Khurram J. Khan

Efficacy of Biological Therapies in Inflammatory Bowel Disease: Systematic Review and Meta-Analysis

OBJECTIVES:Crohns disease (CD) and ulcerative colitis (UC) are inflammatory disorders of the gastrointestinal tract of unknown etiology. Evidence for treatment of the condition with biological therapies exists, but no systematic review and meta-analysis has examined this issue in its entirety.METHODS:MEDLINE, EMBASE, and the Cochrane central register of controlled trials were searched (through to December 2010). Trials recruiting adults with active or quiescent CD or UC and comparing biological therapies (anti-tumor necrosis factor-α (TNFα) antibodies or natalizumab) with placebo were eligible. Dichotomous symptom data were pooled to obtain relative risk (RR) of failure to achieve remission in active disease and RR of relapse of activity in quiescent disease once remission had occurred, with a 95% confidence interval (CI).RESULTS:The search strategy identified 3,061 citations, 27 of which were eligible. Anti-TNFα antibodies and natalizumab were both superior to placebo in inducing remission of luminal CD (RR of no remission=0.87; 95% CI 0.80–0.94 and RR=0.88; 95% CI 0.83–0.94, respectively). Anti-TNFα antibodies were also superior to placebo in preventing relapse of luminal CD (RR of relapse=0.71; 95% CI 0.65–0.76). Infliximab was superior to placebo in inducing remission of moderate to severely active UC (RR=0.72; 95% CI 0.57–0.91).CONCLUSIONS:Biological therapies were superior to placebo in inducing remission of active CD and UC, and in preventing relapse of quiescent CD.

Antibiotic Therapy in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis

The etiology of inflammatory bowel disease (IBD) is unknown but may relate to an unidentified bacterial pathogen or an immunological reaction to gut microbiota. Antibiotics have therefore been proposed as a therapy for Crohns disease (CD) and ulcerative colitis (UC) to induce remission in active disease to prevent relapse. Current data are conflicting and we therefore conducted a systematic review of randomized controlled trials (RCTs) evaluating antibiotics in IBD. Only parallel group RCTs were considered eligible. Studies with adult patients receiving any dose of therapy for at least 7 days and up to 16 weeks for active disease, or at least 6 months of follow-up for preventing relapse in quiescent disease were analyzed. We included any antibiotics alone or in combination using predefined definitions of remission and relapse. Two reviewers independently assessed eligibility and extracted data. The primary outcome was remission or relapse using an intention-to-treat methodology. The data were summarized using relative risk (RR) and pooled using a random effects model. For active CD, there were 10 RCTs involving 1,160 patients. There was a statistically significant effect of antibiotics being superior to placebo (RR of active CD not in remission=0.85; 95% confidence interval (CI)=0.73–0.99, P=0.03). There was moderate heterogeneity between results (I2=48%) and a diverse number of antibiotics were tested (anti-tuberculosis therapy, macrolides, fluroquinolones, 5-nitroimidazoles, and rifaximin) either alone or in combination. Rifamycin derivatives either alone or in combination with other antibiotics appeared to have a significant effect at inducing remission in active CD. In perianal CD fistula there were three trials evaluating 123 patients using either ciprofloxacin or metronidazole. There was a statistically significant effect in reducing fistula drainage (RR=0.8; 95% CI=0.66–0.98) with no heterogeneity (I2=0%) and an number needed to treat 5 (95% CI=3–20). For quiescent CD, there were 3 RCTs involving 186 patients treated with different antibiotics combinations (all including antimycobacterials) vs. placebo. There was a statistically significant effect in favor of antibiotics vs. placebo (RR of relapse=0.62; 95% CI=0.46–0.84), with no heterogeneity (I2=0%). In active UC, there were 9 RCTs with 662 patients and there was a statistically significant benefit for antibiotics inducing remission (RR of UC not in remission=0.64; 95% CI=0.43–0.96). There was moderate heterogeneity (I2=69%) and antibiotics used were all different single or combination drugs. Antibiotic therapy may induce remission in active CD and UC, although the diverse number of antibiotics tested means the data are difficult to interpret. This systematic review is a mandate for further trials of antibiotic therapy in IBD.

