Reliability among central readers in the evaluation of endoscopic findings from patients with Crohn's disease.

OBJECTIVE: The Crohn's Disease Endoscopic Index of Severity (CDEIS) and Simple Endoscopic Score for Crohn's Disease (SES-CD) are commonly used to assess Crohn's disease (CD) activity; however, neither instrument has been fully validated. We assessed intra-rater and inter-rater reliability of these indices. DESIGN: Video recordings of colonoscopies obtained from 50 patients with CD who participated in an induction trial of a biological therapy were triplicated and reviewed in random order by four central readers. Data were used to assess intra-rater and inter-rater reliability for CDEIS, SES-CD and a global evaluation of lesion severity (GELS). Subsequently, readers participated in a consensus process that identified common sources of disagreement. RESULTS: Intraclass correlation coefficients (ICCs) for intra-rater reliability for CDEIS, SES-CD and GELS (95% CIs) were 0.89 (0.86 to 0.93), 0.91 (0.89 to 0.95) and 0.81 (0.77 to 0.89), respectively, with standard error of measurement (SEM) of 2.10, 2.42 and 1.15. The corresponding ICCs for inter-rater reliability were 0.71 (0.63 to 0.76), 0.83 (0.75 to 0.88) and 0.62 (0.52 to 0.70), with SEM of 3.42, 3.07 and 1.63, respectively. Correlation between CDEIS and GELS was 0.75, between SES-CD and GELS was 0.74 and between CDEIS and SES-CD was 0.92. The most common sources of disagreement were interpretation of superficial ulceration, definition of disease site at the ileocolonic anastomosis, assessment of anorectal lesions and grading severity of stenosis. CONCLUSIONS: Central reading of CDEIS and SES-CD had 'substantial' to 'almost perfect' intra-rater and inter-rater reliability; however, the responsiveness of these instruments is yet to be determined. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT01466374.

Interventions for treating collagenous colitis.

BACKGROUND: Collagenous colitis is a cause of chronic diarrhea. Treatment has been based mainly on anecdotal evidence. This review was performed to identify therapies for collagenous colitis that have been proven in randomized trials. OBJECTIVES: To determine effective treatments for patients with collagenous colitis. SEARCH STRATEGY: Relevant papers published between 1970 and December 2007 were identified via the MEDLINE and PUBMED databases. Manual searches from the references of identified papers, as well as review papers on collagenous or microscopic colitis were performed to identify additional studies. Abstracts from major gastroenterological meetings were searched to identify research submitted in abstract form only. Finally, the Cochrane Controlled Trials Register and the Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Group Specialized Trials Register were searched for other studies. SELECTION CRITERIA: Ten randomized trials were identified. Seven of these compared active treatment to placebo for treating active disease. Of these, 1 trial studied bismuth subsalicylate, 1 trial studied Boswellia serrata extract, 3 trials studies budesonide, 1 trial studied prednisolone, and 1 trial studied probiotics. One trial compared mesalamine to mesalamine + cholestyramine for treating active disease. Two trials compared budesonide to placebo in maintaining response induced by budesonide. DATA COLLECTION AND ANALYSIS: Data were extracted independently by each author onto 2x2 tables (treatment versus comparator and response versus no response). For therapies assessed in one trial only, P-values were derived using the chi-square test. For therapies assessed in more than one trial, summary test statistics were derived using the Peto odds ratio and 95% confidence intervals. Data were combined for analysis only if the outcomes were sufficiently similar in definition. MAIN RESULTS: In treating active disease, there were 9 patients with collagenous colitis in the trial studying bismuth subsalicylate (nine 262 mg tablets daily for 8 weeks). Clinical response occurred in 100% of patients who received bismuth subsalicylate compared to 0% of patients who received placebo (P = 0.03). Thirty-one patients were enrolled in the trial studying Boswellia serrata extract (three 400 mg capsules daily for 8 weeks). Clinical response occurred in 44% of patients who received Boswellia serrata extract compared to 27% of patients who received placebo (P = 0.32). A total of 94 patients were enrolled in 3 trials studying budesonide (9 mg daily or in a tapering schedule for 6 to 8 weeks). Clinical response occurred in 81% of patients who received budesonide compared to 17% of patients who received placebo (P < 0.00001). The pooled odds ratio for clinical response to treatment with budesonide was 12.32 (95% CI 5.53 to 27.46), with a number needed to treat of 2 patients. Statistically significant histological response occurred with treatment in all 3 trials studying budesonide therapy. Eleven patients were enrolled in the trial studying prednisolone (50 mg daily for 2 weeks). Clinical response occurred in 63% of patients who received prednisolone compared to 0% who received placebo (P = 0.15). Twenty-nine patients were enrolled in the trial studying probiotics (2 capsules containing 0.5 x 10(10) CFU each of L. acidophilus LA-5 and B. animalis subsp. lactis strain BB-12 twice daily for 12 weeks). Clinical response occurred in 29% of patients who received probiotics compared to 13% of patients who received placebo (P = 0.38). Twenty-three patients were enrolled in the trial studying mesalamine (800 mg three times daily) with or without cholestyramine (4 g daily) for 6 months. Clinical response occurred in 73% of patients who received mesalamine alone compared to 100% of patients who received mesalamine + cholestyramine (P = 0.14). In maintaining response, 80 patients who had responded to open-label budesonide were enrolled in 2 trials studying budesonide (6 mg daily for 6 months). Clinical response was maintained in 83% of patients who received budesonide compared to 28% of patients who received placebo (P = 0.0002). The pooled odds ratio for maintenance of clinical response to treatment with budesonide was 8.40 (95% CI 2.73 to 25.81), with a number needed to treat of 2 patients. Histological response was maintained in 48% of patients who received budesonide compared to 15% of patients who received placebo (P = 0.002). AUTHORS' CONCLUSIONS: Budesonide is effective for inducing and maintaining clinical and histological response in patients with collagenous colitis. The evidence for benefit with bismuth subsalicylate and for mesalamine with or without cholestyramine is weak. There is no evidence for the effectiveness of Boswellia serrata extract, prednisolone, or probiotics. These agents and other therapies require further study.

