Methotrexate for maintenance of remission in ulcerative colitis.

BACKGROUND: Methotrexate, a folate antagonist, is an immunosuppressant drug that is effective for treating several inflammatory disorders including Crohn's disease. Ulcerative colitis, a related chronic inflammatory bowel disease, can be challenging to treat. T his updated systematic review summarizes the current evidence on the use of methotrexate for induction maintenance of remission in ulcerative colitis. OBJECTIVES: The objectives of this review were to assess the efficacy and safety of methotrexate for maintenance of remission in patients with ulcerative colitis. SEARCH METHODS: We searched MEDLINE, EMBASE, CENTRAL and the Cochrane IBD/FBD group specialized trials register from inception to June 26, 2014. Study references and review papers were also searched for additional trials. Abstracts from major gastroenterological meetings were searched to identify research published in abstract form only. SELECTION CRITERIA: Randomized controlled trials in which methotrexate was compared to placebo or an active comparator in patients with quiescent ulcerative were considered for inclusion. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed the risk of bias for each study. The primary outcome was the occurrence of clinical or endoscopic relapse as defined by the primary studies. Secondary outcomes included frequency and nature of adverse events, change of disease activity score and steroid-sparing effect. We calculated the risk ratio and corresponding 95% confidence interval for dichotomous outcomes. Data were analyzed on an intention-to-treat basis. The overall quality of the evidence supporting the outcomes was evaluated using the GRADE criteria. MAIN RESULTS: Three trials (165 patients) fulfilled the inclusion criteria. One study compared oral methotrexate (12.5 mg/week) to placebo, another compared oral methotrexate (15 mg/week) to 6-mercaptopurine (6-MP, 1.5 mg/kg/day) or 5-aminosalicylic acid (5-ASA, 3 g/day) and the other compared methotrexate (15 mg/week) in combination sulfasalazine (3 g/day) to sulfasalazine. The placebo-controlled study was rated as low risk of bias. The study comparing methotrexate to 6-MP and 5-ASA was rated as high risk of bias and the study assessing methotrexate and sulfasalazine was rated as unclear risk of bias for sequence generation, allocation concealment and blinding. The placebo-controlled study found no statistically significant differences in the proportion of patients who maintained remission. At nine months, 36% (5/14) of methotrexate patients maintained remission compared to 54% (10/18) of placebo patients (RR 0.64, 95% CI 0.28 to 1.45). A GRADE analysis indicated that the overall quality of the evidence for this outcome was low due to very sparse data (15 events). The study comparing combination therapy to sulfasalazine found no statistically significant difference in the proportion of patients who maintained remission. At 12 months, 100% (14/14) of patients in the combination group maintained remission compared to 75% (9/12) of sulfasalazine patients (RR 1.32, 95% CI 0.94 to 0.86), A GRADE analysis indicated that the overall quality of the evidence for this outcome was very low due to unknown risk of bias and very sparse data (23 events). There were no statistically significant differences in maintenance of remission rates between methotrexate and 6-MP or between methotrexate and 5-ASA. At 76 weeks, 14% (1/7) of methotrexate patients maintained remission compared to 64% (7/11) of 6-MP patients (RR 0.22, 95% CI 0.03 to 1.45) and 0% (0/2) of 5-ASA patients (RR 1.13, 95% CI 0.06 to 20.71). A GRADE analysis indicated that the overall quality of the evidence from this study was very low due to high risk of bias and very sparse data. Adverse events reported in these studies included transient leucopenia, migraine, nausea and dyspepsia, mild alopecia, mild increase in aspartate aminotransferase levels, peritoneal abscess, hypoalbuminemia, severe rash and atypical pneumonia AUTHORS' CONCLUSIONS: The results for efficacy and safety outcomes between methotrexate and placebo, methotrexate and sulfasalazine, methotrexate and 6-mercaptopurine and methotrexate and 5-aminosalicylic acid were uncertain. Whether a higher dose or parenteral administration of methotrexate would be effective in quiescent ulcerative colitis is unknown. At present there is no evidence supporting the use of methotrexate for maintenance of remission in ulcerative colitis. More studies are needed to determine the efficacy and safety of methotrexate maintenance therapy in patients with quiescent ulcerative colitis. Large scale methodologically rigorous randomized controlled trials are needed. These studies should investigate higher doses of methotrexate (e.g. 15 to 25 mg/week) and parenteral administration.

