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Introduction Patients diagnosed with systemic sclerosis (SSc) exhibit pronounced fibrosis affecting the skin and internal organs due to abnormal extracellular matrix (ECM) remodeling. This study aimed to investigate biomarkers of fibroblast activity and tissue destruction in a large prospective cohort of patients with SSc and evaluate their relationships with comorbidities and prognosis.Material and Methods Patients (n=346) who met the 2013 ACR/EULAR classification criteria for SSc were analyzed. Longitudinal clinical assessments, data, and baseline serum were collected. The collagen biomarkers reflecting fibroblast activity, PRO-C3 and PRO-C6, and tissue destruction, C3M and C6M, were measured in the serum using immunoassays. FVC worsening was defined as an absolute decline of FVC% of >10%, modified Rodnan Skin Score (mRSS) worsening was defined as an increase of mRSS of >5 units or >25% increase in mRSS, and Pulmonary Hypertension (PH) was confirmed by RHC (mPAP >25 mmHg). Analysis included a Mann-Whitney U-test and Cox Proportional Hazard Regression (CPHR) analysis.Results Patients had a mean age of 59.6 (SD: 12.1) years, 80.1% were female, mean mRSS was 5.3 (SD: 7.3), and the median disease duration was 8.9 years (IQR: 5.5-15.8). At baseline, patients with ILD on HRCT (n=203) presented with higher levels of C3M (p=0.0189). Patients with diffuse cutaneous SSc (n=137) had higher PRO-C3 and PRO-C6 levels than those with limited cutaneous SSc (n=183) (p=0.0008 and p=0.0246). The median (IQR) follow-up period for the cohort was 4.29 years (IQR: 1.98-5.67). Twenty-eight out of the 90 patients with long-term follow-up had a pre-defined event (FVC worsening, mRSS worsening, new PH, new LVEF < 45%, or all-cause mortality). Results from the CPHR adjusted for age, disease duration, SSc subtype, and ILD indicated a doubling of PRO-C6 was associated FVC worsening, with a hazard ratio (HR) of 1.91 (95% CI: 1.12-3.24, p=0.0176), and a HR of 4.92 (95% CI: 1.23-19.66, p=0.0241) of new-onset PH. A doubling of PRO-C3 at baseline had an HR of 5.41 (95% CI: 1.08-27.12, p=0.0403) for developing PH. A doubling of the ratio PRO-C3:C3M had an HR of 459.22 (95% CI: 1.75-120461.24, p=0.0310) for mRSS worsening, while PRO-C6:C6M had an HR of 4.09 (95% CI: 1.12-14.95, p=0.0333) for new-onset PH.Conclusions In patients with SSc, circulating markers of fibroblast activity and of tissue destruction were associated with ILD and SSc subtype at baseline, and were prognostic for changes in FVC, development of PH, and mRSS worsening. These results support such biomarkers for identifying disease populations and for predicting disease course.