Efficacy Of Proton Pump Inhibitors Research Articles

Proton pump inhibitors stabilize the expression of PD-L1 on cell membrane depending on the phosphorylation of GSK3β.

Preclinical and clinical evidence indicates that proton pump inhibitors (PPIs) may indirectly diminish the microbiome diversity, thereby reducing the effectiveness of immune checkpoint inhibitors (ICIs). Conversely, recent publications have shown that PPIs could potentially enhance the response to ICIs. The precise mechanism through which PPIs modulate the ICIs remains unclear. In this study, we discovered a novel molecular function of PPIs in regulating immune invasion, specifically through inducing PD-L1 translocation in various tumor cells. C57BL/6 mice subcutaneous transplantation model is used to verify the potential efficacy of PPIs and PD-L1 antibody. Western blotting analysis and phosphorylated chip are used to verify the alteration of PD-L1-related pathways after being treated with PPIs. The related gene expression is performed by qRT-PCR and luciferase reporter analysis. We also collected 60 clinical patients diagnosed with esophageal cancer or reflux esophagitis and then detected the expression of PD-L1 in the tissue samples by immunohistochemistry. We observed that the IC50 of tumor cells in response to PPIs was significantly higher than that of normal epithelial cells. PPIs significantly increased the expression of PD-L1 on cell membrane at clinically relevant concentrations. Furthermore, pre-treatment with PPIs appeared to synergize the efficiency of anti-PD-L1 antibodies in mouse models. However, PPI administration did not alter the transcription or total protein level of PD-L1 in multiple tumor cells. Using a phosphorylated protein chip, we identified that PPIs enhanced the phosphorylation of GSK3β, then leading to PD-L1 protein translocation to the cell membranes. The capacity of PPIs to upregulate PD-L1 was negated following GSK3β knockout. Furthermore, our clinical data showed that the PPIs use resulted in increased PD-L1 expression in esophageal cancer patients. We mainly address a significant and novel mechanism that the usage of PPIs could directly induce the expression of PD-L1 by inducing GSK3β phosphorylation and facilitate primary tumor progression and metastasis.

Clinical progression of parotid salivary gland sialadenosis based on the selected <i>H. pylori</i> eradication therapy

Relevance. In approximately 50.82% of instances, sialadenosis of the parotid salivary gland (PSG) emerges as a sequel to gastrointestinal (GI) disorders. This condition is characterized by diminished saliva production (hyposalivation) and enlargement (hypertrophy) of the gland. In Russia, the prevalence of GI diseases linked to acid-related issues and H. pylori infection (HP) is notably high. The therapeutic approach to this pathology focuses on the eradication of HP, employing various treatment strategies that incorporate the use of a proton pump inhibitor (PPI). The efficacy of PPIs hinges on their ability to inhibit the proton pump, which is situated in the endothelial lining of the smooth muscle vessels, including those that encase the acinar cells of the PSG. An essential aspect of parotid secretion is its protective role, which is executed through the production of secretory immunoglobulin A (sIgA) within the gland's ductal system. Therefore, exploring the clinical progression of PSG sialadenosis under eradication therapy regimens holds substantial significance.Materials and methods. Between 2021 and 2023, 80 patients with parotid salivary gland (PSG) sialadenosis and Helicobacter pylori stomach infection were studied. They were divided into treatment groups: Group I (25 patients, aged 45.81 ± 6.39 years) received quadruple therapy (standard-dose PPI, amoxicillin 1,000 mg, clarithromycin 500 mg twice daily, and bismuthate tripotassium dicitrate 120 mg four times daily); Group II (55 patients, aged 47.79 ± 7.15 years) underwent standard triple therapy (double-dose PPI, amoxicillin 1,000 mg, and clarithromycin 500 mg twice daily). A control group consisted of 20 nearly healthy individuals (average age 26.46 ± 4.12 years). All subjects underwent comprehensive dental and PSG assessments, including questionnaires, sialometry, and measurement of (sIgA) levels in parotid secretion.Results. After eradication therapy, Group I patients treated with quadruple therapy exhibited a 1.2-fold reduction in PSG secretory function (p = 0.048) and a 1.2-fold decrease in sIgA concentration (p = 0.035) compared to initial levels. Group II patients receiving triple therapy demonstrated a significant 3.6-fold decline in PSG sialometry parameters (p = 0.002) and a 1.8-fold reduction in sIgA levels (p = 0.006) by the 14th day post-eradication, relative to pre-treatment figures. Conclusion. Therefore, patients with GI acid-related conditions linked to HP infection should be evaluated by a dentist for potential PSG sialadenosis. The presence of PSG sialadenosis in individuals with HP stomach infection warrants consideration in the selection and administration of eradication therapy.

