What is the role of Azathioprine in treating Autoimmune Inner Ear Disease (AIED)?

Role of Azathioprine in Autoimmune Inner Ear Disease (AIED)

Azathioprine is an effective second-line immunosuppressive agent for patients with Autoimmune Inner Ear Disease (AIED) who cannot tolerate or become refractory to corticosteroid therapy. 1

First-Line Treatment for AIED

AIED is characterized by rapidly progressive sensorineural hearing loss over weeks to months that initially responds to corticosteroid administration. The management algorithm is:

1. Initial therapy: High-dose systemic corticosteroids

   • Prednisolone 0.5-1 mg/kg/day as first-line therapy 2
   • Diagnosis is confirmed by positive therapeutic response to corticosteroids 3

2. Assessment of response: After 4 weeks of corticosteroid therapy

   • If improvement: Continue and gradually taper steroids
   • If no improvement: Consider alternative diagnosis or steroid-refractory disease

Role of Azathioprine in AIED Management

Indications for Azathioprine

Azathioprine should be considered in the following scenarios:

• Patients who cannot be weaned off corticosteroids
• Steroid-dependent patients with severe side effects
• Patients whose disease becomes refractory to corticosteroid treatment
• When long-term immunosuppression is required

Dosing and Administration

• Starting dose: 50 mg/day 4
• Maintenance dose: 1-2 mg/kg/day 4, 2
• Combination therapy: Often used with low-dose prednisolone (30 mg every other day) 1

Efficacy in AIED

A study of 12 AIED patients treated with azathioprine 1 mg/kg daily combined with prednisolone 30 mg every other day showed:

• Statistically significant improvement in hearing in 10/12 patients (83%) 1
• Improvements in both pure tone audiometry and speech discrimination

Monitoring and Side Effects

Monitoring Requirements

• Weekly liver tests and blood counts for the first 4 weeks
• Monthly monitoring once stable 2
• TPMT (thiopurine methyltransferase) testing before initiating therapy to identify patients at risk for severe toxicity 5

Side Effects

• Up to 25% of patients develop side effects requiring withdrawal in about 10% of cases 4
• More common in cirrhotic patients 4
• Early reactions (within days/weeks) may include arthralgias, fever, skin rash, or pancreatitis 4
• Myelosuppression, hepatotoxicity, and increased risk of infections

Alternative Second-Line Agents

If azathioprine is not tolerated, consider:

1. Mycophenolate mofetil (MMF):

   • First choice for azathioprine intolerance 2
   • Starting at 1g daily, increasing to 1.5-2g daily 2
   • Recent evidence suggests MMF may be more effective than azathioprine with:
     • Higher complete biochemical response rates (96% vs 87.2%)
     • Lower serious complications (3.8% vs 18.8%)
     • Lower treatment change rates due to intolerance (11% vs 43.7%) 6

2. Other options:

   • Cyclophosphamide (restricted to patients willing to accept significant risks) 3
   • Methotrexate (note: recent studies show limited efficacy in AIED) 3, 7
   • Biologic agents (infliximab, etanercept, adalimumab, rituximab) for steroid non-responders 7

Treatment Duration and Follow-up

• Long-term maintenance therapy is often required
• Regular audiometric testing to monitor response
• Consider tapering attempts after sustained remission (typically 2-3 years)
• Lifelong monitoring recommended even after treatment cessation

Practical Considerations and Pitfalls

• Contraindications: Severe pre-treatment cytopenia 2
• Drug interactions: Allopurinol significantly increases azathioprine toxicity
• Pregnancy: Azathioprine has FDA pregnancy category D rating 2
• Vaccination: Consider hepatitis A and B vaccination for susceptible patients 2
• Bone health: All patients on concurrent steroids should receive calcium and vitamin D supplementation 2

Key Pitfall to Avoid

Failure to test for TPMT enzyme activity before initiating azathioprine can lead to severe myelosuppression in patients with genetic polymorphisms affecting this enzyme 5. This pharmacogenetic consideration is critical for safe prescribing.