Treatment with bosentan reduced the occurrence of new ischemic digital ulcers in patients with systemic sclerosis, but did not hasten healing of existing ulcers, findings from a study have shown. The dual endothelin receptor antagonist was associated with a 30% reduction in the number of new digital ulcers in a double-blind, placebo-controlled trial reported online in the Annals of the Rheumatic Diseases.

In the United States, the Food and Drug Administration has approved bosentan for the treatment of pulmonary artery hypertension (PAH). Both PAH and digital ulcers are complications of systemic sclerosis (SSc). In Europe, bosentan is approved for pulmonary artery hypertension.

As a follow-up to a previous study of 122 SSc patients in whom bosentan treatment was associated with a 48% reduction, compared with placebo, in the mean number of new digital ulcers but no differences in healing after 16 weeks of treatment, Dr. Marco Matucci-Cerinic, professor of rheumatology and medicine at the University of Florence (Italy) and colleagues designed the current trial to evaluate the effects of the drug in a larger population of patients over a longer period of time.

Toward this end, the investigators enrolled 188 SSc patients with at least one active digital ulcer (the cardinal ulcer) to receive 62.5 mg of bosentan twice daily for 4 weeks and 125 mg twice daily for 20 weeks, or matching placebo. Patients in both groups were at least 18 years old at the time of enrollment (between October 2003 and May 2005) and were well matched with respect to demographics, baseline disease characteristics, and concomitant treatment for digital ulcers at baseline. The study’s primary end points were the number of new digital ulcers and the time to healing of the cardinal ulcer; the secondary end points were pain, disability, and safety, the authors wrote (Ann. Rheum. Dis. 2010 Aug. 30 [doi:10.1136/ard.2010.130658]).

After 24 weeks, the mean total number of digital ulcers per patient was similar in the two groups, but the mean number of new digital ulcers was 1.9 in the treatment group and 2.7 in the placebo group, the authors reported. “Fewer new [digital ulcers] were observed with bosentan than placebo in all subgroups except among current smokers,” they stated. “This included subgroups of limited and diffuse [SSc], with no difference between the two subgroups in the treatment effect.”

In post hoc analysis, more pronounced reductions were seen in patients who had multiple digital ulcers, the authors observed. Specifically, they wrote, “the reduction of new [digital ulcers] appeared to be greater in patients with at least four [digital ulcers] at baseline.”

The reduction of new digital ulcers in bosentan-treated patients “did not translate into a smaller ulcer burden, as was seen in the previous study,” the authors stated, noting that this could be attributed to the fact that 38% of patients in the previous study did not have an active digital ulcer at baseline and had fewer digital ulcers to heal, possibly giving more weight to prevention in the reduction of overall ulcer burden.

In terms of healing, there was no difference in the time to healing of the cardinal ulcer between bosentan treatment and placebo. At 24 weeks, more than half of the patients in both groups had healing of the cardinal ulcer that was maintained for a minimum of 12 weeks, the authors wrote. Additionally, no treatment effects were observed in patient-rated measures of overall hand pain and pain of the cardinal ulcer, as assessed by visual analog scales. Similarly, there were no significant differences in the changes from baseline in the Health Assessment Questionnaire–Disability Index and hand disability index at week 24, they reported.

The fact that the reduction in new ulcers was not associated with decreased pain or disability, relative to placebo, could be explained by the similar number of digital ulcers between treatment groups, or a lack of sensitivity to change and discriminative value in the current instruments that are used to assess hand function in systemic sclerosis, the authors hypothesized. It might also be indicative of the fact that bosentan treatment does not improve pain and disability in spite of the reduction of new digital ulcers, they wrote.

Safety and tolerability assessments showed that serious adverse events occurred in 9.4% and 16.7%, respectively, of patients in the bosentan and placebo groups, and that similar proportions of patients in both groups experienced at least one adverse event, the authors reported. More treatment vs. placebo patients experienced peripheral edema and events denoting elevated aminotransferases.

Laboratory analyses showed increases in aminotransferases in 10.5% of the bosentan patients, compared with 1.1% of the placebo patients, reinforcing “the need for continual monitoring of liver function with this treatment,” the authors wrote.