Oral budesonide for induction of remission in ulcerative colitis.

BACKGROUND: 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. OBJECTIVES: The primary objective was to evaluate the efficacy and safety of oral budesonide for the induction of remission in ulcerative colitis. SEARCH METHODS: 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. SELECTION CRITERIA: 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. DATA COLLECTION AND ANALYSIS: 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. MAIN RESULTS: 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. AUTHORS' CONCLUSIONS: 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.

Budesonide for induction of remission in Crohn's disease.

BACKGROUND: Corticosteroids are commonly used for the induction of remission in Crohn's disease. However, traditional corticosteroids can cause significant adverse events. Budesonide is an alternative glucocorticoid with limited systemic bioavailability. OBJECTIVES: The primary objective was to evaluate the efficacy and safety of oral budesonide for the induction of remission in Crohn's disease. SEARCH METHODS: The following electronic databases were searched up to June 2014: 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. SELECTION CRITERIA: Randomised controlled trials comparing budesonide to a placebo or active comparator were considered for inclusion. DATA COLLECTION AND ANALYSIS: Two independent investigators reviewed studies for eligibility, extracted the 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. Meta-analysis was performed using RevMan 5.3.5 software. The primary outcome was induction of remission (defined by a Crohn's disease activity index (CDAI) < 150) by week 8 to 16 of treatment. Secondary outcomes included: time to remission, mean change in CDAI, clinical, histological or endoscopic improvement, improvement in quality of life, adverse events and early withdrawal. We calculated the relative risk (RR) and corresponding 95% confidence intervals (CIs) for each dichotomous outcome and the mean difference and corresponding 95% CI for each continuous outcome. Data were analyzed on an intention-to-treat basis. A random-effects model was used for the pooled analyses. The overall quality of the evidence supporting the primary outcomes and selected secondary outcomes was evaluated using the GRADE criteria. MAIN RESULTS: Fourteen studies (1805 patients) were included: Nine (779 patients) compared budesonide to conventional corticosteroids, three (535 patients) were placebo-controlled, and two (491 patients) compared budesonide to mesalamine. Ten studies were judged to be at low risk of bias. Three studies were judged to be at high risk of bias due to open label design. One study was judged to be at high risk of bias due to selective reporting. After eight weeks of treatment, 9 mg budesonide was significantly more effective than placebo for induction of clinical remission. Forty-seven per cent (115/246) of budesonide patients achieved remission at 8 weeks compared to 22% (29/133) of placebo patients (RR 1.93, 95% CI 1.37 to 2.73; 3 studies, 379 patients). A GRADE analysis indicated that the overall quality of the evidence for this outcome was moderate due to sparse data (144 events). Budesonide was significantly less effective than conventional steroids for induction of remission at eight weeks. Fifty-two per cent of budesonide patients achieved remission at week 8 compared to 61% of patients who received conventional steroids (RR 0.85, 95% CI 0.75 to 0.97; 8 studies, 750 patients). A GRADE analysis indicated that the overall quality of the evidence for this outcome was moderate due to risk of bias. Budesonide was significantly less effective than conventional steroids among patients with severe disease (CDAI > 300) (RR 0.52, 95% CI 0.28 to 0.95). Studies comparing budesonide to mesalamine were not pooled due to heterogeneity (I(2) = 81%). One study (n = 182) found budesonide to be superior to mesalamine for induction of remission at 8 weeks. Sixty-eight per cent (63/93) of budesonide patients were in remission at 8 weeks compared to 42% (37/89) of mesalamine patients (RR 1.63, 95% CI 1.23 to 2.16). The other study found no statistically significant difference in remission rates at eight weeks. Sixty-nine per cent (107/154) of budesonide patients were in remission at 8 weeks compared to 62% (132/242) of mesalamine patients (RR 1.12, 95% CI 0.95 to 1.32). Fewer adverse events occurred in those treated with budesonide compared to conventional steroids (RR 0.64, 95% CI 0.54 to 0.76) and budesonide was better than conventional steroids in preserving adrenal function (RR for abnormal ACTH test 0.65, 95% CI 0.55 to 0.78). AUTHORS' CONCLUSIONS: Budesonide is more effective than placebo for induction of remission in Crohn's disease. Although short-term efficacy with budesonide is less than with conventional steroids, particularly in those with severe disease or more extensive colonic involvement, the likelihood of adverse events and adrenal suppression with budesonide is lower. The current evidence does not allow for a firm conclusion on the relative efficacy of budesonide compared to 5-ASA products.

