C li n i~al The ~apeu~i ~s~Volu m e 27 N u m be~ 2 i 2

Topical Retinoids in Inflammatory Acne: A Retrospective, Investigator-Blinded, Vehicle-Controlled, Photographic Assessment

JamesJ. Leyden, MD, 1 Alan Shalita, MD, 2 Diane Thiboutot, MD, 3 Kenneth Washenik, MD, PhD, 4 and Guy Webster, MD, PhD s

1Universityof Pennsylvania, Philadelphia, Pennsylvania, 2State Universityof New York Downstate Medical Center, Brooklyn, New York, 3Milton S. Hershey Medical Center, Hershey, Pennsylvania, 4New York UniversityMedical Center, New York, New York, and Sje~erson Medical College, Philadelphia, Pennsylvania
ABSTRACT

Background: Despite published data showing the efficacy of topical retinoids in treating inflammatory ache, in clinical practice topical retinoids tend to be used most commonly for noninflammatory ache. Objective: The goal of this study was to assess the efficacy of topical retinoids as monotherapy in inflammatory ache. Methods: This retrospective, investigator-blinded, vehicle-controlled, photographic assessment study was conducted by 5 investigators. The investigators rated pretreatment and posttreatment photographs of patients who had participated in 12- or 15-week, double-blind comparisons of tazarotene 0.1% gel, adapalene 0.1% gel, tretinoin 0.1% microsponge, tretinoin 0.025% gel, and tazarotene 0.1% cream (vehicle). Ache severity was rated on a 7-point scale. A posttreatment increase or decrease of 1 grade was considered clinically meaningful; _>2 grades was considered an even clearer measure of clinically significant improvement. Investigators also rated global response to treatment on a 7-point scale. A posttreatment increase of _>2 grades was considered a clinically relevant improvement. Results: Each of the 5 investigators rated photographs of 577 patients (-52% women, -48% men; mean age, 18-20 years), for a total of 2885 evaluations (in addition to daily evaluations of the 20 control patients). The treatment groups consisted of tazarotene (252 patients, 1260 evaluations), adapalene (178 patients, 890 evaluations), tretinoin microsponge (47 patients, 235 evaluations), tretinoin gel (39 patients, 195 evaluations), and vehicle (61 patients, 305 evaluations). Inflammatory ache was improved with all 4 retinoids compared with vehicle. In 1905 evaluations in which

pretreatment acne severity was grade _>3 (mild to moderate), the incidences of clinically significant improvements in the tazarotene, adapalene, and tretinoin microsponge groups were 24%, 17%, and 21%, respectively (all, P < 0.001 vs vehicle [7%]). The difference in prevalence of clinically significant improvement was statistically similar between the tretinoin gel and vehicle groups. The incidences of clinically relevant improvement in global response to tazarotene, adapalene, tretinoin microsponge, and tretinoin gel were 36%, 34%, 31%, and 28%, respectively (P __0.001, __0.001, _<0.001, and _<0.01, respectively, vs vehicle [17%]). Conclusions: The results of this study suggest that topical retinoid monotherapy can achieve clinically significant improvements in inflammatory acne. (Clin Tber. 2005;27:216-224) Copyright 2005 Excerpta Medica, Inc. Key words: topical retinoids, inflammatory acne, tazarotene, adapalene.

INTRODUCTION

Retinoids and antibacterials are the mainstays of topical therapy for acne vulgaris. Tretinoin was the first retinoid shown to be effective in the treatment of
The data in this article were presented in poster form at the 26th Hawaii Dermatology Seminar, January 2.%February 2, 2002, Maui, Hawaii; and the 60th Annual Meeting of the American Academy of Dermatology, February 22-27, 2002, New Orleans, Louisiana.