Interventions for treating lymphocytic colitis.

BACKGROUND: Lymphocytic colitis is a cause of chronic diarrhea. Therapy is based mainly on case series and uncontrolled trials, or by extrapolation of data for treating collagenous colitis, a related disorder. This review was performed to identify therapies for lymphocytic colitis that have been proven in randomized controlled trials. OBJECTIVES: To determine effective treatments for patients with clinically active lymphocytic colitis. SEARCH STRATEGY: The MEDLINE, PUBMED and EMBASE databases were searched using the search criteria "microscopic colitis" or "lymphocytic colitis" and "treatment" or "therapy" or "management" to identify relevant papers published between 1970 and December 2007. Manual searches from the references of identified papers and relevant review papers were performed. Abstracts from major gastroenterological meetings were searched to identify research submitted in abstract form only. The trial registry website www.ClinicalTrials.gov was searched to identify registered but unpublished trials. Finally, the Cochrane Central Register of Controlled Trials and the Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Group Specialized Trials Register were searched for other studies. SELECTION CRITERIA: Five randomized controlled trials were identified. Three of these studies, which assessed bismuth subsalicylate vs. placebo, budesonide vs. placebo, and mesalazine vs. mesalazine vs. cholestyramine in treating active disease, are included in this review. DATA COLLECTION AND ANALYSIS: Data were extracted independently by each author onto 2x2 tables (treatment versus placebo or active comparator and response versus no response). For therapies assessed in one trial only, P values were derived using the chi-square test. MAIN RESULTS: Forty-one patients were enrolled in the trial studying budesonide (9 mg/day for 6 weeks versus placebo). Budesonide was more effective than placebo at inducing both clinical (P = 0.004; NNT = 3) and histological responses (P = 0.04; NNT = 3). Forty-one patients were enrolled in the study assessing mesalazine versus mesalazine plus cholestyramine. A high proportion of patients in each group responded to treatment. However, no statistically significant difference in clinical response was found between the two treatment groups (P = 0.95). Five patients were enrolled in the trial studying bismuth subsalicylate (nine 262 mg tablets daily for 8 weeks vs. placebo). There were no differences in clinical (P=0.10) or histological responses (P=0.71) in patients treated with bismuth subsalicylate compared with placebo. AUTHORS' CONCLUSIONS: A single trial studying budesonide suggests that it may be effective for the treatment of active lymphocytic colitis. An ongoing placebo-controlled trial may confirm the benefit of budesonide. There is weaker evidence that mesalazine with or without cholestyramine may be effective for the treatment of lymphocytic colitis, but this benefit needs to be confirmed in a placebo-controlled study. No conclusions can be made regarding bismuth subsalicylate. These agents require further study before they can be recommended as treatment options for lymphocytic colitis. Further trials studying interventions for lymphocytic colitis are warranted.

Methotrexate for induction of remission in ulcerative colitis.

BACKGROUND: Ulcerative colitis is a chronic inflammatory bowel disease. Corticosteroids and 5-aminosalicylates are the most commonly used therapies. However, many patients require immunosuppressive therapy when their disease becomes steroid-refractory or dependent. Methotrexate is a medication that is effective for treating a variety of inflammatory diseases, including Crohn's disease. This review was performed to determine the effectiveness of methotrexate at inducing remission in patients with ulcerative colitis. OBJECTIVES: To review randomized trials examining the efficacy of methotrexate for remission induction in patients with ulcerative colitis. SEARCH STRATEGY: MEDLINE (PUBMED), EMBASE, The Cochrane Central Register of Controlled Trials, the Cochrane IBD/FBD group specialized trials register, review papers on ulcerative colitis, and references from identified papers were searched in an effort to identify all randomized trials studying methotrexate use in patients with ulcerative colitis. Abstracts from major gastroenterological meetings were searched to identify research published in abstract form only. SELECTION CRITERIA: Randomized controlled trials comparing methotrexate with placebo or an active comparator in patients with active ulcerative colitis were considered for inclusion. DATA COLLECTION AND ANALYSIS: Data were extracted independently by each author, analyzed on an intention-to-treat basis, and treated dichotomously. Methotrexate was compared to placebo in one trial. The odds ratio and 95% confidence interval were calculated and P-values were derived using the chi-square test. MAIN RESULTS: Only 1 trial fulfilled the inclusion criteria. This study randomized 30 patients to methotrexate 12.5 mg orally weekly and 37 patients to placebo for 9 months. During the study period, 14/30 patients (47%) assigned to methotrexate, and 18/37 patients (49%) assigned to placebo achieved remission and complete withdrawal from steroids (OR 0.92, 95% CI 0.35-2.42; P = 0.87). The mean time to remission was 4.1 months in the methotrexate group and 3.4 months in the placebo group. AUTHORS' CONCLUSIONS: A single trial of methotrexate 12.5 mg orally weekly showed no benefit over placebo in remission induction in patients with active ulcerative colitis. There is no evidence on which to base recommendations for treating ulcerative colitis patients with methotrexate. However, the possibility of a type 2 error exists, and a higher dose of methotrexate may be effective. A new trial in which adequate numbers of patients are randomized to placebo or a higher dose of methotrexate should be considered.

Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis.

