What are the current treatment guidelines for autoimmune hepatitis, including first‑line corticosteroid plus azathioprine therapy, dosing, alternatives, second‑line agents, special populations, and monitoring?

Current Treatment Guidelines for Autoimmune Hepatitis

First-Line Treatment Regimen

The preferred initial treatment is combination therapy with prednisone 30 mg/day plus azathioprine 50 mg/day (or 1-2 mg/kg/day), which achieves biochemical remission in 80% of patients within 6 months and causes significantly fewer corticosteroid-related side effects than prednisone monotherapy (10% versus 44%). 1

Standard Dosing Schedule

• Week 1: Prednisone 30 mg/day + Azathioprine 50 mg/day (US) or 1-2 mg/kg/day (Europe) 1, 2
• Week 2: Prednisone 20 mg/day + Azathioprine (same dose) 1
• Week 3-4: Prednisone 15 mg/day + Azathioprine (same dose) 1
• Maintenance: Taper prednisone to 10 mg/day or lower while continuing azathioprine until treatment endpoint 1

Important Pre-Treatment Considerations

• Measure thiopurine methyltransferase (TPMT) activity before starting azathioprine to identify patients with homozygous deficiency who are at high risk for severe myelosuppression. 1, 2
• In patients with severe hyperbilirubinemia (bilirubin >6 mg/dL or 100 μmol/L), start prednisone first and add azathioprine after 2 weeks once bilirubin improves. 1, 2
• Do not start azathioprine in patients with severe pre-treatment cytopenia (white blood cell count <2.5 × 10⁹/L or platelet count <50 × 10⁹/L). 1

Alternative First-Line Option: Budesonide

Budesonide 9 mg/day plus azathioprine may be used specifically in treatment-naïve, non-cirrhotic patients with early-stage disease who face high risk of major steroid-specific side effects (psychosis, poorly controlled diabetes, severe osteoporosis, brittle hypertension). 1, 2

• This regimen achieves faster normalization of transaminases and causes fewer side effects than standard prednisone-based therapy in non-cirrhotic patients 1
• Do NOT use budesonide in patients with cirrhosis due to impaired first-pass hepatic metabolism 2, 3
• Do NOT use budesonide in acute severe autoimmune hepatitis 3

Treatment Goals and Monitoring

Target Endpoints

Complete normalization of BOTH serum aminotransferases (ALT/AST) AND IgG levels must be the treatment goal, as persistent elevations predict relapse, ongoing histological activity, progression to cirrhosis, and poor outcomes. 1, 2

Monitoring Schedule

• Weekly laboratory tests (liver enzymes, glucose, complete blood count) during the first 4 weeks 2
• Assess treatment response at 4-8 weeks after initiation; serum aminotransferases should improve within 2 weeks 2, 4, 3
• Monthly monitoring thereafter, then every 1-3 months once biochemical response is stable 2
• Normal liver tests are achieved in 66-91% of treated patients within 2 years, with average duration to normalization being 19 months 2

Bone Health Monitoring

• Obtain baseline DEXA scan before initiating prednisone, with repeat scans every 1-2 years while on corticosteroids 2, 4, 3
• Start calcium and vitamin D supplementation at treatment initiation in all patients 2, 4, 3

Treatment Duration

Continue treatment for at least 2 years AND for at least 12 months after complete normalization of liver enzymes and IgG levels. 2, 4, 3

• The average duration of initial treatment is 18-24 months 2, 4
• Liver biopsy prior to drug withdrawal is preferred but not mandatory in adults; it is required in children 2
• Only 20-28% of patients achieve sustained remission off therapy 2

Management of Treatment Failure or Suboptimal Response

Definition and Approach

If diagnosis is confirmed and adherence verified, treatment failure warrants escalation to high-dose therapy: prednisone 60 mg daily alone OR prednisone 30 mg daily plus azathioprine 150 mg daily (or up to 2 mg/kg/day) for at least 1 month. 1, 2, 3

• After 1 month of high-dose therapy, reduce prednisone by 10 mg and azathioprine by 50 mg each month as clinical and laboratory parameters improve 1
• Non-response should always prompt reconsideration of the diagnosis and re-evaluation of medication adherence 1

Second-Line Agents for Refractory Disease

For steroid-refractory cases after confirmed treatment failure, use alternative second-line agents including tacrolimus, cyclosporine, or mycophenolate mofetil. 2, 3, 5

Calcineurin Inhibitors (Preferred Second-Line)

• Cyclosporine has positive outcomes in 93% of steroid-refractory patients across 10 reports involving 133 patients 5
• Tacrolimus has positive outcomes in 98% of steroid-refractory patients across 3 reports involving 41 patients, and is superior to mycophenolate mofetil at achieving biochemical remission 3, 5

Mycophenolate Mofetil

• Mycophenolate mofetil (2 g daily) has favorable outcomes in 47% of refractory patients, especially those with azathioprine intolerance 1, 5
• As front-line therapy, mycophenolate mofetil normalized liver parameters in 88% and allowed corticosteroid tapering in 58% 5

