Proton Pump Inhibitor Therapy for Eosinophilic Esophagitis: History, Mechanisms, Efficacy, and Future Directions

Abstract

Over the past decade, the role of proton pump inhibitor (PPI) medication has evolved from a diagnostic tool for Eosinophilic Esophagitis (EoE), by excluding patients with PPI responsive esophageal eosinophilia (PPI-REE), to a therapy for EoE. This transition resulted from the Updated International Consensus Diagnostic Criteria for Eosinophilic Esophagitis: Proceedings of the Appraisal of Guidelines for Research and Evaluation II (AGREE) Conference to support PPI therapy for EoE in children and adults. Additional recent advances have suggested a role for genetic variations that might impact response to PPI therapy for EoE. This review article will explore a brief background of EoE, the evolution of PPI therapy for EoE and its proposed mechanisms, efficacy and safety in children and adults, and considerations for future PPI precision medicine in patients with EoE.

Keywords: EoE; PPI; eosinophilic esophagitis; precision medicine; proton pump inhibitor medication.

Figure 1

Eosinophilic esophagitis: clinical & pathophysiologic overview.

Figure 2

Progression of PPI therapy from diagnostic tool to therapy for EoE. Initial belief that EoE was a consequence of GERD led to early interest in PPIs as a therapy for EoE. Next, it was hypothesized that PPI-responsive esophageal eosinophilia (PPI-REE) was a condition distinct from EoE. A lack of response to PPIs was subsequently viewed as an essential diagnostic criterion for EoE. Subsequently, characterizations of PPI-REE and EoE patients at the molecular level showed that the two conditions are virtually identical leading to the hypothesis that they are at different points along a continuum. Recent guidelines, enlightened by this observation, now view PPIs as a therapy rather than a diagnostic for EoE.

Figure 3

Proposed mechanisms of PPI efficacy for EoE. (A) Anti-Secretory Mechanism: Hypothesizes that the integrity of the esophageal epithelium is compromised by exposure to gastric acid leading to ingress of antigens and activation of an immune response. Acid suppression by PPIs allows the esophageal epithelium to heal facilitating resolution of inflammation. (B) Anti-Inflammatory Mechanisms: 1.) PPIs block expression of cell surface adhesion molecules, inhibiting migration of inflammatory cells to the esophageal epithelium; 2.) PPIs block STAT6 mediated expression of eotaxin-3 reducing recruitment of eosinophils to the esophageal epithelium; 3.) PPIs can stimulate the aryl hydrocarbon receptor normalizing expression of genes involved in barrier function including, filaggrin, loricrin, and involucrin through inhibition of the IL-4/IL-13-STAT6 pathway; 4.) PPIs can inhibit the activity of ATP12A, the non-gastric P2-type H⁺, K⁺-ATPase. IL-4 mediated induction of eotaxin-3 secretion is sensitive to inhibition of ATP12A.

Figure 4

PPI efficacy in adults: histologic remission (<15 eos/hpf). The analysis was conducted using the R statistical package metafor, assuming a fixed effects model and using inverse-variance weighting. The reported summary statistic is the back-transformed inverse-variance weighted average for histologic remission across all studies listed in adults. References: Garrean, 2009, Peterson, 2010, Molina-Infante, 2011, Abe, 2011, Fujiwara, 2012, Francis, 2012, Vazquez-Elizondo, 2013, Moawad, 2013, Lee, 2013, Dellon, 2013, Mangla, 2014, Molina-Infante, 2014, Van Rhijn, 2014, Philpott, 2016, Gómez-Torrijos, 2016, Frazzoni, 2021.

Figure 5

PPI efficacy in children: histologic remission (<15 eos/hpf). The analysis was conducted using the R statistical package metafor, assuming a fixed effects model and using inverse-variance weighting. The reported summary statistic is the back-transformed inverse-variance weighted average for histologic remission across all studies listed in children. References: Sayej, 2009, Dranove, 2009, Schroeder, 2013, Rea, 2013, Gutiérrez-Junquera, 2016, Gómez-Torrijos, 2018, Harris, 2018, Vieira, 2020, Rosen, 2021.

Figure 6

Therapy for eosinophilic esophagitis: framework for proposed future directions. Current research is focused on identifying a minimal set of non-invasive informative markers (transcriptomic,,, genomic, proteomic, metabolomic, history, etc.) that predict how a patient will respond to PPIs for EoE. For a review of potentially informative non-invasive biomarkers that predict active EoE, see Votto et al. Some of the biomarkers reviewed by Votto et al may also be informative for a PPI-responsive outcome when assessed prior to PPI therapy. Given this information, patients can potentially be identified as low-dose PPI responders, high-dose PPI responders, PPI non-responders, etc., prior to initiation of therapy, allowing selection of the appropriate therapy to achieve resolution of inflammation.