What is the significance of TPMT (thiopurine methyltransferase) genotype in rheumatology?

TPMT Genotype in Rheumatology: Clinical Significance and Testing

TPMT genotyping should be performed in all rheumatology patients prior to initiating azathioprine therapy to prevent potentially life-threatening myelosuppression in patients with enzyme deficiency. 1

What is TPMT?

Thiopurine methyltransferase (TPMT) is a key enzyme involved in the metabolism of thiopurine drugs commonly used in rheumatology, including azathioprine and 6-mercaptopurine. TPMT catalyzes the S-methylation (inactivation) of these medications through the following process:

• Azathioprine is a prodrug that is converted to 6-mercaptopurine (6-MP) 1
• 6-MP is then metabolized through several pathways:
  • Conversion to active 6-thioguanine nucleotides (6-TGNs), which provide the immunosuppressive effect
  • Inactivation via TPMT to form inactive methyl-mercaptopurine
  • Inactivation via xanthine oxidase to form 6-thiouric acid 2, 3

Genetic Polymorphism and Clinical Significance

TPMT enzyme activity is controlled by genetic polymorphisms with significant clinical implications:

• Homozygous deficiency (two non-functional alleles):

  • Occurs in approximately 0.3% (1:300) of European or African ancestry populations
  • 20.8-fold increased risk of thiopurine-induced leukopenia (95% CI, 3.4-126.9)
  • Can lead to severe and potentially fatal myelosuppression with standard dosing 1, 4

• Heterozygous deficiency (one non-functional allele):

  • Occurs in approximately 4-11% of the population
  • 4.3-fold increased risk of thiopurine-induced leukopenia (95% CI, 2.7-6.9)
  • Results in intermediate enzyme activity and moderate toxicity 1, 4

• Normal/wild-type (two functional alleles):

  • Comprises 86-97% of the population
  • Normal enzyme activity with lower risk of myelosuppression 5

Testing Recommendations

The British Association of Dermatologists strongly recommends:

• TPMT activity should be checked in all patients prior to receiving azathioprine (Strength of recommendation A; level of evidence 1+)
• TPMT genotyping is only required for patients with indeterminate phenotype (borderline values) or those who have had a recent blood transfusion 1

The American Gastroenterological Association conditionally recommends:

• Routine TPMT testing (enzymatic activity or genotype) before starting thiopurines to guide dosing 1

Testing Methods

Two main approaches exist for determining TPMT status:

1. TPMT phenotyping: Measures actual enzyme activity in red blood cells

   • May be affected by recent blood transfusions or concurrent medications
   • Shows ethnic variation that can complicate interpretation 4, 6

2. TPMT genotyping: Detects common mutations in the TPMT gene

   • Most common mutations: TPMT2, TPMT3A, TPMT3B, and TPMT3C
   • These four alleles account for 80-95% of individuals with reduced TPMT activity 1, 7

Dosing Recommendations Based on TPMT Status

• Normal/wild-type: Standard dose (2-2.5 mg/kg/day for azathioprine)
• Heterozygous: 50% dose reduction
• Homozygous deficient: Either avoid thiopurines completely or use extremely reduced doses (0-10% of standard dose) 4

Important Clinical Considerations

1. TPMT testing does not eliminate the need for monitoring:

   • Regular blood count monitoring is mandatory for all patients on azathioprine, regardless of TPMT status 1
   • Myelosuppression can occur through mechanisms unrelated to TPMT status

2. Timing of adverse events:

   • Most leukopenia events occur within 8 weeks of starting therapy
   • However, adverse events can occur after months of therapy 1

3. TPMT status does not predict all adverse events:

   • Only predicts risk of myelosuppression
   • Does not predict other adverse events like hepatotoxicity, pancreatitis, or gastrointestinal intolerance 1, 4

4. Metabolite monitoring:

   • Measuring 6-TGN levels may help guide azathioprine dosage and detect non-adherence
   • Target 6-TGN levels between 230-450 pmol/8×10^8 RBCs when used as monotherapy 1, 4

Adoption in Rheumatology Practice

Despite clear benefits, TPMT testing has had variable adoption across medical specialties. A UK survey found that while nearly all rheumatologists prescribe azathioprine, only 47% routinely performed TPMT testing, compared to 90% of dermatologists and 60% of gastroenterologists 1.

Given the potentially serious consequences of azathioprine treatment in patients with TPMT deficiency, the benefit in terms of safety outweighs arguments against universal testing, making TPMT testing an important part of safe prescribing practices in rheumatology.