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

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.

Collagen Turnover Biomarkers Associate with Active Psoriatic Arthritis and Decrease with Guselkumab Treatment in a Phase 3 Clinical Trial (DISCOVER-2)

“…This work identified C1M as an important biomarker for PsA as C1M levels were found to be elevated in the serum of the patients with PsA. C1M has been reported to be elevated in RA and associated with radiographic progression [ 33 ]. In contrast to the bone resorption marker C-terminal telopeptide of type 1 collagen, C1M is highly correlated with CRP and derived through the action of matrix metalloproteinases, indicating that C1M is a direct marker of inflammation-driven bone degradation [ 34 ].…”

Analyzing the risk of osteoporosis and fracture in rheumatoid arthritis patients who have been treated with various biologics

“…Therefore, we placed medications, tocilizumab, and Janus kinase (JAK) inhibitors, together into one subgroup as medications that could be used as monotherapy, which were named other bDMARDs, in our analysis. Tocilizumab 22,23 and the target synthetic DMARDs, 24 for example, small molecules of medication, could be used as monotherapy which has been well documented. A combination of T‐ or B‐cell modulating therapies was demonstrated with the effect of adjusting adaptive immunity against osteoporosis development and fracture incidence in RA patients 25,26 …”

Epigenome association study for DNA methylation biomarkers in buccal and monocyte cells for female rheumatoid arthritis

“…Although several RA biomarkers and diagnostics have been developed 47 , 48 , none are focused on early-stage biomarkers that can be used prior to the onset of clinical symptoms. The advantage of epimutations such as DNA methylation biomarkers is that they have been shown to develop early in life, or through epigenetic inheritance ancestrally, such that the biomarkers have the potential to act as diagnostics for preventative medicine treatments 41 , 49 . Such an early-stage RA biomarker or diagnostic has not been developed and is the focus of the current study.…”