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Previous Volume 356:580-592 February 8, 2007 Number 6 Next

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ABSTRACT

Background Skin-infiltrating lymphocytes expressing type 1 cytokines have been linked to the pathophysiology of psoriasis. We evaluated the safety and efficacy of a human interleukin-12/23 monoclonal antibody in treating psoriasis.

Methods In this double-blind, placebo-controlled trial, 320 patients with moderate-to-severe plaque psoriasis underwent randomization to treatment with the interleukin-12/23 monoclonal antibody (one 45-mg dose, one 90-mg dose, four weekly 45-mg doses, or four weekly 90-mg doses) or placebo; 64 patients were randomly assigned to each group. Patients assigned to the interleukin-12/23 monoclonal antibody received one additional dose at week 16 if needed. Patients assigned to placebo crossed over to receive one 90-mg dose of interleukin-12/23 monoclonal antibody at week 20.

Results There was at least 75% improvement in the psoriasis area-and-severity index at week 12 (the primary end point) in 52% of patients who received 45 mg of the interleukin-12/23 monoclonal antibody, in 59% of those who received 90 mg, in 67% of those who received four weekly 45-mg doses, and in 81% of those who received four weekly 90-mg doses, as compared with 2% of those who received placebo (P<0.001 for each comparison), and there was at least 90% improvement in 23%, 30%, 44%, and 52%, respectively, of patients who received the monoclonal antibody as compared with 2% of patients who received placebo (P<0.001 for each comparison). Adverse events occurred in 79% of patients treated with the interleukin-12/23 monoclonal antibody as compared with 72% of patients in the placebo group (P=0.19). Serious adverse events occurred in 4% of patients who received the monoclonal antibody and in 1% of those who received placebo (P=0.69).

Conclusions This study demonstrates the therapeutic efficacy of an interleukin-12/23 monoclonal antibody in psoriasis and provides further evidence of a role of the interleukin-12/23 p40 cytokines in the pathophysiology of psoriasis. Larger studies are needed to determine whether serious adverse events might limit the clinical usefulness of this new therapeutic target. (ClinicalTrials.gov number, NCT00320216 [ClinicalTrials.gov] .)

To evaluate the therapeutic effect of blocking interleukin-12 and interleukin-23, a fully human interleukin-12/23 monoclonal antibody (CNTO 1275) was developed. This antibody binds with high affinity to the p40 subunit of human interleukin-12 and interleukin-23, neutralizing their bioactivity by blocking interactions with their cognate cell-surface receptors. Early clinical studies showed no dose-limiting toxic effects and suggested potential therapeutic efficacy in certain immune-mediated diseases.^16,17,18 This phase 2 study evaluated the safety and efficacy of the interleukin-12/23 monoclonal antibody in patients with moderate-to-severe psoriasis.

Methods

Patients

This study was conducted at 46 sites worldwide after approval of the institutional review boards. The first patient consented to participation on June 25, 2003, and the last patient visit occurred on March 9, 2005. After providing written informed consent, men and women (age, 18 years) were eligible if they had a diagnosis of plaque psoriasis for at least 6 months, were candidates for phototherapy or systemic therapy, had a baseline score on the psoriasis area-and-severity index of 12 or higher (on a scale of 0 to 72, with higher scores indicating more severe disease), and had involvement of at least 10% body-surface area.

Patients were ineligible if they had nonplaque forms of psoriasis; had a recent serious systemic or local infection; had active or latent tuberculosis, asthma, or a known malignancy within the previous 5 years (except treated basal-cell skin cancer); had received previous treatment with any agent specifically targeting interleukin-12 or interleukin-23; had received biologic or investigational agents within the previous month or five drug half-lives; had received conventional systemic psoriasis therapy or phototherapy within the previous 4 weeks; or had received topical psoriasis treatment within the previous 2 weeks.

Study Design

This placebo-controlled, double-blind, parallel-group, phase 2 study evaluated the safety and efficacy of single and multiple doses of the interleukin-12/23 monoclonal antibody for the treatment of psoriasis. With the use of adaptive treatment allocation based on a biased-coin minimization algorithm,¹⁹ patients were randomly assigned to one 45-mg subcutaneous dose of the interleukin-12/23 monoclonal antibody, one 90-mg dose, four weekly 45-mg doses, four weekly 90-mg doses, or placebo. Randomization was stratified by investigational site and by the weight of the patient relative to 95 kg. At week 16, patients with a physician's global assessment (termed PGA) of less than excellent (3 on a scale on which 1 is best and 6 is worst) received one additional injection of their originally assigned dose. At week 20, patients in the placebo group crossed over to receive one 90-mg injection of the interleukin-12/23 monoclonal antibody.

