Beyond monotherapy by acid suppression: Reshaping the management of refractory gastroesophageal reflux disease

Abstract

Gastroesophageal reflux disease (GERD) is highly prevalent worldwide. Although standard proton pump inhibitor (PPI) or potassium-competitive acid blocker therapy is effective in most patients, some patients develop refractory GERD (rGERD). Previous studies exploring the characteristics and risk factors for rGERD had substantial limitations. A recent multicenter cross-sectional study conducted across 18 medical centers in Shanghai directly compared GERD and rGERD, and identified prolonged disease duration and anxiety as independent high-risk factors for rGERD. Moderate-intensity physical activity for at least 90 minutes/week was found to be a protective factor. The 8-week PPI/potassium-competitive acid blocker therapy is the standard regimen for GERD, whereas adjustments are needed for rGERD, such as switching or increasing the dose of PPIs or using vonoprazan instead. Additionally, endoscopic interventions and surgeries are supplementary options for patients with rGERD. Anti-anxiety interventions, standardized exercise prescriptions, and lifestyle factors such as sleep and weight management should be explored as a “multidimensional risk-targeted intervention” for the management and treatment of rGERD. This multicenter cross-sectional study offers forward-looking findings for rGERD prevention, but has limitations: A single-region sample lacks representativeness, and its cross-sectional design requires long-term randomized controlled trial for causal evidence.

Key Words: Refractory gastroesophageal reflux disease; Anxiety; Holistic medicine; Endoscopic intervention; Multidisciplinary management

Core Tip: A recent Shanghai study identified prolonged disease duration and anxiety as key risk factors for refractory gastroesophageal reflux disease, whereas moderate physical activity is protective. Management should extend beyond standard acid suppression to include a “multidimensional” strategy incorporating anti-anxiety interventions, exercise prescriptions, and multidisciplinary collaboration. However, the study’s single-region sample and cross-sectional design necessitate future multi-regional, long-term research to validate and establish causality.

INTRODUCTION

Gastroesophageal reflux disease (GERD) is a common disorder with increasing global prevalence[1]. A recent multicenter cross-sectional study conducted across 18 medical centers in Shanghai challenged the conventional approach of treating GERD solely through acid suppression[2]. Refractory GERD (rGERD) is defined as partially responsive or non-responsive to a stable dose of a proton pump inhibitor/potassium-competitive acid blockers during a treatment period of at least 8 weeks in this study. Here, we report the first systematic comparison of GERD and rGERD in a Chinese population, identifying prolonged disease duration and anxiety[3] as independent high-risk factors. Moreover, engaging in moderate-intensity exercise for ≥ 90 minutes weekly demonstrated a protective effect. These findings provide potential criteria for early clinical identification of high-risk patients.

CLINICAL IMPLICATIONS: CONSTRUCTING A STEPPED MULTI-MODAL INTERVENTION PATHWAY FOR RGERD

Therapies for rGERD should move beyond the conventional 8-week proton pump inhibitor/potassium-competitive acid blocker regimen[4] toward individualized strategies. These include adjustments to drug selection and dosing, introduction of novel agents such as vonoprazan[5,6] and incorporation of endoscopic interventions[7] for patients unresponsive to medication. Following these treatments, patients with rGERD whose symptoms persist, particularly those presenting with extra-esophageal manifestations, should be actively considered for surgical intervention. This stepwise multi-modal treatment pathway offers a greater practical feasibility.

CONCEPTUAL EXPANSION: FROM “SINGLE-DIMENSIONAL TREATMENT” TO “PHYSIOLOGY-PSYCHOLOGY-BEHAVIOR” TRINITARIAN MANAGEMENT

Based on the potential triggers of rGERD, the concept of “multidimensional risk-targeted intervention” is proposed. This emphasizes the need to integrate lifestyle factors, such as anti-anxiety interventions, standardized exercise prescriptions, and sleep and weight management, to form a comprehensive management model encompassing physiological, psychological, and behavioral dimensions[8]. A multidisciplinary team involving otolaryngology, respiratory, and psychiatry is required to conduct a comprehensive assessment and provide integrated treatment for the patient. This model not only expands the traditional framework of GERD diagnosis and treatment but also aligns with the contemporary trend in medicine towards holistic approaches[9].

CONCLUSION

This study represents a crucial step in developing prevention and treatment strategies for rGERD, yielding findings that are academically forward-looking and clinically translatable. However, the following limitations and areas for improvement exist: First, the study exclusively enrolled patients from Shanghai, resulting in poor sample representativeness. Future research should adopt a multi-regional, multi-ethnic design (e.g., comparing rGERD prevalence between northern regions with high-salt diets and southern regions) to validate the generalizability of conclusions. Second, the cross-sectional design necessitates the establishment of a prospective, multi-center, randomized controlled trial of patients with rGERD to dynamically observe the impact of “disease duration, anxiety, and physical activity” on disease progression, thereby providing higher-level causal evidence.