Paediatric Rheumatology
Overcoming methotrexate intolerance in a paediatric cohort of patients with rheumatic diseases: successful application of a large interval oral split-dose regimen
S.-J. Bremer1, C. Kleimeyer2, A. Fröhlich3, S. Farmand4, K. Fliegert5, L.S. Hopf6, A.C. Muntau7, I. Müller8, F. Speth9, J. Pagel10
- University Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg; University Children's Research, UCR@Kinder-UKE, University Medical Center Hamburg-Eppendorf, Hamburg; and German Center for Child and Adolescent Health (DZKJ), Hamburg, Germany.
- University Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg; University Children's Research, UCR@Kinder-UKE, University Medical Center Hamburg-Eppendorf, Hamburg; and German Center for Child and Adolescent Health (DZKJ), Hamburg, Germany.
- University Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg; and Division of Paediatric Stem Cell Transplantation and Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- Division of Paediatric Stem Cell Transplantation and Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- University Children's Hospital, University Medical Centre Rostock, Germany.
- University Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg; University Children's Research, UCR@Kinder-UKE, University Medical Center Hamburg-Eppendorf, Hamburg; and German Center for Child and Adolescent Health (DZKJ), Hamburg, Germany.
- University Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg; University Children's Research, UCR@Kinder-UKE, University Medical Center Hamburg-Eppendorf, Hamburg; and German Center for Child and Adolescent Health (DZKJ), Hamburg, Germany.
- German Center for Child and Adolescent Health (DZKJ), Hamburg; and Division of Paediatric Stem Cell Transplantation and Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- University Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg; and Division of Paediatric Stem Cell Transplantation and Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- University Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg; University Children's Research, UCR@Kinder-UKE, University Medical Center Hamburg-Eppendorf, Hamburg; German Center for Child and Adolescent Health (DZKJ), Hamburg; Division of Paediatric Stem Cell Transplantation and Immunology, University Medical Center Hamburg-Eppendorf, Hamburg; and German Center for Infection Research (DZIF), partner site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany. ju.pagel@uke.de
CER19298
Paediatric Rheumatology
PMID: 42207557 [PubMed]
Received: 09/09/2025
Accepted : 10/04/2026
In Press: 22/05/2026
Abstract
OBJECTIVES:
Methotrexate (MTX) is the most commonly used disease-modifying anti-rheumatic drug to treat rheumatic diseases in children. In more than half of the patients, the conventional once-weekly dosage will lead to MTX intolerance. The objective of this study was to investigate whether pre-existing MTX intolerance can be overcome by switching to a large interval oral split-dose (LIOS) MTX regimen.
METHODS:
The clinical data of 26 paediatric patients with rheumatic diseases were analysed retrospectively. All patients included wanted to discontinue their once-weekly MTX therapy due to intolerance that did not improve with standard countermeasures. These patients were switched to the LIOS MTX regimen and received the pre-existing amount of MTX, divided into two equal oral doses three and four days apart. To compare side effects before and after changing the administration regimen, we used the Methotrexate Intolerance Severity Score (MISS), collected data on parental psychological distress, and analysed laboratory parameters.
RESULTS:
All patients were compliant with their MTX treatment for at least eight months after transitioning to the LIOS MTX regimen (median of 22 months). After six months, the average MISS values decreased from 12.3 to 2.8 (p<0.0001), falling below the threshold of 6 points that indicates MTX intolerance. Additionally, parental psychological distress during drug administration improved in 24 out of 26 cases (92%). No significant changes were noted in disease activity or laboratory parameters.
CONCLUSIONS:
Switching patients with MTX intolerance to the LIOS MTX regimen allows for long-term continuation of treatment and maintaining disease remission while significantly reducing side effects.
