Budesonide for maintenance of remission in Crohn's disease

 

Abstract

Background

Corticosteroids have been shown to be effective for induction, but not maintenance of remission in Crohn's disease. However, significant concerns exist regarding their risk for adverse events, particularly when used for long treatment courses. Budesonide is a glucocorticoid with limited systemic bioavailability due to extensive first-pass hepatic metabolism. Budesonide has been shown to be effective for induction of remission in Crohn's disease.

Objectives

To evaluate the efficacy and safety of oral budesonide for maintenance of remission in Crohn's disease.

Search methods

The following electronic databases were searched: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, the Cochrane IBD/FBD Group Specialised Trial Register, and ClinicalTrials.gov. Reference lists of articles, as well as conference proceedings were manually searched. Study authors, study sponsors and pharmaceutical companies were also contacted.

Selection criteria

Randomized controlled trials comparing budesonide to a control treatment, or comparing two doses of budesonide, were included. The study population included patients of any age with Crohn's disease in remission. The primary outcome was maintenance of remission at various reported follow-up times during the study, up to 12 months following enrollment. Secondary outcomes included: time to relapse, mean change in CDAI, clinical, histological or endoscopic improvement, improvement in quality of life, adverse events and study withdrawal.

Data collection and analysis

Two independent investigators reviewed studies for eligibility, extracted the data and assessed study quality using Jadad's criteria. A random or fixed effects model was chosen based on an assessment of heterogeneity, and studies were weighted using the DerSimonian & Laird or the Mantel-Haenszel method accordingly. Meta-analysis was performed using RevMan 4.2.10 software.

Main results

Eleven studies were included in the review: 8 studies compared budesonide with placebo, one compared budesonide to 5-aminosalicylates, one compared budesonide to traditional systemic corticosteroids, and one compared two doses of budesonide with no control group. Eight studies used a controlled ileal release form of budesonide, while three used a pH-modified release formulation. Budesonide 6 mg daily was no more effective than placebo for maintenance of remission at 3 months (RR 1.25; 95% CI 1.00 to 1.58; P = 0.05), 6 months (RR 1.15; 95% CI 0.95 to 1.39; P = 0.14), or 12 months (RR 1.13; 95% CI 0.94 to 1.35; P = 0.19). Budesonide was not more effective than weaning doses of prednisolone for maintenance of remission at 12 months (RR 0.79; 95% CI 0.55 to 1.13; P = 0.20), but was better than mesalamine 3 grams per day (RR of remission 2.51; 95% CI 1.03 to 6.12; P = 0.04). Budesonide 3 mg daily was more effective than placebo at 3 months (RR 1.31; 95% CI 1.03 to 1.67; P = 0.03). This benefit was not sustained at 6 months (RR 1.10; 95% CI 0.81 to 1.50; P = 0.53), or 12 months (RR 1.04; 95% CI 0.84 to 1.30; P = 0.70). No differences in efficacy were detected based on the different formulations of budesonide, methods used to induce remission, or budesonide dose. The use of budesonide 6 mg resulted in slight improvements in CDAI scores when assessed at 6 months (WMD -24.3; 95% CI -46.31 to -2.29; P = 0.03) and 12 months (WMD -23.49; 95% CI -46.65 to -0.32; P = 0.05) and mean time to relapse of disease (WMD 59.93 days; 95% CI 19.02 to 100.84; P = 0.004). Adverse events were more frequent in patients treated with 6 mg of budesonide compared with placebo (RR 1.49; 95% CI 1.01 to 2.19; P = 0.05), but not in patients using lower doses of budesonide. These events were relatively minor and did not result in increased rates of study withdrawal. Abnormal adrenocorticoid stimulation tests were seen more frequently in patients receiving both 6 mg daily (RR 2.88; 95% CI 1.72 to 4.82; P < 0.0001) and 3 mg daily (RR 2.73; 95% CI 1.34 to 5.57; P = 0.006) compared with placebo.

Authors' conclusions

Budesonide is not more effective than placebo or weaning prednisolone for maintenance of remission in Crohn's disease. Some modest benefits are noted in patients receiving budesonide compared with placebo in terms of lower CDAI scores and longer time to relapse of disease. However, these benefits are offset by higher treatment-related adverse event rates and more frequent adrenocorticoid suppression in patients receiving budesonide. Therefore, budesonide is not recommended for maintenance of remission in Crohn's disease.

 

Plain language summary

Budesonide for maintenance of remission in Crohn's disease

Budesonide is a newer corticosteroid drug which is rapidly metabolized by the liver thereby reducing corticosteroid related side effects. Research showing that budesonide is effective in treating active Crohn's disease has led to trials examining the effect of budesonide on reducing disease recurrence in non-active Crohn's disease. However, the use of budesonide (3 mg and 6 mg/day) among patients with non-active Crohn's disease was not effective for maintenance of remission over a 12-month period. Budesonide is not recommended for maintenance therapy in non-active Crohn's disease.

