Early Aggressive Therapy in Juvenile Idiopathic Arthritis

背景：幼年特发性关节炎（JIA）是最常见的儿童风湿病。40%的JIA患儿患有多发性关节炎（poly-JIA），伴有以滑膜炎、关节损伤、身体功能下降和生活质量进行性下降为特征的持续活动性疾病。最近对成人类风湿性关节炎的研究表明，在疾病过程的早期存在一个“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改变。该临床试验旨在确定在poly-JIA发病6个月内开始积极治疗是否能够在发病6个月内诱导非活动性疾病状态（ID）和随后的临床药物缓解（CRM）。方法：本建议是一项随机、多中心、前瞻性临床试验，持续时间长达1年。长达6个月的安慰剂对照双盲期是该试验的关键部分。86名2-17岁近期发病的多发性jia患儿将被随机分配到2个积极治疗方案中的一个：A组=甲氨蝶呤（MTX； 0.5 mg/kg/周；最大40 mg/周SQ） +虚拟依那西普SQ每周+虚拟每日口服强的松；B组= MTX（与A组相同）+依那西普（0.8 mg/kg/周，最大50 mg/周）+强的松（0.5 mg/kg/d，最大剂量为60 mg/d， 17周后逐渐减少到零）。在6个月的访问期间或期间达到ID的受试者将继续额外治疗6个月，以确定是否达到CRM。那些在4个月时未达到ACR儿科70反应或在6个月时未达到ID反应的患者将被给予开放标签治疗组b。初步分析将比较每个治疗组中在6个月时达到ID反应的受试者比例以及治疗组的安全性概况。二次分析将确定实现ID的时间，获得CRM的受试者比例以及CRM对身体功能能力和健康相关生活质量的影响。将在基线和6个月时对30名受试者（A组和B组各15名）的一个膝关节进行IV钆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：如果可以确定一种多jra的治疗策略，增加疾病在病程早期停止的可能性，那么与该疾病相关的许多相关发病率、生活质量下降和医疗保健费用可能可以避免。

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.