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

SPS commentary:

Authors state that the results suggest that RNA sequencing-based stratification of rheumatoid arthritis synovial tissue showed stronger associations with clinical responses compared with histopathological classification.

A related commentary discusses the study and notes that it is the first trial to investigate whether the treatment decision in rheumatoid arthritis can be guided by the results of the synovial biopsy. The authors hypothesised that the clinical response to anti-B-cell therapy (rituximab) should be poorer compared with the clinical response to tocilizumab in patients with low or an absence of B cells in the synovial tissue. Tocilizumab was better in patients classified as B-cell poor according to the RNA sequencing. The trial did not show that the B-cell depletion efficacy is higher in the B-cell rich population; however, the study was not statistically powered to show this.

 

The results of this study  suggest that synovial biopsy with the subsequent analysis of the immunological signature could guide the treatment decision and further studies should follow. For clinical practice, the direct implication and effect of the study are less obvious. First, rituximab is approved in the EU and the USA as a second-line biological DMARD after unsuccessful treatment with at least one TNF inhibitor, and tocilizumab can be used as a first-line biological DMARD; thus, tocilizumab is normally preferred over rituximab for the first-line biological DMARD treatment anyway. Second, the study suggests superiority of IL-6 blockade over B-cell depletion in patients classified as B-cell poor; this means that we know who would be a poor candidate for rituximab  therapy, but it is rather unclear who would be a good candidate for rituximab compared with candidates for tocilizumab and other biological and targeted synthetic DMARDs. Third, synovial biopsy is an invasive procedure (even when done in a minimally invasive way) that would not justify the information gain for the reasons indicated above.

 

In summary, we are still far away from practising precision medicine in rheumatology. Strategy studies with molecular characterisation of the disease on both systemic and local levels with the use of advanced technologies might help to identify specific predictors of response and non-response and to develop individualised treatment approaches.