Adipokines as Biomarkers of Cachexia and High-Risk Rheumatoid Arthritis

脂肪因子作为恶病质和高风险类风湿性关节炎的生物标志物

• 批准号: 10291788
• 负责人: JOSHUA F. BAKER
• 金额: --
• 依托单位: PHILADELPHIA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10291788
• 关键词: Affect; Arthritis; Attenuated; Biological; Biological Markers; Biological Response Modifier Therapy; Blood; Body Composition; Body Weight decreased; Body mass index; Cachexia; Catabolic Process; Catabolism; Cessation of life; Chronic; Chronic Disease; Clinical; Clinical Data; Clinical Trials; Collaborations; Congestive Heart Failure; DNA; Data; Data Set; Desire for food; Development; Diagnosis; Diagnostic radiologic examination; Disease; Disease remission; Elderly; Energy Metabolism; Failure; Fatty acid glycerol esters; Fracture; Fright; Funding; Future; Genes; Goals; Hormonal; Individual; Inflammatory; Intervention; Intramuscular; Kidney; Kidney Diseases; Knowledge; Leptin; Longitudinal cohort; Measures; Mediator of activation protein; Metabolic; Metabolic Pathway; Methotrexate; Muscle; Muscular Atrophy; Names; Obesity; Outcome; Pathway interactions; Patient Monitoring; Patients; Pharmaceutical Preparations; Physicians; Play; Principal Investigator; Process; Prognostic Marker; Refractory; Refractory Disease; Registries; Research Personnel; Rheumatism; Rheumatoid Arthritis; Risk; Role; Sampling; Serum; Signal Transduction; Starvation; System; Testing; Therapy Clinical Trials; Thinness; Time; Treatment Failure; Variant; Weight; Work; adipokines; adiponectin; adverse outcome; arm; arthritis registry; chronic inflammatory disease; clinical biomarkers; clinical care; clinical predictors; cohort; common treatment; cytokine; dashboard; data repository; disability; disability risk; disease phenotype; disorder risk; experience; fracture risk; genetic variant; high risk; improved; innovation; insight; interest; joint injury; mortality; mortality risk; muscle form; osteoporosis with pathological fracture; outcome prediction; precision medicine; predict clinical outcome; predictive marker; preservation; prognostic; prognostic tool; repository; rheumatologist; systemic autoimmune disease; systemic inflammatory response; targeted treatment; tool; tool development; treatment strategy

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease associated with arthritis and significant disability. The disease is also associated with a greater risk of early death. Active RA is also associated with greater use of energy, which results in unhealthy weight loss and muscle loss, and likely contributes to the substantial risk of disability and death. This study focuses on markers that can be measured in the blood that may identify these processes more clearly and identify those at greatest risk of these adverse outcomes. Adipokines, or fat-secreted cytokines, are important regulators of energy usage in the body. For example, adiponectin, aptly named the “starvation signal”, is thought to boost appetite and alter energy usage in an effort to maintain adequate energy availability in lean times. Therefore, high adiponectin levels are likely to be observed in patients who have experienced low energy availability as a result of their disease. High levels of adiponectin may help identify individuals at high risk. High adiponectin levels have been associated with greater mortality in chronic inflammatory conditions such as congestive heart failure and renal disease, and correlated with evidence of muscle loss. While similar studies have not been performed in RA, high adiponectin levels are associated with other adverse outcomes including joint damage progression. While observations in RA have led to speculation that adiponectin may play a causal role in the disease, we instead hypothesize that high serum adiponectin levels are in fact a marker of low energy availability in RA and therefore predictive of adverse outcomes. We previously demonstrated that weight loss in RA is associated with a higher risk of death. Accessible measures that are able to identify at-risk individuals would improve identification of high-risk disease to help focus therapy. This is an issue of precision medicine in the VA, since therapies for RA are expensive and likely over-utilized. Results of this study will affect how researchers consider adipokines and their role in the disease process. Aim 1 will leverage the VA Rheumatoid Arthritis (VARA) registry and National Data Bank (NDB). Each include an extensive DNA and serum repository among patients with RA and linkages to reliable and extensive clinical data. Aim 2 leverages a landmark clinical trial to evaluate prediction of outcomes in two common treatment strategies. Aim 3 is mechanistic and ancillary to Dr. Baker's existing VA- funded cohort with comprehensive longitudinal assessments of muscle and fat mass. Dr. Baker's cohort will be augmented through collaboration with two RA investigators to compile the largest-ever longitudinal RA cohort with muscle and fat assessments. The overall goal is to gain insight into the relationship between adiponectin and the disease, weight, obesity, muscle loss, disability and risk of early death. Aim 1 will determine if circulating adiponectin and variants in the adiponectin gene are associated with sustained remission, progressive disability, osteoporotic fractures, and mortality. We hypothesize that higher circulating adiponectin (but not gene variation) will be associated with greater long-term risks- an effect partly attenuated with adjustment for weight loss and low BMI. Aim 2 will evaluate adiponectin as a prognostic and predictive biomarker for attainment of low disease activity and radiographic progression in the RA: Comparison of Therapies Clinical Trial. We hypothesize that high adiponectin is associated with refractory disease and greater benefit for the biologic therapy arm. Aim 3 is more mechanistic and will determine if progression of muscle loss and altered fat distribution is associated with higher and increasing adiponectin in a longitudinal cohort. We hypothesize that greater increases in adiponectin will be observed among individuals with loss of muscle mass. These independent aims will provide information to guide the interpretation of adipocytokines in chronic inflammatory diseases and will lead to risk calculators that can be incorporated automatically into clinical care. Accessible clinical biomarkers would focus expensive treatments towards individuals at greatest long-term risk and identify individuals who are likely to benefit from interventions specific to their individual risks.

