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

• Published in: Journal of allergy and clinical immunology Vol. 143; no. 1; pp. 142 - 154
• Main Authors: Brunner, Patrick M., Pavel, Ana B., Khattri, Saakshi, Leonard, Alexandra, Malik, Kunal, Rose, Sharon, Jim On, Shelbi, Vekaria, Anjali S., Traidl-Hoffmann, Claudia, Singer, Giselle K., Baum, Danielle, Gilleaudeau, Patricia, Sullivan-Whalen, Mary, Fuentes-Duculan, Judilyn, Li, Xuan, Zheng, Xiuzhong, Estrada, Yeriel, Garcet, Sandra, Wen, Huei-Chi, Gonzalez, Juana, Coats, Israel, Cueto, Inna, Neumann, Avidan U., Lebwohl, Mark G., Krueger, James G., Guttman-Yassky, Emma
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2019; Elsevier Limited
• Subjects: Adult; Antagonism; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal, Humanized; Atopic dermatitis; Biopsy; CCL18 protein; CCL20 protein; CCL22 protein; Cell activation; Clinical trials; Cytokines; Dendritic cells; Dermatitis; Dermatitis, Atopic - drug therapy; Dermatitis, Atopic - immunology; Dermatitis, Atopic - metabolism; Dermatitis, Atopic - pathology; Drug dosages; Eczema; Female; fezakinumab; Gene expression; Gene Expression Regulation - drug effects; Gene Expression Regulation - immunology; Helper cells; Humans; IL-22; immune; Immunohistochemistry; Inflammation; Interleukin 22; Interleukins - biosynthesis; Interleukins - immunology; Lymphocytes T; Male; Middle Aged; moderate-to-severe patients; Patients; Precision medicine; Psoriasis; Skin; Skin - immunology; Skin - metabolism; Skin - pathology; Skin diseases; Software; Studies; Th1 Cells - immunology; Th1 Cells - metabolism; Th1 Cells - pathology; Th17 Cells - immunology; Th17 Cells - metabolism; Th17 Cells - pathology; Th2 Cells - immunology; Th2 Cells - metabolism; Th2 Cells - pathology; treatment; moderate-to-severe patients; treatment; immune; AD; DEG; MADAD; FCH; IL-22; AUC; LCE; Atopic dermatitis; FDR; fezakinumab; precision medicine; cytokines; IL-22R; DC
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2018.07.028

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. We sought to evaluate the cellular and molecular effects of IL-22 blockade in tissues from patients with moderate-to-severe AD. 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. 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. 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.