Incorporation of molecular signatures to predict treatment response in RA

A recent study published in the journal Nature Medicine has concluded that synovial biopsy-based biomarker analysis could  be predictive of  treatment response in RA patients.

The biopsy-based clinical trial  study evaluated the response of 164 arthritis patients to either rituximab or tocilizumab by collecting samples collected from the affected joints.Patients with reduced/absent synovial B cell molecular signature demonstrated a lower response to rituximab (anti-CD20 monoclonal antibody) compared to tocilizumab (anti-IL6R monoclonal antibody). However,  the exact mechanisms of response/non-response are yet to be elucidated. In-depth histological/molecular analyses of R4RA synovial biopsies were carried out to identify specific gene signatures associated with response to rituximab and tocilizumab, and in patients refractory to treatment. Changes in synovial gene expression and cell infiltration  demonstrated that the divergent effects of rituximab and tocilizumab correlated with the differential response/nonresponse mechanisms. The researchers also developed machine learning algorithms, based on ten-by-tenfold nested cross-validation, which predicted response to rituximab (AUC) = 0.74), tocilizumab (AUC = 0.68) and multidrug resistance (AUC = 0.69)

Despite the adoption of treat-to-target strategy in the recent years, nearly 40% of RA patients do not respond to individual agents and  5-20% are resistant to all the currently available drugs for RA. Moreover, due to the heterogeneity of the disease, biomarkers predictive of treatment response are lacking. The study provides insights from analysis of diseased tissue regarding the mechanisms driving treatment response heterogeneity in RA, and underscores the importance of integrating predictive molecular pathology signatures into clinical algorithms to optimize the usage of existing drugs.

Reference: Humby F, Durez P, Buch MH, et al. 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. Lancet. 2021;397(10271):305-317.

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