Document Detail


Assessment of thiopurine S-methyltransferase activity in patients prescribed thiopurines: a systematic review.
MedLine Citation:
PMID:  21690596     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: The evidence for testing thiopurine S-methyltransferase (TPMT) enzymatic activity or genotype before starting therapy with thiopurine-based drugs is unclear.
PURPOSE: 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.
DATA SOURCES: MEDLINE, EMBASE, the Cochrane Library, and Ovid HealthSTAR (from inception to December 2010) and BIOSIS and Genetics Abstracts (to May 2009).
STUDY SELECTION: Two reviewers screened records and identified relevant studies in English.
DATA EXTRACTION: Data on patient characteristics, outcomes, and risk for bias were extracted by one reviewer and independently identified by another.
DATA SYNTHESIS: 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.
LIMITATION: Available evidence was not rigorous and was underpowered to detect a difference in outcomes.
CONCLUSION: 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.
PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.
Authors:
Ronald A Booth; Mohammed T Ansari; Evelin Loit; Andrea C Tricco; Laura Weeks; Steve Doucette; Becky Skidmore; Margaret Sears; Richmond Sy; Jacob Karsh
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.; Review    
Journal Detail:
Title:  Annals of internal medicine     Volume:  154     ISSN:  1539-3704     ISO Abbreviation:  Ann. Intern. Med.     Publication Date:  2011 Jun 
Date Detail:
Created Date:  2011-06-21     Completed Date:  2011-08-19     Revised Date:  2013-06-25    
Medline Journal Info:
Nlm Unique ID:  0372351     Medline TA:  Ann Intern Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  814-23, W-295-8     Citation Subset:  AIM; IM    
Affiliation:
Ottawa Hospital, Ottawa Hospital Research Institute, and University of Ottawa, Ottawa, Ontario, Canada.
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MeSH Terms
Descriptor/Qualifier:
6-Mercaptopurine / adverse effects,  analogs & derivatives,  therapeutic use
Chronic Disease
Genetic Testing
Genotype
Humans
Inflammation / drug therapy*,  enzymology*
Methyltransferases / deficiency,  genetics*,  metabolism*
Purines / adverse effects,  therapeutic use*
Sensitivity and Specificity
Grant Support
ID/Acronym/Agency:
HHSA290-2007-10059-I//PHS HHS
Chemical
Reg. No./Substance:
0/Purines; 0/azathiopurine; 50-44-2/6-Mercaptopurine; EC 2.1.1.-/Methyltransferases; EC 2.1.1.67/thiopurine methyltransferase
Comments/Corrections
Comment In:
Ann Intern Med. 2011 Jun 21;154(12):842-4   [PMID:  21690601 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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