Comparative Efficacy of P-CAB vs Proton Pump Inhibitors for Grade C/D Esophagitis: A Systematic Review and Network Meta-analysis.

INTRODUCTION: Los Angeles grade C/D esophagitis is a severe manifestation of gastroesophageal reflux disease that require active treatment and close follow-up. Potassium competitive acid blockers (P-CAB) are promising alternatives to proton pump inhibitors (PPI). We aimed to compare the efficacy and safety of P-CAB and PPI in healing grade C/D esophagitis to aid clinical decision-making. METHODS: A systematic literature search was performed using PubMed, MEDLINE, and Cochrane Central Register of Controlled Trials. Randomized controlled trials were eligible for inclusion if efficacy of P-CAB and PPI in healing grade C/D esophagitis was reported. Pooled risk ratios and risk difference with 95% credible intervals were used to summarize estimated effect of each comparison. The benefit of treatments was ranked using the surface under the cumulative probability ranking score. RESULTS: Of 5,876 articles identified in the database, 24 studies were eligible. Studies included incorporated 3 P-CAB (vonoprazan, tegoprazan, and keverprazan) and 6 PPI (lansoprazole, esomeprazole, omeprazole, rabeprazole extended-release (ER), pantoprazole, and dexlansoprazole). Based on the failure to achieve mucosal healing, 20 mg of vonoprazan q.d. ranked the first among PPI in initial and maintained healing of grade C/D esophagitis (surface under the cumulative probability ranking score = 0.89 and 0.87, respectively). Vonoprazan had similar risk of incurring adverse events, severe adverse events, and withdrawal to drug when compared with PPI. For those who attempted lower maintenance treatment dose, 10 mg of vonoprazan q.d. was a reasonable choice, considering its moderate efficacy and safety. DISCUSSION: Vonoprazan has considerable efficacy in initial and maintained healing of grade C/D esophagitis compared with PPI, with moderate short-term and long-term safety.

The efficacy and safety of fexuprazan in treating erosive esophagitis: a phase III, randomized, double-blind, multicenter study.

BACKGROUND AND AIM: Fexuprazan is a novel potassium-competitive acid blocker (P-CAB). This study aimed to explore the noninferior efficacy and safety of fexuprazan to esomeprazole in treating erosive esophagitis (EE). METHODS: This was a phase III, randomized, double-blind multicenter study. Patients with endoscopically confirmed EE were randomized to receive fexuprazan 40 mg or esomeprazole 40 mg once a daily for 4-8 weeks. The healing rates of EE, symptom response, GERD-health-related quality life (GERD-HRQL), and treatment-emergent adverse events (TEAEs) were compared between fexuprazan group and esomeprazole group. RESULTS: A total of 332 subjects were included in full analysis set (FAS) and 311 in per-protocol set (PPS). The healing rates of fexuprazan and esomeprazole groups at 8 weeks were 88.5% (146/165) and 89.0% (145/163), respectively, in FAS and 97.3% (145/149) and 97.9% (143/146), respectively, in PPS. Noninferiority of fexuprazan compared with esomeprazole according to EE healing rates at 8 weeks was demonstrated in both FAS and PPS analysis. No significant difference was found between groups in EE healing rates at 4 weeks, symptom responses, and changes of GERD-HRQL. The incidence of drug-related AEs was 19.4% (32/165) in fexuprazan arm and 19.6% (32/163) in esomeprazole arm. CONCLUSION: This study demonstrated noninferior efficacy of fexuprazan to esomeprazole in treating EE. The incidence of TEAEs was similar between fexuprazan and esomeprazole. Trial registration number NCT05813561.

Proton pump inhibitors in esophageal atresia: A systematic review and meta-analysis.

Gastroesophageal reflux disease (GERD) is frequent and prolonged in esophageal atresia (EA) pediatric patients requiring routine use of proton pump inhibitors (PPIs). However, there are still controversies on the prophylactic use of PPIs and the efficacy of PPIs on GERD and EA complications in this special condition. The aim of the study is to assess the prophylactic use of PPIs in pediatric patients with EA and its complications. We, therefore, performed a systematic review including all reports on the subject from 1980 to 2022. We conducted meta-analysis of the pooled proportion of PPI-and no PPI groups using random effect model, meta-regression, and estimate heterogeneity by heterogeneity index I2 . Thirty-eight reports on the topic met the criteria selection, representing a cumulative 6044 patients with EA. Prophylactic PPI prescription during the first year of life does not appear to prevent GERD persistence at follow-up and is not associated with a significantly reduced rate of antireflux surgical procedures (ARP). PPIs improve peptic esophagitis and induce remission of eosinophilic esophagitis at a rate of 50%. Their effect on other GERD outcomes is uncertain. Evidence suggests that PPIs do not prevent anastomotic stricture, Barrett's esophagus, or respiratory complications. PPI use in EA can improve peptic and eosinophilic esophagitis but is ineffective on the other EA complications. Side effects of PPIs in EA are almost unknown.

