Current status and future perspectives on the use of therapeutic drug monitoring of thiopurine metabolites in patients with inflammatory bowel disease

References

• Kaplan GG, Windsor JW. The four epidemiological stages in the global evolution of inflammatory bowel disease. Nat Rev Gastroenterol Hepatol. 2021 Jan;18(1):56–66.
   PubMed Web of Science ®Google Scholar
• Kotze PG, Underwood FE, Damião AOMC, et al. Progression of inflammatory bowel diseases throughout latin america and the Caribbean: a systematic review. Clin Gastroenterol Hepatol. 2020 Feb;18(2):304–312.
   PubMed Web of Science ®Google Scholar
• Ng SC, Shi HY, Hamidi N, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet. 2017 Dec 23;390(10114):2769–2778.
   PubMed Web of Science ®Google Scholar
• de Boer NKH, Thiopurine Working Group. Thiopurine therapy in inflammatory bowel diseases: making new friends should not mean losing old ones. Gastroenterology. 2019 Jan; 156(1):11–14.
   PubMed Web of Science ®Google Scholar
• de Boer NKH, Peyrin-Biroulet L, Jharap B, et al. Thiopurines in inflammatory bowel disease: new findings and perspectives. J Crohns Colitis. 2018 Apr 27;12(5):610–620.
   PubMed Web of Science ®Google Scholar
• Panaccione R, Ghosh S, Middleton S, et al. Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis. Gastroenterology. 2014 Feb;146(2):392,400.e3.
   Web of Science ®Google Scholar
• Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med. 2010 Apr 15;362(15):1383–1395.
   PubMed Web of Science ®Google Scholar
• Privitera G, Pugliese D, Onali S, et al. Combination therapy in inflammatory bowel disease - from traditional immunosuppressors towards the new paradigm of dual targeted therapy. Autoimmun Rev. 2021 Apr 15;20(6):102832.
   PubMed Web of Science ®Google Scholar
• Prefontaine E, Macdonald JK, Sutherland LR. Azathioprine or 6-mercaptopurine for induction of remission in Crohn’s disease. Cochrane Database Syst Rev. 2010 Jun 16;(6):CD000545 doi:https://doi.org/10.1002/14651858.CD000545.
   Google Scholar
• Gisbert JP, Linares PM, McNicholl AG, et al. Meta-analysis: the efficacy of azathioprine and mercaptopurine in ulcerative colitis. Aliment Pharmacol Ther. 2009 Jul 1;30(2):126–137.
   PubMed Web of Science ®Google Scholar
• Jharap B, Seinen ML, de Boer NK, et al. Thiopurine therapy in inflammatory bowel disease patients: analyses of two 8-year intercept cohorts. Inflamm Bowel Dis. 2010 Sep;16(9):1541–1549.
   PubMed Web of Science ®Google Scholar
• Chaparro M, Ordás I, Cabré E, et al. Safety of thiopurine therapy in inflammatory bowel disease: long-term follow-up study of 3931 patients. Inflamm Bowel Dis. 2013 Jun;19(7):1404–1410.
   PubMed Web of Science ®Google Scholar
• Meijer B, Mulder CJ, van Bodegraven AA, et al. How I treat my inflammatory bowel disease-patients with thiopurines? World J Gastrointest Pharmacol Ther. 2016 Nov 6;7(4):524–530.
   PubMedGoogle Scholar
• TDM mongrafie thiopurines [Internet]. 2018. Available from: https://tdm-monografie.org/monografie/thiopurines, website accessed on: Sep 2021.
   Google Scholar
• Feuerstein JD, Nguyen GC, Kupfer SS, et al. American gastroenterological association institute clinical guidelines committee. American gastroenterological association institute guideline on therapeutic drug monitoring in inflammatory bowel disease. Gastroenterology. 2017 Sep;153(3):827–834.
   PubMed Web of Science ®Google Scholar
• Gionchetti P, Dignass A, Danese S, et al. 3rd European evidence-based consensus on the diagnosis and management of Crohn’s disease 2016: part 2: surgical management and special situations. J Crohns Colitis. 2017 Feb;11(2):135–149.
   PubMed Web of Science ®Google Scholar
• Khan A, Berahmana AB, Day AS, et al. New Zealand Society of Gastroenterology guidelines on therapeutic drug monitoring in inflammatory bowel disease. N Z Med J. 2019 Mar 8;132(1491):46–62.
   PubMed Web of Science ®Google Scholar
• Lega S, Bramuzzo M, Dubinsky MC. Therapeutic drug monitoring in pediatric IBD: current application and future perspectives. Curr Med Chem. 2018;25(24):2840–2854.
