Type III and type VI collagen neoepitopes are associated with disease severity in systemic sclerosis.

OBJECTIVE: Dysregulated collagen turnover is implicated in systemic sclerosis (SSc) pathogenesis. We evaluated collagen turnover biomarkers in relation to the severity of fibrotic manifestations, key cytokines, and progression in SSc. METHODS: Baseline and 6-month serum samples of early SSc patients in the CONQUER cohort were analyzed for type III (PRO-C3 and C3M) and type VI (PRO-C6 and C6M) collagen turnover biomarkers, as well as C-reactive protein (CRP), interleukin-6 (IL-6), and interferon (IFN)-inducible proteins. The modified Rodnan skin score (mRSS) and forced vital capacity percent predicted (FVC%) served as surrogate markers of disease severity. RESULTS: 222 patients were included. PRO-C3 (p<0.001) and PRO-C6 (p<0.001) concentrations were higher in patients with diffuse disease, while C6M (p=0.041) was higher in those with ILD. Baseline PRO-C3 (p<0.001) and PRO-C6 (p<0.001) positively correlated with mRSS, whereas C3M (p=0.029) and C6M (p=0.011) negatively correlated with FVC%, although the magnitude of the observed correlations was in the weak range (Rs<0.4). Collagen biomarker concentrations positively correlated with CRP, IL-6, and IFN-inducible proteins at baseline. While changes in CRP correlated positively with changes in collagen degradation protein levels (C3M and C6M), they did not correlate with changes in collagen formation protein levels (PRO-C3 and PRO-C6). In contrast, changes in IFN score showed the highest correlation with changes in PRO-C6. CONCLUSION: PRO-C3 and PRO-C6 correlated with skin disease severity, while C3M and C6M correlated with lung disease severity. Collagen turnover biomarkers correlated with CRP, IL-6, and IFN-inducible proteins, providing support for the link between inflammation and fibrosis in SSc.