The clinical utility of bosentan treatment for digital ulcer prevention in SSc “may be challenged,” the authors wrote. “In a patient encountered with a single [digital ulcer], initiation of bosentan would not be expected to facilitate healing, and at least 66% of all bosentan-treated subjects would develop at least one additional [digital ulcer] over 6 months of follow-up.” However, they noted, bosentan treatment offers greater potential benefit to patients who present with multiple digital ulcers. In this regard, the treatment “may be a useful adjunct in the management of patients with [SSc] and recurrent [digital ulcers].”

This study was funded by Actelion Pharmaceuticals. The authors disclosed financial relationships with Actelion, Pfizer, GlaxoSmithKline Beecham, Encysive, Genzyme, Aspreva, Biovitrum, DiGNA, Gilead, MediQuest, Centocor, FibroGen, Bristol-Myers Squibb, Lilly, and United Therapeutics.

Copyright (c) 2010 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

最新一项双盲、安慰剂对照研究表明，波生坦(bosentan)可使系统性硬化症患者新发缺血性指端溃疡数量减少30%，但不能促进已有溃疡的愈合。

 

波生坦为双重内皮素受体拮抗剂，美国和欧洲药监部门批准用于治疗肺动脉高压(PAH)，PAH和指端溃疡均为系统性硬化症常见并发症。

 

此前对122位系统性硬化症患者为期16周的随访研究显示，与安慰剂相比，波生坦可减少新发指端溃疡平均数的48%，但对溃疡愈合无显著差异。本次由意大利弗洛伦萨大学风湿病学和医学教授Marco Matucci-Cerinic博士领衔的研究，旨在通过对更多患者进行更长时间的研究以评价波生坦的疗效和安全性。

 

本研究共纳入了188位至少有1处活动性指端溃疡的系统性硬化症患者，他们被随机分配至波生坦治疗组(62.5mg，每天2次，连用4周；然后125mg，每天2次，连用20周）和安慰剂组。两组患者的入组年龄均至少为18岁并且在人口统计学、基线疾病特征以及合并用药方面匹配性良好。研究的首要终点为新发指端溃疡数量和原有溃疡愈合时间，次要终点为疼痛、失能和安全性 (Ann. Rheum. Dis. 2010 Aug. 30 [doi:10.1136/ard.2010.130658])。

 

研究结果显示，24周时治疗组和安慰剂组患者平均指端溃疡总数相似，但新发溃疡平均数分别为1.9个和2.7个。除现实吸烟者亚组外，其他所有亚组中接受波生坦治疗的患者新发溃疡数均少于安慰剂组。这些亚组包括局限性和弥漫性系统性硬化症亚组，组间未见疗效差异。多发性指端溃疡患者新发溃疡数减少更为明显，特别是基线溃疡数至少为4个的患者，其新发溃疡数减少最为明显。

 

在溃疡愈合方面，24周时两组中均有一半多的患者原有溃疡（最少持续12周）得以愈合，两组间原有溃疡愈合时间未见差异。此外，患者总的手痛和原有溃疡疼痛视觉模拟量表得分未见治疗效果。同样，健康评估问卷中功能障碍指数和手功能障碍指数与基线相比，也未见显著差异。这或许预示着波生坦虽然能够减少新发指端溃疡，但是并不能改善疼痛和功能障碍。

 

在安全性和耐受性方面，治疗组和安慰剂组严重不良事件发生率分别为9.4%和16.7%，两组患者中出现至少一次不良事件的人数相似。治疗组中较多患者出现外周性水肿和转氨酶升高。

 

临床应用波生坦预防多发性硬化症患者单处指端溃疡效果不佳，但对于多处指端溃疡患者，可能从中受益较多，可能可作为系统性硬化症及复发性指端溃疡患者的一种有效的辅助治疗药物。

 

该研究由Actelion制药公司资助。作者披露与Actelion、辉瑞、葛兰素史克 比切姆、Encysive、健赞、Aspreva、Biovitrum、DiGNA、Gilead、MediQuest、 Centocor、FibroGen、百事美施贵宝、礼来以及United Therapeutics存在经济关系。

 

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