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）是一种慢性全身性自身免疫性疾病， 残疾。这种疾病还与更大的早逝风险有关。活动性RA也与 更多地使用能量，这会导致不健康的体重减轻和肌肉减少，并可能导致 残疾和死亡的巨大风险。这项研究的重点是可以在血液中测量的标志物， 可以更清楚地识别这些过程，并识别这些不良结果的最大风险。 脂肪因子，或脂肪分泌的细胞因子，是体内能量使用的重要调节因子。比如说， 脂联素被恰当地命名为“饥饿信号”，被认为可以促进食欲，改变能量消耗， 以在不景气时期保持足够的能源供应。因此，高脂联素水平可能是 在因疾病而经历低能量可用性的患者中观察到。高水平的 脂联素可能有助于识别高危个体。高脂联素水平与 慢性炎症性疾病如充血性心力衰竭和肾脏疾病的死亡率更高， 与肌肉萎缩有关虽然尚未在RA中进行类似的研究，但高脂联素 水平与包括关节损伤进展在内的其他不良结果相关。虽然观察结果 类风湿性关节炎导致推测脂联素可能在疾病中发挥因果作用，我们相反假设， 高血清脂联素水平实际上是RA患者能量利用率低的标志， 不良后果。我们先前证明，RA患者体重减轻与高风险相关， 死亡能够识别风险个人的可行措施将改善对高风险个人的识别。 疾病，以帮助集中治疗。这是VA中的精确医学问题，因为RA的治疗是 昂贵且可能过度使用。这项研究的结果将影响研究人员如何看待脂肪因子， 在疾病过程中的作用。目标1将利用VA风湿性关节炎（VARA）登记和国家 数据库（NDB）。每一个都包括RA患者中广泛的DNA和血清库， 可靠和广泛的临床数据。Aim 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。目标3是机械的，辅助贝克博士现有的VA- 对肌肉和脂肪质量进行全面纵向评估。贝克博士的队伍 通过与两名RA研究者合作进行增强，编制有史以来最大的纵向RA队列 进行肌肉和脂肪评估总的目标是深入了解脂联素与 以及疾病、体重、肥胖、肌肉损失、残疾和早逝的风险。目标1将决定是否 循环脂联素和脂联素基因的变体与持续缓解相关， 进行性残疾、脊椎骨折和死亡率。我们假设较高的循环脂联素 (but而不是基因变异）将与更大的长期风险相关-这种影响部分减弱， 调整体重减轻和低BMI。目的2将评估脂联素作为预后和预测 RA患者达到低疾病活动度和放射学进展的生物标志物： 治疗临床试验。我们假设高脂联素与难治性疾病相关， 目标3是更机械的，将确定肌肉损失的进展 改变的脂肪分布与纵向队列中较高和增加的脂联素相关。我们 假设在肌肉质量损失的个体中观察到脂联素的更大增加。 这些独立的目的将提供信息，以指导解释脂肪细胞因子在慢性炎症中的作用。 炎症性疾病，并将导致风险计算器，可以自动纳入临床护理。 合理的临床生物标志物将把昂贵的治疗集中在长期风险最大的个体身上 并确定可能从针对其个人风险的干预措施中受益的个人。