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Booth RA, Ansari MT, Tricco AC, et al. Assessment of Thiopurine Methyltransferase Activity in Patients Prescribed Azathioprine or Other Thiopurine-Based Drugs. Rockville (MD): Agency for Healthcare Research and Quality (US); 2010 Dec. (Evidence Reports/Technology Assessments, No. 196.)

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

Cover of Assessment of Thiopurine Methyltransferase Activity in Patients Prescribed Azathioprine or Other Thiopurine-Based Drugs

Assessment of Thiopurine Methyltransferase Activity in Patients Prescribed Azathioprine or Other Thiopurine-Based Drugs.

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Appendix DExcluded Studies

Level II Exclusions by reasons (for all 334 excluded records)

Exclude on record type (editorial, review, commentary, letter, news, report or case report), n=44

  1. Clinical Chemistry and Laboratory Medicine; 17th IFCC-FESCC European Congress of Clilnical Chemistry and Laboratory Medicine/60th National Congress of the Netherlands-Society-for-Clinical-Chemistry-and-Laboratory-Medicine (EUROMEDLAB 2007); Amsterdam, NETHERLANDS. June 03 -07, 2007; 2007. pp. S5pp. S7–S9.pp. S5pp. SS448 [PubMed: 17710743]
  2. American Journal of Clinical Pathology; 43rd Annual Meeting of the Academy-of-Clinical-Laboratory-Physicians-and-Scientists; Philadelphia, PA, USA. June 05 –07, 2008; 2008. pp. 469–91.
  3. Abbott A. With your genes? Take one of these, three times a day.[erratum appears in Nature. 2003 Sep 25;425(6956):337] Nature. 2003 Oct 23;425(6960):760–2. [PubMed: 14574377]
  4. Allorge D, Hamdan R, Broly F, et al. ITPA genotyping test does not improve detection of Crohn’s disease patients at risk of azathioprine/6-mercaptopurine induced myelosuppression. Gut. 2005;54(4) [PMC free article: PMC1774451] [PubMed: 15753546]
  5. Barstad P. Method of determining thiopurine methyltransferase activity. Official Gazette of the United States Patent and Trademark Office Patents. 2003;1271(2)
  6. Bruns T, Stallmach A. Drug monitoring in inflammatory bowel disease: helpful or dispensable? [Review] [117 refs] Digestive Diseases. 2009;27(3):394–403. [PubMed: 19786771]
  7. Buster EH, van Vuuren HJ, Zondervan PE, et al. Thiopurine-methyltransferase and inosine triphosphate pyrophosphatase polymorphism in a liver transplant recipient developing nodular regenerative hyperplasia on low-dose azathioprine. European Journal of Gastroenterology & Hepatology. 2008 Jan;20(1):68–72. [PubMed: 18090994]
  8. Cheung ST, Allan RN. Mistaken identity: misclassification of TPMT phenotype following blood transfusion. European Journal of Gastroenterology & Hepatology. 2003 Nov;15(11):1245–7. [PubMed: 14560161]
  9. De Boer NK, Gilissen LP, Derijks LJ, et al. Hepatotoxicity of long-term and low-dose 6-thioguanine in IBD patients. Gastroenterology. 2006;130(4, Suppl 2):A202–A203.
  10. Derijks LJ, Hommes DW. Thiopurines in inflammatory bowel disease: new strategies for optimization of pharmacotherapy? Current Gastroenterology Reports. 2006;8(2):89–92. [PubMed: 16533469]
  11. Derijks LJJ, Wong DR. Pharmacogenetics of thiopurines in inflammatory bowel disease. Current Pharmaceutical Design. 2010;16(2):145–54. [PubMed: 20205660]
  12. Dubinsky MC. Monitoring of AZA/6-MP treatment in children with IBD is necessary. Inflammatory Bowel Diseases. 2003;9(6):386–8. [PubMed: 14671488]
  13. Escousse A, Mousson C, Santona L, et al. Azathioprine-induced pancytopenia in homozygous thiopurine methyltransferase-deficient renal transplant recipients: a family study. Transplantation Proceedings. 1995;27(2):1739–42. [PubMed: 7725481]
  14. Ford L, Berg J. Adverse reactions to azathioprine. Internal Medicine Journal. 2009;39(12):859–60. [PubMed: 20233255]
  15. Ford LT, Berg JD. Thiopurine S-methyltransferase (TPMT) assessment prior to starting thiopurine drug treatment; a pharmacogenomic test whose time has come. Journal of Clinical Pathology. 2010;63(4):288–95. [PubMed: 20354201]
  16. Fotoohi AK, Coulthard SA, Albertioni F. Thiopurines: Factors influencing toxicity and response. Biochemical Pharmacology. 2010;79(9):1211–20. [PubMed: 20096268]
  17. Frohman EM, Havrdova E, Levinson B, et al. Azathioprine myelosuppression in multiple sclerosis: characterizing thiopurine methyltransferase polymorphisms. Multiple Sclerosis. 2006;12(1):108–11. [PubMed: 16459728]
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  19. Gearry R, Barclay M, Gardiner S, et al. 6-thioguanine nucleotides and thiopurine methyltransferase activity: important factors determining response to treatment and incidence of adverse effects from azathioprine and 6-MP. New Zealand Medical Journal. 2003;2003;116(1178):U531. [PubMed: 12897892]