BACKGROUND: Maintenance of remission is a major issue in inflammatory bowel disease. In ulcerative colitis, the evidence for the effectiveness of azathioprine and 6-mercaptopurine for the maintenance of remission is still controversial. OBJECTIVES: To assess the effectiveness and safety of azathioprine and 6-mercaptopurine for maintaining remission of ulcerative colitis. SEARCH STRATEGY: The MEDLINE database was used to search literature from 1966 to 2006. A manual search was also performed using references from these articles as well as review articles, proceedings from major gastrointestinal meetings and data available from the Cochrane Collaboration database. Authors of maintenance trials were asked about unpublished studies. SELECTION CRITERIA: Randomized controlled trials of at least 12 months duration that compared azathioprine or 6-mercaptopurine with placebo or standard maintenance therapy (mesalamine) were included. DATA COLLECTION AND ANALYSIS: Data were extracted by two raters using standard forms. Disagreements were solved by informal consent, including a third rater. Jadad scores were applied to assess study quality. Analyses were performed separately by type of control (placebo, or active comparator). Pooled odds ratios were calculated based on the fixed effects model unless heterogeneity was shown. MAIN RESULTS: Six studies were identified including 286 patients with ulcerative colitis. The study quality was mostly poor. Azathioprine was shown to be superior for the maintenance of remission as compared to placebo based on four trials (failure to maintain remission: OR 0.41; 95% CI 0.24 to 0.70). Two trials that compared 6-mercaptopurine to mesalazine, or azathioprine to sulfasalazine showed significant heterogeneity. Both studies using active comparators were open label. Adverse effects occurred in 11 of 127 patients receiving azathioprine, including acute pancreatitis (3 cases) and significant bone marrow suppression (5 cases). AUTHORS' CONCLUSIONS: Azathioprine may be an effective maintenance therapy for patients who have failed or cannot tolerate mesalazine or sulfasalazine and for patients who require repeated courses of steroids. More research is needed to evaluate superiority over standard maintenance therapy, especially in the light of a potential for adverse events from azathioprine.

Interventions for treating lymphocytic colitis.

BACKGROUND: Lymphocytic colitis is a cause of chronic diarrhea. Therapy is based mainly on case series and uncontrolled trials, or by extrapolation of data for treating collagenous colitis, a related disorder. This review was performed to identify therapies for lymphocytic colitis that have been proven in randomized controlled trials. OBJECTIVES: To determine effective treatments for patients with clinically active lymphocytic colitis. SEARCH STRATEGY: The MEDLINE, PUBMED and EMBASE databases were searched using the search criteria "microscopic colitis" or "lymphocytic colitis" and "treatment" or "therapy" or "management" to identify relevant papers published between 1970 and September 2006. Manual searches from the references of identified papers and relevant review papers were performed. Abstracts from major gastroenterological meetings were searched to identify research submitted in abstract form only. Finally, the Cochrane Central Register of Controlled Trials and the Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Group Specialized Trials Register was searched for other studies. SELECTION CRITERIA: A single randomized trial published in abstract form only which studied bismuth subsalicylate was identified, and included only 5 patients with lymphocytic colitis (and 9 with collagenous colitis). DATA COLLECTION AND ANALYSIS: Data were extracted independently by each author onto 2x2 tables (treatment versus placebo and response versus no response). For therapies assessed in one trial only, P values were derived using the chi-square test. MAIN RESULTS: There were 5 patients with lymphocytic colitis in the trial studying bismuth subsalicylate (nine 262 mg tablets daily for 8 weeks vs. placebo). Although all three patients on active drug experienced clinical improvement compared to none of the placebo group, there were no statistically significant differences in clinical (P = 0.10) or histological (P = 0.71) improvement. AUTHORS' CONCLUSIONS: A single trial studying bismuth subsalicylate as therapy for lymphocytic colitis suggests that it may be beneficial. However, it included only 5 patients and no firm conclusions can be made from such a small trial. Larger trials studying treatments for lymphocytic colitis are warranted.

Natalizumab for induction of remission in Crohn's disease.