A Meta-analysis of PPIs Plus Alginate Versus PPIs Alone for the Treatment of GERD

To systematically evaluate the clinical efficacy and safety of proton-pump inhibitors (PPIs) combined with alginate versus PPIs alone in the treatment of gastroesophageal reflux disease (GERD). Randomised Controlled Trials (RCTs) of PPIs combined with alginate and PPIs alone for the treatment of GERD in PubMed, Embase, and The Cochrane Library were searched and screened, and the risk assessment of bias and statistical analysis were performed using Rev Man 5.4 software. A total of four RCTs (608 patients) were included. Before and after treatment, the change of heartburn score in the experimental group increased compared with the control group, but the difference was not statistically significant [Standard Mean Difference (SMD)=-0.29, 95%CI (-0.78, 0.19), P>0.05]; The change of HRDQ heartburn score increased, but the difference was not statistically significant [SMD=-0.40, 95%CI (-1.04, 0.24), P>0.05]; The number of days without heartburn during the 28-day treatment period increased, but the difference was not statistically significant [OR=1.16, 95%CI (0.37, 3.61), P>0.05]; The amount of reflux score increased, but the difference was not statistically significant [SMD=-0.30, 95%CI (-0.71, 0.11), P>0.05]; The amount of change in HRDQ regurgitation score increased, but the difference was not statistically significant [SMD=-0.05，95%CI （-1.57，0.17），P>0.05]； There was no statistically significant difference in adverse events with treatment [OR=0.93, 95%CI (0.58, 1.47), P>0.05]. In the treatment of GERD, the efficacy of PPIs combined with alginate is improved compared with PPIs alone, but there is no significant difference, and alginate does not increase the occurrence of adverse events in PPIs treatment. In the future, more subdivisions of GERD subtypes and more high-quality studies are needed to further improve the treatment strategy of GERD-related diseases.

Primary and Specialty Care Trainees' Perceptions About Proton Pump Inhibitor Use.

Proton pump inhibitors (PPIs) are widely prescribed with proven efficacy in many indications, yet longstanding controversy about potential adverse events persists. We aimed to acquire knowledge about perceptions of outpatient PPI long-term prescribing (≥8 wk) among primary and specialty care trainees at 2 Canadian Universities. Family medicine, internal medicine, and gastroenterology trainees completed a web-based survey that included 20 clinical scenarios assessing trainee knowledge about PPI efficacy. Contextual PPI prescribing decisions were also elicited, balancing possible PPI indications versus side effects. Management strategies were compared between junior and senior trainees, as well as across training programs. Over a 4-month period,163 trainees (age <26 y: 12%; age 26 to 45: 88%; 59% females) participated in the survey (family medicine: 51%, internal medicine: 44%, and gastroenterology: 5%); 83% were considered junior residents. Only 42% had received formal education on prescribing PPI long-term. Overall, 93% believed they would benefit from such teaching, with 98% stating they would follow related guidelines. No between-group differences were noted in knowledge of appropriate PPI indications nor possible side effects when comparing juniors to seniors, or among different specialties. Across different management scenarios, inappropriate PPI discontinuation was chosen by 14.3% to 67.2%, whereas inappropriate PPI continuation was reported in up to 57%. Trainee seniority and specialty did not differ in appropriate deprescribing rates. Training level and primary versus specialty care settings are associated with frequent inappropriate PPI prescribing and deprescribing. These findings highlight the need for and may inform future educational programs on PPI usage.

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 EAand 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.

Per-Oral Endoscopic Myotomy-Induced Gastroesophageal Reflux Disease and Review of the Efficacy of Proton Pump Inhibitors as a Management Strategy: Review of the Literature.