  20. George P, Roberts R, Pike L. 6-thioguanine nucleotides and thiopurine methyltransferase activity: important factors determining response to treatment and incidence of adverse effects from azathioprine and 6-MP. New Zealand Medical Journal. 2003 2003 Jul 25;116(1178):U531. [PubMed: 12901364]
  21. Hall A, Rabello C, Jackson G, et al. Congenital deficiency of thiopurine methyltransferase as a cause of pancytopenia in patients treated with azathioprine. British Journal of Haematology. 1996;93
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  23. Katsanos KH, Vermeire S, Claes K, et al. Thiopurine methyl transferase gene single nucleotide polymorphisms in inflammatory bowel disease. Annals of Gastroenterology. 2006;19(1):18–20.
  24. Krynetski EY, Tai HL, Yates CR, et al. Genetic polymorphism of thiopurine S-methyltransferase: clinical importance and molecular mechanisms. [Review] [60 refs] Pharmacogenetics. 1996 Aug;6(4):279–90. [PubMed: 8873214]
  25. Kutscher E, Davies G. Pharmacogenomics: has our history become modern medicine? South Dakota Medicine: The Journal of the South Dakota State Medical Association. 2009;62(4):160–1. [PubMed: 19402301]
  26. Lichtenstein GR. Monitoring 6-mercaptopurine/azathioprine metabolite levels. American Journal of Gastroenterology. 2007;102(Suppl 1):S14–S17.
  27. Oellerich M, von Ahsen N, Shipkova M, et al. Genotypic and phenotypic evaluations in connection with azathioprine toxicity. Toxicological Sciences. 2003;72
  28. Oliveira E, Quental S, Alves S, et al. Do the distribution patterns of polymorphisms at the thiopurine S-methyltransferase locus in sub-Saharan populations need revision? Hints from Cabinda and Mozambique. European Journal of Clinical Pharmacology. 2007;63(7):703–6. [PubMed: 17473918]
  29. Otterness D, Szumlanski C, Weinshilboum R. Human thiopurine methyltransferase pharmacogenetics: Identification of a novel variant allele. Journal of Investigative Medicine. 1996;44(3):248A.
  30. Ozbek U, Sayitoglu MA, Hatirnaz O. Allelotype frequencies of TPMT (thiopurine S-methyltransferase), CYP3A4 and CYP3A5 genes in Turkish population. Leukemia (Basingstoke) 2003;17(3)
  31. Paci D, Ibarreta D. Economic and cost-effectiveness considerations for pharmacogenetics tests: An integral part of translational research and innovation uptake in personalized medicine. Current Pharmacogenomics and Personalized Medicine. 2009;7(4):284–96.
  32. Pavlovic S. TPMT gene polymorphisms: On the doorstep of personalized medicine. Indian Journal of Medical Research. 2009;129(5):478–80. [PubMed: 19675373]
  33. Payne K, Newman W, Fargher E, et al. TPMT testing in rheumatology: any better than routine monitoring? Rheumatology. 2007;46(5):727–9. [PubMed: 17255139]
  34. Payne K, Newman WG, Gurwitz D, et al. TPMT testing in azathioprine: A ‘cost-effective use of healthcare resources’? Personalized Medicine. 2009;6(1):103–13.
  35. Ramsden S, Pushpakom S, Newman W. TARGET - predicting adverse reaction to azathioprine prescription. Journal of Medical Genetics. 2006;43
  36. Relling MV, Pui CH, Cheng C, et al. Thiopurine methyltransferase in acute lymphoblastic leukemia. Blood. 2006 Jan 15;107(2):843–4. [PubMed: 16401827]
  37. Roberts-Thomson IC, Butler WJ. Azathioprine, 6-mercaptopurine and thiopurine S-methyltransferase. Journal of Gastroenterology & Hepatology. 2005;20(6):955. [PubMed: 15946151]
  38. Sarij S, Islam K. TPMT testing and hepatotoxicity in the elderly. American Journal of Gastroenterology. 2008;103
  39. Taniguchi A, Kamatani N. Pharmacogenetic approaches to rheumatoid arthritis. Pharmacogenomics Journal. 2004;4(6):350–3. [PubMed: 15249925]
  40. Teml A, Schaeffeler E, Schwab M. Pretreatment determination of TPMT - state of the art in clinical practice. European Journal of Clinical Pharmacology. 2009 Mar;65(3):219–21. [PubMed: 19198820]
  41. The Netherlands Organisation for Health Research and Development (ZonMw). Pharmacogenetic testing in the clinical setting: is screening for TPMT genotype a cost-effective treatment strategy? The first prospective randomized controlled trial within the Dutch health care system (project) (Project record) 2006. Cochrane ID: HTA-32006001365.
  42. Tsironi E, Browne M, Rampton DS, et al. Expression of thiopurine methyltransferase in South Asians. Gut. 2003;52(6):914–5. [PMC free article: PMC1773676] [PubMed: 12740356]
  43. van Asseldonk DP, de Boer NKH, Peters GJ, et al. On therapeutic drug monitoring of thiopurines in inflammatory bowel disease; pharmacology, pharmacogenomics, drug intolerance and clinical relevance. Current Drug Metabolism. 2009;10(9):981–97. [PubMed: 20214590]
  44. Weinshilboum R. Methyltransferase Pharmacogenetics. Pharmacology and Therapeutics. 1989;43(1):77–90. [PubMed: 2675130]

