从特应性皮炎发病机制谈靶向治疗进展

doi:10.35541/cjd.20230054

Abstract

Abstract: 【Abstract】 The pathogenesis of atopic dermatitis is complex, and mainly related to genetic background, environmental stimuli, epidermal barrier defects, immune disorders, and other factors. Using Th2-type inflammatory cytokines and the JAK-STAT pathway as therapeutic targets has become a hotspot in drug development for atopic dermatitis. By now, multiple monoclonal antibodies and small-molecule drugs have been successfully used in the treatment of atopic dermatitis, marking that the treatment of atopic dermatitis has entered the era of precision therapy and targeted therapy.

Key words: Dermatitis, atopic, Molecular targeted therapy, Biological agents, Janus kinases, Pathogenesis, Precision therapy

Song Zhiqiang, Chen Qiquan, Ge Lan. Insights into the progress in targeted therapy of atopic dermatitis from the perspective of its pathogenesis [J]. Chinese Journal of Dermatology, 2023, 56(8): 718-723.doi:10.35541/cjd.20230054

References ［37］

［1］	Laughter MR, Maymone M, Mashayekhi S, et al. The global burden of atopic dermatitis: lessons from the Global Burden of Disease Study 1990-2017［J］. Br J Dermatol, 2021,184（2）:304⁃309. doi: 10.1111/bjd.19580.
［2］	Sacotte R, Silverberg JI. Epidemiology of adult atopic dermatitis［J］. Clin Dermatol, 2018,36（5）:595⁃605. doi: 10.1016/j.clindermatol.2018.05.007.
［3］	Birdi G, Cooke R, Knibb RC. Impact of atopic dermatitis on quality of life in adults: a systematic review and meta⁃analysis［J］. Int J Dermatol, 2020,59（4）:e75⁃e91. doi: 10.1111/ijd.14763.
［4］	Li W, Man XY. Immunotherapy in atopic dermatitis［J］. Immunotherapy, 2022,14（14）:1149⁃1164. doi: 10.2217/imt⁃2022⁃0054.
［5］	Bieber T. Atopic dermatitis: an expanding therapeutic pipeline for a complex disease［J］. Nat Rev Drug Discov, 2022,21（1）:21⁃40. doi: 10.1038/s41573⁃021⁃00266⁃6.
［6］	Gandhi NA, Bennett BL, Graham NM, et al. Targeting key proximal drivers of type 2 inflammation in disease［J］. Nat Rev Drug Discov, 2016,15（1）:35⁃50. doi: 10.1038/nrd4624.
［7］	Awosika O, Kim L, Mazhar M, et al. Profile of dupilumab and its potential in the treatment of inadequately controlled moderate⁃to⁃severe atopic dermatitis［J］. Clin Cosmet Investig Dermatol, 2018,11:41⁃49. doi: 10.2147/CCID.S123329.
［8］	Chovatiya R, Paller AS. JAK inhibitors in the treatment of atopic dermatitis［J］. J Allergy Clin Immunol, 2021,148（4）:927⁃940. doi: 10.1016/j.jaci.2021.08.009.
［9］	Harb H, Chatila TA. Mechanisms of dupilumab［J］. Clin Exp Allergy, 2020,50（1）:5⁃14. doi: 10.1111/cea.13491.
［10］	Simpson EL, Bieber T, Guttman⁃Yassky E, et al. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis［J］. N Engl J Med, 2016,375（24）:2335⁃2348. doi: 10.1056/NEJMoa 1610020.
［11］	Thaçi D, L Simpson E, Deleuran M, et al. Efficacy and safety of dupilumab monotherapy in adults with moderate⁃to⁃severe atopic dermatitis: a pooled analysis of two phase 3 randomized trials （LIBERTY AD SOLO 1 and LIBERTY AD SOLO 2）［J］. J Dermatol Sci, 2019,94（2）:266⁃275. doi: 10.1016/j.jdermsci. 2019.02.002.
