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Home , Atopic dermatitis, Bullous pemphigoid, Type 2 inflammation

Seidman JS, Eichenfield DZ, Orme CM. Targeting for Treatment of Bullous . J Dermatol & Skin Sci. 2020;2(1):29-33

Mini Review Article Open Access

Targeting Type 2 Inflammation for Treatment of Jason S Seidman1, Dawn Z Eichenfield2, Charisse M Orme2* 1School of Medicine, University of California San Diego, San Diego, California, USA 2Department of , 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 , a monoclonal 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 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 formation in BP involves auto-antibodies directed against proteins BP180 and/or BP230, leading to complement activation, mast

proteolysis at the dermal epidermal junction1,2. First-line treatments forcell BP degranulation, include topical neutrophilic and oral , and with infiltration, steroid sparing and

term management3. Treatment of refractory cases often involves off- immunosuppressivelabel 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.

, achieved satisfactory disease control with dupilumab treatment of atopic (AD), , 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 requires activation by the type 2 IL-5 and does not occur with anti-BP180 or anti-BP230 IgE alone31. leukocytes and secreted proteins, which orchestrate defenseType against 2 inflammation a wide range involves of environmental a 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 . 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 , asthma, and antibody, showed positive results in an open, single arm ADand12 .. 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 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 .16-18. Eosinophils Eosinophil 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 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 21 may 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 significantlya reduction of reducing serum biomarkers surface area for AD, involvement including total and 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 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. IgEtargeting is a hallmark the NC16a of type domain 2 inflammation of BP180 correlate and is present with disease severity26,27. In mouse models, IgE auto-antibodies Patients treated with topical corticosteroids in induce , 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 extracellular trap formation21,30,31. therapy with other systemic medications10. Glucocorticoid

Page 30 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 resistance is a phenomenon that frequently complicates 33, TSLP and neuronal JAKs50. Recently, it has been shown inflammationthat chronic itch include is partly histamine, mediated IL-4 by and the IL-13, actions IL-31, of IL-4 IL- hastreatment also been of observed inflammatory in AD 37 diseases. IL-2, IL-4, such and IL-13 as asthma, evoke 51. This thisrheumatoid phenomenon arthritis, through and inflammatory a variety of mechanisms, bowel disease, which and observation indicates that dupilumab may treat pruritus include altering alternative splicing of the glucocorticoid and IL-13 on IL-4Rα expressed on sensory neurons by directly inhibiting the neuronal sensory pathways that mediatenot only itch.through decreasing type 2 inflammation, but also receptor (GR) to increase the inhibitory GRβ isoform, GR nuclear translocation, and increasing GR degradation Conclusion reducing the affinity of glucocorticoids for GR,37,38 . reducingSince dupilumab inhibits IL-4 and IL-13, it, in turn, may increase The continued expansion of medical knowledge and through posttranslational modifications development of novel targeted therapeutics has led IL-13 mediated glucocorticoid resistance. the efficacy of glucocorticoid therapy by inhibiting IL-4 and interventions based on disease pathogenesis, with genomicsto an increasing data and interestvarious biomarkers in personalizing helping therapeutic to inform in IgE reduction, did not offer improvement in moderate these decisions. Case reports and other descriptive research Interestingly, omalizumab therapy, which also results to severe AD and participants actually developed a slight into off-label usage of biologics provide useful information 39 worsening of itch compared to the control group . We note that helps guide treatment decisions for patients who have that in our reported case, while the patient responded well otherwise exhausted therapeutic options. Furthermore, to dupilumab, his symptoms failed to obtain regression these reports help to generate hypotheses about disease 9. A potential advantage of and controlled clinical trials. This approach is especially with omalizumab treatment intriguingmechanisms in thatdermatology, can be tested where in basic there scientific is an expansive research dupilumab over omalizumab may24. IL-4 be signalingthat blockade is required of IL- set of diseases that individually may have low prevalence for4Rα differentiation represents a moreof TH2 proximal CD4+ T cellspoint and of theirinhibition production in the but share common immunological mechanisms. For BP oftype type 2 inflammatory 2 cytokines pathwayincluding IL-5, IL-13, and eotaxins, isotype class switching to IgE in B cells, and recruitment an important role, further studies can address whether of eosinophils24. Additionally, in atopic diseases, excessive biomarkersand other conditions such as elevated where type serum 2 inflammation IgE and may play regulatory T cells into TH2-40 and TH17-like T cells41. Thus, other therapies targeting this pathway. IL-4Rαdupilumab signaling may impairshelp maintain immune or tolerance re-establish by subverting immune can predict greater beneficial response to dupilumab and Acknowledgements subversion. DE is supported by research grants from the Women’s tolerance by preventing excessive IL-4Rα mediated Dermatologic Society and the Pediatric Dermatology Efficacy of Dupilumab in Other Pruritic Research Alliance. Dermatoses Potential Conflicts of Interest Pruritus is a hallmark feature of BP, and can be the predominant symptom, with some patients never developing classic BP skin lesions2,42. In addition to AD and References BP, dupilumab has shown promising results in other pruritic The authors declare no conflicts of interests. skin conditions, including chronic spontaneous urticaria43, 1. Lo Schiavo A, Ruocco E, Brancaccio G, et al. Bullous pemphigoid: etiology, pathogenesis, and inducing factors: facts and controversies. 44 45 anal and genital itch , allergic , Clin Dermatol. 2013; 31(4): 391-399. nodularis46-48, and other forms of chronic pruritis49. In 2. Schmidt E, Zillikens D. Pemphigoid diseases. 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PhenotypeNapolitano of M, Adult Fabbrocini Atopic Dermatitis. G, Scalvenzi Dermatitis. M, et al. 2020. Effectiveness of Dupilumab for the Treatment of Generalized Prurigo Nodularis

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