THIOPURINE METHYLTRANSFERASE SCREENING BEFORE AZATHIOPRINE PRESCRIPTION: A PHYSICIAN SURVEY
Main Article Content
Keywords
Thiopurine methyltransferase, rheumatology, azathioprine, toxicity
Abstract
Background
In patients treated with azathioprine, deficient thiopurine methyltransferase (TPMT) activity has been associated with haematologic toxicity.
Objectives
To determine how many Saskatchewan rheumatologists routinely pre-screen TPMT activity before prescribing azathioprine. Further, to retrospectively review TPMT activity levels from pre-screening in one patient cohort.
Methods
All rheumatologists practicing in the province of Saskatchewan were surveyed by questionnaire. The questionnaire scrutinized prevalence of routine TPMT screening pre-azathioprine initiation, response to abnormal test results, monitoring frequencies, starting dosages, and attitudes towards potential consensus guidelines or practice standards. For the second objective of this study, health region laboratory database retrieval identified 42 patients who had undergone TPMT phenotype testing within a single rheumatology practice. Chart review of all 42 patients was performed to verify test results.
Results
In a survey of all eleven Saskatchewan rheumatologists, 55% reported routinely pre-screening, compared to 45% who never screen pre-azathioprine. Half of those who pre-screen, report avoidance of azathioprine in both patients with deficiency and those with intermediate activity levels. The majority of respondents indicated they would adjust their practice to conform to future national rheumatology clinical guidelines. A retrospective review in one practice revealed TPMT activity values consistent with deficiency, carrier status, and normal ranges in 2.4%, 21.4%, and 76.2% of patients pre-screened, respectively.
Conclusions
Provincial rheumatologists were divided on the practice of pre-screening TPMT status prior to initiation of azathioprine. Azathioprine may be underutilized by half of those who pre-screen. A need for practice guidelines was recognized by the participants. In this patient group, diminished TPMT activity was observed in 23.8% of those who were tested.
References
2. Sahasranaman S, Howard D, Roy S. Clinical pharmacology and pharmacogenetics of thiopurines. Eur J Clin Pharmacol 2008;64:753- 67.
3. Anstey AV, Wakelin S, Reynolds NJ. Guidelines for prescribing azathioprine in dermatology. Br.J Dermatology 2004;151:1123- 32.
4. Gonzalez-Del Angel A, Bermudez-Lopez C, Alcantara-Ortigoza MA, et al. Thiopurine Smethyltransferase (TPMT) genetic polymorphisms in Mexican newborns. J Clin Pharm Ther 2009;34(6):703-8.
5. Weinshilboum RM, Sladek SL. Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Genet 1980;32:651-662.
6. Donnan JR, Ungar WJ, Mathews M, Rahman P. Systematic review of thiopurine methyltransferase genotype and enzymatic testing strategies. Ther Drug Monit 2011;33:192-9.
7. Booth RA, Ansari MT, Loit E, et al. Assessment of thiopurine s-methyltransferase activity in patients prescribed thiopurines: A systematic review. Ann Int Med 2011;154:814-23.
8. Newman WG, Payne K, Tricker K, et al. A pragmatic randomized controlled trial of thiopurine methyltransferase genotyping prior to azathioprine treatment: the TARGET study. Pharmacogenomics 2011;12;815-26.
9. Higgs JE, Newman WG, Payne K, Roberts C. Are patients with intermediate TPMT activity at increased risk of myelosuppression when taking thiopurine medications? Pharmacogenomics 2010;11: 177-88.
10. Miller AV, Ranatunga SKM. Immunotherapies in rheumatologic disorders. Med Clin N Am 2012;96:475-96.
11. Lacey JM, Magera MJ, Matern D, O’Brien JF. Rapid determination of 6-methylmercaptopurine (6-MMP) for the determination of thiopurine methyltransferase (TPMT) activity by liquid chromatography-tandem mass spectrometry (LC-MS/MS). 50th Annual Meeting of the American Society for Mass Spectrometry Conference (ASMS), Orlando, FL, USA, 2002.
12. Gearry RB, Day AS, Barclay ML, Leong RW, Sparrow MP. Azathioprine and allopurinol: A two-edged interaction. J Gastroenterol Hepatol 2010;25(4):653-5.
13. Szumianski CL, Weinshilboum RM. Sulphasalazine inhibition of thiopurine methyltransferase: possible mechanism for interaction with 6-mercaptopurine and azathioprine. Br. J Clin Pharmacol 1995;39(4):456-9.
14. Dubinsky MC, Yang H, Hassard PV, et al. 6-MP metabolite profiles provide a biochemical explanation for 6-MP resistance in patients with inflammatory bowel disease. Gastroenterology 2002;122: 904-15.
15. Roblin X, Oussalah A, Chevaux JB, Sparrow M, Peyrin-Biroulet L. Use of thiopurine testing in the management of inflammatory bowel diseases in clinical practice: a worldwide survey of experts. Inflamm Bowel Dis 2011;17(12):2480- 7.
16. Fargher EA, Tricker K, Newman W, et al. Current use of pharmacogenetic testing: a national survey of thiopurine methyltransferase testing prior to azathioprine prescription. J Clin Pharm Therapeutics 2007;32:187-95.
17. Relling MV, Gardner EE, Sandborn WJ, et al. Clinical pharmacogenetics implementation consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing. Clin Pharmacol Ther 2011;89(3):387-91.
18. Marra CA, Esdaile JM, Anis AH. Practical pharmacogenetics: the cost-effectiveness of screening for thiopurine s-methyltransferase polymorphisms in patients with rheumatologic conditions treated with azathioprine. J Rheumatol 2002;29:2507-12.