Exclude on study population, n = 159

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Exclude on language (other than English), n = 2

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Exclude on another reason, n = 118

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Excluded at Level III (i.e. not for Q1a or 1b, and not identified previously at level II for any other key question), n = 35

No direct pre-analytic data of relevance, n=32

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  28. Spire-Vayron de la Moureyre, Debuysere H, Mastain B, et al. Genotypic and phenotypic analysis of the polymorphic thiopurine S-methyltransferase gene (TPMT) in a European population. British Journal of Pharmacology. 1998 Oct;125(4):879–87. [PMC free article: PMC1571045] [PubMed: 9831928]
  29. Van Loon JA, Weinshilboum RM. Thiopurine methyltransferase biochemical genetics: human lymphocyte activity. Biochemical Genetics. 1982 Aug;20(7–8):637–58. [PubMed: 7138494]
  30. Weinshilboum RM, Sladek SL. Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. American Journal of Human Genetics. 1980 Sep;32(5):651–62. [PMC free article: PMC1686086] [PubMed: 7191632]
  31. Yan L, Zhang S, Eiff B, et al. Thiopurine methyltransferase polymorphic tandem repeat: genotype-phenotype correlation analysis. Clinical Pharmacology & Therapeutics. 2000 Aug;68(2):210–9. [PubMed: 10976552]
  32. Yates CR, Krynetski EY, Loennechen T, et al. Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance.[see comment] Annals of Internal Medicine. 1997 Apr 15;126(8):608–14. [PubMed: 9103127]

Non-original data, n=1

  1. Bergan S, Rugstad HE, Klemetsdal B, et al. Possibilities for therapeutic drug monitoring of azathioprine: 6-thioguanine nucleotide concentrations and thiopurine methyltransferase activity in red blood cells. Therapeutic Drug Monitoring. 1997 Jun;19(3):318–26. [PubMed: 9200774]

No proficiency, reproducibility and precision data, n=4

  1. Barstad P. Method of determining thiopurine methyltransferase activity. Official Gazette of the United States Patent and Trademark Office Patents. 2006
  2. Dervieux T, Meyer G, Matsutani M, et al. Liquid chromatography tandem mass spectrometry of erythrocyte thiopurine nucleotides: Application at the thiopurine methyltransferase gene locus. Clinical Chemistry. 2005;51 [PubMed: 16166171]
  3. Nishida A, Kubota T, Yamada Y, et al. Thiopurine S-methyltransferase activity in Japanese subjects: metabolic activity of 6-mercaptopurine 6-methylation in different TPMT genotypes. Clinica Chimica Acta. 2002 Sep;323(1–2):147–50. [PubMed: 12135816]
  4. Tomkova J, Friedecky D, Polynkova A, et al. Capillary electrophoresis determination of thiopurine methyl transferase activity in erythrocytes. Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences. 2009;877(20–21):1943–5. [PubMed: 19477696]

