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Among patients with eosinophilic esophagitis (EoE), both those who are responsive to proton pump inhibitors (PPIs) and those who are unresponsive to PPI treatment share similar esophageal protein profiles, which are distinct from those without EoE, according to comparative proteomic analyses.

Notably, after PPI therapy, the protein profiles of responsive patients reverted and appeared similar to non-EoE patients, whereas the profiles of nonresponsive patients remained largely unchanged.

“Identifying protein biomarkers associated with PPI response may help distinguish EoE phenotypes and guide therapy selections,” said senior author Walter Chan, MD, associate professor of medicine in the Division of Gastroenterology, Hepatology, and Endoscopy at Harvard Medical School and director of the center for gastrointestinal motility at Brigham and Women’s Hospital, Boston.

“These findings may provide the framework for developing protein biomarkers to assess response to therapy and monitor disease activity,” he added.

The study was published online in Gastroenterology.

Comparative Proteomic Analyses

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

The research team prospectively enrolled patients undergoing endoscopy for esophageal symptoms or for EoE follow-up, obtaining clinically indicated biopsies as well as extra samples from the midesophagus.

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

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

Overall, the study enrolled 32 patients, including 15 with PPI-R-EoE, eight with PPI-NR-EoE, three with EE, and six with no esophagitis. The demographics, symptoms, and endoscopic findings were similar between the PPI-R-EoE and PPI-NR-EoE patients.

At the index endoscopy, the PPI-R-EoE and PPI-NR-EoE patients had similar esophageal protein profiles, with only 20 proteins differentially expressed at a relaxed cutoff of P < .1. An analysis of the 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 corrected P < .05 — clearly discriminated PPI-R-EoE patients from non-EoE controls, and 255 proteins — including 249 with P < .05 — discriminated PPI-NR-EoE patients from controls. Both types of EoE patients had proteins associated with enhanced inflammation and vasculogenesis, as well as down-regulation of CRISP3 and DSG1 and upregulation of TNFAIP6.

The comparative analyses also showed that the follow-up biopsies of PPI-R-EoE patients had protein profiles that resembled non-EoE controls after PPI therapy.

“This further supports the hypothesis that despite the PPI response, 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-responsive and nonresponsive patients before treatment, a few proteins differed related to gastrointestinal inflammation, the study authors wrote, including some previously implicated in IL4 and IL13 inflammatory pathways.

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

The authors pointed to the small study size as the primary limitation, noting that the pilot study was intended to explore the feasibility of using SOMAscan to assess esophageal protein profiles in different EoE phenotypes. In the future, larger studies with more expansive candidate proteins could help characterize the differences and better identify specific proteins and pathways in EoE, they wrote.

“The takeaway is that PPI responsiveness does not distinguish EoE from GERD but rather PPI is a primary therapy for EoE independent of GERD,” said Marc Rothenberg, MD, director of allergy and immunology and director of the Cincinnati Center for Eosinophilic Disorders at Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio.

Rothenberg, who wasn’t involved with this study, has conducted transcriptome analyses of PPI-R-EoE, which showed PPI-reversible allergic inflammation.

“PPI-R-EoE and PPI-NR-EoE look the same at the molecular level,” he said. “After therapy, PPI-R-EoE normalizes, as per its definition.”

This study was supported by the Campaign Urging Research for Eosinophilic Disease Foundation Grant, the Kenneth and Louise Goldberg Junior Faculty Award, and a National Institutes of Health award. Chan declared advisory board positions with several pharmaceutical companies and Rothenberg reported no relevant disclosures.

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