BACKGROUND: The pathogenesis of Crohn's disease involves migration of leukocytes into gut tissue and subsequent inflammation. Natalizumab (Tysabri(R), Elan Pharmaceuticals and Biogen Idec) a recombinant humanized IgG4 monoclonal antibody that blocks adhesion and subsequent migration of leukocytes into the gut by binding the alpha4 integrin is a member of a new class of molecules known as selective adhesion molecule (SAM) inhibitors. The results of animal studies suggest that alpha4 integrin blockade could be a useful therapy for inflammatory bowel disease. The results of randomized controlled trials suggest that natalizumab may be an effective therapy for active Crohn's disease. This systematic review summarizes the current evidence on the use of natalizumab for the induction of remission in Crohn's disease. OBJECTIVES: To determine the efficacy and safety of natalizumab for induction of remission in Crohn's disease. SEARCH STRATEGY: A computer assisted search of the Cochrane Central Register of Controlled Trials, the Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Review Group Specialized Trials Register, MEDLINE and EMBASE was performed to identify relevant publications between 1966 and September 2006. The medical subject heading (MeSH) terms "Crohn disease" or "inflammatory bowel disease", "Natalizumab" or "Antegren" or "Tysabri" and "Antibodies, Monoclonal" were used to perform key word searches of each database. Manual searches of reference lists from potentially relevant papers were performed in order to identify additional studies that may have been missed using the computer-assisted search strategy. Abstracts from major gastroenterological meetings were searched to identify research submitted in abstract form only. Personal contacts, leaders in the field, and the manufacturers were contacted to identify other studies which may not be published. SELECTION CRITERIA: We included only randomized controlled trials comparing natalizumab to a placebo or control therapy for the induction of remission in Crohn's disease. DATA COLLECTION AND ANALYSIS: Data were analyzed using Review Manager (RevMan 4.2.8). All data were analyzed on an intention-to-treat basis. For pooled data, summary test statistics were derived using the relative risk and 95% confidence intervals. Fixed and random effects models were used where appropriate. The definitions of treatment success, remission and clinical improvement were set by the authors of each paper, and the data were combined for analysis only if these definitions were sufficiently similar. MAIN RESULTS: Pooled data from the four included studies suggest that natalizumab (300 mg or 3 to 4 mg/kg) is effective for induction of clinical response and remission in patients with moderately to severely active Crohn's disease. This benefit is statistically significant for one, two and three infusion treatments. There was a trend toward increased benefit with additional infusions of natalizumab. Natalizumab appears to provide greater benefit for patient subgroups characterized by objective confirmation of active inflammation or chronically active disease despite conventional therapies. These subgroup analyses demonstrated significantly greater clinical response and remission rates for natalizumab compared with placebo in patients with elevated C-reactive protein levels, active disease despite the use of immunosuppressants, or prior anti-tumor necrosis factor therapy. These benefits were apparent for both short term (one infusion) and longer term treatment (two or three infusions). Natalizumab was generally well tolerated and the safety profile observed in the four included studies was similar. Adverse events occurred infrequently and were experienced by a similar proportion of natalizumab and placebo treated patients. There were no statistically significant differences between natalizumab and placebo treated patients in the proportions of patients who withdrew due to adverse events or those who experienced serious adverse events. The included trials lacked adequate power to detect serious adverse events that occur infrequently. Recently, two patients with multiple sclerosis treated with natalizumab in combination with interferon beta-1a and one patient with Crohn's disease treated with natalizumab in combination with azathioprine developed progressive multifocal leukoencephalopathy (PML) resulting in two patient deaths. A retrospective investigation was conducted to assess the risk of PML in natalizumab treated patients and no new cases were identified. AUTHORS' CONCLUSIONS: Pooled data suggest that natalizumab is effective for induction of clinical response and remission in some patients with moderately to severely active Crohn's disease. The clinical benefit of induction therapy with natalizumab in Crohn's disease should be weighed against the potential risk of serious adverse events. Preliminary data from the retrospective investigation of adverse events associated with natalizumab suggest that it may be possible to identify patients at risk for PML by testing for the appearance of JC virus in plasma.

Interventions for treating collagenous colitis.

BACKGROUND: Collagenous colitis is a disorder that is recognized as a cause of chronic diarrhea. Treatment has been based mainly on anecdotal evidence. This review was performed to identify therapies for collagenous colitis that have been proven in randomized trials. OBJECTIVES: To determine effective treatments for patients with clinically active collagenous colitis. SEARCH STRATEGY: Relevant papers published between 1970 and June 2006 were identified via the MEDLINE and PUBMED databases. Manual searches from the references of identified papers, as well as review papers on collagenous or microscopic colitis were performed to identify additional studies. Abstracts from major gastroenterological meetings were searched to identify research submitted in abstract form only. Finally, the Cochrane Controlled Trials Register and the Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Group Specialized Trials Register were searched for other studies. SELECTION CRITERIA: Seven randomized trials were identified. One trial studied bismuth subsalicylate (published in abstract form only), one trial studied Boswellia serrata extract (published in abstract form only), one trial studied probiotics, one trial studied prednisolone, and 3 trials studied budesonide for the therapy of collagenous colitis. DATA COLLECTION AND ANALYSIS: Data were extracted independently by each author onto 2x2 tables (treatment versus placebo and response versus no response). For therapies assessed in one trial only, p-values were derived using the chi-square test. For therapies assessed in more than one trial, summary test statistics were derived using the Peto odds ratio and 95% confidence intervals. Data were combined for analysis only if the outcomes were sufficiently similar in definition. MAIN RESULTS: There were 9 patients with collagenous colitis in the trial studying bismuth subsalicylate (nine 262 mg tablets daily for 8 weeks). Those randomized to active drug were more likely to have clinical (p = 0.003) and histological (p = 0.003) improvement than those assigned to placebo. Eleven patients were enrolled in the trial studying prednisolone (50 mg daily for 2 weeks). There was a trend towards clinical response in patients on active medication compared to placebo (p = 0.064). The effect of prednisolone on histologic improvement was not studied. Thirty-one patients were enrolled in the Boswellia serrata extract trial. Clinical improvement was noted in 44% of patients who received active treatment compared to 27% of patients who received placebo (p = 0.32). Twenty-nine patients were enrolled in the probiotics trial. Clinical improvement was noted in 29% of patients who received probiotics compared to 13% of patients who received placebo (p = 0.635). A total of 94 patients were enrolled in 3 trials studying budesonide (9 mg daily or in a tapering schedule for 6 to 8 weeks). The pooled odds ratio for clinical response to treatment with budesonide was 12.32 (95% CI 5.53-27.46), with a number needed to treat of 2 patients. There was significant histological improvement with treatment in all 3 trials studying budesonide therapy. Budesonide also appears to improve patients' quality of life. AUTHORS' CONCLUSIONS: Budesonide is effective for the treatment of collagenous colitis. The evidence for benefit with bismuth subsalicylate is weaker. The effectiveness of prednisolone, Boswellia serrata extract, probiotics and other therapies for induction or maintenance of remission of collagenous colitis is unknown and requires further study.

Natalizumab for induction of remission in Crohn's disease.

