Thiopurine Immunosuppressives

Azathioprine is a pro-drug that is converted into 6-mercaptopurine (6-MP) and is subsequently metabolized by one of three different enzymes to form either active or inactive metabolites .

There is substantial inter-individual variation in azathioprine metabolism so an understanding of these mechanisms is essential to safe and effective administration of thiopurine therapy. Metabolism of 6-MP by xanthine oxidase produces 6-thiouric acid, which is inactive. Metabolism by hypoxanthine phosphoribosyltransferase produces the active 6-thioguanine (6-TG) nucleotides which are associated with improved efficacy in Crohn's disease, but also an increased risk of leukopenia. Lastly, metabolism by thiopurine methyltransferase (TPMT) produces an inactive metabolite, 6- methylmercaptopurine (6-MMP), which can be hepatotoxic at higher concentrations. The active metabolite, 6-TG, is a purine analogue that incorporates into cellular DNA, inhibits proliferation of lymphocytes, and stimulates apoptosis of T cells in the lamina propria. There are genetic polymorphisms in TPMT enzyme activity that profoundly impact the metabolism of azathioprine. It is advised to check TPMT activity prior to initiating thiopurines in order to select optimal dosing and avoid toxicity. One in 300 patients has very low or absent TPMT activity, which can lead to severe leukopenia even with small doses of azathioprine and another 11 % have intermediate enzyme activity and may require dose reduction . For patients with a high 6-MMP to 6-TG ratio, a xanthine oxidase inhibitor, allopurinol, can be added in conjunction with thiopurine dose reduction in order to favorably alter the 6-TG and 6-MMP metabolite profile. The addition of allopurinol in these patients has been shown to improve disease activity scores, reduce daily prednisone dosage, and decrease aminotransferase levels .

However, this strategy carries a significant risk of leukopenia and requires close follow-up and careful monitoring.

The initial report of successful azathioprine use for IBD was in 1969 in a case series of six patients with severe Crohn's disease .

Subsequently a 2-year randomized controlled trial in Crohn's disease showed patients who received 6-MP were more likely to experience clinical improvement (67 % versus 8 %), closure of fistulas, and reduction in steroid dosing than those who received placebo. The response to azathioprine took between 3 and 6 months to see full effect. A second randomized controlled trial in 1995 evaluated patients concurrently treated with a 12-week tapering course of prednisolone in addition to azathioprine 2.5 mg/kg versus placebo. This landmark trial showed a significant difference in steroid-free remission at 15 months, 39 but no difference at 12 weeks, again suggesting that thiopurines are effective in maintaining remission in Crohn's disease, but may not be effective for short-term induction therapy.

Despite these early studies showing significant benefit for thiopurines, enthusiasm for this class of medication has been tempered by recent prospective studies with larger patient enrollment demonstrating a more modest treatment benefit. A 2013 open-label trial of adults recently diagnosed with Crohn's disease (within 6 months) evaluated the early use of azathioprine compared with conventional management (defined as azathioprine only in case of steroid dependency, frequent flares, severe perianal disease, or poor steroid response). There was no difference in time spent in steroid and anti-TNF free remission during the first 3 years when comparing the two groups, although there was a lower rate of perianal surgery in the early azathioprine group.