Does Aggressive Treatment in Early RA Reduce Biomarkers of Cardiovascular Risk?

描述（由申请人提供）：类风湿性关节炎（RA）是一种全身性自身免疫性疾病，与心血管（CV）发病率和死亡率显著增加相关。活动性RA的全身炎症与RA患者的心血管死亡和亚临床动脉粥样硬化密切相关。传统的心血管风险因素有助于RA的心血管风险，但这些风险因素本身并不足以解释与RA相关的心血管风险的大小。新的危险因素，如高密度脂蛋白（HDL）的质量和数量的变化可能是必要的，以更充分地解释RA的CV风险。 大量证据表明，功能失调的HDL可能在动脉粥样硬化的发展中起作用。在一般人群中，异常促炎性HDL（piHDL）的存在与冠心病（CHD）相关，在RA患者中更为普遍。我们在一个横断面RA队列中的初步数据表明，HDL功能与RA疾病活动和全身炎症显著相关。较高的疾病活动度、ESR和C反应蛋白与HDL功能较差相关。需要进行大型、设计良好的前瞻性临床研究，以进一步评估疾病活动以及疾病治疗对RA患者HDL功能和其他CV风险生物标志物的影响。 我们建议：1）在755例早期RA患者队列中，在两年治疗期间评估疾病活动对CV风险的传统和新型生物标志物的影响，2）评估甲氨蝶呤单药治疗与甲氨蝶呤联合治疗对CV风险的传统和新型生物标志物的影响。 我们推测，活动性RA引起的全身炎症改变了HDL的数量和蛋白质结构/功能，损害了其防止LDL氧化的能力，从而促进了动脉粥样硬化的发展。我们还假设疾病活动性的改善改善了传统和新型CV风险生物标志物，甲氨蝶呤联合治疗可能通过更有效地控制疾病活动性而更有效地改善CV生物标志物。 拟议工作的意义在于其可能最终确定RA疾病活动，治疗和疾病改善对来自大型，755例早期RA患者队列，既往接受过最小程度的疾病缓解抗风湿药物（DMARD）这些患者随机接受甲氨蝶呤单药治疗或甲氨蝶呤与依那西普或羟氯喹/柳氮磺胺吡啶联合治疗，并随访两年。长期降低CV风险生物标志物并积极控制疾病活动将为早期RA的积极治疗提供进一步的依据。然而，目前可用的DMARDS无法改善新型和/或传统CV风险标志物，这将为RA患者增加CV治疗（如他汀类药物和目前正在开发的其他新型CV风险降低药物）的早期治疗提供依据。 公共卫生相关性：类风湿性关节炎（RA）患者比一般人群早3-18年死亡，心血管（CV）疾病是主要死亡原因。本研究将评估使用当前治疗控制侵袭性关节炎是否可以改善随访两年的早期RA患者的CV风险的新型和传统生物标志物。CV风险标志物的改善和疾病控制将为早期RA患者的积极治疗提供进一步的依据，而CV标志物缺乏改善表明需要早期使用CV保护性治疗，如他汀类药物（降胆固醇药物）和/或目前正在开发的其他新型CV风险降低药物。

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is a systemic autoimmune disease associated with significantly increased cardiovascular (CV) morbidity and mortality. Systemic inflammation from active RA has been strongly linked to cardiovascular death and subclinical atherosclerosis in RA patients. Traditional CV risk factors contribute to CV risk in RA, but these risk factors alone are not sufficient to explain the magnitude of CV risk associated with RA. Changes in novel risk factors such as the quality as well as quantity of high density lipoprotein (HDL) may be necessary to more fully explain CV risk in RA. Substantial evidence has accumulated that dysfunctional HDL may play a role in the development of atherosclerosis. The presence of abnormal, pro-inflammatory HDL (piHDL) is associated with coronary heart disease (CHD) in the general population and is more prevalent in patients with RA. Our preliminary data in a cross-sectional RA cohort suggests a significant correlation of HDL function with RA disease activity and systemic inflammation. Higher disease activity, ESR, and C-reactive protein were associated with worse HDL function. Large, well designed prospective clinical studies are needed to further evaluate the effects of disease activity as well as disease treatments on HDL function and other biomarkers of CV risk in patients with RA. We propose: 1)To evaluate the effects of disease activity on traditional and novel biomarkers of CV risk in a 755 patient early RA cohort during two years of treatment, 2)To evaluate the effects of methotrexate monotherapy versus methotrexate combination therapies on traditional and novel biomarkers of CV risk. We hypothesize that systemic inflammation from active RA alters both the quantity and protein structure/function of HDL, impairing its capacity to prevent oxidation of LDL, thus enhancing the development of atherosclerosis. We also hypothesize that improvement in disease activity improves both traditional and novel biomarkers of CV risk, and that methotrexate combination therapy may be more effective at improving CV biomarkers by more effectively controlling disease activity. The significance of the proposed work lies in its potential to conclusively define the effects of RA disease activity, treatment, and disease improvement on both traditional and novel biomarkers of atherosclerotic risk in specimens from a large, 755 patient early RA cohort with minimal prior disease modifying anti-rheumatic drug (DMARD) therapy who were randomized to methotrexate monotherapy or methotrexate combination therapy with etanercept or hydroxychloroquine/sulfasalazine and followed for two years. Long term reduction of CV risk biomarkers with aggressive control of disease activity would provide further rationale for aggressive treatment of early RA. However, the inability to improve novel and/or traditional CV risk markers with currently available DMARDS would provide rationale for the addition of early treatment of RA patients with CV therapies such as statins and other novel CV risk reduction drugs currently in development. PUBLIC HEALTH RELEVANCE: Patients with rheumatoid arthritis (RA) die 3-18 years earlier then members of the general population and cardiovascular (CV) disease is the leading cause of death. This study will evaluate if aggressive arthritis control with current treatments can improve novel and traditional biomarkers of CV risk in early RA patients followed for two years. Improvement in CV risk markers with disease control would provide further rationale for aggressive treatment of early RA patients, while lack of improvement in CV markers would suggest the need for early treatment with CV protective therapies such as statins (cholesterol-lowering medications) and/or other novel CV risk reduction drugs currently in development.