دورية أكاديمية
Effect of abrocitinib on skin biomarkers in patients with moderate-to-severe atopic dermatitis.
| العنوان: | Effect of abrocitinib on skin biomarkers in patients with moderate-to-severe atopic dermatitis. |
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| المؤلفون: | Guttman-Yassky E; Icahn School of Medicine at Mount Sinai Medical Center, New York, New York, USA., Facheris P; Icahn School of Medicine at Mount Sinai Medical Center, New York, New York, USA., Gomez-Arias PJ; Icahn School of Medicine at Mount Sinai Medical Center, New York, New York, USA., Del Duca E; Icahn School of Medicine at Mount Sinai Medical Center, New York, New York, USA., Da Rosa JC; Icahn School of Medicine at Mount Sinai Medical Center, New York, New York, USA., Weidinger S; University Hospital Schleswig-Holstein, Kiel, Germany., Bissonnette R; Innovaderm Research Inc., Montreal, Quebec, Canada., Armstrong AW; University of Southern California, Los Angeles, California, USA., Seneschal J; Department of Dermatology and Pediatric Dermatology, National Reference Center for Rare Skin Disorders, Hospital Saint-André, Bordeaux, France.; Bordeaux University, CNRS UMR 5164, Immunoconcept, Bordeaux, France., Eyerich K; University of Freiburg, Freiburg, Germany., Estrada YD; Icahn School of Medicine at Mount Sinai Medical Center, New York, New York, USA., Bose SN; Icahn School of Medicine at Mount Sinai Medical Center, New York, New York, USA., Xu D; Pfizer Inc., San Diego, California, USA., Chen A; Pfizer Inc., Groton, Connecticut, USA., Tatulych S; Pfizer Inc., Groton, Connecticut, USA., Güler E; Pfizer Inc., Istanbul, Turkey., Chan G; Pfizer Inc., Groton, Connecticut, USA., Page KM; Pfizer Inc., Cambridge, Massachusetts, USA., Kerkmann U; Pfizer Pharma GmbH, Berlin, Germany. |
| المصدر: | Allergy [Allergy] 2024 May; Vol. 79 (5), pp. 1258-1270. Date of Electronic Publication: 2023 Dec 18. |
| نوع المنشور: | Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't; Clinical Trial, Phase II |
| اللغة: | English |
| بيانات الدورية: | Publisher: Wiley-Blackwell Country of Publication: Denmark NLM ID: 7804028 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1398-9995 (Electronic) Linking ISSN: 01054538 NLM ISO Abbreviation: Allergy Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Copenhagen : Wiley-Blackwell Original Publication: Copenhagen, Munksgaard. |
| مواضيع طبية MeSH: | Dermatitis, Atopic*/drug therapy , Biomarkers* , Skin*/pathology , Skin*/metabolism , Skin*/drug effects , Sulfonamides*/therapeutic use , Sulfonamides*/administration & dosage , Severity of Illness Index*, Humans ; Female ; Male ; Adult ; Pyrimidines/therapeutic use ; Pyrimidines/administration & dosage ; Middle Aged ; Treatment Outcome ; Double-Blind Method ; Young Adult |
| مستخلص: | Background: This is the first report on the effects of abrocitinib, a Janus kinase 1-selective inhibitor, on the expression of skin biomarkers in patients with moderate-to-severe atopic dermatitis (AD). Methods: JADE MOA (NCT03915496) was a double-blind Phase 2a trial. Adults were randomly assigned 1:1:1 to receive monotherapy with once-daily abrocitinib 200 mg, abrocitinib 100 mg, or placebo for 12 weeks. The primary endpoint was change from baseline in markers of inflammation (matrix metalloproteinase [MMP]-12), epidermal hyperplasia (keratin-16 [KRT16]), T-helper 2 (Th2) immune response (C-C motif chemokine ligand [CCL]17, CCL18, and CCL26), and Th22 immune response (S100 calcium binding protein A8, A9, and A12 [S100A8, S100A9, and S100A12]) in skin through 12 weeks. Results: A total of 46 patients received abrocitinib 200 mg (n = 14), abrocitinib 100 mg (n = 16), or placebo (n = 16). Abrocitinib improved AD clinical signs and reduced itch. Gene expression of MMP-12, KRT16, S100A8, S100A9, and S100A12 was significantly decreased from baseline with abrocitinib 200 mg (at Weeks 2, 4, and 12) and abrocitinib 100 mg (at Weeks 4 and 12) in a dose-dependent manner. Abrocitinib 200 mg resulted in significant decreases from baseline in CCL17 expression at Week 12 and CCL18 expression at Weeks 2, 4, and 12; no significant decreases were observed for CCL26. Conclusions: Alongside improvements in clinical signs and symptoms of AD, 12 weeks of abrocitinib treatment resulted in downregulation of genes associated with inflammation, epidermal hyperplasia, and Th2 and Th22 immune responses in the skin of patients with moderate-to-severe AD. (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.) |
