Introduction

• Mesalazine remains the first-line drug for the treatment of mild to moderate ulcerative colitis.³
• In the 1940s, the conventional dosing schedule of sulphasalazine was a minimum of twice daily administration.³ Mesalazine was also initially recommended in a twice-daily dosing regimen.a However, new mesalazine formulations such as pH-dependent formulations, time-dependent formulations and a multimatrix system have been developed and can be administered once daily.³
• Although three reviews assessed the efficacy and safety between once daily and multiple daily administration of mesalazine, no meta­analysis has been found that evaluates the efficacy and safety of a once-daily regime compared with a twice-daily regime.³
• The present study is a meta-analysis that compares the efficacy and adverse events of once-daily dosing of mesalazine versus twice­daily dosing in the treatment of ulcerative colitis.³

Methods

• Randomised controlled trials (RCTs) published in English from 1990 to November 2018 were identified in Pubmed, Embase, the Cochrane library and Web of Science.a Manual searching of reference lists from existing review articles was performed to identify additional studies.³
• RCTs were included in the meta-analysis if the study compared once daily mesalazine with twice daily mesalazine for mild to moderate ulcerative colitis. ³
• Eligible patients in the studies were 18 years of age or older, with a confirmed clinical, endoscopic and histological diagnosis of ulcerative colitis and outcomes must include one of clinical and endoscopic remission, clinical remission, mucosal healing and adverse events.³
• The primary outcome of articles included was clinical and endoscopic remission of once-daily compared with twice-daily mesalazine.a
• Secondary outcomes included clinical remission and adverse events (total adverse events, treatment-related adverse events and serious adverse events).³
• All RCTs were evaluated for the risk of bias with the Cochrane Collaboration's Risk of Bias Too1.³
• The risk of bias of the RCTs was assessed using the following items: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting and other biases.³

Results

Description of the studies included

• Seventy-one studies were identified through database searching and other sources.³ Of 71 records screened, 8 RCTs were eligible.³ Table 1 shows characteristics of the 8 studies included.
• The 8 studies included 3495 patients randomised, of whom 1731 (49.5 %) were in the once-daily (OD) mesalazine group and 1764 (50.5 %) were in the twice daily (BD) mesalazine group.³ The number of patients valid for intention-to-treat (ITT) was 3375, of whom 1667 (49.4 %) were in the once-daily mesalazine group and 1708 (50.6 %) were in the twice daily mesalazine group.³

Induction of remission
Clinical and endoscopic remission

• Two RCTs representing 379 patients (OD group, n= 190; BD group, n= 189) reported clinical and endoscopic remission for induction of remission of UC.³
• A pooled analysis implied that there was no significant difference in clinical and endoscopic remission rates between the two groups (Relative Risk (RR) = 1.08, 95 % Confidence Interval (Cl): 0.74-1.57, P=0.71).³ (Figure 1).³

Clinical remission

• Two RCTs representing 379 patients described clinical remission.³
• No notable difference was observed between the two groups (RR = 1.01, 95 % Cl: 0.79-1.29, P=0.95).³ (Figure 2).³

Adverse events

• Adverse events were described in three RCTs.³
• A total of 486 patients (OD group, n=240; BD group, n=246) were identified.³
• There was no significant difference between the two groups in the incidence of total adverse events, treatment-related adverse events and serious adverse events.³ (Figure 3).³

Maintenance of remission
Clinical and endoscopic remission

• Four RCTs reported clinical and endoscopic remission.³
• A total of 1962 patients (OD group, n= 965; BD group, n= 997) were identified.³
• 683 (70.8 %) of patients in the OD group and 688 (69.0 %) of patients in the BD group achieved clinical and endoscopic remission.³
• There was no notable difference in clinical and endoscopic remission rate between the OD and BD mesalazine groups (RR = 1.03, 95 %Cl: 0.94-1.12, P= 0.58).³ (Figure 4.)³

Clinical remission

• Clinical remission was described in three RCTs.³
• A total of 1632 patients (OD group, n=804; BD group, n=828) were identified, and 658 (81.8 %) of patients in the OD group and 655 (79.1 %) of patients in the BD group achieved clinical remission.³
• No obvious difference was observed between the two groups with respect to clinical remission (RR = 1.06, 95 % Cl: 0.92-1.21, P=0.42).³ (Figure 5).³

Adverse events

• Five studies reported adverse events.³
• There was no significant difference between the two groups in the incidence of total adverse events, treatment-related adverse events and serious adverse events.³ (Figure 6).³

Discussion

• The results of this meta-analysis imply that once-daily mesalazine was as effective as twice-daily mesalazine for induction and maintenance of remission of ulcerative colitis.³
• In terms of safety, once-daily mesalazine was as safe as twice-daily mesalazine since the meta-analysis did not identify any differences in total adverse events, treatment-related adverse events and serious adverse events.³

Although there were no differences between the once-daily and twice-daily mesalazine groups, less frequent dosing may improve patients' compliance to treatment for ulcerative colitis.³ Limitations of the study were described as follows: of 8 studies included, 7 studies did not report blinding of outcome assessment, increasing the detection bias of the meta-analysis; in addition, the drug dosage among various studies was inconsistent.³ These limitations may increase the risk of bias of this meta-analysis.³

Conclusion

Once-daily mesalazine is as effective and safe as twice-daily mesalazine for mild-to-moderate ulcerative colitis.³