Thiopurine methyltransferase activity influences clinical response to azathioprine in inflammatory bowel disease

Carmelo Cuffari, Themistocles Dassopoulos, Lisa Turnbough, Richard Thompson, Theodore M Bayless

Research output: Contribution to journalArticle

Abstract

Background & Aims: Genetic polymorphism in thiopurine methyltransferase (TPMT) activity may influence clinical responsiveness to azathioprine (AZA) therapy. Our aim was to determine if the measurement of erythrocyte TPMT enzyme activity could be used to optimize clinical responsiveness to AZA therapy in patients with inflammatory bowel disease (IBD). Methods: A total of 142 consecutive patients were studied. Forty-one patients (32 with Crohn's disease [CD] and 9 with ulcerative colitis [UC]) were enrolled in a 4-month prospective nonrandomized study with AZA, and 101 (65 with CD and 36 with UC) were on either maintenance AZA or 6-mercaptopurine (6-MP). Erythrocyte TPMT activity and AZA metabolite levels were measured blinded to the clinical response. Results: The response rate after 4 months of continuous AZA therapy was 69% (9/13) in those patients with below-average (≤12 U/mL blood) TPMT activity, and 29% (8/27) in patients with enzyme activity levels >12 U/mL blood (P <0.001). Patients with TPMT activity ≤12 achieved a mean (SEM) erythrocyte 6-thioguanine ribonucleotide (6-TGn) level of 394 ± 29 pmol/8 × 108 red blood cells (RBCs); higher than in patients with TPMT activity >12 (218 ± 28), despite similar mean (1.6 mg/kg/day) dosages of AZA (P <0.001). By multivariate logistic regression analysis, patients with a TPMT level 292 pmol/8 × 108 RBCs was associated with a positive predictive value of clinical response of 85.7%. Conclusions: Patients with higher than average TPMT activity (>12) may remain refractory to conventional dosages of AZA, and may require high (>292) 6-TGn levels. Prospective, randomized, controlled trials are needed to determine whether prior TPMT phenotype testing can be used to adjust the dose of AZA effectively to improve clinical response time and rate.

Original languageEnglish (US)
Pages (from-to)410-417
Number of pages8
JournalClinical Gastroenterology and Hepatology
Volume2
Issue number5
DOIs
StatePublished - May 2004

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Keywords

  • 6-mercaptopurine
  • 6-methyl mercaptopurine
  • 6-MMP
  • 6-MP
  • 6-TGn
  • 6-thioguanine ribonucleotide
  • AZA
  • azathioprine
  • Harvey Bradshaw index
  • HBI
  • pharmacokinetic analysis
  • PKA
  • thiopurine methyltransferase
  • TPMT

ASJC Scopus subject areas

  • Gastroenterology

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