硬皮病患者肺动脉高压的治疗选择增多

拉斯维加斯——加州大学洛杉矶分校内科教授、哈伯医疗中心肺动脉高压中心主任Ronald J. Oudiz医生在2013年风湿病学大会上指出，硬皮病患者发展为肺动脉高压（PAH）的风险特别高，但是治疗选择也在增多，若在早期转诊到PAH专家，结局能够得到改善。

现在有9种专门针对PAH的治疗方案，还有更多的方案正处于观察阶段。三种信号通路（包括前列环素、内皮素和一氧化氮通路）构成了针对这种进行性致死性疾病的治疗选择基础，该病的36个月生存率仅约为60%。治疗方法包括环前列环素类似物、内皮素受体拮抗剂和磷酸二酯酶5型（PDE-5）抑制剂。前列环素类似物包括静脉依前列醇，吸入性伊洛前列素和可吸入、静脉或皮下给药的曲前列尼尔。研究显示，这些药物以一种剂量依赖性的方式改善6分钟步行测试的表现。前列环素类似物的副作用包括面部潮红、头痛、皮疹、血小板减少、感染和肠胃道反应，例如腹泻、恶心、体重下降。内皮素受体拮抗剂包括波生坦和安贝生坦，二者均为口服药，这两种药物获准具有“革命性意义”，结束了只有静脉注射用药的时代。内皮素受体拮抗剂的副作用包括肝功能检测异常、头痛、鼻塞和水肿，尽管这些药物通常耐受良好，但肝功能检测异常和水肿对患者和医生来说都很棘手，因为这些状况需要密切监测和剂量调整或中断。PDE-5抑制剂包括西地那非和他达拉非，二者也均为口服药，其副作用类似于内皮素受体拮抗剂，另外还有肌痛、腹泻、消化不良和流鼻血。

研究表明使用PAH药物治疗不仅可以改善运动能力，还可能改善长期生存率。在一项对多种主要PAH药物试验所做的Meta分析中，大多数研究都显示出潜在的死亡率收益（Eur. Heart. J. 2009;30:394-403 ）。8月份发表在《新英格兰医学杂志》上的一项研究中提到，新型内皮素受体拮抗剂macitentan相对于安慰剂而言，与在PAH患者中测得的结局事件数呈剂量依赖性减少有关联，包括死亡、移植和心力衰竭（N. Engl. J. Med. 2013;369:809-18），这些是一些真正重要的终点。

研究者表示，这些进展凸显了增强硬皮病PAH发病风险意识和早期状况识别的重要性，并且因为诊断和管理的细节比较复杂，这些进展也凸显了早期转诊到PAH专家的重要性，“治疗始终是越早越好。”

此次会议由全球医学教育学院（GAME）举办，GAME及该新闻组织隶属于前线医疗通信公司（Frontline Medical Communications）。Oudiz医生获得了由爱可泰隆、拜耳、吉利德、Lung、辉瑞、联合治疗公司（United Therapeutics）提供的经费或研究支持，并担任这些公司的顾问和（或）讲师团成员。

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By: SHARON WORCESTER, Cardiology News Digital Network

LAS VEGAS – Scleroderma patients are at particularly high risk for developing pulmonary arterial hypertension, but treatment options are expanding, and with early referral to a PAH specialist, outcomes can be improved, according to Dr. Ronald J. Oudiz.

"In 1995 we had nothing. Now we have nine treatments specifically for PAH, and more that are being looked at," he said at Perspectives in Rheumatic Diseases 2013.

Three major signaling pathways, including the prostacyclin, endothelin, and nitric oxide pathways, form the basis for the available treatment options for this progressive and deadly disease, which has a 36-month survival rate of only about 60%. The treatments include prostacyclin analogues, endothelin receptor antagonists, and phosphodiesterase type 5 (PDE-5) inhibitors, said Dr. Oudiz, professor of medicine at the University of California, Los Angeles, and director of the Liu Center for Pulmonary Hypertension at Harbor-UCLA Medical Center.

The prostacyclin analogues include intravenous epoprostenol, inhaled iloprost, and treprostinil, which can be inhaled or delivered intravenously or subcutaneously. These have been shown to improve performance on the 6-minute walk test in a dose-dependent fashion, Dr. Oudiz noted.

Side effects with prostacyclin analogues can include flushing, headache, rash, thrombocytopenia, infection, and gastrointestinal effects such as diarrhea, nausea, and weight loss.

The endothelin receptor antagonists include bosentan and ambrisentan, which both are delivered orally. Their approval was "revolutionary, because for a while we only had IV drugs," he said.

Side effects with endothelin receptor antagonists include liver function test abnormalities, headache, nasal congestion, and edema. Although these drugs are generally tolerated well, liver function test abnormalities and edema can be troublesome for both patients and physicians as they require close monitoring and dose modification or interruption, he said.

PDE-5 inhibitors include sildenafil and tadalafil, which also are both oral drugs, and which have side effects that are similar to those seen with the endothelin-receptor antagonists, with the addition of myalgia, diarrhea, dyspepsia, and nose bleeds, he noted.

Overall, studies suggest that treatment with PAH drugs not only leads to improved exercise capacity, but probably improves long-term survival. In a meta-analysis of several major PAH drug trials, the majority of studies showed a potential mortality benefit (Eur. Heart. J. 2009;30:394-403), Dr. Oudiz noted.

"I say potential because we know none of the studies assessed in the meta-analysis were powered to examine mortality ... but nevertheless, we believe we’re doing more than just improving exercise capacity," he said.

In fact, in a study published in August in the New England Journal of Medicine, the new endothelin receptor antagonist macitentan was associated with a dose-dependent decrease in the number of outcome events measured, relative to placebo, including death, transplant, and heart failure in patients with PAH, he noted (N. Engl. J. Med. 2013;369:809-18).

"These are some really important endpoints we’re finally starting to meet," he said.

These advances underscore the importance of increased awareness of the risk of PAH in scleroderma and early recognition of the condition, and – since diagnosis and the subtleties of management are complex – they also underscore the importance of early referral to a PAH specialist, he said.

"Early treatment is always preferable to later treatment," he concluded at the meeting held by Global Academy for Medical Education. GAME and this news organization are owned by Frontline Medical Communications.

Dr. Oudiz has received grant or research support from, served as a consultant to, and/or served on a speakers’ bureau for Actelion, Bayer, Gilead, Ikaria, Lung, Pfizer, and United Therapeutics.