Assessment of thiopurine methyltransferase activity in patients prescribed azathioprine or other thiopurine-based drugs.

Ronald A. Booth, Mohammed T. Ansari, Andrea C. Tricco, Evelin Loit, Laura Weeks, Steve Doucette, Becky Skidmore, Jeffrey S Hoch, Sophia Tsouros, Margaret Sears, Richmond Sy, Jacob Karsh, Suja Mani, James Galipeau, Alexander Yurkiewich, Raymond Daniel, Alexander Tsertsvadze, Fatemeh Yazdi

Research output: Contribution to journalReview article

8 Citations (Scopus)

Abstract

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. 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. 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. 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. 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.

Original languageEnglish (US)
Pages (from-to)1-282
Number of pages282
JournalEvidence report/technology assessment
Issue number196
StatePublished - Dec 2010
Externally publishedYes

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thiopurine methyltransferase
Azathioprine
Pharmaceutical Preparations
Genotype
Leukopenia
Autoimmune Diseases

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Booth, R. A., Ansari, M. T., Tricco, A. C., Loit, E., Weeks, L., Doucette, S., ... Yazdi, F. (2010). Assessment of thiopurine methyltransferase activity in patients prescribed azathioprine or other thiopurine-based drugs. Evidence report/technology assessment, (196), 1-282.

Assessment of thiopurine methyltransferase activity in patients prescribed azathioprine or other thiopurine-based drugs. / Booth, Ronald A.; Ansari, Mohammed T.; Tricco, Andrea C.; Loit, Evelin; Weeks, Laura; Doucette, Steve; Skidmore, Becky; Hoch, Jeffrey S; Tsouros, Sophia; Sears, Margaret; Sy, Richmond; Karsh, Jacob; Mani, Suja; Galipeau, James; Yurkiewich, Alexander; Daniel, Raymond; Tsertsvadze, Alexander; Yazdi, Fatemeh.

In: Evidence report/technology assessment, No. 196, 12.2010, p. 1-282.

Research output: Contribution to journalReview article

Booth, RA, Ansari, MT, Tricco, AC, Loit, E, Weeks, L, Doucette, S, Skidmore, B, Hoch, JS, Tsouros, S, Sears, M, Sy, R, Karsh, J, Mani, S, Galipeau, J, Yurkiewich, A, Daniel, R, Tsertsvadze, A & Yazdi, F 2010, 'Assessment of thiopurine methyltransferase activity in patients prescribed azathioprine or other thiopurine-based drugs.', Evidence report/technology assessment, no. 196, pp. 1-282.
Booth, Ronald A. ; Ansari, Mohammed T. ; Tricco, Andrea C. ; Loit, Evelin ; Weeks, Laura ; Doucette, Steve ; Skidmore, Becky ; Hoch, Jeffrey S ; Tsouros, Sophia ; Sears, Margaret ; Sy, Richmond ; Karsh, Jacob ; Mani, Suja ; Galipeau, James ; Yurkiewich, Alexander ; Daniel, Raymond ; Tsertsvadze, Alexander ; Yazdi, Fatemeh. / Assessment of thiopurine methyltransferase activity in patients prescribed azathioprine or other thiopurine-based drugs. In: Evidence report/technology assessment. 2010 ; No. 196. pp. 1-282.
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author = "Booth, {Ronald A.} and Ansari, {Mohammed T.} and Tricco, {Andrea C.} and Evelin Loit and Laura Weeks and Steve Doucette and Becky Skidmore and Hoch, {Jeffrey S} and Sophia Tsouros and Margaret Sears and Richmond Sy and Jacob Karsh and Suja Mani and James Galipeau and Alexander Yurkiewich and Raymond Daniel and Alexander Tsertsvadze and Fatemeh Yazdi",
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T1 - Assessment of thiopurine methyltransferase activity in patients prescribed azathioprine or other thiopurine-based drugs.

AU - Booth, Ronald A.

AU - Ansari, Mohammed T.

AU - Tricco, Andrea C.

AU - Loit, Evelin

AU - Weeks, Laura

AU - Doucette, Steve

AU - Skidmore, Becky

AU - Hoch, Jeffrey S

AU - Tsouros, Sophia

AU - Sears, Margaret

AU - Sy, Richmond

AU - Karsh, Jacob

AU - Mani, Suja

AU - Galipeau, James

AU - Yurkiewich, Alexander

AU - Daniel, Raymond

AU - Tsertsvadze, Alexander

AU - Yazdi, Fatemeh

PY - 2010/12

Y1 - 2010/12

N2 - 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. 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. 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. 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. 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.

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