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The Korean Association of Immunobiologists (대한면역학회)
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Immunopathology and Immunotherapy of Inflammatory Skin Diseases

  • Ahreum Song (Department of Dermatology, Gangnam Severance Hospital, Cutaneous Biology Research Institute, Yonsei University College of Medicine) ;
  • Sang Eun Lee (Department of Dermatology, Gangnam Severance Hospital, Cutaneous Biology Research Institute, Yonsei University College of Medicine) ;
  • Jong Hoon Kim (Department of Dermatology, Gangnam Severance Hospital, Cutaneous Biology Research Institute, Yonsei University College of Medicine)
  • Received : 2021.12.24
  • Accepted : 2022.01.23
  • Published : 2022.02.28
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Abstract

Recently, there have been impressive advancements in understanding of the immune mechanisms underlying cutaneous inflammatory diseases. To understand these diseases on a deeper level and clarify the therapeutic targets more precisely, numerous studies including in vitro experiments, animal models, and clinical trials have been conducted. This has resulted in a paradigm shift from non-specific suppression of the immune system to selective, targeted immunotherapies. These approaches target the molecular pathways and cytokines responsible for generating inflammatory conditions and reinforcing feedback mechanisms to aggravate inflammation. Among the numerous types of skin inflammation, psoriasis and atopic dermatitis (AD) are common chronic cutaneous inflammatory diseases. Psoriasis is a IL-17-mediated disease driven by IL-23, while AD is predominantly mediated by Th2 immunity. Autoimmune bullous diseases are autoantibody-mediated blistering disorders, including pemphigus and bullous pemphigoid. Alopecia areata is an organ-specific autoimmune disease mediated by CD8+ T-cells that targets hair follicles. This review will give an updated, comprehensive summary of the pathophysiology and immune mechanisms of inflammatory skin diseases. Moreover, the therapeutic potential of current and upcoming immunotherapies will be discussed.

Keywords

Acknowledgement

This study was supported by the National Research Foundation of South Korea (grant NRF-2021R1C1C1007179). The authors thank Medical Illustration & Design, part of the Medical Research Support Services of Yonsei University College of Medicine, for all artistic support related to this work.

References

  1. Greb JE, Goldminz AM, Elder JT, Lebwohl MG, Gladman DD, Wu JJ, Mehta NN, Finlay AY, Gottlieb AB. Psoriasis. Nat Rev Dis Primers 2016;2:16082.
  2. Alinaghi F, Calov M, Kristensen LE, Gladman DD, Coates LC, Jullien D, Gottlieb AB, Gisondi P, Wu JJ, Thyssen JP, et al. Prevalence of psoriatic arthritis in patients with psoriasis: a systematic review and meta-analysis of observational and clinical studies. J Am Acad Dermatol 2019;80:251-265.e219. https://doi.org/10.1016/j.jaad.2018.06.027
  3. Heydendael VM, Spuls PI, Opmeer BC, de Borgie CA, Reitsma JB, Goldschmidt WF, Bossuyt PM, Bos JD, de Rie MA. Methotrexate versus cyclosporine in moderate-to-severe chronic plaque psoriasis. N Engl J Med 2003;349:658-665. https://doi.org/10.1056/NEJMoa021359
  4. Lee E, Trepicchio WL, Oestreicher JL, Pittman D, Wang F, Chamian F, Dhodapkar M, Krueger JG. Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris. J Exp Med 2004;199:125-130. https://doi.org/10.1084/jem.20030451
  5. Nair RP, Duffin KC, Helms C, Ding J, Stuart PE, Goldgar D, Gudjonsson JE, Li Y, Tejasvi T, Feng BJ, et al. Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways. Nat Genet 2009;41:199-204. https://doi.org/10.1038/ng.311
  6. Ghoreschi K, Balato A, Enerback C, Sabat R. Therapeutics targeting the IL-23 and IL-17 pathway in psoriasis. Lancet 2021;397:754-766. https://doi.org/10.1016/S0140-6736(21)00184-7
  7. Nair RP, Stuart PE, Nistor I, Hiremagalore R, Chia NV, Jenisch S, Weichenthal M, Abecasis GR, Lim HW, Christophers E, et al. Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene. Am J Hum Genet 2006;78:827-851. https://doi.org/10.1086/503821
  8. Arakawa A, Siewert K, Stohr J, Besgen P, Kim SM, Ruhl G, Nickel J, Vollmer S, Thomas P, Krebs S, et al. Melanocyte antigen triggers autoimmunity in human psoriasis. J Exp Med 2015;212:2203-2212. https://doi.org/10.1084/jem.20151093
  9. Lande R, Botti E, Jandus C, Dojcinovic D, Fanelli G, Conrad C, Chamilos G, Feldmeyer L, Marinari B, Chon S, et al. The antimicrobial peptide LL37 is a T-cell autoantigen in psoriasis. Nat Commun 2014;5:5621.
  10. Kim JH, Choi YJ, Lee BH, Song MY, Ban CY, Kim J, Park J, Kim SE, Kim TG, Park SH, et al. Programmed cell death ligand 1 alleviates psoriatic inflammation by suppressing IL-17a production from programmed cell death 1-high T cells. J Allergy Clin Immunol 2016;137:1466-1476.e1463. https://doi.org/10.1016/j.jaci.2015.11.021
  11. Nakamizo S, Dutertre CA, Khalilnezhad A, Zhang XM, Lim S, Lum J, Koh G, Foong C, Yong PJ, Tan KJ, et al. Single-cell analysis of human skin identifies CD14+ type 3 dendritic cells co-producing IL1B and IL23A in psoriasis. J Exp Med 2021;218:218.
