Clinician Reviews

Swiss scientists have identified immune system abnormalities in patients with long COVID that might open the door to new diagnostic tests and treatments.

The researchers found that a group of proteins in the blood that are part of the body’s immune response called the “complement system” are not working properly in patients with long COVID.

Blood samples turned up important differences between those who recovered from COVID and those who did not. These differences might be used as biomarkers to diagnose long COVID and might even point the way to new treatments for the condition, the researchers said.

By testing for 6500 blood proteins in about 300 patients, the Swiss researchers found that dysfunctional complement system proteins could possibly explain fatigue and “smoldering inflammation,” said Onur Boyman, MD, a professor of immunology from University Hospital Zurich in Zurich, Switzerland.

Long COVID has been linked to hundreds of symptoms including brain fog, chronic fatigue, pain, and digestive issues. Various factors drive the condition and likely work with one another other, said David Putrino, PhD, from the Icahn School of Medicine at Mount Sinai in New York City. The Swiss study is useful because “we’re trying to best understand how we can explain all of this far-reaching pathobiology,” he said.
 

Testing Across Continents

Dr. Boyman’s team collected blood samples from people with COVID in Europe and New York and tracked them. They compared those who developed long COVID with those who did not. One protein that was most unique to patients with long COVID is a blood complement that activates the immune system, Dr. Boyman said. But in people with long COVID, the immune response stays activated after the virus is gone. He described the response as “smoldering inflammation” in multiple organs, including the lungs and the gastrointestinal system.

The complement system also plays a role in clearing the body of dead cells. If the cells “lie around too much,” they can trigger an immune response, he said.

That may explain exercise intolerance in people with long COVID, Dr. Boyman said. Some people with long COVID have inflammation in the epithelium — the inner layer of their blood vessels. This would make it harder for the circulatory systems to recover from exercise, Dr. Boyman said.

“We think this regulated complement system is actually quite a central piece of the puzzle,” he said.
 

The Microclot Connection

The findings also support past research linking blood clots to long COVID. He suggested that clinicians and researchers consider testing drugs that regulate or inhibit the complementary system as a treatment of long COVID. Dr. Boyman said they are currently used for rare immune diseases.

Resia Pretorius, PhD, a professor of physiological sciences at Stellenbosch University in Stellenbosch, South Africa, said scientists studying the role of microclots in patients with long COVID often see complementary proteins inside the clots, so it has already been associated with long COVID. But she likened this clotting process to a garbage can that “just rolls along and collects everything that gets in its way. I think they are actively driving inflammation and disease.”

One factor complicating long COVID diagnosis and treatment is that it is a complex condition that involves multiple organ systems. That’s why the latest research suggests an underlying driver for the multiple symptoms of long COVID, Dr. Putrino said.

“Not every person has every symptom; not every person has every organ system affected,” Dr. Putrino said. “Whatever is happening is decided across the whole body.”
 

Research Offers New Direction

The Swiss paper contributes to the effort to identify systemic issues contributing to long COVID. It gives researchers one more thing to test for and link to specific, long COVID symptoms, opening the door to new treatments, Dr. Putrino said.

He doesn’t think the study supports treating the complement dysfunction if researchers don’t know what’s driving it. It may be complicated by the body’s failure to clear the virus completely, he said.

Dr. Pretorius recommended doctors test patients with long COVID for specific symptoms that may be treated using existing therapies. “If you think your patient had vascular pathology, you can test for it,” she said.

Some patients have found certain supplements and over-the-counter products helpful, she said. Among them: Coenzyme Q 10 and clot-busters such as streptokinase and Nattokinase (though she noted some doctors may not be comfortable with supplements).

“It’s the only thing we have until we’ve got trials,” she said.

Dr. Putrino said more research is needed to identify potential root causes and symptoms. A common refrain, but the only thing that will lead to specific treatments.

A version of this article appeared on Medscape.com.

Swiss scientists have identified immune system abnormalities in patients with long COVID that might open the door to new diagnostic tests and treatments.

The researchers found that a group of proteins in the blood that are part of the body’s immune response called the “complement system” are not working properly in patients with long COVID.

Blood samples turned up important differences between those who recovered from COVID and those who did not. These differences might be used as biomarkers to diagnose long COVID and might even point the way to new treatments for the condition, the researchers said.

By testing for 6500 blood proteins in about 300 patients, the Swiss researchers found that dysfunctional complement system proteins could possibly explain fatigue and “smoldering inflammation,” said Onur Boyman, MD, a professor of immunology from University Hospital Zurich in Zurich, Switzerland.

Long COVID has been linked to hundreds of symptoms including brain fog, chronic fatigue, pain, and digestive issues. Various factors drive the condition and likely work with one another other, said David Putrino, PhD, from the Icahn School of Medicine at Mount Sinai in New York City. The Swiss study is useful because “we’re trying to best understand how we can explain all of this far-reaching pathobiology,” he said.
 

Testing Across Continents

Dr. Boyman’s team collected blood samples from people with COVID in Europe and New York and tracked them. They compared those who developed long COVID with those who did not. One protein that was most unique to patients with long COVID is a blood complement that activates the immune system, Dr. Boyman said. But in people with long COVID, the immune response stays activated after the virus is gone. He described the response as “smoldering inflammation” in multiple organs, including the lungs and the gastrointestinal system.

The complement system also plays a role in clearing the body of dead cells. If the cells “lie around too much,” they can trigger an immune response, he said.

That may explain exercise intolerance in people with long COVID, Dr. Boyman said. Some people with long COVID have inflammation in the epithelium — the inner layer of their blood vessels. This would make it harder for the circulatory systems to recover from exercise, Dr. Boyman said.

“We think this regulated complement system is actually quite a central piece of the puzzle,” he said.
 

The Microclot Connection

The findings also support past research linking blood clots to long COVID. He suggested that clinicians and researchers consider testing drugs that regulate or inhibit the complementary system as a treatment of long COVID. Dr. Boyman said they are currently used for rare immune diseases.

Resia Pretorius, PhD, a professor of physiological sciences at Stellenbosch University in Stellenbosch, South Africa, said scientists studying the role of microclots in patients with long COVID often see complementary proteins inside the clots, so it has already been associated with long COVID. But she likened this clotting process to a garbage can that “just rolls along and collects everything that gets in its way. I think they are actively driving inflammation and disease.”

One factor complicating long COVID diagnosis and treatment is that it is a complex condition that involves multiple organ systems. That’s why the latest research suggests an underlying driver for the multiple symptoms of long COVID, Dr. Putrino said.

“Not every person has every symptom; not every person has every organ system affected,” Dr. Putrino said. “Whatever is happening is decided across the whole body.”
 

