FRI0008 Tissues are differently modulated by tocilizumab and methotrexate; assessment of connective tissue metabolites in the ambition study
Authors: A.C. Bay-Jensen, A.S. Siebuhr, C.S. Thudium, M.A. Karsdal
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Response to any treatment in rheumatoid arthritis (RA) is assessed by symptomatic changes, such as swollen joint count. Such assessments does not provide information regarding the effect of the treatment at tissue level. Chronic inflammation has a detrimental effect resulting in elevated levels of tissue remodelling 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 remodelling. <h3>Objectives</h3> The purpose was to investigate if tissue remodelling is differently modulated by tocilizumab (TCZ) and methotrexate (MTX). <h3>Methods</h3> 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 remodelling was measured by C3M (type III collagen degradation), basement membrane remodelling 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. <h3>Results</h3> Tissue remodelling was increased by 10% in the placebo group and significantly (p&lt;0.001) inhibited by both MTX and TCZ compared to placebo. Inhibition with TCZ was 14% greater than that of MTX (p=0.0005). Basement membrane remodelling was likewise inhibited by both MTX and TCZ; the effect of TZC was 20% greater than MTX (p&lt;0.0001). MTX had 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&lt;0.001). Only changes in C4M and CRP in the TCZ treatment arms were significantly correlated with DAS changes (rho=0.31, p&lt;0.05). <h3>Conclusions</h3> Chronic inflammation results in an increased amount of tissue remodelling. There was a significant difference in the magnitude of effect MTX and TCZ on tissue remodelling. In addition there was a disconnect between tissue remodelling and change in disease activity, which was treatment dependent. <h3>Disclosure of Interest</h3> A. Bay-Jensen Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, A. S. Siebuhr Employee of: Nordic Bioscience, C. Thudium Employee of: Nordic Bioscience, M. Karsdal Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience