P154 Stage and subset specific profiles of fibrogenesis highlighted through analysis of serum markers across the scleroderma spectrum

Abstract

Abstract Background The striking heterogeneity in skin fibrosis within systemic sclerosis (SSc) is likely to reflect differences between pro- and anti-fibrotic pathways and underlie the spontaneous regression of skin fibrosis observed in late stage diffuse SSc (dcSSc). We studied potential serum markers of profibrotic activity in SSc, aiming to understanding their relationship with progression of fibrosis as measured by the modified Rodnan skin score (MRSS) to improve stratification of patients likely to respond to fibrosis-targeted therapies Methods The BIOPSY cohort are well characterised patients recruited prospectively from across the scleroderma spectrum. Serum and plasma samples were collected from 67 participants were included in the analysis (21 early dcSSc (<5 years disease duration),14 established dcSSc, 16 limited SSc(lcSSc), 16 healthy controls (HC)), with simultaneous MRSS recording. Standard and novel measures of serum or plasma markers were undertaken by immunoassay (20 in total) reflecting extracellular matrix (ECM) turnover or cytokine drivers of fibrosis Results Our results confirmed markers of collagen synthesis were significantly different between the patient subgroups (Pro-C6,Pro-C3,PIIINP), while markers of collagen degradation were not significantly altered (C3M,C6M,C4M2,C7M) (Table 1). Consistent with previous reports, the C3 fibrotic index (Pro-C3:C3M) and the ELF test also showed differentiation across subgroups. Across all tests, this difference was most significant between the early dcSSc subgroup compared with the other subgroups. There was significant upregulation of IL-6, MCP-1, and oncostatin M in SSc compared to HC. There were significant correlations between several candidate profibrotic serum markers and MRSS: Pro-C3, Pro C6, PIIINP, and IL6 (all p < 0.01). Conclusion Our results show the utility of extended patient cohorts to delineate fundamental biology in SSc. We identify key pro-fibrotic molecular markers upregulated in SSc and correlated these to extent of skin fibrosis. Markers of collagen III and collagen VI synthesis are particularly raised, especially in the early stages of the disease. However, markers of collagen degradation did not significantly differ between SSc subgroups and HCs. These promising cross-sectional data suggest that therapies targeting drivers of fibrosis are most likely to show benefit for skin in early dcSSc. This will be further explored longitudinally in the BIOPSY cohort. Disclosures K.E.N. Clark: None. C. Campochiaro: None. K. Nevin: Other; GSK employee. E. Csomor: Other; GSK employee. N. Galwey: Other; GSK employee. M. Morse: Other; GSK employee. N. Wisniacki: Other; GSK employee. S. Flint: Other; GSK employee. V.H. Ong: None. E. Derrett-Smith: None. C.P. Denton: Grants/research support; Actelion, GlaxoSmithKline, Bayer, Sanofi, lnventiva, Boehringer Ingelheim, Roche, Bristol Myers Squibb, CSL Behring, UCB, Leadiant Biosciences.