Per-oral endoscopic myotomy (POEM) is a minimally invasive procedure that is very effective in the treatment of achalasia, a rare esophageal motility disorder. POEM has become the first-line treatment for achalasia, with high success rates reported in the literature. However, a known complication of POEM is gastroesophageal reflux disease (GERD). The exact cause and risk factors of post-POEM GERD are not fully understood; however, a number of factors have played a role in its development. The management of post-POEM GERD is mainly by conservative measures, such as lifestyle changes and medications, like proton pump inhibitors (PPI), which are often the first-line method of treatment. However, surgical procedures, such as fundoplication, may be necessary in some patients. This literature review will discuss the effectiveness of the use of PPIs as a management strategy for post-POEM GERD, the factors that lead to PPI-resistant GERD, and other management strategies utilized in these cases.

Study of the empirical role of proton pump inhibitor therapy on laryngopharyngeal reflux

Background: Laryngopharyngeal reflux (LPR) is a highly prevalent disease and commonly encountered in the otolaryngologist’s office. Study to evaluate the presentation of different signs and symptoms of LPR along with evaluating the role of empiric PPI (proton pump inhibitor) in the management of LPR by observing its effect on RFS and RSI. Methods: A prospective observational study was conducted on 100 cases having different symptoms of LPR. Reflux symptom index (RSI) and Reflux finding score (RFS) were used to diagnose LPR. Patients were put on PPI (Pantoprazole 40 mg OD for 12 weeks) and followed up at 4,8 and 12 weeks and successive RSI and RFS scores were evaluated. The results were compiled and analyzed statistically. Results: Among all symptoms, most common presenting symptom of LPR was foreign body/sensation of something sticking in throat (80%). Upon pharmacological therapy with PPIs (Pantoprazole), the mean RSI score changed from 22.94±5.83 to 11.19±2.97 at 12 weeks of PPI therapy. The mean RFS score changed from 12.93±3.55 to 6.86±2.86 at 12 weeks of PPI therapy. The change in the RFS and RSI score was highly significant (p=0.001). Conclusions: LPR is a common condition presenting in ENT settings, the symptoms and signs of which may be complex. RFS and RSI score are valuable tools for diagnosing LPR. PPIs are proven to be effective therapy for LPR, more studies are encouraged to affirm the efficacy of PPIs over other management options.

Assessing the Therapeutic Efficacy of Proton Transport Inhibitors in a Triple-Negative Breast Cancer Murine Model with Magnetic Resonance Imaging-Chemical Exchange Saturation Transfer Tumor pH Imaging.

Proton transporters play a key role in maintaining the acidic tumor microenvironment; hence, their inhibition has been proposed as a new therapeutic treatment, although few methods can accurately assess their effect in vivo. In this study, we investigated whether MRI-CEST (Magnetic Resonance Imaging-Chemical Exchange Saturation Transfer) tumor pH imaging can be a useful tool to evaluate in vivo the therapeutic efficacy of several Proton Pump Inhibitors (PPIs) in breast cancer. Cell viability and extracellular pH assays were carried out in breast cancer cells cultured at physiological pH (7.4) or acid-adapted (pH of 6.5 and 6.8) following the exposure to inhibitors of V-ATPase (Lansoprazole, Esomeprazole) or NHE1 (Amiloride, Cariporide) at several concentrations. Next, triple-negative breast cancer 4T1 tumor-bearing mice were treated with Lansoprazole or Amiloride and MRI-CEST tumor pH imaging was utilized to assess the in vivo efficacy. Only Lansoprazole induced, in addition to breast cancer cell toxicity, a significant inhibition of proton extrusion. A significant reduction in tumor volume, prolonged survival, and increase in extracellular tumor pH after 1 and 2 weeks were observed after Lansoprazole treatment, whereas no significant changes were detected upon Amiloride treatment. Our results suggested that MRI-CEST tumor pH imaging can monitor the therapeutic efficacy of PPIs in breast cancer murine models.

Comparing the Safety and Efficacy of Proton Pump Inhibitors and Histamine-2 Receptor Antagonists in the Management of Patients With Peptic Ulcer Disease: A Systematic Review.

