ORAL CYCLOPHOSPHAMIDE VS ORAL PLACEBO IN SSC ALVEOLITIS

在系统性硬化症(SSC)中，间质性肺纤维化是常见的(80%)，现在是主要的死亡原因。由于SSC肺纤维化，用力肺活量(FVC)低于预测的50%的患者在SSC发病10年内的死亡率为40%-45%。目前的证据表明，SSC病程早期发生的肺纤维化通常先于炎症，而炎症可以通过对支气管肺泡灌洗(BAL)获得的细胞进行检查来发现。非对照系列研究表明，环磷酰胺(CyC)可稳定或改善伴有活动性肺泡炎的SSc患者的肺功能。我们建议进行一项为期5年、13个中心、平行分组、双盲、随机对照研究，比较口服环磷酰胺(1-2 mg/kg/d)和安慰剂，以评估环磷酰胺对163名已经呼吸困难的早期SSc患者(至少中等程度的功能损害和对Mahler基线呼吸困难指数的任务和努力的感知程度)在稳定或改善FVC进程(如预测的百分比)方面的有效性。FVC低于预计的85%，并表现出活动性肺泡炎，定义为BAL液中中性粒细胞大于或等于3.0%或嗜酸细胞大于或等于2.0%。其次，我们将评估CyC对这些患者的生活质量(SF36)、功能活动(SSC健康评估问卷)、呼吸困难(Mahler过渡性呼吸困难指数)和一氧化碳弥散能力(DLCO)的影响。患者将在最初的3年内被招募进行研究(从6个月开始)。至5年项目期的2年9个月)。随机的参与者将接受为期1年的研究药物治疗，并每隔3个月跟踪治疗2年。整个研究协调和数据收集、管理和分析将集中在加州大学洛杉矶分校。研究人员在以前的硬皮病对照研究中使用了经过验证的以时间为导向的数据分析方法，将用于评估口服环胞素(1-2毫克/公斤/天)在改善或防止FVC(主要结果变量)和b)改善或防止生活质量、功能能力、呼吸困难和DLCO(次要结果变量)恶化方面是否优于安慰剂。

In Systemic Sclerosis (SSc), interstitial pulmonary fibrosis is frequent (80 percent) and is now the leading cause of death. The mortality rate of patients with a forced vital capacity (FVC) less than 50 percent of predicted due to SSc pulmonary fibrosis is 40-45 percent within 10 years of SSc onset. Present evidence suggests that pulmonary fibrosis, which occurs early in the course of SSc, is usually preceded by inflammation which can be detected by examination of cells obtained by bronchoalveolar lavage (BAL). Uncontrolled series suggest that cyclophosphamide (CYC) may stabilize or improve lung function in SSc patients with active alveolitis. We propose to conduct a five-year, 13-center, parallel-group, double-blind, randomized controlled study of oral CYC (1-2 mg/kg/day) versus placebo to assess the efficacy of CYC in stabilizing or improving the course of FVC (as percent predicted) in 163 patients with early SSc (within 5 years of clinical disease onset) who are already dyspneic (at least moderate functional impairment and perceived magnitude of task and effort on the Mahler Baseline Dyspnea Index), have an FVC less than 85 percent of predicted and exhibit active alveolitis defined as greater than or equal to 3.0 percent neutrophils or greater than or equal to 2.0 percent eosinophils in BAL fluid. Secondarily, we will assess the impact of CYC on quality of life (SF36), functional activity (SSc Health Assessment Questionnaire), dyspnea (Mahler Transition Dyspnea Index) and diffusing capacity for carbon monoxide (DLCO) in these patients. Patients will be recruited for study during the first 3 years (from 6 mos. to 2 yrs, 9 mos) of the 5-year project period. Randomized participants will be treated with study drug for 1 year and followed at 3-month intervals for 2 years. Overall study coordination and data collection, management and analysis will be centralized at UCLA. Proven methods for analyzing time- oriented data employed by the investigators in previous controlled studies of scleroderma will be used to evaluate whether oral CYC (1-2 mg/kg/day) is better than placebo a) in improving or preventing worsening of FVC (the primary outcome variable) and b) in improving or preventing worsening of quality of life, functional ability, breathlessness and DLCO (secondary outcome variables).