PPI-refractory Non-erosive Reflux Disease Research Articles

S436 Role of 24 Hours Ambulatory pH Impedance Study and High Resolution Manometry in Patients With PPI Refractory Non-Erosive Reflux Disease

S436 Role of 24 Hours Ambulatory pH Impedance Study and High Resolution Manometry in Patients With PPI Refractory Non-Erosive Reflux Disease

Effect of hiatus hernia on reflux patterns and mucosal integrity in patients with non-erosive reflux disease.

Hiatus hernia (HH) contributes to development of gastroesophageal reflux disease, Barrett's esophagus and esophageal adenocarcinoma. This study was aimed to investigate the influence of HH on reflux patterns and distal esophageal mucosal integrity in non-erosive reflux disease (NERD). We retrospectively analyzed PPI-refractory NERD patients referred to three tertiary referral centers who underwent high-resolution manometry and off-PPI 24-h impedance-pH monitoring (with or without bile spectrophotometry). Patients with HH ≥2cm (HH group, n=42) or no HH (non-HH group, n=40) with similar esophageal acid exposure time (AET 6%-12%) were included. Age, gender, BMI, esophageal motility, AET, and esophageal clearance were similar between the two groups. The HH group had higher numbers of total reflux episodes (p=0.015) with similar proportion of acid/non-acid reflux compared with the non-HH group. Mean nocturnal baseline impedance (MNBI) in the distal esophagus was significantly lower in the HH group than the non-HH group at both 5cm (p=0.002) and 3cm (p=0.015) above the lower esophageal sphincter. Multivariable regression analysis showed that HH, less non-acid reflux and lower post-reflux swallow-induced peristaltic wave index (PSPWI) were independently associated with lower MNBI. Among 31 patients tested with bile spectrophotometry, the HH group had significantly longer bile exposure time than the non-HH group (p=0.011), and bile reflux inversely and significantly correlated with MNBI (rho=-0.75, p < 0.001). Hiatus hernia, less non-acid reflux and lower PSPWI were associated with lower MNBI. HH impairs distal esophageal mucosal integrity, the mechanism of which we speculate to be through excessive bile reflux.

The Ameliorating Effect of Switching to Vonoprazan: A Novel Potassium-Competitive Acid Blocker in Patients with Proton Pump Inhibitor Refractory Non-Erosive Reflux Disease

Introduction: Weakly acidic reflux has been reported to be the major cause of symptoms in patients with proton pump inhibitor (PPI)-refractory nonerosive reflux disease (NERD) undergoing PPI treatment. We previously reported that reflux at pH 4–5 was the main factor that induced symptoms in such patients. The present study aimed to elucidate the symptom-ameliorating effect of vonoprazan (VPZ) by evaluating the change in the pH value of the refluxate using multichannel intraluminal impedance and pH (MII-pH) monitoring. Methods: We retrospectively evaluated the records of MII-pH monitoring in 29 symptom index (SI) and/or symptom association probability (SAP)-positive patients with PPI-refractory NERD. After switching to VPZ 20 mg/day, we performed MII-pH monitoring again. We assessed the change in the score of the frequency scale for the symptoms of gastroesophageal reflux disease (FSSG), the pH value of the refluxate, and the percent times of intragastric pH <4 or <5 before and after switching. We divided the patients into the following 2 groups according to the FSSG score after switching: effective and noneffective groups. Results: Among of the 29 SI/SAP-positive patients, 16 underwent switching to VPZ. Furthermore, of these 16 patients, 10 underwent MII-pH monitoring again after switching. The FSSG score decreased, the pH value of the refluxate increased, and the percent times of intragastric pH <4 or <5 reduced after switching when compared with the findings before switching. In the effective group, both the proportion of reflux at pH <4 and that of reflux at pH 4–5 decreased while taking VPZ when compared with the findings while taking double-dose PPI. In the noneffective group, the proportion of reflux at pH <4 decreased but that of reflux at pH 4–5 increased and that of reflux at pH <5 did not change overall while taking VPZ. In addition, the percent times of intragastric pH <5 values were low in the effective group. Conclusion: Symptom suppression appears to be inadequate in patients with persistent reflux at pH 4–5 even with VPZ 20 mg/day. Strong acid suppressive therapy with VPZ to increase the pH value of the refluxate to ≥5 is useful for symptom improvement.

