Methotrexate Withdrawal at 6 vs 12 Months in Juvenile Idiopathic Arthritis in Remission A Randomized Clinical Trial
Methotrexate Withdrawal at 6 vs 12 Months in Juvenile Idiopathic Arthritis in Remission A Randomized Clinical Trial
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DOI：
10.1001/jama.2010.375
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发表时间：
2010-04-07
影响因子：
120.7
通讯作者：
Roth, Johannes
中科院分区：
文献类型：
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作者：
Foell, Dirk;Wulffraat, Nico;Roth, Johannes
研究背景新的治疗方法提高了包括幼年特发性关节炎（JIA）在内的慢性炎症性疾病的缓解率。因此，逐渐减少治疗的策略和检测亚临床炎症的可靠参数现在已经成为具有挑战性的问题。目的分析在JIA缓解期间更长时间的甲氨蝶呤治疗是否可以预防停药后的发作，以及特定的生物标志物是否可以识别处于发作风险的患者。停药随机临床试验，包括2005年2月至2006年6月在29个国家的61个中心招募的364例JIA患者（中位年龄11.0岁）。患者在首次确认临床缓解时入选，同时继续用药。在停止治疗时，测定吞噬细胞活化标志物髓样相关蛋白8和14异源复合物（MRP 8/14）的水平。（第1组[n = 183]）或12个月（第2组[n = 181]）主要结果测量主要结果是2个治疗组的复发率;次要结果是复发时间。在一个预先指定的队列分析中，MRP 8/14浓度的复发风险的预后准确性进行了assessed.Results意向治疗分析的主要结果显示复发后24个月内纳入研究的98 183例（复发率，56.7%）在组1和94 181（55.6%）在组2。第1组与第2组的比值比为1.02（95% CI，0.82-1.27; P= 0.86）。第1组和第2组入选后的中位无复发间期分别为21.0个月和23.0个月。第1组与第2组的风险比为1.07（95% CI，0.82-1.41; P= 0.61）。第1组和第2组入选后的中位随访时间分别为34.2个月和34.3个月。缓解期MRP 8/14水平在随后发生发作的患者中（中位数，715 [IQR，320-1110] ng/mL）显著高于维持稳定缓解的患者（400 [IQR，220-800] ng/mL; P= 0.003）。低MRP 8/14水平表明在生物标志物检测后3个月内复发的风险较低（受试者工作特征曲线下面积，0.76; 95%CI，0.62-0.90）。结论在缓解期JIA患者中，停用甲氨蝶呤12个月与6个月并不能降低复发率。较高的MRP 8/14浓度与停用甲氨蝶呤后复发的风险相关。
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.