Dupilumab normalizes the eosinophilic esophagitis disease transcriptome

BACKGROUND: Eosinophilic esophagitis (EoE) is a type 2 inflammatory disease of the esophagus, characterized by eosinophilic inflammation and an altered esophageal transcriptome. Dupilumab, a fully human mAb that blocks IL-4 and IL-13 signaling, is approved for use in multiple type 2 inflammatory diseases, including EoE, where it produces histologic, symptomatic, and endoscopic improvements in pediatric, adolescent, and adult patients. OBJECTIVE: We sought to investigate the effect of dupilumab on the dysregulated esophageal transcriptome in pediatric, adolescent, and adult patients with EoE. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT02379052, NCT03633617, and NCT04394351. METHODS: Changes in the esophageal transcriptome were analyzed from pretreatment and posttreatment esophageal biopsy specimens provided by pediatric, adolescent, and adult patients with EoE who participated in 1 of 3 placebo-controlled clinical trials of dupilumab. 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 biological processes dysregulated in EoE that were normalized with dupilumab treatment, including processes likely to be eosinophil independent. Transcriptome changes were comparable and sustained through week 52 across pediatric, adolescent, and adult patients with EoE. CONCLUSIONS: IL-4 and IL-13 are the critical drivers of the molecular differences in the esophageal mucosa of patients with EoE compared with control subjects, consistent with the clinical benefit of dupilumab treatment.