Meta-Analysis: Prevalence of Non-Helicobacter pylori, Non-NSAID Peptic Ulcer Disease.

BACKGROUND: Non-Helicobacter pylori (H. pylori), non-nonsteroidal anti-inflammatory drug (NSAID) peptic ulcer disease (PUD) is increasingly recognized as a distinct subgroup, but its proportion across clinical presentations remains unclear. AIM: We aimed to estimate this proportion. METHODS: We searched MEDLINE, Embase and CENTRAL from their inception to March 2026 for observational studies. The primary outcome was the proportion of non-H. pylori, non-NSAID PUD among adults with overall, bleeding and perforated PUD. Random-effects meta-analysis of logit-transformed proportions was performed using restricted maximum likelihood. Meta-regression assessed associations with study year, country-level H. pylori prevalence and region. Protocol registered in PROSPERO (CRD420251174202). RESULTS: Overall, 92 studies (60,816 patients) from 32 countries were included. The pooled proportions of non-H. pylori, non-NSAID PUD cases were 13.0% (95% confidence interval [CI], 10.4-16.2) in overall PUD, 11.3% (95% CI, 8.8-14.4) in bleeding PUD, and 22.0% (95% CI, 13.1%-34.7%) in perforated PUD. In univariable meta-regression, a more recent study year was associated with a higher proportion of bleeding PUD (β = 0.076; 95% CI, 0.031-0.120). This association remained statistically significant after adjustment for country-level H. pylori prevalence (β = 0.070; 95% CI, 0.026-0.113). Lower H. pylori prevalence was also associated with a higher proportion after further adjustment for region (β = -0.025; 95% CI, -0.046 to -0.005). CONCLUSION: Non-H. pylori, non-NSAID PUD represents a non-negligible but heterogeneous component of PUD. In bleeding PUD, exploratory ecological analyses suggest a temporal increase, potentially reflecting evolving etiologic patterns beyond H. pylori infection and NSAID exposure.