Background/Purpose: Systemic Sclerosis (SSc) is a heterogeneous autoimmune disease characterized by vascular damage, immune dysregulation, and fibrosis. It is typically classified into limited cutaneous (lcSSc) and diffuse cutaneous (dcSSc) subsets, each associated with distinct clinical complications. dcSSc is generally linked to more severe organ involvement and higher mortality, and given the higher disease activity is the cutaneous subset most targetetd in clinical trials. Two independent studies have recently demonstrated the value of serum IFN score activity in stratifying patients for severe outcome ( 1,2). This study aims to evaluate the prognostic value of serum Type I IFN activity in a “basket” observational cohort of lcSSc and dcSSc patients, tested against a time to clinically significant event endpoint.

Methods: A retrospective, longitudinal cohort of patients fulfilling the 2013 ACR/EULAR SSc classification criteria was identified within the STRIKE national, multicentre observational cohort. The combined morbi-mortality endpoint from the MINIMISE trial was used as the clinical outcome in a time-to-event analysis starting from the time of serum analysis. The IFN score was calculated as previously described, derived from the serum concentration of CCL2, CCL8, CCL19, CXCL9, CXCL10, and CXCL11 (Myriad RBM). Patients were characterized according to the EUSTAR MEDS dataset. Time to endpoint was analysed using Kaplan-Meier curves, Log-rank test, and Cox Proportional Hazard regression models.Multivariable Cox regression models were adjusted for prognostic factors identified in univariate analyses, including age, sex, disease duration, Leroy subset, interstitial lung disease, modified Rodnan skin score (mRSS), digital ulcers (DU), and Pulmonary Arterial Hypertension (PAH).

Results: 221 SSc patients (67% lcSSc and 33% dcSSc) were included in the analysis (87% female, mean [SD] age 57 [16] years). Median (IQR) disease duration was 6 (10) years. 100 (45%) patients had a “high” IFN score (above 2 standard deviations from the Healthy Control [HC] mean), while 121 (55%) were classified as “low” IFN. Kaplan-Meier time to event analysis indicated a significantly lower event-free survival in IFN “high” compared to “low” patients (p< 0.001), as well as in diffuse SSc patients compared to limited SSc (p< 0.001). Multivariable Cox proportional hazard models confirmed that a high IFN score was associated with a Hazard Ratio (HR) of 2.57 (95% C.I. 1.64 – 4.03, p< 0.001) compared to IFN low, independent of subset. When used as a continuous variable, the IFN score maintained an HR of 1.60 (95% C.I. 1.18 - 2.16, p=0.002). Importantly, no significant interaction was detected between IFN score and disease subset (p=0.42) in the multivariable model including IFN score, indicating that the prognostic value of IFN score is independent of the cutaneous subset of SSc.

Conclusion: Serum assessment of Type I IFN activity is a valuable prognostic and stratification tool in SSc, providing enrichment for progressive disease independently of cutaneous subset. This approach supports the use of IFN score as a universal biomarker for risk stratification in clinical practice and trial design.

Table 1. Demographic and clinical features of patients in the analysis by LeRoy disease subset.

Figure 1. Kaplan-Meier curves for cumulative morbi-mortality events in SSc 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).

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/interferon-score-effectively-stratifies-for-time-to-clinically-significant-event-accrual-in-systemic-sclerosis-independently-of-cutaneous-subset/