From the Guidelines
Patients with autoimmune hepatitis who stop taking azathioprine are at high risk of relapse, with approximately 50-90% of patients experiencing a disease relapse within 12 months of stopping treatment, as defined by serum ALT >3 times the normal 1. The predictors of relapse in autoimmune hepatitis after azathioprine discontinuation include:
- Shorter duration of treatment
- Incomplete biochemical remission
- Presence of residual inflammation on liver biopsy
- Elevated immunoglobulin G (IgG) levels
- High titers of autoantibodies (particularly anti-smooth muscle antibodies) Patients with type 1 autoimmune hepatitis, younger age at diagnosis, and HLA DR3 serotype also face higher relapse risks 1.
Key Considerations
Before considering azathioprine withdrawal, patients should have maintained complete biochemical remission for at least 2-3 years, with normal transaminases, normal IgG levels, and ideally a liver biopsy showing minimal or no inflammation. Even with these favorable factors, approximately 50-70% of patients will relapse within 3 years of medication discontinuation. Close monitoring is essential after stopping therapy, with liver function tests recommended monthly for the first 3 months, then every 3 months for the first year, and periodically thereafter.
Maintenance Therapy
Due to the high relapse rate, many specialists now recommend lifelong low-dose maintenance therapy rather than complete withdrawal, particularly in high-risk patients 1. The dose of azathioprine should be increased to 2 mg/kg/day as the dose of prednisone is gradually withdrawn, and azathioprine should be continued indefinitely as a continuous maintenance therapy. Patients should be monitored for cytopenias, and the benefits and potential risks of lifelong azathioprine or prednisolone maintenance therapy should be discussed with the patients, taking into consideration individual factors such as the stage of liver disease, severity of initial presentation, and age of the patient.
From the Research
Predictors of Relapse
The predictors of relapse of autoimmune hepatitis after stopping azathioprine include:
- Absence of an identifiable initial disease trigger 2
- Presence of other autoimmune diseases 2
- Longer time to biochemical remission 2
- Elevated serum transaminases on treatment withdrawal 2
Factors Associated with Relapse
Other factors that have been associated with relapse, although with inconsistent reports, include:
Treatment Withdrawal
Treatment withdrawal in patients with autoimmune hepatitis who have achieved remission is a complex decision, with some studies suggesting that:
- A sustained remission after treatment withdrawal is feasible 3
- Relapse rates can be high, up to 90%, even in patients with established histological remission 3
- Patients who relapse after drug withdrawal have a high probability for a re-relapse to occur 3
Considerations for Treatment Withdrawal
Considerations for treatment withdrawal include:
- The risk of disease progression after a single relapse appears low 3
- Patients in longstanding clinical remission on monotherapy, with complete normalisation of aminotransferases and IgG, could be offered one attempt of drug withdrawal 3
- Life-long maintenance therapy should be strongly considered in patients who have multiple relapses, as they are more likely to progress to cirrhosis, liver transplantation, and death from liver failure 3