Research Offers New Direction

The Swiss paper contributes to the effort to identify systemic issues contributing to long COVID. It gives researchers one more thing to test for and link to specific, long COVID symptoms, opening the door to new treatments, Dr. Putrino said.

He doesn’t think the study supports treating the complement dysfunction if researchers don’t know what’s driving it. It may be complicated by the body’s failure to clear the virus completely, he said.

Dr. Pretorius recommended doctors test patients with long COVID for specific symptoms that may be treated using existing therapies. “If you think your patient had vascular pathology, you can test for it,” she said.

Some patients have found certain supplements and over-the-counter products helpful, she said. Among them: Coenzyme Q 10 and clot-busters such as streptokinase and Nattokinase (though she noted some doctors may not be comfortable with supplements).

“It’s the only thing we have until we’ve got trials,” she said.

Dr. Putrino said more research is needed to identify potential root causes and symptoms. A common refrain, but the only thing that will lead to specific treatments.

A version of this article appeared on Medscape.com.

Swiss scientists have identified immune system abnormalities in patients with long COVID that might open the door to new diagnostic tests and treatments.

The researchers found that a group of proteins in the blood that are part of the body’s immune response called the “complement system” are not working properly in patients with long COVID.

Blood samples turned up important differences between those who recovered from COVID and those who did not. These differences might be used as biomarkers to diagnose long COVID and might even point the way to new treatments for the condition, the researchers said.

By testing for 6500 blood proteins in about 300 patients, the Swiss researchers found that dysfunctional complement system proteins could possibly explain fatigue and “smoldering inflammation,” said Onur Boyman, MD, a professor of immunology from University Hospital Zurich in Zurich, Switzerland.

Long COVID has been linked to hundreds of symptoms including brain fog, chronic fatigue, pain, and digestive issues. Various factors drive the condition and likely work with one another other, said David Putrino, PhD, from the Icahn School of Medicine at Mount Sinai in New York City. The Swiss study is useful because “we’re trying to best understand how we can explain all of this far-reaching pathobiology,” he said.
 

Testing Across Continents

Dr. Boyman’s team collected blood samples from people with COVID in Europe and New York and tracked them. They compared those who developed long COVID with those who did not. One protein that was most unique to patients with long COVID is a blood complement that activates the immune system, Dr. Boyman said. But in people with long COVID, the immune response stays activated after the virus is gone. He described the response as “smoldering inflammation” in multiple organs, including the lungs and the gastrointestinal system.

The complement system also plays a role in clearing the body of dead cells. If the cells “lie around too much,” they can trigger an immune response, he said.

That may explain exercise intolerance in people with long COVID, Dr. Boyman said. Some people with long COVID have inflammation in the epithelium — the inner layer of their blood vessels. This would make it harder for the circulatory systems to recover from exercise, Dr. Boyman said.

“We think this regulated complement system is actually quite a central piece of the puzzle,” he said.
 

The Microclot Connection

The findings also support past research linking blood clots to long COVID. He suggested that clinicians and researchers consider testing drugs that regulate or inhibit the complementary system as a treatment of long COVID. Dr. Boyman said they are currently used for rare immune diseases.

Resia Pretorius, PhD, a professor of physiological sciences at Stellenbosch University in Stellenbosch, South Africa, said scientists studying the role of microclots in patients with long COVID often see complementary proteins inside the clots, so it has already been associated with long COVID. But she likened this clotting process to a garbage can that “just rolls along and collects everything that gets in its way. I think they are actively driving inflammation and disease.”

One factor complicating long COVID diagnosis and treatment is that it is a complex condition that involves multiple organ systems. That’s why the latest research suggests an underlying driver for the multiple symptoms of long COVID, Dr. Putrino said.

“Not every person has every symptom; not every person has every organ system affected,” Dr. Putrino said. “Whatever is happening is decided across the whole body.”
 

Research Offers New Direction

The Swiss paper contributes to the effort to identify systemic issues contributing to long COVID. It gives researchers one more thing to test for and link to specific, long COVID symptoms, opening the door to new treatments, Dr. Putrino said.

He doesn’t think the study supports treating the complement dysfunction if researchers don’t know what’s driving it. It may be complicated by the body’s failure to clear the virus completely, he said.

Dr. Pretorius recommended doctors test patients with long COVID for specific symptoms that may be treated using existing therapies. “If you think your patient had vascular pathology, you can test for it,” she said.

Some patients have found certain supplements and over-the-counter products helpful, she said. Among them: Coenzyme Q 10 and clot-busters such as streptokinase and Nattokinase (though she noted some doctors may not be comfortable with supplements).

“It’s the only thing we have until we’ve got trials,” she said.

Dr. Putrino said more research is needed to identify potential root causes and symptoms. A common refrain, but the only thing that will lead to specific treatments.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

Rachel S. Rubin, MD: I’m Dr Rachel Rubin, urologist and sexual medicine specialist in the Washington, DC, area. This is Sex Matters, and I’m here today with my friend and colleague, Dr. Matt Ziegelmann, who is the sexual medicine expert at the Mayo Clinic and who does all things men’s health, including penile curvature, testosterone, and sexual function.

Let’s start with penile curvature. Many men come in very distressed. They felt a lump in their penis and go straight to their primary care physician. What do we do in that situation?

Matthew J. Ziegelmann, MD: Penile curvature (often due to Peyronie’s disease) is actually incredibly common; as many as 10% of men have this condition. We need to normalize it and let men know that this is something we see often, and we have treatments for it. One of the biggest concerns these men have is cancer, but I have yet to see this as an indicator of cancer.

Penile curvature has a significant impact on affected men — their relationships, psychological well-being, sexual functioning, and overall health. We can provide treatment if they are interested. A small subset of men are born with natural penile curvature, which is different from Peyronie’s disease. Natural curvature can still affect their mental health, and we have treatment options.

Rubin: What happens when a patient is referred to urology? We want to tell our patients what to expect. What’s in our toolbox to help patients with penile curvature?

Dr. Ziegelmann: Many patient resources are available. For example, the Sexual Medicine Society of North America (SMSNA) has a patient-facing website on sexual health with lots of information about Peyronie’s disease and other aspects of sexual health.

Patients who are bothered by their penile curvature can be referred to us to find out about treatment options, or even just to get reassurance. It might be as simple as a conversation and a physical exam — that’s all we need to make the diagnosis. We can provide reassurance and get an idea of how bothered they are by this condition without doing anything invasive.

If they are considering definitive treatment, we would need to do more invasive testing. Sometimes we have the patient bring in photos of their erection to help establish the change they see in the shape of their penis.

