Scripties UMCG - Rijksuniversiteit Groningen
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6-Thioguanine: efficacy and safety in the management of inflammatory bowel disease

(2017) Broeders, A.S.

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.

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