A randomized, double-blind, vehicle-controlled,

bilateral comparison trial of bexarotene gel 1% versus

vehicle gel in combination with narrowband UVB
phototherapy for moderate to severe psoriasis vulgaris
Melissa Amy Magliocco, MD, Komal Pandya, MD, RPh, Viktor Dombrovskiy, MD, PhD, MPH,
Linda Christiansen, RN, Yuk Wong, RN, BSN, MA, and Alice Bendix Gottlieb, MD, PhD
New Brunswick, New Jersey

We report results of a randomized, vehicle-controlled, bilateral comparison pilot study of bexarotene gel
1% with narrowband UVB (NBUVB) phototherapy for moderate to severe psoriasis. In all, 9 patients
applied drug or vehicle gel to comparable target lesions up to twice daily for 10 weeks. NBUVB was
initiated 2 weeks after topical therapy began. Limitations include small sample size and interim analysis.
Based on analysis of target lesion scores, bexarotene gel 1%/NBUVB was significantly more effective than
placebo/NBUVB. ( J Am Acad Dermatol 2006;54:115-8.)

T opical and oral retinoids are a mainstay of of synergies between oral retinoids and UVB as
psoriasis therapy. Generally, retinoids inter- treatments for psoriasis.2-4
act with nuclear retinoic acid or retinoid X Bexarotene, a synthetic retinoid, selectively acti-
receptors, which bind their respective response ele- vates retinoid X receptors and, thus, appears to offer
ments to regulate gene transcription. In psoriasis, therapeutic activity and an adverse event profile
these interactions result in normalization of kerati- distinct from retinoic acid receptor retinoids.
nocyte differentiation and proliferation. Topical Systemic bexarotene alone or with UVB has demon-
tazarotene, which selectively activates retinoic acid strated efficacy and tolerability for psoriasis.5-7 The
receptors, has relatively low efficacy in more severe objective of this study was to determine whether
psoriasis, is teratogenic, and has a high incidence of topical bexarotene plus narrowband UVB (NBUVB)
cutaneous toxicity. Oral acitretin rarely clears psori- is more effective than vehicle plus NBUVB for
asis as monotherapy and is teratogenic. We previ- moderate to severe plaque psoriasis.
ously demonstrated its prodrug, etretinate, promotes
terminal differentiation of keratinocytes and thins METHODS
plaques.1 Because limited UVB penetration through Patient population
thick plaques inhibits efficacy, combining retinoids Patients were 18 years of age or older, had
with UVB should enhance efficacy. There are reports moderate to severe psoriasis involving 3% or more
of body surface area, and failed prior topical therapy.
Exclusion criteria included systemic therapies,
From the Psoriasis Center of Excellence, University of Medicine and greater than 15,000 IU/d vitamin A, psoralen-UVA,
Dentistry of New Jersey-Robert Wood Johnson Medical School.
Supported by a grant from Ligand Pharmaceuticals Inc. Narrow- UVB, topical therapies (except over-the-counter
band UVB phototherapy unit was donated by UVBioTek. emollients/shampoos), other retinoids, or investiga-
Conflicts of interest: None identified. tional drugs within 1 month before entry; anticipated
Previously presented as a poster at the Fifth Annual Meeting of prolonged sunlight/other UV exposure during the
the Federation of Clinical Immunology Societies in Boston, study; inability to understand the consent form or
Mass, on May 12-16, 2005.
Accepted for publication September 25, 2005. comply with protocol requirements; contraindica-
Reprint requests: Melissa Amy Magliocco, MD, Psoriasis Center of tion to topical retinoid use; current skin cancer;
Excellence, University of Medicine and Dentistry of New Jersey- history of melanoma or skin-sensitizing diseases; and
Robert Wood Johnson Medical School, 51 French St, New concurrent illness that would preclude participation.
Brunswick, NJ 08901-0019. E-mail: [email protected].
Women of childbearing potential who were preg-
Published online November 29, 2005.
0190-9622/$32.00
nant, lactating, or unwilling to use adequate contra-
ª 2005 by the American Academy of Dermatology, Inc. ception were excluded. Men were excluded if they
doi:10.1016/j.jaad.2005.09.012 would not agree to use condoms with women of

115
116 Magliocco et al J AM ACAD DERMATOL
JANUARY 2006

baseline with readings performed approximately

24 hours later. The first treatment was 60% minimal
erythema dose; dosages were increased in accor-
dance with protocol.

