Early prediction of thiopurine-induced hepatotoxicity in inflammatory bowel disease

D. R. Wong; M. J. H. Coenen; L. J. J. Derijks; S. H. Vermeulen; C. J. van  Marrewijk; O. H. Klungel; H. Scheffer; B. Franke; H. -J. Guchelaar; D. J. de  Jong; L. G. J. B. Engels; A. L. M. Verbeek; TOPIC Recruitment Team; Ad Masclee; P. M. Hooymans

doi:10.1111/apt.13879

Early prediction of thiopurine-induced hepatotoxicity in inflammatory bowel disease

D. R. Wong^*, M. J. H. Coenen, L. J. J. Derijks, S. H. Vermeulen, C. J. van Marrewijk, O. H. Klungel, H. Scheffer, B. Franke, H. -J. Guchelaar, D. J. de Jong, L. G. J. B. Engels, A. L. M. Verbeek, TOPIC Recruitment Team, Ad Masclee, P. M. Hooymans

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

24 Citations (Web of Science)

Abstract

Background

Hepatotoxicity, gastrointestinal complaints and general malaise are common limiting adverse reactions of azathioprine and mercaptopurine in IBD patients, often related to high steady-state 6-methylmercaptopurine ribonucleotide (6-MMPR) metabolite concentrations.

Aim

To determine the predictive value of 6-MMPR concentrations 1 week after treatment initiation (T1) for the development of these adverse reactions, especially hepatotoxicity, during the first 20 weeks of treatment.

Methods

The cohort study consisted of the first 270 IBD patients starting thiopurine treatment as part of the Dutch randomised-controlled trial evaluating pre-treatment thiopurine S-methyltransferase genotype testing (ClinicalTrials.gov NCT00521950). Blood samples for metabolite assessment were collected at T1. Hepatotoxicity was defined by alanine aminotransaminase elevations >2 times the upper normal limit or a ratio of alanine aminotransaminase/alkaline phosphatase >= 5.

Results

Forty-seven patients (17%) presented hepatotoxicity during the first 20 weeks of thiopurine treatment. A T1 6-MMPR threshold of 3615 pmol/8 x 10(8) erythrocytes was defined. Analysis of patients on stable thiopurine dose (n = 174) showed that those exceeding the 6-MMPR threshold were at increased risk of hepatotoxicity: OR = 3.8 (95% CI: 1.8-8.0). Age, male gender and BMI were significant determinants. A predictive algorithm was developed based on these determinants and the 6-MMPR threshold to assess hepatotoxicity risk [AUC = 0.83 (95% CI: 0.75-0.91)]. 6-MMPR concentrations above the threshold also correlated with gastrointestinal complaints: OR = 2.4 (95% CI: 1.4-4.3), and general malaise: OR = 2.0 (95% CI: 1.1-3.7).

Conclusions

In more than 80% of patients, thiopurine-induced hepatotoxicity could be explained by elevated T1 6-MMPR concentrations and the independent risk factors age, gender and BMI, allowing personalised thiopurine treatment in IBD to prevent early failure.

Original language	English
Pages (from-to)	391-402
Number of pages	12
Journal	Alimentary Pharmacology & Therapeutics
Volume	45
Issue number	3
DOIs	https://doi.org/10.1111/apt.13879
Publication status	Published - Feb 2017

Keywords

INDUCED LIVER-INJURY
S-METHYLTRANSFERASE ACTIVITY
AZATHIOPRINE
THERAPY
PHARMACOGENETICS
6-MERCAPTOPURINE
MERCAPTOPURINE
6-THIOGUANINE
PHARMACOKINETICS
ALLOPURINOL

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10.1111/apt.13879

Cite this

Wong, D. R., Coenen, M. J. H., Derijks, L. J. J., Vermeulen, S. H., van Marrewijk, C. J., Klungel, O. H., Scheffer, H., Franke, B., Guchelaar, H. -J., de Jong, D. J., Engels, L. G. J. B., Verbeek, A. L. M., TOPIC Recruitment Team, Masclee, A., & Hooymans, P. M. (2017). Early prediction of thiopurine-induced hepatotoxicity in inflammatory bowel disease. Alimentary Pharmacology & Therapeutics, 45(3), 391-402. https://doi.org/10.1111/apt.13879

