561 Successive Treatment with Cyclosporine and Infliximab in Severe Ulcerative Colitis (UC)

Abstract

Introduction: Higher 6-tioguanine nucleotide (6TGN) concentrations have been related to higher probabilities of achieving clinical remission on thiopurinic therapy, but that has been hardly applied to clinical practice. Aims: To establish the utility of systematic determination of 6TGN as a marker or predictor of AZA/mercaptopurine (MP) efficacy in IBD patients. Methods: Prospective, multicenter study. Serum 6TGN and 6-methylmercaptopurine ribonucleotides (6MMPR) levels of patients starting AZA/MP for steroid dependence or resistance were periodically monitored during steroid tapering and, after withdrawal, until a new activity flare (persistence of steroid resistance or dependence), or for 6 months in those showing maintenance of clinical response. Thiopurine methyl-transferase (TPMT) activity above 5 U/ml was required. Results: 153 patients were included, and 140 finished the study. Mean age was 36 years (range 16-77), 50% were males, and 72% had Crohn's disease. Mean 6TGN levels (and the ratios 6TGN/6MMPR, 6TGN/TPMT) obtained at basal, 2 weeks, and 1, 2, 4 and 6 months after steroid withdrawal were not significantly different between patients that were or were not in clinical remission at each visit. The area under the ROC curve (AUC) evaluating the accuracy of 6TGN levels for the diagnosis of clinical response for each monitoring point was less than 0.7. No cut-off point with useful sensitivity/specificity values was found, including 230 or 260 pmol/8 x 108 (that are commonly proposed in the literature). The AUC assessing the accuracy of the 6TGN determination at 2 weeks, 1, 2 or 4 months after starting AZA/MP to predict the response by the end of the follow-up was also less than 0.7. Once again, no useful cut-off point was found. Thiopurinic-related toxicity was detected in 9 cases (6.4%): No cases of hepatotoxicity were found, and only 3 cases of myelotoxicity were reported. No differences in 6TGN levels were found in patients suffering AZA-related toxicity. Specifically, 6TGN levels could not be related to the risk of developing myelotoxicity. Conclusions: Systematic quantification of thiopurinic metabolites (6TGN/ 6MMPR) in IBD patients receiving AZA/MP with the aim of predicting or assessing treatment response or safety cannot be recommended.