 

摘要

背景

Budesonide維持克羅氏症緩解的效果

皮質類固醇已知可以有效誘導克羅氏症緩解症狀，但未確定能維持克羅氏症緩解狀況。然而，類固醇所引發的不良事件，特別是長期使用，受到特別的關注。Budesonide是在首次通過肝即大量代謝故而全身性生物可利用性有限的腎上腺醣皮質激素。Budesonide已呈現可有效誘導克羅氏症緩解。

目標

評估口服Budesonide對於維持克羅氏症緩解現象的有效性和安全性。

搜尋策略

搜尋下列電子資料庫: MEDLINE、EMBASE、Cochrane Central Register of Controlled Trials, the Cochrane IBD/FBD Group Specialised Trial Register，以及ClinicalTrials.gov。並人工的方式搜尋文章的參考文獻以及研討會手冊。並且聯絡研究作者、研究贊助者以及藥廠。

選擇標準

納入比較budesonide和對照治療或比較兩種劑量的 budesonide的隨機性對照試驗。研究對象包括了所有年齡層克羅氏症緩解的患者。主要結果為追蹤收案高達12個月等不同能維持緩解效果的追蹤時間。次要結果包括復發時間、克隆氏症活性指數(Crohn's Disease Activity Index，CDAI)的平均變化值、臨床、病理或內視鏡檢查的改善狀況、生活品質的改善、不良事件和終止參與試驗。

資料收集與分析

兩個獨立的研究人員會審閱研究的採用、擷取數據和以Jadad's準則來評估試驗品質。根據異質性評估結果決定選用隨機模式效應或固定模式效應，並利用DerSimonian & Laird或是MantelHaenszel方法給予試驗加權評分，以及利用Rev Man 4.2.10軟體呈現統合分析結果。

主要結論

本回顧納入11篇試驗，其中8篇是Budesonide與安慰劑比較，1篇是budesonide與5Aminosalicylic acid (5ASA)比較，1篇是budesonide與傳統全身性類固醇比較，而1篇則是沒對照組下，比較兩種不同劑量的budesonide。有8個試驗使用控制在迴腸釋放型的budesonide，有3個試驗是利用酸鹼值調控釋放劑型。每天6毫克budesonide在3個月(相對風險 1.25，95% 信賴區間 1.00至1.58 ，P = 0.05)、6個月(相對風險 1.15，95% 信賴區間 0.95至1.39，P = 0.14)和12個月(相對風險 1.13，95% 信賴區間 0.94至1.35，P = 0.19)的維持緩解功效未優於安慰劑。在12個月的維持緩解功效，budesonide沒有比戒斷劑量的prednisolone更有效(相對風險0.79，95%信賴區間0.55至1.13，P = 0.20)，但比每天3公克mesalamine的效果好(緩解的相對風險2.51，95%信賴區間1.03至6.12 ，P = 0.04)。在3個月時，每天3毫克budesonide的效果優於安慰劑(相對風險1.31，95%信賴區間1.03至1.67，P = 0.03)。 這效果沒有維持到6個月 (相對風險1.10; 95% 信賴區間0.81至1.50; P = 0.53), 或12個月 (相對風險 1.04; 95% 信賴區間 0.84 至 1.30; P = 0.70).但在使用不同製劑的budesonide、誘發緩解方法或budesonide的劑量，在效果上沒有不同。在6個月(加權平均差異(Weighted mean difference，WMD) −24.3，95%信賴區間 −46.31至−2.29，P = 0.03)和12個月(加權平均差異−23.49，95%信賴區間 −46.65至−0.32，P = 0.05)的評估時，使用6毫克budesonide會在克隆氏症活性指數上有些許輕微的改善效果。疾病的平均復發時間也有改進(加權平均差異59.93天，95%信賴區間 19.02至100.84，P = 0.004)，與使用安慰劑組相比，使用6毫克budesonide發生不良事件的頻率較高(相對風險為)1.94，95%信賴區間1.01至2.19，P = 0.05)，但是在使用較低劑量的budesonide組別中則無此現象。這些事件相對輕微，且沒增加終止參與試驗的機率。與安慰劑相比，每天使用6毫克(相對風險2.88，95%信賴區間1.72至4.82，P<0.0001)與3毫克(相對風險 2.73，95%信賴區間1.34至5.57，P = 0.006) budesonide的病患較容易出現異常腎上腺皮素刺激測試結果。

作者結論

對於維持克隆氏症的緩解效果，budesonide沒有比安慰劑或戒斷劑量的prednisolone好。與安慰劑相比，budesonide在降低克隆氏症活性指數或是延遲疾病復發會有限度的優勢。但是這優勢因有較高相關的不良事件發生率與更易出現腎上腺皮質素抑制而被抵消。所以，不建議budesonide用來維持緩解克隆氏症。

翻譯人

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

總結

Budesonide是一較新型能快速被肝臟代謝降低皮質類固醇相關副作用的皮質類固醇。研究顯示budesonide可以有效治療有症狀的克隆氏症，所以進而進行budesonide對無症狀的克隆氏症降低疾病復發機率的研究。但是，對於無症狀的克隆氏症患者給予budesonide(每天3毫克和每天6毫克)並無法維持緩解效果超過12個月以上。不建議將budesonide使用於維持緩解無症狀的克隆氏症。