Vonoprazan is superior to lansoprazole for healing of severe but not mild erosive esophagitis: A systematic review with meta-analysis of randomized controlled trials.

BACKGROUND AND AIM: Healing rates of severe erosive esophagitis (EE; Los Angeles [LA] Grade C/D) in patients treated with a proton pump inhibitor (PPI) is suboptimal (~60-70%). Vonoprazan, a potassium-competitive acid blocker, is suggested to have better healing rates in patients with severe EE. This meta-analysis compares the efficacy and safety of vonoprazan 20 mg versus lansoprazole 30 mg daily in healing EE, specifically in those with LA Grade C/D. METHODS: We searched MEDLINE, Embase, and CENTRAL on May 24, 2023. Studies that randomized EE patients to vonoprazan 20 mg daily or lansoprazole 30 mg daily and compared healing rates were included. The risk of bias was assessed using Cochrane's Risk of Bias 2 tool. The fixed-effect model was used to obtain the pooled efficacy and safety outcomes. Subgroup analysis was done to compare healing rates in mild (LA Grade A/B) versus severe EE and based on study location. RESULTS: Four randomized controlled trials (RCTs) with low risks of bias comprising 2208 participants were included. Vonoprazan 20 mg was superior to lansoprazole 30 mg daily in healing severe EE at all weeks (Week 2 RR 1.294 [95% CI 1.169-1.433], Week 4 1.160 [1.059-1.270], and Week 8 1.175 [95% CI 1.107-1.247]), but was similar for mild EE at all weeks (P-interaction < 0.01). Vonoprazan 20 mg was more efficacious than lansoprazole 30 mg at Week 8 in Western versus Asian studies (P-interaction < 0.01). Any, serious, and drug-related treatment-emergent adverse events were comparable between groups. CONCLUSION: Vonoprazan 20 mg is superior to lansoprazole 30 mg for healing severe EE but not mild EE. Vonoprazan 20 mg daily has a similar safety profile to lansoprazole 30 mg daily.

Efficacy and safety of HIP1601 (dual delayed-release esomeprazole) 40 mg in erosive esophagitis compared to HGP1705 (delayed-release esomeprazole) 40 mg: a multicenter, randomized, double-blind, non-inferiority study.

BACKGROUND: Proton-pump inhibitors (PPIs) are the most effective drugs for treating acid-related disorders. However, once-daily dosing with conventional PPIs fail to fully control acid secretion over 24 h. This study aimed to compare the efficacy and safety of HIP1601 (dual delayed-release esomeprazole) and HGP1705 (delayed-release esomeprazole) in patients with erosive esophagitis (EE). METHODS: We enrolled 213 patients with EE randomized in a 1:1 ratio to receive 40 mg HIP1601 (n = 107) or HGP1705 (n = 106) once daily for 4 or 8 weeks. The primary endpoint was the EE healing rate, confirmed by endoscopy up to week 8. GERD-related symptoms and treatment-emergent adverse events were compared between both groups. RESULTS: By week 8, the estimated healing rates of EE were 97.8% and 96.8% in the HIP1601 and HGP1705 groups, respectively, with a 95% confidence interval of -4.7 to 7.2. After 4 or 8 weeks of treatment, the EE healing rate at week 4, complete resolution rate of symptoms, time to sustained resolution of symptoms, and number of rescue medications used were similar in both groups. The proportion of heartburn- and acid regurgitation-free nights by week 4 were higher in the HIP1601 group compared to the HGP1705 group, but the difference did not reach clinical significance (87.7% vs. 85.8%, P = 0.514, 87.5% vs. 85.8%, P = 0.774). The number of adverse events did not differ significantly between the two groups. CONCLUSIONS: The efficacy and safety of HIP1601 40 mg were comparable to those of HGP1705 40 mg for the treatment of EE and symptomatic improvement of GERD. TRIAL REGISTRATION: NCT04080726 ( https://classic. CLINICALTRIALS: gov/ct2/show/NCT04080726 ), registration date: 25/10/2018.

