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Cochrane Database of Systematic Reviews: Plain Language Summaries [Internet]. Chichester, UK: John Wiley & Sons, Ltd; 2003-.

Cochrane Database of Systematic Reviews: Plain Language Summaries.

Budesonide for maintenance of remission in Crohn's disease

This version published: 2014; Review content assessed as up-to-date: June 12, 2014.

Plain language summary

Budesonide is a corticosteroid drug which is rapidly broken down by the liver, reducing corticosteroid‐related side effects (e.g., moon face). Research showing that budesonide is effective in treating active Crohn's disease has led to clinical trials examining the effect of budesonide on reducing disease recurrence in non‐active Crohn's disease.

This review identified 12 studies that included a total of 1273 participants. Eight studies compared budesonide with placebo (e.g. a sugar pill), one study compared budesonide to mesalamine (an anti‐inflammatory drug), one study compared budesonide to traditional systemic corticosteroids, one compared budesonide to azathioprine (an immunosuppressive drug), and one compared two doses of budesonide. Pooled analyses show that budesonide 6 mg daily was no more effective than placebo for maintenance of remission at 3 months (6 studies, 540 patients), 6 months (5 studies, 420 patients) or 12 months (5 studies, 420 patients). A pooled analysis showed that budesonide 3 mg daily was more effective than placebo for maintaining remission at 3 months (4 studies, 163 patients). However, there was no difference in continued remission rates between budesonide 3 mg/day and placebo at 6 months (3 studies, 180 patients) or 12 months (5 studies, 442 patients). The overall quality of the evidence from the studies comparing budesonide to placebo was rated as moderate due to lack of precision of the results. One study (90 patients) found no difference in continued remission rates at 12 months between budesonide and prednisolone. The overall quality of the evidence from this study was rated as low due to lack of precision of results and low methodological quality. One study (77 patients) found no difference in continued remission rates at 12 months between budesonide and azathioprine.The overall quality of the evidence from this study was rated as very low due to lack of precision of results and low methodological quality. One study (57 patients) found that budesonide (6 mg/day) was better than mesalamine for continued remission at 12 months. The overall quality of the evidence from this study was rated as very low due to lack of precision of results and low methodological quality. No differences in effectiveness were found for different doses or formulations of budesonide. The use of budesonide 6 mg/day resulted in slight improvements in Crohn's disease activity index (CDAI) scores when assessed at 6 months (5 studies, 420 patients) and 12 months (5 studies, 420 patients) and mean time to relapse of disease (4 studies, 171 patients). Mean time to relapse was significantly shorter for patients receiving budesonide than for those receiving azathioprine. Side effects were not more common in patients treated with budesonide compared to placebo. These side effects were relatively minor and did not result in increased rates of study withdrawal. Commonly reported treatment‐related side effects included acne, round face, body hair growth, mood swings, insomnia, weight gain, stretch marks, and hair loss. Abnormal adrenocorticoid stimulation tests were seen more frequently in patients receiving both budesonide 6 mg daily and 3 mg daily compared to placebo. The results of this review suggest budesonide is not effective for maintenance of remission in Crohn's disease, particularly when used beyond three months following induction of remission. Budesonide does have minor benefits in terms of lower CDAI scores and longer time to relapse of disease. However, these benefits are offset by higher treatment‐related side effect rates and more frequent adrenocorticoid suppression in patients receiving budesonide.

Abstract

Background: Corticosteroids are effective for induction, but not maintenance of remission in Crohn's disease. Significant concerns exist regarding the risk for adverse events, particularly when corticosteroids are used for long treatment courses. Budesonide is a glucocorticoid with limited systemic bioavailability due to extensive first‐pass hepatic metabolism and is 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 databases were searched from inception to 12 June 2014: PubMed, MEDLINE, EMBASE, CENTRAL, the Cochrane IBD/FBD Group Specialised Trial Register, and ClinicalTrials.gov. Reference lists of articles, as well as conference proceedings were manually searched.

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 quiescent Crohn's disease.

Data collection and analysis: Two independent investigators reviewed studies for eligibility, extracted data and assessed study quality using the Cochrane risk of bias tool. The primary outcome was maintenance of remission at various reported follow‐up times during the study. Secondary outcomes included: time to relapse, mean change in CDAI, clinical, histological, improvement in quality of life, adverse events and study withdrawal. We calculated the risk ratio (RR) and corresponding 95% confidence interval (95% CI) for dichotomous outcomes and the mean difference (MD) and 95% CI for continuous outcomes. Data were analysed on an intention‐to‐treat basis. The Chi2 and I2 statistics were used to assess heterogeneity. Random‐effects models were used to allow for expected clinical and statistical heterogeneity. The overall quality of the evidence supporting the primary outcome was assessed using the GRADE criteria.

