Neurology Reviews

The American Heart Association (AHA) has issued a new scientific statement on the link between heart failure, atrial fibrillation, and coronary heart disease and the increased risk for cognitive impairment and dementia.

The statement includes an extensive research review and offers compelling evidence of the inextricable link between heart health and brain health, which investigators said underscores the benefit of early intervention.

The cumulative evidence “confirms that the trajectories of cardiac health and brain health are inextricably intertwined through modifiable and nonmodifiable factors,” the authors wrote.

Investigators say the findings reinforce the message that addressing cardiovascular health early in life may deter the onset or progression of cognitive impairment later on.

And the earlier this is done, the better, said lead author Fernando D. Testai, MD, PhD, a professor of neurology and the vascular neurology section head, Department of Neurology and Rehabilitation, University of Illinois, Chicago.

The statement was published online in Stroke.
 

Bridging the Research Gap

It’s well known that there’s a bidirectional relationship between heart and brain function. For example, heart failure can lead to decreased blood flow that can damage the brain, and stroke in some areas of the brain can affect the heart.

However, that’s only part of the puzzle and doesn’t address all the gaps in the understanding of how cardiovascular disease contributes to cognition, said Testai.

“What we’re trying to do here is to go one step further and describe other connections between the heart and the brain,” he said.

Investigators carried out an extensive PubMed search for heart failure, atrial fibrillation, and coronary heart disease. Researchers detailed the frequency of each condition, mechanisms by which they might cause cognitive impairment, and prospects for prevention and treatment to maintain brain health.

A recurring theme in the paper is the role of inflammation. Evidence shows there are “remarkable similarities in the inflammatory response that takes place,” with both cardiac disease and cognitive decline, said Testai.

Another potential shared mechanism relates to biomarkers, particularly amyloid, which is strongly linked to Alzheimer’s disease.

“But some studies show amyloid can also be present in the heart, especially in patients who have decreased ejection fraction,” said Testai.
 

Robust Heart-Brain Connection

The statement’s authors collected a substantial amount of evidence showing vascular risk factors such as hypertension and diabetes “can change how the brain processes and clears up amyloid,” Testai added.

The paper also provides a compilation of evidence of shared genetic predispositions when it comes to heart and brain disorders.

“We noticed that some genetic signatures that have historically been associated with heart disease seem to also correlate with structural changes in the brain. That means that at the end of the day, some patients may be born with a genetic predisposition to developing both conditions,” said Testai.

This indicates that the link between the two organs “begins as early as conception” and underscores the importance of adopting healthy lifestyle habits as early as possible, he added.

“That means you can avoid bad habits that eventually lead to hypertension, diabetes, and cholesterol, that eventually will lead to cardiac disease, which eventually will lead to stroke, which eventually will lead to cognitive decline,” Testai noted.

However, cardiovascular health is more complicated than having good genes and adhering to a healthy lifestyle. It’s not clear, for example, why some people who should be predisposed to developing heart disease do not develop it, something Testai refers to as enhanced “resilience.”

For example, Hispanic or Latino patients, who have relatively poor cardiovascular risk factor profiles, seem to be less susceptible to developing cardiac disease.
 

More Research Needed

While genetics may partly explain the paradox, Testai believes other protective factors are at play, including strong social support networks.

Testai referred to the AHA’s “Life’s Essential 8” — the eight components of cardiovascular health. These include a healthy diet, participation in physical activity, nicotine avoidance, healthy sleep, healthy weight, and healthy levels of blood lipids, blood glucose, and blood pressure.

More evidence is needed to show that effective management of cardiac disease positively affects cognition. Currently, cognitive measures are rarely included in studies examining various heart disease treatments, said Testai.

“There should probably be an effort to include brain health outcomes in some of the cardiac literature to make sure we can also measure whether the intervention in the heart leads to an advantage for the brain,” he said.

More research is also needed to determine whether immunomodulation has a beneficial effect on the cognitive trajectory, the statement’s authors noted.

They point out that the interpretation and generalizability of the studies described in the statement are confounded by disparate methodologies, including small sample sizes, cross-sectional designs, and underrepresentation of Black and Hispanic individuals.
 

‘An Important Step’

Reached for a comment, Natalia S. Rost, MD, Chief of the Stroke Division at Massachusetts General Hospital and professor of neurology at Harvard Medical School, both in Boston, said this paper “is an important step” in terms of pulling together pertinent information on the topic of heart-brain health.

She praised the authors for gathering evidence on risk factors related to atrial fibrillation, heart failure, and coronary heart disease, which is “the part of the puzzle that is controllable.”

This helps reinforce the message that controlling vascular risk factors helps with brain health, said Rost.

But brain health is “much more complex than just vascular health,” she said. It includes other elements such as freedom from epilepsy, migraine, traumatic brain injury, and adult learning disabilities.

No relevant conflicts of interest were disclosed.

A version of this article first appeared on Medscape.com.

The American Heart Association (AHA) has issued a new scientific statement on the link between heart failure, atrial fibrillation, and coronary heart disease and the increased risk for cognitive impairment and dementia.

The statement includes an extensive research review and offers compelling evidence of the inextricable link between heart health and brain health, which investigators said underscores the benefit of early intervention.

The cumulative evidence “confirms that the trajectories of cardiac health and brain health are inextricably intertwined through modifiable and nonmodifiable factors,” the authors wrote.

Investigators say the findings reinforce the message that addressing cardiovascular health early in life may deter the onset or progression of cognitive impairment later on.

And the earlier this is done, the better, said lead author Fernando D. Testai, MD, PhD, a professor of neurology and the vascular neurology section head, Department of Neurology and Rehabilitation, University of Illinois, Chicago.

The statement was published online in Stroke.
 

Bridging the Research Gap

It’s well known that there’s a bidirectional relationship between heart and brain function. For example, heart failure can lead to decreased blood flow that can damage the brain, and stroke in some areas of the brain can affect the heart.

However, that’s only part of the puzzle and doesn’t address all the gaps in the understanding of how cardiovascular disease contributes to cognition, said Testai.

“What we’re trying to do here is to go one step further and describe other connections between the heart and the brain,” he said.

Investigators carried out an extensive PubMed search for heart failure, atrial fibrillation, and coronary heart disease. Researchers detailed the frequency of each condition, mechanisms by which they might cause cognitive impairment, and prospects for prevention and treatment to maintain brain health.

A recurring theme in the paper is the role of inflammation. Evidence shows there are “remarkable similarities in the inflammatory response that takes place,” with both cardiac disease and cognitive decline, said Testai.

Another potential shared mechanism relates to biomarkers, particularly amyloid, which is strongly linked to Alzheimer’s disease.

“But some studies show amyloid can also be present in the heart, especially in patients who have decreased ejection fraction,” said Testai.
 

Robust Heart-Brain Connection

The statement’s authors collected a substantial amount of evidence showing vascular risk factors such as hypertension and diabetes “can change how the brain processes and clears up amyloid,” Testai added.

The paper also provides a compilation of evidence of shared genetic predispositions when it comes to heart and brain disorders.

“We noticed that some genetic signatures that have historically been associated with heart disease seem to also correlate with structural changes in the brain. That means that at the end of the day, some patients may be born with a genetic predisposition to developing both conditions,” said Testai.

This indicates that the link between the two organs “begins as early as conception” and underscores the importance of adopting healthy lifestyle habits as early as possible, he added.

“That means you can avoid bad habits that eventually lead to hypertension, diabetes, and cholesterol, that eventually will lead to cardiac disease, which eventually will lead to stroke, which eventually will lead to cognitive decline,” Testai noted.

However, cardiovascular health is more complicated than having good genes and adhering to a healthy lifestyle. It’s not clear, for example, why some people who should be predisposed to developing heart disease do not develop it, something Testai refers to as enhanced “resilience.”

For example, Hispanic or Latino patients, who have relatively poor cardiovascular risk factor profiles, seem to be less susceptible to developing cardiac disease.
 

More Research Needed

While genetics may partly explain the paradox, Testai believes other protective factors are at play, including strong social support networks.

Testai referred to the AHA’s “Life’s Essential 8” — the eight components of cardiovascular health. These include a healthy diet, participation in physical activity, nicotine avoidance, healthy sleep, healthy weight, and healthy levels of blood lipids, blood glucose, and blood pressure.

More evidence is needed to show that effective management of cardiac disease positively affects cognition. Currently, cognitive measures are rarely included in studies examining various heart disease treatments, said Testai.

“There should probably be an effort to include brain health outcomes in some of the cardiac literature to make sure we can also measure whether the intervention in the heart leads to an advantage for the brain,” he said.

More research is also needed to determine whether immunomodulation has a beneficial effect on the cognitive trajectory, the statement’s authors noted.

They point out that the interpretation and generalizability of the studies described in the statement are confounded by disparate methodologies, including small sample sizes, cross-sectional designs, and underrepresentation of Black and Hispanic individuals.
 

‘An Important Step’

Reached for a comment, Natalia S. Rost, MD, Chief of the Stroke Division at Massachusetts General Hospital and professor of neurology at Harvard Medical School, both in Boston, said this paper “is an important step” in terms of pulling together pertinent information on the topic of heart-brain health.

She praised the authors for gathering evidence on risk factors related to atrial fibrillation, heart failure, and coronary heart disease, which is “the part of the puzzle that is controllable.”

This helps reinforce the message that controlling vascular risk factors helps with brain health, said Rost.

But brain health is “much more complex than just vascular health,” she said. It includes other elements such as freedom from epilepsy, migraine, traumatic brain injury, and adult learning disabilities.

No relevant conflicts of interest were disclosed.

A version of this article first appeared on Medscape.com.

The American Heart Association (AHA) has issued a new scientific statement on the link between heart failure, atrial fibrillation, and coronary heart disease and the increased risk for cognitive impairment and dementia.

The statement includes an extensive research review and offers compelling evidence of the inextricable link between heart health and brain health, which investigators said underscores the benefit of early intervention.

The cumulative evidence “confirms that the trajectories of cardiac health and brain health are inextricably intertwined through modifiable and nonmodifiable factors,” the authors wrote.

Investigators say the findings reinforce the message that addressing cardiovascular health early in life may deter the onset or progression of cognitive impairment later on.

And the earlier this is done, the better, said lead author Fernando D. Testai, MD, PhD, a professor of neurology and the vascular neurology section head, Department of Neurology and Rehabilitation, University of Illinois, Chicago.

The statement was published online in Stroke.
 

Bridging the Research Gap

It’s well known that there’s a bidirectional relationship between heart and brain function. For example, heart failure can lead to decreased blood flow that can damage the brain, and stroke in some areas of the brain can affect the heart.

However, that’s only part of the puzzle and doesn’t address all the gaps in the understanding of how cardiovascular disease contributes to cognition, said Testai.

“What we’re trying to do here is to go one step further and describe other connections between the heart and the brain,” he said.

Investigators carried out an extensive PubMed search for heart failure, atrial fibrillation, and coronary heart disease. Researchers detailed the frequency of each condition, mechanisms by which they might cause cognitive impairment, and prospects for prevention and treatment to maintain brain health.

A recurring theme in the paper is the role of inflammation. Evidence shows there are “remarkable similarities in the inflammatory response that takes place,” with both cardiac disease and cognitive decline, said Testai.

Another potential shared mechanism relates to biomarkers, particularly amyloid, which is strongly linked to Alzheimer’s disease.

“But some studies show amyloid can also be present in the heart, especially in patients who have decreased ejection fraction,” said Testai.
 

Robust Heart-Brain Connection

The statement’s authors collected a substantial amount of evidence showing vascular risk factors such as hypertension and diabetes “can change how the brain processes and clears up amyloid,” Testai added.

The paper also provides a compilation of evidence of shared genetic predispositions when it comes to heart and brain disorders.

“We noticed that some genetic signatures that have historically been associated with heart disease seem to also correlate with structural changes in the brain. That means that at the end of the day, some patients may be born with a genetic predisposition to developing both conditions,” said Testai.

This indicates that the link between the two organs “begins as early as conception” and underscores the importance of adopting healthy lifestyle habits as early as possible, he added.

“That means you can avoid bad habits that eventually lead to hypertension, diabetes, and cholesterol, that eventually will lead to cardiac disease, which eventually will lead to stroke, which eventually will lead to cognitive decline,” Testai noted.

However, cardiovascular health is more complicated than having good genes and adhering to a healthy lifestyle. It’s not clear, for example, why some people who should be predisposed to developing heart disease do not develop it, something Testai refers to as enhanced “resilience.”

For example, Hispanic or Latino patients, who have relatively poor cardiovascular risk factor profiles, seem to be less susceptible to developing cardiac disease.
 

More Research Needed

While genetics may partly explain the paradox, Testai believes other protective factors are at play, including strong social support networks.

Testai referred to the AHA’s “Life’s Essential 8” — the eight components of cardiovascular health. These include a healthy diet, participation in physical activity, nicotine avoidance, healthy sleep, healthy weight, and healthy levels of blood lipids, blood glucose, and blood pressure.

More evidence is needed to show that effective management of cardiac disease positively affects cognition. Currently, cognitive measures are rarely included in studies examining various heart disease treatments, said Testai.

“There should probably be an effort to include brain health outcomes in some of the cardiac literature to make sure we can also measure whether the intervention in the heart leads to an advantage for the brain,” he said.

More research is also needed to determine whether immunomodulation has a beneficial effect on the cognitive trajectory, the statement’s authors noted.

They point out that the interpretation and generalizability of the studies described in the statement are confounded by disparate methodologies, including small sample sizes, cross-sectional designs, and underrepresentation of Black and Hispanic individuals.
 

‘An Important Step’

Reached for a comment, Natalia S. Rost, MD, Chief of the Stroke Division at Massachusetts General Hospital and professor of neurology at Harvard Medical School, both in Boston, said this paper “is an important step” in terms of pulling together pertinent information on the topic of heart-brain health.

She praised the authors for gathering evidence on risk factors related to atrial fibrillation, heart failure, and coronary heart disease, which is “the part of the puzzle that is controllable.”

This helps reinforce the message that controlling vascular risk factors helps with brain health, said Rost.

But brain health is “much more complex than just vascular health,” she said. It includes other elements such as freedom from epilepsy, migraine, traumatic brain injury, and adult learning disabilities.

No relevant conflicts of interest were disclosed.

A version of this article first appeared on Medscape.com.

SAVANNAH, GEORGIA — There’s no medical treatment for Charcot-Marie-Tooth (CMT) disease, a debilitating neurologic disorder that’s both progressive and incurable. But now, nerve specialists learned, new potential treatments are moving closer to clinical trials.

Genetic-based therapies for CMT are currently in preclinical research phases, and an experimental small-molecule drug has reached phase 3 in humans, neurologists told an audience at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024. But the neurologists also noted challenges, such as determining the best way to track disease progression — which can be slow — and the need to recruit high numbers of patients for trials.
 

A Common Genetic Neuromuscular Disorder

As Mario Saporta, MD, PhD, MBA, of the University of Miami, Coral Gables, Florida, explained, CMT is the most common genetic neuromuscular disorder, affecting 1 in 2500 people or about 130,000-150,000 in the United States. “Typically, it’s a length-dependent neuropathy, where your longest nerves would be affected earlier and more severely. That’s why we see foot deformities, inverted champagne bottle legs, and hand atrophy.”

Most patients with CMT in the United States have type 1A, which is linked to duplication of the PMP22 gene. All types lead to axonal degeneration, which appears to be the main cause of functional disability, Saporta said. “Patients become weaker and then progress with time, following the degree of axonal generation that they have.”

As many as 150 genes may eventually be deemed to cause CMT. The high number of genetically different forms makes diagnosis and genetic therapy difficult, he said, but that’s just part of the picture. Variations among mutations mean there’s “probably actually over 1000 different diseases” within CMT from a biologic perspective.
 

Genetic Therapy

In regard to genetic treatment, Bipasha Mukherjee-Clavin, MD, PhD, of Johns Hopkins University School of Medicine, Baltimore, Maryland, said a key factor is whether the patient’s form of CMT is passed on in an autosomal dominant or autosomal recessive manner.

“Autosomal dominant conditions are typically caused by gain of function mutations. So that means the goal of our genetic therapeutic would be to reduce expression of the mutated gene,” she said. “In contrast, autosomal recessive conditions are caused by loss-of-function mutations, which means the goal of our genetic therapeutic would be to replace the mutated gene with a normal, wild-type copy.”

A tool like CRISPR could be used to directly edit the part of the genome with a CMT-causing mutation or a viral vector could deliver a healthy, wild-type copy of a gene, she said. These approaches are both being tested.

Another approach is to reduce expression at the RNA level. “RNA therapeutics are FDA [Food and Drug Administration]–approved for other neuromuscular indications, and you may well be using some of these in your own clinical practice,” she said.

Currently, about seven different projects are in the works on the RNA therapeutics front in CMT, she said, including six focusing on type 1A. Mukherjee-Clavin believes that this subtype is a “great” target because it’s so common, affecting an estimated 1 in 5000 people.

“You actually have enough patients to power a clinical trial,” she said. Also, “it’s a homogeneous population, both in terms of the genetics and in terms of the clinical presentation.”
 

Preclinical Treatment Approaches

However, there are challenges. Drug delivery to Schwann cells, which insulate axons, is difficult, she said. “The other problem is that we want to avoid overly silencing PMP22 because that runs the theoretical risk of causing a different condition, HNPP [hereditary neuropathy with liability to pressure palsies]. HNPP is caused by deletions of PMP22, so we want to avoid that situation.”