Dr. Rubin: What about the patient who asks, “Doc, did I do this to myself? Did I break my penis? What do I do?”

Dr. Ziegelmann: That’s a common question — “How the heck did this happen?” No, you didn’t do this to yourself. We still have much to understand about why this happens to some men. Our approach is to acknowledge what we do and don’t know, and partner with the patient to discuss treatment.

Dr. Rubin: It’s very important to support your patient’s mental health, because this can be really devastating. So, what are the treatment options from conservative to invasive? What do you recommend for patients?

Dr. Ziegelmann: It can be as simple as observation if the patient is just seeking reassurance that it’s not cancer. This is a benign condition, but for men who are more bothered by their curvature, we’ll talk about options. We have oral medications that help improved the rigidity of the penis. Many men are also suffering from inadequate functioning. We can use devices called traction or vacuum to stretch the area of the penis that’s curved. We can use injections of medications, including FDA-approved agents that are injected into the penis in the outpatient setting. For men who are either later in the treatment protocol or want to resolve the problem right away, we can offer surgical intervention. We have a host of options, and a very individualized approach and a shared decision-making model. It’s not a one-size-fits-all problem.

Dr. Rubin: The real takeaway is that there is a lot of hope for this condition. Many doctors care deeply about these issues and are ready to partner with specialists to figure out the right treatment strategy. The SMSNA is a great place to find a provider like Dr Ziegelmann or myself, or any of our incredible colleagues throughout North America and the world. Thank you for joining us today. 

Dr. Rubin is Assistant Clinical Professor, Department of Urology, Georgetown University, Washington, DC; Private practice, North Bethesda, Maryland. She disclosed ties with Sprout, Maternal Medical, Absorption Pharmaceuticals, GSK, and Endo.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

Rachel S. Rubin, MD: I’m Dr Rachel Rubin, urologist and sexual medicine specialist in the Washington, DC, area. This is Sex Matters, and I’m here today with my friend and colleague, Dr. Matt Ziegelmann, who is the sexual medicine expert at the Mayo Clinic and who does all things men’s health, including penile curvature, testosterone, and sexual function.

Let’s start with penile curvature. Many men come in very distressed. They felt a lump in their penis and go straight to their primary care physician. What do we do in that situation?

Matthew J. Ziegelmann, MD: Penile curvature (often due to Peyronie’s disease) is actually incredibly common; as many as 10% of men have this condition. We need to normalize it and let men know that this is something we see often, and we have treatments for it. One of the biggest concerns these men have is cancer, but I have yet to see this as an indicator of cancer.

Penile curvature has a significant impact on affected men — their relationships, psychological well-being, sexual functioning, and overall health. We can provide treatment if they are interested. A small subset of men are born with natural penile curvature, which is different from Peyronie’s disease. Natural curvature can still affect their mental health, and we have treatment options.

Rubin: What happens when a patient is referred to urology? We want to tell our patients what to expect. What’s in our toolbox to help patients with penile curvature?

Dr. Ziegelmann: Many patient resources are available. For example, the Sexual Medicine Society of North America (SMSNA) has a patient-facing website on sexual health with lots of information about Peyronie’s disease and other aspects of sexual health.

Patients who are bothered by their penile curvature can be referred to us to find out about treatment options, or even just to get reassurance. It might be as simple as a conversation and a physical exam — that’s all we need to make the diagnosis. We can provide reassurance and get an idea of how bothered they are by this condition without doing anything invasive.

If they are considering definitive treatment, we would need to do more invasive testing. Sometimes we have the patient bring in photos of their erection to help establish the change they see in the shape of their penis.

Dr. Rubin: What about the patient who asks, “Doc, did I do this to myself? Did I break my penis? What do I do?”

Dr. Ziegelmann: That’s a common question — “How the heck did this happen?” No, you didn’t do this to yourself. We still have much to understand about why this happens to some men. Our approach is to acknowledge what we do and don’t know, and partner with the patient to discuss treatment.

Dr. Rubin: It’s very important to support your patient’s mental health, because this can be really devastating. So, what are the treatment options from conservative to invasive? What do you recommend for patients?

Dr. Ziegelmann: It can be as simple as observation if the patient is just seeking reassurance that it’s not cancer. This is a benign condition, but for men who are more bothered by their curvature, we’ll talk about options. We have oral medications that help improved the rigidity of the penis. Many men are also suffering from inadequate functioning. We can use devices called traction or vacuum to stretch the area of the penis that’s curved. We can use injections of medications, including FDA-approved agents that are injected into the penis in the outpatient setting. For men who are either later in the treatment protocol or want to resolve the problem right away, we can offer surgical intervention. We have a host of options, and a very individualized approach and a shared decision-making model. It’s not a one-size-fits-all problem.

Dr. Rubin: The real takeaway is that there is a lot of hope for this condition. Many doctors care deeply about these issues and are ready to partner with specialists to figure out the right treatment strategy. The SMSNA is a great place to find a provider like Dr Ziegelmann or myself, or any of our incredible colleagues throughout North America and the world. Thank you for joining us today. 

Dr. Rubin is Assistant Clinical Professor, Department of Urology, Georgetown University, Washington, DC; Private practice, North Bethesda, Maryland. She disclosed ties with Sprout, Maternal Medical, Absorption Pharmaceuticals, GSK, and Endo.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

Rachel S. Rubin, MD: I’m Dr Rachel Rubin, urologist and sexual medicine specialist in the Washington, DC, area. This is Sex Matters, and I’m here today with my friend and colleague, Dr. Matt Ziegelmann, who is the sexual medicine expert at the Mayo Clinic and who does all things men’s health, including penile curvature, testosterone, and sexual function.

Let’s start with penile curvature. Many men come in very distressed. They felt a lump in their penis and go straight to their primary care physician. What do we do in that situation?

Matthew J. Ziegelmann, MD: Penile curvature (often due to Peyronie’s disease) is actually incredibly common; as many as 10% of men have this condition. We need to normalize it and let men know that this is something we see often, and we have treatments for it. One of the biggest concerns these men have is cancer, but I have yet to see this as an indicator of cancer.

Penile curvature has a significant impact on affected men — their relationships, psychological well-being, sexual functioning, and overall health. We can provide treatment if they are interested. A small subset of men are born with natural penile curvature, which is different from Peyronie’s disease. Natural curvature can still affect their mental health, and we have treatment options.

Rubin: What happens when a patient is referred to urology? We want to tell our patients what to expect. What’s in our toolbox to help patients with penile curvature?

Dr. Ziegelmann: Many patient resources are available. For example, the Sexual Medicine Society of North America (SMSNA) has a patient-facing website on sexual health with lots of information about Peyronie’s disease and other aspects of sexual health.

