Ronald A. Booth, PhD; Mohammed T. Ansari, MBBS, MMedSc, MPhil; Evelin Loit, PhD; Andrea C. Tricco, PhD; Laura Weeks, PhD; Steve Doucette, MSc; Becky Skidmore, MLS; Margaret Sears, PhD; Richmond Sy, MD; Jacob Karsh, MDCM
Booth RA, Ansari MT, Loit E, Tricco AC, Weeks L, Doucette S, et al. Assessment of Thiopurine S-Methyltransferase Activity in Patients Prescribed Thiopurines: A Systematic Review. Ann Intern Med. 2011;154:814-823. doi: 10.7326/0003-4819-154-12-201106210-00009
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Published: Ann Intern Med. 2011;154(12):814-823.
The evidence for testing thiopurine S-methyltransferase (TPMT) enzymatic activity or genotype before starting therapy with thiopurine-based drugs is unclear.
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.
MEDLINE, EMBASE, the Cochrane Library, and Ovid HealthSTAR (from inception to December 2010) and BIOSIS and Genetics Abstracts (to May 2009).
Two reviewers screened records and identified relevant studies in English.
Data on patient characteristics, outcomes, and risk for bias were extracted by one reviewer and independently identified by another.
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.
Available evidence was not rigorous and was underpowered to detect a difference in outcomes.
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.
Agency for Healthcare Research and Quality.
Some experts recommend routine measurement of thiopurine S-methyltransferase (TPMT) enzymatic activity before initiating thiopurine therapy.
This systematic review found insufficient evidence that TPMT pretesting guides appropriate prescribing or improves patient outcomes (such as by limiting toxicity) compared with routine blood count monitoring in patients receiving thiopurine therapy. Limited-quality evidence suggested imperfect and imprecise sensitivity but near-perfect specificity of genotyping for identifying patients with low and intermediate TPMT enzymatic activity.
We urgently need more high-quality evidence regarding the utility and costs of routine TPMT pretesting.
Azathiopurine, 6-MP, and 6-TG are enzymatically modified to their active compound, 6-tGN. Decreased TPMT activity increases the amount of prodrug available for conversion to the active compound, thus increasing the risk for toxic levels of 6-tGN. Thiopurine S-methyltransferase also plays a minor role in the inactivation of 6-TG. AO = aldehyde oxidase; AZA = azathiopurine; GD = guanine deaminase; HGPRT = hypoxanthine guanine phosphoribosyltransferase; IMPDH = inosine monophosphate dehydrogenase; MP = mercaptopurine; TG = thioguanine; tGMP = thioguanylic acid; tGN = thioguanine nucleotides; tIMP = thiomercaptopurine; TMPT = thiopurine S-methyltransferase; tXMP = thiooxanthosine; XO = xanthine oxidase.
Appendix Table 1.
* Two records had 2 primary reasons for exclusion at level 3.
FN = false negative; FP = false positive; TN = true negative; TP = true positive; TPMT = thiopurine S-methyltransferase.
† Tested alleles were not reported, so those we assumed most likely to have been tested in 1993 (when the study was conducted) are reported.
FN = false negative; FP = false positive; NA = not applicable; TN = true negative; TP = true positive; TPMT = thiopurine S-methyltransferase.
Appendix Table 2.
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