Mukherjee-Clavin highlighted two RNA therapeutic products that she expects to move from preclinical to clinical research soon.

One is TVR110 by Armatus Bio, a microRNA intrathecal injection product, which aims to reduce PMP22 overexpression. “It targets basically reduces PMP22 mRNA expression and then normalizes the amount of PMP22 protein that is ultimately generated,” she said.

The other therapy, a small interfering RNA intravenous product delivered to Schwann cells, is being developed by DTx Pharma/Novartis.

Outside of the RNA arena, “there are a number of other programs that are in the preclinical phases that I think will be moving through this pipeline,” Mukherjee-Clavin said. “We’ll see if some of these enter first-in-human clinical trials.”

Meanwhile, Saporta highlighted small-molecule strategies that target a subtype of CMT called sorbitol dehydrogenase (SORD) deficiency that’s caused by mutations in the SORD gene. He noted that Applied Therapeutics is testing an investigational drug called govorestat (AT-007) in 56 patients in a double-blind, randomized, placebo-controlled phase 3 registrational study. The company recently reported that interim 12-month results are promising.

Saporta disclosed consulting for DTx Pharma/Novartis, Applied Therapeutics, and Pharnext. Mukherjee-Clavin had no disclosures.

A version of this article first appeared on Medscape.com.

SAVANNAH, GEORGIA — There’s no medical treatment for Charcot-Marie-Tooth (CMT) disease, a debilitating neurologic disorder that’s both progressive and incurable. But now, nerve specialists learned, new potential treatments are moving closer to clinical trials.

Genetic-based therapies for CMT are currently in preclinical research phases, and an experimental small-molecule drug has reached phase 3 in humans, neurologists told an audience at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024. But the neurologists also noted challenges, such as determining the best way to track disease progression — which can be slow — and the need to recruit high numbers of patients for trials.
 

A Common Genetic Neuromuscular Disorder

As Mario Saporta, MD, PhD, MBA, of the University of Miami, Coral Gables, Florida, explained, CMT is the most common genetic neuromuscular disorder, affecting 1 in 2500 people or about 130,000-150,000 in the United States. “Typically, it’s a length-dependent neuropathy, where your longest nerves would be affected earlier and more severely. That’s why we see foot deformities, inverted champagne bottle legs, and hand atrophy.”

Most patients with CMT in the United States have type 1A, which is linked to duplication of the PMP22 gene. All types lead to axonal degeneration, which appears to be the main cause of functional disability, Saporta said. “Patients become weaker and then progress with time, following the degree of axonal generation that they have.”

As many as 150 genes may eventually be deemed to cause CMT. The high number of genetically different forms makes diagnosis and genetic therapy difficult, he said, but that’s just part of the picture. Variations among mutations mean there’s “probably actually over 1000 different diseases” within CMT from a biologic perspective.
 

Genetic Therapy

In regard to genetic treatment, Bipasha Mukherjee-Clavin, MD, PhD, of Johns Hopkins University School of Medicine, Baltimore, Maryland, said a key factor is whether the patient’s form of CMT is passed on in an autosomal dominant or autosomal recessive manner.

“Autosomal dominant conditions are typically caused by gain of function mutations. So that means the goal of our genetic therapeutic would be to reduce expression of the mutated gene,” she said. “In contrast, autosomal recessive conditions are caused by loss-of-function mutations, which means the goal of our genetic therapeutic would be to replace the mutated gene with a normal, wild-type copy.”

A tool like CRISPR could be used to directly edit the part of the genome with a CMT-causing mutation or a viral vector could deliver a healthy, wild-type copy of a gene, she said. These approaches are both being tested.

Another approach is to reduce expression at the RNA level. “RNA therapeutics are FDA [Food and Drug Administration]–approved for other neuromuscular indications, and you may well be using some of these in your own clinical practice,” she said.

Currently, about seven different projects are in the works on the RNA therapeutics front in CMT, she said, including six focusing on type 1A. Mukherjee-Clavin believes that this subtype is a “great” target because it’s so common, affecting an estimated 1 in 5000 people.

“You actually have enough patients to power a clinical trial,” she said. Also, “it’s a homogeneous population, both in terms of the genetics and in terms of the clinical presentation.”
 

Preclinical Treatment Approaches

However, there are challenges. Drug delivery to Schwann cells, which insulate axons, is difficult, she said. “The other problem is that we want to avoid overly silencing PMP22 because that runs the theoretical risk of causing a different condition, HNPP [hereditary neuropathy with liability to pressure palsies]. HNPP is caused by deletions of PMP22, so we want to avoid that situation.”

Mukherjee-Clavin highlighted two RNA therapeutic products that she expects to move from preclinical to clinical research soon.

One is TVR110 by Armatus Bio, a microRNA intrathecal injection product, which aims to reduce PMP22 overexpression. “It targets basically reduces PMP22 mRNA expression and then normalizes the amount of PMP22 protein that is ultimately generated,” she said.

The other therapy, a small interfering RNA intravenous product delivered to Schwann cells, is being developed by DTx Pharma/Novartis.

Outside of the RNA arena, “there are a number of other programs that are in the preclinical phases that I think will be moving through this pipeline,” Mukherjee-Clavin said. “We’ll see if some of these enter first-in-human clinical trials.”

Meanwhile, Saporta highlighted small-molecule strategies that target a subtype of CMT called sorbitol dehydrogenase (SORD) deficiency that’s caused by mutations in the SORD gene. He noted that Applied Therapeutics is testing an investigational drug called govorestat (AT-007) in 56 patients in a double-blind, randomized, placebo-controlled phase 3 registrational study. The company recently reported that interim 12-month results are promising.

Saporta disclosed consulting for DTx Pharma/Novartis, Applied Therapeutics, and Pharnext. Mukherjee-Clavin had no disclosures.

A version of this article first appeared on Medscape.com.

SAVANNAH, GEORGIA — There’s no medical treatment for Charcot-Marie-Tooth (CMT) disease, a debilitating neurologic disorder that’s both progressive and incurable. But now, nerve specialists learned, new potential treatments are moving closer to clinical trials.

Genetic-based therapies for CMT are currently in preclinical research phases, and an experimental small-molecule drug has reached phase 3 in humans, neurologists told an audience at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024. But the neurologists also noted challenges, such as determining the best way to track disease progression — which can be slow — and the need to recruit high numbers of patients for trials.
 

A Common Genetic Neuromuscular Disorder

As Mario Saporta, MD, PhD, MBA, of the University of Miami, Coral Gables, Florida, explained, CMT is the most common genetic neuromuscular disorder, affecting 1 in 2500 people or about 130,000-150,000 in the United States. “Typically, it’s a length-dependent neuropathy, where your longest nerves would be affected earlier and more severely. That’s why we see foot deformities, inverted champagne bottle legs, and hand atrophy.”

Most patients with CMT in the United States have type 1A, which is linked to duplication of the PMP22 gene. All types lead to axonal degeneration, which appears to be the main cause of functional disability, Saporta said. “Patients become weaker and then progress with time, following the degree of axonal generation that they have.”

As many as 150 genes may eventually be deemed to cause CMT. The high number of genetically different forms makes diagnosis and genetic therapy difficult, he said, but that’s just part of the picture. Variations among mutations mean there’s “probably actually over 1000 different diseases” within CMT from a biologic perspective.
 

Genetic Therapy

In regard to genetic treatment, Bipasha Mukherjee-Clavin, MD, PhD, of Johns Hopkins University School of Medicine, Baltimore, Maryland, said a key factor is whether the patient’s form of CMT is passed on in an autosomal dominant or autosomal recessive manner.

“Autosomal dominant conditions are typically caused by gain of function mutations. So that means the goal of our genetic therapeutic would be to reduce expression of the mutated gene,” she said. “In contrast, autosomal recessive conditions are caused by loss-of-function mutations, which means the goal of our genetic therapeutic would be to replace the mutated gene with a normal, wild-type copy.”

A tool like CRISPR could be used to directly edit the part of the genome with a CMT-causing mutation or a viral vector could deliver a healthy, wild-type copy of a gene, she said. These approaches are both being tested.

Another approach is to reduce expression at the RNA level. “RNA therapeutics are FDA [Food and Drug Administration]–approved for other neuromuscular indications, and you may well be using some of these in your own clinical practice,” she said.

Currently, about seven different projects are in the works on the RNA therapeutics front in CMT, she said, including six focusing on type 1A. Mukherjee-Clavin believes that this subtype is a “great” target because it’s so common, affecting an estimated 1 in 5000 people.

“You actually have enough patients to power a clinical trial,” she said. Also, “it’s a homogeneous population, both in terms of the genetics and in terms of the clinical presentation.”
 

Preclinical Treatment Approaches

However, there are challenges. Drug delivery to Schwann cells, which insulate axons, is difficult, she said. “The other problem is that we want to avoid overly silencing PMP22 because that runs the theoretical risk of causing a different condition, HNPP [hereditary neuropathy with liability to pressure palsies]. HNPP is caused by deletions of PMP22, so we want to avoid that situation.”

Mukherjee-Clavin highlighted two RNA therapeutic products that she expects to move from preclinical to clinical research soon.

One is TVR110 by Armatus Bio, a microRNA intrathecal injection product, which aims to reduce PMP22 overexpression. “It targets basically reduces PMP22 mRNA expression and then normalizes the amount of PMP22 protein that is ultimately generated,” she said.

The other therapy, a small interfering RNA intravenous product delivered to Schwann cells, is being developed by DTx Pharma/Novartis.

Outside of the RNA arena, “there are a number of other programs that are in the preclinical phases that I think will be moving through this pipeline,” Mukherjee-Clavin said. “We’ll see if some of these enter first-in-human clinical trials.”

Meanwhile, Saporta highlighted small-molecule strategies that target a subtype of CMT called sorbitol dehydrogenase (SORD) deficiency that’s caused by mutations in the SORD gene. He noted that Applied Therapeutics is testing an investigational drug called govorestat (AT-007) in 56 patients in a double-blind, randomized, placebo-controlled phase 3 registrational study. The company recently reported that interim 12-month results are promising.

Saporta disclosed consulting for DTx Pharma/Novartis, Applied Therapeutics, and Pharnext. Mukherjee-Clavin had no disclosures.

A version of this article first appeared on Medscape.com.

I’d like to talk with you about ultraprocessed foods (UPFs) and risk for cardiovascular disease (CVD) and try to separate some of the facts from the myths. I’d like to discuss a recent report in The Lancet Regional Health that looks at this topic comprehensively and in detail.

This report includes three large-scale prospective cohort studies of US female and male health professionals, more than 200,000 participants in total. It also includes a meta-analysis of 22 international cohorts with about 1.2 million participants. I’d like to acknowledge that I’m a co-author of this study.

What are UPFs, and why are they important? Why do we care, and what are the knowledge gaps? UPFs are generally packaged foods that contain ingredients to extend shelf life and improve taste and palatability. It’s important because 60%-70% of the US diet, if not more, is made up of UPFs. So, the relationship between UPFs and CVD and other health outcomes is actually very important. 

And the research to date on this subject has been quite limited. 

Often, UPFs will include additives, such as preservatives, flavor enhancers, colorants, emulsifiers, and sweeteners, and they tend to have an excess amount of calories, added sugars, added salt, sodium, and saturated fat. The packaging can be high in bisphenols, which have also been linked to some health outcomes.

In other studies, these UPFs have been linked to weight gain and dyslipidemia; some tissue glycation has been found, and some changes in the microbiome. Some studies have linked higher UPF intake with type 2 diabetes. A few have looked at certain selected UPF foods and found a higher risk for CVD, but a really comprehensive look at this question hasn’t been done. 

So, that’s what we did in this paper and in the meta-analysis with the 22 cohorts, and we saw a very clear and distinct significant increase in coronary heart disease by 23%, total CVD by 17%, and stroke by 9% when comparing the highest vs the lowest category [of UPF intake]. When we drilled down deeply into the types of UPFs in the US health professional cohorts, we saw that there were some major differences in the relationship with CVD depending on the type of UPF.

In comparing the highest quintile vs the lowest quintile [of total UPF intake], we saw that some of the UPFs were associated with significant elevations in risk for CVD. These included sugar-sweetened beverages and processed meats. But some UPFs were linked with a lower risk for CVD. These included breakfast cereals, yogurt, some dairy desserts, and whole grains.

Overall, it seemed that UPFs are actually quite diverse in their association with health. It’s not one size fits all. They’re not all created equal, and some of these differences matter. Although overall we would recommend that our diets be focused on whole foods, primarily plant based, lots of fruits and vegetables, whole grains, fish, and other whole foods, it seems from this report and the meta-analysis that certain types of UPFs can be incorporated into a healthy diet and don’t need to be avoided entirely. 

Dr. Manson is Professor of Medicine and the Michael and Lee Bell Professor of Women’s Health, Harvard Medical School, and Chief of the Division of Preventive Medicine, Brigham and Women’s Hospital, both in Boston, Massachusetts. She reported receiving donations and infrastructure support from Mars Symbioscience.

A version of this article first appeared on Medscape.com.

I’d like to talk with you about ultraprocessed foods (UPFs) and risk for cardiovascular disease (CVD) and try to separate some of the facts from the myths. I’d like to discuss a recent report in The Lancet Regional Health that looks at this topic comprehensively and in detail.

This report includes three large-scale prospective cohort studies of US female and male health professionals, more than 200,000 participants in total. It also includes a meta-analysis of 22 international cohorts with about 1.2 million participants. I’d like to acknowledge that I’m a co-author of this study.

What are UPFs, and why are they important? Why do we care, and what are the knowledge gaps? UPFs are generally packaged foods that contain ingredients to extend shelf life and improve taste and palatability. It’s important because 60%-70% of the US diet, if not more, is made up of UPFs. So, the relationship between UPFs and CVD and other health outcomes is actually very important. 

And the research to date on this subject has been quite limited. 

Often, UPFs will include additives, such as preservatives, flavor enhancers, colorants, emulsifiers, and sweeteners, and they tend to have an excess amount of calories, added sugars, added salt, sodium, and saturated fat. The packaging can be high in bisphenols, which have also been linked to some health outcomes.

In other studies, these UPFs have been linked to weight gain and dyslipidemia; some tissue glycation has been found, and some changes in the microbiome. Some studies have linked higher UPF intake with type 2 diabetes. A few have looked at certain selected UPF foods and found a higher risk for CVD, but a really comprehensive look at this question hasn’t been done. 

So, that’s what we did in this paper and in the meta-analysis with the 22 cohorts, and we saw a very clear and distinct significant increase in coronary heart disease by 23%, total CVD by 17%, and stroke by 9% when comparing the highest vs the lowest category [of UPF intake]. When we drilled down deeply into the types of UPFs in the US health professional cohorts, we saw that there were some major differences in the relationship with CVD depending on the type of UPF.

In comparing the highest quintile vs the lowest quintile [of total UPF intake], we saw that some of the UPFs were associated with significant elevations in risk for CVD. These included sugar-sweetened beverages and processed meats. But some UPFs were linked with a lower risk for CVD. These included breakfast cereals, yogurt, some dairy desserts, and whole grains.

Overall, it seemed that UPFs are actually quite diverse in their association with health. It’s not one size fits all. They’re not all created equal, and some of these differences matter. Although overall we would recommend that our diets be focused on whole foods, primarily plant based, lots of fruits and vegetables, whole grains, fish, and other whole foods, it seems from this report and the meta-analysis that certain types of UPFs can be incorporated into a healthy diet and don’t need to be avoided entirely. 

Dr. Manson is Professor of Medicine and the Michael and Lee Bell Professor of Women’s Health, Harvard Medical School, and Chief of the Division of Preventive Medicine, Brigham and Women’s Hospital, both in Boston, Massachusetts. She reported receiving donations and infrastructure support from Mars Symbioscience.

A version of this article first appeared on Medscape.com.

I’d like to talk with you about ultraprocessed foods (UPFs) and risk for cardiovascular disease (CVD) and try to separate some of the facts from the myths. I’d like to discuss a recent report in The Lancet Regional Health that looks at this topic comprehensively and in detail.

This report includes three large-scale prospective cohort studies of US female and male health professionals, more than 200,000 participants in total. It also includes a meta-analysis of 22 international cohorts with about 1.2 million participants. I’d like to acknowledge that I’m a co-author of this study.

What are UPFs, and why are they important? Why do we care, and what are the knowledge gaps? UPFs are generally packaged foods that contain ingredients to extend shelf life and improve taste and palatability. It’s important because 60%-70% of the US diet, if not more, is made up of UPFs. So, the relationship between UPFs and CVD and other health outcomes is actually very important. 

And the research to date on this subject has been quite limited. 

Often, UPFs will include additives, such as preservatives, flavor enhancers, colorants, emulsifiers, and sweeteners, and they tend to have an excess amount of calories, added sugars, added salt, sodium, and saturated fat. The packaging can be high in bisphenols, which have also been linked to some health outcomes.

In other studies, these UPFs have been linked to weight gain and dyslipidemia; some tissue glycation has been found, and some changes in the microbiome. Some studies have linked higher UPF intake with type 2 diabetes. A few have looked at certain selected UPF foods and found a higher risk for CVD, but a really comprehensive look at this question hasn’t been done. 

So, that’s what we did in this paper and in the meta-analysis with the 22 cohorts, and we saw a very clear and distinct significant increase in coronary heart disease by 23%, total CVD by 17%, and stroke by 9% when comparing the highest vs the lowest category [of UPF intake]. When we drilled down deeply into the types of UPFs in the US health professional cohorts, we saw that there were some major differences in the relationship with CVD depending on the type of UPF.

