A 48-year-old man with acetylcholine-receptor-positive myasthenia gravis on prednisone 30 mg daily, pyridostigmine, and IVIG every 4 weeks now has worsening diplopia and proximal weakness; which medication should be added next: azathioprine, cyclophosphamide, mycophenolate mofetil, or rituximab?

Azathioprine Should Be Added Next

This patient with acetylcholine receptor-positive myasthenia gravis experiencing inadequate disease control on prednisone, pyridostigmine, and IVIG should be started on azathioprine as the next steroid-sparing immunosuppressant. 1, 2

Rationale for Azathioprine as First-Line Steroid-Sparing Agent

• Azathioprine is the established first-choice long-term immunosuppressant for myasthenia gravis, typically started together with corticosteroids to allow tapering of steroids to the lowest dose possible 2
• The patient is already on prednisone 30 mg daily but continues to have progressive symptoms (diplopia and proximal weakness), indicating inadequate disease control that requires additional immunosuppression 1
• Nordic MG experts recommend combining corticosteroids at the lowest possible dose with azathioprine as first-line immunosuppressive treatment 1
• In large clinical series, azathioprine was used as the first-choice immunosuppressant with overall remission or minimal manifestation rates of 85% in generalized MG 3

Dosing and Implementation Strategy

• Start azathioprine at 2 mg/kg of ideal body weight in divided doses, typically beginning at 25-50 mg/week with increments of 25-50 mg/week until the goal dosage is reached 4
• Check thiopurine methyltransferase (TPMT) level before initiating therapy to screen for enzyme deficiency, as myelosuppression can occur in patients with TPMT deficiency on standard azathioprine doses 4
• Azathioprine has a delayed onset of action, typically taking 3-6 months to reach full efficacy, so the patient should continue current medications while azathioprine is being titrated 4, 3

Why Not the Other Options

• Mycophenolate mofetil is a second-line agent reserved for patients who are intolerant of or unresponsive to azathioprine 1, 2
• Cyclophosphamide should only be considered as a last resort due to serious adverse events and is reserved for treatment-refractory disease 5, 2
• Rituximab is an alternative first-line option but is typically reserved for patients who fail conventional immunosuppression or have specific contraindications to azathioprine 1, 5

Monitoring and Expected Outcomes

• Common adverse effects of azathioprine include nausea and loose stools; less common effects include fever and liver toxicity 4
• Approximately 82% of MG patients benefit from immunosuppressive treatment, with the combination of prednisone and azathioprine allowing for eventual steroid dose reduction 3
• The patient's IVIG can continue at the current schedule (1 g/kg every 4 weeks) while azathioprine is being initiated and titrated 6

Important Caveats

• This patient denies dysphagia and shortness of breath, which are reassuring signs that he is not in myasthenic crisis and can be managed with oral immunosuppression escalation rather than requiring hospitalization or plasma exchange 4, 6
• The goal is to achieve disease control while tapering prednisone to minimize long-term corticosteroid complications 2, 3
• If the patient fails to respond to azathioprine after 3-6 months or develops intolerance, mycophenolate mofetil (2-3 g/day) would be the appropriate next step 1, 2