Abstract
Background
Rituximab is a potential initial adjuvant therapy for bullous pemphigoid, yet clinical experience is scarce.
Objective
We aimed to examine the clinical outcomes and safety of initial combination therapy with systemic corticosteroids and adjuvant rituximab for the treatment of bullous pemphigoid.
Methods
A retrospective cohort study was performed on 84 patients with bullous pemphigoid, who received systemic corticosteroids with or without initial adjuvant rituximab therapy (defined as rituximab use within 12 weeks after initiation of systemic corticosteroids).
Results
Among the 84 patients included (37 received systemic corticosteroids with rituximab and 47 were treated with systemic corticosteroids without rituximab), the median time to complete remission on minimal therapy or off therapy was 215 days (95% confidence interval 176.9–253.1) in patients receiving rituximab vs 529 days (95% confidence interval 338.6–719.4) in those not receiving rituximab. A Cox regression analysis showed an increased probability of reaching complete remission on minimal therapy or off therapy with the combined therapy (hazard ratio = 2.28 [1.28–4.07], p = 0.005) after age, Bullous Pemphigoid Disease Activity Index score, and underlying diseases were controlled. In multivariate logistic/linear regressions, initial adjuvant rituximab therapy was associated with a higher complete remission rate (odds ratio = 6.63 [2.09–21.03]) and lower cumulative prednisolone (mg)/body weight (kg) (B = −24.86 [−44.06 to −8.29]) within 48 weeks. Risk of hospitalization for infection was not elevated in the group treated with adjuvant rituximab.
Conclusions
Rituximab use as adjuvant therapy within 12 weeks after initiation of systemic corticosteroids was associated with a faster and higher rate of achieving complete remission on minimal therapy or off therapy, as well as a significant corticosteroid-sparing effect and a comparable safety profile in this retrospective study. Hence, initial combination therapy with corticosteroids and adjuvant rituximab could serve as an effective treatment option for bullous pemphigoid, but this requires confirmation in randomized controlled studies.
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References
Persson MSM, Harman KE, Vinogradova Y, Langan SM, Hippisley-Cox J, Thomas KS, et al. Incidence, prevalence, and mortality of bullous pemphigoid in England 1998–2017: a population-based cohort study. Br J Dermatol. 2020;184(1):68–77.
Brick KE, Weaver CH, Lohse CM, Pittelkow MR, Lehman JS, Camilleri MJ, et al. Incidence of bullous pemphigoid and mortality of patients with bullous pemphigoid in Olmsted County, Minnesota, 1960 through 2009. J Am Acad Dermatol. 2014;71(1):92–9.
Rozenblat M, Halaj A, Rozenblat T, Fisher S, Sah M, Dodiuk-Gad RP, et al. Mortality and risk factors among Israeli bullous pemphigoid patients. Arch Dermatol Res. 2019;311(1):19–27.
Kridin K, Shihade W, Bergman R. Mortality in patients with bullous pemphigoid: a retrospective cohort study, systematic review and meta-analysis. Acta Derm Venereol. 2019;99(1):72–7.
Jeon HW, Yun SJ, Lee SC, Won YH, Lee JB. Mortality and comorbidity profiles of patients with bullous pemphigoid in Korea. Ann Dermatol. 2018;30(1):13–9.
Kalinska-Bienias A, Lukowska-Smorawska K, Jagielski P, Kowalewski C, Wozniak K. Mortality in bullous pemphigoid and prognostic factors in 1st and 3rd year of follow-up in specialized centre in Poland. Arch Dermatol Res. 2017;309(9):709–19.
Forsti AK, Jokelainen J, Timonen M, Tasanen K. Risk of death in bullous pemphigoid: a retrospective database study in Finland. Acta Derm Venereol. 2016;96(6):758–61.
Lee JH, Kim SC. Mortality of patients with bullous pemphigoid in Korea. J Am Acad Dermatol. 2014;71(4):676–83.
Cai SC, Allen JC, Lim YL, Chua SH, Tan SH, Tang MB. Mortality of bullous pemphigoid in Singapore: risk factors and causes of death in 359 patients seen at the National Skin Centre. Br J Dermatol. 2014;170(6):1319–26.
Cortes B, Marazza G, Naldi L, Combescure C, Borradori L. Autoimmune Bullous Disease Swiss Study Group Mortality of bullous pemphigoid in Switzerland: a prospective study. Br J Dermatol. 2011;165(2):368–74.
Kalinska-Bienias A, Kowalczyk E, Jagielski P, Bienias P, Kowalewski C, Wozniak K. The association between neurological diseases, malignancies and cardiovascular comorbidities among patients with bullous pemphigoid: case-control study in a specialized Polish center. Adv Clin Exp Med. 2019;28(5):637–42.
Chen CT, Hu HY, Chang YT, Li CP, Wu CY. Cancer is not a risk factor for bullous pemphigoid: 10-year population-based cohort study. Br J Dermatol. 2019;180(3):553–8.
Ren Z, Hsu DY, Brieva J, Silverberg NB, Langan SM, Silverberg JI. Hospitalization, inpatient burden and comorbidities associated with bullous pemphigoid in the USA. Br J Dermatol. 2017;176(1):87–99.
