Association Between Proton Pump Inhibitor Use and Gastric Neuroendocrine Neoplasms in Autoimmune Gastritis: A Real‐World Propensity Score‐Matched Study From the Autoimmune gastRitis Italian netwOrk Study grOup

BACKGROUND AND AIMS: Autoimmune gastritis (AIG) is characterized by chronic hypergastrinemia and is associated with an increased risk of gastric neuroendocrine neoplasms (gNENs). Because proton pump inhibitors (PPIs) further increase gastrin secretion, concerns have been raised regarding a potential additive effect on gastric neoplastic risk. This study aimed to evaluate the association between PPI exposure and gNEN occurrence in patients with AIG using a large real-world database. METHODS: We conducted a retrospective propensity score-matched cohort study using the TriNetX Global Collaborative Network. Patients with AIG were identified using diagnostic codes for chronic atrophic gastritis or pernicious anaemia, excluding Helicobacter pylori infection, gastric cancer, multiple endocrine neoplasia or other competing gastric conditions. Two cohorts were defined: patients with AIG receiving PPIs and patients without PPI exposure. The primary outcome was the overall occurrence of gNENs. A prespecified secondary analysis excluded patients with gNENs diagnosed before the index date to evaluate incident tumours. Secondary outcomes included hypergastrinemia, intestinal metaplasia and gastric polyps. RESULTS: A total of 153,687 patients with AIG were identified. After 1:1 propensity score matching, 40,489 patients were included in each cohort. After propensity score matching, gNENs were recorded in 241 patients (0.60%) without PPI exposure and 360 patients (0.89%) receiving PPIs. PPI exposure was associated with a significantly higher occurrence of gNENs (risk ratio [RR] 1.49, 95% CI 1.27-1.76), which was confirmed by time-to-event analysis (hazard ratio [HR] 1.44, 95% CI 1.22-1.70; log-rank p < 0.001). The association persisted after exclusion of patients with pre-existing gNENs (RR 1.61, 95% CI 1.26-2.06; HR 1.52, 95% CI 1.19-1.95). PPI exposure was also associated with higher occurrences of hypergastrinemia (HR 1.17, 95% CI 1.00-1.37), intestinal metaplasia (HR 1.53, 95% CI 1.36-1.71) and gastric polyps (HR 2.48, 95% CI 2.25-2.73). No gastric adenocarcinomas were identified during follow-up. CONCLUSIONS: In this large real-world propensity score-matched study, PPI exposure was associated with a greater occurrence of both overall and incident gNENs in patients with AIG. PPI use was also consistently associated with gastric mucosal alterations, including hypergastrinemia, intestinal metaplasia and gastric polyps. Although the absolute risk of gNENs remained low, these findings support judicious long-term PPI prescribing in patients with AIG and reinforce the importance of appropriate endoscopic surveillance in this high-risk population.