‘Myasthenia gravis patients unresponsive to existing therapies need reimbursable new drugs'

Myasthenia gravis is a “chronic autoimmune neuromuscular disease” that is characterized as a wildfire that never knows where it will end up.

It is a severe, rare, and life-threatening disease in which autoantibodies against proteins in the neuromuscular junctions throughout the body cause muscle weakness. It initially starts with eye weakness but gradually progresses to throat weakness, which makes swallowing difficult, limb weakness, immobility, and eventually respiratory muscle weakness, making it impossible to breathe properly.

Myasthenia gravis, which can occur in all age groups, from children under five to older adults, is expected to increase in Korea's rapidly aging population due to the high proportion of elderly patients.

However, the current treatment environment for myasthenia gravis in Korea is very poor. It is a disease that has a broad spectrum, with some patients progressing mildly and others suddenly deteriorating severely, so it is crucial to have an environment where patients can receive quick and good treatment when the disease suddenly worsens.

That’s because even if the disease suddenly worsens and muscle strength is sharply reduced, patients can regain muscle strength and return to society if they are treated well. The problem is that about 15 percent of myasthenia gravis patients in Korea do not respond to existing reimbursed drugs.

In a recent interview with Korea Biomedical Review, Professor Shin Ha-young of the Department of Neurology at Severance Hospital said that the fast-track reimbursement of new drugs for myasthenia gravis in Korea will create an environment where patients who do not respond to existing drugs can be adequately treated.

Question: Myasthenia gravis is known to be an autoimmune disease caused by the development of “autoantibodies” against proteins in the mechanism that transmits signals from the nerves to the muscles.

Answer: Right. About 80 percent of people with myasthenia gravis have acetylcholine receptor (AChR) antibodies, and a significant proportion of those without these antibodies are found to have muscle-specific myosin synthase kinase receptor (MuSK) antibodies. In addition, the presence of several autoantibodies, including low-density lipoprotein receptor-related protein 4 (LRP4) antibodies, continues to be recognized in a minority of patients without AChR or MuSK antibodies. These autoantibodies cause disease by affecting proteins at the neuromuscular junction, which transmit signals from nerves to muscles.

In myasthenia gravis, the classic form of the disease, AChR antibody-positive myasthenia gravis, the disease is caused by autoantibodies to a receptor for a neurotransmitter called acetylcholine at the neuromuscular junction. If the AChR antibodies attach to the place where acetylcholine should be, acetylcholine is not able to attach, and if the AChR antibodies attach to the place where acetylcholine should normally attach, the body's complement is activated, causing inflammation and disrupting the signal transduction system, resulting in a decrease in the amount of acetylcholine to the muscles.

This process leads to muscle weakness, which is called myasthenia gravis. In the beginning, the symptoms are most noticeable. It often starts with drooping eyelids and double vision, where the muscles that move the eyes are weak, and you can't focus well, seeing things in two dimensions. Next, there's difficulty swallowing and chewing, speech, and limb weakness. Most dangerously, the respiratory muscles become paralyzed, a condition known as a myasthenic crisis.

Q: Are all cases of myasthenia gravis progressive, meaning that once the disease gets worse, it never comes back?

A: No, it is not. The course of myasthenia gravis varies greatly, with many cases progressing and others stopping. Some patients start very strongly, while others progress more slowly. In some cases, the disease stops in the middle, but that doesn't mean it goes away. The disease is caused by inflammation due to an autoimmune response, which is similar to a forest fire. In some cases, the disease will continue to burn with only smoldering embers, while in others, it will suddenly become so intense that the mountain burns to the ground.

However, one exacerbation of the disease does not mean that the muscles of all people with M.G. are irreversibly damaged. If treated in time, myasthenia gravis is a reversible disease that allows people to regain muscle strength and live a normal life. There have been cases of people who have been unable to perform daily activities due to the worsening of myasthenia gravis, and who have had to give up their jobs due to the ineffectiveness of existing salaried treatments for myasthenia gravis, who have been able to return to work after participating in a clinical trial of a new drug.

Q: People with myasthenia gravis tend to have better symptoms in the morning and worse symptoms in the evening, and symptoms are relieved by resting a little during the day. Why is this?

A: The neuromuscular junction is a very complex and sophisticated structure, and when it is impaired, signals from the motor nerves cannot be transmitted to the muscles. Acetylcholine is contained in vesicles at the end of motor nerves, where it is produced at rest. If the amount of acetylcholine is at a certain level, the signal is transmitted to a certain extent, so if you use your muscles after resting, the symptoms are less, but if the amount of acetylcholine drops below a certain level due to continuous use of muscles, the signal is not transmitted well and the symptoms worsen.

Q: What changes have you seen in the trend of myasthenia gravis patients in Korea, and what changes are expected in the future as the demographic structure of Korea has changed a lot? We also want to know if there are any demographic characteristics of Korean patients.

