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Efficacy of 0.1% Tazarotene Cream for the Treatment of Photodamage
A 12-Month Multicenter, Randomized Trial
Tania J. Phillips, MD;
Alice B. Gottlieb, MD, PhD;
James J. Leyden, MD;
Nicholas J. Lowe, MD;
Deborah A. Lew-Kaya, PharmD;
John Sefton, PhD;
Patricia S. Walker, MD, PhD;
John R. Gibson, MD;
and the Tazarotene Cream Photodamage Clinical Study Group
Arch Dermatol. 2002;138:1486-1493.
ABSTRACT
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Objective To determine the efficacy and safety of 0.1% tazarotene cream for the treatment of photodamage.
Design A 24-week multicenter, double-blind, randomized, vehicle-controlled intervention study followed by a 28-week open-label extension.
Setting Ambulatory patients in private and institutional practice.
Patients Of 563 patients with facial photodamage, 91% and 86% completed the double-blind and open-label phases, respectively. In the double-blind phase, 20 of 283 tazarotene-treated patients and 1 of 280 vehicle-treated patients discontinued treatment owing to adverse events.
Intervention Once-daily application of 0.1% tazarotene cream or nonmedicated vehicle cream to the face for 24 weeks. Then, all continuing patients received treatment with 0.1% tazarotene cream for another 28 weeks.
Main Outcome Measures Primarily, fine wrinkling and mottled hyperpigmentation. Also, lentigines, elastosis, pore size, irregular depigmentation, tactile roughness, coarse wrinkling, telangiectasia, actinic keratoses, overall integrated assessment of photodamage, global response to treatment, patients' overall assessment of photodamage, and plasma levels of tazarotenic acid.
Results Compared with the vehicle, at week 24 tazarotene resulted in a significantly greater incidence of patients achieving treatment success ( 50% global improvement) and at least a 1-grade improvement in fine wrinkling, mottled hyperpigmentation, lentigines, elastosis, pore size, irregular depigmentation, tactile roughness, coarse wrinkling, and the overall integrated assessment of photodamage (P<.01). Additional clinical improvement occurred with continued tazarotene treatment and had not plateaued by week 52. Plasma tazarotenic acid concentrations did not exceed 0.71 ng/mL.
Conclusions Once-daily applications of 0.1% tazarotene cream significantly reduced multiple signs of photodamage. Plasma levels of tazarotenic acid remained below those of endogenous retinoids.
INTRODUCTION
ULTRAVIOLET IRRADIATION can have both acute and chronic deleterious effects on human skin, including sunburn, immune suppression, premature aging (photoaging), and cancer. Sunburn and immune suppression occur acutely in response to excessive exposure to UV light, whereas photoaging and skin cancer result from accumulated damage caused by repeated exposures. The effects of photoaging can be seen clinically as wrinkling, dyspigmentation, laxity, roughness, sallowness, and telangiectasia. Severely photodamaged skin may have actinic keratoses or frank malignancies. Histologically, photodamaged skin may exhibit keratinocytic and melanocytic atypia, a loss of epidermal polarity, degenerative changes in collagen, deposition of abnormal elastic tissue, and twisted, dilated microvasculature.1-2
Tazarotene has been shown to offer efficacy in the treatment of photodamage.3-4 In a pilot, double-blind, randomized, paired comparison of 10 healthy volunteers, once-daily applications of 0.1% tazarotene gel to moderately photodamaged forearm skin for 12 weeks resulted in significantly fewer peaks and valleys in silicone skin surface replicas (indicating smoothening of the skin surface) and significantly reduced pigmentary mottling (P .05).3 Positive changes in cellular architecture were also evident histologically, both in this study3 as well as in a larger histological safety study (unpublished data, 2001), with a reduction in atypia and a restoration of keratinocyte polarity being the primary changes indicating improvement of photodamage.
Clinical efficacy has also been confirmed in a larger 6-month, double-blind, randomized, dose-ranging study involving 349 patients with photodamaged facial skin. The percentage of patients achieving at least a 1-grade improvement in fine wrinkling, mottled hyperpigmentation, lentigines, and elastosis was significantly higher in tazarotene-treated patients than in vehicle-treated patients (P.05).4 In addition, 0.1% tazarotene cream showed greater levels of improvement than lower concentration formulations of tazarotene. To further evaluate the long-term efficacy and safety of 0.1% tazarotene cream in the treatment of photodamage, a 12-month study was performed.