Included Records not reporting relevant data for any key question, n=33

  1. Allan M, Tendler D, Muir A, et al. Utility of thiopurine methyltransferase pharmacogenetic testing and monitoring of azathioprine metabolites in the management of autoimmune hepatitis. Gastroenterology. 2002;122
  2. Alves S, Prata MJ, Ferreira F, et al. Screening of thiopurine S-methyltransferase mutations by horizontal conformation-sensitive gel electrophoresis. Human Mutation. 2000;15(3):246–53. [PubMed: 10679940]
  3. Ansari AR, Soon SY, Lindsay J, et al. Thiopurine methyl transferase activity predicts both toxicity and clinical response to azathioprine in inflammatory bowel disease: The London IBD forum prospective study. Gastroenterology. 2004;126
  4. Bastida G, Nos P, Aguas M, et al. Incidence, risk factors and clinical course of thiopurine-induced liver injury in patients with inflammatory bowel disease. Alimentary Pharmacology and Therapeutics. 2005;22(9):775–82. [PubMed: 16225485]
  5. Campbell S, Kingstone K, Ghosh S. Relevance of thiopurine methyltransferase activity in inflammatory bowel disease patients maintained on low-dose azathioprine. Alimentary Pharmacology & Therapeutics. 2002 Mar;16(3):389–98. [PubMed: 11876691]
  6. Chowdhury J, Kagiala GV, Pushpakom S, et al. Microfluidic platform for single nucleotide polymorphism genotyping of the thiopurine S-methyltransferase gene to evaluate risk for adverse drug events. Journal of Molecular Diagnostics. 2007 Sep;9(4):521–9. [PMC free article: PMC1975104] [PubMed: 17690215]
  7. Colletti RB, Baldassano RN, Milov DE, et al. Variation in care in pediatric crohn disease. J Pediatr Gastroenterol Nutr. 2009 Sep;49(3):297–303. [PubMed: 19590456]
  8. Comer M, James I, D’Cruz D, et al. Erythrocyte thiopurine methyltransferase (TPMT) activity in rheumatoid arthritis patients experiencing azathioprine haematological toxicity. British Journal of Rheumatology. 1998;37
  9. Cuffari C, Dassopoulos T, Turnbough L, et al. Thiopurine methyltransferase activity influences clinical response to azathioprine in inflammatory bowel disease. Clinical Gastroenterology & Hepatology. 2004 May;2(5):410–7. [PubMed: 15118980]
  10. Curvers W, Derijks L, Stokkers P, et al. No Predictive Value of Tpmt Genotyping for Leukopenia Or Hepatotoxicity During Azathioprine Therapy in Inflammatory Bowel Disease. Digestive Disease Week Abstracts and Itinerary Planner. 2003
  11. Curvers W, Gilissen L, Derijks L, et al. Pharmacokinetic Analysis of 6-Mercaptopurine in Patients with Inflammatory Bowel Disease. Digestive Disease Week Abstracts and Itinerary Planner. 2003
  12. Daperno M, Canaparo R, Sostegni R, et al. Genotype and phenotype analysis of thiopurine-methyl-transferase (TPMT) in a northern Italian. Gastroenterology. 2008;134
  13. Domenech E, Garcia-Planella E, Fluvia L, et al. Clinical Implications of Thiopurine-Methyltransferase Activity (Tpmte) Induction by Azathioprine (Aza) Treatment in Patients with Inflammatory Bowel Disease (Ibd) Digestive Disease Week Abstracts and Itinerary Planner. 2003
  14. Gubanich P, Achkar DP, Lashner B, et al. Thiopurine methyl transferase (TPMT) phenotype as a predictor of clinical response and side effect profile in a population of IBD patients. American Journal of Gastroenterology. 2004;99(10, Suppl S):S269–S270.
  15. Heneghan MA, Allan ML, Bornstein JD, et al. Utility of thiopurine methyltransferase genotyping and phenotyping, and measurement of azathioprine metabolites in the management of patients with autoimmune hepatitis. Journal of Hepatology. 2006 Oct;45(4):584–91. [PubMed: 16876902]
  16. Hurlburt K, Mayo M, Yeo A, et al. TPMT activity related to azathioprine dosing and treatment of autoimmune hepatitis. Hepatology. 2005;42(4, Suppl 1):291A.