Type I interferons for induction of remission in ulcerative colitis.

BACKGROUND: Interferons (IFNs) are cytokines which possess immunoregulatory properties and have been used to successfully treat a number of chronic inflammatory disorders. It has been postulated that Type I IFNs may be able to re-establish the Th1/Th2 balance in Th2 predominant diseases like ulcerative colitis. OBJECTIVES: To systematically evaluate the efficacy and safety of type I IFN therapy for induction of remission in ulcerative colitis. SEARCH METHODS: We searched MEDLINE, EMBASE, CENTRAL, the Cochrane IBD/FBD group specialised register, and ClinicalTrials.gov from inception to August 8, 2014. Reference lists of trials and review articles, as well as recent proceedings from major gastroenterology meetings were manually searched. SELECTION CRITERIA: Randomised controlled trials of type I IFNs for induction of remission in UC were included. The study population included patients of any age with active ulcerative colitis. There were no exclusions based on type, dose or duration of IFN treatment. DATA COLLECTION AND ANALYSIS: Two independent authors reviewed studies for eligibility, extracted the data and assessed study quality 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 of ulcerative colitis. Secondary outcomes included: time to remission, mean change in disease activity index score, clinical, histological or endoscopic improvement, improvement in quality of life, and adverse events. We calculated the risk ratio (RR) and corresponding 95% confidence interval (CI) for dichotomous outcomes. We calculated the mean difference and corresponding 95% confidence interval for continuous outcomes. Meta-analysis was performed using RevMan 5.3.5 software. MAIN RESULTS: Six studies were eligible for inclusion (517 patients). Five studies compared type I IFNs to placebo injections (485 patients) and a single study compared IFNs to prednisolone enemas in patients with left-sided colitis (32 patients). The active comparator study was rated as high risk of bias due to an open-label design. Three studies were rated as unclear risk of bias for random sequence generation and allocation concealment. Two studies described as double blind were rated as unclear risk of bias for blinding. There was no significant benefit of type I IFNs over placebo for inducing clinical remission or improvement in patients with active ulcerative colitis. Thirty-six per cent (87/242) of patients in the type I IFNs group achieved clinical remission by 8 to 12 weeks compared to 30% (36/120) of placebo patients (RR 1.16, 95% CI 0.84 to 1.58; 4 studies, 362 patients). A GRADE analysis indicated that the overall quality of the evidence supporting the outcome clinical remission was moderate due to sparse data (123 events). Fifty-six per cent (149/264) of patients in the type I IFNs group improved clinically by 8 to 12 weeks compared to 48% (77/161) of placebo patients (RR 1.16, 95% CI 0.96 to 1.40; 4 studies, 425 patients). A GRADE analysis indicated that the overall quality of the evidence supporting the outcome clinical improvement was moderate due to sparse data (226 events). Patients who received type I IFNs were significantly more likely to withdraw from the studies due to adverse events than those who received placebo. Seven per cent (18/42) of type I IFNs patients withdrew due to adverse events compared to 2% (3/152) of placebo patients (RR 3.16, 95% CI 1.06 to 9.40). A GRADE analysis indicated that the overall quality of the evidence supporting the outcome withdrawal due to adverse events was low due to very sparse data (21 events). The study comparing type I IFNs to prednisolone enemas found no difference between the treatment groups in quality of life or disease activity scores. Common adverse events included headaches, arthralgias, myalgias, fatigue, back pain, nausea, application site reactions, rigors, and fevers. There were no statistically significant differences in the other secondary outcomes. AUTHORS' CONCLUSIONS: Moderate quality evidence suggests that type I IFNs are not effective for the induction of remission in UC. In addition, there are concerns regarding the tolerability of this class of treatment.

