Early prediction of thiopurine-induced hepatotoxicity in inflammatory bowel disease

Dennis 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; P M Hooymans

doi:10.1111/apt.13879

Early prediction of thiopurine-induced hepatotoxicity in inflammatory bowel disease

Dennis 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, P M Hooymans,

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

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 × 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

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10.1111/apt.13879

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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., 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{95248057638749d68f3cb3ff6ef274d2,

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

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 × 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.",

author = "Wong, {Dennis 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 H-J Guchelaar and {de Jong}, {D J} and Engels, {L G J B} and Verbeek, {A L M} and Hooymans, {P M}",

note = "Publisher Copyright: {\textcopyright} 2016 John Wiley & Sons Ltd",

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-Blackwell",

number = "3",

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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, 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, Dennis 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 - Hooymans, P M

PY - 2017/2

Y1 - 2017/2

N2 - 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 × 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.

AB - 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 × 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.

UR - http://www.scopus.com/inward/record.url?scp=85008244136&partnerID=8YFLogxK

U2 - 10.1111/apt.13879

DO - 10.1111/apt.13879

M3 - Article

C2 - 27943397

SN - 0269-2813

VL - 45

SP - 391

EP - 402

JO - Alimentary Pharmacology & Therapeutics

JF - Alimentary Pharmacology & Therapeutics

IS - 3

ER -

Early prediction of thiopurine-induced hepatotoxicity in inflammatory bowel disease

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