Inflammatory bowel disease thiopurines

Fig. 13.3 Clinical response, adverse effects, and hematological parameters were determined and correlated with thiopurine methyl transferase (TPMT) enzyme activity and genotype in 106 patients with inflammatory bowel disease. The odds of achieving complete remission (CR) to azathioprine is approx, five times lower if TPMT is greater than 14 units/mL red blood cells (RBCs). (Reproduced from ref 39.)...

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

Schwab, M Schaffeler, E Marx, C Fischer, C., Lang, T., Behrens, C., Gregor, M., Eichelbaum, M., Zanger, U.U. and Kaskas, B.A. (2002) Azathioprine therapy and adverse drug reactions in patients with inflammatory bowel disease impact of thiopurine s-methyltransferase polymorphism. Pharmacogenetics, 12, 429-438. 

Teml A, Schaeffeler E, Herrlinger KR et al. Thiopurine treatment in inflammatory bowel diseases clinical pharmacology and implication of pharmacogenetically guided dosing. Clin Pharmacokinet 2007 46 187-208. 

Xin H-W, Fischer C, Schwab M et al. Effects of aminosalicylates on thiopurine 5-methyltransferase activity an ex vivo study in patients with inflammatory bowel disease. Aliment Pharmacol Ther 2005 21 1105-1109. 

Derijks U et al Thiopurines in inflammatory bowel disease. Aliment Pharmacol Ther 2006 24 715. [PMID 16918876]... 

In a retrospective analysis of 106 patients with inflammatory bowel disease, to evaluate the importance of thiopurine methyl transferase (TPMT) activity in the management of azathioprine therapy in inflammatory bowel disease, the relation between inherited variations in TPMT enzyme activity and azathioprine toxicity was confirmed (91). 

ESR erythrocyte sedimentation rate IBD inflammatory bowel disease NSAID nonsteroidal anti-inflammatory drug TPMT thiopurine S-methyltransferase TNF-a tumor necrosis factor-alpha... 

Pancreas In a retrospective, multicenter study in 241 patients with inflammatory bowel disease and 108 patients with vasculitis the cumulative incidence of thiopurine-induced acute pancreatitis in Crohn s disease equalled that in ulcerative colitis and vascuhtis (2.6%, 3.7%, and 1.9% respectively) [165 ]. 

However, the stability of thiopurine metabohtes may be a limiting factor in studies of the use of monitoring and correlations with therapeutic outcomes in patients with inflammatory bowel disease [176 ]. 

Teruel C, Lopez-San Roman A, Bermejo F, Taxonera C, Perez-Calle JL, Gisbert JP, Martin-Arranz M, Ponferrada A, Van Domselaar M, Algaba A, Estelles J, Lopez-Serrano P, Linares PM, Muriel A. Outcomes of pregnancies fathered by inflammatory bowel disease patients exposed to thiopurines. Am J Gastroenterol 2010 105(9) 2003-8. 

Takatsu N, Matsui T, Murakami Y, Ishihara H, Hisabe T, Nagahama T, Maki S, Beppu T, Takaki Y, Hirai F, Yao K. Adverse reactions to azathioprine cannot be predicted by thiopurine S-methyltransferase genotype in Japanese patients with inflammatory bowel disease. J Gastroenterol Hepatol 2009 24(7) 1258-64. 

Drug-drug interactions Azathioprine/6-mercaptopurine The association between mesalazine and the induction of myelotoxicity by thiopurine therapy in patients with inflammatory bowel disease was investigated by using both retrospective and prospective studies. Of the 139 patients included in ffie retrospective observational study, 45 were on azathioprine/6-mercaptopurine plus mesalazine, while 94 were on azatiiioprine/6-mercaptopurine alone. The dose of azathioprine in the retrospective study was 2 mg/kg/day, while ffie dose of 6-mercaptopurine was 1 mg/kg/day. Their myelotoxicity rates were 47% and 16%, respectively. Multivariate regression analysis indicated that concomitant mesalazine was the only risk factor associated with myelotoxicity (odds ratio 3.45,95% confidence interval 1.31-9.04, P = 0.01). The prospective study was performed in 16 patients with active disease, treated with azathioprine (50 mg/ day) for 4 weeks followed by concomitant mesalazine (3 g/day) for additional 4 weeks. After 4 weeks on azathioprine no patient developed myelotoxicity. However, after an additional 4 weeks with concomitant mesalazine, two patients developed myelotoxicity. Overall, it appears that the risk of thiopurine-induced myelotoxicity is markedly increased in patients treated with combined mesalazine and 2 mg/kg/day azathioprine. Azathioprine (50 mg, daily) with concomitant mesalazine might help to maintain efficacy without increasing the risk of myelotoxicity [80 ]. 

Gao X, Zhang FB, Ding L, liu H, Wang XD, Chen BL, et al. The potential influence of 5-aminosalicylic acid on the induction of myelotoxicity during thiopurine therapy in inflammatory bowel disease patients. Eur J Gastroenterol Hepatol 2012 24 958-64. 

In a retrospective study, thiopurine treatment in inflammatory bowel disease was associated with flulike S5mdrome, abnormalities of liver function tests and myelotoxicity [70 ]. 

In a retrospective study of inflammatory bowel disease patients treated with co-prescription of thiopurines and allopurinol, 20 of 25 patients with hepatotoxicity tolerated combination treatment and their liver function tests were normalised [75 ]. 

Malignancy In a retrospective study of 123 inflammatory bowel disease patients treated with thiopurine therapy, cancer was identified in 51 patients (4.7%), including colorectal cancer (15 patients), melanoma (2 patients), nonmelanoma skin cancer (7 patients) and non-Hodgkin lymphoma (5 patients). A diagnosis of non-melanoma skin cancer was significantly associated with thiopurine exposiue (OR 5.0, 95% Cl 1.1-22.8). Six of seven non-melanoma skin cancers occurred in Caucasian patients, with a highly significant association with thiopurine use (OR 12.4,95% Cl 2.3-67.4) [79 ]. 

Smith MA, Blaker P, Marinaki AM, Anderson SH, Irving PM, Sanderson JD. Optimising outcome on thiopurines in inflammatory bowel disease by co-prescription of allopurinol. J Crohns Colitis October 2012 6(9) 905-12. PubMed PMID 22386736. Epub 2012/03/06. eng. 

Setshedi M, Epstein D, Winter TA, Myer L, Watermeyer G, Hift R. Use of thiopurines in the treatment of inflammatory bowel disease is associated with an increased risk of non-melanoma skin cancer in an at-risk population a cohort study. J Gastroenterol Hepatol February 2012 27(2) 385-9. PubMed PMID 21793904. Epub 2011/07/29. eng. 

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