  12. Moos S, Mohebiany AN, Waisman A, Kurschus FC. Imiquimod-induced psoriasis in mice depends on the IL-17 signaling of keratinocytes. J Invest Dermatol 2019;139:1110-1117. https://doi.org/10.1016/j.jid.2019.01.006
  13. Kim TG, Jee H, Fuentes-Duculan J, Wu WH, Byamba D, Kim DS, Kim DY, Lew DH, Yang WI, Krueger JG, et al. Dermal clusters of mature dendritic cells and T cells are associated with the CCL20/CCR6 chemokine system in chronic psoriasis. J Invest Dermatol 2014;134:1462-1465. https://doi.org/10.1038/jid.2013.534
  14. Leonardi CL, Powers JL, Matheson RT, Goffe BS, Zitnik R, Wang A, Gottlieb AB; Etanercept Psoriasis Study Group. Etanercept as monotherapy in patients with psoriasis. N Engl J Med 2003;349:2014-2022. https://doi.org/10.1056/NEJMoa030409
  15. Griffiths CE, Strober BE, van de Kerkhof P, Ho V, Fidelus-Gort R, Yeilding N, Guzzo C, Xia Y, Zhou B, Li S, et al. Comparison of ustekinumab and etanercept for moderate-to-severe psoriasis. N Engl J Med 2010;362:118-128. https://doi.org/10.1056/NEJMoa0810652
  16. Gordon KB, Strober B, Lebwohl M, Augustin M, Blauvelt A, Poulin Y, Papp KA, Sofen H, Puig L, Foley P, et al. Efficacy and safety of risankizumab in moderate-to-severe plaque psoriasis (UltIMMa-1 and UltIMMa-2): results from two double-blind, randomised, placebo-controlled and ustekinumab-controlled phase 3 trials. Lancet 2018;392:650-661. https://doi.org/10.1016/S0140-6736(18)31713-6
  17. Diels J, Thilakarathne P, Cameron C, McElligott S, Schubert A, Puig L. Adjusted treatment COMPArisons between guSelkumab and uStekinumab for treatment of moderate-to-severe plaque psoriasis: the COMPASS analysis. Br J Dermatol 2020;183:276-284. https://doi.org/10.1111/bjd.18634
  18. Sbidian E, Chaimani A, Garcia-Doval I, Doney L, Dressler C, Hua C, Hughes C, Naldi L, Afach S, Le Cleach L. Systemic pharmacological treatments for chronic plaque psoriasis: a network meta-analysis. Cochrane Database Syst Rev 2021;4:CD011535.
  19. Thaci D, Blauvelt A, Reich K, Tsai TF, Vanaclocha F, Kingo K, Ziv M, Pinter A, Hugot S, You R, et al. Secukinumab is superior to ustekinumab in clearing skin of subjects with moderate to severe plaque psoriasis: CLEAR, a randomized controlled trial. J Am Acad Dermatol 2015;73:400-409. https://doi.org/10.1016/j.jaad.2015.05.013
  20. Reich K, Pinter A, Lacour JP, Ferrandiz C, Micali G, French LE, Lomaga M, Dutronc Y, Henneges C, Wilhelm S, et al. Comparison of ixekizumab with ustekinumab in moderate-to-severe psoriasis: 24-week results from IXORA-S, a phase III study. Br J Dermatol 2017;177:1014-1023. https://doi.org/10.1111/bjd.15666
  21. Lebwohl M, Strober B, Menter A, Gordon K, Weglowska J, Puig L, Papp K, Spelman L, Toth D, Kerdel F, et al. Phase 3 studies comparing brodalumab with ustekinumab in psoriasis. N Engl J Med 2015;373:1318-1328.  https://doi.org/10.1056/NEJMoa1503824
  22. Reich K, Warren RB, Lebwohl M, Gooderham M, Strober B, Langley RG, Paul C, De Cuyper D, Vanvoorden V, Madden C, et al. Bimekizumab versus secukinumab in plaque psoriasis. N Engl J Med 2021;385:142-152. https://doi.org/10.1056/NEJMoa2102383
  23. Papp K, Gordon K, Thaci D, Morita A, Gooderham M, Foley P, Girgis IG, Kundu S, Banerjee S. Phase 2 trial of selective tyrosine kinase 2 inhibition in psoriasis. N Engl J Med 2018;379:1313-1321. https://doi.org/10.1056/NEJMoa1806382
  24. Forman SB, Pariser DM, Poulin Y, Vincent MS, Gilbert SA, Kieras EM, Qiu R, Yu D, Papacharalambous J, Tehlirian C, et al. Tyk2/JAK1 inhibitor PF-06700841 in patients with plaque psoriasis: phase IIa, randomized, double-blind, placebo-controlled trial. J Invest Dermatol 2020;140:2359-2370.e2355. https://doi.org/10.1016/j.jid.2020.03.962
  25. Murphrey M, Waldman RA, Druso T, Grant-Kels JM. Special editorial: when prescribing Janus kinase inhibitors for dermatologic conditions, be mindful of the fda's 9/1/2021 data safety communication. J Am Acad Dermatol 2022;86:42-43. https://doi.org/10.1016/j.jaad.2021.09.051
  26. Langan SM, Irvine AD, Weidinger S. Atopic dermatitis. Lancet 2020;396:345-360. https://doi.org/10.1016/S0140-6736(20)31286-1
  27. Abuabara K, Hoffstad O, Troxel AB, Gelfand JM, McCulloch CE, Margolis DJ. Patterns and predictors of atopic dermatitis disease control past childhood: an observational cohort study. J Allergy Clin Immunol 2018;141:778-780.e6. https://doi.org/10.1016/j.jaci.2017.05.031
  28. Abuabara K, Yu AM, Okhovat JP, Allen IE, Langan SM. The prevalence of atopic dermatitis beyond childhood: a systematic review and meta-analysis of longitudinal studies. Allergy 2018;73:696-704. https://doi.org/10.1111/all.13320
  29. Sandilands A, Terron-Kwiatkowski A, Hull PR, O'Regan GM, Clayton TH, Watson RM, Carrick T, Evans AT, Liao H, Zhao Y, et al. Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema. Nat Genet 2007;39:650-654. https://doi.org/10.1038/ng2020
  30. Bieber T. Atopic dermatitis: an expanding therapeutic pipeline for a complex disease. Nat Rev Drug Discov 2021;21:21-40. https://doi.org/10.1038/s41573-021-00266-6
