title: Assessment of thiopurine methyltransferase activity in patients prescribed azathioprine or other thiopurine-based drugs.
abstract: OBJECTIVE
  To examine whether pretreatment determination of thiopurine methyltransferase (TPMT) enzymatic activity (phenotyping) or TPMT genotype, to guide thiopurine therapy in chronic autoimmune disease patients, reduces treatment harms. Other objectives included assessing: preanalytic, analytic, and postanalytic requirements for TPMT testing; diagnostic accuracy of TPMT genotyping versus phenotyping; association of thiopurine toxicity with TPMT genotypic or phenotypic status; and costs of testing, care, and treating drug-associated complications.
  
  
  METHODS
  MEDLINE®, EMBASE®, and Healthstar were searched from inception to May 2010; the Cochrane Library® to October 2009; and BIOSIS®, Genetics Abstracts, and EconLit™ to May 2009, for English language records.
  
  
  METHODS
  A reviewer screened records, and a second reviewer verified exclusions and subsequent selection of relevant studies. Studies in patients with leukemia and organ transplant were excluded. Additionally, laboratories that provide TPMT analytical services were surveyed to assess means of TPMT testing in practice. Where possible, risk of bias was assessed using standard criteria. Meta-analyses estimated diagnostic sensitivity, and specificity; and odds ratios of associations.
  
  
  RESULTS
  1790 titles or abstracts, and 538 full text records were screened. 114 observational studies and one RCT were included. Majority of studies were rated fair quality, except for diagnostic studies with 37 percent of studies rated poor. In general, there were few patients who were homozygous (or compound heterozygous) for TPMT variant alleles in the included studies limiting applicability.  There is insufficient evidence examining effectiveness of pretesting in terms of reduction in clinical adverse events.  Sufficient preanalytical data were available regarding preferred specimen collection, stability and storage conditions for TPMT testing. There was no clinically significant effect of age, gender, various coadministered drugs, or most morbidities (with the exception of renal failure and dialysis). TPMT phenotyping methods had coefficients of variation generally below 10 percent. TPMT genotyping reproducibility is generally between 95-100 percent.  The sensitivity of genotyping to identify patients with low or intermediate TPMT enzymatic activity is imprecise, ranging from 70.70 to 82.10 percent (95 percent CI, lower bound range 37.90 to 54.00 percent; upper bound range 84.60 to 96.90 percent). Sensitivity of homozygous TPMT genotype to correctly identify patients with low to absent enzymatic activity was 87.10 percent (95 percent CI 44.30 to 98.30 percent). Genotyping specificity approached 100 percent.  Leukopenia was significantly associated with low and intermediate enzymatic activity (low activity OR 80.00, 95 percent CI 11.5 to 559; and intermediate activity OR 2.96, 95 percent CI 1.18 to 7.42), and homozygous and heterozygous TPMT variant allele genotype (OR 18.60, 95 percent CI 4.12 to 83.60; and 4.62, 95 percent CI 2.34 to 9.16, respectively). In general, TPMT phenotyping costs less than genotyping, although estimates across studies are quite heterogeneous.
  
  
  CONCLUSIONS
  There is insufficient direct evidence regarding the effectiveness of pretesting of TPMT status in patients with chronic autoimmune diseases. Indirect evidence confirms strong association of leukopenia with lower levels of TPMT activity and carrier genotype already established in the literature.
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Booth
authors.forename: Mohammed T
authors.initials: MT
authors.lastname: Ansari
authors.forename: Andrea C
authors.initials: AC
authors.lastname: Tricco
authors.forename: Evelin
authors.initials: E
authors.lastname: Loit
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: Jeffrey S
authors.initials: JS
authors.lastname: Hoch
authors.forename: Sophia
authors.initials: S
authors.lastname: Tsouros
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
authors.forename: Suja
authors.initials: S
authors.lastname: Mani
authors.forename: James
authors.initials: J
authors.lastname: Galipeau
authors.forename: Alexander
authors.initials: A
authors.lastname: Yurkiewich
authors.forename: Raymond
authors.initials: R
authors.lastname: Daniel
authors.forename: Alexander
authors.initials: A
authors.lastname: Tsertsvadze
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Yazdi
mesh_terms: D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000191:economics; D002908:Chronic Disease; D005260:Female; D006801:Humans; D007970:Leukopenia / Q000139:chemically induced / Q000201:enzymology; D008297:Male; D015122:Mercaptopurine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D008780:Methyltransferases / Q000032:analysis* / Q000235:genetics; D015203:Reproducibility of Results
chemical_list: C488629:azathiopurine; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase