Erratum: A 6-Thioguanine Nucleotide Threshold Level of 400 pmol/ 8 × 108 Erythrocytes Predicts Azathioprine Refractoriness in Patients With Inflammatory Bowel Disease and Normal TPMT Activity

Roblin, Xavier; Biroulet, Laurent Peyrin; Phelip, Jean Marc; Nancey, Stéphane; Flourié, Bernard

doi:10.1038/ajg.2009.157

Cited by 3 publications

(8 citation statements)

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“…Approximately, 9% of IBD patients are classified as resistant to thiopurines . This retrospective study showed for the first time that a 6‐TGN level above 405 pmol/8.10 8 RBCs in children with normal TPMT activity who did not achieve steroid‐free clinical remission was predictive of AZA refractoriness, and this is consistent with the result of a previous prospective study in adults in which, a 6‐TGN level threshold of >400 pmol/8.10 8 RBCs was found. This finding supports that serial metabolite monitoring provides a useful tool to identify IBD patients resistant to thiopurine therapy in order to prevent unnecessary and costly escalation of AZA dose.…”

Section: Discussionsupporting

confidence: 90%

“…It is well established that some IBD patients do not respond to thiopurine despite high 6‐TGN levels . Approximately, 9% of IBD patients are classified as resistant to thiopurines .…”

Section: Discussionmentioning

confidence: 99%

“…A 6‐TGN level of ≥235–260 pmol/8 × 10 8 RBCs is desirable to achieve clinical response . Recently, it has been suggested that a 6‐TGN level above 400 pmol/8 × 10 8 RBCs in adult patients with normal TPMT activity and steroid‐dependent or active disease despite an optimal AZA regimen may predict refractoriness to AZA, but no 6‐TGN cutoff value has been determined to date in children. A 6‐TGN level above 450 pmol/8 × 10 8 RBCs may lead to myelotoxicity, while a 6‐MeMPN level above 5,700 pmol/8 × 10 8 RBCs may correlate with hepatotoxicy .…”

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confidence: 99%

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Usefulness of Thiopurine Metabolites in Predicting Azathioprine Resistance in Pediatric IBD Patients

Nguyen

Lachaux

et al. 2013

The Journal of Clinical Pharma

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Few data on azathioprine (AZA) therapy for inflammatory bowel disease (IBD) exist for children. We evaluated whether the 6-thioguanine nucleotides (6-TGN) level predicts AZA refractoriness in children with IBD and whether children benefit an AZA dose escalation. Seventy-eight children with IBD initially treated with an AZA dose of 1.5-2.5 mg/kg/day were retrospectively included. The dose was adjusted based on the clinical status. The receiver operating characteristic curve and logistic regression were used to determine predictors for AZA resistance. Initially, 18 of 40 (45%) patients receiving a dose of <2 mg/kg/day and 11 of 38 (28.9%) patients receiving a dose of 2-2.5 mg/kg/day achieved remission. The 6-TGN level above 250 pmol/8.10(8) RBCs was associated with a higher remission rate, though non-significant. Among 35 patients with a dose escalation due to treatment failure, 12 (34.3%) achieved remission (the median 6-TGN level increased from 260 to 394 pmol/8.10(8) RBCs [P = .002]), 23 (67.6%) were AZA refractory. A 6-TGN level above 405 pmol/8.10(8) RBCs was the only predictor for AZA resistance (sensitivity 78.3%, specificity 75%, OR 10.8 [95% CI: 2.1-55.7, P = .004]). Serial metabolite monitoring is useful to identify children with IBD resistant to AZA. Children who cannot achieve remission despite a 6-TGN level above 405 pmol/8.10(8) RBCs should receive alternative therapies than dose increase.

