Bram D. van Rhijn

Long-Term Loss of Response in Proton Pump Inhibitor-Responsive Esophageal Eosinophilia Is Uncommon and Influenced by CYP2C19 Genotype and Rhinoconjunctivitis

OBJECTIVES:Proton pump inhibitor-responsive esophageal eosinophilia (PPI-REE) is diagnosed in at least one-third of patients with suspected eosinophilic esophagitis (EoE). We aimed to evaluate the durability and factors influencing long-term efficacy of PPI therapy.METHODS:Retrospective multicenter cohort study of patients with PPI-REE who had at least 12 months of follow-up. PPI therapy was tapered to the lowest dose, which maintained clinical remission. Primary outcomes were the proportion of patients with loss of histological response (<15 eos/HPF) and predictors of loss of response. CYP2C19 polymorphisms were determined from blood samples in a subset of patients.RESULTS:Seventy-five PPI-REE patients were included (mean follow-up 26 months (12–85)), of whom fifty-five (73%) had sustained histological remission on low-dose PPI therapy. Loss of response was significantly higher in those patients with a CYP2C19 rapid metabolizer genotype (36% vs. 6%, P = 0.01) and with rhinoconjunctivitis (40% vs. 13%, P = 0.007). On the multivariate analysis, a CYP2C19 rapid metabolizer genotype (odds ratio (OR) 12.5; 95% confidence interval (CI): 1.3–115.9) and rhinoconjunctivitis (OR 8.6; 95% CI: 1.5–48.7) were independent predictors of loss of response. Among relapsing patients, eosinophilia was limited to the distal esophagus in 14/20 (70%). Nine of ten relapsers, with distal eosinophilia, all showing a CYP2C19 rapid metabolizer genotype, regained histological remission after PPI dose intensification.CONCLUSIONS:Most PPI-REE patients remain in long-term remission on low-dose PPI therapy. CYP2C19 rapid metabolizer genotypes and rhinoconjunctivitis were independent predictors of loss of response to PPI, but patients frequently responded to PPI dose escalation.

Prevalence of esophageal motility abnormalities increases with longer disease duration in adult patients with eosinophilic esophagitis

During the natural course of eosinophilic esophagitis (EoE), the risk for esophageal stricture formation increases. It remains unknown whether motility abnormalities in EoE also develop over time. We aimed to determine the relationship between disease duration, clinical characteristics, and manometric pattern of EoE patients.

Oesophageal baseline impedance values are decreased in patients with eosinophilic oesophagitis

Background Gastro-oesophageal reflux has been suggested to play a role in eosinophilic oesophagitis (EoO). Oesophageal acid exposure decreases baseline intraluminal impedance, a marker of mucosal integrity, in patients with gastro-oesophageal reflux disease (GORD). Objectives The aim of this study was to assess oesophageal baseline impedance levels in EoO patients and to investigate their relationship with oesophageal acid exposure. Methods Ambulatory 24-h pH-impedance monitoring was performed in 11 EoO patients and in 11 healthy controls with matched oesophageal acid exposure. We assessed baseline impedance levels in the distal, mid-, and proximal oesophageal impedance channels. Results Baseline impedance levels in EoO patients were markedly lower compared to controls in the distal oesophagus (median (interquartile range): 988 (757–1978) vs. 2259 (1767–2896) Ω, p = 0.015), mid-oesophagus (1420 (836–2164) vs. 2614 (2374–3879) Ω, p = 0.003), and proximal oesophagus (1856 (1006–2625) vs. 2868 (2397–3439) Ω, p = 0.005). Whereas baseline impedance decreased from proximal to distal in healthy subjects (p = 0.037), no such gradient was seen in EoO patients (p = 0.123). Conclusions Throughout the oesophagus, baseline impedance values are decreased in EoO patients, indicating impaired mucosal integrity. Our findings suggest that factors other than acid reflux are the cause of low baseline impedance in EoO.

