Baseline IL22 expression in atopic dermatitis patients stratifies tissue responses to fezakinumab

Publication date: Available online 17 August 2018

Source: Journal of Allergy and Clinical Immunology

Author(s): 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 Gonzalez

Abstract

Background

IL-22 is potentially a pathogenic cytokine in AD, but molecular effects of IL-22 antagonism have not been defined in humans.

Objective

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

Methods

We assessed lesional and non-lesional skin from 59 moderate-to-severe AD patients treated with anti-IL-22 (fezakinumab) vs. placebo (2:1), using transcriptomic and immunohistochemistry analyses.

Results

Greater reversal of the AD genomic profile was seen with fezakinumab vs. placebo, namely 25.3% vs. 10.9% at 4wks (p=1.7*10^-5) and 65.5% vs. 13.9% at 12wks (p=9.5*10^-19), respectively. Since IL-22 blockade showed clinical efficacy only in severe AD, we used baseline median IL22 expression to stratify for high (n=30) and low (n=29) IL22-expression groups. Much stronger mean transcriptomic improvements were seen with fezakinumab in the IL22-high drug group (82.8% and 139.4% at 4 and 12wks, respectively), than in the respective IL22-high placebo (39.6% and 53.6% at 4 and 12wks) or the IL22-low groups. Significant downregulations of multiple immune pathways, including Th1/CXCL9, Th2/CCL18/CCL22, Th17/CCL20/DEFB4A, and Th22/IL22/S100As, were restricted to the IL22-high drug-group (p<0.05). 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 the robust effects in patients with high IL22 baseline expression, suggest a central role for IL-22 in AD, indicating the need for a precision medicine approach for improving therapeutic outcomes in AD.

Clinical Implications

Stratification of cytokine expression at baseline might help future precision medicine approaches to effectively treat atopic dermatitis patient subsets that might benefit from IL-22 antagonism or other specific blockers.

https://ift.tt/2weXETY