Omega 3 fatty acids (fish oil) for maintenance of remission in Crohn's disease.

BACKGROUND: The anti-inflammatory effects of n-3 (omega-3 fatty acids, fish oil) have been suggested to be beneficial in chronic inflammatory disorders such as inflammatory bowel disease. This review is an update of a previously published Cochrane review. OBJECTIVES: To systematically review the efficacy and safety of n-3 for maintenance of remission in Crohn's disease (CD). SEARCH METHODS: The following databases were searched from inception to November 2013 without language restriction: CENTRAL, MEDLINE, EMBASE, HealthSTAR, PubMed, and ACP journal club. SELECTION CRITERIA: Randomized placebo-controlled trials (RCT) of n-3 for maintenance of remission in CD were included. Studies must have enrolled patients of any age group, who were in remission at the time of recruitment, and were followed for at least six months. The intervention must have been fish oil or n-3 given in pre-defined dosage. Co-interventions were allowed only if they were balanced between the study groups. DATA COLLECTION AND ANALYSIS: The primary outcome was the relapse rate and secondary outcomes included change in disease activity scores, time to first relapse and adverse events. Two independent investigators reviewed studies for eligibility, extracted the data and assessed study quality using the Cochrane risk of bias tool. The overall quality of the evidence supporting the primary and selected secondary outcomes was reassessed for the current update using the GRADE system. We used the RevMan software for analyses. We calculated the risk ratio (RR) and corresponding 95% confidence interval (CI) for dichotomous outcomes and the hazard ratio and 95% CI for time-to-event outcomes. Random-effects or fixed-effect models were used according to degree of heterogeneity and sensitivity analyses were performed in an attempt to explore possible sources of heterogeneity. MAIN RESULTS: Six studies with a total of 1039 patients were eligible for inclusion. The two largest studies were rated as low risk of bias for all assessed items. Four studies were rated as unclear risk of bias for randomization and allocation concealment. Two studies were rated as high risk of bias for incomplete outcome data and selective reporting. There was a marginal significant benefit of n-3 therapy for maintenance of remission. Thirty-nine per cent of patients in the n-3 group relapsed at 12 months compared to 47% of placebo patients (6 studies, 1039 patients; RR 0.77, 95% CI 0.61 to 0.98). A GRADE analysis rated the overall quality of the evidence for the primary outcome (i.e. relapse) as very low due to unexplained heterogeneity (I2 = 58%), publication bias, and a high or unknown risk of bias in four studies in the pooled analysis. When two large studies at low risk of bias were considered the benefit was no longer statistically significant. Thirty-seven per cent of patients in the n-3 group relapsed at 12 months compared to 42% of placebo patients (2 studies, 738 patients; RR 0.88, 95% CI 0.74 to 1.05). No significant heterogeneity was identified for this pooled analysis ( I2 = 0%). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was moderate due to sparse data (294 events). No serious adverse events were recorded in any of the studies but in a pooled analyses there was a significantly higher rate of diarrhea (4 studies, 862 patients; RR 1.36 95% CI 1.01 to 1.84) and upper gastrointestinal tract symptoms (5 studies, 999 patients; RR 1.65, 95% CI 1.25 to 2.18) in the n-3 treatment group. AUTHORS' CONCLUSIONS: Evidence from two large high quality studies suggests that omega 3 fatty acids are probably ineffective for maintenance of remission in CD. Omega 3 fatty acids appear to be safe although they may cause diarrhea and upper gastrointestinal tract symptoms.

