Pharmacology and side effects of azathioprine when used in rheumatic diseases
- H Michael Belmont, MD
H Michael Belmont, MD
- Professor of Medicine
- NYU School of Medicine
- Section Editor
- Daniel E Furst, MD
Daniel E Furst, MD
- Section Editor — Treatment Issues in Rheumatology
- Clinical professor, University of Washington, Seattle
- Clinical professor, University of Florence, Florence, Italy
- Professor of Rheumatology, University of California in Los Angeles (Emeritus)
- Director of Research, Pacific Arthritis Associates
Azathioprine (AZA) is the 1-methyl-4-nitro-5-imidazolyl derivative of thioguanine, a purine mimic antimetabolite . Its synthesis evolved from the same antibiotic and purine antimetabolite research in the late 1940s that led to the discovery and subsequent development of allopurinol and acyclovir .
In addition to its use in preventing transplant rejection, AZA became available for use in the treatment of rheumatoid arthritis (RA) in patients who had not responded to less aggressive therapy. Use in RA was the indication that constituted the bulk of its use in the rheumatic diseases before leflunomide and biologic agents became available for the treatment of RA in the late 1990s and early 2000s. AZA has subsequently also been used for the treatment of psoriatic arthritis, psoriasis, reactive arthritis, Behçet’s syndrome, polymyositis, and systemic lupus erythematosus (SLE), and it has been used to sustain remissions in systemic vasculitis.
The pharmacology of AZA, the side effects associated with its use, and the efficacy of AZA in the management of RA will be reviewed here. The role of AZA in the management of the different rheumatic diseases and of transplant recipients is presented in detail separately on the appropriate topic reviews.
Azathioprine (AZA) is well-absorbed from the gastrointestinal tract. It has a serum half-life of 0.2 to 0.5 hours, resulting in a biologic half-life of approximately 24 hours . AZA is a prodrug; the action of glutathione in red blood cells causes the formation of the principal metabolite, 6-mercaptopurine (6-MP) .
Metabolism — The prodrug AZA is approximately 30 percent protein-bound. Forty-five percent of the drug is excreted in the urine; the remainder is metabolized to 6-MP, which is then further metabolized along competing routes:
- Elion GB. The purine path to chemotherapy. Science 1989; 244:41.
- Huskisson EC. Azathioprine. Clin Rheum Dis 1984; 10:325.
- Lennard L, Van Loon JA, Weinshilboum RM. Pharmacogenetics of acute azathioprine toxicity: relationship to thiopurine methyltransferase genetic polymorphism. Clin Pharmacol Ther 1989; 46:149.
- Black AJ, McLeod HL, Capell HA, et al. Thiopurine methyltransferase genotype predicts therapy-limiting severe toxicity from azathioprine. Ann Intern Med 1998; 129:716.
- Jun JB, Cho DY, Kang C, Bae SC. Thiopurine S-methyltransferase polymorphisms and the relationship between the mutant alleles and the adverse effects in systemic lupus erythematosus patients taking azathioprine. Clin Exp Rheumatol 2005; 23:873.
- Relling MV, Hancock ML, Rivera GK, et al. Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst 1999; 91:2001.
- Askanase AD, Wallace DJ, Weisman MH, et al. Use of pharmacogenetics, enzymatic phenotyping, and metabolite monitoring to guide treatment with azathioprine in patients with systemic lupus erythematosus. J Rheumatol 2009; 36:89.
- Stocco G, Martelossi S, Barabino A, et al. Glutathione-S-transferase genotypes and the adverse effects of azathioprine in young patients with inflammatory bowel disease. Inflamm Bowel Dis 2007; 13:57.
- US Food and Drug Administration. Uloric (febuxostat tablets). Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm243770.htm (Accessed on May 06, 2014).
- Elion GB, Hitchings GH. Azathioprine. Handbook Exp Pharmacol 1975; 38:404.
- McKendry RJR. Pruine analogues. In: Second Line Agents in the Treatment of Rheumatic Diseases, Dixon J, Furst BE (Eds), Marcel Decker, New York 1991.
- Trotter JL, Rodey GE, Gebel HM. Azathioprine decreases suppressor T cells in patients with multiple sclerosis. N Engl J Med 1982; 306:365.
- Bacon PA, Salmon M. Modes of action of second-line agents. Scand J Rheumatol Suppl 1987; 64:17.
- Crilly A, McInnes IB, Capell HA, Madhok R. The effect of azathioprine on serum levels of interleukin 6 and soluble interleukin 2 receptor. Scand J Rheumatol 1994; 23:87.
- 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; 111:1133.
- Nyhan WL, Sweetman L, Carpenter DG, et al. Effects of azathiprine in a disorder of uric acid metabolism and cerebral function. J Pediatr 1968; 72:111.
- Currey HL, Harris J, Mason RM, et al. Comparison of azathioprine, cyclophosphamide, and gold in treatment of rheumatoid arthritis. Br Med J 1974; 3:763.
