title: Methotrexate withdrawal at 6 vs 12 months in juvenile idiopathic arthritis in remission: a randomized clinical trial.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  Prospective, open, multicenter, medication-withdrawal 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 myeloid-related proteins 8 and 14 heterocomplex (MRP8/14) were determined.
  
  
  METHODS
  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.
  
  
  METHODS
  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, 320-1 110] 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.
  
  
  BACKGROUND
  isrctn.org Identifier: ISRCTN18186313.
authors.affiliation: Department of Pediatrics, University of Muenster, Albert-Schweitzer-Strasse 33, D-48149 Muenster, Germany. dfoell@uni-muenster.de
authors.forename: Dirk
authors.initials: D
authors.lastname: Foell
authors.forename: Nico
authors.initials: N
authors.lastname: Wulffraat
authors.forename: Lucy R
authors.initials: LR
authors.lastname: Wedderburn
authors.forename: Helmut
authors.initials: H
authors.lastname: Wittkowski
authors.forename: Michael
authors.initials: M
authors.lastname: Frosch
authors.forename: Joachim
authors.initials: J
authors.lastname: Gerss
authors.forename: Valda
authors.initials: V
authors.lastname: Stanevicha
authors.forename: Dimitrina
authors.initials: D
authors.lastname: Mihaylova
authors.forename: Virginia
authors.initials: V
authors.lastname: Ferriani
authors.forename: Florence Kanakoudi
authors.initials: FK
authors.lastname: Tsakalidou
authors.forename: Ivan
authors.initials: I
authors.lastname: Foeldvari
authors.forename: Ruben
authors.initials: R
authors.lastname: Cuttica
authors.forename: Benito
authors.initials: B
authors.lastname: Gonzalez
authors.forename: Angelo
authors.initials: A
authors.lastname: Ravelli
authors.forename: Raju
authors.initials: R
authors.lastname: Khubchandani
authors.forename: Sheila
authors.initials: S
authors.lastname: Oliveira
authors.forename: Wineke
authors.initials: W
authors.lastname: Armbrust
authors.forename: Stella
authors.initials: S
authors.lastname: Garay
authors.forename: Jelena
authors.initials: J
authors.lastname: Vojinovic
authors.forename: Ximena
authors.initials: X
authors.lastname: Norambuena
authors.forename: María Luz
authors.initials: ML
authors.lastname: Gamir
authors.forename: Julia
authors.initials: J
authors.lastname: García-Consuegra
authors.forename: Loredana
authors.initials: L
authors.lastname: Lepore
authors.forename: Gordana
authors.initials: G
authors.lastname: Susic
authors.forename: Fabrizia
authors.initials: F
authors.lastname: Corona
authors.forename: Pavla
authors.initials: P
authors.lastname: Dolezalova
authors.forename: Angela
authors.initials: A
authors.lastname: Pistorio
authors.forename: Alberto
authors.initials: A
authors.lastname: Martini
authors.forename: Nicolino
authors.initials: N
authors.lastname: Ruperto
authors.forename: Johannes
authors.initials: J
authors.lastname: Roth
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000097:blood; D000293:Adolescent; D018501:Antirheumatic Agents / Q000008:administration & dosage*; D001171:Arthritis, Juvenile / Q000188:drug therapy*; D040502:Calgranulin B / Q000097:blood; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage*; D011237:Predictive Value of Tests; D011446:Prospective Studies; D012008:Recurrence; D012074:Remission Induction
chemical_list: C435500:ABCC11 protein, human; D018528:ATP-Binding Cassette Transporters; D018501:Antirheumatic Agents; D040502:Calgranulin B; D008727:Methotrexate