  31. Yang L, Fu J, Zhou Y. Research progress in atopic march. Front Immunol 2020;11:1907.
  32. Byrd AL, Belkaid Y, Segre JA. The human skin microbiome. Nat Rev Microbiol 2018;16:143-155. https://doi.org/10.1038/nrmicro.2017.157
  33. Zipperer A, Konnerth MC, Laux C, Berscheid A, Janek D, Weidenmaier C, Burian M, Schilling NA, Slavetinsky C, Marschal M, et al. Human commensals producing a novel antibiotic impair pathogen colonization. Nature 2016;535:511-516. https://doi.org/10.1038/nature18634
  34. Kobayashi T, Glatz M, Horiuchi K, Kawasaki H, Akiyama H, Kaplan DH, Kong HH, Amagai M, Nagao K. Dysbiosis and staphylococcus aureus colonization drives inflammation in atopic dermatitis. Immunity 2015;42:756-766. https://doi.org/10.1016/j.immuni.2015.03.014
  35. Yoshida K, Kubo A, Fujita H, Yokouchi M, Ishii K, Kawasaki H, Nomura T, Shimizu H, Kouyama K, Ebihara T, et al. Distinct behavior of human Langerhans cells and inflammatory dendritic epidermal cells at tight junctions in patients with atopic dermatitis. J Allergy Clin Immunol 2014;134:856-864. https://doi.org/10.1016/j.jaci.2014.08.001
  36. Hammad H, Lambrecht BN. Barrier epithelial cells and the control of type 2 immunity. Immunity 2015;43:29-40. https://doi.org/10.1016/j.immuni.2015.07.007
  37. Gandhi NA, Bennett BL, Graham NM, Pirozzi G, Stahl N, Yancopoulos GD. Targeting key proximal drivers of type 2 inflammation in disease. Nat Rev Drug Discov 2016;15:35-50. https://doi.org/10.1038/nrd4624
  38. Lee SJ, Kim SE, Shin KO, Park K, Lee SE. Dupilumab therapy improves stratum corneum hydration and skin dysbiosis in patients with atopic dermatitis. Allergy Asthma Immunol Res 2021;13:762-775. https://doi.org/10.4168/aair.2021.13.5.762
  39. Jin M, Yoon J. From bench to clinic: the potential of therapeutic targeting of the il-22 signaling pathway in atopic dermatitis. Immune Netw 2018;18:e42.
  40. Oetjen LK, Mack MR, Feng J, Whelan TM, Niu H, Guo CJ, Chen S, Trier AM, Xu AZ, Tripathi SV, et al. Sensory neurons co-opt classical immune signaling pathways to mediate chronic itch. Cell 2017;171:217-228.e13. https://doi.org/10.1016/j.cell.2017.08.006
  41. Trier AM, Mack MR, Fredman A, Tamari M, Ver Heul AM, Zhao Y, Guo CJ, Avraham O, Ford ZK, Oetjen LK, et al. IL-33 signaling in sensory neurons promotes dry skin itch. J Allergy Clin Immunol 2021. doi: 10.1016/j.jaci.2021.09.014.