Budesonide for maintenance of remission in Crohn's disease.

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 Chi(2) and I(2) 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 (I(2) = 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.

Oral budesonide for induction of remission in ulcerative colitis.

BACKGROUND: Corticosteroids remain one of the most popular medication choices for the induction of remission in ulcerative colitis and Crohn's disease. While corticosteroids may improve symptoms, they do not always result in mucosal healing and have significant adverse effects. Steroids which act topically, with less systemic side-effects may be more desirable. Oral budesonide, a topically acting corticosteroid with extensive first pass hepatic metabolism, is effective in Crohn's disease and in enema formulation for left-sided ulcerative colitis. Data are limited regarding the role of oral budesonide in ulcerative colitis. OBJECTIVES: To systematically review the safety and efficacy of oral budesonide for induction of remission in ulcerative colitis. SEARCH STRATEGY: Electronic searching of the MEDLINE and EMBASE databases was performed. Two authors independently reviewed all identified titles and abstracts. Full text articles of all potentially relevant studies were retrieved. Reference lists of review articles were searched in an attempt to identify additional studies. Abstracts of the major gastroenterology scientific meetings, held over the past 3 years, were hand searched. The ClinicalTrials.gov website as well as the Cochrane Registry of Controlled Trials was searched to identify any ongoing trials. Direct communication with pharmaceutical manufacturers was established to identify any ongoing or unpublished studies. SELECTION CRITERIA: Randomized controlled trials of oral budesonide for the induction of remission in ulcerative colitis, with either a parallel arm or cross-over design, were considered eligible for inclusion. There were no exclusions based on patient age or the type, dose or duration of budesonide therapy. The primary outcome was the induction of clinical remission in ulcerative colitis. Secondary outcomes included clinical, histologic and endoscopic improvement, endoscopic mucosal healing, change in disease activity index scores, adverse events and study withdrawals. DATA COLLECTION AND ANALYSIS: Studies were reviewed for eligibility, data were extracted and quality assessed by 2 independent investigators. It was not possible to perform a meta-analysis of the included studies due to significant heterogeneity, with each study comparing budesonide to a different control medication. MAIN RESULTS: Three studies met the inclusion criteria. 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). There was no significant benefit of oral budesonide in comparison to placebo for inducing clinical remission after 4 weeks of treatment (RR 1.41, 95% CI 0.59 to 3.39). 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). The study was small and not powered to evaluate the impact of budesonide on clinical remission. Suppression of plasma cortisol was significantly more common in prednisolone treated patients (RR 0.02, 95% CI 0.0 to 0.33). Two multicenter studies are ongoing. AUTHORS' CONCLUSIONS: At present, there is no evidence to recommend the clinical use of oral budesonide for the induction of remission in active ulcerative colitis. Mesalamine is superior to budesonide for the treatment of active ulcerative colitis.

Methotrexate for maintenance of remission in ulcerative colitis.

BACKGROUND: Methotrexate, a folate antagonist, is an immunosuppressant drug that is effective for treating several inflammatory disorders including Crohn's disease. Ulcerative colitis, a related chronic inflammatory bowel disease, can be challenging to treat. This review was performed to examine the efficacy of methotrexate for maintenance of remission in ulcerative colitis. OBJECTIVES: To systematically review randomized controlled trials examining the efficacy and safety of methotrexate for maintenance of remission in patients with ulcerative colitis. SEARCH STRATEGY: The Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane IBD/FBD Review Group Specialized Trials Register, MEDLINE (PUBMED), EMBASE (1984 to November 2008), Web of Science, Scopus, Database of Abstracts of Reviews of Effects (DARE), and Clinical trials database (ClinicalTrials.gov) were searched. In addition, references from selected papers and abstracts from Digestive Disease Week were also examined. SELECTION CRITERIA: Only randomized controlled trials (RCT) evaluating the efficacy of methotrexate for maintaining remission in patients with ulcerative colitis compared to placebo or any other intervention were considered for inclusion in this review. DATA COLLECTION AND ANALYSIS: Data were extracted independently by each author. The odds ratio of relapse, 95% confidence interval and P-value were calculated using the Mantel-Haenszel method. An intention to treat analysis was used. MAIN RESULTS: Only one trial fulfilled the inclusion criteria. This trial randomized 30 patients to methotrexate and 37 to placebo. Methotrexate was given orally in a dose of 12.5 mg/week. Fourteen patients in the methotrexate group and 18 patients in the placebo group who entered remission were followed for 9 months or to the time of first relapse. Sixty-four per cent of methotrexate patients relapsed compared to 44% of placebo patients (OR 2.25; 95% CI 0.54 to 9.45; P = 0.27). AUTHORS' CONCLUSIONS: The available evidence is not sufficient to recommend the use of methotrexate to maintain remission in patients with ulcerative colitis. A large scale methodologically rigorous randomized controlled trial is needed. Such a study should investigate higher doses of methotrexate and parenteral administration.