Patients who are bothered by their penile curvature can be referred to us to find out about treatment options, or even just to get reassurance. It might be as simple as a conversation and a physical exam — that’s all we need to make the diagnosis. We can provide reassurance and get an idea of how bothered they are by this condition without doing anything invasive.

If they are considering definitive treatment, we would need to do more invasive testing. Sometimes we have the patient bring in photos of their erection to help establish the change they see in the shape of their penis.

Dr. Rubin: What about the patient who asks, “Doc, did I do this to myself? Did I break my penis? What do I do?”

Dr. Ziegelmann: That’s a common question — “How the heck did this happen?” No, you didn’t do this to yourself. We still have much to understand about why this happens to some men. Our approach is to acknowledge what we do and don’t know, and partner with the patient to discuss treatment.

Dr. Rubin: It’s very important to support your patient’s mental health, because this can be really devastating. So, what are the treatment options from conservative to invasive? What do you recommend for patients?

Dr. Ziegelmann: It can be as simple as observation if the patient is just seeking reassurance that it’s not cancer. This is a benign condition, but for men who are more bothered by their curvature, we’ll talk about options. We have oral medications that help improved the rigidity of the penis. Many men are also suffering from inadequate functioning. We can use devices called traction or vacuum to stretch the area of the penis that’s curved. We can use injections of medications, including FDA-approved agents that are injected into the penis in the outpatient setting. For men who are either later in the treatment protocol or want to resolve the problem right away, we can offer surgical intervention. We have a host of options, and a very individualized approach and a shared decision-making model. It’s not a one-size-fits-all problem.

Dr. Rubin: The real takeaway is that there is a lot of hope for this condition. Many doctors care deeply about these issues and are ready to partner with specialists to figure out the right treatment strategy. The SMSNA is a great place to find a provider like Dr Ziegelmann or myself, or any of our incredible colleagues throughout North America and the world. Thank you for joining us today. 

Dr. Rubin is Assistant Clinical Professor, Department of Urology, Georgetown University, Washington, DC; Private practice, North Bethesda, Maryland. She disclosed ties with Sprout, Maternal Medical, Absorption Pharmaceuticals, GSK, and Endo.

A version of this article appeared on Medscape.com.

Among patients with psoriasis, the risk of mortality was strongly associated with hepatic injury, cardiovascular disease, and psychiatric affective disorders, but was reduced among those who received systemic therapy with biologics, researchers from Canada report.

Those are key findings from a large retrospective registry study of patients with psoriasis, published in The Journal of the American Academy of Dermatology.

“Psoriasis, a chronic inflammatory condition affecting approximately 3% of the western populations, bears a higher risk of mortality compared to healthy individuals, possibly by inducing systemic inflammation associated with numerous comorbidities, especially cardiovascular diseases, metabolic syndrome, and others,” wrote corresponding author Robert Gniadecki, MD, PhD, of the division of dermatology at the University of Alberta, Canada, and colleagues. “It has been argued that the use of systemic immunomodulatory agents quenches systemic inflammation and potentially improves patient survival. However, the evidence to support this hypothesis is limited.”

To investigate the impact of comorbidities and systemic therapies on all-cause mortality in psoriasis, the researchers used the Alberta Health Services Data Repository of Reporting database from January 1, 2012, to June 1, 2019, which represents a population base of 4.47 million individuals. They extracted data on 18,618 psoriasis cases and 55,854 controls, stratified cases according to the Charlson Comorbidity Index (CCI), a surrogate measure for comorbidity burden, and by the type of therapy received, and conducted statistical analyses including Cox proportional hazards regression to determine absolute hazard ratios representing relative effects of specific demographic and comorbidity factors on mortality within groups.

The median age in both cohorts was 48 years, and 51% were male. The researchers observed that mortality in the psoriasis cohort was significantly higher than in the controls (5.7% vs. 3.8%, respectively; P < .05), with a median age at the time of death of 72 vs. 74.4 years.

The CCI and comorbidities strongly predicted mortality, especially drug-induced liver injury (hazard ratio [HR], 1.78), bipolar disorder and suicidal ideation (HR, 1.24-1.58), and major cardiovascular diseases, which included myocardial infarction (MI), congestive heart failure (CHF), and cerebrovascular disease (CVA) (HR, 1.2-1.4).

Among patients in the psoriasis cohort, survival of those treated with biologic agents was higher than in controls, even after matching for CCI (3.2% vs. 4.4%, respectively, P < .05). “These patients also exhibit reduced overall mortality compared to those treated with methotrexate or topical agents,” Dr. Gniadecki and colleagues wrote. “There was no difference in mortality between methotrexate patients and the topical therapy patients, but any of those treatment groups had superior survival compared to the no-treatment cohort.”

They added that despite better survival among patients treated with biologic agents, no significant improvements were detected in their comorbidity profiles. “Notably, the frequency of major cardiovascular disease (MI, CHF, CVA) was the same as in the controls, and overall, the frequency of diseases coded as cardiovascular was slightly increased,” they wrote.

The fact that some factors could not be measured, including the type and severity of psoriasis, response to treatment, smoking history, and alcohol intake, was a study limitation, they noted.

Joel M. Gelfand, MD, director of the psoriasis and phototherapy treatment center at the University of Pennsylvania, Philadelphia, who was asked to comment on the analysis, said the study confirms prior work indicating that having psoriasis is a predictor of mortality. In addition, “there is a strong healthy user affect among patients who take and stay on biologics for psoriasis,” he told this news organization.

Courtesy Dr. Gelfand

Among patients with psoriasis, the risk of mortality was strongly associated with hepatic injury, cardiovascular disease, and psychiatric affective disorders, but was reduced among those who received systemic therapy with biologics, researchers from Canada report.

Those are key findings from a large retrospective registry study of patients with psoriasis, published in The Journal of the American Academy of Dermatology.

“Psoriasis, a chronic inflammatory condition affecting approximately 3% of the western populations, bears a higher risk of mortality compared to healthy individuals, possibly by inducing systemic inflammation associated with numerous comorbidities, especially cardiovascular diseases, metabolic syndrome, and others,” wrote corresponding author Robert Gniadecki, MD, PhD, of the division of dermatology at the University of Alberta, Canada, and colleagues. “It has been argued that the use of systemic immunomodulatory agents quenches systemic inflammation and potentially improves patient survival. However, the evidence to support this hypothesis is limited.”

