Thiopurine undertreatment among inflammatory bowel disease patients referred for anti-TNF therapy

Česká verzia

Authors: V. Suchá ¹; B. Kadlečková ²; B. Repákova ²; Ľ. Krajčíová ³; Ľ. Jurgoš ¹; S. Kiňová ⁴; Z. Zelinková ^2,5
Authors place of work: Gastroenterologická ambulancia, Jurgos s. r. o., Bratislava, Slovenská republika ¹; IBD centrum, Assiduo, Bratislava, Slovenská republika ²; Ústav lekárskej biológie, genetiky a klinickej genetiky, LF UK a UN Bratislava, Slovenská republika ³; I. interná klinika LF UK a UN Bratislava, Slovenská republika ⁴; Gastroenterologické oddelenie a oddelenie digestívnej endoskopie, Nemocnica sv. Michala, a. s., Bratislava, Slovenská republika ⁵
Published in the journal: Gastroent Hepatol 2016; 70(4): 335-339
Category: IDB: Original Article
doi: https://doi.org/10.14735/amgh2016335

Summary

Thiopurines are effective in maintaining remission in inflammatory bowel disease (IBD) patients. Their effect is dose-dependent, and the optimal daily dose of azathioprine (AZA) is 2–2.5 mg/kg. Inadequate dosing may result in lack of efficacy and ensuing premature referral for biological therapy.

Aim:
The aims were to assess the rate of deviation from the normal thiopurine dose among IBD patients referred for biological therapy and to analyze the reasons for this deviation.

Patients and Methods:
All the IBD patients referred for anti-TNF therapy in one referral center by November 2014 were included. The dose of AZA at the time of indication for step-up to anti-TNF was noted, as well as the reasons for the use of a reduced dose of AZA, which was defined as a dose lower than 2 mg/kg.

Results:
In total, 176 IBD patients were included. The mean age was 37 years (range 18–76 years), 92 (52%) were men, 120 (68%) had Crohn‘s disease, 54 (31%) had ulcerative colitis, and two (1%) were IBD unclassified. Twenty-eight patients (16%) were receiving an unreduced dose of AZA; 93 (53%) patients had not used AZA previously (8 patients; 5%) or were using a low dose of AZA (85 patients; 48%) without documented reasons; 55 patients (32%) had discontinued AZA (38 patients; 22%) or undergone a dose reduction (17 patients; 10%) of AZA because of adverse events.

Conclusion:
In a real life clinical practice a substantial proportion of IBD patients referred for anti-TNF therapy are using low dose AZA with only a minority for well documented reasons of biologically-determined intolerance.

Key words:
inflammatory bowel disease – treatment – thiopurines

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE „uniform requirements“ for biomedical papers.

Submitted:
9. 7. 2016

Accepted:
11. 7. 2016

Zdroje

1. Prefontaine E, Sutherland LR, Macdonald JK et al. Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn’s disease. Cochrane Database Syst Rev 2009; 1: CD000067. doi: 10.1002/ 14651858.CD000067.pub2.

2. Prefontaine E, Macdonald JK, Sutherland LR. Azathioprine or 6-mercaptopurine for induction of remission in Crohn’s disease. Cochrane Database Syst Rev 2010; 4: CD000545. doi: 10.1002/ 14651858.CD000545.pub2.

3. Timmer A, McDonald JW, Macdonald JK. Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev 2007; 1: CD000478.

4. Dignass A, Van Assche G, Lindsay JO et al. The second European evidence-based Consensus on the diagnosis and management of Crohn’s disease: current management. J Crohns Colitis 2010; 4(1): 28– 62. doi: 10.1016/ j.crohns.2009.12.002.

5. Lichtenstein GR, Abreu MT, Cohen R et al. American Gastroenterological Association Institute medical position statement on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology 2006; 130(3): 935– 939.

6. Cosnes J, Gower-Rousseau C, Seksik P et al. Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology 2011; 140(6): 1785– 1794. doi: 10.1053/ j.gastro.2011.01.055.