   PubMed Web of Science ®Google Scholar
• Spencer EA, Dubinsky MC. Therapeutic drug monitoring in inflammatory bowel disease: history and future directions. Pediatr Clin North Am. 2017 Dec;64(6):1309–1326.
   PubMed Web of Science ®Google Scholar
• Lee SD, Shivashankar R, Quirk D, et al. Therapeutic drug monitoring for current and investigational inflammatory bowel disease treatments. J Clin Gastroenterol. 2021 Mar 1;55(3):195–206.
   PubMed Web of Science ®Google Scholar
• Seinen ML, De Boer NK, van Bodegraven AA. Key insights from therapeutic drug monitoring in Crohn’s disease patients. Expert Opin Drug Metab Toxicol. 2019 May;15(5):399–406.
   PubMed Web of Science ®Google Scholar
• Derijks LJ, Gilissen LP, Engels LG, et al. Pharmacokinetics of 6-mercaptopurine in patients with inflammatory bowel disease: implications for therapy. Ther Drug Monit. 2004 Jun;26(3):311–318.
   PubMed Web of Science ®Google Scholar
• Wright S, Sanders DS, Lobo AJ, et al. Clinical significance of azathioprine active metabolite concentrations in inflammatory bowel disease. Gut. 2004 Aug;53(8):1123–1128.
   PubMed Web of Science ®Google Scholar
• Derijks LJ, Wong DR. Pharmacogenetics of thiopurines in inflammatory bowel disease. Curr Pharm Des. 2010;16(2):145–154.
   PubMed Web of Science ®Google Scholar
• Eklund BI, Moberg M, Bergquist J, et al. Divergent activities of human glutathione transferases in the bioactivation of azathioprine. Mol Pharmacol. 2006 Aug;70(2):747–754.
   PubMed Web of Science ®Google Scholar
• Stocco G, Cuzzoni E, De Iudicibus S, et al. Deletion of glutathione-S-transferase m1 reduces azathioprine metabolite concentrations in young patients with inflammatory bowel disease. J Clin Gastroenterol. 2014 Jan;48(1):43–51.
   PubMed Web of Science ®Google Scholar
• Simone PD, Pavlov YI, Borgstahl GEO. ITPA (inosine triphosphate pyrophosphatase): from surveillance of nucleotide pools to human disease and pharmacogenetics. Mutat Res. 2013 Oct-Dec;753(2):131–146.
   PubMed Web of Science ®Google Scholar
• Tominaga K, Sugaya T, Tanaka T, et al. Thiopurines: recent topics and their role in the treatment of inflammatory bowel diseases. Front Pharmacol. 2021 Jan;29(11):582291.
   Google Scholar
• Tiede I, Fritz G, Strand S, et al. CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes. J Clin Invest. 2003 Apr;111(8):1133–1145.
   PubMed Web of Science ®Google Scholar
• Van Asseldonk DP, de Boer NK, Peters GJ, et al. On therapeutic drug monitoring of thiopurines in inflammatory bowel disease; pharmacology, pharmacogenomics, drug intolerance and clinical relevance. Curr Drug Metab. 2009 Nov;10(9):981–997.
   PubMed Web of Science ®Google Scholar
• Raju TN. The Nobel chronicles. 1988: James Whyte Black, (b 1924), Gertrude eLion (1918-99), and George H Hitchings (1905-98). Lancet. 2000 Mar 18;355(9208):1022,6736(05)74775–9.
   Google Scholar
• Bayoumy AB, van Liere ELSA, Simsek M, et al. Efficacy, safety and drug survival of thioguanine as maintenance treatment for inflammatory bowel disease: a retrospective multi-centre study in the United Kingdom. BMC Gastroenterol. 2020 Sep 11;20(1):296,020–01441-6.
   PubMed Web of Science ®Google Scholar
• Simsek M, Deben DS, Horjus CS, et al. Sustained effectiveness, safety and therapeutic drug monitoring of tioguanine in a cohort of 274 IBD patients intolerant for conventional therapies. Aliment Pharmacol Ther. 2019 Jul;50(1):54–65.
   PubMed Web of Science ®Google Scholar
• Derijks LJJ, Wong DR, Hommes DW, et al. Clinical pharmacokinetic and pharmacodynamic considerations in the treatment of inflammatory bowel disease. Clin Pharmacokinet. 2018 Sep;57(9):1075–1106.
   PubMed Web of Science ®Google Scholar
• Crouwel F, Simsek M, Mulder CJ, et al. Thioguanine therapy in inflammatory bowel diseases. A practical guide. J Gastrointestin Liver Dis. 2020 Dec 13;29(4):637–645.
