Myasthenia Gravis (MG)

Medical Management

Medical management overview

Many drugs and procedures are available for treating myasthenia gravis (MG), each with distinct advantages and disadvantages. Use of a particular approach may depend on the age of the patient, the severity of the disease, and the pace of progression.

• Targeted therapies (complement inhibitors and neonatal Fc receptor inhibitors)
• Symptomatic treatments (anticholinesterase agents)
• Chronic immunomodulating treatments (glucocorticoids and other immunosuppressive drugs)
• Surgical treatment (thymectomy)
• Rapid immunomodulating treatments (plasmapheresis and intravenous immunoglobulin)

The benefits and risks of these treatments must be weighed against each other and the needs of the patient. A doctor can help you determine which treatments are appropriate.

FDA-approved targeted therapies for MG

To date, a handful of targeted therapies have been approved by the US Food and Drug Administration (FDA) to treat MG. These new therapies fall into two categories, complement inhibitors that block an immune pathway that contributes to MG and neonatal Fc receptor inhibitors that help eliminate abnormal antibodies. The approved therapies are:

Complement inhibitors

• Eculizumab (brand name Soliris) - Developed by Alexion Pharma (now part of Astrazeneca) and approved by the US Food and Drug Administration (FDA) in October 2017 for treatment of gMG.
• Ravulizumab (brand name Ultomiris) - Developed by Bristol Myers Squibb (BMS) and approved by FDA in April 2022 for treatment of gMG.
• Zilucoplan (brand name Zilbrysq) - Developed by UCB and approved by FDA in October 2023 to treat gMG in adults who are anti-AChR antibody positive.

Neonatal Fc receptor inhibitors

• Efgartigimod (brand name Vyvgart) - Developed by Argenx and approved by FDA in December 2021 to treat gMG in adults who are anti-AChR antibody positive.
• Rozanolixizumab (brand name Rystiggo) - Developed by UCB and approved by FDA in June 2023 to treat gMG in adults who are anti-AChR or anti-MuSK antibody positive.

Cholinesterase inhibitors

These drugs, also known as anticholinesterases, have been used to treat MG since the early 1990s and can produce relief from symptoms within minutes. The one most commonly used is pyridostigmine bromide (Mestinon).

Cholinesterase inhibitors boost ACh levels not only at the neuromuscular junction but also in the autonomic nervous system (which controls involuntary bodily functions). Sometimes the drugs can cause diarrhea, abdominal cramps, and/or excessive saliva. To minimize these side effects, a physician might lower the dose of cholinesterase inhibitors or prescribe atropine, which blocks the ACh receptors on nerve cells.

Patients with limb and bulbar symptoms typically respond better to pyridostigmine than those with ptosis and diplopia. In rare cases, cholinesterase inhibitors prove enough for managing MG, but most people also require immunosuppression treatment that restrains the actions of the immune system. The use of cholinesterase inhibitors in synergy with immunosuppressive drugs also allows a physician to reduce the dosage of immunosuppressive medications, something that can reduce side effects associated with it.

Chronic immunotherapies

Another therapeutic modality in MG is the administration of immunomodulating agents called corticosteroids. These drugs (which include prednisone and prednisolone) reproduce the actions of corticosteroid hormones, which are made by the outer layer of the adrenal gland. They have broad anti-immune and anti-inflammatory effects, making them powerful treatments for MG.

They are not as fast-acting as cholinesterase inhibitors, but they are faster than some other immunosuppressants, producing improvement within weeks to months. They are also relatively inexpensive.

A disadvantage of corticosteroids is that they can produce many side effects — some of them potentially serious — including osteoporosis (weakening of bones), mood disturbances, gastrointestinal problems, weight gain, high blood pressure, cataracts, and stunted growth (in children). For many people, these side effects can be managed with other therapies; for example, bisphosphonate drugs can be used to prevent osteoporosis.

For others, corticosteroids are used as a first-line defense against MG, then gradually tapered off and supplemented or replaced with slower-acting immunosuppressants that have fewer side effects. Most of these other drugs were developed to prevent the rejection of transplanted organs but have since been co-opted for use against MG and other autoimmune diseases.

Azathioprine (Imuran) was the first non-steroid immunosuppressant to come into widespread use, in the 1970s, against MG. The drug inhibits the synthesis of nucleic acids and interferes with the proliferation of adaptive immune cells. It is found that the ACh receptor antibody count is reduced with azathioprine treatment. Dosage starts at 50mg daily and can be increased at 50mg increments every two to four weeks until a maintenance dose of 2mg to 3 mg per kilogram of total body weight is reached. Monthly monitoring of one’s complete blood count and liver function is needed every six months. Checks can be less frequent once blood count and liver function stabilizes. Azathioprine acts more slowly than corticosteroids, producing improvement after six to 12 months, and usually has few side effects. Occasionally, however, it can produce serious side effects including inflammation of the pancreas, liver toxicity, bone marrow suppression, and possibly an increased risk of cancer.

Mycophenylate mofetil (CellCept) is a relatively new immunosuppressant but so far it has shown promising results against MG in clinical trials. In two small trials completed in 2001, about 65% of MG patients experienced gains in strength or a reduced need for prednisone after taking CellCept for several months. More recent analyses have shown that some people take longer to respond to the drug but that nearly 75% eventually show improvement, with occasional relatively nonserious side effects such as nausea and diarrhea.

Cyclosporine (Neoral, Sandimmune) is a useful, relatively fast-acting treatment for MG and improves MG symptoms in 90% of patients. However, cyclosporine may have side effects including increased blood pressure, abnormal kidney function, unwanted body hair, and stomach upset.