  42. Simon D, Braathen LR, Simon HU. Eosinophils and atopic dermatitis. Allergy 2004;59:561-570. https://doi.org/10.1111/j.1398-9995.2004.00476.x
  43. Wang F, Trier AM, Li F, Kim S, Chen Z, Chai JN, Mack MR, Morrison SA, Hamilton JD, Baek J, et al. A basophil-neuronal axis promotes itch. Cell 2021;184:422-440.e17. https://doi.org/10.1016/j.cell.2020.12.033
  44. Lee JH, Kim JE, Park GH, Bae JM, Byun JY, Shin MK, Han TY, Hong SP, Jang YH, Kim HO, et al. Consensus update for systemic treatment of atopic dermatitis. Ann Dermatol 2021;33:497-514. https://doi.org/10.5021/ad.2021.33.6.497
  45. Simpson EL, Bieber T, Guttman-Yassky E, Beck LA, Blauvelt A, Cork MJ, Silverberg JI, Deleuran M, Kataoka Y, Lacour JP, et al. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med 2016;375:2335-2348. https://doi.org/10.1056/NEJMoa1610020
  46. Gooderham MJ, Hong HC, Eshtiaghi P, Papp KA. Dupilumab: a review of its use in the treatment of atopic dermatitis. J Am Acad Dermatol 2018;78 Suppl 1:S28-S36. https://doi.org/10.1016/j.jaad.2017.12.022
  47. Beck LA, Thaci D, Hamilton JD, Graham NM, Bieber T, Rocklin R, Ming JE, Ren H, Kao R, Simpson E, et al. Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. N Engl J Med 2014;371:130-139. https://doi.org/10.1056/NEJMoa1314768
  48. Schneeweiss MC, Kim SC, Wyss R, Schneeweiss S, Merola JF. Dupilumab and the risk of conjunctivitis and serious infection in patients with atopic dermatitis: a propensity score-matched cohort study. J Am Acad Dermatol 2021;84:300-311. https://doi.org/10.1016/j.jaad.2020.09.084
  49. Wollenberg A, Blauvelt A, Guttman-Yassky E, Worm M, Lynde C, Lacour JP, Spelman L, Katoh N, Saeki H, Poulin Y, et al. Tralokinumab for moderate-to-severe atopic dermatitis: results from two 52-week, randomized, double-blind, multicentre, placebo-controlled phase III trials (ECZTRA 1 and ECZTRA 2). Br J Dermatol 2021;184:437-449. https://doi.org/10.1111/bjd.19574
  50. Reich K, Teixeira HD, de Bruin-Weller M, Bieber T, Soong W, Kabashima K, Werfel T, Zeng J, Huang X, Hu X, et al. Safety and efficacy of upadacitinib in combination with topical corticosteroids in adolescents and adults with moderate-to-severe atopic dermatitis (AD Up): results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2021;397:2169-2181. https://doi.org/10.1016/S0140-6736(21)00589-4
  51. Guttman-Yassky E, Teixeira HD, Simpson EL, Papp KA, Pangan AL, Blauvelt A, Thaci D, Chu CY, Hong HC, Katoh N, et al. Once-daily upadacitinib versus placebo in adolescents and adults with moderate-to-severe atopic dermatitis (Measure Up 1 and Measure Up 2): results from two replicate double-blind, randomised controlled phase 3 trials. Lancet 2021;397:2151-2168. https://doi.org/10.1016/S0140-6736(21)00588-2
  52. Blauvelt A, Teixeira HD, Simpson EL, Costanzo A, De Bruin-Weller M, Barbarot S, Prajapati VH, Lio P, Hu X, Wu T, et al. Efficacy and safety of upadacitinib vs dupilumab in adults with moderate-to-severe atopic dermatitis: a randomized clinical trial. JAMA Dermatol 2021;157:1047-1055. https://doi.org/10.1001/jamadermatol.2021.3023
  53. Simpson EL, Lacour JP, Spelman L, Galimberti R, Eichenfield LF, Bissonnette R, King BA, Thyssen JP, Silverberg JI, Bieber T, et al. Baricitinib in patients with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids: results from two randomized monotherapy phase III trials. Br J Dermatol 2020;183:242-255. https://doi.org/10.1111/bjd.18898
  54. Papp K, Szepietowski JC, Kircik L, Toth D, Eichenfield LF, Leung DY, Forman SB, Venturanza ME, Sun K, Kuligowski ME, et al. Efficacy and safety of ruxolitinib cream for the treatment of atopic dermatitis: results from 2 phase 3, randomized, double-blind studies. J Am Acad Dermatol 2021;85:863-872. https://doi.org/10.1016/j.jaad.2021.04.085
  55. Nakagawa H, Nemoto O, Igarashi A, Saeki H, Kaino H, Nagata T. Delgocitinib ointment, a topical Janus kinase inhibitor, in adult patients with moderate to severe atopic dermatitis: a phase 3, randomized, double-blind, vehicle-controlled study and an open-label, long-term extension study. J Am Acad Dermatol 2020;82:823-831. https://doi.org/10.1016/j.jaad.2019.12.015
  56. Kabashima K, Matsumura T, Komazaki H, Kawashima M; Nemolizumab-JP01 Study Group. Trial of nemolizumab and topical agents for atopic dermatitis with pruritus. N Engl J Med 2020;383:141-150. https://doi.org/10.1056/NEJMoa1917006
  57. Simpson EL, Sinclair R, Forman S, Wollenberg A, Aschoff R, Cork M, Bieber T, Thyssen JP, Yosipovitch G, Flohr C, et al. Efficacy and safety of abrocitinib in adults and adolescents with moderate-to-severe atopic dermatitis (JADE MONO-1): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet 2020;396:255-266. https://doi.org/10.1016/S0140-6736(20)30732-7
  58. Amagai M, Klaus-Kovtun V, Stanley JR. Autoantibodies against a novel epithelial cadherin in pemphigus vulgaris, a disease of cell adhesion. Cell 1991;67:869-877. https://doi.org/10.1016/0092-8674(91)90360-B
  59. Mahoney MG, Wang Z, Rothenberger K, Koch PJ, Amagai M, Stanley JR. Explanations for the clinical and microscopic localization of lesions in pemphigus foliaceus and vulgaris. J Clin Invest 1999;103:461-468. https://doi.org/10.1172/JCI5252
  60. Samuelov L, Sarig O, Harmon RM, Rapaport D, Ishida-Yamamoto A, Isakov O, Koetsier JL, Gat A, Goldberg I, Bergman R, et al. Desmoglein 1 deficiency results in severe dermatitis, multiple allergies and metabolic wasting. Nat Genet 2013;45:1244-1248. https://doi.org/10.1038/ng.2739
  61. Kim JH, Kim SE, Park HS, Lee SH, Lee SE, Kim SC. A homozygous nonsense mutation in the dsg3 gene causes acantholytic blisters in the oral and laryngeal mucosa. J Invest Dermatol 2019;139:1187-1190. https://doi.org/10.1016/j.jid.2018.09.038
  62. Amagai M, Komai A, Hashimoto T, Shirakata Y, Hashimoto K, Yamada T, Kitajima Y, Ohya K, Iwanami H, Nishikawa T. Usefulness of enzyme-linked immunosorbent assay using recombinant desmogleins 1 and 3 for serodiagnosis of pemphigus. Br J Dermatol 1999;140:351-357. https://doi.org/10.1046/j.1365-2133.1999.02752.x
  63. Payne AS, Ishii K, Kacir S, Lin C, Li H, Hanakawa Y, Tsunoda K, Amagai M, Stanley JR, Siegel DL. Genetic and functional characterization of human pemphigus vulgaris monoclonal autoantibodies isolated by phage display. J Clin Invest 2005;115:888-899. https://doi.org/10.1172/JCI24185
  64. Kasperkiewicz M, Ellebrecht CT, Takahashi H, Yamagami J, Zillikens D, Payne AS, Amagai M. Pemphigus. Nat Rev Dis Primers 2017;3:17026.
