A Molecular Signature Response Classifier to Predict Inadequate Response to Tumor Necrosis Factor-α Inhibitors: The NETWORK-004 Prospective Observational Study.

A blood-based molecular signature response classifier (MSRC) integrating next-generation RNA sequencing data with clinical features predicts the likelihood that a patient with rheumatoid arthritis will have an inadequate response to TNFi therapy. Treatment selection guided by test results, with likely inadequate responders appropriately redirected to a different therapy, could improve response rates to TNFi therapies, generate healthcare cost savings, and increase rheumatologists' confidence in prescribing decisions and altered treatment choices. The MSRC described in this study predicts the likelihood of inadequate response to TNFi therapies among targeted therapy-naïve and TNFi-exposed patients in a multicenter, 24-week blinded prospective clinical study: NETWORK-004. Patients with a molecular signature of non-response are less likely to have an adequate response to TNFi therapies than those patients lacking the signature according to ACR50, ACR70, CDAI, and DAS28-CRP with significant odds ratios of 3.4­8.8 for targeted therapy-naïve patients and 3.3­26.6 for TNFi-exposed patients. This MSRC provides a solution to the long-standing need for precision medicine tools to predict drug response in rheumatoid arthritis­a heterogeneous and progressive disease with an abundance of therapeutic options. These data validate the performance of the MSRC in a blinded prospective clinical study of targeted therapy-naïve and TNFi therapy-exposed patients.