DOES DHEA IMPROVE ENDOTHELIAL DYSFUNCTION IN SLE?

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。系统性红斑狼疮(SLE)患者心脏病发作和中风风险的增加被认为是来自高胆固醇和高血压等传统风险因素，以及SLE中常见的血管疾病。治疗系统性红斑狼疮的心脏病可以改善病情，延长寿命。性激素对狼疮血管壁的影响在狼疮中具有重要意义。在狼疮患者中，雌激素分解是异常的，这表明雌激素等性类固醇的异常可能会增加狼疮发作。众所周知，雌激素可以预防心脏病发作。脱氢表雄酮(DHEA)，一种弱的男性激素，减少狼疮患者对泼尼松的需求，可能是通过减少免疫系统的影响。据报道，DHEA在动物身上可以减少血管中的斑块积聚，使其成为狼疮的一种有吸引力的“附加”疗法。脱氢表雄酮可能会通过雌激素保护血管中的斑块，并通过雄激素削弱免疫系统，从而达到有利的平衡。为了评估脱氢表雄酮对血管壁的影响，我们将测量它在几个方面的影响，这些东西告诉我们患心脏病和中风的风险：血液流经手臂中的一条血管(臂动脉)的超声波图像，以及帮助我们了解一个人患心脏病风险的血液测试。将从风湿病诊所随机挑选20名患有狼疮的成年女性。所有人都将是UMHS风湿科医生或研究员的患者。我们登记的患者仍将有月经期，不会吸烟，不会有糖尿病，并将服用不超过10毫克的泼尼松。我们将详细解释这项研究，并回答有关它的所有问题，然后要求患者阅读并签署同意书，以便他们充分了解参与研究的风险和好处。我们将对研究中患者的任何信息保密，人们的名字不会出现在任何文件上。取而代之的是，患者将被给予一个代码号，这不会向任何查看研究数据的人透露他们是谁。我们认为我们的研究将有大约40%的盎格鲁患者，60%的非裔美国人和亚洲患者。患者将被随机分成两组。一组将接受脱氢表雄酮治疗，另一组将接受为期10周的糖片或安慰剂治疗。然后，两组在服用脱氢表雄酮或糖丸6周后交换治疗。到那时，他们将改用前10周没有服用的平板电脑。我们希望了解DHEA疗法是否不仅可以改善关节疼痛等狼疮症状，还可以帮助预防狼疮患者心脏病发作等事件。有关动脉粥样硬化和狼疮的有趣之处在于性激素对血管内皮细胞的影响。女性狼疮患者雌激素代谢异常，提示性激素异常可能与疾病活动有关。然而，众所周知，雌激素可以上调一氧化氮，作为一种抗动脉粥样硬化、抗增殖和抗血栓因素，对血管内皮细胞起到保护作用。脱氢表雄酮(DHEA)是一种弱雄激素，可能通过免疫抑制作用减少狼疮患者的皮质类固醇需求。DHEA已经在动物研究中被报道可以减少动脉粥样硬化，使其成为狼疮的一种有吸引力的辅助治疗方法。作为狼疮患者性激素水平的调节剂，DHEA可以通过雌激素作用提供动脉粥样硬化保护作用，通过雄激素作用发挥免疫抑制作用，从而达到良好的平衡。为了评估DHEA对内皮功能的影响，我们将测量其对心血管风险的几个标志物的影响：血流介导的臂动脉扩张(FMD)，内皮功能的非侵入性测量，以及心血管疾病的血清生物标志物。符合ACR标准的20名成年女性系统性红斑狼疮患者将从风湿病诊所随机选择。所有患者都将是UMHS教职员工、风湿病专家或研究员。符合条件的患者将是绝经前、非吸烟者、非糖尿病患者，并服用不超过10毫克的泼尼松。将获得书面知情同意，并由研究调查员解释项目。研究记录将是可链接的，但已编码。大约40%的人将是高加索人，60%的人是非洲裔美国人和亚洲人。患者将以双盲方式随机接受脱氢表雄酮或安慰剂治疗10周，然后在6周的洗脱期后交叉进入替代治疗组。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The increased risk of heart attacks and strokes among patients with systemic lupus erythematosus (SLE) was thought to be from "traditional risk factors" such as high cholesterol and high blood pressure, and from blood vessel diseases that are common in SLE. Treating heart disease in SLE could improve illness and increase life span. The effect of sex hormones on the blood vessel wall in important in lupus. Estrogen breakdown is abnormal in women with lupus, suggesting that an abnormality of sex steroids like estrogen may increase lupus flares. Estrogen is known to provide protection against heart attacks. Dehydroepiandrosterone (DHEA), a weak male hormone, decreases prednisone requirements in lupus patients, possibly by decreasing the effects of the immune system. DHEA has been reported in animals to reduce plaque build-up in blood vessels, making it an attractive "add-on" therapy in lupus. DHEA administration may strike a favorable balance by providing protection against plaque build up in blood vessels through estrogen and weaken the immune system through androgen. To evaluate effect of DHEA on blood vessel walls, we will measure its effect on several things that tell us about risk for heart disease and stroke: ultrasound pictures of the blood flowing through one of the blood vessels in the arm (the brachial artery), and blood tests that help us know the risk a person has for heart disease. 