Azathioprine rheumatoid arthritis

Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of thiopurine dmgs, such as 6-mercaptopurine (6-MP), 6-thioguanine and azathioprine, to inactive metabolites [29-32]. Thiopurines form part of the routine treatment for patients with acute lymphoblastic leukemia, rheumatoid arthritis, and autoimmune diseases such as SLE and Crohn s disease, and are used as an immunosuppressant following organ transplantation. 

Stolk, J.N., Boerbooms, A. M., de Abreu, R. A., et al. (1998) Reduced thiopurine methyltrans-ferase activity and development of side effects of azathioprine treatment in patients with rheumatoid arthritis. Arthritis and Rheumatism. 41, 1858-1866. 

Corominas, H., Domenech, M., Laiz, A., et al. (2003) Is thiopuiine methyltransferase genetic polymorphism a major factor for withdrawal of azathioprine in rheumatoid arthritis patients Rheumatology. 42, 40-45. 

For rheumatoid arthritis, the pharmacogenomics of three major diseasemodifying antirhenmatic drags (methotrexate, azathioprine, and sulfasalazine) and one class of biologic antirhenmatic drags (the tumor necrosis factor antagonists) are discnssed in detail. 

Hypersensitivity to azathioprine pregnancy in rheumatoid arthritis patients. 

Sulfasalazine (Azulfidine) is approved for the treatment of rheumatoid arthritis and ulcerative colitis. It is also used to treat ankylosing spondylitis and Crohn s disease. Comparisons of sulfasalazine with other DMARDs suggest that it is more effective than hydroxychloroquine, azathioprine, and oral gold compounds. It is at least as effective as intramuscular gold and penicillamine. It has a greater degree of toxicity than hydroxychloroquine but less than gold compounds and penicillamine. After 5 years, approximately 75% of patients have discontinued sulfasalazine therapy, primarily because of a lack of efficacy as opposed to intolerable side effects. 

Azathioprine also has applications in certain disorders with autoimmune components, most commonly rheumatoid arthritis. It is as effective as cyclophosphamide in the treatment of Wegener s granulomatosis. It has largely been replaced by cyclosporine in immunosuppressive therapy. Relative to other cytotoxic agents, the better oral absorption of azathioprine is the reason for its more widespread clinical use. 

Azathioprine is approved for use in rheumatoid arthritis and is used at a dosage of 2 mg/kg/d. Controlled trials show efficacy in psoriatic arthritis, reactive arthritis, polymyositis, systemic lupus erythematosus, and Behget s disease. 

Azathioprine and mercaptopurine appear to be of definite benefit in maintaining renal allografts and may be of value in transplantation of other tissues. These antimetabolites have been used with some success in the management of acute glomerulonephritis and in the renal component of systemic lupus erythematosus. They have also proved useful in some cases of rheumatoid arthritis, Crohn s disease, and multiple sclerosis. The drugs have been of occasional use in prednisone-resistant antibody-mediated idiopathic thrombocytopenic purpura and autoimmune hemolytic anemias. 

Originally developed for chemotherapy, azathioprine is used today mainly as an immunosuppressive agent and rarely as an antineoplastic drug. It was introduced as an immunosuppressive agent by a British pioneer of tissue transplantation, Roy Caine. Azathioprine was used to prevent rejection after tissue transplantation as a replacement for 6-mercaptopurine because it was less toxic. In addition to tissue transplantation, it is also used for rheumatoid arthritis and Crohn s disease. Azathioprine is a prodrug which in the body is converted to its active metabolites 6-mercaptopurine and 6-thioinosinic acid. Until the discovery of cyclosporine, azathioprine in combination with steroids was the standard treatment to prevent rejection after tissue transplantation. 

Mechanism of Action. The mechanism of action of azathioprine in rheumatoid arthritis is not fully understood. This drug has been shown to impair the synthesis of DNA and RNA precursors, but it is... 

Methotrexate (Folex, Rheumatrex) is an antimetabolite used frequently in the treatment of cancer (see Chapter 36). There is considerable evidence that this drug is also one of the most effective DMARDs.15 76 Methotrexate has been shown to slow the effects of rheumatoid arthritis as evidenced by decreased synovitis, decreased bone erosion, and less narrowing of the joint space.37 The therapeutic effects of methotrexate have also been reported to be equal to, or better than, other DMARDs such as oral gold or azathioprine, and methotrexate may offer an advantage in terms of a rapid onset.68,90 Hence, methotrexate s popularity as a DMARD has increased during the past few years, and this drug is often the first DMARD used to treat rheumatoid arthritis in both adults and children.76... 

