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

  • J Allergy Clin Immunol. 2019 Jan;143(1):142-154. doi: 10.1016/j.jaci.2018.07.028.
Patrick M Brunner  1 ,  Ana B Pavel  2 ,  Saakshi Khattri  2 ,  Alexandra Leonard  2 ,  Kunal Malik  2 ,  Sharon Rose  2 ,  Shelbi Jim On  2 ,  Anjali S Vekaria  2 ,  Claudia Traidl-Hoffmann  3 ,  Giselle K Singer  2 ,  Danielle Baum  2 ,  Patricia Gilleaudeau  1 ,  Mary Sullivan-Whalen  1 ,  Judilyn Fuentes-Duculan  1 ,  Xuan Li  1 ,  Xiuzhong Zheng  1 ,  Yeriel Estrada  2 ,  Sandra Garcet  1 ,  Huei-Chi Wen  2 ,  Juana Gonzalez  1 ,  Israel Coats  1 ,  Inna Cueto  1 ,  Avidan U Neumann  4 ,  Mark G Lebwohl  2 ,  James G Krueger  1 ,  Emma Guttman-Yassky  5
Affiliations
  • 1. Laboratory for Investigative Dermatology, Rockefeller University, New York, NY.
  • 2. Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY.
  • 3. Institute of Environmental Medicine, University Center for Health Sciences at the Klinikum Augsburg, Technical University Munich and Helmholtz Zentrum München-German Research Center for Environmental Health, Augsburg, Germany; Christine Kühne-Center for Allergy Research and Education (CK-CARE), Davos, Switzerland.
  • 4. Institute of Environmental Medicine, University Center for Health Sciences at the Klinikum Augsburg, Technical University Munich and Helmholtz Zentrum München-German Research Center for Environmental Health, Augsburg, Germany.
  • 5. Laboratory for Investigative Dermatology, Rockefeller University, New York, NY; Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY. Electronic address: [email protected].
PMID: 30121291 DOI: 10.1016/j.jaci.2018.07.028
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.

Keywords
Atopic dermatitis; IL-22; cytokines; fezakinumab; immune; moderate-to-severe patients; precision medicine; treatment.