Cyclophosphamide (Cytoxan, Neosar) is considered effective against MG, but because it has many potentially serious side effects, it’s often reserved for use only when other drugs fail. It’s reserved for only severe cases of MG.

Tacrolimus is less nephrotoxic (toxic to the kidneys) than cyclosporine, however it has clinically significant side effects, such as hyperglycemia (high blood sugar), hypomagnesemia (Low Magnesium), tremor, and paresthesias (“pins and needles” sensation).

Methotrexate is an immunosuppressant agent that decreases purine and pyrimidine synthesis (the components that build DNA). Based on results from a study, methotrexate has been suggested as a second line immunosuppressant agent for treating MG.

Drug warnings and other concerns

Many prescription drugs can unmask or worsen symptoms of MG. When taking a new prescription drug for the first time, it is essential to consult a doctor about its possible effects on MG. Also, a MedicAlert bracelet or card to inform emergency medical personnel that a person has MG and that certain drugs can be harmful can be critical for proper emergency care.

Aside from drugs, overexertion, emotional stress, infections (from tooth abscesses to the flu), menstruation, and pregnancy also can lead to increased weakness in MG.

Thymectomy

Thymectomy — surgical removal of the thymus gland — is recommended for thymoma and for most cases of generalized MG. It is believed to be the only therapy capable of producing long-term, drug-free remission from MG, but most data regarding its use have come from case studies rather than clinical trials.

Thymectomy initially was estimated to produce one-year remission from MG in less than 20% of people, but in the last seven to 10 years the remission rate has increased to up to 50%. Thymectomy is also known to increase strength or reduce the need for medication in an additional 50% of patients who receive it. These improvements may take several months to several years after surgery to occur.

Thymectomy usually has the most favorable outcomes in people who are younger than age 60. Also, thymectomy is recommended when symptoms are sufficiently controlled. Because the thymus is required for immune system development, most doctors prefer not to perform the surgery on prepubescent children. The surgery is also not usually recommended for patients older than 60 unless thymoma is present. However, the procedure can still be done depending on a patient’s overall health and if they really wish to undergo the surgery.

Plasmapheresis and intravenous immunoglobulin (IVIG)

In plasmapheresis, also known as plasma exchange, an intravenous line is used to remove antibodies from the blood. IVIG therapy is essentially an injection of a nonspecific antibody (immunoglobulin) that might dial down the immune system’s production of its own antibodies, much as warm air tells a thermostat to stop pumping out heat.

These treatments bring about fast but short-lived relief from MG, and are mostly used until other medications take effect, prior to surgery or for myasthenic crisis. However, some people receive regular plasmapheresis or IVIG as a supplement to immunosuppressant drugs.

Plasmapheresis is not commonly used as a long-term treatment as each treatment requires five plasma exchanges over the course of one or two weeks. This need for repeated exchanges often leads to issues with venous access.

Myasthenic crisis

Especially in people with bulbar or respiratory symptoms, MG can sometimes worsen to the point of myasthenic crisis, a life-threatening condition involving an extreme episode of weakness that culminates in respiratory failure and the need for mechanical ventilation. In some cases, the respiratory muscles themselves give out, and in others, weakness in the throat muscles causes the airway to collapse.

When MG is properly treated, crisis is very rare, with a 2% to 3% risk for MG patients. And when crisis does occur, it has a good rate of recovery thanks to the wide range of treatments for MG and the quality of respiratory care at most hospitals. Most cases of myasthenic crisis take place within the first few years after diagnosis.

Sometimes, myasthenic crisis can occur without warning, but it often has an identifiable trigger, such as fever, respiratory infection, traumatic injury, stress, or ingestion of one of the drug types mentioned on this page. If you have MG, you should have these conditions monitored by a physician, and if you experience labored breathing or unusual weakness, you should seek immediate medical attention.

Evaluation and management of myasthenic crisis:

• Admission to intensive care unit
• Frequent monitoring of respiratory muscle strength
• Elective intubation if clinical evaluation suggests impending respiratory failure (hospital staff will temporarily stop anticholinesterase medications for intubated patients)
• Initiation of rapid therapy with plasma exchange or intravenous immune globulin (IVIG)
• Initiation of immunomodulating therapy with high-dose glucocorticoids; healthcare providers will consider azathioprine, mycophenolate mofetil, or cyclosporine if glucocorticoids are contraindicated or were previously ineffective
• Weaning from mechanical ventilation when respiratory muscle strength is improving, but only after starting treatment with plasma exchange or IVIG

Pregnancy

In rare cases, pregnancy appears to trigger the onset of MG. In women who already have MG, pregnancy can cause a worsening of symptoms (usually after birth but sometimes during the first trimester). These trends are not consistent from one pregnancy to the next.

Some medications for MG are safe to use during pregnancy and nursing, but some others are not recommended. If you are planning to become pregnant, you should consult your physician, and if you are a nursing mother, consult your child’s pediatrician.

Between 10% and 20% of babies born to mothers with MG develop transient neonatal MG because the antibodies that cause MG can pass through the placenta. Symptoms (such as feeble cry, feeding difficulties, or general and respiratory weakness) often are detected within hours to days after birth, and decreased movement may be detected inside the womb.

As the name implies, transient neonatal MG is only temporary. Most babies require medication and supportive care but usually recover completely within a few weeks after birth. Permanent weakness or recurrence of MG later in life is extremely rare.

Additional reading

• Narayanaswami P, Sanders DB, Wolfe G, et al. International consensus guidance for management of myasthenia gravis: 2020 update. Neurology. 2020; https://doi.org/10.1212/wnl.0000000000011124.