Is it safe to reintroduce Imuran (azathioprine) after a 2-week break in a patient with elevated liver enzymes (hypertransaminasemia) for treatment of Behçet's disease?

Reintroduction of Azathioprine After Elevated Liver Enzymes in Behçet's Disease

Yes, it is safe to reintroduce azathioprine after a 2-week break following elevated liver enzymes (ALT 223, AST 118) in a 22-year-old female with Behçet's disease, but this should be done at a reduced dose with careful monitoring. 1

Assessment and Reintroduction Protocol

• A 2-week break that resulted in normalization of liver enzymes suggests a reversible drug effect rather than permanent liver damage, making reintroduction possible 1
• Azathioprine should be reintroduced at a significantly reduced dose (approximately 50 mg/day), with gradual dose escalation over 2-3 weeks while monitoring liver function tests 1, 2
• The reintroduction should aim for a maintenance dose that is lower than the previous dose that caused hepatotoxicity 1
• Azathioprine is considered an effective and safe therapy for severe uveitis in Behçet's disease, with complete response rates of 51.6% and partial response rates of 41.4% in studies 3

Monitoring Requirements

• Liver function tests should be monitored weekly during the first month after reintroduction, twice monthly for the second and third months, then monthly thereafter 1, 4
• Complete blood counts, including platelet counts, should follow the same monitoring schedule to detect potential myelosuppression 4
• Clinical symptoms such as fatigue, nausea, vomiting, right upper quadrant pain, and jaundice should be monitored as they may indicate recurrent hepatotoxicity 1, 4

When to Stop Therapy Again

• Therapy should be stopped immediately if:
  • ALT/AST rises to ≥3× baseline or ≥300 U/L with symptoms 1
  • ALT/AST rises to ≥5× baseline or ≥500 U/L even without symptoms 1
  • Any elevation in bilirubin (≥2× ULN) occurs along with elevated transaminases 1

Importance of Azathioprine in Behçet's Disease

• Azathioprine (2.5 mg/kg/day) combined with corticosteroids is effective for severe uveitis in Behçet's disease, significantly improving visual acuity and allowing reduction in corticosteroid dosage 3
• Long-term studies (up to 10 years) show that azathioprine in combination with cyclophosphamide is effective for ocular manifestations of Behçet's disease 5
• In patients with Behçet's disease, azathioprine alleviated ocular symptoms in 36% of patients and also improved extraocular pathology such as stomatitis, erythema, and arthralgia 6

Alternative Options

• If hepatotoxicity recurs despite dose reduction, alternative immunosuppressive agents should be considered:
  • Mycophenolate mofetil may be used in azathioprine-intolerant patients 2
  • Tacrolimus or cyclosporine may be effective alternatives 2, 1
  • Cyclophosphamide in combination with prednisolone has shown efficacy in Behçet's disease with ocular manifestations 5

Important Considerations

• Azathioprine hepatotoxicity is generally reversible after interruption of the drug 4
• A repeat liver biopsy should be considered if azathioprine hepatotoxicity is suspected, particularly if it is associated with high blood levels of 6-methylmercaptopurine metabolites 2
• The benefit-risk ratio for continued azathioprine use is generally favorable in patients who respond well to the medication 7
• In patients with autoimmune conditions, neither heterozygosity for TPMT nor 6-MP metabolite levels were shown to be reliable predictors of azathioprine efficacy or toxicity 2

By following this protocol for reintroduction and monitoring, azathioprine can be safely restarted in this young patient with Behçet's disease after the transient elevation in liver enzymes has resolved.