Background Rheumatoid arthritis (RA) is a chronic inflammatory disease with highly elevated connective tissue turnover. Matrix Metalloproteinase (MMP) mediated connective tissue destruction is central in RA and results in the release of protein fragments into circulation. C1M measures one of these fragments. The serum levels of C1M have shown to be a direct and sensitive measure of connective tissue turnover. It has shown to be prognostic for structural progression and treatment efficacy in the phase III study LITHE. It is important to identify patients with rapid progression, thus there is a medical need for characterising and validating biomarkers aiding this identification.
Objectives The aim was to investigate whether previous findings on the prognostic ability of the C1M in moderate to severe RA patient could be replicated in a study including patients with early RA. This was done by comparing the results of the LITHE study to a Japanese cohort including patients with early RA.
Methods The placebo group (N=183) of the biomarker study LITHE study included patients with moderate to severe RA (mean disease duration 9.4 years) on stable doses of Methotrexate (MTX; 10-25mg/week). The Japanese cohort included 43 patients with newly diagnosed RA; mean disease duration was 6.4 months. C1M was tested in baseline serum samples. Spearman's correlation, rho, was analyzed between baseline serum C1M (log transformed) levels, JSN, DAS and mTSS.
Results In the LITHE study, baseline C1M was significantly correlated to DAS28 (rho=0.31, p<0.0001), but not to baseline mTSS (rho=0.14) or JSN (rho=0.12). In the Japanese cohort C1M was correlated to mTSS (rho=0.31, p=0.038) at baseline, but not to JSN or DAS28, in contrast to the LITHE results. In the LITHE study baseline serum C1M was significantly correlated with change in JSN (rho=0.63, p<0.0001) and with changes in mTSS (rho=0.58, p<0.0001). This was supported by the results of the Japanese cohort, where there was also a significant correlation to change in mTSS (rho=0.51, p=0.013).
Conclusions There was positive correlation between the MMP-mediated tissue degradation marker C1M and disease activity in patients with moderate to severe disease, but not in those with early disease. In contrast there was an association between mTSS and C1M at baseline in the group with early RA. Thus the diagnostic value seemed to be associated with disease duration. Interestingly, there was a consistent correlation (rho=0.5-0.6) between C1M and radiographic progression across the two cohorts, indicating that C1M may act as a prognostic biomarker of disease progression independent of disease duration.
Disclosure of Interest A. Bay-Jensen Shareholder of: Nordic Bioscience, Grant/research support from: EC FP7 programs, Employee of: Nordic Bioscience, S. Hirata Consultant for: Abbvie, Eisai, Bristol-Myers Squibb, N. Gudmann: None declared, A. Siebuhr Employee of: Nordic Bioscience, C. Christiansen Shareholder of: Nordic Bioscience, Y. Tanaka Grant/research support from: Mitsubishi-Tanabe, Chugai, MSD, Astellas, Novart, Consultant for: Abbvie, Chugai, Astellas, Takeda, Santen, Mitsubishi-Tanabe, Pfizer, Janssen, Eisai, Daiichi-Sankyo, UCB, GlaxoSmithKline, Bristol-Myers, Speakers bureau: Abbvie, Chugai, Astellas, Takeda, Santen, Mitsubishi-Tanabe, Pfizer, Janssen, Eisai, Daiichi-Sankyo, UCB, GlaxoSmithKline, Bristol-Myers, M. Karsdal Shareholder of: Nordic Bioscience, Grant/research support from: EC FP7 programs, Employee of: Nordic Bioscience