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Rheumatology Advance Access originally published online on January 25, 2007
Rheumatology 2007 46(5):727-729; doi:10.1093/rheumatology/kel427
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

EDITORIALS

TPMT testing in rheumatology: any better than routine monitoring?

K. Payne1,2, W. Newman2,5, E. Fargher1,2, K. Tricker1,2, I. N. Bruce3,6 and W. E. R. Ollier4

1Nowgen, The North West Genetics Knowledge Park, 2Academic Unit of Medical Genetics, 3arc Epidemiology Unit, 4Centre for Integrated Genomic Medical Research, The University of Manchester, 5Department of Medical Genetics and 6Rheumatism Research Centre, Central Manchester and Manchester Childrens’ University Hospitals NHS Trust, UK

Correspondence to: Dr Katherine Payne. E-mail: Katherine.payne{at}manchester.ac.uk

Azathioprine has been available as an immunosuppressive agent for over 40 yrs and is used widely in the management of rheumatological and other diseases [1]. In 2004, nearly 0.6 million prescriptions for azathioprine were dispensed in the community in England [2]. Azathioprine is an effective drug but there are concerns about the development of major adverse drug reactions. The past decade has seen a significant change in azathioprine prescribing practice in the UK following the introduction of thiopurine methyltransferase (TPMT) enzyme testing. Azathioprine dose selection based on TPMT enzyme testing to minimize the risk of neutropenia, offers the prospect of safer, more effective treatment.

Azathioprine is metabolized to its active metabolite by a series of enzyme steps, including TPMT. TPMT enzyme activity is highly variable: 90% of individuals have high/normal activity, 10% have intermediate activity and 0.3% low/absent activity [3]. The TPMT gene variant was originally described in 1980 [4], but did not appear in the mainstream medical literature until 1992 [5]; just after the first clinical enzyme testing service for adults in the UK was introduced [6]. In 1997, a survey of UK dermatologists showed no one used pre-treatment TPMT enzyme testing [7]. By 2000 dermatologists made the largest number of requests (54%) for this assay, with just 1% of requests being made by rheumatologists [6]. More recently a UK national survey, with a 70% response rate, reported that virtually all respondents reported prescribing azathioprine, 98% of dermatologists, 96% of gastroenterologists and 98% of rheumatologists, and of these UK clinicians 67% used pre-treatment TPMT enzyme testing. The uptake of testing differed markedly between clinicians with 95% of dermatologists, 60% of gastroenterologists and only 47% of rheumatologists reporting using TPMT testing [1]. High uptake of enzyme testing by dermatologists may reflect national guidelines advocating its use. In 2000 the British Society of Rheumatology (BSR) guidelines published for the pre-treatment assessment and subsequent monitoring of patients requiring azathioprine made no reference to TPMT status [8]. The guidelines recommended regular measurements of full blood counts, liver function tests and electrolyte measurements. Now, the updated BSR guidelines recommend that TPMT enzyme testing ‘should be considered’ prior to prescribing azathioprine [9]. Guidelines from other professional bodies tend to differ. The British Association of Dermatologists are most prescriptive, directing that ‘pre-treatment TPMT measurement should be performed in all patients prescribed azathioprine for treatment of dermatological conditions’ [10]. In contrast, the British Society of Gastroenterology state ‘It cannot yet be recommended as a prerequisite to therapy, because decades of experience has shown clinical azathioprine to be safe in Ulcerative Colitis or Crohn's Disease’ [11].

The debate about the routine use of pre-treatment TPMT testing has raged for a number of years and was highlighted by submissions to the Food and Drug Administration (FDA). In 2004, the FDA approved a TPMT enzyme diagnostic test and made recommendations regarding the inclusion of advice about TPMT testing in thiopurine drug packaging, but deferred from making testing compulsory [12]. Despite strong petitions in favour of TPMT testing, many clinicians argued that it might delay treatment, result in inaccurate dosing or be difficult to interpret. Furthermore, the FDA only considered the case for TPMT testing in the context of thiopurine use in oncology. Importantly TPMT status does not predict all adverse drug reactions (ADRs) associated with thiopurine use and specifically does not identify all individuals at increased risk of haematological toxicity [13]. Although variants in other genes important in azathioprine metabolism, including ITPase, have been associated with other ADRs, the use of these has not translated into clinical practice [14].

