A precision medicine approach to assess progression from undifferentiated arthritis to rheumatoid arthritis

评估从未分化关节炎到类风湿关节炎进展的精准医学方法

• 批准号: 9806817
• 负责人: Damini Jawaheer
• 金额: $ 23.1万
• 依托单位: CHILDREN'S HOSPITAL & RES CTR AT OAKLAND
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-05 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9806817
• 关键词: Adult; Affect; Arthritis; Bioinformatics; Biological; Biological Markers; Candidate Disease Gene; Cartilage; Chronic; Clinic; Code; Costs and Benefits; Data; Development; Diagnosis; Disease; Disease remission; Early Diagnosis; Early treatment; Epigenetic Process; Expression Profiling; Funding; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Polymorphism; Genomics; Grant; Health Benefit; Inflammatory; Joints; Knowledge; Laboratories; Lead; Methods; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Population; Process; Prospective cohort; Quality of life; Quantitative Trait Loci; RNA; Rheumatoid Arthritis; Risk; Risk Factors; Sampling; Sensitivity and Specificity; Spontaneous Remission; Symptoms; Technology; Therapeutic; Time; Translating; Undifferentiated; Untranslated RNA; Work; arthritis therapy; base; bone; burden of illness; clinical predictors; cohort; cost effective; differential expression; disability; effective therapy; experience; follow-up; genomic biomarker; high risk; improved; improved outcome; insight; joint inflammation; potential biomarker; precision medicine; predictive modeling; prevent; side effect; transcriptome; transcriptome sequencing; treatment effect

PROJECT SUMMARY Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease that affects 1% of the adult world population, including 1.5 million adults in the U.S. There is currently no cure for RA. In addition to joint inflammation, the disease can lead to irreversible erosive damage to cartilage and bone, resulting in significant disability and poor quality of life. Since early treatment of RA is beneficial and results in a less severe disease course, it was hypothesized that very early stages of RA may represent a “therapeutic window of opportunity” during which appropriate treatment may be able to alter the course of the disease, preventing further progression, and possibly could switch off the disease process. It has also been shown that it would be more beneficial to identify RA patients closer to the onset of symptoms for early therapy, i.e. when symptoms have been present for less than 3 months. At that time, patients may not even satisfy the criteria for early RA diagnosis but get a diagnosis of “undifferentiated arthritis” (UA), which is the most common diagnosis when arthritis symptoms first appear and patients cannot be diagnosed with any specific disease. Hence, prediction models are needed that can accurately predict who among all UA patients will (a) be among the 30% who progress to RA, and hence, should be started on early aggressive treatment, and (b) will go into remission or will develop other conditions, and hence, should not unnecessarily be given aggressive RA treatment as these are associated with serious side effects. Currently available prediction models do not accurately predict which UA patients will progress to RA. Since genomic markers associated with early RA have not been thoroughly investigated and are not included among existing prediction models, we propose to first identify biomarkers of progression from UA to RA at the levels of gene expression and genetic polymorphisms (expression quantitative trait loci, eQTLs) in a cohort of early UA patients. The biomarkers identified will be included in a prediction model with high specificity and sensitivity that can be applied to accurately predict progression from UA to RA. The use of such a precision medicine approach for early RA treatment will provide significant health and cost benefits. Second, we also propose to investigate biological changes associated with progression from UA to RA over time to gain a better understanding of potential pathways that may be involved in RA pathogenesis.

项目摘要 风湿性关节炎（RA）是一种慢性全身性炎症性疾病，影响1%的成年世界 美国有150万成年人，目前还没有治愈类风湿关节炎的方法。除了联合 炎症，该疾病可导致对软骨和骨的不可逆的侵蚀性损伤， 残疾和生活质量差。由于早期治疗RA是有益的，并导致较轻的疾病 当然，假设RA的非常早期阶段可能代表“治疗机会窗口” 在此期间，适当的治疗可能能够改变疾病的进程，防止进一步的 疾病的进展，并可能关闭疾病的进程。它还表明，它将是更多的 有利于识别更接近症状发作的RA患者进行早期治疗，即当症状 存在不到3个月。那时，患者甚至可能不符合早期RA的标准 诊断，但得到“未分化关节炎”（UA）的诊断，这是最常见的诊断时， 关节炎症状首先出现，患者不能被诊断为任何特定疾病。因此，预测 需要模型，可以准确地预测所有UA患者中谁将（a）在30%的人中， 进展为RA，因此，应开始早期积极治疗，和（B）将进入缓解或 将发展其他条件，因此，不应该不必要地给予积极的RA治疗，因为这些 会产生严重的副作用目前可用的预测模型不能准确地预测 UA患者将进展为RA。由于与早期类风湿关节炎相关的基因组标志物尚未被彻底 调查，并不包括在现有的预测模型，我们建议首先确定生物标志物的 在基因表达和遗传多态性（表达水平）水平上从UA进展为RA 数量性状基因座，eQTL）。确定的生物标志物将纳入 具有高特异性和灵敏度的预测模型，可用于准确预测 我是RA。使用这种精确的医学方法进行早期RA治疗将提供显著的健康 和成本效益。其次，我们还建议调查与从 随着时间的推移UA到RA，以更好地了解可能参与RA的潜在途径 发病机制