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

Ali Y. Ayla, A.Y. Ayla, MD, UTHealth Houston, Division of Rheumatology, Houston, TX, USA.
Elana J. Bernstein, E.J. Bernstein, MD, MSc, Division of Rheumatology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.
Meng Zhang, M. Zhang, MS, UTHealth Houston, Division of Rheumatology, Houston, TX, USA.
John M. VanBuren, J.M. VanBuren, PhD, Division of Pediatric Critical Care, Department of Pediatrics, University of Utah, Salt Lake City, UT, USA.
Flavia V. Castelino, F.V. Castelino, MD, Division of Rheumatology, Massachusetts General Hospital, Boston, MA, USA.
Lorinda Chung, L. Chung, MD, MS, Division of Immunology and Rheumatology, Stanford University and Palo Alto VA Health Care System, Palo Alto, CA, USA.
Luke Evnin, L. Evnin, PhD, Scleroderma Research Foundation, San Francisco, USA.
Tracy M. Frech, T.M. Frech, MD, MS, Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA; Tennessee Valley Health Care System, Veterans Affair Medical Center, Nashville, TN, USA.
Jessica K. Gordon, J.K. Gordon, MD, MSc, Division of Rheumatology, Hospital for Special Surgery, New York City, NY, USA.
Faye N. Hant, F.N. Hant, DO, Division of Rheumatology, Medical University of South Carolina, Charleston, SC, USA.
Laura K. Hummers, L.K. Hummers, MD, MSc, Division of Rheumatology, Johns Hopkins University, Baltimore, MD, USA.
Dinesh Khanna, D. Khanna, MD, MS, University of Michigan Scleroderma Program, Division of Rheumatology, University of Michigan, Ann Arbor, MI, USA.
Kimberly S. Lakin, K.S. Lakin, MD, MS, Division of Rheumatology, Hospital for Special Surgery, New York City, NY, USA.
Dorota Lebiedz-Odrobina, D. Lebiedz-Odrobina, MD, RhMSUS, Division of Rheumatology, Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.
Yiming Luo, Y. Luo, MD, MHS, Division of Rheumatology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.
Ashima Makol, A. Makol, MD, Division of Rheumatology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.
Maureen Mayes, M. Mayes, MD, MPH, UTHealth Houston, Division of Rheumatology, Houston, TX, USA.
Zsuzsanna H. McMahan, Z.H. McMahan, MD, MS, UTHealth Houston, Division of Rheumatology, Houston, TX, USA.
Jerry A. Molitor, J.A. Molitor, MD, PhD, Division of Rheumatic and Autoimmune Diseases, Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
Duncan F. Moore, D.F. Moore, MD, RhMSUS, Division of Rheumatology, Northwestern University, Chicago, IL, USA.
Carrie Richardson, C. Richardson, MD, MHS, Division of Rheumatology, Northwestern University, Chicago, IL, USA.
Nora Sandorfi, N. Sandorfi, MD, Division of Rheumatology, University of Pennsylvania, Philadelphia, PA, USA.
Ami A. Shah, A.A. Shah, MD, MHS, Division of Rheumatology, Johns Hopkins University, Baltimore, MD, USA.
Ankoor Shah, Ankoor Shah, MD, MHS, Division of Rheumatology and Immunology, Duke University, Durham, NC, USA.
Victoria K. Shanmugam, V.K. Shanmugam, MD, The George Washington University School of Medicine and Health Sciences, Department of Anatomy, George Washington University, Washington D.C., USA.
Brian Skaug, B. Skaug, MD, PhD, UTHealth Houston, Division of Rheumatology, Houston, TX, USA.
Virginia D. Steen, V.D. Steen, MD, Georgetown University Medical Center, Washington DC, USA.
Elizabeth R. Volkmann, E.R. Volkmann, MD, MS, Division of Rheumatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
Carleigh Zahn, C. Zahn, DO, University of Michigan Scleroderma Program, Division of Rheumatology, University of Michigan, Ann Arbor, MI, USA.
Wenjin J. Zheng, W.J. Zheng, PhD, UTHealth Houston, School of Biomedical Informatics, Houston, TX, USA.
Shervin Assassi, S. Assassi, MD, MS, UTHealth Houston, Division of Rheumatology, Houston, TX, USA.

Document Type

Journal Article

Publication Date

11-15-2025

Journal

The Journal of rheumatology

DOI

10.3899/jrheum.2025-0532

Abstract

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.

Department

Anatomy and Regenerative Biology

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