Myasthenia Gravis

What is myasthenia gravis (MG)?

MG is a rare, chronic autoimmune disease that affects the way a person’s nerves send signals to muscles. [1, 2] As a result, people with MG experience muscle weakness that can come and go (fluctuate) over time, typically during the course of a single day. [3, 4]

There are two main types of MG: [4]

• Ocular MG, which only affects the muscles that control the movement of the eyes and eyelids
• Generalised MG, which may affect the eye muscles but also muscles in other parts of the body, including those controlling facial expressions, speaking, swallowing, movement of the arms, legs and neck, and breathing.

In generalised MG, muscle weakness may start in the muscles controlling movement of the eyes and eyelids, and then progress to other muscles in the body. Symptoms of generalised MG vary between individuals and can come and go, but the most common symptoms are: [4, 5]

• Droopy eyelids, double or blurred vision
• Difficulties with facial expressions
• Slurred speech, difficulty with chewing and swallowing that may result in gagging and choking
• Weak arms, legs or neck, that may cause problems with movement
• Shortness of breath and occasionally serious breathing difficulties
• Fatigue.

MG can occur at any age, but it most commonly affects women under 40 and men over 60. [6]

What causes MG?

MG is an autoimmune disease. Autoimmune diseases occur when the body’s immune system attacks healthy tissue. In MG, the abnormal immune response attacks the connections between the nerves and muscles; these connections are known as neuromuscular junctions. [5] This interruption makes the muscles weak and easily tired.

Normally, when electrical signals travel down a nerve, the nerve endings release a chemical called acetylcholine. Acetylcholine attaches to proteins in the muscles called acetylcholine receptors. When the acetylcholine attaches to its receptor, this instructs the muscle to contract, resulting in movement. [6]

The majority of people with MG have antibodies (proteins produced by the body’s immune system) that block or damage acetylcholine receptors at the neuromuscular junction, preventing the muscle from contracting properly. These are called autoantibodies, because they attack proteins in normal, healthy tissue by mistake, instead of foreign proteins seen as a threat by the immune system (such as those produced by bacteria and viruses). Some people with MG have antibodies against a protein called muscle-specific kinase (MuSK) or antibodies against the low-density lipoprotein receptor-related protein (LRP4): these two proteins are also involved in maintaining the connection between the nerve and the muscle. [6] A small proportion of people with MG do not have any detectable (measurable) antibodies against these proteins. [7]

A protein called interleukin-6 (IL-6) is thought to drive the production of the antibodies that cause MG. IL-6 has been found at higher levels than normal in the blood of people with generalised MG who have antibodies against acetylcholine receptors. [8]

MG is not inherited (passed down from either parent) and it is not contagious (cannot be caught from another person). [9] Roughly 3–5% of people with MG have family members who also have MG (or another autoimmune disease) but how or why is not fully understood. [10]

How is MG diagnosed?

It may take some time to diagnose MG because many of the symptoms overlap with those seen in other conditions and because symptoms come and go during the day. [3]

MG is usually diagnosed with a combination of tests, including: [3, 9]

• An examination of muscle strength, including the muscles that control eye movements
• A blood test to look for antibodies specific for MG. Presence of the antibodies indicates that the person has MG, although some people with MG, especially ocular MG, may not have detectable antibodies [11]
• Electrodiagnostic tests to measure the electrical activity in the muscles. This involves placing electrodes on the skin and/or inserting needles into the muscles. The electrical recordings can show whether the signals sent from the nerves to the muscles are being disrupted, which may be a sign of MG
• Taking pictures of the inside of the chest using computed tomography (CT) or magnetic resonance imaging (MRI) scans to see if the thymus gland is enlarged or has any abnormalities. The thymus has a role in the immune system and may be associated with MG. It is located in the chest, between the lungs and behind the breastbone.

What treatments are there for MG?

