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.

项目概要 类风湿性关节炎 (RA) 是一种慢性全身炎症性疾病，影响着 1% 的成年人 人口，包括美国 150 万成年人。目前 RA 尚无治愈方法。除了联合 炎症，该疾病可导致软骨和骨骼不可逆的侵蚀性损伤，从而导致严重的 残疾和生活质量差。由于 RA 的早期治疗是有益的并且可以减轻疾病的严重程度 当然，有人假设 RA 的早期阶段可能代表着“治疗机会之窗” 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 进展，并可能终止疾病进程。也已表明，这将更加 有助于识别接近症状出现的 RA 患者以进行早期治疗，即当症状出现时 存在时间少于 3 个月。到时候，患者可能连早期RA的标准都不满足 诊断，但被诊断为“未分化关节炎”（UA），这是最常见的诊断 关节炎症状首先出现，并且患者无法诊断出患有任何特定疾病。因此，预测 需要能够准确预测所有 UA 患者中谁将 (a) 属于 30% 的模型 进展为 RA，因此应开始早期积极治疗，并且 (b) 将进入缓解期或 会出现其他病症，因此，不必要时不应给予积极的 RA 治疗，因为这些 与严重的副作用有关。目前可用的预测模型无法准确预测哪些 UA 患者将进展为 RA。由于与早期 RA 相关的基因组标记尚未得到彻底研究 进行了调查并且未包含在现有的预测模型中，我们建议首先确定以下生物标志物 在基因表达和遗传多态性水平上从 UA 到 RA 的进展（表达 早期 UA 患者队列中的数量性状位点（eQTL）。确定的生物标志物将包含在 具有高特异性和敏感性的预测模型，可用于准确预测疾病进展 UA 到 RA。使用这种精准医学方法进行早期 RA 治疗将显着改善健康状况 和成本效益。其次，我们还建议研究与疾病进展相关的生物学变化 随着时间的推移，从 UA 到 RA，以更好地了解可能涉及 RA 的潜在途径 发病。