ABSTRACT
BACKGROUND: Thiopurine and allopurinol in combination are associated with clinical remission in inflammatory bowel diseases but their influence on subsequent outcomes is unclear. We compared outcomes during exposure to both thiopurines and allopurinol versus thiopurines alone. METHODS: We established a nationwide cohort of patients with inflammatory bowel diseases exposed to thiopurines ± allopurinol during 1999-2014, using registry data. Patients were followed until hospitalization, surgery, anti-TNFα, or death (as a primary composite outcome). We used Poisson regression analyses to calculate incidence rate ratios overall and stratified by calendar period (assuming the combined exposure was unintended before 2009). RESULTS: A total of 10,367 patients with inflammatory bowel diseases (Crohn's disease, n = 5484; ulcerative colitis, n = 4883) received thiopurines. Of these, 217 (2.1%) also received allopurinol. During 24,714 person years of follow-up, we observed 40 outcomes among thiopurine-allopurinol-exposed patients, and 4745 outcomes among those who were thiopurine exposed; incidence rate ratio, 1.26 (95% confidence interval, 0.92-1.73). The incidence rate ratios decreased over time: 4.88 (95% confidence interval 2.53-9.45) for 1999-2003, 2.19 (95% confidence interval, 1.17-4.09) for 2004-2008 and 0.80 (95% confidence interval, 0.52-1.23) for 2009-2014. CONCLUSION: Our nationwide inflammatory bowel disease cohort study shows that concomitant thiopurine-allopurinol is as safe to use as thiopurines alone, with a tendency towards a positive effect on clinical outcomes in recent calendar periods when combined use was intended.
Subject(s)
Allopurinol/administration & dosage , Azathioprine/administration & dosage , Colitis, Ulcerative/drug therapy , Crohn Disease/drug therapy , Immunosuppressive Agents/administration & dosage , Mercaptopurine/administration & dosage , Adult , Allopurinol/adverse effects , Azathioprine/adverse effects , Azathioprine/pharmacokinetics , Colitis, Ulcerative/diagnosis , Colitis, Ulcerative/immunology , Crohn Disease/diagnosis , Crohn Disease/immunology , Denmark , Drug Therapy, Combination/adverse effects , Drug Therapy, Combination/methods , Female , Follow-Up Studies , Hospitalization/statistics & numerical data , Humans , Immunosuppressive Agents/adverse effects , Immunosuppressive Agents/pharmacokinetics , Male , Mercaptopurine/adverse effects , Mercaptopurine/analogs & derivatives , Mercaptopurine/immunology , Mercaptopurine/metabolism , Mercaptopurine/pharmacokinetics , Middle Aged , Remission Induction/methods , Severity of Illness Index , Signal Transduction/drug effects , Signal Transduction/immunology , Thioguanine/immunology , Thioguanine/metabolism , Treatment OutcomeABSTRACT
Thioguanine derivatives with reactive ester groups at positions 6, 7, or 9 of the purine ring were synthesized and coupled to a protein carrier. The purified protein derivative of tuberculin was used as the carrier for immunizing bacillus Calmette-Guerin primed mice. This led to high antibody titers against the homologously coupled hapten, and spleen cells from the immunized mice were used to produce monoclonal antibodies against thioguanine. All monoclonal antibodies were selected for their ability to recognize free thioguanine and were analyzed for their fine specificity by inhibition experiments with a panel of thiopurine derivates. The specificity of the monoclonal antibodies showed a strong dependence on the coupling position of the thioguanine. Within each group of monoclonal antibodies, raised against one of the three different conjugates, there was a high degree of heterogeneity, with antibodies differing in their binding according to the substitution on the thioguanine analogues used in the inhibition experiments. This panel of antibodies may be used for quantitative assays of thiopurines and their metabolites in patients undergoing treatment with thioguanine, 6-mercaptopurine, and azathioprine.