Omega 3 fatty acids (fish oil) for maintenance of remission in Crohn's disease.

BACKGROUND: The anti-inflammatory effects of n-3 (omega-3 fatty acids, fish oil) have been suggested to be beneficial in chronic inflammatory disorders such as inflammatory bowel disease. OBJECTIVES: To systematically review the efficacy and safety of n-3 for maintenance of remission in Crohn's disease (CD). SEARCH STRATEGY: The following databases were searched from their inception without language restriction: Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, Healthstar, PubMed, and ACP journal club. Experts were contacted for unpublished data. SELECTION CRITERIA: Randomized placebo-controlled trials (RCT) of n-3 for maintenance of remission in CD were included. Studies must have enrolled patients of any age group, who were in remission at the time of recruitment, and were followed for at least six months. The intervention must have been fish oil or n-3 given in pre-defined dosage. Co-interventions were allowed only if they were balanced between the study groups. The primary outcome was the relapse rate and secondary outcomes included change in disease activity scores, time to first relapse and adverse events. DATA COLLECTION AND ANALYSIS: Two independent investigators reviewed studies for eligibility, extracted the data and assessed study quality using Jadad's criteria. Meta-analyses were performed using RevMan 4.2 software weighted by the Mantel-Haenszel method. Random or fixed effect models were used according to degree of heterogeneity and subgroup analyses were performed in an attempt to explore possible sources of heterogeneity. MAIN RESULTS: Six studies were eligible for inclusion. There was a marginal significant benefit of n-3 therapy for maintaining remission (RR 0.77 0.; 95%CI 0.61 to 0.98; P = 0.03). However, the studies were both clinically and statistically heterogeneous (P = 0.03, I(2) = 58%). Two large studies showed negative results. When considering the estimated rather than the observed 1-year relapse rate of these two studies, the benefit was no longer statistically significant (RR 0.59; 95% CI 0.34 to 1.03; P=0.06). A funnel plot suggested publication bias. No serious adverse events were recorded in any of the studies but in a pooled analyses there was a significantly higher rate of diarrhea (RR 1.36 95% CI 1.01 to 1.84) and symptoms of the upper gastrointestinal tract (RR 1.98 95% CI 1.38 to 2.85) in the n-3 treatment group. AUTHORS' CONCLUSIONS: Omega 3 fatty acids are safe but probably ineffective for maintenance of remission in CD. The existing data do not support routine maintenance treatment of Crohn's disease with omega 3 fatty acids.

Struggles, strengths, and strategies: an ethnographic study exploring the experiences of adolescents living with an ostomy.