PPI-responsive esophageal eosinophilia cannot be distinguished from eosinophilic esophagitis by endoscopic signs.

BackgroundEosinophilic esophagitis (EoE) is a chronic antigen-mediated disease histologically characterized by eosinophil-predominant inflammation. One-third of patients respond to proton pump inhibitor (PPI) treatment; this group is identified as having PPI-responsive esophageal eosinophilia (PPI-REE). If we could predict the response to PPIs on the basis of endoscopic signs, futile treatment efforts and additional endoscopies to assess treatment response can be prevented. ObjectiveTo determine whether endoscopic signs can distinguish PPI-REE from EoE. MethodsEndoscopic images of 30 EoE and 30 PPI-REE patients were included. Baseline characteristics were compared between groups. Complete clinical remission after a PPI trial for at least 8 weeks was classified as PPI-REE. Per patient, at least three depersonalized images were incorporated into a slideshow. These images were scored by two experienced endoscopists according to a validated classification system. ResultsCharacteristics were highly comparable between EoE and PPI-REE patients. Endoscopic signs were similar and did not enable differentiation between EoE and PPI-REE [presence of: rings (P=0.893), white exudates (P=0.209), furrows (P=0.371), edema (P=0.554), crepe paper esophagus (P=1.000), and strictures (P=0.071)]. ConclusionEndoscopic signs at baseline endoscopy cannot distinguish EoE from PPI-REE before a PPI trial; the demographic and clinical characteristics in both groups are similar. Endoscopic features do not enable differentiation between PPI-REE and EoE.

Interactions between gastro-oesophageal reflux disease and eosinophilic oesophagitis.

Gastro-oesophageal reflux disease (GORD) is the most common oesophageal disorder, whereas eosinophilic oesophagitis (EoE) is an emerging disease unresponsive to PPI therapy. Updated guidelines in 2011 described proton pump inhibitor-responsive esophageal eosinophilia (PPI-REE), a novel phenotype in EoE patients who were responsive to PPIs. This article aims to update the complex interplay between GORD, EoE and PPIs. Oesophageal mucosal integrity is diffusely impaired in EoE and PPI-REE patients. PPI-REE might occur with either normal or pathological pH monitoring. The genetic hallmark of EoE is overlapped in PPI-REE, but not in GORD. PPIs can partially restore epithelial integrity and reverse allergic inflammation gene expression in PPI-REE. Acid hypersensitivity in EoE patients may explain symptomatic but not histological response on PPIs. Unsolved issues with PPI-REE are whether oesophageal barrier impairment is the cause or the effect of oesophageal eosinophilia and whether PPIs primarily targets barrier integrity or oesophageal inflammation.

Esophageal and Small Intestinal Mucosal Integrity in Eosinophilic Esophagitis and Response to an Elemental Diet

Objectives:The esophageal mucosal integrity is impaired in eosinophilic esophagitis (EoE) and it has been suggested that the duodenal permeability is increased. The absence of food allergens may restore the integrity. The aims of this study were to assess duodenal permeability in EoE and to evaluate the effect of an elemental diet on the esophageal and duodenal integrity.Methods:In this prospective study 17 adult EoE patients and 8 healthy controls (HC) were included. Esophageal biopsy specimens were sampled before and after 4 weeks of elemental diet to measure eosinophil counts and gene expression of tight junction and barrier integrity proteins. Esophageal and duodenal impedance were measured by electrical tissue impedance spectroscopy and Ussing chambers were used to measure transepithelial resistance (TER) and transepithelial molecule flux. Small intestinal permeability was measured using a test, measuring lactulose/mannitol (L/M) ratios.Results:In EoE patients, the esophageal but not the duodenal integrity was impaired, compared with HC. We observed no significant difference between L/M ratios of HC and EoE patients. After diet, eosinophil counts decreased significantly, which was paralleled by normalization of esophageal impedance and transepithelial molecule flux. The esophageal TER improved significantly, but did not reach values seen in HC. Esophageal expression of genes encoding for barrier integrity proteins filaggrin and desmoglein-1 was impaired at baseline and restored after diet.Conclusions:An elemental diet restores esophageal integrity, suggesting that it is at least partly secondary to allergen exposure. Duodenal integrity seems not to be affected in EoE, and possibly plays a minor role in its pathophysiology.