In comparing the highest quintile vs the lowest quintile [of total UPF intake], we saw that some of the UPFs were associated with significant elevations in risk for CVD. These included sugar-sweetened beverages and processed meats. But some UPFs were linked with a lower risk for CVD. These included breakfast cereals, yogurt, some dairy desserts, and whole grains.

Overall, it seemed that UPFs are actually quite diverse in their association with health. It’s not one size fits all. They’re not all created equal, and some of these differences matter. Although overall we would recommend that our diets be focused on whole foods, primarily plant based, lots of fruits and vegetables, whole grains, fish, and other whole foods, it seems from this report and the meta-analysis that certain types of UPFs can be incorporated into a healthy diet and don’t need to be avoided entirely. 

Dr. Manson is Professor of Medicine and the Michael and Lee Bell Professor of Women’s Health, Harvard Medical School, and Chief of the Division of Preventive Medicine, Brigham and Women’s Hospital, both in Boston, Massachusetts. She reported receiving donations and infrastructure support from Mars Symbioscience.

A version of this article first appeared on Medscape.com.

“Because you know I’m all about that base, ‘bout that base, no acid.” 

Do those words sound familiar? That’s because they’re the lyrics to Meghan Trainor’s “All About That Bass,” slightly tweaked to function as a medical study tool.

Early in med school, J.C. Sue, DO, now a family medicine physician, refashioned the song’s words to help him prepare for a test on acid extruders and loaders. Sue’s version, “All About That Base,” contained his lecture notes. During the exam, he found himself mentally singing his parody and easily recalling the information. Plus, the approach made cramming a lot more palatable.

Sound silly? It’s not. Sue’s approach is backed up by science. A significant body of research has illuminated the positive association between music and memory. And the benefits last. Recently, a 2024 study from Canada suggested that musical memory doesn’t decrease with age. And a 2023 study revealed music was a better cue than food for helping both young and older adults recall autobiographical memories.

Inspired by his success, Sue gave popular songs a medical spin throughout his medical training. “There’s no rule that says studying must be boring, tedious, or torturous,” Sue said. “If you can make it fun, why not?”

Sue isn’t alone. Many physicians say that writing songs, listening to music, or playing instruments improves their focus, energy, and work performance, along with their confidence and well-being.

Why does music work so well?
 

Tune Your Brain to Work With Tunes

Remember learning your ABCs to the tune of “Twinkle, Twinkle, Little Star?” (Or ask any Gen X person about Schoolhouse Rock.)

In the classroom, music is an established tool for teaching kids, said Ruth Gotian, EdD, MS, chief learning officer and associate professor of education in anesthesiology at Weill Cornell Medicine, New York City. But she said musical strategies make studying easier for adults, too, no matter how complex the material.

Christopher Emdin, PhD, Maxine Greene chair and professor of science education at Teachers College, Columbia University, New York City, shares Gotian’s view. When teaching science, engineering, technology, and mathematics (STEM) subjects to high school kids, he challenged them to write raps about the new concepts.

That’s when he saw visible results: As his students took exams, Emdin noticed them nodding and moving their mouths and heads.

“They were literally performing the songs they’d written for themselves,” Emdin said. “When you write a song to a beat, it’s almost like your heartbeat. You know it so well; you can conjure up your memories by reciting the lyrics.”

If songwriting isn’t in your repertoire, you’ll be glad to hear that just listening to music while studying can help with retention. “Music keeps both sides of the brain stimulated, which has been shown to increase focus and motivation,” explained Anita A. Paschall, MD, PhD, Medical School and Healthcare Admissions expert/director of Medical School and Healthcare Admissions at The Princeton Review.
 

‘Mind on a Permanent Vacation’

Paschall’s enthusiasm comes from personal experience. While preparing for her board exams, Jimmy Buffet’s catalog was her study soundtrack. “His songs stayed in my mind. I could hum along without having to think about it, so my brain was free to focus,” she recalled.

Because Paschall grew up listening to Buffet’s tunes, they also evoked relaxing moments from her earlier life, which she found comforting and uplifting. The combination helped make long, intense study sessions more pleasant. After all, when you’re “wasting away again in Margaritaville,” how can you feel stressed and despondent?

Alexander Remy Bonnel, MD, clinical assistant professor of medicine at the University of Pennsylvania and a physician at Pennsylvania Hospital, both in Philadelphia, found ways to incorporate both auditory and visual stimuli in his med school study routine. He listened to music while color-coding his notes to link both cues to the information. As with Paschall, these tactics helped reduce the monotony of learning reams of material.

That gave Bonnel an easy way to establish an important element for memory: Novelty.

“When you need to memorize so many things in a short amount of time, you’re trying to vary ways of internalizing information,” he observed. “You have a higher chance of retaining information if there’s something unique about it.”
 

Building Team Harmony

“Almost every single OR I rotated through in med school had music playing,” Bonnel also recalled. Furthermore, he noticed a pattern to the chosen songs: Regardless of their age, surgeons selected playlists of tunes that had been popular when they were in their 20s. Those golden oldies, from any era, could turn the OR team into a focused, cohesive unit.

Kyle McCormick, MD, a fifth-year resident in orthopedic surgery at New York–Presbyterian Hospital, Columbia University Irving Medical Center, New York City, has also noticed the ubiquity of background music in ORs. Her observation: Surgeons tend to choose universally popular, inoffensive songs, like tracks from Hall & Oates and Fleetwood Mac.

This meshes with the results of a joint survey of nearly 700 surgeons and other healthcare professionals conducted by Spotify and Figure 1 in 2021; 90% of the surgeons and surgical residents who responded said they listened to music in the OR. Rock and pop were the most popular genres, followed by classical, jazz, and then R&B.

Regardless of genre, music helped the surgical teams focus and feel less tense, the surgeons reported. But when training younger doctors, managing complications, or performing during critical points in surgery, many said they’d lower the volume.

Outside the OR, music can also help foster connection between colleagues. For Lawrence C. Loh, MD, MPH, adjunct professor at Dalla Lana School of Public Health at the University of Toronto in Ontario, Canada, playing guitar and piano has helped him connect with his staff. “I’ve played tunes at staff gatherings and recorded videos as encouragement during the emergency response for COVID-19,” he shared.

In his free time, Loh has also organized outings to his local pub’s weekly karaoke show for more than a decade. His goal: “Promote social cohesion and combat loneliness among my friend and social networks.”
 

Get Your Own Musical Boost

If all this sounds like music to your ears, here are some ways to try it yourself.

Find a study soundtrack. When choosing study music, follow Paschall’s lead and pick songs you know well so they’ll remain in the background. Also, compile a soundtrack you find pleasant and mood-boosting to help relieve the tedium of study and decrease stress.

Keep in mind that we all take in and process information differently, said Gotian. So background music during study sessions might not work for you. According to a 2017 study published in Frontiers in Psychology, it can be a distraction and impair learning for some. Do what works.

Get pumped with a “walkup song.” What songs make you feel like you could conquer the world? asked Emdin. Or what soundtrack would be playing if you were ascending a stage to accept an award or walking out to take the mound in the ninth inning? Those songs should be on what he calls your “superhero” or “walkup” playlist. His prescription: Tune in before you begin your workday or start a challenging procedure.

Paschall agrees and recommends her students and clients listen to music before sitting down for an exam. Forget reviewing flashcards for the nth time, she counseled. Putting on headphones (or earbuds) will put you in a “better headspace.”

Choose work and play playlists. As well as incorporating tunes in your clinic or hospital, music can help relieve stress at the end of the workday. “Medical culture can often be detrimental to doctors’ health,” said Sue, who credits music with helping him maintain equanimity.

Bonnel can relate. Practicing and performing with the Penn Medicine Symphony Orchestra offers him a sense of community and relief from the stress of modern life. “For 2 hours every Tuesday, I put my phone away and just play,” he said. “It’s nice to have those moments when I’m temporarily disconnected and can just focus on one thing: Playing.”
 

Scale Up Your Career

Years after med school graduation, Sue still recalls many of the tunes he wrote to help him remember information. When he sings a song in his head, he’ll get a refresher on pediatric developmental milestones, medication side effects, anatomical details, and more, which informs the treatment plans he devises for patients. To help other doctors reap these benefits, Sue created the website Tune Rx, a medical music study resource that includes many of the roughly 100 songs he’s written.

Emdin often discusses his musical strategies during talks on STEM education. Initially, people are skeptical, he said. But the idea quickly rings a bell for audience members. “They come up to me afterward to share anecdotes,” Emdin said. “If you have enough anecdotes, there’s a pattern. So let’s create a process. Let’s be intentional about using music as a learning strategy,” he urged.

A version of this article first appeared on Medscape.com.

“Because you know I’m all about that base, ‘bout that base, no acid.” 

Do those words sound familiar? That’s because they’re the lyrics to Meghan Trainor’s “All About That Bass,” slightly tweaked to function as a medical study tool.

Early in med school, J.C. Sue, DO, now a family medicine physician, refashioned the song’s words to help him prepare for a test on acid extruders and loaders. Sue’s version, “All About That Base,” contained his lecture notes. During the exam, he found himself mentally singing his parody and easily recalling the information. Plus, the approach made cramming a lot more palatable.

Sound silly? It’s not. Sue’s approach is backed up by science. A significant body of research has illuminated the positive association between music and memory. And the benefits last. Recently, a 2024 study from Canada suggested that musical memory doesn’t decrease with age. And a 2023 study revealed music was a better cue than food for helping both young and older adults recall autobiographical memories.

Inspired by his success, Sue gave popular songs a medical spin throughout his medical training. “There’s no rule that says studying must be boring, tedious, or torturous,” Sue said. “If you can make it fun, why not?”

Sue isn’t alone. Many physicians say that writing songs, listening to music, or playing instruments improves their focus, energy, and work performance, along with their confidence and well-being.

Why does music work so well?
 

Tune Your Brain to Work With Tunes

Remember learning your ABCs to the tune of “Twinkle, Twinkle, Little Star?” (Or ask any Gen X person about Schoolhouse Rock.)

In the classroom, music is an established tool for teaching kids, said Ruth Gotian, EdD, MS, chief learning officer and associate professor of education in anesthesiology at Weill Cornell Medicine, New York City. But she said musical strategies make studying easier for adults, too, no matter how complex the material.

Christopher Emdin, PhD, Maxine Greene chair and professor of science education at Teachers College, Columbia University, New York City, shares Gotian’s view. When teaching science, engineering, technology, and mathematics (STEM) subjects to high school kids, he challenged them to write raps about the new concepts.

That’s when he saw visible results: As his students took exams, Emdin noticed them nodding and moving their mouths and heads.

“They were literally performing the songs they’d written for themselves,” Emdin said. “When you write a song to a beat, it’s almost like your heartbeat. You know it so well; you can conjure up your memories by reciting the lyrics.”

If songwriting isn’t in your repertoire, you’ll be glad to hear that just listening to music while studying can help with retention. “Music keeps both sides of the brain stimulated, which has been shown to increase focus and motivation,” explained Anita A. Paschall, MD, PhD, Medical School and Healthcare Admissions expert/director of Medical School and Healthcare Admissions at The Princeton Review.
 

‘Mind on a Permanent Vacation’

Paschall’s enthusiasm comes from personal experience. While preparing for her board exams, Jimmy Buffet’s catalog was her study soundtrack. “His songs stayed in my mind. I could hum along without having to think about it, so my brain was free to focus,” she recalled.

Because Paschall grew up listening to Buffet’s tunes, they also evoked relaxing moments from her earlier life, which she found comforting and uplifting. The combination helped make long, intense study sessions more pleasant. After all, when you’re “wasting away again in Margaritaville,” how can you feel stressed and despondent?

Alexander Remy Bonnel, MD, clinical assistant professor of medicine at the University of Pennsylvania and a physician at Pennsylvania Hospital, both in Philadelphia, found ways to incorporate both auditory and visual stimuli in his med school study routine. He listened to music while color-coding his notes to link both cues to the information. As with Paschall, these tactics helped reduce the monotony of learning reams of material.

That gave Bonnel an easy way to establish an important element for memory: Novelty.

“When you need to memorize so many things in a short amount of time, you’re trying to vary ways of internalizing information,” he observed. “You have a higher chance of retaining information if there’s something unique about it.”
 

Building Team Harmony

“Almost every single OR I rotated through in med school had music playing,” Bonnel also recalled. Furthermore, he noticed a pattern to the chosen songs: Regardless of their age, surgeons selected playlists of tunes that had been popular when they were in their 20s. Those golden oldies, from any era, could turn the OR team into a focused, cohesive unit.

Kyle McCormick, MD, a fifth-year resident in orthopedic surgery at New York–Presbyterian Hospital, Columbia University Irving Medical Center, New York City, has also noticed the ubiquity of background music in ORs. Her observation: Surgeons tend to choose universally popular, inoffensive songs, like tracks from Hall & Oates and Fleetwood Mac.

This meshes with the results of a joint survey of nearly 700 surgeons and other healthcare professionals conducted by Spotify and Figure 1 in 2021; 90% of the surgeons and surgical residents who responded said they listened to music in the OR. Rock and pop were the most popular genres, followed by classical, jazz, and then R&B.

Regardless of genre, music helped the surgical teams focus and feel less tense, the surgeons reported. But when training younger doctors, managing complications, or performing during critical points in surgery, many said they’d lower the volume.

Outside the OR, music can also help foster connection between colleagues. For Lawrence C. Loh, MD, MPH, adjunct professor at Dalla Lana School of Public Health at the University of Toronto in Ontario, Canada, playing guitar and piano has helped him connect with his staff. “I’ve played tunes at staff gatherings and recorded videos as encouragement during the emergency response for COVID-19,” he shared.

In his free time, Loh has also organized outings to his local pub’s weekly karaoke show for more than a decade. His goal: “Promote social cohesion and combat loneliness among my friend and social networks.”
 

Get Your Own Musical Boost

If all this sounds like music to your ears, here are some ways to try it yourself.

Find a study soundtrack. When choosing study music, follow Paschall’s lead and pick songs you know well so they’ll remain in the background. Also, compile a soundtrack you find pleasant and mood-boosting to help relieve the tedium of study and decrease stress.

Keep in mind that we all take in and process information differently, said Gotian. So background music during study sessions might not work for you. According to a 2017 study published in Frontiers in Psychology, it can be a distraction and impair learning for some. Do what works.

Get pumped with a “walkup song.” What songs make you feel like you could conquer the world? asked Emdin. Or what soundtrack would be playing if you were ascending a stage to accept an award or walking out to take the mound in the ninth inning? Those songs should be on what he calls your “superhero” or “walkup” playlist. His prescription: Tune in before you begin your workday or start a challenging procedure.

Paschall agrees and recommends her students and clients listen to music before sitting down for an exam. Forget reviewing flashcards for the nth time, she counseled. Putting on headphones (or earbuds) will put you in a “better headspace.”

Choose work and play playlists. As well as incorporating tunes in your clinic or hospital, music can help relieve stress at the end of the workday. “Medical culture can often be detrimental to doctors’ health,” said Sue, who credits music with helping him maintain equanimity.

Bonnel can relate. Practicing and performing with the Penn Medicine Symphony Orchestra offers him a sense of community and relief from the stress of modern life. “For 2 hours every Tuesday, I put my phone away and just play,” he said. “It’s nice to have those moments when I’m temporarily disconnected and can just focus on one thing: Playing.”
 

Scale Up Your Career

Years after med school graduation, Sue still recalls many of the tunes he wrote to help him remember information. When he sings a song in his head, he’ll get a refresher on pediatric developmental milestones, medication side effects, anatomical details, and more, which informs the treatment plans he devises for patients. To help other doctors reap these benefits, Sue created the website Tune Rx, a medical music study resource that includes many of the roughly 100 songs he’s written.

Emdin often discusses his musical strategies during talks on STEM education. Initially, people are skeptical, he said. But the idea quickly rings a bell for audience members. “They come up to me afterward to share anecdotes,” Emdin said. “If you have enough anecdotes, there’s a pattern. So let’s create a process. Let’s be intentional about using music as a learning strategy,” he urged.

A version of this article first appeared on Medscape.com.

“Because you know I’m all about that base, ‘bout that base, no acid.” 

Do those words sound familiar? That’s because they’re the lyrics to Meghan Trainor’s “All About That Bass,” slightly tweaked to function as a medical study tool.

Early in med school, J.C. Sue, DO, now a family medicine physician, refashioned the song’s words to help him prepare for a test on acid extruders and loaders. Sue’s version, “All About That Base,” contained his lecture notes. During the exam, he found himself mentally singing his parody and easily recalling the information. Plus, the approach made cramming a lot more palatable.

Sound silly? It’s not. Sue’s approach is backed up by science. A significant body of research has illuminated the positive association between music and memory. And the benefits last. Recently, a 2024 study from Canada suggested that musical memory doesn’t decrease with age. And a 2023 study revealed music was a better cue than food for helping both young and older adults recall autobiographical memories.

Inspired by his success, Sue gave popular songs a medical spin throughout his medical training. “There’s no rule that says studying must be boring, tedious, or torturous,” Sue said. “If you can make it fun, why not?”

Sue isn’t alone. Many physicians say that writing songs, listening to music, or playing instruments improves their focus, energy, and work performance, along with their confidence and well-being.

Why does music work so well?
 

Tune Your Brain to Work With Tunes

Remember learning your ABCs to the tune of “Twinkle, Twinkle, Little Star?” (Or ask any Gen X person about Schoolhouse Rock.)

