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Introduction Systemic sclerosis (SSc) is a heterogeneous autoimmune disease traditionally stratified by cutaneous subset, with diffuse (dcSSc) linked to severe organ involvement and higher mortality, and limited (lcSSc) associated with prevalent vascular morbidity. However, skin phenotype alone may not fully capture disease heterogeneity. Molecular pathways, particularly type I interferon (IFN) activation, have emerged as key pathogenic drivers and potential prognostic biomarkers. Elevated IFN scores correlate with adverse outcomes, yet it remains unclear whether this effect is independent of cutaneous subset. This study evaluates the prognostic role of serum type I IFN activity across lcSSc and dcSSc, testing its independent contribution.Material and Methods The interferon (IFN) score was calculated, as previously described (Ross et al.), from serum concentrations of CCL2, CCL8, CCL19, CXCL9, CXCL10, and CXCL11 (Myriad RBM) in patients with systemic sclerosis (SSc) fulfilling the 2013 ACR/EULAR classification criteria, who were retrospectively selected from the STRIKE national, multicentre observational cohort. The combined morbi-mortality endpoint from the MINIMISE trial (EudraCT: 2019-004139-21) was used as clinical outcome, with time-to-event analyses starting from the date of serum sampling. Baseline characteristics were compared using standard parametric and non-parametric tests, and survival analyses employed Kaplan-Meier curves with Log-rank tests. Risk estimates were derived from Cox regression models, adjusted for established prognostic factors, with proportional hazards assumptions assessed by Schoenfeld residuals.Results Patients with a high IFN score showed significantly reduced event-free survival compared with those with low IFN (Log-rank X 2=22, p<0.001); similarly, dcSSc patients had worse survival than lcSSc (Log-rank X2=17, p<0.001), as shown by Kaplan–Meier time-to-event analysis.A high IFN score conferred a 2.57-fold increased risk of adverse outcomes (95% CI 1.64–4.03, p<0.001, multivariable Cox proportional hazard models) after adjustment for established prognostic factors, including cutaneous subset.The IFN score maintained an hazard ratio of 1.60 (95% CI 1.18–2.16, p=0.002), even when analysed as a continuous variable, suggesting that IFN activation is a robust predictor of adverse outcomes across different disease subsets. The interaction analysis confirmed the independence of IFN, since no significant effect modification was detected between IFN score and cutaneous subset (p=0.42).Conclusions Serum Type I IFN activity demonstrates clear prognostic value in SSc, being strongly associated with morbi-mortaliy outcomes regardless of cutaneous subset. This independence from disease phenotype highlights the IFN score as a robust biomarker for risk stratification in both clinical care and trial design, with potential to enhance patient management and guide the development of targeted therapies.Abstract P.245 Table 1Abstract P.245 Figure 1Kaplan-Meier curves for cumulative morbi-mortality events in SSe patients. A: Cumulative incidence of morbi-mortality events stratified by IFN score, with patients classified as IFN-low (blue) and IFN-high (red). B: Cumulative incidence of morbi-mortality events stratified by LeRoy subset, with patients classified as limited cutaneous SSc (blue) and diffuse cutaneous SSc (red)