When can nonsteroidal (NSAID) medications like azathioprine be stopped in patients with autoimmune hepatitis?

When to Stop Azathioprine in Autoimmune Hepatitis

Azathioprine should be stopped only after at least 2 years of treatment, with a minimum of 12 months of sustained normal liver tests (AST, ALT, bilirubin, and IgG), and ideally after liver biopsy confirms complete histological remission with no interface hepatitis. 1

Critical Prerequisites Before Stopping Azathioprine

Minimum Treatment Duration

• Continue treatment for at least 2 years total, regardless of when biochemical remission is achieved 1
• Maintain normal liver tests for at least 12 consecutive months before considering drug withdrawal 1
• The average time to achieve biochemical normalization is 19 months, with histological resolution requiring an additional 3-8 months 1

Essential Pre-Withdrawal Assessment

• Liver biopsy is strongly recommended before stopping treatment to confirm complete histological remission 1
• Interface hepatitis is found in 55% of patients with normal serum AST and γ-globulin levels during therapy, and these individuals typically relapse after cessation 1
• Only 30% of patients with complete histological resolution on biopsy will relapse, compared to much higher rates without documented histological remission 1

High-Risk Patients Who Should NOT Stop Azathioprine

Continue azathioprine indefinitely as maintenance therapy in the following patients: 1

• After even one relapse - continuation of azathioprine 2 mg/kg/day as long-term maintenance is recommended 1
• Younger patients who have decades of life expectancy 1
• LKM-1 antibody positive patients (higher relapse risk) 1
• SLA/LP antibody positive patients (higher relapse risk) 1
• Patients with cirrhosis or prior decompensation 1
• Those with observed or anticipated prednisolone-related side effects including osteopenia 1
• Patients who had slow biochemical response (took longer to achieve remission) 1
• Those with elevated serum globulin or IgG at time of consideration 1

Lower-Risk Patients Where Withdrawal Can Be Considered

Features favoring withdrawal attempt include: 1

• Absence of cirrhosis or decompensation 1
• Good tolerance of initial prednisolone treatment 1
• Identifiable precipitant for the initial episode (such as drug-induced or documented viral infection) 1
• History of malignancy (where long-term immunosuppression poses additional risk) 1
• Absence of features associated with relapse (see high-risk criteria above) 1

Expected Relapse Rates After Stopping

Relapse is the rule, not the exception:

• 50-90% of adult patients relapse after stopping treatment, even with documented biochemical and histological remission 1
• 60-80% of pediatric patients relapse after drug withdrawal 2
• Only 25-36% achieve "sustained remission" (defined loosely as AST <3× upper limit of normal) 1
• 20-28% relapse even after treatment to normal liver tests AND normal liver tissue 1

Alternative Strategy: Long-Term Azathioprine Monotherapy

The preferred approach for most patients is indefinite azathioprine maintenance rather than complete withdrawal:

• 87% remission rate maintained over median 67 months on azathioprine 2 mg/kg/day monotherapy 3
• 94% showed inactive or minimal histological disease on follow-up biopsies during azathioprine maintenance 3
• Long-term azathioprine monotherapy is well-tolerated in both adults and children 2, 3, 4
• This strategy avoids the high relapse rates and need for repeated high-dose corticosteroid courses 3, 5

Common Pitfalls to Avoid

• Do not stop treatment based on normal liver tests alone - 55% will have active interface hepatitis on biopsy despite normal biochemistry 1
• Do not attempt withdrawal before 2 years total treatment - premature withdrawal at 1 year is associated with 47% relapse rate 6
• Do not assume histological remission without biopsy confirmation - this is the only method to ensure full disease resolution 1
• Do not stop in patients with multiple relapses - these patients have worse outcomes including progression to cirrhosis and liver-related death 1

Monitoring After Withdrawal (If Attempted)

• Lifelong monitoring is mandatory, even after successful withdrawal 1
• Monitor liver tests every 4-6 weeks initially, then at least every 3 months indefinitely 1
• Relapse is defined as AST >2× upper limit of normal - liver biopsy is usually not necessary to confirm relapse due to high predictive value 1
• With mild elevations, repeat liver tests after 1-2 weeks before assuming relapse 1
• More than 80% of patients achieve remission again with retreatment, usually within a few months 1