Baseline IL-22 expression in patients with atopic dermatitis stratifies tissue responses to fezakinumab - 17/09/18
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Abstract |
Background |
IL-22 is potentially a pathogenic cytokine in patients with atopic dermatitis (AD), but the molecular effects of IL-22 antagonism have not been defined in human subjects.
Objective |
We sought to evaluate the cellular and molecular effects of IL-22 blockade in tissues from patients with moderate-to-severe AD.
Methods |
We assessed lesional and nonlesional skin from 59 patients with moderate-to-severe AD treated with anti–IL-22 (fezakinumab) versus placebo (2:1) using transcriptomic and immunohistochemistry analyses.
Results |
Greater reversal of the AD genomic profile was seen with fezakinumab versus placebo, namely 25.3% versus 10.5% at 4 weeks (P = 1.7 × 10−5) and 65.5% versus 13.9% at 12 weeks (P = 9.5 × 10−19), respectively. Because IL-22 blockade showed clinical efficacy only in patients with severe AD, we used baseline median IL-22 mRNA expression to stratify for high (n = 30) and low (n = 29) IL-22 expression groups. Much stronger mean transcriptomic improvements were seen with fezakinumab in the IL-22–high drug-treated group (82.8% and 139.4% at 4 and 12 weeks, respectively) than in the respective IL-22–high placebo-treated group (39.6% and 56.3% at 4 and 12 weeks) or the IL-22–low groups. Significant downregulations of multiple immune pathways, including TH1/CXCL9, TH2/CCL18/CCL22, TH17/CCL20/DEFB4A, and TH22/IL22/S100A's, were restricted to the IL-22–high drug group (P < .05). Consistently, tissue predictors of clinical response were mostly genes involved in T-cell and dendritic cell activation and differentiation.
Conclusions |
This is the first report showing a profound effect of IL-22 blockade on multiple inflammatory pathways in AD. These data, supported by robust effects in patients with high IL-22 baseline expression, suggest a central role for IL-22 in AD, indicating the need for a precision medicine approach for improving therapeutic outcomes in patients with AD.
Le texte complet de cet article est disponible en PDF.Key words : Atopic dermatitis, moderate-to-severe patients, IL-22, fezakinumab, precision medicine, immune, cytokines, treatment
Abbreviations used : AD, AUC, DC, DEG, FCH, FDR, IL-22R, LCE, MADAD
Plan
Supported by National Institutes of Health (NIH)/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) grant no. 1UM1AR063917. P.M.B. was supported in part by grant no. UL1 TR0001866 from the National Center for Advancing Translational Sciences (NCATS), NIH Clinical and Translational Science Award (CTSA) program. Fezakinumab was provided by Pfizer (New York, NY). |
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Disclosure of potential conflict of interest: P.M.B. is an employee of the Rockefeller University and has received personal fees from LEO Pharma, Sanofi Genzyme, and Pfizer. C.T.-H. is an employee of the Technical University Munich and the Helmholtz Zentrum München and has received research support from Danone Nutricia and personal fees from Novartis and La Roche Posay. M.G.L. is an employee of Mount Sinai, which receives research funds from Abbvie, Amgen, Boehringer Ingelheim, Celgene, Eli Lilly, Janssen/Johnson & Johnson, Kadmon, Medimmune/Astra Zeneca, Novartis, Pfizer, Valeant, and ViDac, and is also a consultant for Allergan, Aqua, LEO Pharma, and Promius. J.G.K. is an employee of the Rockefeller University and has received research support (grants paid to his institution) and/or personal fees from Pfizer, Amgen, Janssen, Lilly, Merck, Novartis, Kadmon, Dermira, Boehringer, Innovaderm, Kyowa, BMS, Serono, BiogenIdec, Delenex, AbbVie, Sanofi, Baxter, Paraxel, Xenoport, and Kineta. E.G.-Y. is an employee of Mount Sinai and has received research funds (grants paid to the institution) from Abbvie, Celgene, Eli Lilly, Janssen, MedImmune/Astra Zeneca, Novartis, Pfizer, Regeneron, Vitae, Glenmark, Galderma, Asana, Innovaderm, Dermira, and UCB and is also a consultant for Sanofi Aventis, Regeneron, Stiefel/GlaxoSmithKline, MedImmune, Celgene, Anacor, AnaptysBio, Dermira, Galderma, Glenmark, Novartis, Pfizer, Vitae, LEO Pharma, Abbvie, Eli Lilly, Kyowa, Mitsubishi Tanabe, Asana Biosciences, and Promius. The rest of the authors declare that they have no relevant conflicts of interest. |
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