Clinical and autoantibody associations with malignancy in systemic sclerosis: A systematic review and meta-analysis

Abstract Objective This meta-analysis examines factors associated with malignancy in systemic sclerosis (SSc). Methods A systematic search of Embase, MEDLINE and Cochrane Library databases was conducted from inception to 7 December 2024. Case-control and cohort studies reporting associations with malignancy in SSc were included. Random-effects meta-analyses were performed to pool study results. Mean differences (MD) for age and odds ratios (OR) for binary outcomes using frequency counts were calculated. Study quality was assessed using Newcastle-Ottawa Scale. Results Thirty-five studies comprising 27 624 SSc patients were analysed. Patients with malignancy developed SSc at an older age (MD + 4.01, 95% CI 1.24– 6.78). Significant associations for malignancy included male gender (OR 1.36), smoking (OR 1.27), pulmonary hypertension (PH, OR 1.32), interstitial lung disease (ILD; OR 1.41), diffuse cutaneous SSc (OR 1.14), positive anti-RNAPIII (OR 1.79) and anti-centromere antibody (ACA, OR 0.83) and negative anti-nuclear antibody (OR 1.39). In sensitivity analyses of high quality studies, male gender, smoking, PH and anti-RNAPIII remained significant. Subgroup analyses by malignancy types and development in relation to SSc diagnosis revealed positive associations of lung malignancy with male gender (OR 2.72), smoking (OR 2.38), anti-Scl-70 (OR 2.45) and ILD (OR 2.98), while ACA was inversely associated (OR 0.32). Anti-RNAPIII was associated with breast malignancy (OR 2.17) and early/concurrent malignancy (OR 2.85), and digital ulceration (OR 0.39) with later malignancy development. Conclusion Malignancy association in SSc is influenced by clinical phenotype and autoantibody profile. Our findings suggest a risk-stratified approach to malignancy surveillance rather than uniform screening.