Azathioprine inflammatory bowel disease

Sandborn WJ. A review of immune modifier therapy for inflammatory bowel disease azathioprine, 6-mercaptopurine, cyclosporine, and methotrexate. Am J Gastroenterol 1996 91(3) 423-33. 

Tumorigenidty In a nested case-control study in 15471 patients with inflammatory bowel disease, azathioprine was compared between cases with a diagnosed cancer and control patients without cancer [168 ]. There was no overall increase in the risk of any cancer in patients with inflammatory bowel disease who had taken azathioprine. 

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.)...

Dubinsky, M. C. (2004) Azathioprine, 6-mercaptopurine in inflammatory bowel disease pharmacology, efficacy, and safety. Clin. Gastroenterol. Hepatol. 2, 731-743. 

Winter, J., Walker, A., Shapiro, D., et al. (2004) Cost-effectiveness of thiopuiine methyltransferase genotype screening in patients about to commence azathioprine therapy for treatment of inflammatory bowel disease. Aliment. Pharmacol. Ther. 20, 593-599. 

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. 

Therapeutic pyramid approach to inflammatory bowel diseases. Treatment choice is predicated on both the severity of the illness and the responsiveness to therapy. Agents at the bottom of the pyramid are less efficacious but carry a lower risk of serious adverse effects. Drugs may be used alone or in various combinations. Patients with mild disease may be treated with 5-aminosalicylates (with ulcerative colitis or Crohn s colitis), topical corticosteroids (ulcerative colitis), antibiotics (Crohn s colitis or Crohn s perianal disease), or budesonide (Crohn s ileitis). Patients with moderate disease or patients who fail initial therapy for mild disease may be treated with oral corticosteroids to promote disease remission immunomodulators (azathioprine, mercaptopurine, methotrexate) to promote or maintain disease remission or anti-TNF antibodies. Patients with moderate disease who fail other therapies or patients with severe disease may require intravenous corticosteroids, anti-TNF antibodies, or surgery. Natalizumab is reserved for patients with severe Crohn s disease who have failed immunomodulators and TNF antagonists. Cyclosporine is used primarily for patients with severe ulcerative colitis who have failed a course of intravenous corticosteroids. TNF, tumor necrosis factor. 

In a retrospective study, postoperative infectious complications were evaluated in 159 patients with inflammatory bowel disease undergoing elective surgery (317). Immunosuppression consisted of glucocorticoid monotherapy (n = 56), a glucocorticoid + azathioprine or mercaptopurine (n — 52), and neither a glucocorticoid nor azathioprine or mercaptopurine (n — 51). The adjusted odds ratios for any infection and major infections in patients who took glucocorticoid were 3.69 and 5.54 respectively, and in patients who took azathioprine or mercaptopurine 1.68 and 1.20. Thus, preoperative use of glucocorticoid in patients with inflammatory bowel disease increased the risk of postoperative infectious complications. 

Azathioprine Imuran Kidney, heart, liver, pancreas Rheumatoid arthritis, inflammatory bowel disease, myasthenia gravis, systemic lupus erythematosus (SLE), others... 

Gearry RB, Barclay ML. Azathioprine and 6-mercap-topurine pharmacogenetics and metabolite monitoring in inflammatory bowel disease. J Gastroenterol Hepatol. 2005 20 1149-1157. 

Azathioprine and 6-mercaptopurine have a serum half-life of less than 2 hours however, the active metabolites, 6-thioguanine nucleotides, are concentrated in cells resulting in a prolonged half-life of days. The prolonged kinetics of 6-thioguanine nucleotide results in a median delay of 17 weeks before onset of therapeutic benefit from oral azathioprine or 6-mercaptopurine is observed in patients with inflammatory bowel disease. 

Nielsen OH, Vainer B, Rask-Madsen J. Review article the treatment of inflammatory bowel disease with 6-mercaptopurine or azathioprine. Aliment Pharmacol Ther 2001 15 1699-1708. 

Azathioprine, a prodrug converted to 6-mercaptopurine, is widely used as a post-transplant immunosuppressant and in various autoimmune or chronic inflammatory disorders, such as rheumatoid arthritis, dermatomyositis, systemic lupus eiythematosus, skin diseases, and inflammatory bowel diseases. 

Experience in children with juvenile chronic arthritis or chronic inflammatory bowel disease has also accumulated, and the toxicity profile of azathioprine or mercaptopurine appears to be very similar to that previously found in the adult population (SEDA-21, 381) (SEDA-22, 410). 

Hematological toxicity is the most commonly reported severe adverse effect of azathioprine, and is marked by predominant leukopenia, thrombocytopenia, and pancytopenia (SED-13, 1120). In a 27-year survey of 739 patients treated with azathioprine 2 mg/kg for inflammatory bowel disease, dosage reduction or withdrawal of the drug because of bone marrow toxicity was necessary in 37 patients (5%) (11). There was moderate or severe leukopenia in 3.8% of patients in three patients pancytopenia resulted in severe sepsis or death. 

