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%），现在是死亡的主要原因。 由于SSc肺纤维化，用力肺活量（FVC）低于预测值50%的患者在SSc发作后10年内的死亡率为40- 45%。 目前的证据表明，肺纤维化，这发生在早期的SSc过程中，通常是由炎症，可以检测到的检查细胞获得支气管肺泡灌洗（BAL）。 非对照系列研究表明，环磷酰胺（CYC）可以稳定或改善活动性肺泡炎SSc患者的肺功能。 我们建议进行一项为期5年、13个中心、平行组、双盲、口服CYC的随机对照研究（1-2 mg/kg/天）与安慰剂比较，以评估CYC在稳定或改善FVC病程方面的疗效（按预测百分比计算）（临床疾病发作后5年内）已患有呼吸困难的患者（根据Mahler基线呼吸困难指数，至少有中度功能障碍和感知的任务和努力程度），FVC低于预测值的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%或嗜酸性粒细胞大于或等于2.0%。其次，我们将评估CYC对这些患者的生活质量（SF 36）、功能活动（SSc健康评估问卷）、呼吸困难（Mahler过渡期呼吸困难指数）和一氧化碳弥散量（DLCO）的影响。将在前3年（从6个月开始）招募患者参加研究。至2年9个月）。随机化受试者将接受研究药物治疗1年，并每隔3个月随访2年。 总体研究协调和数据收集、管理和分析将集中在UCLA。 将使用研究者在先前硬皮病对照研究中采用的分析时间导向数据的随机方法来评价口服CYC（1-2 mg/kg/天）是否优于安慰剂a）在改善或预防FVC恶化（主要结果变量）和B）在改善或预防生活质量、功能能力、呼吸困难和DLCO恶化（次要结果变量）方面。

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).