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Health care providers should have higher suspicion for rare diseases
The number of cataloged rare diseases continues to grow every day. According to the National Human Genome Research Institute, more than 6,800 rare diseases have been identified and between 25 million and 30 million Americans are living with rare diseases today.
Rare diseases have collectively emerged as a unique field of medicine with an “entirely new generation of conditions,” said Marshall L. Summar, MD, chief of the division of genetics and metabolism at Children’s National Hospital in Washington, DC. He places the number of rare diseases closer to 8,000, and said it is “growing by a rate of 10 to 12 a week.”
Although the field has made significant advancements in health care providers’ ability to diagnose rare diseases, it has also highlighted what isn’t known as well, said Dr. Summar, who is also past president and a former scientific advisory board member with the National Organization for Rare Disorders (NORD).
Keeping up to date on the latest rare diseases may seem like a daunting task to the average health care professional. However, while rare diseases remain the domain of the subspecialists, the generalist “can make a tremendous impact for their patients” early in the process by having a higher suspicion for rare diseases in their practice, said Dr. Summar.
Thinking of rare diseases in categories
Many patients with undiagnosed rare diseases undergo what’s commonly referred to as a “diagnostic odyssey,” moving from one provider to another to try to find an explanation for a condition they may or may not know is rare. For some patients, this process can take many years or even decades. From the patient’s perspective, the main challenges are recognizing they have a problem that doesn’t fit a common disease model. Once they recognize they have a potential rare disease, working with a provider to find the right diagnosis among the “vast number of disease diagnoses and designations, and actually sifting through it to find the one that’s right for that patient” is the next challenge, said Dr. Summar.
However, knowledge of rare diseases among health care professionals is low, according to a 2019 paper published in the Orphanet Journal of Rare Diseases. In a survey from that paper asking general practitioners, pediatricians, specialists caring for adults, and specialists caring for children to evaluate their own knowledge of rare diseases, 42% of general practitioners said they had poor knowledge and 44% said they had a substandard understanding of rare diseases.
From a clinician’s standpoint, diagnosing rare diseases in their patients can be challenging, with the potential for overreferral or overdiagnosis. However, it is also easy to underdiagnose rare diseases by missing them, noted Dr. Summar. This issue can vary based on the experience of the provider, he said, because while general practitioners who recently began practicing may have had more exposure to rare diseases, for health care professionals who have been practicing for decades, “this is a new arrival in their field.”
During a busy day finding that extra time in an appointment to stop and question whether a patient might have a rare disease is another problem generalists face. “It is really tough for those general practitioners, because if you see 40 or 50 patients per day, how do you know which one of those [patients] were the ones that had something that wasn’t quite fitting or wasn’t quite ordinary?” he said.
When it comes to considering rare diseases in their patients, health care professionals in general practice should think in categories, rather than a particular rare disease, according to Dr. Summar. As the generalist is typically on the front lines of patient care, they don’t necessarily need to know everything about the rare disease they suspect a patient of having to help them. “You don’t need to know the specific gene and the specific mutation to make the diagnosis, or to even move the patient forward in the process,” he said.
The first steps a clinician can take include noticing when something with a patient is amiss, thinking about the disease category, and then creating a plan to move forward, such as referring the patient to a subspecialist. Learning to recognize when a cluster of symptoms doesn’t fit a pattern is important, as patients and their providers tend to gravitate toward diagnoses they are used to seeing, rather than suspecting a disease outside a usual pattern.
The framing of rare diseases as categories is a change in thinking over the last decade, said Dr. Summar. Whereas rare disease diagnoses previously focused on fitting certain criteria, the development of more refined genetic sequencing has allowed specialists to focus on categories and genes that affect rare diseases. “Getting at a diagnosis has really been turned up on its head, so that by employing both next-generation sequencing, newborn screening, and other [tools], we can actually get to diagnoses faster than we could before,” he said.
In terms of assessing for symptoms, health care professionals should be aware that “common” symptoms can be a sign of rare disease. What to look out for are the uncommon symptoms that create an “aha moment.” Having a “good filter” for sensing when something isn’t quite right with a patient is key. “It’s like any time when you’re screening things: You want high sensitivity, but you also have to have high specificity,” he said.
Another clinical pearl is that good communication between patient and provider is paramount. “We’re not always good listeners. Sometimes we hear what we expect to hear,” said Dr. Summar.
Rare disease warning signs
Within the context of rare neurological diseases, Dr. Summar noted one major category is delays in neurological development, which is typically identified in children or adolescents. As the most complex organ in the body, “the brain probably expresses more genes than any other tissue on a regular basis, both in its formation and its function,” said Dr. Summar. He said the single disease that rare disease specialists see most often is Down syndrome.
Another separate but overlapping major category is autism, identified in younger children through trouble with social interaction, lack of eye contact, and delays in speech and communication skills. A third major category is physical manifestations of neurological problems, such as in patients who have epilepsy.
A telltale sign in identifying a child with a potential rare neurological disease is when they are “not thriving in their development or not doing the things on track that you would expect, and you don’t have a really good answer for it,” said Dr. Summar. Generalists are normally on watch for developmental delays in newborns born premature or with a rough course in the nursery, but they should also be aware of delays in children born under otherwise typical circumstances. “If I have a patient who had normal pregnancy, normal labor and delivery, no real illnesses or anything like that, and yet wasn’t meeting those milestones, that’s a patient I would pay attention to,” he said.
Another clue general practitioners can use for suspecting rare diseases is when a patient is much sicker than usual during a routine illness like a cold or flu. “Those are patients we should be paying attention to because it may be there’s an underlying biochemical disorder or some disorder in how they’re responding to stress that’s just not quite right,” said Dr. Summar. How a patient responds to stressful situations can be a warning sign “because that can often unmask more severe symptoms in that rare disease and make it a little more apparent,” he said.
Learning more about rare diseases
Dr. Summar said he and his colleagues in the rare disease field have spent a lot of time working with medical schools to teach this mindset in their curricula. The concept is introduced in basic medical science courses and then reinforced in clinical rotations in the third or fourth year, he explained.
“One of the best places is during the pediatrics rotations in medical school,” he said. “Remember, kids are basically healthy. If a child has a chronic illness or a chronic disease, more often than not, it is probably a rare disease.”
For medical professionals not in pediatric practice, the concept is applied the same way for adult medicine. “You just want to make sure everyone takes a second when they have a patient and try not to assume. Don’t assume it’s exactly what it seems. Look at it carefully and make sure there’s not something else going on,” he said.
Health care professionals in general practice looking to learn more about rare diseases can increasingly find rare disease topics in their CME programs. Rare disease topics in CME programs are “one of the best places” to learn about the latest developments in the field, said Dr. Summar.
Will rare disease screening tools come to primary care?
Asking more doctors to refer out to rare disease specialists raises an issue: There simply aren’t enough rare disease specialists in the field to go around.
Dr. Summar said partnering testing – where a general practitioner contacts a specialist to begin the process of testing based on the suspected condition – is a good stopgap solution. Telemedicine, which rose in popularity during the COVID-19 pandemic, can also play an important role in connecting patients and their providers with rare disease specialists, especially for generalists in remote communities. Dr. Summar noted he continues to see approximately 30% of his patients this way today. Telemedicine appointments can take place in the patient’s home or at the provider’s office.
“It actually provides access to folks who otherwise might not be able to either take off from work for a day – particularly some of our single parent households – or have a child who just doesn’t travel well, or can’t really get there, even if it’s the patient themselves,” he explained. “We can see patients that historically would have had trouble or difficulty coming in, so for me, that’s been a good thing.”
Telemedicine also helps give access to care for more medically fragile patients, many of whom have rare diseases, he added. While some aspects of care need to occur in person, “it’s a good 80% or 90% solution for a lot of these things,” he said.
Sharing educational videos is another way for health care providers in general practice to inform patients and their families about rare diseases. Children’s National Medical Center has created a collection of these videos in a free app called GeneClips, which is available on major smartphone app stores. However, Dr. Summar emphasized that genetic counseling should still be performed by a rare disease specialist prior to testing.
“We’re still at the point where I think having genetic counseling for a family before they’re going into testing is really advisable, since a lot of the results have a probability assigned to them,” he said. “I don’t think we’re really at the level where a practitioner is going to, first of all, have the time to do those, and I don’t think there’s enough general public awareness of what these things mean.”
Although primary care providers may one day be able to perform more generalized sequencing in their own practice, that time has not yet come – but it is closer than you think. “The technology is there, and actually the cost has come down a lot,” said Dr. Summar.
One potential issue this would create is an additional discussion to manage expectations of test results with family when the results are unclear, which “actually takes more time than counseling about a yes or no, or even an outcome that is unexpected,” explained Dr. Summar.
“[W]e’re in a midlife period right now where we’re bringing forward this new technology, but we’ve got to continually prepare the field for it first,” he said. “I think in the future we’ll see that it has much greater utility in the general setting,” he said.
Jeff Craven is a freelance journalist specializing in medicine and health.
Suggested reading
Vandeborne L et al. Information needs of physicians regarding the diagnosis of rare diseases: A questionnaire-based study in Belgium. Orphanet J Rare Dis. 2019;14(1):99.
The number of cataloged rare diseases continues to grow every day. According to the National Human Genome Research Institute, more than 6,800 rare diseases have been identified and between 25 million and 30 million Americans are living with rare diseases today.
Rare diseases have collectively emerged as a unique field of medicine with an “entirely new generation of conditions,” said Marshall L. Summar, MD, chief of the division of genetics and metabolism at Children’s National Hospital in Washington, DC. He places the number of rare diseases closer to 8,000, and said it is “growing by a rate of 10 to 12 a week.”
Although the field has made significant advancements in health care providers’ ability to diagnose rare diseases, it has also highlighted what isn’t known as well, said Dr. Summar, who is also past president and a former scientific advisory board member with the National Organization for Rare Disorders (NORD).
Keeping up to date on the latest rare diseases may seem like a daunting task to the average health care professional. However, while rare diseases remain the domain of the subspecialists, the generalist “can make a tremendous impact for their patients” early in the process by having a higher suspicion for rare diseases in their practice, said Dr. Summar.
Thinking of rare diseases in categories
Many patients with undiagnosed rare diseases undergo what’s commonly referred to as a “diagnostic odyssey,” moving from one provider to another to try to find an explanation for a condition they may or may not know is rare. For some patients, this process can take many years or even decades. From the patient’s perspective, the main challenges are recognizing they have a problem that doesn’t fit a common disease model. Once they recognize they have a potential rare disease, working with a provider to find the right diagnosis among the “vast number of disease diagnoses and designations, and actually sifting through it to find the one that’s right for that patient” is the next challenge, said Dr. Summar.
However, knowledge of rare diseases among health care professionals is low, according to a 2019 paper published in the Orphanet Journal of Rare Diseases. In a survey from that paper asking general practitioners, pediatricians, specialists caring for adults, and specialists caring for children to evaluate their own knowledge of rare diseases, 42% of general practitioners said they had poor knowledge and 44% said they had a substandard understanding of rare diseases.
