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

Patrick M. Brunner, Ana B. Pavel, Saakshi Khattri, Alexandra Leonard, Kunal Malik, Sharon Rose, Shelbi Jim On, Anjali S. Vekaria, Claudia Traidl-Hoffmann, Giselle K. Singer, Danielle Baum, Patricia Gilleaudeau, Mary Sullivan-Whalen, Judilyn Fuentes-Duculan, Xuan Li, Xiuzhong Zheng, Yeriel Estrada, Sandra Garcet, Huei Chi Wen, Juana GonzalezIsrael Coats, Inna Cueto, Avidan U. Neumann, Mark G. Lebwohl, James G. Krueger, Emma Guttman-Yassky

Research output: Contribution to journalArticlepeer-review

118 Scopus citations

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.

Original languageEnglish
Pages (from-to)142-154
Number of pages13
JournalJournal of Allergy and Clinical Immunology
Volume143
Issue number1
DOIs
StatePublished - Jan 2019

Keywords

  • Atopic dermatitis
  • IL-22
  • cytokines
  • fezakinumab
  • immune
  • moderate-to-severe patients
  • precision medicine
  • treatment

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