   PubMed Web of Science ®Google Scholar
• de Hoogd S, Wong DR, de Vries DR, et al. Severe pancytopenia and aspergillosis caused by thioguanine in a thiopurine S-methyltransferase deficient patient: a case report. Eur J Gastroenterol Hepatol. 2019 Dec;31(12):1592–1596.
   PubMed Web of Science ®Google Scholar
• Blaker PA, Arenas-Hernandez M, Smith MA, et al. Mechanism of allopurinol induced TPMT inhibition. Biochem Pharmacol. 2013 Aug 15;86(4):539–547.
   PubMed Web of Science ®Google Scholar
• Conneely SE, Cooper SL, Rau RE. Use of allopurinol to mitigate 6-mercaptopurine associated gastrointestinal toxicity in acute lymphoblastic leukemia. Front Oncol. 2020 Jul 16;10:1129.
   PubMed Web of Science ®Google Scholar
• Seinen ML, de Boer NK, Smid K, et al. Allopurinol enhances the activity of hypoxanthine-guanine phosphoribosyltransferase in inflammatory bowel disease patients during low-dose thiopurine therapy: preliminary data of an ongoing series. Nucleosides Nucleotides Nucleic Acids. 2011 Dec;30(12):1085–1090.
   PubMed Web of Science ®Google Scholar
• Seinen ML, van Asseldonk DP, de Boer NK, et al. The effect of allopurinol and low-dose thiopurine combination therapy on the activity of three pivotal thiopurine metabolizing enzymes: results from a prospective pharmacological study. J Crohns Colitis. 2013 Nov;7(10):812–819.
   PubMed Web of Science ®Google Scholar
• Meijer B, Seinen ML, Hosman T, et al. High inter-individual variability of serum xanthine oxidoreductase activity in IBD patients. Nucleosides Nucleotides Nucleic Acids. 2018;37(6):317–323.
   PubMed Web of Science ®Google Scholar
• Ding L, Zhang FB, Liu H, et al. Xanthine oxidase activity in thiopurine curative Chinese inflammatory bowel disease patients. Pharmacol Res Perspect. 2021 May;9(3):e00764.
   PubMed Web of Science ®Google Scholar
• Pacher P, Nivorozhkin A, Szabó C. Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol. Pharmacol Rev. 2006 Mar;58(1):87–114.
   PubMed Web of Science ®Google Scholar
• Pritsos CA. Cellular distribution, metabolism and regulation of the xanthine oxidoreductase enzyme system. Chem Biol Interact. 2000 Dec 1;129(1–2):195–208.
   PubMed Web of Science ®Google Scholar
• Kudo M, Moteki T, Sasaki T, et al. Functional characterization of human xanthine oxidase allelic variants. Pharmacogenet Genomics. 2008 Mar;18(3):243–251.
   PubMed Web of Science ®Google Scholar
• Wong DR, Derijks LJ, Den Dulk MO, et al. The role of xanthine oxidase in thiopurine metabolism: a case report. Ther Drug Monit. 2007 Dec;29(6):845–848.
   PubMed Web of Science ®Google Scholar
• Moon W, Loftus EV Jr. Review article: recent advances in pharmacogenetics and pharmacokinetics for safe and effective thiopurine therapy in inflammatory bowel disease. Aliment Pharmacol Ther. 2016 Apr;43(8):863–883.
   PubMed Web of Science ®Google Scholar
• Singh A, Mahajan R, Kedia S, et al. Use of thiopurines in inflammatory bowel disease: an update. Intest Res. 2021. doi:https://doi.org/10.5217/ir.2020.00155 .
   Google Scholar
• Appell ML, Berg J, Duley J, et al. Nomenclature for alleles of the thiopurine methyltransferase gene. Pharmacogenet Genomics. 2013 Apr;23(4):242–248.
   PubMed Web of Science ®Google Scholar
• Krynetski EY, Evans WE. Genetic polymorphism of thiopurine S-methyltransferase: molecular mechanisms and clinical importance. Pharmacology. 2000 Sep;61(3):136–146.
   PubMed Web of Science ®Google Scholar
• Jena A, Jha DK, Kumar-M P, et al. Prevalence of polymorphisms in thiopurine metabolism and association with adverse outcomes: a south asian region-specific systematic review and meta-analysis. Expert Rev Clin Pharmacol. 2021 Apr;14(4):491–501.
   PubMed Web of Science ®Google Scholar
• Coenen MJ, de Jong DJ, van Marrewijk CJ, et al. Identification of patients with variants in TPMT and dose reduction reduces hematologic events during thiopurine treatment of inflammatory bowel disease. Gastroenterology. 2015 Oct;149(4):907,17.e7.