［12］	Beck LA, Deleuran M, Bissonnette R, et al. Dupilumab provides acceptable safety and sustained efficacy for up to 4 years in an open⁃label study of adults with moderate⁃to⁃severe atopic dermatitis［J］. Am J Clin Dermatol, 2022,23（3）:393⁃408. doi: 10.1007/s40257⁃022⁃00685⁃0.
［13］	Cork MJ, Thaçi D, Eichenfield LF, et al. Dupilumab provides favourable long⁃term safety and efficacy in children aged ≥ 6 to < 12 years with uncontrolled severe atopic dermatitis: results from an open⁃label phase IIa study and subsequent phaseⅢ open⁃label extension study［J］. Br J Dermatol, 2021,184（5）:857⁃870. doi: 10.1111/bjd.19460.
［14］	Paller AS, Simpson EL, Siegfried EC, et al. Dupilumab in children aged 6 months to younger than 6 years with uncontrolled atopic dermatitis: a randomised, double⁃blind, placebo⁃controlled, phase 3 trial［J］. Lancet, 2022,400（10356）:908⁃919. doi: 10. 1016/S0140⁃6736（22）01539⁃2.
［15］	Jo CE, Finstad A, Georgakopoulos JR, et al. Facial and neck erythema associated with dupilumab treatment: a systematic review［J］. J Am Acad Dermatol, 2021,84（5）:1339⁃1347. doi: 10.1016/j.jaad.2021.01.012.
［16］	Akinlade B, Guttman⁃Yassky E, de Bruin⁃Weller M, et al. Conjunctivitis in dupilumab clinical trials［J］. Br J Dermatol, 2019,181（3）:459⁃473. doi: 10.1111/bjd.17869.
［17］	Papp KA, Hong CH, Lansang MP, et al. Practical management of patients with atopic dermatitis on dupilumab［J］. Dermatol Ther （Heidelb）, 2021,11（5）:1805⁃1828. doi: 10.1007/s13555⁃021⁃00586⁃w.
［18］	Wollenberg A, Blauvelt A, Guttman⁃Yassky E, et al. Tralokinumab for moderate⁃to⁃severe atopic dermatitis: results from two 52⁃week, randomized, double⁃blind, multicentre, placebo⁃controlled phaseⅢ trials （ECZTRA 1 and ECZTRA 2）［J］. Br J Dermatol, 2021,184（3）:437⁃449. doi: 10.1111/bjd. 19574.
［19］	Silverberg JI, Guttman⁃Yassky E, Thaçi D, et al. Two phase 3 trials of lebrikizumab for moderate⁃to⁃severe atopic dermatitis［J］. N Engl J Med, 2023,388（12）:1080⁃1091. doi: 10.1056/NEJMoa2206714.
［20］	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.
［21］	Guttman⁃Yassky E, Brunner PM, Neumann AU, et al. Efficacy and safety of fezakinumab （an IL⁃22 monoclonal antibody） in adults with moderate⁃to⁃severe atopic dermatitis inadequately controlled by conventional treatments: a randomized, double⁃blind, phase 2a trial［J］. J Am Acad Dermatol, 2018,78（5）:872⁃881.e6. doi: 10.1016/j.jaad.2018.01.016.
［22］	Chen YL, Gutowska⁃Owsiak D, Hardman CS, et al. Proof⁃of⁃concept clinical trial of etokimab shows a key role for IL⁃33 in atopic dermatitis pathogenesis［J］. Sci Transl Med, 2019,11（515）:eaax2945. doi: 10.1126/scitranslmed.aax2945.
［23］	Guttman⁃Yassky E, Pavel AB, Zhou L, et al. GBR 830, an anti⁃OX40, improves skin gene signatures and clinical scores in patients with atopic dermatitis［J］. J Allergy Clin Immunol, 2019,144（2）:482⁃493.e7. doi: 10.1016/j.jaci.2018.11.053.
［24］	Bao L, Zhang H, Chan LS. The involvement of the JAK⁃STAT signaling pathway in chronic inflammatory skin disease atopic dermatitis［J］. JAKSTAT, 2013,2（3）:e24137. doi: 10.4161/jkst. 24137.
［25］	Le M, Berman⁃Rosa M, Ghazawi FM, et al. Systematic review on the efficacy and safety of oral janus kinase inhibitors for the treatment of atopic dermatitis［J］. Front Med （Lausanne）, 2021,8:682547. doi: 10.3389/fmed.2021.682547.