Milani-Nejad N, Zhang M, Kaffenberger J. The association between bullous pemphigoid and neurological disorders: a systematic review. Eur J Dermatol. 2017;27(5):472–81.
Kibsgaard L, Bay B, Deleuran M, Vestergaard C. A retrospective consecutive case-series study on the effect of systemic treatment, length of admission time, and co-morbidities in 98 bullous pemphigoid patients admitted to a tertiary centre. Acta Derm Venereol. 2015;95(3):307–11.
Feliciani C, Joly P, Jonkman MF, Zambruno G, Zillikens D, Ioannides D, et al. Management of bullous pemphigoid: the European Dermatology Forum consensus in collaboration with the European Academy of Dermatology and Venereology. Br J Dermatol. 2015;172(4):867–77.
Venning VA, Taghipour K, Mohd Mustapa MF, Highet AS, Kirtschig G. British Association of Dermatologists’ guidelines for the management of bullous pemphigoid 2012. Br J Dermatol. 2012;167(6):1200–14.
Williams HC, Wojnarowska F, Kirtschig G, Mason J, Godec TR, Schmidt E, et al. Doxycycline versus prednisolone as an initial treatment strategy for bullous pemphigoid: a pragmatic, non-inferiority, randomised controlled trial. Lancet. 2017;389(10079):1630–8.
Amagai M, Ikeda S, Hashimoto T, Mizuashi M, Fujisawa A, Ihn H, et al. A randomized double-blind trial of intravenous immunoglobulin for bullous pemphigoid. J Dermatol Sci. 2017;85(2):77–84.
Kremer N, Snast I, Cohen ES, Hodak E, Mimouni D, Lapidoth M, et al. Rituximab and omalizumab for the treatment of bullous pemphigoid: a systematic review of the literature. Am J Clin Dermatol. 2019;20(2):209–16.
Berkani N, Joly P, Golinski ML, Colliou N, Lim A, Larbi A, et al. B-cell depletion induces a shift in self antigen specific B-cell repertoire and cytokine pattern in patients with bullous pemphigoid. Sci Rep. 2019;9(1):3525.
Cho YT, Chu CY, Wang LF. First-line combination therapy with rituximab and corticosteroids provides a high complete remission rate in moderate-to-severe bullous pemphigoid. Br J Dermatol. 2015;173(1):302–4.
Ahmed AR, Shetty S, Kaveri S, Spigelman ZS. Treatment of recalcitrant bullous pemphigoid (BP) with a novel protocol: a retrospective study with a 6-year follow-up. J Am Acad Dermatol. 2016;74(4):700-8.e3.
Amber KT, Maglie R, Solimani F, Eming R, Hertl M. Targeted therapies for autoimmune bullous diseases: current status. Drugs. 2018;78(15):1527–48.
Polansky M, Eisenstadt R, DeGrazia T, Zhao X, Liu Y, Feldman R. Rituximab therapy in patients with bullous pemphigoid: a retrospective study of 20 patients. J Am Acad Dermatol. 2019;81(1):179–86.
Lamberts A, Euverman HI, Terra JB, Jonkman MF, Horvath B. Effectiveness and safety of rituximab in recalcitrant pemphigoid diseases. Front Immunol. 2018;9:248.
Lourari S, Herve C, Doffoel-Hantz V, Meyer N, Bulai-Livideanu C, Viraben R, et al. Bullous and mucous membrane pemphigoid show a mixed response to rituximab: experience in seven patients. J Eur Acad Dermatol Venereol. 2011;25(10):1238–40.
Joly P, Courville P, Lok C, Bernard P, Saiag P, Dreno B, et al. Clinical criteria for the diagnosis of bullous pemphigoid: a reevaluation according to immunoblot analysis of patient sera. Dermatology. 2004;208(1):16–20.
Murrell DF, Daniel BS, Joly P, Borradori L, Amagai M, Hashimoto T, et al. Definitions and outcome measures for bullous pemphigoid: recommendations by an international panel of experts. J Am Acad Dermatol. 2012;66(3):479–85.
Murrell DF, Ramirez-Quizon M. Management and prognosis of bullous pemphigoid. In: Post TW, editor. UpToDate, Waltham, MA. https://www.uptodate.com/contents/management-and-prognosis-of-bullous-pemphigoid?search=bullous%20pemphigoid&source=search_result&selectedTitle=1~135&usage_type=default&display_rank=1#H24368306. Accessed 10 Feb 2022.
Hertl M, Jedlickova H, Karpati S, Marinovic B, Uzun S, Yayli S, et al. Pemphigus. S2 Guideline for diagnosis and treatment: guided by the European Dermatology Forum (EDF) in cooperation with the European Academy of Dermatology and Venereology (EADV). J Eur Acad Dermatol Venereol. 2015;29(3):405–14.
Joly P, Horvath B, Patsatsi A, Uzun S, Bech R, Beissert S, et al. Updated S2K guidelines on the management of pemphigus vulgaris and foliaceus initiated by the European Academy of Dermatology and Venereology (EADV). J Eur Acad Dermatol Venereol. 2020;34(9):1900–13.
