Persistent Esophageal Changes Following Histologic Remission in Eosinophilic Esophagitis
Melanie A. Ruffner MD PhD,1,2*,# Tetsuo Shoda MD, PhD,3* Megha Lal PhD,2 Zoe Mrozek,2 Amanda B. Muir MD,1,4 Jonathan M. Spergel MD, PhD,1,2 Evan S. Dellon MD,5 Marc E. Rothenberg MD, PhD3
Background: Eosinophilic esophagitis (EoE) is characterized by persistent or relapsing allergic inflammation, and both clinical and histologic features of esophageal inflammation persist over time in most individuals. Mechanisms contributing to EoE relapse are not understood. Chronic EoE-directed therapy is required to prevent long-term fibrostenotic sequelae. In this study, we investigated whether patients with EoE in histologic remission have persistent dysregulation of esophageal gene expression.
Methods: Esophageal biopsies from pediatric (n = 51) and adult (n = 52) subjects with EoE in histopathologic remission (<15 eosinophils/high-power field [eos/HPF]) and control (n = 48 pediatric, n = 167 adult) subjects from multiple institutions were subjected to molecular profiling by the EoE Diagnostic Panel (EDP), a set of 94 esophageal transcripts differentially expressed in active EoE.
Results: We identified 51 and 32 differentially expressed genes in pediatric and adult patients with EoE in remission (<15 eos/HPF) compared to control individuals, respectively (FDR < 0.05). Using the stringent definition of remission (0 eos/HPF), the adult and pediatric cohorts continued to have 18 and 25 differentially expressed genes (FDR < 0.05). Among 6 shared genes between adults and children, cadherin 26 (CDH26) was upregulated in both children and adults; immunohistochemistry demonstrated increased cadherin 26 staining in the epithelium of patients with EoE in remission compared to non-EoE controls. In the adult cohort, POSTN expression correlated with the Endoscopic Reference Score (Spearman r = 0.35, p = 0.011), specifically correlating with the rings EREFS subscore (r = 0.53, p = 0.004).
Conclusion: We have identified persistent EoE-associated esophageal gene expression in patients with deep remission. These data suggest potential inflammation-induced epigenetic mechanisms may influence gene expression during remission in EoE and provide insight into possible mechanisms that underlie relapse in EoE.
Author Affiliations: *Contributed equally. #ruffnerm@chop.edu. 1Department of Pediatrics, University of Pennsylvania Perelman School of Medicine; 2Division of Allergy & Immunology, Children’s Hospital of Philadelphia, Philadelphia PA; 3Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio; 4Division of Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Philadelphia, Philadelphia PA; 5Division of Gastroenterology and Hepatology, Department of Medicine, Center for Esophageal Diseases and Swallowing, University of North Carolina School of Medicine
