Methotrexate withdrawal at 6 vs 12 months in juvenile idiopathic arthritis in remission: a randomized clinical trial.
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.
Foell
Dirk
D
Department of Pediatrics, University of Muenster, Albert-Schweitzer-Strasse 33, D-48149 Muenster, Germany. dfoell@uni-muenster.de
Wulffraat
Nico
N
Wedderburn
Lucy R
LR
Wittkowski
Helmut
H
Frosch
Michael
M
Gerss
Joachim
J
Stanevicha
Valda
V
Mihaylova
Dimitrina
D
Ferriani
Virginia
V
Tsakalidou
Florence Kanakoudi
FK
Foeldvari
Ivan
I
Cuttica
Ruben
R
Gonzalez
Benito
B
Ravelli
Angelo
A
Khubchandani
Raju
R
Oliveira
Sheila
S
Armbrust
Wineke
W
Garay
Stella
S
Vojinovic
Jelena
J
Norambuena
Ximena
X
Gamir
María Luz
ML
García-Consuegra
Julia
J
Lepore
Loredana
L
Susic
Gordana
G
Corona
Fabrizia
F
Dolezalova
Pavla
P
Pistorio
Angela
A
Martini
Alberto
A
Ruperto
Nicolino
N
Roth
Johannes
J
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
C435500:ABCC11 protein, human; D018528:ATP-Binding Cassette Transporters; D018501:Antirheumatic Agents; D040502:Calgranulin B; D008727:Methotrexate