类风湿性关节炎（RA）是一种与关节炎相关的慢性全身性自身免疫性疾病， 该疾病还与较高的早期死亡风险相关。 更多地使用能量，导致不健康的体重减轻和肌肉损失，并可能导致 这项研究的重点是可以在血液中测量的标记物。 可以更清楚地识别这些过程，并识别那些面临这些不良结果风险最大的人。 脂肪因子或脂肪分泌细胞因子是体内能量使用的重要调节剂。 脂联素被恰当地称为“饥饿信号”，被认为可以增强食欲并改变能量消耗 因此，脂联素水平可能会很高。 在因疾病而导致能量可用性低的患者中观察到。 脂联素可能有助于识别高风险人群。 充血性心力衰竭和肾脏疾病等慢性炎症性疾病的死亡率更高，以及 虽然在 RA 中尚未进行类似的研究，但高脂联素与肌肉损失的证据相关。 水平与其他不良后果相关，包括关节损伤进展。 RA 导致人们猜测脂联素可能在该疾病中发挥因果作用，但我们反驳这一观点 高血清脂联素水平实际上是 RA 能量利用率低的标志，因此可预测 我们之前证明，RA 患者体重减轻与较高的风险相关。 能够识别高危人群的可行措施将改善对高风险人群的识别。 这是 VA 精准医学的一个问题，因为 RA 的治疗方法是 昂贵且可能被过度利用，这项研究的结果将影响研究人员如何看待脂肪因子和 他们在疾病过程中的作用将利用 VA 类风湿关节炎 (VARA) 登记处和国家机构。 每个数据库 (NDB) 都包含 RA 患者的广泛 DNA 和血清存储库以及相关性。 目标 2 利用具有里程碑意义的临床试验来评估预测。 目标 3 是贝克博士现有 VA- 的机械性和辅助性治疗策略。 贝克博士的队列将获得对肌肉和脂肪量进行全面纵向评估的队列的资助。 通过与两名 RA 研究人员合作，编制了有史以来最大的纵向 RA 队列 肌肉和脂肪评估的总体目标是深入了解脂联素之间的关系。 疾病、体重、肥胖、肌肉损失、残疾和过早死亡的风险将决定是否。 循环脂联素和脂联素基因变异体与持续缓解相关， 我们追求更高的循环脂联素。 （但不是基因变异）将与更大的长期风险相关——这种影响会部分减弱 目标 2 将评估脂联素作为预后和预测因素的调整。 RA 中实现低疾病活动度和放射学进展的生物标志物：比较 治疗临床试验。我们勇敢地承认高脂联素与难治性疾病和更大的疾病有关。 目标 3 的益处更加机械化，将决定肌肉损失是否进展。 脂肪分布的改变与纵向队列中较高且不断增加的脂联素相关。 研究发现，在肌肉质量损失的个体中，脂联素会出现更大的增加。 这些独立的目标将提供信息来指导慢性疾病中脂肪细胞因子的解释。 炎症性疾病，并将导致风险计算器可以自动纳入临床护理。 可获得的临床生物标志物将把昂贵的治疗集中于长期风险最大的个体 并确定可能从针对其个人风险的干预措施中受益的个人。