METHODS
STUDY POPULATION
Male or female patients with facial photodamage were eligible for recruitment into the present study if they had at least mild severity of both fine wrinkling and mottled hyperpigmentation and at least moderate severity of one of these. Patients were required to be at least 18 years of age and to have skin type I, II, III, or IV.
Women of childbearing potential were excluded if they were pregnant, nursing, or planning a pregnancy during the study. Other exclusion criteria included use of vitamin A supplements in excess of 5000 IU/d or vitamin E supplements in excess of 400 IU/d in the preceding week; topical use of glycolic acid,  -hydroxy acid, salicylic acid, lactic acid,  -hydroxy acid, or products containing vitamin A, ascorbic acid, or vitamin E within the preceding 2 weeks; use of topical retinoids in the preceding month; use of systemic retinoids in the preceding 6 months; a history of basal cell or squamous cell carcinoma on the face within the preceding 3 months; anticipated prolonged exposure to UV light during the study; and an unwillingness to use a sunscreen of at least sun protection factor 15 during the study.
The present study was approved by the appropriate institutional review boards, and all clinical investigations were conducted according to the Declaration of Helsinki principles. Written informed consent was obtained from all patients.
RANDOMIZATION AND BLINDING PROCEDURES
Enrolled patients were assigned a unique patient number obtained from a computer-generated randomization schedule (using a block size of 4) provided by the sponsor. The assignment of numbers was not necessarily continuous (as one investigator may have received noncontiguous blocks of numbers), but was always in blocks of 4. The labels on the medication tubes were concealed.
STUDY MEDICATIONS
Patients were randomized in a 1:1 ratio to receive 0.1% tazarotene cream (Allergan Inc, Irvine, Calif) or nonmedicated vehicle cream in the 24-week double-blind phase. All continuing patients received 0.1% tazarotene cream in the 28-week open-label phase.
TREATMENT REGIMEN
Patients were instructed to apply a pea-sized amount of the study medication (to lightly cover their entire face) once daily in the evening. Patients were instructed to ensure that their face was clean, free of makeup, and dry before applying the medication. Use of a nonmedicated facial moisturizer was permitted, providing that it was not applied at the same time as the study medication (to ensure the skin was dry before application of either product). Patients were requested to avoid excessive exposure to UV light (eg, from sunbathing or the use of tanning booths), to wear protective clothing (eg, hat or visor) when exposed to sunlight, and to apply a sunscreen of at least sun protection factor 15 every morning.
In an attempt to maximize patient compliance with the protocol, patients were educated on how to use the study medication and were asked to bring back all tubes of study medication (regardless of how much or little medication they still contained) at each study visit during the treatment period. In addition, patients were asked at every study visit if there were any changes in concomitant medications they were taking. Patients were allowed to temporarily omit applications of study drug in the event of irritation.
EFFICACY MEASURES
Clinical evaluations were made at the screening visit (day -21 to -1 from baseline) and at weeks 0, 2, 4, 8, 12, 16, 20, 24, 28, 36, 44, and 52. Primary efficacy measures were fine wrinkling and mottled hyperpigmentation. Other efficacy measures were lentigines, elastosis, pore size, irregular depigmentation, tactile roughness, coarse wrinkling, telangiectasia, actinic keratoses, overall integrated assessment of photodamage, global response to treatment, and patients' overall assessment of photodamage.
A 5-point scale (0 = none, 1 = minimal, 2 = mild, 3 = moderate, and 4 = severe) was used to grade fine wrinkling, mottled hyperpigmentation, lentigines, elastosis, irregular depigmentation, tactile roughness, coarse wrinkling, and telangiectasia. Clinical improvement was defined as an improvement from baseline of at least 1 full grade. The 5-point scale was designed so that each grade on the scale reflected a clinically meaningful degree of photodamage; a 1-grade improvement was considered to be both noticeable and relevant to the patient as well as to the investigator. Pore size was assessed using a different 5-point scale (0 = barely visible, 1 = very small, 2 = small, 3 = medium, and 4 = large). The numbers of actinic keratoses were counted. The overall integrated assessment of photodamage was assessed using a 6-point scale (0 = none, 1 = minimal, 2 = mild, 3 = moderate, 4 = severe, and 5 = very severe). For fine wrinkling, mottled hyperpigmentation, and overall integrated assessment of photodamage variables, photonumeric guidelines illustrating each grade were provided to assist investigators in determining the grades. For each of the signs of photodamage, the interrater and intrarater reliability of the ratings have been validated separately (unpublished data, 2001).
