Despite considerable progress in our knowledge and understanding of the disease, treatment of UC remains a challenge.1
Mesalazine has proven to be effective orally for extensive disease and locally (enemas, foams, or suppositories) in the treatment of distal forms of the disease. It has been established that the optimal dose of mesalazine is 3–4 g/day for oral administration and 1 g/day for rectal administration.1,2,4,7,9,14
Prolonging the combination of oral (2.4 g) and rectal mesalazine (2 g) from four to eight weeks did not increase the remission rate.16
In order to further optimise the treatment, some authors examined combining rectal and oral administration in patients with distal colitis, and showed that this combined strategy was more effective than oral treatment alone.3,8,11
Our study is the first randomised controlled trial that assessed the efficacy of a combined strategy in patients with extensive UC.
The results obtained in this study for patients treated with 4 g oral mesalazine alone (plus placebo enema) are consistent with previous studies that demonstrated the efficacy of oral mesalazine for distal UC.1,2,4,19,20
Adding a daily 1 g mesalazine enema in mild/moderate active extensive UC for the first four weeks of an eight week course of daily oral mesalazine 4 g resulted in significantly higher improvement rates at weeks 4 and 8 and significantly higher remission rates at week 8. The primary end point (remission rate at week 4), although higher in the mesalazine enema group (44% v
34%), did not reach statistical significance.
A possible reason may be that more than four weeks are required for the healing process of the colonic mucosa. We arbitrarily chose remission at four weeks as our primary end point as there were no previous randomised controlled trials in this field, and we used strict criteria for remission (that is, a UCDAI of 0 or 1). In the study by Vecchi et a.
, there was no significant difference in the effects of 4 g 5-ASA orally versus 2 g orally combined with 2 g as an enema in patients with ulcerative colitis but it is important to consider that this study included very few subjects with extensive colitis and that a very high rate of remission (>80%) was reached in both groups.15
Furthermore, different oral doses of 5-ASA were used in this study while equal doses with or without 5-ASA rectally were used in our trial.
All included patients had either an established or a new diagnosis of extensive colitis. For practical reasons full colonoscopies were not requested throughout the study. As 100 ml enemas usually only reach the splenic flexure, we cannot speculate on the evolution of lesions upstream. Using full colonoscopy to assess the results would have provided such data but we chose not to insist on this.
The expected number of patients included could not be reached within the study period, although extended by three months, because of considerable difficulties in recruiting patients in our Western European countries. Many patients with active extensive colitis met our exclusion criteria (for example, they were receiving treatment with high doses of salicylates, local treatments, oral steroids, or immunosuppressive agents). As UC is a chronic disorder, patients are used to rapidly adjusting their treatment when they have a flare up; sometimes they adapt it by themselves or on the advice of their general practitioners. Patients may have been reluctant to use a rectal enema for four weeks and undergo rectosigmoidoscopy three times within two months. These issues should be considered in the design of new studies in UC.
In general, our results showed that the combined strategy was more effective and safe. Addition of 1 g mesalazine/100 ml enema (Pentasa) for the initial four weeks of an eight week oral therapy regimen with mesalazine 4 g/day (Pentasa 1 g sachets, twice daily dosing) resulted in improvement rates of 89% at four weeks and 86% at eight weeks compared with 62% and 68% in the standard treatment group. Rectal bleeding stopped in significantly more patients in the active enema group compared with the placebo group. Despite the higher mesalazine load of the oral/enema mesalazine combination, no concerns were raised with respect to the safety profile, and the combination treatment was highly accepted by patients.
Overall, this study has demonstrated the beneficial effects of adding a daily 1 g Pentasa enema for the initial four weeks during eight weeks of treatment with Pentasa 4 g orally. We believe that owing to the superiority of the combined approach, it should be used as a firstline treatment in patients with mild to moderate extensive UC.
In our view, this treatment may also be used in preference to steroids (which have more side effects) as secondline treatment if the disease is not severe, but this needs to be studied in a prospective randomised controlled trial.