Background/Purpose: The response to any treatment in rheumatoid arthritis (RA) is assessed by symptomatic changes, such as swollen joint count and DAS28. However, such assessments does not provide information regarding the effect of the treatment at the tissue level. Chronic inflammation has a detrimental effect resulting in elevated levels of tissue remodeling and the release of extracellular matrix (ECM) metabolites into the circulation. The tissues consist mainly of interstitial matrix, basement membrane and cells, which are all affected by auto-immune disorders. Tissue metabolites can be measured in serum as biomarkers of tissue remodeling and may give insight to effect at the tissue level of different interventions. The purpose was to investigate if tissue remodeling is differently modulated by tocilizumab (TCZ) and methotrexate (MTX). This was conducted by measurement of tissue metabolites in serum of the RA patients participating in the phase III clinical trial.

Methods: The AMBITION study, a phase III RCT with tocilizumab vs. Methotrexate in which TCZ monotherapy (8 mg/kg every 4 weeks) was compared to methotrexate monotherapy over 24 weeks in patients with moderate-severe RA (AMBITION, NCT00109408). TCZ is a compound that inhibits the IL-6 receptor. Tissue metabolites were measured in baseline and 8-weeks sera (n=319) by ECM specific ELISAs: Connective tissue remodeling was measured by C3M (type III collagen degradation), basement membrane remodeling by C4M (type IV collagen), inflammation by C-reactive protein (CRP) and its metabolite CRPM. Comparison between groups were done by ANCOVA adjusting for age, gender, BMI and disease duration.

Results: Tissue remodeling was increased by 10% in the placebo group. The connective tissue remodeling was significantly (p<0.001) inhibited by both MTX and TCZ compared to placebo. The inhibition with TCZ was 14% greater than that of MTX (P=0.0005). Basement membrane remodeling was likewise inhibited by both MTX and TCZ; the effect of TZC was 20% greater than MTX (p<0.0001). In contrast, MTX had no or limited effect on CRP and its metabolite CRPM compared to placebo or baseline. TCZ reduced the level to 27% and 73% of baseline, respectively. Although the effect of TCZ was much greater when assessing CRP, this was the least significant response marker, due to the huge placebo modulation, as well as the general high variation in response. Only changes in CRP was correlated to 8-week changes in DAS (rho=0.27, p=0.001) in the TCZ group. In the MTX group all changes in markers were correlated to change in DAS (rho=0.28 to 0.41, p<0.001). In contrast, only changes in C4M and CRP were significantly correlated with DAS changes (rho=0.31, p<0.05).

Conclusion: Chronic inflammation results in an increased amount of tissue remodeling. There was a significant difference in the magnitude of effect MTX and TCZ on tissue remodeling. In addition there was a disconnect between tissue remodeling and change in disease activity, which was treatment dependent.

« Back to 2017 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/tissues-are-differently-modulated-by-tocilizumab-and-methotrexate-assessment-of-connective-tissue-metabolites-in-the-ambition-study/