环磷酰胺治疗CTD-ILD的疗效与安全性分析 | 引经据典[8] · 协和呼吸
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随着多种新型免疫抑制剂的推广应用，传统老药环磷酰胺在治疗CTD-ILD的地位究竟如何呢？
本/期/解/读
环磷酰胺治疗结缔组织疾病相关性间质性肺病的疗效与安全性分析
Cyclophosphamide for connective tissue disease-associated interstitial lung disease
关键词
环磷酰胺，结缔组织疾病相关性间质性肺病，疗效，安全性
作者：
Barnes H, et. al
翻译：
北京协和医院呼吸内科 孙宇新 黄慧
文献来源：
Cochrane Database Syst Rev. 2018 Jan 3;1:CD010908
DOI:
10.1002/14651858.CD010908
背 景
间质性肺病（ILD）是结缔组织疾病（CTD）常见的呼吸系统并发症，对CTD患者的生活质量、生存影响甚大。环磷酰胺（CTX）是自身免疫病、炎症性疾病的诱导缓解、维持治疗中常用的免疫抑制剂，不过，CTX也有恶心、出血性膀胱炎、骨髓抑制、潜在的致癌作用等副作用。本文将对于CTX治疗CTD-ILD的相关文献进行系统复习，以评价CTX对于CTD-ILD的疗效及安全性。
方 法
通过CENTRAL、MEDLINE、Embase、CINAHL、Web of science等数据库，检索2017年以前的关于CTX的随机、对照试验，CTX的治疗期至少6月，疗效随访至少12月。
结 果
1、入选4个临床试验（大多是系统性硬化症相关性ILD）共495例受试者:CTX与安慰剂对照（2个临床试验，195例），CTX与吗替麦考芬酯对照（2个临床试验，300例）；
2、疗效：（1）CTX相对于安慰剂而言，能改善CTD-ILD患者的用力肺活量（FVC）[治疗后FVC%预计值改善2.83%，95%可信区间（CI）0.8-4.87，p=0.006）]；未能延缓一氧化氮弥散率（DLCO%）的下降[治疗后DLCO%预计值下降1.68%预计值，95% CI -4.37-1.02，p=0.88]。其中一个试验提示CTX组的生活质量较安慰剂组有改善，一个临床试验提示CTX组呼吸困难较安慰剂组有改善，但两组之间死亡率无差异。（2）CTX相对于吗替麦考芬酯:在肺功能指标FVC、DLCO方面（入组12月时）两者无差异。FVC%预计值的差异-0.82%，95%CI -3.95-2.31，p=0.61；DLCO%预计值的差异-1.41%, 95% CI-10.4-7.58, p=0.76。两组间在生活质量、全因死亡率、呼吸困难及咳嗽严重程度等方面，CTX组与吗替麦考芬酯组之间无显著性差异。
图 环磷酰胺和安慰剂效果比较（Barnes H, 2018）
3、副作用：（1）CTX相对于安慰剂而言，副作用明显增加，主要表现为血尿、白细胞减少、恶心。（2）CTX相对于吗替麦考芬酯: CTX组更易出现白细胞减少、血小板减少。
结 论
相对于安慰剂而言，CTX组能改善CTD-ILD的肺功能指标中的FVC%预计值，但DLCO%预计值两组间无差异；CTX组与吗替麦考芬酯组之间在肺功能指标上无差异。CTX治疗可改善CTD-ILD患者的呼吸困难。鉴于副作用在CTX组更多见，建议在CTX治疗期间及停药后一段时间，监测CTX相关的毒副作用。
展 望
建议在将来的临床试验中：
1、可以分不同的亚组进行分层分析，包括胸HRCT的ILD严重程度、SSc患者的皮肤病变程度等方面；
2、纳入不同种类的CTD患者；
3、比较CTX与抗纤维化药物、比较CTX+抗纤维化制剂与安慰剂在CTD-ILD中的作用，尤其是对于快速进展的纤维化型CTD-ILD患者。
Abstract
Background
Approximately one-third of individuals with interstitial lung disease (ILD) have associated connective tissue disease (CTD). Although many people with CTD-ILD do not develop progressive lung disease, a significant proportion do progress, leading to reduced physical function, decreased quality of life, and death. ILD is now the major cause of death amongst individuals with systemic sclerosis. Cyclophosphamide is a highly potent immunosuppressant that has demonstrated efficacy in inducing and maintaining remission in autoimmune and inflammatory illnesses. However this comes with potential toxicities, including nausea, haemorrhagic cystitis, bladder cancer, bone marrow suppression, increased risk of opportunistic infections, and haematological and solid organ malignancies.