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

The second approach to prolonged therapeutic action is based on the controlled rate of conversion of the promoiety into the active compound in vivo. This approach requires particularly detailed study of the kinetics of prodrug-drug conversion. A classic example is bioconversion of azathioprine to 6-mercaptopurine. Azathioprine is used commonly in kidney transplantation, rheumatoid arthritis, and the treatment of various skin disorders. After administration, azathioprine undergoes slow... 

Cyclosporine is an important drug in preventing rejection after kidney, hver, heart and other organ transplantation (Haberal et al., 2004). Cyclosporine usually is combined with other immunosuppressives especially glucocorticoids and either azathioprine or mycophenolate mofedl and sirolimus (Krensky et al., 2005). In renal alio transplants it has improved graft acceptance in most clinics to 95 percent. In addition to its use in transplantation cyclosporine is used for the treatment of a number of autoimmune diseases. In autoimmune diseases, as might be anticipated, cyclosporine is most effective in those which are T cell mediated. These include several forms of psoriasis, rheumatoid arthritis refractive to all other therapy, uveitis, nephrotic syndrome and type I diabetes mellitus. 

Methotrexate is used widely as a DMARD for rheumatoid arthritis, psoriatic arthritis, and for its steroid-sparing effects in many other conditions, especially if azathioprine is not tolerated. In high dose, with folinic acid rescue, methotrexate is used to treat solid and haematological malignancies (see p. 612). Low dose methotrexate slows the progression of rheumatoid arthritis. The evidence for a true disease-modifying effect on psoriatic arthritis is less definite, but methotrexate is often preferred to other DMARDs for its beneficial effect on the skin lesions. 

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. 

In 43 patients with rheumatoid arthritis, methotrexate was thought to have increased the risk of the azathioprine-induced hjq)ersensitivity sjmdrome (106). 

Jeurissen ME, Boerbooms AM, van de Putte LB, Kruijsen MW. Azathioprine induced fever, chills, rash, and hepatotoxicity in rheumatoid arthritis. Ann Rheum Dis 1990 49(l) 25-7. 

Meys E, Devogelaer JP, Geubel A, Rahier J, Nagant de Deuxchaisnes C. Fever, hepatitis and acute interstitial nephritis in a patient with rheumatoid arthritis. Concurrent manifestations of azathioprine hypersensitivity. J Rheumatol 1992 19(5) 807-9. 

Silman AJ, Petrie J, Hazleman B, Evans SJ. Lymphoprohferative cancer and other malignancy in patients with rheumatoid arthritis treated with azathioprine a 20 year follow up study. Ann Rheum Dis 1988 47(12) 988-92. 

Kerstens PJ, Stolk JN, De Abreu RA, Lambooy LH, van de Pntte LB, Boerbooms AA. Azathioprine-related bone marrow toxicity and low activities of purine enzymes in patients with rheumatoid arthritis. Arthritis Rheum 1995 38(l) 142-5. 

Blanco R, Martinez-Taboada VM, Gonzalez-Gay MA, Armona J, Fernandez-Sueiro JL, Gonzalez-Vela MC, Rodriguez-Valverde V. Acute febrile toxic reaction in patients with refractory rheumatoid arthritis who are receiving combined therapy with methotrexate and azathioprine. Arthritis Rheum 1996 39(6) 1016-20. 

A 57-year-old man took prednisone 20-30 mg/day for 13 years for rheumatoid arthritis (45). He had been treated unsuccessfully with gold, azathioprine, hydroxychloroquine, and sulfasalazine tapering his glucocorticoid dosage had been unsuccessful. He developed worsening back pain in his thoracic spine and lateral... 

A-60-year-old woman with rheumatoid arthritis who was taking prednisone, azathioprine, suhndac,... 

Methotrexate-related immunosuppression can be expected to increase the likelihood of infections. The infection rate reported in patients taking low-dose methotrexate has varied from one study to another. In a literature review focusing on patients with rheumatoid arthritis taking methotrexate, the mean infection rate was 1.8% in retrospective studies, 4.6% in open studies, and 11.6% in double-blind studies (97). Infections usually occurred within 1.5 years of starting treatment and mostly comprised common respiratory or cutaneous bacterial infections, Herpes zoster, and, more rarely, opportunistic infections. In one comparative study, the overall risk of infections was considered to be low and similar in patients taking methotrexate and azathioprine (97), but others have found a higher prevalence of infections and an increase in antibiotic use in patients with rheumatoid arthritis taking methotrexate as compared to other DMARDs, except cyclophosphamide (98,99). 

Mycophenolate has also been studied in various chronic inflammatory disorders, such as rheumatoid arthritis, pemphigus vulgaris, and psoriasis. In 70 patients with chronic active Crohn s disease, mycophenolate plus glucocorticoids produced benefit on disease activity comparable to azathioprine plus glucocorticoids (7). Two of the 35 patients randomized to mycophenolate had significant adverse effects that required drug withdrawal, namely rashes and vomiting. 

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