Accepted for publication November 22, 2004.

doi:q 0.q 0q 6/j.clinthera.2005.02.009 0q 49-29q 8/05/$~ 9.OO Printed in the USA. Reproduction in whole or part is not permitted. Copyright 2005 Excerpta Medica, Inc.

acne. ~ The subsequent discovery of specific retinoid receptors led to the development of 2 next-generation retinoids, tazarotene and adapalene, which also have been shown to be effective against acne. Retinoids counteract the abnormal desquamation process, and their use results in significant reductions in noninflammatory lesion counts. 2-7 Consequently, dermatologists use this class of drug primarily in patients with a predominance of noninflammatory lesions. However, clinical trials with topical retinoids have also reported a substantial decrease in inflammatory lesions, indicating that topical retinoids are beneficial in both inflammatory and noninflammatory acne. 2-7 Following the introduction of tazarotene and adapalene, Phase 4 trials were conducted to compare the efficacy of various formulations of topical retinoids, and the effects of treatment were documented photographically. In this article, we describe the results of an evaluation of photographs from these trials to determine the effect of topical retinoids as monotherapy for inflammatory acne.

system with a calibrated lens set for a fixed reproduction ratio). Photographs of all patients in the trials were included for evaluation in this study, provided that a complete set of right, front, and left view photographs were available both before treatment (week 0) and after treatment (week 12 or 15). All Phase 4 studies were approved by the institutional review board at each study site.

Display of Photographs
Photographs were displayed in slide form in a blinded fashion to each of 5 investigators in 3 sessions over 3 consecutive days. No discussion was allowed between investigators while the photographs were being displayed. For each patient, the display consisted of 6 photographs shown simultaneously: right, front, and left views before and after treatment. The series of control photographs was displayed 3 times, once each day, to allow assessment of intrainvestigator and interinvestigator grading precision.

Randomization MATERIALS AND METHODS Collection of Photographs

Pretreatment and posttreatment photographs of patients with facial acne vulgaris were collected from 7 Phase 4, multicenter, double-blind, randomized, parallel-group trials comparing topical retinoids. 2~,7,s All completed comparative studies available from the sponsor were included in which both pretreatment and posttreatment photographs of evaluable patients were available. These studies compared tazarotene 0.1% gel, adapalene 0.1% gel, tretinoin 0.1% microsponge, tretinoin 0.025% gel, and tazarotene 0.1% cream (vehicle). Because no photographs of patients undergoing treatment with vehicle gel for any of the retinoid formulations were available (ie, none were taken), photographs of treatment with vehicle cream (as used in tazarotene cream formulations) were used. These photographs were obtained from pivotal trials comparing tazarotene 0.1% cream with vehicle cream. The methodologic details of all trials were published previously. 2~,7,8 Medications were applied once daily for 12 or 15 weeks, except for alternate-day dosing of tazarotene in one trial, s All photographs were taken using a standardized protocol prescribed by Canfield Scientific, Inc., Fairfield, New Jersey (including use of a stereotactic device to position the head and a standardized camera Photographs of each patient were presented in a randomized fashion, regardless of treatment group, according to a computer-generated randomization code. The identification codes were kept at a location separate from the study site. To reduce the potential for bias, the slides were loaded into carousels and projected by staff from Canfield Scientific, Inc. No patientidentification codes appeared on the photographs; investigators identified photographs by the carousel number and slide number within that carousel.

Assessment of Photographs
Each investigator assessed the overall severity of each patient's inflammatory acne before and after treatment and global response to treatment. Overall acne severity was assessed using a modified version of a scale published by Allen and Smith 9 (~able i9). This assessment rates severity on a 7-point scale (grade 0 = no acne, to grade 6 = severe acne). The panel considered a 1-grade improvement or deterioration on this scale to be clinically meaningful. In addition, an improvement or deterioration of >2 grades was considered clearly clinically significant ( ~igure 1). Global response to treatment was assessed using a 7-point scale (Table ii) in which responses ranged from a clinically relevant worsening in inflammatory lesions (grade -2) to clear/nearly clear (grade +4). A

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Table I. Overall inflammatory acne severity scale. Reproduced with permission. 9 Grade 0 I 2 3 4 5 6 Descripcion None * Mild * Moderate * Severe Def3nicion Clear, no inflammacory lesions Only an occasional small inflammaEory lesion Few scaEEered small inflammaEory lesions, wiEh mild eryEhema presenE on less Ehan half oFEhe Face Moderace number oF inflammacory lesions over a wide area oFche Face, wkh increasing eryt:hema Moderate number oF inflammatory lesions, some large, over a wide area oFche Face, wich increasing erychema Papules and pust:ules wit:h larger inflamed lesions over much oFt:he Face, wit:h pronounced eryt:hema Large papules and pust:ules wit:h pronounced eryt:hema involving most: oFt:he Face

Grades 1, 3, and 5 were used to designate intermediate evaluations.

