Advanced therapies in JIA: toward predictive treatment

目前对儿童特发性关节炎(JIA)的治疗方法已导致疾病控制方面的显著改善，甲氨蝶呤(MTX)和抗肿瘤坏死因子(anti-TNF)生物疗法作为高级治疗的基石。目前，70%的患者JIA症状有70%的改善，高达50%的患者在治疗过程中将出现临床不活跃的疾病。这种显著的改善在很大程度上是由于在JIA的早期治疗中经常使用的抗肿瘤坏死因子生物疗法，尽管仅MTX一项最终将使50%以上的JIA患者表现出至少70%的改善。相反，在接受抗肿瘤坏死因子生物制剂治疗的患者中，60%的儿童在治疗期间表现出临床上不活跃的疾病，在停止治疗后的3到12个月内，疾病将出现明显的和临床上重要的恶化。我们目前无法准确预测哪些JIA患者将对MTX表现出良好的临床反应，将表现出对抗肿瘤坏死因子治疗的良好临床反应，或已在抗肿瘤坏死因子治疗中获得临床非活动期疾病，并可以在没有疾病爆发的情况下停止治疗。 这个项目将使用基因表达谱来识别解决上述每个问题的分子标记。主要目标将是开发基因表达生物标记物，以准确识别哪些患者使用MTX或抗肿瘤坏死因子生物制剂的高级治疗将非常成功，哪些患者可以有效地阻止抗肿瘤坏死因子药物。对于每个特定的目的，有两个假设-一个是测试我们之前在治疗初期的多关节JIA患者中发现的外周血单核细胞(PBMC)基因表达特征的预测能力，另一个假设是为了更好地了解MTX和抗肿瘤坏死因子治疗在JIA中的生物效应。我们的具体目标将是：1)确定甲氨蝶呤治疗与JIA患者PBMC基因表达的关系；2)确定抗肿瘤坏死因子治疗与JIA患者PBMC基因表达的关系；3)确定JIA患者停用抗肿瘤坏死因子治疗与PBMC基因表达的关系。如果成功，该项目将提高对甲氨蝶呤和抗肿瘤坏死因子生物制剂在JIA的临床使用的了解，从而允许更安全和更具成本效益地使用这些基石疗法。

Current treatment approaches for children with Juvenile Idiopathic Arthritis (JIA) have resulted in dramatic improvements in disease control with Methotrexate (MTX) and anti-tumor necrosis factor (anti-TNF) biologic therapies as cornerstones of advanced therapy. At the present time, =70% of patients demonstrate 70% improvement in JIA manifestations, and up to 50% of patients will demonstrate clinically inactive disease while on treatment. Much of this profound improvement is due to anti-TNF biologic therapies that are often used early in the treatment of JIA, though MTX alone will eventually result in over 50% of JIA patients demonstrating at least 70% improvement. Conversely, in patients treated with anti-TNF biologies, =60% of children who demonstrate clinically inactive disease while on treatment will demonstrate an obvious and clinically important worsening of disease within 3 to 12 months of treatment withdrawal. We currently are unable to accurately predict which JIA patients will demonstrate an excellent clinical response to MTX, will demonstrate an excellent clinical response to anti-TNF therapy, or have achieved clinically inactive disease on anti-TNF therapy and can discontinue treatment without having disease flare. This project will use gene expression profiling to identify molecular markers that address each of the issues raised above. The primary goal will be to develop gene expression biomarkers to accurately identify patients in whom advanced therapy with either MTX or anti-TNF biologies will be highly successful, and in whom anti-TNF agents can be effectively stopped. For each specific aim there are two hypotheses - one testing the predictive ability of peripheral blood mononuclear cell (PBMC) gene expression signatures that we have previously identified in treatment-naive polyarticular JIA patients, and the other hypothesis is directed at improved understanding of the biologic effects of MTX and anti-TNF therapies in JIA. Our Specific Aims will be: 1) determine relationship of MTX therapy to PBMC gene expression in JIA, 2) determine relationship of anti-TNF therapy to PBMC gene expression in JIA, and 3) determine relationship of stopping anti-TNF therapy to PBMC gene expression in JIA with S6 months of clinically inactive disease. If successful, this project will improve understanding of the clinical use of MTX and anti-TNF biologies in JIA allowing safer and more cost-effective utilization of these cornerstone therapies.