From a clinician’s standpoint, diagnosing rare diseases in their patients can be challenging, with the potential for overreferral or overdiagnosis. However, it is also easy to underdiagnose rare diseases by missing them, noted Dr. Summar. This issue can vary based on the experience of the provider, he said, because while general practitioners who recently began practicing may have had more exposure to rare diseases, for health care professionals who have been practicing for decades, “this is a new arrival in their field.”
During a busy day finding that extra time in an appointment to stop and question whether a patient might have a rare disease is another problem generalists face. “It is really tough for those general practitioners, because if you see 40 or 50 patients per day, how do you know which one of those [patients] were the ones that had something that wasn’t quite fitting or wasn’t quite ordinary?” he said.
When it comes to considering rare diseases in their patients, health care professionals in general practice should think in categories, rather than a particular rare disease, according to Dr. Summar. As the generalist is typically on the front lines of patient care, they don’t necessarily need to know everything about the rare disease they suspect a patient of having to help them. “You don’t need to know the specific gene and the specific mutation to make the diagnosis, or to even move the patient forward in the process,” he said.
The first steps a clinician can take include noticing when something with a patient is amiss, thinking about the disease category, and then creating a plan to move forward, such as referring the patient to a subspecialist. Learning to recognize when a cluster of symptoms doesn’t fit a pattern is important, as patients and their providers tend to gravitate toward diagnoses they are used to seeing, rather than suspecting a disease outside a usual pattern.
The framing of rare diseases as categories is a change in thinking over the last decade, said Dr. Summar. Whereas rare disease diagnoses previously focused on fitting certain criteria, the development of more refined genetic sequencing has allowed specialists to focus on categories and genes that affect rare diseases. “Getting at a diagnosis has really been turned up on its head, so that by employing both next-generation sequencing, newborn screening, and other [tools], we can actually get to diagnoses faster than we could before,” he said.
In terms of assessing for symptoms, health care professionals should be aware that “common” symptoms can be a sign of rare disease. What to look out for are the uncommon symptoms that create an “aha moment.” Having a “good filter” for sensing when something isn’t quite right with a patient is key. “It’s like any time when you’re screening things: You want high sensitivity, but you also have to have high specificity,” he said.
Another clinical pearl is that good communication between patient and provider is paramount. “We’re not always good listeners. Sometimes we hear what we expect to hear,” said Dr. Summar.
Rare disease warning signs
Within the context of rare neurological diseases, Dr. Summar noted one major category is delays in neurological development, which is typically identified in children or adolescents. As the most complex organ in the body, “the brain probably expresses more genes than any other tissue on a regular basis, both in its formation and its function,” said Dr. Summar. He said the single disease that rare disease specialists see most often is Down syndrome.
Another separate but overlapping major category is autism, identified in younger children through trouble with social interaction, lack of eye contact, and delays in speech and communication skills. A third major category is physical manifestations of neurological problems, such as in patients who have epilepsy.
A telltale sign in identifying a child with a potential rare neurological disease is when they are “not thriving in their development or not doing the things on track that you would expect, and you don’t have a really good answer for it,” said Dr. Summar. Generalists are normally on watch for developmental delays in newborns born premature or with a rough course in the nursery, but they should also be aware of delays in children born under otherwise typical circumstances. “If I have a patient who had normal pregnancy, normal labor and delivery, no real illnesses or anything like that, and yet wasn’t meeting those milestones, that’s a patient I would pay attention to,” he said.
Another clue general practitioners can use for suspecting rare diseases is when a patient is much sicker than usual during a routine illness like a cold or flu. “Those are patients we should be paying attention to because it may be there’s an underlying biochemical disorder or some disorder in how they’re responding to stress that’s just not quite right,” said Dr. Summar. How a patient responds to stressful situations can be a warning sign “because that can often unmask more severe symptoms in that rare disease and make it a little more apparent,” he said.
Learning more about rare diseases
Dr. Summar said he and his colleagues in the rare disease field have spent a lot of time working with medical schools to teach this mindset in their curricula. The concept is introduced in basic medical science courses and then reinforced in clinical rotations in the third or fourth year, he explained.
“One of the best places is during the pediatrics rotations in medical school,” he said. “Remember, kids are basically healthy. If a child has a chronic illness or a chronic disease, more often than not, it is probably a rare disease.”
For medical professionals not in pediatric practice, the concept is applied the same way for adult medicine. “You just want to make sure everyone takes a second when they have a patient and try not to assume. Don’t assume it’s exactly what it seems. Look at it carefully and make sure there’s not something else going on,” he said.
Health care professionals in general practice looking to learn more about rare diseases can increasingly find rare disease topics in their CME programs. Rare disease topics in CME programs are “one of the best places” to learn about the latest developments in the field, said Dr. Summar.
Will rare disease screening tools come to primary care?
Asking more doctors to refer out to rare disease specialists raises an issue: There simply aren’t enough rare disease specialists in the field to go around.
Dr. Summar said partnering testing – where a general practitioner contacts a specialist to begin the process of testing based on the suspected condition – is a good stopgap solution. Telemedicine, which rose in popularity during the COVID-19 pandemic, can also play an important role in connecting patients and their providers with rare disease specialists, especially for generalists in remote communities. Dr. Summar noted he continues to see approximately 30% of his patients this way today. Telemedicine appointments can take place in the patient’s home or at the provider’s office.
“It actually provides access to folks who otherwise might not be able to either take off from work for a day – particularly some of our single parent households – or have a child who just doesn’t travel well, or can’t really get there, even if it’s the patient themselves,” he explained. “We can see patients that historically would have had trouble or difficulty coming in, so for me, that’s been a good thing.”
Telemedicine also helps give access to care for more medically fragile patients, many of whom have rare diseases, he added. While some aspects of care need to occur in person, “it’s a good 80% or 90% solution for a lot of these things,” he said.
Sharing educational videos is another way for health care providers in general practice to inform patients and their families about rare diseases. Children’s National Medical Center has created a collection of these videos in a free app called GeneClips, which is available on major smartphone app stores. However, Dr. Summar emphasized that genetic counseling should still be performed by a rare disease specialist prior to testing.
“We’re still at the point where I think having genetic counseling for a family before they’re going into testing is really advisable, since a lot of the results have a probability assigned to them,” he said. “I don’t think we’re really at the level where a practitioner is going to, first of all, have the time to do those, and I don’t think there’s enough general public awareness of what these things mean.”
Although primary care providers may one day be able to perform more generalized sequencing in their own practice, that time has not yet come – but it is closer than you think. “The technology is there, and actually the cost has come down a lot,” said Dr. Summar.
One potential issue this would create is an additional discussion to manage expectations of test results with family when the results are unclear, which “actually takes more time than counseling about a yes or no, or even an outcome that is unexpected,” explained Dr. Summar.
“[W]e’re in a midlife period right now where we’re bringing forward this new technology, but we’ve got to continually prepare the field for it first,” he said. “I think in the future we’ll see that it has much greater utility in the general setting,” he said.
Jeff Craven is a freelance journalist specializing in medicine and health.
Suggested reading
Vandeborne L et al. Information needs of physicians regarding the diagnosis of rare diseases: A questionnaire-based study in Belgium. Orphanet J Rare Dis. 2019;14(1):99.
The number of cataloged rare diseases continues to grow every day. According to the National Human Genome Research Institute, more than 6,800 rare diseases have been identified and between 25 million and 30 million Americans are living with rare diseases today.
Rare diseases have collectively emerged as a unique field of medicine with an “entirely new generation of conditions,” said Marshall L. Summar, MD, chief of the division of genetics and metabolism at Children’s National Hospital in Washington, DC. He places the number of rare diseases closer to 8,000, and said it is “growing by a rate of 10 to 12 a week.”
Although the field has made significant advancements in health care providers’ ability to diagnose rare diseases, it has also highlighted what isn’t known as well, said Dr. Summar, who is also past president and a former scientific advisory board member with the National Organization for Rare Disorders (NORD).
Keeping up to date on the latest rare diseases may seem like a daunting task to the average health care professional. However, while rare diseases remain the domain of the subspecialists, the generalist “can make a tremendous impact for their patients” early in the process by having a higher suspicion for rare diseases in their practice, said Dr. Summar.
Thinking of rare diseases in categories
Many patients with undiagnosed rare diseases undergo what’s commonly referred to as a “diagnostic odyssey,” moving from one provider to another to try to find an explanation for a condition they may or may not know is rare. For some patients, this process can take many years or even decades. From the patient’s perspective, the main challenges are recognizing they have a problem that doesn’t fit a common disease model. Once they recognize they have a potential rare disease, working with a provider to find the right diagnosis among the “vast number of disease diagnoses and designations, and actually sifting through it to find the one that’s right for that patient” is the next challenge, said Dr. Summar.
However, knowledge of rare diseases among health care professionals is low, according to a 2019 paper published in the Orphanet Journal of Rare Diseases. In a survey from that paper asking general practitioners, pediatricians, specialists caring for adults, and specialists caring for children to evaluate their own knowledge of rare diseases, 42% of general practitioners said they had poor knowledge and 44% said they had a substandard understanding of rare diseases.
From a clinician’s standpoint, diagnosing rare diseases in their patients can be challenging, with the potential for overreferral or overdiagnosis. However, it is also easy to underdiagnose rare diseases by missing them, noted Dr. Summar. This issue can vary based on the experience of the provider, he said, because while general practitioners who recently began practicing may have had more exposure to rare diseases, for health care professionals who have been practicing for decades, “this is a new arrival in their field.”
During a busy day finding that extra time in an appointment to stop and question whether a patient might have a rare disease is another problem generalists face. “It is really tough for those general practitioners, because if you see 40 or 50 patients per day, how do you know which one of those [patients] were the ones that had something that wasn’t quite fitting or wasn’t quite ordinary?” he said.
When it comes to considering rare diseases in their patients, health care professionals in general practice should think in categories, rather than a particular rare disease, according to Dr. Summar. As the generalist is typically on the front lines of patient care, they don’t necessarily need to know everything about the rare disease they suspect a patient of having to help them. “You don’t need to know the specific gene and the specific mutation to make the diagnosis, or to even move the patient forward in the process,” he said.
The first steps a clinician can take include noticing when something with a patient is amiss, thinking about the disease category, and then creating a plan to move forward, such as referring the patient to a subspecialist. Learning to recognize when a cluster of symptoms doesn’t fit a pattern is important, as patients and their providers tend to gravitate toward diagnoses they are used to seeing, rather than suspecting a disease outside a usual pattern.
The framing of rare diseases as categories is a change in thinking over the last decade, said Dr. Summar. Whereas rare disease diagnoses previously focused on fitting certain criteria, the development of more refined genetic sequencing has allowed specialists to focus on categories and genes that affect rare diseases. “Getting at a diagnosis has really been turned up on its head, so that by employing both next-generation sequencing, newborn screening, and other [tools], we can actually get to diagnoses faster than we could before,” he said.
In terms of assessing for symptoms, health care professionals should be aware that “common” symptoms can be a sign of rare disease. What to look out for are the uncommon symptoms that create an “aha moment.” Having a “good filter” for sensing when something isn’t quite right with a patient is key. “It’s like any time when you’re screening things: You want high sensitivity, but you also have to have high specificity,” he said.
