Among patients with eosinophilic esophagitis (EoE), those who respond to proton pump inhibitors (PPIs) and those who do not respond to PPI therapy share similar esophageal protein profiles, distinct from those without EoE, according to comparative proteomic analyses.

Notably, after PPI treatment, the protein profiles of reactive patients reversed and appeared similar to those of non-EoE patients, whereas the profiles of non-reactive patients remained largely unchanged.

“Identifying protein biomarkers associated with response to PPIs may help distinguish EoE phenotypes and guide therapeutic choices,” said lead author Walter Chan, MD, associate professor of medicine in the Division of Gastroenterology, d of hepatology and endoscopy at Harvard Medical School and director of the center. for gastrointestinal motility at Brigham and Women’s Hospital in Boston.

“These results could provide a framework for the development of protein biomarkers to assess treatment response and monitor disease activity,” he added.

The study was published online In Gastroenterology.

Comparative proteomic analyzes

Chan and colleagues conducted a prospective exploratory pilot study to identify differences in esophageal protein profiles between PPI-sensitive EoE controls (PPI-R-EoE), PPI-non-responsive EoE (PPI-NR-EoE), and non-EoE controls using SOMAscan, a proteomics platform that allows the simultaneous detection of 1305 human proteins.

The research team prospectively recruited patients undergoing endoscopy for esophageal symptoms or for EoE follow-up, obtaining clinically indicated biopsies as well as additional midesophageal samples.

Patients diagnosed with EoE (at 15 or more eosinophils per high-power field, or eos/hpf) were treated with 20 mg omeprazole twice daily for 8 weeks, followed by repeat biopsies to assess the response to treatment.

Patients with histological remission (less than 15 eos/hpf) were classified as PPI-R-EoE, while those with persistently active disease were classified as PPI-NR-EoE. Patients without EoE served as controls and were classified as having erosive esophagitis (EE) or no esophagitis.

In total, the study enrolled 32 patients, including 15 with PPI-R-EoE, eight with PPI-NR-EoE, three with EE, and six without esophagitis. Demographics, symptoms, and endoscopic findings were similar between PPI-R-EoE and PPI-NR-EoE patients.

At index endoscopy, PPI-R-EoE and PPI-NR-EoE patients had similar esophageal protein profiles, with only 20 proteins differentially expressed at a relaxed threshold of P. < .1. An analysis of all 20 proteins predicted lower expression of six proteins that may be associated with gastrointestinal inflammation in nonresponsive patients, including STAT1, STAT3, CFB, interleukin (IL)-17RA, TNFRSF1A, and SERPINA3.

In addition, 136 proteins — including 15 with correction P. < 0.05 — PPI-R-EoE patients clearly discriminated from non-EoE controls, and 255 proteins — including 249 with P. < 0.05 — PPI-NR-EoE patients discriminated compared to controls. Both types of EoE patients exhibited proteins associated with increased inflammation and vasculogenesis, as well as downregulation of CRISP3 and DSG1 and upregulation of TNFAIP6.

Comparative analyzes also showed that follow-up biopsies from PPI-R-EoE patients had protein profiles that resembled non-EoE controls after PPI treatment.

“This further supports the hypothesis that despite response to PPI, PPI-R-EoE represents a subtype of EoE rather than gastroesophageal reflux disease (GERD),” Chan said.

Future EoE Considerations

Although most expressed proteins appeared similar between PPI-sensitive and non-sensitive patients before treatment, a few proteins differed due to gastrointestinal inflammation, the study authors wrote, including some previously implicated in the inflammatory pathways of IL4 and IL13.

“Further study of these proteins could provide insights into the pathogenic EoE pathway, explore their potential to predict response to PPIs at diagnosis, and identify possible therapeutic targets,” they wrote.

The authors highlighted the small study size as the main limitation, noting that the pilot study aimed to explore the feasibility of using SOMAscan to assess esophageal protein profiles in different EoE phenotypes. In the future, larger studies investigating broader candidate proteins could help characterize differences and better identify specific proteins and pathways in EoE, they wrote.

“The bottom line is that responsiveness to PPI does not distinguish EoE from GERD, but rather PPI is a primary treatment for EoE independent of GERD,” said Marc Rothenberg , MD, chair of the Department of Allergy and Immunology and director of the Cincinnati Center for Eosinophilic Disorders at Cincinnati Children’s Hospital. Hospital Medical Center, Cincinnati, Ohio.

Rothenberg, who was not involved in this study, conducted transcriptome analyzes of PPI-R-EoE, which showed reversible allergic inflammation to PPIs.

“PPI-R-EoE and PPI-NR-EoE look similar at the molecular level,” he said. “After treatment, PPI-R-EoE normalizes, according to its definition.”

This study was supported by the Urging Research for Eosinophilic Disease Foundation Grant, the Kenneth and Louise Goldberg Junior Professor Award, and an award from the National Institutes of Health. Chan has reported advisory board positions at several pharmaceutical companies and Rothenberg has not reported any relevant disclosures.

Carolyn Crist is a health and medical journalist who has reported on the latest studies for MDedge, Medscape Medical News and WebMD.