Ulcerative colitis (UC) is a relatively common inflammatory

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2012;10: Efficacy of Topical 5-Aminosalicylates in Preventing Relapse of Quiescent Ulcerative Colitis: A Meta-analysis ALEXANDER C. FORD,*, KHURRAM J. KHAN, WILLIAM J. SANDBORN, STEPHEN B. HANAUER, and PAUL MOAYYEDI *Leeds Gastroenterology Institute, Leeds General Infirmary, Leeds, United Kingdom; Leeds Institute of Molecular Medicine, University of Leeds, Leeds, United Kingdom; Gastroenterology Division, McMaster University, Health Sciences Center, Hamilton, Ontario, Canada; Division of Gastroenterology, University of California San Diego, La Jolla, California; and Department of Medicine and Committee on Clinical Pharmacology, Section of Gastroenterology, Hepatology, and Nutrition, University of Chicago Medical Center, Chicago, Illinois 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. RE- SULTS: 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, ; 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, ). 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. Keywords: Clinical Trial; Drug Treatment; Inflammation; Colon. Ulcerative colitis (UC) is a relatively common inflammatory disorder of the gastrointestinal tract, with an incidence of 7 9 per 100,000 people and a prevalence of approximately per 100, The disease tends to follow a relapsing and remitting course, with sufferers experiencing intermittent flare-ups of disease activity. The majority of these are treated with medical therapy by using either oral or topical 5-aminosalicylates (5-ASAs) for mild to moderate attacks, with oral or intravenous glucorticosteroids reserved for those with more severe disease activity. Meta-analyses consistently demonstrate that both these drugs are of proven benefit in these situations. 6 9 Once induction of remission has been successfully achieved, there remains a risk of relapse of disease activity. Oral 5-ASAs are efficacious in preventing relapse of quiescent UC, 7,10 with an estimated number needed to treat (NNT) to prevent one relapse of only 4 in a recent meta-analysis that examined this issue. 7 Current United Kingdom and European guidelines for the management of UC recommend that oral 5-ASAs be prescribed by physicians for maintenance of remission 11,12 rather than topical 5-ASAs, even in those with distal disease, whereas US guidelines recommend topical 5-ASA therapy first-line for prevention of relapse in individuals with left-sided UC. 13 Despite these recommendations, in a critical evaluation of published studies examining the medical management of quiescent left-sided UC and ulcerative proctitis, 14 the authors concluded that topical 5-ASAs were also effective for preventing relapse. In a meta-analysis published in 2000, 15 maintenance of remission rates of 80% 90% were reported with topical 5-ASA therapy. However, no formal quantitative analysis of data including randomized controlled trials (RCTs) was performed in either of these reviews. A protocol for a meta-analysis of the efficacy of topical 5-ASAs in preventing relapse of quiescent UC is registered with the Cochrane collaboration 16 but has yet to be completed. There is therefore a clear need for a contemporary study to summarize the current literature to date that has examined this issue. We have conducted a systematic review and meta-analysis to assess the efficacy of topical 5-ASAs, compared with placebo, in preventing relapse of quiescent UC. Methods Search Strategy and Study Selection A search of the medical literature was conducted by using MEDLINE (1966 to July 2011), EMBASE (1984 to July 2011), the Cochrane central register of controlled trials (issue 2, April 2011), and the Cochrane Inflammatory Bowel Disease Group Specialized Trials Register. Randomized controlled trials examining the effect of topical 5-ASA drugs in adult patients ( 90% of participants older than the age of 16 years) with quiescent UC were eligible for inclusion (Table 1). The first period of crossover RCTs were also eligible for inclusion. The control arm was required to receive placebo. Duration of ther- Abbreviations used in this paper: 5-ASA, 5-aminosalicylate; CI, confidence interval; NNT, number needed to treat; RCT, randomized controlled trial; RR, relative risk; UC, ulcerative colitis by the AGA Institute /$36.00 doi: /j.cgh

