Thiopurine methyltransferase activity and the use of azathioprine in inflammatory bowel disease

Ansari, Azhar; Hassan, Cesare; Duley, John A.; Shobowale-Bakre, El-Monsor; Seed, Paul; Meenan, John; Yim, Andrew Y. Li; Sanderson, Jeremy

doi:10.1046/j.1365-2036.2002.01353.x

Cited by 223 publications

(182 citation statements)

References 25 publications

(37 reference statements)

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“…On the contrary, several studies in Western samples have addressed the impact of TPMT activity and genotype on the clinical response of IBD patients treated with AZA/6-MP and suggested that measurement of TPMT activity might predict clinical response to AZA/6-MP. 15,16 At present, the reasons for discrepancies among these studies are unclear. However, one possible explanation for these discrepancies is that the Asian population has genetic backgrounds of TPMT that are different from those of the Caucasian population.…”

Section: Discussionmentioning

confidence: 99%

Correlation of genotypes for thiopurine methyltransferase and inosine triphosphate pyrophosphatase with long-term clinical outcomes in Korean patients with inflammatory bowel diseases during treatment with thiopurine drugs

et al. 2009

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There is a lack of research describing the associations between thiopurine methyltransferase (TPMT)/inosine triphosphate pyrophosphatase (ITPA) genotypes and long-term clinical outcomes. We investigated whether TPMT/ITPA genotypes predicted long-term clinical response in Korean patients with inflammatory bowel diseases (IBDs) undergoing thiopurine treatment. A total of 204 patients with IBD in whom thiopurine treatment was indicated were enrolled and categorized by TPMT and ITPA genotypes. Long-term follow-up clinical data for these patients were analyzed with specific focus on disease relapse. Of the 204 patients, 162 (79.4%) patients using thiopurines achieved remission and were included in an analysis of long-term clinical outcomes. There were no significant differences in disease relapse-free survival between wild and mutant types of TPMT (P¼0.903) or ITPA (P¼0.392), according to the results of the log-rank analysis. Our study suggests that TPMT and ITPA genotypes may not affect the rates of disease relapse in IBD patients treated with thiopurines. Further studies are indicated to confirm the utility of TPMT/ITPA genotyping to guide clinicians formulating individualized treatments for IBD patients requiring thiopurine therapy. Keywords: azathioprine; inflammatory bowel disease; inosine triphosphate pyrophosphatase; relapse; thiopurine S-methyl transferase INTRODUCTION Thiopurine drugs, 6-Mercaptopurine (6-MP) and its prodrug azathioprine (AZA), are effective for the induction and maintenance of remission in patients with inflammatory bowel disease (IBD). 1,2 There has been tremendous interest with regard to thiopurine metabolism as a means of identifying ways in which individual therapy might maximize clinical response and minimize adverse effects. Genetic polymorphisms in the thiopurine S-methyl transferase (TPMT) gene have been associated with decreased TPMT activity and the development of myelotoxicity due to high thioguanine metabolite concentrations. 3,4 Moreover, inosine triphosphate pyrophosphatase (ITPA) deficiency has recently been associated with AZA toxicity because of the accumulation of 6-thioinosine-triphosphate. 5,6 Theoretically, low TPMT activity might also augment the therapeutic efficacy of thiopurines and lead to better long-term clinical outcomes. To confirm the usefulness of the TPMT/ITPA genotype or TPMT activity in clinical prediction, research regarding the relevance of measurement for prevention of both adverse effects and clinical outcomes is necessary. However, the impact of the TPMT/ITPA genotype on long-term clinical response of IBD patients treated with AZA/6-MP has not yet been examined. In this study, we investigated whether TPMT/ ITPA genotypes could affect long-term clinical outcomes as measured by disease relapse in Korean patients with IBD undergoing AZA or 6-MP treatment. MATERIALS AND METHODSA total of 204 patients with IBD (105 patients with Crohn's disease, 59 with ulcerative colitis and 40 with intestinal Behcet's disease) were initiated on AZA treatment during the s...

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Section: Discussionmentioning

confidence: 99%

Correlation of genotypes for thiopurine methyltransferase and inosine triphosphate pyrophosphatase with long-term clinical outcomes in Korean patients with inflammatory bowel diseases during treatment with thiopurine drugs

et al. 2009

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“…There is potentially a wealth of knowledge contained within the known IBD loci [121], and fine mapping of the genes within these regions will identify novel genetic influences. Pharmacogenomics may play an increasing role, and has been introduced by advances in the understanding of thiopurine metabolism [141]. Awareness of genetic influences such as MDR1 polymorphisms [142] may help tailor therapy to individuals.…”