  17. Katsanos K, Ferrante M, Joossens M, et al. The MDR1 G2677T polymorphism is associated with gastrointestinal intolerance to azathioprine. Gastroenterology. 2006;130(4, Suppl 2):A199–A200.
  18. Kerstens PJ, Stolk JN, De Abreu RA, et al. Azathioprine-related bone marrow toxicity and low activities of purine enzymes in patients with rheumatoid arthritis. Arthritis & Rheumatism. 1995 Jan;38(1):142–5. [PubMed: 7818564]
  19. Kwan LY, Devlin SM, Mirocha JM, et al. Thiopurine methyltransferase activity combined with 6-thioguanine metabolite levels predicts clinical response to thiopurines in patients with inflammatory bowel disease. Digestive & Liver Disease. 2008 Jun;40(6):425–32. [PubMed: 18304898]
  20. Moloney M, Langley P, McFarlane I. Azathioprine tolerance is related to TPMT activity in autoimmune hepatitis (AIH) Gastroenterology. 1997;112
  21. Naughton MA, Battaglia E, O’Brien S, et al. Identification of thiopurine methyltransferase (TPMT) polymorphisms cannot predict myelosuppression in systemic lupus erythematosus patients taking azathioprine. Rheumatology. 1999 Jul;38(7):640–4. [PubMed: 10461478]
  22. Pageaux G, Masbou J, Brunschwig C, et al. Are hepatic toxic effects of thiopurine derivatives drugs related to thiopurine methyltransferase activity deficiency. Gastroenterology. 1997;112
  23. Qasim A, Molley C, McLoughlin R, et al. Absolute Leukocyte Count and Its Correlation with Thiopurine Methyl Transferase (Tpmt) Activity in Inflammatory Bowel Disease (Ibd) Patients Receiving Azathioprine (Aza)/6-Mercaptopurine (6Mp) Digestive Disease Week Abstracts and Itinerary Planner. 2003
  24. Rietdijk ST, Bartelsman J, Hommes DW, et al. Genetic polymorphisms of the thiopurine S-methyltransferase (TPMT) locus in patients treated with azathioprine for inflammatory bowel disease. Gastroenterology. 2001;120
  25. Schaeffeler E, Zanger UM, Eichelbaum M, et al. Highly multiplexed genotyping of thiopurine s-methyltransferase variants using MALD-TOF mass spectrometry: reliable genotyping in different ethnic groups.[see comment] Clinical Chemistry. 2008 Oct;54(10):1637–47. [PubMed: 18687736]
  26. Shobowale-Bakre M, Hassan C, Ansari A, et al. Predicting drug toxicity and non-response: Azathioprine and thiopurine methyltransferase as a metabolic model. Journal of Inherited Metabolic Disease. 2000;23
  27. Stolk J, Boerbooms A, De Abreu R, et al. The predictive value of thiopurine-methyltransferase activity for the development of toxicity of azathioprine in the treatment of rheumatoid arthritis. British Journal of Rheumatology. 1997;36
  28. Taylor E, Matsutani M, Barry M, et al. TPMT (thiopurine methyltransferase) genotype-phenotype accuracy in IBD patients. Gastroenterology. 2002;122(4 Suppl 1):A-222.
  29. Vestergaard T, Bygum A. An audit of thiopurine methyltransferase genotyping and phenotyping before intended azathioprine treatment for dermatological conditions. Clinical and Experimental Dermatology. 2010;35(2):140–4. [PubMed: 19663853]
  30. Walsh M, Royston C, Srinivas M, et al. Monitoring azathioprine (AZA) treatment in inflammatory bowel disease (IED): Rituals RE-visited but not revised! Gastroenterology. 2008;134(4 Suppl 1)
  31. Watanabe K, Simmons J, Orchard T, et al. Allelic variants of thiopurine methyl transferase are associated with azathioprine induced leukopaenia. Gut. 2000;46(11)
  32. Wong JL, Lowes J, Biggs L, et al. The role of thiopurine methyltransferase (TPMT) activity assay before commencing thiopurine drugs in inflammatory bowel disease (IBD) Gastroenterology. 2002;122(4 Suppl 1):A-222.
  33. Zelinkova Z, Derrijks L, Stokkers P, et al. Inosine triphosphate pyrophosphatase gene mutation predicts myelosuppression in IBD patients treated with azathioprine. Gastroenterology. 2004;126

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