［26］	Guttman⁃Yassky E, Teixeira HD, Simpson EL, 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［J］. Lancet, 2021,397（10290）:2151⁃2168. doi: 10.1016/S0140⁃6736（21）00588⁃2.
［27］	Simpson EL, Sinclair R, Forman S, 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［J］. Lancet, 2020,396（10246）:255⁃266. doi: 10.1016/S0140⁃6736（20）30732⁃ 7.
［28］	Ständer S, Bhatia N, Gooderham MJ, et al. High threshold efficacy responses in moderate⁃to⁃severe atopic dermatitis are associated with additional quality of life benefits: pooled analyses of abrocitinib monotherapy studies in adults and adolescents［J］. J Eur Acad Dermatol Venereol, 2022,36（8）:1308⁃1317. doi: 10.1111/jdv.18170.
［29］	Simpson EL, Forman S, Silverberg JI, et al. Baricitinib in patients with moderate⁃to⁃severe atopic dermatitis: results from a randomized monotherapy phase 3 trial in the United States and Canada （BREEZE⁃AD5）［J］. J Am Acad Dermatol, 2021,85（1）:62⁃70. doi: 10.1016/j.jaad.2021.02.028.
［30］	Nakagawa H, Nemoto O, Igarashi A, et al. 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］. J Am Acad Dermatol, 2020,82（4）:823⁃831. doi: 10.1016/j.jaad.2019.12.015.
［31］	Papp K, Szepietowski JC, Kircik L, et al. Efficacy and safety of ruxolitinib cream for the treatment of atopic dermatitis: results from 2 phase 3, randomized, double⁃blind studies［J］. J Am Acad Dermatol, 2021,85（4）:863⁃872. doi: 10.1016/j.jaad.2021. 04.085.
［32］	Paller AS, Tom WL, Lebwohl MG, et al. Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 （PDE4） inhibitor for the topical treatment of atopic dermatitis （AD） in children and adults［J］. J Am Acad Dermatol, 2016,75（3）:494⁃503.e6. doi: 10.1016/j.jaad.2016.05.046.
［33］	Reich K, Thyssen JP, Blauvelt A, et al. Efficacy and safety of abrocitinib versus dupilumab in adults with moderate⁃to⁃severe atopic dermatitis: a randomised, double⁃blind, multicentre phase 3 trial［J］. Lancet, 2022,400（10348）:273⁃282. doi: 10.1016/S0140⁃6736（22）01199⁃0.
［34］	Blauvelt A, Teixeira HD, Simpson EL, et al. Efficacy and safety of upadacitinib vs dupilumab in adults with moderate⁃to⁃severe atopic dermatitis: a randomized clinical trial［J］. JAMA Dermatol, 2021,157（9）:1047⁃1055. doi: 10.1001/jamadermatol.2021.3023.
［35］	Drucker AM, Morra DE, Prieto⁃Merino D, et al. Systemic immunomodulatory treatments for atopic dermatitis: update of a living systematic review and network meta⁃analysis［J］. JAMA Dermatol, 2022,158（5）:523⁃532. doi: 10.1001/jamadermatol.2022. 0455.
［36］	Lin CM, Cooles FA, Isaacs JD. Basic mechanisms of JAK inhibition［J］. Mediterr J Rheumatol, 2020,31（Suppl 1）:100⁃104. doi: 10.31138/mjr.31.1.100.
［37］	Makhoba XH, Viegas C Jr, Mosa RA, et al. Potential impact of the multi⁃target drug approach in the treatment of some complex diseases［J］. Drug Des Devel Ther, 2020,14:3235⁃3249. doi: 10.2147/DDDT.S257494.

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Insights into the progress in targeted therapy of atopic dermatitis from the perspective of its pathogenesis

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