  65. Cho A, Caldara AL, Ran NA, Menne Z, Kauffman RC, Affer M, Llovet A, Norwood C, Scanlan A, Mantus G, et al. Single-cell analysis suggests that ongoing affinity maturation drives the emergence of pemphigus vulgaris autoimmune disease. Cell Rep 2019;28:909-922.e906. https://doi.org/10.1016/j.celrep.2019.06.066
  66. Cho MJ, Lo AS, Mao X, Nagler AR, Ellebrecht CT, Mukherjee EM, Hammers CM, Choi EJ, Sharma PM, Uduman M, et al. Shared VH1-46 gene usage by pemphigus vulgaris autoantibodies indicates common humoral immune responses among patients. Nat Commun 2014;5:4167.
  67. Kim AR, Han D, Choi JY, Seok J, Kim SE, Seo SH, Takahashi H, Amagai M, Park SH, Kim SC, et al. Targeting inducible costimulator expressed on cxcr5(+)pd-1(+) th cells suppresses the progression of pemphigus vulgaris. J Allergy Clin Immunol 2020;146:1070-1079.e1078.  https://doi.org/10.1016/j.jaci.2020.03.036
  68. Holstein J, Solimani F, Baum C, Meier K, Pollmann R, Didona D, Tekath T, Dugas M, Casadei N, Hudemann C, et al. Immunophenotyping in pemphigus reveals a TH17/TFH17 cell-dominated immune response promoting desmoglein1/3-specific autoantibody production. J Allergy Clin Immunol 2021;147:2358-2369. https://doi.org/10.1016/j.jaci.2020.11.008
  69. Kim MR, Kim HC, Kim SC. Long-term prognosis of pemphigus in Korea: retrospective analysis of 199 patients. Dermatology 2011;223:182-188. https://doi.org/10.1159/000332848
  70. Amagai M, Ikeda S, Shimizu H, Iizuka H, Hanada K, Aiba S, Kaneko F, Izaki S, Tamaki K, Ikezawa Z, et al. A randomized double-blind trial of intravenous immunoglobulin for pemphigus. J Am Acad Dermatol 2009;60:595-603. https://doi.org/10.1016/j.jaad.2008.09.052
  71. Joly P, Mouquet H, Roujeau JC, D'Incan M, Gilbert D, Jacquot S, Gougeon ML, Bedane C, Muller R, Dreno B, et al. A single cycle of rituximab for the treatment of severe pemphigus. N Engl J Med 2007;357:545-552. https://doi.org/10.1056/NEJMoa067752
  72. Kim JH, Kim YH, Kim MR, Kim SC. Clinical efficacy of different doses of rituximab in the treatment of pemphigus: a retrospective study of 27 patients. Br J Dermatol 2011;165:646-651. https://doi.org/10.1111/j.1365-2133.2011.10411.x
  73. Werth VP, Joly P, Mimouni D, Maverakis E, Caux F, Lehane P, Gearhart L, Kapre A, Pordeli P, Chen DM, et al. Rituximab versus mycophenolate mofetil in patients with pemphigus vulgaris. N Engl J Med 2021;384:2295-2305. https://doi.org/10.1056/NEJMoa2028564
  74. Wang HH, Liu CW, Li YC, Huang YC. Efficacy of rituximab for pemphigus: a systematic review and meta-analysis of different regimens. Acta Derm Venereol 2015;95:928-932. https://doi.org/10.2340/00015555-2116
  75. Joly P, Maho-Vaillant M, Prost-Squarcioni C, Hebert V, Houivet E, Calbo S, Caillot F, Golinski ML, Labeille B, Picard-Dahan C, et al. First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux 3): a prospective, multicentre, parallel-group, open-label randomised trial. Lancet 2017;389:2031-2040. https://doi.org/10.1016/S0140-6736(17)30070-3
  76. Schmidt E, Kasperkiewicz M, Joly P. Pemphigus. Lancet 2019;394:882-894. https://doi.org/10.1016/S0140-6736(19)31778-7
  77. Ellebrecht CT, Bhoj VG, Nace A, Choi EJ, Mao X, Cho MJ, Di Zenzo G, Lanzavecchia A, Seykora JT, Cotsarelis G, et al. Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease. Science 2016;353:179-184. https://doi.org/10.1126/science.aaf6756
  78. Lee J, Lundgren DK, Mao X, Manfredo-Vieira S, Nunez-Cruz S, Williams EF, Assenmacher CA, Radaelli E, Oh S, Wang B, et al. Antigen-specific B cell depletion for precision therapy of mucosal pemphigus vulgaris. J Clin Invest 2020;130:6317-6324. https://doi.org/10.1172/JCI138416
  79. Murrell DF, Patsatsi A, Stavropoulos P, Baum S, Zeeli T, Kern JS, Roussaki-Schulze AV, Sinclair R, Bassukas ID, Thomas D, et al. Proof of concept for the clinical effects of oral rilzabrutinib, the first Bruton tyrosine kinase inhibitor for pemphigus vulgaris: the phase II BELIEVE study. Br J Dermatol 2021;185:745-755. https://doi.org/10.1111/bjd.20431
  80. Yamagami J, Ujiie H, Aoyama Y, Ishii N, Tateishi C, Ishiko A, Ichijima T, Hagihara S, Hashimoto K, Amagai M. A multicenter, open-label, uncontrolled, single-arm phase 2 study of tirabrutinib, an oral Bruton's tyrosine kinase inhibitor, in pemphigus. J Dermatol Sci 2021;103:135-142. https://doi.org/10.1016/j.jdermsci.2021.07.002
  81. Goebeler M, Bata-Csorgo Z, De Simone C, Didona B, Remenyik E, Reznichenko N, Stoevesandt J, Ward ES, Parys W, de Haard H, 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 2021. doi: 10.1111/bjd.20782.
