Progress in pemphigus: Solidifying rituximab’s role
By Warren R. Heymann, MD, FAAD
July 7, 2021
Vol. 3, No. 27
“Now what do I do?”
That question, asked by dermatologists every day about patients who are not responding to therapy, was posed in the preface of the first (and every subsequent) edition of Treatment of Skin Disease: Comprehensive Therapeutic Strategies. (1)
It has been an honor and privilege to work with Drs. Mark Lebwohl, John Berth-Jones, and Ian Coulson for the first five editions of the textbook, and most recently, Dedee Murrell for the upcoming sixth edition (Dr. Berth-Jones has retired). Editing chapters over two decades offers a perspective of how therapy has — or has not — changed. The astonishing biologics have revolutionized dermatoses such as psoriasis, atopic dermatitis, and others. Sadly, for many orphan skin diseases, many therapeutic maneuvers are the same in the sixth edition as they were in the first, published in 2002.
Rituximab was first mentioned as a second-line treatment for pemphigus in our second edition, referencing Dupuy et al, who reported a complete response in 2 of 3 patients with recalcitrant pemphigus vulgaris. The authors concluded: “These patients’ response suggests that rituximab may be a valuable treatment for refractory PV and warrants further studies to evaluate the risk-benefit ratio in patients with PV showing resistance to classic therapy.” (2) In our sixth edition, there are two first-line therapies with an evidence level of “A” — oral corticosteroids and rituximab. (3)
Rituximab is an anti-CD20 monoclonal antibody that induces cell death by several mechanisms, including antibody-dependent cell-mediated cytotoxicity, complement-mediated-cytotoxicity, antibody-dependent phagocytosis, and direct effects of binding of rituximab to CD20. The effect of rituximab in autoimmune disease is presumed to be depletion of anti-CD20+ B cells, leading to a decrease in pathogenic antibody production. Rituximab is FDA-approved for CD20 positive B-cell non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, microscopic polyangiitis, granulomatosis with polyangiitis, and pemphigus vulgaris. (4) There are multiple off-label uses, including other pemphigus variants, bullous pemphigoid, and lupus erythematosus, among others.
According to Lemieux and Joly: “Very few randomized controlled trials (RCT) are available for pemphigus given the rarity of the disease, and guidelines or recommendations are mostly based on experts’ opinions and consensus. The initial investigation should always include a thorough evaluation of the patient’s medications to exclude drug-induced pemphigus. Pemphigus treatments must be adapted to the patient’s comorbidities and initial disease extent.” Second-line therapies include mycophenolate mofetil (or mycophenolic acid), azathioprine, high-dose intravenous immunoglobulins, immunoadsorption, and pulsed intravenous corticosteroids. Third-line therapies include cyclophosphamide (oral or pulsed intravenous), methotrexate, topical or intralesional corticosteroids, and intralesional rituximab. Occasionally, dapsone, sulfasalazine, tetracycline, and chlorambucil are utilized. (3). Dapsone may be of particular value in neutrophil-rich IgA pemphigus. (5)
Montagnon et al note that most data on the treatment of pemphigus are based on studies of pemphigus vulgaris (PV) and pemphigus foliaceous (PF). Unless contraindicated, the first-line treatment for significant and extensive PV and PF is considered to be intravenous rituximab (anti-CD20 therapy) with a tapering course of prednisone (starting at 0.5 mg/kg daily over 3 months for significant disease and starting at 1.0 mg/kg daily over 6 months for extensive disease). In comparison to chronic corticosteroid monotherapy, rituximab with corticosteroids has been found to be more effective with a decrease in relapse rate and with a more favorable safety profile. Regarding rituximab dosing, both the rheumatoid arthritis protocol (2 doses of 1000 mg intravenously administered 2 weeks apart) and the lymphoma protocol (375 mg/m2 intravenous rituximab administered weekly for 4 weeks) have been studied in PV and PF and have been found to have comparable response rates. The FDA approved the RA protocol for treatment of pemphigus in 2018. (6) A retrospective study of 112 PV and PF patients demonstrated that patients treated with the lymphoma protocol were 2.7 times more likely to achieve complete remission off therapy compared to patients treated with the RA protocol. (7)