Long-Term Clinical Course after Successful Initial Treatment in Patients with Mild Erosive Esophagitis: A Prospective Follow-Up Study.

INTRODUCTION: This study aimed to investigate the clinical course of patients with healed mild erosive esophagitis and clarify the predictive factors for continuous treatment. METHOD: Fifty-one patients with mild erosive esophagitis who confirmed mucosal healing by endoscopy after initial treatment with vonoprazan (VPZ) were enrolled. The patients continued subsequent treatment of their choice: maintenance therapy with VPZ 10 mg (n = 15), on-demand therapy with VPZ 20 mg (n = 19), or no medication (n = 17). Each patient was prospectively followed up for over 2 years, and the treatment was switched to other options appropriately according to their symptoms. RESULTS: During the mean follow-up period of 3.1 years (range: 2.0-3.9 years), 2 patients who chose maintenance therapy switched to on-demand therapy. One patient who chose on-demand therapy switched to maintenance therapy, while 3 patients switched to no medication. Recurrence of symptoms occurred in 9 patients who chose no medication. They were administered maintenance therapy and five of them were subsequently switched to on-demand therapy. Ultimately, the proportion of patients receiving each treatment was 35.3% (18/51) for maintenance therapy, 43.1% (22/51) for on-demand therapy, and 21.6% (11/51) for no medication. A predictive factor for the need for continuous treatment was the presence of esophageal hiatal hernia (odds ratio: 6.03, 95% confidence interval: 1.43-25.3, p = 0.014). CONCLUSION: Among patients with healed mild erosive esophagitis, 78.4% required continuous treatment with VPZ, while 21.6% remained symptom free with no medication. On-demand therapy was the most common treatment, and continuous treatment may be recommended for patients with esophageal hiatal hernia.

Proton Pump Inhibitor Treatment Has Little Effects on Secretion of Saliva in Patients with Proton Pump Inhibitor-Responsive Mild Reflux Esophagitis and Non-Erosive Reflux Disease.

INTRODUCTION: The secretion of saliva, which is triggered by acid reflux into the esophagus via the esophagosalivary reflex, plays a crucial role in the defensive mechanisms of the esophagus. The volume of saliva secreted in patients with gastroesophageal reflux disease (GERD) is reduced. However, the effects of proton pump inhibitors (PPI) on the secretion of saliva have rarely been reported. Therefore, the present study investigated changes in the volume and pH of saliva after the cessation of PPI. MATERIALS AND METHODS: We retrospectively reviewed the records of consecutive patients previously diagnosed with mild reflux esophagitis (RE) or non-erosive reflux disease (NERD) controlled with PPI (including vonoprazan) who performed the salivary secretion test before and after a 2-week cessation of PPI. The volume, pH, and pH after acid loading (buffering capacity) of saliva were compared before and after the cessation of PPI. RESULTS: Thirty-two patients (25 NERD, 7 mild RE) were included. The second saliva test was performed a median interval of 14 months [12.0-15.3] after the first test. No significant differences were observed in the volume of saliva secreted before and after the cessation of PPI (before 4.0 mL [2.7-6.0] vs. after 4.0 mL [2.3-5.9], p = 0.894). No significant differences were noted in pH or changes in pH after acid loading before and after the cessation of PPI (pH: before 7.1 ± 0.24 vs. after 7.0 ± 0.24, p = 0.1. Delta pH after acid loading: before 1.0 [0.8-1.2] vs. after 1.0 [0.8-1.2], p = 0.844). CONCLUSION: The cessation of PPI did not appear to affect the volume, pH, or buffering capacity of saliva in patients with PPI-responsive mild RE and NERD.

Therapeutic Effect of Polaprezinc on Reflux Esophagitis in the Rat Model.