BACKGROUND: The pathogenesis of Crohn's disease involves migration of leukocytes into gut tissue and subsequent inflammation. Natalizumab (Tysabri, Elan Pharmaceuticals and Biogen Idec) a recombinant humanized IgG4 monoclonal antibody that blocks adhesion and subsequent migration of leukocytes into the gut by binding the alpha4 integrin is a member of a new class of molecules known as selective adhesion molecule (SAM) inhibitors. The results of animal studies suggest that alpha4 integrin blockade could be a useful therapy for inflammatory bowel disease. The results of randomized controlled trials suggest that natalizumab may be an effective therapy for active Crohn's disease. This systematic review summarizes the current evidence on the use of natalizumab for the induction of remission in Crohn's disease. OBJECTIVES: To determine the efficacy and safety of natalizumab for induction of remission in Crohn's disease. SEARCH STRATEGY: A computer assisted search of the Cochrane Central Register of Controlled Trials, the Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Review Group Specialized Trials Register, MEDLINE and EMBASE was performed to identify relevant publications between 1966 and June 2005. The medical subject heading (MeSH) terms "Crohn disease" or "inflammatory bowel disease", "Natalizumab" or "Antegren" or "Tysabri" and "Antibodies, Monoclonal" were used to perform key word searches of each database. Manual searches of reference lists from potentially relevant papers were performed in order to identify additional studies that may have been missed using the computer-assisted search strategy. Abstracts from major gastroenterological meetings were searched to identify research submitted in abstract form only. Personal contacts, leaders in the field, and the manufacturers were contacted to identify other studies which may not be published. SELECTION CRITERIA: We included only randomized controlled trials comparing natalizumab to a placebo or control therapy for the induction of remission in Crohn's disease. DATA COLLECTION AND ANALYSIS: Data were analyzed using Review Manager (RevMan 4.2.8). All data were analyzed on an intention-to-treat basis. For pooled data, summary test statistics were derived using the relative risk and 95% confidence intervals. Fixed and random effects models were used where appropriate. The definitions of treatment success, remission and clinical improvement were set by the authors of each paper, and the data were combined for analysis only if these definitions were sufficiently similar. MAIN RESULTS: Pooled data from the three included studies suggest that natalizumab (3 to 4 mg/kg) may be effective for induction of clinical response and remission in patients with moderately to severely active Crohn's disease. This benefit is statistically significant for one, two and three infusion treatments. There was a trend toward increased benefit with additional infusions of natalizumab. Natalizumab appears to provide greater benefit for patient subgroups characterized by objective confirmation of active inflammation or chronically active disease despite conventional therapies. These subgroup analyses demonstrated significantly greater clinical response and remission rates for natalizumab compared with placebo in patients with elevated C-reactive protein levels, active disease despite the use of immunosuppressants, or prior anti-tumor necrosis factor therapy. These benefits were apparent for both short term (one infusion) and longer term treatment (two or three infusions). Natalizumab was generally well tolerated and the safety profile observed in the three included studies was similar. Adverse events occurred infrequently and were experienced by a similar proportion of natalizumab and placebo treated patients. There were no statistically significant differences between natalizumab and placebo treated patients in the proportions of patients who withdrew due to adverse events or those who experienced serious adverse events. The included trials lacked adequate power to detect serious adverse events that occur infrequently. Recently, two patients with multiple sclerosis treated with natalizumab in combination with interferon beta-1a and one patient with Crohn's disease treated with natalizumab in combination with azathioprine developed progressive multifocal leukoencephalopathy (PML) resulting in two patient deaths. As a result all dosing in clinical trials and commercial use of natalizumab has been suspended. A retrospective investigation was conducted to assess the risk of PML in natalizumab treated patients and no new cases were identified. AUTHORS' CONCLUSIONS: Pooled data and the results of an ongoing study suggest that natalizumab may be effective for induction of clinical response and remission in patients with moderately to severely active Crohn's disease. The clinical benefit of induction therapy with natalizumab in Crohn's disease should be weighed against the potential risk of serious adverse events. Currently natalizumab is not available on the market for routine clinical use as a consequence of the unexpected association with PML. However, preliminary data from the retrospective investigation of adverse events associated with natalizumab suggest that it may be possible to identify patients at risk for PML by testing for the appearance of JC virus in plasma.

Interventions for treating collagenous colitis.

BACKGROUND: Collagenous colitis is a disorder that is recognized as a cause of chronic diarrhea. Treatment has been based mainly on anecdotal evidence. This review was performed to identify therapies for collagenous colitis that have been proven in randomized trials. OBJECTIVES: To determine effective treatments for patients with clinically active collagenous colitis. SEARCH STRATEGY: Relevant papers published between 1970 and June 2005 were identified via the MEDLINE and PUBMED databases. Manual searches from the references of identified papers, as well as review papers on collagenous or microscopic colitis were performed to identify additional studies. Abstracts from major gastroenterological meetings were searched to identify research submitted in abstract form only. Finally, the Cochrane Controlled Trials Register and the Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Group Specialized Trials Register were searched for other studies. SELECTION CRITERIA: Six randomized trials were identified. One trial studied bismuth subsalicylate (published in abstract form only), one trial studied Boswellia serrata extract (published in abstract form only), one trial studied prednisolone, and 3 trials studied budesonide in the therapy of collagenous colitis. DATA COLLECTION AND ANALYSIS: Data were extracted independently by each author onto 2x2 tables (treatment versus placebo and response versus no response). For therapies assessed in one trial only, p-values were derived using the chi-square test. For therapies assessed in more than one trial, summary test statistics were derived using the Peto odds ratio and 95% confidence intervals. Data were combined for analysis only if the outcomes were sufficiently similar in definition. MAIN RESULTS: There were 9 patients with collagenous colitis in the trial studying bismuth subsalicylate (nine 262 mg tablets daily for 8 weeks). Those randomized to active drug were more likely to have clinical (p = 0.003) and histological (p = 0.003) improvement than those assigned to placebo. Eleven patients were enrolled in the trial studying prednisolone (50 mg daily for 2 weeks). There was a trend towards clinical response in patients on active medication compared to placebo (p = 0.064). The effect of prednisolone on histologic improvement was not studied. Thirty-one patients were enrolled in the Boswellia serrata extract trial. Clinical improvement was noted in 44% of patients who received active treatment compared to 27% of patients who received placebo (p = 0.32). A total of 94 patients were enrolled in 3 trials studying budesonide (9 mg daily or in a tapering schedule for 6 to 8 weeks). The pooled odds ratio for clinical response to treatment with budesonide was 12.32 (95% CI 5.53 - 27.46), with a number needed to treat of 2 patients. There was significant histological improvement with treatment in all 3 trials studying budesonide therapy. Budesonide also appears to improve patients' quality of life. AUTHORS' CONCLUSIONS: Budesonide is effective for the treatment of collagenous colitis. The evidence for benefit with bismuth subsalicylate is weaker. The effectiveness of prednisolone and Boswellia serrata extract and other therapies for induction or maintenance of remission of collagenous colitis is unknown and requires further study.

