When to taper and stop azathioprine (Imuran) in patients with autoimmune diseases?

When to Taper and Stop Azathioprine in Autoimmune Diseases

Azathioprine should be continued indefinitely as maintenance therapy in most autoimmune diseases after achieving remission, with tapering considered only after sustained remission of at least 1-2 years, and complete withdrawal attempted only in select patients with multiple years of stable disease. 1, 2

Criteria for Considering Azathioprine Tapering

• Tapering of azathioprine should only be considered after complete biochemical and clinical remission has been maintained for at least 1 year 1
• Before attempting withdrawal, patients should demonstrate:
  • Normalized serum aminotransferases, bilirubin, and immunoglobulin levels 1
  • Resolution of symptoms 1
  • Normal hepatic tissue or inactive cirrhosis (in autoimmune hepatitis) 1
  • Stable disease without flares for at least 12 months 1, 3

Tapering Protocol

• When tapering is deemed appropriate, a gradual approach is essential:
  • For autoimmune hepatitis, reduce azathioprine dose from 2 mg/kg/day maintenance dose by small increments (0.5 mg/kg) at 3-month intervals 1, 4
  • Monitor laboratory parameters (transaminases, inflammatory markers, disease-specific antibodies) every 3 weeks during tapering and for at least 3 months after withdrawal 1
  • If any signs of disease activity appear during tapering, immediately return to the previous effective dose 1, 4

When to Maintain Long-Term Therapy

• Long-term maintenance therapy with azathioprine (without attempting withdrawal) is recommended for:
  • Patients with cirrhosis or history of decompensated liver disease 1
  • Those with multiple previous relapses after treatment withdrawal 1
  • Patients with predictors of relapse (LKM or SLA antibody positivity in autoimmune hepatitis) 1
  • Patients who cannot tolerate corticosteroids 1, 3
  • Patients with aggressive disease at initial presentation 1

Evidence on Withdrawal Outcomes

• Studies show high relapse rates after azathioprine withdrawal:
  • In autoimmune hepatitis, 50% of patients relapse after withdrawal even after 5 years of stable therapy 1
  • In Crohn's disease, 53% of patients relapse within 1 year after azathioprine withdrawal even after >2 years of stable therapy 5
  • In ocular inflammatory diseases, discontinuation due to disease remission occurs at a rate of only 0.09 per person-year 6

Maintenance Strategies After Achieving Remission

• Two main strategies exist for long-term management after achieving remission:

  1. Preferred approach: Steroid-free azathioprine monotherapy at 2 mg/kg/day indefinitely 1, 2

     • This approach minimizes steroid-related side effects
     • Studies show 83% of patients maintain remission with this strategy over a median follow-up of 67 months 2

  2. Alternative approach: Low-dose prednisolone maintenance (median 7.5 mg/day) with or without azathioprine 1, 4

     • This may be preferred in patients intolerant to azathioprine
     • However, long-term steroid exposure carries significant side effect risks 1, 3

Monitoring During Maintenance and After Withdrawal

• During maintenance therapy:

  • Monitor complete blood counts every 3-6 months to detect myelosuppression 1
  • Check liver function tests every 3-6 months 1
  • Consider yearly dermatologic screening for skin cancer in long-term users 1

• After withdrawal:

  • Monitor closely for at least 12 months, as most relapses occur within this timeframe 1
  • Laboratory assessments should be performed every 3 months for the first year after withdrawal 1

Special Considerations

• TPMT testing should be considered before initiating azathioprine, especially in patients with pre-existing cytopenia 1, 7
• Patients on long-term azathioprine should avoid excessive sun exposure due to increased skin cancer risk 1
• In pregnancy, azathioprine has FDA category D rating and should be discontinued if possible 1

Conclusion for Clinical Practice

The evidence strongly supports indefinite azathioprine maintenance therapy at 2 mg/kg/day for most patients with autoimmune diseases after achieving remission, particularly in autoimmune hepatitis. Withdrawal should only be attempted in carefully selected patients after prolonged remission, with close monitoring for relapse.