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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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ID 3552
Moeder ID 3463
Volgorde Broeders, A.S.
Naam BroedersAS
Publiceren yes
OAI-naam Student_thesis
Path root/geneeskunde/2017/BroedersAS/
Gemaakt op: 2017-08-22 08:36:45
Gemodificeerd op: 2017-08-22 08:36:45
Digitaal ID 599bed1e0d3b1
Afstudeerrichting opleiding/afstudeerrichting 1
Studierichting Studierichting 1
Titel 6-Thioguanine: efficacy and safety in the management of inflammatory bowel disease
Ruilverkeer mogelijk no
Printen in opdracht no
Aantal pagina's 29
Publicatiejaar 2017
Taal en
Engelse samenvatting 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.
Nederlandse samenvatting Achtergrond Inflammatoire darmziekten (IBD), waaronder de Ziekte van Crohn (ZvC),
colitis ulcerosa (CU) en indeterminate colitis (IC) vallen, is een chronische aandoening
gekarakteriseerd door langdurige ontsteking van het maagdarmkanaal. Bij de behandeling van
IBD worden vaak thiopurines toegepast zoals azathioprine (AZA), 6- mercaptopurine (6-MP)
en 6-thioguanine (6-TG). In bijna de helft van de patiënten behandeld met AZA of 6-MP
worden echter ernstige bijwerkingen gerapporteerd, wat bij 10-20% van de patiënten leidt tot
het staken van de behandeling. Een interessant alternatief lijkt behandelen met 6-TG; een stof
verderop in de enzymatische pathway en daarmee mogelijkerwijs leidend tot minder
bijwerkingen. Alhoewel de eerste resultaten veelbelovend waren werd dit enthousiasme
getemperd toen verschillende studies een verband tussen 6-TG gebruik en het optreden van
leverafwijkingen als nodulaire regeneratieve hyperplasie (NRH) aantoonden. Recentere
studies laten echter een dosis-afhankelijk effect zien tussen 6-TG en het optreden van NHR.
Uit voorafgaande onderzoeken blijkt dat er onduidelijkheid bestaat over de effectiviteit, lange
termijn veiligheid van 6-TG en de daadwerkelijke oorzaak en diagnose van NHR, waarvan de
interobserver correlatie slecht is en daarnaast ook voorkomt bij patiënten behandeld met
andere thiopurines en zelfs zonder thiopurine behandeling.
Het doel van deze studie is het onderzoeken van de effectiviteit en veiligheid van 6-TG
behandeling bij patiënten met IBD.
Materiaal en Methoden Alle patiënten die van Januari 2008 tot december 2016 in verband
met IBD zijn behandeld met 6-TG in het Deventer Ziekenhuis werden geïncludeerd in deze
retrospectieve studie. Patiënten werden geëxcludeerd bij twijfel over de therapietrouw of bij
onvoldoende documentatie over de effectiviteit danwel opgetreden bijwerkingen. Effectiviteit
van 6-TG werd bepaald door de individuele ziekte status gebaseerd op physician global
assessment (PGA) voor en tijdens 6-TG behandeling. Indien beschikbaar werd ook C-reactief
proteïne (CRP) en fecale calprotectine (FCP) gebruikt om de ziekteactiviteit te bepalen.
Secundaire uitkomstmaten waren het optreden van bijwerkingen, RBC 6-
thioguaninenucleotide (6-TGN) levels en laboratorium parameters.
Resultaten Zesennegentig patiënten voldeden aan de inclusiecriteria; 57 patiënten met de
Ziekte van Crohn, 31 met colitis ulcerosa en 8 met indeterminate colitis. De mediane duur van
de 6-TG behandeling was 27 maanden (range 1-109) en de gemiddelde dosis 0.27 ± 0.04
mg/kg/dag. Ziekte activiteit was verbeterd in 51%, 64% en 70% van de patiënten op maand 1,
3 en 6 respectievelijk, ten opzichte van de ziekteactiviteit voor behandeling met 6-TG.
Ontstekingsparameter FCP was significant lager na 6 maanden 6-TG wanneer vergeleken met
waarden voor 6-TG behandeling. 6-TG werd goed verdragen in 83 van de 96 patiënten (86%).
In totaal ontwikkelden 35 patiënten bijwerkingen tijdens behandeling met 6-TG, waarvan 16
gerelateerd of waarschijnlijk gerelateerd waren aan het gebruik van 6-TG. De meest
voorkomende bijwerkingen waren misselijkheid (4.2%), leucocytopenie (4.2%) en
hepatotoxiciteit (8.3%). Vrouwen ontwikkelden significant vaker bijwerkingen (OR 4.3; 95%
CI, 1.67-10.85; p = 0.002). Door het optreden van bijwerkingen stopten 13 van de 96 (14%)
patiënten met de behandeling. Bij 6 van deze patiënten werd 6-TG herstart, 2 patiënten
ontwikkelden opnieuw bijwerkingen. Mediane RBC 6-GN levels waren significant hoger in
de patiëntgroep met bijwerkingen in het algemeen (p = 0.034).
Conclusie Onze resultaten wijzen er op dat 6-TG een effectieve en goed verdragen
behandeloptie is bij patiënten met een inadequate reactie op andere thiopurines. Bij een
gemiddelde follow-up van meer dan twee jaar werden geen patiënten met klinische
leverziekte aangetroffen.
Onderwijsinstelling Medical Sciences
Type embargo abstract openbaar, scriptie op aanvraag
Auteur(s) Broeders, A.S.
Begeleider(s) opleidingsinstelling Supervisor; Borg, Dr. F. ter; Department of Gastroenterology and Hepatology, Deventer Hosp
Auteur(s) Broeders, A.S.


 
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