In the classroom, music is an established tool for teaching kids, said Ruth Gotian, EdD, MS, chief learning officer and associate professor of education in anesthesiology at Weill Cornell Medicine, New York City. But she said musical strategies make studying easier for adults, too, no matter how complex the material.

Christopher Emdin, PhD, Maxine Greene chair and professor of science education at Teachers College, Columbia University, New York City, shares Gotian’s view. When teaching science, engineering, technology, and mathematics (STEM) subjects to high school kids, he challenged them to write raps about the new concepts.

That’s when he saw visible results: As his students took exams, Emdin noticed them nodding and moving their mouths and heads.

“They were literally performing the songs they’d written for themselves,” Emdin said. “When you write a song to a beat, it’s almost like your heartbeat. You know it so well; you can conjure up your memories by reciting the lyrics.”

If songwriting isn’t in your repertoire, you’ll be glad to hear that just listening to music while studying can help with retention. “Music keeps both sides of the brain stimulated, which has been shown to increase focus and motivation,” explained Anita A. Paschall, MD, PhD, Medical School and Healthcare Admissions expert/director of Medical School and Healthcare Admissions at The Princeton Review.
 

‘Mind on a Permanent Vacation’

Paschall’s enthusiasm comes from personal experience. While preparing for her board exams, Jimmy Buffet’s catalog was her study soundtrack. “His songs stayed in my mind. I could hum along without having to think about it, so my brain was free to focus,” she recalled.

Because Paschall grew up listening to Buffet’s tunes, they also evoked relaxing moments from her earlier life, which she found comforting and uplifting. The combination helped make long, intense study sessions more pleasant. After all, when you’re “wasting away again in Margaritaville,” how can you feel stressed and despondent?

Alexander Remy Bonnel, MD, clinical assistant professor of medicine at the University of Pennsylvania and a physician at Pennsylvania Hospital, both in Philadelphia, found ways to incorporate both auditory and visual stimuli in his med school study routine. He listened to music while color-coding his notes to link both cues to the information. As with Paschall, these tactics helped reduce the monotony of learning reams of material.

That gave Bonnel an easy way to establish an important element for memory: Novelty.

“When you need to memorize so many things in a short amount of time, you’re trying to vary ways of internalizing information,” he observed. “You have a higher chance of retaining information if there’s something unique about it.”
 

Building Team Harmony

“Almost every single OR I rotated through in med school had music playing,” Bonnel also recalled. Furthermore, he noticed a pattern to the chosen songs: Regardless of their age, surgeons selected playlists of tunes that had been popular when they were in their 20s. Those golden oldies, from any era, could turn the OR team into a focused, cohesive unit.

Kyle McCormick, MD, a fifth-year resident in orthopedic surgery at New York–Presbyterian Hospital, Columbia University Irving Medical Center, New York City, has also noticed the ubiquity of background music in ORs. Her observation: Surgeons tend to choose universally popular, inoffensive songs, like tracks from Hall & Oates and Fleetwood Mac.

This meshes with the results of a joint survey of nearly 700 surgeons and other healthcare professionals conducted by Spotify and Figure 1 in 2021; 90% of the surgeons and surgical residents who responded said they listened to music in the OR. Rock and pop were the most popular genres, followed by classical, jazz, and then R&B.

Regardless of genre, music helped the surgical teams focus and feel less tense, the surgeons reported. But when training younger doctors, managing complications, or performing during critical points in surgery, many said they’d lower the volume.

Outside the OR, music can also help foster connection between colleagues. For Lawrence C. Loh, MD, MPH, adjunct professor at Dalla Lana School of Public Health at the University of Toronto in Ontario, Canada, playing guitar and piano has helped him connect with his staff. “I’ve played tunes at staff gatherings and recorded videos as encouragement during the emergency response for COVID-19,” he shared.

In his free time, Loh has also organized outings to his local pub’s weekly karaoke show for more than a decade. His goal: “Promote social cohesion and combat loneliness among my friend and social networks.”
 

Get Your Own Musical Boost

If all this sounds like music to your ears, here are some ways to try it yourself.

Find a study soundtrack. When choosing study music, follow Paschall’s lead and pick songs you know well so they’ll remain in the background. Also, compile a soundtrack you find pleasant and mood-boosting to help relieve the tedium of study and decrease stress.

Keep in mind that we all take in and process information differently, said Gotian. So background music during study sessions might not work for you. According to a 2017 study published in Frontiers in Psychology, it can be a distraction and impair learning for some. Do what works.

Get pumped with a “walkup song.” What songs make you feel like you could conquer the world? asked Emdin. Or what soundtrack would be playing if you were ascending a stage to accept an award or walking out to take the mound in the ninth inning? Those songs should be on what he calls your “superhero” or “walkup” playlist. His prescription: Tune in before you begin your workday or start a challenging procedure.

Paschall agrees and recommends her students and clients listen to music before sitting down for an exam. Forget reviewing flashcards for the nth time, she counseled. Putting on headphones (or earbuds) will put you in a “better headspace.”

Choose work and play playlists. As well as incorporating tunes in your clinic or hospital, music can help relieve stress at the end of the workday. “Medical culture can often be detrimental to doctors’ health,” said Sue, who credits music with helping him maintain equanimity.

Bonnel can relate. Practicing and performing with the Penn Medicine Symphony Orchestra offers him a sense of community and relief from the stress of modern life. “For 2 hours every Tuesday, I put my phone away and just play,” he said. “It’s nice to have those moments when I’m temporarily disconnected and can just focus on one thing: Playing.”
 

Scale Up Your Career

Years after med school graduation, Sue still recalls many of the tunes he wrote to help him remember information. When he sings a song in his head, he’ll get a refresher on pediatric developmental milestones, medication side effects, anatomical details, and more, which informs the treatment plans he devises for patients. To help other doctors reap these benefits, Sue created the website Tune Rx, a medical music study resource that includes many of the roughly 100 songs he’s written.

Emdin often discusses his musical strategies during talks on STEM education. Initially, people are skeptical, he said. But the idea quickly rings a bell for audience members. “They come up to me afterward to share anecdotes,” Emdin said. “If you have enough anecdotes, there’s a pattern. So let’s create a process. Let’s be intentional about using music as a learning strategy,” he urged.

A version of this article first appeared on Medscape.com.

SAVANNAH, GEORGIA – The investigational monoclonal antibody nipocalimab (Johnson & Johnson) is associated with significant improvement in patients with generalized myasthenia gravis (gMG) over a 24-week period, according to topline results from the phase 3 VIVACITY-MG3 study.

The VIVACITY-MG3 trial is the first registrational study of a neonatal fragment crystallizable receptor (FcRn) blocker to show sustained efficacy through 6 months of fixed schedule dosing.

Lead investigator Tuan Vu, MD, professor of neurology at the University of South Florida in Tampa, presented the findings at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024. 
 

Autoantibody Depletion

FcRN plays a crucial role in the transport of immunoglobulin G. Blocking it can reduce circulating immunoglobulin G antibodies, including pathogenic gMG autoantibodies. 

The double-blind, placebo-controlled trial included 196 adults with a broad range of seropositive gMG – who account for approximately 95% of the gMG patient population – and 42 seronegative patients.

The mean age was 52 years, 92% were female, and 63% were White. The mean disease duration was about 8 years. Among seropositive patients, 87.6% were acetylcholine receptor autoantibody-positive (AChR+), 10.5% were muscle-specific kinase autoantibody-positive (MuSK+), and 2% were low-density lipoprotein receptor-related protein 4 antibody positive.

They were randomly assigned 1:1 to receive either nipocalimab IV plus standard of care, or placebo plus standard of care for 24 weeks. A total of 87 patients in the nipocalimab arm and 82 in the placebo arm completed the study.

The primary efficacy endpoint was the Myasthenia Gravis Activities of Daily Living (MG-ADL) score. Participants treated with nipocalimab demonstrated a statistically significant improvement of 4.70 points from baseline, compared to the 3.25-point improvement in those treated with placebo (P =.002). 
 

Clinically Meaningful Changes?

“For someone living with gMG, a 1 to 2-point improvement on MG-ADL may be the difference between normal eating and frequent choking on food, or shortness of breath at rest and being on a ventilator,” the drug’s manufacturer noted in a release. 

Secondary endpoints were also better in the nipocalimab group, compared with participants on placebo. Specifically, on the 13-item clinician assessed Quantitative Myasthenia Gravis disease severity score, patients who received nipocalimab had an average reduction of 4.86 points from baseline compared to a reduction of 2.05 points in the placebo arm (P <.001). 

Similarly, MG-ADL response (defined as ≥ 2-point improvement from baseline) was significantly greater in the nipocalimab versus placebo arms (68.8% vs 52.6%; P =.021).

Subgroup analysis revealed similar results for the different types of seropositive patients, but there was no statistically significant difference in results for seronegative patients treated with nipocalimab versus placebo.

“The drug was pretty well tolerated and there was little difference, other than more patients with muscle spasm in the nipocalimab group (12.2% vs 3.1%),” said Vu. 

In addition, peripheral edema occurred in 11.2% of the nipocalimab group and none of the placebo-treated patients. Cholesterol levels were also higher in the nipocalimab arm, but there were no cardiac side effects, he added.
 

Encouraging Findings

Commenting on the findings, Neelam Goyal, MD, clinical professor of neurology and neurological sciences at Stanford University School of Medicine in Palo Alto, California, was encouraged.

“It’s a phase 3 trial, it’s positive, which is great, so it’ll be another drug on the market, another option for our patients,” she said. However, she cautioned, “their placebo arm did better than most placebos, so I think the delta is not as robust, but it was still statistically significant.” 

Goyal noted that, if approved, nipocalimab will be the third FcRn inhibitor in the MG field, preceded by efgartigimod (Vyvgart), which is approved for AChR antibody-positive disease, and rozanolixizumab-noli (Rystiggo) which is approved for both for AChR and MUSK antibody positive disease. 

“Its target of action is similar to the two drugs that are already on the market, but one thing that is unique about nipocalimab is that it is continuous dosing versus the other two medications that are given cyclically,” she said. 

“The reason that’s an upside, is that with cyclical dosing, patients have a return of symptoms. We treat, they get better, and then they get worse. That’s very disconcerting to patients. So, they want to be treated continuously.”

Additionally, she said there are some early data suggesting its safety in pregnancy.

Vu disclosed he is the USF Site Principal Investigator for MG clinical trials sponsored by Alexion/ AstraZeneca Rare Disease, Amgen, argenx, Cartesian Therapeutics, COUR Pharmaceuticals, Dianthus Therapeutics, Immunovant, Johnson & Johnson, NMD Pharmaceuticals, Regeneron Pharmaceuticals, and UCB, and has served as a speaker for Alexion/AstraZeneca Rare Disease, argenx, and CSL Behring. He performs consulting work for Alexion/AstraZeneca Rare Disease, argenx, Dianthus Therapeutics, ImmunAbs, and UCB. Goyal disclosed consultant, advisory or grant support from argenx, UCB, Alexion, and Janssen. The study was funded by Janssen. 
 

A version of this article appeared on Medscape.com.

SAVANNAH, GEORGIA – The investigational monoclonal antibody nipocalimab (Johnson & Johnson) is associated with significant improvement in patients with generalized myasthenia gravis (gMG) over a 24-week period, according to topline results from the phase 3 VIVACITY-MG3 study.

The VIVACITY-MG3 trial is the first registrational study of a neonatal fragment crystallizable receptor (FcRn) blocker to show sustained efficacy through 6 months of fixed schedule dosing.

Lead investigator Tuan Vu, MD, professor of neurology at the University of South Florida in Tampa, presented the findings at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024. 
 

Autoantibody Depletion

FcRN plays a crucial role in the transport of immunoglobulin G. Blocking it can reduce circulating immunoglobulin G antibodies, including pathogenic gMG autoantibodies. 

The double-blind, placebo-controlled trial included 196 adults with a broad range of seropositive gMG – who account for approximately 95% of the gMG patient population – and 42 seronegative patients.

The mean age was 52 years, 92% were female, and 63% were White. The mean disease duration was about 8 years. Among seropositive patients, 87.6% were acetylcholine receptor autoantibody-positive (AChR+), 10.5% were muscle-specific kinase autoantibody-positive (MuSK+), and 2% were low-density lipoprotein receptor-related protein 4 antibody positive.

They were randomly assigned 1:1 to receive either nipocalimab IV plus standard of care, or placebo plus standard of care for 24 weeks. A total of 87 patients in the nipocalimab arm and 82 in the placebo arm completed the study.

The primary efficacy endpoint was the Myasthenia Gravis Activities of Daily Living (MG-ADL) score. Participants treated with nipocalimab demonstrated a statistically significant improvement of 4.70 points from baseline, compared to the 3.25-point improvement in those treated with placebo (P =.002). 
 

Clinically Meaningful Changes?

“For someone living with gMG, a 1 to 2-point improvement on MG-ADL may be the difference between normal eating and frequent choking on food, or shortness of breath at rest and being on a ventilator,” the drug’s manufacturer noted in a release. 

Secondary endpoints were also better in the nipocalimab group, compared with participants on placebo. Specifically, on the 13-item clinician assessed Quantitative Myasthenia Gravis disease severity score, patients who received nipocalimab had an average reduction of 4.86 points from baseline compared to a reduction of 2.05 points in the placebo arm (P <.001). 

Similarly, MG-ADL response (defined as ≥ 2-point improvement from baseline) was significantly greater in the nipocalimab versus placebo arms (68.8% vs 52.6%; P =.021).

Subgroup analysis revealed similar results for the different types of seropositive patients, but there was no statistically significant difference in results for seronegative patients treated with nipocalimab versus placebo.

“The drug was pretty well tolerated and there was little difference, other than more patients with muscle spasm in the nipocalimab group (12.2% vs 3.1%),” said Vu. 

In addition, peripheral edema occurred in 11.2% of the nipocalimab group and none of the placebo-treated patients. Cholesterol levels were also higher in the nipocalimab arm, but there were no cardiac side effects, he added.
 

Encouraging Findings

Commenting on the findings, Neelam Goyal, MD, clinical professor of neurology and neurological sciences at Stanford University School of Medicine in Palo Alto, California, was encouraged.

“It’s a phase 3 trial, it’s positive, which is great, so it’ll be another drug on the market, another option for our patients,” she said. However, she cautioned, “their placebo arm did better than most placebos, so I think the delta is not as robust, but it was still statistically significant.” 

Goyal noted that, if approved, nipocalimab will be the third FcRn inhibitor in the MG field, preceded by efgartigimod (Vyvgart), which is approved for AChR antibody-positive disease, and rozanolixizumab-noli (Rystiggo) which is approved for both for AChR and MUSK antibody positive disease. 

“Its target of action is similar to the two drugs that are already on the market, but one thing that is unique about nipocalimab is that it is continuous dosing versus the other two medications that are given cyclically,” she said. 

“The reason that’s an upside, is that with cyclical dosing, patients have a return of symptoms. We treat, they get better, and then they get worse. That’s very disconcerting to patients. So, they want to be treated continuously.”

Additionally, she said there are some early data suggesting its safety in pregnancy.

Vu disclosed he is the USF Site Principal Investigator for MG clinical trials sponsored by Alexion/ AstraZeneca Rare Disease, Amgen, argenx, Cartesian Therapeutics, COUR Pharmaceuticals, Dianthus Therapeutics, Immunovant, Johnson & Johnson, NMD Pharmaceuticals, Regeneron Pharmaceuticals, and UCB, and has served as a speaker for Alexion/AstraZeneca Rare Disease, argenx, and CSL Behring. He performs consulting work for Alexion/AstraZeneca Rare Disease, argenx, Dianthus Therapeutics, ImmunAbs, and UCB. Goyal disclosed consultant, advisory or grant support from argenx, UCB, Alexion, and Janssen. The study was funded by Janssen. 
 

A version of this article appeared on Medscape.com.

SAVANNAH, GEORGIA – The investigational monoclonal antibody nipocalimab (Johnson & Johnson) is associated with significant improvement in patients with generalized myasthenia gravis (gMG) over a 24-week period, according to topline results from the phase 3 VIVACITY-MG3 study.

The VIVACITY-MG3 trial is the first registrational study of a neonatal fragment crystallizable receptor (FcRn) blocker to show sustained efficacy through 6 months of fixed schedule dosing.

Lead investigator Tuan Vu, MD, professor of neurology at the University of South Florida in Tampa, presented the findings at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024. 
 

Autoantibody Depletion

FcRN plays a crucial role in the transport of immunoglobulin G. Blocking it can reduce circulating immunoglobulin G antibodies, including pathogenic gMG autoantibodies. 

The double-blind, placebo-controlled trial included 196 adults with a broad range of seropositive gMG – who account for approximately 95% of the gMG patient population – and 42 seronegative patients.

The mean age was 52 years, 92% were female, and 63% were White. The mean disease duration was about 8 years. Among seropositive patients, 87.6% were acetylcholine receptor autoantibody-positive (AChR+), 10.5% were muscle-specific kinase autoantibody-positive (MuSK+), and 2% were low-density lipoprotein receptor-related protein 4 antibody positive.

They were randomly assigned 1:1 to receive either nipocalimab IV plus standard of care, or placebo plus standard of care for 24 weeks. A total of 87 patients in the nipocalimab arm and 82 in the placebo arm completed the study.

The primary efficacy endpoint was the Myasthenia Gravis Activities of Daily Living (MG-ADL) score. Participants treated with nipocalimab demonstrated a statistically significant improvement of 4.70 points from baseline, compared to the 3.25-point improvement in those treated with placebo (P =.002). 
 

