Background: Limited cutaneous SSc (lcSSc) is the understudied clinical subset of SSc, despite representing more than 60% of patients. Recently, the analysis of a large single center observational cohort, has identified nature and rate of clinically meaningful events in lcSSc. This has informed the design of a combined Morbi-mortality endpoint for clinical trials in lcSSc (MINIMISE, EudraCT: 2019-004139-21). Type I IFN activation is associated with high disease activity and poor outcome in diffuse cutaneous SSc[1]. Objectives: To study the value of serum Type I IFN in stratifying for outcome in lcSSc according to the MINIMISE combined Morbi-mortality endpoint. Methods: A retrospective, longitudinal cohort of lcSSc patients was identified within a national, multicenter observational cohort. The MINIMISE, combined Morbi-mortality endpoint was used as clinical outcome starting from time of serum analysis. IFN score was calculated, as previously described[2], derived from the serum concentration of CCL2, CCL8, CCL19, CXCL9, CXCL10, and CXCL11 (Myriad RBM). Patients were characterized according to EUSTAR MEDS dataset. Student's t, Wilcoxon's, Pearson Chi-squared, and Fisher's tests were employed for analysis, as appropriate. Kaplan-Meier curves, Log-rank test and Cox Proportional Hazard regression models were employed for time to endpoint analysis. Results: 149 lcSSc patients (median [IQR] follow up 65 [39] months) were identified for analysis (146 female, mean [SD] age 59 [12] years). Median (IQR) disease duration was 13 (12) years. 67 (45%) patients had high IFN score (two SD above Healthy Control [HC] threshold), whereas 82 (55%) were within HC range "IFN low". 37/67 (55%) patients with high IFN score vs 10/82 (12%) (p<0.001) met the combined endpoint during follow-up (Figure 1). Overall, 79% of patients meeting the endpoint were IFN High. Accordingly, IFN Low patients presented a higher event-free survival (Log rank Chi-Sq=12, df=1, p<0.001) (Figure 2). Age, presence of ACA antibodies alone, ILD, DU, or PAH were the other baseline variables predicting outcome over time, independently of IFN score. Cox Proportional Hazard models defined high IFN score being associated with 5.5 Hazard Ratio (HR) compared to IFN low (95% C.I. 2.68-11.3, p<0.001). IFN score maintained a HR of 2.2 (95% C.I. 1.38-3.49, p<.001) also when used as continuous variable, independently of other clinical variables. Conclusion: Serum assessment of Type I IFN activity could be a useful test to stratify for severe outcome in lcSSc and as such, contribute to enrichment and/or stratification strategies in clinical trial design. REFERENCES: [1] Kakkar V, Assassi S, Allanore Y, Kuwana M, Denton CP, Khanna D, Del Galdo F. Type 1 interferon activation in systemic sclerosis: a biomarker, a target or the culprit. Curr Opin Rheumatol. 2022 Nov 1;34(6):357-364. doi: 10.1097/BOR.0000000000000907. Epub 2022 Sep 16. PMID: 36125916; PMCID: PMC9594133. [2] Carriero A, Abignano G, et al FRI0315 SERUM INTERFERON SCORE PREDICTS CLINICAL OUTCOME AT 12 MONTHS IN DIFFUSE CUTANEOUS SYSTEMIC SCLEROSIS AS MEASURED BY GLOBAL RANKED COMPOSITE SCORE (GRCS) AND COMPOSITE RESPONSE INDEX IN SSC(CRISS). Annals of the Rheumatic Diseases 2019; 78: 839. Acknowledgements: NIL. Disclosure of Interests: Stefano Di Donato: None declared, Rebecca Ross: None declared, Ranjitha Karanth: None declared, Vishal Kakkar: None declared, Enrico De Lorenzis: None declared, Giuseppina Abignano: None declared, Kristina Clark: None declared, Christopher P Denton: None declared, Francesco Del Galdo AstraZeneca, Abbvie, AstraZeneca, Boehringer-Ingelheim, Capella Biosciences, Chemomab Therapeutics, Ergomed, GSK, Janssen, Mitsubishi-Tanabe, AstraZeneca, Janssen, Boehringer-Ingelheim, Mitsubishi-Tanabe, Abbvie.
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Donato et al. (2024) studied this question.