| References: | Bieber T. Atopic dermatitis: an expanding therapeutic pipeline for a complex disease. Nat Rev Drug Discov. 2022;21(1):21‐40. Weidinger S, Beck LA, Bieber T, Kabashima K, Irvine AD. Atopic dermatitis. Nat Rev Dis Primers. 2018;4(1):1. Czarnowicki T, He H, Krueger JG, Guttman‐Yassky E. Atopic dermatitis endotypes and implications for targeted therapeutics. J Allergy Clin Immunol. 2019;143(1):1‐11. Cibinqo (abrocitinib). Prescribing information. Pfizer Labs; 2022. 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. Lancet. 2020;396(10246):255‐266. Silverberg JI, Simpson EL, Thyssen JP, et al. Efficacy and safety of abrocitinib in patients with moderate‐to‐severe atopic dermatitis: a randomized clinical trial. JAMA Dermatol. 2020;156(8):863‐873. Bieber T, Simpson EL, Silverberg JI, et al. Abrocitinib versus placebo or dupilumab for atopic dermatitis. N Engl J Med. 2021;384(12):1101‐1112. Eichenfield LF, Flohr C, Sidbury R, et al. Efficacy and safety of abrocitinib in combination with topical therapy in adolescents with moderate‐to‐severe atopic dermatitis: the JADE TEEN randomized clinical trial. JAMA Dermatol. 2021;157(10):1165‐1173. 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. Lancet. 2022;400(10348):273‐282. Vazquez ML, Kaila N, Strohbach JW, et al. Identification of N‐{cis‐3‐[methyl(7H‐pyrrolo[2,3‐d]pyrimidin‐4‐yl)amino]cyclobutyl}propane‐1‐sulfonamide (PF‐04965842): a selective JAK1 clinical candidate for the treatment of autoimmune diseases. J Med Chem. 2018;61(3):1130‐1152. Eyerich S, Eyerich K, Cavani A, Schmidt‐Weber C. IL‐17 and IL‐22: siblings, not twins. Trends Immunol. 2010;31(9):354‐361. Ghosh D, Ding L, Sivaprasad U, et al. Multiple transcriptome data analysis reveals biologically relevant atopic dermatitis signature genes and pathways. PloS One. 2015;10(12):e0144316. Martel BC, Litman T, Hald A, et al. Distinct molecular signatures of mild extrinsic and intrinsic atopic dermatitis. Exp Dermatol. 2016;25(6):453‐459. Hamilton JD, Suárez‐Fariñas M, Dhingra N, et al. Dupilumab improves the molecular signature in skin of patients with moderate‐to‐severe atopic dermatitis. J Allergy Clin Immunol. 2014;134(6):1293‐1300. Pavel AB, Zhou L, Diaz A, et al. The proteomic skin profile of moderate‐to‐severe atopic dermatitis patients shows an inflammatory profile. J Am Acad Dermatol. 2020;82(3):690‐699. Bissonnette R, Pavel AB, Diaz A, et al. Crisaborole and atopic dermatitis skin biomarkers: an intrapatient randomized trial. J Allergy Clin Immunol. 2019;144(5):1274‐1289. He H, Del Duca E, Diaz A, et al. Mild atopic dermatitis lacks systemic inflammation and shows reduced nonlesional skin abnormalities. J Allergy Clin Immunol. 2021;147(4):1369‐1380. Del Duca E, Ruano Ruiz J, Pavel AB, et al. Frontal fibrosing alopecia shows robust T helper 1 and Janus kinase 3 skewing. Br J Dermatol. 2020;183(6):1083‐1093. Renert‐Yuval Y, Guttman‐Yassky E. New treatments for atopic dermatitis targeting beyond IL‐4/IL‐13 cytokines. Ann Allergy Asthma Immunol. 2020;124(1):28‐35. 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. JAMA Dermatol. 2021;157(9):1047‐1055. Gittler JK, Shemer A, Suárez‐Fariñas M, et al. Progressive activation of T(H)2/T(H)22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitis. J Allergy Clin Immunol. 2012;130(6):1344‐1354. Brunner PM, Guttman‐Yassky E, Leung DY. The immunology of atopic dermatitis and its reversibility with broad‐spectrum and targeted therapies. J Allergy Clin Immunol. 2017;139(4S):S65‐S76. Pan Y, Du D, Wang L, Wang X, He G, Jiang X. The role of T helper 22 cells in dermatological disorders. Front Immunol. 2022;13:911546. Renert‐Yuval Y, Del Duca E, Pavel AB, et al. The molecular features of normal and atopic dermatitis skin in infants, children, adolescents, and adults. J Allergy Clin Immunol. 2021;148(1):148‐163. Brunner PM, Israel A, Zhang N, et al. Early‐onset pediatric atopic dermatitis is characterized by TH2/TH17/TH22‐centered inflammation and lipid alterations. J Allergy Clin Immunol. 2018;141(6):2094‐2106. Pavel AB, Renert‐Yuval Y, Wu J, et al. Tape strips from early‐onset pediatric atopic dermatitis highlight disease abnormalities in nonlesional skin. Allergy. 