2 514 FORD ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 5 Table 1. Eligibility Criteria Randomized controlled trials Adults ( 90% of patients aged 16 years) with quiescent UC Compared topical 5-ASAs a with placebo Minimum duration of therapy of 6 months (24 weeks) Assessment of relapse of disease activity at last time point of assessment in the trial b a Sulfasalazine, mesalamine, balsalazide, or olsalazine. b Preferably using evidence of endoscopic relapse, but if this outcome measure was not reported, then other measures were permissible according to a predefined hierarchy (Table 2). apy had to be at least 6 months (24 weeks). Trials that used any dose of topical 5-ASA drug were considered eligible. Studies had to report an assessment of relapse of disease activity in quiescent UC at last time point of assessment in the trial, preferably by using evidence of endoscopic relapse, but if this outcome measure was not reported, then other measures were permissible according to a predefined hierarchy (Table 2). First and senior authors of studies were contacted to provide additional information on trials where required. The literature search was performed as part of a broader exercise to inform on the update of the American College of Gastroenterology s monograph for the management of inflammatory bowel disease. Specifically, studies on UC were identified with the terms ulcerative colitis, inflammatory bowel disease, or colitis (both as medical subject headings [MeSH] and free text terms). These were combined by using the set operator AND with studies identified with the terms sulfasalazine, mesalamine, or aminosalicylic acid (both as MeSH terms and free text terms) or the following free text terms: balsalazide, olsalazine, mesalazine, pentasa, asulfidine$, azulfadine$, azulfidine$, sulfasalazine$, salazopyrin$, salazosulfapyridine, 5-ASA, 5ASA, 5-aminosalicylic$, 5-aminosalicylate$, 5aminosalicylic$, or5aminosalicylate$. There were no language restrictions. Abstracts of the articles identified by the initial search were evaluated by the lead investigator for appropriateness to the study question. All potentially relevant articles were obtained and evaluated in detail. Foreign language articles were translated where necessary. Abstract books of conference proceedings between 2002 and 2011 were hand-searched to identify potentially eligible studies published only in abstract form. The bibliographies of all identified relevant studies were used to perform a recursive search of the literature. Articles were assessed independently by 2 investigators who used predesigned eligibility forms, according to the eligibility criteria stated previously. Any disagreement between investigators was resolved by discussion with a third investigator. Outcome Assessment The primary outcome assessed was the efficacy of topical 5-ASA drugs compared with placebo for the prevention of relapse of disease activity in quiescent UC by using any of the definitions used by individual studies, but with data extracted according to our predefined hierarchy (Table 2). Secondary outcomes included assessing adverse events occurring as a result of therapy (overall numbers as well as individual adverse events such as anal canal pain during enema or suppository insertion, upper or lower gastrointestinal disturbances [nausea, vomiting, diarrhea], dermatologic problems [rash], and systemic effects [myalgia, fever, headache, lethargy]). Data Extraction All data were extracted independently by 2 investigators onto a Microsoft Excel spreadsheet (XP professional edition; Microsoft Corp, Redmond, WA) as dichotomous outcomes (relapse or no relapse of disease activity) (Table 2). In addition, the following clinical data were extracted for each trial where available: demographic data of trial participants (age, gender, and ethnicity), distribution of UC, number of centers, country of origin, dosage and schedule of topical 5-ASA drug used, duration of therapy, number of individuals incurring each (or any) of the adverse events of interest, primary outcome measure used to define relapse during therapy, and duration of follow-up. Data were extracted as intention-to-treat analyses, where all dropouts are assumed to be treatment failures (ie, disease activity relapsed), wherever trial reporting allowed this. Assessment of Risk of Bias This was performed independently by 2 investigators, with disagreements resolved by discussion with a third investigator. Risk of bias was assessed as described in the Cochrane handbook 17 by recording the method used to generate the randomization schedule, the method used to conceal allocation, whether blinding was implemented, what proportion of patients completed follow-up, whether an intention-to-treat analysis was extractable, and whether there was evidence of selective reporting of outcomes. Data Synthesis and Statistical Analysis Data were pooled by using a random effects model to give a more conservative estimate of the effect of topical 5-ASAs, allowing for any heterogeneity between studies. 18 The impact of therapy was expressed as a relative risk (RR) of relapse of disease activity in quiescent UC with topical 5-ASA drugs compared with placebo, along with a 95% confidence interval (CI). The last time point of assessment in the trial was used for analysis. The NNT and 95% CIs were calculated from the reciprocal of the risk difference from the meta-analysis. Adverse events were summarized with RRs and 95% CIs. The results of individual studies can be diverse, and this inconsistency within a single meta-analysis can be quantified with a statistical test of heterogeneity to assess whether the variation across trials is due to true heterogeneity or chance. This quantity is termed I 2, and its value ranges from 0% 100%, with 0% representing no observed heterogeneity and larger values indicating increasing heterogeneity. A value below 25%, accompanied by a P value.10 for the 2 test, was chosen to represent low levels of heterogeneity. 