To investigate the impact of comorbidities and systemic therapies on all-cause mortality in psoriasis, the researchers used the Alberta Health Services Data Repository of Reporting database from January 1, 2012, to June 1, 2019, which represents a population base of 4.47 million individuals. They extracted data on 18,618 psoriasis cases and 55,854 controls, stratified cases according to the Charlson Comorbidity Index (CCI), a surrogate measure for comorbidity burden, and by the type of therapy received, and conducted statistical analyses including Cox proportional hazards regression to determine absolute hazard ratios representing relative effects of specific demographic and comorbidity factors on mortality within groups.

The median age in both cohorts was 48 years, and 51% were male. The researchers observed that mortality in the psoriasis cohort was significantly higher than in the controls (5.7% vs. 3.8%, respectively; P < .05), with a median age at the time of death of 72 vs. 74.4 years.

The CCI and comorbidities strongly predicted mortality, especially drug-induced liver injury (hazard ratio [HR], 1.78), bipolar disorder and suicidal ideation (HR, 1.24-1.58), and major cardiovascular diseases, which included myocardial infarction (MI), congestive heart failure (CHF), and cerebrovascular disease (CVA) (HR, 1.2-1.4).

Among patients in the psoriasis cohort, survival of those treated with biologic agents was higher than in controls, even after matching for CCI (3.2% vs. 4.4%, respectively, P < .05). “These patients also exhibit reduced overall mortality compared to those treated with methotrexate or topical agents,” Dr. Gniadecki and colleagues wrote. “There was no difference in mortality between methotrexate patients and the topical therapy patients, but any of those treatment groups had superior survival compared to the no-treatment cohort.”

They added that despite better survival among patients treated with biologic agents, no significant improvements were detected in their comorbidity profiles. “Notably, the frequency of major cardiovascular disease (MI, CHF, CVA) was the same as in the controls, and overall, the frequency of diseases coded as cardiovascular was slightly increased,” they wrote.

The fact that some factors could not be measured, including the type and severity of psoriasis, response to treatment, smoking history, and alcohol intake, was a study limitation, they noted.

Joel M. Gelfand, MD, director of the psoriasis and phototherapy treatment center at the University of Pennsylvania, Philadelphia, who was asked to comment on the analysis, said the study confirms prior work indicating that having psoriasis is a predictor of mortality. In addition, “there is a strong healthy user affect among patients who take and stay on biologics for psoriasis,” he told this news organization.

Courtesy Dr. Gelfand

Among patients with psoriasis, the risk of mortality was strongly associated with hepatic injury, cardiovascular disease, and psychiatric affective disorders, but was reduced among those who received systemic therapy with biologics, researchers from Canada report.

Those are key findings from a large retrospective registry study of patients with psoriasis, published in The Journal of the American Academy of Dermatology.

“Psoriasis, a chronic inflammatory condition affecting approximately 3% of the western populations, bears a higher risk of mortality compared to healthy individuals, possibly by inducing systemic inflammation associated with numerous comorbidities, especially cardiovascular diseases, metabolic syndrome, and others,” wrote corresponding author Robert Gniadecki, MD, PhD, of the division of dermatology at the University of Alberta, Canada, and colleagues. “It has been argued that the use of systemic immunomodulatory agents quenches systemic inflammation and potentially improves patient survival. However, the evidence to support this hypothesis is limited.”

To investigate the impact of comorbidities and systemic therapies on all-cause mortality in psoriasis, the researchers used the Alberta Health Services Data Repository of Reporting database from January 1, 2012, to June 1, 2019, which represents a population base of 4.47 million individuals. They extracted data on 18,618 psoriasis cases and 55,854 controls, stratified cases according to the Charlson Comorbidity Index (CCI), a surrogate measure for comorbidity burden, and by the type of therapy received, and conducted statistical analyses including Cox proportional hazards regression to determine absolute hazard ratios representing relative effects of specific demographic and comorbidity factors on mortality within groups.

The median age in both cohorts was 48 years, and 51% were male. The researchers observed that mortality in the psoriasis cohort was significantly higher than in the controls (5.7% vs. 3.8%, respectively; P < .05), with a median age at the time of death of 72 vs. 74.4 years.

The CCI and comorbidities strongly predicted mortality, especially drug-induced liver injury (hazard ratio [HR], 1.78), bipolar disorder and suicidal ideation (HR, 1.24-1.58), and major cardiovascular diseases, which included myocardial infarction (MI), congestive heart failure (CHF), and cerebrovascular disease (CVA) (HR, 1.2-1.4).

Among patients in the psoriasis cohort, survival of those treated with biologic agents was higher than in controls, even after matching for CCI (3.2% vs. 4.4%, respectively, P < .05). “These patients also exhibit reduced overall mortality compared to those treated with methotrexate or topical agents,” Dr. Gniadecki and colleagues wrote. “There was no difference in mortality between methotrexate patients and the topical therapy patients, but any of those treatment groups had superior survival compared to the no-treatment cohort.”

They added that despite better survival among patients treated with biologic agents, no significant improvements were detected in their comorbidity profiles. “Notably, the frequency of major cardiovascular disease (MI, CHF, CVA) was the same as in the controls, and overall, the frequency of diseases coded as cardiovascular was slightly increased,” they wrote.

The fact that some factors could not be measured, including the type and severity of psoriasis, response to treatment, smoking history, and alcohol intake, was a study limitation, they noted.

Joel M. Gelfand, MD, director of the psoriasis and phototherapy treatment center at the University of Pennsylvania, Philadelphia, who was asked to comment on the analysis, said the study confirms prior work indicating that having psoriasis is a predictor of mortality. In addition, “there is a strong healthy user affect among patients who take and stay on biologics for psoriasis,” he told this news organization.

Courtesy Dr. Gelfand

The US Food and Drug Administration (FDA) is warning against the use of smartwatches and rings that are claimed to measure a person’s glucose levels without piercing the skin.

The warning doesn’t apply to authorized smartwatch applications that display glucose values from an FDA-approved continuous glucose monitor with a sensor implanted under the skin.

Rather, the warning pertains to watches or rings sold through online marketplaces or directly from sellers who claim that the devices measure blood sugar noninvasively without requiring the wearer to prick their finger or pierce their skin. These products are manufactured by dozens of companies and sold under many different brand names. The FDA’s warning applies to all of them.

These devices have not been evaluated by the FDA for safety and effectiveness, and their use by people with diabetes could result in inaccurate blood glucose measurements, with potentially serious consequences if relied upon for medication dosing.

“The FDA has not authorized, cleared, or approved any smartwatch or smart ring that is intended to measure or estimate blood glucose values on its own,” the agency said in a statement issued on February 21, 2024.

They added, “The agency is working to ensure that manufacturers, distributors, and sellers do not illegally market unauthorized smartwatches or smart rings that claim to measure blood glucose levels.”

