Advanced therapies in JIA: toward predictive treatment

JIA 的先进疗法：走向预测性治疗

• 批准号: 8380027
• 负责人: DANIEL Joe LOVELL
• 金额: $ 2.2万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-22 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8380027
• 关键词: Address; Affect; Anti-Tumor Necrosis Factor Therapy; Arthritis; B-Lymphocytes; Biological; Biological Markers; Biological Response Modifier Therapy; Biology; Blood; Blood Cells; Blood specimen; Categories; Child; Childhood; Chronic Childhood Arthritis; Classification; Clinical; Data Set; Disease; Family; Flare; Funding; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Goals; Individual; Knowledge; Measures; Methotrexate; Pathologic Processes; Patients; Pattern; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Physicians; Polyarthritides; Process; Prospective Studies; Research Infrastructure; Research Personnel; Rheumatoid Factor; Sampling; T-Lymphocyte; TNF gene; Technology; Testing; Time; Toxic effect; Tumor Necrosis Factor-alpha; United States National Institutes of Health; Withdrawal; clinical remission; cost effective; disorder control; expectation; experience; improved; molecular marker; monocyte; novel marker; programs; response

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.

目前治疗幼年特发性关节炎（JIA）儿童的方法已导致疾病控制的显着改善，其中甲氨蝶呤（MTX）和抗肿瘤坏死因子（抗TNF）生物疗法作为先进治疗的基石。目前，≥ 70%的患者表现出70%的JIA表现改善，高达50%的患者在治疗期间将表现出临床非活动性疾病。这种深刻的改善大部分是由于抗肿瘤坏死因子生物疗法，通常用于治疗JIA的早期，虽然MTX单独将最终导致超过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将在停药后3 - 12个月内表现出明显且具有临床意义的疾病恶化。我们目前无法准确预测哪些JIA患者将表现出对MTX的良好临床应答，哪些将表现出对抗TNF治疗的良好临床应答，哪些在抗TNF治疗后已达到临床非活动性疾病，哪些可以停止治疗而不会出现疾病发作。 该项目将使用基因表达谱来确定解决上述每个问题的分子标记。主要目标是开发基因表达生物标志物，以准确识别MTX或抗TNF生物制剂的高级治疗将非常成功的患者，以及可以有效停止抗TNF药物的患者。对于每一个特定的目标，有两个假设-一个测试外周血单核细胞（PBMC）的基因表达特征的预测能力，我们已经确定了治疗初治的多关节JIA患者，另一个假设是针对改善的理解甲氨蝶呤和抗肿瘤坏死因子治疗JIA的生物学效应。我们的具体目标是：1）确定MTX治疗与JIA中PBMC基因表达的关系，2）确定抗TNF治疗与JIA中PBMC基因表达的关系，和3）确定停止抗TNF治疗与JIA中PBMC基因表达的关系，其中临床非活动性疾病为S6个月。如果成功，该项目将提高对MTX和抗TNF生物制剂在JIA中的临床应用的理解，从而更安全和更具成本效益地利用这些基础疗法。