Introduction

Antireflux surgery (fundoplication) may counteract gastroesophageal reflux of all types of carcinogenic gastric contents, not only acid, and reduce esophageal acid exposure to a greater extent than antireflux medication (proton pump inhibitors). We therefore examined the hypothesis that antireflux surgery prevents esophageal adenocarcinoma to a larger degree than antireflux medication in high-risk patients of esophageal adenocarcinoma, i.e. those with Barrett’s esophagus.

Aims & Methods

This multi-national and population-based cohort study included all patients with a recorded diagnosis of Barrett’s esophagus from Denmark (in 2012-2020), Finland (1987-1996 and 2010-2020), Norway (2008-2020), or Sweden (2006-2020) in a national patient registry. Patients who underwent antireflux surgery were compared with non-operated patients using antireflux medication. The risk of esophageal adenocarcinoma was calculated using multivariable Cox regression, providing hazard ratios (HR) with 95% confidence intervals (CI) adjusted for age, sex, country, calendar year, and comorbidity.

Results

The cohort consisted of 33,939 patients with Barrett’s esophagus. Of these, 542 (1.6%) had undergone antireflux surgery. During up to 32 years of follow-up, the overall HR was not decreased in patients having undergone antireflux surgery compared to non-operated patients using antireflux medications, but rather increased (adjusted HR 1.9, 95% CI 1.1-3.5). The point estimates did not decrease with longer follow-up, but instead increased for each follow-up category, from 1.8 (95% CI 0.6-5.0) within 1-4 years of follow-up to 4.4 (95% CI 1.4-13.5) after >10 years of follow-up.

Conclusion

Antireflux surgery does not seem to be superior to antireflux medication in the prevention of esophageal adenocarcinoma among patients with Barrett’s esophagus.

Introduction

Ulcerative colitis (UC) occurs in genetically predisposed individuals. The influence of environmental factors and the gastrointestinal microbiome is thought to be of particular importance in this disorder. Proton pump inhibitors (PPIs) affect the microbiome along the entire GI tract and PPI use is the single factor that influences fecal microbial composition to the largest extent at a population level. Only few studies have previously investigated the association between PPI use and UC, but these suggest that PPIs may increase the risk of UC and possibly also affect the disease course. The objective of the study was to examine how PPI exposure is associated with disease course in a large national cohort of newly diagnosed UC patients.

Aims & Methods

Nationwide data from the Norwegian Patient Registry (NPR) and the Norwegian Prescription Database (NorPD) were linked and a study cohort including all newly diagnosed UC patients in Norway between 2010 and 2020 was drawn based on predefined case definitions. PPI exposure was included as a time dependent variable and defined as PPI dispensal of at least 0.5 defined daily doses for 28 days. A 30 day time lag from dispensal was added and the exposure period extended 60 days after the duration of the prescription. Outcomes were classed by use of advanced therapies (adalimumab, infliximab, golimumab, vedolizumab, ustekinumab and tofacitinib), systemic glucocorticoids, and starting any additional systemic anti-inflammatory medication and colectomy during follow-up. Time-dependent Cox regressions included the variables PPI use (time-dependent), first systemic glucocorticoid prescription (time-dependent), first UC hospitalization (time-dependent), age-groups 0-19, 20-39, 40-59, 60+ years and sex. In the multivariate analyses using systemic glucocorticoids and colectomy as outcomes, advanced therapies was also included as a variable. Patients were followed from time of diagnosis until the outcome of interest, death or December 2020, whichever came first.

Results

There were 10149 patients in the study cohort. The median age was 40 years (IQR 27-56) and 56% were males. PPI use independently increased the risk of starting glucocorticoids (HR 1.20, 95% CI 1.07-1.34), advanced therapies (HR 1.54, 95% CI 1.36-1.73), any additional anti-inflammatory treatment (HR 1.18, 95%CI 1.05-1.32) and undergoing colon surgery (HR 1.52, 95%CI 1.17-1.98). The strongest risk factor for starting glucocorticoids were hospitalization (HR 4.35 95%CI 3.96-4.77), while young age also was a significant risk factor. Use of glucocorticoids was the strongest risk factor for starting treatment advanced therapies (HR 13.19, 95%CI 11.12-15.63) and younger age was also a significant risk factor in this analysis. In the sensitivity analysis using outcomes occurring without time lag and with 60 days lag, the HR of PPI use were similar. In analyses where patients exposed to NSAID were excluded, PPI use remained a significant risk factor for starting advanced therapies HR 1.66 (1.47-1.88) and undergoing colectomy HR 1.64 (1.25-2.15), but PPI use was no longer a risk factor for starting glucocorticoids or starting any anti-inflammatory treatment.

Conclusion

In this national cohort of newly diagnosed patients with UC, PPI use was a risk factor for unfavorable outcomes including advanced therapy initiation, additional anti-inflammatory medications and undergoing colectomy. Although further studies are needed, the evidence suggests that PPIs could affect the course of UC and should be used cautiously in UC patients.

Disclosure

The project was funded by Takeda. The author SSL reports research funding from Takeda during the conduct of the study. RF has received lecture fee from Takeda. MLH reports investigator research grants from Takeda, Pfizer, Tillotts and Ferring, and speaker fees from Tillotts, Ferring, Galapagos, BMS, MSD and AbbVie as well as Advisory board honoraria from Takeda and AbbVie.