Dynamics of Therapeutic Response Within the TREAT Trial

描述（由申请人提供）：人们不常说，但必须承认：目前对多关节幼年特发性关节炎（JIA）的治疗只不过是一种“追逐失败”的练习。也就是说，只有在孩子对最初的治疗没有反应后，才增加药物或调整剂量。结果，当然，是数周或数月的不必要的痛苦和限制的功能受影响的孩子。在儿童风湿病学中，我们迫切需要的是一种方法，在治疗开始时确定哪些儿童对相对保守的治疗（例如，甲氨蝶呤加非甾体抗炎药）有反应，哪些儿童对甲氨蝶呤加生物治疗有更好的反应。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，这些生物标志物将对多关节性JIA的治疗反应进行建模和预测。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。在青少年特发性关节炎的早期积极治疗（TREAT）试验（R01 AR04962, Carol Wallace， M.D， P.I）中，我们有一个千年一遇的机会来解决有关治疗和治疗反应的令人烦恼的问题，这些问题阻碍了我们领域的临床和科学进步。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研究的研究者收集全血样本（PAXgene）用于辅助的转译研究。我们将使用这些样本：(1)在开发治疗反应的阵列预后生物标志物方面迈出第一步；(2)建立反应/无反应的分子动力学模型。在实现这些目标的过程中，我们也期望对疾病的发病机制有新的认识，产生可测试的模型，这些模型逃避了还原论的方法来理解这种疾病。在这个应用中，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研究和这里提出的转化研究将提供一个迫切需要的平台，使儿童风湿病学坚定地进入后基因组时代，并开始实现个体化治疗的希望。

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.