Hydroxychloroquine to Improve Insulin Sensitivity in Rheumatoid Arthritis

描述（由申请人提供）：我们有能力更好地控制类风湿性关节炎（RA）的疼痛和残疾，现在专注于减少RA相关合并症的影响。类风湿性关节炎中最常见的死亡原因是心血管（CV）疾病，类风湿性关节炎中心肌梗死和中风的风险约为两倍。类风湿关节炎中CV风险的决定因素包括传统的CV风险因素以及定义类风湿关节炎的炎症过程。ra相关炎症可能通过直接影响内皮细胞和间接影响胰岛素代谢加速动脉粥样硬化。几项研究报告RA患者中胰岛素抵抗的患病率增加。然而，目前尚不清楚RA的炎症是否会导致胰岛素抵抗。皮质类固醇和下丘脑-垂体轴的异常也可能导致糖代谢异常。对于RA患者糖尿病前期胰岛素抵抗状态的指导管理信息很少。羟氯喹（Hydroxychloroquine， HCQ）是RA早期常用的药物，可能在改善胰岛素抵抗中起作用。先前的几项试验证明了HCQ降低糖尿病患者血糖水平的能力，一项大型流行病学研究发现，使用HCQ的RA患者患糖尿病的可能性较小。在动物模型中，抗疟疾药物通过减缓胰岛素代谢来降低血糖。由于心血管疾病是类风湿关节炎的主要合并症，胰岛素抵抗可能是心血管风险的主要决定因素，干预研究需要开始将先前的工作转化为临床治疗。我们提出以下试点试验：目的1：测试HCQ是否能改善非糖尿病类风湿性关节炎患者的胰岛素抵抗。我们将在RA患者中进行双盲随机对照试验，以验证HCQ改善胰岛素敏感性的假设。目的2将使用试验数据来确定RA中胰岛素抵抗的决定因素。我们假设RA与胰岛素抵抗的风险增加有关，RA中胰岛素抵抗增加的独立危险因素包括较高的BMI，急性期反应物升高，脂肪与肌肉的比例增加以及体力活动减少。

DESCRIPTION (provided by applicant): Our ability to better control the pain and disability of rheumatoid arthritis (RA) now focuses attention on reducing the impact of RA-associated comorbidities. The most common cause of death in RA is cardiovascular (CV) disease, and the risk of myocardial infarction and stroke are approximately doubled in RA. The determinants of CV risk in RA include traditional CV risk factors as well as aspects of the inflammatory process defining RA. It is likely that RA-associated inflammation accelerates atherosclerosis through direct effects on the endothelium as well as indirect effects on insulin metabolism. Several studies report an increased prevalence of insulin resistance among persons with RA. However, it is not clear whether the inflammation of RA causes insulin resistance. Corticosteroids and abnormalities in the hypothalamic-pituitary axis may also contribute to abnormal glucose metabolism. Little information is available to guide management of a pre-diabetic insulin resistance state in RA. Hydroxychloroquine (HCQ), a commonly used medicine early in RA, may play a role in improving insulin resistance. Several previous trials demonstrated the ability of HCQ to reduce blood glucose levels in diabetics, and a large epidemiologic study found that subjects with RA using HCQ were less likely to develop diabetes. In animal models, anti-malarials lower blood glucose through slowing insulin metabolism. With CV disease a major comorbidity in RA and insulin resistance possibly a major determinant of CV risk, intervention studies need to begin to translate prior work into clinical therapeutics. We propose the following pilot trial: Aim 1: To test whether HCQ improves insulin resistance in non-diabetic subjects with RA. We will conduct a double-blind randomized controlled trial in subjects with RA to test the hypothesis that HCQ improves insulin sensitivity. Aim 2 will use date from the trial to identify determinants of insulin resistance in RA. We hypothesize that RA will be associated with an increased risk of insulin resistance and that independent risk factors for increased insulin resistance in RA include higher BMI, elevated acute phase reactants, greater fat to muscle ratio, and less physical activity. PUBLIC HEALTH RELEVANCE: If this study demonstrates a beneficial effect of HCQ on insulin resistance among the randomized subjects, this would provide strong evidence that HCQ has benefits beyond RA and SLE disease activity. Currently, HCQ is stopped in many patients as they "step-up" to more aggressive DMARD treatments, or HCQ may never be tried in some patients who present with RA carrying with poor prognosis. If HCQ improves insulin sensitivity, there may be rationale for continuing HCQ chronically in patients with RA. As well, a larger clinical endpoint study would be strongly considered.