Cyclosporine for induction of remission in Crohn's disease.

BACKGROUND: Cyclosporine was first found to be an effective and well-tolerated immunosuppressive agent in organ transplant recipients, and subsequently in several autoimmune diseases. It was reported in open studies that cyclosporine is effective for induction of remission in Crohn's disease. Four randomized controlled trials have been performed to determine whether the results observed in these open studies were valid. This systematic review summarizes the evidence on the use of oral cyclosporine for the induction of remission in Crohn's disease. OBJECTIVES: To evaluate the effectiveness of oral cyclosporine for induction of remission in patients with active Crohn's disease in the presence and absence of concomitant steroid therapy. Secondary objectives were to evaluate clinical response rates and adverse events associated with cyclosporine. SEARCH STRATEGY: Computer-assisted searches of the on-line bibliographic databases MEDLINE and EMBASE were performed to identify potentially relevant publications between 1980 and July 2004. The MeSH terms "Crohn Disease" or "Inflammatory Bowel disease" and "Cyclosporin" (exploded) were used to perform key word searches of the databases. Manual searches of reference lists from potentially relevant papers were performed in order to identify additional studies that may have been missed. Abstracts from major gastroenterological meetings, The Cochrane Central Register of Controlled Trials and the Cochrane Inflammatory Bowel Disease Group Specialized Trials Register were also searched for relevant studies. Appropriate officials at Sandoz Corporation were contacted to seek information on any unpublished trials. SELECTION CRITERIA: Prospective, randomized, double-blinded, placebo-controlled trials of parallel design with treatment duration of a minimum 12 weeks comparing oral cyclosporine therapy with placebo for treatment of patients with active Crohn's disease were eligible for inclusion. DATA COLLECTION AND ANALYSIS: All data were analyzed on an intention-to-treat basis. Data were extracted from the original research articles and converted into 2x2 tables (cyclosporine vs. placebo). Where available, individual 2x2 tables for strata within studies were also used. Heterogeneity was assessed using the chi-square test (p < 0.10 was regarded as statistically significant). For non-pooled data, p-values were derived using the chi-square test. For pooled data, summary test statistics were derived using the Peto odds ratio and 95% confidence intervals. A fixed effects model was used for pooling of data. For continuous data, summary test statistics were derived using the weighted mean difference and 95% confidence intervals. The definitions of treatment success, remission and clinical improvement were set by the authors of each paper, and the data were combined for analysis only if these definitions were sufficiently similar. MAIN RESULTS: Brynskov 1989a found that patients receiving high dose cyclosporine (median 7.6 mg/kg/day) had statistically significant clinical improvement at 12 weeks compared to placebo patients. None of the other studies found any statistically significant benefit for clinical improvement or induction of remission for low dose cyclosporine treatment (5 mg/kg/day) used by itself or in combination with corticosteroids compared to placebo. Cyclosporine was associated with a significantly higher proportion of adverse events and withdrawals due to adverse events relative to placebo. AUTHORS' CONCLUSIONS: Brynskov 1989a enrolled a small number of patients and the modified clinical grading scale used in the study has not been validated in other studies. Furthermore, statistically significant clinical improvement does not imply induction of clinical remission. Indeed, Brynskov 1989a found no statistically significant differences in the mean Crohn's Disease Activity Index score at 12 weeks indicating that cyclosporine was no more effective than placebo for induction of remission in Crohn's disease. The results of this review demonstrate that low dose (5 mg/kg/day) oral cyclosporine is not effective for the induction of remission in Crohn's disease. Patients treated with low dose oral cyclosporine are more likely than placebo treated patients to experience adverse events including renal dysfunction. The use of low dose oral cyclosporine for the treatment of chronic active Crohn's disease does not appear to be justified. Oral dosing at higher levels or parenteral administration of cyclosporine have not been adequately evaluated in controlled clinical trials. Higher doses of cyclosporine are not likely to be useful for the long-term management of Crohn's disease because of the risk of nephrotoxicity and the availability of other proven interventions.

Methotrexate for induction of remission in refractory Crohn's disease.

