Thiopurine Methyltransferase Activity in Spain: A Study of 14,545 Patients

Gisbert, Javier P.; Gomollón, Fernando; Cuite, Cara L.; Luna, Marta; González-Lama, Yago; Jm, Pajares García; Maté, José; Guijarro, Luis G.

doi:10.1007/s10620-006-9119-z

Cited by 85 publications

(53 citation statements)

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“…26 The cost for determining TPMT by this method is h40 per determination. Assuming a rate of 1:200 for TMPT deficiency 24 one arrives at a highend average cost of h8000 per identified TPMT-deficient individual for Spain (Table 2). Wider application of TPMT testing in Spain would likely lead to substantially reduced costs.…”

Section: Methodsmentioning

confidence: 99%

Improving pharmacovigilance in Europe: TPMT genotyping and phenotyping in the UK and Spain

et al. 2009

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Thiopurine S-methyltransferase (TPMT) is the rate-limiting step in the conversion of thiopurine drugs including azathioprine (AZA) to inactive metabolites. Heritable deficiency of TPMT activity increases risk for adverse events, most notably, myelosuppression leading to leukopenia and neutropenic sepsis. The reported European Commission study was undertaken to identify current evidence for the clinical utility of testing for TPMT status and extent of uptake, by either genotyping or phenotyping, in the clinical setting. Data presented here for the UK and Spain indicate that there has been a considerable increase in the uptake of TPMT testing in recent years. There are some data that support routine TPMT testing before AZA prescribing for reducing AZA-related adverse events. Key data include evidence in favor of TPMT testing in addition to the current practice of routine monitoring for reducing the number of AZA-related episodes of myelosuppression, averting deaths from neutropenic sepsis and improving health-related quality of life. Further data are needed for determining the cost-effectiveness of routine TPMT testing.

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Section: Methodsmentioning

confidence: 99%

Improving pharmacovigilance in Europe: TPMT genotyping and phenotyping in the UK and Spain

et al. 2009

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“…99 Prevalence of TPMT activity originated from a population-based cohort study of the distribution of phenotypic TPMT activity in 14,545 Spanish patients with diseases amenable to treatment with azathioprine. 101 Gisbert and colleagues 101 found that TPMT activity was low in 0.5% of the cohort, intermediate in 11.9% and high in 87.6%. Treatment efficacy was assessed through disease progression, defined by a decline in FVC of at least 10%.…”

Section: Modelling Approachmentioning

confidence: 99%

The clinical effectiveness and cost-effectiveness of treatments for idiopathic pulmonary fibrosis: a systematic review and economic evaluation

Loveman

Copley

Colquitt

et al. 2015

Health Technology Assessment

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BackgroundIdiopathic pulmonary fibrosis (IPF) is a life-limiting lung disease that generally affects people over 60 years old. The main symptoms are shortness of breath and cough, and as the disease progresses there is a considerable impact on day-to-day life. Few treatments are currently available.ObjectivesTo conduct a systematic review of clinical effectiveness and an analysis of cost-effectiveness of treatments for IPF based on an economic model informed by systematic reviews of cost-effectiveness and quality of life.Data sourcesEleven electronic bibliographic databases, including MEDLINE, EMBASE, Web of Science, and The Cochrane Library and the Centre for Reviews and Dissemination databases, were searched from database inception to July 2013. Reference lists of relevant publications were also checked and experts consulted.MethodsTwo reviewers independently screened references for the systematic reviews, extracted and checked data from the included studies and appraised their risk of bias. An advisory group was consulted about the choice of interventions until consensus was reached about eligibility. A narrative review with meta-analysis was undertaken, and a network meta-analysis (NMA) was performed. A decision-analytic Markov model was developed to estimate cost-effectiveness of pharmacological treatments for IPF. Parameter values were obtained from NMA and systematic reviews. Univariate and probabilistic sensitivity analyses were undertaken. The model perspective is NHS and Personal Social Services, and discount rate is 3.5% for costs and health benefits.ResultsFourteen studies were included in the review of clinical effectiveness, of which one evaluated azathioprine, threeN-acetylcysteine (NAC) (alone or in combination), four pirfenidone, one BIBF 1120, one sildenafil, one thalidomide, two pulmonary rehabilitation, and one a disease management programme. Study quality was generally good, with a low risk of bias. The current evidence suggests that some treatments appear to be clinically effective. The model base-case results show increased survival for five pharmacological treatments, compared with best supportive care, at increased cost. General recommendations cannot be made of their cost-effectiveness owing to limitations in the evidence base.LimitationsFew direct comparisons of treatments were identified. An indirect comparison through a NMA was performed; however, caution is recommended in the interpretation of these results. In relation to the economic model, there is an assumption that pharmacological treatments have a constant effect on the relative rate of per cent predicted forced vital capacity decline.ConclusionsFew interventions have any statistically significant effect on IPF and a lack of studies on palliative care approaches was identified. Research is required into the effects of symptom control interventions, in particular pulmonary rehabilitation and thalidomide. Other research priorities include a well-conducted randomised controlled trial on inhaled NAC therapy and an updated evidence synthesis once the results of ongoing studies are reported.Study registrationThis study is registered as PROSPERO CRD42012002116.FundingThe National Institute for Health Research Health Technology Assessment programme.