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):1404–9.
Masmoudi W, Vaillant M, Vassileva S, Patsatsi A, Quereux G, Moltrasio C, et al. International validation of the Bullous Pemphigoid Disease Area Index severity score and calculation of cut-off values for defining mild, moderate and severe types of bullous pemphigoid. Br J Dermatol. 2021;184(6):1106–12.
Thomas RM, Colon A, Motaparthi K. Rituximab in autoimmune pemphigoid diseases: indications, optimized regimens, and practice gaps. Clin Dermatol. 2020;38(3):384–96.
Tovanabutra N, Payne AS. Clinical outcome and safety of rituximab therapy for pemphigoid diseases. J Am Acad Dermatol. 2020;82(5):1237–9.
Volmer T, Effenberger T, Trautner C, Buhl R. Consequences of long-term oral corticosteroid therapy and its side-effects in severe asthma in adults: a focused review of the impact data in the literature. Eur Respir J. 2018;52(4):1800703.
Hebert V, Bastos S, Drenovska K, Meijer J, Ingen-Housz-Oro S, Bedane C, et al. International multicentre observational study to assess the efficacy and safety of a 0.5 mg kg-1 per day starting dose of oral corticosteroids to treat bullous pemphigoid. Br J Dermatol. 2021;185(6):1232–9.
Yoo DS, Lee JH, Kim SC, Kim JH. Mortality and clinical response of patients with bullous pemphigoid treated with rituximab. Br J Dermatol. 2021;185(1):210–2.
Liu YD, Wang YH, Ye YC, Zhao WL, Li L. Prognostic factors for mortality in patients with bullous pemphigoid: a meta-analysis. Arch Dermatol Res. 2017;309(5):335–47.
Gea-Banacloche JC. Rituximab-associated infections. Semin Hematol. 2010;47(2):187–98.
Kelesidis T, Daikos G, Boumpas D, Tsiodras S. Does rituximab increase the incidence of infectious complications? A narrative review. Int J Infect Dis. 2011;15(1):e2-16.
Randall KL. Rituximab in autoimmune diseases. Aust Prescr. 2016;39(4):131–4.
Amber KT, Lamberts A, Solimani F, Agnoletti AF, Didona D, Euverman I, et al. Determining the incidence of pneumocystis pneumonia in patients with autoimmune blistering diseases not receiving routine prophylaxis. JAMA Dermatol. 2017;153(11):1137–41.
Limper AH, Knox KS, Sarosi GA, Ampel NM, Bennett JE, Catanzaro A, et al. An official American Thoracic Society statement: treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med. 2011;183(1):96–128.
Sepkowitz KA. Opportunistic infections in patients with and patients without acquired immunodeficiency syndrome. Clin Infect Dis. 2002;34(8):1098–107.
Zalmanovich A, Ben-Ami R, Rahav G, Alon D, Moses A, Olshtain-Pops K, et al. Rituximab identified as an independent risk factor for severe PJP: a case-control study. PLoS ONE. 2020;15(9):e0239042.
Krstajic D. How real is the random censorship model in medical studies? arXiv. 2017;1703.01237.
Rashid H, Meijer JM, Bolling MC, Horvath B. Clinical response to rituximab and improvement in quality of life in patients with bullous pemphigoid and mucous membrane pemphigoid. Br J Dermatol. 2021. https://doi.org/10.1111/bjd.20881.
Joly P, Roujeau JC, Benichou J, Delaporte E, D’Incan M, Dreno B, et al. A comparison of two regimens of topical corticosteroids in the treatment of patients with bullous pemphigoid: a multicenter randomized study. J Invest Dermatol. 2009;129(7):1681–7.
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No sources of funding were received for the preparation of this article.
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Yung-Tsu Cho and Chia-Yu Chu have received lecture fees from Roche Taiwan Co. Ltd. Yun-Ju Tsai has no conflicts of interest directly relevant to the content of this article.
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The study was approved by the National Taiwan University Hospital Research Ethics Committee (201703053RIND).
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Not applicable. The results presented in the current study do not risk compromising the complete anonymity of patients included.
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The datasets analyzed during the current study are not publicly available because of the regulations of our institute on patient confidentiality and anonymity, but are available from the corresponding author on reasonable request.
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All codes for statistical data analysis were performed with either publicly or commercially available statistical software or modules, including IBM SPSS Statistics 19, GraphPad Prism, and modules in R language.
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All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Yun-Ju Tsai. The first draft of the manuscript was written by Yun-Ju Tsai and all authors contributed to the critical revision and editing on previous versions of the manuscript. All authors read and approved the final manuscript.
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Tsai, YJ., Cho, YT. & Chu, CY. Clinical Effectiveness and Safety of Initial Combination Therapy with Corticosteroids and Rituximab in Bullous Pemphigoid: A Retrospective Cohort Study. Am J Clin Dermatol 23, 571–585 (2022). https://doi.org/10.1007/s40257-022-00688-x
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DOI: https://doi.org/10.1007/s40257-022-00688-x