Influence of the pH Value of Refluxate and Proximal Extent on Heartburn Perception in Patients with Proton Pump Inhibitor-Refractory Non-Erosive Reflux Disease

Background and Objectives: Weakly acidic reflux has been reported as the major cause of symptom occurrence in patients with proton pump inhibitor (PPI)-refractory non-erosive reflux disease (NERD). This study is aimed at clarifying whether the pH value of weakly acidic reflux affects the induction of symptoms. Methods: We retrospectively evaluated the records of combined multichannel intraluminal impedance and pH monitoring in 57 patients with PPI-refractory NERD. Weakly acidic refluxes were divided into 3 categories based on the pH value of the refluxate: pH 4–5, 5–6, and 6–7. Results: A total of 29 patients were positive in the symptom index. The symptom provocation rate in reflux of pH 4–5 (19%) was much higher than in that of pH 5–6 (11%) and pH 6–7 (12%). In the reflux at pH 4–5, the symptom provocation rate in the proximal reflux was higher than that in the distal reflux (p < 0.05), whereas the reflux at pH 5–6 and pH 6–7 was not significantly different in the symptom provocation rate between the proximal and distal refluxes. Conclusion: Reflux at pH <5 reaching the proximal esophagus was the main factor in the induced symptoms of patients with PPI-refractory NERD.

Esophageal Motility and Rikkunshito Treatment for Proton Pump Inhibitor-Refractory Nonerosive Reflux Disease: A Prospective, Uncontrolled, Open-Label Pilot Study Trial

BackgroundOnly a few reports focused on esophageal motility in patients with proton pump inhibitor (PPI)-refractory nonerosive reflux disease (NERD) and there has been no established strategy for treatment. ObjectiveTo clarify the characteristics of esophageal motility in patients with PPI-refractory NERD, we evaluated esophageal function using combined multichannel intraluminal impedance and esophageal manometry (MII-EM). In addition, we evaluated the efficacy of rikkunshito (RKT), which is a gastrointestinal prokinetic agent. MethodsThirty patients with NERD were enrolled and underwent MII-EM. After 8 weeks of RKT (7.5 g/d) treatment, MII-EM was repeated on patients with PPI-refractory NERD. Symptoms were assessed by the Gastrointestinal Symptom Rating Scale. ResultsIn patients with PPI-refractory NERD, measures of complete bolus transit, peristaltic contractions, and residual pressure of the lower esophageal sphincter during swallowing deviated from the standard values and esophageal clearance was found to be deteriorated. RKT significantly improved the peristaltic contractions (P < 0.05), the complete bolus transit (P < 0.01), and the residual pressure of lower esophageal sphincter (P < 0.05) in these patients. The overall score (P < 0.01) and the subscale scores of acid reflux syndrome (P < 0.05), abdominal pain (P < 0.05), and indigestion syndrome (P < 0.01) in the Gastrointestinal Symptom Rating Scale were significantly improved by the 8-week RKT treatment. ConclusionsIn the pilot study, patients with PPI-refractory NERD had disorders of esophageal and lower esophageal sphincter motility that were improved by RKT. Further studies examining esophageal motor activity of RKT in PPI-refractory NERD are required. University hospital Medical Information Network (UMIN) Clinical Trial Registry identifier: UMIN000003092.

The added diagnostic value of postreflux swallow-induced peristaltic wave index and nocturnal baseline impedance in refractory reflux disease studied with on-therapy impedance-pH monitoring.