Acute Severe Autoimmune Hepatitis

Treat acute severe autoimmune hepatitis immediately with high-dose intravenous corticosteroids (≥1 mg/kg) as early as possible. 1, 2, 3

• If no improvement occurs within 7 days (lack of improvement in bilirubin and MELD score), list for emergency liver transplantation 1, 2, 3
• Young, non-Caucasian patients with acute or fulminant presentation and confluent necrosis on biopsy have higher risk of treatment failure 1

Management of Relapse

Relapse occurs in 50-90% of patients within 12 months of stopping treatment, even after achieving complete biochemical and histological remission. 1, 2, 4, 3

After First Relapse

• Re-treat with the original regimen (prednisone plus azathioprine) 1, 6
• Continue until remission is re-achieved

After Multiple Relapses

After relapse more than once, institute long-term maintenance therapy with azathioprine 2 mg/kg/day while tapering prednisone to the lowest effective dose or discontinuing it altogether. 1, 2, 4, 3

• 87% of adult patients remain in remission on long-term azathioprine maintenance during median follow-up of 67 months 1, 4
• Withdrawal arthralgia occurs in 63% of patients on chronic azathioprine but is usually manageable 1
• Monitor for myelosuppression (7%) and lymphopenia (57%) 1

Special Populations

Children

All children in whom the diagnosis of autoimmune hepatitis has been established should be treated, as the disease is more severe at presentation and delays in treatment adversely affect long-term outcome. 1

• Prednisone 1-2 mg/kg daily (up to 60 mg/day) for 2 weeks, then taper over 6-8 weeks to 0.1-0.2 mg/kg daily or 5 mg daily with azathioprine 3
• More than 50% of children have cirrhosis at presentation 1
• Early use of azathioprine is recommended for all children without contraindications 3

Pregnancy

• Azathioprine can be continued throughout pregnancy 2
• Prednisone is generally safe during pregnancy 2
• Mycophenolate mofetil is contraindicated in pregnancy 2

Cirrhotic Patients

Initiate combination immunosuppressive therapy (prednisone 30 mg daily plus azathioprine 1-2 mg/kg daily) immediately in patients with cirrhosis, as this regimen can reverse fibrosis and cirrhosis and markedly improves survival even when cirrhosis is already established. 2, 6

• Use standard prednisone/prednisolone plus azathioprine instead of budesonide in cirrhotic patients due to impaired first-pass metabolism 2
• Conduct hepatic ultrasonography every 6 months in all cirrhotic patients to screen for hepatocellular carcinoma 2

Liver Transplantation

Refer patients for liver transplantation evaluation when MELD score ≥15, decompensated cirrhosis develops despite optimal immunosuppression, or hepatocellular carcinoma meeting transplant criteria emerges. 1, 2

• Five-year survival rate post-transplant is 75-92%; ten-year survival is approximately 75% 2
• Recurrent autoimmune hepatitis occurs in about 30% of recipients post-transplant 2
• Treat recurrent autoimmune hepatitis post-transplant with prednisone and azathioprine in adjusted doses, or increased corticosteroids with optimization of calcineurin inhibitor levels (preferably tacrolimus) 1
• If response is incomplete, add mycophenolate mofetil (2 g daily) to the regimen of corticosteroid and calcineurin inhibitor 1

Contraindications to Treatment

Do not institute immunosuppressive treatment in patients with:

• Minimal or no disease activity or inactive cirrhosis (continue close follow-up every 3-6 months) 1
• Serious pre-existing comorbid conditions (vertebral compression, psychosis, brittle diabetes, uncontrolled hypertension) unless disease is severe and progressive and adequate control measures for comorbidities can be instituted 1

Prevention of Treatment Complications

Corticosteroid-Related Side Effects

• Common side effects include weight gain, mood changes, increased appetite, hyperglycemia, and hypertension 2
• Severe complications (osteoporosis, vertebral compression, diabetes, cataracts, hypertension, psychosis) typically develop after 18 months of therapy at prednisone doses >10 mg daily 4
• Screen for steroid-induced cataracts and glaucoma after ≥12 months of prednisone exposure 2

Azathioprine-Related Side Effects

• Regular complete blood count monitoring is required because azathioprine can cause bone marrow suppression 2
• Lymphopenia occurs in about 57% but is usually well tolerated 1

Vaccination

• Screen for hepatitis A and B immunity and vaccinate if non-immune prior to starting immunosuppression 2, 4

Common Pitfalls to Avoid

• Do not accept partial biochemical improvement as adequate; both transaminases AND IgG must normalize completely 1, 2
• Do not use budesonide in cirrhotic patients or those with acute severe disease 2, 3
• Do not withhold treatment solely because cirrhosis is present; cirrhosis is an indication for treatment, not a contraindication 2
• Do not start azathioprine in patients with severe cytopenia without first checking TPMT status 1, 2
• Do not delay listing for transplantation in acute severe cases that fail to improve within 7 days of high-dose corticosteroids 1, 2, 3