People who experience any problems with inaccurate blood glucose measurement or experience any adverse events from using an unauthorized smartwatch or smart ring are urged to report it to the FDA through its MedWatch program.

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) is warning against the use of smartwatches and rings that are claimed to measure a person’s glucose levels without piercing the skin.

The warning doesn’t apply to authorized smartwatch applications that display glucose values from an FDA-approved continuous glucose monitor with a sensor implanted under the skin.

Rather, the warning pertains to watches or rings sold through online marketplaces or directly from sellers who claim that the devices measure blood sugar noninvasively without requiring the wearer to prick their finger or pierce their skin. These products are manufactured by dozens of companies and sold under many different brand names. The FDA’s warning applies to all of them.

These devices have not been evaluated by the FDA for safety and effectiveness, and their use by people with diabetes could result in inaccurate blood glucose measurements, with potentially serious consequences if relied upon for medication dosing.

“The FDA has not authorized, cleared, or approved any smartwatch or smart ring that is intended to measure or estimate blood glucose values on its own,” the agency said in a statement issued on February 21, 2024.

They added, “The agency is working to ensure that manufacturers, distributors, and sellers do not illegally market unauthorized smartwatches or smart rings that claim to measure blood glucose levels.”

People who experience any problems with inaccurate blood glucose measurement or experience any adverse events from using an unauthorized smartwatch or smart ring are urged to report it to the FDA through its MedWatch program.

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) is warning against the use of smartwatches and rings that are claimed to measure a person’s glucose levels without piercing the skin.

The warning doesn’t apply to authorized smartwatch applications that display glucose values from an FDA-approved continuous glucose monitor with a sensor implanted under the skin.

Rather, the warning pertains to watches or rings sold through online marketplaces or directly from sellers who claim that the devices measure blood sugar noninvasively without requiring the wearer to prick their finger or pierce their skin. These products are manufactured by dozens of companies and sold under many different brand names. The FDA’s warning applies to all of them.

These devices have not been evaluated by the FDA for safety and effectiveness, and their use by people with diabetes could result in inaccurate blood glucose measurements, with potentially serious consequences if relied upon for medication dosing.

“The FDA has not authorized, cleared, or approved any smartwatch or smart ring that is intended to measure or estimate blood glucose values on its own,” the agency said in a statement issued on February 21, 2024.

They added, “The agency is working to ensure that manufacturers, distributors, and sellers do not illegally market unauthorized smartwatches or smart rings that claim to measure blood glucose levels.”

People who experience any problems with inaccurate blood glucose measurement or experience any adverse events from using an unauthorized smartwatch or smart ring are urged to report it to the FDA through its MedWatch program.

A version of this article appeared on Medscape.com.

Postinfectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS) is a distinct, centrally mediated condition, with evidence of autonomic, immune, and metabolic dysfunction, new "deep phenotyping" data suggested.

The study was initiated in 2016 at the US National Institutes of Health. Its aim was to better elucidate the underlying pathophysiology of ME/CFS, a multisystem disorder characterized by persistent and disabling fatigue, post-exertional malaise, cognitive complaints, and other physical symptoms. A total of 17 carefully selected individuals with PI-ME/CFS onset within the prior 5 years were compared with 21 healthy volunteers on a more extensive set of biologic measurements than has been examined in any prior study of the condition.

Overall, the findings suggested that ME/CFS is “a distinct entity characterized by somatic and cognitive complaints that are centrally mediated,” with fatigue that is “defined by effort preferences and central autonomic dysfunction,” Brian T. Walitt, MD, of the National Institute of Neurological Disorders and Stroke (NINDS), Bethesda, Maryland, and colleagues wrote in the paper, published on February 21 in Nature Communications.

In addition, “there are distinct sex signatures of immune and metabolic dysregulation which suggest persistent antigenic stimulation.” Physical deconditioning over time, while not the source of the condition, “is an important consequence,” the authors added.

Asked to comment, Hector Bonilla, MD, director of the ME/CFS Clinic and codirector of the Stanford Post-Acute COVID-19 Syndrome Clinic, Atherton, California, pointed out that the sample was small and the study was cross-sectional and therefore likely missed dynamic changes in the patients.

Nonetheless, Dr. Bonilla told this news organization, “they have shown clear objective changes in patients with ME/CFS not seen in the controls. These are present in the microbiome, in the immune system, and in metabolites, especially in spinal fluid, that lead to a neuroinflammatory condition. And these are linked with autonomic dysfunction that can explain many of the symptoms that patients experience ... The symptoms are not manufactured by them.”

Thus far, the only treatments for ME/CFS are symptomatic. Understanding the pathophysiology is essential to identifying disease-modifying therapy, study lead author Avindra Nath, MD, Senior Investigator and Clinical Director of Intramural Research at NINDS, told this news organization.

“The disease is real. But our medical profession is limited in what they can do to diagnose or impact them ... The first thing we need to do is try to understand the pathophysiology. So that’s why the study was put together,” Dr. Nath said.

Postinfectious syndromes including ME/CFS have been given many names, including post-Lyme disease, Gulf War illness, and more recently, long COVID. With ME/CFS, the Epstein-Barr virus has historically been one of the most commonly associated triggers, although several other viral, bacterial, and environmental toxins have been implicated.

“There are a whole host of these things that have very similar symptoms or overlapping symptoms ... It’s quite possible that the underlying pathophysiology overlaps between all these syndromes,” Dr. Nath noted.

Another ME/CFS expert not involved in the study, researcher Michael VanElzakker, PhD, of the Neurotherapeutics Division at Harvard Medical School and Massachusetts General Hospital, Boston, said that the possibility of antigen persistence of the infectious pathogen arising from the immune system profiling conducted in the study is noteworthy and merits further study.

“To me, the obvious next step would be techniques like tissue-based assays and T-cell sequencing to try and understand what exactly those antigens are and what their source might be. Importantly, it is probably not the same antigen or pathogen source in all patients, but that’s a question that needs an answer,” Dr. VanElzakker said.

Of note, the 17 study participants had been adjudicated by an expert panel from an initial 484 inquiries and 217 who underwent detailed case reviews. They had to meet at least one of three published ME/CFS criteria and to have moderate to severe clinical symptom severity as determined by several fatigue scores. None met the criteria for psychiatric diagnoses.

Yet, even in the cases that met study criteria, underlying causes emerged in 20% of the participants over time, suggesting diagnostic misattribution. “This misclassification bias has important ramifications on the interpretation of the existing ME/CFS research literature,” the authors wrote.

