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See article on page 625
As knowledge of the overactive immune response becomes clearer, the treatment of inflammatory bowel disease (IBD) continues to evolve rapidly from the use of anti-inflammatory agents to the use of immunomodulatory agents. A wide variety of medications have been shown to be effective in both uncontrolled and controlled trials in either or both ulcerative colitis and Crohn’s disease.1 These include 6-mercaptopurine (6-MP), azathioprine, methotrexate, cyclosporine,2 tacrolimus, interleukin 10, ISIS 2302, and infliximab (a monoclonal antibody against tumour necrosis factor α).
In this issue (see page 625) a randomised trial reports that treatment with mycofenolate mofetil (MMF) plus steroids was as effective as the combination of azathioprine plus steroids in obtaining a clinical response in chronic active Crohn’s disease. The study further suggests that onset of remission was more rapid in those patients with highly active disease and that there were few adverse side effects.
6-Mercaptopurine and its parent drug azathioprine are currently the agents of choice for the treatment of Crohn’s disease (and in my experience, for ulcerative colitis as well). Several enzyme systems convert 6-MP to either inactive metabolites or to the 6-thioguanine nucleotides which are purine antagonists and inhibit synthesis of protein, RNA and DNA.
Although 6-MP and azathioprine are effective in the treatment of Crohn’s disease, there was an unfortunate delay in the acceptance of the efficacy of these agents because of the faulty design in the National Cooperative Crohn’s Disease Study.3 This trial studied three agents: steroids, sulfasalazine and azathioprine. The 17 week design failed to account for the slow onset of action of azathioprine (mean of 3.1 months) and missed potential late responders. However, it has become clear from multiple trials and a meta-analysis4 that azathioprine/6-MP are effective both in treating active Crohn’s disease and in maintaining remission. Complete closure of fistula is observed in about 30% of patients with improvement in another 25%, whereas consistent response of fistula has not been observed with either 5-aminosalicylic acid agents or steroids. Although the role of combined anti-metabolites and steroids has been controversial because of limited data, the meta-analysis suggests this combination may lead to a higher response rate, with the requirement for less steroids in the long term. Steroid sparing has been confirmed in most studies as well as in the meta-analysis. As regards toxicity, the long term use of azathioprine/6-MP has not been associated with an increase in the development of carcinomas or lymphomas. Several reports in patients with IBD, other immune disorders and transplant patients have also shown no problem with the use of these agents in pregnancy.
Although there are few controlled trials, several uncontrolled studies have shown that azathioprine/6-MP have a similar efficacy in ulcerative colitis. The response rate in the largest series has shown complete clinical remission in over 60% and a partial response in 24% of patients.5 A single controlled trial has also demonstrated maintenance of remission with azathioprine compared with placebo. Several smaller series have shown that azathioprine/6-MP can maintain remission in severe steroid refractory ulcerative colitis once remission has been induced by cyclosporine. Some clinicians have failed to recognise that early institution of azathioprine/6-MP will significantly reduce the need for subsequent colectomy. A multicentre placebo controlled trial is starting in this year to evaluate the maintenance of efficacy of azathioprine after a severe attack of ulcerative colitis.
With such a clear record of efficacy for azathioprine/6-MP, how should we now evaluate the role of MMF in the treatment of Crohn’s disease (and possibly ulcerative colitis)? MMF is a non-competitive selective and reversible inhibitor of inosine monophosphate dehydrogenase (IMP).6 Inhibition of IMP depletes guanosine nucleotides in B and T lymphocytes. As it inhibits the de novo pathway of purine synthesis that is used differentially by lymphocytes, it might be predicted to have a greater immunosuppressive activity than azathioprine, especially in relation to toxicity.
There have been three randomised placebo controlled trials in transplant patients comparing MMF with either placebo or azathioprine in combination therapy with cyclosporine and steroids. Acute rejection was significantly reduced with MMF compared with either placebo or azathioprine. However, there were no differences between the groups at six and 12 months in terms of graft loss or death. Therefore, significant long term data are limited.
Toxicity of MMF is dose related, with gastrointestinal disturbances (in which diarrhoea and vomiting are most prominent) as well as leucopenia and infectious events. Data on malignancies are limited, but results of initial studies seem to be similar to those seen with azathioprine. The drug is teratogenic in animals and patients are currently advised to avoid pregnancy.
In light of the this information, how should this initial report of the efficacy of MMF in the treatment of chronic active Crohn’s disease be evaluated and what recommendations should be made? Although the study was performed well, it has several flaws. Firstly, neither patients nor investigators were blinded as to which medication they were receiving. All patients were said to have chronically active disease, but the severity of a similar degree is questionable as several patients entered into the trial had Crohn’s disease activity indexes (CDAI) under 200. A CDAI of this level would constitute mild disease. Secondly, as 5 mg prednisolone was given as maintenance treatment we cannot evaluate complete steroid sparing. I have always felt that complete steroid withdrawal is essential when evaluating the efficacy of any drug in the treatment of Crohn’s disease.
If future trials confirm a more rapid short term response in severe disease, it would be a strong indication for the use of MMF. However, before MMF can be considered superior to current treatment, controlled trials will be required to show complete steroid sparing, long term efficacy as a maintenance agent, and less toxicity than azathioprine/ 6-MP. For the moment, other than being studied in a controlled trial, I agree with the authors that treatment with MMF should be strongly considered in chronically ill patients with IBD who are either allergic to or have not responded to azathioprine/6-MP.
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