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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.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.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.Split-dose TG seemed well tolerated and efficacious in this retrospective study of patients with difficult inflammatory bowel disease.