Clinically Meaningful Changes?

“For someone living with gMG, a 1 to 2-point improvement on MG-ADL may be the difference between normal eating and frequent choking on food, or shortness of breath at rest and being on a ventilator,” the drug’s manufacturer noted in a release. 

Secondary endpoints were also better in the nipocalimab group, compared with participants on placebo. Specifically, on the 13-item clinician assessed Quantitative Myasthenia Gravis disease severity score, patients who received nipocalimab had an average reduction of 4.86 points from baseline compared to a reduction of 2.05 points in the placebo arm (P <.001). 

Similarly, MG-ADL response (defined as ≥ 2-point improvement from baseline) was significantly greater in the nipocalimab versus placebo arms (68.8% vs 52.6%; P =.021).

Subgroup analysis revealed similar results for the different types of seropositive patients, but there was no statistically significant difference in results for seronegative patients treated with nipocalimab versus placebo.

“The drug was pretty well tolerated and there was little difference, other than more patients with muscle spasm in the nipocalimab group (12.2% vs 3.1%),” said Vu. 

In addition, peripheral edema occurred in 11.2% of the nipocalimab group and none of the placebo-treated patients. Cholesterol levels were also higher in the nipocalimab arm, but there were no cardiac side effects, he added.
 

Encouraging Findings

Commenting on the findings, Neelam Goyal, MD, clinical professor of neurology and neurological sciences at Stanford University School of Medicine in Palo Alto, California, was encouraged.

“It’s a phase 3 trial, it’s positive, which is great, so it’ll be another drug on the market, another option for our patients,” she said. However, she cautioned, “their placebo arm did better than most placebos, so I think the delta is not as robust, but it was still statistically significant.” 

Goyal noted that, if approved, nipocalimab will be the third FcRn inhibitor in the MG field, preceded by efgartigimod (Vyvgart), which is approved for AChR antibody-positive disease, and rozanolixizumab-noli (Rystiggo) which is approved for both for AChR and MUSK antibody positive disease. 

“Its target of action is similar to the two drugs that are already on the market, but one thing that is unique about nipocalimab is that it is continuous dosing versus the other two medications that are given cyclically,” she said. 

“The reason that’s an upside, is that with cyclical dosing, patients have a return of symptoms. We treat, they get better, and then they get worse. That’s very disconcerting to patients. So, they want to be treated continuously.”

Additionally, she said there are some early data suggesting its safety in pregnancy.

Vu disclosed he is the USF Site Principal Investigator for MG clinical trials sponsored by Alexion/ AstraZeneca Rare Disease, Amgen, argenx, Cartesian Therapeutics, COUR Pharmaceuticals, Dianthus Therapeutics, Immunovant, Johnson & Johnson, NMD Pharmaceuticals, Regeneron Pharmaceuticals, and UCB, and has served as a speaker for Alexion/AstraZeneca Rare Disease, argenx, and CSL Behring. He performs consulting work for Alexion/AstraZeneca Rare Disease, argenx, Dianthus Therapeutics, ImmunAbs, and UCB. Goyal disclosed consultant, advisory or grant support from argenx, UCB, Alexion, and Janssen. The study was funded by Janssen. 
 

A version of this article appeared on Medscape.com.

SAVANNAH, GEORGIA — Inebilizumab, a first-in-class anti-CD19 B-cell depleting agent, demonstrated both safety and superior efficacy compared with placebo in patients with seropositive generalized myasthenia gravis (gMG), new phase 3 data showed.

“Based on these results, we have demonstrated that targeting B cells, including the antibody-secreting cells, is beneficial, and there is likely a role for this kind of therapeutic strategy for patients with myasthenia gravis,” said senior investigator Richard Nowak, MD.

The findings were published and presented at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.
 

Largest Cohort of Muscle-Specific Kinase (MuSK) Antibody–Positive Disease

The Myasthenia Gravis INebilizumab Trial study enrolled 238 participants, 60.8% women, mean age 47.5 years, from 79 sites in 18 countries. The participants were divided into two cohorts: 190 acetylcholine receptor (AChR) autoantibody–positive patients and 48 MuSK autoantibody–positive patients.

“This is the largest enrolled cohort of MuSK antibody–positive disease in a placebo-controlled trial to date,” said Nowak, director of the Yale Myasthenia Gravis Clinic and associate professor of neurology at Yale School of Medicine, in New Haven, Connecticut.

Both groups had similar gMG duration (mean 6.7 and 5.2 years for AChR+ and MuSK+ patients, respectively) and disease severity based on Myasthenia Gravis Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) baseline score. In addition, more than 80% of participants were on a prednisone equivalent dose greater than 5 mg daily at study entry.

Participants were randomly assigned to receive intravenous (IV) inebilizumab or IV placebo for 52 weeks (AChR+ group) or 26 weeks (MuSK+ group). In addition, study participants who were taking corticosteroids were tapered down starting at week 4 to prednisone 5 mg per day by week 24.

The trial met its primary endpoint, with a statistically significant change from baseline in MG-ADL and with a reduction of 4.2 points for inebilizumab versus 2.2 for placebo (P < .0001) at week 26 for the combined study population.

“You can see that the trend is actually going toward separation of the two groups after week 8 in the combined population,” said Nowak. Key secondary endpoints also showed statistically significant and clinically meaningful change from baseline compared with placebo.

This included a statistically significant change in QMG score inebilizumab compared with placebo for the combined population, a reduction of 4.8 versus 2.3 points, respectively, at week 26 (P = .0002).

In addition, both MG-ADL and QMG scores in the AChR+ subgroup were superior for inebilizumab versus placebo at week 26, with reductions of 4.2 versus 2.4, and 4.4 versus 2.0; P = .0015 and P = .0011, respectively.

In the MuSK+ subgroup, inebilizumab-treated patients had better MG-ADL scores than placebo-treated patients, with reductions of 3.9 versus 1.7 points, respectively, at week 26, although this difference did not meet statistical significance.

“There were no increased safety incidents in the inebilizumab-treated patients versus placebo, and a similar percentage of safety incidents in the AChR–positive and MuSK–positive groups. There were three deaths reported, all likely related to myasthenic crisis,” he said.

Nowak said that inebilizumab is “unique from the other currently FDA-approved medications for myasthenia gravis in that it’s targeting the upstream immunopathogenic mechanism of disease, specifically B cells — and B cells that are actually antibody-secreting cells.”

“It is targeting the factories of autoantibody production, whereas an FcRn antagonist, for example, is not targeting those factories but rather targeting what’s being produced — the immunoglobulins, IgGs in general,” he added.

Nowak said that what is particularly exciting about the drug is that the schedule is not very frequent. It begins with an initial IV infusion, followed by a second infusion 2 weeks later and a third infusion 6 months after that, so that patients are treated approximately every 6 months. This is in contrast to some other targeted therapies, where failing to address the underlying factors driving immunopathogenesis necessitates more regular and frequent medication administration.
 

New, Novel, Exciting

Commenting on the research, Neelam Goyal, MD, who chaired the session, said, “It’s definitely new, novel, interesting, exciting.”

Goyal, clinical professor of neurology and neurological sciences at Stanford University School of Medicine in Palo Alto, California, also noted that while B-cell depletion has shown some previous success in MG, it was with rituximab, a CD20 B-cell depleting agent.

She noted that unlike rituximab, which targets CD20, inebilizumab targets CD19, although both medications lead to B-cell depletion. Rituximab has proven effective for MUSK–positive MG, which accounts for approximately 5% of cases.

However, Goyal noted that the results for AChR–positive MG have been mixed — “the BeatMG trial was negative and the RINOMAX trial was positive. So, I think this is really interesting. It is exciting, and this drug is already on the market.”

She added that although inebilizumab is already US Food and Drug Administration–approved for the treatment of neuromyelitis optica, it still faces approval and indication hurdles for MG.

The future of this drug in the management algorithm for MG remains uncertain. Goyal noted that it’s “quite costly,” and although its benefits are evident — particularly for FcRn and complement inhibitors — some early data from chimeric antigen receptor T-cell therapy studies appear significantly more impressive.

Nowak disclosed research support from the National Institutes of Health, Genentech, Alexion Pharmaceuticals, argenx, Annexon Biosciences, Ra Pharmaceuticals (now UCB S.A.), the Myasthenia Gravis Foundation of America, Momenta Pharmaceuticals (now Janssen), Immunovant, Grifols, S.A., and Viela Bio, Horizon Therapeutics (now Amgen). Served as a consultant and advisor for Alexion Pharmaceuticals, argenx, Cabaletta Bio, Cour Pharmaceuticals, Ra Pharmaceuticals (now UCB S.A.), Immunovant, Momenta Pharmaceuticals (now Janssen), and Viela Bio (Horizon Therapeutics, now Amgen).

Goyal disclosed consultant, advisory, or grant support from argenx, UCB, Alexion, and Janssen. The study was funded by Amgen.
 

A version of this article appeared on Medscape.com.

SAVANNAH, GEORGIA — Inebilizumab, a first-in-class anti-CD19 B-cell depleting agent, demonstrated both safety and superior efficacy compared with placebo in patients with seropositive generalized myasthenia gravis (gMG), new phase 3 data showed.

“Based on these results, we have demonstrated that targeting B cells, including the antibody-secreting cells, is beneficial, and there is likely a role for this kind of therapeutic strategy for patients with myasthenia gravis,” said senior investigator Richard Nowak, MD.

The findings were published and presented at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.
 

Largest Cohort of Muscle-Specific Kinase (MuSK) Antibody–Positive Disease

The Myasthenia Gravis INebilizumab Trial study enrolled 238 participants, 60.8% women, mean age 47.5 years, from 79 sites in 18 countries. The participants were divided into two cohorts: 190 acetylcholine receptor (AChR) autoantibody–positive patients and 48 MuSK autoantibody–positive patients.

“This is the largest enrolled cohort of MuSK antibody–positive disease in a placebo-controlled trial to date,” said Nowak, director of the Yale Myasthenia Gravis Clinic and associate professor of neurology at Yale School of Medicine, in New Haven, Connecticut.

Both groups had similar gMG duration (mean 6.7 and 5.2 years for AChR+ and MuSK+ patients, respectively) and disease severity based on Myasthenia Gravis Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) baseline score. In addition, more than 80% of participants were on a prednisone equivalent dose greater than 5 mg daily at study entry.

Participants were randomly assigned to receive intravenous (IV) inebilizumab or IV placebo for 52 weeks (AChR+ group) or 26 weeks (MuSK+ group). In addition, study participants who were taking corticosteroids were tapered down starting at week 4 to prednisone 5 mg per day by week 24.

The trial met its primary endpoint, with a statistically significant change from baseline in MG-ADL and with a reduction of 4.2 points for inebilizumab versus 2.2 for placebo (P < .0001) at week 26 for the combined study population.

“You can see that the trend is actually going toward separation of the two groups after week 8 in the combined population,” said Nowak. Key secondary endpoints also showed statistically significant and clinically meaningful change from baseline compared with placebo.

This included a statistically significant change in QMG score inebilizumab compared with placebo for the combined population, a reduction of 4.8 versus 2.3 points, respectively, at week 26 (P = .0002).

In addition, both MG-ADL and QMG scores in the AChR+ subgroup were superior for inebilizumab versus placebo at week 26, with reductions of 4.2 versus 2.4, and 4.4 versus 2.0; P = .0015 and P = .0011, respectively.

In the MuSK+ subgroup, inebilizumab-treated patients had better MG-ADL scores than placebo-treated patients, with reductions of 3.9 versus 1.7 points, respectively, at week 26, although this difference did not meet statistical significance.

“There were no increased safety incidents in the inebilizumab-treated patients versus placebo, and a similar percentage of safety incidents in the AChR–positive and MuSK–positive groups. There were three deaths reported, all likely related to myasthenic crisis,” he said.

Nowak said that inebilizumab is “unique from the other currently FDA-approved medications for myasthenia gravis in that it’s targeting the upstream immunopathogenic mechanism of disease, specifically B cells — and B cells that are actually antibody-secreting cells.”

“It is targeting the factories of autoantibody production, whereas an FcRn antagonist, for example, is not targeting those factories but rather targeting what’s being produced — the immunoglobulins, IgGs in general,” he added.

Nowak said that what is particularly exciting about the drug is that the schedule is not very frequent. It begins with an initial IV infusion, followed by a second infusion 2 weeks later and a third infusion 6 months after that, so that patients are treated approximately every 6 months. This is in contrast to some other targeted therapies, where failing to address the underlying factors driving immunopathogenesis necessitates more regular and frequent medication administration.
 

New, Novel, Exciting

Commenting on the research, Neelam Goyal, MD, who chaired the session, said, “It’s definitely new, novel, interesting, exciting.”

Goyal, clinical professor of neurology and neurological sciences at Stanford University School of Medicine in Palo Alto, California, also noted that while B-cell depletion has shown some previous success in MG, it was with rituximab, a CD20 B-cell depleting agent.

She noted that unlike rituximab, which targets CD20, inebilizumab targets CD19, although both medications lead to B-cell depletion. Rituximab has proven effective for MUSK–positive MG, which accounts for approximately 5% of cases.

However, Goyal noted that the results for AChR–positive MG have been mixed — “the BeatMG trial was negative and the RINOMAX trial was positive. So, I think this is really interesting. It is exciting, and this drug is already on the market.”

She added that although inebilizumab is already US Food and Drug Administration–approved for the treatment of neuromyelitis optica, it still faces approval and indication hurdles for MG.

The future of this drug in the management algorithm for MG remains uncertain. Goyal noted that it’s “quite costly,” and although its benefits are evident — particularly for FcRn and complement inhibitors — some early data from chimeric antigen receptor T-cell therapy studies appear significantly more impressive.

Nowak disclosed research support from the National Institutes of Health, Genentech, Alexion Pharmaceuticals, argenx, Annexon Biosciences, Ra Pharmaceuticals (now UCB S.A.), the Myasthenia Gravis Foundation of America, Momenta Pharmaceuticals (now Janssen), Immunovant, Grifols, S.A., and Viela Bio, Horizon Therapeutics (now Amgen). Served as a consultant and advisor for Alexion Pharmaceuticals, argenx, Cabaletta Bio, Cour Pharmaceuticals, Ra Pharmaceuticals (now UCB S.A.), Immunovant, Momenta Pharmaceuticals (now Janssen), and Viela Bio (Horizon Therapeutics, now Amgen).

Goyal disclosed consultant, advisory, or grant support from argenx, UCB, Alexion, and Janssen. The study was funded by Amgen.
 

A version of this article appeared on Medscape.com.

SAVANNAH, GEORGIA — Inebilizumab, a first-in-class anti-CD19 B-cell depleting agent, demonstrated both safety and superior efficacy compared with placebo in patients with seropositive generalized myasthenia gravis (gMG), new phase 3 data showed.

“Based on these results, we have demonstrated that targeting B cells, including the antibody-secreting cells, is beneficial, and there is likely a role for this kind of therapeutic strategy for patients with myasthenia gravis,” said senior investigator Richard Nowak, MD.

The findings were published and presented at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.
 

Largest Cohort of Muscle-Specific Kinase (MuSK) Antibody–Positive Disease

The Myasthenia Gravis INebilizumab Trial study enrolled 238 participants, 60.8% women, mean age 47.5 years, from 79 sites in 18 countries. The participants were divided into two cohorts: 190 acetylcholine receptor (AChR) autoantibody–positive patients and 48 MuSK autoantibody–positive patients.

“This is the largest enrolled cohort of MuSK antibody–positive disease in a placebo-controlled trial to date,” said Nowak, director of the Yale Myasthenia Gravis Clinic and associate professor of neurology at Yale School of Medicine, in New Haven, Connecticut.

Both groups had similar gMG duration (mean 6.7 and 5.2 years for AChR+ and MuSK+ patients, respectively) and disease severity based on Myasthenia Gravis Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) baseline score. In addition, more than 80% of participants were on a prednisone equivalent dose greater than 5 mg daily at study entry.

Participants were randomly assigned to receive intravenous (IV) inebilizumab or IV placebo for 52 weeks (AChR+ group) or 26 weeks (MuSK+ group). In addition, study participants who were taking corticosteroids were tapered down starting at week 4 to prednisone 5 mg per day by week 24.

The trial met its primary endpoint, with a statistically significant change from baseline in MG-ADL and with a reduction of 4.2 points for inebilizumab versus 2.2 for placebo (P < .0001) at week 26 for the combined study population.

“You can see that the trend is actually going toward separation of the two groups after week 8 in the combined population,” said Nowak. Key secondary endpoints also showed statistically significant and clinically meaningful change from baseline compared with placebo.

This included a statistically significant change in QMG score inebilizumab compared with placebo for the combined population, a reduction of 4.8 versus 2.3 points, respectively, at week 26 (P = .0002).

In addition, both MG-ADL and QMG scores in the AChR+ subgroup were superior for inebilizumab versus placebo at week 26, with reductions of 4.2 versus 2.4, and 4.4 versus 2.0; P = .0015 and P = .0011, respectively.

In the MuSK+ subgroup, inebilizumab-treated patients had better MG-ADL scores than placebo-treated patients, with reductions of 3.9 versus 1.7 points, respectively, at week 26, although this difference did not meet statistical significance.

“There were no increased safety incidents in the inebilizumab-treated patients versus placebo, and a similar percentage of safety incidents in the AChR–positive and MuSK–positive groups. There were three deaths reported, all likely related to myasthenic crisis,” he said.

