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Introduction Type VII collagen is a key component of the skin. It is produced by epidermal keratinocytes and dermal fibroblasts, and is located at the dermal-epidermal junction, where it connects epidermis and dermis. Patients with systemic sclerosis (SSc) present with extensive fibrosis of the skin and internal organs, where type VII collagen is a part of the extracellular matrix (ECM), that is being remodeled. This study aimed to investigate biomarkers of type VII collagen in a large prospective cohort of patients with SSc and evaluate their relationships with co-morbidities and prognosis.Material and Methods Patients (n=346) meeting the 2013 ACR/EULAR classification criteria for SSc were analyzed. The collagen biomarkers reflecting type VII collagen synthesis, PRO-C7, and degradation, C7M, were measured in serum by ELISAs. 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). Statistical analysis included the Mann-Whitney U test and Cox Proportional Hazard Regression analysis.Results Patients had a mean age of 59.6 (SD: 12.1) years, 80.1% were female, the 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 PRO-C7 and C7M (p=0.0182 and p=0.0095). 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 Cox Proportional Hazard Regression adjusted for age, disease duration, SSc subtype, and ILD, indicated that a doubling of PRO-C7 at baseline were associated to FVC worsening with a hazard ratio (HR) of 3.21 (95% CI: 1.36-7.57), and a risk of mRSS wosening with a HR of 22.40 (95% CI: 1.41-357.14). In addition, a doubling of the ratio of PRO-C7:C7M was associated with a higher risk of mRSS worsening, with an HR of 56.93 (95% CI: 2.12-1530.77).Conclusions Changes in biomarkers of type VII collagen were linked to ILD at baseline, while new synthesis of type VII collagen was prognostic for FVC and mRSS worsening. These data support collagen biomarkers as potential new biomarkers to identify patients with active diseases and predict their disease course.