Methotrexate Withdrawal at 6 vs 12 Months in Juvenile Idiopathic Arthritis in Remission A Randomized Clinical Trial

被引：210

作者：

Foell, Dirk ^{[1
]}

Wulffraat, Nico ^{[3
]}

Wedderburn, Lucy R. ^{[4
]}

Wittkowski, Helmut ^{[1
]}

Frosch, Michael ^{[1
]}

Gerss, Joachim ^{[5
]}

Stanevicha, Valda ^{[6
]}

Mihaylova, Dimitrina ^{[7
]}

Ferriani, Virginia ^{[8
]}

Tsakalidou, Florence Kanakoudi ^{[9
]}

Foeldvari, Ivan ^{[10
]}

Cuttica, Ruben ^{[11
]}

Gonzalez, Benito ^{[12
]}

Ravelli, Angelo ^{[13
,14
]}

Khubchandani, Raju ^{[15
]}

Oliveira, Sheila ^{[16
]}

Armbrust, Wineke ^{[17
]}

Garay, Stella ^{[18
]}

Vojinovic, Jelena ^{[19
]}

Norambuena, Ximena ^{[20
]}

Gamir, Maria Luz ^{[21
]}

Garcia-Consuegra, Julia ^{[22
]}

Lepore, Loredana ^{[23
]}

Susic, Gordana ^{[24
]}

Corona, Fabrizia ^{[25
]}

Dolezalova, Pavla ^{[26
,27
]}

Pistorio, Angela ^{[28
]}

Martini, Alberto ^{[13
,14
]}

Ruperto, Nicolino ^{[29
]}

Roth, Johannes ^{[2
]}

机构：

[1] Univ Munster, Dept Pediat, D-48149 Munster, Germany

[2] Univ Munster, Inst Immunol, D-48149 Munster, Germany

[3] Wilhelmina Childrens Hosp, Dept Paediat Immunol & Rheumatol, Utrecht, Netherlands

[4] UCL, Inst Child Hlth, Rheumatol Unit, London, England

[5] Univ Munster, Dept Med Informat & Biomath, D-4400 Munster, Germany

[6] Riga Stradins Univ, Riga, Latvia

[7] Univ Childrens Hosp, Sofia, Bulgaria

[8] Univ Sao Paulo, Hosp Clin, Fac Med Ribeirao Preto, Sao Paulo, Brazil

[9] Aristotle Univ Thessaloniki, Ippokrat Gen Hosp, Thessaloniki, Greece

[10] Praxis Kinder & Jugendrheumatol, Hamburg, Germany

[11] Hosp Gen Ninos Pedro de Elizalde, Buenos Aires, DF, Argentina

[12] Hosp Ninos Luis Calvo Mackenna, Santiago, Chile

[13] Univ Genoa, IRCCS G Gaslini, Genoa, Italy

[14] Univ Genoa, Dipartimento Pediat, Genoa, Italy

[15] Jaslok Hosp & Res Ctr, Mumbay, India

[16] Univ Fed Rio de Janeiro, Rio De Janeiro, Brazil

[17] Univ Groningen, Univ Med Ctr Groningen, Beatrix Kinderkliniek, NL-9713 AV Groningen, Netherlands

[18] Hosp Sor Maria Ludov, La Plata, Buenos Aires, Argentina

[19] Univ Clin Ctr, Nish, Serbia

[20] Hosp Dr Exequiel Gonzalez Cortes, Santiago, Chile

[21] Hosp Ramon & Cajal, E-28034 Madrid, Spain

[22] Hosp Univ La Paz, Madrid, Spain

[23] Univ Trieste, Trieste, Italy

[24] Inst Rheumatol Belgrade, Belgrade, Serbia

[25] IRCCS Policlin Mangiagalli Regina Elena, Milan, Italy

[26] First Fac Med, Prague, Czech Republic

[27] Gen Fac Hosp, Prague, Czech Republic

[28] IRCCS G Gaslini, Serv Epidemiol & Biostat, Genoa, Italy

[29] IRCCS G Gaslini, PRINTO, Genoa, Italy

来源：

JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION | 2010年 / 303卷 / 13期

关键词：

RHEUMATOID-ARTHRITIS; SELECT CATEGORIES; DISEASE-ACTIVITY; PROTEINS; 8; CRITERIA; DISCONTINUATION; INFLAMMATION; VALIDATION; CHILDREN; THERAPY;

D O I：

10.1001/jama.2010.375

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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, 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. 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.

引用

页码：1266 / 1273

页数：8

共 32 条

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