Assessing methotrexate intolerance and its prevalence in rheumatoid arthritis: Development and validation of the MISA...

Methotrexate (MTX) intolerance refers to unpleasant symptoms that accompany use of MTX. Although a validated questionnaire on MTX intolerance exists for children with juvenile idiopathic arthritis, it is lacking for adult rheumatoid arthritis (RA) patients.

A 10-item questionnaire called Methotrexate Intolerance and Severity assessment in Adults (MISA) was developed to assess MTX intolerance. On receiver operating characteristic analysis, its predictive ability was compared to Methotrexate Intolerance Severity Score (MISS), a validated questionnaire for children. Subsequently, prevalence and associations of intolerance were assessed in 414 RA patients. After 1 year, discontinuation of MTX was compared between patients with and without MTX intolerance.

MISA score had a good predictive ability (area under the curve [AUC] of 0.904), with sensitivity and specificity of 91.4% and 84.3% (cut-off ≥1) to correctly classify MTX intolerance and was better than MISS score (AUC of 0.823). Among 414 RA patients, 159 (38.4%) had MTX intolerance, with common symptoms being nausea, lethargy, irritability and loss of appetite. On multivariable analysis, age (odds ratio 0.972) and body mass index (odds ratio 1.061) were significant predictors of MTX intolerance. At 1 year, a higher proportion of patients with intolerance than without intolerance had discontinued MTX (odds ratio 2.4, P = 0.02). To classify severity of intolerance, another score, MISA-cross-product, was developed and validated, with an AUC of 0.899.

The newly developed MISA questionnaire and score had good predictive ability to diagnose MTX intolerance. Intolerance to MTX was common, being found in one-third of RA patients. Patients with intolerance were twice more likely to discontinue MTX at 1 year.