大约三分之一的间质性肺病(ILD)患者伴有结缔组织病(CTD)。最常见的与ILD相关的结缔组织病症包括硬皮病/系统性硬化症(SSc)，类风湿性关节炎，多发性肌炎/皮肌炎和干燥综合征。尽管许多CTD-ILD患者不发展为进行性肺部疾病，但其中很大一部分病情进展，导致身体各器官功能降低，生活质量下降和死亡。 ILD现在是系统性硬化症患者死亡的主要原因。环磷酰胺是一种高度有效的免疫抑制剂，在诱导和维持自身免疫性和炎症性疾病缓解方面疗效显著。然而，这伴随着潜在的毒性，包括恶心，出血性膀胱炎，膀胱癌，骨髓抑制，机会性感染等风险增加，以及血液和实体器官恶性肿瘤增加。用CTD-ILD治疗个体的决策非常困难;临床医师需要确定那些将发展为进行性疾病的患者，并衡量严重不适患者群体的高水平治疗需求与高毒性治疗不良反应的潜在可能性之间的平衡，但目前仅有相对有限的数据疗效。同样，尚不清楚组织学亚型，疾病持续时间或疾病程度是否可用于预测治疗反应性。

        目的：

        评估环磷酰胺在治疗CTD -ILD患者中的疗效和不良反应。

        方法：

        我们进行在2017年5月之前在CENTRAL，MEDLINE，Embase，CINAHL和Web ofScience上进行搜索。我们手工检索了评论文章，临床试验注册表和检索条目的参考文献列表。

        选择标准：

        我们纳入了随机对照平行组试验，将环磷酰胺任何形式，单独使用或与其他免疫调节疗法一起使用，与使用非环磷酰胺治疗至少6个月，从治疗开始至少12个月随访。

        数据收集与分析：

        搜索参考管理数据库。我们检索了相关研究的全文版本，两位评论作者独立提取数据。主要结局指标是肺功能的变化(预计用力肺活量(FVC)%预计值和肺一氧化碳扩散能力(DLCO)%预计值)，不良事件以及与健康相关的生活质量指标。次要终点包括全因死亡率，呼吸困难，咳嗽和功能锻炼测试。适当时，我们根据肺功能严重程度，结缔组织病诊断和纤维化的放射模式进行荟萃分析和亚组分析。我们使用建议评估，发展和评估评级(GRADE)方法评估证据，并创建了“发现摘要”表。

        主要结果：

        我们纳入了495名参与者(大多数患有系统性硬化症)的分析中的四项试验。我们形成了两个独立的比较：环磷酰胺与安慰剂(两项试验，195名参与者)和环磷酰胺与霉酚酸酯(两项试验，300名参与者)。我们发现证据质量较差，因为干预组的失访率很高，而且我们注意到影响结果精确度的效应周围存在宽泛的置信区间，影响结果的精确度。数据显示肺功能显着改善(治疗后FVC%平均差异(MD)2.83,95%置信区间(CI)0.80-4.87; P = 0.006)，但治疗后DLCO无显着差异(%MD -1.68,95%CI -4.37至1.02; P = 0.22;两项试验，182名参与者)。与安慰剂组相比，环磷酰胺治疗组的不良反应风险增加，特别是血尿，白细胞减少症和恶心，导致停用率升高。

        数据表明，在一项有利于环磷酰胺的试验中，一项生存质量的统计学显效性改善优于安慰剂，一项有利于环磷酰胺的试验的临床和统计学显着改善，与安慰剂相比，对死亡率没有显注影响。试验组报告没有显注影响(FVC%MD -0.82,95%CI-3.95至2.31; P = 0.61;两项试验，149名参与者; DLCO%MD -1.41,95%CI-10.40至95%CI)的肺功能与使用环磷酰胺7.58; P = 0.76;两项试验，149名参与者)。环磷酰胺与霉酚酸酯相比，副作用的风险增加，特别是白细胞减少症和血小板减少症。数据表明对健康相关生活质量，全因死亡率，呼吸困难或咳嗽严重程度的环磷酰胺组与霉酚酸组相比。没有试验报告与功能性运动试验相关的结果。我们进行亚组分析以确定肺功能，结缔组织疾病诊断或放射模式的严重程度是否对结果有任何影响。一项试验报道，环磷酰胺能够防止纤维化评分较差的患者的FVC下降，并且还显示环磷酰胺可能对肺功能更差的患者更有效。

        研究结论：

        本综述基于不同方法学质量的研究，表明总体而言，在这一人群中，小环境的好处可能来源于使用环磷酰胺与安慰剂相比，%FVC的平均差异，但不是%DLCO的差异，或者与霉酚酸酯相比。使用环磷酰胺可能会引起呼吸困难的临床改善。临床实践指南应该建议临床医生考虑个体患者的特征，并且期望在保留FVC方面仅有适度的益处。临床医生应仔细监测治疗期间以及此后几年的不良反应。需要进一步研究检查环磷酰胺的使用情况;他们应该有足够的能力来比较不同亚组内的结果，特别是根据高分辨率计算机断层扫描(HRCT)肺部浸润程度和SSc皮肤受累程度进行分层。需要研究其他形式的结缔组织疾病。研究人员可能会考虑比较环磷酰胺(一种有效的免疫抑制剂)与抗纤维化药物，或者比较两种药物与安慰剂，特别是那些有快速进展性纤维化疾病证据的患者，这些患者可能获益最多。

        参考文献：Approximately one-third ofindividuals with interstitial lung disease (ILD) have associated connectivetissue disease (CTD)

