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- Subjects and methods
Crohn's disease (CD) is a chronic inflammatory bowel disorder, and no curative therapy for it has been established yet. Thus, the goal of treatment was to maintain the patients in remission for as long as possible after this has been induced. Although corticosteroids and sulfasalazine have long been used to induce remission, these drugs have little effect in preventing a relapse of CD.1–4 In Western countries, the effectiveness of immunosuppressive agents, such as azathioprine or mercaptopurine (6-mercaptopurine) as maintenance therapy has been reported, but they may increase the risk of malignancy, severe opportunistic infection and bone marrow or liver toxicity.5–14 There is a considerable number of patients intolerant or resistant to these drugs and for them an alternative effective maintenance therapy is needed.5–9
Dietary therapy has played an important role in the treatment of CD patients both to induce remission and to sustain it. Using an elemental diet (ED), home enteral nutrition (HEN) has become an effective maintenance therapy with long-term safety.15 HEN therapy usually consists of nocturnal ED administration through a self-inserted feeding tube and daytime intake of low-residue and low-fat food.15
Matsueda et al., in a study involving 410 patients with CD, reported that both the cumulative remission rate and non-hospitalization rate in the HEN group were significantly higher than those in the drug-treated group.15 Another study involving 84 patients with CD by Hirakawa et al. showed that the cumulative continuous remission rate after 4 years was 63% in the group receiving HEN, 66% in the group receiving HEN and drugs, 0% in the group receiving drugs and 0% in the group receiving no maintenance therapy, demonstrating that HEN effectively contributed to the maintenance of remission in CD.16 Verma et al. showed that oral supplementation of ED in addition to a normal diet was effective to maintain remission in 39 patients with CD.17
The main limitations of these previous studies were that: (i) none of them was a randomized-controlled trial and (ii), as they did not determine the amount of regular calories from ED and diet, there was considerable variation in calories intake among individual cases. The effectiveness of ED as maintenance therapy for CD patients should be evaluated by well-designed randomized-controlled trials.
In this study, we examined the effectiveness of ‘half ED’, in which the patients took half of their daily calories by ED and the remaining half by usual meals. The patients could choose the route of ED administration, i.e. through a feeding tube and/or oral intake at any time they preferred. This half ED could possibly enhance the quality of life of patients with CD and improve long-term compliance. The aim of this study was to investigate the effectiveness of half ED as maintenance therapy for CD patients.
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- Subjects and methods
In the present study, the frequency of relapse was significantly lower in the half ED group than in the free diet group. The effectiveness of HEN in lieu of food intake as a maintenance therapy for CD has been noted in several studies, and ED has also been reported to be effective as a primary therapy for active CD.15–17, 24–26 In most trials underwent in Western countries, enteral nutrition showed in adult patients with active disease a response rate similar or slightly inferior to the response to corticosteroids obtained in adults with a lower compliance; and polymeric formulas were as effective as elemental formulas.26–29 The response rates are better in children.30 There is a high relapse rate, however, and maintenance therapy is greatly limited by adherence to therapy.30 The present randomized-controlled trial has demonstrated the effectiveness of half ED as maintenance therapy for the first time. Some CD patients intolerant or resistant to thiopurines can benefit greatly from the results of this trial.
One of the characteristics of this trial was that patients in the half ED group were required to take half their daily allowance of calories by ED and the remaining half by usual unrestricted meals. The detailed mechanism by which half ED maintains patients with CD in remission remains unknown. One possible explanation is the response related to the low content of lipids in the diet. The fat profile of the feed was proposed to reduce proinflammatory eicosanoid synthesis and modify disease activity.31 Because Elental contains indeed only marginal amounts of lipids, the overall lipid intake could be less in the half ED group. Apart from this factor, reduced antigenic load, nutritional benefits, the supply of trophic amino acids, modification of the gut flora, intestinal permeability, faecal pH and bowel rest, among others, have been proposed as potential factors contributing to the maintenance of remission.31, 32
At the fourth interim data analysis, the trial was stopped for safety of the patients because a significant difference in the relapse rate was found between the two groups, in spite of the smaller number of study patients than we had assumed prior to the start of the trial. However, there seemed to be little possibility that a type I error had occurred in these analyses because the difference in the relapse rate between the two groups had kept on being larger each time, which was also shown by the Kaplan–Meier method.
In the present study, relapse of CD was defined as a CDAI of more than 200, or the need for therapy to induce remission, based on the data from a retrospective follow-up study of patients carried out at Tohoku University Hospital. This definition indeed seemed to be clinically practical as the CDAI in most of the cases who required inductive therapies exceeded 200 in this study. In a previous report, relapse was defined as a CDAI of more than 250, a CDAI between 150 and 250 during 3 consecutive weeks with an increase of at least 75 points above the baseline value, and/or the need of surgery for CD.33 The definition of relapse in the present study included even transient increases of the CDAI that resulted from causes other than ‘real’ relapse, such as intestinal infection. However, given the actual clinical course, such a definition was certainly appropriate. The results of the current study showed that patients with CD administered half ED were clinically stable with a CDAI under 200 and were unlikely to have flare-ups.
In the present study, the compliance demonstrated in the half ED group was similar to that of the free diet group and there was no adverse event in the half ED group, which itself was noteworthy as a maintenance therapy for CD.
The purpose of this study was to evaluate the effectiveness of half ED itself as maintenance therapy for CD patients, not to assess the nutritional status of the patients. Thus, this was not examined in detail, for example, vitamins, trace elements, which was a limitation of this study. In the present study, only four patients of the 51 (7.8%) had achieved remission by drug therapy prior to entering the maintenance trial although the CDAI was lower than 150 in all the 51 patients at the start of the trial. This was also a limitation of this study.
In conclusion, this trial has shown the effectiveness of half ED, which can be a promising maintenance therapy for CD, especially in some patients intolerant or resistant to immunosuppressive agents.