風濕

環磷酰胺治療結締組織病相關性間質性肺病的優缺點

作者:翻譯者:巴燕娜,西京醫院臨床免疫科 來源: 西京風濕免疫 日期:2018-05-03
導讀

         環磷酰胺治療結締組織病相關性間質性肺病的優缺點

關鍵字:  環磷酰胺 |  

        大約三分之一的間質性肺病(ILD)患者伴有結締組織病(CTD)。最常見的與ILD相關的結締組織病症包括硬皮病/係統性硬化症(SSc),類風濕性關節炎,多發性肌炎/皮肌炎和幹燥綜合征。盡管許多CTD-ILD患者不發展為進行性肺部疾病,但其中很大一部分病情進展,導致身體各器官功能降低,生活質量下降和死亡。 ILD現在是係統性硬化症患者死亡的主要原因。環磷酰胺是一種高度有效的免疫抑製劑,在誘導和維持自身免疫性和炎症性疾病緩解方麵療效顯著。然而,這伴隨著潛在的毒性,包括惡心,出血性膀胱炎,膀胱癌,骨髓抑製,機會性感染等風險增加,以及血液和實體器官惡性腫瘤增加。用CTD-ILD治療個體的決策非常困難;臨床醫師需要確定那些將發展為進行性疾病的患者,並衡量嚴重不適患者群體的高水平治療需求與高毒性治療不良反應的潛在可能性之間的平衡,但目前僅有相對有限的數據療效。同樣,尚不清楚組織學亞型,疾病持續時間或疾病程度是否可用於預測治療反應性。

        目的:

        評估環磷酰胺在治療CTD -ILD患者中的療效和不良反應。

        方法:

        我們進行在2017年5月之前在CENTRAL,MEDLINE,Embase,CINAHL和Web ofScience上進行搜索。我們手工檢索了評論文章,臨床試驗注冊表和檢索條目的參考文獻列表。

        選擇標準:

        我們納入了隨機對照平行組試驗,將環磷酰胺任何形式,單獨使用或與其他免疫調節療法一起使用,與使用非環磷酰胺治療至少6個月,從治療開始至少12個月隨訪。

        數據收集與分析:

        搜索參考管理數據庫。我們檢索了相關研究的全文版本,兩位評論作者獨立提取數據。主要結局指標是肺功能的變化(預計用力肺活量(FVC)%預計值和肺一氧化碳擴散能力(DLCO)%預計值),不良事件以及與健康相關的生活質量指標。次要終點包括全因死亡率,呼吸困難,咳嗽和功能鍛煉測試。適當時,我們根據肺功能嚴重程度,結締組織病診斷和纖維化的放射模式進行薈萃分析和亞組分析。我們使用建議評估,發展和評估評級(GRADE)方法評估證據,並創建了“發現摘要”表。

        主要結果:

        我們納入了495名參與者(大多數患有係統性硬化症)的分析中的四項試驗。我們形成了兩個獨立的比較:環磷酰胺與安慰劑(兩項試驗,195名參與者)和環磷酰胺與黴酚酸酯(兩項試驗,300名參與者)。我們發現證據質量較差,因為幹預組的失訪率很高,而且我們注意到影響結果精確度的效應周圍存在寬泛的置信區間,影響結果的精確度。數據顯示肺功能顯著改善(治療後FVC%平均差異(MD)2.83,95%置信區間(CI)0.80-4.87; P = 0.006),但治療後DLCO無顯著差異(%MD -1.68,95%CI -4.37至1.02; P = 0.22;兩項試驗,182名參與者)。與安慰劑組相比,環磷酰胺治療組的不良反應風險增加,特別是血尿,白細胞減少症和惡心,導致停用率升高。

        數據表明,在一項有利於環磷酰胺的試驗中,一項生存質量的統計學顯效性改善優於安慰劑,一項有利於環磷酰胺的試驗的臨床和統計學顯著改善,與安慰劑相比,對死亡率沒有顯注影響。試驗組報告沒有顯注影響(FVC%MD -0.82,95%CI-3.95至2.31; P = 0.61;兩項試驗,149名參與者; DLCO%MD -1.41,95%CI-10.40至95%CI)的肺功能與使用環磷酰胺7.58; P = 0.76;兩項試驗,149名參與者)。環磷酰胺與黴酚酸酯相比,副作用的風險增加,特別是白細胞減少症和血小板減少症。數據表明對健康相關生活質量,全因死亡率,呼吸困難或咳嗽嚴重程度的環磷酰胺組與黴酚酸組相比。沒有試驗報告與功能性運動試驗相關的結果。我們進行亞組分析以確定肺功能,結締組織疾病診斷或放射模式的嚴重程度是否對結果有任何影響。一項試驗報道,環磷酰胺能夠防止纖維化評分較差的患者的FVC下降,並且還顯示環磷酰胺可能對肺功能更差的患者更有效。

        研究結論:

        本綜述基於不同方法學質量的研究,表明總體而言,在這一人群中,小環境的好處可能來源於使用環磷酰胺與安慰劑相比,%FVC的平均差異,但不是%DLCO的差異,或者與黴酚酸酯相比。使用環磷酰胺可能會引起呼吸困難的臨床改善。臨床實踐指南應該建議臨床醫生考慮個體患者的特征,並且期望在保留FVC方麵僅有適度的益處。臨床醫生應仔細監測治療期間以及此後幾年的不良反應。需要進一步研究檢查環磷酰胺的使用情況;他們應該有足夠的能力來比較不同亞組內的結果,特別是根據高分辨率計算機斷層掃描(HRCT)肺部浸潤程度和SSc皮膚受累程度進行分層。需要研究其他形式的結締組織疾病。研究人員可能會考慮比較環磷酰胺(一種有效的免疫抑製劑)與抗纖維化藥物,或者比較兩種藥物與安慰劑,特別是那些有快速進展性纖維化疾病證據的患者,這些患者可能獲益最多。

        參考文獻: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.

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