Efficacy of Immunosuppressive Therapy for Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis

OBJECTIVES:There remains controversy regarding the efficacy of thiopurine analogs (azathioprine (AZA) and 6-mercaptopurine (6-MP)), methotrexate (MTX), and cyclosporine for the treatment of inflammatory bowel disease (IBD). We performed an updated systematic review of the literature to clarify the efficacy of immunosuppressive therapy at inducing remission and preventing relapse in ulcerative colitis (UC) and Crohns disease (CD).METHODS:Only parallel group randomized controlled trials (RCTs) were considered eligible. Studies with adult IBD patients receiving immunosuppressive therapy compared with placebo for at least 14 days and up to 17 weeks for active disease, or at least 6 months in quiescent disease were analyzed. Two reviewers independently assessed eligibility and extracted data. The primary outcome was remission or relapse using an intention-to-treat analysis. The data were summarized using relative risk (RR) and pooled using a random effects model.RESULTS:Data on MTX and cyclosporine in IBD were limited although there were some data to support the use of intramuscular MTX in CD but not UC. There were five trials of AZA/6-MP in 380 active CD patients and there was no significant effect of therapy inducing remission (RR=0.87; 95% confidence interval (CI)=0.71–1.06). In quiescent CD, there were two trials involving 198 patients with no significant benefit of active therapy preventing relapse compared with placebo (RR=0.64; 95% CI=0.34–1.23). There were, however, three additional AZA withdrawal trials in 163 patients that indicated continuing medication did prevent relapse (RR=0.39; 95% CI=0.21–0.74). There were two AZA RCTs in 130 active UC patients that suggested a trend for benefit of therapy, but this did not reach statistical significance (RR=0.85; 95% CI=0.71–1.01). In quiescent UC, there were three trials involving 127 patients and there was a statistically significant benefit of AZA preventing relapse (RR=0.60; 95% CI=0.37–0.95).CONCLUSIONS:Most evidence relates to AZA/6-MP where there is no statistically significant benefit at inducing remission in active CD and UC. Thiopurine analogs may prevent relapse in quiescent UC and CD. However, there is a paucity of data for immunosuppressive therapy in IBD and more research is needed.

Glucocorticosteroid Therapy in Inflammatory Bowel Disease: Systematic Review and Meta-Analysis

OBJECTIVES:The use of glucocorticosteroids to treat both Crohns disease (CD) and ulcerative colitis (UC) is widespread, but no systematic review and meta-analysis has examined the issue of efficacy of these agents in its entirety.METHODS:MEDLINE, EMBASE, and the Cochrane central register of controlled trials were searched (through December 2010). Randomized controlled trials (RCTs) recruiting adults with active or quiescent CD comparing standard glucocorticosteroids or budesonide with placebo or each other, or comparing standard glucocorticosteroids with placebo in active UC, were eligible. Dichotomous data were extracted to obtain relative risk (RR) of failure to achieve remission in active disease, and RR of relapse of activity in quiescent disease, with a 95% confidence interval (CI). Adverse events data were extracted where reported.RESULTS:The search identified 3,061 citations, and 20 trials were eligible. Only one trial was at low risk of bias. Standard glucocorticosteroids were superior to placebo for UC remission (RR of no remission=0.65; 95% CI 0.45–0.93). Both trials of standard glucocorticosteroids in CD remission reported a statistically significant effect, but because of heterogeneity between studies, the overall effect was not significant (RR=0.46; 95% CI 0.17–1.28). Budesonide was superior to placebo for CD remission (RR=0.73; 95% CI 0.63–0.84), but not in preventing CD relapse (RR=0.93; 95% CI 0.83–1.04). Standard glucocorticosteroids were superior to budesonide for CD remission (RR=0.82; 95% CI 0.68–0.98), but glucocorticosteroid-related adverse events were commoner (RR=1.64; 95% CI 1.34–2.00).CONCLUSIONS:Standard glucocorticosteroids are probably effective in inducing remission in UC, and may be of benefit in CD. Budesonide induces remission in active CD, but is less effective than standard glucocorticosteroids, and is of no benefit in preventing CD relapse.

Efficacy of 5-Aminosalicylates in Ulcerative Colitis: Systematic Review and Meta-Analysis

OBJECTIVES:The efficacy of 5-aminosalicylic acids (5-ASAs) in ulcerative colitis (UC) has been studied previously in meta-analyses. However, several randomized controlled trials (RCTs) have been published recently, and no previous meta-analysis has studied the effect of 5-ASA dosage used.METHODS:MEDLINE, EMBASE, and the Cochrane central register of controlled trials were searched (through December 2010). Eligible trials recruited adults with active or quiescent UC, comparing different doses of 5-ASAs with themselves or placebo. Dichotomous data were pooled to obtain relative risk (RR) of failure to achieve remission in active UC, and RR of relapse of disease activity in quiescent UC, with a 95% confidence interval (CI). The number needed to treat (NNT) was calculated from the reciprocal of the risk difference.RESULTS:The search identified 3,061 citations, and 37 RCTs were eligible. Of these, 11 compared 5-ASA with placebo in active UC remission, with the RR of no remission with 5-ASAs of 0.79 (95% CI 0.73–0.85; NNT=6). Doses of ≥2.0 g/day were more effective than <2.0 g/day for remission (RR=0.91; 95% CI 0.85–0.98). There were 11 RCTs comparing 5-ASAs with placebo in preventing relapse of quiescent UC, with the RR of relapse of 0.65 (95% CI 0.55–0.76; NNT=4). Doses of ≥2.0 g/day appeared more effective than <2.0 g/day for preventing relapse (RR=0.79; 95% CI 0.64–0.97).CONCLUSIONS:5-ASAs are highly effective for inducing remission and preventing relapse in UC. Evidence suggests that doses of ≥2.0 g/day have greater efficacy, although doses >2.5 g/day do not appear to lead to higher remission rates.