7. Chouchana L, Narjoz C, Beaune P et al. Review article: the benefits of pharmacogenetics for improving thiopurine therapy in inflammatory bowel disease. Aliment Pharmacol Ther 2012; 35(1): 15– 36. doi: 10.1111/ j.1365-2036.2011.04905.x.

8. Ansari A, Hassan C, Duley J et al. Thiopurine methyltransferase activity and the use of azathioprine in inflammatory bowel disease. Aliment Pharmacol Ther 2002; 16(10): 1743– 1750.

9. Jharap B, Seinen ML, de Boer NK et al. Thiopurine therapy in inflammatory bowel disease patients: analyses of two 8-year intercept cohorts. Inflamm Bowel Dis 2010; 16(9): 1541– 1549. doi: 10.1002/ ibd.21221.

10. 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; 24(2): 331– 342.

11. Costantino G, Furfaro F, Belvedere Aet al. Thiopurine treatment in inflammatory bowel disease: response predictors, safety, and with-drawal in follow-up. J Crohns Colitis 2012; 6(5): 588– 596. doi: 10.1016/ j.crohns.2011.11.007.

12. Frei P, Biedermann L, Nielsen OH et al. Use of thiopurines in inflammatory bowel disease. World J Gastroenterol 2013; 19(7): 1040– 1048. doi: 10.3748/ wjg.v19.i7.1040.

13. Goel RM, Blaker P, Mentzer A et al. Optimizing the use of thiopurines in inflammatory bowel disease. Ther Adv Chronic Dis 2015; 6(3): 138– 146. doi: 10.1177/ 2040622315579063.

14. Greguš M. Riziká imunosupresívnej liečby tiopurínmi u IBD pacientov. Gastroenterol Prax 2013; 12(3): 130– 133.

15. Kopylov U, Ben-Horin S, Seidman E. Therapeutic drug monitoring in inflammatory bowel disease. Ann Gastroenterol 2014; 27(4): 304– 312.

16. Lichtenstein GR, Abreu MT, Cohen R et al. American Gastroenterological Association Institute medical position statement on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology 2006; 130(3): 935– 939. doi: 10.1038/ clpt.2010.320.

17. Relling MV, Gardner EE, Sandborn WJet al. Clinical pharmacogenetics implementation consortium guidelines for thiopurine me-thyltransferase genotype and thiopurine dosing. Clin Pharmacol Ther 2011; 89(3): 387– 391. doi: 10.1038/ clpt.2010.320.

18. Weinshilboum RM, Sladek SL. Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Genet 1980; 32(5): 651– 662.

19. Chevaux JB, Peyrin-Biroulet L, Sparrow MP. Optimizing therapy in inflammatory bowel disease. Inflamm Bowel Dis 2011; 17(6): 1428– 1435. doi: 10.1002/ ibd.21494.

20. Ansari A, Patel N, Sanderson J et al. Low-dose azathioprine or mercaptopurine in combination with allopurinol can bypass many adverse drug reactions in patients with inflammatory bowel disease. Aliment Pharmacol Ther 2010; 31(6): 640– 647. doi: 10.1111/ j.1365-2036.2009.04221.x.

21. de Boer NK, Wong DR, Jharap B et al. Dose-dependent influence of 5-aminosalicylates on thiopurine metabolism. Am J Gastroenterol 2007; 102(12): 2747– 2753.

22. Sparrow MP, Hande SA, Friedman Set al. Allopurinol safely and effectively optimizes tioguanine metabolites in inflammatory bowel disease patients not responding to azathioprine and mercaptopurine. Aliment Pharmacol Ther 2005; 22(5): 441– 446.

23. Hoentjen F, Seinen ML, Hanauer SB et al. Safety and effectiveness of long-term allopurinol-thiopurine maintenance treatment in inflammatory bowel disease. Inflamm Bowel Dis 2013; 19(2): 363– 369. doi: 10.1002/ ibd.23021.

24. Smith MA, Blaker P, Marinaki AM et al. Optimising outcome on thiopurines in inflammatory bowel disease by co-prescription of allopurinol. J Crohns Colitis 2012; 6(9): 905– 912. doi: 10.1016/ j.crohns.2012.02.007.