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Intolerance in oral versus subcutaneous administration of methotrexate in patients with juvenile idiopathic arthritis: a cross-sectional, observational study


Methotrexate (MTX) is the cornerstone disease-modifying anti-rheumatic drug in juvenile idiopathic arthritis (JIA), because of its efficacy. Moreover, serious adverse events are rare. However, in Dutch patients, MTX intolerance, defined as gastro-intestinal side effects occurring not only after, but also before administration of MTX and when thinking of the drug, occurred frequently. MTX intolerance could lead to non-compliance and hence to decreased efficacy, eventually resulting in the necessity to replace it by more costly biologicals. Furthermore, it was observed significantly more often with subcutaneous (SC) than oral (PO) administration, contrary to widely held views. This finding was unexpected and the question about the choice of route of administration when starting MTX in daily clinical practice is still unsolved.


The aim of this study was to assess the prevalence of MTX intolerance and its association with the route of administration in a German cohort of JIA patients to aid physicians in the choice of route of administration.


A cross-sectional study of JIA patients on MTX was performed. Primary outcome was intolerance to MTX, which was determined using the validated Methotrexate Intolerance Severity Score (MISS) questionnaire. Clinical and laboratory parameters, among which the route of administration, were compared between the intolerant and tolerant groups in univariate and multivariate analysis.


Of 179 JIA patients on MTX, 73 (40.8%) were intolerant. Of the 46 patients who received exclusively MTX subcutaneous, 43.5% were intolerant versus 29.5% of 95 who received exclusively MTX PO (P = 0.100). The former experienced significantly more behavioural complaints (76.1% versus 47.4%, P = 0.001) and showed a trend towards more abdominal pain after MTX intake (43.5% versus 27.4%, P = 0.056). Route of administration was associated with MTX intolerance in multivariate analysis, next to the duration of MTX use and the number of active joints.


The prevalence of MTX intolerance was high. It was higher in patients on MTX SC, but not significantly, and they did experience more adverse effects than those on MTX PO. Therefore, and in the light of other studies in the field demonstrating more adverse effects in patients on MTX SC, PO administration of MTX should be favoured over SC administration when starting MTX.

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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.

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Van Dijkhuizen, P., Pouw, J., Scheuern, A. et al. Intolerance in oral versus subcutaneous administration of methotrexate in patients with juvenile idiopathic arthritis: a cross-sectional, observational study. Pediatr Rheumatol 12 (Suppl 1), P131 (2014).

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