There is currently no cure for MG but, for most people, the symptoms can be managed reasonably well with treatment. [9]

There are three general types of treatment for MG:

1. Treatment of symptoms   
   The first treatment used for MG is usually a medication called pyridostigmine. This medication works by preventing the breakdown of acetylcholine at the neuromuscular junction, [12] which helps the transmission of signals from the nerves to the muscles. Because the effect only lasts for several hours, this medication usually needs to be taken multiple times a day. [13]
   
   
2. Treatment with medications that block or change the way the immune system acts
   If pyridostigmine does not help or is not tolerated because of side effects, medicines that suppress the immune system (called immunosuppressants) are typically started. These include corticosteroids (steroids), such as prednisone, and other immunosuppressants such as azathioprine and mycophenolate. [9] Immunosuppressants in MG work by dampening down the body’s immune response to prevent it from attacking the communication between the nerves and muscles. [12] Steroids, especially at higher doses and over a long period of time, cause side effects such as weight gain, high blood sugar/diabetes, high blood pressure, bone loss/weakness, cataracts (clouding of the eye lens) and high pressure inside the eye, sleeping difficulties, and changes in mood, so every attempt is typically made to replace steroids with other immunosuppressants. Azathioprine and mycophenolate take a long time to work (up to nine months for the full effect), so patients need to be on both steroids and azathioprine or mycophenolate for months. Importantly, all immunosuppressants can cause an increased risk of infection and other side effects, so patients need to be monitored regularly. [12]
      
   Plasmapheresis and intravenous immunoglobulin may be options for severe cases of MG or cases that have not responded to medications. These treatments remove the destructive antibodies from the bloodstream. They usually only work for a number of weeks. [9, 12]
       
   Monoclonal antibody treatments (commonly referred to as ‘biologics’) target specific proteins involved in the MG disease process. Eculizumab is a monoclonal antibody that targets a protein called complement component 5 (C5) and suppresses the process by which antibodies damage the neuromuscular junction. It is approved by the FDA (Food and Drug Administration) for the treatment of generalised MG in adults who test positive for antibodies against the acetylcholine receptor and is given as an infusion into a vein every two weeks. [14] It is also approved by the EMA (European Medicines Agency), but only if the generalised MG is refractory (does not respond) to other treatments. [15]
   
   
3. Removal of the thymus gland (thymectomy)
   Surgery to remove the thymus gland, known as a thymectomy, is sometimes carried out in patients with MG. Thymectomy has been shown to be helpful in reducing symptoms and lowering the dose of immunosuppressants necessary in patients with generalised MG who have antibodies against the acetylcholine receptor in their blood. [9]
   
   These treatment approaches all have their limitations: long-term side effects with steroids and other immunosuppressants, delayed responses with certain immunosuppressants, and short-lived effects and side effects with plasmapheresis and intravenous immunoglobulin. Some patients may also consider the dosing regimens of these treatments to be inconvenient. With this in mind, research is ongoing to identify new, targeted treatments for MG that work well without as many unwanted side effects.

What is the outlook for MG?

Satralizumab is a monoclonal antibody that blocks the activity of IL-6 by targeting the IL-6 receptor. It is given by an injection under the skin (subcutaneously), once a month. [16] As described above, IL-6 is thought to be involved in the MG disease process. Satralizumab has been shown to be well tolerated and effective in controlling symptoms in another autoimmune disease of the nervous system called NMOSD (neuromyelitis optica spectrum disorder). [17] A clinical trial to look at the effects of satralizumab in people with generalised MG is currently underway. 

In addition to developing new medications, researchers are trying to find better ways to diagnose and treat MG. For example, research is being done to understand why the immune system attacks the neuromuscular junction. This research could reveal new therapies for neuromuscular diseases like MG.

Researchers are also trying to develop new tools to establish a cause of MG in people who do not have detectable antibodies. It is hoped that research will also identify potential biomarkers (signs that can help diagnose or measure the progression of a disease) to predict a patient’s response to different medicines, so that patients receive the most appropriate treatment.