Systematic review: The effectiveness of 6-thioguanine nucleotide-based dose optimisation of thiopurines in the treatment of inflammatory bowel disease

Introduction: Clinical guidelines highlight the potential utility of metabolite-based thiopurine dose optimisation strategies in inflammatory bowel disease (IBD). The aim of this review was to summarise the evidence of effectiveness and safety of a 6-thioguanine nucleotide (6-TGN) metabolite-based dosing strategy for maintenance of remission using azathioprine or mercaptopurine in Crohn's disease and ulcerative colitis. Methods: We searched the Cochrane central register of controlled trials, EMBASE, clinicaltrials.gov, the WHO international clinical trials registry platform, and relevant grey literature, up to 1 December 2021. Inclusion criteria were: all randomised (active comparator) controlled trials of azathioprine or mercaptopurine used for the purposes of maintenance of remission in Crohn's disease or ulcerative colitis where the dose in the intervention arm was optimised based on 6-TGN metabolite assay results. Studies of any duration were eligible for inclusion, and no age restrictions were applied. Results: No studies met the eligibility criteria for this review. Four randomised controlled studies (two of which are currently underway) were identified that assessed the effectiveness of metabolite-based dose optimisation for thiopurine therapy, but were not eligible either because they did not differentiate between induction and maintenance therapy or because of a lack of an appropriate active comparator. Conclusions: There is no RCT-based evidence for dose optimisation using a 6-TGN metabolite-based dosing strategy for maintenance of remission in Crohn's disease or ulcerative colitis. Where evidence is available from combination induction and maintenance trials, it suggests that such a strategy is no better than weight-based dosing. Cochrane protocol registration: CD014795