Efficacy and Safety Evaluations

Efficacy evaluations were performed through week 32. The psoriasis area-and-severity index (termed PASI) combines assessments of the extent of body-surface involvement in four anatomical regions (head, trunk, arms, and legs) and the severity of desquamation, erythema, and plaque induration (thickness) in each region, yielding an overall score of 0 (no psoriasis) to 72 (severe disease).²⁰ The physician's global assessment rates the patient's psoriasis overall relative to baseline as 1 (clear), 2 (excellent), 3 (good), 4 (fair), 5 (poor), or 6 (worse) and considers involvement of body-surface area, induration, scaling, and erythema. The 10-item Dermatology Life Quality Index questionnaire, completed by the patient, measures whether psoriasis has an effect on the patient's quality of life, with scores ranging from 0 ("not at all") to 30 ("very much").

We assessed the safety and tolerability of the interleukin-12/23 monoclonal antibody by monitoring adverse events and routine laboratory values through week 36. Serum samples collected through week 52 were tested for antibodies to the interleukin-12/23 monoclonal antibody with the use of an antigen-bridging enzyme immunoassay.¹⁶

Statistical Analysis

Efficacy data from all patients who underwent randomization were analyzed according to the treatment group. Missing values at week 12 were replaced with the most recently available values for all efficacy variables; missing data at other time points were not imputed. Patients in the placebo group were included in efficacy summaries after week 20 if they had crossed over to receive the interleukin-12/23 monoclonal antibody. Safety data were summarized according to the actual treatment received.

The data-analysis plan was specified before the treatment assignments were revealed. According to these prespecified rules, the proportions of patients responding to treatment were compared using the Cochran–Mantel–Haenszel chi-square test stratified according to low and high body weight. Continuous response variables were compared with the use of analysis of covariance for van der Waerden normal scores²¹ with weight as a binary covariate. We used Fisher's exact test to compare safety-event rates. All statistical tests were two-sided and were performed at an alpha level of 0.05.

The primary efficacy end point — the proportion of patients achieving at least 75% improvement from baseline in the psoriasis area-and-severity index at week 12 — was analyzed on an intention-to-treat basis to include data from all patients who had undergone randomization; no interim analyses were performed. Patients who discontinued study treatment because of lack of efficacy or loss of response or who used prohibited medications were considered to have had no response. An overall type I error rate of 0.05 was maintained by performing four pairwise comparisons, one between each active-treatment group and placebo sequentially, from the group that received the highest dose to the group that received the lowest dose of the interleukin-12/23 monoclonal antibody.²² If a comparison was not significant at an alpha level of 0.05, subsequent sequential comparisons were considered nonsignificant. Assuming 60 patients per group and response rates of 50% for each treatment group and 10% for the placebo group, this study had more than 99% power at the 5% level of significance to detect at least one pairwise treatment effect.

The steering committee of the CNTO 1275 Psoriasis Study Group and Centocor designed and conducted this study. Centocor analyzed the data, and the steering committee and Centocor jointly interpreted the data and contributed to the manuscript. The academic authors had full access to the data, and all authors vouch for the integrity and completeness of the data and analyses.

Results

Characteristics of the Patients

Most of the 320 patients randomly assigned to the five trial groups (Figure 1) were men. Baseline demographics and disease characteristics were similar among the trial groups (Table 1). Among the five groups, the average body-surface area affected by psoriasis was approximately 25% and the average duration of psoriasis ranged from approximately 17 to 20 years.

View larger version (33K): [in this window] [in a new window]   Figure 1. Enrollment and Treatment of Patients in the Study. At week 16, all patients in the active-treatment groups who had a physician's global assessment of 3 or higher received the assigned treatment, and those who had an assessment of less than 3 received placebo. The placebo group at week 16 does not include one patient who received a single 90-mg dose of interleukin-12/23 monoclonal antibody. At week 20, all patients in the placebo group were expected to receive a single 90-mg dose of interleukin-12/23 monoclonal antibody, but one patient received placebo in error.

 

View this table: [in this window] [in a new window]   Table 1. Baseline Characteristics of the Patients.

