Mycophenolate mofetil for Crohn's disease?

Submission to The Lancet’s Electronic Research Archive in international health and eprint server ERA-International health

We will consider for self-archiving by investigators any paper that concerns aspects of health in the developing world. ● File submission formats are shown on our website (www.thelancet.com/newlancet/eprint). ● After preliminary editorial screening, the eprint will be posted on our website and comments invited. ● The site will be maintained by The Lancet, but eprints will be owned by authors and posting will not constitute formal publication in the journal. ● The eprint citation will be “Lancet ERA-Internat-Health/ 19990000”. Eprint server ● We will consider any submitted eprint concerning human health for eventual publication in The Lancet. ● File submission formats are available on our website (www.thelancet.com/newlancet/eprint). ● After editorial screening, the eprint will be posted on our website and comments invited. ● After 4–6 weeks of electronic peer review, a decision about the fate of the eprint will be made—it can be left for further comments, it can be rejected, or it can be negotiated upon with the authors with a view to formal publication. ● If a revised manuscript is acceptable, it will be published in The Lancet, both in print and electronic formats. ●

access to research from the developing world. We hope that that aim at least will draw support from investigators and readers alike to encourage self-archiving. John McConnell, Richard Horton The Lancet, London WC1B 3SL, UK 1 2 3

4 5

6 7 8 9 10 11

Varmus H. E-Biomed: a proposal for electronic publications in the biomedical sciences. www.nih.gov/welcome/director/ebiomed/ebi.htm Editorial. NIH E-biomed proposal: a welcome jolt. Lancet 1999; 353: 1985. Relman AS. The NIH “E-BIOMED” proposal; a potential threat to the evaluation and orderly dissemination of new clinical studies. N Engl J Med 1999; 340: 1793–94. Delamothe T, Smith R. Moving beyond journals: the future arrives with a crash. BMJ 1999; 318: 1637–39. Haddad H, Macleod S. Access to medical and health information in the developing world: an essential tool for change in medical education. CMAJ 1999; 160: 63–64. Gibbs WW. Lost science in the third world. Sci Am 1995; August: 76–83. McConnell J, Horton R. Having electronic preprints is logical. BMJ 1998; 316: 1907. Kassirer JP. Posting presentations at medical meetings on the Internet. N Engl J Med 1999; 340: 803. Bachrach S, Berry RS, Blume M, et al. Who should own scientific papers? Science 1998; 281: 1459–60. Canhos V, Chan L, Giaquinto F, Kirsop B, O’Donnell A, Ugonna J. Close the South-North knowledge gap. Nature 1999; 397: 201. Begg C, Cho M, Eastwood S, et al. Improving the quality of reporting of randomised controlled trials: the CONSORT statement.JAMA 1996; 276: 637–39.

Mycophenolate mofetil for Crohn’s disease? Mycophenolate mofetil is one of the newer immunosuppressants that has lately been advocated as an alternative to azathioprine or mercaptopurine for treatment of Crohn’s disease.1 Although only one randomised trial of mycophenolate mofetil for this disorder has been completed, the drug can now be included in a growing list of immunomodulators with reported benefits for treatment

