Mapping atopic dermatitis and anti-IL-22 response signatures to Type 2-low severe neutrophilic asthma.

BACKGROUND

Transcriptomic changes in patients who respond clinically to biological therapies may identify responses in other tissues or diseases.

OBJECTIVE

To determine whether a disease signature identified in atopic dermatitis (AD) is seen in adults with severe asthma (SA) and whether a transcriptomic signature for AD patients who respond clinically to anti-IL-22 (Fezakinumab, FZ) is enriched in SA.

METHODS

An AD disease signature was obtained from analysis of differentially expressed genes (DEGs) between AD lesional and non-lesional skin biopsies. DEGs from lesional skin from therapeutic super-responders before and after 12 weeks FZ treatment defined the FZ-response signature. Gene Set Variation Analysis (GSVA) was used to produce enrichment scores (ES) of AD and FZ-response signatures in the U-BIOPRED asthma cohort.

RESULTS

The AD disease signature (112 up-regulated genes) encompassing inflammatory, T-cell, Th2 and Th17/Th22 pathways was enriched in the blood and sputum of asthmatics with increasing severity. Asthmatics with sputum neutrophilia and mixed granulocyte phenotypes were the most enriched (p<0.05). The FZ-response signature (296 down-regulated genes) was enriched in asthmatic blood (p<0.05) and particularly in neutrophilic and mixed granulocytic sputum (p<0.05). These data were confirmed in sputum of the ADEPT (Airway Disease Endotyping for Personalized Therapeutics) cohort. IL-22 mRNA across tissues did not correlate with FZ-response ES, but this response signature correlated with Th22/IL-22 pathways.

CONCLUSIONS

The FZ-response signature in AD identifies severe neutrophilic asthmatics as potential responders to FZ therapy. This approach will help identify patients for future asthma clinical trials of drugs used successfully in other chronic diseases.