Efficacy of Oral, Topical, or Combined Oral and Topical 5-Aminosalicylates, in Ulcerative Colitis: Systematic Review and Network Meta-Analysis

Abstract

Background: 5-aminosalicylates (5-ASAs) are the mainstay of treatment for mild to moderately active ulcerative colitis (UC). The optimum 5-ASA preparation, dose, and route of administration for UC remains unclear. We conducted a network meta-analysis to compare and rank efficacy and safety of oral, topical, or combined oral and topical 5-ASAs for induction of remission of active UC and prevention of relapse of quiescent UC. Methods: We searched MEDLINE, EMBASE, EMBASE Classic, and the Cochrane central register of controlled trials from inception to July 2020. We included all available randomised controlled trials (RCTs) comparing oral 5-ASAs, topical 5-ASAs, or combined oral and topical 5-ASAs, with each other, or with placebo in induction of remission and prevention of relapse of UC. The efficacy and safety of all treatments were reported as a pooled relative risk (RR) with 95% confidence intervals (CIs) to summarise effect of each comparison tested, with treatments ranked according to their P-score. Findings: We identified 40 RCTs for induction of remission and 23 RCTs for prevention of relapse. Topical mesalazine alone (P-score 0.99), or a combination of oral and topical mesalazine (P-score 0.87) ranked first and second with regards to clinical and endoscopic remission combined. Findings were similar for clinical, endoscopic, and histological remission. Combined oral and topical mesalazine was ranked first for trials in which ≥50% of patients had left-sided or extensive disease, and topical mesalazine first in trials in which ≥50% of patients had proctitis or proctosigmoiditis. However, high-dose (≥3.3g/day) oral mesalazine ranked third in most analyses and had the most trials and most patients. For prevention of relapse, combined oral and topical mesalazine and high-dose oral mesalazine ranked first and second (P-scores 0.91 and 0.75 respectively), with topical mesalazine third. Only topical mesalazine was superior to placebo for prevention of relapse in trials in which ≥50% of patients had proctitis or proctosigmoiditis. 5-ASAs were safe and well tolerated, regardless of treatment regimen. Interpretation: In general, our results support current recommendations for use of 5-ASAs in induction of remission of UC, and prevention of relapse. However, higher doses of oral mesalazine (≥3.3g/day) had more evidence for efficacy in induction of remission than combined therapy and were significantly more efficacious than lower doses. Future RCTs should aim to better establish the role of combined oral and topical therapy for induction of remission, as well as optimal doses of oral 5-ASAs to prevent relapse of disease activity. The study protocol was published on the PROSPERO international prospective register of systematic reviews (registration number CRD42020185839). Funding Statement: None. Declaration of Interests: Brigida Barberio: none. Jonathan P. Segal: none. M. Nabil Quraishi: none. Christopher J. Black: none. Edoardo V. Savarino: none. Alexander C. Ford: none