THE LANCET • Vol 354 • July 3, 1999

of Crohn’s disease. The list includes azathioprine, mercaptopurine, methotrexate, cyclosporin, tacrolimus, interleukins 10 and 11, antisense oligo-nucleotides to intercellular adhesion molecule 1 (ISIS 2302), thalidomide, infliximab and CDP571 (monoclonal antibodies against tumour necrosis factor), and Antegren (a monoclonal antibody against 4 integrin). Mycophenolic acid is the active moiety that gives the drug its immunosuppressive property.2 This substance is an uncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase; inhibition of this enzyme decreases de-novo synthesis of guanosine nucleotides. Mycophenolic acid has a directed action against T and B lymphocytes, since they depend on the de-novo synthesis of purines for proliferation, whereas other cell types, such as neutrophils and macrophages, can use salvage pathways.2 It can also inhibit growth of intestinal smooth-muscle and synthesis of fibronectin, a component of extracellular matrix.3 Thus, in addition to its anti-lymphocyte effects, mycophenolate mofetil may theoretically be useful in preventing smooth-muscle hyperplasia and stricture formation in Crohn’s disease. The most thorough studies of the drug have been in the context of cardiac and renal transplantation. It has been compared with either placebo or azathioprine in combination therapy with cyclosporin and steroids in three randomised controlled trials among kidney-transplant patients.4–6 In all three studies, patients receiving mycophenolate mofetil had significantly fewer biopsyproven rejection episodes, but there was no difference in graft loss or mortality at 12 months4–6 or 3 years.6 Patients receiving 2 g daily had an overall better safety profile than did those receiving 3 g daily,4–6 and in two studies, the cumulative incidence of combined graft loss and death of the patient was lower with the smaller dose.4,5 For treatment of acute or chronic Crohn’s disease, mycophenolate mofetil must ultimately be compared with azathioprine or with mercaptopurine, the gold standard for treatment of Crohn’s disease. In a meta-analysis of nine randomised, placebo-controlled trials, the odds ratio for response to azathioprine or mercaptopurine compared with placebo was 3·09 (95% CI 2·45–3·91) among patients with active Crohn’s disease.7 The odds ratio for response in quiescent Crohn’s disease was 2·27 (1·76–2·93). In addition, there was a steroid-sparing effect in both active (3·69 [2·12–6·42]) and quiescent disease (4·64 [1·0–21·5]).7 These results are superior to those for the 5aminosalicylates, and the safety profile of azathioprine or mercaptopurine is notably better than that for steroids. In view of the good track record of azathioprine and mercaptopurine, what role could mycophenolate mofetil have in the treatment of Crohn’s disease? Two small uncontrolled series8,9 and one randomised trial1 suggest that it has therapeutic potential. In one of the series,8 six patients with Crohn’s disease who were intolerant of azathioprine received mycophenolate mofetil 2 g daily for a median of 8 months. All patients improved, and for three of four patients with perianal disease, perianal fistulae closed for the first time.8 In the other series, of six patients with severe disease (Crohn’s disease activity index [CDAI]>300) treated with mycophenolate mofetil 2 g daily, five patients improved clinically and one withdrew early because of nausea and vomiting. All three patients with perianal disease responded favourably.9 In the only published randomised trial of mycophenolate mofetil versus azathioprine, 70 patients with steroid3

dependent chronic active Crohn’s disease (CDAI>150) received either mycophenolate mofetil 15 mg/kg daily (about 1·5 g daily) or azathioprine 2·5 mg/kg daily, as well as prednisolone 50 mg daily, which was tapered by schedule to a maintenance dose of 5 mg daily.1 Clinical scores were given after 1, 2, 3, and 6 months. Among patients with moderately active disease (CDAI 150–300), decline in clinical activity with mycophenolate mofetil was similar to that with azathioprine. However, among patients with highly active disease (CDAI>300), those treated with mycophenolate mofetil had a significantly greater decrease in the CDAI score after the first month of treatment than did those treated with azathioprine (mean decline 265 vs 117 points) Perhaps because the dose of mycophenolate mofetil used was lower than that in the transplantation trials, only two patients had side-effects (drug rash, vomiting), compared with seven in the azathioprine group.1 Although the issue is clouded because both treatment groups received therapeutic doses of prednisolone, data from this limited trial suggest that, among patients with severe disease, the response may be earlier with mycophenolate mofetil than with azathioprine. This difference could be a real effect of mycophenolate mofetil, and might be accounted for by its more selective (antilymphocyte) and direct (reversible enzyme inhibition) action. The purine antagonist azathioprine, on the other hand, requires a steady-state accumulation of the 6thioguanine nucleotides to interfere with DNA, RNA, and protein synthesis.10 Unfortunately, the more selective activity of mycophenolate mofetil may also be accompanied by higher risk: after follow-up of 3 years, a slightly higher proportion of renal-transplant patients receiving mycophenolate mofetil 2 g or 3 g daily than of patients treated with azathioprine developed a lympho-proliferative disorder (3·0 vs 0·6%).6 In addition, the teratogenicity of mycophenolate mofetil would exclude its use for pregnant women with Crohn’s disease, whereas azathioprine may be used cautiously in this group. What studies are needed before mycophenolate mofetil can clearly be advocated as a therapeutic alternative to azathioprine or mercaptopurine? First, a double-blind placebo-controlled trial of mycophenolate mofetil for the treatment of active Crohn’s disease needs to be done. In addition, to better compare its steroid-sparing capabilities with those of azathioprine or mercaptopurine, steroids should be completely withdrawn either before enrolment or during the course of the study. Finally, the safety and efficacy of mycophenolate mofetil as maintenance therapy for Crohn’s disease should be addressed, not only because of the chronicity of the disease and the usual requirement for lengthy therapy, but also to investigate the other potential long-term attributes of the drug, such as reduction of stricture formation by inhibition of smoothmuscle proliferation. Outside of these studies, mycophenolate mofetil should for now be reserved for patients who either have not responded to or are intolerant of azathioprine and mercaptopurine. Philip W Lowry, William J Sandborn, *James J Lipsky Division of Gastroenterology and Hepatology, Department of Internal Medicine, and *Department of Pharmacology, Clinic Pharmacology Unit, Mayo Clinic and Mayo Foundation,Rochester, MN 55905, USA 1

