Jeffrey R. Curtis; Vibeke Strand; Steven Golombek; Lixia Zhang; Angus Wong; Mark C. Zielinski; Viatcheslav R. Akmaev; Alif Saleh; Sam Asgarian; and Johanna B. Withers

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.

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