880 Acid Suppression Restores Impaired Esophageal Mucosal Integrity in Patients With Esophageal Eosinophilia

Introduction: Gastroesophageal reflux and allergies are both thought to play a role in the pathophysiology of eosinophilic esophagitis (EoE). It has been suggested that acid-induced esophageal mucosal damage promotes transepithelial allergen flux. Anecdotal evidence suggests that patients with typical signs and symptoms of EoE benefit from acid-suppressive therapy. The aim of our study was to evaluate esophageal mucosal integrity in patients with significant esophageal eosinophilia (SEE) and to study the effects of acid-suppressive therapy with PPI on symptoms, endoscopic signs, mucosal integrity, dilation of epithelial intercellular spaces (DIS), and peak eosinophilia and mastocytosis. Methods: We included 11 untreated adults with SEE (.15 eosinophils/hpf) and predominant symptoms of dysphagia and/or food impaction and typical endoscopic signs of EoE, and 11 controls. All study subjects underwent endoscopy at baseline; in SEE patients endoscopy was repeated after 8 weeks of esomeprazole 40 mg BID. Esophageal mucosal integrity was measured in vivo during endoscopy with a through-the-scope electrical tissue impedance spectroscopy probe (ETIS) at 5 cm proximal of the LES. At the same location, we obtained 2 biopsies for electron microscopic analysis of DIS and 4 biopsies for mucosal integrity experiments in Ussing chambers. In the Ussing chambers, we measured transepithelial electrical resistance (TER) and transmucosal flux of fluorescently-labelled molecules sized 0.3 and 40 kDa (size of food allergens) during 1 hour. In SEE patients, we additionally scored symptoms and endoscopic signs of EoE. Furthermore, eosinophilia and mastocytosis were scored in biopsies taken at the proximal, midand distal esophagus of SEE patients at each endoscopy. Results: Both structural (DIS) and in vivo and in vitro functional measurements (ETIS, TER, and molecule flux) of mucosal integrity showed significant impairment in SEE patients compared to HC (table 1). After acid-suppressive therapy, mucosal integrity was significantly improved in patients with SEE, but still did not reach the levels seen in controls. Esophageal peak eosinophilia andmastocytosis as well as dysphagia and endoscopic signs of EoE also decreased after acid-suppressive therapy. Conclusion: Patients with SEE have an impaired esophageal mucosal integrity, which is partially restored after acid-suppressive therapy. The observed reduction of transmucosal flux of molecules with a similar size as food allergens after acidsuppressive therapy supports the hypothesis that acid-induced mucosal damage facilitates transepithelial food allergen flux, which results in esophageal eosinophilia. Study parameters in HC and SEE patients

Disease activity in eosinophilic esophagitis is associated with impaired esophageal barrier integrity