BACKGROUND/AIMS: To explore the protective effects and therapeutic mechanism of Esomeprazole (PPI), polaprezinc granule (PZ), and PPI + PZ on reflux esophagitis (RE) in the rat model. METHODS: Wistar rats were randomly divided into 9 groups, which contain the control group, the acid cessation group (0.7% HCl, Q3D × 4), and the acid persistence group (0.7% HCl, Q3D × 11). PPI was administered by gavage at 8 mg·kg-1 body weight and PZ was administered by gavage at 120 mg·kg-1 body weight once a day for 15 days. The gastric cardia tissue of the feeding tube was observed under the light microscope, and the levels of interleukin-8 (IL-8) and prostaglandin E2 (PGE2) were measured by ELISA. The expression of EGFR, Akt, p-Akt, and p-mTOR was detected by Western blot. RESULTS: The ELISA results showed that the levels of IL-8 and PGE2 were significantly increased in the model group, but decreased in all groups after treatment. In the acid cessation group, PZ treatment had the most significant effect on reducing IL-8 levels and PPI + PZ treatment had the most significant effect on reducing PGE2 levels. In the acid persistence group, the PPI treatment had the most significant effect on reducing the levels of IL-8 and PGE2, and the PZ treatment could also significantly reduce their levels, close to the normal value. Western blot results showed that the expression of PI3K/Akt/mTOR pathway protein was increased in the model group, while its expression was decreased after treatment. CONCLUSIONS: Polaprezinc has a significant therapeutic effect on RE in rats, which can reduce the levels of IL-8 and PGE2 and downregulate the expression of PI3K/Akt/mTOR signal pathway protein. The efficacy of polaprezinc in the treatment of reflux esophagitis is comparable to that of PPI, and the combination of them is more effective in the reflux esophagitis treatment.

Analysis of Barrett's Esophagus and Its Risk Factors: A Cross-Sectional Study of 10,122 Subjects at a Japanese Health Examination Center.

INTRODUCTION: Helicobacter pylori eradication is expected to significantly change the prevalence of Barrett's esophagus (BE). However, few reports on this relationship exist. We analyzed the risk factors of BE using the current consensus on length of BE considering H. pylori infection status. METHODS: We analyzed 10,122 individuals (5,962 men; mean age = 52.9 ± 9.9 years) who had undergone esophagogastroduodenoscopy as part of a medical checkup. Correlations among factors including H. pylori infectious status, endoscopic findings, and BE ≥1 cm were analyzed. RESULTS: Prevalence of BE, long-segment BE, and esophageal adenocarcinoma was 22.5%, 0.014%, and 0%, respectively. Logistic regression analysis showed that the risk factors for BE were hiatal hernia (odds ratio [OR]: 2.89 [2.59-3.24]), female sex (OR: 0.52 [0.46-0.59]), social drinking (OR:0.77 [0.68-0.87]), H. pylori eradication therapy (OR: 1.34 [1.19-1.51]), proton pump inhibitor (PPI) use (OR: 1.52 [1.18-1.96]), bile reflux (OR: 1.18 [1.04-1.33]), age ≥50 years (OR: 1.13 [1.02-1.26]), and nonsteroidal anti-inflammatory drug (NSAID) use (OR: 1.29 [1.02-1.62]). Although reflux esophagitis (RE) was more common in H. pylori-negative patients (17.2%) than in those after H. pylori eradication therapy (11.8%, p < 0.00001), the latter was correlated with BE, disputing RE as a strong risk factor for BE. Therefore, we conducted a subgroup analysis; most of the risk factors except for PPI use (p = 0.75), H2-receptor antagonist use (p = 0.078), and atrophic gastritis absence (p = 0.72) were positively correlated with BE after H. pylori eradication therapy compared with H. pylori-negative status. CONCLUSIONS: H. pylori eradication, bile reflux, PPI use, and NSAID use were risk factors for BE along with hiatal hernia, male sex, and older age.

Endoscopic Management of GERD.

Gastroesophageal reflux disease (GERD) has consistently been the most frequently diagnosed gastrointestinal malady in the USA. The mainstay of therapy has traditionally been medical management, including lifestyle and dietary modifications as well as antacid medications. In those patients found to be refractory to medical management or with a contraindication to medications, the next step up has been surgical anti-reflux procedures. Recently, though innovative advancements in therapeutic endoscopy have created numerous options for the endoscopic management of GERD, in this review, we discuss the various endoscopic therapy options, as well as suggested strategies we use to recommend the most appropriate therapy for patients.

Upper Esophageal Sphincter Compression Device as an Adjunct to Proton Pump Inhibition for Laryngopharyngeal Reflux.

