Treatment options for patients with MG can be grouped into the following categories, where disease management often involves the combined use of the below:1,3
Although treatment for MG is individualised, first-line therapy typically begins with treating the patient’s symptoms with acetylcholinesterase (AChE) inhibitors.2-6
AChE inhibitors bind the enzyme AChE and inhibit the hydrolysis of acetylcholine (ACh) into its components (choline and acetate) at the neuromuscular junction (NMJ).1,7 In healthy individuals, this process is required in order for a neuron to return to its resting state after activation.7 In patients with MG, inhibiting the hydrolysis of ACh increases both its bioavailability and its duration of action at the postsynaptic membrane.1,3
AChE inhibitors provide temporary relief of symptoms with an onset of approximately 30 minutes and effects lasting around 4 hours.3 Most patients with MG respond to treatment with AChE inhibitors, though variable improvements in strength are observed.1,3 Patients harbouring autoantibodies against muscle-specific kinase (MuSK) however are usually unresponsive to AChE inhibitors and can experience intolerable adverse effects.1,8
Dose optimisation is an essential step in the use of AChE inhibitors, both for improving treatment efficacy and minimising potential adverse effects.1,3 Excessive use of AChE inhibitors can lead to accumulation of ACh at the NMJ resulting in cholinergic crisis – symptoms of which can cause worsening of muscle weakness.3,8
The mechanism of action of AChE inhibitors is illustrated here12,14:
When an optimised treatment regimen with AChE inhibitors does not adequately control the symptoms of a patient with MG, second-line treatment usually involves the use of chronic IS therapy with corticosteroids or non-steroidal immunosuppressants.1,2
Corticosteroids are first-line immunosuppressants for MG as they have a relatively rapid onset of action, are low-cost and have demonstrated efficacy over decades of clinical use.1,5,10 They can be initiated at low doses with gradual dose escalation in patients with mild to moderate disease or at high doses in patients with severe disease.1
Although poorly understood, broad suppression of the immune system is thought to be achieved via several different mechanisms.5,11 These include:11
- Reducing leukocyte distribution and trafficking
- Inhibiting lymphocyte recruitment and migration to an inflammatory site
- Blocking T cell function
- Reducing the production and secretion of cytokines and other immune mediators from macrophages or T cells
- Decreasing dendritic cell maturation
Retrospective clinical studies have shown that about 70–80% of patients with MG experienced improved symptoms within several weeks to months of starting treatment with corticosteroids.8 A rapid response, typically within 2–4 weeks after treatment initiation, has been reported when high-dose corticosteroid regimens were used.1,5
Temporary exacerbation of symptoms can occur after initiating high doses of corticosteroids within the first 7–10 days and can last for several days.3 Initiating treatment at a low dose with slow titration can help mitigate transient worsening of muscle weakness.5
Long-term use of corticosteroids is accompanied by several adverse effects.1,10 These include osteoporosis, weight gain, impaired glucose tolerance, skin atrophy, mood disorders, glaucoma and increased risk of infection.1 The number and severity of adverse effects increase with the duration and cumulative dosage of the corticosteroid treatment.8
Long-term use of corticosteroids is accompanied by several adverse effects.1,10 These include osteoporosis, weight gain, impaired glucose tolerance, skin atrophy, mood disorders, glaucoma and increased risk of infection.1 The number and severity of adverse effects increase with the duration and cumulative dosage of the corticosteroid treatment.8
NS-IS therapies are recommended for all subtypes of MG and can be used in combination with corticosteroids or as a monotherapy when corticosteroids are contraindicated.1,2,5
The mechanism of action of NS-IS therapies is variable depending on the agent. Some NS-IS agents block T cell activation, whereas others reduce the proliferation of B and T cells and/or interfere with DNA replication and synthesis.1
NS-IS therapies have a delayed onset ranging from months to years after initiation that is variable depending on the therapy.1,5 Approximately 70–80% of patients with MG are thought to respond to treatment with NS-IS therapies.1
A number of NS-IS agents have demonstrated efficacy in patients with MG,1 though deciding which to initiate is based on a number of factors, such as the patient’s specific needs, severity of adverse effects and accessibility of each medication in different countries.1,5