   PubMed Web of Science ®Google Scholar
• Voskuil MD, Bangma A, Weersma RK, et al. Predicting (side) effects for patients with inflammatory bowel disease: the promise of pharmacogenetics. World J Gastroenterol. 2019 Jun 7;25(21):2539–2548.
   PubMed Web of Science ®Google Scholar
• Seinen ML, van Bodegraven AA, van Kuilenburg AB, et al. High TPMT activity as a risk factor for severe myelosuppression during thiopurine therapy. Neth J Med. 2013 May;71(4):222.
   PubMed Web of Science ®Google Scholar
• Roberts RL, Wallace MC, Seinen ML, et al. Nonsynonymous polymorphism in guanine monophosphate synthetase is a risk factor for unfavorable thiopurine metabolite ratios in patients with inflammatory bowel disease. Inflamm Bowel Dis. 2018 Nov 29;24(12):2606–2612.
   PubMed Web of Science ®Google Scholar
• van Egmond R, Chin P, Zhang M, et al. High TPMT enzyme activity does not explain drug resistance due to preferential 6-methylmercaptopurine production in patients on thiopurine treatment. Aliment Pharmacol Ther. 2012 May;35(10):1181–1189.
   PubMed Web of Science ®Google Scholar
• Stocco G, Cheok MH, Crews KR, et al. Genetic polymorphism of inosine triphosphate pyrophosphatase is a determinant of mercaptopurine metabolism and toxicity during treatment for acute lymphoblastic leukemia. Clin Pharmacol Ther. 2009 Feb;85(2):164–172.
   PubMed Web of Science ®Google Scholar
• Burgis NE. A disease spectrum for ITPA variation: advances in biochemical and clinical research. J Biomed Sci. 2016 Oct 22;23(1):73,016–0291-y.
   PubMedGoogle Scholar
• Marinaki AM, Ansari A, Duley JA, et al. Adverse drug reactions to azathioprine therapy are associated with polymorphism in the gene encoding inosine triphosphate pyrophosphatase (ITPase). Pharmacogenetics. 2004 Mar;14(3):181–187.
   PubMedGoogle Scholar
• Xiong H, Xin HW, Wu XC, et al. Association between inosine triphosphate pyrophosphohydrolase deficiency and azathioprine-related adverse drug reactions in the Chinese kidney transplant recipients. Fundam Clin Pharmacol. 2010 Jun;24(3):393–400.
   PubMed Web of Science ®Google Scholar
• Zelinkova Z, Derijks LJ, Stokkers PC, et al. Inosine triphosphate pyrophosphatase and thiopurine s-methyltransferase genotypes relationship to azathioprine-induced myelosuppression. Clin Gastroenterol Hepatol. 2006 Jan;4(1):44–49.
   PubMed Web of Science ®Google Scholar
• Von Ahsen N, Armstrong VW, Behrens C, et al. Association of inosine triphosphatase 94C>A and thiopurine S-methyltransferase deficiency with adverse events and study drop-outs under azathioprine therapy in a prospective Crohn's disease study. Clin Chem. 2005 Dec;51(12):2282–2288.
   PubMed Web of Science ®Google Scholar
• van Dieren JM, van Vuuren AJ, Kusters JG, et al. van der Woude CJ. ITPA genotyping is not predictive for the development of side effects in AZA treated inflammatory bowel disease patients. Gut. 2005 Nov;54(11):1664.
   PubMed Web of Science ®Google Scholar
• Hindorf U, Lindqvist M, Hildebrand H, et al. Adverse events leading to modification of therapy in a large cohort of patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2006 Jul 15;24(2):331–342.
   PubMed Web of Science ®Google Scholar
• Hindorf U, Lindqvist M, Peterson C, et al. Pharmacogenetics during standardised initiation of thiopurine treatment in inflammatory bowel disease. Gut. 2006 Oct;55(10):1423–1431.
   PubMed Web of Science ®Google Scholar
• Van Dieren JM, Hansen BE, Kuipers EJ, et al. Van der Woude CJ. Meta-analysis: inosine triphosphate pyrophosphatase polymorphisms and thiopurine toxicity in the treatment of inflammatory bowel disease. Aliment Pharmacol Ther. 2007 Sep 1;26(5):643–652.
   PubMed Web of Science ®Google Scholar
• Bessman MJ, Frick DN, O’Handley SF. The MutT proteins or “nudix” hydrolases, a family of versatile, widely distributed, “housecleaning” enzymes. J Biol Chem. 1996 Oct 11;271(41):25059–25062.
   PubMed Web of Science ®Google Scholar
• Valerie NC, Hagenkort A, Page BD, et al. NUDT15 hydrolyzes 6-thio-DeoxyGTP to mediate the anticancer efficacy of 6-thioguanine. Cancer Res. 2016 Sep 15;76(18):5501–5511.