BACKGROUND: The Reflux Band, an external upper esophageal sphincter (UES) compression device, reduces esophago-pharyngeal reflux events. This study aimed to assess device efficacy as an adjunct to proton pump inhibitor (PPI) therapy in patients with laryngopharyngeal reflux (LPR). METHODS: This two-phase prospective clinical trial enrolled adults with at least 8 weeks of laryngeal symptoms (sore throat, throat clearing, dysphonia) not using PPI therapy at two tertiary care centers over 26 months. Participants used double dose PPI for 4 weeks in Phase 1 and the external UES compression device nightly along with PPI for 4 weeks in Phase 2. Questionnaire scores and salivary pepsin concentration were measured throughout the study. The primary endpoint of symptom response was defined as reflux symptom index (RSI) score ≤ 13 and/or > 50% reduction in RSI. RESULTS: Thirty-one participants completed the study: 52% male, mean age 47.9 years (SD 14.0), and mean body mass index (BMI) 26.2 kg/m2 (5.1). Primary endpoint was met in 11 (35%) participants after Phase 1 (PPI alone) and 17 (55%) after Phase 2 (Device + PPI). Compared to baseline, mean RSI score (24.1 (10.9)) decreased at end of Phase 1 (PPI alone) (21.9 (9.7); p = 0.06) and significantly decreased at end of Phase 2 (Device + PPI) (15.5 (10.3); p < 0.01). Compared to non-responders, responders to Device + PPI had a significantly lower BMI (p = 0.02) and higher salivary pepsin concentration (p = 0.01). CONCLUSION: This clinical trial highlights the potential efficacy of the external UES compression device (Reflux Band) as an adjunct to PPI for patients with LPR (ClinicalTrials.Gov NCT03619811).

Transoral incisionless fundoplication with Medigus ultrasonic surgical endostapler (MUSE) for the treatment of gastro-esophageal reflux disease: outcomes up to 3 years.

BACKGROUND: Transoral incisionless fundoplication (TIF) with Medigus Ultrasonic Surgical Endostapler (MUSE) is a new intervention for treatment of gastro-esophageal reflux disease (GERD). We aimed at assessing the clinical, functional, and endoscopic effects of TIF by MUSE. METHODS: Forty-six patients underwent TIF. Proton pump inhibitor (PPI) consumption, GERD-health-related quality of life (HRQL) and reflux symptom index (RSI) questionnaires, upper gastrointestinal (GI) endoscopy, esophageal 24-h pH-impedance recording, and high-resolution manometry (HRM) were done before TIF and scheduled 6 and 12 months later (HRM only at 6-month). PPI consumption and symptoms were then assessed yearly. Data up to 3 years are reported in this study (PP- and ITT-analysis). RESULTS: TIF was successfully performed in 45/46 patients; in one patient esophageal intubation was impossible. Perforation occurred in two cases. One patient required surgery within 6 months. Clinical follow-up was available for 42 patients at 6 months and 1 year, 35 patients at 2 years, and 31 patients at 3 years. At 1, 2, and 3 years, PPI consumption was stopped, respectively, in 64.3%, 62.9%, and 74.2% of cases (ITT-analysis: 58.7%, 56.4%, and 65.7%). GERD-HRQL and RSI scores decreased at least 50%, respectively, in 71.5% and 76.2%, 71.4% and 68.6%, and 67.7% of cases (ITT-analysis: 65.2% and 69.6%, 64.1% and 61.5%, and 60%). A significant improvement of both scores was observed up to 3 years. 6-month and 1-year functional follow-up were possible in 31 and 20 patients. HRM showed significant increase of the median lower esophageal sphincter length and rate of peristaltic waves. Esophageal pH-impedance recording found significantly fewer acid, proximal and total refluxes, and percentage of esophageal pH < 4 total time at 6 months, but not at 1 year. CONCLUSION: TIF by MUSE significantly improved symptoms and PPIs consumption up to 3 years. However, esophagitis still persisted in one-third of cases at 1 year and functional improvement at 6 months was not confirmed at 1 year. Severe complications requiring surgery occurred in two cases. CLINICALTRIALS: GOV: ID: NCT03669874.

Outcomes of endoscopic submucosal dissection for gastroesophageal reflux disease (ESD-G) for medication-refractory gastroesophageal reflux disease: 35 cases underwent ESD-G including 15 cases followed more than 5 years.