19 We planned to conduct sensitivity analyses according to disease distribution, dosage Table 2. Data Extraction Methodology Outcome of interest: relapse of disease activity in quiescent UC Hierarchy of reporting of outcomes used: endoscopic evidence of any degree of relapse, endoscopic evidence and clinical assessment as relapsed, clinical assessment as relapsed, recognized scoring system as relapsed (eg, Truelove and Witt), or other author-defined criteria for relapse Time of assessment: last time point of assessment in the trial Denominator used: true intention-to-treat analysis; if not available, then all evaluable patients

3 May 2012 TOPICAL 5-ASAs IN QUIESCENT UC: A META-ANALYSIS 515 Figure 1. Flow diagram of assessment of studies identified in the systematic review. schedule of therapy, total weekly dose of 5-ASA, criteria used to define relapse, and high risk of bias and unclear risk of bias vs low risk of bias trials, where trial reporting allowed this. These were exploratory analyses only and might explain some of the observed variability, but the results should be interpreted with caution. We compared individual RRs between these analyses by using the Cochran Q statistic. Review Manager version (RevMan for Windows 2008; Nordic Cochrane Centre, Copenhagen, Denmark) and StatsDirect version (StatsDirect Ltd, Sale, Cheshire, England) were used to generate Forest plots of pooled RRs and risk differences for primary and secondary outcomes with 95% CIs, as well as funnel plots. We planned to assess these for evidence of asymmetry and therefore possible publication bias or other small study effects by using the Egger test, 20 if there were sufficient (10 or more) eligible studies included in the meta-analysis, in line with recent recommendations. 21 Results The search strategy used to inform the American College of Gastroenterology monograph identified 3061 citations, 2985 of which were excluded after examining the title and abstract. There were a total of 76 RCTs reporting on efficacy of topical 5-ASAs in UC that were retrieved and evaluated in more detail. Sixty-nine of these were excluded for various reasons, leaving 7 RCTs eligible for inclusion, which contained 555 patients (Figure 1) For detailed characteristics of individual studies see Table 3. None of the RCTs were at low risk of bias. All trials were conducted in Europe or North America. Disease extent was confirmed endoscopically at study entry. Three studies recruited only patients with disease confined to the rectum, 23,26,27 one recruited only proctitis or proctosigmoiditis patients, 25 two included left-sided colitis only, 24,28 and the seventh trial also Table 3. Characteristics of RCTs of Topical 5-ASAs vs Placebo in Preventing Relapse in Quiescent UC Duration of therapy (mo) Methodology No. of patients 5-ASA used Country, and no. of centers Disease distribution Criteria used to define relapse Study 25 Mesalamine enema 1 g od 12 Randomization and concealment USA, 1 site 100% left-sided colitis Erythematous, edematous, and friable mucosa at sigmoidoscopy Biddle et al, Randomization stated, concealment 30 Mesalamine suppositories 400 mg bid Blackstone s modified endoscopic scoring criteria of 1 at sigmoidoscopy Italy, 1 site 43% proctosigmoiditis, 57% proctitis D Arienzo et al, Randomization and concealment 157 Mesalamine (Rowasa) enema 4 g od, 4 g every other day, or 4 g every 3 days 100% left-sided colitis Rectal bleeding or increased stool frequency for 3 consecutive days and active inflammation at endoscopy, or moderate mucosal inflammation alone at endoscopy USA, no. of sites unclear Miner et al, Randomization stated, concealment Erythematous and friable mucosa at endoscopy 72 Mesalamine enema 4 g twice weekly Italy, 3 sites 14% pancolitis, 53% left-sided colitis, 33% proctosigmoiditis D Albasio et al, Randomization and concealment 111 Mesalamine (Asacol) suppositories 500 mg bid or 500 mg od Development of symptoms and a Baron score of 1 at sigmoidoscopy Italy, 7 sites 100% ulcerative proctitis ( 15 cm from the anus) D Albasio et al, Randomization unclear, concealment stated, double-blind 95 Mesalamine (Pentasa) suppositories 1 g thrice weekly France, 22 sites 100% ulcerative proctitis Clinical symptoms and an increase in the endoscopy score of 1 Marteau et al, Randomization and concealment 65 Mesalamine (Rowasa) suppositories 500 mg od Rectal bleeding or increase in stool frequency for 1 wk and evidence of endoscopic inflammation 100% ulcerative proctitis ( 15 cm from the anus) USA and Canada, 9 sites Hanauer et al, bid, twice daily; od, once daily.