        Abstract background:The connective tissue disorders most commonly associatedwith ILD include scleroderma/systemic sclerosis (SSc), rheumatoid arthritis,polymyositis/dermatomyositis, and Sj?gren's syndrome. Although many people withCTD-ILD do not develop progressive lung disease, a significant proportion doprogress, leading to reduced physical function, decreased quality of life, anddeath. ILD is now the major cause of death amongst individuals with systemic sclerosis.Cyclophosphamideis a highly potent immunosuppressant that has demonstrated efficacy in inducingand maintaining remission in autoimmune and inflammatory illnesses. Howeverthis comes with potential toxicities, including nausea, haemorrhagic cystitis,bladder cancer, bone marrow suppression, increased risk of opportunisticinfections, and haematological and solid organ malignancies.Decision-making inthe treatment of individuals with CTD-ILD is difficult; the clinician needs toidentify those who will develop progressive disease, and to weigh up thebalance between a high level of need for therapy in a severely unwell patientpopulation against the potential for adverse effects from highly toxic therapy,for which only relatively limited data on efficacy can be found. Similarly, itis not clear whether histological subtype, disease duration, or disease extentcan be used to predict treatment responsiveness.OBJECTIVES: To assess theefficacy and adverse effects of cyclophosphamide in the treatment of individualswith CTD-ILD.SEARCH METHODS: We performed searches on CENTRAL, MEDLINE, Embase,CINAHL, and Web of Science up to May 2017. We handsearched review articles,clinical trial registries, and reference lists of retrieved articles.SELECTIONCRITERIA: We included randomised controlled parallel-group trials that comparedcyclophosphamide in any form, used individually or concomitantly with otherimmunomodulating therapies, versus non-cyclophosphamide-containing therapiesfor at least six months, with follow-up of at least 12 months from the start oftreatment.DATA COLLECTION AND ANALYSIS: We imported studies identified by thesearch into a reference manager database. We retrieved the full-text versionsof relevant studies, and two review authors independently extracted data.Primary outcomes were change in lung function (change in forced vital capacity(FVC) % predicted and diffusing capacity of the lung for carbon monoxide (DLCO)% predicted), adverse events, and health-related quality of life measures. Secondaryoutcomes included all-cause mortality, dyspnoea, cough, and functional exercisetesting. When appropriate, we performed meta-analyses and subgroup analyses byseverity of lung function, connective tissue disease diagnosis, andradiological pattern of fibrosis. We assessed the evidence using the Grading ofRecommendations Assessment, Development and Evaluation (GRADE) approach andcreated 'Summary of findings' tables.MAIN RESULTS: We included in the analysisfour trials with 495 participants (most with systemic sclerosis). We formed twoseparate comparisons: cyclophosphamide versus placebo (two trials, 195participants) and cyclophosphamide versus mycophenolate (two trials, 300participants). We found evidence to be of low quality, as dropout rates werehigh in the intervention groups, and as we noted a wide confidence intervalaround the effect with small differences, which affected the precision ofresults.The data demonstrates significant improvement in lung function withcyclophosphamide compared with placebo (post-treatment FVC % mean difference(MD) 2.83, 95% confidence interval (CI) 0.80 to 4.87; P = 0.006) but nosignificant difference in post-treatment DLCO (% MD -1.68, 95% CI -4.37 to1.02; P = 0.22; two trials, 182 participants).Risk of adverse effects wasincreased in the cyclophosphamide treatment groups compared with the placebogroups, in particular, haematuria, leukopenia, and nausea, leading to a higherrate of withdrawal from cyclophosphamide treatment. The data demonstratesstatistically significant improvement in one-measure of quality of life in onetrial favouring cyclophosphamide over placebo and clinically and statisticallysignificant improvement in breathlessness in one trial favouringcyclophosphamide compared with placebo, with no significant impact onmortality.Trialists reported no significant impact on lung function whencyclophosphamide was used compared with mycophenolate at 12 months (FVC % MD-0.82, 95% CI -3.95 to 2.31; P = 0.61; two trials, 149 participants; DLCO % MD-1.41, 95% CI -10.40 to 7.58; P = 0.76; two trials, 149 participants).Risk ofside effects was increased with cyclophosphamide versus mycophenolate, inparticular, leukopenia and thrombocytopenia.The data demonstrates nosignificant impact on health-related quality of life, all-cause mortality,dyspnoea, or cough severity in the cyclophosphamide group compared with themycophenolate group. No trials reported outcomes associated with functionalexercise tests.We performed subgroup analysis to determine whether severity oflung function, connective tissue disease diagnosis, or radiological pattern hadany impact on outcomes. One trial reported that cyclophosphamide protectedagainst decreased FVC in individuals with worse fibrosis scores, and alsoshowed that cyclophosphamide may be more effective in those with worse lungfunction. No association could be made between connective tissue diseasediagnosis and outcomes.AUTHORS' CONCLUSIONS: This review, which is based onstudies of varying methodological quality, demonstrates that overall, in thispopulation, small benefit may be derived from the use of cyclophosphamide interms of mean difference in % FVC when compared with placebo, but not of thedifference in % DLCO, or when compared with mycophenolate. Modest clinicalimprovement in dyspnoea may be noted with the use of cyclophosphamide. Clinicalpractice guidelines should advise clinicians to consider individual patientcharacteristics and to expect only modest benefit at best in preserving FVC.Clinicians should carefully monitor for adverse effects during treatment and inthe years thereafter.Further studies are required to examine the use ofcyclophosphamide; they should be adequately powered to compare outcomes withindifferent subgroups, specifically, stratified for extent of pulmonaryinfiltrates on high-resolution computed tomography (HRCT) and skin involvementin SSc. Studies on other forms of connective tissue disease are needed.Researchers may consider comparing cyclophosphamide (a potent immunosuppressant)versus antifibrotic agents, or comparing both versus placebo, in particular,for those with evidence of rapidly progressive fibrotic disease, who maybenefit the most.