Nowak said that inebilizumab is “unique from the other currently FDA-approved medications for myasthenia gravis in that it’s targeting the upstream immunopathogenic mechanism of disease, specifically B cells — and B cells that are actually antibody-secreting cells.”

“It is targeting the factories of autoantibody production, whereas an FcRn antagonist, for example, is not targeting those factories but rather targeting what’s being produced — the immunoglobulins, IgGs in general,” he added.

Nowak said that what is particularly exciting about the drug is that the schedule is not very frequent. It begins with an initial IV infusion, followed by a second infusion 2 weeks later and a third infusion 6 months after that, so that patients are treated approximately every 6 months. This is in contrast to some other targeted therapies, where failing to address the underlying factors driving immunopathogenesis necessitates more regular and frequent medication administration.
 

New, Novel, Exciting

Commenting on the research, Neelam Goyal, MD, who chaired the session, said, “It’s definitely new, novel, interesting, exciting.”

Goyal, clinical professor of neurology and neurological sciences at Stanford University School of Medicine in Palo Alto, California, also noted that while B-cell depletion has shown some previous success in MG, it was with rituximab, a CD20 B-cell depleting agent.

She noted that unlike rituximab, which targets CD20, inebilizumab targets CD19, although both medications lead to B-cell depletion. Rituximab has proven effective for MUSK–positive MG, which accounts for approximately 5% of cases.

However, Goyal noted that the results for AChR–positive MG have been mixed — “the BeatMG trial was negative and the RINOMAX trial was positive. So, I think this is really interesting. It is exciting, and this drug is already on the market.”

She added that although inebilizumab is already US Food and Drug Administration–approved for the treatment of neuromyelitis optica, it still faces approval and indication hurdles for MG.

The future of this drug in the management algorithm for MG remains uncertain. Goyal noted that it’s “quite costly,” and although its benefits are evident — particularly for FcRn and complement inhibitors — some early data from chimeric antigen receptor T-cell therapy studies appear significantly more impressive.

Nowak disclosed research support from the National Institutes of Health, Genentech, Alexion Pharmaceuticals, argenx, Annexon Biosciences, Ra Pharmaceuticals (now UCB S.A.), the Myasthenia Gravis Foundation of America, Momenta Pharmaceuticals (now Janssen), Immunovant, Grifols, S.A., and Viela Bio, Horizon Therapeutics (now Amgen). Served as a consultant and advisor for Alexion Pharmaceuticals, argenx, Cabaletta Bio, Cour Pharmaceuticals, Ra Pharmaceuticals (now UCB S.A.), Immunovant, Momenta Pharmaceuticals (now Janssen), and Viela Bio (Horizon Therapeutics, now Amgen).

Goyal disclosed consultant, advisory, or grant support from argenx, UCB, Alexion, and Janssen. The study was funded by Amgen.
 

A version of this article appeared on Medscape.com.

Adults with bipolar disorder showed a decline in total white matter volume, but stability in other brain features over time compared to healthy controls, based on data from 88 individuals.

Patients with bipolar disorder demonstrate cognitive impairment and brain structure abnormalities, including global white matter loss, that have been associated with poor outcomes, but data on the stability or progression of neuroanatomical changes are limited, wrote Julian Macoveanu, PhD, of Copenhagen University Hospital, Denmark, and colleagues.

In a study published in The Journal of Affective Disorders, the researchers identified 97 adults aged 18 to 60 years with recently diagnosed bipolar disorder and matched them with 66 healthy controls. Participants were enrolled in the larger Bipolar Illness Onset (BIO) study. All participants underwent structural MRI and neuropsychological testing at baseline and were in full or partial remission based on total scores of 14 or less on the Hamilton Depression Rating Scale and the Young Mania Rating Scale. Approximately half of the participants (50 bipolar patients and 38 controls) participated in follow-up scans and testing after 6-27 months (mean 16 months), because of limited resources, according to the researchers.

The researchers compared changes in cortical gray matter volume and thickness, total cerebral white matter, hippocampal and amygdala volumes, estimated brain age, and cognitive functioning over time. In addition, they examined within-patient associations between baseline brain structure abnormalities and later mood episodes.

Overall, bipolar patients (BD) showed a significant decrease in total cerebral white matter from baseline, compared with healthy controls (HC) in mixed models (P = .006). “This effect was driven by BD patients showing a decrease in WM volume over time compared to HC who remained stable,” the researchers wrote, and the effect persisted in a post hoc analysis adjusting for subsyndromal symptoms and body mass index.

BD patients also had a larger amygdala volume at baseline and follow-up than HC, but no changes were noted between the groups. Changes in hippocampal volume also remained similar between the groups.

Analysis of cognitive data showed no significant differences in trajectories between BD patients and controls across cognitive domains or globally; although BD patients performed worse than controls at both time points.

BD patients in general experienced lower functioning and worse quality of life, compared with controls, but the trajectories of each group were similar for both functional and quality of life.

The researchers found no significant differences over time in total white matter, hippocampus, or amygdala volumes between BD patients who experienced at least one mood episode during the study period and those who remained in remission.

The findings were limited by several factors including the small sample size and limited generalizability of the findings because of the restriction to patients in full or partial remission, the researchers noted. Other limitations included the variation in follow-up time and the potential impact of psychotropic medication use.

However, the results were strengthened by the use of neuropsychiatric testing in addition to MRI to compare brain structure and cognitive function, the researchers said. The data suggest that both amygdala volume and cognitive impairment may be stable markers of BD soon after diagnosis, but that decreases in white matter may stem from disease progression.

The BIO study is funded by the Mental Health Services, Capital Region of Denmark, the Danish Council for Independent Research, Medical Sciences, Weimans Fund, Markedsmodningsfonden, Gangstedfonden, Læge Sofus Carl Emil og hustru Olga Boris Friis’ legat, Helsefonden, Innovation Fund Denmark, Copenhagen Center for Health Technology (CACHET), EU H2020 ITN, Augustinusfonden, and The Capital Region of Denmark. Macoveanu had no financial conflicts to disclose.

Adults with bipolar disorder showed a decline in total white matter volume, but stability in other brain features over time compared to healthy controls, based on data from 88 individuals.

Patients with bipolar disorder demonstrate cognitive impairment and brain structure abnormalities, including global white matter loss, that have been associated with poor outcomes, but data on the stability or progression of neuroanatomical changes are limited, wrote Julian Macoveanu, PhD, of Copenhagen University Hospital, Denmark, and colleagues.

In a study published in The Journal of Affective Disorders, the researchers identified 97 adults aged 18 to 60 years with recently diagnosed bipolar disorder and matched them with 66 healthy controls. Participants were enrolled in the larger Bipolar Illness Onset (BIO) study. All participants underwent structural MRI and neuropsychological testing at baseline and were in full or partial remission based on total scores of 14 or less on the Hamilton Depression Rating Scale and the Young Mania Rating Scale. Approximately half of the participants (50 bipolar patients and 38 controls) participated in follow-up scans and testing after 6-27 months (mean 16 months), because of limited resources, according to the researchers.

The researchers compared changes in cortical gray matter volume and thickness, total cerebral white matter, hippocampal and amygdala volumes, estimated brain age, and cognitive functioning over time. In addition, they examined within-patient associations between baseline brain structure abnormalities and later mood episodes.

Overall, bipolar patients (BD) showed a significant decrease in total cerebral white matter from baseline, compared with healthy controls (HC) in mixed models (P = .006). “This effect was driven by BD patients showing a decrease in WM volume over time compared to HC who remained stable,” the researchers wrote, and the effect persisted in a post hoc analysis adjusting for subsyndromal symptoms and body mass index.

BD patients also had a larger amygdala volume at baseline and follow-up than HC, but no changes were noted between the groups. Changes in hippocampal volume also remained similar between the groups.

Analysis of cognitive data showed no significant differences in trajectories between BD patients and controls across cognitive domains or globally; although BD patients performed worse than controls at both time points.

BD patients in general experienced lower functioning and worse quality of life, compared with controls, but the trajectories of each group were similar for both functional and quality of life.

The researchers found no significant differences over time in total white matter, hippocampus, or amygdala volumes between BD patients who experienced at least one mood episode during the study period and those who remained in remission.

The findings were limited by several factors including the small sample size and limited generalizability of the findings because of the restriction to patients in full or partial remission, the researchers noted. Other limitations included the variation in follow-up time and the potential impact of psychotropic medication use.

However, the results were strengthened by the use of neuropsychiatric testing in addition to MRI to compare brain structure and cognitive function, the researchers said. The data suggest that both amygdala volume and cognitive impairment may be stable markers of BD soon after diagnosis, but that decreases in white matter may stem from disease progression.

The BIO study is funded by the Mental Health Services, Capital Region of Denmark, the Danish Council for Independent Research, Medical Sciences, Weimans Fund, Markedsmodningsfonden, Gangstedfonden, Læge Sofus Carl Emil og hustru Olga Boris Friis’ legat, Helsefonden, Innovation Fund Denmark, Copenhagen Center for Health Technology (CACHET), EU H2020 ITN, Augustinusfonden, and The Capital Region of Denmark. Macoveanu had no financial conflicts to disclose.

Adults with bipolar disorder showed a decline in total white matter volume, but stability in other brain features over time compared to healthy controls, based on data from 88 individuals.

Patients with bipolar disorder demonstrate cognitive impairment and brain structure abnormalities, including global white matter loss, that have been associated with poor outcomes, but data on the stability or progression of neuroanatomical changes are limited, wrote Julian Macoveanu, PhD, of Copenhagen University Hospital, Denmark, and colleagues.

In a study published in The Journal of Affective Disorders, the researchers identified 97 adults aged 18 to 60 years with recently diagnosed bipolar disorder and matched them with 66 healthy controls. Participants were enrolled in the larger Bipolar Illness Onset (BIO) study. All participants underwent structural MRI and neuropsychological testing at baseline and were in full or partial remission based on total scores of 14 or less on the Hamilton Depression Rating Scale and the Young Mania Rating Scale. Approximately half of the participants (50 bipolar patients and 38 controls) participated in follow-up scans and testing after 6-27 months (mean 16 months), because of limited resources, according to the researchers.

The researchers compared changes in cortical gray matter volume and thickness, total cerebral white matter, hippocampal and amygdala volumes, estimated brain age, and cognitive functioning over time. In addition, they examined within-patient associations between baseline brain structure abnormalities and later mood episodes.

Overall, bipolar patients (BD) showed a significant decrease in total cerebral white matter from baseline, compared with healthy controls (HC) in mixed models (P = .006). “This effect was driven by BD patients showing a decrease in WM volume over time compared to HC who remained stable,” the researchers wrote, and the effect persisted in a post hoc analysis adjusting for subsyndromal symptoms and body mass index.

BD patients also had a larger amygdala volume at baseline and follow-up than HC, but no changes were noted between the groups. Changes in hippocampal volume also remained similar between the groups.

Analysis of cognitive data showed no significant differences in trajectories between BD patients and controls across cognitive domains or globally; although BD patients performed worse than controls at both time points.

BD patients in general experienced lower functioning and worse quality of life, compared with controls, but the trajectories of each group were similar for both functional and quality of life.

The researchers found no significant differences over time in total white matter, hippocampus, or amygdala volumes between BD patients who experienced at least one mood episode during the study period and those who remained in remission.

The findings were limited by several factors including the small sample size and limited generalizability of the findings because of the restriction to patients in full or partial remission, the researchers noted. Other limitations included the variation in follow-up time and the potential impact of psychotropic medication use.

However, the results were strengthened by the use of neuropsychiatric testing in addition to MRI to compare brain structure and cognitive function, the researchers said. The data suggest that both amygdala volume and cognitive impairment may be stable markers of BD soon after diagnosis, but that decreases in white matter may stem from disease progression.

The BIO study is funded by the Mental Health Services, Capital Region of Denmark, the Danish Council for Independent Research, Medical Sciences, Weimans Fund, Markedsmodningsfonden, Gangstedfonden, Læge Sofus Carl Emil og hustru Olga Boris Friis’ legat, Helsefonden, Innovation Fund Denmark, Copenhagen Center for Health Technology (CACHET), EU H2020 ITN, Augustinusfonden, and The Capital Region of Denmark. Macoveanu had no financial conflicts to disclose.

MOA — Mechanism of action — gets bandied about a lot.

Drug reps love it. Saying your product is a “first-in-class MOA” sounds great as they hand you a glossy brochure. It also features prominently in print ads, usually with pics of smiling people.

It’s a good thing to know, too, both medically and in a cool-science-geeky way. We want to understand what we’re prescribing will do to patients. We want to explain it to them, too.

It certainly helps to know that what we’re doing when treating a disorder using rational polypharmacy.

But at the same time we face the realization that it may not mean as much as we think it should. I don’t have to go back very far in my career to find Food and Drug Administration–approved medications that worked, but we didn’t have a clear reason why. I mean, we had a vague idea on a scientific basis, but we’re still guessing.

This didn’t stop us from using them, which is nothing new. The ancients had learned certain plants reduced pain and fever long before they understood what aspirin (and its MOA) was.

At the same time we’re now using drugs, such as the anti-amyloid treatments for Alzheimer’s disease, that should be more effective than one would think. Pulling the damaged molecules out of the brain should, on paper, make a dramatic difference ... but it doesn’t. I’m not saying they don’t have some benefit, but certainly not as much as you’d think. Of course, that’s based on our understanding of the disease mechanism being correct. We find there’s a lot more going on than we know.

Like so much in science (and this aspect of medicine is a science) the answers often lead to more questions.

Observation takes the lead over understanding in most things. Our ancestors knew what fire was, and how to use it, without any idea of what rapid exothermic oxidation was. (Admittedly, I have a degree in chemistry and can’t explain it myself anymore.)

The glossy ads and scientific data about MOA doesn’t mean much in my world if they don’t work. I’d rather have a drug that works, even if the MOA isn’t clear, than a known MOA without clinical benefit. My patients would say the same.

Clinical medicine, after all, is both an art and a science.

Dr. Block has a solo neurology practice in Scottsdale, Arizona.

MOA — Mechanism of action — gets bandied about a lot.

Drug reps love it. Saying your product is a “first-in-class MOA” sounds great as they hand you a glossy brochure. It also features prominently in print ads, usually with pics of smiling people.

It’s a good thing to know, too, both medically and in a cool-science-geeky way. We want to understand what we’re prescribing will do to patients. We want to explain it to them, too.

It certainly helps to know that what we’re doing when treating a disorder using rational polypharmacy.

But at the same time we face the realization that it may not mean as much as we think it should. I don’t have to go back very far in my career to find Food and Drug Administration–approved medications that worked, but we didn’t have a clear reason why. I mean, we had a vague idea on a scientific basis, but we’re still guessing.

This didn’t stop us from using them, which is nothing new. The ancients had learned certain plants reduced pain and fever long before they understood what aspirin (and its MOA) was.

At the same time we’re now using drugs, such as the anti-amyloid treatments for Alzheimer’s disease, that should be more effective than one would think. Pulling the damaged molecules out of the brain should, on paper, make a dramatic difference ... but it doesn’t. I’m not saying they don’t have some benefit, but certainly not as much as you’d think. Of course, that’s based on our understanding of the disease mechanism being correct. We find there’s a lot more going on than we know.

Like so much in science (and this aspect of medicine is a science) the answers often lead to more questions.

Observation takes the lead over understanding in most things. Our ancestors knew what fire was, and how to use it, without any idea of what rapid exothermic oxidation was. (Admittedly, I have a degree in chemistry and can’t explain it myself anymore.)

The glossy ads and scientific data about MOA doesn’t mean much in my world if they don’t work. I’d rather have a drug that works, even if the MOA isn’t clear, than a known MOA without clinical benefit. My patients would say the same.

Clinical medicine, after all, is both an art and a science.

Dr. Block has a solo neurology practice in Scottsdale, Arizona.

MOA — Mechanism of action — gets bandied about a lot.

Drug reps love it. Saying your product is a “first-in-class MOA” sounds great as they hand you a glossy brochure. It also features prominently in print ads, usually with pics of smiling people.

It’s a good thing to know, too, both medically and in a cool-science-geeky way. We want to understand what we’re prescribing will do to patients. We want to explain it to them, too.

It certainly helps to know that what we’re doing when treating a disorder using rational polypharmacy.

But at the same time we face the realization that it may not mean as much as we think it should. I don’t have to go back very far in my career to find Food and Drug Administration–approved medications that worked, but we didn’t have a clear reason why. I mean, we had a vague idea on a scientific basis, but we’re still guessing.

This didn’t stop us from using them, which is nothing new. The ancients had learned certain plants reduced pain and fever long before they understood what aspirin (and its MOA) was.

At the same time we’re now using drugs, such as the anti-amyloid treatments for Alzheimer’s disease, that should be more effective than one would think. Pulling the damaged molecules out of the brain should, on paper, make a dramatic difference ... but it doesn’t. I’m not saying they don’t have some benefit, but certainly not as much as you’d think. Of course, that’s based on our understanding of the disease mechanism being correct. We find there’s a lot more going on than we know.

Like so much in science (and this aspect of medicine is a science) the answers often lead to more questions.

Observation takes the lead over understanding in most things. Our ancestors knew what fire was, and how to use it, without any idea of what rapid exothermic oxidation was. (Admittedly, I have a degree in chemistry and can’t explain it myself anymore.)

The glossy ads and scientific data about MOA doesn’t mean much in my world if they don’t work. I’d rather have a drug that works, even if the MOA isn’t clear, than a known MOA without clinical benefit. My patients would say the same.

