SNOWMASS, Colorado (EGMN) – Until further testing confirms or disproves the promise of an oral formulation of treprostinil that is making its way through the developmental pipeline for management of Raynaud’s phenomenon and the ischemic finger, rheumatologists will have to continue to make do with modestly efficacious agents that all are best employed in conjunction with background therapy using a long-acting calcium channel blocker titrated to the maximum tolerated dose.
Calling the developmental oral treprostinil agents particularly exciting, Dr. Frederick M. Wigley noted that the prostacyclin analogs are highly effective in cases of Raynaud’s with severe digital ischemia, but the ones available now have to be given intravenously, which is costly and inconvenient.
An effective oral prostacyclin would be a major development. The early clinical trials of oral treprostinil have been quite promising, and the drug is now moving into advanced trials for Raynaud’s phenomenon as well as for pulmonary arterial hypertension, according to Dr. Wigley, professor of medicine and director of the scleroderma center at Johns Hopkins University, Baltimore.
However, for now, “the kingpin of our therapy is usually the calcium channel blocker,” he observed at a symposium sponsored by the American College of Rheumatology.
He highlighted the agents variously prescribed for Raynaud’s and how they fit into his management strategy – and in some cases, why they do not.
His first-line drug for Raynaud’s and the ischemic finger is amlodipine, at a starting dose of 5 mg that is titrated to 20 mg/day. This typically results in a 35%-40% reduction in patient-rated symptom severity scores, which he characterized as “a modest benefit.” In addition, full-dose calcium channel blocker therapy also appears to reduce the incidence of digital ulcers, in Dr. Wigley’s experience.
Other medications often used for Raynaud’s phenomenon include:
•Topical nitrates: This popular therapy improves blood flow in affected fingers, but at the price of headaches and other side effects that many patients find intolerable.
“In my practice, I generally use topical nitrates when I have a patient with one finger that’s in trouble and I’m trying to get a bit of blush to the surface of the skin. It’s a therapy that’s generally not tolerated when used on a daily basis on all the fingers,” the rheumatologist said.
•Other topicals: EMLA cream (2.5% lidocaine/2.5% prilocaine in a eutectic mixture) provides numbing as well as vasodilation. “I use it often in patients who have painful fingertips. It’s probably not quite as potent as the topical nitrates,” Dr. Wigley said.
Several studies have shown that topical minoxidil is ineffective. Topical niacin is helpful in bringing a blush to ischemic skin, but it doesn’t address deeper ischemic events.
•ACE inhibitors and angiotensin-receptor blockers: ACE inhibitors are famously effective in preventing fatal renal crisis in scleroderma patients, but they don’t reduce the frequency or severity of Raynaud’s episodes, as was demonstrated in a large, randomized, double-blind clinical trial (Arthritis Rheum. 2007;56:3837-46).
In contrast, the angiotensin receptor blocker losartan at 50 mg/day has been shown in a randomized trial to be an effective alternative to calcium channel blocker therapy (Arthritis Rheum. 1999;42:2646-55). However, Dr. Wigley said his own clinical experience has been that losartan’s benefits are milder than with a long-acting calcium channel blocker pushed to the maximum tolerated dose.
•Selective serotonin reuptake inhibitors: Activated platelets in Raynaud’s release serotonin, a vasoconstrictor. In a 53-patient randomized, crossover trial, fluoxetine (Prozac) at 20 mg/day resulted in greater reductions in the frequency, duration, and severity of Raynaud’s attacks compared to baseline than did nifedipine at 40 mg/day (Rheumatology 2001;40:1038-43).
•Alpha adrenergic blockers: Prazosin was once a very popular treatment, but it has given way to the long-acting calcium channel blockers, which are more effective. Prazosin is primarily an alpha-1 inhibitor, and there aren’t a lot of alpha-1 receptors on vascular smooth muscle cells. The alpha-2C receptor is the key player at that site. Selective alpha-2C receptor inhibitors are in development.
•Phosphodiesterase inhibitors: “I must say that I’m generally disappointed with these drugs, and when I use them I do so in conjunction with a calcium channel blocker for their best benefit,” Dr. Wigley said.
•Prostaglandins: A Cochrane review of seven clinical trials in patients with Raynaud’s phenomenon and scleroderma concluded that prostacyclin analogs reduced attack frequency and severity, improved digital lesions, and resulted in favorable physician assessments of treatment outcome (Cochrane Database of Syst. Rev., 1998, Issue 2, Art. No. CD000953).