On-therapy impedance-pH monitoring in proton pump inhibitor (PPI)-refractory gastroesophageal reflux disease (GERD) yielded conflicting results. We aimed to assess the diagnostic value of postreflux swallow-induced peristaltic wave (PSPW) index and mean nocturnal baseline impedance (MNBI) in PPI-refractory heartburn. On-therapy impedance-pH tracings from 189 consecutive patients with PPI-refractory heartburn were blindly reviewed. Patients were subdivided into refractory reflux esophagitis (RRE), healed reflux esophagitis (HRE), non-erosive reflux disease (NERD), and functional heartburn (FH) according to endoscopic and conventional impedance-pH findings. The diagnostic accuracy of PSPW index and MNBI in separating NERD from FH was assessed with receiver-operating-characteristic (ROC) analysis. Objectively documented persistent reflux remission at 3-year follow-up in 53 patients who underwent laparoscopic fundoplication served to evaluate PSPW index and MNBI as independent predictors of PPI-refractory GERD confirmed by positive surgical outcome. Median PSPW index and MNBI values were significantly lower in 39 RRE (16%; 1145Ω) than in 41 HRE (25%; 1741Ω) and in 68 NERD (29%; 2374Ω) patients, and in all three GERD subgroups compared to 41 FH cases (67%; 3488Ω) (P<.008). At ROC analysis, comparing NERD to FH the area under the curve was 0.886 with PSPW index and 0.677 with MNBI (P=.005). PSPW index was an independent predictor of PPI-refractory GERD (odds ratio 0.6983, P=.012). At on-therapy impedance-pH monitoring, PSPW index and MNBI efficiently distinguish PPI-refractory NERD from FH. The PSPW index represents an independent predictor of PPI-refractory GERD.

Usefulness of baseline impedance in patients with proton pump inhibitor-refractory nonerosive reflux disease.

Approximately more than half of patients with non-erosive reflux disease (NERD) do not respond to proton pump inhibitor (PPI) therapy. Although NERD is a heterogeneous entity, previous study showed that multichannel intraluminal impedance (MII)-pH monitoring could distinguish reflux-related disease from PPI-refractory NERD. The aim of this study was to examine the usefulness of baseline impedance in PPI-refractory NERD patients. We used MII-pH monitoring to analyze reflux parameters, symptom index (SI), and baseline impedance in 37 PPI-refractory NERD patients on PPI. Reflux was divided into acid (nadir pH ≤ 4) and non-acid (nadir pH > 4). Subjects were classified as having reflux-related disease based on abnormal reflux parameters or positive SI (≥ 50%), or non-reflux-related disease, including functional heartburn, based on negative SI with normal reflux parameters. A total of 26 of the 37 subjects were diagnosed with reflux-related disease, including eight with acid-reflux type and 18 with non-acid-reflux type, and nine with functional heartburn and two with pseudohypersalivation. There were no significant differences in the clinical characteristics of the acid-reflux type, non-acid-reflux type, and functional heartburn groups. The baseline impedance value in the acid-reflux type (1245 ± 392 Ω) was significantly lower than that in the non-acid-reflux type (2824 ± 1160 Ω) and functional heartburn (3546 ± 1353 Ω) groups. Baseline impedance values inversely correlated with reflux percent time, acid-reflux time, and acid exposure time. Among patients with PPI-refractory NERD, acid-reflux type was associated with lower baseline impedance compared with non-acid-reflux type and functional heartburn.

Clinical characteristics of elderly patients with proton pump inhibitor-refractory non-erosive reflux disease from the G-PRIDE study who responded to rikkunshito.

