UNASSIGNED: Refractory gastroesophageal reflux disease (refractory GERD) is a heterogeneous disease characterized by unresponsiveness or poor efficacy to proton-pump inhibitors (PPIs). This chronic disorder substantially weakens patients\' mental wellbeing and quality of life, increasing the financial burden on society. Multiple articles have been reported in this area. However, literature involving scientometric analysis of refractory GERD is absent. Therefore, it is necessary to understand the evolution of research themes and the main hotspots of refractory GERD through bibliometric methods.
UNASSIGNED: All documents related to refractory GERD based on the WOS Core Collection from January 2000 to November 2023 were selected for analysis. Citespace V 6.1 R6, VOSviewer V 1.6.20, and Scimago Graphica V 1.0.38 were used to perform bibliometric analysis.
UNASSIGNED: We collected a total of 241 research articles from 36 countries and 322 institutions, contributed by over 1,000 authors. Over the last 20 years, the number of articles in this field has increased year by year, and since 2011, the number of publications has increased dramatically, with 85.89% of the papers. These countries are led by the United States and Japan. GUT had the highest number of citations and DIGESTION had the highest number of publications. Research on standardized diagnosis and management, mechanisms, novel monitoring methods, and innovative drugs and procedures for refractory GERD are the main topics and hotspots in this field. This study also found that neuroimmune interaction is closely related to refractory GERD, which may be a new direction for future mechanism research.
UNASSIGNED: Our study is the first bibliometric analysis of the global literature on refractory GERD. This research provides valuable insights for researchers, enabling them to quickly understand the research frontier and hot topics of this field.

<b><br>Introduction:</b> Gastroesophageal reflux (GERD) is one of the most common disorders of the alimentary tract. Apart from troublesome symptoms, untreated GERD can lead to Barrett\'s esophagus and, as a consequence, esophageal adenocarcinoma. As for now, the most common treatment of GERD is PPI pharmacotherapy. However, in a number of cases, this treatment is not sufficient or the patient does not tolerate PPI-group drugs. In such cases, interventional therapy is recommended. So far, laparoscopic fundoplication has been the only suggested option. Other, minimally invasive procedures such as Stretta, MUSE, TIFF, or EsophyX were not recommended due to the lack of clinical data. In 2014, Professor H.Inoue from the Digestive Diseases Center, Showa University in Japan reported on the first series of novel, endoscopic, anti-reflux procedures: anti-reflux mucosectomy (ARMS) and anti-reflux mucosal ablation (ARMA).</br> <b><br>Methods:</b> We conducted our prospective, single-center study in 30 patients (14 female, 16 male) with PPI-refractory GERD. All patients underwent FSSG and GERD-HRQL evaluation and GE junction pressure study prior, 6 weeks and 6 months after the procedures. After the procedure, all patients received PPI treatment for 4 weeks.</br> <b><br>Results:</b> We successfully completed the procedures in all 30 patients. The mean procedure time was 42 minutes. No complications occurred. In 86.67% (26) of our patients, we achieved total remission of GERD symptoms, FSSG scores < 6 and GERD-HRQL scores < 8.</br> <b><br>Conclusions:</b> The results of our study show that ARMS and ARMA are simple, safe, improve GERD-related symptoms, and restore the GE junction\'s anti-reflux capacity.</br>.

OBJECTIVE: Up to 40% of gastroesophageal reflux disease (GERD) patients experience inadequate symptom relief with a proton pump inhibitor (PPI), termed PPI-resistant or refractory GERD. Vonoprazan, a potassium-competitive acid blocker, has better efficacy than PPI in suppressing gastric acid secretion. This meta-analysis summarizes the efficacy and safety of vonoprazan for treating PPI-resistant GERD (both erosive esophagitis [EE] and non-erosive reflux disease [NERD]).
METHODS: Four electronic databases (Medline, Embase, SCOPUS, and CENTRAL) were searched for studies indexed until August 1, 2023. Both observational studies and clinical trials assessing the efficacy and safety of vonoprazan in PPI-resistant GERD were included. Efficacy outcomes included healing and maintenance rates of EE and improvement of the Frequency Scale for Symptoms of GERD (FSSG) scores. Serious adverse events (SAEs) were considered a safety outcome. The modified Newcastle-Ottawa Scale (NOS) was used to assess study quality.
RESULTS: Twelve studies were included in this meta-analysis. Healing rates of PPI-resistant EE with vonoprazan 20 mg were 91.7% (95% CI 86.8-94.8%) and 88.5% (95% CI 69.7-96.2%) at weeks 4 and 8, respectively. For healed PPI-resistant EE, the overall maintenance rates with vonoprazan 10 mg were 82.6% (95% 61.2-95.0%) at week 8, 86.0% (95% CI 72.1-94.7%) at week 24, and 93.8% (95% CI 69.8-99.8%) at week 48. FSSG scores were improved in 74.6% (95% CI 65.8-81.7%) and 51.9% (95% CI 37.8-65.7%) of patients at weeks 4 and 8. Overall, no SAE was reported.
CONCLUSIONS: Vonoprazan demonstrated high efficacy in the healing and maintenance of PPI-resistant EE and moderate efficacy for the improvement of FSSG score. Vonoprazan was well tolerated in PPI-resistant GERD patients.