BACKGROUND: Adolescents with IBD requiring ostomy surgery experience perioperative needs that may exceed those of patients experiencing other major abdominal surgery 1. This procedure requires ongoing and vigilant daily care and management. Gastrointestinal symptoms and complications impose psychological and social stresses on young patients 2, and the procedure results in body image changes and daily regimens of self-care. This study aimed to explore adolescents' experiences and quality of life following ostomy surgery. METHODS: Ethnographic interviews and a subsequent focus group were conducted with 20 adolescents with an ostomy or j-pouch being treated at the Hospital for Sick Children in Toronto, Canada. Interviews were transcribed verbatim and subjected to theme generation. RESULTS: Findings suggest that adolescents are profoundly affected by their ostomy. Adolescents convey strength as well as adjustment struggles. Identified impacts include body intrusion and body image changes, decreased independence, secrecy about the ostomy, adjustment over time, challenges for the family, and strategies for constructively moving forward. CONCLUSION: Implications address the importance of ensuring meaningful opportunities to understand and reframe the stresses of illness. An ongoing clinical challenge involves the promotion of a healthy self-esteem and psychosocial adjustment for these adolescents and their families. Finding effective ways to minimize stress and embarrassment and reframe personal shame, constitute important clinical priorities. Opportunities for peer support and family dialogue may assist in clarifying worries and easing the burden carried by these young persons. Flexible and adequately funded resources are advocated in fostering quality of life.

Type I interferons for induction of remission in ulcerative colitis.

BACKGROUND: Interferons (IFNs) are cytokines which possess immunoregulatory properties and have been used to successfully treat a number of chronic inflammatory disorders. It has been postulated that Type I IFNs may be able to re-establish the Th1/Th2 balance in Th2 predominant diseases like ulcerative colitis. OBJECTIVES: To systematically evaluate the efficacy and safety of type I IFN therapy for induction of remission in ulcerative colitis. SEARCH STRATEGY: The following electronic databases were searched: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, the Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders (IBD/FBD) Group Specialised Trial Register, and http://ClinicalTrials.gov. Reference lists of trials and review articles, as well as recent proceedings from major gastroenterology meetings were manually searched. Contact was made with pharmaceutical companies manufacturing type I IFNs. SELECTION CRITERIA: Randomised controlled trials of type I IFNs for induction of remission in UC were included. The study population included patients of any age with active ulcerative colitis. There were no exclusions based on type, dose or duration of IFN treatment. The primary outcome was induction of remission of ulcerative colitis. Secondary outcomes included: time to remission, mean change in disease activity index score, clinical, histological or endoscopic improvement, improvement in quality of life, and adverse events. 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: Four studies were eligible for inclusion. Three studies compared type I IFNs to placebo and a single study compared IFNs to prednisolone enemas in patients with left-sided colitis. Meta-analysis was based on the three IFN-placebo studies. There was no significant benefit of type I IFNs over placebo for inducing remission in ulcerative colitis (RR 1.24; 95% CI 0.81 to 1.90). There were no statistically significant differences in any of the secondary outcome variables. AUTHORS' CONCLUSIONS: The existing literature does not support the efficacy of type I IFNs for induction of remission in patients with UC. Given concerns regarding the tolerability of IFN therapy, we suggest that the results of two ongoing trials are evaluated for efficacy and safety prior to development or commencement of further randomised controlled trials of type I IFNs in UC.

Budesonide for induction of remission in Crohn's disease.

