title: Splitting a therapeutic dose of thioguanine may avoid liver toxicity and be an efficacious treatment for severe inflammatory bowel disease: a 2-center observational cohort study.
abstract: BACKGROUND
  Thioguanine (TG) is a treatment for inflammatory bowel disease, but association with nodular regenerative hyperplasia has restricted its use. We conjectured that splitting a therapeutic daily dose of TG would be efficacious and should avoid liver toxicity.
  
  
  METHODS
  We report on 62 patients with severe inflammatory bowel disease not responding to prednisolone, conventional thiopurines, biologics, or calcineurin inhibitors. Patients were prescribed oral split-daily TG to avoid individual doses >0.3 mg/kg. Data on concomitant medication, clinical efficacy measured by Harvey-Bradshaw Index for Crohn's, or Simple Clinical Colitis Score for ulcerative/indeterminate colitis (UC), and some paired endoscopies were available. Safety was followed clinically and with bloods at 2 centers. All patients at the U.K. center had a liver biopsy or magnetic resonance imaging after 6 months. Twenty-one patients had serial ultrasounds at the Australian center.
  
  
  RESULTS
  At 6 months, 19/21 of patients with Crohn's disease and 27/38 with ulcerative colitis had improved clinical activity. At study end, 53% of patients maintained improved clinical activity of steroids. Median duration of TG was 8 (0.3-45) months, median dose was 0.6 (0.3-1) mg/kg per day. Previous thiopurine-related adverse reactions were not encountered. Twenty-nine patients withdrew because of loss to follow-up, medical adverse events, or surgery. Possible early nodular regenerative hyperplasia was found on liver biopsy in 1 patient who was heterozygote deficient for thiopurine methyltransferase; the TG dose was lowered. TG was discontinued in a patient with nodular regenerative hyperplasia and concomitant antiphospholipid syndrome. There was 1 successful term pregnancy; cord blood and breast milk TG were low.
  
  
  CONCLUSIONS
  Split-dose TG seemed well tolerated and efficacious in this retrospective study of patients with difficult inflammatory bowel disease.
authors.affiliation: *Department for Digestive Diseases, Surrey and Sussex Healthcare NHS Trust, East Surrey Hospital, Redhill, United Kingdom; †Mater Research Institute, University of Queensland, Woolloongabba, Australia; ‡Mater Pathology Service, South Brisbane, Australia; and §Department of Gastroenterology, Mater Health Services, South Brisbane, Australia.
authors.forename: Polychronis
authors.initials: P
authors.lastname: Pavlidis
authors.forename: Azhar
authors.initials: A
authors.lastname: Ansari
authors.forename: John
authors.initials: J
authors.lastname: Duley
authors.forename: Iulia
authors.initials: I
authors.lastname: Oancea
authors.forename: Timothy
authors.initials: T
authors.lastname: Florin
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000473:pathology; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006965:Hyperplasia / Q000188:drug therapy* / Q000473:pathology; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012720:Severity of Illness Index; D013866:Thioguanine / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D000964:Antimetabolites, Antineoplastic; D013866:Thioguanine