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Figure 1. Varying acne severities before and after 12 or 15 weeks oFtreatment with a retinoid: A-C; Typical presentations oF pretreatment acne severity grade 5 (leFt panels), with clinical improvement to grade 3 (right panels). D: Typical presentation oF pretreatment acne grade 4 (leFt panel), with clinical improvement to grade 3 (right panel). Mean overall inflammatory acne severity scores among investigators: A, 4.8; B, 4.4; C, 5.6; D, 4.0 (see Table I For overall inflammatory acne severity scale). (A, Courtesy oFZoe Draelos, MD; B, Courtesy oF Emil Tanghecd, MD; C, Courtesy oFYves Poulin, MD.)

Table II. Global response to treatment scale.

Grade 4 3 Description Clear/ nearly clear Marked improvement Clinically relevant improvement Slight improvement No improvement Slight deterioration Clinically relevant decerio ratio n Definition Very significant improvement, with few inflammatory lesions remaining except for residual macular erythema Significant improvement, some inflammatory lesions remain Improvement between marked and slight Some improvement, but significant inflammatory lesions remain No detectable change from preCreaCmenC Some worsening, with a definite increase in inflammatory lesions Significant worsening, with numerous additional inflammatory lesions

I 0 -I -2

posttreatment increase of _>2 grades was considered a

clinically relevant improvement.

Statistical Analysis

(ie, grade _>2;Table ii) on this scale were also analyzed using the P _ 0.01 level.

Assessment of lntrainvestigator Consistency

Unpaired t tests were used to compare investigator ratings of the control photographs on each of the 3 evaluation days. ~ The test for statistical significance was set at P < 0.05. SAS version 8.02 (SAS Institute Inc., Cary, North Carolina) was used for all statistical analyses.

Assessment of lnterinvestigator Consistency

Correlation analysis (the Pearson correlation coefficient) was used to determine consistency of ratings by each investigator over the 3-day period) Specifically, the pretreatment daily ratings of the control photographs made by each investigator were analyzed for correlation.

RES U LTS Photographs Each of the 5 investigators rated photographs of 577 patients (-52% women, -48% men; mean age, 18-20 years), for a total of 2885 evaluations (in addition to daily evaluations of the 20 control patients). The treatment groups consisted of tazarotene (252 patients, 1260 evaluations), adapalene (178 patients, 890 evaluations), tretinoin microsponge (47 patients, 235 evaluations), tretinoin gel (39 patients, 195 evaluations), and vehicle (61 patients, 305 evaluations). Intrainvestigator Consistency No significant day-to-day differences were found between each investigator's ratings of the control photographs.

Treatment Effect The study was powered to 95% to detect a 1-grade difference in inflammatory acne score. Betweengroup differences in the proportion of evaluations indicating an improvement of 1 or >2 grades or a decline of 1 grade in overall acne severity score were analyzed using the chi-square test. ~ To control for multiple between-group comparisons, a stringent level for statistical significance (P < 0.01) was set according to the Bonferroni adjustment. Betweengroup differences in the proportion of evaluations indicating at least a clinically relevant improvement

Interinvestigator Consistency
Correlation coefficients between pairs of investigators ranged from 0.648 to 1.000 (Table iii).

Treatment Effect

Change in Overall Inflammatory Acne Severity

The proportions of evaluations showing clinical improvement with each retinoid are shown in }igures 2 and 3 and Table i~. Across 2 clinical measures (clinically meaningful improvement and clinically significant improvement), topical retinoid therapy resulted in clinically and statistically significantly greater im-

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Table III. Pearson's correlation coefficients between pairs of investigators.*

Invesrigaror No. .................................................................................................................................................................................................................... I 2 3 4 5 1.000 0.714 0.836 0.824 0.709 0.714 1.000 0.780 0.703 0.648 0.836 0.780 1.000 0.785 0.708 0.824 0.703 0.785 1.000
0.661

Invesrigaror No. 1 2 3 4 5

0.709 0.648 0.708

0.661 1.000

*Sixty observations were used in these c o m p u t a t i o n s ( p h o t o g r a p h s o f 20 patients were assessed on each of" 3 consecutive days).