  82. Werth VP, Culton DA, Concha JS, Graydon JS, Blumberg LJ, Okawa J, Pyzik M, Blumberg RS, Hall RP 3rd. Safety, tolerability, and activity of alxn1830 targeting the neonatal fc receptor in chronic pemphigus. J Invest Dermatol 2021;141:2858-2865.e4. https://doi.org/10.1016/j.jid.2021.04.031
  83. Lee H, Chung HJ, Pawar A, Patorno E, Kim DH. Evaluation of risk of bullous pemphigoid with initiation of dipeptidyl peptidase-4 inhibitor vs second-generation sulfonylurea. JAMA Dermatol 2020;156:1107-1114. https://doi.org/10.1001/jamadermatol.2020.2158
  84. Wongvibulsin S, Pahalyants V, Kalinich M, Murphy W, Yu KH, Wang F, Chen ST, Reynolds K, Kwatra SG, Semenov YR. Epidemiology and risk factors for the development of cutaneous toxicities in patients treated with immune-checkpoint inhibitors: a United States population-level analysis. J Am Acad Dermatol 2021. doi: 10.1016/j.jaad.2021.03.094. 
  85. Lai YC, Yew YW, Lambert WC. Bullous pemphigoid and its association with neurological diseases: a systematic review and meta-analysis. J Eur Acad Dermatol Venereol 2016;30:2007-2015. https://doi.org/10.1111/jdv.13660
  86. Tedbirt B, Gillibert A, Andrieu E, Hebert V, Bastos S, Korman NJ, Tang MB, Li J, Borradori L, Cortes B, et al. Mixed individual-aggregate data on all-cause mortality in bullous pemphigoid: a meta-analysis. JAMA Dermatol 2021;157:421-430. https://doi.org/10.1001/jamadermatol.2020.5598
  87. Kobayashi M, Amagai M, Kuroda-Kinoshita K, Hashimoto T, Shirakata Y, Hashimoto K, Nishikawa T. BP180 ELISA using bacterial recombinant NC16a protein as a diagnostic and monitoring tool for bullous pemphigoid. J Dermatol Sci 2002;30:224-232. https://doi.org/10.1016/S0923-1811(02)00109-3
  88. van Beek N, Luttmann N, Huebner F, Recke A, Karl I, Schulze FS, Zillikens D, Schmidt E. Correlation of serum levels of IgE autoantibodies against BP180 with bullous pemphigoid disease activity. JAMA Dermatol 2017;153:30-38. https://doi.org/10.1001/jamadermatol.2016.3357
  89. Nishie W, Sawamura D, Goto M, Ito K, Shibaki A, McMillan JR, Sakai K, Nakamura H, Olasz E, Yancey KB, et al. Humanization of autoantigen. Nat Med 2007;13:378-383. https://doi.org/10.1038/nm1496
  90. Fairley JA, Burnett CT, Fu CL, Larson DL, Fleming MG, Giudice GJ. A pathogenic role for IgE in autoimmunity: bullous pemphigoid IgE reproduces the early phase of lesion development in human skin grafted to nu/nu mice. J Invest Dermatol 2007;127:2605-2611. https://doi.org/10.1038/sj.jid.5700958
  91. Nelson KC, Zhao M, Schroeder PR, Li N, Wetsel RA, Diaz LA, Liu Z. Role of different pathways of the complement cascade in experimental bullous pemphigoid. J Clin Invest 2006;116:2892-2900. https://doi.org/10.1172/JCI17891
  92. Leyendeckers H, Tasanen K, Bruckner-Tuderman L, Zillikens D, Sitaru C, Schmitz J, Hunzelmann N. Memory B cells specific for the NC16A domain of the 180 kDa bullous pemphigoid autoantigen can be detected in peripheral blood of bullous pemphigoid patients and induced in vitro to synthesize autoantibodies. J Invest Dermatol 2003;120:372-378. https://doi.org/10.1046/j.1523-1747.2003.12071.x
  93. Liu Z, Dang E, Li B, Qiao H, Jin L, Zhang J, Wang G. Dysfunction of CD19+CD24hiCD27+ B regulatory cells in patients with bullous pemphigoid. Sci Rep 2018;8:703.
