title: Thiopurine metabolite ratios for monitoring therapy in pediatric Crohn disease.
abstract: OBJECTIVE
  Thiopurines (azathioprine, 6-mercaptopurine) are a mainstay of treatment in Crohn disease (CD). Monitoring intracellular metabolite (6-thioguanine nucleotides [6-TGN] and 6-methylmercaptopurine [6-MMP]) levels can help optimize therapeutic efficacy and minimize potential toxicity. Determination of 6-MMP/6-TGN ratios may provide additional useful information, such as the identification of individuals with excessive thiopurine methyltransferase activity and disadvantageous 6-MMP overproduction. These patients are at increased risk of therapeutic failure and hepatotoxicity. The aim of the study was to evaluate the correlation of 6-MMP/6-TGN ratios with therapeutic efficacy and risk of hepatotoxicity in CD.
  
  
  METHODS
  The present study was a single-center cross-sectional study including pediatric patients with CD studied prospectively with clinical and laboratory assessments along with serial measurements of 6-MMP and 6-TGN. Clinical response was determined using established clinical indices.
  
  
  RESULTS
  The study included 238 pediatric patients with CD with a total of 1648 evaluation points. The patients were in steroid-free remission at 59.1% of the evaluation points. 6-MMP/6-TGN ratios of 4 to 24 were protective against relapse (odds ratio [OR] 0.52, 95% confidence interval [CI] -0.39 to 0.69, P = 0.001). Hepatotoxicity was associated with high 6-MMP levels (>3919  pmol/8 × 10 red blood cell count: OR 7.65, 95% CI 3.7-15.9, P = 0.001) and high 6-MMP/6-TGN ratios (>24: OR 5.35, 95% CI -3.43 to 8.43, P = 0.001).
  
  
  CONCLUSIONS
  We observed significant associations between 6-MMP/6-TGN ratios and clinical response, and risk of hepatotoxicity. Our results suggest that determination of thiopurine metabolite ratios is a valuable tool for identification of patients at increased risk of therapeutic failure and hepatotoxicity.
authors.affiliation: *Division of Gastroenterology, McGill University Health Center †Department of Pediatrics, Research Center, Sainte Justine Hospital, University of Montreal, Quebec, Canada.
authors.forename: U
authors.initials: U
authors.lastname: Kopylov
authors.forename: D
authors.initials: D
authors.lastname: Amre
authors.forename: Y
authors.initials: Y
authors.lastname: Theoret
authors.forename: C
authors.initials: C
authors.lastname: Deslandres
authors.forename: E G
authors.initials: EG
authors.lastname: Seidman
mesh_terms: D000293:Adolescent; D001379:Azathioprine / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000517:prevention & control; D002648:Child; D003424:Crohn Disease / Q000378:metabolism / Q000628:therapy*; D005260:Female; D006150:Guanine Nucleotides / Q000378:metabolism*; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D008297:Male; D015122:Mercaptopurine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000627:therapeutic use; D008780:Methyltransferases / Q000378:metabolism; D016017:Odds Ratio; D013873:Thionucleotides / Q000378:metabolism*; D017211:Treatment Failure
chemical_list: D006150:Guanine Nucleotides; D007166:Immunosuppressive Agents; D013873:Thionucleotides; C003964:6-thioguanylic acid; C010240:6-methylthiopurine; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine