Publishers Version online available 09/2021 Free by publisher as soon as is submitted to ZB.
Baseline IL-22 expression in patients with atopic dermatitis stratifies tissue responses to fezakinumab.
J. Allergy Clin. Immunol. 143, 142-154 (2019)
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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Publication type Article: Journal article
Document type Scientific Article
Keywords Atopic Dermatitis ; Moderate-to-severe Patients ; Il-22 ; Fezakinumab ; Precision Medicine ; Immune ; Cytokines ; Treatment; Genome-wide Association; Skin; Psoriasis; Immune; Inflammation; Cells; Biomarkers; Cytokines; Barrier; Il-17
Institute(s) Institute of Environmental Medicine (IEM)