Cyclosporine A for induction of remission in severe ulcerative colitis

  • Review
  • Intervention




Ulcerative colitis (UC) is characterized by a life-long chronic course with remissions and exacerbations. Approximately 15% of patients have a severe attack requiring hospitalization at some time during their illness. These patients are traditionally treated with intravenous corticosteroids, with a response rate of approximately 60%. The patients who do not respond to steroid treatment usually require surgical removal of the large bowel (proctocolectomy or colectomy with an anal pouch). This surgical procedure essentially cures the patient from the disease but is associated with complications such as pouchitis. Few alternative treatments exist for severe ulcerative colitis: immunosuppressive medications (such as azathioprine) have a slow onset of action and are therefore usually ineffective. Antibiotics are not proven to be effective and biological treatments such as infliximab are still under investigation. The introduction of cyclosporine-A (CsA) for use in patients with severe ulcerative colitis (UC) has provided an alternative to patients previously facing only surgical options. Cyclosporine acts mainly by inhibiting T lymphocyte function, which is essential for the propagation of inflammation. Unlike most other immunosuppressive agents, CsA does not suppress the activity of other hematopoietic cells, does not cause bone marrow suppression and has a rapid onset of action. This reviews aims to systematically assess the effectiveness and safety of CsA for severe UC.


This review aimed to evaluate the effectiveness of cyclosporine A for patients with severe ulcerative colitis.

Search methods

Electronic searches of The Cochrane Library (Issue 2, 2008), EMBASE (1980-2008), and MEDLINE (1966-2008); hand searching the references of all identified studies; contacting the first author of each included trial.

Selection criteria

Randomised clinical trials comparing cyclosporine A with placebo or no intervention to obtain and maintain remission of idiopathic ulcerative colitis.

Data collection and analysis

Two reviewers independently appraised the quality of each trial and extracted the data from the included trials. Relative risks (RR) with 95% confidence intervals (CI) were estimated. The reviewers assumed an intention to treat analysis for the outcome measures.

Main results

An updated literature search performed in July 2008 did not identify any new trials. Only two randomized controlled trials were identified that satisfied the inclusion criteria. These two trials could not be pooled for analysis because of major differences in design and patient populations. In the first trial, 11 patients received intravenous cyclosporine (4 mg/kg) and 9 received placebo. Two of 11 in the treatment group failed to respond to therapy compared with nine of nine in the placebo group (RR 0.18, 95% CI 0.05 - 0.64). However, 3/11 and 4/9 eventually underwent colectomy in the treatment and placebo groups respectively and follow-up was less than a month. In the second trial 15 patients were treated with intravenous cyclosporine and 15 with intravenous methylprednisolone. Five of 15 patients in the cyclosporine group failed to respond to therapy as compared to 7/15 in the methylprednisolone group (RR 0.71, 95% CI 0.29 - 1.75). After 1 year 7/9 responders in the cyclosporine group were still in remission compared with 4/8 in the steroid group (p > 0.05) and the colectomy rate was similar in both groups. The mean time to response in the cyclosporine group in the 2 trials was short (7 days and 5.2 days). These results should be interpreted with caution given the small numbers of trials and patients evaluated for comparison, and limited follow-up (few weeks in one trial to a year in the other). The precise assessment of the occurrence of adverse events was difficult because the trials described different adverse reactions, which reversed after discontinuation of cyclosporine. There was no evidence in the trials reviewed that cyclosporine was more effective than standard treatment for preventing colectomy but this effect cannot be excluded due to the small sample size and rarity of this outcome. Additional limitations of current research include lack of data on quality of life, costs and long-term results of cyclosporine therapy.

Authors' conclusions

There is limited evidence that cyclosporine is more effective than standard treatment alone for severe ulcerative colitis. The relatively quick response makes the short-term use of cyclosporine potentially attractive, but the long-term benefit is unclear, when adverse events such as cyclosporine-induced nephrotoxicity may become more obvious. There is a need for additional research on quality of life, costs and long-term results from cyclosporine therapy in severe ulcerative colitis.



