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

描述(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，与显著增加的心血管(CV)发病率和死亡率有关。活动期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导致了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。改变新的危险因素，如高密度脂蛋白(高密度脂蛋白)的质量和数量可能是必要的，以更全面地解释类风湿关节炎的心血管风险。大量证据表明，功能失调的高密度脂蛋白可能在动脉粥样硬化的发生发展中起一定作用。在普通人群中，异常的促炎性高密度脂蛋白(PiHDL)的存在与冠心病(CHD)有关，在RA患者中更为常见。我们在横断面RA队列中的初步数据表明，高密度脂蛋白功能与类风湿性关节炎疾病活动性和全身性炎症显著相关。疾病活动性、血沉和C反应蛋白越高，高密度脂蛋白功能越差。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和疾病治疗对类风湿关节炎患者高密度脂蛋白功能和其他心血管风险生物标志物的影响。我们建议：1)评估疾病活动性对755名早期RA患者在两年治疗期间心血管风险的传统和新生物标记物的影响；2)评估甲氨蝶呤单一治疗与甲氨蝶呤联合治疗对传统和新的心血管风险生物标记物的影响。我们假设活动期RA的全身性炎症改变了高密度脂蛋白的数量和蛋白质的结构/功能，削弱了其防止低密度脂蛋白氧化的能力，从而促进了动脉粥样硬化的发展。我们还假设，疾病活动的改善改善了心血管风险的传统和新型生物标记物，并且甲氨蝶呤联合治疗可能通过更有效地控制疾病活动来更有效地改善心血管生物标记物。这项拟议工作的意义在于，它有可能最终确定RA疾病活动、治疗和疾病改善对动脉粥样硬化风险的传统和新生物标记物的影响，这些样本来自755名早期RA患者，他们接受了最小限度的既往疾病修饰抗风湿药物(DMARD)治疗，这些患者被随机分为甲氨蝶呤单一疗法或甲氨蝶呤与依那西普或羟氯喹/柳氮磺吡啶的联合疗法，并进行了两年的跟踪观察。长期减少心血管风险生物标记物，积极控制疾病活动，将为积极治疗早期RA提供进一步的理论基础。然而，目前可用的DMARDS无法改善新的和/或传统的心血管风险标记物，这将为增加使用他汀类药物和目前正在开发的其他新型心血管风险降低药物等心血管疗法对RA患者进行早期治疗提供理由。 公共卫生相关性：类风湿性关节炎(RA)患者比普通人群早3-18年死亡，心血管疾病(CV)是主要的死亡原因。这项研究将评估用目前的治疗方法控制侵袭性关节炎是否可以改善追踪两年的早期RA患者心血管风险的新的和传统的生物标志物。心血管风险标记物在疾病控制方面的改善将为早期RA患者的积极治疗提供进一步的理论依据，而如果心血管标记物缺乏改善，则表明有必要早期使用他汀类药物(降胆固醇药物)和/或其他目前正在开发的新型心血管风险降低药物进行心血管保护治疗。

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.