4 516 FORD ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 5 included those with extensive disease. 22 Mean duration of disease was reported in 4 trials 22,23,25,26 and ranged from 5 7 years. All 7 trials used topical mesalamine, and one was a doseranging study with mesalamine enemas administered daily, on alternate days, or every 3 days. 28 One trial used combined oral and topical 5-ASA therapy in one treatment arm and oral 5-ASA therapy with placebo enemas in the other arm, 22 one trial allowed the continued use of previously prescribed oral 5-ASAs, 27 providing the dose remained stable, and in the remaining 5 RCTs topical 5-ASAs or placebo were given as sole therapy ,28 Four of the trials recruited patients who were in sustained remission at the time of study entry. 23,25,26,28 In one of these studies, some of the patients were receiving 5-ASAs for maintenance of remission, and these were discontinued at the time of enrollment. 25 Two RCTs recruited patients who had experienced 2 or more relapses of disease activity in the last 12 months and who had been in remission for less than 2 weeks 27 and 3 months, 22 respectively. The seventh study recruited patients who had had a recent flare of UC and who had entered remission with 5-ASA enemas and then randomized them to continued topical 5-ASA or withdrawal of active therapy and substitution with placebo enemas. 24 Efficacy of Topical 5-Aminosalicylates vs Placebo in Preventing Relapse of Quiescent Ulcerative Colitis There were 122 of 331 patients (36.9%) allocated to topical mesalamine who experienced a relapse of disease activity, compared with 153 of 224 patients (68.3%) assigned to placebo. The RR of relapse of disease activity with topical mesalamine compared with placebo in quiescent UC was 0.60 (95% CI, ) (Figure 2). The NNT with topical mesalamine to prevent one patient experiencing a relapse of disease activity was 3 (95% CI, 2 5). There was no significant heterogeneity detected between studies (I 2 21%, P.27). Because there were only 7 trials, we did not assess for evidence of funnel plot asymmetry. Two trials reported data concerning mean time to relapse in both arms. 23,27 In a trial conducted in France that contained 95 patients with ulcerative proctitis, mean time to relapse was 239 days in those treated with topical mesalamine, compared with 166 days among those receiving placebo (P.07). 27 In the second trial conducted in Canada and the United States during a period of 2 years that recruited 65 patients with ulcerative proctitis, mean time to relapse was 453 days for mesalaminetreated patients compared with 158 days for placebo (P.001). 23 Sensitivity analyses were conducted (Table 4). There were trends toward a greater effect size in trials that used endoscopic criteria to define relapse, trials that recruited patients with disease that was not confined to the rectum, trials that used a total weekly dose of mesalamine of 7 g or more, and particularly in trials that used continuous, rather than intermittent, therapy where the difference between summary effect sizes approached statistical significance (P.06). There was also a greater effect size in the 6 RCTs that compared topical mesalamine with placebo, compared with the single trial that compared combined oral and topical mesalamine with oral mesalamine alone. Safety of Topical 5-Aminosalicylates vs Placebo in Preventing Relapse of Quiescent Ulcerative Colitis Six trials, which contained 398 patients, reported total adverse events data Overall, 22 of 218 patients (10.1%) receiving topical mesalamine reported at least one adverse event, compared with 19 of 180 patients (10.6%) randomized to placebo. The RR of adverse events with topical mesalamine compared with placebo was 1.01 (95% CI, ). Individual adverse events were not well reported, but 4 RCTs did provide data concerning anal canal pain during enema or suppository insertion. 23,24,26,27 There were 13 of 167 patients (7.8%) assigned to topical mesalamine who experienced this, compared with 12 of 129 (9.3%) allocated to placebo (RR 0.87; 95% CI, ). Discussion This systematic review and meta-analysis has studied the efficacy of topical 5-ASAs for the prevention of relapse of quiescent UC. It has demonstrated that topical mesalamine is more effective than placebo for the prevention of relapse of disease activity in quiescent UC, with an NNT of 3. Time to relapse was longer with topical mesalamine in the 2 RCTs that reported this outcome, and there was a trend toward a greater effect size with continuous topical therapy, compared with intermittent. Because of the variation in dosing regimens, we were able to assess whether there was a dose-response effect, Figure 2. Forest plot of RCTs of topical 5-ASAs vs placebo in preventing relapse in quiescent UC.

