Иммуносупрессоры в современных подходах к терапии воспалительных заболеваний кишечника

Цель исследования. Охарактеризовать встречаемость мутаций гена TPMT у больных воспалительными заболеваниями кишечника (ВЗК) с миелосупрессией и оценить значение этих мутаций в прогнозе формирования миелосупрессии у этой категории больных, получающих терапию тиопуринами.
Материал и методы. Из общего регистра больных ВЗК были выделены пациенты (n=21), у которых в анамнезе наблюдалось развитие миелотоксичности на фоне приема иммуносупрессоров, для определения аллельных вариантов гена TPMT методом полимеразной цепной реакции.
Результаты. Лишь у одного пациента (4,7%) с болезнью Крона, с лейкопенией (3,85·10⁹/л) и тромбоцитопенией (80·10⁹/л), развившимися в отдаленные сроки (61 нед) после начала приема азатиоприна, был выявлен полиморфизм TPMT*3A, характеризующийся точечными мутациями 460 G>A и 719A>G. Во всех остальных случаях (20 больных) был найден аллельный вариант TPMT*1 с нормальной продукцией фермента
Выводы. Отсутствует необходимость исследования генетических мутаций перед назначением тиопуринов, однако применение эффективных методов оценки прогноза развития миелотоксичности остается актуальной проблемой. Требуется тщательный контроль лабораторных показателей миелосупрессии в течение терапии тиопуринами. В случае их непереносимости или возникновения миелотоксичности назначают метотрексат.

1. Aberra F.N., Lichtenstein G.R. Review article: monitoring of immunomodulators in inflammatory bowel disease // Aliment. Pharmacol. Ther. – 2005. – Vol. 21. – P. 307–319.

2. Ardizzone S., Cassinotti A., Manes G., Porro G.B. Immunomodulators for all patients with inflammatory bowel disease? // Therap. Adv. Gastroenterol. – 2010. – Vol. 3, N 1. – P. 31–42.

3. Chande N., Abdelgadir I., Gregor J. The safety and tolerability of methotrexate for treating patients with Crohn’s disease // J. Clin. Gastroenterol. – 2011. – Vol. 45, N 7. – P. 599–601.

4. Colombel J.F., Ferrari N., Debuysere H. et al. Genotypic analysis of thiopurine S-methyltransferase in patients with Crohn’s disease and severe myelosuppression during azathioprine therapy // Gastroenterology. – 2000. – Vol. 118, N 6. – P. 1025–1030.

5. Cuffari C., Dassopoulos T., Turnbough L. et al. Thiopurine methyltransferase activity influences clinical response to azathioprine in inflammatory bowel disease // Clin. Gastroenterol. Hepatol. – 2004. – Vol. 2. – P. 410–417.

6. Dignass A., Assche G., Lindsay J.O. et al. The second European evidence-based consensus on the diagnosis and management of Crohn’s disease: Current management // J. Crohn`s Colitis. – 2010. – Vol. 4, N 1. – P. 28–62.

7. Dignass A., Lindsay J.O., Sturm A. et al. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis Part 2: Current management // J. Crohn`s Colitis. – 2012. – Vol. 6, N 10. – P. 991–1030.

8. Dubinsky M.C. Optimizing immunomodulator therapy for inflammatory bowel disease // Curr. Gastroenterol. Rep. – 2003. – Vol. 5. – P. 506–511.

9. Dubinsky M.C., Lamothe S., Yang H.Y. Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease // Gastroenterology. – 2000. – Vol. 118. – P. 705–713.

10. Fangbin Z., Xiang G., Minhu C. et al. Should thiopurine methyltransferase genotypes and phenotypes be measured before thiopurine therapy in piatients with inflammatory bowel disease? // Ther. Drug Monit. – 2012. – Vol. 34, N 6. – P. 695–701.

11. Fraser A.G., Orchard T.R., Jewell D.P. The efficacy of azathioprine for the treatment of inflammatory bowel disease: a 30 year review // Gut. – 2002. – Vol. 50. – P. 485–489.

12. Fraser A.G. Methotrexate: first or second-line immunomodulator? // Eur. J. Gastroenterol. Hepatol. – 2003. – Vol. 15. – P. 225–231.

13. Gearry R.B., Barclay M.L., Burt M.J. et al. Thiopurine drug adverse effects in a population of New Zealand patients with inflammatory bowel disease // Pharmacoepidemiol. Drug. Saf. –2004. – Vol. 13. – P. 563–567.

14. Gilissen L.P., Wong D.R., Engels L.G. et al. Therapeutic drug monitoring of thiopurine metabolites in adult thiopurine tolerant IBD patients on maintenance therapy // J. Crohn`s Colitis. – 2012. – Vol. 6, N 6. – P. 698–707.

15. Gisbert J.P., Chaparro M., Gomollon F. Common misconceptions about 5-aminosalicylates and thiopurines in inflammatory bowel disease // World J. Gastroenterol. – 2011. – Vol. 17, N 30. – P. 3467–3478.

16. Gurwitz D., Rodriguez-Antona C., Payne K. Improving pharmacovigilance in Europe: TPMT genotyping and phenotyping in the UK and Spain // Eur. J. Hum. Genet. – 2009. – Vol. 17. – P. 991–998.

