Improved Understanding of the Biology and Use of the TNF Inhibition in JIA

提高对 TNF 抑制剂在 JIA 中的生物学和应用的了解

• 批准号: 7475984
• 负责人: DANIEL Joe LOVELL
• 金额: $ 27.06万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7475984
• 关键词: Aftercare; Anti-Tumor Necrosis Factor Therapy; Area; Biological; Biological Assay; Biological Factors; Biological Markers; Biological Response Modifier Therapy; Biology; Blood Cells; Calgranulin A; Candidate Disease Gene; Child; Childhood; Chronic Childhood Arthritis; Clinical; Complex; Data; Data Set; Disease; Enrollment; Flare; Frequencies; Funding; Gene Expression; Gene Expression Profiling; Genes; Genome; Glass; Goals; Inflammation; Leukocyte L1 Antigen Complex; Maintenance; Measures; Messenger RNA; Methodology; Methods; Molecular; Molecular Profiling; Monoclonal Antibodies; Monoclonal Antibody Therapy; Myelogenous; Onset of illness; Outcome; Pathologic; Patients; Polymerase Chain Reaction; Predictive Value; Principal Investigator; Process; Production; Proteins; ROC Curve; Rate; Research Design; Research Personnel; Rheumatology; S100A9 gene; Sensitivity and Specificity; Serum; TNF gene; Testing; Time; Toxic effect; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Withdrawal; adalimumab; cost effective; cytokine; experience; follow-up; human TNF protein; improved; in vivo; infliximab; novel; peripheral blood; programs; response; success

BACKGROUND. Current treatment for children with Polyarticular Juvenile Idiopathic Arthritis (Poly JIA) results in approximately 50% of the patients demonstrating clinically inactive disease (CID) while on treatment. Over 40% of the children with Poly JIA are treated with a TNF antagonist biologic that is often started ¿ 6 months (mos) of disease onset. Over 50% of those demonstrating CID for up to 12 mos will worsen significantly within 3-12 mos after treatment withdrawal. SPECIFIC AIMS. In children with Poly JIA who have demonstrated CID for ¿6 continuous mos on anti-TNF biologic therapy who then discontinue the anti-TNF therapy: Aim 1. Assess the ability of quantitation of the serum level of the protein complex of Myeloid Related Proteins S100A8 and S100A9 (S100A8/S100A9) to effectively and accurately predict who will demonstrate disease flare within 8 mos; Aim 2. Assess the ability of an in vivo cytokine capture assay (IVCCA) that quantitates the in vivo production of TNF in those patients on anti-TNF monoclonal antibody therapy (infliximab or adalimumab) to predict those patients who will demonstrate disease flare within 8 mos; Aim 3. Use whole-genome gene expression profiling to identify genes that are differentially expressed in peripheral blood cells after >6 mos of CID and at time of disease flare to better understand the underlying biology of these clinical states and possibly identify important targets for the maintenance and loss of clinical and biological inactivity. METHODOLOGY. In 5 pediatric rheumatology centers, 120 children with Poly JIA demonstrating CID while on anti-TNF therapy will be enrolled and followed for up to 14 mos. In those demonstrating CID for >6 continuous mos, the anti-TNF therapy will be stopped. The primary outcome variable (POV) is disease flare within the next 8 months using a validated definition of disease flare. The sensitivity, specificity, + and - predictive values, and area under the ROC curve of S100A8/S100A9 and IVCCA assay to predict the POV will be determined. IVCCA results will be compared to real-time PCR for TNF mRNA. Peripheral blood whole genome expression will be determined using Affymetrix chips after ¿6 mos of CID and at disease flare. Gene expression analyses will identify differences between patients in CID that do and do not flare after stopping anti-TNF therapy and also compare CID and disease flare. This study leverages ongoing participation of 3 of the 4 centers in a NIAMS funded project to identify gene expression in all JIA patients. SIGNIFICANCE. If successful, this study will result in a better understanding of the effect of TNF antagonist therapy on the biology of JIA and a safer and more cost effective approach to the use of these profoundly important new therapies.

背景儿童多关节型幼年特发性关节炎（Poly JIA）的治疗现状 导致大约50%的患者在治疗期间表现出临床非活动性疾病（CID）， 治疗超过40%的Poly JIA患儿接受TNF拮抗剂生物制剂治疗， 疾病发作开始时间为6个月（mos）。超过50%的CID持续时间长达12个月， 在停药后3-12个月内显著恶化。 具体目标。在连续<$6个月抗TNF治疗显示CID的Poly JIA儿童中 生物治疗，然后停止抗TNF治疗： 目标1.评估定量测定骨髓相关抗原蛋白复合物血清水平的能力 蛋白质S100 A8和S100 A9（S100 A8/S100 A9），以有效和准确地预测谁将证明 8个月内疾病发作; Aim 2.评估体内细胞因子捕获试验（IVCCA）的能力， 定量体内产生的TNF在这些患者的抗TNF单克隆抗体治疗 （英夫利昔单抗或阿达木单抗）预测将在8个月内表现出疾病发作的患者;目的3。 使用全基因组基因表达谱鉴定外周血中差异表达的基因 在CID>6个月后和疾病发作时检测血细胞，以更好地了解 这些临床状态，并可能确定重要的目标，为维护和损失的临床和 生物活性。 方法论在5个儿童风湿病中心，120例Poly JIA儿童表现为CID， 将入组接受抗TNF治疗的受试者，并随访长达14个月。在显示CID>6的那些中， 如果持续3个月，则将停止抗TNF治疗。主要结局变量（RR）是疾病发作 在接下来的8个月内，使用经过验证的疾病爆发定义。灵敏度、特异性、+和- 预测值，以及S100 A8/S100 A9和IVCCA测定的ROC曲线下面积，以预测S100 A8/S100 A9和IVCCA测定的ROC曲线下面积。 将被确定。将IVCCA结果与TNF mRNA的实时PCR进行比较。外周血 在CID后约6个月和疾病时，将使用Affyssin芯片测定全基因组表达。 照明弹基因表达分析将确定CID患者之间的差异， 在停止抗TNF治疗后，还比较CID和疾病发作。这项研究利用了正在进行的 4个中心中的3个参与NIAMS资助的项目，以确定所有JIA患者的基因表达。 意义如果成功，这项研究将导致更好地了解TNF拮抗剂的作用 治疗JIA的生物学和一个更安全，更具有成本效益的方法来使用这些深刻的 重要的新疗法。