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Prediction of clinical non-response to methotrexate treatment in juvenile idiopathic arthritis
  1. Maja Bulatović1,
  2. Marloes W Heijstek1,
  3. E H Pieter Van Dijkhuizen1,
  4. Nico M Wulffraat1,
  5. Saskia M F Pluijm2,
  6. Robert de Jonge3
  1. 1Department of Pediatric Immunology, University Medical Center Utrecht, Wilhelmina Children's Hospital, Utrecht, The Netherlands
  2. 2Department of Public Health, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands
  3. 3Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands
  1. Correspondence to Maja Bulatovic, University Medical Center Utrecht, Wilhelmina Children's Hospital, Department of Pediatric Immunology, 3508AB Utrecht, The Netherlands; m.bulatovic{at}


Objectives Methotrexate (MTX) is a cheap and efficacious drug in juvenile idiopathic arthritis (JIA) treatment. If JIA patients are unresponsive to MTX, early and effective combination treatment with biologicals is required to prevent joint damage. The authors developed a prediction model to identify JIA patients not responding to MTX.

Methods In a cohort of 183 JIA patients, clinical variables and single nucleotide polymorphisms (SNPs) in genes involved in the mechanism of action of MTX were determined at the start of MTX treatment. These variables were used to construct a prediction model for non-response to MTX treatment during the first year of treatment. Non-response to MTX was defined according the American College of Rheumatology paediatric 70 criteria. The prediction model was validated in a cohort of 104 JIA patients.

Results The prediction model included: erythrocyte sedimentation rate and SNPs in genes coding for methionine synthase reductase, multidrug resistance 1 (MDR-1/ABCB1), multidrug resistance protein 1 (MRP-1/ABCC1) and proton-coupled folate transporter (PCFT). The area under the receiver operating characteristics curve (AUC) was 0.72 (95% CI: 0.63 to 0.81). In the validation cohort, the AUC was 0.65 (95% CI: 0.54 to 0.77). The prediction model was transformed into a total risk score (range 0–11). At a cut-off of ≥3, sensitivity was 78%, specificity 49%, positive predictive value was 83% and negative predictive value 41%.

Conclusions The prediction model that we developed and validated combines clinical and genetic variables to identify JIA patients not responding to MTX treatment. This model could assist clinicians in making individualised treatment decisions.

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  • Funding Funding provided by the Dutch Arthritis Association and MEDAC GmbH, Germany.

  • Competing interests None.

  • Ethics approval Approval provided by the Medical Ethics Committee of the University Medical Centre Utrecht (UMCU).

  • Provenance and peer review Not commissioned; externally peer reviewed.

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