Assessment of thiopurine methyltransferase enzyme activity is superior to genotype in predicting myelosuppression following azathioprine therapy in patients with inflammatory bowel disease

Winter, J.; Gaffney, Dairena; Shapiro, David E.; Spooner, R J; Marinaki, A.; Sanderson, Jeremy; Mills, Peter R.

doi:10.1111/j.1365-2036.2007.03301.x

Cited by 100 publications

(80 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The proportion of these three enzymes determines the effective 6-TGN level. In case of low TPMT activity (due to enzyme polymorphisms) metabolism shifts to the production of 6-TGN, where high concentrations are associated with efficacy, but above a certain level (> 450 pmol/108 erythrocyte), 6-TGN has a myelotoxic effects [16] . Bone marrow depression that is a late toxic reaction usually occurs in the first three months [17] .…”

Section: Discussionmentioning

confidence: 99%

Efficacy of 6-mercaptopurine treatment after azathioprine hypersensitivity in inflammatory bowel disease

Nagy¹,

Molnár²,

Szepes³

et al. 2008

WJG

View full text Add to dashboard Cite

AIM:To investigate the efficacy of 6-mercaptopurine (6-MP) in cases of azathioprine (AZA) hypersensitivity in patients with inflammatory bowel disease. METHODS: Twenty nine previously confirmed Crohn's disease (CD) (n = 14) and ulcerative colitis (UC) (n = 15) patients with a known previous (AZA) hypersensitivity reaction were studied prospectively. The 6-MP doses were gradually increased from 0.5 up to 1.0-1.5 mg/kg per day. Clinical activity indices (CDAI/ CAI), laboratory variables and daily doses of oral 5-ASA, corticosteroids, and 6-MP were assessed before and in the first, sixth and twelfth months of treatment. RESULTS: In 9 patients, 6-MP was withdrawn in the first 2 wk due to an early hypersensitivity reaction. Medication was ineffective within 6 mo in 6 CD patients, and myelotoxic reaction was observed in two. Data were evaluated at the end of the sixth month in 12 (8 UC, 4 CD) patients, and after the first year in 9 (6 UC, 3 CD) patients. CDAI decreased transiently at the end of the sixth month, but no significant changes were observed in the CDAI or the CAI values at the end of the year. Leukocyte counts (P = 0.01), CRP (P = 0.02), and serum iron (P = 0.05) values indicated decreased inflammatory reactions, especially in the UC patients at the end of the year, making the possibility to taper oral steroid doses. CONCLUSION: About one-third of the previously AZAintolerant patients showed adverse effects on taking 6MP. In our series, 20 patients tolerated 6MP, but it was ineffective in 8 CD cases, and valuable mainly in ulcerative colitis patients.

show abstract

Section: Discussionmentioning

confidence: 99%

Efficacy of 6-mercaptopurine treatment after azathioprine hypersensitivity in inflammatory bowel disease

Nagy¹,

Molnár²,

Szepes³

et al. 2008

WJG

View full text Add to dashboard Cite

show abstract

“…This resulted in two strata for the test of deficient TPMT enzyme activity/homozygous TPMT mutation versus the rest of the population: (1) studies where the genotype test only considered TPMT*2 and *3, [33][34][35][36][37][38][39][40][41][42] and (2) studies where the genotype test considered TPMT*2, TPMT*3 and additional polymorphisms. [43][44][45] There were three strata for the test of low or intermediate TPMT enzyme activity/ homozygous or heterozygous TPMT mutation versus the rest of the population: (1) studies where the genotype test only considered TPMT*3, 46,47 (2) studies where the genotype test considered TPMT*2 and TPMT*3, 6,[33][34][35][36][37][38][39][40][41][42][48][49][50][51][52][53][54][55][56] and (3) studies where the genotype test considered TPMT*2, TPMT*3 and additional polymorphisms. [42][43][44][45]57,58 The meta-analysis used a Bayesian model.…”

Section: Meta-analysis Statistical Methodsmentioning

confidence: 99%

“…Phenotype tests that measure levels of TPMT enzyme activity in vitro are common. [2][3][4][5][6] Alternatively, genotype tests are available that detect the presence of variants in the genes responsible for expressing the TPMT enzyme. [7][8][9] Both tests have associated challenges and it remains uncertain whether an enzyme activity (phenotype) or genotype diagnostic test is the most appropriate strategy.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

View full text Add to dashboard Cite

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.

show abstract

“…However, in 15-30% of patients, these drugs have to be discontinued due to adverse effects including bone marrow suppression, hepatotoxicity, pancreatitis, fever, rash and gastrointestinal intolerance (4)(5)(6)(7)(8)(9). Furthermore, an AZA dosage of 2-3 mg/kg is recommended for the treatment of IBD patients in Western countries (10), but lower doses of AZA (0.6-1.2 mg/kg/day) are used in Japanese patients due to their relatively heightened sensitivity (11).…”

Section: Introductionmentioning

confidence: 99%

Accuracy of genotyping using the TaqMan PCR assay for single nucleotide polymorphisms responsible for thiopurine sensitivity in Japanese patients with inflammatory bowel disease

Osaki¹,

Imaeda²,

Ban³

et al. 2011

Experimental and Therapeutic Medicine

View full text Add to dashboard Cite

Abstract. Thiopurine drugs are the most common drugs used to maintain clinical remission in inflammatory bowel disease (IBD). Three single-nucleotide polymorphisms (SNPs), TPMT A719G (rs1142345), inosine triphosphate pyrophosphatase (ITPase) C94A (rs1127354) and multidrug resistance protein 4 MRP4 G2269A (rs3765534), have been reported to account for heightened sensitivity to thiopurine drugs in the Japanese population. We investigated the usefulness of the TaqMan ® PCR assay (Applied Biosystems) for the rapid detection of these SNPs to improve the safety of thiopurine therapy. We enrolled 44 healthy volunteers and 235 IBD patients. Genotyping of the SNPs was performed using Custom TaqMan SNP genotyping assays, direct sequencing and PCR-RFLP. Genotyping for MRP4 G2269A by the TaqMan PCR assay was successfully achieved in all samples. Comparison with our previous data using direct sequencing indicated one discordant result, and re-sequencing showed that the TaqMan PCR assay was correct. The overall accuracy of the TaqMan assay for MRP4 G2269A was 100%. The TaqMan PCR genotyping for TPMT A719G and ITPase C94A was successfully performed in all samples. The results of TPMT A719G by the TaqMan assay were identical with those of PCR-RFLP. In ITPase C94A, a comparison of the TaqMan assay and PCR-RFLP yielded 12 discordant results, and direct sequencing showed that the TaqMan PCR assay was correct. The allelic frequency determined by the TaqMan assay was 0.145 for MRP4 G2269A, 0.009 for TPMT A719G and 0.121 for ITPase C94A, respectively. In conclusion, the TaqMan ® PCR assay is useful for genotyping of SNPs responsible for thiopurine sensitivity in Japanese IBD patients.

show abstract

Assessment of thiopurine methyltransferase enzyme activity is superior to genotype in predicting myelosuppression following azathioprine therapy in patients with inflammatory bowel disease

Cited by 100 publications

References 42 publications

Efficacy of 6-mercaptopurine treatment after azathioprine hypersensitivity in inflammatory bowel disease

Efficacy of 6-mercaptopurine treatment after azathioprine hypersensitivity in inflammatory bowel disease

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

Accuracy of genotyping using the TaqMan PCR assay for single nucleotide polymorphisms responsible for thiopurine sensitivity in Japanese patients with inflammatory bowel disease

Contact Info

Product

Resources

About