BACKGROUND: Corticosteroids play a key role in the induction of remission in Crohn's disease. However, corticosteroids can cause significant adverse events. Budesonide is an alternate enteral glucocorticoid with limited systemic bioavailability. OBJECTIVES: The primary objective was to evaluate the efficacy and safety of oral budesonide for the induction 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. Pharmaceutical companies were also contacted. SELECTION CRITERIA: Randomized controlled trials comparing budesonide to a control treatment were included. The study population included patients of any age with active Crohn's disease (CDAI > 150). The primary outcome was induction of remission (CDAI < 150) by week 8 to 16 of treatment. Secondary outcomes included: time to remission, mean change in CDAI, clinical, histological or endoscopic improvement, improvement in quality of life, adverse events and early withdrawal. DATA COLLECTION AND ANALYSIS: Two independent investigators reviewed studies for eligibility, extracted the data and assessed study quality. A random effects model was used and studies were weighted using the DerSimonian & Laird method. Meta-analysis was performed using RevMan 4.2.10 software. MAIN RESULTS: Twelve studies were included: 9 compared budesonide with conventional corticosteroids, 2 were placebo-controlled, and 1 compared budesonide with mesalamine. After 8 weeks of treatment, budesonide was significantly more effective than placebo (RR 1.96, 95% CI 1.19 to 3.23) or mesalamine (RR 1.63; 95% CI 1.23 to 2.16) for induction of remission. Budesonide was significantly less effective than conventional steroids for induction of remission (RR 0.86, 95% CI 0.76 to 0.98), particularly among patients with severe disease (CDAI > 300) (RR 0.52, 95% CI 0.28 to 0.95). Fewer adverse events occurred in those treated with budesonide compared to conventional steroids (RR 0.64, 95% CI 0.54 to 0.76) and budesonide was better able to preserve adrenal function (RR for abnormal ACTH test 0.65, 95% CI 0.55 to 0.78). AUTHORS' CONCLUSIONS: Budesonide is more effective than placebo or mesalamine for induction of remission in Crohn's disease. Although short-term efficacy with budesonide is less than with conventional steroids, particularly in those with severe disease or more extensive colonic involvement, the likelihood of adverse events and adrenal suppression is lower.

Review and clinical perspectives for the use of infliximab in ulcerative colitis.

Infliximab is a chimeric, monoclonal anti-tumour necrosis factor-alpha antibody. It has been previously demonstrated to be an effective treatment for patients with Crohn's disease who do not achieve the desired response with conventional treatments. Although the etiology of ulcerative colitis (UC) differs from that of Crohn's disease, randomized controlled trials have demonstrated that infliximab is also beneficial for the treatment of moderate to severe UC in patients who are either intolerant of or refractory to immunosuppressant agents or steroids, or those who are steroid-dependent. A review of the literature is followed by practical recommendations regarding infliximab that address the needs of clinicians and UC patients. Where there is a lack of evidence-based information, the expert panel provides its combined opinion derived from the members' clinical experiences.

Budesonide for the Induction and Maintenance of Remission in Crohn's Disease: Systematic Review and Meta-Analysis for the Cochrane Collaboration.

BACKGROUND: Budesonide is an oral glucocorticoid designed for the treatment of inflammatory bowel disease (IBD) that may reduce systemic adverse events (AEs). This review examined the efficacy and safety of budesonide for the induction and maintenance of clinical remission in Crohn's disease (CD). METHODS: MEDLINE, EMBASE, other electronic databases, reference lists and conference proceedings were searched to November 2017 to identify randomized controlled trials of budesonide. Outcomes were the induction and maintenance of remission at eight weeks and one year, respectively, as well as corticosteroid-related AEs and abnormal adrenocorticotropic hormone (ACTH) tests. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were estimated using random effects models. RESULTS: Thirteen induction and 10 maintenance trials were included. Budesonide 9 mg/day was more effective than placebo (RR 1.93; 95% CI, 1.37-2.73; GRADE: moderate) but less effective than conventional steroids (RR 0.85; 95% CI, 0.75-0.97; GRADE: moderate) to induce remission. Corticosteroid-related AEs occurred less often with induction doses of budesonide than steroids (RR 0.64; 95% CI, 0.54-0.76; GRADE: moderate); budesonide did not increase AEs relative to placebo (RR 0.97; 95% CI, 0.76-1.23; GRADE: moderate). Budesonide 6 mg/day was not different from placebo for maintaining remission (RR 1.13; 95% CI, 0.94-1.35; GRADE: moderate). Both induction (GRADE: low for 3 mg/day, moderate for 9 mg/day) and maintenance budesonide treatment (GRADE: very low for 3 mg/day, low for 6 mg/day) increased the risk of an abnormal ACTH test compared with placebo, but less than conventional steroids (GRADE: very low for both induction and maintenance). CONCLUSION: For induction of clinical remission, budesonide was more effective than placebo, but less effective than conventional steroids. Budesonide was not effective for the maintenance of remission. Budesonide was safer than conventional steroids, but the long-term effects on the adrenal axis and bone health remain unknown.