDE-4 polycyclic aromatic hydrocarbons and digoxin-like

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Box 1. Biologics for the Treatment of Psoriasis Box 2. Small Molecules for the Treatment of Psoriasis
AntieTNF-a: Phosphodiesterase inhibitors
Etanercept Apremilast systemic
Adalimumab Roflumilast topical1
Infliximab TYK2 inhibitors
Certolizumab Deucravacitinib systemic
AntieIL-17 PF-06826647 systemic1
AntieIL-17 A Brepocitinib systemic1
Secukinumab Aryl hydrocarbon receptor agonist
Ixekizumab Tapinarof1
AntieIL-17A/F 1
Not yet approved by European Medicines Agency and Food and Drug
Bimekizumab1 Administration.
AntieIL-17 receptor
Brodalumab
AntieIL-12/23 (p40 chain)
Ustekinumab
understood, and studies on psoriasis of the skin and comor-
AntieIL-23 (p19 chain) bidities are fragmented by the borders of medical specialties.
Risankizumab Psoriasis is a multifactorial disease, and treatment de-
Guselkumab cisions involve a host of factors. Computational approaches
Tildrakizumab
1
reconciling a multitude of factors may provide unique
Approved by European Medicines Agency and not yet by Food and Drug
opportunities in the future. One single factor in isolation is
Administration.
unlikely to be informative, but one factor in the context of
the complexity of the disease matters. In the individual
patient, a host of data from system medicine, biological
compounds. There is evidence that crude coal tar therapy systems, and consumer lifestyles have to be registered, and
may show some efficacy by activation of the AHR. AHR is following big data analytics, personalized treatment de-
a transcription factor, which is translocated into the nu- cisions will become possible as a proactive approach,
cleus. Subsequently, gene transcription is modulated, improving the course of the disease and preventing
comprising downmodulation of cytokines including those comorbidities from reactive to proactive medicine (Cesario
relevant to psoriasis and atopic dermatitis, an antioxidant et al., 2014).
response, and finally improved barrier formation by FLG
upregulation (Bissonnette et al., 2021; Di Meglio et al.,
CONCLUSION
2014). Tapinarof is an AHR agonist and as topical ther-
During the previous 50 years, our insights in the immuno-
apy proved to result in a 75% improvement of PASI in
pathogenesis of psoriasis have been evolved into a branching
36e47% of the patients (Robbins et al., 2019).
model of innate and acquired immunity. Insights into the
genetics of psoriasis have revealed a constellation of sus-
STRATIFICATION OF PSORIASIS ceptibility loci, entirely congruent to this model. Inspired by
To predict the course of psoriasis in the individual patient and these insights, pathogenesis-based treatments have emerged
to guide the selection of adequate treatment, we need bio- with unprecedented efficacy and sustainability, reconfirming
markers. Research groups over the world attempt to provide that these steps in pathogenesis are relevant to the disease.
disease stratifications on the basis of biomarkers and disease Psoriasis research and development are a showcase par
characteristics. For example, early-onset psoriasis proved to excellence of translational medicine.
be associated with HLA-C*06:02 carriers. The HLA-C*06:02
allele proved to be a modest predictor for responding to ORCID
ustekinumab treatment (Li et al., 2016). Peter CM van de Kerkhof: http://orcid.org/0000-0003-0084-3131

Generalized pustular psoriasis (GPP) is a showcase for

Disclaimer
disease stratification with genetic biomarkers. Loss of func- The contents of this review have been presented at the virtual meeting of the
tion mutations of IL36RN proved to be associated with GPP. European Society for Dermatological Research 2021.
Pathogenesis-based drug development was successful based
CONFLICT OF INTEREST
on this new knowledge (Hussain et al., 2015; Marrakchi PCMvdK received fees for consultancy service or lectureships from Almirall,
et al., 2011). In a phase 1 study on GPP, inhibition of the AbbVie, Eli Lilly, Novartis, Janssen Pharmaceuticals, Leo Pharma, Bristol
IL-36 pathway with the inhibitor BI 655130 resulted in a Mayer Squibb, UCB, Boehringer Ingelheim, and Dermavant Sciences.
marked improvement in majority of the patients (Bachelez PCMvdK is a chief medical officer at International Psoriasis Council.

et al., 2019).
ACKNOWLEDGMENTS
Comorbidities of psoriasis are arthritis, enthesitis, dactyli- The author wishes to acknowledge Rogier Trompert Medical Arts for
tis, hypertension, obesity, type 2 diabetes, dyslipidemia, providing the license to publish Figure 1 in the Journal of Investigative
cardiovascular disease, depression, suicide and suicidal Dermatology.
ideation, sleep disorders, inflammatory bowel disease,
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