Association of onset age with features of patients with systemic sclerosis in the Renji Scleroderma Longitudinal...

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).

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.

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.

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.