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Section: Discussionsupporting

confidence: 90%

“…It is well established that some IBD patients do not respond to thiopurine despite high 6‐TGN levels . Approximately, 9% of IBD patients are classified as resistant to thiopurines .…”

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Usefulness of Thiopurine Metabolites in Predicting Azathioprine Resistance in Pediatric IBD Patients

Nguyen

Lachaux

et al. 2013

The Journal of Clinical Pharma

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“…Thiopurine‐induced liver toxicity has been divided into three categories: hypersensitivity, idiosyncratic cholestatic reactions and nodular regenerative hyperplasia . Regular monitoring of 6MMPR concentrations and liver transaminases may be useful for identification of patients at risk of hepatotoxicity .…”

Section: Introductionmentioning

confidence: 99%

“…Production of 6TGN is catalyzed by IMPDH. Concentrations ≥235 pmol/8 × 10 8 RBC and ≥450 pmol/8 × 10 8 RBC have been associated with clinical remission and haematological toxicity respectively . Haematological toxicity, commonly manifesting as leucopenia, has been linked to homozygous recessive TPMT genotype and intermediate or low TPMT activity .…”

Section: Introductionmentioning

confidence: 99%

Thiopurine monitoring in children with inflammatory bowel disease: a systematic review

Konidari

Anagnostopoulos

Bonnett

et al. 2014

Brit J Clinical Pharma

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Aims The aim was to systematically review the evidence on the clinical usefulness of thiopurine metabolite and white blood count (WBC) monitoring in the assessment of clinical outcomes in children with inflammatory bowel disease (IBD). Methods Medline, Embase, Cochrane Central Register of controlled trials and http://www.clinicaltrials.gov were screened in adherence to the PRISMA statement by two independent reviewers for identification of eligible studies. Eligible studies were randomized controlled trials (RCTs), cohort studies and large case series of children with inflammatory bowel disease (IBD) (<18 years) who underwent monitoring of thiopurine metabolites and/or WBC. Results Fifteen papers were identified (n = 1026). None of the eligible studies were RCTs. High 6‐thioguanine nucleotide (6TGN) concentrations were not consistently associated with leucopenia. Leucopenia was not associated with achievement of clinical remission. A positive but not consistent correlation between 6TGN and clinical remission was reported. Haematological toxicity could not be reliably assessed with 6TGN measurements only. A number of studies supported the use of high 6‐methylmercaptopurine ribonucleotides (6MMPR) as an indicator of hepatotoxicity. Low thiopurine metabolite concentration may be indicative of non‐compliance. Conclusion Thiopurine metabolite testing does not safely predict clinical outcome, but may facilitate toxicity surveillance and treatment optimization in poor responders. Current evidence favours the combination of thiopurine metabolite/WBC monitoring and clinic follow‐up for prompt identification of haematologic/hepatic toxicity safe dose adjustment, and treatment modification in cases of suboptimal clinical outcome or non‐compliance. Well designed RCTs for the identification of robust surrogate markers of thiopurine efficacy and toxicity are required.

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The Role of Laboratory Tests in Crohn's Disease

Cappello

Morreale

2016

Clin Med Insights Gastroenterol

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In the past, laboratory tests were considered of limited value in Crohn’s disease (CD). In the era of biologics, laboratory tests have become essential to evaluate the inflammatory burden of the disease (C-reactive protein, fecal calprotectin) since symptoms-based scores are subjective, to predict the response to pharmacological options and the risk of relapse, to discriminate CD from ulcerative colitis, to select candidates to anti-tumor necrosis factors [screening tests looking for hepatitis B virus and hepatitis C virus status and latent tuberculosis], to assess the risk of adverse events (testing for thiopurine metabolites and thiopurine-methyltransferase activity), and to personalize and optimize therapy (therapeutic drug monitoring). Pharmacogenetics, though presently confined to the assessment of thiopurineme methyltransferase polymorphisms and hematological toxicity associated with thiopurine treatment, is a promising field that will contribute to a better understanding of the molecular mechanisms of the variability in response to the drugs used in CD with the attempt to expand personalized care and precision medicine strategies.

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Erratum: A 6-Thioguanine Nucleotide Threshold Level of 400 pmol/ 8 × 108 Erythrocytes Predicts Azathioprine Refractoriness in Patients With Inflammatory Bowel Disease and Normal TPMT Activity

Cited by 3 publications

References 0 publications

Usefulness of Thiopurine Metabolites in Predicting Azathioprine Resistance in Pediatric IBD Patients

Usefulness of Thiopurine Metabolites in Predicting Azathioprine Resistance in Pediatric IBD Patients

Thiopurine monitoring in children with inflammatory bowel disease: a systematic review

The Role of Laboratory Tests in Crohn's Disease

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