Neurath MF, Wanitschke R, Peters M, Krummenauer F, Meyer züm Buschenfelde, Schlaak JF. Randomized trial of mycophenolate mofetil versus azathioprine for treatment of chronic active Crohn’s disease. Gut 1999; 44: 625–28. 2 Lipsky JJ. Mycophenolate mofetil. Lancet 1996; 348: 1357–59.

4

3

Zeeh JM, Riley NR, Hoffman O, Goebell H, Guerkin G. Mycophenolate mofetil inhibits growth and expression of extracellular matrix in human intestinal and rate colonic smooth muscle cells. Gastroenterology 1999; 116: G4128 (abstr). 4 Wiesel M, Carl S, European Mycophenolate Mofetil Cooperative Study Group. A placebo controlled study of mycophenolate mofetil used in combination with cyclosporine and corticosteroids for the prevention of acute rejection in renal allograft recipients: 1 year results. J Urol 1998; 159: 28–33. 5 Sollinger HW, US Renal Transplant Mycophenolate Mofetil Study Group. Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. Transplantation 1995; 60: 225–32. 6 Mathew TH, The Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group. A blinded, long-term,randomized multicenter study of mycophenolate mofetil in cadaveric renal transplantation: results at 3 years. Transplantation 1998; 65: 1450–54. 7 Pearson DC, May GR, Fick GH, Sutherland LR. Azathioprine and 6mercaptopurine in Crohn’s disease: a meta-analysis. Ann Intern Med 1995; 122: 132–42. 8 Fickert P, Hinterleitner TA, Wenzl HH, Aichbichler BW, Petritsch W. Mycophenolate mofetil in patients with Crohn’s disease. Am J Gastroenterol 1998; 93: 2529–32. 9 Florin THJ,Roberts RK, Watson MR, Radford-Smith GL. Treatment of steroid refractory inflammatory bowel disease (IBD) with mycophenolate mofetil (MMF). Aust NZ J Med 1998; 28: 334–45. 10 Sandborn WJ. A review of immune modifier therapy for inflammatory bowel disease: azathioprine,6-mercaptopurine, cyclosporine and methotrexate. Am J Gastroenterol 1996; 91: 423–33.

Consensus and controversy over resuscitation of the ne wborn infant Resuscitation organisations represented on the International Liaison Committee on Resuscitation (ILCOR), together with two paediatric resuscitation organisations and WHO, have produced a consensus statement on advanced life support for newborn babies.1 Basic life support for these children had been addressed in a previous statement.2 The issues addressed in the new statement will have a broad impact. WHO estimates that every year there are one million neonatal deaths attributable to birth asphyxia.3 The impact of birth asphyxia is smaller in more developed countries; in the USA, only 3378 deaths out of almost 4 million births can be ascribed to birth asphyxia (456 deaths) or other complications related to delivery (2922 deaths).4 The consensus statement is important in the development of clear guidelines for resuscitation of the newborn baby. The introduction of such guidelines in less technically developed countries has improved neonatal outcomes. In such places, methods of resuscitation may include inappropriate practices long abandoned in the developed world—for instance, injections of sodium bicarbonate or glucose into the umbilical vein instead of bag-and-mask ventilation.5 In Zhuhai, China, introduction of the neonatal resuscitation programme guidelines (NRPG) developed by the American Academy of Pediatrics and the American Heart Association led to a three-fold reduction in perinatal neonatal mortality.6 Improved identification of the delivery at risk, anticipation of the needs of the mother and newborn baby, and the commitment of appropriate resources are critical to improving outcome at birth. Perhaps the most important effect of the NRPG recommendations is to direct attention to the newborn baby as a valid consumer of precious resources. In part, the new ILCOR recommendations are based on the ease with which the resuscitation measures can be taught and the degree to which the skill taught can be retained (“construct validity”). This feature is important to the reality of emergency medical practice. Simplification of algorithms—for instance, by making the unequivocal

THE LANCET • Vol 354 • July 3, 1999