Gastroenterology
Volume 137, Issue 4 , Pages 1535-1536, October 2009

Patients With Drug-Induced Microscopic Colitis Should Not Be Included in Controlled Trials Assessing the Efficacy of Anti-Inflammatory Drugs in Microscopic Colitis

  • Laurent Beaugerie

      Affiliations

    • Department of Gastroenterology, Hôpital Saint-Antoine and UPMC University of Paris, Paris, France
    • ,
  • Darrell S. Pardi

      Affiliations

    • Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota

published online 31 August 2009.

Article Outline

 

Dear Sir:

We read with interest in the Journal the report of 2 randomized, double-blind, placebo-controlled trials by Miehlke et al demonstrating the efficacy of budesonide in the short-term treatment of lymphocytic colitis1 and in the maintenance treatment of collagenous colitis.2 In these trials, although the authors state that the development of lymphocytic or collagenous colitis may be associated with the use of drugs, only patients treated with budesonide, aminosalicylates, steroids, or antibiotics during the 4 weeks before randomization were excluded.

The first well-documented case of drug-induced microscopic colitis was published in 1994.3 In this report, a woman treated with a French phlebotonic drug developed histologically proven lymphocytic colitis. Diarrhea ceased rapidly after drug withdrawal and recurred with drug rechallenge. Sigmoid biopsies were taken immediately before drug rechallenge and after 48 hours of drug rechallenge. Immunopathologic features of mucosal immune cell activation—CD25 expression in lamina propria mononuclear cells and increased HLA-DR expression on epithelial cells—were only present after drug rechallenge, demonstrating with a high level of evidence that microscopic colitis can be drug induced.

In the following years, the role of several drugs in causing microscopic colitis has been raised, either with strong clinical and/or histologic evidence after drug rechallenge or based on isolated chronological4 and/or frequency arguments.5 In 2005, we proposed a scoring system for drug-induced microscopic colitis,6 adapting existing criteria of drug causality.7, 8, 9, 10 We also reviewed the literature using this framework. Based on this review, 8 drugs achieved a high level of likelihood of being able to cause lymphocytic or collagenous colitis (acarbose, aspirin, Cyclo3Fort, lansoprazole, nonsteroidal anti-inflammatory drugs, ranitidine, sertraline, and ticlopidine). Finally, we made suggestions for the clinical management of individual patients suspected of having drug-induced microscopic colitis according to the level of evidence in the literature that the drug may cause colitis.

We thus believe that any case of microscopic colitis that can be cured by withdrawal of a drug must be identified. This should be the case for routine clinical practice, but also when patients are considered for enrollment in a controlled trial testing the efficacy of any drug in the treatment of microscopic colitis. In the latter context, maintaining the cause of the symptoms (ie, the responsible drug) in the placebo group may influence the response rate. In our review, taking into account all the previously published cases of potential drug-induced microscopic colitis, we reported a range of time between withdrawal of the suspected drug and cessation of diarrhea of 2–30 days, with a median interval of 5 days.6 Thus, we suggest that patients with clinically active microscopic colitis considered for enrollment in a therapeutic trail, and receiving a drug that may cause microscopic colitis, should be observed during a 1- or 2-week drug holiday before enrollment. For drugs for which a complete drug holiday might be considered hazardous (eg, ticlopidine or sertraline), a drug with similar efficacy but from a different class of compounds should be considered. In patients with persistent diarrhea despite drug withdrawal, enrollment in the therapeutic trial may be considered without any ethical or methodologic concerns.

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References 

  1. Miehlke S, Madisch A, Karimi D, et al. A randomized double-blind placebo-controlled study showing that budesonide is effective in treating lymphocytic colitis. Gastroenterology. 2009;136:2092–2100
  2. Miehlke S, Madisch A, Bethke B, et al. Oral budesonide for maintenance treatment of collagenous colitis: a randomized, double-blind, placebo-controlled trial. Gastroenterology. 2008;135:1510–1516
  3. Beaugerie L, Luboinski J, Brousse N, et al. Drug induced lymphocytic colitis. Gut. 1994;35:426–428
  4. Thomson RD, Lestina LS, Bensen SP, et al. Lansoprazole-associated microscopic colitis: a case series. Am J Gastroenterol. 2002;97:2908–2913
  5. Fernandez-Banares F, Esteve M, Espinos JC, et al. Drug consumption and the risk of microscopic colitis. Am J Gastroenterol. 2007;102:324–330
  6. Beaugerie L, Pardi DS. Review article: drug-induced microscopic colitis—proposal for a scoring system and review of the literature. Aliment Pharmacol Ther. 2005;22:277–284
  7. Macedo AF, Marques FB, Ribeiro CF, et al. Causality assessment of adverse drug reactions: comparison of the results obtained from published decisional algorithms and from the evaluations of an expert panel, according to different levels of imputability. J Clin Pharm Ther. 2003;28:137–143
  8. Begaud B, Evreux JC, Jouglard J, et al. [Imputation of the unexpected or toxic effects of drugs. Actualization of the method used in France]. Therapie. 1985;40:111–118
  9. Marteau P, Lavergne-Slove A, Lemann M, et al. Primary ileal villous atrophy is often associated with microscopic colitis. Gut. 1997;41:561–564
  10. Colombel JF, Loftus EV, Tremaine WJ, et al. The safety profile of infliximab in patients with Crohn's disease: the Mayo clinic experience in 500 patients. Gastroenterology. 2004;126:19–31

 Conflicts of interest The authors disclose no conflicts.

PII: S0016-5085(09)01396-1

doi:10.1053/j.gastro.2009.04.067

Gastroenterology
Volume 137, Issue 4 , Pages 1535-1536, October 2009

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