O0072 6-MMP/6-TG METABOLITE LEVELS & THEIR RATIO GUIDE THIOPURINE TREATMENT IN ULCERATIVE COLITIS

Abstract

Introduction: The efficient conversion of the thiopurine drugs azathioprine (AZA) and 6-mercaptopurine (6-MP) to the immunosuppressive metabolites, the 6-thioguanine nucleotides (6-TG), is determinant to its clinical efficacy. The major catabolic metabolite, 6-methylmercaptopurine (6-MMP), is formed via the competing pathway by thiopurine methyltransferase. Measurement of these metabolites in Crohn’s disease patients has been shown to be helpful in titrating dose to enhance efficacy, to explain therapeutic failures and to identify non-adherence. However, little information has been reported in patients with ulcerative colitis (UC). Aim: To assess the clinical utility of repeated 6-MP drug metabolite measurements in a cohort of pediatric patients with ulcerative colitis. Methods: 6-MP metabolite levels were measured prospectively at 6 monthly intervals, or at the time of a clinical relapse, in 25 pediatric patients with UC receiving 6-MP or AZA. Therapeutic response was determined by UC activity index and physical exam was ascertained at each clinic visit corresponding to a 6-MP metabolite measurement (clinical evaluation point). Erythrocyte 6-TG and 6-MMP concentrations (pmol/8x108 RBC) were measured by HPLC assay at Ste Justine Hospital. Logistic regression analysis using generalized estimation equations (GEE) was carried out accounting for correlation between repeated measures. Results: Mean age (SD) was 10.2 (3.6) years. 13/25 patients (52%) had one or more relapses, and 30% of all the 103 clinical evaluation points corresponded to disease relapses. Mean 6-TG level in remission was higher (244, SD 205) compared to patients with active disease (183, SD 113) (p<0.05). After controlling for time since diagnosis and age at diagnosis, clinical remission was strongly correlated with higher erythrocyte 6-TG levels (OR=0.21; 95% CI= [0.06–0.8], p= 0.02), but neither with 6-MMP levels nor dose of 6-MP/AZA. An increased risk for relapse was associated with above average (35.7 mean, SD 80.7) ratios of 6-MMP/6-TG: odds ratio (OR) = 1.65; 95% CI= [0.99 - 2.7], p<0.001. With a 5 log unit increase in the ratio, the risk for relapse among the UC patients increased 12 fold. Baseline (close to diagnosis of disease) ratios of 6-MMP/6-TG were good predictors of future relapse (Area under the curve, AUC=0.70, 95% CI= [0.45–0.95]). Conclusion: 6-MP metabolite levels and 6-MMP/6-TG ratio determination provide clinicians with useful tools for optimizing therapeutic response to thiopurine drugs in UC. An excessive 6-MMP/6-TG ratio supports the use of other, non-thiopurine drugs.