Seidman JS, Eichenfield DZ, Orme CM. Targeting Type 2 Inflammation for Treatment of Bullous Pemphigoid. J Dermatol & Skin Sci. 2020;2(1):29-33 Mini Review Article Open Access Targeting Type 2 Inflammation for Treatment of Bullous Pemphigoid Jason S Seidman1, Dawn Z Eichenfield2, Charisse M Orme2* 1School of Medicine, University of California San Diego, San Diego, California, USA 2Department of Dermatology, University of California San Diego, San Diego, California, USA Article Info Abstract Article Notes Bullous pemphigoid (BP) is an autoimmune blistering condition, often Received: April 23, 2020 presenting in elderly individuals with pruritis and tense bullae. While standard Accepted: April 28, 2020 treatment involves steroids, steroid sparing agents, and anti-inflammatory *Correspondence: therapies, clinicians are increasingly utilizing novel biologics off-label for *Dr. Charisse M. Orme, 8899 University Center Lane, Suite refractory cases. We recently reported a case of successful treatment of BP 350, San Diego, California 92122, Tel: 858-657-8322, Email: using dupilumab, a monoclonal interleukin 4 receptor alpha (IL-4Rα) antibody [email protected]. that modulates type 2 inflammation through dual inhibition of IL-4 and IL-13 signaling. Here, we discuss how the reported efficacy of dupilumab and certain ©2020 Orme CM. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License. other biologics in treating BP implicates type 2 inflammation as an important driver of BP pathogenesis. Furthermore, reports of dupilumab successfully Keywords: treating patients with other pruritic dermatologic diseases highlight the Dupilumab importance of type 2 inflammation, particularly through IL-4R signaling, in Bullous pemphigoid chronic pruritis. The rapid development of these biologic therapies presents Pruritus new opportunities for research and treatment of inflammatory dermatologic TH2 Cytokines Type 2 Inflammation disorders. IL-4 IL-13 IL-4Rα Introduction Bullous pemphigoid (BP) is an autoimmune blistering disease that commonly presents in elderly adults with clinical features of tense bullae and pruritis. Subepidermal blister formation in BP involves auto-antibodies directed against hemidesmosome proteins BP180 and/or BP230, leading to complement activation, mast proteolysis at the dermal epidermal junction1,2. First-line treatments forcell BPdegranulation, include topical neutrophilic and oral corticosteroids, and eosinophil with infiltration, steroid sparing and term management3. Treatment of refractory cases often involves off- labelimmunosuppressive use of biologic agentsand anti-inflammatory such as rituximab agents4-6 utilized for long6-8. We recently reported a case of an elderly man with BP and intractable pruritis, who after failing conventional treatments and omalizumaband a trial of 9. omalizumab, achieved satisfactory disease control with dupilumab treatment of atopic dermatitis (AD), asthma, and chronic sinusitis Dupilumab is a human monoclonal IL-4Rα antibody approved for inhibition of IL-4 and IL-13 signaling10. Here, we discuss how with nasal polyposis, which modulates type 2 inflammation through that this pathway may be an important driver of BP pathogenesis. recent reports of biologics targeting type 2 inflammation suggest other chronic pruritic diseases indicate that it may be an especially usefulAdditionally, anti-pruritic numerous agent. reports The increasing of the efficacy development of dupilumab and usage in relevant pathways represents an emerging paradigm in the study of biologic therapies that potently and specifically inhibit disease and treatment of autoimmune and inflammatory diseases. Page 29 of 33 Seidman JS, Eichenfield DZ, Orme CM. Targeting Type 2 Inflammation for Journal of Dermatology and Skin Science Treatment of Bullous Pemphigoid. J Dermatol & Skin Sci. 2020;2(1):29-33 Type 2 Inflammation in Bullous Pemphigoid IgE-mediated DEJ splitting by eosinophils requires activation by the type 2 cytokine IL-5 and does not occur with anti-BP180 or anti-BP230 IgE autoantibodies alone31. leukocytes and secreted proteins, which orchestrate defenseType against2 inflammation a wide range involves of environmentala complex milieu insults, of Efficacy of Anti-Type 2 Inflammation Biologics in including helminths, xenobiotics, and irritants11. The Bullous Pemphigoid principal effectors include TH2 CD4+ T cells and group 2 innate lymphoid cells that produce type 2 cytokines IL-4, axis have shown promise in the treatment of BP. IL-5, and IL-13, B cells that secrete IgE, and granulocytes Multiple biologics that target the type 2 inflammatory such as eosinophils, mast cells, and basophils. The actions of this pathway enable the body to remove offenders by inOmalizumab, 20097. Subsequently, a