Does Sildenafil Improve Endothelial Dysfunction in Rheumatoid Arthritis?

摘要 类风湿性关节炎(RA)与心血管疾病(CVD)的风险增加2倍相关， 不能仅用传统的心血管(CV)风险因素来解释；这种风险可能部分地通过 全身炎症。事实上，类风湿关节炎本身被认为具有相当于糖尿病(DM)的心血管风险。 然而，与DM不同的是，RA缺乏最佳的简历管理策略。尽管有了改进的反 炎症疗法治疗类风湿性关节炎，与普通人群相比，类风湿性关节炎的死亡率差距仍在扩大， 部分原因是RA的初级和次级心血管预防护理不够理想。到目前为止，还没有 发表了RA初级心血管疾病预防的对照干预试验，尽管这显然是迫切的未得到满足的需求。 动脉粥样硬化形成的早期阶段之一是内皮功能障碍，而针对改善动脉粥样硬化的药物 这是预防心血管疾病的很有前途的新策略。内皮功能障碍的基本特征是 一氧化氮(NO)生物利用度受损。西地那非通过增加NO信号改善内皮功能 通过抑制磷酸二酯酶-5(PDE5)。PDE5抑制剂改善肺血管内皮细胞功能 高血压和糖尿病，对有勃起功能障碍和其他心血管疾病的患者安全且耐受性良好。 合并症。此外，PDE抑制剂具有免疫调节特性，可用于治疗 自身免疫性疾病，如类风湿性关节炎。我们的中心假设是西地那非是一种唯一合适的药物。 靶向内皮功能障碍作为一种新的辅助心血管预防策略和免疫调节 RA的特工。具体地说，我们的目标是确定在RA中使用西地那非是否可以改善内皮功能障碍和 动脉粥样硬化生物标志物。 建议的研究是一项II期随机、双盲、安慰剂对照的交叉疗效试验，共60例。 RA患者，无已知的心血管病史，但至少有一个传统的心血管危险因素，基线剂量稳定 RA药物；随机1：1接受西地那非50毫克或安慰剂口服，每天一次，持续3个月， 在交叉阶段之前进行为期2周的洗涤，再持续3个月。经验证的血管研究 评估内皮功能障碍和选定动脉粥样硬化生物标记物的实验室研究将是 在基线、洗涤前和洗涤后3个月以及6个月进行。不良事件将被收集到 评估安全性。我们的具体目标是： 1.确定西地那非在RA中的应用是否导致血管功能参数的改善； 确认其安全配置文件。 2.确定西地那非在RA中的应用是否与动脉粥样硬化生物标志物的改善有关。 这项研究的结果将作为未来评估西地那非作为CV的更大规模试验的初步数据 减少类风湿关节炎患者内皮功能障碍的预防策略。它将提供有关潜在好处的必要数据 在这一高危人群中使用西地那非进行免疫调节和预防心血管疾病。

ABSTRACT Rheumatoid arthritis (RA) is associated with a 2-fold increased risk of cardiovascular disease (CVD), which is not explained by traditional cardiovascular (CV) risk factors alone; this risk is likely mediated in part through systemic inflammation. Indeed, RA itself is deemed to impart a CV risk equivalent to diabetes mellitus (DM). However, unlike in DM, optimal CV management strategies in RA are lacking. Despite improved anti- inflammatory therapies for RA, the mortality gap in RA compared to the general population is still widening, in part due to suboptimal primary and secondary CV preventive care in RA. To date, there have been no published controlled intervention trials for primary CV prevention in RA, despite this clearly urgent unmet need. One of the early stages of atherogenesis is endothelial dysfunction, and drugs that target improvement in this are promising novel strategies for CVD prevention. The fundamental feature of endothelial dysfunction is impaired nitric oxide (NO) bioavailability. Sildenafil improves endothelial function by increasing NO signaling by inhibition of phosphodiesterase-5 (PDE5). PDE5 inhibitors improve endothelial function in pulmonary hypertension and DM, and were safe and well tolerated in patients with erectile dysfunction and other CV comorbidities. Furthermore, PDE inhibitors have immunomodulatory properties that may be utilized to treat autoimmune conditions like RA. Our central hypothesis is that sildenafil is a uniquely suited agent targeting endothelial dysfunction as a novel adjunctive CV prevention strategy and immunomodulatory agent in RA. Specifically, our goal is to determine if sildenafil use in RA improves endothelial dysfunction and atherosclerosis biomarkers. The proposed study is a phase II, randomized double-blind placebo-controlled crossover efficacy trial of 60 RA patients, with no known history of CVD but at least one traditional CV risk factor, on stable baseline doses of RA medications; randomized 1:1 to receive either sildenafil 50 mg or placebo orally once daily for 3 months, with a 2-week washout before the crossover phase for another 3 months. Vascular studies validated in assessing endothelial dysfunction and laboratory studies for selected atherosclerosis biomarkers will be performed at baseline, 3 months pre- and post-washout, and 6 months. Adverse events will be collected to assess safety. Our Specific Aims are: 1. To determine whether sildenafil use in RA leads to improvement in parameters of vascular function; and to confirm its safety profile. 2. To determine whether sildenafil use in RA is associated with improvement in atherosclerosis biomarkers. The results of this study will serve as preliminary data for future larger trials evaluating sildenafil as a CV prevention strategy by reducing endothelial dysfunction in RA. It will provide needed data on potential benefits of sildenafil for immunomodulation and CV prevention in this high-risk population.