Fiorentino DF, Garcia MS, Rehmus W, Kimball AB. A Pilot Study of Etanercept Treatment for Pemphigus Vulgaris. Arch Dermatol. 2011;147(1):117–118. doi:10.1001/archdermatol.2010.409
Pemphigus vulgaris (PV) is a chronic autoimmune blistering disease associated with a high morbidity rate and potential mortality. Current therapies are not uniformly effective and are associated with potential adverse effects; thus, there is a need for new therapeutic options for PV.
Data from in vitro experiments and mouse models suggest that tumor necrosis factor (TNF) has a role in PV pathogenesis. Etanercept is a recombinant fusion protein of the extracellular ligand-binding domain of human 75-kDa TNF receptor and the Fc portion of human IgG1 that acts as a competitive inhibitor of TNF. We conducted a pilot study to evaluate the efficacy and safety of etanercept for PV therapy.
This double-blinded, randomized, placebo-controlled trial was approved by the institutional review board. All patients were older than 18 years and had undergone a skin biopsy with findings consistent with PV on both routine histologic analysis and direct immunofluorescence microscopy. They had no alteration in systemic or topical immunomodulatory therapy for 4 weeks prior to enrollment.
Subjects were randomized at a ratio of 2:1 to receive etanercept (50 mg) or placebo (saline) subcutaneous (SC) injections once weekly for 16 weeks. The primary end point of the study was the mean time to achieve 50% reduction in the number of active lesions. Power analysis yielded a sample size of 13 to detect a difference of 35 days between placebo and etanercept therapy, assuming an SD of 30 days in both groups at α = .05 and a power of 0.8.
Owing to slow enrollment and a futility analysis suggesting that study completion would not change our conclusions, the trial was halted after enrollment of 8 participants. Two patients dropped out of the study (both in the etanercept group)—one at week 4 secondary to a PV flare and the other at week 8 secondary to a hip fracture. The primary end point of 50% reduction in lesion number was met by 3 of the 6 subjects completing the study (2 in the placebo group, 1 in the etanercept group) (Table). Of the 3 participants in the etanercept group for whom the treatment failed, 1 (patient 5) experienced clinical improvement and was able to taper his prednisone dose. There were no serious adverse events or laboratory abnormalities.
Previous case reports (6 total patients in 3 reports1- 3) describe uniformly effective results for the use of etanercept in PV. Our randomized, controlled study suggests that the response to etanercept is heterogeneous, although the small sample size precludes definitive conclusions. We observed 2 meaningful responses in the 4 patients who received etanercept and completed the study, although the use of azathioprine 1 month before etanercept initiation confounds the results for 1 of these 2 patients. It is possible that a higher dose of etanercept (eg, 50 mg twice weekly) might have conferred additional efficacy. The apparent placebo response is complicated by concurrent initiation of topical therapy in one patient and a questionably meaningful improvement in the other.
One weakness of our study is the lack of a well-validated end point—we noted cases of discordance between changes in lesion number and physician global assessment. Since this study was designed, an international consensus statement has emerged regarding definitions of disease end points and response,4 and, in addition, 2 novel outcome instruments for PV have been partially validated.5
Correspondence: Dr Fiorentino, Department of Dermatology, Stanford University School of Medicine, 450 Broadway Pavilion C, C-234, Stanford, CA 94063 (firstname.lastname@example.org).
Accepted for Publication: July 21, 2010.
Author Contributions: All authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Kimball. Acquisition of data: Fiorentino, Rehmus, and Kimball. Analysis and interpretation of data: Fiorentino, Garcia, Rehmus, and Kimball. Drafting of the manuscript: Fiorentino and Garcia. Critical revision of the manuscript for important intellectual content: Rehmus and Kimball. Statistical analysis: Rehmus. Administrative, technical, and material support: Garcia. Study supervision: Fiorentino, Rehmus, and Kimball.
Financial Disclosure: Dr Fiorentino has received grants from Centocor and Abbott Labs and honoraria from Amgen, Centocor, Chemocentryx, MedImmune, Abbott, Arcutis, Celtix, Combinent, Follica, Galderma, Intendis, Johnson & Johnson, Magen, Neostrata, NetEffects, Nuskin, Obaji, Procter & Gamble, Serentis, and Unilever; he filed patent No. 12/694,980 on January 27, 2010, for “Profiling for Determination of Response to Treatment for Inflammatory Disease.” Dr Kimball has served as a consultant for Abbott, Arcutis, Celtix, Combinent, Follica, Galderma, Intendis, Johnson & Johnson, Neostrata, NetEffects, Obaji, Procter & Gamble, Serentis, and Unilever. Drs Fiorentino and Kimball are paid investigators and advisors for and receive honoraria from Amgen Inc. Dr Fiorentino has received a grant for fellowship funding from Amgen Inc.
Funding/Support: Amgen Inc provided partial financial and material support for this study.
Role of the Sponsors: The sponsors had no role in the design and conduct of the study; in the collection, analysis, and interpretation of data; or in the preparation of the manuscript. They did review and approve the manuscript before submission with no changes suggested.