Early Aggressive Therapy in Juvenile Idiopathic Arthritis

描述(申请人提供)：背景：幼年型特发性关节炎(JIA)是儿童最常见的风湿性疾病。40%的JIA儿童患有多发性关节炎(PolyJIA)，这与以滑膜炎、关节损伤、身体功能能力下降和生活质量进行性下降为特征的持续性活动疾病有关。最近对成人类风湿性关节炎的研究表明，在病程的早期就存在一个“机会之窗”，在此期间，积极的治疗方法会导致疾病进展的深刻变化。这项临床试验旨在确定在PolyJIA发病后6个月内开始积极治疗是否能够在开始治疗后6个月内导致非活动期疾病(ID)状态，并随后临床缓解(CRM)。研究方法：本研究是一项随机、多中心、前瞻性临床试验，为期1年。安慰剂对照的双盲期长达6个月，是该试验的关键部分。86名新近发病的2-17岁多发JIA儿童将被随机分成两种积极治疗方案中的一种：A组=甲氨蝶呤(MTX；0.5 mg/kg/wk；最大40 mg/wk sq)+每周模拟依那西普sq+模拟每日口服泼尼松；B组=MTX(与A组相同)+etanercept(0.8 mg/kg/wk sq，最大50 mg/wk)+强的松(0.5 mg/kg/d；最大剂量60 mg/d，17周后逐渐减少到零)。在6个月内或在6个月时达到ID的受试者将继续治疗6个月以确定是否实现了CRM。那些在4个月或6个月后仍未达到ACR儿科70反应或ID的患者将被提供开放标签治疗组B。初步分析将比较每个治疗组中在6个月后达到ID的受试者的比例和治疗组的安全性。二次分析将确定达到ID的时间、达到CRM的受试者比例以及CRM对身体机能能力和健康相关生活质量的影响。在基线和6个月后，对30名受试者的1个膝关节(A、B臂各15个)进行静脉注射Gd的MRI检查，以观察活动性和非活动性疾病的生物学相关性。意义：如果能够确定一种治疗多发性JRA的策略，增加疾病在病程早期平静的可能性，很大程度上可以避免与这种疾病相关的发病率、生活质量下降和医疗费用。

DESCRIPTION (provided by applicant): BACKGROUND: Juvenile Idiopathic Arthritis (JIA) is the most prevalent pediatric rheumatologic illness. Forty percent of children with JIA have polyarthritis (poly-JIA), which is associated with persistently active disease characterized by synovitis, joint damage, decreased physical functional ability, and a progressive decrease in quality of life. Recent studies in adult rheumatoid arthritis suggest there exists a "window of opportunity" very early in the disease course during which aggressive therapeutic approaches result in profound alteration of disease progression. This clinical trial seeks to determine if aggressive treatment initiated within 6 months of the onset of poly-JIA is capable of inducing a state of inactive disease (ID) within 6 months of initiation and later clinical remission on medication (CRM). METHODOLOGY: This proposal is a randomized, multi-center, prospective clinical trial up to 1 year in duration. A placebo-controlled double-blind phase of up to 6 months represents the pivotal portion of the trial. 86 children aged 2-17 years with poly-JIA of recent onset will be randomized to 1 of 2 aggressive treatment regimens: Arm A = Methotrexate (MTX; 0.5 mg/kg/wk; max 40 mg/wk SQ) + dummy etanercept SQ weekly + dummy daily oral prednisone; Arm B = MTX (as in Arm A) + etanercept (0.8 mg/kg/wk SQ, max 50 mg/wk) + prednisone (0.5 mg/kg/d; max dose of 60 mg/d tapered to zero by 17 weeks). Subjects who achieve ID by or at the 6 month visit will continue treatment for an additional 6 months to determine if CRM is achieved. Those patients who do not achieve an ACR Pediatric 70 response by 4 months, or ID by 6 months will be offered open label Treatment Arm B. The primary analyses will compare the proportions of subjects in each treatment arm that achieve ID by 6 months and the safety profiles of the treatment groups. Secondary analyses will determine time to achieve ID, the proportion of subjects that attain CRM and the effect of CRM on physical functional ability and health related quality of life. MRI with IV gadolinium will be performed at baseline and at 6 months on 1 knee of 30 subjects (15 each from Arm A and B) to observe biologic correlates of active and inactive disease. SIGNIFICANCE: If a therapeutic strategy for poly-JRA can be identified that increases the likelihood of disease quiescence early in the disease course, much of the associated morbidity, decreased quality of life, and health care costs associated with this illness likely can be avoided.