Section: Expert Commentary and Five-year Viewmentioning

confidence: 99%

Crohn’s disease as an immunodeficiency

Hayee

Rahman

Sewell

et al. 2010

Expert Review of Clinical Immunology

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The pathogenesis of Crohn's disease (CD) has widely been regarded as the consequence of a dysregulated T-cell-mediated response to intestinal microbes, and the majority of the worldwide research effort has focused on characterizing and treating the chronic inflammatory phase of the disease. However, recent molecular biological and clinical investigations indicate that CD is actually a primary immunodeficiency. At first counter-intuitive, the apparent paradox of a pathogenic innate immune defect can be linked mechanistically to the granulomatous chronic inflammation characteristic of the disease. Genome-wide association studies have corroborated the involvement of innate immune dysfunction in the pathogenesis of CD, but less than 20% of the heritable risk is accounted for. By contrast, in vitro and in vivo stimulation of the immune system has highlighted novel areas of interest that may lead to the development of targeted therapeutic and diagnostic tools. Keywordsbacteria; Crohn's disease; immunodeficiency; innate immunity; macrophage; neutrophil Established intestinal lesions in Crohn's disease (CD) contain a massive, mixed inflammatory cell infiltrate associated with a complex storm of cytokines in a selfperpetuating, chronic inflammatory response [1][2][3]. Most research to date has focused on the the immunological characteristics of established lesions and drawn inferences about their initiation. The predominance of a classically Th1-associated cytokine profile in these lesions led to the assumption that T lymphocytes were central to the initial pathogenesis. More recently, the role of regulatory (Treg) FoxP3 + and IL-23-induced responsive Th17-type T lymphocytes has gained popularity [2,4,5]. Treg cell populations are diminished in patients with CD [6] and, although the hypothesis of CD as an immunodeficiency does not necessarily exclude defects in T-cell function, to date, no convincing intrinsic (primary) defect has been identified to implicate these cells in the pathogenesis of human CD.The hypothesis that immunodeficiency underpins the development of CD seems, at first, to be in direct contrast with histological observations of established intestinal lesions and the † Author for correspondence: Tel.: +44 207 679 6170 Fax: +44 207 679 0967 b.hayee@nhs.net. Financial & competing interests disclosure The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Europe PMC Funders Group Association between immunodeficiency diseases & CDThere is a well-known and strong association between primary immunodeficiency disorders and non-infectious granulomatous intestinal inflammation. Chronic granulomatous disease (CGD), glycogen storage disease type 1b, leukocyte adhesion deficiency, Chediak-Higashi and Hermansky-Pudlak syndromes are all strongly associated with intestinal inflammation that is indistinguishable from CD [...

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“…47,48 However, it is also associated with additional adverse e¡ects, particularly nausea. 9 A number of factors may in£uence the development of toxicity in heterozygotes, including starting dose, rate of dose escalation, compliance and the co-administration of corticosteroids (which may mask neutropaenia by causing relative neutrophilia). Overall, heterozygous TPMT activity is associated with a 435% risk of toxicity on standard doses of AZA or 6-MP.…”

Section: Tpmt and Thiopurine Therapymentioning

confidence: 99%

Thiopurine methyltransferase: should it be measured before commencing thiopurine drug therapy?

et al. 2004

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Thiopurines [azathioprine (AZA), 6-mercaptopurine (6-MP) and thioguanine (6-TG)] have a well-established role as immunosuppressive agents in a variety of chronic inflammatory conditions, haematological neoplasia and in transplant rejection. Despite good overall clinical response rates, particularly when used as steroid sparing agents, adverse effects are a limiting problem leading to withdrawal in up to a quarter of patients. Severe myelosuppression is the most serious toxicity occurring early or occasionally later during treatment.An understanding of the competing pathways involved in the metabolism of thiopurines has important implications for predicting some of the more severe toxicity seen with these drugs. Thiopurine methyl transferase (TPMT) is an enzyme catalysing the methylation of 6-MP, competing with xanthine oxidase (XO) and hypoxanthine guanine phosphoribosyl transferase (HGPRT) to determine the amount of 6-MP metabolised to cytotoxic thioguanine nucleotides. Allelic polymorphisms in the TPMT gene predict the activity of the enzyme such that 1 in 10 of the population are heterozygous and have approximately 50% of normal activity, whilst 1 in 300 are completely deficient. As a result, these individuals are at high risk of severe myelosuppression. Conversely, individuals with very high levels of TPMT activity are hyper-methylators in whom clinical response is less likely.Prior knowledge of TPMT status avoids exposure of individuals with zero TPMT to potentially fatal treatment with AZA or 6-MP and provides one of the best examples of predictive pharmacogenetics in therapeutics. This article reviews literature on the role of TPMT measurement prior to treatment with thiopurines and provides some guidance to the use of TPMT as a guide to tailoring thiopurine therapy.

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Thiopurine methyltransferase activity and the use of azathioprine in inflammatory bowel disease

Cited by 223 publications

References 25 publications

Correlation of genotypes for thiopurine methyltransferase and inosine triphosphate pyrophosphatase with long-term clinical outcomes in Korean patients with inflammatory bowel diseases during treatment with thiopurine drugs

Correlation of genotypes for thiopurine methyltransferase and inosine triphosphate pyrophosphatase with long-term clinical outcomes in Korean patients with inflammatory bowel diseases during treatment with thiopurine drugs

Crohn’s disease as an immunodeficiency

Thiopurine methyltransferase: should it be measured before commencing thiopurine drug therapy?

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