Mary E Sherlock, John K MacDonald, Anne Marie Griffiths, A Hillary Steinhart, Cynthia H Seow

Corticosteroids are first-line therapy for induction of remission in ulcerative colitis. Although corticosteroids may improve symptoms, they have significant adverse effects. Steroids which act topically, with less systemic side-effects may be more desirable. Budesonide is a topically acting corticosteroid with extensive first pass hepatic metabolism. There are currently three formulations of budesonide: two standard formulations including a controlled-ileal release capsule and a pH-dependent capsule both designed to release the drug in the distal small intestine and right colon; and the newer Budesonide-MMX® capsule designed to release the drug throughout the entire colon. The primary objective was to evaluate the efficacy and safety of oral budesonide for the induction of remission in ulcerative colitis. We searched MEDLINE, EMBASE, CENTRAL, and the Cochrane IBD Group Specialised Register from inception to April 2015. We also searched reference lists of articles, conference proceedings and ClinicalTrials.gov. Randomised controlled trials comparing oral budesonide to placebo or another active therapy for induction of remission in ulcerative colitis were considered eligible. There were no exclusions based on patient age or the type, dose, duration or formulation of budesonide therapy. Two independent investigators reviewed studies for eligibility, extracted data and assessed study quality. Methodological quality was assessed using the Cochrane risk of bias tool. The overall quality of the evidence supporting the outcomes was evaluated using the GRADE criteria. The primary outcome was induction of remission (as defined by the primary studies) at week eight. Secondary outcomes included clinical, endoscopic and histologic improvement, adverse events and early withdrawal. We calculated the risk ratio (RR) and corresponding 95% confidence interval (CI) for each dichotomous outcome and the mean difference (MD) and corresponding 95% CI for each continuous outcome. Data were analysed on an intention-to-treat basis. Six studies (1808 participants) were included. Four studies compared budesonide-MMX® with placebo, one small pilot study looked at clinical remission at week four, and was subsequently followed by three large, studies that assessed combined clinical and endoscopic remission at week eight. Although two placebo-controlled studies had mesalamine and Entocort (standard budesonide) treatment arms, these studies were not sufficiently powered to compare Budesonide-MMX® with these active comparators. One small study compared standard budesonide with prednisolone and one study compared standard budesonide to mesalamine. Four studies were rated as low risk of bias and two studies had an unclear risk of bias. A pooled analysis of three studies (900 participants) showed that budesonide-MMX® 9 mg was significantly superior to placebo for inducing remission (combined clinical and endoscopic remission) at 8 weeks. Fifteen per cent (71/462) of budesonide-MMX® 9 mg patients achieved remission compared to 7% (30/438) of placebo patients (RR 2.25, 95% CI 1.50 to 3.39). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was moderate due to sparse data (101 events). A subgroup analysis by concurrent mesalamine use suggests higher efficacy in the 442 patients who were not considered to be mesalamine-refractory (RR 2.89, 95% CI 1.59 to 5.25). A subgroup analysis by disease location suggests budesonide is most effective in patients with left-sided disease (RR 2.98, 95% CI 1.56 to 5.67; 289 patients). A small pilot study reported no statistically significant difference in endoscopic remission between budesonide and prednisolone (RR 0.75, 95% CI 0.23 to 2.42; 72 patients). GRADE indicated that the overall quality of the evidence supporting this outcome was very low due to unclear risk of bias and very sparse data (10 events). Standard oral budesonide was significantly less likely to induce clinical remission than oral mesalamine after 8 weeks of therapy (RR 0.72, 95% CI 0.57 to 0.91; 1 study, 343 patients). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was moderate due to sparse data (161 events). Another study found no difference in remission rates between budesonide-MMX® 9 mg and mesalamine (RR 1.48, 95% CI 0.81 to 2.71; 247 patients). GRADE indicated that the overall quality of the evidence supporting this outcome was low due to very sparse data (37 events). One study found no difference in remission rates between budesonide-MMX® 9 mg and standard budesonide 9 mg (RR 1.38, 95% CI 0.72 to 2.65; 212 patients). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to very sparse data (32 events). Suppression of plasma cortisol was more common in prednisolone-treated patients (RR 0.02, 95% CI 0.0 to 0.33). While budesonide does appear to suppress morning cortisol to some extent, mean morning cortisol values remained within the normal range in 2 large studies (n = 899) and there was no difference in glucocorticoid-related side-effects across different treatment groups. Further, study withdrawal due to adverse events was not more common in budesonide compared with placebo treated patients (RR 0.85, 95% CI 0.53 to 1.38). Common adverse events included worsening ulcerative colitis, headache, pyrexia, insomnia, back pain, nausea, abdominal pain, diarrhoea, flatulence and nasopharyngitis. Moderate quality evidence to supports the use of oral budesonide-MMX® at a 9 mg daily dose for induction of remission in active ulcerative colitis, particularly in patients with left-sided colitis. Budesonide-MMX® 9 mg daily is effective for induction of remission in the presence or absence of concurrent 5-ASA therapy. Further, budesonide-MMX® appears to be safe, and does not lead to significant impairment of adrenocorticoid function compared to placebo. Moderate quality evidence from a single study suggests that mesalamine may be superior to standard budesonide for the treatment of active ulcerative colitis. Low quality evidence from one study found no difference in remission rates between budesonide MMX® and mesalamine. Very low quality evidence from one small study showed no difference in endoscopic remission rates between standard budesonide and prednisolone. Low quality evidence from one study showed no difference in remission rates between budesonide-MMX® and standard budesonide. Adequately powered studies are needed to allow conclusions regarding the comparative efficacy and safety of budesonide versus prednisolone, budesonide-MMX® versus standard budesonide and budesonide versus mesalamine.