Background Extracellular matrix (ECM) unbalance of the skin is a hallmark of systemic sclerosis (SSc). However, currently there is no objective tool to monitor the ECM unbalance in SSc patients allowing for better understanding of the disease stage and activity.
Objectives We investigated the potential of serological biomarkers of ECM turnover (collagen formation and degradation) as biomarkers of skin fibrosis and internal organ involvement in SSc patients.
Methods Peripheral blood obtained from 79 SSc patients and 19 healthy subjects was included in the study. Type I, III, IV, V and VI collagen formation (P1NP, PRO-C3, P4NP7S, PRO-C5, PRO-C6) and degradation (C3M, C4M2, C5M, C6M) biomarkers were detected by ELISA in serum. Modified Rodnan skin score (mRSS) and extent of internal organ involvement (renal, lung, vasculopathy and gastrointestinal) were recorded for SSc patients with a scoring between 0 and 4, with 0 being no involvement and 4 being severe involvement. Mann-Whitney t-test was used to test difference in the biomarker levels between the patient groups and in groups with and without internal organ involvement. Spearman's correlation coefficient investigated the association between biomarkers and clinical manifestations.
Results SSc patients had a mean age of 63.0 years, mean disease duration of 98.3 months and a mean mRSS of 11.1. SSc patients compared to healthy individuals had higher levels of C5M, C6M and PRO-C6 (p=0.0001, p<0.0001, p<0.0001, respectively). The levels of type VI collagen formation and degradation (PRO-C6 and C6M) were twice as that of healthy controls (12.6 vs. 5.4 and 26.0 vs 16.7 ng/ml, respectively). C4M2, PRO-C3 and PRO-C6 was associated with skin fibrosis assessed by mRSS (Spearman's rho=0.24, 0.39 and 0.29, respectively). Patients with signs and manifestation of lower gastrointestinal lesion compared to patients without lesion had higher levels of C3M (median 10.7 vs 13.8ng/mL, p=0.017; figure). PRO-C6 was higher in patients with pulmonary hypertension compared to patients without any signs of pulmonary hypertension (median 9.6 vs 14.3ng/mL, p=0.006) with a Spearman's correlation coefficient of 0.31. C6M was higher in patients with definite pulmonary hypertension (>1) compared to patients with signs of or no pulmonary hypertension (median 22.1 vs 29.9ng/mL, p=0.026). P1NP was lower in patients with interstitial pneumonia, whereas C6M was higher. There was no difference in the biomarker levels with and without upper gastrointestinal lesions, renal dysfunction or vasculopathy.
Conclusions Serological biomarkers of type V and VI turnover (C5M, C6M, PRO-C6) were associated with SSc, but not serological biomarkers of type I, III and IV collagen. Especially, turnover of type VI collagen was associated with skin sclerosis, pulmonary hypertension, interstitial pneumonia and renal dysfunction. This study indicates that biomarkers of collagen turnover have a potential as new objective tool of skin fibrosis and internal organ involvement in SSc.
Disclosure of Interest S. Kubo Speakers bureau: Bristol-Myers, A. S. Siebuhr Employee of: Nordic Bioscience, A.-C. Bay-Jensen Employee of: Nordic Bioscience, P. Juhl Employee of: Nordic Bioscience, M. A. Karsdal Employee of: Nordic Bioscience, K. Nakano: None declared, S. Nakayamada: None declared, Y. Tanaka Grant/research support from: Mitsubishi-Tanabe, Takeda, Daiichi-Sankyo, Chugai, Bristol-Myers, MSD, Astellas, Abbvie, Eisai, Speakers bureau: Abbvie, Chugai, Daiichi-Sankyo, Bristol-Myers, MitsubishiTanabe, Astellas, Takeda, Pfizer, Teijin, Asahi-kasei, YL Biologics, Sanofi, Janssen, Eli Lilly, GlaxoSmithKline