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Cyclosporine for induction of remission in Crohn's disease

  • Review
  • Intervention

Authors


Abstract

Background

Cyclosporine was first found to be an effective and well-tolerated immunosuppressive agent in organ transplant recipients, and subsequently in several autoimmune diseases. It was reported in open studies that cyclosporine is effective for induction of remission in Crohn's disease. Four randomized controlled trials have been performed to determine whether the results observed in these open studies were valid. This systematic review summarizes the evidence on the use of oral cyclosporine for the induction of remission in Crohn's disease.

Objectives

To evaluate the effectiveness of oral cyclosporine for induction of remission in patients with active Crohn's disease in the presence and absence of concomitant steroid therapy. Secondary objectives were to evaluate clinical response rates and adverse events associated with cyclosporine.

Search methods

Computer-assisted searches of the on-line bibliographic databases MEDLINE and EMBASE were performed to identify potentially relevant publications between 1980 and June 2008. The MeSH terms "Crohn Disease" or "Inflammatory Bowel disease" and "Cyclosporin" (exploded) were used to perform key word searches of the databases. Manual searches of reference lists from potentially relevant papers were performed in order to identify additional studies that may have been missed. Abstracts from major gastroenterological meetings, The Cochrane Central Register of Controlled Trials and the Cochrane Inflammatory Bowel Disease Group Specialized Trials Register were also searched for relevant studies. Appropriate officials at Sandoz Corporation were contacted to seek information on any unpublished trials.

Selection criteria

Prospective, randomized, double-blinded, placebo-controlled trials of parallel design with treatment duration of a minimum 12 weeks comparing oral cyclosporine therapy with placebo for treatment of patients with active Crohn's disease were eligible for inclusion.

Data collection and analysis

All data were analyzed on an intention-to-treat basis. Data were extracted from the original research articles and converted into 2x2 tables (cyclosporine vs. placebo). Where available, individual 2x2 tables for strata within studies were also used. Heterogeneity was assessed using the chi-square test (p < 0.10 was regarded as statistically significant). For non-pooled data, p-values were derived using the chi-square test. For pooled data, summary test statistics were derived using the Peto odds ratio and 95% confidence intervals. A fixed effects model was used for pooling of data. For continuous data, summary test statistics were derived using the weighted mean difference and 95% confidence intervals. The definitions of treatment success, remission and clinical improvement were set by the authors of each paper, and the data were combined for analysis only if these definitions were sufficiently similar.

Main results

Brynskov 1989a found that patients receiving high dose cyclosporine (median 7.6 mg/kg/day) had statistically significant clinical improvement at 12 weeks compared to placebo patients. None of the other studies found any statistically significant benefit for clinical improvement or induction of remission for low dose cyclosporine treatment (5 mg/kg/day) used by itself or in combination with corticosteroids compared to placebo. Cyclosporine was associated with a significantly higher proportion of adverse events and withdrawals due to adverse events relative to placebo.

Authors' conclusions

Brynskov 1989a enrolled a small number of patients and the modified clinical grading scale used in the study has not been validated in other studies. Furthermore, statistically significant clinical improvement does not imply induction of clinical remission. Indeed, Brynskov 1989a found no statistically significant differences in the mean Crohn's Disease Activity Index score at 12 weeks indicating that cyclosporine was no more effective than placebo for induction of remission in Crohn's disease. The results of this review demonstrate that low dose (5 mg/kg/day) oral cyclosporine is not effective for the induction of remission in Crohn's disease. Patients treated with low dose oral cyclosporine are more likely than placebo treated patients to experience adverse events including renal dysfunction. The use of low dose oral cyclosporine for the treatment of chronic active Crohn's disease does not appear to be justified. Oral dosing at higher levels or parenteral administration of cyclosporine have not been adequately evaluated in controlled clinical trials. Higher doses of cyclosporine are not likely to be useful for the long-term management of Crohn's disease because of the risk of nephrotoxicity and the availability of other proven interventions.

摘要

使用Cyclosporine緩解克隆氏症

研究背景

Cyclosporine是第一個被發現對於器官移植患者功效及耐受度良好的免疫抑制劑,後續也被發現對於部分自體免疫疾病有療效。有公開的研究指出Cyclosporine具有緩解克隆氏症緩解的效果,有四個隨機性對照試驗可以被用來決定這些開放性研究中的哪些結果是有效度的。本系統性文獻回顧總結了使用口服Cyclosporine緩解克隆氏症效果的證據。

研究目的

評估對於已經使用類固醇治療或沒有使用類固醇治療的活性克隆氏症患者來說,使用口服Cyclosporine狀緩解效果的成效,其次是要評估臨床反應率和與Cyclosporine有關的不良事件。