   PubMed Web of Science ®Google Scholar
• Yang SK, Hong M, Baek J, et al. A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia. Nat Genet. 2014 Sep;46(9):1017–1020.
   PubMed Web of Science ®Google Scholar
• Walker GJ, Harrison JW, Heap GA, et al. Association of genetic variants in NUDT15 with thiopurine-induced myelosuppression in patients with inflammatory bowel disease. Jama. 2019 Feb 26;321(8):773–785.
   PubMed Web of Science ®Google Scholar
• Relling MV, Schwab M, Whirl-Carrillo M, et al. Clinical pharmacogenetics implementation consortium guideline for thiopurine dosing based on TPMT and NUDT15 genotypes: 2018 update. Clin Pharmacol Ther. 2019 May;105(5):1095–1105.
   PubMed Web of Science ®Google Scholar
• Chao K, Huang Y, Zhu X, et al. Randomised clinical trial: dose optimising strategy by NUDT15 genotyping reduces leucopenia during thiopurine treatment of Crohn’s disease. Aliment Pharmacol Ther. 2021;54(9):1124–1133. doi:https://doi.org/10.1111/apt.16600 .
   PubMed Web of Science ®Google Scholar
• Dickson AL, Daniel LL, Zanussi J, et al. TPMT and NUDT15 variants predict discontinuation of azathioprine for myelotoxicity in patients with inflammatory disease: real-world clinical results. Clin Pharmacol Ther. 2022;111(1):263–271. doi:https://doi.org/10.1002/cpt.2428 .
   PubMed Web of Science ®Google Scholar
• Seinen ML, van Nieuw Amerongen GP, de Boer NK, et al. Rac1 as a potential pharmacodynamic biomarker for thiopurine therapy in inflammatory bowel disease. Ther Drug Monit. 2016 Oct;38(5):621–627.
   PubMed Web of Science ®Google Scholar
• Citalan-Madrid AF, Garcia-Ponce A, Vargas-Robles H, et al. Small GTPases of the ras superfamily regulate intestinal epithelial homeostasis and barrier function via common and unique mechanisms. Tissue Barriers. 2013 Dec 1;1(5):e26938.
   PubMedGoogle Scholar
• Seinen ML, van Nieuw Amerongen GP, de Boer NK, et al. Rac attack: modulation of the small GTPase rac in inflammatory bowel disease and thiopurine therapy. Mol Diagn Ther. 2016 Dec;20(6):551–557.
   PubMed Web of Science ®Google Scholar
• Poppe D, Tiede I, Fritz G, et al. Azathioprine suppresses ezrin-radixin-moesin-dependent T cell-APC conjugation through inhibition of vav guanosine exchange activity on rac proteins. J Immunol. 2006 Jan 1;176(1):640–651.
   PubMed Web of Science ®Google Scholar
• Deben DS, van Adrichem AJ, Drent R, et al. Rac1/pSTAT3 expression: a pharmacodynamic marker panel as a first step towards optimization of thiopurine therapy in IBD patients. Cytometry A. 2021. doi:https://doi.org/10.1002/cyto.a.24506 .
   Google Scholar
• Gilissen LP, Derijks LJ, Verhoeven HM, et al. Pancytopenia due to high 6-methylmercaptopurine levels in a 6-mercaptopurine treated patient with Crohn’s disease. Dig Liver Dis. 2007 Feb;39(2):182–186.
   PubMedGoogle Scholar
• Meijer B, Kreijne JE, van Moorsel SAW, et al. 6-methylmercaptopurine-induced leukocytopenia during thiopurine therapy in inflammatory bowel disease patients. J Gastroenterol Hepatol. 2017 Jun;32(6):1183–1190.
   PubMed Web of Science ®Google Scholar
• Osterman MT, Kundu R, Lichtenstein GR, et al. Association of 6-thioguanine nucleotide levels and inflammatory bowel disease activity: a meta-analysis. Gastroenterology. 2006 Apr;130(4):1047–1053.
   PubMed Web of Science ®Google Scholar
• Lennard L. The clinical pharmacology of 6-mercaptopurine. Eur J Clin Pharmacol. 1992;43(4):329–339.
   PubMed Web of Science ®Google Scholar
• Dubinsky MC, Lamothe S, Yang HY, et al. Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease. Gastroenterology. 2000 Apr;118(4):705–713.
   PubMed Web of Science ®Google Scholar
• Cuffari C, Hunt S, Bayless T. Utilisation of erythrocyte 6-thioguanine metabolite levels to optimise azathioprine therapy in patients with inflammatory bowel disease. Gut. 2001 May;48(5):642–646.
