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.

Introduction

The PROTDILAT study (Loras et al. Lancet Gastroenterol Hepatol. 2022) at 1-year follow-up showed greater efficacy of EBD vs SEMS for the treatment of short strictures in CD. However, long term efficacy of endoscopic treatmetn is still debated, especially for EDB.

Aims & Methods

Aims: To assess the long-term evolution of patients included in PROTDILAT study. 1). Percentage of patients free of surgery; 2) Factors related to surgery; 3) Need for endoscopic retreatments; 4) Effectiveness related to the type of initial endoscopic treatment (EBD vs SEMS); 5) Complications related to endoscopic or surgical treatment.
Methods: Retrospective study based on PROTDILAT trial database (patients with CD, obstructive symptoms, with stenosis <10cm). Data on medical, endoscopic and surgical treatment and smoking habits were collected. The effectiveness of endoscopic treatment is defined by the percentage of patients free of surgery and endoscopic retreatment at the end of follow-up.

Results

Information available on 80/80 patients (39 SEMS, 41 EBD), 39 women, age (median): 45y (IQR: 38-55); median stricture length 3.4cm (IQR: 2-5.5), 42.5% being anastomotic. Thirty-one percent (25/80) of patients required surgical resection [(median time to surgery 30.61 months (6.35-55.24)). Factors associated to surgery: non-intensification of therapy (HR 0.26 (0.10-0.68)), treatment with EBD exclusively (HR 0.22 (0.08-0.58)) (with respect to treatment with EBD + SEMS) and number of stents (HR 2.31 (1.10-4.84)). Of the 55 patients free of surgery, during the entire follow-up (median 84 months (74.7-84.0)), a median of 2 endoscopic procedures (1-3) were performed: EBD in 45 cases (80.0%) and SEMS in 26 cases (46%). Thirty-eight-point seventy-five percent (31/80 patients) did not require neither surgery nor endoscopic retreatment during the follow-up. The long-term effectiveness of endoscopic treatment was 45% for SEMS and 57.6% for EBD (p=0.374). The complications related to endoscopic or surgical treatment were 8.75% (7/80) versus 36% (9/25) respectively (p=0.002). As for the severity of complications (AGREE/CLAVIEN-DINDO ≥ III), it was observed that surgical treatment presented more severe complications than endoscopic treatment (Endoscopic vs surgical treatment: 38% (3/8) vs 84% (10/12), p=0.011).

Conclusion

Endoscopic treatment (predominantly EBD) avoids surgery in most cases, requiring a low number of endoscopic treatments in the long-term. Patients at higher risk for surgery are those with a greater number of endoscopic treatments that include SEMS and EBD. On the contrary, protective factors are non-intensificationof therapy and having been treated exclusively with EBD. Although there are no significant differences in the long effectiveness between SEMS and EBD, a trend for a better outcome is observed for EBD. To highlight a significant higher rate of complications observed in surgicaltreatment compared to endoscopic treatment.

References

Loras et al. Lancet Gastroenterol Hepatol. 2022

Disclosure

No conflict of Interest