European physicians have pioneered cyclic therapy with intravenous iloprost in patients with severe Raynaud’s, giving it daily, weekly, or monthly during the winter months and less frequently as needed during warmer weather. Dr. Wigley said that he utilizes intravenous epoprostenol as a key part of his approach to patients with an acute digital ischemic crisis.
•Botulinum toxin type A: Vascular surgeons report glowing results, with rapid improvement after injection of Botox at the base of the finger. But there have been no controlled trials and Dr. Wigley said that he remains skeptical, having used it in a critical situation, with a disappointing lack of acute vasodilation.
“I don’t know if it really works or not. We’ll have to wait for a good study,” he said.
•Bosentan: In the Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Assess the Effect of Bosentan on Healing and Prevention of Ischemic Digital Ulcers in Patients With Systemic Sclerosis (RAPIDS-1) trial, patients treated with the endothelin inhibitor had a 48% decrease in new ulcers compared to placebo during a 16-week period. They also experienced significantly improved hand function, although there was no benefit in terms of healing of existing ulcers or patient-assessed Raynaud’s severity (Arthritis Rheum. 2004;50:3985-93). These findings suggest bosentan may have a role in a protective strategy aimed at reducing ischemic events, according to Dr. Wigley.
•Antioxidants: Most studies have been negative.
At the Johns Hopkins scleroderma center, the management approach taken in a new patient with Raynaud’s phenomenon with digital ischemia is to first stop the aggravating environmental factors: cold, trauma, smoking, and stress.
“None of the drugs we have is more potent than warm temperatures,” the rheumatologist stressed.
Dr. Wigley puts the patient on amlodipine along with aspirin at 81 mg/day, aimed at preventing vascular occlusion. If the patient remains severely ischemic despite maximum-dose amlodipine or has digital ulcers he adds a second vasodilator, typically a phosphodiesterase inhibitor such as sildenafil, which has been shown to reduce the frequency and duration of Raynaud’s attacks compared to placebo in a small, double-blind, crossover, randomized trial (Circulation 2005;112:2980-5).
He said he has a low threshold for putting Raynaud’s patients on statin therapy as a vascular protection strategy. Dr. Wigley said that he was favorably impressed by findings from a randomized trial in which scleroderma patients placed on atorvastatin at 40 mg/day had a significant decrease in new ulcers compared to placebo, as well as better scores on pain scales and improved endothelial markers (J. Rheumatol. 2008;35:1801-9).