Werth et al performed a randomized, controlled trial, assigning patients with moderate-to-severe pemphigus vulgaris in a 1:1 ratio to receive intravenous rituximab (n=67, 1000 mg on days 1, 15, 168, and 182) or oral mycophenolate mofetil (n=68, 2 g per day), in addition to an oral glucocorticoid administered on the same tapering schedule in the two groups. The primary end point was sustained complete remission at week 52, defined as the healing of lesions with no new active lesions, as reflected by a Pemphigus Disease Area Index (PDAI) activity score of 0, for at least 16 weeks without the use of glucocorticoids. Secondary end points were the cumulative dose of glucocorticoids, the number of disease flares, and the change from baseline in the score on the Dermatology Life Quality Index (DLQI). At week 52, sustained complete remission was observed in 25 patients (40%) in the rituximab group and in 6 (10%) in the mycophenolate mofetil group (P<0.001). The mean cumulative glucocorticoid dose during the 52-week treatment period was 3545 mg in the rituximab group and 5140 mg in the mycophenolate mofetil group (P<0.001). There were 6 disease flares in the rituximab group and 44 in the mycophenolate mofetil group (P<0.001). The mean change in DLQI score was −8.87 points and −6.00 points, respectively (P = 0.001). Serious adverse events (infections) occurred in 15 of 67 patients (22%) in the rituximab group and in 10 of 68 (15%) in the mycophenolate mofetil group. The authors concluded that rituximab is superior to mycophenolate mofetil in producing sustained complete remission at 52 weeks in patients with pemphigus vulgaris. Rituximab resulted in a greater reduction in glucocorticoid use than mycophenolate mofetil, but more patients in the rituximab group had serious adverse events. Further trials are needed to determine the comparative efficacy and safety of rituximab and mycophenolate mofetil beyond a year of treatment. (8)
When it comes to treating pemphigus, answering the question “Now what do I do?” has changed dramatically from 20 years ago. Certainly, the twelfth edition of the Treatment of Skin Disease to be published in 2046 will offer different guidance. For now, we can take comfort in knowing that we can help many patients with this potentially devastating disease get into remission.
Point to Remember: Comparative studies of therapeutic options for treating pemphigus have been lacking. Evidence now exists that when utilized with steroids, rituximab is superior to mycophenolate mofetil in producing a sustained, complete remission.
Our expert's viewpoint
Victoria P. Werth, MD, FAAD
Professor of Dermatology and Medicine, University of Pennsylvania Perelman School of Medicine
When I entered the field of dermatology, management of glucocorticoids became a large focus of mine because of pemphigus and the severe impact steroids had on patients. That, along with steroid-sparing medications, were the main approaches for management of moderate to severe pemphigus. The pemphigus community worked hard to standardize definitions and tools to measure disease severity in pemphigus. In 2007, Pascal Joly published the NEJM open label study showing that 86% of patients had remission 3 months after receiving one course of lymphoma dosing with rituximab, and half of those in remission relapsed a mean of 18 months later. Advances in trial design and outcomes have contributed to the approval of rituximab by the FDA, based on a successful trial led by Pascal Joly and published in the Lancet in 2017 (9). Even after rituximab approval by the FDA, the international blistering community considered either treatment with steroids and immunosuppressives or rituximab to be first-line treatments for moderate to severe pemphigus (10). The current study just published in the NEJM comparing Rituximab + steroids to MMF + steroids clearly shows the superiority of rituximab over MMF, and rituximab should be given strong consideration as initial treatment for patients with moderate to severe disease (8). In this era of the COVID-19 pandemic, both steroids and rituximab can lead to a poor response to the vaccine. Thus, vaccinating patients prior to treatment when possible or prior to the next treatment is important to consider. There is more to learn about optimal dosing and retreatment for rituximab, but clearly rituximab has made an enormous difference for many patients and can lead to durable remissions off therapy for many patients who in the past would have been managed with longer and higher doses of steroid and immunosuppressives.
