生物制剂在大疱性类天疱疮治疗中的应用

doi:10.35541/cjd.20201200

中华皮肤科杂志 ›› 2023, Vol. 56 ›› Issue (8): 789-793.doi: 10.35541/cjd.20201200

生物制剂在大疱性类天疱疮治疗中的应用

周彤耿松梅

西安交通大学第二附属医院皮肤科，西安 710004

收稿日期:2020-12-15 修回日期:2021-08-31 发布日期:2023-08-07
通讯作者: 耿松梅 E-mail:gsm312@yahoo.com

Application of biologic agents in the treatment of bullous pemphigoid

Zhou Tong, Geng Songmei

Department of Dermatology, The Second Affiliated Hospital of Xi′an Jiaotong University, Xi′an 710004, China

Received:2020-12-15 Revised:2021-08-31 Published:2023-08-07
Contact: Geng Songmei E-mail:gsm312@yahoo.com

摘要/Abstract

摘要： 【摘要】近年大疱性类天疱疮（BP）新的治疗靶点不断出现，针对BP的致病性抗体、补体、辅助性T淋巴细胞2（Th2）及Th17轴细胞因子的新型生物制剂也陆续进入临床试验，其中靶向CD20的利妥昔单抗及靶向IgE的奥马珠单抗等已在临床中应用，并使部分难治性BP患者受益。本文综述BP生物制剂治疗策略相关的文献及临床试验，分析并讨论新型生物制剂在BP中的临床应用，为难治性BP的治疗提供新思路。

关键词: 类天疱疮, 大疱性, 生物制剂, 治疗, 临床试验, 利妥昔单抗, 奥马珠单抗

Abstract: 【Abstract】 In recent years, new therapeutic targets for bullous pemphigoid (BP) have continued to emerge, and new biologic agents targeting pathogenic antibodies, complements, T helper type 2 (Th2) and Th17 cytokines in BP have also successively entered clinical trials, e.g., the CD20-targeting antibody rituximab and the IgE-targeting antibody omalizumab have been applied in clinical practice and have benefited some patients with refractory BP. This review summarizes the literature and clinical trials related to biologic agents as the treatment strategy for BP, analyzes and discusses clinical application of new biological agents in BP, in order to provide new ideas for the treatment of refractory BP.

Key words: Pemphigoid, bullous, Biologic agent, Treatment, Clinical trial, Rituximab, Omalizumab

周彤耿松梅. 生物制剂在大疱性类天疱疮治疗中的应用[J]. 中华皮肤科杂志, 2023,56(8):789-793. doi:10.35541/cjd.20201200

Zhou Tong, Geng Songmei. Application of biologic agents in the treatment of bullous pemphigoid[J]. Chinese Journal of Dermatology, 2023, 56(8): 789-793.doi:10.35541/cjd.20201200

