Does Sildenafil Improve Endothelial Dysfunction in Rheumatoid Arthritis?

摘要 风湿性关节炎（RA）与心血管疾病（CVD）风险增加2倍相关， 传统的心血管（CV）风险因素不能单独解释;这种风险可能部分通过以下途径介导： 全身炎症。事实上，RA本身被认为具有与糖尿病（DM）相当的CV风险。 然而，与DM不同，RA缺乏最佳CV管理策略。尽管抗- 尽管RA的炎症治疗，RA与普通人群相比的死亡率差距仍在扩大， 部分原因是RA患者的初级和二级CV预防护理欠佳。到目前为止，还没有 发表的用于RA一级CV预防的对照干预试验，尽管这一需求显然迫切未得到满足。 动脉粥样硬化形成的早期阶段之一是内皮功能障碍，而靶向改善内皮功能障碍的药物， 这是预防CVD的有希望的新策略。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信号通路改善内皮功能 通过抑制磷酸二酯酶-5（PDE5）。PDE5抑制剂改善肺动脉内皮功能 高血压和糖尿病，并且在勃起功能障碍和其他CV患者中安全且耐受良好 合并症。此外，PDE抑制剂具有免疫调节特性，其可用于治疗 自身免疫性疾病比如类风湿性关节炎我们的中心假设是，西地那非是一个独特的适合代理 靶向内皮功能障碍作为一种新的连续性CV预防策略和免疫调节 在RA的代理。具体来说，我们的目标是确定西地那非在RA中的使用是否改善了内皮功能障碍， 动脉粥样硬化生物标志物。 该研究是一项II期、随机、双盲、安慰剂对照、交叉、疗效试验， 无已知CVD病史但至少有一种传统CV风险因素的RA患者，接受稳定的基线剂量 RA药物;按1：1的比例随机接受西地那非50 mg或安慰剂口服，每日一次，持续3个月， 在交叉期之前进行2周洗脱，再进行3个月。血管研究验证于 评估内皮功能障碍和选定动脉粥样硬化生物标志物的实验室研究将是 在基线、洗脱前和洗脱后3个月以及6个月进行。将收集不良事件， 评估安全性。我们的具体目标是： 1.确定西地那非在RA中的使用是否导致血管功能参数的改善;以及 确认其安全性。 2.确定西地那非治疗RA是否与动脉粥样硬化生物标志物的改善相关。 本研究的结果将作为未来评估西地那非作为CV的大型试验的初步数据 预防策略，减少内皮功能障碍的RA。它将提供有关潜在效益的所需数据 西地那非在该高危人群中用于免疫调节和CV预防。

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.