Dr. Werth had disclosed financial relationships with the following to the AAD at the time of publication: AbbVie, arGEN-X , AstraZeneca, Biogen, BMS, Celgene Corporation, CSL, CSL Behring, Corbus Pharmaceuticals, Cugene, EMD Serono, Genentech, Inc., Gilead Sciences, Idera Pharmaceuticals, Inc., Immune Pharmaceuticals, Immunotherapeutics, Janssen Pharmaceuticals, Inc, Lilly ICOS LLC, Lupus Foundation of America, Medimmune, Neovacs, Octapharma, Pfizer Inc., Principia Biopharma Inc., Resolve Therapeutics, Roche Laboratories, Stiefel a GSK company, Syntimmune, Inc., UV Therapeutics, Viela Bio. Full disclosure information is available at coi.aad.org.
Lebwohl MG, Heymann WR, Coulson IH, Murrell DF (eds.). Treatment of Skin Disease: Comprehensive Therapeutic Strategies, Sixth edition. Elsevier (in press).
Dupuy A, Viguier M, Bédane C, Cordoliani F, Blaise S, Aucouturier F, Bonnetblanc JM, Morel P, Dubertret L, Bachelez H. Treatment of refractory pemphigus vulgaris with rituximab (anti-CD20 monoclonal antibody). Arch Dermatol. 2004 Jan;140(1):91-6. doi: 10.1001/archderm.140.1.91. PMID: 14732665.
Lemieux A, Joly P. Pemphigus. In Lebwohl MG, Heymann WR, Coulson IH, Murrell D (eds.). Treatment of Skin Disease: Comprehensive Therapeutic Strategies, Sixth edition. Elsevier (in press).
Hanif N, Anwer F. Rituximab. 2020 Nov 3. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan–. PMID: 33232044.
Kridin K, Patel PM, Jones VA, Cordova A, Amber KT. IgA pemphigus: A systematic review. J Am Acad Dermatol. 2020 Jun;82(6):1386-1392. doi: 10.1016/j.jaad.2019.11.059. Epub 2019 Dec 5. PMID: 31812619.
Montagnon CM, Lehman JS, Murrell DF, Camilleri MJ, Tolkachjov SN. Intraepithelial autoimmune bullous dermatoses disease activity assessment and therapy. J Am Acad Dermatol. 2021 Jun;84(6):1523-1537. doi: 10.1016/j.jaad.2021.02.073. Epub 2021 Mar 5. PMID: 33684497.
Kushner CJ, Wang S, Tovanabutra N, Tsai DE, Werth VP, Payne AS. Factors Associated With Complete Remission After Rituximab Therapy for Pemphigus. JAMA Dermatol. 2019 Dec 1;155(12):1404-1409. doi: 10.1001/jamadermatol.2019.3236. PMID: 31642878; PMCID: PMC6813574.
Werth VP, Joly P, Mimouni D, Maverakis E, et al. Rituximab versus mycophenolate mofetil in patients with pemphigus vulgaris. N Engl J Med 2021; May 19. DOI: 10.1056/NEJMoa2028564.
Joly P, Maho-Vaillant M, Prost-Squarcioni C, et al. First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux 3): a prospective, multicentre, parallel-group, open-label randomised trial. Lancet. 2017;389(10083):2031-2040. doi:10.1016/S0140-6736(17)30070-3.
Murrell DF, Peña S, Joly P, et al. Diagnosis and management of pemphigus: Recommendations of an international panel of experts. J Am Acad Dermatol. 2020;82(3):575-585.e1. doi:10.1016/j.jaad.2018.02.021
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