参考文献 56

［1］	Heymann WR. Bullous pemphigoid: rituximab to the rescue?［J］. J Am Acad Dermatol, 2020,82（5）:1089⁃1090. doi: 10.1016/j.jaad.2020.02.058.
［2］	Hébert V, Bastos S, Drenovska K, et al. International multicentre observational study to assess the efficacy and safety of a 0.5 mg/kg/day starting dose of oral corticosteroids to treat bullous pemphigoid［J］. Br J Dermatol, 2021,185（6）:1232⁃1239. doi: 10.1111/bjd.20593.
［3］	Lonowski S, Sachsman S, Patel N, et al. Increasing evidence for omalizumab in the treatment of bullous pemphigoid［J］. JAAD Case Rep, 2020,6（3）:228⁃233. doi: 10.1016/j.jdcr.2020.01.002.
［4］	Tie D, Da X, Natsuga K, et al. Bullous pemphigoid IgG induces cell dysfunction and enhances the motility of epidermal keratinocytes via rac1/proteasome activation［J］. Front Immunol, 2019,10:200. doi: 10.3389/fimmu.2019.00200.
［5］	Freire PC, Muñoz CH, Stingl G. IgE autoreactivity in bullous pemphigoid: eosinophils and mast cells as major targets of pathogenic immune reactants［J］. Br J Dermatol, 2017,177（6）:1644⁃1653. doi: 10.1111/bjd.15924.
［6］	Chen DM, Odueyungbo A, Csinady E, et al. Rituximab is an effective treatment in patients with pemphigus vulgaris and demonstrates a steroid⁃sparing effect［J］. Br J Dermatol, 2020,182（5）:1111⁃1119. doi: 10.1111/bjd.18482.
［7］	Szabolcs P, Reese M, Yancey KB, et al. Combination treatment of bullous pemphigoid with anti⁃CD20 and anti⁃CD25 antibodies in a patient with chronic graft⁃versus⁃host disease［J］. Bone Marrow Transplant, 2002,30（5）:327⁃329. doi: 10.1038/sj.bmt. 1703654.
［8］	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［J］. Br J Dermatol, 2015,173（1）:302⁃304. doi: 10.1111/bjd.13633.
［9］	Tovanabutra N, Payne AS. Clinical outcome and safety of rituximab therapy for pemphigoid diseases［J］. J Am Acad Dermatol, 2020,82（5）:1237⁃1239. doi: 10.1016/j.jaad.2019.11. 023.
［10］	Chee R, Nagendran V, Bansal A, et al. B⁃cell targeted therapy alone may not be effective in bullous pemphigoid［J］. Clin Exp Dermatol, 2007,32（1）:111⁃112. doi: 10.1111/j.1365⁃2230.2006. 02267.x.
［11］	Hall RP 3rd, Streilein RD, Hannah DL, et al. Association of serum B⁃cell activating factor level and proportion of memory and transitional B cells with clinical response after rituximab treatment of bullous pemphigoid patients［J］. J Invest Dermatol, 2013,133（12）:2786⁃2788. doi: 10.1038/jid.2013.236.
［12］	Polansky M, Eisenstadt R, DeGrazia T, et al. Rituximab therapy in patients with bullous pemphigoid: a retrospective study of 20 patients［J］. J Am Acad Dermatol, 2019,81（1）:179⁃186. doi: 10.1016/j.jaad.2019.03.049.
［13］	Watson N, Carrozzo M, Hampton P. A retrospective cohort study reporting rituximab treatment for 33 patients with immunobullous disease［J］. J Oral Pathol Med, 2021,50（1）:92⁃97. doi: 10.1111/jop.13123.
［14］	Schmidt E, Seitz CS, Benoit S, et al. Rituximab in autoimmune bullous diseases: mixed responses and adverse effects［J］. Br J Dermatol, 2007,156（2）:352⁃356. doi: 10.1111/j.1365⁃2133.2006. 07646.x.
［15］	Adler BL, Crew AB, Woodley DT. Early⁃onset neutropenia after rituximab therapy for bullous pemphigoid［J］. Clin Exp Dermatol, 2019,44（3）:334⁃336. doi: 10.1111/ced.13726.
［16］	Schmidt E, Hunzelmann N, Zillikens D, et al. Rituximab in refractory autoimmune bullous diseases［J］. Clin Exp Dermatol, 2006,31（4）:503⁃508. doi: 10.1111/j.1365⁃2230.2006.02151.x.
［17］	Maglie R, Antiga E, Quintarelli L, et al. Dramatic exacerbation of bullous pemphigoid following rituximab and successful treatment with omalizumab［J］. Eur J Dermatol, 2019,29（2）:213⁃215. doi: 10.1684/ejd.2019.3499.
［18］	Ahmed AR, Shetty S, Kaveri S, et al. Treatment of recalcitrant bullous pemphigoid （BP） with a novel protocol: a retrospective study with a 6⁃year follow⁃up［J］. J Am Acad Dermatol, 2016,74（4）:700⁃708.e3. doi: 10.1016/j.jaad.2015.11.030.
［19］	Vollono L, Piccolo A, Lanna C, et al. Omalizumab for chronic spontaneous urticaria in "complex" patients: data from real⁃life clinical practice［J］. Drug Des Devel Ther, 2019,13:3181⁃3186. doi: 10.2147/DDDT.S214307.