Main results: Twelve studies (n = 1273 patients) were included in the review: eight studies compared budesonide to placebo, one compared budesonide to 5‐aminosalicylates, one compared budesonide to traditional systemic corticosteroids, one compared budesonide to azathioprine, and one compared two doses of budesonide. Nine studies used a controlled ileal release form of budesonide, while three used a pH‐modified release formulation. Nine studies were judged to be at low risk of bias. Three studies were judged to be at high risk of bias due to blinding and one of these studies also had inadequate allocation concealment. Budesonide 6 mg daily was no more effective than placebo for maintenance of remission at 3 months, 6 months or 12 months. At three months 64% of budesonide 6 mg patients remained in remission compared to 52% of placebo patients (RR 1.25, 95% CI 1.00 to 1.58; 6 studies, 540 patients). A GRADE analysis indicated that the overall quality of the evidence for this outcome was low due to moderate heterogeneity (I2 = 56%) and sparse data (315 events). At six months 61% of budesonide 6 mg patients remained in remission compared to 52% of placebo patients (RR 1.15, 95% CI 0.95 to 1.39; 5 studies, 420 patients). A GRADE analysis indicated that the overall quality of the evidence for this outcome was moderate due to sparse data (238 events). At 12 months 55% of budesonide 6 mg patients remained in remission compared to 48% of placebo patients (RR 1.13; 95% CI 0.94 to 1.35; 5 studies, 420 patients). A GRADE analysis indicated that the overall quality of the evidence for this outcome was moderate due to sparse data (215 events). Similarly, there was no significant benefit for budesonide 3 mg compared to placebo at 6 and 12 months. There was no statistically significant difference in continued remission at 12 months between budesonide and weaning doses of prednisolone (RR 0.79; 95% CI 0.55 to 1.13; 1 study, 90 patients). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to sparse data (51 events) and high risk of bias (no blinding). Budesonide 6 mg was better than mesalamine 3 g/day at 12 months (RR 2.51, 95% CI 1.03 to 6.12; 1 study, 57 patients). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was very low due to very sparse data (18 events) and high risk of bias (no blinding). There was no statistically significant difference in continued remission at 12 months between budesonide and azathioprine (RR 0.81; 95% CI 0.61 to 1.08; 1 study 77 patients). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was very low due to sparse data (55 events) and high risk of bias (single‐blind and no allocation concealment). The use of budesonide 6 mg resulted in slight improvements in CDAI scores when assessed at 6 months (MD ‐24.30, 95% CI ‐46.31 to ‐2.29) and 12 months (MD ‐23.49, 95% CI ‐46.65 to ‐0.32) and mean time to relapse of disease (MD 59.93 days, 95% CI 19.02 to 100.84). Mean time to relapse was significantly shorter for patients receiving budesonide than for those receiving azathioprine (MD ‐58.00, 95% CI ‐96.68 to ‐19.32). Adverse events were not more common in patients treated with budesonide compared to placebo (6 mg: RR 1.51, 95% CI 0.90 to 2.52; 3 mg: RR 1.19, 95% CI 0.63 to 2.24). These events were relatively minor and did not result in increased rates of study withdrawal. Commonly reported treatment‐related adverse effects included acne, moon facies, hirsutism, mood swings, insomnia, weight gain, striae, and hair loss. Abnormal adrenocorticoid stimulation tests were seen more frequently in patients receiving both 6 mg (RR 2.88, 95% CI 1.72 to 4.82) and 3 mg daily (RR 2.73, 95% CI 1.34 to 5.57) compared to placebo.

Authors' conclusions: These data suggest budesonide is not effective for maintenance of remission in CD, particularly when used beyond three months following induction of remission. Budesonide does have minor benefits 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.

Editorial Group: Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Group.

Publication status: New search for studies and content updated (no change to conclusions).

Citation: Kuenzig ME, Rezaie A, Seow CH, Otley AR, Steinhart AH, Griffiths AM, Kaplan GG, Benchimol EI. Budesonide for maintenance of remission in Crohn's disease. Cochrane Database of Systematic Reviews 2014, Issue 8. Art. No.: CD002913. DOI: 10.1002/14651858.CD002913.pub3. Link to Cochrane Library. [PubMed: 25141071]

Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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