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“…11. Low TPMT activity and high 6-TGN concentrations have been linked to therapeutic success and myelosuppression in IBD patients treated with thiopurines [3,8]. Yet, none of these metabolites or activities was measured in the study.…”

mentioning

confidence: 97%

Is Less More: Does Leukopenia Predict Remission in Patients with Inflammatory Bowel Disease Receiving Thiopurine Treatment?

Gisbert

2014

Dig Dis Sci

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The thiopurine drugs azathioprine (AZA) and mercaptopurine (MP) effectively maintain remission in patients with inflammatory bowel disease (IBD) [1]. Dosing of AZA and MP is generally weight based, with the intention of achieving the highest therapeutic efficacy and, at the same time, reducing the incidence of adverse effects. Several strategies have been proposed to optimally dose thiopurines with the intention, on the one hand, to identify patients at risk of adverse effects (mainly myelotoxicity) and, on the other hand, to detect patients with subtherapeutic doses and inadequate immunosuppression [2]. These strategies include monitoring changes in the red cell mean corpuscular volume, induction of leukopenia, quantification of 6-thioguanine nucleotides (6-TGN), and the monitoring of thiopurine methyltransferase (TPMT) activity.Mild or chronic leukopenia, generally defined as a white cell count between 3,000 and 4,000/lL, is the commonest hematologic effect of thiopurines, appearing in 5-25 % of the patients receiving these drugs [3]. The incidence rate of myelotoxicity in IBD patients receiving AZA/MP has been calculated, in a recent systematic review, to be approximately 3 %/patient-year of treatment [3]. Although leukopenia is a well-recognized effect of AZA/MP treatment, its association with therapeutic efficacy has yet to be determined, although the induction of leukopenia is probably closely related to the therapeutic mechanisms of thiopurines.In this context, the aim of the study by Park et al. [4] published in this issue of Digestive Diseases and Sciences was to evaluate the correlation between thiopurine-induced leukopenia and clinical outcomes in Korean IBD patients who achieved clinical remission with thiopurines. The authors included 196 IBD patients [45 with ulcerative colitis (UC), 68 with Crohn's disease (CD), and 83 with intestinal Behçet's disease] who were treated with AZA/ MP and had achieved remission. Then, the authors retrospectively analyzed the lowest white blood cell (WBC) count during AZA/MP treatment, duration of remission, and the occurrence of relapse and compared the clinical evolution between leukopenic (WBC count \4,000/lL) and non-leukopenic patients. The authors reported that the cumulative relapse-free survival rate was higher in the leukopenic group. Thus, relapse occurred in 31 % of leukopenic patients and in 54 % of non-leukopenic patients (P = 0.001). Using multivariate analysis, the presence of leukopenia was inversely associated with relapse. Therefore, the authors concluded that leukopenia occurring during thiopurine maintenance therapy is associated with prolonged remission in patients with IBD, including those with Behçet's disease.Although undoubtedly interesting and clinically relevant, this study has several limitations that should be taken into account:1. The first and obvious shortcoming is the retrospective design of the study. 2. Korean patients seem to become leukopenic at a higher rate than Western patients. Compared with previous reports based on Western po...

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Thiopurine Methyltransferase Activity in Spain: A Study of 14,545 Patients

Cited by 85 publications

References 40 publications

Improving pharmacovigilance in Europe: TPMT genotyping and phenotyping in the UK and Spain

Improving pharmacovigilance in Europe: TPMT genotyping and phenotyping in the UK and Spain

The clinical effectiveness and cost-effectiveness of treatments for idiopathic pulmonary fibrosis: a systematic review and economic evaluation

Is Less More: Does Leukopenia Predict Remission in Patients with Inflammatory Bowel Disease Receiving Thiopurine Treatment?

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