@article{86066f25a2224a528d2776358e5f09a3,

title = "Early prediction of thiopurine-induced hepatotoxicity in inflammatory bowel disease",

abstract = "BackgroundHepatotoxicity, gastrointestinal complaints and general malaise are common limiting adverse reactions of azathioprine and mercaptopurine in IBD patients, often related to high steady-state 6-methylmercaptopurine ribonucleotide (6-MMPR) metabolite concentrations.AimTo determine the predictive value of 6-MMPR concentrations 1 week after treatment initiation (T1) for the development of these adverse reactions, especially hepatotoxicity, during the first 20 weeks of treatment.MethodsThe cohort study consisted of the first 270 IBD patients starting thiopurine treatment as part of the Dutch randomised-controlled trial evaluating pre-treatment thiopurine S-methyltransferase genotype testing (ClinicalTrials.gov NCT00521950). Blood samples for metabolite assessment were collected at T1. Hepatotoxicity was defined by alanine aminotransaminase elevations >2 times the upper normal limit or a ratio of alanine aminotransaminase/alkaline phosphatase >= 5.ResultsForty-seven patients (17%) presented hepatotoxicity during the first 20 weeks of thiopurine treatment. A T1 6-MMPR threshold of 3615 pmol/8 x 10(8) erythrocytes was defined. Analysis of patients on stable thiopurine dose (n = 174) showed that those exceeding the 6-MMPR threshold were at increased risk of hepatotoxicity: OR = 3.8 (95% CI: 1.8-8.0). Age, male gender and BMI were significant determinants. A predictive algorithm was developed based on these determinants and the 6-MMPR threshold to assess hepatotoxicity risk [AUC = 0.83 (95% CI: 0.75-0.91)]. 6-MMPR concentrations above the threshold also correlated with gastrointestinal complaints: OR = 2.4 (95% CI: 1.4-4.3), and general malaise: OR = 2.0 (95% CI: 1.1-3.7).ConclusionsIn more than 80% of patients, thiopurine-induced hepatotoxicity could be explained by elevated T1 6-MMPR concentrations and the independent risk factors age, gender and BMI, allowing personalised thiopurine treatment in IBD to prevent early failure.",

keywords = "INDUCED LIVER-INJURY, S-METHYLTRANSFERASE ACTIVITY, AZATHIOPRINE, THERAPY, PHARMACOGENETICS, 6-MERCAPTOPURINE, MERCAPTOPURINE, 6-THIOGUANINE, PHARMACOKINETICS, ALLOPURINOL",

author = "Wong, {D. R.} and Coenen, {M. J. H.} and Derijks, {L. J. J.} and Vermeulen, {S. H.} and {van Marrewijk}, {C. J.} and Klungel, {O. H.} and H. Scheffer and B. Franke and Guchelaar, {H. -J.} and {de Jong}, {D. J.} and Engels, {L. G. J. B.} and Verbeek, {A. L. M.} and {TOPIC Recruitment Team} and Ad Masclee and Hooymans, {P. M.}",

year = "2017",

month = feb,

doi = "10.1111/apt.13879",

language = "English",

volume = "45",

pages = "391--402",

journal = "Alimentary Pharmacology & Therapeutics",

issn = "0269-2813",

publisher = "Wiley",

number = "3",

}

Wong, DR, Coenen, MJH, Derijks, LJJ, Vermeulen, SH, van Marrewijk, CJ, Klungel, OH, Scheffer, H, Franke, B, Guchelaar, H-J, de Jong, DJ, Engels, LGJB, Verbeek, ALM, TOPIC Recruitment Team, Masclee, A & Hooymans, PM 2017, 'Early prediction of thiopurine-induced hepatotoxicity in inflammatory bowel disease', Alimentary Pharmacology & Therapeutics, vol. 45, no. 3, pp. 391-402. https://doi.org/10.1111/apt.13879

TY - JOUR

T1 - Early prediction of thiopurine-induced hepatotoxicity in inflammatory bowel disease

AU - Wong, D. R.

AU - Coenen, M. J. H.

AU - Derijks, L. J. J.

AU - Vermeulen, S. H.

AU - van Marrewijk, C. J.

AU - Klungel, O. H.

AU - Scheffer, H.

AU - Franke, B.

AU - Guchelaar, H. -J.

AU - de Jong, D. J.

AU - Engels, L. G. J. B.

AU - Verbeek, A. L. M.

AU - TOPIC Recruitment Team

AU - Masclee, Ad

AU - Hooymans, P. M.

