Association of onset age with features among patients with systemic sclerosis in the Renji Scleroderma Longitudinal Cohort (Renji-SLOC)

Objectives To investigate associations between age at systemic sclerosis (SSc) onset and serologic, clinical, and proteomic characteristics in the Renji Scleroderma Longitudinal Cohort (Renji-SLOC). Methods We analyzed 390 SSc patients from the prospective Renji-SLOC cohort, stratified by onset age: early-onset (<40 years, n = 73), standard-onset (40–60 years, n = 219), and late-onset (>60 years, n = 98). Baseline serologic/clinical data were compared. Plasma proteomic profiling was performed from 131 patients. Results Early- and late-onset groups had higher diffuse cutaneous SSc (dcSSc: 42.5% vs 23.3% vs 36.7%, p= 0.002) and elevated Modified Rodnan Skin Score (mRSS) (7.0[9.0] vs 4.0[6.0] vs 6.0[14.0], p= 0.002). Early-onset patients showed increased risks of severe skin involvement (mRSS > 7: OR = 2.34, p= 0.005) and ILD (OR = 2.35, p= 0.005). Late-onset patients had higher cardiopulmonary (ILD: OR = 1.93, p= 0.016; PAH: OR = 3.46, p< 0.001; diastolic dysfunction: OR = 3.11, p< 0.001), gastrointestinal (weight loss: OR = 2.67, p= 0.043), and joint involvement risks (OR = 1.68, p= 0.038). No progression differences were observed during the median follow-up period of 15 months. Proteomic analysis of 131 patients detected a total of 909 proteins following quality control, with early-onset patients showing 20 upregulated proteins linked to severe cutaneous involvement and pulmonary fibrosis, while late-onset patients exhibited 90 upregulated proteins enriched in extracellular matrix (ECM)-associated proteins, ILD-related biomarkers and SSc progression and complication markers. Conclusion Non-standard onset age predicts distinct organ-specific risks in SSc. Early-onset patients prioritize cutaneous and pulmonary monitoring, while late-onset patients require vigilance for cardiopulmonary and gastrointestinal complications. Proteomic signatures mechanistically underlie this phenotypic heterogeneity. Patients with non-standard onset age require enhanced surveillance for organ-specific manifestations.