A Prospective Study Evaluating Metabolic Capacity of Thiopurine and Associated Adverse Reactions in Japanese Patients with Inflammatory Bowel Disease (IBD)

Odahara, Shunichi; Uchiyama, Kan; Kubota, Takeshi; Ito, Zensho; Takami, Shiro; Kobayashi, Hiroko; Saito, Keisuke; Koido, Shigeo; Ohkusa, Toshifumi

doi:10.1371/journal.pone.0137798

Cited by 26 publications

(18 citation statements)

References 33 publications

(42 reference statements)

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“…However, discontinuation of AZA due to cytopenic AEs was more frequent in the present study than in previous studies: 0-1.3% in AAV (5, 6), 1.9-4.5% in SLE (18, 20), and 8.3% in IBD (9). The initial dose of AZA was lower in the present study (0.63 mg/kg/day) than in a previous study (2 mg/kg/day for maintenance therapy during the first year).…”

Section: Discussioncontrasting

confidence: 74%

Azathioprine Intolerance in Japanese Patients with Antineutrophil Cytoplasmic Antibody-associated Vasculitis

et al. 2017

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Objective To assess the safety of azathioprine (AZA) in Japanese patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Methods We retrospectively enrolled 67 consecutive AAV patients who had initiated AZA treatment from January 2006 to August 2014 at Okayama University Hospital. We evaluated the development of severe adverse events (AEs), AZA discontinuation due to total AEs (severe AEs included) within 1 year, and AZA-associated risk factors. Results The patients' median age was 70 years old. Forty-nine women and 18 men participated at the initiation of the study. Fifty-eight (87%) patients experienced AEs, and 36 experienced severe AEs (21 hepatic and 11 cytopenic severe AEs). Thirty-one (46%) patients discontinued treatment because of AEs. Abnormal hepatic laboratory test results at the treatment initiation were more frequent in patients with hepatic severe AEs and were associated with treatment discontinuation. The leukocyte and neutrophil counts at the treatment initiation were lower in the patients who discontinued treatment because of cytopenic AEs than in those who continued treatment. Only two patients experienced flare-ups during treatment. Conclusion The AE-associated AZA discontinuation rate in Japanese AAV patients was relatively high. AZA use warrants caution in patients with abnormal hepatic laboratory test results or low leukocyte or neutrophil counts.

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Section: Discussioncontrasting

confidence: 74%

Azathioprine Intolerance in Japanese Patients with Antineutrophil Cytoplasmic Antibody-associated Vasculitis

et al. 2017

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“…More data on the relationship between ITPA genotype and ADRs of thiopurine drugs have been reported in the literature . Some studies concerning the paediatric population are available with only two studies on paediatric patients with immune disease (IBD) .…”

Section: Discussionmentioning

confidence: 99%

“…TPMT polymorphism explains only 30% to 60% of all cases with thiopurine intolerance . Among various other possible candidate enzymes involved in the metabolism of thiopurines, ITPA has been associated with the occurrence of adverse events (ADRs) in patients treated with AZA or 6‐MP in phenotypic and genotypic studies .…”

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confidence: 99%

“…The potential implication of ITPA in the occurrence of ADRs of AZA has been investigated. However, a number of contradictory results have been reported, from an impact of ITPA polymorphism on toxicity to no significant association . This issue remains unresolved, and no obvious statement about the benefit of introducing ITPA assay into clinical practice is currently available .…”

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confidence: 99%

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ITPA Activity in Children Treated by Azathioprine: Relationship to the Occurrence of Adverse Drug Reactions and Inflammatory Response

