Abstract
BACKGROUND: Biomarkers of rheumatoid arthritis (RA) disease activity typically measure inflammation or autoimmunity (e.g. CRP, RF). C1M and C3M, metabolites of type I and III collagen, are markers reflecting tissue metabolism. These markers have been documented to provide additional prognostic and predictive value compared to commonly used biomarkers. We investigated the relationship of high serum levels of C1M or C3M to radiographic progression, and benchmarked them to CRP and RF. METHODS: Placebo treated patients of the OSK1, 2 and 3 studies (Phase III clinical trials testing efficacy of fostamatinib) with baseline serum biomarkers C1M, C3M, CRP and RF were included (n(BL) = 474). Van der Heijde mTSS was calculated at baseline and 24-week (n(24) = 261). Progression was defined as moderate or rapid by ΔmTSS ≥0.5 or ≥ 5 units/year. Patients were divided into subgroups; low (L), high (H) or very high (V) C1M, C3M and CRP, or RF negative, positive and high positive. Difference in clinical parameters were analyzed by Mann-Whitney or χ(2)tests, and modelling for prediction of progression by logistic regression including covariates (age, gender, BMI, and clinical assessment scores). RESULTS: Levels of C1M, C3M, CRP and RF were significantly (p < 0.05) associated with measures of disease activity and mTSS at baseline. For prognostic measures, there were 2.5 and 4-fold as many rapid progressors in the C1M(H) and CRP(H) (p < 0.05), and in the C1M(V) and CRP(V) groups (p < 0.001) compared C1M(L) and CRP(L), respectively. C1M and CRP performed similarly in the predictive analysis, where high levels predicted moderate and rapid progression with odds ratio of 2.1 to 3.8 and 3.7 to 13.1 after adjustment for covariates. C3M and RF did not provide prognostic value alone. DISCUSSION: Serum C1M and CRP showed prognostic value and may be tools for enrichment of clinical trials with structural progressor. The two markers reflect two different aspect of disease pathogenesis (tissue turnover vs. inflammation), thus may provide individual and supplementary information.