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: 10417098
• 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 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10417098
• 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; 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; Persons; 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; radiological imaging; 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.

类风湿关节炎（RA）是一种与关节炎相关的慢性全身自身免疫性疾病 残疾。该疾病还与早期死亡的更大风险有关。活性RA也与 能源的更多使用，这会导致体重减轻和肌肉损失，并可能有助于 残疾和死亡的重大风险。这项研究的重点是可以在血液中测量的标记 可能会更清楚地确定这些过程，并确定这些过程最大的不良结果风险。 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。例如， 脂联素，恰当地命名为“饥饿信号”，被认为可以增强食欲并改变能源的使用。 在精益时期保持足够的能源可用性。因此，高脂联素水平可能是 在由于疾病导致能量供应率低的患者中观察到。高水平 脂联素可以帮助识别有高风险的个体。高脂联素水平与 在慢性炎症状况中的死亡率更高，例如充血性心力衰竭和肾脏疾病，以及 与肌肉损失的证据相关。虽然在RA中尚未进行类似的研究，但高脂联素 水平与其他不利结果有关，包括关节损伤进展。同时观察 RA导致人们猜测脂联素可能在该疾病中起因果作用，而是假设 高血清脂联素水平实际上是RA中低能量可利用率的标志物，因此可以预测 不利的结果。我们以前证明了RA中的减肥与更高的风险有关 死亡。能够识别高危个人的无障碍措施将改善高风险的识别 疾病以帮助重点疗法。这是VA中精确医学的问题，因为RA的疗法是 昂贵且可能过度利用。这项研究的结果将影响研究人员如何考虑脂肪因子和 它们在疾病过程中的作用。 AIM 1将利用VA类风湿关节炎（VARA）注册表和国家 数据库（NDB）。每种都包括RA和连锁患者的大量DNA和血清存储库 可靠和广泛的临床数据。目标2利用具有里程碑意义的临床试验来评估 两种常见治疗策略的结果。 AIM 3是Baker博士现有VA-的机械和辅助 资助的队列，对肌肉和脂肪质量进行全面的纵向评估。贝克博士的队列将 通过与两名RA调查人员的合作进行增强，以编译有史以来最大的纵向RA队列 进行肌肉和脂肪评估。总体目标是深入了解脂联素之间的关系 以及疾病，体重，肥胖，肌肉丧失，残疾和早期死亡的风险。 AIM 1将确定是否 脂联素基因中循环脂联素和变体与持续缓解相关， 进行性残疾，骨质疏松性骨折和死亡率。我们假设较高的循环脂联素 （但不是基因变异）将与更大的长期风险有关 - 这种影响部分衰减 调整体重减轻和低BMI。 AIM 2将评估脂联素作为预后和预测性 在RA中获得低疾病活性和放射线进展的生物标志物：比较 治疗临床试验。我们假设高脂联素与难治性疾病有关 生物治疗部门的好处。 AIM 3是更机械的，将确定肌肉损失的进展是否 脂肪分布改变与纵向队列中脂联素较高和增加有关。我们 假设在肌肉质量损失的个体中，将观察到脂联素的增加。 这些独立的目标将提供信息，以指导慢性脂肪细胞因子的解释 炎症性疾病将导致可自动纳入临床护理的风险计算器。 可访问的临床生物标志物将把昂贵的治疗集中在最大的长期风险的个人身上 并确定可能受益于特定个人风险的干预措施的个人。