Efficacy of 5-Aminosalicylates in Crohn's Disease: Systematic Review and Meta-Analysis

OBJECTIVES:Crohns disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract. Evidence for treatment with 5-aminosalicylic acid (5-ASA) drugs is conflicting. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to examine this issue.METHODS:MEDLINE, EMBASE, and the Cochrane central register of controlled trials were searched (through December 2010). Authors of studies were contacted to provide additional information on trials where required, and experts in the field were contacted to identify unpublished studies. Eligible trials recruited adults with active or quiescent CD and compared 5-ASAs with placebo, or no treatment. Dichotomous data were pooled to obtain relative risk (RR) of failure to achieve remission in active CD, and RR of relapse of disease activity in quiescent CD, with a 95% confidence interval (CI). The number needed to treat (NNT) was calculated from the reciprocal of the risk difference.RESULTS:The search identified 3,061 citations. Twenty-two RCTs were eligible. Six RCTs compared 5-ASA with placebo in active CD remission. There was a trend towards a benefit with sulfasalazine over placebo (two RCTs, RR of failure to achieve remission=0.83; 95% CI=0.69–1.00), but no definite benefit of mesalamine over placebo (four RCTs, RR=0.91; 95% CI=0.77–1.06). Neither sulfasalazine nor mesalamine were effective in preventing quiescent CD relapse, but in a per protocol analysis mesalamine appeared to reduce risk of relapse (RR=0.79; 95% CI=0.66–0.95, NNT=13).CONCLUSIONS:The role of 5-ASAs in inducing remission of active CD and preventing relapse of quiescent CD remains uncertain, and more RCTs are required.

5-Aminosalicylates Prevent Relapse of Crohn's Disease After Surgically Induced Remission: Systematic Review and Meta-Analysis

OBJECTIVES:Evidence from randomized controlled trials (RCTs) for the use of 5-aminosalicylic acid (5-ASA) drugs in Crohns disease (CD) in remission after a surgical resection is conflicting. We conducted a systematic review and meta-analysis of RCTs to examine this issue.METHODS:MEDLINE, EMBASE, and the Cochrane central register of controlled trials were searched (through April 2010). Eligible trials recruited adults with luminal CD in remission after a surgical resection and compared 5-ASAs with placebo, or no treatment. Dichotomous data were pooled to obtain relative risk (RR) of relapse of disease activity, with a 95% confidence interval (CI). The number needed to treat (NNT) was calculated from the reciprocal of the risk difference.RESULTS:The search strategy identified 3,061 citations. Eleven RCTs were eligible for inclusion containing 1,282 patients. The RR of relapse of CD in remission after surgery with 5-ASA vs. placebo or no therapy was 0.86 (95% CI=0.74–0.99) (NNT=13). Sulfasalazine was of no benefit in preventing relapse in 448 patients (RR=0.97; 95% CI=0.72–1.31), but mesalamine was more effective than placebo or no therapy (RR=0.80; 95% CI=0.70–0.92) in 834 patients, with an NNT of 10.CONCLUSIONS:Mesalamine is of modest benefit in preventing relapse of CD in remission after surgery. Its use should be considered in those in whom immunosuppressive therapy is either not warranted or contraindicated.