5 May 2012 TOPICAL 5-ASAs IN QUIESCENT UC: A META-ANALYSIS 517 Table 4. Sensitivity Analyses of Effect of Topical 5-ASAs vs Placebo in Preventing Relapse in Quiescent UC No. of studies No. of subjects RR of relapse of disease activity 95% CI I 2 value (%) Cochrane Q for the difference in relative risks P value for Cochrane Q All studies NA NA Criteria used to define relapse Endoscopic Clinical and endoscopic Disease distribution Rectum only Sigmoid colon and beyond Dosing schedule Continuous 5 a Intermittent 3 a Total weekly dose 7 g 4 b g 4 b Comparison made Topical 5-ASA vs placebo Combined oral and topical 5-ASA vs oral 5-ASA and placebo NA NA, not applicable. a Miner et al 28 contributed data to both continuous and intermittent analyses. b D Albasio et al 26 contributed data to both 7 g per wk and 7 g per wk analyses. with lower relapse rates when a higher total weekly dose of topical mesalamine was used, a phenomenon we observed recently with higher total daily doses of oral 5-ASA therapy for the prevention of relapse of quiescent UC. 7 There was a greater effect size in trials that used a weekly dose of 7gormore of mesalamine, but this was not statistically significant. Topical mesalamine was well tolerated during therapy for between 12 and 24 months, with no significant increase in adverse events over placebo detected in the 6 trials that reported these data. The strengths of the present study include the rigorous methodology used. We used an exhaustive and contemporaneous search strategy to maximize the chance that all eligible trials examining the efficacy of topical 5-ASAs in the prevention of relapse of quiescent UC were identified and included. We also described our eligibility criteria and data extraction processes in detail. In addition, independent data extraction was undertaken by 2 reviewers, and discrepancies were checked and resolved. Finally, we used an intention-to-treat analysis and pooled data with a random effects model to reduce the likelihood that the benefit of topical 5-ASAs in quiescent UC has been overestimated. Limitations of any systematic review and meta-analysis arise from the quality of the included RCTs. In the case of this meta-analysis, none of the trials we identified were at low risk of bias according to the criteria we used, meaning that the efficacy of topical mesalamine in preventing relapse of quiescent UC might have been overestimated. In terms of outcomes reporting, 4 of the RCTs did not report endoscopic relapse, 23,26 28 which was the preferred outcome of interest according to our predefined hierarchy. Because the majority of studies only recruited patients with left-sided disease or proctitis, the efficacy of topical mesalamine for relapse prevention in patients with more extensive quiescent UC remains unknown. Finally, there was significant heterogeneity when data were pooled for studies that recruited patients with disease extending beyond the rectum, suggesting the efficacy of topical 5-ASAs in preventing relapse of quiescent left-sided UC might be less clear. There has been a Cochrane collaboration systematic review and meta-analysis that has examined the efficacy of topical 5-ASAs in inducing remission of active UC. 8 This concluded that 5-ASAs were more effective than placebo in this situation, with superiority demonstrated for clinical, endoscopic, and histologic remission and excellent safety and tolerability. However, no meta-analysis has studied the efficacy of topical 5-ASAs in preventing relapse of quiescent UC, so our findings are novel, and the summary data, suggesting that only 3 patients need to be treated with topical mesalamine over placebo to prevent one patient relapsing, are important information for both clinicians and patients. The data from this systematic review and metaanalysis support the use of topical mesalamine, but not other available topical 5-ASAs (sulfasalzine, olsalazine, and balsalazide), for preventing relapse of quiescent UC. Absolute numbers of adverse events were not significantly higher with topical mesalamine than with placebo, even though these were prevention of relapse trials, where duration of therapy was at least 12 months in trials that provided these data. Current guidelines are conflicting in their recommendations for the use of topical 5-ASAs for relapse prevention in quiescent UC, with only those from the American College of Gastroenterology recommending their use first-line in patients with left-sided disease. 