Clinical medicine, after all, is both an art and a science.

Dr. Block has a solo neurology practice in Scottsdale, Arizona.

Depending on one’s perspective, “mast cell activation syndrome (MCAS)” is either a relatively rare, narrowly defined severe allergic condition or a vastly underrecognized underlying cause of multiple chronic inflammatory conditions that affect roughly 17% of the entire population. 

Inappropriate activation of mast cells — now termed mast cell activation disease (MCAD) — has long been known to underlie allergic symptoms and inflammation, and far less commonly, neoplasias such as mastocytosis. The concept of chronic, persistent MCAS associated with aberrant growth and dystrophism is more recent, emerging only in the last couple of decades as a separate entity under the MCAD heading. 

Observational studies and clinical experience have linked signs and symptoms of MCAS with other inflammatory chronic conditions such as hypermobile Ehlers-Danlos Syndrome (EDS), postural orthostatic tachycardia syndrome (POTS), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and recently, long COVID. However, those conditions themselves are diagnostically challenging, and as yet there is no proof of causation.

The idea that MCAS is the entity — or at least, a key one — at the center of “a confoundingly, extraordinarily heterogeneous chronic multisystem polymorbidity” was the theme of a recent 4-day meeting of a professional group informally dubbed “Masterminds.” Since their first meeting in 2018, the group has grown from about 35 to nearly 650 multidisciplinary professionals. 

Stephanie L. Grach, MD, assistant professor of medicine at the Mayo Clinic, Rochester, Minnesota, gave an introductory talk about the importance of changing “the medical paradigm around complex chronic illness.” Much of the rest of the meeting was devoted to sharing approaches for managing MCAS comorbidities, including dysautonomia, hypermobility, and associated craniocervical dysfunction, and various other multi-system conditions characterized by chronic pain and/or fatigue. Several talks covered the use of agents that block mast cell activity as potential treatment. 

In an interview, Grach said “the meeting was an exciting example of how not only research, but also medicine, is moving forward, and it’s really cool to see that people are independently coming to very similar conclusions about shared pathologies, and because of that, the importance of overlap amongst complex medical conditions that historically have really been poorly addressed.”

She added, “mast cell activation, or mast cell hyperactivity, is one part of the greater picture. What’s important about the mast cell component is that of the multiple different targetable pathologies, it’s one that currently has potential available therapies that can be explored, some of them relatively easily.”

But Christopher Chang, MD, PhD, chief of the Pediatric Allergy and Immunology program, Joe DiMaggio Children’s Hospital, Hollywood, Florida, sees it differently. In an interview, he noted that the reason for disagreement over what constitutes MCAS is that “it doesn’t have a lot of objective findings that we can identify. ... We know that mast cells are important immune cells, just like all immune cells are important. It seems like whenever someone has unexplained symptoms, people try to blame it on mast cells. But it’s very hard to prove that.” 
 

Two Definitions Characterize the Illness Differently

One proposed “consensus” MCAS definition was first published in 2011 by a group led by hematologist Peter Valent, MD, of the Medical University of Vienna in Austria. It has been revised since, and similar versions adopted by medical societies, including the American Academy of Allergy, Asthma & Immunology (AAAAI). The most recent versions propose three core MCAS criteria: 

• Typical clinical signs of severe, recurrent (episodic) systemic (at least two organ systems) MCA are present (often in the form of anaphylaxis).
• The involvement of mast cells (MCs) is documented by biochemical studies, preferably an increase in serum tryptase levels from the individual’s baseline to plus 20% + 2 ng/mL.
• Response of symptoms to therapy with MC-stabilizing agents, drugs directed against MC mediator production, or drugs blocking mediator release or effects of MC-derived mediators.

The following year, a separate publication authored by Gerhard J. Molderings, MD, University of Bonn in Germany, and colleagues proposed a much broader MCAS definition. Also revised since, the latest “consensus-2” was published in 2020. This definition consists of one major criterion: “A constellation of clinical complaints attributable to pathologically increased MC activity, ie, MC mediator release syndrome.” This “constellation” involves conditions of nearly every organ system that, taken together, are estimated to affect up to 17% of the entire population. These are just a few examples: 

• Constitutional: Chronic fatigue, flushing, or sweats
• Dermatologic: Rashes or lesions
• Ophthalmologic: dry eyes
• Oral: Burning or itching in mouth
• Pulmonary: Airway inflammation at any/all levels
• Cardiovascular: Blood pressure lability or codiagnosis of POTS is common
• Gastrointestinal: Reflux, dysphagia, or malabsorption
• Genitourinary: Endometriosis, dysmenorrhea, or dyspareunia
• Musculoskeletal/connective tissue: Fibromyalgia or diagnosis of hypermobile EDS is common
• Neurologic: Headaches or sensory neuropathies
• Psychiatric: Depression or anxiety
• Endocrinologic: Thyroid disease or dyslipidemia
• Hematologic: Polycythemia or anemia (after ruling out other causes)

The diagnosis is made by fulfilling that major criterion, plus at least one objective assessment of pathologically increased release of MC mediators, including infiltrates, abnormal MC morphology, or MC genetic changes shown to increase MC activity. Other alternatives include evidence of above-normal levels of MC mediators, including tryptase, histamine or its metabolites, heparin, or chromatin A, in whole blood, serum, plasma, or urine. Symptomatic response to MC activation inhibitors can also be used but isn’t required as it is in the other definition. 
 

Underdiagnosis vs Overdiagnosis

Lawrence B. Afrin, MD, senior consultant in hematology/oncology at the AIM Center for Personalized Medicine, Westchester, New York, and lead author of the 2020 update of the broader “consensus-2” criteria, said in an interview, “we now know MCAS exists, and it’s prevalent, even though, for understandable and forgivable reasons, we’ve been missing it all along. ... If you see a patient who has this chronic, multisystem unwellness with general themes of inflammation plus or minus allergic issues and you can’t find some other rational explanation that better accounts for what’s going on ... then it’s reasonable to think to include MCAS in the differential diagnosis. If the patient happens not to fit the diagnostic criteria being advanced by one group, that doesn’t necessarily rule out the possibility that this is still going on.”

Afrin, along with his coauthors, faulted the narrower “consensus-1” definition for lacking data to support the “20% + 2” criteria for requiring the difficult determination of a patient’s “baseline” and for requiring evidence of response to treatment prior to making the diagnosis. Not all patients will respond to a given histamine blocker, he noted. 

But Lawrence B. Schwartz, MD, PhD, an author on both the Valent and AAAAI criteria, disagreed, noting that the narrower criteria “appear to have a high degree of specificity and sensitivity when the reaction is systemic and involves hypotension. Less severe clinical events, particularly involving the gastrointestinal or central nervous systems, do not have precise clinical or biomarker criteria for identifying mast cell involvement.” 

Added Schwartz, who is professor of medicine and chair of the Division of Rheumatology, Allergy, and Immunology and program director of Allergy and Immunology, Virginia Commonwealth University (VCU), Richmond, “when mast cell activation events occur only in the skin, we refer to it as chronic urticaria and in the airways or conjunctiva of allergic individuals as allergic asthma, rhinitis, and/or conjunctivitis. The absence of specific criteria for mast cell activation in the GI [gastrointestinal] tract or CNS [central nervous system] neither rules in mast cell involvement nor does it rule out mast cell involvement. Thus, more research is needed to find better diagnostic criteria.”

Schwartz also pointed to a recent paper reporting the use of artificial intelligence models to “quantify diagnostic precision and specificity” of “alternative” MCAS definitions. The conclusion was a “lack of specificity is pronounced in relation to multiple control criteria, raising the concern that alternative criteria could disproportionately contribute to MCAS overdiagnosis, to the exclusion of more appropriate diagnoses.”

During the meeting, Afrin acknowledged that the broader view risks overdiagnosis of MCAS. However, he also referenced Occam’s razor, the principle that the simplest explanation is probably the best one. “Which scenario is more likely? Multiple diagnoses and problems that are all independent of each other vs one diagnosis that’s biologically capable of causing most or all of the findings, ie, the simplest solution even if it’s not the most immediately obvious solution?”

He said in an interview: “Do we have any proof that MCAS is what’s underlying hypermobile Ehlers-Danlos or POTS or chronic fatigue? No, we don’t have any proof, not because anybody has done studies that have shown there to be no connection but simply because we’re so early in our awareness that the disease even exists that the necessary studies haven’t even been done yet.”

At the meeting, Afrin introduced proposals to turn the “Masterminds” group into a formal professional society and to launch a journal. He also gave an update on progress in developing a symptom assessment tool both for clinical use and to enable clinical trials of new drugs to target mast cells or their mediators. The plan is to field test the tool in 2025 and publish those results in 2026. 

Grach, Afrin, and Chang had no disclosures. Schwartz discovered tryptase and invented the Thermo Fisher tryptase assay, for which his institution (VCU) receives royalties that are shared with him. He also invented monoclonal antibodies used for detecting mast cells or basophils, for which VCU receives royalties from several companies, including Millipore, Santa Cruz, BioLegend, and Hycult Biotech, that are also shared with him. He is a paid consultant for Blueprint Medicines, Celldex Therapeutics, Invea, Third Harmonic Bio, HYCOR Biomedical, Jasper, TerSera Therapeutics, and GLG. He also serves on an AstraZeneca data safety monitoring board for a clinical trial involving benralizumab treatment of hypereosinophilic syndrome and receives royalties from UpToDate (biomarkers for anaphylaxis) and Goldman-Cecil Medicine (anaphylaxis).

A version of this article first appeared on Medscape.com.

Depending on one’s perspective, “mast cell activation syndrome (MCAS)” is either a relatively rare, narrowly defined severe allergic condition or a vastly underrecognized underlying cause of multiple chronic inflammatory conditions that affect roughly 17% of the entire population. 

Inappropriate activation of mast cells — now termed mast cell activation disease (MCAD) — has long been known to underlie allergic symptoms and inflammation, and far less commonly, neoplasias such as mastocytosis. The concept of chronic, persistent MCAS associated with aberrant growth and dystrophism is more recent, emerging only in the last couple of decades as a separate entity under the MCAD heading. 

Observational studies and clinical experience have linked signs and symptoms of MCAS with other inflammatory chronic conditions such as hypermobile Ehlers-Danlos Syndrome (EDS), postural orthostatic tachycardia syndrome (POTS), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and recently, long COVID. However, those conditions themselves are diagnostically challenging, and as yet there is no proof of causation.

The idea that MCAS is the entity — or at least, a key one — at the center of “a confoundingly, extraordinarily heterogeneous chronic multisystem polymorbidity” was the theme of a recent 4-day meeting of a professional group informally dubbed “Masterminds.” Since their first meeting in 2018, the group has grown from about 35 to nearly 650 multidisciplinary professionals. 

Stephanie L. Grach, MD, assistant professor of medicine at the Mayo Clinic, Rochester, Minnesota, gave an introductory talk about the importance of changing “the medical paradigm around complex chronic illness.” Much of the rest of the meeting was devoted to sharing approaches for managing MCAS comorbidities, including dysautonomia, hypermobility, and associated craniocervical dysfunction, and various other multi-system conditions characterized by chronic pain and/or fatigue. Several talks covered the use of agents that block mast cell activity as potential treatment. 

In an interview, Grach said “the meeting was an exciting example of how not only research, but also medicine, is moving forward, and it’s really cool to see that people are independently coming to very similar conclusions about shared pathologies, and because of that, the importance of overlap amongst complex medical conditions that historically have really been poorly addressed.”

She added, “mast cell activation, or mast cell hyperactivity, is one part of the greater picture. What’s important about the mast cell component is that of the multiple different targetable pathologies, it’s one that currently has potential available therapies that can be explored, some of them relatively easily.”

But Christopher Chang, MD, PhD, chief of the Pediatric Allergy and Immunology program, Joe DiMaggio Children’s Hospital, Hollywood, Florida, sees it differently. In an interview, he noted that the reason for disagreement over what constitutes MCAS is that “it doesn’t have a lot of objective findings that we can identify. ... We know that mast cells are important immune cells, just like all immune cells are important. It seems like whenever someone has unexplained symptoms, people try to blame it on mast cells. But it’s very hard to prove that.” 
 

Two Definitions Characterize the Illness Differently

One proposed “consensus” MCAS definition was first published in 2011 by a group led by hematologist Peter Valent, MD, of the Medical University of Vienna in Austria. It has been revised since, and similar versions adopted by medical societies, including the American Academy of Allergy, Asthma & Immunology (AAAAI). The most recent versions propose three core MCAS criteria: 

• Typical clinical signs of severe, recurrent (episodic) systemic (at least two organ systems) MCA are present (often in the form of anaphylaxis).
• The involvement of mast cells (MCs) is documented by biochemical studies, preferably an increase in serum tryptase levels from the individual’s baseline to plus 20% + 2 ng/mL.
• Response of symptoms to therapy with MC-stabilizing agents, drugs directed against MC mediator production, or drugs blocking mediator release or effects of MC-derived mediators.

The following year, a separate publication authored by Gerhard J. Molderings, MD, University of Bonn in Germany, and colleagues proposed a much broader MCAS definition. Also revised since, the latest “consensus-2” was published in 2020. This definition consists of one major criterion: “A constellation of clinical complaints attributable to pathologically increased MC activity, ie, MC mediator release syndrome.” This “constellation” involves conditions of nearly every organ system that, taken together, are estimated to affect up to 17% of the entire population. These are just a few examples: 

• Constitutional: Chronic fatigue, flushing, or sweats
• Dermatologic: Rashes or lesions
• Ophthalmologic: dry eyes
• Oral: Burning or itching in mouth
• Pulmonary: Airway inflammation at any/all levels
• Cardiovascular: Blood pressure lability or codiagnosis of POTS is common
• Gastrointestinal: Reflux, dysphagia, or malabsorption
• Genitourinary: Endometriosis, dysmenorrhea, or dyspareunia
• Musculoskeletal/connective tissue: Fibromyalgia or diagnosis of hypermobile EDS is common
• Neurologic: Headaches or sensory neuropathies
• Psychiatric: Depression or anxiety
• Endocrinologic: Thyroid disease or dyslipidemia
• Hematologic: Polycythemia or anemia (after ruling out other causes)

The diagnosis is made by fulfilling that major criterion, plus at least one objective assessment of pathologically increased release of MC mediators, including infiltrates, abnormal MC morphology, or MC genetic changes shown to increase MC activity. Other alternatives include evidence of above-normal levels of MC mediators, including tryptase, histamine or its metabolites, heparin, or chromatin A, in whole blood, serum, plasma, or urine. Symptomatic response to MC activation inhibitors can also be used but isn’t required as it is in the other definition. 
 

Underdiagnosis vs Overdiagnosis

Lawrence B. Afrin, MD, senior consultant in hematology/oncology at the AIM Center for Personalized Medicine, Westchester, New York, and lead author of the 2020 update of the broader “consensus-2” criteria, said in an interview, “we now know MCAS exists, and it’s prevalent, even though, for understandable and forgivable reasons, we’ve been missing it all along. ... If you see a patient who has this chronic, multisystem unwellness with general themes of inflammation plus or minus allergic issues and you can’t find some other rational explanation that better accounts for what’s going on ... then it’s reasonable to think to include MCAS in the differential diagnosis. If the patient happens not to fit the diagnostic criteria being advanced by one group, that doesn’t necessarily rule out the possibility that this is still going on.”

Afrin, along with his coauthors, faulted the narrower “consensus-1” definition for lacking data to support the “20% + 2” criteria for requiring the difficult determination of a patient’s “baseline” and for requiring evidence of response to treatment prior to making the diagnosis. Not all patients will respond to a given histamine blocker, he noted. 

But Lawrence B. Schwartz, MD, PhD, an author on both the Valent and AAAAI criteria, disagreed, noting that the narrower criteria “appear to have a high degree of specificity and sensitivity when the reaction is systemic and involves hypotension. Less severe clinical events, particularly involving the gastrointestinal or central nervous systems, do not have precise clinical or biomarker criteria for identifying mast cell involvement.” 

Added Schwartz, who is professor of medicine and chair of the Division of Rheumatology, Allergy, and Immunology and program director of Allergy and Immunology, Virginia Commonwealth University (VCU), Richmond, “when mast cell activation events occur only in the skin, we refer to it as chronic urticaria and in the airways or conjunctiva of allergic individuals as allergic asthma, rhinitis, and/or conjunctivitis. The absence of specific criteria for mast cell activation in the GI [gastrointestinal] tract or CNS [central nervous system] neither rules in mast cell involvement nor does it rule out mast cell involvement. Thus, more research is needed to find better diagnostic criteria.”

Schwartz also pointed to a recent paper reporting the use of artificial intelligence models to “quantify diagnostic precision and specificity” of “alternative” MCAS definitions. The conclusion was a “lack of specificity is pronounced in relation to multiple control criteria, raising the concern that alternative criteria could disproportionately contribute to MCAS overdiagnosis, to the exclusion of more appropriate diagnoses.”

During the meeting, Afrin acknowledged that the broader view risks overdiagnosis of MCAS. However, he also referenced Occam’s razor, the principle that the simplest explanation is probably the best one. “Which scenario is more likely? Multiple diagnoses and problems that are all independent of each other vs one diagnosis that’s biologically capable of causing most or all of the findings, ie, the simplest solution even if it’s not the most immediately obvious solution?”

