Ikuo Hirano1, Marc E. Rothenberg2, Jonathan M. Spergel3, Seema Aceves4, Matthew Greenhawt5, Alain M. Schoepfer6, Zhen Chen7, Angela Khodzhayev7, Yamo Deniz7, Paul J. Rowe8, Juby A. Jacob-Nara8
1Northwestern University Feinberg School of Medicine, Chicago, IL, USA; 2Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH, USA; 3Children's Hospital of Philadelphia, Philadelphia, PA, USA; 4University of California, San Diego, CA, USA; 5Children’s Hospital Colorado, Aurora, CO, USA; 6Lausanne University Hospital, Lausanne, Switzerland; 7Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA; 8Sanofi, Bridgewater, NJ, USA
Objectives: Eosinophilic esophagitis (EoE) is a chronic, progressive type 2 inflammatory disease of the esophagus. Although eosinophils are the hallmark of EoE diagnosis, and threshold levels are required for diagnosis, their exact role in the disease is unclear. The EoE-Endoscopic Reference Score (EREFS) assesses severity of endoscopically identified inflammatory (edema, exudate, furrows) and remodeling (rings, strictures) aspects of disease activity. The objective of this study is to examine the relationship between eosinophilic inflammation and endoscopic disease activity. Correlations were assessed between peak esophageal intraepithelial eosinophil count (eosinophils/high-power field [eos/hpf]) and EREFS in EoE patients receiving placebo in two clinical trials: the 12-week phase 2 proof-of-concept study in adults (POC; NCT02379052; n=24) and the 24-week Part A of the 3-part, phase 3 TREET study in adolescents and adults (P3PA; NCT03633617; n=39).
Methods: Endoscopic examination was performed at baseline (BL) and end of treatment (EOT) and scored for inflammatory subscore (the sum of edema, exudates, and furrows), remodeling subscore (sum of rings and strictures), and total score using EREFS (higher scores indicate greater severity). For POC this was based on one endoscopy (score range 0–8); for P3PA, endoscopies from proximal and distal regions were summed (score range 0–18). Eos/hpf was measured from pinch biopsies of proximal, mid, and distal esophagus at BL and EOT. For P3PA, peak eos/hpf was the maximum eosinophils in the most inflamed hpf across the 3 regions; for POC, the peak eos/hpf was the mean of the 3 regions. Pearson correlations were performed between eos/hpf and EREFS total, inflammation and remodeling subscores, and components at BL, EOT, and change from BL at EOT (∆EOT).
Results: Some strong correlations (correlation coefficient > 0.5) were observed between EREFS and eos/hpf in patients receiving placebo from both studies. Moderate-to-strong correlations were observed between EREFS total score and eos/hpf in P3PA (BL 0.5625 [P < 0.001], EOT 0.4677 [P = 0.01] [∆EOT 0.0422, P = 0.8]), but not POC (BL 0.3472 [P = 0.10], EOT 0.2854 [P = 0.2], ∆EOT 0.3382 [P = 0.12]). Moderate-to-strong correlations were observed in both studies between eos/hpf and the EREFS inflammation subscore (POC: BL 0.3591 [P = 0.09], EOT 0.4858 [P = 0.02], ΔEOT 0.4532 [P = 0.03]; P3PA: BL 0.5482 [P < 0.001] , EOT 0.3627 [P = 0.06], ΔEOT 0.1128 [P = 0.58]), and inflammatory components of edema (POC: BL 0.3431 [P = 0.10], EOT 0.3522 [P = 0.11], ΔEOT 0.4100 [P = 0.06]; P3PA: BL 0.2922 [P = 0.07], EOT –0.0635 [P = 0.76], ΔEOT 0.1111 [P = 0.96]), exudates (POC: BL 0.3075 [P = 0.15], EOT 0.5195 [P = 0.01], ΔEOT 0.4412 [P = 0.04]; P3PA: BL 0.4735 [P < 0.01], EOT 0.3987 [P = 0.04], ΔEOT 0.2695 [P = 0.18]), and furrows (POC: BL 0.1981 [P = 0.36], EOT 0.1688 [P = 0.46], ΔEOT 0.2415 [P = 0.28]; P3PA: BL 0.3803 [P = 0.02], EOT 0.3807 [P = 0.05], ΔEOT –0.0798 [P = 0.70]). All correlations of eos/hpf to the EREFS remodeling subscore and rings/stricture components were weak-to-moderate and not statistically significant.
Conclusions: In these patients with EoE, moderate-to-strong correlations were observed between eos/hpf and endoscopic markers of inflammation as assessed by EREFS. No strong correlations were observed between eos/hpf and endoscopic remodeling. These data support a role for intact eosinophils in inflammatory changes in the esophagus in EoE and demonstrate the need for both histologic and endoscopic assessment to provide a more comprehensive characterization of disease activity. Further study, with larger sample sizes, is required to verify these findings in other contexts.
Reference: PAGE 30 (2022) Abstr 10192 [www.page-meeting.org/?abstract=10192]
Poster: Drug/Disease Modelling - Other Topics