Prediction of primary non-response to methotrexate therapy using demographic, clinical and psychosocial variables: results from the UK Rheumatoid Arthritis Medication Study (RAMS)

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.Electronic supplementary materialThe online version of this article (10.1186/s13075-018-1645-5) contains supplementary material, which is available to authorized users.

Development and validation of a methotrexate adherence assay

“…The single-centre diagnostic accuracy study ( Me asurement of MTX and 7-OH-MTX m etabolites in urine o f patients with rheumatoid arthritis; the MEMO study) included patients who were at least 18 years of age, had a physician diagnosis of RA and were commencing MTX as part of their usual care. Patients were identified from the Rheumatoid Arthritis Medication Study (RAMS) study, a 1-year prospective multicentre observational study in the UK designed to identify predictors of response to MTX in patients with RA 11. Eligible and consenting patients recruited to RAMS between 2014 and 2015 were invited to participate in the MEMO study.…”

Long-term outcomes of patients who rate symptoms of rheumatoid arthritis as ‘satisfactory’

“…This analysis included patients with RA commencing MTX for the first time. Patients were recruited to the Rheumatoid Arthritis Medication Study (RAMS), a prospective observational cohort study recruiting patients from 38 secondary healthcare centres across the UK, commencing in 2008 [ 11 ]. All included patients received a diagnosis of RA or inflammatory arthritis from their rheumatologist and were about to receive their first treatment of MTX at recruitment.…”

Validation of a Prognostic Multivariable Prediction Model for Insufficient Clinical Response to Methotrexate in Early Rheumatoid Arthritis and Its Clinical Application in Evidencio

“…Patients on MTX who do not show improvement at 3 months (insufficient responders) or do not reach the treatment target of low disease activity/remission at 6 months (non-responders) are switched to biologic disease-modifying anti-rheumatoid drug (bDMARD) therapies or novel targeted synthetic DMARD (tsDMARD) therapies, including, e.g., Janus kinase (JAK) inhibitors [1,4,5], with or without concomitant MTX treatment. To ensure that only patients unresponsive to MTX receive early (additional) treatment with b/tsDMARDs and those responsive to MTX are spared costly biologics or synthetic drugs, we and others have constructed models to predict MTX (non)-response [6][7][8][9]. Our prognostic multivariable prediction model for the prediction of insufficient response, defined as: disease activity score 28 (DAS28 [ 3.2) at 3 months of MTX therapy, was constructed in the treatment in the Rotterdam Early Arthritis Cohort (tREACH) and included clinical predictors (DAS28 and Health Assessment Questionnaire [HAQ]), life-style predictors (smoking and BMI) and laboratory parameters involved in MTX metabolism (erythrocyte folate and single-nucleotide polymorphisms: SNPs) [9].…”