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Azathioprine – clinical implications of its use

Azathioprine (AZA) is probably the most common immunosupresive drug used in autoimmune diseases such as systemic lupus erythematosus (SLE) or Crohn’s disease. It is not used specifically for acute treatment of active disease manifestations but as steroid sparing-agent, in patients who are steroid dependent or who have recurrent diseases exacerbations necessitating reinstitution of steroids. Maintenance treatment with azathioprine in doses of 1.5-2.5 mg/kg/day has been shown to be associated with a lower development rate of severe forms of SLE, such as nephritis, or central nervous system involvement. In doses 1.25-3.0 mg/kg/day it is clearly more effective than placebo in rheumatoid arthritis (RA), there appears to be a dose-response relationship. In RA probably it is not as effective as methotrexate, though data are inconsistent. In long term studies it is proved to be more effective than steroids alone in psoriatic arthritis, polymyositis/dermatomyositis, Behçet’s syndrome, reactive arthritis (Reiter’s syndrome). It is now a widely accepted opinion among rheumatologists and obstetricians that AZA can be safely continued during pregnancy, in women with lupus it may in fact help to preserve the pregnancy by preventing a disease exacerbation. In rheumatoid arthritis AZA reduces the numbers of circulating B and T Lymphocytes (particularly suppresser, or CD8+ cells) mixed lymphocyte reactivity, immunoglobulin M and IgG synthesis and interleukin-2 secretion. Its immunosuppressive action appears to be derived from the suppression of DNA synthesis by interference with adenine and guanine ribonucleotides. Its main active metabolite 6-thioguanine (6-TGN), another metabolite of azathioprine’s principal metabolic product 6-mercaptopurine (6-MP), inhibits the enzymatic conversion of inosinic acid to xanthylic acid, and of adenylsuccinic acid to adenylic acid. The metylation of 6-MP to active 6-TGN is catalyzed by thiopurine methyltransferase (TPMT), an enzyme that exhibits interindividual variations as a result of a known genetic polymorphism of its alleles. 89% of subjects have a normal to high level of TMPT activity, 11% have intermediate activity and 0.3% have low or absent TPMT activity. This last group of subjects is at high risk of bone marrow immunosupression, whereas the rest have a lower frequency of toxicity. Patients with intermediate levels of activity have a relative risk of 3.1 for development of severe side effects...


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