Baseline IL-22 expression in patients with atopic dermatitis stratifies tissue responses to fezakinumab

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:143

Article

Brunner, Patrick M.¹  Pavel, Ana B.²  Khattri, Saakshi²  Leonard, Alexandra²  Malik, Kunal²  Rose, Sharon²  On, Shelbi Jim²  Vekaria, Anjali S.²  Traidl-Hoffmann, Claudia^3,4,5  Singer, Giselle K.²  Baum, Danielle²  Gilleaudeau, Patricia¹  Sullivan-Whalen, Mary¹  Fuentes-Duculan, Judilyn¹  Li, Xuan¹  Zheng, Xiuzhong¹  Estrada, Yeriel²  Garcet, Sandra¹  Wen, Huei-Chi²  Gonzalez, Juana¹  Coats, Israel¹  Cueto, Inna¹  Neumann, Avidan U.^3,4  Lebwohl, Mark G.²  Krueger, James G.¹  Guttman-Yassky, Emma^1,2 

[1] Rockefeller Univ, Lab Investigat Dermatol, 1230 York Ave, New York, NY 10021 USA

[2] Icahn Sch Med Mt Sinai, Dept Dermatol, 5 E 98th St, New York, NY 10029 USA

[3] Tech Univ Munich, Klinikum Augsburg, Univ Ctr Hlth Sci, Inst Environm Med, Augsburg, Germany

[4] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Augsburg, Germany

[5] Christine Kuhne Ctr Allergy Res & Educ CK CARE, Davos, Switzerland

关键词: Atopic dermatitis;    moderate-to-severe patients;    IL-22;    fezakinumab;    precision medicine;    immune;    cytokines;    treatment;   

DOI  :  10.1016/j.jaci.2018.07.028

来源: Elsevier

【 摘 要 】

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 x 10(-5)) and 65.5% versus 13.9% at 12 weeks (P = 9.5 3 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 T(H)1/CXCL9, T(H)2/CCL18/CCL22, T(H)17/CCL20/DEFB4A, and T(H)22/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.

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