In eosinophilic esophagitis (EoE), the esophageal barrier integrity is impaired. Integrity can be assessed with different techniques. To assess the correlations between esophageal eosinophilia and various measures of mucosal integrity and to evaluate whether endoscopic impedance measurements can predict disease activity, endoscopies and mucosal integrity measurements were performed in adult EoE patients with active disease (≥15 eosinophils/high-power field) at baseline (n = 32) and after fluticasone (n = 15) and elemental dietary treatment (n = 14) and in controls (n = 19). Mucosal integrity was evaluated during endoscopy using electrical tissue spectroscopy (ETIS) measuring mucosal impedance and transepithelial electrical resistance (TER) and transepithelial molecule-flux through biopsy specimens in Ussing chambers. We included 61 measurements; 32 of patients at baseline and 29 after treatment, 3 patients dropped out. After treatment, 20 patients were in remission (≤15 eosinophils/high-power field) and these measurements were compared with 41 measurements of patients with active disease (at baseline or after failed treatment). All four mucosal integrity measures showed significant impairment in active EoE compared with remission. Eosinophilia was negatively correlated with ETIS and TER and positively with transepithelial molecule flux (P ≤ 0.001). The optimal ETIS cutoff to predict disease activity was 6,000 Ω·m with a sensitivity of 79% [95% confidence interval (CI) 54-94%], specificity of 84% (95% CI 69-94%), positive predictive values of 89% (95% CI 77-95%) and negative predictive values of 71% (95% CI 54-84%). In EoE patients, markers of mucosal integrity correlate with esophageal eosinophilia. Additionally, endoscopic mucosal impedance measurements can predict disease activity.NEW & NOTEWORTHY In adult patients with eosinophilic esophagitis (EoE), the mucosal integrity, measured by making use of four different parameters, correlates strongly with esophageal eosinophilia. The accuracy of endoscopically measured mucosal impedance to distinguish active disease from remission was acceptable with moderate specificity and sensitivity. Mucosal impedance measurements can predict disease activity in adult EoE patients.

Heterogeneity in Clinical, Endoscopic, and Histologic Outcome Measures and Placebo Response Rates in Clinical Trials of Eosinophilic Esophagitis: A Systematic Review

BACKGROUND & AIMS: Agents are being developed for treatment of eosinophilic esophagitis (EoE). However, it is not clear what outcome measures would best determine the efficacy and safety of these agents in clinical trials. We performed a systematic review of outcomes used in randomized placebo‐controlled trials of EoE and we estimate the placebo response and rates of remission. METHODS: We searched MEDLINE, Embase, CENTRAL, ClinicalTrials.gov, and the EU Clinical Trials Register from inception through February 20, 2018 for randomized controlled trials of pharmacologic therapies for EoE. Efficacy outcome definitions, measurement tools, and the proportion of patients responding to placebo were collected and stratified by based on histologic, endoscopic, and patient‐reported outcomes. RESULTS: We analyzed data from 22 placebo‐controlled trials, comprising 1112 patients with EoE. Ten additional active registered trials were identified. Most published trials evaluated topical corticosteroid therapy (13/22, 59.1%). Histologic outcomes measuring eosinophil density and patient‐reported outcomes were reported in 21/22 published trials (95.5%). No consistently applied definitions of histologic or patient‐reported response or remission were identified. Endoscopic outcomes were described in 60% (12/20) of published trials. The EoE Endoscopic Reference Score is the most commonly applied tool for describing changes in endoscopic appearance. The median histologic response to placebo was 3.7% (range, 0%–31.6%) and the median rate of remission in patients given placebo was 0.0% (range, 0%–11.0%). The median patient‐reported response to placebo was 14.4% (range, 8.6%–77.8%) and rate of remission in patients given placebo was 26.2% (range, 13.2%–35.7%). CONCLUSIONS: In a systematic review of the literature, we found that no standardized definitions of histologic, endoscopic, or patient‐reported outcomes are used to determine whether pharmacologic agents produce a response or remission in patients with EoE. A core outcome set is needed to reduce heterogeneity in outcome reporting and facilitate trial interpretation and comparison of results from trials.

Management of Eosinophilic Esophagitis Based on Pathophysiological Evidence

Over the past decades eosinophilic esophagitis (EoE) has been increasingly diagnosed, and significant progress has been made in our understanding of its pathophysiology. As EoE cannot be cured yet, treatment goals are suppression of disease activity and symptoms as well as the prevention of progression to a more severe disease phenotype. Disease-modifying treatment options can be divided into dietary therapy and immunosuppressive medications, of which topical steroids have been most investigated, yet are still prescribed off-label. In this review, we will summarize recent advances in our understanding of EoE and discuss the mechanisms of action of current treatment options, with emphasis on the role of the esophageal epithelial barrier and the effects of proton-pump inhibitors in the management of patients with EoE.