O07 Randomised, open labelled clinical trial to investigate synovial mechanisms determining response: resistance to rituximab versus tocilizumab in RA patients failing TNF inhibitor therapy

Abstract

Background/Purpose : Although biologic therapies have transformed the outlook for rheumatoid arthritis (RA), the lack of a major treatment response in over 50% of patients, the potential side effects and the high cost of these drugs have highlighted the need to define predictive markers of response and to stratify patients according to therapeutic outcome. B-cells are pivotal to RA pathogenesis, validated by the efficacy demonstrated by the B cell depleting agent rituximab (RTX). RTX is licensed for use following failure of conventional synthetic (cs)-DMARDs and TNF inhibitor (TNFi) therapy. However, in this increasing therapeutically resistant cohort only 30% of patients achieve an ACR50 response at 6 months. We have recently demonstrated in an early RA cohort 1 synovial heterogeneity with over 50% of patients showing low/absence of synovial B-cell infiltration. This prompted us to test the hypothesis that in these patients an alternative biologic agent targeting alternative pathways maybe more effective. We report results from the first pathobiology-driven randomised controlled trial (RCT) in RA (R4RA) evaluating whether patient stratification according to the synovial B-cell rich/poor status enriches for response/non response to RTX. Methods : R4RA is a 48 week phase IV open-label RCT conducted in 19 European centres that recruited patients failing or intolerant to csDMARD therapy and at least one TNFi. Synovial tissue was obtained at trial entry and classified histologically as B-cell rich (BCR) or B-cell poor (BCP). Patients were randomised to receive standard therapy with RTX or tocilizumab (TCZ) stratified according to histological classification. The study was powered to test in the BCP population superiority of TCZ over RTX at 16 weeks. The primary and co-primary end-points were defined respectively as Clinical Disease Activity Index (CDAI) >=50% improvement from baselineand Major Treatment response (MTR) = CDAI improvement >= 50% and CDAI