Peptic ulcer disease (PUD) refers to the occurrence of an open erosion in the inner lining of the stomach, duodenum, or sometimes lower esophagus. Treatments like proton pump inhibitors (PPIs) or histamine 2 receptor antagonists (H2RAs) are available on the market to efficiently treat the break in the mucosal lining. However, there is little evidence about the effects of the medication on the type and location of the ulcer and the epigastric pain caused by disintegration and increased acidity in the stomach. Given the above, we conducted a systematic review comparing the safety and efficacy of PPIs and H2RAs in various ulcer locations (gastric, duodenal, and pre-pyloric) and the effect of prolonging the treatment with the same medication or changing into a drug from another class in treatment-resistant ulcers. We employed major research literature databases and search engines such as PubMed, Medical Literature Analysis and Retrieval System Online (MEDLINE), Science Direct, and Google Scholar to find relevant articles. After a thorough screening, a quality check using various tools, and applying filters that suited our eligibility criteria, we identified eight articles, of which five were random clinical trials (RCTs), two review articles, and one meta-analysis. This study compares the different side effects of PPIs and H2RAs. Most studies concluded that omeprazole is superior in healing ulcers and bringing pain relief and that patients resistant to H2RAs can be treated better when switched to a PPI. This study also discusses the adverse effects of chronic use, such as diarrhea, constipation, headaches, and gastrointestinal infections. Patients on long-term PPI therapy are required to take calcium supplements to prevent the risk of fractures in older adults. Regarding long-term outcomes, PPIs remain the mainstay of treatment for peptic ulcer disease, based on the papers we reviewed.

Therapeutic efficacy of proton pump inhibitor (omeprazole) on cryptosporidiosis parvum in immunosuppressed experimental mice.

Cryptosporidiosis is one of the most frequent food and water-borne diseases. The disease might be life-threatening in immunosuppressed patients. Unfortunately, the only approved drug, nitazoxanide, is with variable efficacies, particularly in malnourished children and immunocompromised patients. Therefore, there is a need to discover an alternative treatment that could be achieved by targeting the metabolic pathways. One of the important enzymes in the glycolysis pathway of C. parvum is triosephosphate isomerase, which could be hindered by the proton pump inhibitor (PPI) omeprazole. In this study, omeprazole was repurposed against C. parvum infection in experimentally immunosuppressed mice. This study was conducted on five mice groups (n = 10). Group I (Normal Control), group II (Infected Control): Mice were infected orally with 1 × 105 C. parvum oocysts on the 15th day of DEX induced immunosuppression. Group III (NTZ-treated): infected and treated by NTZ. Group IV (Omeprazole-treated), and lastly, Group V (NTZ + Omeprazole-treated). The result obtained with omeprazole alone was better than nitazoxanide regarding oocyst shedding reduction percentages (84.9% & 56.1%, respectively). Also, it was better regarding restoration of histopathological and ultrastructural architectures, improvement of liver enzymes (alanine aminotransferase and aspartate aminotransferase) and renal functions (urea and creatinine), and the reduction of C. parvum triosephosphate isomerase (TIM) gene expression by RT-PCR. However, the best results were obtained with the combined treatment. Hence, omeprazole could be considered a novel drug option to treat this life-threatening parasitic infection either alone or combined with NTZ, especially in immunosuppressed patients.

Safety and efficacy of proton pump inhibitors in preterm infants with gastroesophageal reflux disease

Objectives This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the safety and efficacy of proton pump inhibitors (PPIs) for the treatment of preterm infants with diagnosed or suspected gastroesophageal reflux disease (GERD).

Treatment of eosinophilic esophagitis - advancements and perspectives

In recent years significant progress has been made in the treatment of eosinophilic esophagitis (EoE), especially in the area of topical corticosteroids. Novel EoE-specific formulations have been developed and first approvals have been obtained for induction and maintenance of remission in adult EoE patients with the orodispersible budesonide tablet in Germany and other European and non-EU countries. A novel budesonide oral suspension is currently under priority review by the FDA for first approval in the U.S. In contrast, the scientific evidence on the efficacy of proton pump inhibitors remains limited. Moreover, new biologicals have been identified which showed promising results in phase 2 trials and are now being studied in phase 3. This article aims to summarize and discuss recent advances and perspectives in the treatment of EoE.

Proton Pump Inhibitor Therapy in Pediatric Eosinophilic Esophagitis: Predictive Factors and Long-Term Step-Down Efficacy.

