Abstract
BackgroundMethotrexate (MTX) remains the disease-modifying anti-rheumatic drug of first choice in rheumatoid arthritis (RA) but response varies. Predicting non-response to MTX could enable earlier access to alternative or additional medications and control of disease progression. We aimed to identify baseline predictors of non-response to MTX and combine these into a prediction algorithm.MethodsThis study included patients recruited to the Rheumatoid Arthritis Medication Study (RAMS), a UK multi-centre prospective observational study of patients with RA or undifferentiated polyarthritis, commencing MTX for the first time. Non-response to MTX at 6 months was defined as “no response” using the European League Against Rheumatism (EULAR) response criteria, discontinuation of MTX due to inefficacy or starting biologic therapy. The association of baseline demographic, clinical and psychosocial predictors with non-response was assessed using logistic regression. Predictive performance was assessed using the area under the receiver operating characteristic curve (AUC) and calibration plots.ResultsOf 1050 patients, 449 (43%) were classified as non-responders. Independent multivariable predictors of MTX non-response (OR (95% CI)) were rheumatoid factor (RF) negativity (0.62 (0.45, 0.86) for RF positivity versus negativity), higher Health Assessment Questionnaire score (1.64 (1.25, 2.15)), higher tender joint count (1.06 (1.02, 1.10)), lower Disease Activity score in 28 joints (0.29 (0.23, 0.39)) and higher Hospital Anxiety and Depression Scale anxiety score (1.07 (1.03, 1.12)). The optimism-corrected AUC was 0.74.ConclusionsThis is the first model for MTX non-response to be developed in a large contemporary study of patients commencing MTX in which demographic, clinical and psychosocial predictors were considered. Patient anxiety was a predictor of non-response and could be addressed at treatment commencement.
Highlights
Methotrexate (MTX) remains the disease-modifying anti-rheumatic drug of first choice in rheumatoid arthritis (RA) but response varies
In order to be classified as a responder to MTX by achieving a moderate or good European League Against Rheumatism (EULAR) response, it is necessary for a patient’s Disease Activity Score in 28 joints (DAS28) score to fall by at least 0.6
On average the model would need to be applied to 17 patients to identify one individual at high risk of non-response (“number needed to test”). In this large observational study investigating response to MTX among patients with RA in the current era, 43% of patients were classified as non-responders by 6 months after starting treatment, with those discontinuing MTX due to adverse events excluded from the analysis
Summary
Methotrexate (MTX) remains the disease-modifying anti-rheumatic drug of first choice in rheumatoid arthritis (RA) but response varies. Methotrexate (MTX) is the conventional synthetic disease-modifying antirheumatic drug (csDMARD) of first choice, either as monotherapy or combination therapy, for most patients with rheumatoid arthritis (RA) [1]. This is emphasised in a number of international and national guidelines [2,3,4,5]. Patient-related factors such as female gender and current smoking are associated with MTX non-response [6, 7] Disease related factors such as disease duration, disease activity, rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) status are moderately predictive of inefficacy [6, 7]. Genetic or other biological factors may influence drug response [6, 7]
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