Dynamics of Therapeutic Response Within the TREAT Trial

描述(申请人提供)：这不是经常说的，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，只有在儿童对最初的治疗无效后，才会增加药物或调整剂量。当然，其结果是对受影响的儿童来说，几周或几个月的不必要的疼痛和功能限制。我们在儿科风湿病学中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疗法(例如，甲氨蝶呤加非类固醇抗炎药)会有反应，哪些儿童对甲氨蝶呤加生物疗法会有更好的反应。我们的实验室已经证明了开发基于基因阵列的生物标记物的可行性，该生物标记物将对多关节JIA的治疗反应进行建模和预测。然而，我们一直受制于治疗的经验性，因为它是在典型的临床环境中给予的。在青少年特发性关节炎的早期积极疗法(Treat)试验(R01 AR04962，Carol Wallace，M.D.，P.I.)中，我们有一个千载难逢的机会来解决困扰我们领域临床和科学进步的治疗和治疗反应问题。这项试验将匹配两种治疗手段，甲氨蝶呤与甲氨蝶呤+依那西普(一种基因工程的肿瘤坏死因子α抑制剂)，用于新诊断的多关节形式的JIA儿童。此外，美国国立卫生研究院要求治疗研究的研究人员收集全血样本(PAX基因)，用于辅助翻译研究。我们将使用这些样本：(1)为治疗反应开发基于阵列的预后生物标记物的第一步，(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，我们也希望对疾病的发病机制有新的了解，产生可测试的模型，这些模型已经避开了简化论方法来理解这种疾病。在这一应用中，我们讨论了全血RNA图谱的局限性和进一步研究的必要性。然而，这里提出的治疗研究和转化性研究都将提供一个迫切需要的平台，使儿科风湿病学坚定地进入后基因组时代，并开始实现个性化治疗的前景。

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.