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Comparative efficacy and tolerability of pharmacological agents for management of mild to moderate ulcerative colitis: a systematic review and network meta-analyses

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Summary

Background

The majority of patients with ulcerative colitis have mildly to moderately active disease. To inform the management of patients with left-sided or extensive mildly to moderately active ulcerative colitis, we assessed the comparative efficacy and tolerability of different therapies.

Methods

In this systematic review and network meta-analysis, we searched Epub, MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Scopus, and Web of Science from inception to Dec 14, 2015, and updated on MEDLINE on March 1, 2018, for randomised controlled trials in adults (age ≥17 years) with left-sided or extensive mild to moderate ulcerative colitis. Studies were included if patients were treated with oral sulfasalazine, diazo-bonded 5-aminosalicylates (5-ASAs), mesalazine (low dose <2 g/day, standard dose 2–3 g/day, or high dose >3 g/day), controlled ileal-release budesonide, or budesonide multimatrix, alone or in combination with rectal 5-ASA therapy, and were compared with each other or placebo for induction or maintenance of clinical remission. The minimum duration of therapy was 4 weeks for trials of induction and 24 weeks for trials of maintenance therapy. We did pairwise and random-effects network meta-analysis using a frequentist approach, and calculated odds ratios (ORs) and 95% CIs; agents were ranked using surface under the cumulative ranking (SUCRA) probabilities. We used Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria to appraise quality of evidence. We examined heterogeneity with the I2 statistic.

Findings

Our search identified 1316 unique studies, from which 75 randomised trials with 12 215 patients were eligible for analysis. Based on 48 induction randomised trials (8020 participants) that met inclusion criteria, combined oral and rectal 5-ASAs (SUCRA 0·99) and high-dose mesalazine (>3 g/day; SUCRA 0·82) were ranked highest for induction of remission. Both interventions were superior to standard-dose mesalazine (2–3 g/day; failure to induce remission with combined oral and rectal 5-ASAs OR 0·41, 95% CI 0·22–0·77; high-dose mesalazine 0·78, 0·66–0·93) with moderate confidence in estimates. On the basis of 28 randomised trials (4218 participants) that met inclusion criteria, all interventions were superior to placebo for maintenance of remission; however, neither combined oral and rectal 5-ASAs nor high-dose mesalazine were superior to standard-dose mesalazine.

Interpretation

In patients with mildly to moderately active left-sided or extensive ulcerative colitis, combined oral and topical mesalazine therapy and high-dose mesalazine are superior to standard-dose mesalazine for induction of remission, but not maintenance of remission. Standard-dose mesalazine might be preferred for maintenance in most patients.

Funding

None.

Introduction

Ulcerative colitis is a chronic disabling inflammatory bowel disease that generally begins in early adulthood. Although the incidence and prevalence of ulcerative colitis have stabilised in western Europe and North America (affecting >0·2% of the population) since 1990, its incidence continues to rise in newly industrialised countries.1 Longitudinal population-based cohort studies indicate less than 20% of patients with ulcerative colitis have an aggressive disease course, and most have a mild to moderate course, which is generally most active at diagnosis and then in varying periods of remission or mild activity.2, 3, 4, 5, 6, 7, 8 More than 90% of patients receive 5-aminosalicylates (5-ASAs) within 1 year of diagnosis for management of ulcerative colitis, and on long-term follow-up, 60–87% of patients continue 5-ASA use. Only 50% of patients receive corticosteroids, and even fewer receive immunosuppressive (20%) and biological therapies (5–10%).2, 3, 4, 5, 6, 7, 8

Despite most patients with ulcerative colitis having mild to moderate disease activity, practice varies considerably between inflammatory bowel disease specialists, gastroenterologists, and primary care physicians.9 Important areas of variability include the dosing of mesalazine for induction and maintenance of remission, comparative efficacy of diazo-bonded 5-ASAs and mesalazine, role of combined oral and topical 5-ASA, and positioning of budesonide multimatrix in the management of patients with extensive mild to moderate ulcerative colitis. Previous pairwise meta-analyses focusing on head-to-head comparisons, although thorough and informative, have not adequately informed comparative efficacy of different approaches in the management of mild to moderate ulcerative colitis because of paucity of head-to-head trials for some key comparisons (eg, role of a high-dose [>3 g/day] vs standard-dose [2–3 g/day] 5-ASA, and positioning of budesonide multimatrix).10, 11, 12 By contrast, network meta-analyses, which combine direct (from head-to-head trials) and indirect (comparisons of different interventions against a common comparator) evidence might better inform the comparative efficacy of different treatment approaches.13

