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PWE-093 Splitting The Normal Daily Dose Of Thioguanine May Be Efficacious Treatment For Inflammatory Bowel Disease And Avoid Hepatic Toxicity
  1. P Pavlidis1,
  2. A Ansari1,
  3. J Duley2,
  4. I Oancea3,
  5. T Florin4
  1. 1Digestive Diseases, Surrey and Sussex Healthcare NHS Trust, East Surrey Hospital, Redhill, UK
  2. 2Pharmacy, University of Queensland, Woolloongabba, Australia
  3. 3Translational Research Institute, Immunity, Infection, and Inflammation Program, Mater Research Institute, University of Queensland, Woolloongabba, Australia
  4. 4Mater Research Institute, University of Queensland, South Brisbane, Australia

Abstract

Introduction 6-thioguanine (TG) is a treatment for inflammatory bowel disease (IBD). However, its association with nodular regenerative hyperplasia (NRH) and portal hypertension has restricted its utilisation. A murine model has provided evidence that splitting a normal daily dose of TG could prevent exposure of the liver to harmful levels of TG; furthermore safety has not been an issue in human studies with low dose TG.

Methods We report from two centres on a retrospective experience of the safety and efficacy of an oral split-daily TG dose regimen, to avoid any individual dose >0.3 mg/kg, in 62 IBD patients who were unresponsive or had suffered adverse drug reactions to conventional therapies including thiopurines (60), biologics (18) and calcineurin inhibitors (17). Clinical response was measured using the Harvey Bradshaw Index for Crohn’s, or the Simple Clinical Colitis Score for ulcerative and indeterminate colitis. Patients were followed regularly in clinic with bloods, liver biopsy (9) and progress ultrasound at 6 months (21) or MR imaging (2).

Results Median duration of TG treatment was 7.8 (0.3–45) months. Median TG dose used was 0.6 (0.3–1) mg/kg/d. Of patients attaining 6 months of TG therapy, 91% (19/21) of Crohn’s patients and 71% (27/38) with ulcerative or indeterminate colitis had a clinically significant response, off steroids. At study end, 33 (53%) patients maintained their good clinical response off steroids; 12 of these had continued with concomitant biologic or calcineurin inhibitor therapy.

Previous thiopurine-related adverse reactions were not encountered. 29 (47%) patients withdrew from the study because of loss to follow-up (5), medical adverse events (2) or surgery (22). Possible early NRH was found on liver biopsy in 1 patient who was heterozygote-deficient for thiopurine methyltransferase (TPMT); the patient continued TG at a lower dose. TG was discontinued in a patient found to have NRH and concomitant anti-phospholipid syndrome. There was one successful term pregnancy; cord blood and breast milk TG were low.

Conclusion A split-dose regimen of TG appeared well-tolerated, efficacious and safe for selected IBD patients. Close monitoring, knowledge of TPMT and exclusion of risk factors for NRH prior to treatment are warranted to maximise safety.

References Dubinsky MC, Vasiliauskas EA, Singh H, et al. 6-thioguanine can cause serious liver injury in inflammatory bowel disease patients. Gastroenterology 2003:125:298–303

Oancea I, Png CW, Das I, et al. A novel mouse model of veno-occlusive disease provides strategies to prevent thioguanine-induced hepatic toxicity. Gut 2013:62:594–605

Disclosure of Interest None Declared.

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