P125 Using a novel event driven composite endpoint to evaluate differences in long term outcomes across systemic sclerosis subgroups

Abstract Background/Aims Evaluating long-term outcomes in limited cutaneous systemic sclerosis (lcSSc) is challenging due to later-onset and less-frequent organ involvement compared to diffuse cutaneous systemic sclerosis (dcSSc). We evaluated a novel composite ‘time to clinically meaningful progression’ endpoint (MINIMISE) in a large cohort of SSc patients to evaluate its potential role as a future clinical trial endpoint. Differences in outcomes were explored in those with anti-centromere antibody (ACA+) and those without (ACA-) hypothesising that ACA- show greater rates of disease progression which could be informative in clinical trials. Methods Demographic, clinical, and serological data were explored in 2894 SSc patients followed in our centre. We assessed time taken to reach a clinically significant MINIMISE endpoint defined as: evidence of interstitial lung disease (ILD) with forced vital capacity (FVC) 70% predicted or worsening of established ILD (reduction in FVC ≥10% in 12 months, or reduction in FVC 5-9% with reduction in diffusing capacity (DLCO) ≥15%), pulmonary arterial hypertension (PAH) at right heart catheterisation (according to haemodynamic definition at time of diagnosis), scleroderma renal crisis, severe gastrointestinal (GI) involvement (enteral nutrition ≥3 weeks or any parenteral feeding or hospital admission for intestinal pseudo-obstruction or obstruction), cardiac involvement attributed to SSc (left ventricular ejection fraction 45% or pericardial effusion impairing cardiac function or arrhythmia requiring antiarrhythmic therapy or need for a cardiac device), severe digital vasculopathy requiring hospitalisation, progressive skin disease (increase ≥5 modified Rodnan skin score) or all-cause mortality. We performed a time to event analysis for the MINIMISE composite outcome from SSc onset, defined as first non-Raynaud’s manifestation. Kaplan Meier survival failure estimates curves and Cox proportional hazards regression analysis compared across disease and ACA subsets. P 0.05 considered significant. Results Around one third of SSc cases had dcSSc and as expected this was associated with more frequent disease complications except for PAH and severe GI involvement that were most prevalent in lcSSc. 902 (31.6%) patients met the MINIMISE outcome in the first 10 years of the disease with 543 in the lcSSc group. Survival analysis revealed a significantly higher frequency of events in dcSSc compared to lcSSc, hazard ratio (HR) over 10 years: 4.93 (95% CI: 4.09-5.93, p 0.001). For lcSSc, ACA positive patients had significantly fewer MINIMISE events over time than those without ACA, HR 0.49 (95% CI: 0.36-0.67, p 0.001). Conclusion In lcSSc, clinically meaningful progression, defined by the MINIMISE endpoint, is more frequent in ACA-negative patients. This subgroup may have greatest clinical need and benefit from disease-modifying treatment earlier to reduce long-term morbidity and mortality. This could be explored further in a long-term event driven study with our data suggesting a large cohort and long term follow up will be essential to show benefit in lcSSc. Disclosure P. Yee: None. M. Kanitkar: None. S. Rodolfi: None. V.H. Ong: None. C. Denton: Consultancies; Abbvie, Janssen, GlaxoSmithKline, Bayer, Sanofi-Aventis, Galapagos, Inventiva, Boehringer Ingelheim, Roche, CSL Behring, Corbus, Acceleron, Horizon, Arxx Therapeutics, Lilly, Novartis, Certa, Zurabio. Member of speakers’ bureau; Boehringer Ingelheim, Janssen, GlaxoSmithKline. Grants/research support; Abbvie, Arxx Therapeutics, Horizon, GlaxoSmithKline, CSL Behring, Servier.