 
Efficacy

Thirty-three of 64 patients (52%) treated with one 45-mg dose of the interleukin-12/23 monoclonal antibody, 38 of 64 (59%) treated with one 90-mg dose, 43 of 64 (67%) treated with four weekly 45-mg doses, and 52 of 64 (81%) treated with four weekly 90-mg doses had at least 75% improvement in the psoriasis area-and-severity index at week 12 (the primary end point), as compared with only 1 of 64 patients (2%) receiving placebo (P<0.001 for each comparison) (Table 2 and Figure 2A). Similar proportions of patients were assessed as being clear or having an excellent response according to physicians' global assessments, with all active-treatment groups significantly improved as compared with the placebo group (P<0.001 for each comparison) (Table 2 and Figure 2B).

View this table: [in this window] [in a new window]   Table 2. Clinical Responses at Week 12 as Reported by Physicians and Patients.

 

View larger version (28K): [in this window] [in a new window]   Figure 2. Clinical Response to the Interleukin-12/23 Monoclonal Antibody, as Measured by the Psoriasis Area-and-Severity Index (PASI) and the Physician's Global Assessment over Time. Panel A shows the percentage of patients who had at least 75% improvement in the psoriasis area-and-severity index during the trial, and Panel B shows the percentage of patients who had a physician's global assessment score of "clear" or "excellent." Panel C shows the percentage of patients who had at least 50% improvement in the psoriasis area-and-severity index, and Panel D shows the percentage of patients who had at least 90% improvement. Asterisks indicate statistically significant differences between each active-treatment group and placebo. The dashed vertical line shows the time at which the placebo group crossed over to receive one dose of the interleukin-12/23 monoclonal antibody. At week 16, because of a physician's global assessment score of less than excellent, 32 of 64 patients in the group receiving 45 mg of interleukin-12/23 monoclonal antibody, 26 of 64 patients in the 90-mg group, 18 of 64 in the group receiving four weekly 45-mg doses, and 11 of 64 in the group receiving four weekly 90-mg doses received one additional dose of the interleukin-12/23 monoclonal antibody at their randomly assigned dose. Of 64 patients randomly assigned to placebo, 47 patients crossed over to receive a single 90-mg dose of the interleukin-12/23 monoclonal antibody at week 20. Panel E shows mean scores on the Dermatology Life Quality Index at baseline, 12 weeks, and 24 weeks (lower scores indicate better quality of life).

 
Marked clinical responses were observed in significantly more patients in each active-treatment group than in the placebo group, as measured by at least 90% improvement in the psoriasis area-and-severity index at week 12 (P<0.001 for each comparison) (Table 2 and Figure 2D). Significantly more patients in the three higher-dose groups than in the placebo group had 100% improvement in the psoriasis area-and-severity index or had a physician's global assessment of clear (P0.001 for each comparison with placebo) (Table 2). At least 75% of patients in all active-treatment groups had at least 50% improvement in the psoriasis area-and-severity index score (P<0.001 for each comparison with placebo) (Table 2 and Figure 2C). The percentage improvements in the psoriasis area-and-severity index score from baseline were significant for all active-treatment groups by week 2 (P<0.001 for each comparison with placebo).

The Dermatology Life Quality Index showed significant improvements in quality of life for all active-treatment groups at week 12 (P<0.001 for each comparison with placebo) (Table 2) and week 24 (Figure 2E). Significantly more patients in all active-treatment groups reported that their psoriasis had no measurable effect on their quality of life, as indicated by a Dermatology Life Quality Index score of 0 at week 12 (P<0.001 for each comparison with placebo) (Table 2).

Of 237 patients in the interleukin-12/23 monoclonal antibody groups continuing study treatments at week 16, only 87 patients (37%) were eligible to receive one additional dose at week 16 on the basis of a response of less than excellent according to physicians' global assessments (Figure 1). Nevertheless, the proportions of patients with at least 50%, 75%, and 90% improvement in the psoriasis area-and-severity index or with an excellent response or better according to physicians' global assessments remained relatively stable through week 24 (Figure 2A through 2D). Response rates declined after treatment was discontinued. Efficacy in those patients in the placebo group who received one 90-mg injection of the interleukin-12/23 monoclonal antibody at week 20 mirrored the improvements observed in patients originally assigned to one 90-mg dose at baseline (Figure 2A through 2D).