Another clinical pearl is that good communication between patient and provider is paramount. “We’re not always good listeners. Sometimes we hear what we expect to hear,” said Dr. Summar.
Rare disease warning signs
Within the context of rare neurological diseases, Dr. Summar noted one major category is delays in neurological development, which is typically identified in children or adolescents. As the most complex organ in the body, “the brain probably expresses more genes than any other tissue on a regular basis, both in its formation and its function,” said Dr. Summar. He said the single disease that rare disease specialists see most often is Down syndrome.
Another separate but overlapping major category is autism, identified in younger children through trouble with social interaction, lack of eye contact, and delays in speech and communication skills. A third major category is physical manifestations of neurological problems, such as in patients who have epilepsy.
A telltale sign in identifying a child with a potential rare neurological disease is when they are “not thriving in their development or not doing the things on track that you would expect, and you don’t have a really good answer for it,” said Dr. Summar. Generalists are normally on watch for developmental delays in newborns born premature or with a rough course in the nursery, but they should also be aware of delays in children born under otherwise typical circumstances. “If I have a patient who had normal pregnancy, normal labor and delivery, no real illnesses or anything like that, and yet wasn’t meeting those milestones, that’s a patient I would pay attention to,” he said.
Another clue general practitioners can use for suspecting rare diseases is when a patient is much sicker than usual during a routine illness like a cold or flu. “Those are patients we should be paying attention to because it may be there’s an underlying biochemical disorder or some disorder in how they’re responding to stress that’s just not quite right,” said Dr. Summar. How a patient responds to stressful situations can be a warning sign “because that can often unmask more severe symptoms in that rare disease and make it a little more apparent,” he said.
Learning more about rare diseases
Dr. Summar said he and his colleagues in the rare disease field have spent a lot of time working with medical schools to teach this mindset in their curricula. The concept is introduced in basic medical science courses and then reinforced in clinical rotations in the third or fourth year, he explained.
“One of the best places is during the pediatrics rotations in medical school,” he said. “Remember, kids are basically healthy. If a child has a chronic illness or a chronic disease, more often than not, it is probably a rare disease.”
For medical professionals not in pediatric practice, the concept is applied the same way for adult medicine. “You just want to make sure everyone takes a second when they have a patient and try not to assume. Don’t assume it’s exactly what it seems. Look at it carefully and make sure there’s not something else going on,” he said.
Health care professionals in general practice looking to learn more about rare diseases can increasingly find rare disease topics in their CME programs. Rare disease topics in CME programs are “one of the best places” to learn about the latest developments in the field, said Dr. Summar.
Will rare disease screening tools come to primary care?
Asking more doctors to refer out to rare disease specialists raises an issue: There simply aren’t enough rare disease specialists in the field to go around.
Dr. Summar said partnering testing – where a general practitioner contacts a specialist to begin the process of testing based on the suspected condition – is a good stopgap solution. Telemedicine, which rose in popularity during the COVID-19 pandemic, can also play an important role in connecting patients and their providers with rare disease specialists, especially for generalists in remote communities. Dr. Summar noted he continues to see approximately 30% of his patients this way today. Telemedicine appointments can take place in the patient’s home or at the provider’s office.
“It actually provides access to folks who otherwise might not be able to either take off from work for a day – particularly some of our single parent households – or have a child who just doesn’t travel well, or can’t really get there, even if it’s the patient themselves,” he explained. “We can see patients that historically would have had trouble or difficulty coming in, so for me, that’s been a good thing.”
Telemedicine also helps give access to care for more medically fragile patients, many of whom have rare diseases, he added. While some aspects of care need to occur in person, “it’s a good 80% or 90% solution for a lot of these things,” he said.
Sharing educational videos is another way for health care providers in general practice to inform patients and their families about rare diseases. Children’s National Medical Center has created a collection of these videos in a free app called GeneClips, which is available on major smartphone app stores. However, Dr. Summar emphasized that genetic counseling should still be performed by a rare disease specialist prior to testing.
“We’re still at the point where I think having genetic counseling for a family before they’re going into testing is really advisable, since a lot of the results have a probability assigned to them,” he said. “I don’t think we’re really at the level where a practitioner is going to, first of all, have the time to do those, and I don’t think there’s enough general public awareness of what these things mean.”
Although primary care providers may one day be able to perform more generalized sequencing in their own practice, that time has not yet come – but it is closer than you think. “The technology is there, and actually the cost has come down a lot,” said Dr. Summar.
One potential issue this would create is an additional discussion to manage expectations of test results with family when the results are unclear, which “actually takes more time than counseling about a yes or no, or even an outcome that is unexpected,” explained Dr. Summar.
“[W]e’re in a midlife period right now where we’re bringing forward this new technology, but we’ve got to continually prepare the field for it first,” he said. “I think in the future we’ll see that it has much greater utility in the general setting,” he said.
Jeff Craven is a freelance journalist specializing in medicine and health.
Suggested reading
Vandeborne L et al. Information needs of physicians regarding the diagnosis of rare diseases: A questionnaire-based study in Belgium. Orphanet J Rare Dis. 2019;14(1):99.
A note from NORD
The National Organization for Rare Disorders (NORD)is tremendously grateful to the dedicated healthcare professionals who, despite long days and heavy workloads, continue to seek the latest information on medical advances that might be helpful to their patients. Please know that your commitment and support are tremendously important to the patients and families whom we serve.
As you may be aware, NORD is a nonprofit organization that was established in 1983 to provide advocacy, education, patient/family services and research on behalf of all Americans affected by rare diseases and the medical professionals providing their care.
As we approach NORD’s 40th anniversary, it is astonishing to realize how far we all have come since the early 1980s, when rare disease patients and their medical providers were essentially on their own to navigate the challenging waters of rare disease diagnosis and treatment.
Today, we are living in one of the most exciting periods in medical history, with innovative new diagnostics and treatments being developed or on the horizon. You’ll find information about these medical advances, as well as resources for yourself and your patients, on the NORD website including our Rare Disease Database, Video Library, CME programs and resources, and newsletter for medical professionals.
You’ll also find information about the annual NORD Rare Diseases and Orphan Products Breakthrough Summit, the largest annual conference for professionals and patients in the rare community, along with our annual conference specifically for patients and families, the “Living Rare, Living Stronger Family Forum.”
This issue of the Rare Neurological Diseases Special Report features articles from rare disease medical experts on specific diseases, including spinal muscular atrophy, Pompe disease, and Rett syndrome, as well as more general topics such as genetic therapies for neuromuscular diseases.
Also in this issue are articles on new and exciting initiatives such as the “NORD Rare Disease Centers of Excellence.” These 31 centers, geographically dispersed across the nation, represent an attempt to provide a strong, national network of support for both patients and medical professionals to promote earlier diagnosis and optimal care, regardless of location.
An interview in this issue with one of NORD’s longtime medical advisors and a leading rare disease expert provides advice for community physicians and other HCPs related to diagnosing rare diseases and approaches that may help shorten the diagnostic odyssey for patients. In addition, you can read about how patient advocacy organizations are collecting and managing a precious asset – patient data – to advance understanding of diseases, even extremely rare ones, and support research.
We are grateful for the work you do and for your commitment to your patients, including those with extremely rare or newly identified diseases. We invite you to visit the NORD website often, sign up for our newsletter for medical professionals and contact NORD at any time if we can be helpful to you.
Peter L. Saltonstall, president and CEO
National Organization for Rare Disorders (NORD)
The National Organization for Rare Disorders (NORD)is tremendously grateful to the dedicated healthcare professionals who, despite long days and heavy workloads, continue to seek the latest information on medical advances that might be helpful to their patients. Please know that your commitment and support are tremendously important to the patients and families whom we serve.
As you may be aware, NORD is a nonprofit organization that was established in 1983 to provide advocacy, education, patient/family services and research on behalf of all Americans affected by rare diseases and the medical professionals providing their care.
As we approach NORD’s 40th anniversary, it is astonishing to realize how far we all have come since the early 1980s, when rare disease patients and their medical providers were essentially on their own to navigate the challenging waters of rare disease diagnosis and treatment.
Today, we are living in one of the most exciting periods in medical history, with innovative new diagnostics and treatments being developed or on the horizon. You’ll find information about these medical advances, as well as resources for yourself and your patients, on the NORD website including our Rare Disease Database, Video Library, CME programs and resources, and newsletter for medical professionals.
You’ll also find information about the annual NORD Rare Diseases and Orphan Products Breakthrough Summit, the largest annual conference for professionals and patients in the rare community, along with our annual conference specifically for patients and families, the “Living Rare, Living Stronger Family Forum.”
This issue of the Rare Neurological Diseases Special Report features articles from rare disease medical experts on specific diseases, including spinal muscular atrophy, Pompe disease, and Rett syndrome, as well as more general topics such as genetic therapies for neuromuscular diseases.
Also in this issue are articles on new and exciting initiatives such as the “NORD Rare Disease Centers of Excellence.” These 31 centers, geographically dispersed across the nation, represent an attempt to provide a strong, national network of support for both patients and medical professionals to promote earlier diagnosis and optimal care, regardless of location.
An interview in this issue with one of NORD’s longtime medical advisors and a leading rare disease expert provides advice for community physicians and other HCPs related to diagnosing rare diseases and approaches that may help shorten the diagnostic odyssey for patients. In addition, you can read about how patient advocacy organizations are collecting and managing a precious asset – patient data – to advance understanding of diseases, even extremely rare ones, and support research.
We are grateful for the work you do and for your commitment to your patients, including those with extremely rare or newly identified diseases. We invite you to visit the NORD website often, sign up for our newsletter for medical professionals and contact NORD at any time if we can be helpful to you.
Peter L. Saltonstall, president and CEO
National Organization for Rare Disorders (NORD)
The National Organization for Rare Disorders (NORD)is tremendously grateful to the dedicated healthcare professionals who, despite long days and heavy workloads, continue to seek the latest information on medical advances that might be helpful to their patients. Please know that your commitment and support are tremendously important to the patients and families whom we serve.
As you may be aware, NORD is a nonprofit organization that was established in 1983 to provide advocacy, education, patient/family services and research on behalf of all Americans affected by rare diseases and the medical professionals providing their care.
As we approach NORD’s 40th anniversary, it is astonishing to realize how far we all have come since the early 1980s, when rare disease patients and their medical providers were essentially on their own to navigate the challenging waters of rare disease diagnosis and treatment.
Today, we are living in one of the most exciting periods in medical history, with innovative new diagnostics and treatments being developed or on the horizon. You’ll find information about these medical advances, as well as resources for yourself and your patients, on the NORD website including our Rare Disease Database, Video Library, CME programs and resources, and newsletter for medical professionals.
You’ll also find information about the annual NORD Rare Diseases and Orphan Products Breakthrough Summit, the largest annual conference for professionals and patients in the rare community, along with our annual conference specifically for patients and families, the “Living Rare, Living Stronger Family Forum.”
This issue of the Rare Neurological Diseases Special Report features articles from rare disease medical experts on specific diseases, including spinal muscular atrophy, Pompe disease, and Rett syndrome, as well as more general topics such as genetic therapies for neuromuscular diseases.
