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

Abstract Objective The objective of this study was to investigate associations between age at SSc onset and serologic, clinical, and proteomic characteristics in the Renji Scleroderma Longitudinal Cohort (Renji-SLOC). Methods We analysed 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 for 131 patients. Results Early- and late-onset groups had higher percentages of dcSSc (early-onset SSc 42.5% vs standard-onset SSc 23.3% vs late-onset SSc 36.7%, P = 0.002) and elevated modified Rodnan Skin Score (mRSS) [early-onset SSc 7.0 (9.0) vs standard-onset SSc 4.0 (6.0) vs late-onset SSc 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 interstitial lung disease (ILD) (OR = 2.35, P = 0.005). Late-onset patients had higher cardiopulmonary (ILD: OR = 1.93, P = 0.016; pulmonary arterial hypertension: 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–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 require prioritizing of 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.