Stolk et al. (1998) [15] reported that 14 of 33 patients prescribed azathioprine for rheumatoid arthritis rapidly developed severe side-effects especially gastrointestinal intolerance. More severe ADRs include profound neutropenia, hepatotoxicity and pancreatitis. Black (1998) [16] found that 37% of 67 patients with rheumatic diseases taking azathioprine stopped the drug because of nausea, abnormal liver function tests or low leucocyte counts. To minimize gastrointestinal ADRs and because of concerns relating to profound neutropenia, prescribers often introduce azathioprine treatment incrementally using weight-based dosing but this may delay when therapeutic levels are achieved. The high incidence of ADRs has made routine monitoring while patients continue to take the drug the standard in clinical practice.

TPMT enzyme activity is largely influenced by variants (polymorphisms) in the TPMT gene. Over 23 variants in the TPMT gene, associated with decreased TPMT activity, have been identified [17]. Three variant alleles, TPMT*2, TPMT*3A and TPMT*3C, account for 80–95% of intermediate or low activity cases [18]. Although the overall prevalence of TPMT deficiency is similar between different ethnic groups, the frequency of variant alleles differs between different populations, for example, there is a higher representation of the TMPT*3A allele in South Asians compared with the high carriage of TPMT*3C in East and West Africans [19].

Genotyping or phenotyping techniques can be used to identify TPMT status and the possible risk of developing profound neutropenia [20]. TPMT phenotyping is currently available at Guy's Hospital, London and City Hospital, Birmingham; whereas genotyping is not available as part of the routine UK clinical practice. TPMT enzyme measurement is based on the red cell activity levels, which can be distorted following blood transfusion. Up to 10% of inflammatory bowel disease (IBD) patients undergoing TPMT assessment have had a blood transfusion in the previous 4 months (M. Schwab, personal communication). In addition, TPMT enzyme analysis is technically challenging and results are prone to variation. The development of an external quality assessment service (UK NEQAS) for TPMT activity analysis should diminish these concerns. Genotyping for the common TPMT variants is technically straightforward. However, genotyping may not identify all TPMT deficient individuals. Genotyping and phenotyping have similar costs and clinical report turnaround times of 1 week and when the majority of known TPMT gene variants were assessed, the concordance rate between TPMT genetics and phenotypes was 98.4% [21]. Therefore, TPMT phenotyping and genotyping may be complimentary. Phenotyping may be the preferable routine test with genotyping reserved for individuals post blood transfusion or who are taking drugs that can alter TPMT activity, e.g. aspirin and sulphasalazine. Given the test variability and confounding due to commonly co-prescribed medications and co-interventions, robust evidence is needed to support the universal use of these tests. The true impact of introducing a genotype or phenotype test pre-prescription of azathioprine cannot be known without studies that examine in detail the introduction of such tests into routine clinical practice.

There is some evidence that suggests pre-treatment TPMT testing may be effective in reducing the number of profound neutropaenic episodes experienced by patients prescribed azathioprine but there is less evidence about its role in achieving improved drug efficacy [16]. To date there have been no large prospective randomized controlled trials (PRCTs) to assess the value of TPMT testing prior to azathioprine treatment in terms of the impact on safety and effectiveness. The BSR Guidelines suggest that the role of TPMT in predicting haematotoxicity in rheumatological diseases could be considered for future PRCTs [9]. Such a trial is currently in progress: the TARGET (TPMT: Azathioprine Response to Genotyping and Enzyme Testing) study funded by the Department of Health [22]. This study aims to establish the clinical utility and cost-effectiveness of TPMT genotyping in reducing the number of ADRs associated with prescribing azathioprine. The primary outcome for the TARGET study is reducing or stopping azathioprine due to a white blood cell count falling below 4 x 109/l in the first 4 months of treatment. TARGET is designed to detect a reduction from 14% to 8% in the primary outcome measure and 80% power will be achieved if 500 patients are randomized to each arm. One vital question is what is the added value of the genotype or phenotype testing? Laboratories currently charge around £30 per TPMT enzyme test [23]. However, the total cost to the NHS for providing the genotype or phenotype test is not known. The NHS is funded from a finite set of resources and evidence of clinical efficacy alone is no longer considered sufficient to inform which interventions should be offered to patient populations. National decision-making bodies, such as the National Institute for Health and Clinical Excellence, appraise new interventions based on evidence of their clinical and cost-effectiveness. The cost of TPMT testing may be offset by improved patient benefits and quality of life, by reducing the incidence of severe and costly ADRs and reducing the need for routine blood monitoring. There is limited evidence for the economic impact of introducing genotype tests to tailor the prescription of drugs for individual patients’ needs [24].