Dr. VanElzakker noted, “The fact that this research study was probably the most detailed workup many of these patients had ever gotten is a serious indictment of our current profit-based healthcare system’s prioritization of 15-minute doctor’s appointments. It is almost certain that other patients would also benefit from an intensive detailed workup.”
 

Multiple Abnormalities Identified

There were no differences between the PI-ME/CFS and control groups in ventilatory function, muscle oxygenation, mechanical efficiency, resting energy expenditure, basal mitochondrial function of immune cells, muscle fiber composition, or body composition, suggesting the absence of a resting low-energy state, the authors said.

In 40-minute head-up tilt-table testing, there were no differences between the ME/CFS and control groups in frequency or orthostatic hypotension or extensive orthostatic tachycardia. However, a 24-hour ambulatory electrocardiogram showed that the patients with PI-ME/CFS had diminished heart rate variability. They also showed increased heart rate throughout the day, suggesting increased sympathetic activity, and a diminished drop in nighttime heart rate, suggesting decreased parasympathetic activity.

“Considered together, these data suggest that there is an alteration in autonomic tone, implying central nervous system regulatory change,” Dr. Walitt and colleagues wrote.

On the “Effort-Expenditure for Rewards Task,” the participants with PI-ME/CFS showed significant differences in “effort preference,” or a tendency to avoid the harder tasks, as well as a slowing of button-pushing over time, compared with the controls, even with easier tasks. This pattern suggests that those with PI-ME/CFS were “pacing to limit exertion and associated feelings of discomfort,” the authors wrote.

Dr. Nath describes this behavior as akin to “if you develop a flu, you feel that you just want to lay down in bed and not hurt yourself. It’s not that you’re not capable of doing [the task], but your body tells you don’t do it. Your body just wants to fight the infection ... these people just never bounce back.”

Compared with the controls, the participants with PI-ME/CFS failed to maintain a moderate grip force even though there was no difference in maximum grip strength or arm muscle mass. This performance difference correlated with decreased activity of the right temporal-parietal junction, a novel observation suggesting that the fatigue in the PI-ME/CFS group “is due to dysfunction of integrative brain regions that drive the motor cortex, the cause of which needs to be further explored,” Dr. Walitt and colleagues wrote.

On cardiopulmonary testing, peak power, peak respiratory rate, peak heart rate, and peak VO₂ were all lower in the PI-ME/CFS group, correlating to a difference of approximately 3.3 metabolic equivalent of task units. The differential cardiorespiratory performance relates to “autonomic function, hypothalamic-pituitary-adrenal axis hyporesponsiveness, and muscular deconditioning from disuse that clinically impacts activities of daily life,” they said.

In the participants with PI-ME/CFS, catechol levels in cerebrospinal fluid correlated with grip strength and effort preference, and several metabolites of the dopamine pathway correlated with several cognitive symptoms.

“This suggests that central nervous system catechol pathways are dysregulated in PI-ME/CFS and may play a role in effort preference and cognitive complaints,” as well as decreased central catecholamine biosynthesis. Similar findings have been seen in patients with long COVID, the authors noted.

There were increased naive B cells and decreased switched memory B cells in blood of participants with PI-ME/CFS. Contrary to prior studies, there was no consistent pattern of autoimmunity across all participants with PI-ME/CFS, and no previously undescribed antibodies were identified.

However, programmed cell death protein 1, a marker of T-cell exhaustion and activation, was elevated in the cerebrospinal fluid of the patients with PI-ME/CFS.

Several sex-based differences were noted, including in immune cell expression in cerebrospinal fluid, peripheral blood mononuclear cell gene expression, and muscle gene expression. Males and females also differed in the cerebrospinal metabolomics that distinguished the participants with PI-ME/CFS from controls.
 

What Do These Findings Suggest About Treatment?

The data point to several treatment implications. For one, the finding of possible immune exhaustion suggests that immune checkpoint inhibitors may be therapeutic by promoting clearance of foreign antigens. Immune dysfunction leads to neurochemical alterations that affect neuronal circuits, which may be another point of intervention, the authors suggested.

On the other hand, “attempting to target downstream mechanisms with exercise, cognitive behavioral therapy, or autonomic directed therapies may have limited impact on symptom burden, as it would not address the root cause of PI-ME/CFS,” they noted.

Combination therapy targeting multiple pathways along with a personalized medicine approach should be considered, they said.

“I think the most important thing is not to discount these patients,” Dr. Nath told this news organization. “They have a real disease, and we need to be empathetic towards them. We also need to make sure that they don’t have something underlying that is treatable, and then treat them symptomatically the best that you can. If not, then refer them to ME/CFS studies or clinics where people specialize in these conditions and work with them.”

The study authors and Dr. VanElzakker reported no relevant financial relationships. Dr. Bonilla consults for United Health and Resverlogix.
 

A version of this article appeared on Medscape.com.

Postinfectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS) is a distinct, centrally mediated condition, with evidence of autonomic, immune, and metabolic dysfunction, new "deep phenotyping" data suggested.

The study was initiated in 2016 at the US National Institutes of Health. Its aim was to better elucidate the underlying pathophysiology of ME/CFS, a multisystem disorder characterized by persistent and disabling fatigue, post-exertional malaise, cognitive complaints, and other physical symptoms. A total of 17 carefully selected individuals with PI-ME/CFS onset within the prior 5 years were compared with 21 healthy volunteers on a more extensive set of biologic measurements than has been examined in any prior study of the condition.

Overall, the findings suggested that ME/CFS is “a distinct entity characterized by somatic and cognitive complaints that are centrally mediated,” with fatigue that is “defined by effort preferences and central autonomic dysfunction,” Brian T. Walitt, MD, of the National Institute of Neurological Disorders and Stroke (NINDS), Bethesda, Maryland, and colleagues wrote in the paper, published on February 21 in Nature Communications.

In addition, “there are distinct sex signatures of immune and metabolic dysregulation which suggest persistent antigenic stimulation.” Physical deconditioning over time, while not the source of the condition, “is an important consequence,” the authors added.

Asked to comment, Hector Bonilla, MD, director of the ME/CFS Clinic and codirector of the Stanford Post-Acute COVID-19 Syndrome Clinic, Atherton, California, pointed out that the sample was small and the study was cross-sectional and therefore likely missed dynamic changes in the patients.

Nonetheless, Dr. Bonilla told this news organization, “they have shown clear objective changes in patients with ME/CFS not seen in the controls. These are present in the microbiome, in the immune system, and in metabolites, especially in spinal fluid, that lead to a neuroinflammatory condition. And these are linked with autonomic dysfunction that can explain many of the symptoms that patients experience ... The symptoms are not manufactured by them.”