Citterio-Quentin

Moulsma

Gustin

et al. 2018

Basic Clin Pharma Tox

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Azathioprine (AZA), a thiopurine drug, is widely used in the treatment of children with immunological diseases such as inflammatory bowel disease (IBD) and autoimmune hepatitis (AIH); however, interindividual variability in the occurrence of adverse drug reactions (ADRs) and drug response is observed. This study investigated (i) the relationships between inosine triphosphate pyrophosphatase (ITPA) activity, an enzyme involved in thiopurine metabolism, and the occurrence of ADRs in children with immunological disease on AZA therapy, and (ii) the relationship between ITPA activity and the inflammatory activity observed in children with IBD. ITPA and TPMT activities were determined in 106 children with immunological disease on AZA therapy. Markers of hepatotoxicity, myelotoxicity, pancreatitis and inflammation as well as clinical information were retrospectively collected during regular medical visits. No significant association was found between ITPA activity and hepatotoxicity or clinical ADRs such as cutaneous reactions, arthralgia, flulike symptoms and gastrointestinal disorders. Concerning myelotoxicity, a significant relation was observed between ITPA activity and RBC mean corpuscular volume (MCV; p=0.003). This observation may be related to the significant relationship found between high ITPA activity and the increase in γ-globulin level reflecting inflammation (p=0.005). In our study, ITPA activity was not associated with occurrence of ADRs, but a relationship between high ITPA activity and γ-globulin, a marker of inflammation, was found in children with IBD. Therefore, measurement of ITPA activity may help to identify children with IBD predisposed to residual inflammation on AZA therapy. Further prospective studies are needed to confirm this result.

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“…The conflicting data underscores the fact that many different gene products have a role in thiopurine metabolism (at least 20), and phenotypic variation among patients may mask effects of ITPA variation in certain studies [ 70 ]. Indeed, studies that do not find a correlation between ITPA variation and drug toxicity identify small sample size, ethnicity, drug interactions and the retrospective nature of their studies as shortcomings [ 73 , 74 , 76 , 77 ]. In 2014, Matimba et al used a “three-tiered” experimental strategy to overcome some of the shortcomings associated with clinical studies.…”

Section: Introductionmentioning

confidence: 99%

A disease spectrum for ITPA variation: advances in biochemical and clinical research

Burgis

2016

J Biomed Sci

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Human ITPase (encoded by the ITPA gene) is a protective enzyme which acts to exclude noncanonical (deoxy)nucleoside triphosphates ((d)NTPs) such as (deoxy)inosine 5′-triphosphate ((d)ITP), from (d)NTP pools. Until the last few years, the importance of ITPase in human health and disease has been enigmatic. In 2009, an article was published demonstrating that ITPase deficiency in mice is lethal. All homozygous null offspring died before weaning as a result of cardiomyopathy due to a defect in the maintenance of quality ATP pools. More recently, a whole exome sequencing project revealed that very rare, severe human ITPA mutation results in early infantile encephalopathy and death. It has been estimated that nearly one third of the human population has an ITPA status which is associated with decreased ITPase activity. ITPA status has been linked to altered outcomes for patients undergoing thiopurine or ribavirin therapy. Thiopurine therapy can be toxic for patients with ITPA polymorphism, however, ITPA polymorphism is associated with improved outcomes for patients undergoing ribavirin treatment. ITPA polymorphism has also been linked to early-onset tuberculosis susceptibility. These data suggest a spectrum of ITPA-related disease exists in human populations. Potentially, ITPA status may affect a large number of patient outcomes, suggesting that modulation of ITPase activity is an important emerging avenue for reducing the number of negative outcomes for ITPA-related disease. Recent biochemical studies have aimed to provide rationale for clinical observations, better understand substrate selectivity and provide a platform for modulation of ITPase activity.

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A Prospective Study Evaluating Metabolic Capacity of Thiopurine and Associated Adverse Reactions in Japanese Patients with Inflammatory Bowel Disease (IBD)

Cited by 26 publications

References 33 publications

Azathioprine Intolerance in Japanese Patients with Antineutrophil Cytoplasmic Antibody-associated Vasculitis

Azathioprine Intolerance in Japanese Patients with Antineutrophil Cytoplasmic Antibody-associated Vasculitis

ITPA Activity in Children Treated by Azathioprine: Relationship to the Occurrence of Adverse Drug Reactions and Inflammatory Response

A disease spectrum for ITPA variation: advances in biochemical and clinical research

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