Gastroesophageal reflux disease (GERD) is common, with increasing worldwide disease prevalence and high economic burden. A significant number of patients will remain symptomatic following an empiric proton pump inhibitor (PPI) trial. Persistent symptoms despite PPI therapy are often mislabeled as refractory GERD. For patients with no prior GERD evidence (unproven GERD), testing is performed off antisecretory therapy to identify objective evidence of pathologic reflux using criteria outlined by the Lyon consensus. In proven GERD, differentiation between refractory symptoms (persisting symptoms despite optimized antisecretory therapy) and refractory GERD (abnormal reflux metrics on ambulatory pH impedance monitoring and/or persistent erosive esophagitis on endoscopy while on optimized PPI therapy) can direct subsequent management. While refractory symptoms may arise from esophageal hypersensitivity or functional heartburn, proven refractory GERD requires personalization of the management approach, tapping from an array of non-pharmacologic, pharmacologic, endoscopic, and surgical interventions. Proper diagnosis and management of refractory GERD is critical to mitigate undesirable long-term complications such as strictures, Barrett\'s esophagus, and esophageal adenocarcinoma. This review outlines the diagnostic workup of patients presenting with refractory GERD symptoms, describes the distinction between unproven and proven GERD, and provides a comprehensive review of the current treatment strategies available for the management of refractory GERD.

BACKGROUND: Gastroesophageal reflux disease (GERD) affects a significant proportion of individuals, with life stress being a contributing factor. This study aimed to investigate the correlation between psychosomatic evaluations, heart rate variability (HRV), and GERD in a cohort of individuals. Additionally, the study aimed to analyze the sequencing changes following proton pump inhibitor (PPI) treatment and identify predictive factors associated with refractory GERD.
METHODS: A prospective cohort of 105 individuals with reflux esophagitis and a control group of 50 participants without acid reflux symptoms were enrolled. Psychosomatic evaluations, including GERDQ, GERDQLQ, RSI, BAI, BDI, and SSS-8, were assessed at baseline and during treatment. HRV parameters were also evaluated. Multivariate analysis was used to identify predictive factors for refractory GERD. PPIs were administered regularly for the initial 2 months and then used on-demand. Refractory GERD was defined as less than 50% improvement in symptom relief or GERDQLQ score ≥ 20 after 8 weeks of PPI treatment.
RESULTS: The GERD group had higher scores in all psychosomatic evaluations compared to the control group (all p-values < 0.001). There were no significant changes in any parameters of HRV before and after treatment in the GERD group. Strong and consistent correlations were observed between GERD symptoms and psychological scores (BAI, BDI, and SSS-8) across all time points (W0, W4, and W8). Sequential reductions in GERD symptom scores and psychosomatic evaluations were observed during the initial eight weeks of treatment. Higher GERDQ (≥10) and SSS-8 (≥12) scores were predictive of refractory GERD (p = 0.004 and p = 0.009, respectively).
CONCLUSIONS: This study emphasizes the importance of considering physiological and psychological factors in the management of GERD. Psychosomatic evaluations provide valuable insights for assessing and treating GERD patients. Integrating stress management and comprehensive assessments into personalized treatment strategies is crucial.

