6-Thioguanine: efficacy and safety in the management of inflammatory bowel disease

Broeders, A.S. (2017) 6-Thioguanine: efficacy and safety in the management of inflammatory bowel disease. thesis, Medicine.

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Abstract

Background Inflammatory bowel disease (IBD), including Crohn’s disease (CD), ulcerative colitis (UC) and indeterminate colitis (IC), involves a group of diseases characterized by prolonged inflammation of the gastrointestinal tract. Different kinds of medications are used in the treatment of IBD including thiopurines as azathioprine (AZA), 6-mercaptopurine (6- MP) and 6-thioguanine (6-TG). However, in up to almost half of the patients treated with AZA or 6-MP serious adverse events are reported resulting in treatment cessation in 10-20% of the cases. 6-TG seems to be an interesting alternative since it’s metabolic pathway is less complicated and thereby less side products are generated. Although, the initial results of 6-TG treatment were very promising, its use was largely abandoned when several studies demonstrated a strong association between 6-TG and the occurrence of liver abnormalities as nodular regenerative hyperplasia (NHR). More recent studies demonstrated evidence for a dose-dependent effect. Overall, conflicting data exist about the efficacy and mainly long-term safety of 6-TG and the true cause and diagnosis of NRH, which has a poor interobserver correlation and is also found in patients treated with other thiopurines or even naïve for thiopurines. The aim of this study was to report our clinical experience with the efficacy and safety of 6-TG treatment in IBD patients. Material and Methods All patients attending the outpatient department of Deventer Hospital who were diagnosed with IBD and received 6-TG between January 2008 and September 2016 were included in this retrospective study. Patients were excluded if there was reasonable doubt about compliance or when documentation about efficacy or adverse events was insufficient. Efficacy of 6-TG was determined by the individual clinical disease status based on physician global assessment (PGA) before and during 6-TG treatment. Whenever available, C-reactive protein (CRP) and fecal calprotectin (FCP) levels were also used to determine disease activity. Secondary outcome measures included the occurrence of adverse events, RBC 6-thioguaninenucleotide (6-TGN) levels and laboratory parameters. Results Ninety-six patients fulfilled the inclusion criteria, 57 with Crohn’s disease, 31 with ulcerative colitis and 8 with indeterminate colitis. The median duration of 6-TG treatment was 27 months (range 1-109) and the mean dose was 0.27 ± 0.04 mg/kg/day. Disease activity improved in 51%, 64% and 70% of patients at month 1, 3 and 6 respectively, compared to that before 6-TG treatment. Inflammatory marker FCP was significantly lower after 6 months of 6-TG treatment compared to that before treatment. 6-TG was well tolerated in 83 of 96 patients (86%). In total, 35 patients developed adverse events during 6-TG treatment, of which 16 were related or probably related to the use of 6-TG. Most frequent adverse events were nausea (4.2%), leucocytopenia (4.2%) and hepatotoxicity (8.3%). Adverse events in general were statistically more common in women (OR 4.3; 95% CI, 1.67-10.85; p = 0.002). Overall, 13 of 96 (14%) patients had to discontinue 6-TG treatment due to adverse events. In 6 of these patients 6-TG treatment was reintroduced and 2 of them developed the adverse event again. Median RBC 6-TGN levels were significantly higher in the patient group with adverse events in general (p = 0.034). Conclusion Our experience indicates that 6-TG is an effective and well-tolerated treatment option in patients failing on the larger thiopurines. No patients with clinically overt liver disease were encountered during an average follow-up of more than two years.

Item Type:	Thesis (Thesis)
Supervisor name:	Supervisor and Borg, Dr. F. ter and Department of Gastroenterology and Hepatology, Deventer Hosp
Faculty:	Medical Sciences
Date Deposited:	25 Jun 2020 10:43
Last Modified:	25 Jun 2020 10:43
URI:	https://umcg.studenttheses.ub.rug.nl/id/eprint/466

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