Patients with MG are often treated with rapid, short-term IS therapy using plasma exchange (PE) or intravenous immunoglobulin (IVIg) administration to manage acute, severe or life-threatening myasthenic crises.1,2 Both treatments may also be used to prevent or minimise deterioration in patients at the start of steroid therapy or in preparation for thymectomy and other surgeries in patients with marked bulbar dysfunction.1,2 A valid alternative to PE is immunoadsorption (IA).1,6,8,12 A relatively new alternative to IVIg is subcutaneous immunoglobulin (SCIg) administration, though the clinical experience with SCIg is still limited.1,13
PE acts by removing key immune molecules from a patient’s plasma, including antibodies, complement components, cytokines and various adhesion molecules.1 IA is a more selective technique than PE, as it removes circulating immunoglobulin G (IgG) from the circulation but leaves other plasma components unaltered.1,8
IVIg administration has widespread effects on a patient’s immune system by suppressing antibody production, inhibiting complement deposition and neutralising inflammatory cytokines and antibodies.1,3 The main difference between IVIg and SCIg is the lower absorption rate and initial bioavailability for SCIg compared to IVIg, as subcutaneously administered Ig first reaches the lymphatic system before entering the blood circulation.14
Short-term IS therapies are fast-acting, though additional immunotherapy is usually needed as the therapeutic effect of PE and IVIg is short-lived (4–12 weeks).1 Both therapies are considered equally effective in cases of severe gMG, though PE may be more effective than IVIg in patients seropositive for autoantibodies against muscle-specific kinase (MuSK).2,12 IA is considered equally effective to PE.6,8,12 It was reported that SCIg was effective and well tolerated for the management of MG in uncontrolled observations.13
The choice between short-term IS therapies depends on several parameters, including individual patient factors, efficacy, safety considerations and the availability of each therapy at the healthcare setting.1,2,8,12
Thymectomy is considered for almost all patients with thymoma, and as early as possible in nonthymomatous adult patients with early-onset gMG seropositive for anti-acetylcholine receptors (AChR) antibodies.1,6,12,15 It is also considered in patients who do not respond to immunosuppressive (IS) therapy or who experience intolerable adverse effects from that therapy.15
It was reported that thymectomy can improve clinical outcomes, decrease the need for IS drugs and reduce exacerbations in adult patients with early-onset gMG seropositive for anti-AChR antibodies.1,5 The benefit from thymectomy in patients older than 50 years of age and in those with long disease duration is still controversial.1
Thymectomy is an elective procedure where stable control of MG symptoms needs to be achieved ahead of the procedure.1,15 It is generally not recommended in patients with MG harbouring autoantibodies against muscle-specific kinase (MuSK), low-density lipoprotein receptor-related protein 4 (LRP4) or other postsynaptic membrane molecules, as its clinical efficacy has not been demonstrated in these patient groups.1,5
A number of new therapies for patients with MG are available or under clinical study, aiming to weaken the autoimmune response.1 These include:1
- Selective depletion of MG-specific autoantibodies during IgG apheresis
- Biologics that:
- Inhibit key complement components
- Inhibit receptors expressed by various immune cells
- Degrade pathogenic immunoglobulins involved in the pathophysiology of MG
- Autologous haematopoietic stem cell transplants in patients with severe or life-threatening MG
A smaller number of investigational therapies are aimed at strengthening the mechanisms involved at neuromuscular synapses.1
Another treatment goal of therapies that have been recently developed or are currently under development is to reduce adverse events related to conventional treatments, such as long-term or high-dose corticosteroid treatment.10,12,16
ACh, acetylcholine; AChE, acetylcholinesterase; AChR, acetylcholine receptor; gMG, generalised myasthenia gravis; IA, immunoadsorption; IgG, immunoglobulin G; IS, immunosuppressive; IVIg, intravenous immunoglobulin; LRP4, low-density lipoprotein receptor-related protein 4; MG, myasthenia gravis; MuSK, muscle-specific kinase; NMJ, neuromuscular junction; NS-IS, non-steroidal immunosuppressive; PE, plasma exchange; SCIg, subcutaneous immunoglobulin.