Efficacy of oral vs topical, or combined oral and topical 5-aminosalicylates, in ulcerative colitis: systematic review and meta-analysis

OBJECTIVES:Efficacy of 5-aminosalicylic acids (5-ASAs) in ulcerative colitis (UC) has been studied previously in meta-analyses. However, no recent meta-analysis has studied the relative efficacies of differing routes of administration.METHODS:MEDLINE, EMBASE, and the Cochrane central register of controlled trials were searched (through May 2011). Eligible trials recruited adults with mildly to moderately active UC, or quiescent UC, and compared oral 5-ASAs with either topical 5-ASAs or a combination of oral and topical 5-ASAs. Dichotomous data were pooled to obtain relative risk (RR) of failure to achieve remission in active UC, and RR of relapse of disease activity in quiescent UC, with a 95% confidence interval (CI). The number needed to treat (NNT) was calculated from the reciprocal of the risk difference.RESULTS:The search identified 3,061 citations, and 12 randomized controlled trials (RCTs) were eligible. Four compared topical with oral 5-ASAs in active UC remission, with an RR of no remission with topical 5-ASAs of 0.82 (95% CI=0.52–1.28). Four trials compared combined with oral 5-ASAs in active UC (RR of no remission=0.65; 95% CI=0.47–0.91; NNT=5). Three RCTs compared intermittent topical with oral 5-ASAs in preventing relapse of quiescent UC (RR=0.64; 95% CI=0.43–0.95; NNT=4), and two compared combined with oral 5-ASAs (RR of relapse=0.48; 95% CI=0.17–1.38).CONCLUSIONS:Combined 5-ASA therapy appeared superior to oral 5-ASAs for induction of remission of mildly to moderately active UC. Intermittent topical 5-ASAs appeared superior to oral 5-ASAs for preventing relapse of quiescent UC.

Once-daily dosing vs. conventional dosing schedule of mesalamine and relapse of quiescent ulcerative colitis: systematic review and meta-analysis.

OBJECTIVES:Maintenance therapy with 5-aminosalicylates (5-ASAs) is recommended in patients with quiescent ulcerative colitis (UC), but compliance rates are low. Once-daily dosing may improve adherence, but impact on the relapse of disease activity is unclear as no previous meta-analysis has studied this issue.METHODS:MEDLINE, EMBASE, and the Cochrane central register of controlled trials were searched (through April 2011). Eligible randomized controlled trials (RCTs) recruited adults with quiescent UC, and compared once-daily dosing of 5-ASAs with a more frequent dosing schedule of an identical total daily dose of the same 5-ASA drug. Minimum treatment duration was 6 months. Trials reported a dichotomous assessment of relapse of disease activity at last point of follow-up. Data concerning non-compliance and adverse events were extracted, where reported. Effect of once-daily vs. more frequent dosing schedule was reported as relative risk (RR) of relapse with a 95% confidence interval (CI).RESULTS:The search identified 3,061 citations, and seven RCTs containing 2,745 patients were eligible. All RCTs used mesalamine. Relapse rates were not significantly different between once-daily and conventional dosing schedules for mesalamine (RR of relapse=0.94; 95% CI: 0.82–1.08). Non-compliance (RR=0.87; 95% CI: 0.46–1.66) and adverse events were no more likely with once-daily dosing (RR=1.08; 95% CI: 0.97–1.20).CONCLUSIONS:Once-daily dosing with mesalamine is as effective as conventional dosing schedules for the prevention of relapse of quiescent UC, although there is no definitive evidence that compliance with once-daily dosing is better. Adverse events occur at a similar frequency.

Efficacy of Topical 5-Aminosalicylates in Preventing Relapse of Quiescent Ulcerative Colitis: A Meta-analysis

BACKGROUND & AIMS Topical 5-aminosalicylates (5-ASAs) such as mesalamine are effective in inducing remission in patients with mild to moderately active ulcerative colitis (UC). However, there has been no meta-analysis of their efficacy in preventing relapse of quiescent UC. METHODS We searched MEDLINE, EMBASE, and the Cochrane central register of controlled trials through July 2011 for randomized controlled trials comparing the effects of topical 5-ASAs with placebo in adults with quiescent UC. Dichotomous data were pooled to obtain relative risk (RR) of relapse of disease activity. The number needed to treat (NNT) was calculated from the reciprocal of the risk difference. Adverse events data were summarized. RESULTS The search identified 3061 citations; we analyzed data from seven (555 patients). All trials used mesalamine, but only one included patients with extensive disease. The duration of therapy ranged from 6-24 months. The RR of relapse of disease activity in patients with quiescent UC who were given topical mesalamine, compared with placebo, was 0.60 (95% confidence interval, 0.49-0.73; NNT = 3); there was no significant heterogeneity between studies (I(2) = 21%, P = .27). No significant differences in rates of adverse events rates were detected (RR = 1.01; 95% confidence interval, 0.59-1.72). CONCLUSIONS On the basis of a meta-analysis of 7 randomized controlled trials, topical mesalamine is effective in preventing relapse of quiescent UC, with no greater number of adverse events than placebo. However, because most studies included only patients with left-sided disease or proctitis, the efficacy of topical mesalamine in preventing relapse in patients with more extensive quiescent UC is not known.