BACKGROUND: Although some kinds of endoluminal surgery for patients with proton pump inhibitor (PPI)-refractory gastroesophageal reflux disease (GERD) have been reported, there are few reports on their long-term outcomes. In 2014, we reported the effectiveness of endoscopic surgery for PPI-refractory GERD, which we invented and named endoscopic submucosal dissection for GERD (ESD-G) in 2008. Thereafter, we accumulated more cases and monitored the patients' condition postoperatively and describe the outcomes herein. PATIENTS AND METHODS: This single-center, single-arm trial was conducted at the Osaka Medical and Pharmaceutical University Hospital. We compared outcomes between before and 3-6 months after ESD-G. Additionally, we investigated the outcomes of patients 5 or more years after ESD-G. RESULTS: We performed 42 ESD-G procedures in 35 patients between 2008 and 2020. In seven patients, ESD-G was performed twice for various reasons. The frequency scale for the symptoms of GERD score was significantly improved 3-6 months after ESD-G (22 → 10, p < 0.0001); the Los Angeles classification for reflux esophagitis was clearly improved after ESD-G (p = 0.0423). The number of reflux episodes was not decreased by ESD-G. There was a significant difference in the potency unit of gastric acid secretion suppressants for controlling GERD-related symptoms between baseline and 3-6 months after ESD-G (p = 0.0009). In patients without a history of distal gastrectomy who underwent ESD-G, the potency unit of gastric acid secretion suppressants significantly decreased 5 or more years after ESD-G (p = 0.0121). CONCLUSION: ESD-G may be effective in patients with refractory GERD-related symptoms without a history of distal gastrectomy.

Efficacy of Vonoprazan for Refractory Reflux Esophagitis after Esophagectomy.

BACKGROUND: Refractory reflux esophagitis (RRE), unresponsive to conventional proton-pump inhibitors (PPIs), is a complication in esophagectomy with gastric pull-up. Vonoprazan (VPZ), a novel potassium-competitive acid blocker, has been available in Japan since 2015. Here, we investigated the efficacy of VPZ on PPI-resistant RRE after esophagectomy with gastric pull-up. METHODS: This was a single-center retrospective study. We used the revised Los Angeles (r-LA) classification based on the Los Angeles classification and the modified Los Angeles classification to evaluate abnormal forms of mucosal breaks such as lateral spreading consistently. Patients who underwent esophagectomy with gastric pull-up and had RRE grade B-D as per the r-LA classification, despite using standard-dose PPIs or double dose of rabeprazole, were included. Sixteen patients who switched to VPZ (20 mg/day) and 14 patients who continued PPIs were assigned to the VPZ and PPI groups, respectively. Endoscopic observations were reviewed by 3 endoscopists using the r-LA classification to ensure consistent diagnosis, while the treatment arm and patient information were blinded to evaluators. We defined mucosal breaks that improved by at least one grade after treatment as improved mucosa and recovery to grade M or N as mucosal healing. RESULTS: The percentage of patients with improved mucosa in the VPZ and PPI groups was 81.3 and 14.3%, respectively (p < 0.001). The rate of mucosal healing was 68.8 and 7.1%, respectively (p = 0.001). CONCLUSION: VPZ significantly improved PPI-resistant RRE after esophagectomy with gastric pull-up.

Impaired Mucosal Integrity in Proximal Esophagus Is Involved in Development of Proton Pump Inhibitor-Refractory Nonerosive Reflux Disease.

BACKGROUND AND OBJECTIVE: Weakly acidic reflux reaching to the proximal esophagus is closely related to the perception of gastroesophageal reflux in patients with nonerosive reflux disease despite treatment with a proton pump inhibitor (PPI). However, little is known about the involvement of the patients' mucosal integrity of the proximal esophagus. METHODS: We recruited 15 symptomatic nonerosive gastroesophageal reflux disease (GERD) patients with a positive symptom index despite PPI treatment and 11 healthy asymptomatic volunteers as controls. The biopsy specimens obtained from the proximal and distal esophagus were applied to a mini-Ussing chamber system to measure transepithelial electrical resistance (TEER) against a pH 4 weak acid. The esophageal biopsy samples were subjected to quantitative real-time PCR and immunohistochemical analysis. RESULTS: In the proximal esophagus, the weak acid exposure reduced the TEER in the PPI-refractory patients compared to that in the controls. The frequency of the reflux extending to the proximal esophagus had a significant correlation with the reduction in the proximal esophageal TEER in the patients. The reduced TEER in the proximal esophagus was accompanied by an increase in IL-8 and IL-1ß mRNA and a decrease in occludin mRNA levels. The proximal esophageal mucosa in the patients presented infiltration of CD3-positive lymphocytes and an increased expression of solute carrier organic anion transporter family member 2A1 (SLCO2A1), a passage gate of reflux symptom-evoking molecules. CONCLUSIONS: The reflux perception is related to an impairment of the proximal esophageal mucosal integrity in patients with nonerosive reflux disease despite PPI.

