Patient outcomes improve when a molecular signature test guides treatment decision-making in rheumatoid arthritis

ABSTRACT Background The molecular signature response classifier (MSRC) predicts tumor necrosis factor-ɑ inhibitor (TNFi) non-response in rheumatoid arthritis. This study evaluates decision-making, validity, and utility of MSRC testing. Methods This comparative cohort study compared an MSRC-tested arm (N = 627) from the Study to Accelerate Information of Molecular Signatures (AIMS) with an external control arm (N = 2721) from US electronic health records. Propensity score matching was applied to balance baseline characteristics. Patients initiated a biologic/targeted synthetic disease-modifying antirheumatic drug, or continued TNFi therapy. Odds ratios (ORs) for six-month response were calculated based on clinical disease activity index (CDAI) scores for low disease activity/remission (CDAI-LDA/REM), remission (CDAI-REM), and minimally important differences (CDAI-MID) . Results In MSRC-tested patients, 59% had a non-response signature and 70% received MSRC-aligned therapy . In TNFi-treated patients, the MSRC had an 88% PPV and 54% sensitivity. MSRC-guided patients were significantly (p < 0.0001) more likely to respond to b/tsDMARDs than those treated according to standard care (CDAI-LDA/REM: 36.0% vs 21.9%, OR 2.01[1.55–2.60]; CDAI-REM: 10.4% vs 3.6%, OR 3.14 [1.94–5.08]; CDAI-MID: 49.5% vs 32.8%, OR 2.01[1.58–2.55]). Conclusion MSRC clinical validity supports high clinical utility: guided treatment selection resulted in significantly superior outcomes relative to standard care; nearly three times more patients reached CDAI remission. Plain Language Summary Clinicians can offer rheumatoid arthritis patients many types of therapies but the response rate for each of these drugs is low. For example, within the first year of treatment, just about one-half of patients respond to the first-line drug, csDMARD. Only one-third of methotrexate-unresponsive patients will respond to the most common second-line agent, a tumor necrosis factor-α inhibitor. These low response rates present a critical challenge to treating patients. Clinicians try different cs- and b/tsDMARD and fail to quickly identify the most effective options. Then, disease will progress, irreversibly destroying patient joints, diminishing patient health-related quality of life, and increasing risks of cardiovascular disease, cancer, and death. To help clinicians quickly identify the best drugs for patients in a treat-to-target approach, a precision-medicine test was developed to identify patients unlikely to respond to tumor necrosis factor-α inhibitors. This molecular signature response classifier considers both molecular features (patient RNA-expression levels) and clinical features (e.g. body mass index, sex) to predict patient response. To evaluate the effectiveness of this test, the outcomes of patients treated with classifier-selected drugs (in a large, tested cohort) were compared with outcomes of patients treated with conventionally selected therapies (in an external cohort of electronic-health-record data). Patients treated with classifier-selected therapies were approximately three times as likely to achieve remission than were patients treated with conventionally selected drugs. These results suggest that this molecular signature response classifier is a valuable tool for more quickly identifying optimal therapies to treat rheumatoid arthritis.