Budesonide-MMX for Mild-to-Moderate Ulcerative Colitis
Induction Treatment. About one-third of patients with UC experience a clinical remission when treated with 5-ASA. In a meta-analysis of 11 randomised controlled trials (RCTs), clinical remission was achieved more often in UC patients treated with 5-ASA than in those treated with a placebo. The corresponding pooled relative risk (RR) of failure to achieve remission was 0.79 (95% CI 0.73–0.85); the number of patients needed to treat (NNT) to achieve one remission was 6.
A pooled analysis of 10 RCTs recently demonstrated that 5-ASA (oral and rectal) may be administered once daily without loss of efficacy vs. multiple times daily (P = 0.5212; RR = 1.0013). Ford et al., and others, confirmed these data and reported benefit for one of every five patients that received dual treatment with oral and topic therapies (RR = 0.65; 95% CI = 0.47–0.91).
Even though a 2 g daily dose of oral mesalazine is needed to be significantly more effective than placebo (RR = 0.91, 95% CI 0.85–0.987), the superiority of 4 g daily vs. 2 g daily, currently recommended in induction treatment, was not demonstrated in post hoc analysis from ASCEND I and II trials, or in other studies (RR = 1.03, 95% CI 0.82–1.29). ASCEND III, designed to prospectively study 2.4 g vs. 4.8 g showed that higher doses are only helpful in a subgroup of patients with prior use of steroids or prior failure to 5-ASAs. For local 5-ASA, no dose effect was reported in the two small RCTs assessing 2 g/day vs. 4 g/day in enema or 0.5 g vs. 1 g/day in suppository.
Maintenance Treatment. In a meta-analysis of 11 RCTs, the RR of relapse was 0.65 (95% CI 0.55–0.76) for patients treated with 5-ASA vs. placebo (NNT = 4). The corresponding relapse rates after over 6 months' treatment were 41% vs. 58% respectively, and 28% vs. 70% in patients treated by local 5-ASA vs. placebo after over 1 year respectively.
Similar to induction therapy, mesalazine taken once daily was as efficient as multiple daily doses, with a pooled risk of relapse of 0.94 (95% CI: 0.82–1.08) after over 6 months' treatment, according to results of a 11 RCTs meta-analysis. The relapse rate at 1 year was estimated to be 30%.
In the four RCTs that compared the oral/rectal 5-ASA combination with oral 5-ASA, the pooled RR of failure to achieve remission was 0.65 (95% CI 0.47–0.91), therefore favouring combination therapy and corresponding to one patient treated in five who benefits from the combined approach.
The benefit of oral 5-ASA vs. placebo has been demonstrated for mucosal healing (RR = 0.69, 95% CI 0.62–0.77), whatever the frequency of administration (once or multiple times daily), in induction (P = 0.23) and maintenance (P = 0.78). Endoscopic remission rate with combined oral and topical 5-ASA therapy has not been compared with that seen with monotherapy. A dose effect was reported in post hoc analysis of the ASCEND I and II trials, which compared mucosal healing rates with 4.8 g/day mesalazine vs. 2.4 g/day, at week 3 (65% vs. 58%, respectively, P = 0.219) and statistically significant at week 6 (80% vs. 68%, respectively, P = 0.012).
Overall, toxicities related to 5-ASA are very rare in clinical practice. In RCTs, of 30% of patients who reported AE related to oral 5-ASA, only 1–2% were severe. The main symptoms associated with oral mesalazine include flatulence, abdominal pain, nausea, diarrhoea and worsening headache. The rate of AEs was similar to placebo, and sulphasalazine (RR = 0.76, 95% CI 0.46–1.3, P = 0.33). The occurrence of renal toxicity specifically related to interstitial nephritis is debated, and the relationship is unclear. A systematic review suggests a rate of approximately two to three people per 1000 patient-years and recommends following serum creatinine at some regular interval.
The main side effects of topical 5-ASA include anal/rectal irritation, and abdominal pain with an incidence rate that is also similar to that for placebo (17% vs. 12%, RR = 1.35, 95% CI 0.63–2.89, P = 0.44).
According to the ECCO consensus, mesalazine 1 g suppository once daily is the preferred initial treatment for mild or moderately active proctitis; mesalazine foam enemas are an alternative. Suppositories may deliver drug more effectively to the rectum and are better tolerated than enemas. Combining topical mesalazine with oral mesalazine or topical steroid is more effective than either alone and should be considered for escalation of treatment. Oral mesalazine alone is less effective.
Left-sided and extensive active UC of mild–moderate severity should initially be treated with an aminosalicylate enema 1 g/day combined with oral mesalazine 2 g/day. Topical therapy with steroids or aminosalicylates alone as well as monotherapy with oral aminosalicylates is less effective than oral plus topical 5-ASA therapy. Topical mesalazine is more effective than topical steroids. Systemic corticosteroids are appropriate if symptoms of active colitis do not respond to mesalazine.
