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Mycophenolate mofetil for Crohn's disease
  1. J C ATHERTON
  1. Division of Gastroenterology
  2. University Hospital
  3. Nottingham NG7 2UH,UK
    1. M NEURATH
    1. Laboratory of Immunology
    2. I. Medical Clinic
    3. University of Mainz
    4. Langenbeckstrasse, 55116 Mainz
    5. Germany

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      Editor,—On the basis of a study reported recently by Neurath et al(Gut1999;44:625–628), commentaries inGut 1 and theLancet 2 suggested that mycophenolate mofetil (MMF) should be used in patients with Crohn's disease who have either not responded to or are intolerant of azathioprine or 6-mercaptopurine. This advice is premature: firstly, because the study was flawed and, secondly, because it examined only management of acute inflammation, not the place of MMF in maintaining remission and in steroid sparing (a fact acknowledged in both commentaries).

      The study by Neurath et al compared the effect of MMF 15 mg/kg daily with azathioprine 2.5 mg/kg daily, both with high dose steroids, in the treatment of active chronic Crohn's disease (six months' follow up). The main conclusions were that activity, as measured by the Crohn's disease activity index (CDAI), dropped further at one month in patients given MMF plus steroids than in those given azathioprine plus steroids, and that this was as a result of a faster effect in more severe disease. The major drawbacks of the study were as follows. As pointed out by the authors, neither patients nor investigators were blinded. Four (11%) of 35 patients in the MMF group were lost to follow up compared with none in the azathioprine group: thus results may have looked different if analysed on an intention to treat basis. The MMF group had higher starting CDAIs: if the levels of CDAI reached at one month were compared between groups, rather than the fall of CDAI, the groups may not have been significantly different. The division of patients into those with moderate and severe activity was retrospective: thus conclusions based on this division should be regarded as hypothesis generating only, especially as differences between the groups do not reach formal statistical significance if adjustments for multiple comparisons are made. Finally, steroid usage in the two groups is not recorded: one can imagine a scenario where a poor early response would lead to more steroids being given and so to a better overall result.

      I agree with the authors and commentators that alternatives to azathioprine/6-mercaptopurine are needed. I also agree that the therapeutic effect of MMF in chronic active Crohn's disease should be assessed in properly performed trials, and perhaps more importantly that its effect in maintaining remission and in steroid sparing should be assessed. However, until then, MMF should be considered to have no clear indications for use in Crohn's disease.

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      Editor,—Mycophenolate mofetil (MMF) is an immunosuppressive drug that is often used in organ transplantation.1-1 It is an ester prodrug of mycophenolic acid that inhibits inosine monophosphate dehydrogenase and potently suppresses lymphocyte proliferation.1-2-1-4 Furthermore various clinical trials have shown its efficacy in suppressing autoimmune and chronic inflammatory disorders, such as rheumatoid arthritis,1-5 pemphigus vulgaris,1-6 and psoriasis.1-7 There are several case reports1-8 1-9 and also our controlled study indicating that MMF can be successfully used in patients with Crohn's disease. In our study treatment of patients with moderately active Crohn's disease with MMF/cortisone led to a significant reduction in clinical activity scores comparable with treatment with azathioprine/cortisone. These data suggested that treatment of chronic active Crohn's disease with MMF/cortisone would be effective in inducing remission. As corticosteroids were given to patients in addition to MMF, the data available do not show unequivocally that MMF alone is effective in the maintenance of remission in Crohn's disease. This question is currently under study in a double blind, randomised controlled trial in Europe and the USA, in which the effects of MMF on maintenance of remission will be analysed.

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