Synovial B Cells and Therapy Response (R4RA) Scouting Report

Written by: Vanderbilt University Medical Center Rheumatology Fellowship

Based on: Humby et al. Rituximab versus tocilizumab in anti-TNF inadequate responder patients with rheumatoid arthritis (R4RA): 16-week outcomes of a stratified, biopsy-driven, multicentre, open-label, phase 4 randomised controlled trial. Lancet.2021;397(10271):305-17 (pubmed link)

Topic Overview

R4RA (Humby et al, Lancet. 2021) is a biopsy-driven, multicenter, phase 4 randomized controlled trial that pits rituximab vs tocilizumab against each other in 161 patients with rheumatoid arthritis who have failed DMARD and TNFi therapy, either by intolerance or lack of efficacy. The patients are stratified by histology on synovial biopsy and RNA seq on synovial biopsy as either being “B-cell rich” or “B-cell poor.” This paper presents the 16 week outcomes, of which the primary outcome is difference in Clinical Disease Activity Index (CDAI) by 50% or more (CDAI50%). Other secondary endpoints were examined as well and include other disease activity measures (DAS-ESR, etc), functional outcomes (eg, HAQ), as well as quality of life outcomes (eg, SF-36). Ultimately, the authors show no statistically significant difference in achievement of the primary endpoint in patients who were characterized B-cell poor by histologic characterization (rituximab group with 17 [45%] of 38 patients and tocilizumab group with 23 [56%] of 41 patients; difference 11% [95% CI –11 to 33], p=0·31). However, there was a difference in patients characterized as B-cell poor by molecular RNA sequencing of the synovial sample (rituximab group 12 [36%] of 33 patients vs tocilizumab group 20 [63%] of 32 patients; difference 26% [2 to 50], p=0·035). Occurrence of adverse and serious adverse were not significantly different between treatment groups.

Implications for Patients, Providers, & Researchers

Current implications: Current treatment patterns in patients with RA rely on historical availability, insurance access, and relative contraindications. Historical response rates are limited in RA and could be optimized with a more targeted, personalized approach. There is an associated cost as well as side effect potential with multiple medications in patients with RA. R4RA provides that personalized approach, albeit with invasive testing. This is the first biopsy-driven trial in RA to show a differential treatment response. This paper confirms the translational suspicion that there are different endotypes of RA with corresponding differential responses to therapy. Researchers will continue to flesh this out and potentially find a less invasive means to sort these patients.

Future implications: It is not hard to see the future of a paper like this: Precision rheumatology! Our oncologic colleagues have been doing this for years, but the potential in selecting on the front end a treatment that will have more benefit in the patient in front of us is quite exciting.

Will R4RA Win its First Round Match-up?

R4RA stands a good chance to advance past the first round as its competitor, PRIME cells in RA (Orange et al, NEJM. 2020) is further from the bedside and does not suggest a therapeutic intervention and thusly cannot close a game down the stretch. R4RA needs to watch out though, as the PRIME illustration (Table 5) is sure to be a long-term teaching tool for future rheumatology fellows.

Could R4RA Win it All?

As exciting as the paper is, it will be a challenge for R4RA to win it all. While it might progress in the early rounds, it will find it difficult to overcome the powerhouses present in the AAV/SLE bracket. R4RA’s “Moneyball”-like approach in determining RA treatment therapy is clever, as it gives providers a biomarker to specifically guide therapy. This paper also adds to the few head-to-head trials we have in RA to help guide therapy. Ultimately though, synovial biopsy is invasive, and there will be questions about applicability of this trial to current care paradigms as well as limitations in it being an open label trial.


  1. Humby et al. Lancet.2021;397(10271):305-17
  2. Orange et al. NEJM.2020;383(3):218-28

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