What is the recommended treatment approach for a relapse of autoimmune hepatitis?

Treatment of Autoimmune Hepatitis Relapse

Relapse should be treated by restarting the same initial treatment regimen of prednisolone plus azathioprine, which is equally effective as primary induction therapy, followed by long-term maintenance azathioprine 2 mg/kg/day to prevent future relapses. 1

Definition of Relapse

• Relapse is defined as ALT elevation >3 times the upper limit of normal (ULN), though it may also present with milder ALT elevations and/or increased IgG levels 1
• Liver biopsy is usually not necessary to confirm relapse, as ALT elevations are highly predictive of histological activity 1
• Relapse occurs in 50-90% of patients within the first 12 months after stopping treatment, though later relapses can occur years afterward 1, 2

Treatment Approach for Relapse

Reinduction therapy: Restart prednisolone and azathioprine using the same dosing as initial treatment 1

• Standard combination: Prednisolone 30 mg/day tapered to 10 mg/day over 4 weeks, plus azathioprine 1-2 mg/kg/day 2
• This regimen is equally effective in inducing remission as primary induction therapy 1
• Close monitoring after treatment withdrawal allows lower doses of immunosuppressants to re-induce full remission if relapse is detected early 1

Long-term maintenance strategy: After achieving remission from relapse, transition to indefinite azathioprine maintenance therapy 1

• Increase azathioprine to 2 mg/kg/day while gradually withdrawing prednisolone 1
• Continue azathioprine indefinitely as chronic maintenance therapy 1
• This strategy maintains remission in 87% of patients during median follow-up of 67 months 1

Critical Rationale for Long-Term Maintenance

Patients with multiple relapses experience significantly worse outcomes: 1

• Progression to cirrhosis occurs in 38% of multiple relapsers versus 4% in sustained remitters (P = 0.004) 1
• Death from liver failure or need for transplantation occurs in 20% of multiple relapsers versus 0% in sustained remitters (P = 0.008) 1
• Drug-related side effects are more common in relapsing patients (54% versus 26%, P = 0.05) 1
• The number of relapse episodes directly correlates with disease progression and adverse clinical outcomes 1

Therefore, long-term, probably permanent, maintenance treatment is advisable in patients after a relapse 1

Monitoring During Maintenance Therapy

• Follow-up liver biopsy assessments show inactive or minimal histological disease in 94% of patients on azathioprine maintenance 1
• Monitor for withdrawal arthralgia (occurs in 63% of patients), myelosuppression (7%), and lymphopenia (57%) 1
• Lifelong monitoring is required even on maintenance therapy, as late relapses can occur 1

Alternative Maintenance Strategies

Low-dose prednisolone maintenance (less preferred): 1

• For patients who relapse on azathioprine maintenance, add low-dose prednisolone (median 7.5 mg/day) in addition to azathioprine 1
• This approach reduces severity of steroid side effects compared to repeated high-dose induction cycles 1
• However, progression to cirrhosis remains common (55%), with 2 deaths and 2 transplants in one series of 22 patients 1

Second-line agents for azathioprine-intolerant patients: 1, 2

• Mycophenolate mofetil may be considered as maintenance therapy in azathioprine-intolerant patients 1, 2
• Tacrolimus, cyclosporine, or other immunosuppressants are alternatives, though efficacy is less well-documented 1

Common Pitfalls to Avoid

• Do not attempt treatment withdrawal after a first relapse - the optimal time to prevent consequences of repeated relapse is after the first relapse by instituting indefinite maintenance therapy 1
• Do not use suboptimal maintenance doses - azathioprine must be increased to 2 mg/kg/day for effective relapse prevention 1
• Do not assume relapse risk decreases over time - late relapses can occur many years after stopping treatment, requiring lifelong monitoring 1