A high-confidence definition of therapeutic response in rheumatoid arthritiss using a Monte Carlo simulation approach

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V. Strand, S. Cohen, L. Zhang, T. Mellors, A. Jones, J. Withers, V. Akmaev

Annals of the Rheumatic Diseases 2021;80:1097-1098.


Background: Therapy choice and therapy change depend on the ability to accurately assess patients’ disease activity. The clinical assessments used to evaluate treatment response in rheumatoid arthritis have inherent variability, normally considered as measurement error, intra-observer variability or within subject variability. Each contribute to variability in deriving response status as defined by composite measures such as the ACR or EULAR criteria, particularly when a one-time observed measurement lies near the boundary defining response or non-response. To select an optimal therapeutic strategy in the burgeoning age of precision medicine in rheumatology, achieve the lowest disease activity and maximize long-term health outcomes for each patient, improved treatment response definitions are needed.

Objectives: Develop a high-confidence definition of treatment response and non-response in rheumatoid arthritis that exceeds the expected variability of subcomponents in the composite response criteria

Methods: A Monte Carlo simulation approach was used to assess ACR50 and EULAR response outcomes in 100 rheumatoid arthritis patients who had been treated for 6 months with a TNF inhibitor therapy. Monte Carlo simulations were run with 2000 iterations implemented with measurement variability derived for each clinical assessment: tender joint count, swollen joint count, Health Assessment Questionnaire disability index (HAQ-DI), patient pain assessment, patient global assessment, physician global assessment, serum C-reactive protein level (CRP) and disease activity score 28-joint count with CRP.1-3 Each iteration of the Monte Carlo simulation generated one outcome with a value of 0 or 1 indicating non-responder or responder, respectively

Results: A fidelity score, calculated separately for ACR50 and EULAR response, was defined as an aggregated score from 2000 iterations reported as a fraction that ranges from 0 to 1. The fidelity score depicted a spectrum of response covering strong non-responders, inconclusive statuses and strong responders. A fidelity score around 0.5 typified a response status with extreme variability and inconclusive clinical response to treatment. High-fidelity scores were defined as >0.7 or <0.3 for responders and non-responders, respectively, meaning that the simulated clinical response status label among all simulations agreed at least 70% of the time. High-confidence true responders were considered as those patients with high-fidelity outcomes in both ACR50 and EULAR outcomes.

Conclusion: A definition of response to treatment should exceed the expected variability of the clinical assessments used in the composite measure of therapeutic response. By defining high-confidence responders and non-responders, the true impact of therapeutic efficacy can be determined, thus forging a path to development of better treatment options and advanced precision medicine tools in rheumatoid arthritis.

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