Myasthenia Gravis: New Drugs and a Road to Individualized Treatment

Myasthenia gravis is a complex autoimmune disease that interferes with the communication between nerves and muscles. The hallmark symptom is muscle weakness that worsens after activity and improves with rest. It might start in the mouth or face muscles, causing slurring of speech or drooping eyelids. It also can affect other muscles that move the arms and legs, resulting in difficulty with walking or getting up from a chair.

For some people, a few of these symptoms are a minor annoyance; others, however, lose the ability to walk, talk, or even breathe properly. As a result, some people can’t attend school, care for a family, or hold a job.

Fortunately, there has been encouraging progress in treatments for the condition. “If we go even a few years back—prior to 2017—there were no Food and Drug Administration [FDA]-approved medications for myasthenia gravis,” says Yale Medicine neurologist Richard J. Nowak, MD, MS, founding director of the Yale Medicine Myasthenia Gravis Program. Treatments such as steroids, which had debilitating side effects, and other broad immunosuppressive therapies were prescribed off-label, meaning they were used for a purpose other than that for which they were initially approved.

Today, five FDA-approved medications for myasthenia gravis are helping more patients than before manage their symptoms and lead active lives. However, there are still some questions in many cases about which medicine will work best for which patients. “The science has moved forward so rapidly and deeply in understanding the disease that the new therapeutics can be applied with some level of confidence,” says Yale neuroimmunologist Kevin O’Connor, PhD, a National Institutes of Health (NIH)-funded researcher. At the same time, scientists have learned that different patients may, in fact, have pathologies due to different mechanisms, and a medicine that makes one patient symptom-free may not work at all for another, he adds.

Dr. Nowak treats patients with myasthenia gravis from Connecticut and beyond. The Yale Myasthenia Gravis Program, established over a decade ago, is one of the largest programs of its kind in the U.S. Dr. Nowak and O’Connor have been working together for over a dozen years to further research and provide better care for patients.

They answer questions (below) about how knowledge of myasthenia gravis is changing.

Myasthenia gravis is a rare, chronic neuromuscular disease that affects an estimated 75,000-100,000 people in the United States. “The disease is caused by autoantibodies that target proteins in the neuromuscular junction [where nerves and muscle fibers meet] so that the muscle does not receive the signal from the nerve, and, as a result, the muscle doesn't move as it should,” O’Connor says. (While antibodies recognize foreign substances, such as viruses, and neutralize them, autoantibodies react to elements made by a person’s own body.)

This leads to muscular weakness and fatigue. The symptoms may affect only certain muscles, such as the eyelids, facial muscles, the muscles that affect speech, or the upper arms and legs. Myasthenia gravis can be ocular, appearing in the muscles that control eye movements, or generalized, affecting muscles around the eyes, mouth, arms, legs, and respiratory system.

The condition affects people of all ages, although it tends to become apparent in adulthood, and commonly impacts women under 40 and men over 60.

While most people with myasthenia gravis have moderate disease, about one-fifth have mild disease with a symptom such as eyelid drooping that is easily managed with medication. Another one-fifth have severe disease with life-threatening muscle weakness—swallowing difficulty may cause them to choke, for example, or they may need mechanical ventilation to help them breathe. “We see the latter in 15% to 20% of individuals at some point, especially early in the progression of the disease, when a patient can have what's termed a ‘myasthenic crisis’ or exacerbation,” Dr. Nowak says.

The latest knowledge about myasthenia gravis has changed how experts view the disease. “It turns out that within that whole population of myasthenia gravis patients, there are different autoantibodies that target different parts of the neuromuscular junction,” says O’Connor.

Two myasthenia gravis phenotypes are well known. In the most common type (an estimated 80%-85% of cases), the body’s immune system targets a protein on muscle cells required for muscle contraction called the acetylcholine receptor (AChR), weakening the muscle over time. About 15% of people with the condition don’t have detectable AChR in their blood, but about half of these will have autoantibodies to another protein called muscle-specific kinase (MuSK).

“If you were to meet patients in either of these two categories—AChR or MuSK—all of them would have muscle weakness and be diagnosed with myasthenia gravis,” O’Connor says. But the autoantibody subtypes separate them into two types of autoimmunity—and within each of those two groups of patients, there are variations that may affect responses to treatment, he adds.

“We're trying to understand the mechanisms within these patient groups more deeply so we can understand why two different patients can have the same disease and autoantibodies, but one patient will respond remarkably well to a particular therapeutic and the other won’t. That's where we're headed,” says O'Connor.