Leukopenia is the most serious adverse effect of azathioprine in patients with inflammatory bowel disease (12). It is variable and unpredictable and occurs 2 weeks to 11 years after the start of treatment (median 9 months) most cases recover 1 month after withdrawal. 

In two cases, azathioprine caused severe gastrointestinal symptoms that could have been easily confused with an acute exacerbation of the underljdng inflammatory bowel disease (20). 

Pancreatitis due to azathioprine or mercaptopurine has usually been reported as part of the hypersensitivity syndrome (SEDA-16,520) (SEDA-20,341). It has mostly been observed in patients with inflammatory bowel disease, and required withdrawal of treatment in 1.3% of patients with Crohn s disease (3). Pancreatitis was not dose-related within the therapeutic range of doses and often recurred in patients who were rechallenged with either drug (SEDA-20, 341) (35). Fatal hemorrhagic pancreatitis occurred in one patient, but a role of concomitant drugs was also possible (SEDA-20, 341). Pancreatitis or hyperamylasemia were not significantly different in renal transplant patients randomly assigned to receive azathioprine or ciclosporin, and other causative factors were found in most patients with pancreatitis (36). 

In a review of definite or probable drug-associated pancreatitis spontaneously reported to the Dutch adverse drug reactions system during 1977-98, azathioprine was the suspected drug in four of 34 patients, two of whom had positive rechallenge (37). Although most of the carefully described reports of azathioprine-induced pancreatitis were found in patients with inflammatory bowel disease, transplant recipients can also suffer this complication. 

In cases of inflammatory bowel disease, no overall increased incidence of cancer was noted after a median of 9 years follow-up in 755 patients who had taken less than 2 mg/kg/day of azathioprine over a median period of 12.5 years (69). Only colorectal cancers (mostly adenocarcinoma) were more frequent, but their incidence was also increased in chronic inflammatory bowel diseases. More specifically, there was no excess of non-Hodgkin s lymphoma, but the power of the study to detect an increased risk of this disorder was low. 

In 626 patients with inflammatory bowel disease who had taken azathioprine for a mean duration of 27 months (mean follow-up 6.9 years), there was no increased risk of cancer (colorectal or other) (70). 

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). 

BQrschner BS. Safety of azathioprine and 6-mercaptopur-ine in pediatric patients with inflammatory bowel disease. Gastroenterology 1998 115(4) 813-21. 

Connell WR, Kamm MA, Ritchie JK, Lennard-Jones JE. Bone marrow toxicity caused by azathioprine in inflammatory bowel disease 27 years of experience. Gut 1993 34(8) 1081-5. 

Fraser AG, Orchard TR, Robinson EM, Jewell DP. Longterm risk of malignancy after treatment of inflammatory bowel disease with azathioprine. Aliment Pharmacol Ther 2002 16(7) 1225-32. 

Cnffari C, Hnnt S, Bayless T. Utilisation of erythrocyte 6-thiognanine metabolite levels to optimise azathioprine therapy in patients with inflammatory bowel disease. Gnt 2001 48(5) 642-6. 

Ansari A, Hassan C, Duley J, Marinaki A, Shobowale-Bakre EM, Seed P, Meenan J, Yim A, Sanderson J. Thiopurine methyltransferase activity and the use of azathioprine in inflammatory bowel disease. Aliment Pharmacol Ther 2002 16(10) 1743-50. 

Patients with inflammatory bowel disease unresponsive to azathioprine or intolerant of it may benefit from mycophenolate mofetil. Of 12 patients so treated, three had minor adverse effects (headache, nausea, arthralgia). Three with ulcerative colitis developed rectal bleeding while taking mycophenolate mofetil. Histological features of the mucosa were highly... 

Shipkova M, Franz J, Abe M, Klett C, Wieland E, Andus T (2011) Association between adverse effects under azathioprine therapy and inosine triphosphate pyrophosphatase activity in patients with chronic inflammatory bowel disease. Ther Drug Monit 33 321-328... 

Stocco G, Martelossi S, Barabino A, Decorti G, Bartoli F, Montico M et al (2004) Glutathione-S-transferase genotypes and the adverse effects of azathioprine in young patients with inflammatory bowel disease. Inflamm Bowel Dis 13 57-64... 

Stocco G, Cuzzoni E, De Iudicibus S, Franca R, Favretto D, Malusa N et al (2013) Deletion of glutathione-S-transferase Ml reduces azathioprine metabolite concentrations in young patients with inflammatory bowel disease. J Clin Gastroenterol 48(1) 43-51... 

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