5-ASA Remain the Backbone Therapy for Mild-to-Moderate UC
Efficacy
Induction Treatment. About one-third of patients with UC experience a clinical remission when treated with 5-ASA. In a meta-analysis of 11 randomised controlled trials (RCTs), clinical remission was achieved more often in UC patients treated with 5-ASA than in those treated with a placebo. The corresponding pooled relative risk (RR) of failure to achieve remission was 0.79 (95% CI 0.73–0.85); the number of patients needed to treat (NNT) to achieve one remission was 6.
A pooled analysis of 10 RCTs recently demonstrated that 5-ASA (oral and rectal) may be administered once daily without loss of efficacy vs. multiple times daily (P = 0.5212; RR = 1.0013). Ford et al., and others, confirmed these data and reported benefit for one of every five patients that received dual treatment with oral and topic therapies (RR = 0.65; 95% CI = 0.47–0.91).
Even though a 2 g daily dose of oral mesalazine is needed to be significantly more effective than placebo (RR = 0.91, 95% CI 0.85–0.987), the superiority of 4 g daily vs. 2 g daily, currently recommended in induction treatment, was not demonstrated in post hoc analysis from ASCEND I and II trials, or in other studies (RR = 1.03, 95% CI 0.82–1.29). ASCEND III, designed to prospectively study 2.4 g vs. 4.8 g showed that higher doses are only helpful in a subgroup of patients with prior use of steroids or prior failure to 5-ASAs. For local 5-ASA, no dose effect was reported in the two small RCTs assessing 2 g/day vs. 4 g/day in enema or 0.5 g vs. 1 g/day in suppository.
Maintenance Treatment. In a meta-analysis of 11 RCTs, the RR of relapse was 0.65 (95% CI 0.55–0.76) for patients treated with 5-ASA vs. placebo (NNT = 4). The corresponding relapse rates after over 6 months' treatment were 41% vs. 58% respectively, and 28% vs. 70% in patients treated by local 5-ASA vs. placebo after over 1 year respectively.
Similar to induction therapy, mesalazine taken once daily was as efficient as multiple daily doses, with a pooled risk of relapse of 0.94 (95% CI: 0.82–1.08) after over 6 months' treatment, according to results of a 11 RCTs meta-analysis. The relapse rate at 1 year was estimated to be 30%.
In the four RCTs that compared the oral/rectal 5-ASA combination with oral 5-ASA, the pooled RR of failure to achieve remission was 0.65 (95% CI 0.47–0.91), therefore favouring combination therapy and corresponding to one patient treated in five who benefits from the combined approach.
Mucosal Healing
The benefit of oral 5-ASA vs. placebo has been demonstrated for mucosal healing (RR = 0.69, 95% CI 0.62–0.77), whatever the frequency of administration (once or multiple times daily), in induction (P = 0.23) and maintenance (P = 0.78). Endoscopic remission rate with combined oral and topical 5-ASA therapy has not been compared with that seen with monotherapy. A dose effect was reported in post hoc analysis of the ASCEND I and II trials, which compared mucosal healing rates with 4.8 g/day mesalazine vs. 2.4 g/day, at week 3 (65% vs. 58%, respectively, P = 0.219) and statistically significant at week 6 (80% vs. 68%, respectively, P = 0.012).
Safety
Overall, toxicities related to 5-ASA are very rare in clinical practice. In RCTs, of 30% of patients who reported AE related to oral 5-ASA, only 1–2% were severe. The main symptoms associated with oral mesalazine include flatulence, abdominal pain, nausea, diarrhoea and worsening headache. The rate of AEs was similar to placebo, and sulphasalazine (RR = 0.76, 95% CI 0.46–1.3, P = 0.33). The occurrence of renal toxicity specifically related to interstitial nephritis is debated, and the relationship is unclear. A systematic review suggests a rate of approximately two to three people per 1000 patient-years and recommends following serum creatinine at some regular interval.
The main side effects of topical 5-ASA include anal/rectal irritation, and abdominal pain with an incidence rate that is also similar to that for placebo (17% vs. 12%, RR = 1.35, 95% CI 0.63–2.89, P = 0.44).
ECCO Guidelines
According to the ECCO consensus, mesalazine 1 g suppository once daily is the preferred initial treatment for mild or moderately active proctitis; mesalazine foam enemas are an alternative. Suppositories may deliver drug more effectively to the rectum and are better tolerated than enemas. Combining topical mesalazine with oral mesalazine or topical steroid is more effective than either alone and should be considered for escalation of treatment. Oral mesalazine alone is less effective.
Left-sided and extensive active UC of mild–moderate severity should initially be treated with an aminosalicylate enema 1 g/day combined with oral mesalazine 2 g/day. Topical therapy with steroids or aminosalicylates alone as well as monotherapy with oral aminosalicylates is less effective than oral plus topical 5-ASA therapy. Topical mesalazine is more effective than topical steroids. Systemic corticosteroids are appropriate if symptoms of active colitis do not respond to mesalazine.
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