Proton Pump Inhibitor-responsive Esophageal Eosinophilia: Still a Valid Diagnosis?

Javier Molina-Infante; Pedro L. Gonzalez-Cordero; Alfredo J. Lucendo

Disclosures

Curr Opin Gastroenterol. 2017;33(4):285-292. 

In This Article

Research Agenda for the Future

Type, Doses, Interval Dosing and Duration for Acid Suppressive Drugs

An important recent breakthrough is the first series of four patients with suspected EoE unresponsive to PPI therapy, who achieved complete remission on vonoprazan.[41] Vonoprazan is a novel potassium-competitive acid blocker with a different mechanism of action than PPIs. Vonoprazan has a more potent and sustained acid suppressive effect and is less affected by CYP2C19 polymorphisms than PPIs. The main criticism of this study relates to the adequacy of the PPI doses and interval dosing regimens (esomeprazole 20 mg daily), which raises concerns about underestimation of the response to PPI therapy. This dose might suffice for mild reflux symptoms, but not for a chronic immuno-allergic disorder. All available guidelines recommend a minimum dose of 20–40 mg twice daily for a minimum of 8 weeks to adequately assess the response to PPI therapy.[1,3,4,36] In this regard, a case report has recently described a patient who achieved histologic improvement but no remission after a 2-month course of PPI therapy (dexlansoprazole 60 mg once daily), and who finally achieved remission after four months on the same drug in the same dose.[42] This study suggests the existence of a subset of slow responders to PPIs who may need more than 2 months for complete resolution. Undoubtedly, more studies on this issue and on vonoprazan are warranted.

Potential Interactions Between Gastroesophageal Reflux Disease and Eosinophilic Esophagitis

Presently, EoE is defined as an immune/antigen-driven disease, and no allergic disease has been shown to respond completely to acid suppressive drugs. Some recent studies have advocated the importance of GERD as a potential trigger for EoE that responds to PPIs.[41,43,44] GERD and EoE, triggering Th1-mediated and Th2-mediated immune response, respectively, are not mutually exclusive disorders anymore.[34] Extrapolating data from studies on asthma, Fig. 2 summarizes potential mechanisms of interactions between Th1 and Th2 inflammatory responses.[45]

Figure 2.

Interactions between GERD (Th1 immune response) and EoE (Th2 immune response). Extrapolation from development of immune response in asthma [45]: overexpression of Th1 activity and epithelial integrity impairment may promote subsequent recruitment of Th2 cells, providing a setting for enhanced allergen responsiveness (top figures). Alternatively, nonallergen-driven local production of Th1 cytokines (eg, viruses in airway tract, GERD in esophagus) may be redirected to production of Th2 cytokines (bottom figures). EoE, eosinophilic esophagitis; GERD, gastroesophageal reflux disease

Mechanisms Involved in Response of Eosinophilic Esophagitis to Proton Pump Inhibitor Therapy

The most accepted hypotheses for the mechanism whereby PPIs are beneficial in EoE include their direct acid suppressive effects or their anti-inflammatory effects that are independent of acid suppression.[44] PPI therapy has recently been shown to down-regulate Th2 allergic esophageal inflammation[5,23,24] but it is not certain whether this is a direct (primary anti-inflammatory effect) or indirect (primary acid inhibition leading to secondary inflammation healing) effect.

As for acid suppression, it is important to note that GERD has been historically deemed to develop as a chemical injury starting at the epithelial surface. The acid-induced death of surface cells is assumed to stimulate hyperplasia of papillae and basal cells, provoking an inflammatory Th1 cascade, mainly made up of granulocytes and lymphocytes. If GERD is assumed to be the event that triggers EoE in patients who respond to PPIs, and PPIs are thought to act solely through gastric acid suppression, then it is crucial to appreciate that these PPI responders do not have just conventional GERD. As mentioned, EoE patient who respond to PPI therapy (ie, PPI-REE – a term we prefer not to use) exhibit the same genetic and molecular Th2 features as EoE patients who do not respond to PPIs[35] Of note, an alternative concept for GERD pathogenesis recently has been proposed based on an earlier study in a murine model[46] and later confirmed in a study in humans.[47] The authors demonstrated that refluxed gastric material did not appear to damage esophageal epithelial cells directly, but stimulated them to secrete cytokines that attracted immune cells, which ultimately damaged the mucosa. In other words, GERD might be a cytokine-mediated disease rather than a chemical injury-mediated disease. This revolutionary new concept opens up a number of hypotheses to explain responsiveness to acid suppressive drugs, including PPIs and vonoprazan. Might there be an 'allergic' form GERD, in which gastroesophageal reflux incites a conventional Th1 response that triggers Th2 inflammation in a subset of atopic patients? (See Fig. 2) In the first study to demonstrate esophageal anti-inflammatory effects of PPI therapy, esophageal squamous cells from EoE patients and from GERD patients both exhibited a similar increase in the expression of the eosinophil chemoattractant eotaxin-3 when they were stimulated with a Th2 cytokine (IL-4), suggesting that the esophagus of GERD patients might be driven to a Th2 inflammatory cascade given the appropriate stimulus.[48]

Regarding anti-inflammatory effects, omeprazole, in concentrations in vitro equivalent to those achieved in blood with conventional dosing, inhibits Th2 cytokine-stimulated eotaxin-3 secretion in isolated esophageal epithelial cells by blocking binding of the transcription factor STAT6 to the eotaxin-3 promoter.[48] Anti-inflammatory effects of PPIs have been demonstrated only in studies using EoE cells in vitro. While omeprazole in vitro is present in the culture media for up to 48 h, the short half-life for PPI drugs (1–2 h active) makes it unclear if a sustained anti-inflammatory effect is maintained in vivo. Nevertheless, recent studies showing PPIs downregulating effects of eotaxin-3 in murine asthma[49] and chronic rhinosinusitis with nasal polyps, both in vitro and in vivo,[50] corroborate that PPIs might have anti-inflammatory effects unrelated to acid suppression. Further studies evaluating these novel anti-inflammatory effects of PPIs are definitely warranted.

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