BACKGROUND: Although corticosteroids are effective for induction of remission of Crohn's disease, approximately 20% of patients who respond relapse when steroids are withdrawn and become steroid dependent (Binder 1985). Furthermore, corticosteroids exhibit significant adverse effects. The success of methotrexate as a treatment for rheumatoid arthritis led to its evaluation in patients with refractory Crohn's disease. Methotrexate has been studied for induction of remission of refractory Crohn's disease and has become the principal alternative to azathioprine/6MP therapy. The evidence for its effectiveness has not been subjected to a systematic review. OBJECTIVES: To conduct a systematic review of the evidence for effectiveness of methotrexate for induction of remission in patients with active Crohn's disease in the presence and absence of concomitant steroid therapy. SEARCH STRATEGY: A computer-assisted search of MEDLINE and EMBASE for relevant studies published in English, French, Spanish, Italian and German between 1966 and July 2004. Manual searches of reference lists from potentially relevant papers were performed to identify additional studies. The Cochrane Controlled Trials Register and the IBD Review Group Specialized Trials Register were also searched. SELECTION CRITERIA: Randomized controlled trials involving patients of age > 17 years with refractory Crohn's disease defined by conventional clinical, radiological and endoscopic criteria, which was categorized as being active (Crohn's disease activity index >150). OUTCOME MEASURES: The outcome measure was the rate of induction of remission and complete withdrawal from steroids in the treatment and control groups after > 16 weeks of treatment. A secondary outcome was induction of remission with reduction in steroid dose of at least 50%. Selection of trials: The results of the searches above were reviewed independently by two observers and relevant studies selected according to the predefined selection criteria. Any disagreement among reviewers was resolved by consensus. The same two reviewers assessed the methodological quality of each trial (details of randomization method, including whether intention-to-treat analysis was possible from the published data, number of patients lost to follow-up, and if a blinded outcome assessment was used). A standard data extraction form was used. Appropriateness of combining results: Trials were first reviewed to assess the clinical comparability of trial protocols and study populations. MAIN RESULTS: Five randomized trials were identified. The five studies differed with respect to participants, intervention, and outcomes to the extent that it was considered to be inappropriate to combine the data statistically. Three small studies which employed low doses of methotrexate orally showed no statistically significant difference between methotrexate and placebo/control medication treated patients. One small study which used a higher dose of intravenous/oral methotrexate showed no statistically significant difference between methotrexate and azathioprine. A larger study which employed a higher dose of methotrexate intramuscularly showed substantial benefit (number needed to treat, NNT=5). Adverse effects were more common with high dose intramuscular methotrexate therapy than with placebo. AUTHORS' CONCLUSIONS: There is evidence from a single large randomized trial on which to recommend the use of methotrexate 25 mg intramuscularly weekly for induction of remission and complete withdrawal from steroids in patients with refractory Crohn's disease. Although adverse effects were more common than with placebo, they were not severe. There is no evidence on which to base a recommendation for use of lower dose oral methotrexate.

Transdermal nicotine for induction of remission in ulcerative colitis.

BACKGROUND: Ulcerative colitis is largely a disease of nonsmokers. Intermittent smokers often experience improvement in their symptoms while smoking. Nonsmokers with ulcerative colitis who begin smoking may go into remission. Randomized controlled trials were developed to test the efficacy of transdermal nicotine for the induction of remission in ulcerative colitis. OBJECTIVES: (1) To determine the efficacy of transdermal nicotine for induction of remission in ulcerative colitis. (2) To assess adverse events associated with transdermal nicotine therapy for ulcerative colitis SEARCH STRATEGY: The MEDLINE (via PubMed) and EMBASE databases were searched using the search criteria "ulcerative colitis" and "transdermal nicotine" or "nicotine" to identify relevant papers published between 1970 and December 2003. Manual searches of reference lists from potentially relevant papers were performed to identify additional studies. Abstracts from major gastroenterological meetings were searched to identify research submitted in abstract form only. The Cochrane Central Register of Controlled Trials and the Cochrane Inflammatory Bowel Disease Group Specialized Trials Register were also searched. SELECTION CRITERIA: We included only randomized controlled trials in which patients with active mild to moderate ulcerative colitis were randomly allocated to receive transdermal nicotine (15 to 25 mg/day) or a placebo or another treatment (corticosteroids or mesalamine). DATA COLLECTION AND ANALYSIS: Data extraction and assessment of the methodological quality of each trial were independently performed by each author. Any disagreement among reviewers was resolved by consensus. The primary outcome measure was the number of patients achieving clinical or sigmoidoscopic remission as defined by the primary studies (e.g. no symptoms of ulcerative colitis), and expressed as a percentage of the patients randomized (intention to treat analysis). Secondary outcomes included clinical response, adverse events and withdrawal because of adverse events. MAIN RESULTS: Seven studies were identified, five of which met the inclusion criteria. A meta-analysis of two trials in which 71 patients were randomized to nicotine and 70 to placebo showed a statistically significant benefit for nicotine treatment. After four to six weeks of treatment 19 of 71 patients treated with transdermal nicotine were in clinical remission compared to 9 of 70 treated with placebo (OR=2.56, 95% CI 1.02-6.45). In the same group of patients improvement or remission was noted in 29 of the 71 patients assigned to nicotine compared to 14 of 70 patients assigned to placebo (OR=2.72, 95% CI 1.28 - 5.81). For patients with left sided colitis the odds ratio was 2.31 (95% CI 1.05-5.10). When transdermal nicotine was compared to standard medical therapy no significant benefit for nicotine was observed. After four to six weeks of standard therapy (oral prednisone or mesalamine), 34 of 63 patients were in clinical or sigmoidoscopic remission compared to 33 of 66 patients treated with transdermal nicotine (OR=0.77, 95% CI 0.37-1.60). A meta-analysis of all five studies which included 137 patients treated with transdermal nicotine and 133 patients treated with a placebo or standard therapy demonstrated no statistically significant benefit of nicotine therapy (OR=1.23; 95% CI 0.71-2.14). Patients treated with transdermal nicotine were significantly more likely to withdrawal due to adverse events than patients treated with placebo or standard medical therapy (OR=5.82, 95% CI, 1.66 - 20.47) and were significantly more likely to suffer from an adverse event than patients treated with placebo or standard medical therapy (OR=3.54, 95% CI, 2.07 - 6.08). REVIEWERS' CONCLUSIONS: The results of this review provide evidence that transdermal nicotine is superior to placebo for the induction of remission in patient's with ulcerative colitis. The review did not identify any significant advantage for transdermal nicotine therapy compared to standard medical therapy. Adverse events associated with transdermal nicotine are significant and limit its use in some patients.