Efficacy and safety evaluations

Evaluations were performed at baseline, then
weekly for 8 weeks, starting at the initiation of
phototherapy. Efficacy was assessed using the target
lesion score (a modified Psoriasis Area and Severity
Index) and photography. Right- and left-side target
lesions were scored for erythema, scaling, and
thickness, each on a scale of 0 to 4 (0 = none, 1 =
mild, 2 = moderate, 3 = severe, 4 = very severe). The
parameter scores were summed, giving a score
ranging from 0 to 12. Physical examination and
adverse event monitoring were performed at each
Fig 1. Participant flow and follow-up. visit. Women of childbearing potential had urine
pregnancy tests at screening, baseline, 4 weeks, and
childbearing potential during the treatment period the final visit.
and at least 1 month afterward. This study was
approved by our institutional review board and Statistical analysis
conducted in compliance with the Declaration of Mean changes in scores from baseline were com-
Helsinki. pared for bexarotene- and vehicle-treated sides.
Considering small sample size, the Wilcoxon rank
Study design sum test was used to analyze differences between
This pilot study was a randomized, double-blind, two groups. Because we tested a directional alterna-
vehicle-controlled, bilateral comparison of bexaro- tive hypothesis that the experimental treatment is
tene 1% versus placebo, combined with NBUVB more effective than placebo, we used a 1-tailed test.
phototherapy, for moderate to severe psoriasis. This
interim analysis was planned a priori, as we wished RESULTS
to determine feasibility of a larger trial. The assign- Patients
ment of placebo or drug to a specific side of the body In all, 11 patients (9 men, 2 women; age 31-77
was randomized using software (Excel, Microsoft, years) were consented and screened. One patient
Redmond, Wash). lacked adequate body surface area involvement. Of
10 enrolled patients, 9 (90%) completed the trial.
Treatments One withdrew during the second week because of
Medications evaluated were bexarotene 1% and skin irritation. Because he only had baseline scores,
vehicle gels (Ligand Pharmaceuticals Inc, San Diego, he was considered inevaluable. Fig 1 shows partic-
Calif). Each patient received a kit comprising two ipant flow and follow-up.
similar tubes, labeled with a number and treatment
assignment side. One tube contained placebo and Clinical evaluations
the other contained bexarotene; both gels were Efficacy. Bexarotene 1% plus NBUVB was sig-
indistinguishable from each other. Patients applied nificantly more effective than vehicle plus NBUVB
gels liberally to symmetric, comparable target lesions for moderate to severe psoriasis. Changes in target
on the assigned sides of the body for 10 weeks. lesion scores were compared for drug- and placebo-
Applications were every other day during the first treated sides (Fig 2). The mean decrease in score
week, once daily the second week, then twice daily, from baseline for bexarotene-treated lesions was
as tolerated. If a lesion became irritated, treatment 67.6% (95% confidence interval 50.9%-84.3%); that of
frequency was reduced. Patients were not to use vehicle-treated lesions was 48.2% (95% confidence
emollients before assessments. To ensure compli- interval 24.0%-72.5%). Using Wilcoxon rank sums,
ance, tube weights were measured and recorded at score improvement with drug use was significantly
each visit. Patients received NBUVB thrice weekly greater compared with placebo use (P = .04). Score
for 8 weeks, starting 2 weeks after topical therapy components (scaling, erythema, induration) were
began. Minimal erythema dose was determined at analyzed separately (not shown). The percent
J AM ACAD DERMATOL Magliocco et al 117
VOLUME 54, NUMBER 1