  94. Muramatsu K, Ujiie H, Kobayashi I, Nishie W, Izumi K, Ito T, Yoshimoto N, Natsuga K, Iwata H, Shimizu H. Regulatory t-cell dysfunction induces autoantibodies to bullous pemphigoid antigens in mice and human subjects. J Allergy Clin Immunol 2018;142:1818-1830.e1816. https://doi.org/10.1016/j.jaci.2018.03.014
  95. Haeberle S, Wei X, Bieber K, Goletz S, Ludwig RJ, Schmidt E, Enk AH, Hadaschik EN. Regulatory t-cell deficiency leads to pathogenic bullous pemphigoid antigen 230 autoantibody and autoimmune bullous disease. J Allergy Clin Immunol 2018;142:1831-1842.e1837. https://doi.org/10.1016/j.jaci.2018.04.006
  96. McGinness JL, Bivens MM, Greer KE, Patterson JW, Saulsbury FT. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) associated with pemphigoid nodularis: a case report and review of the literature. J Am Acad Dermatol 2006;55:143-148. https://doi.org/10.1016/j.jaad.2005.08.047
  97. Joly P, Roujeau JC, Benichou J, Picard C, Dreno B, Delaporte E, Vaillant L, D'Incan M, Plantin P, Bedane C, et al. A comparison of oral and topical corticosteroids in patients with bullous pemphigoid. N Engl J Med 2002;346:321-327. https://doi.org/10.1056/NEJMoa011592
  98. Feliciani C, Joly P, Jonkman MF, Zambruno G, Zillikens D, Ioannides D, Kowalewski C, Jedlickova H, Karpati S, Marinovic B, 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;172:867-877. https://doi.org/10.1111/bjd.13717
  99. Williams HC, Wojnarowska F, Kirtschig G, Mason J, Godec TR, Schmidt E, Chalmers JR, Childs M, Walton S, Harman K, et al. Doxycycline versus prednisolone as an initial treatment strategy for bullous pemphigoid: a pragmatic, non-inferiority, randomised controlled trial. Lancet 2017;389:1630-1638. https://doi.org/10.1016/S0140-6736(17)30560-3
  100. Sticherling M, Franke A, Aberer E, Glaser R, Hertl M, Pfeiffer C, Rzany B, Schneider S, Shimanovich I, Werfel T, et al. An open, multicentre, randomized clinical study in patients with bullous pemphigoid comparing methylprednisolone and azathioprine with methylprednisolone and dapsone. Br J Dermatol 2017;177:1299-1305.  https://doi.org/10.1111/bjd.15649
  101. Park CS, Kim SH, Lee CK. Immunotherapy of autoimmune diseases with nonantibiotic properties of tetracyclines. Immune Netw 2020;20:e47.
  102. Yoo DS, Lee JH, Kim SC, Kim JH. Mortality and clinical response of patients with bullous pemphigoid treated with rituximab. Br J Dermatol 2021;185:210-212. https://doi.org/10.1111/bjd.19890
  103. Amagai M, Ikeda S, Hashimoto T, Mizuashi M, Fujisawa A, Ihn H, Matsuzaki Y, Ohtsuka M, Fujiwara H, Furuta J, et al. A randomized double-blind trial of intravenous immunoglobulin for bullous pemphigoid. J Dermatol Sci 2017;85:77-84. https://doi.org/10.1016/j.jdermsci.2016.11.003
  104. De D, Kaushik A, Handa S, Mahajan R, Schmidt E. Omalizumab: an underutilized treatment option in bullous pemphigoid patients with co-morbidities. J Eur Acad Dermatol Venereol 2021;35:e469-e472. https://doi.org/10.1111/jdv.17229
  105. Freire PC, Munoz CH, Derhaschnig U, Schoergenhofer C, Firbas C, Parry GC, Panicker S, Gilbert JC, Stingl G, Jilma B, et al. Specific inhibition of the classical complement pathway prevents c3 deposition along the dermal-epidermal junction in bullous pemphigoid. J Invest Dermatol 2019;139:2417-2424.e2412. https://doi.org/10.1016/j.jid.2019.04.025
  106. Mirzoyev SA, Schrum AG, Davis MD, Torgerson RR. Lifetime incidence risk of alopecia areata estimated at 2.1% by Rochester Epidemiology Project, 1990-2009. J Invest Dermatol 2014;134:1141-1142. https://doi.org/10.1038/jid.2013.464
  107. Trueb RM, Dias MF. Alopecia areata: a comprehensive review of pathogenesis and management. Clin Rev Allergy Immunol 2018;54:68-87. https://doi.org/10.1007/s12016-017-8620-9
  108. Martinez-Mir A, Zlotogorski A, Gordon D, Petukhova L, Mo J, Gilliam TC, Londono D, Haynes C, Ott J, Hordinsky M, et al. Genomewide scan for linkage reveals evidence of several susceptibility loci for alopecia areata. Am J Hum Genet 2007;80:316-328. https://doi.org/10.1086/511442
  109. Eckert J, Church RE, Ebling FJ. The pathogenesis of alopecia areata. Br J Dermatol 1968;80:203-210. https://doi.org/10.1111/j.1365-2133.1968.tb11960.x
  110. Whiting DA. Histopathologic features of alopecia areata: a new look. Arch Dermatol 2003;139:1555-1559. https://doi.org/10.1001/archderm.139.12.1555
  111. Paus R, Ito N, Takigawa M, Ito T. The hair follicle and immune privilege. J Investig Dermatol Symp Proc 2003;8:188-194. https://doi.org/10.1046/j.1087-0024.2003.00807.x
  112. Bodemer C, Peuchmaur M, Fraitaig S, Chatenoud L, Brousse N, De Prost Y. Role of cytotoxic T cells in chronic alopecia areata. J Invest Dermatol 2000;114:112-116. https://doi.org/10.1046/j.1523-1747.2000.00828.x
  113. Gilhar A, Laufer-Britva R, Keren A, Paus R. Frontiers in alopecia areata pathobiology research. J Allergy Clin Immunol 2019;144:1478-1489. https://doi.org/10.1016/j.jaci.2019.08.035
  114. Petukhova L, Duvic M, Hordinsky M, Norris D, Price V, Shimomura Y, Kim H, Singh P, Lee A, Chen WV, et al. Genome-wide association study in alopecia areata implicates both innate and adaptive immunity. Nature 2010;466:113-117. https://doi.org/10.1038/nature09114
  115. Xing L, Dai Z, Jabbari A, Cerise JE, Higgins CA, Gong W, de Jong A, Harel S, DeStefano GM, Rothman L, et al. Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nat Med 2014;20:1043-1049. https://doi.org/10.1038/nm.3645
  116. Ito T, Ito N, Saatoff M, Hashizume H, Fukamizu H, Nickoloff BJ, Takigawa M, Paus R. Maintenance of hair follicle immune privilege is linked to prevention of NK cell attack. J Invest Dermatol 2008;128:1196-1206. https://doi.org/10.1038/sj.jid.5701183
  117. Borcherding N, Crotts SB, Ortolan LS, Henderson N, Bormann NL, Jabbari A. A transcriptomic map of murine and human alopecia areata. JCI Insight 2020;5:e137424.
