Biopsy-driven trial a milestone towards precision medicine in RA

Abstract

0123456789();: Nature reviews | Rheumatology The results of R4RA, the first biopsydriven, multicentre randomized controlled trial (RCT) in rheumatoid arthritis (RA), suggest that direct assessment of synovial tissue pathology could be used to guide the choice of treatment for patients with RA. If replicated and validated in independent cohorts, the findings could represent an important step forward in precision medicine for the disease. “Precision medicine aims to tailor treatment to distinct features of an individual patient’s condition,” explains Laura Donlin, who was not involved in R4RA. In oncology, for example, stratification of patients and tailoring of treatment according to tumourspecific molecular profiles is routine in clinical practice. “RA represents a promising test case for precision medicine amongst rheumatic diseases,” says Donlin, pointing out that the range of medi cations available for RA have shown differential efficacy among patients with the disease, and that the past few years have seen major gains in knowledge of the molecular and cellular features of RAaffected joints. “The challenge now is in identifying which of these molecular features relates to the responsivity of an individual to a given medication,” she adds. The R4RA investigators focused on the extent of B cell infiltration in the RA joint tissue (synovium) as a predictor of an individual patient’s responsiveness to a treatment that targets B cells. “In prior studies, we identified that approximately 40% of patients have few B cells infiltrating the synovium while still displaying active arthritis,” says coauthor Felice Rivellese. “On this basis, we hypothesized that, in these patients, joint inflammation is driven by alternative cell types and/or pathways and they would be less likely to respond to the B cell depleting biologic rituximab and more likely to respond to a different biologic, such as tocilizumab.” This hypothesis was supported by the results of a small pilot study of patients with established RA and an inadequate response to TNF inhibitor therapy, in which having few or no CD20+ B cells was an independent predictor of nonresponse to rituximab. In the phase IV R4-RA RCT, the presence of B cells in a patient’s actively swollen joint was assessed by histological assessment of biopsy-obtained synovial tissue. The patients, who had all previously failed to respond to treatment with TNF inhibitors, were then classified as ‘B cell rich’ or ‘B cell poor’ and randomly assigned to receive either rituximab (n = 83) or tocilizumab (n = 81). Synovial tissue was also classified by B cell molecular signature using RNA sequencing. Among patients histologically classified as B cell poor, there was no statistically significant difference in the proportion meeting the primary end point (improvement from baseline in clinical disease activity index score of 50% or more (CDAI50%) at week 16) between those treated with tocilizumab or rituximab (56% versus 45%). However, more patients in the tocilizumab group achieved a major treatment response (CDAIMTR; defined as CDAI50% plus CDAI score <10.1) than in the rituximab group (46% versus 24%; P = 0.035). Notably, when joint tissue was assessed using RNA sequencing, the response rate was significantly higher in the tocilizumab group for both CDAI50% (63% versus 36%; P = 0.035) and CDAIMTR (50% versus 12%; P = 0.0012). Rituximab seemed to be as effective as tocilizumab for patients classified as B cell rich, although the study was not powered to evaluate their comparative efficacy. “The ability to target biological therapies to the right patients would significantly impact the health economics of RA with reduced exposure of patients to expensive and potentially toxic drugs, while reducing suffering and disability for patients and huge costs to society,” notes Costantino Pitzalis, coauthor and chief investigator of R4RA. Although the study has some limitations, the results suggest that assessing B cell expression signatures in synovial tissue could help identify patients who might not respond to treatment with rituximab. “This is an outstanding first step towards implementing evidencebased precision medicine approaches for patients with rheumatic diseases,” notes Donlin. Sarah Onuora C L I N I C A L T R I A L S