IL-6 receptor inhibition modulates type III collagen and C-reactive protein degradation in rheumatoid arthritis patients with an inadequate response to anti-tumour necrosis factor therapy: analysis of connective tissue turnover in the tocilizumab RADIATE study.

The objective of this study was to examine the tissue degradation in response to anti-IL6 receptor treatment in rheumatoid arthritis (RA) patients which are anti-TNF-α inadequate responders.RADIATE was a randomised, double-blinded, placebo-controlled, parallel-group, phase III trial. RA patients with previous inadequate response to anti-TNFα therapy (n=299) were randomly assigned to tocilizumab 4 or 8 mg/kg with methotrexate (10-25 mg weekly) or placebo with methotrexate. Type III collagen degradation (C3M) and CRP degradation (CRPM) were analysed in serum samples at baseline and 16 weeks.Treatment with 4 and 8 mg/kg tocilizumab significantly decreased C3M (p=0.0001 and p=0.0007) and CRPM (p<0.0001) levels after 16 weeks. Changes in C3M and CRPM levels after 16 weeks correlated well with the changes in disease activity score 28 (DAS28). Change in CRPM levels furthermore correlated moderately with the change in patient pain (VAS) (rpartial of 0.20) and Health assessment questionnaire disability index (HAQ-DI) (rpartial of 0.24). Changes in biomarker levels above median change led to an odds ratio of 1.95 (C3M) and 3.00 (CRPM) for achieving the American College of Rheumatology 20% improvement criteria (ACR20).This study shows that a decrease in inflammation leads to a decrease in excessive extracellular matrix degradation. It furthermore supports earlier shown evidence that tocilizumab works in the treatment of RA patients, although there is a clear need for identifying and selecting patients who are more likely to respond to treatment.