  118. Lee H, Jeong S, Shin EC. Significance of bystander t cell activation in microbial infection. Nat Immunol 2021. doi: 10.1038/s41590-021-00985-3.
  119. Freyschmidt-Paul P, McElwee KJ, Hoffmann R, Sundberg JP, Vitacolonna M, Kissling S, Zoller M. Interferon-gamma-deficient mice are resistant to the development of alopecia areata. Br J Dermatol 2006;155:515-521. https://doi.org/10.1111/j.1365-2133.2006.07377.x
  120. Rajabi F, Drake LA, Senna MM, Rezaei N. Alopecia areata: a review of disease pathogenesis. Br J Dermatol 2018;179:1033-1048. https://doi.org/10.1111/bjd.16808
  121. Alkhalifah A, Alsantali A, Wang E, McElwee KJ, Shapiro J. Alopecia areata update: part II. Treatment. J Am Acad Dermatol 2010;62:191-202. https://doi.org/10.1016/j.jaad.2009.10.031
  122. Kim BJ, Min SU, Park KY, Choi JW, Park SW, Youn SW, Park KC, Huh CH. Combination therapy of cyclosporine and methylprednisolone on severe alopecia areata. J Dermatolog Treat 2008;19:216-220. https://doi.org/10.1080/09546630701846095
  123. Joly P. The use of methotrexate alone or in combination with low doses of oral corticosteroids in the treatment of alopecia totalis or universalis. J Am Acad Dermatol 2006;55:632-636. https://doi.org/10.1016/j.jaad.2005.09.010
  124. Gordon PM, Aldrige RD, McVittie E, Hunter JA. Topical diphencyprone for alopecia areata: evaluation of 48 cases after 30 months' follow-up. Br J Dermatol 1996;134:869-871. https://doi.org/10.1046/j.1365-2133.1996.119854.x
  125. Uchiyama M, Egusa C, Hobo A, Irisawa R, Yamazaki M, Tsuboi R. Multivariate analysis of prognostic factors in patients with rapidly progressive alopecia areata. J Am Acad Dermatol 2012;67:1163-1173. https://doi.org/10.1016/j.jaad.2012.06.006
  126. Wang EH, Sallee BN, Tejeda CI, Christiano AM. Jak inhibitors for treatment of alopecia areata. J Invest Dermatol 2018;138:1911-1916. https://doi.org/10.1016/j.jid.2018.05.027
  127. Leonard WJ, Lin JX. Cytokine receptor signaling pathways. J Allergy Clin Immunol 2000;105:877-888. https://doi.org/10.1067/mai.2000.106899
  128. Schwartz DM, Kanno Y, Villarino A, Ward M, Gadina M, O'Shea JJ. JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat Rev Drug Discov 2017;17:78.
  129. Liu LY, Craiglow BG, Dai F, King BA. Tofacitinib for the treatment of severe alopecia areata and variants: a study of 90 patients. J Am Acad Dermatol 2017;76:22-28. https://doi.org/10.1016/j.jaad.2016.09.007
  130. Almutairi N, Nour TM, Hussain NH. Janus kinase inhibitors for the treatment of severe alopecia areata: An open-label comparative study. Dermatology 2019;235:130-136. https://doi.org/10.1159/000494613
  131. King B, Ko J, Forman S, Ohyama M, Mesinkovska N, Yu G, McCollam J, Gamalo M, Janes J, Edson-Heredia E, et al. Efficacy and safety of the oral Janus kinase inhibitor baricitinib in the treatment of adults with alopecia areata: Phase 2 results from a randomized controlled study. J Am Acad Dermatol 2021;85:847-853. https://doi.org/10.1016/j.jaad.2021.05.050
  132. King B, Guttman-Yassky E, Peeva E, Banerjee A, Sinclair R, Pavel AB, Zhu L, Cox LA, Craiglow B, Chen L, et al. A phase 2a randomized, placebo-controlled study to evaluate the efficacy and safety of the oral Janus kinase inhibitors ritlecitinib and brepocitinib in alopecia areata: 24-week results. J Am Acad Dermatol 2021;85:379-387. https://doi.org/10.1016/j.jaad.2021.03.050