Also in this issue are articles on new and exciting initiatives such as the “NORD Rare Disease Centers of Excellence.” These 31 centers, geographically dispersed across the nation, represent an attempt to provide a strong, national network of support for both patients and medical professionals to promote earlier diagnosis and optimal care, regardless of location.
An interview in this issue with one of NORD’s longtime medical advisors and a leading rare disease expert provides advice for community physicians and other HCPs related to diagnosing rare diseases and approaches that may help shorten the diagnostic odyssey for patients. In addition, you can read about how patient advocacy organizations are collecting and managing a precious asset – patient data – to advance understanding of diseases, even extremely rare ones, and support research.
We are grateful for the work you do and for your commitment to your patients, including those with extremely rare or newly identified diseases. We invite you to visit the NORD website often, sign up for our newsletter for medical professionals and contact NORD at any time if we can be helpful to you.
Peter L. Saltonstall, president and CEO
National Organization for Rare Disorders (NORD)
Editor’s note
Thankfully, the COVID pandemic has not killed the spirit of innovation and the relentless search for answers in the rare disease community. There were several notable FDA approvals in 2021 and early 2022, emerging genetic therapies for monogenetic disorders, and recent advances in rare disease diagnosis and testing. This 7th annual issue of the Rare Neurological Disease Special Report highlights some of these developments.
For those of you who have been following the Rare Neurological Disease Special Report over the years, it is with great pride that I report that last year’s issue won a prestigious B2B award. The 2021 issue, our 6th annual issue, won an American Society of Business Publication Editors (ASBPE) Silver Regional Award for excellence in an annual publication. It has been our honor over the years to partner with the National Organization for Rare Disorders (NORD) to serve the rare neurological disease community. That effort is rewarding enough. Winning an award is icing on the cake but much appreciated.
—Glenn Williams, VP, Group Editor; Neurology Reviews and MDedge Neurology
Thankfully, the COVID pandemic has not killed the spirit of innovation and the relentless search for answers in the rare disease community. There were several notable FDA approvals in 2021 and early 2022, emerging genetic therapies for monogenetic disorders, and recent advances in rare disease diagnosis and testing. This 7th annual issue of the Rare Neurological Disease Special Report highlights some of these developments.
For those of you who have been following the Rare Neurological Disease Special Report over the years, it is with great pride that I report that last year’s issue won a prestigious B2B award. The 2021 issue, our 6th annual issue, won an American Society of Business Publication Editors (ASBPE) Silver Regional Award for excellence in an annual publication. It has been our honor over the years to partner with the National Organization for Rare Disorders (NORD) to serve the rare neurological disease community. That effort is rewarding enough. Winning an award is icing on the cake but much appreciated.
—Glenn Williams, VP, Group Editor; Neurology Reviews and MDedge Neurology
Thankfully, the COVID pandemic has not killed the spirit of innovation and the relentless search for answers in the rare disease community. There were several notable FDA approvals in 2021 and early 2022, emerging genetic therapies for monogenetic disorders, and recent advances in rare disease diagnosis and testing. This 7th annual issue of the Rare Neurological Disease Special Report highlights some of these developments.
For those of you who have been following the Rare Neurological Disease Special Report over the years, it is with great pride that I report that last year’s issue won a prestigious B2B award. The 2021 issue, our 6th annual issue, won an American Society of Business Publication Editors (ASBPE) Silver Regional Award for excellence in an annual publication. It has been our honor over the years to partner with the National Organization for Rare Disorders (NORD) to serve the rare neurological disease community. That effort is rewarding enough. Winning an award is icing on the cake but much appreciated.
—Glenn Williams, VP, Group Editor; Neurology Reviews and MDedge Neurology
Myasthenia gravis: Finding strength in treatment options
The term myasthenia gravis (MG), from the Latin “grave muscle weakness,” denotes the rare autoimmune disorder characterized by dysfunction at the neuromuscular junction.1 The clinical presentation of the disease is variable but most often includes ocular symptoms, such as ptosis and diplopia, bulbar weakness, and muscle fatigue upon exertion.2,3 Severe symptoms can lead to myasthenic crisis, in which generalized weakness can affect respiratory muscles, leading to possible intubation or death.2,3
Onset of disease ranges from childhood to late adulthood, and largely depends on the subgroup of disease and the age of the patient.4 Although complications from MG can arise, treatment methods have considerably reduced the risk of MG-associated mortality, with the current rate estimated to be 0.06 to 0.89 deaths for every 1 million person-years (that is, approximately 5% of cases).3,5
Pathophysiology
MG is caused by binding of autoimmune antibodies to postsynaptic receptors and by molecules that prevent signal transduction at the muscle endplate.2,4,6,7 The main culprit behind the pathology (in approximately 85% of cases) is an autoimmune antibody for the acetylcholine receptor (AChR); however, other offending antibodies – against muscle-specific serine kinases (MuSK), low-density lipoprotein receptor-related protein 4 (LRP4), and the proteoglycan agrin – are known, although at a lower frequency (in approximately 15% of cases).4,8 These antibodies prevent signal transmission by blocking, destroying, or disrupting the clustering of AChR at the muscle endplate, a necessary step in formation of the neuromuscular junction.4,8,9
The activity of these antibodies is key to understanding the importance of subgrouping the types of MG on the basis of antigen-specific autoimmune interactions. Specifically, the four categories of disease following a diagnosis of MG2,7 are:
- AChR antibody-positive.
- MuSK antibody-positive.
- LRP4 antibody-positive.
- Seronegative MG.
Classifying MG into subgroups gives insight into the functional expectations and potential treatment options for a given patient, although expectations can vary.2
Regrettably, the well-understood pathophysiology, diagnosis, and prognosis of MG have limited investigation and development of new therapies. Additionally, mainstay treatments, such as thymectomy and prednisone, work to alleviate symptoms for most patients, and have also contributed to periods of slowed research and development. However, treatment of refractory MG has, in recent years, become the subject of research on new therapeutic options, aimed at treating heterogeneous disease populations.10
In this review, we discuss the diagnosis of, and treatment options for, MG, and provide an update on promising options in the therapeutic pipeline.
Diagnosis
Distinguishing MG from other neuromuscular junction disorders is a pertinent step before treatment. Although the biomarkers discussed in this section are sensitive for making a diagnosis of MG, additional research is needed to classify seronegative patients who do not have circulating autoantibodies that are pathognomonic for MG.11
Upon clinical examination of observable myasthenic weakness, next steps would require assays for anti-AChR and anti-MuSK.1 If either of those tests are inconclusive, assays for anti-LRP4 are available (although the LRP4 antibody is also a marker in other neurological disorders).12
In the MG diagnostic algorithm, next steps include an electromyography repetitive stimulation test, which, if inconclusive, is followed by single-fiber electromyography.1 If any of these tests return positive, computed tomography or magnetic resonance imaging is necessary for thymus screening.
What follows this diagnostic schema is pharmacotherapeutic or surgical intervention to reduce, or even eliminate, symptoms of MG.1
Consensus on treatment standards
A quantitative assessment of best options for treating MG was conducted by leading experts,13 who reached consensus that primary outcomes in treating MG are reached when a patient presents without symptoms or limitations on daily activities; or has only slight weakness or fatigue in some muscles.13
Pyridostigmine, an acetylcholinesterase inhibitor, is recommended as part of the initial treatment plan for MG patients. Pyridostigmine prevents normal breakdown of acetylcholine, thus increasing acetylcholine levels and allowing signal transmission at the neuromuscular junction.14 Not all patients reach the aforementioned treatment goals when taking pyridostigmine, however; some require corticosteroids or immunosuppressive agents, or both, in addition.
Steroids, such as prednisone and prednisolone, occupy the second line in MG patients because of their ability to produce a rapid response, availability, and economy.1,15 Initial dosages of these medications are gradually adjusted to a maintenance dosage and schedule, as tolerated, to maintain control of symptoms.15
In MG patients who are in respiratory crisis, it is recommended that high-dosage prednisone be given in conjunction with plasmapheresis or intravenous immunoglobulin (IVIg).15 When the response to steroids is inadequate, adverse effects cannot be tolerated, or the patient experiences symptomatic relapse, nonsteroidal immunosuppressive agents are started.
Immunosuppressives are used to weaken the immune response or block production of self-antibodies. Several agents have been identified for use in MG, including azathioprine and mycophenolate mofetil; their use is limited, however, by a lack of supporting evidence from randomized clinical trials or the potential for serious adverse effects.13
Referral and specialized treatments. Patients who are refractory to all the aforementioned treatments should be referred to a physician who is expert in the management of MG. At this point, treatment guidelines recommend chronic IVIg infusion or plasmapheresis, which removes complement, cytokines, and antibodies from the blood.14 Additionally, monoclonal antibody therapies, such as eculizumab, have been shown to have efficacy in severe, refractory AChR antibody–positive generalized MG.16
Thymectomy has been a mainstay and, sometimes, first-line treatment of MG for nearly 80 years.15 The thymus has largely been implicated in the immunopathology of AChR-positive MG. Models suggest that increased expression of inflammatory factors causes an imbalance among immune cells, resulting in lymphofollicular hyperplasia or thymoma.17
Despite the growing body of evidence implicating the thymus in the progression of MG, some patients and physicians are reluctant to proceed with surgical intervention. This could be due to a disparity in surgical treatment options offered by surgeons, and facilities, with varying experience or ability to conduct newer techniques. Minimally invasive approaches, such as video-assisted thoracoscopic surgery and robotic thymectomy, have been found to be superior to traditional open surgical techniques.18,19 Minimally invasive techniques result in significantly fewer postoperative complications, less blood loss, and shorter length of hospital stay.19
In addition to the reduced risk offered by newer operative techniques, thymectomy has also been shown to have a beneficial effect by allowing the dosage of prednisone to be reduced in MG patients. In a randomized clinical trial conducted by Wolfe and coworkers,20 thymectomy produced improvement in two endpoints after 3 years in patients with nonthymomatous MG: the Quantitative MG Score and a lower average prednisone dosage. Although thymectomy is not a necessary precursor to remission in MG patients, it is still pertinent in reducing the adverse effects of long-term steroid use – providing objective evidence to support thymectomy as a treatment option.