Objectives
To assess the efficacy and adverse effects of cyclophosphamide in the treatment of individuals with 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.
Selection criteria
We included randomised controlled parallel-group trials that compared cyclophosphamide in any form, used individually or concomitantly with other immunomodulating therapies, versus non-cyclophosphamide-containing therapies for at least six months, with follow-up of at least 12 months from the start of treatment.
Data collection and analysis
We imported studies identified by the search into a reference manager database. We retrieved the full-text versions of 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. Secondary outcomes included all-cause mortality, dyspnoea, cough, and functional exercise testing. When appropriate, we performed meta-analyses and subgroup analyses by severity of lung function, connective tissue disease diagnosis, and radiological pattern of fibrosis. We assessed the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach and created ’Summary of findings’ tables.
Main results
1. We included in the analysis four trials with 495 participants (most with systemic sclerosis).We formed two separate comparisons: cyclophosphamide versus placebo (two trials, 195 participants) and cyclophosphamide versus mycophenolate (two trials, 300 participants). We found evidence to be of low quality, as dropout rates were high in the intervention groups, and as we noted a wide confidence interval around the effect with small differences, which affected the precision of results.
2. The data demonstrates significant improvement in lung function with cyclophosphamide compared with placebo (post-treatment FVC % mean difference (MD) 2.83, 95% confidence interval (CI) 0.80 to 4.87; P = 0.006) but no significant difference in post-treatment DLCO (% MD -1.68, 95% CI -4.37 to 1.02; P = 0.22; two trials, 182 participants). Risk of adverse effects was increased in the cyclophosphamide treatment groups compared with the placebo groups, in particular, haematuria, leukopenia, and nausea, leading to a higher rate of withdrawal from cyclophosphamide treatment. The data demonstrates statistically significant improvement in one-measure of quality of life in one trial favouring cyclophosphamide over placebo and clinically and statistically significant improvement in breathlessness in one trial favouring cyclophosphamide compared with placebo, with no significant impact on mortality.
3. Trialists reported no significant impact on lung function when cyclophosphamide was used compared with mycophenolate at 12months (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 of side effects was increased with cyclophosphamide versus mycophenolate, in particular, leukopenia and thrombocytopenia.
4. The data demonstrates no significant impact on health-related quality of life, all-cause mortality, dyspnoea, or cough severity in the cyclophosphamide group compared with the mycophenolate group. No trials reported outcomes associated with functional exercise tests.
5. We performed subgroup analysis to determine whether severity of lung function, connective tissue disease diagnosis, or radiological pattern had any impact on outcomes. One trial reported that cyclophosphamide protected against decreased FVC in individuals with worse fibrosis scores, and also showed that cyclophosphamide may be more effective in those with worse lung function. No association could be made between connective tissue disease diagnosis and outcomes.
Authors’ conclusions
This review, which is based on studies of varying methodological quality, demonstrates that overall, in this population, small benefit may be derived from the use of cyclophosphamide in terms of mean difference in % FVC when compared with placebo, but not of the difference in % DLCO, or when compared with mycophenolate. Modest clinical improvement in dyspnoea may be noted with the use of cyclophosphamide. Clinical practice guidelines should advise clinicians to consider individual patient characteristics and to expect only modest benefit at best in preserving FVC. Clinicians should carefully monitor for adverse effects during treatment and in the years thereafter.
Further studies are required to examine the use of cyclophosphamide; they should be adequately powered to compare outcomes within different subgroups, specifically, stratified for extent of pulmonary infiltrates on high-resolution computed tomography (HRCT) and skin involvement in 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 may benefit the most.
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作者介绍
孙宇新
北京协和医院呼吸内科硕士在读
北京协和医院呼吸内科2018级硕士研究生，所在课题组主要从事间质性肺病方向的临床和基础研究。
往期经典
文字来源：孙宇新 黄慧
栏目负责：黄慧
版面编辑：陈珂琪
图片来源：部分来源于网络，如有侵权，请联系删除
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