Connective tissue remodelling is differently modulated by tocilizumab versus methotrexate monotherapy in patients with early rheumatoid arthritis: the AMBITION study

Abstract

Abstract Objective Associations between rheumatoid arthritis (RA) and effect of treatment at the tissue levels are poorly understood. We investigated the scope of released extracellular matrix (ECM) metabolites as a consequence of tissue remodelling in patients treated with methotrexate (MTX) and tocilizumab (TCZ) compared to placebo. Methods Tissue metabolites from 387 RA patients treated with either TCZ (8 mg/kg) or MTX monotherapy (7.5–20 mg/kg) were measured at baseline and 8 weeks sera by validated ELISA assays. The levels of collagen biomarkers (C1M, C2M, C3M and C4M) together with C-reactive protein (CRP) and CRP metabolite (CRPM) were investigated. Baseline levels of biomarkers have been compared with 72 age- and gender-matched healthy controls. Comparison between treatment and response groups were done by ANCOVA, Spearman’s correlation and logistic regression adjusted for age, gender, BMI and disease duration. Results C1M and C3M were significantly (P < 0.05) inhibited by TCZ and C3M by MTX (P < 0.01) compared to placebo. C1M and C3M inhibition with TCZ was respectively 23% and 16% greater than that of MTX (P < 0.01 and P < 0.0001). C4M was inhibited by TCZ and MTX, but the effect of TCZ was 22% greater than MTX (P < 0.0001). TCZ and MTX had minimal effect on C2M levels. MTX had no effect on CRP and CRPM, whereas TCZ reduced their levels to 69% and 27% from baseline. Investigated biomarkers revealed a significant (P < 0.05) difference in biomarker profiles of MTX ACR50 treatment responders and non-responders. Change to week 8 in levels of C3M, C4M, CRP and CRPM in MTX patients correlated significantly (rho = 0.41 to 0.18, P < 0.0001 to 0.039) with change in disease activity (DAS28) at weeks 8, 16 and 24, whereas only CRP in TCZ patients (rho = 0.32 to 0.21, P < 0.0001 to 0.01). Conclusion Patients receiving TCZ treatment for 8 weeks had higher suppression of tissue remodelling and inflammatory biomarkers over patients treated with MTX. Measured biomarkers enabled for a discrimination of biomarker profiles of ACR50 treatment responding patients and identification of those who benefit at the early time point. Week 8 change in levels of C3M, C4M, CRP and CRPM significantly predicted clinical response to treatment and correlated with DAS28 at all time points. Trial registration ClinicalTrials.gov, NCT00109408. Date of registration: July 2005. Name of the registry: A Study to Assess the Safety and Efficacy of Tocilizumab in Patients with Active Rheumatoid Arthritis.