   PubMed Web of Science ®Google Scholar
• Cuffari C, Théorêt Y, Latour S, et al. 6-mercaptopurine metabolism in Crohn’s disease: correlation with efficacy and toxicity. Gut. 1996 Sep;39(3):401–406.
   PubMed Web of Science ®Google Scholar
• Dubinsky MC, Yang H, Hassard PV, et al. 6-MP metabolite profiles provide a biochemical explanation for 6-MP resistance in patients with inflammatory bowel disease. Gastroenterology. 2002 Apr;122(4):904–915.
   PubMed Web of Science ®Google Scholar
• Kreijne JE, Seinen ML, Wilhelm AJ, et al. Routinely established skewed thiopurine metabolism leads to a strikingly high rate of early therapeutic failure in patients with inflammatory bowel disease. Ther Drug Monit. 2015 Dec;37(6):797–804.
   PubMed Web of Science ®Google Scholar
• Moreau AC, Paul S, Del Tedesco E, et al. Association between 6-thioguanine nucleotides levels and clinical remission in inflammatory disease: a meta-analysis. Inflamm Bowel Dis. 2014 Mar;20(3):464–471.
   PubMed Web of Science ®Google Scholar
• Cornish JS, Wirthgen E, Däbritz J. Biomarkers predictive of response to thiopurine therapy in inflammatory bowel disease. Front Med (Lausanne). 2020 Jan;29(7):8.
   Google Scholar
• Gisbert JP, Gomollón F. Thiopurine-induced myelotoxicity in patients with inflammatory bowel disease: a review. Am J Gastroenterol. 2008 Jul;103(7):1783–1800.
   PubMed Web of Science ®Google Scholar
• Meijer B, Wilhelm AJ, Mulder CJJ, et al. Pharmacology of thiopurine therapy in inflammatory bowel disease and complete blood cell count outcomes: a 5-year database study. Ther Drug Monit. 2017 Aug;39(4):399–405.
   PubMed Web of Science ®Google Scholar
• Kopylov U, Battat R, Benmassaoud A, et al. Hematologic indices as surrogate markers for monitoring thiopurine therapy in IBD. Dig Dis Sci. 2015 Feb;60(2):478–484.
   PubMed Web of Science ®Google Scholar
• Nguyen TM, Le Gall C, Lachaux A, et al. High thiopurine metabolite concentrations associated with lymphopenia in inflammatory bowel disease (IBD) pediatric patients receiving aminosalicylates combined with azathioprine. Int J Clin Pharmacol Ther. 2010 Apr;48(4):275–281.
   PubMed Web of Science ®Google Scholar
• Lancaster DL, Patel N, Lennard L, et al. Leucocyte versus erythrocyte thioguanine nucleotide concentrations in children taking thiopurines for acute lymphoblastic leukaemia. Cancer Chemother Pharmacol. 2002 Jul;50(1):33–36.
   PubMed Web of Science ®Google Scholar
• Wong DR, Coenen MJ, Vermeulen SH, et al. Early assessment of thiopurine metabolites identifies patients at risk of thiopurine-induced leukopenia in inflammatory bowel disease. J Crohns Colitis. 2017 Feb;11(2):175–184.
   PubMed Web of Science ®Google Scholar
• Fraser AG, Orchard TR, Jewell DP. The efficacy of azathioprine for the treatment of inflammatory bowel disease: a 30 year review. Gut. 2002 Apr;50(4):485–489.
   PubMed Web of Science ®Google Scholar
• Wong DR, Coenen MJ, Derijks LJ, et al. Early prediction of thiopurine-induced hepatotoxicity in inflammatory bowel disease. Aliment Pharmacol Ther. 2017 Feb;45(3):391–402.
   PubMed Web of Science ®Google Scholar
• van Asseldonk DP, Jharap B, Verheij J, et al. The prevalence of nodular regenerative hyperplasia in inflammatory bowel disease patients treated with thioguanine is not associated with clinically significant liver disease. Inflamm Bowel Dis. 2016 Sep;22(9):2112–2120.
   PubMed Web of Science ®Google Scholar
• Meijer B, Seinen ML, van Egmond R, et al. Optimizing thiopurine therapy in inflammatory bowel disease among 2 real-life intercept cohorts: effect of allopurinol comedication? Inflamm Bowel Dis. 2017 Nov;23(11):2011–2017.
   PubMed Web of Science ®Google Scholar
• Dubinsky MC, Vasiliauskas EA, Singh H, et al. 6-thioguanine can cause serious liver injury in inflammatory bowel disease patients. Gastroenterology. 2003 Aug;125(2):298–303.
   PubMed Web of Science ®Google Scholar
• Seinen ML, van Asseldonk DP, de Boer NK, et al. Nodular regenerative hyperplasia of the liver in patients with IBD treated with allopurinol-thiopurine combination therapy. Inflamm Bowel Dis. 2017 Mar;23(3):448–452.