2021;76(1):314‐325. He H, Bissonnette R, Wu J, et al. Tape strips detect distinct immune and barrier profiles in atopic dermatitis and psoriasis. J Allergy Clin Immunol. 2021;147(1):199‐212. Sanyal RD, Pavel AB, Glickman J, et al. Atopic dermatitis in African American patients is TH2/TH22‐skewed with TH1/TH17 attenuation. Ann Allergy Asthma Immunol. 2019;122(1):99‐110.e6. Chan TC, Sanyal RD, Pavel AB, et al. Atopic dermatitis in Chinese patients shows T(H)2/T(H)17 skewing with psoriasiform features. J Allergy Clin Immunol. 2018;142(3):1013‐1017. Lang CCV, Renert‐Yuval Y, Del Duca E, et al. Immune and barrier characterization of atopic dermatitis skin phenotype in Tanzanian patients. Ann Allergy Asthma Immunol. 2021;127(3):334‐341. Renert‐Yuval Y, Thyssen JP, Bissonnette R, et al. Biomarkers in atopic dermatitis‐a review on behalf of the International Eczema Council. J Allergy Clin Immunol. 2021;147(4):1174‐1190.e1. Fania L, Moretta G, Antonelli F, et al. Multiple roles for cytokines in atopic dermatitis: from pathogenic mediators to endotype‐specific biomarkers to therapeutic targets. Int J Mol Sci. 2022;23(5):2684. Bangert C, Rindler K, Krausgruber T, et al. Persistence of mature dendritic cells, T(H)2A, and Tc2 cells characterize clinically resolved atopic dermatitis under IL‐4Rα blockade. Sci Immunol. 2021;6(55):eabe2749. Guttman‐Yassky E, Bissonnette R, Ungar B, et al. Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis. J Allergy Clin Immunol. 2019;143(1):155‐172. Kishi R, Toyoma S, Tominaga M, et al. Effects of dupilumab on itch‐related events in atopic dermatitis: implications for assessing treatment efficacy in clinical practice. Cells. 2023;12(2):239. Harb H, Chatila TA. Mechanisms of dupilumab. Clin Exp Allergy. 2020;59(1):5‐14. Sabat R, OuYang W, Wolk K. Therapeutic opportunities of the IL‐22‐IL‐22R1 system. Nat Rev Drug Discov. 2014;13(1):21‐38. Furue M, Furue M. Interleukin‐22 and keratinocytes; pathogenic implications in skin inflammation. Explor Immunol. 2021;1:37‐47. Günther C, Bello‐Fernandez C, Kopp T, et al. CCL18 is expressed in atopic dermatitis and mediates skin homing of human memory T cells. J Immunol. 2005;174(3):1723‐1728. Guttman‐Yassky E, Lowes MA, Fuentes‐Duculan J, et al. Major differences in inflammatory dendritic cells and their products distinguish atopic dermatitis from psoriasis. J Allergy Clin Immunol. 2007;119(5):1210‐1217. Klaeschen AS, Nümm TJ, Herrmann N, et al. JAK1/2 inhibition impairs the development and function of inflammatory dendritic epidermal cells in atopic dermatitis. J Allergy Clin Immunol. 2021;147(6):2202‐2212. Tsoi LC, Rodriguez E, Stölzl D, et al. Progression of acute‐to‐chronic atopic dermatitis is associated with quantitative rather than qualitative changes in cytokine responses. J Allergy Clin Immunol. 2020;145(5):1406‐1415. Furue M. Regulation of skin barrier function via competition between AHR axis versus IL‐13/IL‐4–JAK–STAT6/STAT3 axis: pathogenic and therapeutic implications in atopic dermatitis. J Clin Med. 2020;9(11):3741. Vestergaard C, Bang K, Gesser B, Yoneyama H, Matsushima K, Larsen CG. A Th2 chemokine, TARC, produced by keratinocytes may recruit CLA+CCR4+ lymphocytes into lesional atopic dermatitis skin. J Invest Dermatol. 2000;115(4):640‐646. Brandt EB, Sivaprasad U. Th2 cytokines and atopic dermatitis. J Clin Cell Immunol. 2011;2(3):110. Pavel AB, Song T, Kim HJ, et al. Oral Janus kinase/SYK inhibition (ASN002) suppresses inflammation and improves epidermal barrier markers in patients with atopic dermatitis. J Allergy Clin Immunol. 2019;144(4):1011‐1024. Kim K, Kim H, Sung GY. An interleukin‐4 and interleukin‐13 induced atopic dermatitis human skin equivalent model by a skin‐on‐a‐chip. Int J Mol Sci. 2022;23(4):2116. |
| معلومات مُعتمدة: | Pfizer Inc., New York, NY, USA |
| فهرسة مساهمة: | Keywords: atopic dermatitis; biomarkers; dermatology |
| المشرفين على المادة: | 0 (Biomarkers) 73SM5SF3OR (abrocitinib) 0 (Sulfonamides) 0 (Pyrimidines) |
| تواريخ الأحداث: | Date Created: 20231218 Date Completed: 20240501 Latest Revision: 20240710 |
| رمز التحديث: | 20240710 |
| DOI: | 10.1111/all.15969 |
| PMID: | 38108208 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1398-9995 |
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| DOI: | 10.1111/all.15969 |