Adipokines as Biomarkers of Cachexia and High-Risk Rheumatoid Arthritis

类风湿关节炎(RA)是一种与关节炎相关的慢性全身性自身免疫性疾病。 残疾。这种疾病还与更大的过早死亡风险有关。活动RA还与 更多地使用能量，这会导致不健康的体重减轻和肌肉损失，并可能导致 有很大的残疾和死亡风险。这项研究的重点是可以在血液中测量的标志物 可能会更清楚地确定这些过程，并确定哪些人面临这些不利后果的最大风险。 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素。例如, 脂联素，恰如其分地被称为“饥饿信号”，被认为可以提高食欲，改变能量消耗。 在经济不景气的时候保持充足的能源供应。因此，高脂联素水平很可能是 在因疾病导致能量供应不足的患者中观察到。高水平的 脂联素可能有助于识别高危个体。高水平的脂联素与 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，以及 与肌肉萎缩的证据相关联。虽然类似的研究还没有在RA中进行，但高脂联素 水平与其他不良后果相关，包括关节损害进展。当观察到 RA导致了脂联素可能在疾病中发挥因果作用的猜测，我们转而假设 高血清脂联素水平实际上是类风湿性关节炎能量利用率低的标志，因此预测 不利的结果。我们先前证明，类风湿性关节炎患者的体重减轻与罹患 死亡。能够识别高危个体的可获得的措施将改进对高危个体的识别 疾病有助于集中治疗。这是退伍军人管理局的精准医学问题，因为RA的治疗方法是 价格昂贵，而且可能被过度利用。这项研究的结果将影响研究人员如何看待脂肪因子和 它们在疾病过程中的作用。AIM 1将利用VA类风湿性关节炎(VARA)注册和国家 数据库(NDB)。每一个都包括一个广泛的DNA和血清库，用于RA和LINKS患者 到可靠和广泛的临床数据。AIM 2利用一项里程碑式的临床试验来评估预测 两种常见治疗策略的结果。目标3是机械的，是贝克博士现有退伍军人管理局的辅助- 资助对肌肉和脂肪质量进行全面纵向评估的队列。贝克博士的队友将是 通过与两名RA调查人员合作，编制了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与 以及疾病、体重、肥胖、肌肉萎缩、残疾和过早死亡的风险。目标1将决定是否 循环中的脂联素和脂联素基因的变异与持续缓解有关， 进行性残疾、骨质疏松性骨折和死亡率。我们假设循环中较高的脂联素 (但不是基因变异)将与更大的长期风险相关--这种影响部分地被 体重减轻和低BMI的调整。Aim 2将评估脂联素作为预后和预测性指标 获得RA低疾病活动性和放射学进展的生物标记物：比较 治疗临床试验。我们假设高脂联素与难治性疾病和更大的 对生物治疗臂有好处。目标3更机械化，将决定肌肉损失的进展 在纵向队列中，脂肪分布的改变与脂联素的升高和增加有关。我们 假设在肌肉质量丧失的个体中将观察到脂联素的更大增加。 这些独立的目标将提供信息，以指导解释脂肪细胞因子在慢性 并将导致可自动纳入临床护理的风险计算器。 可获得的临床生物标记物将把昂贵的治疗集中在具有最大长期风险的个人身上 并确定可能从针对其个人风险的干预措施中受益的个人。

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.