Hydroxychloroquine to Improve Insulin Sensitivity in Rheumatoid Arthritis

描述(由申请人提供)：我们能够更好地控制类风湿性关节炎(RA)的疼痛和残疾，现在重点关注减少RA相关并发症的影响。类风湿性关节炎最常见的死亡原因是心血管疾病，心梗和中风的风险在类风湿性关节炎中几乎翻了一番。RA心血管风险的决定因素包括传统的心血管风险因素以及定义RA的炎症过程的各个方面。类风湿关节炎相关炎症可能通过直接影响血管内皮细胞和间接影响胰岛素代谢来加速动脉粥样硬化。几项研究报告说，类风湿性关节炎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。皮质类固醇激素和下丘脑-垂体轴的异常也可能导致糖代谢异常。很少有信息可用于指导类风湿关节炎糖尿病前期胰岛素抵抗状态的治疗。羟氯喹(HCQ)是RA早期常用的药物，可能在改善胰岛素抵抗方面发挥作用。之前的几项试验证明了HCQ能够降低糖尿病患者的血糖水平，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性关节炎的主要共病，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。我们建议进行以下先导性试验：目的1：测试氢氯喹酮是否能改善非糖尿病类风湿关节炎患者的胰岛素抵抗。我们将在RA患者中进行一项双盲随机对照试验，以检验HCQ改善胰岛素敏感性的假设。AIM 2将使用试验数据来确定类风湿关节炎患者胰岛素抵抗的决定因素。我们假设类风湿性关节炎与胰岛素抵抗风险增加相关，类风湿性关节炎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、较大的脂肪/肌肉比和较少的体力活动。 公共卫生相关性： 如果这项研究证明了氢氯喹酮对随机受试者中胰岛素抵抗的有益影响，这将提供强有力的证据，证明氢氯喹酮的益处超出了RA和SLE的疾病活动。目前，在许多患者“逐步”接受更积极的DMARD治疗时，HCQ被停止，或者可能永远不会在一些患有RA且预后较差的患者中尝试HCQ。如果HCQ改善了胰岛素敏感性，那么在RA患者中继续使用HCQ可能是有道理的。此外，还将强烈考虑进行更大规模的临床终点研究。

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.