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 strategy: 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.