provements in acne severity compared with vehicle. Overall, 46% (1178/2576) of evaluations of the topical retinoid groups showed clinically meaningful improvement in ache severity compared with 28% (85/305) of the vehicle group (P _<0.001). The percentages of evaluations showing clinically meaningful improvement in ache severity in each retinoid group were greater relative to the vehicle group (all, P _<0.001) ( ~igure 2A). Overall, 14% (369/2580) of evaluations showed clinically significant improvement in ache severity with a topical retinoid compared with 5% (16/305) with vehicle (P _ 0.001). The incidence of clinically significant improvement was higher in the tazarotene, adapalene, and tretinoin microsponge groups cornA

pared with the vehicle group (P _ 0.001, ___0.01, and ___0.001, respectively) ( ~igure 2]~ ). This difference was most pronounced in the tazarotene and tretinoin microsponge groups, which showed a -3-fold higher incidence of clinically significant improvement compared with the vehicle group. Between-retinoid comparisons showed significantly greater incidences of clinically significant improvement in the tazarotene group compared with the groups receiving adapalene (P _ 0.001) or tretinoin gel (P _ 0.01).

Global Response
On global response to treatment, overall, 34% (884/2580) of evaluations of retinoid-treated patients
B
30

60

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20-

0Tazarotene Adapalene Tretinoin Tretinoin Vehicle 0.1%gel 0.1%gel 0.1%MS 0.025%gei (n=305) (n=1260) (n=886) (n=235) (n=195) Tazarotene Adapalene Tretinoin Tretinoin Vehicle 0.1%gel 0.1%gel 0.1%MS 0.025%gei (n=305) (n=1260) (n=890) (n=235) (n=195)

Figure 2. Evaluations showing clinically meaningful (A) or clinically significant (B) improvement in acne severity after 12 or IS weeks o f treatment with a retinoid or vehicle. MS = microsponge. *P <_ 0.001 versus vehicle; t p _<0.001 versus adapalene 0.1% gel; SP _<0.01 versus tretinoin 0.025% gel; P _<0.01 versus vehicle.

A 301 *~

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10-

> iii

r~

0-

Tazarotene Adapalene Tretinoin Tretinoin Vehicle 0.q%gel 0.q%gel 0.1%M5 0.025%gel (n=230) (n=821) (n=566) (n=161)(n=127)

Tazarotene Adapalene Tretinoin Tretinoin Vehicle 0.q%gel 0.q%gel 0.1%M5 0.025%gel (n=115) (n=383) (n=241) (n=72) (n=66)

Figure 3. Relationship between pretreatment acne severity and clinical improvement after 12 or 15 weeks of treatment with a retinoid or vehicle. Evaluations of pretreatment acne severity grades >3 (A) and >4 (B) showing clinically significant improvement. MS = microsponge. *P < 0.001 versus vehicle; *P < 0.001 versus adapalene 0.1% gel; *P < 0.01 versus tretinoin 0.025% gel; P < 0.001 versus tretinoin 0.025% gel.

showed at least a clinically relevant improvement (Table ii) compared with 17% (51/305) of vehicle evaluations (P < 0.001). The incidences of clinically relevant improvement were significantly higher in the tazarotene (36%), adapalene (34%), tretinoin microsponge (31%), and tretinoin gel (28%) groups compared with the vehicle group (P < 0.001, <0.001, <0.001, and <0.01, respectively) (Table i ~ .

nificantly different between the retinoid and vehicle groups--13% (324/2580) versus 17% (51/305) ( }igure 4).

Relationship Between Pretreatment Acne Severity and Clinical Improvement

Overall Inflammatory Acne Severity

Clinical improvement increased as pretreatment acne severity increased ( }igure 3). Of evaluations with pretreatment acne severity grade >3 (Table i), 20% (343/1675) showed clinically significant improvement with a topical retinoid, compared with 7% (16/230)

Deterioration
The number of evaluations showing slight deterioration in acne severity was small and was not sigTable IV.

Evaluations showing at least a clinically relevant improvement (>2 grades) on the global response to treatment scale.