Dr. Wigley declared that he receives consulting fees and/or research grants from Actelion, Amira, Kinemed, Medimmune, Novartis, Orion, Pfizer, and United Therapeutics.
Copyright (c) 2010 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.
科罗拉多州斯诺马斯(EGMN)——曲前列环素(treprostinil)口服制剂正处于研发中，在有进一步的证据证实或否定其治疗雷诺现象合并手指缺血的前景之前，风湿病专家还得继续在使用长效钙通道阻滞剂治疗的基础上联用疗效有限的药物进行治疗，同时长效钙通道阻滞剂的剂量需逐渐增至最大耐受剂量。
美国巴尔的摩约翰·霍普金斯大学硬皮病中心主任兼医学教授Frederick M. Wigley博士在由美国风湿病学会主办的专题研讨会上指出，前列环素类似物对雷诺现象合并手指(脚趾)重度缺血有强效，但这类药物目前上市的只有费用昂贵且使用不便的静脉注射制剂，因此亟待研制出有效的口服制剂。早期的临床试验显示了口服曲前列环素巨大的应用前景，目前该药即将进入治疗雷诺现象和肺动脉高压的后期试验阶段。当前的主要治疗方法是钙通道阻滞剂。
Wigley博士在治疗雷诺现象合并手指缺血时使用的一线药物是氨氯地平，起始剂量为5 mg，逐渐增量至20 mg/日。这一方案通常可使患者自评症状严重程度评分(patient-rated symptom severity scores)减少35%~40%，他本人将其定性为“适度收益”。此外，据Wigley博士的治疗经验，全量钙通道阻滞剂疗法似乎还可以降低手指(足趾)溃疡的发病率。
治疗雷诺现象的其他常用药物包括：
•外用硝酸盐类药：这种治疗药应用广泛，可改善患指的血流量，但是会引起头痛以及许多患者无法耐受的其他副作用。
•其他外用药：恩纳乳膏(一份低熔混合制剂，含2.5%利多卡因和2.5%丙胺卡因)具有麻醉和舒张血管的功能。Wigley博士称其常对指尖疼痛的患者使用此药，其药效或许不及外用硝酸盐类药。另外，多项研究表明外用米诺地尔无效，而外用尼亚新有助于缺血皮肤变潮红，但不能处理更深部位的缺血事件。
•血管紧张素转换酶(ACE)抑制剂和血管紧张素Ⅱ受体阻滞剂: 一项大型随机、双盲临床试验证实，ACE抑制剂预防硬皮病患者致死性肾危象的效果卓著，但不能降低雷诺现象的发生率或减轻其严重程度(Arthritis Rheum. 2007;56:3837-46)。相比之下，一项随机试验表明血管紧张素Ⅱ受体阻滞剂氯沙坦50 mg/日是钙通道阻滞剂疗法的一种有效替代药(Arthritis Rheum. 1999;42:2646-55)。但Wigley博士的临床经验是，氯沙坦的治疗收益小于长效钙通道阻滞剂。
•选择性5-羟色胺再摄取抑制剂：雷诺现象中活化的血小板可释放一种缩血管物质——5-羟色胺。一项纳入53例患者的随机交叉试验显示，氟西汀(百忧解)20 mg/日使用者的雷诺现象的发生率、病程以及严重程度相对于基线时的降幅，均大于硝苯地平40 mg/日使用者(Rheumatology 2001;40:1038-43)。
•α肾上腺素受体阻滞剂：哌唑嗪曾是一种非常普及的治疗药，但现已被疗效更佳的长效钙通道阻滞剂所取代。哌唑嗪主要阻断α1受体，而血管平滑肌细胞中的α1受体较少，主要是α-2C受体。选择性α-2C受体阻滞剂正处于研发阶段。
•磷酸二酯酶抑制剂：Wigley博士称这类药物通常不理想，如若使用，则应与一种钙通道阻滞剂联用以达到其最佳收益。
•前列腺素类药：一项Cochrane系统评价纳入7项针对雷诺现象合并硬皮病患者的临床试验，结果显示，前列环素类似物可降低该病的发作频率和减轻其严重程度、改善手指(足趾)病变并有助于医生评估治疗预后(Cochrane Database of Syst. Rev., 1998, Issue 2, Art. No. CD000953)。
对于雷诺现象严重的患者，欧洲医生开创了静脉用伊洛前列腺素周期疗法，在冬季每日1次、每周1次或每月1次给药，而在天气较暖时则按需减少用药频率。对于发生急性手指(足趾)缺血危象的患者，Wigley博士使用静脉用依前列醇作为主要治疗方法。
•A型肉毒杆菌毒素：据血管外科医生的报告，在手指基部注射保妥适后症状迅速改善，不过目前还没有相应的对照试验，Wigley博士对此仍持怀疑态度，他本人曾使用此药处理危重情况，但结果令其失望。
•波生坦：评估采用波生坦治愈和预防系统性硬化症患者缺血性手指(足趾)溃疡效果 (RAPIDS-1) 的随机、双盲、安慰剂对照、多中心研究显示，内皮素受体拮抗剂治疗组患者在16周内的新发溃疡相对于安慰剂对照组减少48%。虽然在治愈已有的溃疡或减轻患者自评的雷诺现象严重程度方面没有收益，但患者的手功能有显著改善(Arthritis Rheum. 2004;50:3985-93)。这些结果表明，波生坦在以减少缺血事件为目的的预防策略中可能有一定的作用。
•抗氧化剂：大多数研究的结果都是负面的。
约翰·霍普金斯大学硬皮病中心对新发雷诺现象合并手指(足趾)缺血患者采用的治疗方法是首先阻止加重病情的环境因素，如寒冷、创伤、吸烟和应激。
Wigley博士对患者使用氨氯地平联合阿司匹林81 mg/日进行治疗，目的是预防血管闭塞。若患者在使用最大有效量的氨氯地平后缺血症状仍严重或发生手指(足趾)溃疡，则加用一种第二代血管舒张药——通常是西地那非等磷酸二酯酶抑制剂。一项小型的双盲、随机、交叉试验显示，西地那非相对于安慰剂可降低雷诺现象的发生率和缩短病程(Circulation 2005;112:2980-5)。此外，一项随机试验显示，与安慰剂相比，硬皮病患者使用阿托伐他汀40 mg/日治疗后新发溃疡显著减少、疼痛量表评分较佳、血管内皮标志物改善(J. Rheumatol. 2008;35:1801-9)。
Wigley博士声明收到Actelion公司、Amira公司、Kinemed公司、Medimmune公司、诺华公司、奥立龙公司、辉瑞公司和United Therapeutic公司的咨询酬金和(或)研究经费。
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