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.
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.
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 Appropriate officials at Sandoz Corporation were contacted to seek information on any unpublished trials.
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.
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.
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.
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。
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(chisquare 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。