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）是一种与心血管（CV）发病率和死亡率显著增加相关的系统性自身免疫性疾病。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。传统的心血管危险因素有助于类风湿关节炎患者的心血管危险，但仅凭这些危险因素不足以解释类风湿关节炎患者的心血管危险程度。新的危险因素的变化，如高密度脂蛋白（HDL）的质量和数量，可能是更充分地解释类风湿关节炎心血管风险的必要因素。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，异常的促炎HDL （piHDL）与冠心病（CHD）有关，在RA患者中更为普遍。我们在横断面RA队列中的初步数据表明HDL功能与RA疾病活动性和全身性炎症有显著相关性。较高的疾病活动性、ESR和c反应蛋白与较差的HDL功能相关。需要大规模、设计良好的前瞻性临床研究来进一步评估疾病活动度和疾病治疗对RA患者HDL功能和其他心血管风险生物标志物的影响。我们建议：1)评估疾病活动度对755例早期RA队列患者在两年治疗期间传统和新型CV风险生物标志物的影响；2)评估甲氨蝶呤单药治疗与甲氨蝶呤联合治疗对传统和新型CV风险生物标志物的影响。我们假设活动性RA引起的全身性炎症改变了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度的改善可以改善传统和新型的CV风险生物标志物，并且甲氨蝶呤联合治疗可能通过更有效地控制疾病活动度来更有效地改善CV生物标志物。这项工作的意义在于，它有可能最终确定类风湿关节炎疾病活动、治疗和疾病改善对大型动脉粥样硬化标本中传统和新型生物标志物的影响。755例早期RA患者，既往最少疾病改善抗风湿药物（DMARD）治疗，随机分为甲氨蝶呤单药治疗或甲氨蝶呤联合依那西普或羟氯喹/磺胺嘧啶治疗，随访2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理论依据。然而，目前可用的DMARDS无法改善新型和/或传统的CV风险标志物，这将为类风湿关节炎患者添加CV治疗（如他汀类药物和其他目前正在开发的新型CV风险降低药物）的早期治疗提供理由。

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.