Azathioprine: Uses and Dosing Guidelines for Autoimmune Diseases
Azathioprine is a first-line immunosuppressant used in combination with corticosteroids for treating autoimmune hepatitis (AIH) and other autoimmune conditions, with standard dosing of 1-2 mg/kg/day after initial dose titration. 1
Primary Uses of Azathioprine
Autoimmune Hepatitis
- First-line therapy: Used in combination with predniso(lo)ne as standard treatment 1
- Maintenance therapy: Used as steroid-sparing agent to maintain remission 1
- Monotherapy: Can be used as steroid-free maintenance therapy at doses of 2 mg/kg/day 1
Other Autoimmune Conditions
- Immune thrombocytopenia (ITP) 1
- Inflammatory bowel disease
- Rheumatoid arthritis
- Post-organ transplantation immunosuppression 2
Standard Dosing Protocol for Autoimmune Hepatitis
Initial Treatment Phase
Starting dose: 50 mg/day (delayed start approach) 1
- Begin azathioprine 2 weeks after starting steroid therapy
- Only start when bilirubin levels are below 6 mg/dl (100 μmol/L)
Dose titration: Gradually increase to maintenance dose of 1-2 mg/kg/day 1
- Adjust based on response and toxicity
Combination therapy schedule (for a 60kg patient) 1:
Week Prednisolone (mg/day) Azathioprine (mg/day) 1 60 - 2 50 - 3 40 50 4 30 50 5 25 100* 6 20 100* 7-8 15 100* 9-10 12.5 100* >10 10 100* *Azathioprine dose of 1-2 mg/kg according to body weight
Maintenance Therapy
- Target dose: 2 mg/kg/day for steroid-free maintenance 1
- Duration: Indefinite maintenance therapy often required 1
- Monitoring: Regular blood tests every 1-3 months during maintenance 1
Genetic Testing and Dose Adjustments
TPMT Testing
- Mandatory: Check thiopurine methyltransferase (TPMT) activity before starting therapy 1, 2, 3
- Dose adjustments based on TPMT status:
NUDT15 Testing
- Consider NUDT15 genotyping, particularly in Asian patients 2, 3
- Dose reduction similar to TPMT intermediate metabolizers for patients with NUDT15 variants 3
Monitoring Requirements
Initial Monitoring
- Complete blood count (CBC) weekly during first month 2
- CBC twice monthly for second and third months 2
- Liver function tests every 2-4 weeks initially 1
Long-term Monitoring
- CBC monthly or more frequently if dose changes 2
- Liver function tests every 3-6 months 1
- Monitor for signs of myelosuppression (leukopenia, thrombocytopenia) 2, 4
Common Side Effects and Management
Hematologic
- Leukopenia/neutropenia: Most common dose-limiting toxicity 2, 4
- Reduce dose or temporarily withdraw if severe
- Consider checking 6-TG metabolite levels (target: 235-450 pmol per 8×10^8 RBCs) 1
Gastrointestinal
- Nausea/vomiting: Occurs in approximately 12% of patients 2
- Administer in divided doses and/or after meals
- Consider dose reduction if severe
Hepatotoxicity
- Liver enzyme elevations: Monitor regularly 2
- Veno-occlusive disease: Rare but serious; permanently withdraw if suspected 2
Special Considerations
Pregnancy
- FDA pregnancy category D 1
- Discontinue if possible during pregnancy 1
- Consider risks vs. benefits if continuation necessary 1
Drug Interactions
- Allopurinol: Reduces azathioprine metabolism; reduce azathioprine dose to 1/3-1/4 of usual dose 2
- Aminosalicylates: May inhibit TPMT; use with caution 2
- ACE inhibitors: May cause anemia and leukopenia; monitor closely 2
- Ribavirin: May increase myelotoxicity; avoid combination 2
Treatment Response Assessment
Remission Criteria
- Normalization of transaminases and IgG levels 1
- Resolution of clinical symptoms 1
- Histological improvement (if biopsy performed) 1
Management of Suboptimal Response
- Increase prednisolone dose and/or azathioprine dose 1
- Consider alternative immunosuppressants like mycophenolate mofetil 1, 5
- Reassess diagnosis and medication adherence 1
Long-term Management
Treatment Duration
- Minimum 2 years of treatment 1
- Continue for at least 12 months after normalization of transaminases 1
- Many patients require lifelong therapy 1
Relapse Management
- Relapse is common (50-90%) after drug withdrawal 1
- Reinstitute induction therapy followed by maintenance therapy 5
- Consider long-term azathioprine monotherapy (2 mg/kg/day) for multiple relapses 5
Cautions and Pitfalls
- Never start azathioprine without checking TPMT status - severe myelosuppression can occur in TPMT-deficient patients 1, 2
- Delayed onset of action - therapeutic effects may take several months 2
- Risk of malignancy - long-term use associated with increased lymphoma risk 2, 6
- Avoid in severe hepatic impairment - increased risk of toxicity 2
- Monitor for infections - secondary to bone marrow suppression 2