Research in context

Evidence before this study

We searched PubMed from inception to May 31, 2018, for previously published meta-analyses on pharmacological interventions for mild to moderate ulcerative colitis using the search terms “ulcerative colitis” and “treatment” without any language restrictions. Our search identified 869 systematic reviews, but no network meta-analyses. Previous traditional pairwise meta-analyses provide a limited synthesis of comparative efficacy of different interventions, limited to head-to-head trials, without incorporating indirect evidence. Additionally, the quality of this evidence has not been critically examined, which might inform clinical guidelines.

Added value of this study

Our study provides the first network meta-analysis of all pharmacological interventions for management of mild to moderate ulcerative colitis, with systematic assessment of quality of the evidence using Grading of Recommendations Assessment, Development and Evaluation methodology. Through a systematic review with network meta-analysis, including 48 randomised trials (8020 participants) comparing eight active interventions for induction of remission, and 28 randomised trials (4218 participants) comparing six active interventions for maintenance of remission in patients with left-sided or extensive ulcerative colitis, we are able to inform the treatment approach in these patients. For induction of remission, a combined oral and rectal 5-aminosalicylate (ASA) is the most effective treatment strategy, followed by high-dose mesalazine (moderate confidence in estimates); standard-dose mesalazine is similar to diazo-bonded 5-ASAs, but superior to sulfasalazine. For maintenance of remission, standard-dose and high-dose mesalazine are similar (low confidence in estimates), and superior to low-dose mesalazine (high confidence in estimates). Budesonide multimatrix is not more effective than a combined oral and rectal 5-ASA or high-dose mesalazine and has inferior tolerability.

Implications of all the available evidence

Contextualising findings on comparative efficacy and tolerability, coupled with patients' values and preference, and cost and resource use considerations, our findings can directly inform treatment guidelines. Patients with mild ulcerative colitis are likely to achieve remission with standard-dose mesalazine or a diazo-bonded 5-ASA. A subset of patients, particularly those with more moderately active disease, or who live in areas where high-unit dose forms of mesalazine are available at a low cost, physicians might reasonably decide to use high-dose oral mesalazine for induction of remission. In patients with extensive colitis, a rectal 5-ASA might be added either upfront to standard-dose or high-dose oral mesalazine, or in 4–6 weeks in a subset of patients with suboptimal response to oral therapy. Likewise, budesonide multimatrix might be considered as monotherapy or in addition to 5-ASA therapy in patients with moderately active disease, either upfront or in the case of suboptimal response to optimised 5-ASA therapy. For maintenance of remission, standard-dose mesalazine and a diazo-bonded 5-ASA might be preferred options. High-dose mesalazine with or without a rectal 5-ASA is no more effective than standard-dose mesalazine, and consideration should be made to cautiously de-escalate patients who required high-dose mesalazine for induction of remission to standard dose, after 6–12 months.

Hence, we did a systematic review with pairwise and network meta-analyses to compare the efficacy and tolerability of candidate agents in patients with extensive or left-sided mild to moderate ulcerative colitis. We used Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria for network meta-analysis to appraise quality of evidence.14

Section snippets

Search strategy and selection criteria

We did this systematic review and network meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension statement for systematic reviews, incorporating network meta-analyses for health-care interventions and also following an a priori established protocol (appendix, pp 2–11).15 For our research protocol, we followed good research practices, as outlined in the International Society for Pharmacoeconomics and Outcomes Research report on

Results

From 1316 unique citations identified through our comprehensive search strategy, 1195 were excluded because they did not meet inclusion criteria, were basic science, editorials, or review articles, were observational studies, or did not assess medical interventions (figure 1). 121 full-length articles and abstracts were assessed, after which 46 further articles were excluded because they did not meet inclusion criteria. 75 randomised trials were included, with 12 215 patients. One trial covered

Discussion

In this systematic review and network meta-analysis, which included 48 randomised trials (8020 participants) comparing eight active interventions for induction of remission, and 28 randomised trials (4218 participants, including 575 placebo-treated patients) comparing six active interventions for maintenance of remission in patients with left-sided or extensive ulcerative colitis, we were able to inform the treatment approach in these patients. For induction of remission, combined oral and

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