Stimulated saliva secretion is reduced in proton pump inhibitor-resistant severe reflux esophagitis patients.

BACKGROUND: Salivary secretion in patients with proton-pump inhibitor (PPI)-resistant severe reflux esophagitis has not been examined. In this study, saliva secretion and salivary epidermal growth factor (EGF) in patients with PPI-resistant severe reflux esophagitis were investigated. METHODS: We recruited 22 PPI-resistant and 22 PPI-responsive severe reflux esophagitis patients who were not infected with Helicobacter pylori. Saliva secretion testing and esophageal manometry using high-resolution manometry were performed. Saliva secretion was assessed as follows: each patient chewed sugar-free gum for 3 min prior to endoscopy and the amount and pH of saliva as well as the pH of saliva after acid loading as an index of the acid-buffering capacity were measured. The salivary EGF concentration was assessed by ELISA. RESULTS: The amount of saliva secreted was significantly lower in the PPI-resistant group than in the PPI-responsive group, with medians (25th-75th percentile) of 3.7 (2.2-6.8) and 4.9 (4.0-7.8) mL, respectively (p = 0.029). Salivary pH was significantly lower in the PPI-resistant group [6.9 (6.7-7.2)] than in the PPI-responsive group [7.2 (7.1-7.4), p = 0.001]. Salivary pH after acid loading was significantly lower in the PPI-resistant group [5.6 (5.3-5.9)] than in the PPI-responsive group [6.4 (6.1-6.5), p = 0.002]. The salivary EGF concentration was significantly higher in the PPI-resistant group [3211.5 (1865.0-4121.5)] than in the PPI-responsive group [1816.0 (1123.5-2792.3), p = 0.041]. No significant differences were observed in the proportion of esophageal motility abnormalities. CONCLUSION: Stimulated saliva secretion was reduced in PPI-resistant severe reflux esophagitis patients.

Novel physiologic nomogram discriminates symptom outcome in patients with erosive esophagitis.

BACKGROUND AND AIM: Most of patients with erosive esophagitis (EE) are of LA grade A&B with low reflux burden, therefore require further esophageal function tests (EFTs). One-third of them respond poorly to pump proton inhibitor (PPI) treatment. The aim was to establish and validate a physiologic nomogram to discriminate symptom outcome to PPI treatment in patients with EE. METHODS: A total of 79 EE patients with heartburn who underwent EFTs and received PPI therapy were randomly assigned into a training set (n = 55) and a validation set (n = 24). Clinical data including physiologic parameters from EFTs were collected. Significant factors for the positive symptomatic outcome were identified using logistic regression analysis. Physiologic signature was developed using the least absolute shrinkage and selection operator algorithm. The nomogram was established by combining significant factors and physiologic signature, and its performance was evaluated and validated in the training and validation set. The clinical value of the nomogram was measured by decision curve analysis. RESULTS: Significant factors for positive symptomatic response to PPI treatment were identified as follows: acid exposure time, total number of reflux episodes, and two novel metrics including mean nocturnal baseline impedance and post-reflux swallow-induced peristaltic wave index. The nomogram which incorporated both significant factors and physiologic signature demonstrated good performance in the training and validation sets [C-index: 0.938 (95% CI 0.882-0.995); 0.839 (95% CI 0.678-0.995), respectively]. Decision curves showed significant clinical usefulness. CONCLUSION: The first physiologic nomogram was developed to discriminate the individualized response to PPI therapy among EE patients.

The early therapeutic response at 2 weeks is a crucial predictor of proton pump inhibitor-refractory gastroesophageal reflux disease.