Safety

Through week 20 (the placebo-controlled portion of the study), 79% of patients who received active treatment had adverse events (mean duration of follow-up, 19.7 weeks) as compared with 72% who received placebo (mean duration of follow-up, 17.9 weeks; P=0.19). Adverse events leading to the discontinuation of treatment occurred in 4% of patients who received active treatment as compared with 3% who received placebo (P=1.00). Forty-three percent of patients who received active treatment and 39% of patients who received placebo had infections. We observed no obvious association between a higher dose and an increased rate of adverse events or infections. Serious adverse events,²³ all of which were classified as serious because the patients required hospitalization, were observed in 4% of patients treated with the interleukin-12/23 monoclonal antibody (9 of 252) and 1% of patients in the placebo group (1 of 67, P=0.69). In the groups that received the interleukin-12/23 monoclonal antibody, two patients were hospitalized for infection (one for cellulitis and one for pneumonia), two patients (a 61-year-old man with diabetes and hypertension and a 54-year-old man with diabetes) had myocardial infarctions and required coronary bypass surgery for multivessel coronary artery disease, and one patient (a 59-year-old woman with hypertension and hyperlipidemia) had a stroke and subsequently underwent endarterectomy. In the placebo group, one serious adverse event (aggravated psoriasis) resulted in hospitalization. One patient (1%) in the placebo group had basal-cell skin cancer, and three patients (2%) who received the interleukin-12/23 monoclonal antibody had cancer (one had basal-cell skin cancer, one squamous-cell skin cancer, and one prostate cancer). Injection-site reactions were observed in 2% of injections of the interleukin-12/23 monoclonal antibody (17 of 706) and 2% of injections of placebo (17 of 819) (Table 3).

View this table: [in this window] [in a new window]   Table 3. Adverse Events during the Placebo-Controlled Phase (Weeks 0 to 20) and through the End of the Study (Weeks 0 to 36).

 
Through week 20, the proportions of patients who had significant abnormalities in laboratory values for hematologic and blood chemical tests were low and similar between the groups receiving active treatment and the placebo group. A nonsignificantly greater proportion of patients treated with the interleukin-12/23 monoclonal antibody than with placebo had elevated glucose levels while in a nonfasting state (24 of 252 [10%] vs. 3 of 67 [4%], P=0.23). No significant differences between the active-treatment groups and the placebo group were observed in changes in absolute lymphocyte counts or lymphocyte subsets (data not shown).

Adverse events observed in the overall study population after patients in the placebo group crossed over were similar to the pattern of adverse events observed during the placebo-controlled portion of the study. A small number of patients had serious adverse events, including one occurrence each of coronary artery disorder, congestive heart failure, viral syndrome, urinary tract infection, cellulitis in a surgical wound, and elevated liver-enzyme levels. In addition, the patient in the placebo group in whom basal-cell skin cancer was diagnosed had a second basal-cell cancer reported after crossover to active treatment. Of the 293 patients treated with the interleukin-12/23 monoclonal antibody, antibodies to the study agent were detectable in 12 patients (4%) once or more during the 52 weeks of monitoring for these antibodies. Neither the presence of nor the levels of antibodies were associated with injection-site reactions.

Discussion

Our findings demonstrate the efficacy and adverse-event profile of an interleukin-12/23 monoclonal antibody in the treatment of psoriasis. They also establish a central role for the interleukin-12/23 p40 cytokines in the pathophysiology of psoriasis. The percentage of patients who had at least 75% improvement in the psoriasis area-and-severity index at week 12 increased in a dose-dependent manner. Marked clearance of psoriatic skin lesions was noted in many patients; significant proportions of patients had at least 90% improvement in the psoriasis area-and-severity index, and significant proportions of patients had complete clearance of psoriasis. Almost all patients had clinically meaningful improvement, as measured by 50% improvement in the psoriasis area-and-severity index.²⁴

Patient-reported outcome measures improved significantly in patients treated with the interleukin-12/23 monoclonal antibody. Significantly more patients treated with the interleukin-12/23 monoclonal antibody than with placebo reported improvement of their overall skin condition at week 12, and this improvement was accompanied by quality-of-life improvements reflected in the Dermatology Life Quality Index. Many patients indicated that psoriasis had no detectable adverse effect on their quality of life after active treatment. Elevated levels of interleukin-12 have been associated with major depression.²⁵ Whether quality-of-life improvements resulted from a reduction in the levels of interleukin-12, independent of improvements in overall skin condition, warrants further evaluation.

