Methotrexate withdrawal at 6 vs 12 months in juvenile idiopathic arthritis in remission a randomized clinical trial

Dirk Foell, Nico Wulffraat, Lucy R. Wedderburn, Helmut Wittkowski, Michael Frosch, Joachim Gerß, Valda Stanevicha, Dimitrina Mihaylova, Virginia Ferriani, Florence Kanakoudi Tsakalidou, Ivan Foeldvari, Ruben Cuttica, Benito Gonzalez, Angelo Ravelli, Raju Khubchandani, Sheila Oliveira, Wineke Armbrust, Stella Garay, Jelena Vojinovic, Ximena NorambuenaMaría Luz Gamir, Julia García-Consuegra, Loredana Lepore, Gordana Susic, Fabrizia Corona, Pavla Dolezalova, Angela Pistorio, Alberto Martini, Nicolino Ruperto, Johannes Roth

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Abstract

Context Novel therapies have improved the remission rate in chronic inflammatory disorders including juvenile idiopathic arthritis (JIA). Therefore, strategies of tapering therapy and reliable parameters for detecting subclinical inflammation have now become challenging questions. Objectives To analyze whether longer methotrexate treatment during remission of JIA prevents flares after withdrawal of medication and whether specific biomarkers identify patients at risk for flares. Design, Setting, and Patients Prospective, open, multicenter, medicationwithdrawal randomized clinical trial including 364 patients (median age, 11.0 years) with JIA recruited in 61 centers from 29 countries between February 2005 and June 2006. Patients were included at first confirmation of clinical remission while continuing medication. At the time of therapy withdrawal, levels of the phagocyte activation marker myeloidrelated proteins 8 and 14 heterocomplex (MRP8/14) were determined. Intervention Patients were randomly assigned to continue with methotrexate therapy for either 6 months (group 1 [n=183]) or 12 months (group 2 [n=181]) after induction of disease remission. Main Outcome Measures Primary outcome was relapse rate in the 2 treatment groups; secondary outcome was time to relapse. In a prespecified cohort analysis, the prognostic accuracy of MRP8/14 concentrations for the risk of flares was assessed. Results Intention-to-treat analysis of the primary outcome revealed relapse within 24 months after the inclusion into the study in 98 of 183 patients (relapse rate, 56.7%) in group 1 and 94 of 181 (55.6%) in group 2. The odds ratio for group 1 vs group 2 was 1.02 (95% CI, 0.82-1.27; P=.86). The median relapse-free interval after inclusion was 21.0 months in group 1 and 23.0 months in group 2. The hazard ratio for group 1 vs group 2 was 1.07 (95% CI, 0.82-1.41; P=.61). Median follow-up duration after inclusion was 34.2 and 34.3 months in groups 1 and 2, respectively. Levels of MRP8/14 during remission were significantly higher in patients who subsequently developed flares (median, 715 [IQR, 320-1110] ng/mL) compared with patients maintaining stable remission (400 [IQR, 220-800] ng/mL; P=.003). Low MRP8/14 levels indicated a low risk of flares within the next 3 months following the biomarker test (area under the receiver operating characteristic curve, 0.76; 95% CI, 0.62-0.90). Conclusions In patients with JIA in remission, a 12-month vs 6-month withdrawal of methotrexate did not reduce the relapse rate. Higher MRP8/14 concentrations were associated with risk of relapse after discontinuing methotrexate. Trial Registration isrctn.org Identifier: ISRCTN18186313.

Original languageEnglish
Pages (from-to)1266-1273
Number of pages8
JournalJournal of the American Medical Association
Volume303
Issue number13
DOIs
Publication statusPublished - Apr 7 2010

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ASJC Scopus subject areas

  • Medicine(all)

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Foell, D., Wulffraat, N., Wedderburn, L. R., Wittkowski, H., Frosch, M., Gerß, J., Stanevicha, V., Mihaylova, D., Ferriani, V., Tsakalidou, F. K., Foeldvari, I., Cuttica, R., Gonzalez, B., Ravelli, A., Khubchandani, R., Oliveira, S., Armbrust, W., Garay, S., Vojinovic, J., ... Roth, J. (2010). Methotrexate withdrawal at 6 vs 12 months in juvenile idiopathic arthritis in remission a randomized clinical trial. Journal of the American Medical Association, 303(13), 1266-1273. https://doi.org/10.1001/jama.2010.375