Pretreatment Acne Severity Grade* Treatment

Tazarotene 0.1% gel Adapalene 0.1% gel Tretinoin 0.1% microsponge Tretinoin 0.025% gel Vehicle >3 >4 >5 All Evaluations

379/821 238/566 60/161 42/127

(46%)** (42%)* (37%)* (33%)

47/230 (20%)

224/383 141/241 36/72 25/66 32/115

(58%)** (59%)** (50%) (38%) (28%)

82/114 44/60 15/18 6/21 9/28

(72%)* (73%)* (29%) (32%)

(83%)*

456/1260 301/890 73/235 54/195 51/305

(36%)* (34%)* (31%)* (28%) (17%)

*See Table I for overall inflammatory acne severity scale. fP _<0.001 versus vehicle. SP _<0.01 versus tretinoin 0.025% gel. P _<0.01 versus vehicle.

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Tazarotene Adapalene Tretinoin 0.1% gel 0.1%gel 0.1% MS 0

Tretinoin 0.025% gel

Vehicle

0 ~

10

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r~

20

Figure 4. Evaluations showing slight deterioration in acne severity after 12 or 15 weeks of treatment with a retinoid or vehicle. All evaluations are included regardless of pretreatment acne severity. MS = microsponge.

with vehicle (P < 0.001). The incidences of clinically significant improvement were statistically significantly higher in the tazarotene (24%), adapalene (17%), and tretinoin microsponge (21%) groups compared with the vehicle group (all, P < 0.001) (}igure 3A). Between-retinoid comparisons showed a significantly greater frequency of clinically significant improvement in the tazarotene group compared with the adapalene and tretinoin gel groups (P < 0.001 and <0.01, respectively). Of evaluations with pretreatment acne severity grade >-4 (moderate severity) (Table i), 33% (248/762) showed clinically significant improvement with a topical retinoid compared with 10% (11/115) with vehicle (P < 0.001). The incidence of clinically significant improvement was -3- to 4-fold greater in the tazarotene, adapalene, and tretinoin microsponge groups compared with the vehicle group (all, P < 0.001) (}igure 31~). Between-retinoid comparisons showed a significantly greater incidence of clinically significant improvement in the tazarotene group compared with the adapalene and tretinoin gel groups (both, P < 0.001). Similarly, of the subset of evaluations that had ache severity grade >-5 before treatment, 52% (110/213) showed clinically significant improvement with a topical retinoid, compared with 14% (4/28) with vehicle (P < 0.001). There were too few patients with pretreatment acne severity grade >-5 to make betweenretinoid comparisons.

Global Response
This increasing prevalence of clinical improvement with increasing pretreatment ache severity was paralleled in evaluations of global response to treatment liable i ~ . The greatest difference in the proportion of evaluations of retinoid-treated patients versus vehicle patients showing clinically relevant improvement was in patients with pretreatment acne severity grade >_5 (69% [147/213] vs 32% [9/28]; P < 0.001), followed by grade >-4 (56% [426/762] vs 28% [32/115]; P < 0.001) and grade >-3 (43% [719/1675] vs 20% [47/230]; P < 0.001). Between-retinoid comparisons showed a significantly greater frequency of clinically relevant improvement on the global response to treatment scale in the tazarotene group compared with the tretinoin gel group in patients with pretreatment acne severity grade >-3 (P < 0.01). In patients with grade >-4 ache before treatment, a significantly greater frequency of clinically relevant improvement on the global response to treatment scale was found in the tazarotene and adapalene groups versus the tretinoin gel group (P < 0.01). There were too few patients with pretreatment acne severity grade >-5 to make such between-retinoid comparisons.
DISCUSSION

This retrospective assessment of photographic documentation from clinical trials suggests that monotherapy with topical retinoids may provide clinical benefit in the inflammatory phase of acne. The investigator ratings in this study showed intrainvestigator and in-