［20］	Seyed Jafari SM, Gadaldi K, Feldmeyer L, et al. Effects of omalizumab on FcεRI and IgE expression in lesional skin of bullous pemphigoid［J］. Front Immunol, 2019,10:1919. doi: 10.3389/fimmu.2019.01919.
［21］	Fairley JA, Baum CL, Brandt DS, et al. Pathogenicity of IgE in autoimmunity: successful treatment of bullous pemphigoid with omalizumab［J］. J Allergy Clin Immunol, 2009,123（3）:704⁃705. doi: 10.1016/j.jaci.2008.11.035.
［22］	Yu KK, Crew AB, Messingham KA, et al. Omalizumab therapy for bullous pemphigoid［J］. J Am Acad Dermatol, 2014,71（3）:468⁃474. doi: 10.1016/j.jaad.2014.04.053.
［23］	James T, Salman S, Stevenson B, et al. IgE blockade in autoimmunity: omalizumab induced remission of bullous pemphigoid［J］. Clin Immunol, 2019,198:54⁃56. doi: 10.1016/j.clim.2018.12.015.
［24］	Vico⁃Alonso C, Calleja⁃Algarra A, Aragón⁃Miguel R, et al. Omalizumab as an alternative therapeutic tool in the treatment of bullous pemphigoid: a case report［J］. Dermatol Ther, 2019,32（2）:e12829. doi: 10.1111/dth.12829.
［25］	Menzinger S, Kaya G, Schmidt E, et al. Biological and clinical response to omalizumab in a patient with bullous pemphigoid［J］. Acta Derm Venereol, 2018,98（2）:284⁃286. doi: 10.2340/00015555⁃2845.
［26］	Balakirski G, Alkhateeb A, Merk HF, et al. Successful treatment of bullous pemphigoid with omalizumab as corticosteroid⁃sparing agent: report of two cases and review of literature［J］. J Eur Acad Dermatol Venereol, 2016,30（10）:1778⁃1782. doi: 10.1111/jdv. 13758.
［27］	London VA, Kim GH, Fairley JA, et al. Successful treatment of bullous pemphigoid with omalizumab［J］. Arch Dermatol, 2012,148（11）:1241⁃1243. doi: 10.1001/archdermatol.2012.1604.
［28］	Navarro⁃Triviño FJ, Llamas⁃Molina JM, Ayen⁃Rodriguez A, et al. Dramatic improvement of bullous pemphigoid with omalizumab in an elderly patient［J］. Eur J Hosp Pharm, 2021,28（6）:350⁃352. doi: 10.1136/ejhpharm⁃2020⁃002418.
［29］	Sinha S, Agrawal D, Sardana K, et al. Complete remission in a patient with treatment refractory bullous pemphigoid after a single dose of omalizumab［J］. Indian Dermatol Online J, 2020,11（4）:607⁃611. doi: 10.4103/idoj.IDOJ_438_19.
［30］	Garrido PM, Alexandre MI, Travassos AR, et al. Dipeptidyl⁃peptidase IV inhibitor⁃associated bullous pemphigoid efficiently treated with omalizumab［J］. Dermatol Ther, 2020,33（6）:e14160. doi: 10.1111/dth.14160.
［31］	De D, Kaushik A, Handa S, et al. Omalizumab: an underutilized treatment option in bullous pemphigoid patients with co⁃morbidities［J］. J Eur Acad Dermatol Venereol, 2021,35（7）:e469⁃e472. doi: 10.1111/jdv.17229.
［32］	Neumark M, Tal Y, Zlotogorski A, et al. Effective treatment for bullous pemphigoid with omalizumab［J］. Harefuah, 2020,159（1）:29⁃30.
［33］	Ewy S, Pham H, Quan K, et al. Successful omalizumab therapy for bullous pemphigoid despite transient reaction［J］. J Drugs Dermatol, 2019,18（9）:947⁃949.
［34］	Gönül MZ, Keseroglu HO, Ergin C, et al. Bullous pemphigoid successfully treated with omalizumab［J］. Indian J Dermatol Venereol Leprol, 2016,82（5）:577⁃579. doi: 10.4103/0378⁃6323. 183628.
［35］	Bilgiç Temel A, Bassorgun CI, Akman⁃Karakaş A, et al. Successful treatment of a bullous pemphigoid patient with rituximab who was refractory to corticosteroid and omalizumab treatments［J］. Case Rep Dermatol, 2017,9（1）:38⁃44. doi: 10. 1159/000452828.
［36］	Adachi M, Kozawa M, Yoshisue H, et al. Real⁃world safety and efficacy of omalizumab in patients with severe allergic asthma: a long⁃term post⁃marketing study in Japan［J］. Respir Med, 2018,141:56⁃63. doi: 10.1016/j.rmed.2018.06.021.
［37］	Lapeere H, Baeck M, Stockman A, et al. A retrospective analysis omalizumab treatment patterns in patients with chronic spontaneous urticaria: a real⁃world study in Belgium［J］. J Eur Acad Dermatol Venereol, 2020,34（1）:127⁃134. doi: 10.1111/jdv. 15684.