Global response to treatment was assessed using a 7-point scale (0 = complete response, 1 = approximately 90% improvement, 2 = approximately 75% improvement, 3 = approximately 50% improvement, 4 = approximately 25% improvement, 5 = no response, and 6 = worsening). The patient self-assessment was evaluated using a 5-point scale (1 = much improved, 2 = somewhat improved, 3 = no change, 4 = somewhat worse, and 5 = much worse).
TOLERABILITY EVALUATIONS
Patients were monitored for signs and symptoms of adverse events at every postbaseline study visit.
THERAPEUTIC DRUG MONITORING
Plasma levels of the active metabolite of tazarotenic acid (the main active metabolite of tazarotene) were measured at 5 study sites at weeks 2, 12, 24, 36, and 52 using a validated gas chromatography–tandem mass spectrometry (GC-MS/MS) method with a lower limit of quantitation of 0.005 ng/mL. Plasma levels of tazarotene were not specifically measured because these are generally undetectable after application of the medication to the face only. Patients applied the study medication during the study visits, and their blood was drawn 3 to 10 hours after application. Patients were instructed to resume applying the study medication on the evening of the next day.
STATISTICAL ANALYSES
The clinical hypothesis under evaluation in the present study was that 0.1% tazarotene cream is more effective than vehicle in reducing the severity of photodamaged facial skin at week 24 (the end of the double-blind period), as measured by the incidence of patients with at least a 1-grade improvement from baseline in fine wrinkling and/or mottled hyperpigmentation. Assuming a type I error rate of 0.025 (2-sided), it was calculated a priori that a sample size of 212 patients per group would provide an 80% power to detect a 15% difference in response rates between the 2 treatment groups for improvement in mottled hyperpigmentation and fine wrinkling, if the actual response rates for tazarotene were 70% and 45%, respectively.
Double-blind Period
The primary time point of analysis was the study end point, defined as the last observation for each patient. The null hypothesis of no difference in clinical improvement rates between treatment groups was tested by the Cochran-Mantel-Haenszel (CMH) test, stratified by investigator. To adjust for multiple comparisons due to the 2 primary efficacy analyses, the Hochberg procedure was used.5 This procedure rejects both null hypotheses if the 2 P values are .05 or less simultaneously. Otherwise, if the smaller of 2 P values is .025 or less, the procedure rejects the null hypothesis associated with the smaller P value. The CMH test was used for between-group comparisons of all investigator assessments of efficacy, as well as patients' overall self-assessment of photodamage, using the intent-to-treat population. The Pearson  2 test or the Fisher exact test was used for between-group comparisons of adverse events.
Open-Label Period
The primary emphasis during open-label treatment was safety (in terms of plasma levels of tazarotenic acid), and no statistical analyses were performed on efficacy and adverse event data during this phase. The safety population was defined as all patients who were randomized and treated and was used for all safety and exposure analyses.
RESULTS
PATIENTS
A total of 563 patients were enrolled from 15 investigational sites in the United States (see box of principal study group investigators on last page of this article for site locations). The sites included both private and institutional practice, and enrollment was generally performed by investigators from their existing patients or from patients who responded to an advertisement. The study was started on September 30, 1999, and completed on March 16, 2001. Of the 563 patients, 283 were treated with 0.1% tazarotene cream and 280 were treated with vehicle during the double-blind phase (Figure 1). Of the 563 patients, 511 (91%) completed the double-blind phase and 482 (86%) completed the open-label phase. Of the subgroup of 511 patients continuing to the open-label phase, 482 (94%) completed treatment.
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Figure 1. Flowchart showing progression of patients through the trial.
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The study population was generally at least middle aged, with 93% of the patients aged at least 40 years and 22% older than 65 years. At baseline, most patients had at least moderate fine wrinkling (468 [83%]) and at least moderate mottled hyperpigmentation (363 [64%]). Demographic details for the patients entered into the double-blind phase of the study are summarized in Table 1.
