What is reactive thiopurine metabolite monitoring?

Reactive Thiopurine Metabolite Monitoring

Reactive thiopurine metabolite monitoring is a clinical strategy where thiopurine metabolite levels are measured in patients with active inflammatory bowel disease (IBD) symptoms or suspected toxicity to guide treatment adjustments. The American Gastroenterological Association (AGA) conditionally recommends reactive thiopurine metabolite monitoring to guide treatment changes in adult patients with active IBD or adverse effects thought to be due to thiopurine toxicity. 1

What is Reactive Thiopurine Metabolite Monitoring?

• Reactive monitoring measures two key metabolites in patients already on thiopurine therapy (azathioprine or 6-mercaptopurine) who have:

  • Active IBD symptoms despite treatment 1
  • Suspected adverse effects from thiopurine therapy 1

• The two key metabolites measured are:

  • 6-thioguanine nucleotides (6-TGN): the active therapeutic metabolite 1
  • 6-methylmercaptopurine (6-MMP): associated with hepatotoxicity when elevated 1

• Measurements are typically performed in red blood cells (RBCs) and reported as pmol per 8 × 10^8 RBCs 1

Clinical Application and Target Levels

• For patients on thiopurine monotherapy, the target 6-TGN level is between 230 and 450 pmol/8 × 10^8 RBCs 1

• Interpretation of results follows this algorithm:

  • Low 6-TGN (<230 pmol/8 × 10^8 RBCs) with active disease: Consider dose optimization 1
  • Therapeutic 6-TGN (230-450 pmol/8 × 10^8 RBCs) with active disease: Consider switching medication 1
  • High 6-TGN (>450 pmol/8 × 10^8 RBCs): Risk of myelosuppression, consider dose reduction 1
  • High 6-MMP (>5700 pmol/8 × 10^8 RBCs): Risk of hepatotoxicity 2

• 6-MMP/6-TGN ratio can provide additional information:

  • Ratio between 4-24: Associated with better therapeutic outcomes (OR 0.52,95% CI 0.39-0.69) 2
  • Ratio >24: Higher risk of hepatotoxicity (OR 5.35,95% CI 3.43-8.43) 2

Evidence Supporting Reactive Monitoring

• Patients who received treatment adjustments based on metabolite levels (algorithm-concordant care) were 5.15 times more likely to respond to therapy compared to those who received algorithm-discordant care (RR 5.15,95% CI 1.82-14.56) 1

• Patients with 6-TGN levels ≥230 pmol/8 × 10^8 RBCs had 40% higher rates of remission compared to those with lower levels (RR 1.4,95% CI 1.2-1.6) 1

Important Considerations and Limitations

• The evidence supporting reactive monitoring is of very low quality, based primarily on observational studies with small sample sizes 1

• Optimal 6-TGN cutoff is uncertain when thiopurines are used in combination with anti-TNF agents 1

• Sample handling is critical:

  • Whole blood samples should be preprocessed as soon as possible as 6-TGN decreases by approximately 20% after 4 days of storage at 4°C 3
  • Preprocessed samples are stable at -70°C for up to 6 months, but 6-TGN decreases by 30% when stored at -20°C for 180 days 3

• Potential harms of reactive monitoring include:

  • Additional burden of laboratory monitoring with each dose adjustment 1
  • Potential delay in switching to alternative effective therapies 1

Contrasting with Routine Monitoring

• Unlike reactive monitoring, routine (proactive) thiopurine metabolite monitoring in patients with quiescent IBD is not recommended by the AGA (conditional recommendation, very low quality evidence) 1

• Two randomized controlled trials (107 patients total) showed no significant difference in:

  • Clinical remission rates (RR 1.44,95% CI 0.59-3.52) 1
  • Serious adverse events (RR 1.20,95% CI 0.50-2.91) 1

• These studies had limitations including failure to reach recruitment targets and limited ability to optimize therapy beyond dose escalation 1

Special Patient Populations

• Patients with intermediate TPMT activity (10-11% of population) require lower azathioprine doses and more careful monitoring 4

• Patients with TPMT or NUDT15 deficiency accumulate excessive 6-TGN concentrations and are at higher risk for severe myelosuppression 5

• In pediatric patients with IBD and autoimmune hepatitis, those with optimal 6-TGN levels showed higher remission rates (88%) compared to under- or overdosed patients (60% and 69%, respectively) 6