What is the usage and dosage of Azothioprine (Imuran) in treating autoimmune diseases and preventing organ rejection?

Azathioprine Usage and Dosing in Autoimmune Diseases and Organ Transplantation

Azathioprine should be dosed at 1-2 mg/kg/day for autoimmune diseases and organ transplantation, with mandatory TPMT testing prior to initiation to guide dosing and prevent toxicity. 1, 2

Indications and Mechanism of Action

Azathioprine is an immunosuppressive agent used for:

• Autoimmune diseases:

  • Licensed for dermatomyositis, systemic lupus erythematosus, and pemphigus vulgaris 1
  • Off-label for autoimmune hepatitis (AIH), atopic dermatitis, and other autoimmune conditions 1, 2

• Transplantation:

  • Prevention of organ rejection, particularly in liver transplantation 1

Azathioprine works as a purine analogue that inhibits DNA synthesis, affecting T and B lymphocyte proliferation. It's rapidly converted to 6-mercaptopurine (6-MP) in the liver and erythrocytes, with the active metabolites being 6-thioguanine nucleotides (6-TGNs) 3.

Dosing Protocol

Initial Dosing

1. Starting dose:

   • 50 mg/day initially 2
   • Gradually increase to maintenance dose based on response and tolerance

2. Maintenance dose:

   • Normal TPMT activity: 1-2 mg/kg/day 1, 2
   • Intermediate (heterozygous) TPMT activity: Reduce dose by 30-50% 1, 2
   • Absent TPMT activity: Avoid azathioprine or use extremely low doses with careful monitoring 1, 2

Combination Therapy for Autoimmune Hepatitis

For AIH, azathioprine is typically combined with prednisolone 1:

• Prednisolone 30 mg/day (reducing to 10 mg/day over 4 weeks)
• Plus azathioprine 1 mg/kg/day
• Higher doses of prednisolone (up to 1 mg/kg/day) may be used for more rapid normalization of transaminases

Pre-treatment Assessment

Mandatory testing before starting azathioprine 1, 2:

• TPMT activity measurement
• Complete blood count (CBC) with differential
• Liver function tests
• Renal function tests

TPMT testing is critical as approximately 0.3% of patients have little or no TPMT activity (homozygous deficient) and 10% have intermediate activity (heterozygous deficient), putting them at high risk for severe myelosuppression 3.

Monitoring Protocol

1. Initial monitoring (first 8 weeks):

   • CBC: Every 1-2 weeks
   • Liver function tests: Every 2 weeks

2. Maintenance monitoring:

   • CBC: Every 3 months
   • Liver function tests: Every 3-6 months
   • Renal function tests: Every 3 months 2

Treatment Duration

• Autoimmune hepatitis: At least 2 years and for at least 12 months after normalization of transaminases 1, 2
• Transplantation: Often lifelong therapy 1

Managing Side Effects and Toxicity

Common Side Effects

• Myelosuppression (leukopenia, thrombocytopenia)
• Nausea and vomiting
• Rash
• Pancreatitis
• Hypersensitivity reactions 1

Strategies to Minimize Side Effects

• Start with lower doses and gradually increase
• Consider divided doses to reduce gastrointestinal side effects
• Ensure adequate hydration
• Monitor blood counts regularly

Special Considerations

Pregnancy and Breastfeeding

• FDA pregnancy category D
• Risks and benefits must be carefully weighed if continuation during pregnancy is necessary 2

Treatment Failure

For patients not responding to standard therapy:

1. Increase prednisolone dose
2. Increase azathioprine dose to 2 mg/kg/day
3. Consider alternative immunosuppressants like mycophenolate mofetil 2

Relapse Management

• Reinstitute induction therapy followed by maintenance therapy
• Consider long-term azathioprine monotherapy (2 mg/kg/day) for multiple relapses 1, 2

Contraindications

• Severe infections
• Severely impaired hepatic or bone marrow function
• Pancreatitis
• Live vaccines
• Known malignancy (relative contraindication)
• Homozygous TPMT deficiency (relative contraindication) 1, 3

Azathioprine remains a cornerstone immunosuppressive therapy for autoimmune diseases and transplantation when properly dosed and monitored according to individual patient characteristics, particularly TPMT status.