Emerging therapies
Although conventional treatments for MG are well-established, 10% to 20% of MG patients remain refractory to therapeutic intervention.21 These patients are more susceptible to myasthenic crisis, which can result in hospitalization, intubation, and death.21 As mentioned, rescue therapies, including plasmapheresis and IVIg, are imperative to achieve remission of refractory MG, but such remission is unsustainable. Risks associated with these therapies, including contraindications and patient comorbidity, and their limited availability have prevented plasmapheresis and IVIg from being reliable interventions.12
These shortcomings, along with promising results from randomized clinical trials of newer modes of pharmacotherapeutic intervention, have increased interest in new therapies for MG. For example, complement pathway and neonatal Fc receptor (FcRn) inhibitors have recently shown promise in removing pathogenic autoimmune antibodies.18
Efgartigimod. FcRn is of interest in treating generalized MG because of its capacity to recycle and extend the half-life of IgG.22 Efgartigimod is a high-affinity FcRn inhibitor that simultaneously reduces IgG recycling and increases its degradation.22 This therapy is unique: it is highly selective for IgG, whereas other FcRn therapies are nonspecific, causing an undesirable decrease in other immunoglobulin and albumin levels.22 In December 2021, the Food and Drug Administration approved efgartigimod for the treatment of AChR-positive generalized MG.23
Zilucoplan is a subcutaneously administered complement inhibitor that has completed phase 3 clinical trials.18,24 The drug works by inhibiting cleavage of proteins C5a and C5b in the terminal complement complex, a necessary step in forming cytotoxic pores on targeted cells.18,24 Zilucoplan also prevents tissue damage and destruction of signal transmission at the postsynaptic membrane.25 Clinical trials have already established improvement in the Quantitative MG Score and the Myasthenia Gravis Activities of Daily Living Score in patients with generalized MG.18,24
Zilucoplan is similar to eculizumab, but targets a different binding site, allowing for treatment of heterogeneous MG populations who have a mutation in the eculizumab target antigen.26 Additionally, due to specific drug-body interactions, parameters for treatment using zilucoplan are broader than for therapies such as eculizumab. In a Zilucoplan press-release, the complement inhibitor showed statistically significant improvement in the treatment group of generalized, AChR-positive MG patients compared to the placebo group. Tolerability and safety was also a favorable finding in this study. However, a similar rate of treatment-emergent adverse events were recorded between the treatment group (76.7%) and placebo group (70.5%) which could indicate that the clinical application of this treatment is still forthcoming.27 If zilucoplan is approved by the FDA, it will be used earlier in disease progression and for a larger subset of patients.26
Nipocalimab is another immunoglobulin G1, FcRn antibody that reduces IgG levels in blood.27,28 A phase 2 clinical study in patients with AChR-positive or MuSK antibody–associated MG showed that 52% of patients who received nipocalimab had a significant reduction in the Myasthenia Gravis Activities of Daily Living Score 4 weeks after infusion.28 Phase 3 studies for adults with generalized MG are underway and are expected to conclude in April 2026.29
Looking forward
Despite emerging therapies aimed at treating IgG in both refractory and nonrefractory MG, there is still a need for research into biomarkers that further differentiate disease. Developing research into new biomarkers, such as circulating microRNAs, gives insight into the promise of personalized medicine, which can shape the landscape of MG and other disorders.30 As of August 2022, only two clinical trials are slated for investigation into new biomarkers for MG.
Although the treatment of MG might have once been considered stagnant, newer expert consensus and novel research are generating optimism for innovative therapies in coming years.
Mr. van der Eb is a second-year candidate in the master’s of science in applied life sciences program, Keck Graduate Institute, Claremont, Calif.; he has an associate’s degree in natural sciences from Pasadena City College, Calif., and a bachelor’s degree in biological sciences from the University of California, Irvine. Ms. Toruno is a graduate from the master’s of science in applied life sciences program, Keck Graduate Institute; she has a bachelor’s degree in psychology, with a minor in biological sciences, from the University of California, Irvine. Dr. Laird is director of clinical education and professor of practice for the master’s of science in physician assistant studies program, Keck Graduate Institute; he practices clinically in general and thoracic surgery.
References
1. Gilhus NE et al. Myasthenia gravis. Nat Rev Dis Primers. 2019 May 2;5(1):30. doi: 10.1038/s41572-019-0079-y.
2. Gilhus NE, Verschuuren JJ. Myasthenia gravis: Subgroup classification and therapeutic strategies. Lancet Neurol. 2015 Oct;14(10):1023-36. doi: 10.1016/S1474-4422(15)00145-3.
3. Dresser L et al. Myasthenia gravis: Epidemiology, pathophysiology and clinical manifestations. J Clin Med. 2021 May;10(11):2235. doi: 10.3390/jcm10112235.
4. Iyer SR et al. The neuromuscular junction: Roles in aging and neuromuscular disease. Int J Mol Sci. 2021 Jul;22(15):8058. doi: 10.3390/ijms22158058.
5. Hehir MK, Silvestri NJ. Generalized myasthenia gravis: Classification, clinical presentation, natural history, and epidemiology. Neurol Clin. 2018 May;36(2):253-60. doi: 10.1016/j.ncl.2018.01.002.
6. Prüss H. Autoantibodies in neurological disease. Nat Rev Immunol. 2021 Dec;21(12):798-813. doi: 10.1038/s41577-021-00543-w.
7. Drachman DB et al. Myasthenic antibodies cross-link acetylcholine receptors to accelerate degradation. N Engl J Med. 1978 May 18;298(20):1116-22. doi: 10.1056/NEJM197805182982004.
8. Meriggioli MN. Myasthenia gravis with anti-acetylcholine receptor antibodies. Front Neurol Neurosci. 2009;26:94-108. doi: 10.1159/000212371.
9. Zhang HL, Peng HB. Mechanism of acetylcholine receptor cluster formation induced by DC electric field. PLoS One. 2011;6(10):e26805. doi: 10.1371/journal.pone.0026805.
10. Fichtner ML et al. Autoimmune pathology in myasthenia gravis disease subtypes is governed by divergent mechanisms of immunopathology. Front Immunol. 2020 May 27;11:776. doi: 10.3389/fimmu.2020.00776.
11. Tzartos JS et al. LRP4 antibodies in serum and CSF from amyotrophic lateral sclerosis patients. Ann Clin Transl Neurol. 2014 Feb;1(2):80-87. doi: 10.1002/acn3.26.
12. Narayanaswami P et al. International consensus guidance for management of myasthenia gravis: 2020 update. Neurology. 2021;96(3):114-22. doi: 10.1212/WNL.0000000000011124.
13. Cortés-Vicente E et al. Myasthenia gravis treatment updates. Curr Treat Options Neurol. 2020 Jul 15;22(8):24. doi: 10.1007/s11940-020-00632-6.
14. Tannemaat MR, Verschuuren JJGM. Emerging therapies for autoimmune myasthenia gravis: Towards treatment without corticosteroids. Neuromuscul Disord. 2020 Feb;30(2):111-9. doi: 10.1016/j.nmd.2019.12.003.
15. Silvestri NJ, Wolfe GI. Treatment-refractory myasthenia gravis. J Clin Neuromuscul Dis. 2014 Jun;15(4):167-78. doi: 10.1097/CND.0000000000000034.
16. Sanders DB et al. International consensus guidance for management of myasthenia gravis: Executive summary. Neurology. 2016 Jul 26;87(4):419-25. doi: 10.1212/WNL.0000000000002790.
17. Evoli A, Meacci E. An update on thymectomy in myasthenia gravis. Expert Rev Neurother. 2019 Sep;19(9):823-33. doi: 10.1080/14737175.2019.1600404.
18. Habib AA et al. Update on immune-mediated therapies for myasthenia gravis. Muscle Nerve. 2020 Nov;62(5):579-92. doi: 10.1002/mus.26919.
19. O’Sullivan KE et al. A systematic review of robotic versus open and video assisted thoracoscopic surgery (VATS) approaches for thymectomy. Ann Cardiothorac Surg. 2019 Mar;8(2):174-93. doi: 10.21037/acs.2019.02.04.
20. Wolfe GI et al; MGTX Study Group. Randomized trial of thymectomy in myasthenia gravis. N Engl J Med. 2016;375(6):511-22. doi: 10.1056/NEJMoa1602489.
21. Schneider-Gold C et al. Understanding the burden of refractory myasthenia gravis. Ther Adv Neurol Disord. 2019 Mar 1;12:1756286419832242. doi: 10.1177/1756286419832242.
22. Howard JF Jr et al; . Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT): A multicentre, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2021 Jul;20(7):526-36. doi: 10.1016/S1474-4422(21)00159-9.
23. U.S. Food and Drug Administration. FDA approves new treatment for myasthenia gravis. News release. Dec 17, 2021. Accessed Feb 21, 2022. http://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-myasthenia-gravis.
24. Ra Pharmaceuticals. A phase 3, multicenter, randomized, double blind, placebo-controlled study to confirm the safety, tolerability, and efficacy of zilucoplan in subjects with generalized myasthenia gravis. ClinicalTrials.gov Identifier: NCT04115293. Updated Jan 28, 2022. Accessed Feb 21, 2022. https://clinicaltrials.gov/ct2/show/NCT04115293.
25. Howard JF Jr et al. Zilucoplan: An investigational complement C5 inhibitor for the treatment of acetylcholine receptor autoantibody–positive generalized myasthenia gravis. Expert Opin Investig Drugs. 2021 May;30(5):483-93. doi: 10.1080/13543784.2021.1897567.
26. Albazli K et al. Complement inhibitor therapy for myasthenia gravis. Front Immunol. 2020 Jun 3;11:917. doi: 10.3389/fimmu.2020.00917.
27. UCB announces positive Phase 3 results for rozanolixizumab in generalized myasthenia gravis. UCB press release. December 10. 2021. Accessed August 15, 2022. https://www.ucb.com/stories-media/Press-Releases/article/UCB-announces-positive-Phase-3-results-for-rozanolixizumab-in-generalized-myasthenia-gravis.
28. Keller CW et al. Fc-receptor targeted therapies for the treatment of myasthenia gravis. Int J Mol Sci. 2021 May;22(11):5755. doi: 10.3390/ijms22115755.
29. Janssen Research & Development LLC. Phase 3, multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of nipocalimab administered to adults with generalized myasthenia gravis. ClinicalTrials.gov Identifier: NCT04951622. Updated Feb 17, 2022. Accessed Feb 21, 2022. https://clinicaltrials.gov/ct2/show/NCT04951622.
30. Sabre L et al. Circulating miRNAs as potential biomarkers in myasthenia gravis: Tools for personalized medicine. Front Immunol. 2020 Mar 4;11:213. doi: 10.3389/fimmu.2020.00213.
The term myasthenia gravis (MG), from the Latin “grave muscle weakness,” denotes the rare autoimmune disorder characterized by dysfunction at the neuromuscular junction.1 The clinical presentation of the disease is variable but most often includes ocular symptoms, such as ptosis and diplopia, bulbar weakness, and muscle fatigue upon exertion.2,3 Severe symptoms can lead to myasthenic crisis, in which generalized weakness can affect respiratory muscles, leading to possible intubation or death.2,3
Onset of disease ranges from childhood to late adulthood, and largely depends on the subgroup of disease and the age of the patient.4 Although complications from MG can arise, treatment methods have considerably reduced the risk of MG-associated mortality, with the current rate estimated to be 0.06 to 0.89 deaths for every 1 million person-years (that is, approximately 5% of cases).3,5
Pathophysiology
MG is caused by binding of autoimmune antibodies to postsynaptic receptors and by molecules that prevent signal transduction at the muscle endplate.2,4,6,7 The main culprit behind the pathology (in approximately 85% of cases) is an autoimmune antibody for the acetylcholine receptor (AChR); however, other offending antibodies – against muscle-specific serine kinases (MuSK), low-density lipoprotein receptor-related protein 4 (LRP4), and the proteoglycan agrin – are known, although at a lower frequency (in approximately 15% of cases).4,8 These antibodies prevent signal transmission by blocking, destroying, or disrupting the clustering of AChR at the muscle endplate, a necessary step in formation of the neuromuscular junction.4,8,9
The activity of these antibodies is key to understanding the importance of subgrouping the types of MG on the basis of antigen-specific autoimmune interactions. Specifically, the four categories of disease following a diagnosis of MG2,7 are:
- AChR antibody-positive.
