Advanced therapies in JIA: toward predictive treatment

目前针对儿童特发性关节炎（JIA）的治疗方法，以甲氨蝶呤（MTX）和抗肿瘤坏死因子（anti-TNF）生物疗法为基础，显著改善了疾病控制。目前，70%的患者JIA表现改善70%，高达50%的患者在治疗期间会出现临床不活跃的疾病。这种显著的改善很大程度上是由于抗肿瘤坏死因子生物疗法，这种疗法通常用于JIA的早期治疗，尽管单独使用甲氨蝶呤最终会导致超过50%的JIA患者表现出至少70%的改善。相反，在接受抗tnf生物制剂治疗的患者中，60%在治疗期间表现出临床非活动性疾病的儿童在停药后3至12个月内表现出明显且临床上重要的疾病恶化。我们目前无法准确预测哪些JIA患者对MTX表现出良好的临床反应，哪些患者对抗tnf治疗表现出良好的临床反应，哪些患者在抗tnf治疗中达到临床无活性，可以停止治疗而不会出现疾病爆发。

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.