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

115
116 Magliocco et al
Fig 1. Participant flow and follow-up.
childbearing potential during the treatment period
and at least 1 month afterward. This study was
approved by our institutional review board and
conducted in compliance with the Declaration of
Helsinki.
Study design
This pilot study was a randomized, double-blind,
vehicle-controlled, bilateral comparison of bexaro-
tene 1% versus placebo, combined with NBUVB
phototherapy, for moderate to severe psoriasis. This
interim analysis was planned a priori, as we wished
to determine feasibility of a larger trial. The assign-
ment of placebo or drug to a specific side of the body
was randomized using software (Excel, Microsoft,
Redmond, Wash).
Treatments
Medications evaluated were bexarotene 1% and
vehicle gels (Ligand Pharmaceuticals Inc, San Diego,
Calif). Each patient received a kit comprising two
similar tubes, labeled with a number and treatment
assignment side. One tube contained placebo and
the other contained bexarotene; both gels were
indistinguishable from each other. Patients applied
gels liberally to symmetric, comparable target lesions
on the assigned sides of the body for 10 weeks.
Applications were every other day during the first
week, once daily the second week, then twice daily,
as tolerated. If a lesion became irritated, treatment
frequency was reduced. Patients were not to use
emollients before assessments. To ensure compli-
ance, tube weights were measured and recorded at
each visit. Patients received NBUVB thrice weekly
for 8 weeks, starting 2 weeks after topical therapy
began. Minimal erythema dose was determined at
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
visit. Women of childbearing potential had urine
pregnancy tests at screening, baseline, 4 weeks, and
the final visit.
Statistical analysis
Mean changes in scores from baseline were com-
pared for bexarotene- and vehicle-treated sides.
Considering small sample size, the Wilcoxon rank
sum test was used to analyze differences between
two groups. Because we tested a directional alterna-
tive hypothesis that the experimental treatment is
more effective than placebo, we used a 1-tailed test.
RESULTS
Patients
In all, 11 patients (9 men, 2 women; age 31-77
years) were consented and screened. One patient
lacked adequate body surface area involvement. Of
10 enrolled patients, 9 (90%) completed the trial.
One withdrew during the second week because of
skin irritation. Because he only had baseline scores,
he was considered inevaluable. Fig 1 shows partic-
ipant flow and follow-up.
Clinical evaluations
Efficacy. Bexarotene 1% plus NBUVB was sig-
nificantly more effective than vehicle plus NBUVB
for moderate to severe psoriasis. Changes in target
lesion scores were compared for drug- and placebo-
treated sides (Fig 2). The mean decrease in score
from baseline for bexarotene-treated lesions was
67.6% (95% confidence interval 50.9%-84.3%); that of
vehicle-treated lesions was 48.2% (95% confidence
interval 24.0%-72.5%). Using Wilcoxon rank sums,
score improvement with drug use was significantly
greater compared with placebo use (P = .04). Score
components (scaling, erythema, induration) were
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
(P = .042); changes in scaling and erythema (P = .176
and P = .059, respectively) were not.
Safety. The most common dermatologic adverse
events encountered in evaluable patients were
macular erythematous rash (22%, 2 of 9) and skin
irritation (22%, 2 of 9). The patient who withdrew did
so because the gels irritated his hands (his target
lesions). Worsening/fluctuating hypertension was
observed in 4 patients, but deemed unrelated to
study agents and appeared more likely a result of
noncompliance with concomitant antihypertensive
treatments, natural variations in blood pressures, or
both.
DISCUSSION
The results of this study demonstrated therapy
with topical bexarotene 1% combined with NBUVB
was more effective for moderate to severe plaque
psoriasis than vehicle combined with NBUVB (es-
sentially NBUVB alone). Retinoids have demon-
strated anti-inflammatory effects: etretinate was found
to decrease epidermal thickness, normalize kera-
tinocyte differentiation, decrease T-cell infiltration
118 Magliocco et al
by approximately 50%, and decrease intercellular
adhesion molecule-1 expression.1 Thus, we believe
that bexarotene was not merely acting as a
keratolytic.
An important limitation of this pilot study was its
very small size; however, clinically meaningful and
statistically significant improvement was seen with
bexarotene. In addition, this was an interim analysis
in advance of a larger trial. Treatment with bexar-
otene is expensive; one cost-reducing strategy is to
apply it to the thickest plaques. Further studies are
warranted, which include larger safety, efficacy, and
pharmacoeconomic analysis to justify the high cost
of treatment.
We gratefully acknowledge the assistance of the
staff of Ligand Pharmaceuticals Inc, particularly Steven
D. Steckel, PharmD.
REFERENCES
1. Gottlieb SL, Hayes E, Gilleaudeau P, Cardinale I, Gottlieb AB,
Krueger JG. Cellular actions of etretinate in psoriasis: enhanced
J AM ACAD DERMATOL
JANUARY 2006
epidermal differentiation and reduced cell-mediated inflamma-
tion are unexpected outcomes. J Cutan Pathol 1996;23:404-18.
2. Lowe NJ, Prystowsky JH, Bourget T, Edelstein J, Nychay S,
Armstrong R. Acitretin plus UVB therapy for psoriasis: compar-
isons with placebo plus UVB and acitretin alone. J Am Acad
Dermatol 1991;24:591.
3. Spuls PI, Rozenblit M, Lebwohl M. Retrospective study of the
efficacy of narrowband UVB and acitretin. J Dermatol Treat
2003;14:17-20.
4. Orfanos CE, Steigleder GK, Pullmann H, Bloch PH. Oral retinoid
and UVB radiation: a new, alternative treatment for psoriasis on
an outpatient basis. Acta Derm Venereol 1979;59:241-4.
5. Smit JV, De Jong EM, Van Hooijdonk CA, Otero ME, Boezeman
JB, Van De Kerkhof PC. Systemic treatment of psoriatic patients
with bexarotene decreases epidermal proliferation and param-
eters for inflammation, and improves differentiation in lesional
skin. J Am Acad Dermatol 2004;51:257-64.
6. Smit JV, Franssen ME, De Jong EM, Lambert J, Roseeuw DI, De
Weert J, et al. A phase II multicenter clinical trial of systemic
bexarotene in psoriasis. J Am Acad Dermatol 2004;51:249-56.
7. Moore AY. Oral bexarotene and narrowband UVB phototherapy
in the treatment of moderate-to-severe plaque psoriasis. Poster
613 presented at: 61st Annual Meeting of the American
Academy of Dermatology; March 21-26, 2003; San Francisco,
CA.