检索策略

電腦輔助搜尋線上書目型資料庫 MEDLINE以及EMBASE 以找出介於1980年及2004年7月間的相關研究。使用的MeSH 辭彙包括“Crohn Disease” 或“Inflammatory Bowel disease” 以及 “Cyclosporin” (exploded)以利在該資料庫當中進行關鍵字搜尋。人工搜尋相關研究的參考文獻清單以找出可能遺漏掉的研究。並搜尋主要的腸胃道會議、Cochrane Central Register of Controlled Trials and Cochrane Inflammatory Bowel Disease Group Specialized Trials Register were 的摘要以找出相關研究。並與Sandoz Corporation合適的官員聯絡以取得未發表試驗的資訊。

标准/纳入排除标准

前瞻性、隨機性、雙盲性、具有安慰劑對照組的平行設計,以12星期為最短治療時間,並比較使用口服Cyclosporine和安慰劑對於活性克隆氏症患者治療效果的試驗符合納入標準。

数据收集与分析

所有數據都以治療意向為基礎進行分析,由原始研究文獻所摘錄出數據會被整合轉換成2×2的表格(Cyclosporine和安慰劑)。在可行的狀況下,也會使用研究內各層個別的2×2表格,利用卡方試驗(chisquare test)計算研究的異質性(p值小於0.01時視為具有統計學上的顯著性),對於沒有匯整的數據,也可利用卡方試驗來計算出p值,對於可以整合的數據,利用勝算比(Peto odds ratio)和95%CI來描述檢驗統計結果。對於匯整的數據也會採用固定效應模式。 此外對於連續性的數據,則是利用加權平均差異和95%CI來呈現檢測統計結果。治療成功、緩解和臨床上改善…等定義則是由每個研究的作者自行訂定,當定義都十分雷同時,便可以將數據集合並加以分析。

主要结果

Brynskov(1989a)發現,使用高劑量Cyclosporine(每天每公斤患者使用的劑量中間值為7.6毫克)的患者在第12週時,統計上明顯比使用安慰劑的病患出現更好的臨床改善。 但是不論是單獨或搭配糖皮質類處固醇使用低劑量的Cyclosporine(每天每公斤使用的劑量為5.0毫克)時,則沒有其他研究顯示出Cyclosporine會比安慰劑更能在統計學上明顯的出現臨床改善效益或是可以緩解克隆氏症。相對於使用安慰劑來說,使用Cyclosporine顯著與不良事件有關。

作者结论

Brynskov(1989a)納入較少的試驗者並且修飾了其研究中的臨床評分標準,此臨床評分標準並無法適用於其他研究,此外,對於臨床上改善的統計顯著性不能暗示可以引起臨床緩解效果。的確,Brynskov(1989a)發現在第12週時,平均克隆氏症活性指標並沒有顯著差異,這說明了Cyclosporine對於產生克隆氏症的緩解效果並不會比安慰劑更好。 本文獻回顧的結果證明了低劑量(每天每公斤體重施以5毫克)的口服Cyclosporine並不會產生引發克隆氏症緩解的效果,而且使用低劑量口服Cyclosporine治療的患者可能會比與使用安慰劑的患者更容易出現不良事件,例如腎臟功能不全症。因此似乎是沒有理由使用低劑量的口服Cyclosporine來緩解克隆氏症,但是關於使用口服高劑量Cyclosporine或使用非口服Cyclosporine的效果並沒有在對照的臨床試驗中獲得適當的評估,高劑量的Cyclosporine因為具有可能引發腎毒性的風險和其他介入治療的功效,所以無法用來長期使用以維持克隆氏症的緩解功效。

Plain language summary

Cyclosporine for treatment of active Crohn's disease

The results of this review demonstrate that low dose oral cyclosporine is not effective for treatment of active Crohn's disease. Studies indicate that Crohn's patients treated with low dose (5 mg/kg/day) oral cyclosporine could experience side effects including kidney problems. Therefore the use of this medication for the treatment of chronic active Crohn's disease is not advisable. Higher oral doses and injections of cyclosporine have not been sufficiently evaluated. Larger doses of cyclosporine are not likely to be useful for the long-term management of Crohn's disease due to the risk of kidney damage and the availability of other proven medications.

概要

低劑量口服Cyclosporine並無法用來治療活性克隆氏症,本文獻回顧的結果證明了低劑量的Cyclosporine並不具有治療活性克隆氏症的功效,多個研究顯示克隆氏症患者接受低劑量(每天每公斤體重使用5毫克)口服Cyclosporine治療時,可能會出現包括腎臟問題在內的副作用,所以並不建議使用這個要劑來治療慢性活性克隆氏症,高口服劑量和針劑Cyclosporine的效果並未受到有效評估,因為有可能會產生腎臟損傷的風險,和有其他可選用的藥物的情況下,似乎不應該長期使用較高劑量的Cyclosporine治療克隆氏症。

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