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Table 1. Patient Demographics at Baseline (Double-blind Period)
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EFFICACY MEASURES
Double-blind Period
Compared with vehicle, tazarotene treatment resulted in a significantly greater incidence of patients achieving clinical improvement (at least a 1-grade improvement) in both fine wrinkling (from weeks 8 to 24) and mottled hyperpigmentation (from weeks 2 to 24) (Figure 2). Tazarotene treatment also resulted in a significantly greater incidence of patients achieving clinical improvement in lentigines, elastosis, pore size, irregular depigmentation, tactile roughness, coarse wrinkling, and the overall integrated assessment of photodamage (Figure 3). Significant between-group differences were achieved as early as week 2 for the overall integrated assessment, week 4 for lentigines and irregular depigmentation, and week 12 for elastosis, pore size, tactile roughness, and coarse wrinkling.
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Figure 3. Incidence of patients achieving at least a 1-grade improvement in lentigines (A), elastosis (B), pore size (C), irregular depigmentation (D), tactile roughness (E), coarse wrinkling (F), and overall integrated assessment of photodamage (G). Grades are defined in the "Efficacy Measures" subsection of the "Methods" section. Patients received either 0.1% tazarotene cream or vehicle cream until week 24 (double-blind phase, nonshaded area) and only 0.1% tazarotene cream thereafter (open-label phase, shaded area). Asterisk indicates P.05 vs vehicle; dagger, P.01 vs vehicle; and double dagger, P.001 vs vehicle.
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The incidence of patients achieving treatment success (50% global improvement) was also significantly higher with tazarotene compared with vehicle (Figure 4). The patients' self-assessments showed that more than 60% of patients considered their photodamage to be somewhat or much improved by week 4, and more than 80% of patients considered their photodamage to be somewhat or much improved from week 12 onward (Figure 5). The distribution of scores for the patients' overall self-assessment of photodamage in the tazarotene group demonstrated significantly greater improvement from baseline at weeks 4 through 24 compared with the vehicle group (P.001 vs vehicle). Photographic documentation of the extent of improvement attained in 2 patients is shown in Figure 6. Telangiectasia and actinic keratoses were not significantly improved after 24 weeks of tazarotene treatment.
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Figure 4. Treatment success: incidence of patients achieving 50% or greater global improvement. Patients received either 0.1% tazarotene cream or vehicle cream until week 24 (double-blind phase, nonshaded area) and only 0.1% tazarotene cream thereafter (open-label phase, shaded area). Double dagger indicates P.001 vs vehicle.
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Figure 5. Patients' overall assessment of photodamage: incidence of patients reporting improvement in their photodamage. Patients received either 0.1% tazarotene cream or vehicle cream until week 24 and only 0.1% tazarotene cream thereafter.
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Figure 6. Improvement in photodamage during treatment with 0.1% tazarotene cream for 52 weeks. A, Baseline; B, week 24; and C, week 53 (1-week posttreatment) (A-C: left, patient 1; right, patient 2).
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Open-Label Period
Patients previously treated with 0.1% tazarotene cream showed further clinical improvement with continued treatment for the following variables: fine wrinkling, mottled hyperpigmentation, lentigines, elastosis, pore size, irregular depigmentation, tactile roughness, coarse wrinkling, overall integrated assessment of photodamage, and treatment success (Figure 2, Figure 3, and Figure 4). Patients previously treated with vehicle showed a similar magnitude and speed of improvement in all variables as the other treatment group had shown in their first few months of tazarotene treatment. The patients' self-assessments showed that the patients who were treated with tazarotene during the double-blind period continued to shift toward a "much improved" response during the open-label phase (Figure 5).
THERAPEUTIC DRUG MONITORING
In the first 24 weeks of treatment (the double-blind period), pharmacokinetic analyses were based on data from 60 of the tazarotene-treated patients. In the ensuing 28 weeks of therapy (the open-label period), pharmacokinetic analyses were based on data from 48 patients who had been previously treated with 0.1% tazarotene cream. Mean plasma levels of tazarotenic acid were consistently less than 0.13 ng/mL, and maximum levels did not exceed 0.71 ng/mL (Table 2). The levels did not increase with the duration of therapy, indicating a lack of accumulation of the drug systemically.