A: I once investigated the scale of myasthenia gravis in Korea, and the incidence of myasthenia gravis in Korea (the actual rate of the disease among the total population) has been increasing from 1.18 per 100,000 people in 2010 to 1.81 in 2018. The prevalence rate of myasthenia gravis (the prevalence of the disease among the total population) also increased from 7.5 per 100,000 in 2010 to 11.15 per 100,000 in 2018. Based on these trends, it is estimated that the number of myasthenia gravis patients in Korea is currently around 10,000, and the number of myasthenia gravis patients is expected to increase shortly due to the aging population.

Myasthenia gravis is known to have similar demographic characteristics around the world. However, there are demographic characteristics of myasthenia gravis patients in Korea, Japan, China, and Taiwan that are slightly higher than those in Western countries, such as a slightly higher proportion of patients under the age of five. In addition, myasthenia gravis typically develops after the onset of secondary sexual characteristics and is more prevalent among older individuals. However, in Korea, it is more common among the elderly, and elderly patients are often associated with thymic tumors.

Q: The cause of myasthenia gravis is still unclear, but are there any known risk factors for the disease? It is also commonly associated with thymoma, a cancer of the immune system that develops after puberty, but how much of a connection is there?

A: Myasthenia gravis is associated with a higher risk of developing autoimmune disease in people with a family history of the disease, but the relationship is not as clear-cut as it is for hereditary diseases. Currently, it may be a combination of genetic and environmental predisposition. Another hypothesis is that the risk of autoimmune diseases increases as the immune system ages. It is also believed that thymoma is more common in older people, which may be related to the age of the thymoma. About 30 percent of people with thymomas develop myasthenia gravis.

There was also a multinational study of younger patients with AChR antibody-positive myasthenia gravis without thymoma in which half underwent thymectomy and half did not. The thymectomy group had better symptom control and lower steroid doses. In addition, the thymectomy group had normal thymus glands on imaging tests, but when biopsies were taken, they were found to have abnormal thymus glands with large clusters of B cells.

Q: Rare diseases are often difficult to diagnose. Is myasthenia gravis diagnosed early?

A: There are no significant diagnostic difficulties now because there is more awareness of myasthenia gravis than in the past, but I know there are rare cases where it isn't easy to diagnose. Myasthenia gravis is such a diverse condition that it's hard to generalize. Some patients may have a “myasthenia gravis crisis” from the start, which can lead to respiratory failure, and it's known that some patients with myasthenia gravis are diagnosed late, putting them in a perilous situation.

Some patients with myasthenia gravis have had repeated surgeries because they thought they had simple ptosis due to aging. In contrast, others have double vision that improves with a bit of rest, and others have been living with one eye closed because they see two objects as one when they close the other eye. In general, it takes about half a year nowadays for patients with myasthenia gravis to realize something is wrong and visit a specialist for the first time.

Myasthenia gravis is characterized by its main symptom, “muscle weakness,” which is characterized by “diurnal fluctuations.” And if you suspect it, you can usually diagnose it. Of course, some patients may have all the tests needed to diagnose myasthenia gravis and come back normal. This is not uncommon so that the diagnosis can be ambiguous. Also, the MuSK antibody test is essential, but it's not available in Korea, so we have to send the sample overseas for testing, which takes about 30 days.

Q: How is myasthenia gravis diagnosed?

A: Nerve conduction studies and tests to check for autoantibodies. The antibody test is essential because the treatment is different depending on the type of antibody. There is also a drug response test to see if the patient's symptoms of myasthenia gravis improve after receiving a drug. In the case of AChR antibody-positive patients, an acetylcholinergic agent is injected to see if the symptoms change. In addition, in myasthenia gravis, muscle function improves when the temperature is lowered, so ice is applied to the affected area, and imaging tests, such as CT, are performed to check for thymoma.

Q: How is myasthenia gravis treated, and what are the unmet medical needs in current treatment?

A: Currently, myasthenia gravis is treated with medication, surgery, and plasma exchange. Drug treatment is usually based on pyridostigmine, a cholinesterase inhibitor, in AChR antibody-positive patients. If cholinesterase inhibitors do not control symptoms, steroids or immunosuppressants are added. For patients with systemic AChR antibody-positive myasthenia gravis whose symptoms remain uncontrolled despite these treatments, thymectomy is performed even if the thymoma is not present.

In some cases, thymectomy is performed before significantly increasing steroid doses. For patients with myasthenia gravis who suddenly stop breathing because their symptoms are not controlled by medication and surgery, intravenous immunoglobulin is administered to help them recover quickly. Plasma exchange (an emergency treatment that removes the patient's plasma with apheresis to remove autoantibodies, which are disease-causing antibodies present in the patient's plasma, and infuses supplemental fluids) is performed.

This is the current treatment coverage for myasthenia gravis in Korea. There are about 15 percent of myasthenia gravis patients whose symptoms are not controlled by these treatments. These patients are not in crisis, but regular immunoglobulin injections can help control their symptoms, which are currently not covered. Depending on the dose, immunoglobulin injections can cost millions of dollars for a single injection. For this reason, some patients who would like to receive immunoglobulin injections are unable to do so because of the cost.

