Ab1151 Circulating Cthrc1 Levels Are Associated With Disease Severity and Predict Survival in Systemic Sclerosis

Background: Despite recent advances in systemic sclerosis (SSc), there remains a paucity of clinically actionable biomarkers to assess disease severity and predict progression. Collagen triple helix repeat containing-1 (CTHRC1), a protein secreted during tissue-repair that regulates fibroblast function and vascular remodeling after arterial injury, has been reported to be a marker for a subpopulation of pathologic fibroblasts uniquely found in fibrotic lung disease, including SSc-ILD. However, its association with disease severity and other disease manifestations in SSc is unknown. Objectives: The aim of this study was to determine whether serum levels of circulating CTHRC1 are associated with specific disease manifestations and predict clinical outcomes in SSc. Methods: Retrospective cohort study was performed using two large, well characterized, cohorts of SSc patients followed at University of California San Francisco (UCSF, discovery) and Stanford (validation). Serum levels of CTHRC1 were measured by ELISA in 377 UCSF and 370 SSc Stanford patients, and 40 healthy controls (Table 1). SSc patients were stratified by quartiles of CTHRC1 serum level for analysis with Q1 having the lowest serum level and Q4 the highest. Quartile characteristics were compared using ANOVA/Chi-Square and mixed models were utilized to assess the association of CTHRC1 serum level with SSc disease manifestations and severity, including skin disease, interstitial lung disease (ILD), pulmonary arterial hypertension (PAH), and peripheral vascular disease. Survival analysis, defined by time to death or lung transplantation, was assessed by Kaplan-Meier analysis between quartiles with long-rank test. To examine CTHRC1 expression in relevant tissue, we probed publicly available single cell RNAseq dataset of the SSc skin (GSE138669) and compared gene expression of CTHRC1 between SSc and healthy controls among cell types. Results: Serum CTHRC1 was significantly increased in SSc patients compared to healthy controls (Figure 1a). After controlling for age, sex, race, disease duration and SSc antibody status, elevated CTHRC1 was independently associated with skin disease severity in both discovery and validation cohorts (p<0.05) and PAH in the UCSF cohort (p=0.02) with a trend in the Stanford cohort (p=0.19). Patients with diffuse skin disease had significantly higher CTHRC1 than limited skin disease (p<0.03) (Figure 1b) and elevated CTHRC1 was associated with both increased MRSS at time of serum measurement and worst MRSS recorded (p=0.004) (Figure 1c). CTHRC1 was not associated with the presence of ILD in our study, however, was significantly associated with markers of PAH severity, including decreased DLCO% predicted (p<0.001) and elevated RVSP (p=0.01). Elevated CTHRC1 serum level was associated with worse 5-year survival among SSc patients (Figure 1d). When probing publicly available gene expression data of skin, we found CTHRC1 expression was higher in SSc and was primarily expressed in SSc fibroblasts and to a lesser degree SSc endothelial cells (Figure 1e). Among fibroblast subgroups, CTHRC1 was highly expressed in a subset of dermal fibroblasts (SFRP2 high) found primarily in SSc patients (Figure 1f), with 3.7-fold increase compared to controls (p<0.001). This fibroblast population has been shown to express Col1A1 and hypothesized to be a progenitor for fibrogenic fibroblasts in SSc. Conclusion: Circulating CTHRC1 levels are increased in SSc patients and exhibit a significant association with more severe skin disease, PAH severity, and worse survival. The presence of CTHRC1 expressing fibroblasts in affected skin of SSc patients suggests they may be implicated in disease pathogenesis and warrants further investigation.REFERENCES: NIL. Table 1. Demographic and clinical characteristics of SSc patients and healthy controls Acknowledgements: NIL. Disclosure of Interests: Monica Yang: None declared, Michael Wax: None declared, Puneet Kapoor: None declared, Seoyeon Lee: None declared, Lisa Hazelwood Employee of Abbvie, Tatsuya Tsukui: None declared, Dean Sheppard Served as a consultant for Amgen, Genentech, Lila Bioscience, Pliant Therapeutics, Received research support from Abbvie and Pfizer, Lorinda Chung: None declared, Francesco Boin: None declared, Paul J. Wolters Served as a consultant for Blade therapeutics, Received research support from Genentech, Boehringer Ingelheim and Sanofi.