Synovial Tissue Signature Guiding Targeted IL-6 Therapy in RA Save

RNA sequencing and classification of rheumatoid arthritis (RA) subsets has proven useful. RNA sequencing-based stratification of rheumatoid arthritis synovial tissue showed stronger associations with clinical responses compared with histopathological classification. Additionally, for patients with low or absent B-cell lineage expression signature in synovial tissue, tocilizumab is more effective than rituximab.

Prior studies have suggested that most therapies are ineffective in at least 40% of RA patients, and that 50% of RA patients have low or absent CD20 B cells, thereby questioning the rationale for using therapies such as rituximab (RTX).

The R4RA study was a 48-week, biopsy-driven, multicentre, open-label, phase 4 randomised controlled trial compared the clinical efficacy of tocilizumab vs. rituxi mab in patients RA patients who had an inadequate response to anti-tumour necrosis factor (TNF); but with treatment choices stratified by synovial B-cell status.

Patients were stratified according to baseline synovial biopsy with patients classified histologically as B-cell poor or rich. Patients were randomly assigned (1:1) to receive either two 1000 mg rituximab infusions at an interval of 2 weeks (rituximab group) or 8 mg/kg tocilizumab infusions at 4-week intervals.

Baseline synovial biopsies from all participants were subjected to RNA sequencing and reclassified by B-cell molecular signature. The study was powered to test the superiority of tocilizumab over rituximab in the B-cell poor population at 16 weeks with a primary endpoint was defined as a 50% improvement in Clinical Disease Activity Index (CDAI50%) from baseline.

A total of 164 RA patients were classified histologically and were randomly assigned to either RTX or TCZ.

In those histologically classified as B-cell poor, there was no statistically significant difference in CDAI50 responses in those treated with RTX (45%) or TCZ (56%) (p=0·31).

However, in those classified as B-cell poor with RNA sequencing, the TCZ group had a significantly greater CDAI50 response (63% vs. 36% in RTX; p=0·035).  Adverse events were the same between groups, as were serious adverse events (RTX 7% vs TCZ 10%). 

In this study, it appears that RNA sequencing-based treatment choices yielded superior outcomes compared to treatment based on synovial tissue histology.  The presence of a low or absent B-cell expression signature was associated with better tocilizumab oucomes (compared to rituximab).