BackgroundThe incidence and severity of gastroesophageal reflux disease (GERD) in Japan tends to increase in elderly women. Rikkunshito (RKT), a traditional Japanese medicine, acts as a prokinetic agent and improves gastric emptying and gastric accommodation. Our previous prospective randomized placebo-controlled study showed that RKT combined with a standard-dose of rabeprazole (RPZ) significantly improved the acid-related dysmotility symptoms (ARD) in elderly patients with proton pump inhibitor (PPI)-refractory non-erosive reflux disease (NERD). This study aimed to evaluate clinical characteristics of elderly PPI-refractory NERD patients with ARD symptoms who responded to RKT.MethodsTwo hundred forty-two patients with PPI-refractory NERD were randomly assigned to 8 weeks of either RPZ (10 mg/q.d.) + RKT (7.5 g/t.i.d.) (RKT group) or RPZ + placebo (PL group). Among them, 95 were elderly (≥65 years) with ARD (RKT group: n = 52; PL group: n = 43). We analyzed the changes using the 12 subscale score of frequency scale for the symptoms of GERD (FSSG) and 15 items of the Gastrointestinal Symptom Rating Scale at 4 and 8 weeks and compared the therapeutic efficacy between the 2 groups.ResultsThere were no marked differences in baseline demographic or clinical characteristics in the 2 groups except for rate of current smoking. The FSSG score (mean ± SD at 0, 4, and 8 weeks) in both the RKT (16.0 ± 7.0; 9.9 ± 8.4; 7.0 ± 6.4) and PL (15.1 ± 6.4; 10.9 ± 6.7, 11.1 ± 8.5) groups significantly decreased after treatment. However, the degree of improvement of total and ARD scores of FSSG after the 8-week treatment was significantly greater in the RKT group than in the PL group. Combination therapy with RKT for 8 weeks showed significant improvement in 3 subscale scores (abdominal bloating, heavy feeling in stomach and sick feeling after meals) of the ARD domain and 1 subscale score (heartburn after meals) of the reflux symptom domain.ConclusionsRKT may be useful for improving GERD symptoms in elderly PPI-refractory NERD patients with ARD. Thus, RKT was particularly effective for resolving postprandial GERD symptoms (heavy feeling in stomach, sick feeling, and heartburn after meals).Trial registration(UMIN000005880)

Sa1093 Clinical Characteristics of Elderly Patients With PPI-Refractory NERD From the G-PRIDE Study Who Responded to Rikkunshito

Background/Aim: One of the features of gastroesophageal reflux disease (GERD) in Japan is that its frequency and severity tend to increase in elderly women. In addition, elderly patients (≥65 years) with non-erosive reflux disease (NERD) present with typical symptoms more frequently than do non-elderly patients with NERD. Rikkunshito (RKT), a traditional Japanese medicine, acts as a prokinetic agent and enhances gastric emptying and improves gastric accommodation. Our previous prospective randomized multicenter placebo-controlled study, the G-GRIDE study, showed that RKT combined with a standard-dose of rabeprazole (RPZ) therapy significantly improved the acid-related dysmotility (ARD) symptoms in elderly patients with PPI-refractory NERD. The aim of this study was to evaluate clinical characteristics of elderly PPI-refractory NERD patients with ARD symptoms who responded to RKT. Methods: Two hundred forty-two patients with PPI-refractory NERD were enrolled from August 2011 to July 2012 at 71 hospitals in Japan. Patients were randomly assigned to 8 weeks of either RPZ (10 mg/q.d.) plus rikkunshito (7.5 g/t.i.d.) (RKT group) or RPZ plus placebo (PL group) therapy. Of the 242 patients, 95 were elderly patients (≥65 years) with ARD (RKT group: n=52, PL group: n=43). We analyzed the changes using the 12 subscale score of the frequency scale for the symptoms of GERD (FSSG) at 4 and 8 weeks and compared the therapeutic efficacy between the 2 groups. Results: No significant differences were seen between the 2 groups in terms of subject background. The FSSG score (mean±SD; at 0, 4, and 8 weeks) in both the RKT [16.0±7.0; 9.9±8.4; 7.0±6.4] and PL [15.1±6.4; 10.9±6.7, 11.1±8.5] groups significantly decreased after the treatment. However, the degree of improvement of total and ARD scores of FSSG after 8 weeks of treatment was significantly greater in the RKT group than in the PL group. Combination therapy with RKT for 8 weeks showed significant improvement in 3 subscale scores (abdominal bloating, heavy feeling in stomach after meals, and sick feeling after meals) of the ARD domain and 1 subscale score (heartburn after meals) of the reflux symptom domain. Conclusion: RKT may be useful for improving GERD symptoms in elderly PPI-refractory NERD patients with ARD. RKT was especially effective for resolving postprandial GERD symptoms (heavy feeling in stomach after meals, sick feeling after meals, and heartburn after meals).

