title: Assessment of thiopurine S-methyltransferase activity in patients prescribed thiopurines: a systematic review.
abstract: BACKGROUND
  The evidence for testing thiopurine S-methyltransferase (TPMT) enzymatic activity or genotype before starting therapy with thiopurine-based drugs is unclear.
  
  
  OBJECTIVE
  To examine the sensitivity and specificity of TPMT genotyping for TPMT enzymatic activity, reducing harm from thiopurine by pretesting, and the association of thiopurine toxicity with TPMT status in adults and children with chronic inflammatory diseases.
  
  
  METHODS
  MEDLINE, EMBASE, the Cochrane Library, and Ovid HealthSTAR (from inception to December 2010) and BIOSIS and Genetics Abstracts (to May 2009).
  
  
  METHODS
  Two reviewers screened records and identified relevant studies in English.
  
  
  METHODS
  Data on patient characteristics, outcomes, and risk for bias were extracted by one reviewer and independently identified by another.
  
  
  RESULTS
  54 observational studies and 1 randomized, controlled trial were included. Insufficient evidence addressed the effectiveness of pretesting. Genotyping sensitivity to identify patients with low and intermediate TPMT enzymatic activity ranged from 70.33% to 86.15% (lower-bound 95% CI, 54.52% to 70.88%; upper-bound CI, 78.50% to 96.33%). Sparse data precluded estimation of genotype sensitivity to identify patients with low to absent enzymatic activity. Genotyping specificity approached 100%. Compared with noncarriers, heterozygous and homozygous genotypes were both associated with leukopenia (odds ratios, 4.29 [CI, 2.67 to 6.89] and 20.84 [CI, 3.42 to 126.89], respectively). Compared with intermediate or normal activity, low TPMT enzymatic activity was significantly associated with myelotoxicity and leukopenia.
  
  
  CONCLUSIONS
  Available evidence was not rigorous and was underpowered to detect a difference in outcomes.
  
  
  CONCLUSIONS
  Insufficient evidence addresses the effectiveness of TPMT pretesting in patients with chronic inflammatory diseases. Estimates of the sensitivity of genotyping are imprecise. Evidence confirms the known associations of leukopenia or myelotoxicity with reduced TPMT activity or variant genotype.
  
  
  BACKGROUND
  Agency for Healthcare Research and Quality.
authors.affiliation: Ottawa Hospital, Ottawa Hospital Research Institute, and University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Booth
authors.forename: Mohammed T
authors.initials: MT
authors.lastname: Ansari
authors.forename: Evelin
authors.initials: E
authors.lastname: Loit
authors.forename: Andrea C
authors.initials: AC
authors.lastname: Tricco
authors.forename: Laura
authors.initials: L
authors.lastname: Weeks
authors.forename: Steve
authors.initials: S
authors.lastname: Doucette
authors.forename: Becky
authors.initials: B
authors.lastname: Skidmore
authors.forename: Margaret
authors.initials: M
authors.lastname: Sears
authors.forename: Richmond
authors.initials: R
authors.lastname: Sy
authors.forename: Jacob
authors.initials: J
authors.lastname: Karsh
mesh_terms: D002908:Chronic Disease; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000201:enzymology*; D015122:Mercaptopurine / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D008780:Methyltransferases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D011687:Purines / Q000009:adverse effects / Q000627:therapeutic use*; D012680:Sensitivity and Specificity
chemical_list: D011687:Purines; C488629:azathiopurine; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase