Prediction of methotrexate intolerance in juvenile idiopathic arthritis: a prospective, observational cohort study.
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 12 months 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.


BACKGROUND
ISRCTN register, www.isrctn.com, ISRCTN13524271.
Department of Paediatric Immunology, University Medical Centre Utrecht, Wilhelmina Children's Hospital, Utrecht, The Netherlands ; Pediatria II, Reumatologia, IRCCS G. Gaslini, Largo Gaslini 5, 16147 Genova, Italy.
Evert Hendrik Pieter
EH
van Dijkhuizen
Department of Paediatric Immunology, University Medical Centre Utrecht, Wilhelmina Children's Hospital, Utrecht, The Netherlands.
Maja
M
Bulatović Ćalasan
Department of Paediatric Haemato-Oncology, Erasmus University Medical Centre Rotterdam, Sophia Children's Hospital, Rotterdam, The Netherlands.
Saskia M F
SM
Pluijm
Department of Clinical Chemistry, Erasmus University Medical Centre Rotterdam, Rotterdam, The Netherlands.
Maurits C F J
MC
de Rotte
Department of Paediatric Immunology, University Medical Centre Utrecht, Wilhelmina Children's Hospital, Utrecht, The Netherlands.
Sebastiaan J
SJ
Vastert
Department of Paediatric Rheumatology, Erasmus University Medical Centre Rotterdam, Sophia Children's Hospital, Rotterdam, The Netherlands.
Sylvia
S
Kamphuis
Department of Clinical Chemistry, Erasmus University Medical Centre Rotterdam, Rotterdam, The Netherlands.
Robert
R
de Jonge
Department of Paediatric Immunology, University Medical Centre Utrecht, Wilhelmina Children's Hospital, Utrecht, The Netherlands.
Nico M
NM
Wulffraat
D000293:Adolescent; D000410:Alanine Transaminase / Q000097:blood; D000974:Antibodies, Antinuclear / Q000097:blood; D018501:Antirheumatic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001171:Arthritis, Juvenile / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003404:Creatinine / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced* / Q000453:epidemiology*; D006801:Humans; D007223:Infant; D016015:Logistic Models; D008297:Male; D008727:Methotrexate / Q000009:adverse effects* / Q000627:therapeutic use; D015233:Models, Statistical; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011237:Predictive Value of Tests; D011446:Prospective Studies; D012307:Risk Factors; D012680:Sensitivity and Specificity; D016896:Treatment Outcome
D000974:Antibodies, Antinuclear; D018501:Antirheumatic Agents; D003404:Creatinine; D000410:Alanine Transaminase; D008727:Methotrexate
Adverse events; Juvenile idiopathic arthritis; Methotrexate; Methotrexate intolerance; Prediction model; Predictor