Maintenance Therapy Treatment of Crohn's Disease

Spontaneous clinical remission and frequent symptomatic relapse are prominent clinical features of both ulcerative colitis and Crohn's disease. However, whereas the importance of maintenance therapy in ulcerative colitis was established in the 1960s, its effectiveness in Crohn's disease remains controversial. The availability of mesalazine preparations (5-aminosalicylic acid, known as mesalamine in the USA) has prompted several investigations to evaluate their effectiveness in both active and quiescent Crohn's disease. New formulations have permitted delivery of higher doses of mesalazine to various sites in the small bowel as well as the colon. Thus, 1 g of sulphasalazine delivers about 400 mg of mesalazine to the colon, so it would take 6 g of sulphasalazine to provide 2-4 g of mesalazine to the colon, the dose that is recommended for mesalazine. For sulphasalazine, the dose-response relation is clearly established, but recent trials of mesalazine analogues in the treatment of Crohn's disease have used doses ranging from 1 to 4 g. The evidence suggests that higher doses of mesalazine are required to sustain remission in Crohn's disease than in ulcerative colitis.

The effectiveness of medical therapy in Crohn's disease is difficult to evaluate because of the propensity for the disease to recur and because of the various clinical presentations related to site and extent of disease, duration of disease before therapy is initiated, previous unsuccessful therapy, and earlier surgical procedures. In the National Cooperative Crohn's Disease Trial, patients with colonic disease responded favourably to medical therapy with sulphasalazine if three criteria obtained: (a) duration of symptom less than six months; (b) no previous medical therapy; and (c) no previous surgical therapy. Patients with ileal or ileocolonic disease are more likely to develop specific complications--eg, perforation--than are patients with disease confined to the colon. Consequently, in placebe-controlled trials that examine the efficacy of various drugs in Crohn's disease patients should be stratified for variables such as those mentioned above and equivalence between treatment groups must be assured.

The main treatment objectives in Crohn's disease are to induce symptomatic remission, suppress inflammation, control complications, and maintain remission. Although there is no consensus about maintenance therapy in Crohn's disease, our own experience in Kansas accords with a recent meta-analysis which suggests that maintenance therapy is effective in suppressing manifestations of the disease. The distinction between remission of disease and the presence of symptomless disease has important practical and scientific implications. Several studies have documented complete remission of symptoms but persistence of endoscopic evidence of disease. Modigliani et al looked at the disparity between clinical remission induced by corticosteroid treatment and regression of mucosal lesions as determined by serial endoscopic examinations in patients with active Crohn's disease. Orally administered prednisone (1 mg/kg per day) induced a clinical remission in 92% of patients within seven weeks. However, only 38 (29%) of the 131 patients in clinical remission also achieved endoscopic remission. Maintenance therapy focuses on suppression of symptoms. Not surprisingly, when therapy is discontinued or interrupted, recurrent symptoms herald relapse of the disease. In reality, the disease may never have been in remission but rather the manifestations of the disease were suppressed. The relevance of this observation to clinical trials designed to assess the efficacy of maintenance therapy in Crohn's disease is that absence of symptoms and a low Crohn's disease activity index score are not necessarily equivalent to remission.

The meta-analysis reported by Messori et al should be interpreted cautiously because of several limitations. As the researchers acknowledge, five clinical trials published as full articles and four published as abstracts were heterogeneous in terms of dose schedule, site of disease, number of postoperative patients, definition of relapse, and time from remission to beginning of maintenance therapy. Drug dose merits special emphasis, since higher doses of mesalazine analogues--ie, 3-4 g per day--are probably required to maintain remission in Crohn's disease.[2] In the meta-analysis, the dose of mesalazine was less than 2 g per day in eight of the nine trials. Moreover, controlled studies of mesalazine in a group of 310 patients with active Crohn's disease who received higher doses indicated a significant therapeutic effect with 4 g compared with a 2 g dose or placebe. These and other similar studies suggest that earlier trials that failed to show a benefit for mesalazine analogues may have done so because the doses were inadequate.

Messori et al suggest that maintenance therapy with mesalazine at a dosage of 2 g per day is cost effective. We believe this assertion goes beyond the data presented for several reasons: (a) the 2 g dose that is suggested is lower than the 3 g-4 g dose which seems more likely to be effective as maintenance therapy; (b) the costs of managing a relapse in Crohn's disease vary considerably depending on factors such as the physician (primary care doctor vs gastroenterologist), nature of the relapse, extent of diagnostic studies carried out, use of combination therapies, number of follow-up visits, and use of surgical intervention. For example, Sutherland et al suggested that metronidazole has an important role in the management of Crohn's disease, and a one month supply of metronidazole costs less than one day's treatment with the new mesalazine drugs. Combined treatment with mesalazine and metronidazole should be explored.

Despite the limitations of the published trials and the meta-analysis, we believe that maintenance therapy is appropriate for patients with Crohn's disease in remission. Although maintenance of remission may be more likely in patients who have undergone recent surgery, the evidence suggests that maintenance therapy may also be effective in patients without previous surgical intervention. Combination therapy will probably become the norm for patients with Crohn's disease, both for induction of remission and for maintenance. In this respect azathioprine combined with prednisolone may be better than prednisolone alone in patients with active Crohn's disease. With the combined therapy, remission is achieved more safely, more often, and more quickly with a lower dose of prednisolone.

Last updated Jan 4/07