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Extended report
Time spent in inactive disease before MTX withdrawal is relevant with regard to the flare risk in patients with JIA
  1. Jens Klotsche1,2,
  2. Kirsten Minden1,3,
  3. Martina Niewerth1,
  4. Gerd Horneff4,5
  1. 1 Epidemiology Unit, German Rheumatism Research Centre Berlin, A Leibniz Institute, Berlin, Germany
  2. 2 Institute for Social Medicine, Epidemiology and Health Economics, Charité Universitätsmedizin Berlin, Berlin, Germany
  3. 3 Children’s University Hospital, Charité Universitätsmedizin Berlin, Berlin, Germany
  4. 4 Department of Pediatrics, Asklepios Clinic Sankt Augustin, Sankt Augustin, Germany
  5. 5 Department of Pediatric and Adolescents medicine, Medical faculty, University Hospital of Cologne, Cologne, Germany
  1. Correspondence to Dr Jens Klotsche, German Rheumatism Research Centre, a Leibniz Institute, Berlin 10117, Germany; jens.klotsche{at}


Objectives To determine the reasons of methotrexate (MTX) discontinuation, frequency of adverse events (AE) and whether the time in inactive disease before MTX withdrawal disease is associated with the risk of disease flare.

Methods Patients with juvenile idiopathic arthritis (JIA) beginning treatment with MTX were prospectively observed in the national JIA biologic register Biologika in der Kinderrheumatologie/Biologics in Paediatric Rheumatology and its follow-up register Juvenile arthritis Methotrexate/Biologics long-term Observation. Inactive disease was defined by a clinical Juvenile Arthritis Disease Activity Score ≤1, flare after MTX discontinuation by reoccurrence of at least moderate disease activity or restart of treatment with a disease-modifying antirheumatic drug .

Results MTX treatment was initiated in 1514 patients after a mean disease duration of 2.1 years (SD=2.8). 40% of the patients experienced oligoarticular onset of JIA. MTX was discontinued in 982 (64.9%) patients. Ineffectiveness (36.9%) and achieving inactive disease (32.1%) were the most common reasons. Among the latter (n=316), 184 (58.2%) patients experienced a flare on follow-up. The likelihood of a flare was a function of time in inactive disease prior to MTX discontinuation (HR 0.95; 95% CI 0.92 to 0.97). Patients with inactive disease for longer than 12 months had a significantly lower flare rate (58 of 119, 48.7%; HR 0.48; 95% CI 0.34 to 0.69). The most frequently reported AE was MTX intolerance, including nausea, aversion and vomiting, accounting for 441 events (13.0 events/100 exposure years) in 307 (20.3%) patients.

Conclusions Patients who spent at least 12 months in inactive disease before MTX discontinuation had a significantly lower flare rate.

  • juvenile idiopathic arthritis
  • methotrexate
  • inactive disease
  • flare
  • treatment discontinuation
  • safety

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  • Handling editor Tore K Kvien

  • Contributors All the authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All the authors substantially contributed to the study concept and design, analysis and interpretation of data, drafting of the manuscript and critical revision of the manuscript for important intellectual content. KM, MN and GH were responsible for the acquisition of data. Statistical analysis was done by JK. KM and GH obtained the funding for the study and supervised the study. Administrative, technical or material support was done by MN.

  • Funding BiKeR register: Joint unconditional grant from Pfizer, Abbvie, Novartis and Roche; JuMBO register: Joint unconditional grant from Pfizer, Abbvie and Roche; Pfizer, Abbvie, Novartis and Roche had no role in the study design or in the collection, analysis or interpretation of the data, the writing of the manuscript or the decision to submit the manuscript for publication. The JuMBO register was supported by the Pharmachild project, what was funded funded by the European Union (EU) within the FP7 framework.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval BiKeR was approved by the ethics committee of the Medical Council of North-Rhine Westfalia, Duesseldorf, Germany, and all patients provided informed consent. JuMBO was approved by the ethics committee of the Charité University Medicine Berlin. Young adults provided informed consent to participate in JuMBO.

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