The following FDA-approved medications for generalized myasthenia gravis don’t cure the disease, but they may lessen the symptoms:

• Eculizumab (brand name Soliris®). This medication, approved in 2017, blocks an immune mechanism called the complement system, which plays a key role in the disease. Eculizumab is given to patients in weekly intravenous (IV) infusions for four weeks, followed by maintenance doses every two weeks.
• Efgartigimod (brand name Vyvgart®). This drug, approved in 2021, lowers the level of antibodies (and pathogenic autoantibodies) in the body below the threshold that allows the disease to remain active. It’s given in treatment cycles, each consisting of one IV infusion treatment a week for four weeks with a break between cycles.
• Ravulizumab (brand name Ultomiris®). This treatment, approved in 2022, is the first long-acting complement inhibitor, and its mechanism of action is similar to eculizumab. After the first treatment, given by IV infusion, maintenance doses are given every eight weeks.
• Rozanolixizumab-noli (brand name Rystiggo®). Approved in 2023, this is the first FDA-approved treatment for both anti-AChR and anti-MuSK antibody-positive myasthenia gravis. It targets a receptor that can stop harmful antibodies from being broken down by the cells’ natural waste clearance system. It’s administered by subcutaneous (under the skin) infusion once a week for six weeks.
• Zilucoplan (brand name ZILBRYSQ®). This was also approved in 2023, and it’s the first myasthenia gravis therapy for self-administration by a daily injection. It works using a targeted mechanism to inhibit damage to the neuromuscular junction.

None of these medications are 100% effective for all patients, Dr. Nowak explains. “They are beneficial for about 60%-70% of patients, which leaves 30%-40% without any meaningful improvements,” Dr. Nowak says. But, he adds, many patients do well when the treatment is well-matched to their pathology.

For patients with myasthenia gravis characterized by the MuSK autoantibodies, another treatment called rituximab (brand name Rituxan®), also given by infusion, is an option, O’Connor adds.

Rituximab is approved to treat non-Hodgkin lymphoma and rheumatoid arthritis but is used off-label to suppress the production of abnormal antibodies in people with MuSK myasthenia gravis, he explains. “Rituximab depletes many of your B-cells [immune cells that play a role in the disease]. That medication doesn’t work well in some AChR patients, but it works remarkably well in MuSK patients,” O’Connor says. “When MuSK patients are treated with rituximab, often they will go into complete remission and require no additional immunotherapy for years. That's something that wasn't established a decade ago.”

“Rituximab has become a go-to option for many of our patients with MuSK Myasthenia gravis,” adds Dr. Nowak.

The newer medications have an established safety profile in myasthenia gravis, although there are still concerns—as there are with many medicines. For instance, patients taking eculizumab are at risk for developing life-threatening meningococcal infections, so anyone considering that medication must receive meningococcal vaccinations before their first dose.

By comparison, some older medications have led to serious complications, including an increased risk of cancer in young people who take them for decades. They’re also not used in individuals considering pregnancy, adds Dr. Nowak.

Corticosteroids, such as prednisone, used at significant doses for years predispose people to such conditions as bone loss, diabetes, high blood pressure, and obesity. “So, we tend to shy away from the long-term use of corticosteroids, especially in younger patients,” he says. “But, if a patient is older and only a small dose of prednisone is needed, this still might be the best and safest strategy when considering possible risks and benefits.”

Physical activity and maintaining a healthy diet are important, explains Dr. Nowak. “Patients may get deconditioned due to weakness when myasthenia gravis is active, so we recommend physical therapy and general, light exercise and stretching to counter this,” says Dr. Nowak. “It may seem counterintuitive, but with this condition, the less you do—the less you will be able to do.”

That said, it’s important to listen to your body and work with your doctor, he adds.

While symptoms like muscle weakness may be a clue that a person has myasthenia gravis, it can take years to diagnose in some cases; Dr. Nowak says many patients report a diagnosis delay of up to two years. This is partly because the condition can be confusing, starting with a mild symptom, such as a minor eyelid droop that comes and goes. “This is a rare disease, so someone could be seeing a primary care doctor who doesn’t find any specific abnormalities on an exam or consider that they could have myasthenia gravis,” says Dr. Nowak. “The condition can fluctuate in that individuals might be completely fine in the morning and develop double vision or slurred speech only at the end of the day. If a doctor is not looking for or familiar with myasthenia gravis, it may be hard to diagnose.”

A neurologist who suspects the condition will perform a physical and neurological examination. There are imaging studies, including brain imaging in some cases, since some symptoms of myasthenia gravis are similar to those of stroke or other brain conditions. There are also tests for eye muscle weakness and other specific electrodiagnostic tests, such as electromyography (EMG), which measures muscle response or electrical activity in response to a nerve's stimulation of the muscle. A pulmonary function test can help in cases of possible myasthenic crisis. And blood tests can detect the presence of AChR or MuSK autoantibodies.

About 70% to 80% of myasthenia gravis patients will test positive for autoantibodies specific to the condition, explains Dr. Nowak, including whether a patient has AChR or MuSK autoantibodies. “Then, we have a group of people, about 20% to 25%, who are ‘seronegative,’ meaning that the autoantibody tests come back negative,” he adds. “That doesn't mean that the individual doesn't have autoimmune myasthenia gravis—it’s more a matter of the testing that we have available likely not picking up any autoantibodies.”

