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Introduction Pulmonary arterial hypertension (PAH) is a major cause of death in systemic sclerosis (SSc) and, despite significant advances, still responds poorly to vasodilator therapy. Histopathological and experimental data suggest an immune-mediated vascular mechanism, raising the hypothesis that immunosuppressive therapy could prevent PAH onset. We aimed to evaluate whether exposure to immunosuppressive agents was associated with a reduced risk of incident PAH in a large SSc cohort.Material and Methods We analyzed data from 1,294 SSc patients without prevalent PAH at enrollment in the Canadian Scleroderma Research Group registry (2004-2020). Incident PAH was defined by right heart catheterization (mean pulmonary artery pressure >/= 25 mmHg, pulmonary capillary wedge pressure <15 mmHg) or by echocardiographic criteria combined with PAH-specific treatment. On echocardiography, PAH was defined as systolic pulmonary arterial pressure (sPAP) >/=40 mmHg with at least mild tricuspid regurgitation. Exposure to immunosuppressive agents (methotrexate, mycophenolate mofetil, azathioprine, cyclophosphamide, tacrolimus, leflunomide, rituximab, tocilizumab) was modeled as a time-varying variable, lagged by one visit. A marginal structural Cox model weighted by inverse probability of treatment weights (IPTW) was fitted to estimate hazard ratios (HR) for PAH incidence, with multiple imputation for missing data. IPTWs were derived from logistic regression models including age, sex, disease duration, cutaneous subtype, interstitial lung disease, calcinosis, telangiectasias, anticentromere antibodies, DLCO, and FVC/DLCO ratio.Results At baseline, the 1,294 SSc patients had a mean age of 55.2 ± 12.0 years; 88% were women, 37% had diffuse and 63% limited cutaneous subtype, and the median disease duration was 7.6 years (IQR 3.6–15.4). Out of 6,617 person-visits, 53 incident PAH cases occurred (4.1%). Among them, 38.6% had been exposed to immunosuppression, most commonly methotrexate (56%) and mycophenolate mofetil (26%). In the weighted model, immunosuppression was not significantly associated with PAH risk (HR = 0.76, 95% CI: 0.29-1.98; p = 0.57). In exploratory stratified analyses, there was a non-significant trend toward a protective effect in late SSc (above 7 years of disease duration, HR = 0.45, 95% CI: 0.07-2.70) and in patients with mild ILD (HR 0.77, 95% CI: 0.26-2.32). Point estimates from models for specific immunosuppressive drugs also suggested a protective effect with mycophenolate mofetil (HR = 0.21, 95% CI: 0.03-1.52), although with wide confidence intervals.Conclusions In this large prospective SSc cohort, immunosuppressive therapy was not significantly associated with reduced PAH incidence. Trends toward differential effects according to disease duration highlight the need for further research into the potential preventive role of immunomodulation in SSc-PAH.Abstract P.130 Table 1