- Weinshilboum RM, Sladek SL. Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Genet 1980; 32:651.
- Van Loon JA, Weinshilboum RM. Thiopurine methyltransferase biochemical genetics: human lymphocyte activity. Biochem Genet 1982; 20:637.
- Woodson LC, Dunnette JH, Weinshilboum RM. Pharmacogenetics of human thiopurine methyltransferase: kidney-erythrocyte correlation and immunotitration studies. J Pharmacol Exp Ther 1982; 222:174.
- Ragab AH, Gilkerson E, Myers M. The effect of 6-mercaptopurine and allopurinol on granulopoiesis. Cancer Res 1974; 34:2246.
- Pinals RS. Azathioprine in the treatment of chronic polyarthritis: longterm results and adverse effects in 25 patients. J Rheumatol 1976; 3:140.
- Singh G, Fries JF, Spitz P, Williams CA. Toxic effects of azathioprine in rheumatoid arthritis. A national post-marketing perspective. Arthritis Rheum 1989; 32:837.
- Mok MY, Ng WL, Yuen MF, et al. Safety of disease modifying anti-rheumatic agents in rheumatoid arthritis patients with chronic viral hepatitis. Clin Exp Rheumatol 2000; 18:363.
- Penn I. Cancers complicating organ transplantation. N Engl J Med 1990; 323:1767.
- Bernatsky S, Clarke AE, Suissa S. Hematologic malignant neoplasms after drug exposure in rheumatoid arthritis. Arch Intern Med 2008; 168:378.
- Silman AJ, Petrie J, Hazleman B, Evans SJ. Lymphoproliferative cancer and other malignancy in patients with rheumatoid arthritis treated with azathioprine: a 20 year follow up study. Ann Rheum Dis 1988; 47:988.
- Asten P, Barrett J, Symmons D. Risk of developing certain malignancies is related to duration of immunosuppressive drug exposure in patients with rheumatic diseases. J Rheumatol 1999; 26:1705.
- Kaiser R. Incidence of lymphoma in patients with rheumatoid arthritis: a systematic review of the literature. Clin Lymphoma Myeloma 2008; 8:87.
- Kaczmorski S, Doares W, Winfrey S, et al. Gout and transplantation: new treatment option-same old drug interaction. Transplantation 2011; 92:e13.
- Urowitz MB, Gordon DA, Smythe HA, et al. Azathioprine in rheumatoid arthritis. A double-blind, cross over study. Arthritis Rheum 1973; 16:411.
- Hunter T, Urowitz MB, Gordon DA, et al. Azathioprine in rheumatoid arthritis: a long-term follow-up study. Arthritis Rheum 1975; 18:15.
- Cade R, Stein G, Pickering M, et al. Low dose, long-term treatment of rheumatoid arthritis with azathioprine. South Med J 1976; 69:388.
- Mason M, Currey HL, Barnes CG, et al. Azathioprine in rheumatoid arthritis. Br Med J 1969; 1:420.
- Woodland J, Chaput de Saintonge DM, Evans SJ, et al. Azathioprine in rheumatoid arthritis: double-blind study of full versus half doses versus placebo. Ann Rheum Dis 1981; 40:355.
- Jeurissen ME, Boerbooms AM, van de Putte LB, et al. Influence of methotrexate and azathioprine on radiologic progression in rheumatoid arthritis. A randomized, double-blind study. Ann Intern Med 1991; 114:999.
- Perdriger A, Mariette X, Kuntz JL, et al. Safety of infliximab used in combination with leflunomide or azathioprine in daily clinical practice. J Rheumatol 2006; 33:865.
- Caramaschi P, Canestrini S, Biasi D, et al. [Infliximab in aggressive and refractory rheumatoid arthritis. A pilot study]. Recenti Prog Med 2002; 93:19.
- Brandwein S, Esdaile J, Danoff D, Tannenbaum H. Wegener's granulomatosis. Clinical features and outcome in 13 patients. Arch Intern Med 1983; 143:476.
- Leib ES, Restivo C, Paulus HE. Immunosuppressive and corticosteroid therapy of polyarteritis nodosa. Am J Med 1979; 67:941.
- Lanham JG, Elkon KB, Pusey CD, Hughes GR. Systemic vasculitis with asthma and eosinophilia: a clinical approach to the Churg-Strauss syndrome. Medicine (Baltimore) 1984; 63:65.
- Pagnoux C, Mahr A, Hamidou MA, et al. Azathioprine or methotrexate maintenance for ANCA-associated vasculitis. N Engl J Med 2008; 359:2790.
- Pharmacogenetics and TPMT testing
- Drug interactions
- MECHANISM OF ACTION
- ADVERSE EFFECTS
- Gastrointestinal problems
- Bone marrow suppression
- Risk of xanthine oxidase inhibitors
- USE IN RHEUMATIC DISEASES
- DOSING AND MONITORING
- SUMMARY AND RECOMMENDATIONS