17. Hindorf U., Appell M.L. Genotyping should be considered the primary choice for pre-treatment evaluation of thiopurine methyltransferase function // J. Crohn`s Colitis. – 2012. – Vol. 6, N 6. – P. 655–659.

18. Hindorf U., Lindqvist M., Hildebrand H. et al. Adverse events leading to modification of therapy in a large cohort of patients with inflammatory bowel disease // Aliment. Pharmacol. Ther. – 2006. – Vol. 24, N 2. – P. 331–342.

19. Kaskas B.A., Louis E., Hindorf U. Safe treatment of thiopurine S-methyltransferase deficient Crohn’s disease patients with azathioprine // Gut. – 2003. – Vol. 52. – P. 140–142.

20. Kennedy N., Gambles C., Musy R. et al. Predictive factors of disease relapse following thiopurine withdrawal for sustained clinical remission of IBD // J. Crohn`s Colitis. – 2012. – DOI:10.1016/S1873-9946(12)60415-2

21. Kremer J.M. Toward a better understanding of methotrexate // Arthritis Rheum. – 2004. – Vol. 50, N 5. – P. 1370–1382.

22. Kurnik D., Loebstein R., Fishbein E. et al. Bioavailability of oral vs. subcutaneous low-dose methotrexate in patients with Crohn’s disease // Aliment. Pharmacol. Ther. – 2003. – Vol. 18. – P. 57–63.

23. Larussa T., Suraci E., Lentini M. et al. High prevalence of polymorphism and low activity of thiopurine methyltransferase in patients with inflammatory bowel disease // Eur. J. Intern. Med. – 2012. – Vol. 23, N 3. – P. 273–277.

24. Lennard L., Loon J.A., Weinshilboum R.M. Pharmacogenetics of acute azathioprine toxicity: relationship to thiopurine methyltransferase genetic polymorphism // Clin. Pharmacol. Ther. – 1989. – Vol. 46. – P. 149–154.

25. Lowry P.W., Franklin C.L., Weaver A.L. Leucopenia resulting from a drug interaction between azathioprine or 6-mercaptopurine and mesalamine, sulphasalazine, or balsalazide // Gut. – 2001. – Vol. 49. – P. 656–664.

26. Lysaa R.A., Giverhaug T., Wold H.L., Aarbakke J. Inhibition of human thiopurine methyltransferase by furosemide, bendroflumethiazide and trichlormethiazide // Eur. J. Clin. Pharmacol. – 1996. – Vol. 49. – P. 393–396.

27. Nasedkina T.V., Fedorova O.E., Glotov A.S. et al. Rapid genotyping of common deficient thiopurine S-methyltransferase alleles using the DNA-microchip technique // Eur. J. Hum. Genet. – 2006. – Vol. 14, N 9. – P. 991–998.

28. Prefontaine E., Sutherland L.R., MacDonald J.K. et al. Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn’s disease // Cochrane Database Syst. Rev. – 2009. – Vol. 21, N 1. – CD000067.

29. Reinisch W., Angelberger S., Petritsch W. et al. A double-blind, double-dummy, randomized, controlled, multicenter trial on the efficacy and safety of azathioprine vs mesalamine for prevention of clinical relapses in Crohn’s disease patients with postoperative moderate or severe endoscopic recurrence // Gastroenterology. – 2008. – Vol. 134, N 4 (suppl. 1). – P. 70.

30. Roqler G. Gastrointestinal and liver adverse effects of drugs used for treating IBD // Best Prac. Rest. Clin. Gastroenterol. – 2010. – Vol. 24, N 2. – P. 157–165. 13

31. Rosenberg J.L., Levin B., Wall A.J., Kirsner J.B. A controlled trial of azathioprine in Crohn’s disease // Am. J. Dig. Dis. – 1975. – Vol. 20. – P. 721–726.

32. Schmidt C., Dignass A., Hartmann F. et al. IBD ahead 2010 – Answering important questions in Crohn’s disease treatment // Z. Gastroenterol. – 2011. – Vol. 49, N 9. – P. 1246–1254.

33. Teml A., Schaeffeler E., Herrlinger K.R. et al. Thiopurine treatment in inflammatory bowel disease: clinical pharmacology and implication of pharmacogenetically guided dosing // Clin. Pharmacokinet. – 2007. – Vol. 46. – P. 187–208.

34. Tiede I., Fritz G., Strand S. et al. CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes // J. Clin. Invest. – 2003. – Vol. 111, N 8. – P. 1133–1145.

35. Willoughby J.M., Beckett J., Kumar et P.J. et al. Controlled trial of azathioprine in Crohn’s disease // Lancet. – 1971. – Vol. 2, N 7731. – P. 944–947.

36. Zabala-Fernandez W., Barreiro-de Acosta M., Echarri A. et al. A pharmacogenetics study of TPMT and ITPA genes detects a relationship with side effects and clinical response in patients with inflammatory bowel disease receiving Azathioprine // J. Gastrointestin. Liver Dis. – 2011. – Vol. 20, N 3. – P. 247–253.

37. Zhu Q., Cao Q. Thiopurine methyltransferase gene polymorphisms and activity in Chinese patients with inflammatory bowel disease treated with azathioprine // Chin. Med. J. – 2012. – Vol. 125, N 20. – P. 3665–3670.