BACKGROUND: In recent years, the prevalence of proton pump inhibitor (PPI)-refractory gastroesophageal reflux disease (GERD) has been increasing, posing a clinical obstacle to improving the management of GERD patients. The ability of known predictive factors to explain therapeutic response to PPI remains insufficient. Therefore, we examined whether the addition of early therapeutic response to PPI as an explanatory variable may increase the predictive power for PPI-refractory GERD. METHODS: The severity and therapeutic response of GERD symptoms to PPI were evaluated using the GastroEsophageal Reflux and Dyspepsia Therapeutic Efficacy and Satisfaction Test (GERD-TEST) questionnaire at baseline and at 2 and 4 weeks after treatment. The relevance of the therapeutic effect of PPI at 2 weeks compared to that at 4 weeks was examined in 301 patients with GERD. Independent predictive factors for refractory GERD at 4 weeks of PPI therapy were examined in 182 patients. The effect of various clinical factors, including the early response to PPI, was assessed using multiple regression analysis. RESULTS: The number of PPI-therapy responders increased significantly with the duration of treatment (p < 0.0001). The response to PPI therapy at 2 weeks was significantly correlated with that at 4 weeks (p < 0.0001). Multiple regression analysis revealed that the therapeutic response to PPI at 2 weeks was by far the strongest predictor of the therapeutic effect at 4 weeks among all clinical factors. CONCLUSIONS: Medication change for PPI-refractory GERD at 2 weeks may be an efficacious therapeutic strategy to improve patients' quality of life.

Relationship between gastroesophageal reflux disease (GERD) and constipation: laxative use is common in GERD patients.

BACKGROUND: The relationship between gastroesophageal reflux disease (GERD) and constipation has not yet been examined in Japan. We herein analyzed the use of laxatives by GERD and non-GERD patients to clarify the relationship between GERD and constipation. METHODS: This was a retrospective observational study designed to examine the use of laxatives by GERD and non-GERD patients. A total of 118 patients (mean age 69.7 years, 50 males) with reflux esophagitis (RE) and non-erosive reflux disease (NERD) who received maintenance acid-suppressive therapy for more than 1 year were included in the GERD group (83 RE patients, 35NERD patients). Similarly, 61 patients (mean age 69.4 years, 28 males) who received regular acid-suppressive therapy for reasons other than GERD were included in the non-GERD group. We also investigated demographic factors associated with the onset of GERD, including body mass index (BMI), age, and sex. RESULTS: The frequency of laxative use was significantly higher in the GERD group (38.1%) than in the non-GERD group (21.3%). No significant differences were observed in dose frequencies between the groups. The type of laxative used also did not significantly differ between the groups. Furthermore, no significant differences were noted in sex, age, or BMI between the groups. CONCLUSIONS: The use of laxatives was significantly more common in GERD patients than in non-GERD patients. The present results suggest that a relationship exists between GERD and constipation.

Phase III, randomised, double-blind, multicentre study to evaluate the efficacy and safety of vonoprazan compared with lansoprazole in Asian patients with erosive oesophagitis.

OBJECTIVE: To establish the non-inferior efficacy of vonoprazan versus lansoprazole in the treatment of Asian patients with erosive oesophagitis (EO). DESIGN: In this phase III, double-blind, multicentre study, patients with endoscopically confirmed EO were randomised 1:1 to receive vonoprazan 20 mg or lansoprazole 30 mg, once daily for up to 8 weeks. The primary endpoint was EO healing rate at 8 weeks. The secondary endpoints were EO healing rates at 2 and 4 weeks. Safety endpoints included treatment-emergent adverse events (TEAEs). RESULTS: In the vonoprazan (n=238) and lansoprazole (n=230) arms, 8-week EO healing rates were 92.4% and 91.3%, respectively (difference 1.1% (95% CI -3.822% to 6.087%)). The respective 2-week EO healing rates were 75.0% and 67.8% (difference 7.2% (95% CI -1.054% to 15.371%)), and the respective 4-week EO healing rates were 85.3% and 83.5% (difference 1.8% (95% CI -4.763% to 8.395%)). In patients with baseline Los Angeles classification grade C/D, 2-week, 4-week and 8-week EO healing rates were higher with vonoprazan versus lansoprazole (2 weeks: 62.2% vs 51.5%, difference 10.6% (95% CI -5.708% to 27.002%); 4 weeks: 73.3% vs 67.2%, difference 6.2% (95% CI -8.884 to 21.223); and 8 weeks: 84.0% vs 80.6%, difference 3.4% (95% CI -9.187% to 15.993%)). Overall, EO healing rates appeared higher with vonoprazan versus lansoprazole. TEAE rates were 38.1% and 36.6% in the vonoprazan and lansoprazole group, respectively. CONCLUSION: Our findings demonstrate the non-inferior efficacy of vonoprazan versus lansoprazole in terms of EO healing rate at 8 weeks in this population. Safety outcomes were similar in the two treatment arms. TRIAL REGISTRATION NUMBER: NCT02388724.