- MuSK antibody-positive.
- LRP4 antibody-positive.
- Seronegative MG.
Classifying MG into subgroups gives insight into the functional expectations and potential treatment options for a given patient, although expectations can vary.2
Regrettably, the well-understood pathophysiology, diagnosis, and prognosis of MG have limited investigation and development of new therapies. Additionally, mainstay treatments, such as thymectomy and prednisone, work to alleviate symptoms for most patients, and have also contributed to periods of slowed research and development. However, treatment of refractory MG has, in recent years, become the subject of research on new therapeutic options, aimed at treating heterogeneous disease populations.10
In this review, we discuss the diagnosis of, and treatment options for, MG, and provide an update on promising options in the therapeutic pipeline.
Diagnosis
Distinguishing MG from other neuromuscular junction disorders is a pertinent step before treatment. Although the biomarkers discussed in this section are sensitive for making a diagnosis of MG, additional research is needed to classify seronegative patients who do not have circulating autoantibodies that are pathognomonic for MG.11
Upon clinical examination of observable myasthenic weakness, next steps would require assays for anti-AChR and anti-MuSK.1 If either of those tests are inconclusive, assays for anti-LRP4 are available (although the LRP4 antibody is also a marker in other neurological disorders).12
In the MG diagnostic algorithm, next steps include an electromyography repetitive stimulation test, which, if inconclusive, is followed by single-fiber electromyography.1 If any of these tests return positive, computed tomography or magnetic resonance imaging is necessary for thymus screening.
What follows this diagnostic schema is pharmacotherapeutic or surgical intervention to reduce, or even eliminate, symptoms of MG.1
Consensus on treatment standards
A quantitative assessment of best options for treating MG was conducted by leading experts,13 who reached consensus that primary outcomes in treating MG are reached when a patient presents without symptoms or limitations on daily activities; or has only slight weakness or fatigue in some muscles.13
Pyridostigmine, an acetylcholinesterase inhibitor, is recommended as part of the initial treatment plan for MG patients. Pyridostigmine prevents normal breakdown of acetylcholine, thus increasing acetylcholine levels and allowing signal transmission at the neuromuscular junction.14 Not all patients reach the aforementioned treatment goals when taking pyridostigmine, however; some require corticosteroids or immunosuppressive agents, or both, in addition.
Steroids, such as prednisone and prednisolone, occupy the second line in MG patients because of their ability to produce a rapid response, availability, and economy.1,15 Initial dosages of these medications are gradually adjusted to a maintenance dosage and schedule, as tolerated, to maintain control of symptoms.15
In MG patients who are in respiratory crisis, it is recommended that high-dosage prednisone be given in conjunction with plasmapheresis or intravenous immunoglobulin (IVIg).15 When the response to steroids is inadequate, adverse effects cannot be tolerated, or the patient experiences symptomatic relapse, nonsteroidal immunosuppressive agents are started.
Immunosuppressives are used to weaken the immune response or block production of self-antibodies. Several agents have been identified for use in MG, including azathioprine and mycophenolate mofetil; their use is limited, however, by a lack of supporting evidence from randomized clinical trials or the potential for serious adverse effects.13
Referral and specialized treatments. Patients who are refractory to all the aforementioned treatments should be referred to a physician who is expert in the management of MG. At this point, treatment guidelines recommend chronic IVIg infusion or plasmapheresis, which removes complement, cytokines, and antibodies from the blood.14 Additionally, monoclonal antibody therapies, such as eculizumab, have been shown to have efficacy in severe, refractory AChR antibody–positive generalized MG.16
Thymectomy has been a mainstay and, sometimes, first-line treatment of MG for nearly 80 years.15 The thymus has largely been implicated in the immunopathology of AChR-positive MG. Models suggest that increased expression of inflammatory factors causes an imbalance among immune cells, resulting in lymphofollicular hyperplasia or thymoma.17
Despite the growing body of evidence implicating the thymus in the progression of MG, some patients and physicians are reluctant to proceed with surgical intervention. This could be due to a disparity in surgical treatment options offered by surgeons, and facilities, with varying experience or ability to conduct newer techniques. Minimally invasive approaches, such as video-assisted thoracoscopic surgery and robotic thymectomy, have been found to be superior to traditional open surgical techniques.18,19 Minimally invasive techniques result in significantly fewer postoperative complications, less blood loss, and shorter length of hospital stay.19
In addition to the reduced risk offered by newer operative techniques, thymectomy has also been shown to have a beneficial effect by allowing the dosage of prednisone to be reduced in MG patients. In a randomized clinical trial conducted by Wolfe and coworkers,20 thymectomy produced improvement in two endpoints after 3 years in patients with nonthymomatous MG: the Quantitative MG Score and a lower average prednisone dosage. Although thymectomy is not a necessary precursor to remission in MG patients, it is still pertinent in reducing the adverse effects of long-term steroid use – providing objective evidence to support thymectomy as a treatment option.
Emerging therapies
Although conventional treatments for MG are well-established, 10% to 20% of MG patients remain refractory to therapeutic intervention.21 These patients are more susceptible to myasthenic crisis, which can result in hospitalization, intubation, and death.21 As mentioned, rescue therapies, including plasmapheresis and IVIg, are imperative to achieve remission of refractory MG, but such remission is unsustainable. Risks associated with these therapies, including contraindications and patient comorbidity, and their limited availability have prevented plasmapheresis and IVIg from being reliable interventions.12
These shortcomings, along with promising results from randomized clinical trials of newer modes of pharmacotherapeutic intervention, have increased interest in new therapies for MG. For example, complement pathway and neonatal Fc receptor (FcRn) inhibitors have recently shown promise in removing pathogenic autoimmune antibodies.18
Efgartigimod. FcRn is of interest in treating generalized MG because of its capacity to recycle and extend the half-life of IgG.22 Efgartigimod is a high-affinity FcRn inhibitor that simultaneously reduces IgG recycling and increases its degradation.22 This therapy is unique: it is highly selective for IgG, whereas other FcRn therapies are nonspecific, causing an undesirable decrease in other immunoglobulin and albumin levels.22 In December 2021, the Food and Drug Administration approved efgartigimod for the treatment of AChR-positive generalized MG.23
Zilucoplan is a subcutaneously administered complement inhibitor that has completed phase 3 clinical trials.18,24 The drug works by inhibiting cleavage of proteins C5a and C5b in the terminal complement complex, a necessary step in forming cytotoxic pores on targeted cells.18,24 Zilucoplan also prevents tissue damage and destruction of signal transmission at the postsynaptic membrane.25 Clinical trials have already established improvement in the Quantitative MG Score and the Myasthenia Gravis Activities of Daily Living Score in patients with generalized MG.18,24
Zilucoplan is similar to eculizumab, but targets a different binding site, allowing for treatment of heterogeneous MG populations who have a mutation in the eculizumab target antigen.26 Additionally, due to specific drug-body interactions, parameters for treatment using zilucoplan are broader than for therapies such as eculizumab. In a Zilucoplan press-release, the complement inhibitor showed statistically significant improvement in the treatment group of generalized, AChR-positive MG patients compared to the placebo group. Tolerability and safety was also a favorable finding in this study. However, a similar rate of treatment-emergent adverse events were recorded between the treatment group (76.7%) and placebo group (70.5%) which could indicate that the clinical application of this treatment is still forthcoming.27 If zilucoplan is approved by the FDA, it will be used earlier in disease progression and for a larger subset of patients.26
Nipocalimab is another immunoglobulin G1, FcRn antibody that reduces IgG levels in blood.27,28 A phase 2 clinical study in patients with AChR-positive or MuSK antibody–associated MG showed that 52% of patients who received nipocalimab had a significant reduction in the Myasthenia Gravis Activities of Daily Living Score 4 weeks after infusion.28 Phase 3 studies for adults with generalized MG are underway and are expected to conclude in April 2026.29
Looking forward
Despite emerging therapies aimed at treating IgG in both refractory and nonrefractory MG, there is still a need for research into biomarkers that further differentiate disease. Developing research into new biomarkers, such as circulating microRNAs, gives insight into the promise of personalized medicine, which can shape the landscape of MG and other disorders.30 As of August 2022, only two clinical trials are slated for investigation into new biomarkers for MG.
Although the treatment of MG might have once been considered stagnant, newer expert consensus and novel research are generating optimism for innovative therapies in coming years.
Mr. van der Eb is a second-year candidate in the master’s of science in applied life sciences program, Keck Graduate Institute, Claremont, Calif.; he has an associate’s degree in natural sciences from Pasadena City College, Calif., and a bachelor’s degree in biological sciences from the University of California, Irvine. Ms. Toruno is a graduate from the master’s of science in applied life sciences program, Keck Graduate Institute; she has a bachelor’s degree in psychology, with a minor in biological sciences, from the University of California, Irvine. Dr. Laird is director of clinical education and professor of practice for the master’s of science in physician assistant studies program, Keck Graduate Institute; he practices clinically in general and thoracic surgery.
References
1. Gilhus NE et al. Myasthenia gravis. Nat Rev Dis Primers. 2019 May 2;5(1):30. doi: 10.1038/s41572-019-0079-y.
2. Gilhus NE, Verschuuren JJ. Myasthenia gravis: Subgroup classification and therapeutic strategies. Lancet Neurol. 2015 Oct;14(10):1023-36. doi: 10.1016/S1474-4422(15)00145-3.
3. Dresser L et al. Myasthenia gravis: Epidemiology, pathophysiology and clinical manifestations. J Clin Med. 2021 May;10(11):2235. doi: 10.3390/jcm10112235.
4. Iyer SR et al. The neuromuscular junction: Roles in aging and neuromuscular disease. Int J Mol Sci. 2021 Jul;22(15):8058. doi: 10.3390/ijms22158058.
5. Hehir MK, Silvestri NJ. Generalized myasthenia gravis: Classification, clinical presentation, natural history, and epidemiology. Neurol Clin. 2018 May;36(2):253-60. doi: 10.1016/j.ncl.2018.01.002.
6. Prüss H. Autoantibodies in neurological disease. Nat Rev Immunol. 2021 Dec;21(12):798-813. doi: 10.1038/s41577-021-00543-w.
7. Drachman DB et al. Myasthenic antibodies cross-link acetylcholine receptors to accelerate degradation. N Engl J Med. 1978 May 18;298(20):1116-22. doi: 10.1056/NEJM197805182982004.
8. Meriggioli MN. Myasthenia gravis with anti-acetylcholine receptor antibodies. Front Neurol Neurosci. 2009;26:94-108. doi: 10.1159/000212371.