The proportions of patients who had adverse events and serious adverse events were higher among patients treated with the interleukin-12/23 monoclonal antibody than among those treated with placebo; the differences were not statistically significant, but the trial was not large enough to detect differences in uncommon serious adverse events. Rates of injection-site reactions were similar between patients treated with the interleukin-12/23 monoclonal antibody and those who received placebo. Development of antibodies to the interleukin-12/23 monoclonal antibody occurred in 4% of patients. The relationship between treatment with the interleukin-12/23 monoclonal antibody and glucose abnormalities in nonfasting patients, cancer, and the serious adverse events observed (including serious infections and myocardial infarctions) requires further study. Neither tuberculosis nor opportunistic infections developed in any patients, although both have been reported in persons congenitally deficient in interleukin-12 p40 or interleukin-12 receptor β1.^26,27 The moderate size of the study precludes meaningful assessment of the effect that blocking interleukin-12 and interleukin-23 can have on the risk of cancer. Preclinical models suggest that the interleukin-12/23 p40 cytokines play a role in tumor immunity, though it remains unclear whether blocking the interleukin-12 and interleukin-23 cytokines will affect the risk of cancer in humans or whether any effects would be detrimental or potentially protective.^28,29,30

Our findings support previous studies showing an immune basis for psoriasis.^4,5,6,31,32 The high proportion of patients responding to the interleukin-12/23 monoclonal antibody and the high level of response of the patients implicate the p40 subunit, shared by the interleukin-12 and interleukin-23 cytokines, as a key mediator of psoriasis. Produced by antigen-presenting cells, such as Langerhans' cells in the skin, interleukin-12 activates CD4+ T cells and natural killer cells to induce expression of type 1 cytokines, such as interferon- and tumor necrosis factor , which have been shown to be important in the pathophysiology of psoriasis.³³ Interleukin-23 activates a distinct T-cell lineage that expresses interleukin-17 and increases keratinocyte expression of inducible nitric oxide synthase, which has also been implicated in the pathophysiology of psoriasis.³⁴ The relative contributions of interleukin-12 and interleukin-23 to the pathophysiology of psoriasis are incompletely understood, though recent evidence supports a prominent role of interleukin-23.¹²

These results indicate that the interleukin-12/23 p40 cytokines may be an important new therapeutic target for patients with psoriasis. Although we recognize the limitations of comparisons across studies, the high level of efficacy observed in this study compares favorably with the efficacy reported for currently available intramuscularly or subcutaneously administered biologic therapeutics for psoriasis.^6,31,32 Administration of the interleukin-12/23 monoclonal antibody led to pharmacodynamic effects that were sustained for many weeks and provided significant and prolonged efficacy after only one dose or four weekly doses. This trial was not designed to evaluate the efficacy and safety of long-term use. Additional studies are needed to characterize the safety and efficacy of the interleukin-12/23 monoclonal antibody in patients with psoriasis and to define the dose schedule that will safely maintain the high level of response.

Supported by Centocor, Malvern, PA.

Dr. Krueger reports receiving fees as a consultant or advisory board member for Abbott, Almirall, Alza, Amgen, Astellas, Boehringer Ingelheim, Barrier Therapeutics, Bristol-Myers Squibb, Centocor, Connetics, and Genentech; Dr. Langley, for Centocor, Abbott, and Amgen/Wyeth; Dr. Leonardi, for Abbott, Amgen, Centocor, and Genentech; and Dr. Lebwohl, for Abbott, Amgen, Astellas, Centocor, Connetics, Galderma, Genentech, Novartis, PharmaDerm, and Warner Chilcott. Dr. Krueger reports receiving lecture fees from Abbott, Amgen, Boehringer Ingelheim, Centocor, and Connetics; Dr. Langley, from Abbott and Amgen/Wyeth; Dr. Leonardi, from Abbott, Amgen, Centocor, and Genentech; and Dr. Lebwohl, from Abbott, Astellas, Amgen, Centocor, Connetics, Galderma, Genentech, PharmaDerm, and Warner Chilcott. Dr. Krueger reports receiving stipends for a clinical research fellowship from Amgen and Centocor; Dr. Langley, grant support from Centocor, Abbott, and Amgen/Wyeth; Dr. Leonardi, educational grants from Amgen and Genentech; and Dr. Lebwohl, grants from Abbott, Amgen, Astellas, Centocor, Connetics, Galderma, Genentech, PharmaDerm, and Warner Chilcott. Drs. Yeilding, Guzzo, Wang, and Dooley report being employees of Centocor. Dr. Krueger reports owning stock options from ZARS Pharma; Drs. Yeilding, Guzzo, and Dooley report holding stock and stock options in Johnson & Johnson; and Dr. Wang reports being a stockholder in Johnson & Johnson. No other potential conflict of interest relevant to this article was reported.

