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Brunner, P.M.* ; Pavel, A.B.* ; Khattri, S.* ; Leonard, A.* ; Malik, K.A.* ; Rose, S.* ; On, S.J.* ; Vekaria, A.S.* ; Traidl-Hoffmann, C. ; Singer, G.K.* ; Baum, D.* ; Gilleaudeau, P.* ; Sullivan-Whalen, M.* ; Fuentes-Duculan, J.* ; Li, X.* ; Zheng, X.* ; Estrada, Y.* ; Garcet, S.* ; Wen, H.C.* ; Gonzalez, J.R.* ; Coats, I.* ; Cueto, I.* ; Neumann, A.U. ; Lebwohl, M.G.* ; Krueger, J.G.* ; Guttman-Yassky, E.*

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

J. Allergy Clin. Immunol. 143, 142-154 (2019)

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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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