Molecular Characterization of Non‐Specific Esophagitis Reveals a Distinct Non‐Eosinophilic Phenotype With Fibrotic Traits

BACKGROUND: Non-specific esophagitis has been recently described in patients with dysphagia not fulfilling criteria for eosinophilic esophagitis (EoE). Whether it is a distinct entity and how dysphagia can develop in the absence of eosinophilic infiltration remains unknown. OBJECTIVE: In this study, we comprehensively characterized non-specific esophagitis aiming to elucidate eosinophil-independent fibrosis mechanisms. METHODS: We cross-sectionally and longitudinally analyzed treatment-naïve patients presenting with non-specific esophagitis defined by esophageal dysfunction and low-grade lymphocytic infiltration (< 30 lymphocytes/hpf) in the absence of tissue eosinophilia and reflux disease (GERD). We compared clinical, endoscopic, (immuno)-histological disease activity to EoE, lymphocytic esophagitis, and GERD. RNA sequencing was performed to investigate disease mechanisms. RESULTS: We identified 19 patients (6 males, median age 48 years), with a follow-up of 20 months (IQR 10-41). Clinical disease burden was considerable, contrasting mild endoscopic activity (EREFS 0, IQR 0-2). Immunostaining of esophageal biopsies did not reveal increased numbers of eosinophils or mast cells as contributors to the disease. Lymphocytic infiltration (15/hpf, IQR 9-24) was not increased compared to healthy controls (9/hpf, IQR 9-10) or GERD patients (13/hpf, IQR 9-23); 14 (73.6%) patients were treated with topical steroids (symptomatic response in 85.7%) and 6 patients (31.6%) underwent endoscopic dilation. Progression to EoE was observed in 1 patient, while esophageal eosinophilia (< 15 eos/hpf) developed in 3 patients. RNA sequencing (n = 10) revealed a distinct transcriptomic profile, with highly enriched fibrosis-related pathways. Immunostaining for E-Cadherin/Vimentin as a marker for epithelial-mesenchymal transition (EMT, n = 10) confirmed increased EMT compared to controls. CONCLUSION: Non-specific esophagitis appears to be a distinct non-eosinophilic phenotype with fibrotic traits. Our data suggest eosinophil-independent development of fibrosis.