What is the risk of tuberculosis (TB) reactivation in patients taking azathioprine and how should it be managed?

Azathioprine and TB Risk: Management Guidelines

Azathioprine alone does not increase the risk of tuberculosis reactivation compared to placebo, and therefore no treatment of latent tuberculosis infection (LTBI) is recommended for patients on azathioprine monotherapy. 1

Risk Assessment for TB Reactivation with Azathioprine

• Azathioprine monotherapy does not significantly increase TB reactivation risk when compared with placebo alone 1
• However, when azathioprine is combined with anti-TNF agents, the risk of TB reactivation increases 13-fold compared to anti-TNF monotherapy 1
• A systematic review demonstrated that the combination of anti-TNF agents with methotrexate or azathioprine results in a significantly higher TB reactivation risk (OR 13.3; 95% CI 3.7-100) compared to anti-TNF monotherapy 2
• While reactivation of latent TB has been reported in isolated cases of patients taking azathioprine, particularly when switching from azathioprine to other immunosuppressants like mycophenolate mofetil 3, 4

TB Screening Recommendations

• TB screening is not routinely required before starting azathioprine monotherapy 1
• However, careful selection of patients is still recommended prior to starting azathioprine, as reactivation of latent infections such as tuberculosis has been reported in rare cases 1
• If azathioprine will be used in combination with anti-TNF agents or JAK inhibitors, TB screening becomes essential 1
• TB screening should include:
  • Patient clinical data and epidemiological risk factors assessment
  • Chest X-ray
  • Tuberculin skin test (TST) or interferon-gamma release assay (IGRA) or both, according to local availability and national recommendations 1

Management Considerations

• For patients on azathioprine monotherapy:

  • No specific LTBI treatment is recommended 1
  • Regular monitoring for signs and symptoms of TB is still prudent, especially in endemic areas 5

• For patients on combination therapy (azathioprine + anti-TNF):

  • Screen for LTBI before initiating combination therapy 1
  • Treat LTBI if detected before starting anti-TNF therapy 1
  • Consider annual re-screening for patients with higher TB risk (living or traveling in intermediate or high TB incidence areas) 1

• For patients with history of TB who need immunosuppression:

  • More careful monitoring is warranted even with azathioprine monotherapy 3
  • Consider prophylactic anti-TB treatment if switching from azathioprine to more potent immunosuppressants 3, 4

Special Considerations

• The risk of TB in patients on immunosuppressive therapy depends on the local disease burden of TB 1
• Patients with IBD in endemic areas have shown increased TB risk when anti-TNF is combined with azathioprine (17.8 times higher than conventional treatment) 5
• Both TST and IGRA sensitivity are negatively affected by immunosuppressive therapy, so TB screening should ideally be performed before starting any immunosuppressive treatment 1