   PubMed Web of Science ®Google Scholar
• Gracia-Sancho J, Caparrós E, Fernández-Iglesias A, et al. Role of liver sinusoidal endothelial cells in liver diseases. Nat Rev Gastroenterol Hepatol. 2021 Jun;18(6):411–431.
   PubMed Web of Science ®Google Scholar
• De Boer NK, Tuynman H, Bloemena E, et al. Histopathology of liver biopsies from a thiopurine-naïve inflammatory bowel disease cohort: prevalence of nodular regenerative hyperplasia. Scand J Gastroenterol. 2008;43(5):604–608.
   PubMed Web of Science ®Google Scholar
• van Asseldonk DP, Simsek M, de Boer NKH, et al. Limited relevance and progression of histological alterations in the liver during thioguanine therapy in inflammatory bowel disease patients. Scand J Gastroenterol. 2019 Jun;54(6):753–760.
   PubMed Web of Science ®Google Scholar
• Jharap B, van Asseldonk DP, de Boer NK, et al. Diagnosing nodular regenerative hyperplasia of the liver is thwarted by low interobserver agreement. PLoS One. 2015 Jun 8;10(6):e0120299.
   PubMed Web of Science ®Google Scholar
• Derijks LJ, Gilissen LP, Engels LG, et al. Pharmacokinetics of 6-thioguanine in patients with inflammatory bowel disease. Ther Drug Monit. 2006 Feb;28(1):45–50.
   PubMed Web of Science ®Google Scholar
• Lenti MV, Selinger CP. Medication non-adherence in adult patients affected by inflammatory bowel disease: a critical review and update of the determining factors, consequences and possible interventions. Expert Rev Gastroenterol Hepatol. 2017 Mar;11(3):215–226.
   PubMed Web of Science ®Google Scholar
• Selinger CP, Ochieng AO, George V, et al. The accuracy of adherence self-report scales in patients on thiopurines for inflammatory bowel disease: a comparison with drug metabolite levels and medication possession ratios. Inflamm Bowel Dis. 2019 Apr 11;25(5):919–924.
   PubMed Web of Science ®Google Scholar
• Kopylov U, Ben-Horin S, Seidman E. Therapeutic drug monitoring in inflammatory bowel disease. Ann Gastroenterol. 2014;27(4):304–312.
   PubMedGoogle Scholar
• van der Valk ME, Mangen MJ, Leenders M, et al. Healthcare costs of inflammatory bowel disease have shifted from hospitalisation and surgery towards anti-TNFalpha therapy: results from the COIN study. Gut. 2014 Jan;63(1):72–79.
   PubMed Web of Science ®Google Scholar
• Steenholdt C, Brynskov J, Thomsen OØ, et al. Individualized therapy is a long-term cost-effective method compared to dose intensification in Crohn’s disease patients failing infliximab. Dig Dis Sci. 2015 Sep;60(9):2762–2770.
   PubMed Web of Science ®Google Scholar
• Vande Casteele N, Ferrante M, Van Assche G, et al. Trough concentrations of infliximab guide dosing for patients with inflammatory bowel disease. Gastroenterology. 2015 Jun;148(7):1320,9.e3.
   PubMed Web of Science ®Google Scholar
• McNeill RP, Barclay ML. Cost-effectiveness of therapeutic drug monitoring in inflammatory bowel disease. Curr Opin Pharmacol. 2020 Dec;55:41–46.
   PubMed Web of Science ®Google Scholar
• Zeng D, Huang X, Lin S, et al. Cost-effectiveness analysis of genotype screening and therapeutic drug monitoring in patients with inflammatory bowel disease treated with azathioprine therapy: a Chinese healthcare perspective using real-world data. Ann Transl Med. 2021 Jul;9(14):1138,21–1980.
   Web of Science ®Google Scholar
• Lennard L, Singleton HJ. High-performance liquid chromatographic assay of the methyl and nucleotide metabolites of 6-mercaptopurine: quantitation of red blood cell 6-thioguanine nucleotide, 6-thioinosinic acid and 6-methylmercaptopurine metabolites in a single sample. J Chromatogr. 1992 Nov 27;583(1):83–90.
   PubMed Web of Science ®Google Scholar
• Gilissen LP, Wong DR, Engels LG, et al. Therapeutic drug monitoring of thiopurine metabolites in adult thiopurine tolerant IBD patients on maintenance therapy. J Crohns Colitis. 2012 Jul;6(6):698–707.
