962 L E T T E R S T O T H E E D I T O R S
M. CHAPARRO, M. TRAPEROM A R U G A´ N , R . M O R E N O - O T E R O & J. P. GISBERT Gastroenterology and Hepatology Unit of La Princesa University Hospital (Madrid) and Centro de Investigacio´n Biome´dica en Red de Enfermedades Hepa´ticas y Digestivas (CIBEREHD), Spain. E-mail:
[email protected];
[email protected]. doi:10.1111/j.1365-2036.2009.04109.x
Azathioprine plus ribavirin treatment and pancytopenia SIRS, We read with interest the article by Peyrin-Biroulet et al.1 that aimed to underline the interaction of ribavirin, an ionosine monophosphate dehydrogenase (IMPDH) inhibitor, with azathioprine metabolism, potentially leading to myelotoxicity. They reported eight cases of severe pancytopenia in patients receiving azathioprine for inflammatory bowel disease and ribavirin plus peginterferon for chronic hepatitis C (CHC). Their thipurine methyltransferase (TPMT) genotype was normal. In all cases, blood tests returned to normal after drug withdrawal. In no patient, haematological toxicity occurred after reintroduction of azathioprine or CHC therapy alone. The authors prospectively monitored azathioprine metabolites in two of these patients and found a dramatic increase in methylated metabolite levels accompanying myelotoxicity. Recently, we admitted a 39-year-old man presented with pancytopenia. In June 2004, he had to undergo surgery for Crohn’s disease (CD) stenosis. Azathioprine was started at a dose of 2.5mg ⁄ kg ⁄ day after the surgery. His TPMT activity was normal. Peginterferon alfa-2b (1.5 lg ⁄ kg ⁄ week) plus ribavirin 800 mg daily was initiated in December 2008 for CHC (genotype 2, stiffness 27.7 KPa). Haematological counts were within the normal range before initiation of CHC therapy. Blood tests during CHC therapy revealed an abrupt decrease in neutrophil count (1.05 · 103 ⁄ mm3) with anaemia (6 g ⁄ dL) occurring 12 weeks after starting the treatment and all returned to normal values 4 weeks after drug (peginterferon, ribavirin and azathioprine) discontinuation. In May 2009, peginterferon plus ribavirin without azathioprine was reintroduced uneventfully. Crohn’s disease patients have prevalence of CHC similar or slightly higher than that in general population.2 Anti-viral therapy has shown to be effective and safe in the majority of these patients.3, 4 However, our experience is in accord with that reported previously,1, 5, 6 suggesting that ribavirin interacts with azathioprine metabolism, increasing the risk of developing myelotoxicity. Taking into account these observations, treatment with IMPDH inhibitors and purine analogues should be individualized and patients closely monitored.
ACKNOWLEDGEMENTS Declaration of personal and funding interests: The writing of this paper was funded by CIBEREHD and Instituto de Salud Carlos III, Madrid, Spain.
REFERENCES 1 Peyrin-Biroulet L, Cadranel JF, Nousbaum JB, et al. Interaction of ribavirin with azathioprine metabolism potentially induces myelosuppression. Aliment Pharmacol Ther 2008; 28: 984–93.
2 Loras C, Saro C, Gonzalez-Huix F, et al. Prevalence and factors related to hepatitis B and C in inflammatory bowel disease patients in Spain: a nationwide, multicenter study. Am J Gastroenterol 2009; 104: 57– 63.
Aliment Pharmacol Ther 30, 955–963 ª 2009 Blackwell Publishing Ltd
LETTER TO THE EDITORS 963 3 Bargiggia S, Thorburn D, Anderloni A, et al. Is interferon-alpha therapy safe and effective for patients with chronic hepatitis C and inflammatory bowel disease? A casecontrol study Aliment Pharmacol Ther 2005; 22: 209–15. 4 Salcedo-Mora X, Mate J, Medina J, Nam Cha SJ, Gisbert JP, Moreno-Otero R. Chronic hepatitis C and Crohn’s disease: nosocomial infection treatment with PEG-interferon plus ribavirin. Digestion 2006; 73: 210–4.
Aliment Pharmacol Ther 30, 955–963 ª 2009 Blackwell Publishing Ltd
5 Hindorf U, Lindqvist M, Peterson C, et al. Pharmacogenetics during standardised initiation of thiopurine treatment in inflammatory bowel disease. Gut 2006; 55: 1423–31. 6 Gilissen LP, Derijks LJ, Verhoeven HM, et al. Pancytopenia due to high 6-methylmercaptopurine levels in a 6-mercaptopurine treated patient with Crohn’s disease. Dig Liver Dis 2007; 39: 182–6.
