Risk of major cardiovascular events in patients with systemic sclerosis: insights into an underestimated concern from a systematic literature review and meta-analysis

Objectives: Systemic sclerosis (SSc) is a chronic autoimmune disease characterised by skin and internal organ involvement. Despite the acknowledgment that cardiovascular (CV) complications are a leading cause of death in SSc, the extent of CV risk and major adverse cardiac events (MACEs) remains unclear. Aim of this study is to evaluate the association between SSc and the risk of MACEs through a systematic literature review and meta-analysis, focusing on non-fatal stroke (nfS) and non-fatal myocardial infarction (nfMI) as secondary outcomes. Methods: We systematically searched for cohort and prospective studies published up to November 2024. We included studies reporting hazard ratios (HRs) with 95% confidence intervals (CIs) for SSc and cardiovascular outcomes. Random-effects meta-analyses were conducted to estimate pooled HRs. Heterogeneity was assessed using the I² statistic, and publication bias was evaluated via Egger's test. Results: Eleven studies (n=12,235 SSc patients included) were included initially; SSc was associated with an increased risk of MACE (pooled HR 1.8, 95% CI 1.4-2.3), albeit with high heterogeneity (I²=89.2%). Removal of overlapping datasets confirmed a significantly elevated risk (pooled HR 1.9, 95% CI 1.3-2.7), with persistent heterogeneity (I²=88.72%). Subgroup analyses showed significant geographic variation. For secondary outcomes, SSc was associated with higher risks of nfS (pooled HR 1.5, 95% CI 1.2-1.9) and nfMI (pooled HR 2.5, 95% CI 1.9-3.5), with a decrease in heterogeneity. Conclusions: Patients with SSc face a significantly increased risk of major CV events, including stroke and myocardial infarction. These findings underscore the need for tailored CV risk assessment and management strategies in SSc.