以環孢靈素A(Cyclosporine, CSA)緩解重度潰瘍性大腸炎

潰瘍性大腸炎(ulcerative colitis,UC)是終身反覆緩解和惡化的慢性疾病。大約15%的病患在其病程中某一時段會嚴重到需要住院。傳統上這些病患會接受靜脈注射皮質類固醇治療,其中有60%的患者會改善。類固醇治療沒改善的患者通常需要手術切除大腸(直腸或結腸切除加人工肛門)。這手術基本上可治癒病患,但常會併發如囊炎(pouchitis)之類的併發症。有些許替代療法可用來治療重度潰瘍性大腸炎:免疫抑制劑(如Azathioprine)藥效起始慢且因此常無效;抗生素未被證實有效;像infliximab的生物治療效果仍在研究階段。當重度潰瘍性大腸炎患者面對只有手術的選擇時,環孢靈素A曾考慮為另一個替代性選擇。環孢靈素主要是藉由抑制造成發炎反應擴大主要因素的T淋巴球。不像其他多數的免疫抑制劑抑制其他造血細胞的活性,環孢靈素A不會引發骨髓抑制現象,並且療效起始快。本回顧目的在評估全身性投與環孢靈素A對重度潰瘍性大腸炎的效果與安全性。




電腦搜尋The Cochrane Library (Issue1, 2004)、 EMBASE (1980年至2004年)及MEDLINE (1966年至2004年);人工搜尋所有找到試驗的參考文獻,並與各收納試驗的第一作者聯絡。










此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。
















2008年7月に実施された最新の文献検索から、新たな試験は同定されなかった。選択基準を満たしたランダム化比較試験はわずか2件が同定されたにすぎない。試験デザインおよび患者集団に重大な差があったため、これらの試験2件を解析のための統合はできなかった。最初の試験では、患者11例で静注シクロスポリン(4mg/kg)が投与され、9例でプラセボが投与されていた。治療群の患者11例のうち奏効がみられなかったのは2例であったのに対し、プラセボ群では9例のうち9例で奏効がみられなかった(RR 0.18、95%CI 0.05~0.64)。しかし、治療群11例のうち3例およびプラセボ群9例のうち4例でそれぞれ最終的に結腸切除術が施行されており、経過観察期間は1ヶ月未満であった。2番目の試験では、患者15例が静注シクロスポリンで治療され、患者15例が静注メチルプレドニゾロンで治療されていた。シクロスポリン群の患者15例のうち5例で奏効はみられず、対してメチルプレドニゾロン群では15例のうち7例で奏効がみられなかった(RR0.71、95%CI 0.29~1.75)。1年後、シクロスポリン群の治療に奏効した9例のうち7例は依然として寛解期にあったが、対するステロイド群では8例のうち4例が寛解期にあり(p>0.05)、結腸切除術を受けた患者の割合は両群とも同様であった。2試験ともシクロスポリン群の奏効に至る平均日数は短かった(7日および5.2日)。これらの結果は、比較のために評価された試験数も患者数も少なく、経過観察期間も限られていた(試験1件では数週間、別の試験では1年)ことから、慎重な解釈が必要である。試験では、シクロスポリン中止後に回復していたが異なる有害反応が報告されていたことから、有害事象の発現についての正確な評価は困難であった。レビューした試験には、結腸切除術を回避するためにシクロスポリンが標準療法よりも有効であるというエビデンスはなかったが、サンプルサイズが小さく、このアウトカムもまれであるため、この薬剤の効果を除外することはできない。最近の研究は他にも、生活の質、経費、シクロスポリン療法の長期的な結果に関するデータが欠如していることから限界がある。




監  訳: 柴田 実,2009.2.24

実施組織: 厚生労働省委託事業によりMindsが実施した。

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Plain language summary

Cyclosporine A for induction of remission in severe ulcerative colitis

Ulcerative colitis (UC) is a chronic inflammation of the large bowel. Symptoms include bloody diarrhea and abdominal pain. The disease can also have manifestations outside the bowel with involvement of the joints, skin, eyes and liver. While the 'first line' treatment for a severe attack of UC is usually steroids (either as pills or intravenously) the options for patients not responding to steroids are limited and include surgical removal of the large bowel. Cyclosporine A (CsA), a drug effective in preventing transplant organ rejection by suppressing the immune system, was tried in severe UC with encouraging results in the early 1990's. The aim of this review was to assess the effectiveness of CsA for severe UC. The literature search identified 36 studies. Only 2 studies were of high methodological quality and both support the use of CsA in UC patients with a severe attack. However, both studies were small (involving only 50 patients altogether) and limited in the length of follow-up (from a few weeks up to a year). There is limited evidence that cyclosporine is more effective than standard treatment for severe ulcerative colitis. The conclusion of the review is that while the data concerning the use of CsA in severe UC are encouraging, more studies are needed.