A randomized, placebo-controlled, double-blind clinical trial of rikkunshito for patients with non-erosive reflux disease refractory to proton-pump inhibitor: the G-PRIDE study

The aim of this study was to investigate the efficacy of rikkunshito (RKT), a traditional Japanese medicine, combined with proton pump inhibitor (PPI) in patients with PPI-refractory non-erosive reflux disease (NERD). Patients with PPI-refractory NERD (n = 242) were randomly assigned to the RKT group [rabeprazole (10 mg/day) + RKT (7.5 g/t.i.d.) for 8 weeks] or the placebo group (rabeprazole + placebo). After the 4- and 8-week treatments, we assessed symptoms and quality of life (QOL) using the Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease (FSSG), Gastrointestinal Symptom Rating Scale (GSRS), and Short-Form Health Survey-8 (SF-8). There were no significant differences in FSSG and GSRS score improvement between these groups after the 4- and 8-week treatments. The mental component summary (MCS) scores of the SF-8 improved more in the RKT group (from 45.8 ± 8.1 to 48.5 ± 7.4) than in the placebo group (from 47.7 ± 7.1 to 48.4 ± 7.5) after the 4-week treatment (P < 0.05). The 8-week treatment with RKT was more effective for improvement of the degree of MCS score in patients with a low body mass index (<22) (P < 0.05) and significantly improved the acid-related dysmotility symptoms of FSSG in female and elderly patients (≥ 65 years). There were no significant differences in improvement of GERD symptoms in patients with PPI-refractory NERD between these groups. However, RKT may be useful for improving mental QOL in non-obese patients and acid-related dyspeptic symptoms, especially in women and the elderly.

The Role of Gastroesophageal Reflux in Relation to Symptom Onset in Patients with Proton Pump Inhibitor-Refractory Nonerosive Reflux Disease Accompanied by an Underlying Esophageal Motor Disorder

Background: The symptom improvement rate is low with proton pump inhibitors (PPIs) in nonerosive reflux disease (NERD). The underlying pathogenic mechanism is complex. Esophageal motility disorders (EMDs) are thought to be a factor, but their prevalence, type, symptoms and the role played by gastroesophageal reflux (GER) in symptom onset have not been fully investigated. Aim: To investigate the role of GER in symptom onset in PPI-refractory NERD patients with EMDs. Methods: This study comprised 76 patients with PPI-refractory NERD. Manometry was performed during PPI treatment and patients were divided into an EMD group and normal motility (non-EMD) group. Then, multichannel intraluminal impedance-pH monitoring was performed and medical interviews were conducted. Results: Nineteen patients (25%) had an EMD. Data were compared between 17 patients, excluding 2 with achalasia and 57 non-EMD patients. No significant differences were observed between groups in 24-hour intraesophageal pH <4 holding time (HT), mean number of GER episodes or mean number of proximal reflux episodes. The reflux-related symptom index (≥50%) showed a relationship between reflux and symptoms in 70.5% of EMD patients and 75% of non-EMD patients. In the EMD group, the score for FSSG (Frequency Scale for the Symptoms of GERD) question (Q)10 was significantly correlated with the number of GER episodes (r = 0.58, p = 0.02) and the number of proximal reflux episodes (r = 0.63, p = 0.02). In addition, the score for Q9 tended to be correlated with the number of GER episodes (r = 0.44, p = 0.06). Conclusion: Our results suggest that some PPI-refractory NERD patients have EMDs, and that GER plays a role in symptom onset.

Pathogenesis of proton‐pump inhibitor‐refractory non‐erosive reflux disease according to multichannel intraluminal impedance‐pH monitoring

Proton-pump inhibitor (PPI) therapy is the first-line treatment for gastroesophageal reflux disease; however, there are some reports of PPI failure in cases of non-erosive reflux disease (NERD). Among the pathogenic factors associated with PPI-refractory NERD, reflux other than acid reflux can not be detected by conventional pH monitoring. The purpose of this study was to clarify the usefulness of multichannel intraluminal impedance-pH (MII-pH) monitoring for PPI-refractory NERD patients and examine the pathogenesis. We used MII-pH monitoring to examine 29 PPI-refractory NERD patients on PPI treatment. Reflux parameters, symptom index (SI: positive if ≥ 50%), and proximal migration were analyzed. The acidity of the reflux was divided into acid (nadir pH ≤ 4) and non-acid (nadir pH > 4). Subjects were classified into reflux-related disease (abnormal reflux parameters or positive SI) and non-reflux-related disease (normal reflux parameters and negative SI). Of the 29 subjects, 21 were diagnosed with reflux-related disease, including 6 with acid reflux type and 15 with non-acid reflux type, and 8 were diagnosed with non-reflux-related disease. Of the total 1816 liquid reflux episodes, 834 showed proximal migration, which was more common in symptomatic reflux than in asymptomatic reflux. MII-pH monitoring could distinguish reflux-related disease (especially non-acid type) from PPI-refractory NERD. Proximal migration was associated with symptomatic reflux in PPI-refractory NERD patients.

