Available Biomarkers for Personalized Prognostication in Early and Very Early Systemic Sclerosis: A Narrative Review of the Current Literature

Background: Systemic sclerosis (SSc) is a heterogeneous autoimmune disease characterized by inflammation, vasculopathy, and fibrosis. It is associated with the highest mortality among rheumatic diseases. Very early SSc may represent a critical phase with risk of developing progressive disease. Although timely treatment may be effective in patients with progressive disease, it carries risks of adverse events, underscoring the need for early identification of individuals at risk. Biomarkers for progression in the early stage offer opportunities for timely intervention and improved long-term outcomes. Therefore, validating biomarkers that predict progression is an important research priority. In this narrative literature review, we summarize and evaluate blood circulating biomarkers associated with different progression endpoints in (very) early SSc. Methods: The literature search was conducted using PubMed. Eligible studies assessed biomarkers in very early SSc or early SSc cohorts with longitudinal follow-up and progression-related outcomes. Results: The identified studies investigated biomarkers associated with interstitial lung disease (ILD), skin progression, overall disease progression, and mortality. Anti-topoisomerase I was associated with ILD development. A high interferon score was linked to reduced lung function and mortality. KL-6 was associated with progression in early SSc-ILD. PRO-C3 and PRO-C6 showed the strongest associations with skin involvement. Finally, IgG anti-centromere antibody was associated with organ involvement and progression to definite SSc. CXCL10 and TNFRII were linked to progression and significant survival differences in the discovery and replication cohorts. However, effect sizes were often modest, and findings were inconsistent across cohorts. Substantial heterogeneity in study design, populations, endpoints, and biomarker assessment methods limited comparability. Moreover, most biomarkers demonstrated associations at the group level but lacked sufficient discriminatory power for individual risk prediction. Only a minority of studies included validation cohorts, and replication of findings was limited. Conclusions: Multiple biomarkers show promising associations with progression in very early and early SSc, but a single biomarker is unlikely to reliably predict disease progression.