Mercaptopurine and Azathioprine

These drugs are among the few agents that have demonstrated efficacy in fistulizing CD in controlled clinical trials. Although these agents are discussed interchangeably, there have been uncontrolled trials directly comparing these medications in the treatment of inflammatory bowel disease.

The effect of 6-MP on fistulizing CD was first evaluated by Present [25] in a randomized, placebo-controlled trial (2 years with a crossover after 1 year). The superiority of the drug over the placebo in fistula healing (31% vs. 6%) was not significant because of the small number of patients.

An uncontrolled follow-up extended the study of 6-MP (1.5 mg/kg/day) to a total of 34 patients with fistulae (perirectal 18, abdominal wall 8, enteroen-teric 7, rectovaginal 6, vulvar 2). Complete closure was observed in 39% of patients, a partial response in 26% and no response in 35%. Response was slow and required more than 3 months in 32% of the patients. Six out of the 13 with complete healing continued therapy and all maintained the response; 5 out of the 7 who discontinued therapy had a relapse and healed again when the therapy was restarted [26].

A meta-analysis of five controlled trials of AZA and 6-MP in CD confirmed these results: 54% of 41 patients receiving the active drug responded compared with 21% of 29 patients receiving placebo [27], resulting in a pooled odds ratio for fistula healing of 4.4. These results must be interpreted with some caution, since 66% of the 70 studied patients came from a single study [25]. Dosing and administration of AZA and 6-MP has not been standardized. Controlled trials indicate that AZA at doses of

2-3 mg/kg/day and 6-MP at a dose of 1.5 mg/kg/day are effective for the treatment of CD. Although titration of either drug to a specified blood 6-thioguanine nucleotide metabolite concentration (6-thioguanine >235 pM/108 erytrocytes) has been suggested for improving therapeutic efficacy, this has not been demonstrated convincingly in the treatment of Crohn's fistulae [28].

We can conclude that AZA/6-mercaptopurine is effective both in healing and maintaining fistula closure. Furthermore, there is evidence of long-term safety in terms of neoplasia of super-infections. Adverse events are reported to occur in 9-15% of patients receiving AZA or 6-MP for inflammatory bowel disease. The most serious adverse events are pancreatitis (3%), allergic reactions (2%) and drug induced hepatitis (0.3%). A small percentage of patients who are thiopurine methyltransferase deficient may also develop leukopenia (2%) [29]. These drugs have also been proven to be safe when taken during pregnancy, since they did not increase the number of fetal damage or abortions [30].

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