20 adult women with lupus will be randomly picked from the rheumatology clinics. All will be patients of UMHS rheumatologists or fellows. Patients whom we enroll will still have menstrual periods, will not smoke, will not have diabetes and will be taking no more than 10mg of prednisone. We will fully explain the study and answer all questions about it, then ask patients to read and sign a consent form so that they fully understand the risks and benefits of being in the study. We will keep any information about patients in the study confidential, and people's names will not be on any documents. Instead, patients will be given a code number, which will not reveal who they are to anyone looking at the study data. We think our study will have around 40% Anglo patients, 60% African-American and Asian patients. Patients will randomly be put into one of two groups. One group will get DHEA and one group will get a sugar tablet or "placebo" for 10 weeks. Then, the two groups will switch treatments after 6 weeks of taking either DHEA or sugar pill. At that time, they will switch to the tablets that they were not taking during the first 10 weeks. We hope to learn if DHEA therapy can not only improves lupus symptoms like joint pain, but can also help prevent events like heart attacks in lupus patients. Of interest in atherosclerosis and lupus is the effect of sex hormones on the vascular endothelium. Estrogen metabolism is abnormal in women with lupus, suggesting that an abnormality of sex steroids may contribute to disease activity. However estrogen is known to upregulate nitric oxide, providing a protective effect on vascular endothelium as an antiatherogenic, antiproliferative and antithrombotic factor. Dehydroepiandrosterone (DHEA), a weak androgen, decreases corticosteroid requirements in lupus patients, possibly through immunosuppressive effects. DHEA has been reported in animal studies to reduce atherosclerosis, making it an attractive adjuvant therapy in lupus. As a proposed modulator of sex hormone levels in lupus patients, DHEA administration may strike a favorable balance by providing protection against atherosclerosis through estrogenic effects and an immunosuppressive role through androgenic effects. To evaluate effect of DHEA on endothelial function, we will measure its effect on several markers of cardiovascular risk: flow-mediated dilatation of the brachial artery (FMD), a noninvasive measure of endothelial function, and serum biomarkers of cardiovascular disease. 20 adult female patients meeting ACR criteria for SLE willbe randomly selected from the rheumatology clinics. All will be patients of UMHS faculty rheumatologists or fellows. Eligible patients will be premenopausal, non-smokers, non-diabetic and on a dose of prednisone no greater than 10mg. Written informed consent will be obtained, and the project explained by a study investigator. Research records will be linkable but coded. Approximately 40% will be Caucasian, 60% African-American and Asian. Patients will be randomized in double-blinded fashion to DHEA or placebo for 10 weeks, then crossed-over to the alternate treatment arm after a six week washout period.