Response of Eosinophilic Oesophagitis to Proton Pump Inhibitors Is Associated With Impedance-pH Parameters Implying Anti-reflux Mechanism of Action

Marzio Frazzoni; Leonardo Frazzoni; Nicola De Bortoli; Salvatore Russo; Salvatore Tolone; Elena Arsiè; Rita Conigliaro; Roberto Penagini; Edoardo Savarino

Disclosures

Aliment Pharmacol Ther. 2021;53(11):1183-1189. 

In This Article

Abstract and Introduction

Abstract

Background: Proton pump inhibitors (PPIs) are effective therapies for eosinophilic oesophagitis (EoE), but the mechanism of action is uncertain. At on-PPI impedance-pH monitoring, improvement in oesophageal chemical clearance assessed with post-reflux swallow-induced peristaltic wave (PSPW) index characterises PPI-responsive EoE and reflux disease. Off-PPI, higher efficacy of the oesophago-salivary reflex as measured with PSPW-associated pH increments characterises PPI-responsive reflux disease and could typify PPI-responsive EoE as well.

Aim: To establish whether PPI responsiveness in EoE is associated with higher efficacy of the oesophago-salivary reflex.

Methods: Prospective multicentre study in EoE patients investigated with impedance-pH monitoring before starting PPI. Impedance-pH parameters in PPI-responsive and PPI-refractory cases were compared. PPI response was defined histologically.

Results: Considerable PSPW-associated pH increments (median 1.4 units) were found in 80 EoE patients, with significantly higher values in 48 PPI-responsive than in 32 PPI-refractory cases (1.8 vs 1.0, P = 0.02). Mucosal integrity, as measured with mean nocturnal baseline impedance was more severely impaired in the distal oesophagus in PPI-responsive cases, the gradient between mid and distal oesophagus being significantly higher (546 vs 137 Ω, P = 0.0002). PSPW-associated pH increments and the baseline impedance gradient between mid and distal oesophagus were independently associated with histological response at multivariable logistic regression; at receiver operating characteristic analysis, the area under the curve of PPI response calculated by combined assessment was 0.88.

Conclusion:Higher efficacy of oesophago-salivary reflex and more severe mucosal damage in the distal oesophagus are associated with EoE response to PPIs, implying an anti-reflux mechanism of action as most likely.

Introduction

Eosinophilic oesophagitis (EoE) is a chronic inflammatory oesophageal disease characterised by symptoms related to oesophageal dysfunction, that is, recurrent food impaction and dysphagia, and by an eosinophil-predominant infiltration of the oesophageal mucosa.[1,2] Overlap between EoE and gastro-oesophageal reflux disease (GERD) has long been recognised: indeed, the two disorders may coexist and influence each other.[3] Proton pump inhibitors (PPIs), the mainstay of medical treatment for GERD, represent an effective option for inducing[4–6] and maintaining[7] clinical and histological remission in approximately half of patients with EoE, currently representing first-line treatment in clinical practice in several countries.[8] Unfortunately, clinical, endoscopic and pH-metric findings do not predict PPI response.[9,10] Indeed, the mechanism underlying PPI efficacy in EoE has not yet been elucidated: in vitro studies suggested direct anti-inflammatory properties of acid-activated omeprazole.[11] However, PPIs are prodrugs requiring an acidic environment to be activated but normal acid exposure time (AET) has been reported in two thirds of EoE patients.[10]

GERD pathophysiology is due to the complex interplay between noxious gastric contents and defence mechanisms, the latter including oesophageal clearance. Experimental studies showed that oesophageal clearance consists of volume and chemical clearance, the former removing the bulk of refluxate and the latter restoring oesophageal pH by means of bicarbonate-containing saliva, swallowed in response to a vagal oesophago-salivary reflex.[12] Chemical clearance can be assessed at impedance-pH monitoring with the post-reflux swallow-induced peristaltic wave (PSPW) index[13] and is impaired in typical GERD, that is, reflux-related heartburn.[14] In a recent prospective multicentre study,[15] AET was not significantly higher in 60 EoE patients as compared to 60 gender- and age-matched healthy controls, whereas reflux burden as measured with the number of total reflux episodes was significantly higher, and chemical clearance as measured with the PSPW index was significantly impaired. Interestingly, PSPW index improved on therapy in PPI-responsive but not in PPI-refractory EoE patients[15] similar to what happens in typical GERD.[16] Further, baseline off-therapy oesophageal mucosal damage as measured with mean nocturnal baseline impedance (MNBI) was more severe in the distal than in the mid oesophagus in PPI-responsive EoE, similar to typical GERD cases, while no significant differences were found in PPI-refractory EoE cases.[15] Overall, these findings suggested that reflux plays some role in the pathogenesis of EoE.

Recently, we have shown that PSPWs are associated with considerable pH increments (ΔpH) in GERD, showing that PSPWs reveal the occurrence of the oesophago-salivary reflex in clinical setting.[17] Moreover, we found that higher PSPW-associated ΔpH values efficiently predict PPI response in GERD,[17] indicating that the oesophago-salivary reflex represents a major defence mechanism against reflux and a key factor in PPI responsiveness. Demonstration that oesophago-salivary reflex is associated with PPI response in EoE would imply anti-reflux mechanism of action.

The aim of the present study was to assess whether PSPW-associated ΔpH and other impedance-pH parameters are associated with PPI responsiveness in EoE.

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