Su1278 Efficacy of Endoluminal Gastroplication in Japanese Patients With Proton Pump Inhibitor-Resistant, Non-Erosive Esophagitis

Non-erosive reflux disease (NERD) accounts for more than half of cases of gastro-esophageal reflux disease. Its pathology is complex, and the disease is often not amenable to treatment with proton pump inhibitor (PPI), which are used as front-line drugs. Though surgical therapy has been reported to be effective as an alternative to drug therapy in NERD, the efficacy of endoscopic treatment in PPI-refractory NERD has not yet been studied. The aim of this study was to evaluate efficacy, safety, and long-term outcomes of endoluminal gastroplication (ELGP) in patients with PPI-resistant NERD.

Efficacy of endoluminal gastroplication in Japanese patients with proton pump inhibitor-resistant, non-erosive esophagitis

To evaluate the efficacy, safety, and long-term outcomes of endoluminal gastroplication (ELGP) in patients with proton pump inhibitor (PPI)-resistant, non-erosive reflux disease (NERD). The subjects were NERD patients, diagnosed by upper endoscopy before PPI use, who had symptoms such as heartburn or reflux sensations two or more times a week even after 8 wk of full-dose PPI treatment. Prior to ELGP, while continuing full-dose PPI medication, patients' symptoms and quality of life (QOL) were assessed using the questionnaire for the diagnosis of reflux disease, the frequency scale for symptoms of gastro-esophageal reflux disease (FSSG), gastrointestinal symptoms rating scale, a 36-item short-form. In addition, 24-h esophageal pH monitoring or 24-h intraesophageal pH/impedance (MII-pH) monitoring was performed. The Bard EndoCinch(TM) was used for ELGP, and 2 or 3 plications were made. After ELGP, all acid reducers were temporarily discontinued, and medication was resumed depending on the development and severity of symptoms. Three mo after ELGP, symptoms, QOL, pH or MII-pH monitoring, number of plications, and PPI medication were evaluated. Further, symptoms, number of plications, and PPI medication were evaluated 12 mo after ELGP to investigate long-term effects. The mean FSSG score decreased significantly from before ELGP to 3 and 12 mo after ELGP (19.1 ± 10.5 to 10.3 ± 7.4 and 9.3 ± 9.9, P < 0.05, respectively). The total number of plications decreased gradually at 3 and 12 mo after ELGP (2.4 ± 0.8 to 1.2 ± 0.8 and 0.8 ± 1.0, P < 0.05, respectively). The FSSG scores in cases with no remaining plications and in cases with one or more remaining plications were 4.4 and 2.7, respectively, after 3 mo, and 2.0 and 2.8, respectively, after 12 mo, showing no correlation to plication loss. On pH monitoring, there was no difference in the percent time pH < 4 from before ELGP to 3 mo after. Impedance monitoring revealed no changes in the number of reflux episodes or the symptom index for reflux events from before ELGP to 3 mo after, but the symptom sensitivity index decreased significantly 3 mo after ELGP (16.1 ± 12.9 to 3.9 ± 8.3, P < 0.01). At 3 mo after ELGP, 6 patients (31.6%) had reduced their PPI medication by 50% or more, and 11 patients (57.9%) were able to discontinue PPI medication altogether. After 12 mo, 3 patients (16.7%) were able to reduce the amount of PPI medication by 50% or more, and 12 patients (66.7%) were able to discontinue PPI medication altogether. A high percentage of cases with remaining plications had discontinued PPIs medication after 3 mo, but there was no difference after 12 mo. No serious complications were observed in this study. ELGP was safe, resulted in significant improvement in subjective symptoms, and allowed less medication to be used over the long term in patients with PPI-refractory NERD.