terinvestigator consistency.11 Using a stringent criterion of an improvement in inflammatory acne severity _>2 grades, clinically significant improvement was seen with 3 of the 4 retinoids studied. In addition, topical retinoid therapy was not associated with worsening of inflammatory acne after 12 or 15 weeks of therapy. Of interest, the percentage of evaluations showing clinically relevant improvement was higher in the more severe cases, perhaps because the evaluations with lesser grades of inflammatory acne had less room for improvement than those with more severe grades. The number of patients with severe acne before treatment was small (n = 29); therefore, conclusions regarding this group of patients could not be made. Between-retinoid comparisons indicated that the greatest efficacy occurred on the overall inflammatory acne severity and global response scales with tazarotene 0.1% gel, which showed statistically and clinically significant improvement over vehicle for all measures of clinical improvement as well as statistically and clinically significant improvement relative to adapalene and tretinoin gel on measures of acne severity. However, a head-to-head trial comparing all 4 treatments would be required to determine the relative efficacy of these therapies in treating inflammatory acne. This photographic assessment study is limited by its retrospective design. However, the results are in agreement with published data from clinical trials in which the inflammatory phase of acne was shown to be improved with retinoid treatment. 2-6 The concern is that topical retinoids might intensify inflammation and be difficult to use in patients with inflammatory acne. This concern was not evident in these analyses: clinical deterioration was seen in 12% to 14% of patients compared with 17% receiving vehicle. However, any irritation in the early phase of these studies would not have been seen in these photographs, which were taken before and after 12 or 15 weeks of treatment. The potential clinical benefit of retinoid treatment in the inflammatory phase of acne may be the result of the anti-inflammatory effect of this drug class. ~2qs In vitro ~3 and animal ~2 studies suggest that retinoids may have inherent "anti-inflammatory activity" and appear to inhibit the release of proinflammatory cytokines through down-regulation of the expression of toll-like receptors on monocytes. TM Activation of these receptors, leading to a triggering of inflammatory cytokine responses, is believed to be a mechanism by which bacteria can initiate inflammation. ~s

Peptidoglycans in the cell walls of Propionibacterium acnes appear to activate toll-like receptor 2 on monocytes, resulting in the release of proinflammatory cytokines, including interleukins 1, 8, and 12 and tumor necrosis factor-~.~4,~5 By down-regulating the expression of these toll-like receptors, retinoids may reduce the release of proinflammatory cytokines and ultimately reduce the inflammatory component of acne.
CONCLUSIONS

The results of this study suggest that topical retinoid therapy has benefit in inflammatory acne when used as monotherapy. Although topical retinoids offer potential efficacy against inflammatory acne lesions, these results do not indicate that treatment should consist of retinoid therapy alone.
ACKNOWLEDGMENTS

This study was supported by Allergan, Inc., Irvine, California. We thank Gill Shears, PhD, for her editorial assistance in the development of the manuscript. Dr. Leyden has served as a consultant and participated in advisory boards and clinical trials, for Ortho Dermatological (Raritan, New Jersey), Galderma Laboratories, L.P. (Fort Worth, Texas), Allergan, Inc., Dermik Laboratories, Inc. (Berwyn, Pennsylvania), and Medicis Pharmaceutical Corporation (Scottsdale, Arizona). Dr. Shalita has served as a consultant and participated in advisory boards and clinical trials for Ortho Dermatological, Galderma Laboratories, L.P., Allergan, Inc., Dermik Laboratories, Inc., Medicis Pharmaceutical Corporation, and Stiefel Laboratories, Inc. (Coral Gables, Florida). Dr. Thiboutot has participated in advisory boards and clinical trials for Galderma Laboratories, L.P., Allergan, Inc., and Dermik Laboratories, Inc. Dr. Washenik has served as a consultant and speaker and participated in advisory boards and clinical trials for Allergan, Inc., Medicis Pharmaceutical Corporation, CollaGenex Pharmaceuticals Inc. (Newtown, Pennsylvania), Wyeth Pharmaceuticals (Madison, New Jersey), and Merck & Co., Inc. (Rahway, New Jersey). Dr. Webster has received research grants from and/or served as a consultant for Allergan, Inc., Ortho Dermatological, Galderma Laboratories, L.P., Dermik Laboratories, Inc., and Roche Laboratories, Inc. (Indianapolis, Indiana).

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'........................................................................................................................................................................................................................... A d d r e s s c o r r e s p o n d e n c e to: J a m e s ]. L e y d e n , M D , D e p a r t m e n t o f Dermatology,University of Pennsylvania Hospital, Philadelphia, PA 1 9 1 0 4 .

E-mail:jjleyden@mindspring.com
V~lume 27i N umbe~