Interventions for treating collagenous colitis.

BACKGROUND: Collagenous colitis is a disorder that is recognized as a cause of chronic diarrhea. Treatment has been based mainly on anecdotal evidence. This review was performed to identify therapies for collagenous colitis that have been proven in randomized trials. OBJECTIVES: To determine effective treatments for patients with clinically active collagenous colitis. SEARCH STRATEGY: Relevant papers published between 1970 and August 2003 were identified via the MEDLINE and PUBMED databases. Manual searches from the references of identified papers, as well as review papers on collagenous or microscopic colitis were performed to identify additional studies. Abstracts from major gastroenterological meetings were searched to identify research submitted in abstract form only. Finally, the Cochrane Controlled Trials Register and the Cochrane Inflammatory Bowel Disease Group Specialized Trials Register were searched for other studies. SELECTION CRITERIA: Five randomized trials were identified. One trial studied bismuth subsalicylate (published in abstract form only), one trial studied prednisolone, and 3 trials studied budesonide in the therapy of collagenous colitis. DATA COLLECTION AND ANALYSIS: Data were extracted independently by each author onto 2x2 tables (treatment versus placebo and response versus no response). For therapies assessed in one trial only, p-values were derived using the chi-square test. For therapies assessed in more than one trial, summary test statistics were derived using the Peto odds ratio and 95% confidence intervals. Data were combined for analysis only if the outcomes were sufficiently similar in definition. MAIN RESULTS: There were 9 patients with collagenous colitis in the trial studying bismuth subsalicylate (nine 262 mg tablets daily for 8 weeks). Those randomized to active drug were more likely to have clinical (p=0.003) and histological (p=0.003) improvement than those assigned to placebo. Eleven patients were enrolled in the trial studying prednisolone (50 mg daily for 2 weeks). There was a trend towards clinical response in patients on active medication compared to placebo (p=0.064). The effect of prednisolone on histologic improvement was not studied. A total of 94 patients were enrolled in 3 trials studying budesonide (9 mg daily or in a tapering schedule for 6 to 8 weeks). The pooled odds ratio for clinical response to treatment with budesonide was 12.32 (95% CI 5.53-27.46), with a number needed to treat of 2 patients. There was significant histological improvement with treatment in all 3 trials studying budesonide therapy. REVIEWER'S CONCLUSIONS: Budesonide is effective for the treatment of collagenous colitis. The evidence for benefit with bismuth subsalicylate is weaker. Prednisolone may be effective for treatment of collagenous colitis, but only a single very small study has been reported. The effectiveness of these and other therapies for induction or maintenance of remission (as opposed to producing clinical or histological improvement) of collagenous colitis is unknown.

Interventions for treating collagenous colitis.

BACKGROUND: Collagenous colitis is a disorder that is recognized as a cause of chronic diarrhea. Treatment has been based mainly on anecdotal evidence. This review was performed to identify therapies for collagenous colitis that have been proven in randomized trials. OBJECTIVES: To determine effective treatments for patients with clinically active collagenous colitis. SEARCH STRATEGY: Relevant papers published between 1970 and April 2003 were identified via the MEDLINE and PUBMED databases. Manual searches from the references of identified papers, as well as review papers on collagenous or microscopic colitis were performed to identify additional studies. Abstracts from major gastroenterological meetings were searched to identify research submitted in abstract form only. Finally, the Cochrane Controlled Trials Register and the Cochrane Inflammatory Bowel Disease Group Specialized Trials Register were searched for other studies. SELECTION CRITERIA: Four randomized trials were identified. One trial studied bismuth subsalicylate (published in abstract form only), and 3 trials studied budesonide in the therapy of collagenous colitis. DATA COLLECTION AND ANALYSIS: Data were extracted independently by each author onto 2x2 tables (treatment versus placebo and response versus no response). For therapies assessed in one trial only, p-values were derived using the chi-square test. For therapies assessed in more than one trial, summary test statistics were derived using the Peto odds ratio and 95% confidence intervals. Data were combined for analysis only if the outcomes were sufficiently similar in definition. MAIN RESULTS: There were 9 patients with collagenous colitis in the trial studying bismuth subsalicylate (nine 262 mg tablets daily for 8 weeks). Those randomized to active drug were more likely to have clinical (p=0.003) and histological (p=0.003) improvement than those assigned to placebo. A total of 94 patients were enrolled in 3 trials studying budesonide (9 mg daily or in a tapering schedule for 6 to 8 weeks). The pooled odds ratio for clinical response to treatment with budesonide was 12.32 (95% CI 5.53-27.46), with a number needed to treat of 2 patients. There was significant histological improvement with treatment in all 3 trials studying budesonide therapy. REVIEWER'S CONCLUSIONS: Budesonide is effective in the treatment of collagenous colitis. The evidence for bismuth subsalicylate is weaker, but still important. The roles of these and other therapies in inducing or maintaining remission (as opposed to clinical or histological improvement) of collagenous colitis are unknown.