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. Epub 2018 Aug 17.

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.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Antibodies, Monoclonal / administration & dosage*
  • Antibodies, Monoclonal, Humanized
  • Dermatitis, Atopic / drug therapy*
  • Dermatitis, Atopic / immunology
  • Dermatitis, Atopic / metabolism
  • Dermatitis, Atopic / pathology
  • Female
  • Gene Expression Regulation / drug effects*
  • Gene Expression Regulation / immunology
  • Humans
  • Interleukin-22
  • Interleukins / biosynthesis*
  • Interleukins / immunology
  • Male
  • Middle Aged
  • Skin / immunology
  • Skin / metabolism*
  • Skin / pathology
  • 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

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Interleukins
  • fezakinumab