Effect of allopurinol on clinical outcomes in inflammatory bowel disease nonresponders to azathioprine or 6-mercaptopurine

Background & Aims: Many IBD patients not responding to azathioprine (AZA) or 6-mercaptopurine (6-MP) preferentially metabolize 6-MP to 6-methylmercaptopurine (6-MMP). We describe the use of allopurinol. in AZA/6-MP nonresponders to deliberately shunt metabolism of 6-MP toward 6-thioguanine (6-TGN) and improve clinical responses. Methods: Twenty outpatients who were AZA/ 6-MP nonresponders and had high 6-MMP metabolite levels were included. Subjects were commenced on allopurinol 100 mg daily, and the dose of 6-MP/AZA was reduced to 25%-50% of the original dose. Result: After allopurinol was started, mean 6-TGN levels increased from 191.3 (+/- standard error of the mean) +/- 17.1 to 400.3 +/- 36.9 pmol/8 X 10(8) red blood cells (P < .001), whereas mean 6-MMP levels decreased from 10,604.7 +/- 1278.2 to 2000.6 +/- 437.1 pmol/8 X 10(8) red blood cells (P < .001). The addition of allopurinol led to a reduction in the mean partial Harvey Bradshaw Index in Crohn's disease patients from 4.9 +/- 1.0 to 1.5 +/- 0.3 points (P =.001), and in ulcerative colitis patients mean Mayo Scores decreased from 4.1 +/- 0.7 to 2.9 +/- 0.7 points (P = .13). The addition of allopurinol enabled a reduction in mean daily prednisone dosage from 17.6 +/- 3.9 to 1.8 +/- 0.7 mg (P < .001) and led to normalization of transaminase levels, with mean AST levels reducing from 42.5 +/- 8.1 to 23.5 +/- 1.6 IU (P =.12) and mean ALT levels reducing from 101.6 +/- 26.9 to 33.9 +/- 5.2 IU (P =.01). Conclusions: The addition of allopurinol to thiopurine nonresponders with high 6-MMP metabolite levels is an effective and safe means of optimizing 6-TGN production, leading to improved disease activity scores, reduced corticosteroid requirements, and normalization of liver enzymes.