PY - 2017/2

Y1 - 2017/2

N2 - BackgroundHepatotoxicity, gastrointestinal complaints and general malaise are common limiting adverse reactions of azathioprine and mercaptopurine in IBD patients, often related to high steady-state 6-methylmercaptopurine ribonucleotide (6-MMPR) metabolite concentrations.AimTo determine the predictive value of 6-MMPR concentrations 1 week after treatment initiation (T1) for the development of these adverse reactions, especially hepatotoxicity, during the first 20 weeks of treatment.MethodsThe cohort study consisted of the first 270 IBD patients starting thiopurine treatment as part of the Dutch randomised-controlled trial evaluating pre-treatment thiopurine S-methyltransferase genotype testing (ClinicalTrials.gov NCT00521950). Blood samples for metabolite assessment were collected at T1. Hepatotoxicity was defined by alanine aminotransaminase elevations >2 times the upper normal limit or a ratio of alanine aminotransaminase/alkaline phosphatase >= 5.ResultsForty-seven patients (17%) presented hepatotoxicity during the first 20 weeks of thiopurine treatment. A T1 6-MMPR threshold of 3615 pmol/8 x 10(8) erythrocytes was defined. Analysis of patients on stable thiopurine dose (n = 174) showed that those exceeding the 6-MMPR threshold were at increased risk of hepatotoxicity: OR = 3.8 (95% CI: 1.8-8.0). Age, male gender and BMI were significant determinants. A predictive algorithm was developed based on these determinants and the 6-MMPR threshold to assess hepatotoxicity risk [AUC = 0.83 (95% CI: 0.75-0.91)]. 6-MMPR concentrations above the threshold also correlated with gastrointestinal complaints: OR = 2.4 (95% CI: 1.4-4.3), and general malaise: OR = 2.0 (95% CI: 1.1-3.7).ConclusionsIn more than 80% of patients, thiopurine-induced hepatotoxicity could be explained by elevated T1 6-MMPR concentrations and the independent risk factors age, gender and BMI, allowing personalised thiopurine treatment in IBD to prevent early failure.

AB - BackgroundHepatotoxicity, gastrointestinal complaints and general malaise are common limiting adverse reactions of azathioprine and mercaptopurine in IBD patients, often related to high steady-state 6-methylmercaptopurine ribonucleotide (6-MMPR) metabolite concentrations.AimTo determine the predictive value of 6-MMPR concentrations 1 week after treatment initiation (T1) for the development of these adverse reactions, especially hepatotoxicity, during the first 20 weeks of treatment.MethodsThe cohort study consisted of the first 270 IBD patients starting thiopurine treatment as part of the Dutch randomised-controlled trial evaluating pre-treatment thiopurine S-methyltransferase genotype testing (ClinicalTrials.gov NCT00521950). Blood samples for metabolite assessment were collected at T1. Hepatotoxicity was defined by alanine aminotransaminase elevations >2 times the upper normal limit or a ratio of alanine aminotransaminase/alkaline phosphatase >= 5.ResultsForty-seven patients (17%) presented hepatotoxicity during the first 20 weeks of thiopurine treatment. A T1 6-MMPR threshold of 3615 pmol/8 x 10(8) erythrocytes was defined. Analysis of patients on stable thiopurine dose (n = 174) showed that those exceeding the 6-MMPR threshold were at increased risk of hepatotoxicity: OR = 3.8 (95% CI: 1.8-8.0). Age, male gender and BMI were significant determinants. A predictive algorithm was developed based on these determinants and the 6-MMPR threshold to assess hepatotoxicity risk [AUC = 0.83 (95% CI: 0.75-0.91)]. 6-MMPR concentrations above the threshold also correlated with gastrointestinal complaints: OR = 2.4 (95% CI: 1.4-4.3), and general malaise: OR = 2.0 (95% CI: 1.1-3.7).ConclusionsIn more than 80% of patients, thiopurine-induced hepatotoxicity could be explained by elevated T1 6-MMPR concentrations and the independent risk factors age, gender and BMI, allowing personalised thiopurine treatment in IBD to prevent early failure.

KW - INDUCED LIVER-INJURY

KW - S-METHYLTRANSFERASE ACTIVITY

KW - AZATHIOPRINE

KW - THERAPY

KW - PHARMACOGENETICS

KW - 6-MERCAPTOPURINE

KW - MERCAPTOPURINE

KW - 6-THIOGUANINE

KW - PHARMACOKINETICS

KW - ALLOPURINOL

U2 - 10.1111/apt.13879

DO - 10.1111/apt.13879

M3 - Article

C2 - 27943397

VL - 45

SP - 391

EP - 402

JO - Alimentary Pharmacology & Therapeutics

JF - Alimentary Pharmacology & Therapeutics

SN - 0269-2813

IS - 3

ER -