Dynamics of Therapeutic Response Within the TREAT Trial

描述（申请人提供）：虽然不常说，但必须承认：目前治疗多关节幼年特发性关节炎（JIA）的方法只不过是一种“追逐失败”的练习。“也就是说，只有在儿童对初始治疗没有反应后才添加药物或调整剂量。结果，当然，是几个星期或几个月的不必要的痛苦和功能的限制，为受影响的儿童。我们在儿科风湿病学中迫切需要的是一种在治疗开始时确定哪些儿童将对相对保守的治疗（例如，甲氨蝶呤加非甾体抗炎药），以及哪些儿童对甲氨蝶呤加生物疗法反应更好。我们的实验室已经证明了开发基于基因阵列的生物标志物的可行性，这些生物标志物将模拟和预测多关节JIA治疗的反应。然而，我们一直受到经验性质的治疗，因为它是在典型的临床设置。在幼年特发性关节炎的早期侵袭性治疗（TREAT）试验中（R 01 AR 04962，Carol Wallace，M.D.，对于那些阻碍我们领域的临床和科学进步的治疗和治疗反应的棘手问题，我们有一个千载难逢的机会来解决。该试验将在新诊断为多关节型JIA的儿童中匹配两个治疗组，甲氨蝶呤与甲氨蝶呤+依那西普（一种基因工程TNF α抑制剂）。此外，NIH要求TREAT研究者采集全血样本（PAXgene）用于辅助转化研究。我们将使用这些样本：（1）在开发治疗反应的基于阵列的预后生物标志物方面迈出第一步，以及（2）对反应/无反应的分子动力学进行建模。在实现这些目标的过程中，我们还希望对疾病的发病机制有新的认识，产生可测试的模型，这些模型避开了理解这种疾病的简化方法。在本申请中，我们讨论了全血RNA分析的局限性和进一步研究的必要性。然而，TREAT研究和此处提出的转化研究都将提供一个急需的平台，从该平台将儿科风湿病学牢固地置于后基因组时代，并开始实现个体化治疗的承诺。

DESCRIPTION (provided by applicant): It's not often said but it must be admitted: current therapy for polyarticular juvenile idiopathic arthritis (JIA) is little more than an exercise in "chasing failure." That is, medications are added or doses adjusted only after a child has failed to respond to the initial therapy. The result, of course, is weeks or months of unnecessary pain and limitation of function for the affected children. What we urgently need in pediatric rheumatology is a method to determine at the outset of treatment which children will respond to relatively conservative therapies (e.g., methotrexate plus non-steroidal anti-inflammatory drugs), and which children will respond better to methotrexate plus biological therapies. Our laboratory has shown the feasibility of developing gene-array based biomarkers that will both model and predict responses to therapy in polyarticular JIA. However, we have been hampered by the empiric nature of therapy as it is given in the typical clinical setting. In the Trial of Early Aggressive Therapy (TREAT) for Juvenile Idiopathic Arthritis (R01 AR04962, Carol Wallace, M.D., P.I), we have a once-in-a-generation opportunity to address vexing questions about treatment and response to therapy that have hindered both the clinical and scientific progress of our field. The trial will match two treatment arms, methotrexate vs. methotrexate + etanercept (a genetically-engineered inhibitor of TNF alpha), in children newly diagnosed with the polyarticular form of JIA. Furthermore, NIH has required the TREAT study investigators to collect whole blood samples (PAXgene) for adjunct, translational studies. We will use those samples to: (1) take the first steps in developing array-base prognostic biomarkers for treatment response and (2) model the molecular dynamics of response/non-response. In accomplishing these aims, we also expect to shed new light on disease pathogenesis, generating testable models that have eluded reductionist approaches to understanding this disease. In this application, we discuss the limits of whole blood RNA profiling and the need for further studies. However, both the TREAT study and the translational research proposed here will provide a critically-needed platform from which to set pediatric rheumatology firmly in the post-genomic era and begin to realize the promise of individualized therapy.