Circulating collagen neo-epitopes and their role in the prediction of fibrosis in patients with systemic sclerosis: a multicentre cohort study.

ABSTRACT

BACKGROUND: Extracellular matrix remodelling is a hallmark of systemic sclerosis. We evaluated extracellular matrix neo-epitopes as potential serum biomarkers for progression of fibrosis in systemic sclerosis. METHODS: We included patients meeting the 2013 American College of Rheumatology and European League Against Rheumatism criteria and healthy controls from a derivation and validation cohort. The primary outcome was progression of fibrosis at follow-up, defined as decline in percentage of predicted forced vital capacity of 10% or more in patients with interstitial lung disease or increase in modified Rodnan skin score of 25% or more and more than 5 points at a 1-year follow-up visit. Longitudinal assessment and biobanking followed European Scleroderma Trials and Research standards. Extracellular matrix-degradation (BGM, C3M, C4M, and C6M) and extracellular matrix-formation neo-epitopes (PRO-C1, PRO-C3, PRO-C4, PRO-C5, and PRO-C6) were measured in serum using validated ELISAs. FINDINGS: Between Aug 18, 2011, and Jan 19, 2015, 149 patients with systemic sclerosis (27 [18%] progressors and 122 [82%] non-progressors) and 29 healthy controls were included in the derivation cohort. Concentrations of type III and IV collagen neo-epitopes were higher in patients with systemic sclerosis compared with healthy controls and were significantly associated with systemic sclerosis in univariable logistic regression. Concentrations of degradation neo-epitopes of type III and IV collagens and their turnover ratios distinguished between progressors and non-progressors (C3M area under the curve 0·77 [95% CI 0·67-0·86], p<0·0001; PRO-C3C3M 0·70 [0·59-0·80], p=0·0013; C4M 0·73 [0·63-0·82], p<0·0001; PRO-C4C4M 0·75 [0·64-0·86], p<0·0001). 384 patients with systemic sclerosis (73 [19%] progressors) and 60 healthy controls were included in the multicentre validation cohort between April 17, 2003, and Jan 24, 2017. Analysis of the validation cohort confirmed that neo-epitopes of type III and IV collagens are changed in progressors. In a pooled analysis of both cohorts, the serum concentrations of formation neo-epitopes PRO-C3 and PRO-C4 and the turnover ratio of type IV collagen (PRO-C4C4M) were higher in skin progressors. The turnover ratio of type IV collagen and PRO-C3 significantly predicted skin progression in a multivariable model adjusted for modified Rodnan skin score, sex, and age. INTERPRETATION: These data suggest that neo-epitopes of type III and IV collagens are promising biomarkers for the assessment and prediction of extracellular matrix remodelling in systemic sclerosis. They could be used in clinical practice to risk stratify patients at risk of progression of fibrosis. FUNDING: None.