To assess the short- and long-term efficacy of proton pump inhibitor (PPI) therapy for pediatric eosinophilic esophagitis (EoE) in real-world practice with a step-down strategy, and to evaluate factors predictive of PPI responsiveness. We collected data regarding the efficacy of PPIs during this cross-sectional analysis of the prospective nationwide RENESE registry. Children with EoE treated with PPI monotherapy were included. Histological remission was defined as a peak eosinophilic count of <15 eosinophils (eos)/high-power field (hpf). Factors associated with PPI responsiveness were identified using multivariate logistic regression analysis. After induction therapy, histological and clinico-histological remission were observed in 51.4% (n = 346) and 46.5% of children, respectively. Normal endoscopic appearance of the esophagus was associated with a higher possibility [odds ratio (OR), 9.20; 95% confidence interval (CI), 2.10-40.16], and fibrostenotic phenotype was associated with a lower possibility (OR, 0.36; 95% CI, 0.18-0.74) of histological remission. Long-term therapy with a step-down strategy effectively maintained histological remission in 68.5% and 85.3% of children at 7 months (n = 108) and 16 months (n = 34), respectively. Complete initial histological remission (≤5 eos/hpf) was associated with a higher possibility of sustained histological remission (OR, 5.08; 95% CI, 1.75-14.68). Adverse events were infrequent and mild. We confirmed the efficacy of PPIs for a large cohort of children with EoE with sustained histological remission using a step-down strategy. Children with fibrostenotic phenotypes are less likely to respond to induction therapy. Furthermore, patients with complete initial histological remission are more likely to experience long-term histological remission.

PPI efficacy in the reduction of variceal bleeding incidence and mortality, a meta-analysis

ObjectiveTo review the efficacy and safety of proton pump inhibitors (PPIs) in gastroesophageal varices (GEVs).MethodsWe searched PubMed MEDLINE, Scopus, and Web of Science for studies that measured the effect of PPI for prophylaxis and treatment of post-band ligation ulcers up to July 20, 2021. We included studies that measured the effect of PPI as treatment or prophylaxis for post-band ligation ulcers; articles that were published in peer-reviewed international journals and had enough data for qualitative and quantitative analysis were included with no language restriction. Heterogeneity was evaluated using the inconsistency (I2) and chi-squared (χ2) test. I2 > 50% was considered substantial heterogeneity in the studies, and a P value less than 0.05 was considered statistically significant. The data was continuous, and we used the standardized mean difference (MD) and risk ratio (RR) with a 95% confidence interval to assess the estimated effect measure.ResultsA total of 7 studies with 2030 patients were included in our study of which 1480 participants were males (72%) and 550 females (18%). Mean age was 59.7 years old. Rebleeding post-band ligation was compared between PPI and placebo with significant favor for PPI (p = 0.00001). The pooled risk ratio was 0.53 (95% CI of 0.41, 0.68); furthermore, bleeding-related death at a 1-month period was compared between PPI and placebo with significant favor for PPI (p = 0.00001). The pooled risk ratio was significant at 0.33 (95% CI of 0.20, 0.53). The length of hospital stay postoperative was compared between PPI and placebo with cumulative mean difference of 0.13 (95% CI of −1.13, 1.39), yet without significance.ConclusionsThe study suggests a twofold reduction in the risk of bleeding and a threefold reduction in the risk of bleeding-related death with the use of PPI following EVL.

A Randomized, Double-Blind, Active-Control, Noninferiority, Multicenter, Phase 4 Study to Evaluate the Efficacy and Safety of Esomeprazole/Sodium Bicarbonate 20/800 mg in Patients with Nonerosive Gastroesophageal Reflux Disease.

