At ODAC 2023, we had the opportunity to learn about the latest in treatments for blistering diseases from Dr. Karl Saardi, Associate Professor and Director of Inpatient Dermatology at George Washington University. We focused on the pemphigus and pemphigoid group of diseases, which we will review and summarize here.
Pemphigus
The pemphigus group of diseases is characterized by intraepidermal autoimmune blistering that is almost purely B-cell mediated. Rituximab is the only FDA-approved treatment based on its approval in 2016, though prednisone is also regarded as the standard of care.
Rituximab
This is an anti-CD20 monoclonal antibody with several biosimilar agents, though only the Rituxan version is FDA-approved. There is limited data on biosimilars in pemphigus in the United States. Because it has many uses, there are many doses to choose from, including:
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- Lymphoma dosing (375 mg/m2 weekly for 4 doses)
- Rheumatoid arthritis dosing (1000mg/ m2 twice two weeks apart)
Considerations to help guide the choice of dosing includes body mass index, insurance coverage, and prior treatment.
Mycophenolate
Mycophenolate mofetil is often used as a steroid-sparing agent in pemphigus. However, it is not FDA-approved. In the PEMPHIX study, rituximab was found to be superior to mycophenolate for sustained remission at 52 weeks in patients with pemphigus vulgaris. However, it had fewer adverse effects compared with rituximab.
Intravenous Immunoglobulin
Intravenous immunoglobulin, or IVIg, is used off-label for the treatment of pemphigus. It has no inherent disease-modifying effect. Results are mostly mixed in the existing cohort studies, particularly since there are minimal clear outcomes-focused randomized controlled trials for its use. Furthermore, insurance coverage is challenging.
Clinical Tip: Consider that active treatment with these immunosuppressive or immunomodulatory agents may result in a suboptimal COVID-19 vaccine response. However, following the American College of Rheumatology guidelines is likely the safest approach to prevent any severe COVID.
Other Therapies
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- Efgartigimod blocks FcRn, leading to IgG elimination. It was well-tolerated in a Phase II study and showed an early effect on the activity of the disease and outcomes.
- DSG3-CAART (Desmoglein 3 Chimeric Autoantibody Receptor T cell) is being studied for use in pemphigus, particularly mucosal variants.
Disease and Drug Monitoring
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- Disease Activity: PDAI score (cumbersome), body surface area, weight loss or number of blisters/month (e.g., mucosal pemphigus vulgaris)
- Pre-Administration: Hepatitis B testing, Hepatitis C testing, HIV, Tuberculosis, Immunoglobulin levels, CBC, CMP, UPT, COVID spike antibody if vaccinated
- During Therapy: CBC, CMP, IgG level (every 1-2 months), Desmoglein 1/3 antibodies, Flow cytometry
Pemphigoid
Blistering pemphigoid diseases have multifactorial pathogenesis, but they result in antibody-mediated subepidermal blisters. Potential targets for medications focus on anti-BP180/IgE, eosinophils/IL-5, eotaxin, TH2 cytokines (e.g., IL-4, IL-13), and TH17 cells (IL-17).
Mepolizumab
This medication is an anti-IL-5 antibody currently approved for asthma, eosinophilic granulomatosis with polyangiitis, and hypereosinophilic syndrome. There is presumed to be some role of eosinophils in blister formation, so this may play a role in pemphigoid.
Rituximab and omalizumab
Both of these medications are used off-label for bullous pemphigoid to target the antibody-mediated blistering (rituximab) and potential role of autoreactive IgE in the disease’s initiation and maintenance (omalizumab). A 2019 systematic review showed ~85% complete response rate for both.
Dupilumab
A Chinese series in 2021 studied 24 hospitalized patients who had dupilumab as an add-on therapy in addition to steroids and azathioprine. They found that there was no difference in complete remission rates. However, this is an active area of study with ongoing trials.
Other Therapies
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- Bertilimumab is an eotaxin-1 inhibitor in ongoing study
- Lazucirnon is a CCR3/eotaxin-1 pathway inhibitor in ongoing study
- Avdoralimab is a C5aR1 inhibitor (C5aR2 thought to be protective) in ongoing study
- Baricitinib (JAK1/2 inhibitor) and rituximab/cyclophosphamide are effective therapies for mucous membrane pemphigoid
Clinical Tip: For all patients, class 1 topical corticosteroids should be part of the treatment regimen.
Although blistering diseases can be challenging to manage, there are so many new therapies in the works and ones that exist already. While there is much work to be done, there should be promise for current and future therapies for patients with blistering and immunobullous diseases.
References
Abdat R, Waldman RA, de Bedout V, et al. Dupilumab as a novel therapy for bullous pemphigoid: A multicenter case series. J Am Acad Dermatol.2020;83(1):46-52.
Amagai M, Ikeda S, Shimizu H, et al. A randomized double-blind trial of intravenous immunoglobulin for pemphigus. J Am Acad Dermatol. 2009;60(4):595-603.
Brown AE, Motaparthi K, Hsu S. Rituximab and intravenous immunoglobulin as alternatives to long-term systemic corticosteroids in the treatment of pemphigus: a single center case series of 63 patients. Dermatol Online J. 2018;23(12):13030/qt96v387cj.
Genovese G, Di Zenzo G, Cozzani E, Berti E, Cugno M, Marzano AV. New insights into the pathogenesis of bullous pemphigoid: 2019 update. Front Immunol. 2019;10:1506
Goebeler M, Bata-Csörgő Z, De Simone C, et al. Treatment of pemphigus vulgaris and foliaceus with efgartigimod, a neonatal Fc receptor inhibitor: a phase II multicentre, open-label feasibility trial. Br J Dermatol. 2022;186(3):429-439.
Khalid SN, Khan ZA, Ali MH, Almas T, Khedro T, Raj Nagarajan V. A blistering new era for bullous pemphigoid: A scoping review of current therapies, ongoing clinical trials, and future directions. Ann Med Surg (Lond). 2021;70:102799.
Kremer N, Snast I, Cohen ES, et al. Rituximab and omalizumab for the treatment of bullous pemphigoid: a systematic review of the literature. AmJ Clin Dermatol. 2019;20(2):209-216.
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;155(12):1404-1409.
Rico MJ, Benning C, Weingart ES, Streilein RD, Hall RP. Characterization of skin cytokines in bullous pemphigoid and pemphigus vulgaris. Br J Dermatol. 1999;140(6):1079-1086.
Waljee AK, Rogers MAM, Lin P, et al. Short term use of oral corticosteroids and related harms among adults in the United States: population based cohort study. BMJ. 2017;357:j1415
Werth VP, Joly P, Mimouni D, et al. Rituximab versus Mycophenolate Mofetil in Patients with Pemphigus Vulgaris. N Engl J Med. 2021;384(24):2295-2305.
Zhang Y, Xu Q, Chen L, et al. Efficacy and safety of dupilumab in moderate-to-severe bullous pemphigoid. Front Immunol. 2021;12:738907.
This information was presented by Dr. Karl Saardi during the 2023 ODAC Dermatology, Aesthetic and Surgical Conference. The above highlights from his lecture were written and compiled by Dr. Nishad Sathe.
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