title: Identification of Patients With Variants in TPMT and Dose Reduction Reduces Hematologic Events During Thiopurine Treatment of Inflammatory Bowel Disease.
abstract: OBJECTIVE
  More than 20% of patients with inflammatory bowel disease (IBD) discontinue thiopurine therapy because of severe adverse drug reactions (ADRs); leukopenia is one of the most serious ADRs. Variants in the gene encoding thiopurine S-methyltransferase (TPMT) alter its enzymatic activity, resulting in higher levels of thiopurine metabolites, which can cause leukopenia. We performed a prospective study to determine whether genotype analysis of TPMT before thiopurine treatment, and dose selection based on the results, affects the outcomes of patients with IBD.
  
  
  METHODS
  In a study performed at 30 Dutch hospitals, patients were assigned randomly to groups that received standard treatment (control) or pretreatment screening (intervention) for 3 common variants of TPMT (TPMT*2, TPMT*3A, and TPMT*3C). Patients in the intervention group found to be heterozygous carriers of a variant received 50% of the standard dose of thiopurine (azathioprine or 6-mercaptopurine), and patients homozygous for a variant received 0%-10% of the standard dose. We compared, in an intention-to-treat analysis, outcomes of the intervention (n = 405) and control groups (n = 378) after 20 weeks of treatment. Primary outcomes were the occurrence of hematologic ADRs (leukocyte count < 3.0*10(9)/L or reduced platelet count < 100*10(9)/L) and disease activity (based on the Harvey-Bradshaw Index for Crohn's disease [n = 356] or the partial Mayo score for ulcerative colitis [n = 253]).
  
  
  RESULTS
  Similar proportions of patients in the intervention and control groups developed a hematologic ADR (7.4% vs 7.9%; relative risk, 0.93; 95% confidence interval, 0.57-1.52) in the 20 weeks of follow-up evaluation; the groups also had similar mean levels of disease activity (P = .18 for Crohn's disease and P = .14 for ulcerative colitis). However, a significantly smaller proportion of carriers of the TPMT variants in the intervention group (2.6%) developed hematologic ADRs compared with patients in the control group (22.9%) (relative risk, 0.11; 95% confidence interval, 0.01-0.85).
  
  
  CONCLUSIONS
  Screening for variants in TPMT did not reduce the proportions of patients with hematologic ADRs during thiopurine treatment for IBD. However, there was a 10-fold reduction in hematologic ADRs among variant carriers who were identified and received a dose reduction, compared with variant carriers who did not, without differences in treatment efficacy. ClinicalTrials.gov number: NCT00521950.
authors.affiliation: Department of Human Genetics, Radboud Institute for Health Sciences, Radboud university medical center, Nijmegen, The Netherlands. Electronic address: marieke.coenen@radboudumc.nl.
authors.forename: Marieke J H
authors.initials: MJ
authors.lastname: Coenen
authors.affiliation: Department of Gastroenterology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: de Jong
authors.affiliation: Department of Human Genetics, Radboud Institute for Health Sciences, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Corine J
authors.initials: CJ
authors.lastname: van Marrewijk
authors.affiliation: Department of Clinical Pharmacy, Máxima Medical Centre, Veldhoven, The Netherlands.
authors.forename: Luc J J
authors.initials: LJ
authors.lastname: Derijks
authors.affiliation: Department of Human Genetics, Radboud Institute for Health Sciences, Radboud university medical center, Nijmegen, The Netherlands; Radboud Institute for Health Sciences, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Sita H
authors.initials: SH
authors.lastname: Vermeulen
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Orbis Medical Center, Sittard-Geleen, The Netherlands.
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Wong
authors.affiliation: Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: Olaf H
authors.initials: OH
authors.lastname: Klungel
authors.affiliation: Radboud Institute for Health Sciences, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Andre L M
authors.initials: AL
authors.lastname: Verbeek
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Orbis Medical Center, Sittard-Geleen, The Netherlands.
authors.forename: Piet M
authors.initials: PM
authors.lastname: Hooymans
authors.affiliation: Department of Gastroenterology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Wilbert H M
authors.initials: WH
authors.lastname: Peters
authors.affiliation: Department of Gastroenterology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Rene H M
authors.initials: RH
authors.lastname: te Morsche
authors.affiliation: Centre for Genomic Medicine, St Mary's Hospital, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom.
authors.forename: William G
authors.initials: WG
authors.lastname: Newman
authors.affiliation: Department of Human Genetics, Donders Centre for Neuroscience, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Scheffer
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: Guchelaar
authors.affiliation: Department of Human Genetics, Donders Centre for Neuroscience, Radboud university medical center, Nijmegen, The Netherlands; Department of Psychiatry, Donders Centre for Neuroscience, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Barbara
authors.initials: B
authors.lastname: Franke
mesh_terms: D000328:Adult; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism; D001379:Azathioprine / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism; D003093:Colitis, Ulcerative / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D003424:Crohn Disease / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D054796:Drug Dosage Calculations; D005260:Female; D005765:Gastrointestinal Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism; D005820:Genetic Testing; D014644:Genetic Variation; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007970:Leukopenia / Q000139:chemically induced / Q000517:prevention & control*; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism; D008780:Methyltransferases / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009426:Netherlands; D010597:Pharmacogenetics; D010641:Phenotype; D011237:Predictive Value of Tests; D011446:Prospective Studies; D012307:Risk Factors; D013921:Thrombocytopenia / Q000139:chemically induced / Q000517:prevention & control*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000893:Anti-Inflammatory Agents; D005765:Gastrointestinal Agents; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine
keywords: Adverse Event; Leukocyte; Pharmacogenetic; Side Effect