Efficacy of proton pump inhibitors is limited in patients with nonerosive reflux disease (NERD). The aim of this study was to comparatively evaluate the efficacy and safety of esomeprazole with sodium bicarbonate and esomeprazole alone. This was a multicenter, randomized, double-blind, active-controlled, noninferiority comparative study. A total of 379 patients with NERD were randomly allocated to receive either EsoduoⓇ (esomeprazole 20 mg with sodium bicarbonate 800 mg) or NexiumⓇ (esomeprazole 20 mg) once daily for 4 weeks from January 2019 to December 2019. The patients had a history of heartburn for at least 2 days in the week before randomization as well as in the last 3 months and no esophageal mucosal breaks on endoscopy. The primary endpoint was a complete cure of heartburn at week 4. The secondary and exploratory endpoints as well as the safety profiles were compared in the groups at weeks 2 and 4. A total of 355 patients completed the study (180 in the EsoduoⓇ group and 175 in the NexiumⓇ group). The proportions of patients without heartburn in the entire 4th week of treatment were not different between the two groups (33.33% in the EsoduoⓇ group and 35% in the NexiumⓇ group, p=0.737). There were no significant differences in most of the secondary and exploratory endpoints as well as the safety profiles. EsoduoⓇ is as effective and safe as NexiumⓇ for managing typical symptoms in patients with NERD (ClinicalTrial.gov identifier: NCT03928470).

Effect of Proton Pump Inhibitors on Reflux Symptom Index (RSI) and Reflux Finding Score (RFS) in Patients with Laryngopharyngeal Reflux: A Systematic Review and Meta-Analysis

ABSTRACT Objectives: The purpose of this study was to determine the efficacy of proton pump inhibitor (PPI) therapy in treating the symptoms and laryngeal findings of laryngopharyngeal reflux (LPR). Methods: Placebo-controlled, randomized clinical trials published after June 2001 to January 2021 which used PPI as the sole intervention and the RSI or RFS as outcome measures were eligible for inclusion. Studies that were published prior to June 2001, those which only made use of questionnaires other than the RSI or RFS, those which used PPI in combination with other treatments, or those with unavailable full-text manuscripts were excluded. These studies were identified from MEDLINE, Scopus, Cochrane Library, Embase, and HERDIN Plus databases which were searched from May 21 to 26, 2020. The primary outcome was the mean difference between baseline/pre-treatment and post-treatment RSI scores for both PPI and placebo groups. The secondary outcome was the mean difference between pre-treatment and post-treatment RFS scores for PPI and placebo groups. Aggregate results of these outcomes were analyzed using forest plots. Heterogeneity was determined through prediction intervals. Risk of bias of individual studies was assessed using the Cochrane Collaboration’s Tool in Assessing Risk of Bias. Results: Nine randomized control trials were included with a total of 737 patients randomized and 595 patients analyzed – 294 from the PPI group and 301 from the placebo group. There were notable variations among the studies in terms of choice of PPI, dosage and frequency. Out of nine studies, four used both RSI and RFS in their analysis. Two studies used RSI alone and three used the RFS in combination with symptom questionnaires other than the RSI. There was a significant decrease in the RSI of the PPI group versus the placebo group with a mean difference of -2.83 (95% CI, -5.13 to -0.53, p = .02). However, there was no significant decrease in the RFS between PPI and placebo groups with a mean difference of -0.84 (95% CI, -2.66 to 0.98, p = .37). For two clinical trials which only reported post-treatment RFS, there was also no significant difference between the two treatment groups with a mean difference of 1.27 (95% CI, -0.22 to 2.76, p = .10). Conclusion: This meta-analysis found that, although a statistically significant benefit in RSI was noted with PPI therapy, this difference may not translate to a clinically significant change in symptoms; therefore, there is insufficient evidence to recommend for or against the treatment of LPR with PPIs.

Long-term efficacy of proton pump inhibitors as a treatment modality for eosinophilic esophagitis

BackgroundProton pump inhibitors (PPIs) are a first-line treatment for EoE, but data are limited concerning response durability. We aimed to determine long-term outcomes in EoE patients responsive to PPI-therapy. MethodsWe conducted a retrospective cohort study of newly diagnosed adults with EoE who had initial histologic response (<15 eosinophils per high-power-field) to PPI-only therapy. We extracted data regarding their subsequent clinical course and outcomes. We compared findings between the initial PPI-response endoscopy and the final endoscopy, and assessed factors associated with loss of PPI response. ResultsOf 138 EoE patients with initial histologic response to PPI, 50 had long-term endoscopic follow-up, 40 had clinical follow-up, 10 changed treatments, and 38 had no long-term follow-up. Of those with endoscopic follow-up, mean follow-up-time was 3.6 ± 2.9 years; 30 and 32 patients (60%; 64%) maintained histologic and symptom responses, respectively. However, fibrotic endoscopic findings of EoE were unchanged. Younger age (aOR 1.05, 95% CI: 1.01–1.11) and dilation prior to PPI treatment (aOR 0.21, 95% CI: 0.05–0.83) were the only factors associated with long-term loss of PPI response. ConclusionsLong-term histologic and clinical response rates for PPI therapy were 60% and 64%, respectively. Younger age and dilation at baseline were associated with histologic loss of response. These data can inform long-term EoE treatment selection.