Seronegative results can be frustrating and lead to delays in diagnosis, Dr. Nowak says. But the clinical examination and electrodiagnostic testing can be sensitive and specific enough to confirm myasthenia gravis diagnosis in those patients, he adds.

“The Yale Medicine Myasthenia Gravis Program is very personalized, with an eye towards precision medicine health care,” Dr. Nowak says. “But it can be a journey.” A particular patient may need to try different medications, he adds. “There may be fine-tuning in terms of the treatments that we offer each individual.” For example, people can develop myasthenia gravis at any age, from younger than 10 to older than 90, and the medications can have different effects, depending on a person’s age, he explains. “The treatment strategies we use for younger patients might not be the same as those we use for older people. The same can be said for those with mild versus severe disease.”

But “myasthenia gravis is a treatable disease for most patients once we find the right treatment strategy for them,” Dr. Nowak says, and the medications are likely helping more patients to achieve better outcomes, he adds.

Close and careful follow-up care with a neurologist is essential. “The first two to three years from initial symptom onset is sometimes the most challenging and critical because patients can progress from mild to very severe disease during this time,” he says.

Patients may go into remission or have disease relapse, and even the mechanisms driving their disease might change, so the therapeutics used may change over time, too. While there are more available treatment options, we still do not have a way to predict which treatments will work the best for which patients. “This represents a knowledge gap we’re hoping to address,” Dr. Nowak says.

A surgery called a thymectomy (removal of the thymus gland) can lessen symptoms and the need for medication. An international clinical trial published in the New England Journal of Medicine in 2016 addressed a question doctors have sought to clarify for decades about the efficacy of thymectomy in patients without thymoma, “providing evidence that supported the use of thymectomy for improving clinical outcomes and reducing the need for immunosuppressive therapy in patients with myasthenia gravis,” according to the authors. In the study, thymectomy was associated with a more favorable outcome than treatment with prednisone alone.

Those diagnosed with myasthenia gravis in their 20s, 30s, and 40s, for instance, sometimes have an enlarged thymus gland, called thymic hyperplasia, explains Dr. Nowak. “For younger patients with AChR myasthenia gravis, we recommend elective thymectomy based on available evidence,” he says.

In about 10% of patients, a benign tumor in the thymus gland (called a thymoma) is detected, and in those cases, a thymectomy is typically needed. That’s why patients diagnosed with myasthenia gravis are given a CT scan of the chest as part of their diagnostic workup. When a thymoma is diagnosed, surgeons can remove it and the thymus tissue surgically—commonly using a minimally invasive approach.

“As we age, the thymus shrinks, so the utility of an elective thymectomy in individuals without a thymoma later in life is not established and thought to not be beneficial,” says Dr. Nowak.

Both O’Connor and Dr. Nowak hope to see a continuing paradigm shift in myasthenia gravis treatment in the next seven to ten years based on research. Doctors are already moving away from the traditional practice of treating myasthenia gravis symptomatically and then giving patients global immunosuppressive therapies without a specific focus, Dr. Nowak explains. The new therapeutics target specific parts of the immune system, he adds.

Still, “all of these therapeutics, while effective, are only eliminating the immunological activity,” O’Connor says, explaining that researchers want to target the source of that irregular activity. “The body is not supposed to make antibodies to itself. Your system has built-in checkpoints that prohibit that from happening, and they're not functioning properly in these patients—or in any patient with an autoimmune disease.”

Fixing the defect or defects that allow the autoantibodies to be produced would be closer to a cure and eliminate the need for chronic therapy, he adds.

While rare diseases tend not to get as much attention and funding as such common ones as diabetes and heart disease, myasthenia gravis research got a boost from a 2019 NIH grant to develop the Myasthenia Gravis Rare Disease Research Network or MGNet.

Yale is one of only a handful of centers in the United States that is part of MGNet, a consortium of academic medical centers and others working together to improve the fundamental understanding of and enhance therapeutic development for myasthenia gravis.

“One of the main projects is a natural history study, EXPLORE-MG2, where we're following newly diagnosed patients for a minimum of 2 years in an effort to obtain a deeper characterization of the disease over time. We are not only monitoring patients clinically but also exploring how their immune system changes from diagnosis to six months, one year, and two years down the line,” Dr. Nowak says. “Research efforts such as these are the foundation to a path toward precision medicine health care, and hopefully will help us not only identify but validate treatment-predictive biomarkers.”

For most patients, myasthenia gravis can now be considered a chronic disease that is treatable with the right individual treatment strategy—making the condition much less threatening than it was even five to 10 years ago, Dr. Nowak explains.

“Soliris, the first of the new drugs, was transformative in that for many of those patients, we had exhausted our treatment options, and when this new medication became available, their myasthenia gravis could be managed a lot better,” he says. “Helping patients with myasthenia gravis who need more options is a driving force behind research to find new treatments with improved outcomes."

As more options become available, we will need to be equally focused on understanding which strategies are best for which patients, he adds.