We thank Cynthia Arnold and Mary Whitman for their editorial assistance; Daniel Hofstaedter, Eric Zhang, and Stephen Xu for their programming assistance; and Jacqueline Benson for her critical review of the manuscript.

^* The investigators for the CNTO 1275 Psoriasis Study Group are listed in the Appendix.

Source Information

From the University of Utah, Salt Lake City (G.G.K.); Dalhousie University, Halifax, NS, Canada (R.G.L.); Saint Louis University, St. Louis (C.L.); Centocor, Malvern, PA (N.Y., C.G., Y.W., L.T.D.); and Mount Sinai School of Medicine, New York (M.L.).

Address reprint requests to Dr. Krueger at 30 N. 1900 East, Suite 4B-454, Salt Lake City, UT 84132, or to gerald.krueger{at}derm.med.utah.edu.

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Investigators in the CNTO 1275 Psoriasis Study Group include the following: P. Altmeyer, St. Josef Hospital, Bochum, Germany; R. Bissonnette, Innovaderm Research, Montreal; R. Blum and M. Lebwohl, Mt. Sinai School of Medicine, New York; M. Bourcier, Dermatology Clinic, Moncton, NB, Canada; W. Carey, Royal Victoria Hospital, Montreal; M. Chambers, Radiant Research, Columbus, OH; D. Fiorentino (replaced A. Kimball), Stanford University School of Medicine, Stanford, CA; S. Fretzin, Dawes Fretzin Clinical Research Group, Indianapolis; D. Gratton, International Dermatology Research, Montreal; L. Guenther, Guenther Dermatology Research Centre, London, ON, Canada; R. Hamlin, Associates in Research, Fresno, CA; D. Harvey, Jacksonville Center for Clinical Research, Jacksonville, FL; C. Hudson, Research Solutions, Evansville, IN; R. Kaufmann, Johann Wolfgang Goethe Universität, Frankfurt, Germany; L. Kircik, Physicians Skin Care, Louisville, KY; R. Kirsner, Veterans Affairs Medical Center, Miami; N. Korman, University Hospitals of Cleveland, Cleveland; G. Krueger, University of Utah, Salt Lake City; P. Krusinski and M. Zavod, Fletcher Allen Health Care, Burlington, VT; J. Lambert, Universiteitsziekenhuis Antwerpen Dermatologie, Edegem, Belgium; R. Langley, Eastern Canada Cutaneous Research Associates, Halifax, NS, Canada; C. Leonardi, Central Dermatology, St. Louis; M. Ling, Medaphase, Newnan, GA; B. Lubin, Hampton Roads Center for Clinical Research, Norfolk, VA; T. Luger, Universität Münster, Münster, Germany; L. Marot, Université Catholique de Louvain, Hospital Saint-Luc, Brussels; R. Matheson, Oregon Medical Research Center, Portland; A. Menter, Texas Dermatology Research Institute, Dallas; A. Nayak, Sneeze, Wheeze, and Itch Associates, Normal, IL; D. Nieves (replaced J. Bagel), Psoriasis Treatment Center of Central New Jersey, East Windsor; T. Nigra, Dermatology Associates, Washington, DC; B. Packman (replaced A. Mangione), Radiant Research, Philadelphia; K. Papp, Probity Medical Research, Waterloo, ON, Canada; Y. Poulin, Centre Dermatologique du Québec Metropolitain, Sainte-Foy, QC, Canada; K. Reich, Georg-August-Universität, Göttingen, Germany; P. Rich, Northwest Cutaneous Research Specialists, Portland, OR; L. Rosoph, Probity Medical Research, North Bay, ON, Canada; J. Sobell, ORA Clinical Research and Development, North Andover, MA; J. Swinehart, Colorado Medical Research Center, Denver; Z. Tomi, New Lab Clinical Research, St. John's, NL, Canada; D. Toth, Probity Medical Research, Windsor, ON, Canada; A. Truett III, Pedia Research, Owensboro, KY; E. Tschen, Academic Dermatology Associates, Albuquerque, NM; N. Wasel, Edmonton, AB, Canada; and M. Zanolli, Dermatology Consultants, Nashville.

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