Assessment of Thiopurine S-Methyltransferase Activity in Patients Prescribed Thiopurines: A Systematic Review

Booth, Ronald A.; Ansari, Mohammed; Loit, Evelin; Tricco, Andrea C.; Doucette, Steve; Skidmore, Becky; Sears, Margaret; Sy, Richmond; Karsh, Jacob

doi:10.7326/0003-4819-154-12-201106210-00009

Cited by 90 publications

(83 citation statements)

References 86 publications

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“…In fact, thiopurine-related myelotoxicity can, at least partly, be predicted by TPMT genotyping [66,67]; however, other side effects, including fever, arthralgia, hepatitis, and pancreatitis, are independent of TPMT status in up to 70 % of patients [62,66]. To date, more than 35 variants of the TPMT gene have been associated with decreased enzymatic TPMT activity [68][69][70][71][72][73].…”

Section: Genotypingmentioning

confidence: 97%

“…Accordingly, TPMT testing prior to the initiation of thiopurine therapy has been acknowledged and recommended by several published guidelines to prevent myelotoxicity [55][56][57][58][59]. However, the European Crohn's and Colitis Organisation (ECCO) does not have this recommendation in its recent guidelines [60,61], and a comprehensive systematic review concluded that insufficient evidence exists that this strategy is effective in reducing harm or is superior to the well-established clinical standard of hematologic monitoring [62]. Thus, the clinical and economic benefits of these tests in practice still remain controversial.…”

Section: Thiopurine S-methyltransferase Testingmentioning

confidence: 98%

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Pharmacology and Optimization of Thiopurines and Methotrexate in Inflammatory Bowel Disease

et al. 2015

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Improving the efficacy and reducing the toxicity of thiopurines and methotrexate (MTX) have been areas of intense basic and clinical research. An increased knowledge on pharmacodynamics and pharmacokinetics of these immunomodulators has optimized treatment strategies in inflammatory bowel disease (IBD). This review focuses on the metabolism and mode of action of thiopurines and MTX, and provides an updated overview of individualized treatment strategies in which efficacy in IBD can be increased without compromising safety. The patient-based monitoring instruments adapted into clinical practice include pretreatment thiopurine S-methyltransferase testing, thiopurine metabolite monitoring, and blood count measurements that may help guiding the dosage to improve clinical outcome. Other approaches for optimizing thiopurine therapy in IBD include combination therapy with allopurinol, 5-aminosalicylates, and/or biologics. Similar strategies are yet to be proven effective in improving the outcome of MTX therapy. Important challenges for the management of IBD in the future relate to individualized dosing of immunomodulators for maximal efficacy with minimal risk of side effects. As low-cost conventional immunomodulators still remain a mainstay in pharmacotherapy of IBD, more research remains warranted, especially to substantiate these tailored management strategies in controlled clinical trials.

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Section: Genotypingmentioning

confidence: 97%

Section: Thiopurine S-methyltransferase Testingmentioning

confidence: 98%

Pharmacology and Optimization of Thiopurines and Methotrexate in Inflammatory Bowel Disease

et al. 2015

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“…60 A meta-analysis by Booth et al for discriminating between patients with low or intermediate TPMT enzyme activity (homozygous or heterozygous TPMT mutations) and the rest of the population reported a sensitivity range of 70.33-86.15% (lower-bound 95% CI, 54.52-70.88%; upper-bound CI, 78.50-96.33% for phenotype tests and a pooled estimate of 79.90% (95% CI, 74.81-84.55%) for genotype tests. 61 Due to the rarity of the homozygous mutation, Booth et al did not meta-analyze tests discriminating between patients with deficient TPMT enzyme activity (homozygous TPMT mutation) and the rest of the population.…”

Section: Discussionmentioning

confidence: 99%

Thiopurine S-methyltransferase testing for averting drug toxicity: a meta-analysis of diagnostic test accuracy

et al. 2016

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Thiopurine S-methyltransferase (TPMT) deficiency increases the risk of serious adverse events in persons receiving thiopurines. The objective was to synthesize reported sensitivity and specificity of TPMT phenotyping and genotyping using a latent class hierarchical summary receiver operating characteristic meta-analysis. In 27 studies, pooled sensitivity and specificity of phenotyping for deficient individuals was 75.9% (95% credible interval (CrI), 58.3-87.0%) and 98.9% (96.3-100%), respectively. For genotype tests evaluating TPMT*2 and TPMT*3, sensitivity and specificity was 90.4% (79.1-99.4%) and 100.0% (99.9-100%), respectively. For individuals with deficient or intermediate activity, phenotype sensitivity and specificity was 91.3% (86.4-95.5%) and 92.6% (86.5-96.6%), respectively. For genotype tests evaluating TPMT*2 and TPMT*3, sensitivity and specificity was 88.9% (81.6-97.5%) and 99.2% (98.4-99.9%), respectively. Genotyping has higher sensitivity as long as TPMT*2 and TPMT*3 are tested. Both approaches display high specificity. Latent class meta-analysis is a useful method for synthesizing diagnostic test performance data for clinical practice guidelines.

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“…On the other hand, there are research groups that do not advocate for TPMT genotyping before treatment with thiopurines (Booth et al, 2011). The Agency for Healthcare Research and Quality (AHRQ) concluded that ″there is currently insufficient evidence regarding the effectiveness of determining TPMT status prior to thiopurine treatment in terms of improvement in clinical outcomes and incident myelotoxicity in comparison with routine monitoring of full blood counts and adverse events″ (http://www.ahrq.gov/clinic/tp/tpmttp.htm#Report).…”

Section: Guidelines For Thiopurine Dosing Based On Tpmt Genotypementioning

confidence: 99%

Pharmacogenomics of Thiopurine S-Methyltransferase: Clinical Applicability of Genetic Variants

Pavlović¹,

Zukić²,

Nikčević³

2012

Clinical Applications of Pharmacogenetics

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Assessment of Thiopurine S-Methyltransferase Activity in Patients Prescribed Thiopurines: A Systematic Review

Abstract: Agency for Healthcare Research and Quality.

Cited by 90 publications

References 86 publications

Pharmacology and Optimization of Thiopurines and Methotrexate in Inflammatory Bowel Disease

Pharmacology and Optimization of Thiopurines and Methotrexate in Inflammatory Bowel Disease

Thiopurine S-methyltransferase testing for averting drug toxicity: a meta-analysis of diagnostic test accuracy

Pharmacogenomics of Thiopurine S-Methyltransferase: Clinical Applicability of Genetic Variants

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