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Table 2. Plasma Concentration of Tazarotenic Acid in Patients Treated With 0.1% Tazarotene Cream Once Daily
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TOLERABILITY
Double-blind Period
The incidence of adverse events considered to be possibly, probably, or definitely related to the study medication was significantly higher in the tazarotene group than in the vehicle group. The adverse events were primarily signs and symptoms of local skin irritation (Table 3) and were generally mild or moderate in severity. Relatively few patients discontinued treatment owing to an adverse event (20 [7%] of 283 in the tazarotene group and 1 [0.4%] of 280 in the vehicle group).
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Table 3. Skin-Related Adverse Events Considered by the Investigator to Be Possibly, Probably, or Definitely Related to Treatment and Occurring in at Least 4% of Patients*
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Open-Label Period
Treatment-related adverse events were more common in patients previously treated with vehicle than in patients previously treated with tazarotene. No patient who had previously been treated with tazarotene during the double-blind phase discontinued treatment owing to adverse events during the open-label phase, and 4 (2%) of 263 patients who switched from vehicle to tazarotene discontinued treatment owing to adverse events.
COMMENT
The results of the present study show that, compared with vehicle, tazarotene treatment can result in clinically and statistically significant improvements in multiple signs of photodamage (ie, fine wrinkling, mottled hyperpigmentation, lentigines, elastosis, pore size, irregular depigmentation, tactile roughness, and coarse wrinkling). The pigmentary changes were the first to be evident, with mottled hyperpigmentation and the overall integrated assessment showing statistically significant improvements over vehicle after only 2 weeks of therapy, and lentigines, irregular depigmentation, and patient self-assessment significantly improved over vehicle by week 4. Following this, fine wrinkling was significantly improved over vehicle by week 8, and elastosis, pore size, tactile roughness, and coarse wrinkling were significantly improved over vehicle by week 12. All of these parameters showed continually increasing improvements as the duration of therapy lengthened. Furthermore, none appeared to have plateaued by the end of the 52-week treatment period, suggesting that additional improvements may be possible with continued treatment.
Some clinical improvements were evident in the vehicle-treated patients, and these may be attributable to the emollient activity of the vehicle cream and to the requirement for patients to use a sunscreen and restrict their exposure to UV light (both of which can help the body repair existing photodamage and prevent additional photodamage1).
Despite the fact that the study was not powered to detect differences in the secondary variables, tazarotene did show statistically significant improvements in 8 different signs of photodamage—a multiplicity of action that has not previously been reported with any other retinoid to our knowledge. Although further research is needed to understand how tazarotene (or any topical retinoid) helps to reverse the pigmentary changes evident in photodamaged skin, its efficacy in reducing wrinkling, could be due to induction of transforming growth factor , which results in activation of fibroblasts to increase collagen synthesis.7
The efficacy of tazarotene in reducing pore size may be related to its anti-acne activity, ie, its ability to help normalize the differentiation of follicular epithelium, which promotes the clearance of comedones and microcomedones and prevents further follicular buildup. Presumably, by clearing follicles tazarotene allows them to become visibly smaller. Pore size is of great importance to many patients and, to our knowledge, tazarotene is the only medication for which investigator assessments of pore size have demonstrated significant superiority relative to vehicle.
Although tazarotene treatment did not result in a significant reduction in telangiectasia or actinic keratosis count, the present study was only designed to detect differences in the 2 primary variables (fine wrinkling and mottled hyperpigmentation) and was not powered to detect differences in the other variables. The results of a previous study have suggested that tazarotene has efficacy against basal cell carcinoma.8
Localized skin irritation (eg, desquamation, erythema, and burning) can occur with any topical retinoid, but it generally occurs only transiently during the first few weeks of therapy. Tolerability improves with continued treatment as the skin becomes accommodated to the retinoid. (No patients treated with tazarotene throughout this trial discontinued treatment owing to adverse events in the open-label phase when they had already received more than 24 weeks of treatment.) Of the topical retinoids that have been shown to have efficacy in photodamage, 0.1% tretinoin cream,2 0.05% tretinoin emollient cream,9 0.02% tretinoin emollient cream,10 and 0.1% isotretinoin cream11 have all been associated with irritation in most patients, as was 0.1% tazarotene cream in the present study. Although all investigator assessments performed during the first 6 months of the study were performed under double-blind conditions, the possibility that the presence of localized skin irritation could have introduced clinical bias cannot be excluded.