Some evidence supporting the cost-effectiveness of pre-treatment TPMT testing exists. Sayani et al. [25] prospectively randomized 29 Canadian patients with IBD to TPMT enzyme testing or no testing pre-azathioprine and concluded that patients who received TPMT testing incurred higher healthcare costs but there was no correlation between TPMT activity and azathioprine-induced ADRs. This study should be interpreted with caution due to the small sample size. Dubinsky et al. [26] developed a one-year economic model comparing TPMT testing, and/or metabolite monitoring with standard practice in community care in patients with Crohn's disease. Each strategy was shown to dominate (more effective and less costly) community care. The model was limited in that it did not consider the impact of factors that might interfere with metabolite monitoring and most model inputs were based on expert opinion rather than trial data. Winter et al. [27] modelled the cost-effectiveness of TPMT genotyping in 1000 patients starting azathioprine for IBD. The cost-effectiveness of genotyping varied depending on the age of the individual with estimates of £347 per life-yr saved for a 30-yr old and £817 per life-yr saved for a 60-yr old. The model assumed that 32 people would develop leucopenia and genotyping avoided one death. Healthcare resources associated with testing and treating ADRs were estimated rather than based on actual NHS data. In rheumatic diseases, Marra et al. (2004) [28] modelled the cost-effectiveness of pre-treatment TPMT genotyping compared with no testing. The model assumed that genotyping would eliminate 50% of the cases of haematological toxicity. Cost data were estimated by interviewing a haematologist. The results were very sensitive to the cost of the genetic test, estimating a threshold test cost of US$114, and the intervention ranged from being slightly cost saving to relatively modest increases in cost compared with the standard practice. Oh et al. [29] designed an economic model to compare genotype-based dosing with conventional dosing in a Korean patient population with rheumatological conditions. Genotyping was suggested to be more effective, measured as the neutropenia-induced drop-out rate, and less costly than conventional dosing. The results from this model should also be interpreted with caution, since the model used prevalence rates of TPMT activity from a Caucasian, rather than Korean, population, whereas the data on resource use came from Korean hospitals. The model suffers from inclusion of mixed data from potentially non-comparable patient populations. Furthermore, the model may not accurately reflect clinical practice as it ignored issues such as adherence to azathioprine dependent on other more common side effects or patient preference. These retrospective modelling studies are a useful start to exploring cost-effectiveness, however, they fall short of being robust evidence with which to inform decision-making. The interventions described may not reflect clinical practice in terms of standard care and management of ADRs and the actual impact on NHS resources and patient benefit was not measured. All the studies used existing prevalence data on TPMT enzyme status and omitted key variables such as the impact on quality of life.

Lack of health economic data is a key barrier hindering the implementation of pharmacogenetics into clinical practice. A PRCT evaluating the clinical utility and cost-effectiveness in appropriate patient populations is a prerequisite to develop a sufficient evidence base to inform clinical practice and guideline development. We fear that future PRCT evaluating pharmacogenetics may be hindered because clinicians are reluctant to ignore professional body guidelines and enrol patients in a study that offers a 50:50 chance of being offered genotyping. Yet without such trial evidence we may never know whether introducing such promising technologies has any added value to the patient over that conferred by routine clinical practice. We will also never know whether there are groups of patients in which we can safely dispense with rigorous and costly blood monitoring when newer tests reassure us that no harm will arise. Although there is persuasive evidence for recommending the adoption of routine TPMT testing, the evidence base remains suboptimal. Suspending or not starting routine use of TPMT testing to enrol patients in a trial to determine the clinical utility of this test is consistent with the clinical equipoise of determining the true benefit of TPMT testing [30]. We therefore encourage all rheumatologists to consider recruiting subjects to PRCTs to establish the value of pharmacogenetic testing and believe that results from such trials will truly enhance safe clinical practice.

Acknowledgements

The authors are funded through the Department of Health, UK Pharmacogenetics programme and are members of the TARGET study.

K.P., W.N., I.B. and W.O. are investigators on the Department of Health funded TARGET study.

E.F. and K.T. are researchers on the Department of Health funded TARGET study.

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Accepted 30 November 2006


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