   PubMed Web of Science ®Google Scholar
• Dervieux T, Boulieu R. Simultaneous determination of 6-thioguanine and methyl 6-mercaptopurine nucleotides of azathioprine in red blood cells by HPLC. Clin Chem. 1998 Mar;44(3):551–555.
   PubMed Web of Science ®Google Scholar
• Shipkova M, Armstrong VW, Wieland E, et al. Differences in nucleotide hydrolysis contribute to the differences between erythrocyte 6-thioguanine nucleotide concentrations determined by two widely used methods. Clin Chem. 2003 Feb;49(2):260–268.
   PubMed Web of Science ®Google Scholar
• Robijns K, van Luin M, Jansen RTP, et al. A design for external quality assessment for the analysis of thiopurine drugs: pitfalls and opportunities. Clin Chem Lab Med. 2018 Sep 25;56(10):1715–1721.
   PubMed Web of Science ®Google Scholar
• de Boer NK, van Bodegraven AA, de Graaf P, et al. Paradoxical elevated thiopurine S-methyltransferase activity after pancytopenia during azathioprine therapy: potential influence of red blood cell age. Ther Drug Monit. 2008 Jun;30(3):390–393.
   PubMed Web of Science ®Google Scholar
• Simsek M, Meijer B, Mulder CJJ, et al. Analytical pitfalls of therapeutic drug monitoring of thiopurines in patients with inflammatory bowel disease. Ther Drug Monit. 2017 Dec;39(6):584–588.
   PubMed Web of Science ®Google Scholar
• Neurath MF, Kiesslich R, Teichgräber U, et al. 6-thioguanosine diphosphate and triphosphate levels in red blood cells and response to azathioprine therapy in Crohn’s disease. Clin Gastroenterol Hepatol. 2005 Oct;3(10):1007–1014.
   PubMed Web of Science ®Google Scholar
• Higgs JE, Payne K, Roberts C, et al. Are patients with intermediate TPMT activity at increased risk of myelosuppression when taking thiopurine medications? Pharmacogenomics. 2010 Feb;11(2):177–188.
   PubMed Web of Science ®Google Scholar
• Sluiter RL, Van Marrewijk C, De Jong D, et al. Genotype-guided thiopurine dosing does not lead to additional costs in patients with inflammatory bowel disease. J Crohns Colitis. 2019 Jul 25;13(7):838–845.
   PubMed Web of Science ®Google Scholar
• McGovern DP, Travis SP, Duley J, et al. Azathioprine intolerance in patients with IBD may be imidazole-related and is independent of TPMT activity. Gastroenterology. 2002 Mar;122(3):838–839.
   PubMed Web of Science ®Google Scholar
• Meijer B, Seinen ML, Leijte NN, et al. Clinical value of mercaptopurine after failing azathioprine therapy in patients with inflammatory bowel disease. Ther Drug Monit. 2016 Aug;38(4):463–470.
   PubMed Web of Science ®Google Scholar
• Broekman MMTJ, Coenen MJH, van Marrewijk CJ, et al. More dose-dependent side effects with mercaptopurine over azathioprine in IBD treatment due to relatively higher dosing. Inflamm Bowel Dis. 2017 Oct;23(10):1873–1881.
   PubMed Web of Science ®Google Scholar
• Shih DQ, Nguyen M, Zheng L, et al. Split-dose administration of thiopurine drugs: a novel and effective strategy for managing preferential 6-MMP metabolism. Aliment Pharmacol Ther. 2012 Sep;36(5):449–458.
   PubMed Web of Science ®Google Scholar
• Kreijne JE, de Veer RC, de Boer NK, et al. Real-life study of safety of thiopurine-allopurinol combination therapy in inflammatory bowel disease: myelotoxicity and hepatotoxicity rarely affect maintenance treatment. Aliment Pharmacol Ther. 2019 Aug;50(4):407–415.
   PubMed Web of Science ®Google Scholar
• Houwen JPA, Egberts ACG, de Boer A, et al. Influence of allopurinol on thiopurine associated toxicity: a retrospective population-based cohort study. Br J Clin Pharmacol. 2021 May;87(5):2333–2340.
   PubMed Web of Science ®Google Scholar
• Meijer B, Mulder CJ, Peters GJ, et al. Efficacy of thioguanine treatment in inflammatory bowel disease: a systematic review. World J Gastroenterol. 2016 Oct 28;22(40):9012–9021.
   PubMed Web of Science ®Google Scholar
• Meijer B, Mulder CJJ, Bouma G, et al. Methotrexate and thioguanine rescue therapy for conventional thiopurine failing ulcerative colitis patients: a multi-center database study on tolerability and effectiveness. Inflamm Bowel Dis. 2018 Jun 8;24(7):1558–1565.
   PubMed Web of Science ®Google Scholar