The histological classification of rheumatoid arthritis (RA) synovial tissue was impervious in assessing therapeutic response, but the sequencing-based grouping had significant connections with clinical responses. Also, low or no B-cell lineage expression signature tocilizumab illustrated superiority than rituximab concerning the number of patients with CDAI 50%, and other secondary endpoints.

The goal of this multicentre, phase 4, open-label, 48-week, biopsy-driven randomized controlled trial was to assess if tocilizumab (interleukin-6 receptor inhibitor) is superior to rituximab in terms of improving clinical outcomes in RA patients who had unsatisfactory response to anti-tumor necrosis factor (TNF) stratified for synovial B-cell status.

In this study (rituximab vs tocilizumab in anti-TNF inadequate responder patients with rheumatoid arthritis; R4RA), 164 RA patients (aged 18 years or older) were included. The patients were labeled histologically as B-cell poor or rich after a standard synovial biopsy. Subjects were stratified into two groups: (i) Rituximab group (n=83): Participants received two 1000 mg rituximab infusions at an interval of  two weeks, and (ii) Tocilizumab group (n=81): Participants received tocilizumab 8 mg/kg infusions at an interval of four weeks.

To improve the precision of the stratification of B-cell poor and rich patients, RNA sequencing of the standard synovial biopsies was done and again classified by B-cell molecular signature. In B-cell poor population, tocilizumab's superiority over rituximab was evaluated at 16 weeks. A 50% improvement in Clinical Disease Activity Index (CDAI 50%) from the starting point was the major outcome parameter.

In patients histologically categorized as B-cell poor, no substantial differences in CDAI 50% were witnessed between rituximab and tocilizumab group. But, as compared to the rituximab arm, the tocilizumab arm had a remarkably greater response rate for CDAI 50% in the synovial biopsies categorized as B-cell poor with RNA sequencing.

No statistically significant difference was found in terms of the incidence of adverse events and serious adverse events between both the groups, as illustrated below:

RNA sequencing-based stratification displayed a stronger link with clinical responses than with histopathological classification in RA patients. Furthermore, for patients categorized as B-cell poor in synovial tissue tocilizumab was more effective as compared to rituximab.