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

To investigate the association between proton pump inhibitor (PPI) use, all-cause mortality, and interstitial lung disease (ILD) progression in systemic sclerosis (SSc).

SSc patients enrolled in the EUSTAR registry with at least two clinical visits were included (EUSTAR CP141). PPI exposure was modeled 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.

Out of 10,660 patients enrolled, 8,637 (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.

PPI are commonly used in SSc characterised by a more severe multisystem phenotype. Only a marginal attenuation of ILD progression is observed, although absolute effects were small. These findings favour the generalised use of PPIs for symptomatic gastroesophageal reflux in SSc.