Denton C P, Humbert M, Rubin L, Black C M
Centre for Rheumatology, Royal Free Hospital, Pond Street, London, NW3 2QG, UK.
Ann Rheum Dis. 2006 Oct;65(10):1336-40. doi: 10.1136/ard.2005.048967. Epub 2006 Jun 22.
Endothelin-1 is considered to be a central pathogenic factor in connective tissue diseases (CTDs) such as systemic sclerosis (SSc), leading to vasoconstriction, fibrosis, hypertrophy and inflammation. A frequent complication of CTD is pulmonary arterial hypertension (PAH), which has a major effect on functioning and quality of life, and is associated with a particularly poor prognosis.
To present a subgroup analysis that summarises experiences from the pivotal studies and their open-label extensions with the oral dual endothelin-1 receptor antagonist bosentan in patients with PAH and CTD, mostly SSc and lupus erythematosus.
66 patients with PAH secondary to CTD, in World Health Organization functional class III or IV, were randomised to two double-blind, placebo-controlled studies and followed up for 12 and 16 weeks, respectively. The primary end point was change in exercise capacity, assessed using the 6-min walk test. In both studies and their extensions, survival was assessed from start of treatment to death or data cut-off and analysed as Kaplan-Meier estimates.
44 patients with PAH secondary to CTD who were treated with bosentan were stable in 6-min walk distance at the end of the study (+19.5 m, 95% confidence interval (CI) -3.2 to 42.2), whereas patients treated with placebo deteriorated (-2.6 m, 95% CI -54.0 to 48.7). 64 patients subsequently received bosentan in an open-label long-term extension study. Mean (standard deviation (SD)) exposure to bosentan was 1.6 (0.9) years, and duration of observation was 1.8 (0.8) years. 8 (16%) patients received epoprostenol as add-on treatment and 7 (14%) after discontinuation of bosentan. Survival in those receiving bosentan was 85.9% after 1 year and 73.4% after 2 years.
Short-term bosentan treatment in a subgroup of patients with PAH secondary to CTD seems to have a favourable effect compared with placebo. The long-term follow-up of these patients suggests that first-line bosentan, with the subsequent addition of other PAH treatments if required, is safe for long-term treatment and may have a positive effect on outcome.
内皮素-1被认为是系统性硬化症（SSc）等结缔组织病（CTD）的核心致病因素，可导致血管收缩、纤维化、肥大和炎症。CTD的常见并发症是肺动脉高压（PAH），其对功能和生活质量有重大影响，且预后特别差。
进行一项亚组分析，总结关键研究及其开放标签扩展研究中，口服双重内皮素-1受体拮抗剂波生坦治疗PAH合并CTD（主要是SSc和红斑狼疮）患者的经验。
66例CTD继发PAH、世界卫生组织功能分级为III或IV级的患者，被随机分配到两项双盲、安慰剂对照研究中，分别随访12周和16周。主要终点是运动能力的变化，采用6分钟步行试验进行评估。在两项研究及其扩展研究中，从治疗开始至死亡或数据截止评估生存率，并作为Kaplan-Meier估计值进行分析。
44例CTD继发PAH且接受波生坦治疗的患者在研究结束时6分钟步行距离保持稳定（增加19.5米，95%置信区间（CI）-3.2至42.2），而接受安慰剂治疗的患者则出现恶化（减少2.6米，95%CI -54.0至48.7）。64例患者随后在一项开放标签长期扩展研究中接受了波生坦治疗。波生坦的平均（标准差（SD））暴露时间为1.6（0.9）年，观察时间为1.8（0.8）年。8例（16%）患者接受依前列醇作为附加治疗，7例（14%）在停用波生坦后接受该治疗。接受波生坦治疗的患者1年后生存率为85.9%，2年后为73.4%。
与安慰剂相比，短期使用波生坦治疗CTD继发PAH的亚组患者似乎有有益效果。对这些患者的长期随访表明，一线使用波生坦，必要时随后添加其他PAH治疗方法，长期治疗是安全的，可能对预后有积极影响。