On-therapy impedance-pH monitoring is recommended in patients with documented GERD and PPI-refractory heartburn in order to establish whether the unremitting symptom is reflux-related or not.
To define on-PPI cut-offs of impedance-pH metrics allowing proper interpretation of on-therapy impedance-pH monitoring.
Blinded expert review of impedance-pH tracings performed during double-dosage PPI, prospectively collected from 150 GERD patients with PPI-refractory heartburn and 45 GERD patients with PPI-responsive heartburn but persisting extra-esophageal symptoms. Acid exposure time (AET), number of total refluxes (TRs), post-reflux swallow-induced peristaltic wave (PSPW) index, and mean nocturnal baseline impedance (MNBI) were assessed. On-PPI cut-offs were defined and evaluated with ROC analysis and the area under curve (AUC).
All the four impedance-pH metrics significantly differed between PPI-refractory and PPI-responsive heartburn cases. At ROC analysis, AUC was 0.73 for AET, 0.75 for TRs, 0.81 for PSPW index, and 0.71 for MNBI; best cut-offs were ≥1.7% for AET, ≥45 for TRs, ≤36% for PSPW index, and ≤ 1847 Ω for MNBI; AUC of such cut-offs was 0.66, 0.71, 0.73, and 0.68, respectively. Analysis of PSPW index and MNBI added to assessment of AET and TRs significantly increased the yield of on-therapy impedance-pH monitoring in the PPI-refractory cohort (97% vs. 83%, p < 0.0001). Notably, suboptimal acid suppression as shown by AET ≥1.7% was detected in 43% of 150 PPI-refractory cases.
We have defined on-PPI cut-offs of impedance-pH metrics by which comprehensive assessment of impedance-pH tracings, including analysis of PSPW index and MNBI can efficiently characterize PPI-refractory GERD and support treatment escalation.

Magnetic sphincter augmentation (MSA) is a surgical intervention for well-characterized gastroesophageal reflux disease (GERD), where the esophagogastric junction barrier is augmented using a bracelet of magnetized titanium beads. MSA could be an attractive option for patients with documented GERD who wish to avoid long-term pharmacologic therapy or whose symptoms are not adequately managed with lifestyle modifications and pharmacologic therapy. The \'ideal\' MSA patient is one with prominent regurgitation, without dysphagia or esophageal motor dysfunction, with objective evidence of GERD on upper endoscopy and/or ambulatory reflux monitoring. Appropriate candidates with significant hiatus hernia may pursue MSA with concomitant hiatus hernia repair. The increasing adoption of MSA in the GERD treatment pathway reflects research that shows benefits in long-term outcomes and healthcare costs compared with other established therapies in appropriate clinical settings.

Refractory Gastroesophageal Reflux Disease (GERD) is a typical GERD that does not respond to Proton Pump Inhibitor (PPI) treatment for 8-12 weeks. One of the differential diagnoses for refractory GERD is eosinophilic esophagitis which is characterized by eosinophilic infiltration into the esophagus endothelium. However, to date, eosinophilic esophagitis is still poorly understood and data is still limited. The aim was to describe the profile and characteristics of patients with eosinophilic esophagitis presenting with refractory GERD in Makassar, Indonesia. This descriptive study involved patients with refractory GERD from two hospitals. In addition to basic demographic data, history, and body mass index, all subjects underwent peripheral blood tests to measure eosinophil level and flexible esophagoscopy, from which esophageal biopsy was done to assess the tissue eosinophil level. Eosinophilic esophagitis was established based on the examination of >15 eosinophils/high power field. Out of 32 subjects, two subjects were diagnosed with eosinophilic esophagitis (6.3%). Both subjects were male with normal BMI in the age range of 36-55 years and none had peripheral blood eosinophilia. Symptoms of eosinophilic esophagitis were similar to refractory GERD. Peripheral blood eosinophilia was not associated with incidence of eosinophilic esophagitis.

Post-fundoplication dyspepsia is a common complication of gastric fundoplication surgeries. This can be attributable to the loss of fundal relaxation, decreased gastric accommodation, and/or alterations in gastric motility and sensitivity following fundoplication. The role of neuromodulators in the management of such symptoms is unknown. We retrospectively assessed the efficacy of neuromodulators such as tricyclic antidepressants, buspirone, and mirtazapine for the management of post-fundoplication dyspepsia.

Endoscopic therapies in proton pump inhibitors (PPI) dependent/refractory gastroesophageal reflux disease (GERD) are increasingly indicated in patients who are not suitable or willing for chronic medical therapy and surgical fundoplication. Currently available endoluminal anti-reflux procedures include radiofrequency therapy (Stretta), suturing/plication and mucosal ablation/resection techniques at the gastroesophageal junction. Meticulous work up and patient selection results in a favorable outcome with these endoscopic therapies, especially the quality of life and partially the PPI independence. Stretta can be considered in patients with PPI refractory GERD and might have a role in patients with reflux hypersensitivity and functional heartburn. Endoscopic fundoplication using the Esophyx device and the GERD-X device have strong evidence (multiple randomized controlled trials) in patients with small hiatus hernia and high volume reflux episodes. Mucosal resection/ablation techniques like anti-reflux mucosectomy and anti-reflux mucosal ablation have shown promising results but need long term follow-up studies to prove their efficacy. The subset of PPI dependent GERD population will benefit from endoscopic therapies and the future of endoscopic management of GERD looks promising.