Biopsy-driven RA trial may lead the way for precision medicine
medwireNews: Findings from the R4RA trial suggest that tocilizumab may be a more appropriate second-line biologic choice than rituximab for rheumatoid arthritis (RA) patients with a low or absent B-cell expression signature based on synovial tissue RNA sequencing.
This study is “the first biopsy-driven randomised clinical trial in rheumatoid arthritis” and “represents a milestone in the mechanistic investigation at the disease tissue level of the relationship between drug mode of action and clinical response,” say the investigators in The Lancet.
They explain that response to the B-cell depleting drug rituximab is “heterogeneous” in RA patients, despite the “important role” of B cells in the disease process, highlighting the need to understand the mechanisms of response.
The phase 4 study, conducted across five European countries, included 164 RA patients with an inadequate response to tumor necrosis factor inhibitors who were categorized as B-cell poor or B-cell rich based on histologic classification of baseline synovial biopsy samples. Participants were randomly assigned to receive the interleukin-6 inhibitor tocilizumab at a dose of 8 mg/kg once monthly or two infusions of rituximab 1000 mg spaced 2 weeks apart.
The researchers then carried out RNA sequencing and reclassified the samples by B-cell molecular signature “[t]o enhance the accuracy of the stratification.”
Costantino Pitzalis (Queen Mary University of London, UK) and colleagues report that among the 79 participants histologically classified as B-cell poor, there was no significant difference in the proportion of patients achieving the primary endpoint of a 50% improvement in CDAI score (CDAI50) at week 16 in the tocilizumab versus rituximab groups, at rates of 56% and 45%, respectively.
However, among the 65 patients categorized as B-cell poor based on RNA sequencing, CDAI50 response rates were significantly higher among those given tocilizumab compared with those given rituximab, at 63% versus 36%.
Pitzalis and team also found that the proportion of B-cell poor patients with a CDAI major treatment response at week 16 – defined as a CDAI50 response and a score of less than 10.1 points – was significantly higher in the tocilizumab than the rituximab arm, both when participants were classified histologically (46 vs 24%) and by RNA sequencing (50 vs 12%).
Conversely, “rituximab was as effective as tocilizumab” for the majority of endpoints in patients categorized as B-cell rich, they say, but caution that “the study was not powered for the comparative analysis of B-cell rich populations in each treatment group.”
In the safety analysis, a numerically higher proportion of participants treated with tocilizumab versus rituximab experienced adverse events (80 vs 70%) and serious adverse events (10 vs 7%), but the team says that “these appeared largely unrelated to study drug, and there was no statistically significant difference between the two groups.”
Writing in an accompanying comment, Denis Poddubnyy (Charité-Universitätsmedizin Berlin, Germany) says that the R4RA findings “suggest that synovial biopsy with the subsequent analysis of the immunological signature could guide the treatment decision and further studies should follow.”
However, he notes that the “direct implication” for current clinical practice is “less obvious,” because “tocilizumab is normally preferred over rituximab for the first-line biological DMARD,” and “synovial biopsy is an invasive procedure (even when done in a minimally invasive way) that would not justify the information gain.”
Furthermore, “we know who would be a poor candidate for rituximab therapy” based on the trial results, but “it is rather unclear who would be a good candidate for rituximab,” he adds.
“In summary, we are still far away from practicing precision medicine in rheumatology,” concludes Poddubnyy.
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