Combination of thiopurines and allopurinol: adverse events and clinical benefit in IBD

Abstract

Background and aims: Allopurinol has been presented as a safe and effective adjunct to thiopurine therapy in inflammatory bowel disease (IBD). We aimed to determine the rate of infectious complications and clinical successes with a combination of thiopurine/allopurinol in IBD, and to identify which variables predict 6-thioguanine, 6-methylmercaptopurine, and white blood cell levels. Additionally we aimed to identify which variables predict complications.

Methods: A retrospective database search identified patients with inflammatory bowel disease on both thiopurines and allopurinol. Regression modeling was used to identify which variables predicted metabolite levels, white blood cell levels, and complications.

Results: Twenty-seven subjects were found, with 20 treated intentionally and 7 inadvertently after a concurrent gout diagnosis. Thirteen of 20 patients had a major clinical improvement and 7 of 16 stopped steroids. Five infectious complications occurred. These included 2 cases of shingles, and one each of PCP, EBV, and viral meningitis. Significant predictors of metabolite levels included the dose of thiopurine and allopurinol, age, and BMI. Low white blood cell count levels were associated with increased doses, high BMI, and older age. Despite having only 5 events, there was a difference in absolute lymphocyte count between patients with and without infection (median 200 per mm³ vs 850 per mm³ respectively, p=0.0503).

Conclusions: Adjunctive allopurinol therapy in shunting patients produced major clinical improvement in 48% of patients. However, a surprising number of opportunistic infections have occurred. Low absolute lymphocyte count may be a previously unrecognized indicator of risk of opportunistic infections.

Figure 1

Metabolism of the thiopurines^, . The pool of 6-TGN consists of 6-TGMP, 6-TGDP, and 6-TGTP. Abbreviations: 6-MP, 6-mercaptopurine; 6-MMP, 6-methylmercaptopurine; 6-MMPR, 6-methylmercaptopurine ribonucleotide; 6-TU, 6-thiouric acid; 6-TIDP, 6-thioinosine 5’-diphosphate; 6-TIMP, 6-thioinosine 5’-monophosphate; 6-TITP, 6-thioinosine 5’-triphosphate; 6-TG; 6-thioguanine; 6-TGDP, 6-thioguanosine 5’-diphosphate; 6-TGMP, 6-thioguanosine 5’-monophosphate; 6-TGN, 6-thioguanine nucleotides; 6-TGTP, 6-thioguanosine triphosphate; 6-TXMP, 6-thioxanthosine monophosphate; AZA, azathioprine; GMPS, guanosine monophosphate synthetase; HPRT, hypoxanthine phosphoribosyltransferase; IMPDH, inosine monophosphate dehydrogenase; ITPase, inosine triphosphate pyrophosphatase; TPMT, thiopurine methyltransferase; XO, xanthine oxidase;

Figure 2

6-TGN (pmol/8 × 10⁸ RBCs) change with addition of allopurinol. Gray lines represent individual patients. The black line represents the mean. The dotted line represents 235 pmol/8 × 10⁸ RBCs.

Figure 3

6-MMP (pmol/8 × 10⁸ RBCs) change with addition of allopurinol. Gray lines represent the individual patients. The black line presents the mean and the dotted line represents 5700 pmol/8 × 10⁸ RBCs.

Figure 4

Predictors of Infection. The plot on the left depicts absolute lymphocyte count (ALC) among those with and without infection. The solid line indicates the median value for the 2 groups. The plot on the right shows the patient age in those with and without infection.