Dupilumab normalizes the eosinophilic esophagitis disease transcriptome.
Academic Article
Overview
abstract
BACKGROUND: Eosinophilic esophagitis (EoE) is a type 2 inflammatory disease (T2ID) of the esophagus, characterized by eosinophilic inflammation and an altered esophageal transcriptome. Dupilumab, a fully human monoclonal antibody which blocks interleukin (IL)-4 and IL-13 signaling, is approved in multiple T2IDs, including EoE, where it produces histologic, symptomatic, and endoscopic improvements in pediatric, adolescent, and adult patients with EoE. OBJECTIVE: We investigated the effect of dupilumab on the dysregulated esophageal transcriptome in pediatric, adolescent, and adult patients with EoE. METHODS: Changes in the esophageal transcriptome were analyzed from pre- and post-treatment esophageal biopsies provided by patients with EoE who participated in one of three placebo-controlled clinical trials of dupilumab including pediatric, adolescent, and adult patients. RESULTS: Dupilumab treatment resulted in marked normalization of the EoE disease transcriptome, including gene signatures associated with eosinophils as well as other aspects of type 2 inflammation and esophageal dysfunction including mast cells, fibrosis, barrier function, and other cell functions and pathways. Overall, gene ontology enrichment analysis identified 41 biologic processes dysregulated in EoE that were normalized with dupilumab treatment, including those likely to be eosinophil independent. Transcriptome changes were comparable and sustained through week 52 across pediatric, adolescent, and adult patients with EoE. CONCLUSION: IL-4/IL-13 are the critical drivers of the molecular differences in the esophageal mucosa of patients with EoE compared with controls, consistent with the clinical benefit of dupilumab treatment.
