Skip to main content
  • Letter to the Editor
  • Open access
  • Published:

Contradictory and weak evidence on the effectiveness of anti-emetics for MTX-intolerance in JIA-patients

Methotrexate (MTX) is an effective, relatively safe, and low-cost treatment for children with JIA, but its use is often limited by the occurrence of so called intolerance in a significant number of patients [1, 2]. Many JIA patients receive anti-emetics as a co-medication to prevent or treat MTX-intolerance. In a recent review in this journal Falvey et al. concluded: “Co-medication with anti-emetics, such as ondansetron, appears to be a highly effective approach” [2]. In our view this firm conclusion was based on weak and indirect evidence. Here, we aim to put into perspective both the timing of the outcome measures and the population size of the studies Falvey referred to.

To underpin their conclusion Falvey et al. referred essentially to two studies (references 27 and 28) [2]. Kempinska et al. performed a Randomized Controlled Trial (RCT) in patients with Crohn’s disease. The outcomes were measured 3 months after the start of MTX. From other studies we know that for most JIA patients MTX-intolerance rarely starts before 4 months [1, 3]. Blanco et al. performed an observational study in 9 adult rheumatoid arthritis (RA) patients. It was a very small study, lacking a control group. The other papers on ondansetron Falvey et al. referred to (their references 18, 24–26) were not relevant for MTX-intolerance, as the authors already stated [2].

Recently two large studies on anti-emetics for MTX-intolerance in pediatric patients have been published, providing some evidence against the conclusion by Falvey et al. [4, 5]. Scheuern et al. described the results of a prospective, observational study in 196 JIA patients. They concluded that “various modalities used as countermeasures against nausea (…) showed no discernible effect” [4]. Dupont-Lucas et al. performed an observational study in 102 pediatric IBD patients. They concluded: “Prophylactic prescription of anti-emetics (…) did not prevent symptoms of MTX intolerance” [5]. Both studies were not randomized, so firm conclusions cannot be drawn from these studies either.

In conclusion: thus far, there is only weak and contradictory evidence on the effectiveness of the (prophylactic) use of anti-emetics for prevention or treatment of MTX-intolerance in JIA. We will need a large, double blind RCT in JIA patients on the prophylactic use of anti-emetics to establish its effectiveness in preventing intolerance. In our view this is a very relevant research question for JIA patients, parents and clinicians.


  1. Bulatović M, Heijstek MW, Verkaaik M, van Dijkhuizen EH, Armbrust W, Hoppenreijs EP, Kamphuis S, Kuis W, Egberts TC, Sinnema G, Rademaker CM, Wulffraat NM. High prevalence of methotrexate intolerance in juvenile idiopathic arthritis: development and validation of a methotrexate intolerance severity score. Arthritis Rheum. 2011;63:2007–13.

    Article  PubMed  Google Scholar 

  2. Falvey S, Shipman L, Ilowite N, Beukelman T. Methotrexate-induced nausea in the treatment of juvenile idiopathic arthritis. Pediatr Rheumatol Online J. 2017;15:52.

    Article  PubMed  PubMed Central  Google Scholar 

  3. van Dijkhuizen EH, Wulffraat NM. Prediction of methotrexate efficacy and adverse events in patients with juvenile idiopathic arthritis: a systematic literature review. Pediatr Rheumatol Online J. 2014;12:51.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Scheuern A, Tyrrell PN, Haas JP, Hügle B. Countermeasures against methotrexate intolerance in juvenile idiopathic arthritis instituted by parents show no effect. Rheumatology. 2017;56(6):901–6.

    PubMed  Google Scholar 

  5. Dupont-Lucas C, Grandjean-Blanchet C, Leduc B, Tripcovici M, Larocque C, Gervais F, Jantchou P, Amre D, Deslandres C. Prevalence and risk factors for symptoms of methotrexate intolerance in pediatric inflammatory bowel disease. Inflamm Bowel Dis. 2017;23:298–303.

    Article  PubMed  Google Scholar 

Download references


Not applicable.


Not applicable.

Availability of data and materials

Not applicable.

Author information

Authors and Affiliations



CS wrote the first draft of the letter. SV and PvD commented; all authors approved of the final version.

Corresponding author

Correspondence to Casper G. Schoemaker.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Schoemaker, C.G., van Dijkhuizen, E.H.P. & Vastert, S.J. Contradictory and weak evidence on the effectiveness of anti-emetics for MTX-intolerance in JIA-patients. Pediatr Rheumatol 16, 13 (2018).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: