Sustained effectiveness, safety and therapeutic drug monitoring of tioguanine in a cohort of 274 IBD patients intolerant for conventional therapies

Melek Simsek, Debbie S. Deben, Carmen S. Horjus, Melanie V. Bénard, Birgit I. Lissenberg-Witte, Hans J.C. Buiter, Matthijs van Luin, Margien L. Seinen, Chris J.J. Mulder, Dennis R. Wong, Nanne K.H. de Boer, Adriaan A. van Bodegraven

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Background: Tioguanine (or thioguanine) is an alternative drug for IBD patients who fail prior conventional immunomodulating therapy. Aim: To report effectiveness, safety and therapeutic drug monitoring in a cohort of patients with prolonged tioguanine maintenance therapy. Methods: In this nationwide, multicentre study, medical records of tioguanine- using IBD patients were retrospectively reviewed. Response to therapy was defined as clinical effectiveness without (re)initiation of corticosteroids, concurrent biological therapy or surgical intervention. All adverse events that occurred during the follow-up were listed and graded according to the common terminology criteria (CTC). Results: Two hundred and seventy-four patients (female 63%, Crohn's disease in 68%) were included with median treatment duration of 51 months, 1567 patient-years of follow-up and median 20 mg/d tioguanine dosage. Tioguanine was tolerated in 79%, clinical effectiveness at 6 months was documented in 66% and sustained clinical effectiveness during 12 months in 51% of patients. Forty-one per cent of patients developed adverse events: 5% were graded as severe. Adverse events comprised infection requiring hospitalisation in three and skin cancer in eight patients (two melanomas). Asymptomatic nodular regenerative hyperplasia of the liver occurred in two out of 52 patients with liver biopsies (3.8%) and portal hypertension in three whereof one potentially associated with tioguanine (0.4%). Clinical effectiveness was correlated with 6-thioguanine nucleotide threshold concentrations >682 pmol/8×108RBC (P < 0.05). Conclusions: Long-term tioguanine therapy for at least 12 months was effective in 51% and well tolerated as a maintenance treatment for IBD in about 70% of patients. Adverse events were common, but mainly mild or moderate. 6-Thioguanine nucleotide threshold concentration ≥ 700 pmol/8×108RBC is proposed as target level with higher odds for clinical effectiveness.

Original languageEnglish
Pages (from-to)54-65
Number of pages12
JournalAlimentary Pharmacology and Therapeutics
Volume50
Issue number1
DOIs
Publication statusPublished - 1 Jul 2019

Cite this

@article{f3ad6ac9e8e946bb885ad0b09ece11c7,
title = "Sustained effectiveness, safety and therapeutic drug monitoring of tioguanine in a cohort of 274 IBD patients intolerant for conventional therapies",
abstract = "Background: Tioguanine (or thioguanine) is an alternative drug for IBD patients who fail prior conventional immunomodulating therapy. Aim: To report effectiveness, safety and therapeutic drug monitoring in a cohort of patients with prolonged tioguanine maintenance therapy. Methods: In this nationwide, multicentre study, medical records of tioguanine- using IBD patients were retrospectively reviewed. Response to therapy was defined as clinical effectiveness without (re)initiation of corticosteroids, concurrent biological therapy or surgical intervention. All adverse events that occurred during the follow-up were listed and graded according to the common terminology criteria (CTC). Results: Two hundred and seventy-four patients (female 63{\%}, Crohn's disease in 68{\%}) were included with median treatment duration of 51 months, 1567 patient-years of follow-up and median 20 mg/d tioguanine dosage. Tioguanine was tolerated in 79{\%}, clinical effectiveness at 6 months was documented in 66{\%} and sustained clinical effectiveness during 12 months in 51{\%} of patients. Forty-one per cent of patients developed adverse events: 5{\%} were graded as severe. Adverse events comprised infection requiring hospitalisation in three and skin cancer in eight patients (two melanomas). Asymptomatic nodular regenerative hyperplasia of the liver occurred in two out of 52 patients with liver biopsies (3.8{\%}) and portal hypertension in three whereof one potentially associated with tioguanine (0.4{\%}). Clinical effectiveness was correlated with 6-thioguanine nucleotide threshold concentrations >682 pmol/8×108RBC (P < 0.05). Conclusions: Long-term tioguanine therapy for at least 12 months was effective in 51{\%} and well tolerated as a maintenance treatment for IBD in about 70{\%} of patients. Adverse events were common, but mainly mild or moderate. 6-Thioguanine nucleotide threshold concentration ≥ 700 pmol/8×108RBC is proposed as target level with higher odds for clinical effectiveness.",
author = "Melek Simsek and Deben, {Debbie S.} and Horjus, {Carmen S.} and B{\'e}nard, {Melanie V.} and Lissenberg-Witte, {Birgit I.} and Buiter, {Hans J.C.} and {van Luin}, Matthijs and Seinen, {Margien L.} and Mulder, {Chris J.J.} and Wong, {Dennis R.} and {de Boer}, {Nanne K.H.} and {van Bodegraven}, {Adriaan A.}",
year = "2019",
month = "7",
day = "1",
doi = "10.1111/apt.15280",
language = "English",
volume = "50",
pages = "54--65",
journal = "Alimentary Pharmacology and Therapeutics",
issn = "0269-2813",
number = "1",

}

Sustained effectiveness, safety and therapeutic drug monitoring of tioguanine in a cohort of 274 IBD patients intolerant for conventional therapies. / Simsek, Melek; Deben, Debbie S.; Horjus, Carmen S.; Bénard, Melanie V.; Lissenberg-Witte, Birgit I.; Buiter, Hans J.C.; van Luin, Matthijs; Seinen, Margien L.; Mulder, Chris J.J.; Wong, Dennis R.; de Boer, Nanne K.H.; van Bodegraven, Adriaan A.

In: Alimentary Pharmacology and Therapeutics, Vol. 50, No. 1, 01.07.2019, p. 54-65.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Sustained effectiveness, safety and therapeutic drug monitoring of tioguanine in a cohort of 274 IBD patients intolerant for conventional therapies

AU - Simsek, Melek

AU - Deben, Debbie S.

AU - Horjus, Carmen S.

AU - Bénard, Melanie V.

AU - Lissenberg-Witte, Birgit I.

AU - Buiter, Hans J.C.

AU - van Luin, Matthijs

AU - Seinen, Margien L.

AU - Mulder, Chris J.J.

AU - Wong, Dennis R.

AU - de Boer, Nanne K.H.

AU - van Bodegraven, Adriaan A.

PY - 2019/7/1

Y1 - 2019/7/1

N2 - Background: Tioguanine (or thioguanine) is an alternative drug for IBD patients who fail prior conventional immunomodulating therapy. Aim: To report effectiveness, safety and therapeutic drug monitoring in a cohort of patients with prolonged tioguanine maintenance therapy. Methods: In this nationwide, multicentre study, medical records of tioguanine- using IBD patients were retrospectively reviewed. Response to therapy was defined as clinical effectiveness without (re)initiation of corticosteroids, concurrent biological therapy or surgical intervention. All adverse events that occurred during the follow-up were listed and graded according to the common terminology criteria (CTC). Results: Two hundred and seventy-four patients (female 63%, Crohn's disease in 68%) were included with median treatment duration of 51 months, 1567 patient-years of follow-up and median 20 mg/d tioguanine dosage. Tioguanine was tolerated in 79%, clinical effectiveness at 6 months was documented in 66% and sustained clinical effectiveness during 12 months in 51% of patients. Forty-one per cent of patients developed adverse events: 5% were graded as severe. Adverse events comprised infection requiring hospitalisation in three and skin cancer in eight patients (two melanomas). Asymptomatic nodular regenerative hyperplasia of the liver occurred in two out of 52 patients with liver biopsies (3.8%) and portal hypertension in three whereof one potentially associated with tioguanine (0.4%). Clinical effectiveness was correlated with 6-thioguanine nucleotide threshold concentrations >682 pmol/8×108RBC (P < 0.05). Conclusions: Long-term tioguanine therapy for at least 12 months was effective in 51% and well tolerated as a maintenance treatment for IBD in about 70% of patients. Adverse events were common, but mainly mild or moderate. 6-Thioguanine nucleotide threshold concentration ≥ 700 pmol/8×108RBC is proposed as target level with higher odds for clinical effectiveness.

AB - Background: Tioguanine (or thioguanine) is an alternative drug for IBD patients who fail prior conventional immunomodulating therapy. Aim: To report effectiveness, safety and therapeutic drug monitoring in a cohort of patients with prolonged tioguanine maintenance therapy. Methods: In this nationwide, multicentre study, medical records of tioguanine- using IBD patients were retrospectively reviewed. Response to therapy was defined as clinical effectiveness without (re)initiation of corticosteroids, concurrent biological therapy or surgical intervention. All adverse events that occurred during the follow-up were listed and graded according to the common terminology criteria (CTC). Results: Two hundred and seventy-four patients (female 63%, Crohn's disease in 68%) were included with median treatment duration of 51 months, 1567 patient-years of follow-up and median 20 mg/d tioguanine dosage. Tioguanine was tolerated in 79%, clinical effectiveness at 6 months was documented in 66% and sustained clinical effectiveness during 12 months in 51% of patients. Forty-one per cent of patients developed adverse events: 5% were graded as severe. Adverse events comprised infection requiring hospitalisation in three and skin cancer in eight patients (two melanomas). Asymptomatic nodular regenerative hyperplasia of the liver occurred in two out of 52 patients with liver biopsies (3.8%) and portal hypertension in three whereof one potentially associated with tioguanine (0.4%). Clinical effectiveness was correlated with 6-thioguanine nucleotide threshold concentrations >682 pmol/8×108RBC (P < 0.05). Conclusions: Long-term tioguanine therapy for at least 12 months was effective in 51% and well tolerated as a maintenance treatment for IBD in about 70% of patients. Adverse events were common, but mainly mild or moderate. 6-Thioguanine nucleotide threshold concentration ≥ 700 pmol/8×108RBC is proposed as target level with higher odds for clinical effectiveness.

UR - http://www.scopus.com/inward/record.url?scp=85066996013&partnerID=8YFLogxK

U2 - 10.1111/apt.15280

DO - 10.1111/apt.15280

M3 - Article

VL - 50

SP - 54

EP - 65

JO - Alimentary Pharmacology and Therapeutics

JF - Alimentary Pharmacology and Therapeutics

SN - 0269-2813

IS - 1

ER -