What are the treatment options for checkpoint inhibitor-induced hepatitis?

Management of Checkpoint Inhibitor Hepatitis

The management of checkpoint inhibitor-induced hepatitis requires a stepwise approach with corticosteroids as first-line therapy, followed by mycophenolate mofetil for steroid-refractory cases, and consideration of tacrolimus as third-line therapy for severe refractory cases. 1

Medications That Can Cause Checkpoint Inhibitor Hepatitis

1. CTLA-4 inhibitors (e.g., ipilimumab) - associated with higher incidence (up to 10% of cases) 1
2. PD-1 inhibitors (e.g., nivolumab, pembrolizumab) - cause hepatitis in 5-10% of patients 1, 2
3. PD-L1 inhibitors - similar mechanism to PD-1 inhibitors 2
4. Combination immunotherapy - particularly CTLA-4 plus PD-1 inhibitors, which significantly increases risk (25-30% incidence with 15% being grade 3) 1

Treatment Options for Checkpoint Inhibitor Hepatitis

1. Corticosteroids

• First-line therapy for moderate to severe cases

• For Grade 2 hepatitis (AST/ALT >3-5× ULN):

  • Prednisone 0.5-1.0 mg/kg/day or equivalent 1
  • Hold checkpoint inhibitor therapy temporarily 1

• For Grade 3-4 hepatitis (AST/ALT >5× ULN):

  • Methylprednisolone 1-2 mg/kg/day or equivalent 1
  • Permanently discontinue checkpoint inhibitor therapy 1
  • Recent evidence suggests that 1 mg/kg/day may be as effective as higher doses with fewer complications 3

2. Mycophenolate Mofetil

• Second-line therapy for steroid-refractory cases
• Add if no response to corticosteroids within 2-3 days
• Typical dosing: 1000 mg twice daily 1
• Particularly useful for Grade 3-4 hepatitis not responding to steroids 1

3. Tacrolimus

• Third-line therapy for cases refractory to both steroids and mycophenolate
• Can be successful when other immunosuppressants fail 4
• Consider in consultation with hepatology specialists 1

4. Azathioprine

• Alternative second/third-line agent for steroid-refractory cases
• May be beneficial in steroid-refractory immune-related hepatitis 1
• Should test for thiopurine methyltransferase deficiency before use 1

Management Algorithm Based on Severity

Grade 1 (AST/ALT 1-3× ULN)

• Continue checkpoint inhibitor therapy
• Monitor liver function tests more frequently (1-2 times weekly)
• No specific treatment required 1

Grade 2 (AST/ALT >3-5× ULN)

1. Temporarily hold checkpoint inhibitor therapy
2. Discontinue hepatotoxic medications
3. Monitor transaminases twice weekly
4. If persistent >1-2 weeks, start prednisone 0.5-1 mg/kg/day
5. Resume checkpoint inhibitor after improvement to Grade 1 and steroid taper to ≤10 mg/day 1

Grade 3 (AST/ALT >5-20× ULN)

1. Consider permanently discontinuing checkpoint inhibitor therapy
2. Start methylprednisolone 1-2 mg/kg/day immediately
3. Monitor labs daily or every other day
4. If no improvement in 2-3 days, add mycophenolate mofetil 1000 mg twice daily
5. Consider hepatology consultation and liver biopsy
6. Taper steroids over 4-6 weeks when improved to Grade 1 1

Grade 4 (AST/ALT >20× ULN)

1. Permanently discontinue checkpoint inhibitor therapy
2. Hospitalize patient, preferably at a tertiary care center
3. Start methylprednisolone 2 mg/kg/day
4. If no response within 3 days (transaminases drop <50%), add second-line agent
5. Consider hepatology consultation and liver biopsy
6. Consider transfer to liver transplant center if signs of liver failure 1

Important Caveats and Pitfalls

• Avoid infliximab in checkpoint inhibitor hepatitis - contraindicated due to potential hepatotoxicity 1
• Rule out other causes of hepatitis before attributing to checkpoint inhibitors (viral hepatitis, alcohol, medications, disease progression) 1
• Liver biopsy should be considered for steroid-refractory cases or when diagnosis is uncertain 1
• Monitor for infections and hyperglycemia in patients on high-dose steroids, as these are common complications 3
• Antimicrobial prophylaxis should be considered for patients on multiple immunosuppressive agents 4
• Checkpoint inhibitor hepatitis is often asymptomatic and detected on routine blood monitoring 1

By following this systematic approach to management, most cases of checkpoint inhibitor-induced hepatitis can be effectively treated while minimizing complications from both the hepatitis itself and its treatment.