13 Data from this systematic review and metaanalysis would support this recommendation. An indirect comparison of the results of this study with those of a previous meta-analysis examining the efficacy of oral 5-ASAs for relapse prevention in quiescent UC reveals that topical mesalamine appears to be of comparable efficacy in terms of the NNT to prevent one patient relapsing. 7 There have been previous RCTs comparing oral with topical 5-ASAs directly for relapse prevention Results from all of these suggest that topical 5-ASAs are at least as effective as oral 5-ASAs in this regard, and a recent

6 518 FORD ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 5 meta-analysis that pooled data from all these trials suggested that intermittent topical 5-ASAs were probably superior to daily oral 5-ASA in terms of preventing relapse of quiescent left-sided UC, with an NNT of However, patient preference and its potential impact on adherence to therapy will continue to dictate how these drugs are administered. There is limited evidence to suggest that patients prefer to receive 5-ASAs orally, 33 although more studies that examine this issue are required. There are also few data concerning the impact of intermittent vs continuous topical 5-ASA therapy in quiescent UC in terms of either efficacy or adherence to treatment. Other unresolved issues include whether either the dose used or the delivery system, including suppository, foam enema, liquid enema, or suspension, has any influence on efficacy and tolerability of topical mesalamine. In summary, this systematic review and meta-analysis has demonstrated a clear benefit of topical mesalamine over placebo in the prevention of relapse of quiescent UC. Whether this holds true for other topical 5-ASA therapies is uncertain. In addition, the impact of continuous vs intermittent administration, dose, and delivery system used on efficacy of topical 5-ASAs and patient adherence and preference remains unclear. These are areas for future research. References 1. Cosnes J, Gower-Rousseau C, Seksik P, et al. Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology 2011;140: Kappelman MD, Rifas-Shiman SL, Kleinman K, et al. The prevalence and geographic distribution of Crohn s disease and ulcerative colitis in the United States. Clin Gastroenterol Hepatol 2007;5: Loftus EV Jr, Silverstein MD, Sandborn WJ, et al. Ulcerative colitis in Olmsted County, Minnesota, : incidence, prevalence, and survival. Gut 2000;46: Loftus CG, Loftus EV Jr, Harmsen WS, et al. 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Efficacy of oral versus topical, or combined oral and topical 5-aminosalicylates, in ulcerative

7 May 2012 TOPICAL 5-ASAs IN QUIESCENT UC: A META-ANALYSIS 519 colitis: systematic review and meta-analysis. Am J Gastroenterol 2011 Nov 22 [Epub ahead of print]. 33. Moody GA, Eaden JA, Helyes Z, et al. Oral or rectal administration of drugs in IBD? Aliment Pharmacol Ther 1997;11: Reprint requests Address requests for reprints to: Alex Ford, MD, Leeds Gastroenterology Institute, D Floor, Clarendon Wing, Leeds General Infirmary, Great George Street, Leeds, United Kingdom LS1 3EX. alexf12399@yahoo.com; fax: (44) Conflicts of interest These authors disclose the following: William J. Sandborn has served as a consultant to Ferring Pharmaceuticals, Proctor and Gamble Pharmaceuticals, Salix Pharmaceuticals, Shire Pharmaceuticals, and Warner Chilcott and has received research support from Proctor and Gamble Pharmaceuticals, Salix Pharmaceuticals, Shire Pharmaceuticals, and Warner Chilcott. Stephen B. Hanauer has served as a consultant to Centocor, Abbott, UCB Pharma, Elan, and Biogen and has received research support from Centocor, Abbott, and UCB Pharma. Paul Moayyedi serves as chair at McMaster University that is partly funded by an unrestricted donation by AstraZeneca and has received consultant s and speaker s bureau fees from AstraZeneca, AxCan Pharma, Nycomed, and Johnson and Johnson. The remaining authors disclose no conflicts. Funding Supported by the American College of Gastroenterology.