A129 CYP2C19 PHARMACOGENETIC TESTING IN PAEDIATRIC PATIENTS WITH EOSINOPHILIC ESOPHAGITIS INFLUENCES DOSING OF PROTON-PUMP-INHIBITORS AND RESPONSE TO THERAPY

BackgroundEosinophilic esophagitis (EoE) is a chronic inflammatory disorder that can be treated with a proton pump inhibitor (PPI). Pharmacogenetics (PGx) is the study of how variations in an individual’s genome influences drug response. Genetic variation in the metabolism gene CYP2C19 can produce differences in enzyme activity which is known to be a contributing factor for therapeutic failure with PPI treatment. Use of 2nd generation PPI (rabeprazole) can be beneficial in some as this PPI is less effected by CYP2C19 metabolism. PGx has been studied in PPI therapy for peptic ulcer disease but has not been demonstrated in patients with EoE.AimsTo describe the CYP2C19 metabolism in patients with EoE on PPI and to estimate the clinical utility of PGx testing in directing subsequent changes in therapy with improvement in remission rates.MethodsInterim analyses of a single centre, non-interventional, ongoing descriptive pilot study investigating CYP2C19 metabolism in patients with EoE, as part of a larger PGx pilot study and EoE- AHEAD Registry Study at SickKids. Patients with EoE that were newly diagnosed and started PPI or those not in remission on current non-PPI therapy or not in remission on dose PPI (2 mg/kg/day, max 30 mg lansoprazole BID) were included. Active disease was defined as a peak eosinophil count >15/hpf.Results37 patients met the inclusion criteria with completed PGx test; mean age was 13 years, 29(78%) were male, and 13(35%) had concurrent atopic disease. PGx testing showed that 12(32%) and 4(11%) were rapid (RM) and ultrarapid metabolizers (URM) respectively (Fig.1), which is significantly higher than the population average. Of this subgroup, 9 started rabeprazole, 3 had a lansoprazole dose increase, and 4 had no changes. Overall, changes in therapy based on PGx testing were made in 29(78%) patients, 8 are awaiting follow-up (Fig 2). Currently, the patients with available repeat biopsy results after PGx test-guided therapy changes is limited due COVID-19 related delays in endoscopies.ConclusionsThe preliminary findings of our study using PGx to guide PPI dosing in pediatric patients with EoE demonstrate that PGx test results lead to a change in clinical management in most patients. In RM and URM, PGx results trigger an adjustment of PPI dose or type could lead to earlier disease remission in PPI-responsive patients, thereby optimizing PPI efficacy. PGx may support dose reduction in poor metabolizers aiming to avoid long-term adverse events.Further correlation with endoscopy and histology findings of patients after PGx-guided therapy changes will follow. Furthermore, it is important to examine if CYP2C19 variant information available before PPI therapy further streamlines an initial phase of the treatment. Funding AgenciesDr. Marcon: J Garfield Campbell Fund, Dr. Hulst: Start-up Funds from the Department of Pediatrics at SickKids

Proton pump inhibitor treatment initiated prior to endoscopic diagnosis in upper gastrointestinal bleeding.

