What is the mechanism of action of disease-modifying treatments for myasthenia gravis?

Mechanisms of Action of Disease-Modifying Treatments for Myasthenia Gravis

Disease-modifying treatments for myasthenia gravis target the autoimmune attack on acetylcholine receptors at the neuromuscular junction through various mechanisms including acetylcholinesterase inhibition, immunosuppression, antibody depletion, and complement inhibition. 1

Pathophysiology of Myasthenia Gravis

Myasthenia gravis (MG) is an autoimmune disorder characterized by:

• Antibody-mediated attack on the neuromuscular junction
• Primarily targeting acetylcholine receptors (AChRs) in 80-90% of patients with generalized MG 2
• In some seronegative patients, antibodies target muscle-specific kinase (MuSK) or lipoprotein-related protein 4 (LRP4) 1
• Reduced acetylcholine receptor density at the neuromuscular junction 3
• Complement-mediated destruction of the postsynaptic endplate membrane 4

First-Line Treatment: Acetylcholinesterase Inhibitors

Pyridostigmine Bromide

• Mechanism: Inhibits acetylcholinesterase enzyme, preventing breakdown of acetylcholine at the neuromuscular junction
• Effect: Increases concentration of acetylcholine available to bind to remaining functional receptors
• Limitations: About 50% of patients with strabismus-associated myasthenia show minimal response 1
• Administration: Typically given orally 2-4 times daily 1

Immunosuppressive Therapies

Corticosteroids

• Mechanism: Broad immunosuppression through inhibition of T-cell function and cytokine production
• Efficacy: 66-85% of patients show positive response 1
• Limitations: Long-term use associated with significant side effects

Azathioprine and Other Cytostatic Agents

• Mechanism: Inhibits DNA synthesis in rapidly dividing cells, including immune cells
• Effect: Suppresses production of autoantibodies
• Evidence: Known to be effective in MG 1

Targeted Immunotherapies

Efgartigimod alfa-fcab

• Mechanism: Binds to neonatal Fc receptor (FcRn), preventing recycling of IgG antibodies including pathogenic autoantibodies
• Indication: FDA approved for patients who test positive for anti-acetylcholine receptor antibodies 1
• Advantage: More targeted approach than general immunosuppression

Complement Inhibitors (Eculizumab/Ravulizumab)

• Mechanism: Inhibit complement-mediated destruction of the postsynaptic membrane
• Status: Approved in Russia and other countries 5
• Benefit: Rapid onset of action with minimal side effects compared to traditional immunosuppressants

Surgical Intervention: Thymectomy

• Mechanism: Removes thymus gland, which may be involved in the production of autoantibodies
• Indication: Always indicated in presence of thymoma; also beneficial for specific age-based and immune-based characteristics 1
• Effect: May substantially reduce clinical symptoms in certain subpopulations 1

Treatment Algorithm

1. Initial treatment: Pyridostigmine bromide as symptomatic therapy
2. If inadequate response: Add corticosteroids
3. For long-term management: Consider steroid-sparing immunosuppressants (azathioprine)
4. For refractory cases: Consider targeted therapies like efgartigimod alfa-fcab
5. Surgical evaluation: Thymectomy for patients with thymoma or specific characteristics
6. For stabilized disease: Consider surgical intervention for persistent strabismus after 2-3 years of treatment 1

Clinical Pearls and Pitfalls

• Diagnostic challenge: MG can mimic many neuromuscular diseases and conditions like depression and chronic fatigue syndrome 2
• Treatment resistance: Approximately 15% of patients show inadequate response to standard therapies 6
• Anesthetic risk: Special care is needed with anesthetic agents in MG patients due to potential respiratory muscle weakness 1
• Variable response: Strabismus and diplopia in MG are highly variable and not easily corrected with prisms 1
• Treatment goal: The ultimate aim is to induce and maintain remission, often requiring combinations of short-term and long-term immunosuppressive agents 4

Emerging Therapies

Recent advances in molecular therapies include:

• B cell-depleting agents
• Fc receptor antagonists
• CAR T cell-based therapies

These newer approaches offer more targeted mechanisms for interrupting the autoimmune process with potentially fewer side effects than traditional immunosuppressants 6.