Proton pump inhibitor use and long-term outcomes in SSc: a real-life analysis from the EUSTAR database

Abstract Objectives To investigate the association between proton pump inhibitor (PPI) use, all-cause mortality and interstitial lung disease (ILD) progression in SSc. Methods SSc patients enrolled in the EUSTAR registry with at least two clinical visits were included (EUSTAR CP141). PPI exposure was modelled as a time-varying variable. Inverse probability of treatment weighting (IPTW) based on propensity scores was applied to address confounding by indication. All-cause mortality was analysed using IPTW-weighted time-varying Cox models. ILD progression was assessed using functional endpoints (FVC decline ≥10% and ≥5%; DLCO decline ≥10%). Restricted mean survival time (RMST) was used to quantify absolute effects. Sensitivity analyses included a 6-month lag time. Results Out of 10 660 patients enrolled, 8637 (81.0%) were exposed to PPIs during a mean follow-up of 5.7 ± 4.3 years. They exhibited a more severe multisystem disease phenotype, including greater gastrointestinal, pulmonary and vascular involvement. After adjustment, PPI exposure was associated with higher all-cause mortality (HR 1.88, 95% CI 1.40–2.54), although the RMST difference at 5 years was minimal. As cause-specific mortality was unavailable, this association might reflect underlying disease severity rather than a direct drug effect. The use of PPI was not associated with a reduced risk of clinically meaningful FVC decline, while a modest attenuation of DLCO decline was observed, and absolute progression-free differences were limited. Conclusions PPI is commonly used in SSc characterized by a more severe multisystem phenotype. Only a marginal attenuation of ILD progression is observed, although absolute effects were small. These findings favour the generalized use of PPIs for symptomatic gastroesophageal reflux in SSc.