Upper gastrointestinal (GI) bleeding is a common reason for emergency hospital admission. Proton pump inhibitors (PPIs) reduce gastric acid production and are used to manage upper GI bleeding. However, there is conflicting evidence regarding the clinical efficacy of proton pump inhibitors initiated before endoscopy in people with upper gastrointestinal bleeding. To assess the effects of PPI treatment initiated prior to endoscopy in people with acute upper GI bleeding. We searched the CENTRAL, MEDLINE, Embase and CINAHL databases and major conference proceedings to October 2008, for the previous versions of this review, and in April 2018, October 2019, and 3 June 2021 for this update. We also contacted experts in the field and searched trial registries and references of trials for any additional trials. We selected randomised controlled trials (RCTs) that compared treatment with a PPI (oral or intravenous) versus control treatment with either placebo, histamine-2 receptor antagonist (H2RA) or no treatment, prior to endoscopy in hospitalised people with uninvestigated upper GI bleeding. At least two review authors independently assessed study eligibility, extracted study data and assessed risk of bias. Outcomes assessed at 30 days were: mortality (our primary outcome), rebleeding, surgery, high-risk stigmata of recent haemorrhage (active bleeding, non-bleeding visible vessel or adherent clot) at index endoscopy, endoscopic haemostatic treatment at index endoscopy, time to discharge, blood transfusion requirements and adverse effects. We used standard methodological procedures expected by Cochrane. We included six RCTs comprising 2223 participants. No new studies have been published after the literature search performed in 2008 for the previous version of this review. Of the included studies, we considered one to be at low risk of bias, two to be at unclear risk of bias, and three at high risk of bias. Our meta-analyses suggest that pre-endoscopic PPI use may not reduce mortality (OR 1.14, 95% CI 0.76 to 1.70; 5 studies; low-certainty evidence), and may reduce rebleeding (OR 0.81, 95% CI 0.62 to 1.06; 5 studies; low-certainty evidence). In addition, pre-endoscopic PPI use may not reduce the need for surgery (OR 0.91, 95% CI 0.65 to 1.26; 6 studies; low-certainty evidence), and may not reduce the proportion of participants with high-risk stigmata of recent haemorrhage at index endoscopy (OR 0.80, 95% CI 0.52 to 1.21; 4 studies; low-certainty evidence). Pre-endoscopic PPI use likely reduces the need for endoscopic haemostatic treatment at index endoscopy (OR 0.68, 95% CI 0.50 to 0.93; 3 studies; moderate-certainty evidence). There were insufficient data to determine the effect of pre-endoscopic PPI use on blood transfusions (2 studies; meta-analysis not possible; very low-certainty evidence) and time to discharge (1 study; very low-certainty evidence). There was no substantial heterogeneity amongst trials in any analysis. There is moderate-certainty evidence that PPI treatment initiated before endoscopy for upper GI bleeding likely reduces the requirement for endoscopic haemostatic treatment at index endoscopy. However, there is insufficient evidence to conclude whether pre-endoscopic PPI treatment increases, reduces or has no effect on other clinical outcomes, including mortality, rebleeding and need for surgery. Further well-designed RCTs that conform to current standards for endoscopic haemostatic treatment and appropriate co-interventions, and that ensure high-dose PPIs are only given to people who received endoscopic haemostatic treatment, regardless of initial randomisation, are warranted. However, as it may be unrealistic to achieve the optimal information size, pragmatic multicentre trials may provide valuable evidence on this topic.

Duodenal Dysbiosis and Relation to the Efficacy of Proton Pump Inhibitors in Functional Dyspepsia.

Proton pump inhibitors (PPI) may improve symptoms in functional dyspepsia (FD) through duodenal eosinophil-reducing effects. However, the contribution of the microbiome to FD symptoms and its interaction with PPI remains elusive. Aseptic duodenal brushings and biopsies were performed before and after PPI intake (4 weeks Pantoprazole 40 mg daily, FD-starters and controls) or withdrawal (2 months, FD-stoppers) for 16S-rRNA sequencing. Between- and within-group changes in genera or diversity and associations with symptoms or duodenal factors were analyzed. In total, 30 controls, 28 FD-starters and 19 FD-stoppers were followed. Mucus-associated Porphyromonas was lower in FD-starters vs. controls and correlated with symptoms in FD and duodenal eosinophils in both groups, while Streptococcus correlated with eosinophils in controls. Although clinical and eosinophil-reducing effects of PPI therapy were unrelated to microbiota changes in FD-starters, increased Streptococcus was associated with duodenal PPI effects in controls and remained higher despite withdrawal of long-term PPI therapy in FD-stoppers. Thus, duodenal microbiome analysis demonstrated differential mucus-associated genera, with a potential role of Porphyromonas in FD pathophysiology. While beneficial effects of short-term PPI therapy were not associated with microbial changes in FD-starters, increased Streptococcus and its association with PPIeffects in controls suggest a role for duodenal dysbiosis after long-term PPI therapy.