He said in an interview: “Do we have any proof that MCAS is what’s underlying hypermobile Ehlers-Danlos or POTS or chronic fatigue? No, we don’t have any proof, not because anybody has done studies that have shown there to be no connection but simply because we’re so early in our awareness that the disease even exists that the necessary studies haven’t even been done yet.”

At the meeting, Afrin introduced proposals to turn the “Masterminds” group into a formal professional society and to launch a journal. He also gave an update on progress in developing a symptom assessment tool both for clinical use and to enable clinical trials of new drugs to target mast cells or their mediators. The plan is to field test the tool in 2025 and publish those results in 2026. 

Grach, Afrin, and Chang had no disclosures. Schwartz discovered tryptase and invented the Thermo Fisher tryptase assay, for which his institution (VCU) receives royalties that are shared with him. He also invented monoclonal antibodies used for detecting mast cells or basophils, for which VCU receives royalties from several companies, including Millipore, Santa Cruz, BioLegend, and Hycult Biotech, that are also shared with him. He is a paid consultant for Blueprint Medicines, Celldex Therapeutics, Invea, Third Harmonic Bio, HYCOR Biomedical, Jasper, TerSera Therapeutics, and GLG. He also serves on an AstraZeneca data safety monitoring board for a clinical trial involving benralizumab treatment of hypereosinophilic syndrome and receives royalties from UpToDate (biomarkers for anaphylaxis) and Goldman-Cecil Medicine (anaphylaxis).

A version of this article first appeared on Medscape.com.

Depending on one’s perspective, “mast cell activation syndrome (MCAS)” is either a relatively rare, narrowly defined severe allergic condition or a vastly underrecognized underlying cause of multiple chronic inflammatory conditions that affect roughly 17% of the entire population. 

Inappropriate activation of mast cells — now termed mast cell activation disease (MCAD) — has long been known to underlie allergic symptoms and inflammation, and far less commonly, neoplasias such as mastocytosis. The concept of chronic, persistent MCAS associated with aberrant growth and dystrophism is more recent, emerging only in the last couple of decades as a separate entity under the MCAD heading. 

Observational studies and clinical experience have linked signs and symptoms of MCAS with other inflammatory chronic conditions such as hypermobile Ehlers-Danlos Syndrome (EDS), postural orthostatic tachycardia syndrome (POTS), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and recently, long COVID. However, those conditions themselves are diagnostically challenging, and as yet there is no proof of causation.

The idea that MCAS is the entity — or at least, a key one — at the center of “a confoundingly, extraordinarily heterogeneous chronic multisystem polymorbidity” was the theme of a recent 4-day meeting of a professional group informally dubbed “Masterminds.” Since their first meeting in 2018, the group has grown from about 35 to nearly 650 multidisciplinary professionals. 

Stephanie L. Grach, MD, assistant professor of medicine at the Mayo Clinic, Rochester, Minnesota, gave an introductory talk about the importance of changing “the medical paradigm around complex chronic illness.” Much of the rest of the meeting was devoted to sharing approaches for managing MCAS comorbidities, including dysautonomia, hypermobility, and associated craniocervical dysfunction, and various other multi-system conditions characterized by chronic pain and/or fatigue. Several talks covered the use of agents that block mast cell activity as potential treatment. 

In an interview, Grach said “the meeting was an exciting example of how not only research, but also medicine, is moving forward, and it’s really cool to see that people are independently coming to very similar conclusions about shared pathologies, and because of that, the importance of overlap amongst complex medical conditions that historically have really been poorly addressed.”

She added, “mast cell activation, or mast cell hyperactivity, is one part of the greater picture. What’s important about the mast cell component is that of the multiple different targetable pathologies, it’s one that currently has potential available therapies that can be explored, some of them relatively easily.”

But Christopher Chang, MD, PhD, chief of the Pediatric Allergy and Immunology program, Joe DiMaggio Children’s Hospital, Hollywood, Florida, sees it differently. In an interview, he noted that the reason for disagreement over what constitutes MCAS is that “it doesn’t have a lot of objective findings that we can identify. ... We know that mast cells are important immune cells, just like all immune cells are important. It seems like whenever someone has unexplained symptoms, people try to blame it on mast cells. But it’s very hard to prove that.” 
 

Two Definitions Characterize the Illness Differently

One proposed “consensus” MCAS definition was first published in 2011 by a group led by hematologist Peter Valent, MD, of the Medical University of Vienna in Austria. It has been revised since, and similar versions adopted by medical societies, including the American Academy of Allergy, Asthma & Immunology (AAAAI). The most recent versions propose three core MCAS criteria: 

• Typical clinical signs of severe, recurrent (episodic) systemic (at least two organ systems) MCA are present (often in the form of anaphylaxis).
• The involvement of mast cells (MCs) is documented by biochemical studies, preferably an increase in serum tryptase levels from the individual’s baseline to plus 20% + 2 ng/mL.
• Response of symptoms to therapy with MC-stabilizing agents, drugs directed against MC mediator production, or drugs blocking mediator release or effects of MC-derived mediators.

The following year, a separate publication authored by Gerhard J. Molderings, MD, University of Bonn in Germany, and colleagues proposed a much broader MCAS definition. Also revised since, the latest “consensus-2” was published in 2020. This definition consists of one major criterion: “A constellation of clinical complaints attributable to pathologically increased MC activity, ie, MC mediator release syndrome.” This “constellation” involves conditions of nearly every organ system that, taken together, are estimated to affect up to 17% of the entire population. These are just a few examples: 

• Constitutional: Chronic fatigue, flushing, or sweats
• Dermatologic: Rashes or lesions
• Ophthalmologic: dry eyes
• Oral: Burning or itching in mouth
• Pulmonary: Airway inflammation at any/all levels
• Cardiovascular: Blood pressure lability or codiagnosis of POTS is common
• Gastrointestinal: Reflux, dysphagia, or malabsorption
• Genitourinary: Endometriosis, dysmenorrhea, or dyspareunia
• Musculoskeletal/connective tissue: Fibromyalgia or diagnosis of hypermobile EDS is common
• Neurologic: Headaches or sensory neuropathies
• Psychiatric: Depression or anxiety
• Endocrinologic: Thyroid disease or dyslipidemia
• Hematologic: Polycythemia or anemia (after ruling out other causes)

The diagnosis is made by fulfilling that major criterion, plus at least one objective assessment of pathologically increased release of MC mediators, including infiltrates, abnormal MC morphology, or MC genetic changes shown to increase MC activity. Other alternatives include evidence of above-normal levels of MC mediators, including tryptase, histamine or its metabolites, heparin, or chromatin A, in whole blood, serum, plasma, or urine. Symptomatic response to MC activation inhibitors can also be used but isn’t required as it is in the other definition. 
 

Underdiagnosis vs Overdiagnosis

Lawrence B. Afrin, MD, senior consultant in hematology/oncology at the AIM Center for Personalized Medicine, Westchester, New York, and lead author of the 2020 update of the broader “consensus-2” criteria, said in an interview, “we now know MCAS exists, and it’s prevalent, even though, for understandable and forgivable reasons, we’ve been missing it all along. ... If you see a patient who has this chronic, multisystem unwellness with general themes of inflammation plus or minus allergic issues and you can’t find some other rational explanation that better accounts for what’s going on ... then it’s reasonable to think to include MCAS in the differential diagnosis. If the patient happens not to fit the diagnostic criteria being advanced by one group, that doesn’t necessarily rule out the possibility that this is still going on.”

Afrin, along with his coauthors, faulted the narrower “consensus-1” definition for lacking data to support the “20% + 2” criteria for requiring the difficult determination of a patient’s “baseline” and for requiring evidence of response to treatment prior to making the diagnosis. Not all patients will respond to a given histamine blocker, he noted. 

But Lawrence B. Schwartz, MD, PhD, an author on both the Valent and AAAAI criteria, disagreed, noting that the narrower criteria “appear to have a high degree of specificity and sensitivity when the reaction is systemic and involves hypotension. Less severe clinical events, particularly involving the gastrointestinal or central nervous systems, do not have precise clinical or biomarker criteria for identifying mast cell involvement.” 

Added Schwartz, who is professor of medicine and chair of the Division of Rheumatology, Allergy, and Immunology and program director of Allergy and Immunology, Virginia Commonwealth University (VCU), Richmond, “when mast cell activation events occur only in the skin, we refer to it as chronic urticaria and in the airways or conjunctiva of allergic individuals as allergic asthma, rhinitis, and/or conjunctivitis. The absence of specific criteria for mast cell activation in the GI [gastrointestinal] tract or CNS [central nervous system] neither rules in mast cell involvement nor does it rule out mast cell involvement. Thus, more research is needed to find better diagnostic criteria.”

Schwartz also pointed to a recent paper reporting the use of artificial intelligence models to “quantify diagnostic precision and specificity” of “alternative” MCAS definitions. The conclusion was a “lack of specificity is pronounced in relation to multiple control criteria, raising the concern that alternative criteria could disproportionately contribute to MCAS overdiagnosis, to the exclusion of more appropriate diagnoses.”

During the meeting, Afrin acknowledged that the broader view risks overdiagnosis of MCAS. However, he also referenced Occam’s razor, the principle that the simplest explanation is probably the best one. “Which scenario is more likely? Multiple diagnoses and problems that are all independent of each other vs one diagnosis that’s biologically capable of causing most or all of the findings, ie, the simplest solution even if it’s not the most immediately obvious solution?”

He said in an interview: “Do we have any proof that MCAS is what’s underlying hypermobile Ehlers-Danlos or POTS or chronic fatigue? No, we don’t have any proof, not because anybody has done studies that have shown there to be no connection but simply because we’re so early in our awareness that the disease even exists that the necessary studies haven’t even been done yet.”

At the meeting, Afrin introduced proposals to turn the “Masterminds” group into a formal professional society and to launch a journal. He also gave an update on progress in developing a symptom assessment tool both for clinical use and to enable clinical trials of new drugs to target mast cells or their mediators. The plan is to field test the tool in 2025 and publish those results in 2026. 

Grach, Afrin, and Chang had no disclosures. Schwartz discovered tryptase and invented the Thermo Fisher tryptase assay, for which his institution (VCU) receives royalties that are shared with him. He also invented monoclonal antibodies used for detecting mast cells or basophils, for which VCU receives royalties from several companies, including Millipore, Santa Cruz, BioLegend, and Hycult Biotech, that are also shared with him. He is a paid consultant for Blueprint Medicines, Celldex Therapeutics, Invea, Third Harmonic Bio, HYCOR Biomedical, Jasper, TerSera Therapeutics, and GLG. He also serves on an AstraZeneca data safety monitoring board for a clinical trial involving benralizumab treatment of hypereosinophilic syndrome and receives royalties from UpToDate (biomarkers for anaphylaxis) and Goldman-Cecil Medicine (anaphylaxis).

A version of this article first appeared on Medscape.com.

TOPLINE:

Deprescribing antihypertensive medications is associated with a 12% lower likelihood of cognitive decline in older nursing home residents, a new study suggests. The association was strongest among those with dementia.

METHODOLOGY:

• The cohort study included 12,644 long-term care residents (mean age, 77.7 years; 97% men; 17.5% Black) with stays of at least 12 weeks from 2006 to 2019.
• Residents who experienced either a reduction in the total number of antihypertensive medications or a sustained 30% decrease in dosage for at least 2 weeks were classified as deprescribing users (n = 1290). Those with no medication changes were considered stable users (n = 11,354).
• The primary outcome was cognitive impairment assessed using the four-point Cognitive Function Scale (CFS), with the score proportional to the severity of impairment.
• The median follow-up duration was 23 weeks for the deprescribing users and 21 weeks for the stable users.

TAKEAWAY:

• Deprescribing antihypertensives was associated with a 12% lower likelihood of progressing to a worse CFS score per 12-week period (odds ratio [OR], 0.88; 95% CI, 0.78-0.99), compared with stable users.
• Among residents with dementia, deprescribing was associated with a 16% reduced likelihood of cognitive decline per 12-week period (OR, 0.84; 95% CI, 0.72-0.98).
• At the end of follow-up, 12% of residents had a higher CFS score and 7.7% had a lower CFS score.
• In the intention-to-treat analysis, the association between deprescribing antihypertensive medications and reduced cognitive decline remained consistent (OR, 0.94; 95% CI, 0.90-0.98).

IN PRACTICE:

“This work highlights the need for patient-centered approaches to deprescribing, ensuring that medication regimens for older adults are optimized to preserve cognitive function and minimize potential harms,” the study authors wrote.

SOURCE:

The study was led by Bocheng Jing, MS, Department of Medicine, University of California, San Francisco. It was published online in JAMA Internal Medicine.

LIMITATIONS:

The study population included predominantly men and White individuals, limiting the generalizability of the results to women and other racial and ethnic groups. The findings may not be applicable to patients with heart failure owing to their noninclusion. The specificity of dementia diagnosis was limited, as this study combined various forms of dementia, making it challenging to differentiate the impacts among subgroups.

DISCLOSURES:

This study was supported by the US National Institute on Aging. Two authors reported receiving grants, honoraria, consulting fees, or royalties from various sources. Details are provided in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Deprescribing antihypertensive medications is associated with a 12% lower likelihood of cognitive decline in older nursing home residents, a new study suggests. The association was strongest among those with dementia.

METHODOLOGY:

• The cohort study included 12,644 long-term care residents (mean age, 77.7 years; 97% men; 17.5% Black) with stays of at least 12 weeks from 2006 to 2019.
• Residents who experienced either a reduction in the total number of antihypertensive medications or a sustained 30% decrease in dosage for at least 2 weeks were classified as deprescribing users (n = 1290). Those with no medication changes were considered stable users (n = 11,354).
• The primary outcome was cognitive impairment assessed using the four-point Cognitive Function Scale (CFS), with the score proportional to the severity of impairment.
• The median follow-up duration was 23 weeks for the deprescribing users and 21 weeks for the stable users.

TAKEAWAY:

• Deprescribing antihypertensives was associated with a 12% lower likelihood of progressing to a worse CFS score per 12-week period (odds ratio [OR], 0.88; 95% CI, 0.78-0.99), compared with stable users.
• Among residents with dementia, deprescribing was associated with a 16% reduced likelihood of cognitive decline per 12-week period (OR, 0.84; 95% CI, 0.72-0.98).
• At the end of follow-up, 12% of residents had a higher CFS score and 7.7% had a lower CFS score.
• In the intention-to-treat analysis, the association between deprescribing antihypertensive medications and reduced cognitive decline remained consistent (OR, 0.94; 95% CI, 0.90-0.98).

IN PRACTICE:

“This work highlights the need for patient-centered approaches to deprescribing, ensuring that medication regimens for older adults are optimized to preserve cognitive function and minimize potential harms,” the study authors wrote.

SOURCE:

The study was led by Bocheng Jing, MS, Department of Medicine, University of California, San Francisco. It was published online in JAMA Internal Medicine.

LIMITATIONS:

The study population included predominantly men and White individuals, limiting the generalizability of the results to women and other racial and ethnic groups. The findings may not be applicable to patients with heart failure owing to their noninclusion. The specificity of dementia diagnosis was limited, as this study combined various forms of dementia, making it challenging to differentiate the impacts among subgroups.

DISCLOSURES:

This study was supported by the US National Institute on Aging. Two authors reported receiving grants, honoraria, consulting fees, or royalties from various sources. Details are provided in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Deprescribing antihypertensive medications is associated with a 12% lower likelihood of cognitive decline in older nursing home residents, a new study suggests. The association was strongest among those with dementia.

METHODOLOGY:

• The cohort study included 12,644 long-term care residents (mean age, 77.7 years; 97% men; 17.5% Black) with stays of at least 12 weeks from 2006 to 2019.
• Residents who experienced either a reduction in the total number of antihypertensive medications or a sustained 30% decrease in dosage for at least 2 weeks were classified as deprescribing users (n = 1290). Those with no medication changes were considered stable users (n = 11,354).
• The primary outcome was cognitive impairment assessed using the four-point Cognitive Function Scale (CFS), with the score proportional to the severity of impairment.
• The median follow-up duration was 23 weeks for the deprescribing users and 21 weeks for the stable users.

TAKEAWAY:

• Deprescribing antihypertensives was associated with a 12% lower likelihood of progressing to a worse CFS score per 12-week period (odds ratio [OR], 0.88; 95% CI, 0.78-0.99), compared with stable users.
• Among residents with dementia, deprescribing was associated with a 16% reduced likelihood of cognitive decline per 12-week period (OR, 0.84; 95% CI, 0.72-0.98).
• At the end of follow-up, 12% of residents had a higher CFS score and 7.7% had a lower CFS score.
• In the intention-to-treat analysis, the association between deprescribing antihypertensive medications and reduced cognitive decline remained consistent (OR, 0.94; 95% CI, 0.90-0.98).

IN PRACTICE:

“This work highlights the need for patient-centered approaches to deprescribing, ensuring that medication regimens for older adults are optimized to preserve cognitive function and minimize potential harms,” the study authors wrote.

SOURCE:

The study was led by Bocheng Jing, MS, Department of Medicine, University of California, San Francisco. It was published online in JAMA Internal Medicine.

LIMITATIONS:

The study population included predominantly men and White individuals, limiting the generalizability of the results to women and other racial and ethnic groups. The findings may not be applicable to patients with heart failure owing to their noninclusion. The specificity of dementia diagnosis was limited, as this study combined various forms of dementia, making it challenging to differentiate the impacts among subgroups.

DISCLOSURES:

This study was supported by the US National Institute on Aging. Two authors reported receiving grants, honoraria, consulting fees, or royalties from various sources. Details are provided in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.