In clinical practice, a gentler initiation to therapy than what is possible in the confines of a clinical trial can help minimize the potential for irritation. Thus, initiating therapy with alternate-day applications for the first few weeks (and less frequently for patients with sensitive skin) helps minimize the risk of irritation while the skin is accommodating to the retinoid. Ensuring that patients apply only a pea-sized amount of medication and use a gentle skin care regimen (avoiding abrasives and using a gentle nonsoap cleanser and moisturizer as needed) also helps to minimize the potential for irritation.
There was no systemic accumulation of drug, and the plasma concentration of tazarotenic acid did not exceed 0.71 ng/mL at any point during the 1-year treatment period. This is substantially lower than the total endogenous plasma concentration of retinoids (6.6 ng/mL for the sum of all-trans-retinoic acid, 13-cis-retinoic acid, and 13-cis-4-oxo-retinoic acid).12 Repeated facial applications of tretinoin (all-trans-retinoic acid) or isotretinoin (13-cis-retinoic acid) have also been reported to not significantly affect the endogenous plasma concentration of retinoids and to not result in systemic accumulation of drug.11, 13
CONCLUSIONS
The results from this trial confirm those of previous trials and show that once-daily applications of 0.1% tazarotene cream to photodamaged facial skin for 6 months are significantly more effective than vehicle in achieving clinically relevant reductions in fine wrinkling, mottled hyperpigmentation, lentigines, elastosis, pore size, irregular depigmentation, tactile roughness, coarse wrinkling, and an overall integrated assessment of photodamage. Efficacy was further improved with continued treatment and had not plateaued after 12 months, suggesting that additional efficacy may be achievable with longer-term treatment. Plasma levels of tazarotenic acid remained lower than levels of endogenous retinoids, and no systemic accumulation of drug was evident.
AUTHOR INFORMATION
Accepted for publication June 25, 2002.
This research and manuscript development was funded by Allergan Inc, Irvine, Calif.
We thank the patients in this study for their cooperation; Katherine Stern, MS, for performing the statistical analyses; and Gill Shears, PhD, for her contribution in developing the manuscript.
| Clinical Study Group
Principal Investigators in the Tazarotene Cream Photodamage Clinical Study Group
Denise M. Buntin, MD (Hermitage, Tenn), George Burch Fisher, Jr, MD (Pensacola, Fla), William P. Coleman III, MD (Metairie, La), Toni Funicella, MD (Austin, Tex), Alice B. Gottlieb, MD, PhD (New Brunswick, NJ), Michael P. Heffernan, MD (St Louis, Mo), Norman Levine, MD (Tucson, Ariz), James J. Leyden, MD (Philadelphia, Pa), Robert W. Loss, Jr, MD (Rochester, NY), Nicholas J. Lowe, MD (Santa Monica, Calif), Tania J. Phillips, MD (Boston, Mass), Nancy G. Silvis, MD (Tucson, Ariz), Leonard J. Swinyer, MD (Salt Lake City, Utah), David N. Tashjian, MD (Fresno, Calif), Kenneth J. Washenik, MD, PhD (New York, NY), Kevin L. Welch, MD (Pensacola, Fla), David C. Wilson, MD (Lynchburg, Va).
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Corresponding author: Tania J. Phillips, MD, Boston University School of Medicine, Boston, MA 02118 (e-mail: tphill{at}BU.edu).
Reprints: Patricia S. Walker, MD, PhD, Allergan Skin Care Pharmaceuticals, 2525 Dupont Dr T2-4C, Irvine, CA 92612 (e-mail: walker_patricia{at}allergan.com).
From Boston University School of Medicine, Boston, Mass (Dr Phillips); University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick (Dr Gottlieb); University of Pennsylvania Hospital, Philadelphia (Dr Leyden); Clinical Research Specialists, Santa Monica, Calif (Dr Lowe); and Allergan, Inc, Irvine, Calif (Drs Lew-Kaya, Sefton, Walker, and Gibson).
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