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 类风湿关节炎（RA）是一种慢性全身性炎症性疾病，影响成年世界的1％ 人口，包括美国150万成年人，目前无法治愈RA。除了关节 炎症，这种疾病会导致对软骨和骨骼的不可逆侵蚀损害，从而显着 残疾和生活质量差。由于RA的早期治疗是有益的，并且导致严重疾病不那么严重 当然，据推测，RA的早期阶段可能代表了“机会的治疗窗口” 在此期间，适当的治疗可能能够改变疾病的病程，以防进一步 进展，可能会关闭疾病过程。也已经证明它会更多 有益于识别RA患者更接近早期治疗症状的发作 我们出席了不到3个月。当时，患者甚至可能无法满足早期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 关节炎症状首先出现，无法诊断出患有任何特定疾病。因此，预测 需要模型可以准确预测所有UA患者中的谁（a）是30％的人之一 RA的进展，因此应在早期的侵略性治疗中开始，（b）将恢复或 将发展其他条件，因此，不必为此提供积极的RA治疗 与严重的副作用有关。当前可用的预测模型无法准确预测哪个 UA患者将发展为RA。由于与早期RA相关的基因组标记尚未得到彻底 被调查并不包括在现有的预测模型中，我们建议首先识别 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患者队列中的定量性状基因座，eqtls）。确定的生物标志物将包括 具有高特异性和灵敏度的预测模型，可以应用于准确预测从 UA到RA。使用这种精确医学方法来早期RA治疗将提供重要的健康 和成本收益。其次，我们还建议研究与从 随着时间的流逝，UA可以更好地了解RA可能涉及的潜在途径 发病。