humanized there monoclonal have been antibody multiple that reports binds eliciting physiologic responses such as mucous production ofIgE, successful was first reportedoff-label touse successfully in cases oftreat refractory refractory BP BP6,8. More recently, bertilumab, an anti-eoxtaxin-1 monoclonal development of atopic disease such as allergy, asthma, and antibody, showed positive results in an open, single arm ADand12 itch.. Overactivity of type 2 inflammation is vital to the phase II clinical trial and has been granted fast track Several lines of evidence point to a prominent type 2 designation for the treatment of BP32 successful treatment of BP with dupilumab was reported in of TH2 cytokines and chemokines, eosinophils, and IgE. 2018. This patient initiated dupilumab therapy. The first after case failing of Increasedinflammatory expression response of in IL-4 BP, which and IL-13 include13,14 important roles two prednisone tapers and positive screening results for homing of IL-4 and IL-13 producing T cells15 have been Mycobacterium tuberculosis and hepatitis B core antibody, and amplified which limited his therapeutic options33. We reported IL-5 and eoxtaxins CCL11 and CCL26 are also found in high a second case representative of a more typical clinical identified in BP skin lesions.16-18. EosinophilsEosinophil chemoattractant themselves are scenario warranting a trial of dupilumab - an elderly man abundant in the lesions and peripheral blood of BP patients who failed numerous conventional treatments and a trial withlevels recent in BP studies blister suggesting fluid that peripheral and lesional eosinophils are directly correlated with disease severity19. trial of dupilumab9. Our patient experienced substantial These observations have sparked interest in eosinophils as of the more widely used omalizumab before initiating a well as the cytokines and chemokines that regulate their with resolution of blisters in the following weeks. Since 20,21 biological functions in BP pathogenesis . Intralesional ourreduction report, in a caseitching series after has the been first published injection demonstrating of dupilumab clinical improvement in 12 out of 13 BP patients treated response by releasing additional cytokines and with dupilumab, with 7 patients achieving complete eosinophils 21may amplify a local type 2 inflammatory chemokines , such as eotaxin and MCP-4, which function disease clearance34. A phase 2/3 clinical trial evaluating the in a positive feedback loop and cause the recruitment of 22 additional eosinophils . Furthermore, eosinophils are an to start in June 2020 (NCT04206553). important source of the pruritogenic cytokine IL-3123, and efficacy and safety of dupilumab in BP is currently planned have also been proposed to promote itch in BP through Dupilumab has been approved for moderate to severe pathways involving substance P, nerve growth factor, cross- inadequately controlled AD, a more widely studied pruritic 10,35 talk with mast cells, and direct interactions with sensory . and autonomic nerves21. In clinical trials, dupilumab has been effective in dermatologic condition involving type 2 inflammation While anti-BP180 and anti-BP230 IgG autoantibodies severity of AD, as well as pruritis10,35. These studies showed are well-established drivers of BP pathogenesis, IgE asignificantly reduction ofreducing serum biomarkers surface area for AD,involvement including totaland antibodies against these epitopes have also been shown to IgE and CCL17. Skin lesions from AD patients treated with 1,2,7,19 play an important role . IgE production depends on IL-4 dupilumab showed reduced expression of TH2 cytokines 12,24 and IL-13 induced B cell class switching . Elevated serum and decreased activation of T cells, dendritic cells, and eosinophils, representative of a gene expression pattern 25 in patients with BP , and increased IgE auto-antibodies more similar to normal skin than affected skin10,35,36. targetingIgE is a hallmark the NC16a of type domain 2 inflammation of BP180 correlateand is present with disease severity26,27. In mouse models, IgE auto-antibodies Patients treated with topical corticosteroids in induce erythema, pruritis, blistering, and eosinophila28,29. combination with dupilumab showed a greater reduction Further studies have shown that eosinophils are necessary in disease severity compared to corticosteroids for anti-BP180 IgE-mediated skin blistering and participate plus placebo10,35. In these studies, patients treated in dermal epidermal junction (DEJ) separation through dupilumab were also able to reduce their usage of topical reactive oxygen species generation, release of eosinophilic corticosteroids and were less likely to require rescue granules, and eosinophil