9. Zhang HL, Peng HB. Mechanism of acetylcholine receptor cluster formation induced by DC electric field. PLoS One. 2011;6(10):e26805. doi: 10.1371/journal.pone.0026805.
10. Fichtner ML et al. Autoimmune pathology in myasthenia gravis disease subtypes is governed by divergent mechanisms of immunopathology. Front Immunol. 2020 May 27;11:776. doi: 10.3389/fimmu.2020.00776.
11. Tzartos JS et al. LRP4 antibodies in serum and CSF from amyotrophic lateral sclerosis patients. Ann Clin Transl Neurol. 2014 Feb;1(2):80-87. doi: 10.1002/acn3.26.
12. Narayanaswami P et al. International consensus guidance for management of myasthenia gravis: 2020 update. Neurology. 2021;96(3):114-22. doi: 10.1212/WNL.0000000000011124.
13. Cortés-Vicente E et al. Myasthenia gravis treatment updates. Curr Treat Options Neurol. 2020 Jul 15;22(8):24. doi: 10.1007/s11940-020-00632-6.
14. Tannemaat MR, Verschuuren JJGM. Emerging therapies for autoimmune myasthenia gravis: Towards treatment without corticosteroids. Neuromuscul Disord. 2020 Feb;30(2):111-9. doi: 10.1016/j.nmd.2019.12.003.
15. Silvestri NJ, Wolfe GI. Treatment-refractory myasthenia gravis. J Clin Neuromuscul Dis. 2014 Jun;15(4):167-78. doi: 10.1097/CND.0000000000000034.
16. Sanders DB et al. International consensus guidance for management of myasthenia gravis: Executive summary. Neurology. 2016 Jul 26;87(4):419-25. doi: 10.1212/WNL.0000000000002790.
17. Evoli A, Meacci E. An update on thymectomy in myasthenia gravis. Expert Rev Neurother. 2019 Sep;19(9):823-33. doi: 10.1080/14737175.2019.1600404.
18. Habib AA et al. Update on immune-mediated therapies for myasthenia gravis. Muscle Nerve. 2020 Nov;62(5):579-92. doi: 10.1002/mus.26919.
19. O’Sullivan KE et al. A systematic review of robotic versus open and video assisted thoracoscopic surgery (VATS) approaches for thymectomy. Ann Cardiothorac Surg. 2019 Mar;8(2):174-93. doi: 10.21037/acs.2019.02.04.
20. Wolfe GI et al; MGTX Study Group. Randomized trial of thymectomy in myasthenia gravis. N Engl J Med. 2016;375(6):511-22. doi: 10.1056/NEJMoa1602489.
21. Schneider-Gold C et al. Understanding the burden of refractory myasthenia gravis. Ther Adv Neurol Disord. 2019 Mar 1;12:1756286419832242. doi: 10.1177/1756286419832242.
22. Howard JF Jr et al; . Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT): A multicentre, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2021 Jul;20(7):526-36. doi: 10.1016/S1474-4422(21)00159-9.
23. U.S. Food and Drug Administration. FDA approves new treatment for myasthenia gravis. News release. Dec 17, 2021. Accessed Feb 21, 2022. http://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-myasthenia-gravis.
24. Ra Pharmaceuticals. A phase 3, multicenter, randomized, double blind, placebo-controlled study to confirm the safety, tolerability, and efficacy of zilucoplan in subjects with generalized myasthenia gravis. ClinicalTrials.gov Identifier: NCT04115293. Updated Jan 28, 2022. Accessed Feb 21, 2022. https://clinicaltrials.gov/ct2/show/NCT04115293.
25. Howard JF Jr et al. Zilucoplan: An investigational complement C5 inhibitor for the treatment of acetylcholine receptor autoantibody–positive generalized myasthenia gravis. Expert Opin Investig Drugs. 2021 May;30(5):483-93. doi: 10.1080/13543784.2021.1897567.
26. Albazli K et al. Complement inhibitor therapy for myasthenia gravis. Front Immunol. 2020 Jun 3;11:917. doi: 10.3389/fimmu.2020.00917.
27. UCB announces positive Phase 3 results for rozanolixizumab in generalized myasthenia gravis. UCB press release. December 10. 2021. Accessed August 15, 2022. https://www.ucb.com/stories-media/Press-Releases/article/UCB-announces-positive-Phase-3-results-for-rozanolixizumab-in-generalized-myasthenia-gravis.
28. Keller CW et al. Fc-receptor targeted therapies for the treatment of myasthenia gravis. Int J Mol Sci. 2021 May;22(11):5755. doi: 10.3390/ijms22115755.
29. Janssen Research & Development LLC. Phase 3, multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of nipocalimab administered to adults with generalized myasthenia gravis. ClinicalTrials.gov Identifier: NCT04951622. Updated Feb 17, 2022. Accessed Feb 21, 2022. https://clinicaltrials.gov/ct2/show/NCT04951622.
30. Sabre L et al. Circulating miRNAs as potential biomarkers in myasthenia gravis: Tools for personalized medicine. Front Immunol. 2020 Mar 4;11:213. doi: 10.3389/fimmu.2020.00213.
The term myasthenia gravis (MG), from the Latin “grave muscle weakness,” denotes the rare autoimmune disorder characterized by dysfunction at the neuromuscular junction.1 The clinical presentation of the disease is variable but most often includes ocular symptoms, such as ptosis and diplopia, bulbar weakness, and muscle fatigue upon exertion.2,3 Severe symptoms can lead to myasthenic crisis, in which generalized weakness can affect respiratory muscles, leading to possible intubation or death.2,3
Onset of disease ranges from childhood to late adulthood, and largely depends on the subgroup of disease and the age of the patient.4 Although complications from MG can arise, treatment methods have considerably reduced the risk of MG-associated mortality, with the current rate estimated to be 0.06 to 0.89 deaths for every 1 million person-years (that is, approximately 5% of cases).3,5
Pathophysiology
MG is caused by binding of autoimmune antibodies to postsynaptic receptors and by molecules that prevent signal transduction at the muscle endplate.2,4,6,7 The main culprit behind the pathology (in approximately 85% of cases) is an autoimmune antibody for the acetylcholine receptor (AChR); however, other offending antibodies – against muscle-specific serine kinases (MuSK), low-density lipoprotein receptor-related protein 4 (LRP4), and the proteoglycan agrin – are known, although at a lower frequency (in approximately 15% of cases).4,8 These antibodies prevent signal transmission by blocking, destroying, or disrupting the clustering of AChR at the muscle endplate, a necessary step in formation of the neuromuscular junction.4,8,9
The activity of these antibodies is key to understanding the importance of subgrouping the types of MG on the basis of antigen-specific autoimmune interactions. Specifically, the four categories of disease following a diagnosis of MG2,7 are:
- AChR antibody-positive.
- MuSK antibody-positive.
- LRP4 antibody-positive.
- Seronegative MG.
Classifying MG into subgroups gives insight into the functional expectations and potential treatment options for a given patient, although expectations can vary.2
Regrettably, the well-understood pathophysiology, diagnosis, and prognosis of MG have limited investigation and development of new therapies. Additionally, mainstay treatments, such as thymectomy and prednisone, work to alleviate symptoms for most patients, and have also contributed to periods of slowed research and development. However, treatment of refractory MG has, in recent years, become the subject of research on new therapeutic options, aimed at treating heterogeneous disease populations.10
In this review, we discuss the diagnosis of, and treatment options for, MG, and provide an update on promising options in the therapeutic pipeline.
Diagnosis
Distinguishing MG from other neuromuscular junction disorders is a pertinent step before treatment. Although the biomarkers discussed in this section are sensitive for making a diagnosis of MG, additional research is needed to classify seronegative patients who do not have circulating autoantibodies that are pathognomonic for MG.11
Upon clinical examination of observable myasthenic weakness, next steps would require assays for anti-AChR and anti-MuSK.1 If either of those tests are inconclusive, assays for anti-LRP4 are available (although the LRP4 antibody is also a marker in other neurological disorders).12
In the MG diagnostic algorithm, next steps include an electromyography repetitive stimulation test, which, if inconclusive, is followed by single-fiber electromyography.1 If any of these tests return positive, computed tomography or magnetic resonance imaging is necessary for thymus screening.
What follows this diagnostic schema is pharmacotherapeutic or surgical intervention to reduce, or even eliminate, symptoms of MG.1
Consensus on treatment standards
A quantitative assessment of best options for treating MG was conducted by leading experts,13 who reached consensus that primary outcomes in treating MG are reached when a patient presents without symptoms or limitations on daily activities; or has only slight weakness or fatigue in some muscles.13
Pyridostigmine, an acetylcholinesterase inhibitor, is recommended as part of the initial treatment plan for MG patients. Pyridostigmine prevents normal breakdown of acetylcholine, thus increasing acetylcholine levels and allowing signal transmission at the neuromuscular junction.14 Not all patients reach the aforementioned treatment goals when taking pyridostigmine, however; some require corticosteroids or immunosuppressive agents, or both, in addition.
Steroids, such as prednisone and prednisolone, occupy the second line in MG patients because of their ability to produce a rapid response, availability, and economy.1,15 Initial dosages of these medications are gradually adjusted to a maintenance dosage and schedule, as tolerated, to maintain control of symptoms.15
In MG patients who are in respiratory crisis, it is recommended that high-dosage prednisone be given in conjunction with plasmapheresis or intravenous immunoglobulin (IVIg).15 When the response to steroids is inadequate, adverse effects cannot be tolerated, or the patient experiences symptomatic relapse, nonsteroidal immunosuppressive agents are started.
Immunosuppressives are used to weaken the immune response or block production of self-antibodies. Several agents have been identified for use in MG, including azathioprine and mycophenolate mofetil; their use is limited, however, by a lack of supporting evidence from randomized clinical trials or the potential for serious adverse effects.13
Referral and specialized treatments. Patients who are refractory to all the aforementioned treatments should be referred to a physician who is expert in the management of MG. At this point, treatment guidelines recommend chronic IVIg infusion or plasmapheresis, which removes complement, cytokines, and antibodies from the blood.14 Additionally, monoclonal antibody therapies, such as eculizumab, have been shown to have efficacy in severe, refractory AChR antibody–positive generalized MG.16
Thymectomy has been a mainstay and, sometimes, first-line treatment of MG for nearly 80 years.15 The thymus has largely been implicated in the immunopathology of AChR-positive MG. Models suggest that increased expression of inflammatory factors causes an imbalance among immune cells, resulting in lymphofollicular hyperplasia or thymoma.17
Despite the growing body of evidence implicating the thymus in the progression of MG, some patients and physicians are reluctant to proceed with surgical intervention. This could be due to a disparity in surgical treatment options offered by surgeons, and facilities, with varying experience or ability to conduct newer techniques. Minimally invasive approaches, such as video-assisted thoracoscopic surgery and robotic thymectomy, have been found to be superior to traditional open surgical techniques.18,19 Minimally invasive techniques result in significantly fewer postoperative complications, less blood loss, and shorter length of hospital stay.19
In addition to the reduced risk offered by newer operative techniques, thymectomy has also been shown to have a beneficial effect by allowing the dosage of prednisone to be reduced in MG patients. In a randomized clinical trial conducted by Wolfe and coworkers,20 thymectomy produced improvement in two endpoints after 3 years in patients with nonthymomatous MG: the Quantitative MG Score and a lower average prednisone dosage. Although thymectomy is not a necessary precursor to remission in MG patients, it is still pertinent in reducing the adverse effects of long-term steroid use – providing objective evidence to support thymectomy as a treatment option.
