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

Molecular and Genetic Basis Underlying Response to Proton Pump Inhibitor Therapy

A response to PPI therapy was assumed to establish the diagnosis of GERD in 2007,[1] and was still out of the EoE spectrum in 2011[3] and 2013.[4] Nevertheless, the phenotypic expression of PPI responders and nonresponders (including clinical, endoscopic, esophageal pH monitoring, and histologic features) is virtually indistinguishable.[2,5–7,10,11,17–19] Hence, it would be important to characterize the molecular and genetic basis of patients with suspected EoE who respond to PPIs. EoE is well known to be a chronic immunoallergic disorder characterized by an aberrant Th2 inflammatory response involving IL-5 and IL-13 and local production of CCL26 (eotaxin-3), a chemokine that specifically attracts eosinophils to the esophageal mucosa. When activated, the eosinophils cause local tissue damage and recruit and/or activate other effector cells, such as mast cells, which are key modulators of esophageal fibrous remodeling.[20] Moreover, a molecular EoE diagnostic panel has been recently developed by using whole-genome transcript expression profiling of esophageal tissue.[21] This panel comprises 94 EoE genes and accurately distinguishes patients with EoE from GERD and control subjects.[21] Regarding the molecular basis, baseline expression of markers of eosinophilic inflammation (eosinophil derived major basic protein and CCL26), and genes modulating mast cell signature or involved in type 2 (Th2) associated allergic inflammation (including CCL26, IL-5, IL-13, thymic stromal lymphopoietin and periostin (POSTN)) in esophageal tissue have demonstrated largely overlapping patterns between nonresponders and responders to PPI therapy.[5,22,23] A first milestone study from the United States[24] and a very recent study from Japan[25] have demonstrated that, unlike GERD patients, responders to PPI therapy have a transcriptome that nearly completely overlaps with that in nonresponders to PPIs, including the hallmark EoE genes for eosinophil chemotaxis (CCL26), barrier molecules (desmoglein DSG1), tissue remodeling (POSTN), and mast cells (CPA3). Recent genome wide association studies in EoE have identified two replicated susceptibility loci at 2p23 and 5q22, regions that encode the epithelial gene products CAPN14 and TSLP. [26–28] Susceptibility loci were equally present in PPI responders and nonresponders, reinforcing the idea that both groups of patients, independent of PPI stratification, share a similar molecular and genetic etiology.

Moreover, recent clinical studies have shown that PPI monotherapy in PPI-REE patients can almost completely reverse the Th2 signature (CCL26, IL-5, IL-13, POSTN)[5,23,24] while concurrently inducing normalization of mast cell genes (CPA3, TPSAB2), Th2 inflammation indicators (TNFAIP6, ALOX15), epithelial barrier genes (DSG1, CDH26, FLG), tissue fibrosis markers (e.g. KRT13), and IL-13/IL-4–induced genes (POSTN, MUC4).[24] These effects are similar to those of topical steroids[29,30] or anti-IL-13 biological drugs in EoE patients.[31] Finally, two recent series have described EoE patients who initially responded to diet and topical steroid therapy and who were later found to respond to PPI therapy, and vice versa.[32,33] Therefore, PPI therapy has similar clinical, histologic, molecular, and genetic effects in PPI-responto those shown for conventional EoE therapies (eg, diet and steroids).

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