Fig 2. A, Target lesion score improvement in drug and placebo groups. (Percent reduction
from initial score, mean 6 SD.) Left (B) and right (C) posterior forearm target lesion at baseline.
D, Left posterior forearm target lesion after drug treatment plus narrowband UVB (NBUVB).
Lesion was flat, had minimal scale, and had slight macular erythema secondary to drug. E, Right
posterior forearm target lesion after placebo treatment plus NBUVB. Residual scaling,
erythema, and induration were present.

reduction in induration was statistically significant treatments, natural variations in blood pressures, or
(P = .042); changes in scaling and erythema (P = .176 both.
and P = .059, respectively) were not.
Safety. The most common dermatologic adverse DISCUSSION
events encountered in evaluable patients were The results of this study demonstrated therapy
macular erythematous rash (22%, 2 of 9) and skin with topical bexarotene 1% combined with NBUVB
irritation (22%, 2 of 9). The patient who withdrew did was more effective for moderate to severe plaque
so because the gels irritated his hands (his target psoriasis than vehicle combined with NBUVB (es-
lesions). Worsening/fluctuating hypertension was sentially NBUVB alone). Retinoids have demon-
observed in 4 patients, but deemed unrelated to strated anti-inflammatory effects: etretinate was found
study agents and appeared more likely a result of to decrease epidermal thickness, normalize kera-
noncompliance with concomitant antihypertensive tinocyte differentiation, decrease T-cell infiltration
118 Magliocco et al J AM ACAD DERMATOL
JANUARY 2006

by approximately 50%, and decrease intercellular epidermal differentiation and reduced cell-mediated inflamma-
adhesion molecule-1 expression.1 Thus, we believe tion are unexpected outcomes. J Cutan Pathol 1996;23:404-18.
2. Lowe NJ, Prystowsky JH, Bourget T, Edelstein J, Nychay S,
that bexarotene was not merely acting as a Armstrong R. Acitretin plus UVB therapy for psoriasis: compar-
keratolytic. isons with placebo plus UVB and acitretin alone. J Am Acad
An important limitation of this pilot study was its Dermatol 1991;24:591.
very small size; however, clinically meaningful and 3. Spuls PI, Rozenblit M, Lebwohl M. Retrospective study of the
statistically significant improvement was seen with efficacy of narrowband UVB and acitretin. J Dermatol Treat
2003;14:17-20.
bexarotene. In addition, this was an interim analysis 4. Orfanos CE, Steigleder GK, Pullmann H, Bloch PH. Oral retinoid
in advance of a larger trial. Treatment with bexar- and UVB radiation: a new, alternative treatment for psoriasis on
otene is expensive; one cost-reducing strategy is to an outpatient basis. Acta Derm Venereol 1979;59:241-4.
apply it to the thickest plaques. Further studies are 5. Smit JV, De Jong EM, Van Hooijdonk CA, Otero ME, Boezeman
warranted, which include larger safety, efficacy, and JB, Van De Kerkhof PC. Systemic treatment of psoriatic patients
with bexarotene decreases epidermal proliferation and param-
pharmacoeconomic analysis to justify the high cost eters for inflammation, and improves differentiation in lesional
of treatment. skin. J Am Acad Dermatol 2004;51:257-64.
6. Smit JV, Franssen ME, De Jong EM, Lambert J, Roseeuw DI, De
We gratefully acknowledge the assistance of the
Weert J, et al. A phase II multicenter clinical trial of systemic
staff of Ligand Pharmaceuticals Inc, particularly Steven
bexarotene in psoriasis. J Am Acad Dermatol 2004;51:249-56.
D. Steckel, PharmD. 7. Moore AY. Oral bexarotene and narrowband UVB phototherapy
in the treatment of moderate-to-severe plaque psoriasis. Poster
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