In addition, new treatment alternatives are needed not only for “patients who are not well treated with existing drugs,” but also for “patients with myasthenia gravis,” who have thinned skin due to steroid treatment and tear at the slightest bump, develop diabetes due to uncontrolled blood sugar and are exposed to other risks due to diabetes, or develop severe osteoporosis. Currently, several new drugs, such as Ultomiris, Rystiggo, Zilbryscq, and Vyvgart, have been introduced in Korea. However, all of them are expensive and remain unreimbursed, making them difficult to use in practice.

Q: What is the current situation for people with refractory myasthenia gravis who do not respond to conventional treatments?

A: People with refractory myasthenia gravis who are not responding to conventional treatments continue to live their lives, but are unable to move and have a social life, so they are largely housebound. People with drug-refractory myasthenia gravis who have been in the intensive care unit after another myasthenia gravis crisis are mentally overwhelmed by the prospect of going to the intensive care unit again. And while mortality rates have decreased significantly due to faster diagnosis and better treatments, a myasthenia gravis crisis can still be life-threatening.

However, with the proper treatment, many people with incurable myasthenia gravis can lead everyday lives. Three patients with refractory G.E. at Severance Hospital participated in a clinical trial of a new drug that allowed them to get out of the house and work. They are now being treated with the new drug thanks to the generosity of the pharmaceutical company, even though the study has ended. In this way, changing the treatment environment for patients with myasthenia gravis can change their lives. With treatment, it gets better.

Q: The global treatment environment for myasthenia gravis has changed a lot recently with the introduction of many new drugs. For these new treatments to be introduced in Korea, there should be evidence-based treatment guidelines rather than reimbursement-based treatment. How do Korean doctors treat the disease, and what efforts are they making to keep up with the global treatment environment?

A: Because myasthenia gravis is a rare disease, there are many different ways to treat it, depending on the doctor. However, in December last year, a group of Korean doctors specializing in myasthenia gravis gathered to create a consensus on the treatment of patients with intractable myasthenia gravis. Recently, several guidelines for myasthenia gravis have recommended the use of new drugs, such as newly developed complement inhibitors and neonatal Fc receptor inhibitors, in the treatment of patients with refractory myasthenia gravis with high disease activity, so the consensus statement also includes treatment with these new drugs.

The consensus statement recommends treatment of AChR antibody-positive patients with refractory severe myasthenia gravis with complement inhibitors such as ravulizumab (Ultomiris) and zilucoplan (Zilbrysq), and neonatal Fc receptor inhibitors such as rozanolixizumab (Rystiggo) and efgartigimod (Vyvgart). It also states that patients with MuSK antibody-positive refractory severe myasthenia gravis can be treated with rozanolixizumab and efgartigimod.

Q: There are many exacerbating factors for myasthenia gravis. What are some of these? What precautions do they need to take, and what do you recommend for daily health care?

A: Immunizations are critical because infections can make the disease worse. However, people with myasthenia gravis who take immunosuppressants should never receive live vaccines. In addition, many medications can worsen the condition, including antibiotics, general anesthetics, and blood pressure medications, so it's essential to disclose that you have myasthenia gravis when you're prescribed medication.

Surgery can also worsen the condition. This is because there’s a residual inflammation in the body, and surgery can cause another inflammation. Excessive activity or mental stress can also cause inflammation, which is not suitable for people with myasthenia gravis. It’s essential to have a routine and manage stress, and to do as much physical activity as you can without feeling exhausted when you wake up in the morning.

The muscles that help you swallow food are also weakened in myasthenia gravis, so you may have trouble swallowing food or saliva, which increases your risk of aspiration pneumonia. They should also avoid eating foods such as s'mores because they may not be able to swallow them. In terms of nutrition, you should watch out for magnesium. This is because too much magnesium prevents the muscles from contracting. Magnesium is okay to take as part of your daily diet, but you shouldn’t take it as a nutritional supplement if you have myasthenia gravis.

It's also worth noting that magnesium is used as a treatment for pre-eclampsia when women with myasthenia gravis become pregnant, which can be dangerous. It’s also important to note that people with myasthenia gravis who are on steroids can become very bloated, and it’s been reported that increasing protein and decreasing carbohydrates can help with weight management. It’s a good idea to eat one less spoonful of rice and one more piece of meat.

Q: What do you wish to say to friends and family of people with myasthenia gravis?

A: People with myasthenia gravis have a lot on their plates. They are depressed and anxious because they don't know when a myasthenia gravis crisis will come, and others do not understand them because they are too weak to show it. They have to take steroids, immunosuppressants, and other medications for a long time, which have many side effects. However, there are positive patients, and I see a lot of them get better in the end.

Mental stress affects the disease, so it's essential to have a positive attitude and communicate well with your doctor to continue treatment. In addition, new drugs that are known to be highly effective are being introduced in Korea, and I have experienced the effects of new drugs in clinical trials, so if you can endure the current situation and continue treatment, the future will be much better. If you live positively and gratefully every day, good days will surely come.