［38］	邱于芳, 钟珊, 王佩茹, 等. 利妥昔单抗联合糖皮质激素治疗难治性大疱性皮肤病临床分析［J］. 临床皮肤科杂志, 2011,40（9）:536⁃539. doi: 10.3969/j.issn.1000⁃4963.2011.09.008.
［39］	敖俊红. 奥马珠单抗成功治疗大疱性类天疱疮［J］. 实用皮肤病学杂志, 2013,6（01）:63.
［40］	Russo R, Cozzani E, Gasparini G, et al. Targeting interleukin 4 receptor α: a new approach to the treatment of cutaneous autoimmune bullous diseases?［J］. Dermatol Ther, 2020,33（1）:e13190. doi: 10.1111/dth.13190.
［41］	Seidman JS, Eichenfield DZ, Orme CM. Dupilumab for bullous pemphigoid with intractable pruritus［J］. Dermatol Online J, 2019,25（11）:13030/qt25q9w6r9.
［42］	Lee JK, Simpson RS. Dupilumab as a novel therapy for difficult to treat chronic spontaneous urticaria［J］. J Allergy Clin Immunol Pract, 2019,7（5）:1659⁃1661.e1. doi: 10.1016/j.jaip.2018.11.018.
［43］	Seyed Jafari SM, Feldmeyer L, Bossart S, et al. Case report: combination of omalizumab and dupilumab for recalcitrant bullous pemphigoid［J］. Front Immunol, 2020,11:611549. doi: 10.3389/fimmu.2020.611549.
［44］	Suzuki M, Yamaguchi Y, Nakamura K, et al. Serum thymus and activation⁃regulated chemokine （TARC/CCL17） may be useful to predict the disease activity in patients with bullous pemphigoid［J］. J Eur Acad Dermatol Venereol, 2021,35（2）:e121⁃e124. doi: 10.1111/jdv.16851.
［45］	Kowalski EH, Kneibner D, Kridin K, et al. Serum and blister fluid levels of cytokines and chemokines in pemphigus and bullous pemphigoid［J］. Autoimmun Rev, 2019,18（5）:526⁃534. doi: 10.1016/j.autrev.2019.03.009.
［46］	Kaye A, Gordon SC, Deverapalli SC, et al. Dupilumab for the treatment of recalcitrant bullous pemphigoid［J］. JAMA Dermatol, 2018,154（10）:1225⁃1226. doi: 10.1001/jamadermatol.2018.2526.
［47］	Abdat R, Waldman RA, de Bedout V, et al. Dupilumab as a novel therapy for bullous pemphigoid: a multicenter case series［J］. J Am Acad Dermatol, 2020,83（1）:46⁃52. doi: 10.1016/j.jaad.2020.01.089.
［48］	Valdebran M, Kowalski EH, Kneiber D, et al. Epidermal expression of eotaxins and thymic stromal lymphopoietin in eosinophil rich dermatoses［J］. Arch Dermatol Res, 2019,311（9）:705⁃710. doi: 10.1007/s00403⁃019⁃01954⁃5.
［49］	Kushner CJ, Payne AS. Increasing the complement of therapeutic options in bullous pemphigoid［J］. J Invest Dermatol, 2018,138（2）:246⁃248. doi: 10.1016/j.jid.2017.09.026.
［50］	Freire PC, Muñoz CH, Derhaschnig U, et al. Specific inhibition of the classical complement pathway prevents C3 deposition along the dermal⁃epidermal junction in bullous pemphigoid［J］. J Invest Dermatol, 2019,139（12）:2417⁃2424.e2. doi: 10.1016/j.jid.2019.04.025.
［51］	Bernstein JA, Singh U, Rao MB, et al. Benralizumab for chronic spontaneous urticaria［J］. N Engl J Med, 2020,383（14）:1389⁃1391. doi: 10.1056/NEJMc2016395.
［52］	Giusti D, Bini E, Terryn C, et al. NET Formation in bullous pemphigoid patients with relapse is modulated by IL⁃17 and IL⁃23 interplay［J］. Front Immunol, 2019,10:701. doi: 10.3389/fimmu.2019.00701.
［53］	Tukaj S, Kleszczyński K, Vafia K, et al. Aberrant expression and secretion of heat shock protein 90 in patients with bullous pemphigoid［J/OL］. PLoS One, 2013,8（7）:e70496［2020⁃11⁃11］. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3728143/. doi: 10.1371/journal.pone.0070496.
［54］	Margaroli C, Bradley B, Thompson C, et al. Distinct compartmentalization of immune cells and mediators characterizes bullous pemphigoid disease［J］. Exp Dermatol, 2020,29（12）:1191⁃1198. doi: 10.1111/exd.14209.
［55］	Hashimoto T, Kursewicz CD, Fayne RA, et al. Pathophysiologic mechanisms of itch in bullous pemphigoid［J］. J Am Acad Dermatol, 2020,83（1）:53⁃62. doi: 10.1016/j.jaad.2019.07.060.
［56］	Kabashima K, Matsumura T, Komazaki H, et al. Trial of nemolizumab and topical agents for atopic dermatitis with pruritus［J］. N Engl J Med, 2020,383（2）:141⁃150. doi: 10.1056/NEJMoa1917006.

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生物制剂在大疱性类天疱疮治疗中的应用

Application of biologic agents in the treatment of bullous pemphigoid

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