Emerging therapies
Although conventional treatments for MG are well-established, 10% to 20% of MG patients remain refractory to therapeutic intervention.21 These patients are more susceptible to myasthenic crisis, which can result in hospitalization, intubation, and death.21 As mentioned, rescue therapies, including plasmapheresis and IVIg, are imperative to achieve remission of refractory MG, but such remission is unsustainable. Risks associated with these therapies, including contraindications and patient comorbidity, and their limited availability have prevented plasmapheresis and IVIg from being reliable interventions.12
These shortcomings, along with promising results from randomized clinical trials of newer modes of pharmacotherapeutic intervention, have increased interest in new therapies for MG. For example, complement pathway and neonatal Fc receptor (FcRn) inhibitors have recently shown promise in removing pathogenic autoimmune antibodies.18
Efgartigimod. FcRn is of interest in treating generalized MG because of its capacity to recycle and extend the half-life of IgG.22 Efgartigimod is a high-affinity FcRn inhibitor that simultaneously reduces IgG recycling and increases its degradation.22 This therapy is unique: it is highly selective for IgG, whereas other FcRn therapies are nonspecific, causing an undesirable decrease in other immunoglobulin and albumin levels.22 In December 2021, the Food and Drug Administration approved efgartigimod for the treatment of AChR-positive generalized MG.23
Zilucoplan is a subcutaneously administered complement inhibitor that has completed phase 3 clinical trials.18,24 The drug works by inhibiting cleavage of proteins C5a and C5b in the terminal complement complex, a necessary step in forming cytotoxic pores on targeted cells.18,24 Zilucoplan also prevents tissue damage and destruction of signal transmission at the postsynaptic membrane.25 Clinical trials have already established improvement in the Quantitative MG Score and the Myasthenia Gravis Activities of Daily Living Score in patients with generalized MG.18,24
Zilucoplan is similar to eculizumab, but targets a different binding site, allowing for treatment of heterogeneous MG populations who have a mutation in the eculizumab target antigen.26 Additionally, due to specific drug-body interactions, parameters for treatment using zilucoplan are broader than for therapies such as eculizumab. In a Zilucoplan press-release, the complement inhibitor showed statistically significant improvement in the treatment group of generalized, AChR-positive MG patients compared to the placebo group. Tolerability and safety was also a favorable finding in this study. However, a similar rate of treatment-emergent adverse events were recorded between the treatment group (76.7%) and placebo group (70.5%) which could indicate that the clinical application of this treatment is still forthcoming.27 If zilucoplan is approved by the FDA, it will be used earlier in disease progression and for a larger subset of patients.26
Nipocalimab is another immunoglobulin G1, FcRn antibody that reduces IgG levels in blood.27,28 A phase 2 clinical study in patients with AChR-positive or MuSK antibody–associated MG showed that 52% of patients who received nipocalimab had a significant reduction in the Myasthenia Gravis Activities of Daily Living Score 4 weeks after infusion.28 Phase 3 studies for adults with generalized MG are underway and are expected to conclude in April 2026.29
Looking forward
Despite emerging therapies aimed at treating IgG in both refractory and nonrefractory MG, there is still a need for research into biomarkers that further differentiate disease. Developing research into new biomarkers, such as circulating microRNAs, gives insight into the promise of personalized medicine, which can shape the landscape of MG and other disorders.30 As of August 2022, only two clinical trials are slated for investigation into new biomarkers for MG.
Although the treatment of MG might have once been considered stagnant, newer expert consensus and novel research are generating optimism for innovative therapies in coming years.
Mr. van der Eb is a second-year candidate in the master’s of science in applied life sciences program, Keck Graduate Institute, Claremont, Calif.; he has an associate’s degree in natural sciences from Pasadena City College, Calif., and a bachelor’s degree in biological sciences from the University of California, Irvine. Ms. Toruno is a graduate from the master’s of science in applied life sciences program, Keck Graduate Institute; she has a bachelor’s degree in psychology, with a minor in biological sciences, from the University of California, Irvine. Dr. Laird is director of clinical education and professor of practice for the master’s of science in physician assistant studies program, Keck Graduate Institute; he practices clinically in general and thoracic surgery.
References
1. Gilhus NE et al. Myasthenia gravis. Nat Rev Dis Primers. 2019 May 2;5(1):30. doi: 10.1038/s41572-019-0079-y.
2. Gilhus NE, Verschuuren JJ. Myasthenia gravis: Subgroup classification and therapeutic strategies. Lancet Neurol. 2015 Oct;14(10):1023-36. doi: 10.1016/S1474-4422(15)00145-3.
3. Dresser L et al. Myasthenia gravis: Epidemiology, pathophysiology and clinical manifestations. J Clin Med. 2021 May;10(11):2235. doi: 10.3390/jcm10112235.
4. Iyer SR et al. The neuromuscular junction: Roles in aging and neuromuscular disease. Int J Mol Sci. 2021 Jul;22(15):8058. doi: 10.3390/ijms22158058.
5. Hehir MK, Silvestri NJ. Generalized myasthenia gravis: Classification, clinical presentation, natural history, and epidemiology. Neurol Clin. 2018 May;36(2):253-60. doi: 10.1016/j.ncl.2018.01.002.
6. Prüss H. Autoantibodies in neurological disease. Nat Rev Immunol. 2021 Dec;21(12):798-813. doi: 10.1038/s41577-021-00543-w.
7. Drachman DB et al. Myasthenic antibodies cross-link acetylcholine receptors to accelerate degradation. N Engl J Med. 1978 May 18;298(20):1116-22. doi: 10.1056/NEJM197805182982004.
8. Meriggioli MN. Myasthenia gravis with anti-acetylcholine receptor antibodies. Front Neurol Neurosci. 2009;26:94-108. doi: 10.1159/000212371.
9. Zhang HL, Peng HB. Mechanism of acetylcholine receptor cluster formation induced by DC electric field. PLoS One. 2011;6(10):e26805. doi: 10.1371/journal.pone.0026805.
10. Fichtner ML et al. Autoimmune pathology in myasthenia gravis disease subtypes is governed by divergent mechanisms of immunopathology. Front Immunol. 2020 May 27;11:776. doi: 10.3389/fimmu.2020.00776.
11. Tzartos JS et al. LRP4 antibodies in serum and CSF from amyotrophic lateral sclerosis patients. Ann Clin Transl Neurol. 2014 Feb;1(2):80-87. doi: 10.1002/acn3.26.
12. Narayanaswami P et al. International consensus guidance for management of myasthenia gravis: 2020 update. Neurology. 2021;96(3):114-22. doi: 10.1212/WNL.0000000000011124.
13. Cortés-Vicente E et al. Myasthenia gravis treatment updates. Curr Treat Options Neurol. 2020 Jul 15;22(8):24. doi: 10.1007/s11940-020-00632-6.
14. Tannemaat MR, Verschuuren JJGM. Emerging therapies for autoimmune myasthenia gravis: Towards treatment without corticosteroids. Neuromuscul Disord. 2020 Feb;30(2):111-9. doi: 10.1016/j.nmd.2019.12.003.
15. Silvestri NJ, Wolfe GI. Treatment-refractory myasthenia gravis. J Clin Neuromuscul Dis. 2014 Jun;15(4):167-78. doi: 10.1097/CND.0000000000000034.
16. Sanders DB et al. International consensus guidance for management of myasthenia gravis: Executive summary. Neurology. 2016 Jul 26;87(4):419-25. doi: 10.1212/WNL.0000000000002790.
17. Evoli A, Meacci E. An update on thymectomy in myasthenia gravis. Expert Rev Neurother. 2019 Sep;19(9):823-33. doi: 10.1080/14737175.2019.1600404.
18. Habib AA et al. Update on immune-mediated therapies for myasthenia gravis. Muscle Nerve. 2020 Nov;62(5):579-92. doi: 10.1002/mus.26919.
19. O’Sullivan KE et al. A systematic review of robotic versus open and video assisted thoracoscopic surgery (VATS) approaches for thymectomy. Ann Cardiothorac Surg. 2019 Mar;8(2):174-93. doi: 10.21037/acs.2019.02.04.
20. Wolfe GI et al; MGTX Study Group. Randomized trial of thymectomy in myasthenia gravis. N Engl J Med. 2016;375(6):511-22. doi: 10.1056/NEJMoa1602489.
21. Schneider-Gold C et al. Understanding the burden of refractory myasthenia gravis. Ther Adv Neurol Disord. 2019 Mar 1;12:1756286419832242. doi: 10.1177/1756286419832242.
22. Howard JF Jr et al; . Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT): A multicentre, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2021 Jul;20(7):526-36. doi: 10.1016/S1474-4422(21)00159-9.
23. U.S. Food and Drug Administration. FDA approves new treatment for myasthenia gravis. News release. Dec 17, 2021. Accessed Feb 21, 2022. http://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-myasthenia-gravis.
24. Ra Pharmaceuticals. A phase 3, multicenter, randomized, double blind, placebo-controlled study to confirm the safety, tolerability, and efficacy of zilucoplan in subjects with generalized myasthenia gravis. ClinicalTrials.gov Identifier: NCT04115293. Updated Jan 28, 2022. Accessed Feb 21, 2022. https://clinicaltrials.gov/ct2/show/NCT04115293.
25. Howard JF Jr et al. Zilucoplan: An investigational complement C5 inhibitor for the treatment of acetylcholine receptor autoantibody–positive generalized myasthenia gravis. Expert Opin Investig Drugs. 2021 May;30(5):483-93. doi: 10.1080/13543784.2021.1897567.
26. Albazli K et al. Complement inhibitor therapy for myasthenia gravis. Front Immunol. 2020 Jun 3;11:917. doi: 10.3389/fimmu.2020.00917.
27. UCB announces positive Phase 3 results for rozanolixizumab in generalized myasthenia gravis. UCB press release. December 10. 2021. Accessed August 15, 2022. https://www.ucb.com/stories-media/Press-Releases/article/UCB-announces-positive-Phase-3-results-for-rozanolixizumab-in-generalized-myasthenia-gravis.
28. Keller CW et al. Fc-receptor targeted therapies for the treatment of myasthenia gravis. Int J Mol Sci. 2021 May;22(11):5755. doi: 10.3390/ijms22115755.
29. Janssen Research & Development LLC. Phase 3, multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of nipocalimab administered to adults with generalized myasthenia gravis. ClinicalTrials.gov Identifier: NCT04951622. Updated Feb 17, 2022. Accessed Feb 21, 2022. https://clinicaltrials.gov/ct2/show/NCT04951622.
30. Sabre L et al. Circulating miRNAs as potential biomarkers in myasthenia gravis: Tools for personalized medicine. Front Immunol. 2020 Mar 4;11:213. doi: 10.3389/fimmu.2020.00213.
