Prediction of Methotrexate Intolerance in Juvenile Idiopathic Arthritis: A prospective, observational cohort study

Evert H.P.V. Dijkhuizen, Maja B. Ćalasan, Saskia M.F. Pluijm, Maurits C.F.J.D. Rotte, Sebastiaan J. Vastert, Sylvia Kamphuis, Robert D. Jonge, Nico M. Wulffraat

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37 Citations (Scopus)


Background: Methotrexate (MTX) is an effective and safe drug in the treatment of juvenile idiopathic arthritis (JIA). Despite its safety, MTX-related gastrointestinal adverse effects before and after MTX administration, termed MTX intolerance, occur frequently, leading to non-compliance and potentially premature MTX termination. The aim of this study was to construct a risk model to predict MTX intolerance. Methods: In a prospective JIA cohort, clinical variables and single nucleotide polymorphisms were determined at MTX start. The Methotrexate Intolerance Severity Score was employed to measure MTX intolerance in the first year of treatment. MTX intolerance was most prevalent at 6 or 12months after MTX start, which was defined as the outcome for the prediction model. The model was developed in 152 patients using multivariable logistic regression analysis and subsequently internally validated using bootstrapping. Results: The prediction model included the following predictors: JIA category, antinuclear antibody, parent/patient assessment of pain, Juvenile Arthritis Disease Activity Score-27, thrombocytes, alanine aminotransferase and creatinine. The model classified 77.5% of patients correctly, and 66.7% of patients after internal validation by bootstrapping. The lowest predicted risk of MTX intolerance was 18.9% and the highest predicted risk was 85.9%. The prediction model was transformed into a risk score (range 0-17). At a cut-off of 6, sensitivity was 82.0%, specificity 56.1%, positive predictive value was 58.7% and negative predictive value 80.4%. Conclusions: This clinical prediction model showed moderate predictive power to detect MTX intolerance. To develop into a clinically usable tool, it should be validated in an independent cohort and updated with new predictors. Such an easy-to-use tool could then assist clinicians in identifying patients at risk to develop MTX intolerance, and in turn to monitor them closely and intervene timely in order to prevent the development of MTX intolerance.

Original languageEnglish
Article number5
JournalPediatric Rheumatology
Issue number1
Publication statusPublished - 18 Feb 2015
Externally publishedYes


  • Adverse events
  • Juvenile idiopathic arthritis
  • Methotrexate
  • Methotrexate intolerance
  • Prediction model
  • Predictor


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