Thus far, the only treatments for ME/CFS are symptomatic. Understanding the pathophysiology is essential to identifying disease-modifying therapy, study lead author Avindra Nath, MD, Senior Investigator and Clinical Director of Intramural Research at NINDS, told this news organization.

“The disease is real. But our medical profession is limited in what they can do to diagnose or impact them ... The first thing we need to do is try to understand the pathophysiology. So that’s why the study was put together,” Dr. Nath said.

Postinfectious syndromes including ME/CFS have been given many names, including post-Lyme disease, Gulf War illness, and more recently, long COVID. With ME/CFS, the Epstein-Barr virus has historically been one of the most commonly associated triggers, although several other viral, bacterial, and environmental toxins have been implicated.

“There are a whole host of these things that have very similar symptoms or overlapping symptoms ... It’s quite possible that the underlying pathophysiology overlaps between all these syndromes,” Dr. Nath noted.

Another ME/CFS expert not involved in the study, researcher Michael VanElzakker, PhD, of the Neurotherapeutics Division at Harvard Medical School and Massachusetts General Hospital, Boston, said that the possibility of antigen persistence of the infectious pathogen arising from the immune system profiling conducted in the study is noteworthy and merits further study.

“To me, the obvious next step would be techniques like tissue-based assays and T-cell sequencing to try and understand what exactly those antigens are and what their source might be. Importantly, it is probably not the same antigen or pathogen source in all patients, but that’s a question that needs an answer,” Dr. VanElzakker said.

Of note, the 17 study participants had been adjudicated by an expert panel from an initial 484 inquiries and 217 who underwent detailed case reviews. They had to meet at least one of three published ME/CFS criteria and to have moderate to severe clinical symptom severity as determined by several fatigue scores. None met the criteria for psychiatric diagnoses.

Yet, even in the cases that met study criteria, underlying causes emerged in 20% of the participants over time, suggesting diagnostic misattribution. “This misclassification bias has important ramifications on the interpretation of the existing ME/CFS research literature,” the authors wrote.

Dr. VanElzakker noted, “The fact that this research study was probably the most detailed workup many of these patients had ever gotten is a serious indictment of our current profit-based healthcare system’s prioritization of 15-minute doctor’s appointments. It is almost certain that other patients would also benefit from an intensive detailed workup.”
 

Multiple Abnormalities Identified

There were no differences between the PI-ME/CFS and control groups in ventilatory function, muscle oxygenation, mechanical efficiency, resting energy expenditure, basal mitochondrial function of immune cells, muscle fiber composition, or body composition, suggesting the absence of a resting low-energy state, the authors said.

In 40-minute head-up tilt-table testing, there were no differences between the ME/CFS and control groups in frequency or orthostatic hypotension or extensive orthostatic tachycardia. However, a 24-hour ambulatory electrocardiogram showed that the patients with PI-ME/CFS had diminished heart rate variability. They also showed increased heart rate throughout the day, suggesting increased sympathetic activity, and a diminished drop in nighttime heart rate, suggesting decreased parasympathetic activity.

“Considered together, these data suggest that there is an alteration in autonomic tone, implying central nervous system regulatory change,” Dr. Walitt and colleagues wrote.

On the “Effort-Expenditure for Rewards Task,” the participants with PI-ME/CFS showed significant differences in “effort preference,” or a tendency to avoid the harder tasks, as well as a slowing of button-pushing over time, compared with the controls, even with easier tasks. This pattern suggests that those with PI-ME/CFS were “pacing to limit exertion and associated feelings of discomfort,” the authors wrote.

Dr. Nath describes this behavior as akin to “if you develop a flu, you feel that you just want to lay down in bed and not hurt yourself. It’s not that you’re not capable of doing [the task], but your body tells you don’t do it. Your body just wants to fight the infection ... these people just never bounce back.”

Compared with the controls, the participants with PI-ME/CFS failed to maintain a moderate grip force even though there was no difference in maximum grip strength or arm muscle mass. This performance difference correlated with decreased activity of the right temporal-parietal junction, a novel observation suggesting that the fatigue in the PI-ME/CFS group “is due to dysfunction of integrative brain regions that drive the motor cortex, the cause of which needs to be further explored,” Dr. Walitt and colleagues wrote.

On cardiopulmonary testing, peak power, peak respiratory rate, peak heart rate, and peak VO₂ were all lower in the PI-ME/CFS group, correlating to a difference of approximately 3.3 metabolic equivalent of task units. The differential cardiorespiratory performance relates to “autonomic function, hypothalamic-pituitary-adrenal axis hyporesponsiveness, and muscular deconditioning from disuse that clinically impacts activities of daily life,” they said.

In the participants with PI-ME/CFS, catechol levels in cerebrospinal fluid correlated with grip strength and effort preference, and several metabolites of the dopamine pathway correlated with several cognitive symptoms.

“This suggests that central nervous system catechol pathways are dysregulated in PI-ME/CFS and may play a role in effort preference and cognitive complaints,” as well as decreased central catecholamine biosynthesis. Similar findings have been seen in patients with long COVID, the authors noted.

There were increased naive B cells and decreased switched memory B cells in blood of participants with PI-ME/CFS. Contrary to prior studies, there was no consistent pattern of autoimmunity across all participants with PI-ME/CFS, and no previously undescribed antibodies were identified.

However, programmed cell death protein 1, a marker of T-cell exhaustion and activation, was elevated in the cerebrospinal fluid of the patients with PI-ME/CFS.

Several sex-based differences were noted, including in immune cell expression in cerebrospinal fluid, peripheral blood mononuclear cell gene expression, and muscle gene expression. Males and females also differed in the cerebrospinal metabolomics that distinguished the participants with PI-ME/CFS from controls.
 

What Do These Findings Suggest About Treatment?

The data point to several treatment implications. For one, the finding of possible immune exhaustion suggests that immune checkpoint inhibitors may be therapeutic by promoting clearance of foreign antigens. Immune dysfunction leads to neurochemical alterations that affect neuronal circuits, which may be another point of intervention, the authors suggested.

On the other hand, “attempting to target downstream mechanisms with exercise, cognitive behavioral therapy, or autonomic directed therapies may have limited impact on symptom burden, as it would not address the root cause of PI-ME/CFS,” they noted.

Combination therapy targeting multiple pathways along with a personalized medicine approach should be considered, they said.

“I think the most important thing is not to discount these patients,” Dr. Nath told this news organization. “They have a real disease, and we need to be empathetic towards them. We also need to make sure that they don’t have something underlying that is treatable, and then treat them symptomatically the best that you can. If not, then refer them to ME/CFS studies or clinics where people specialize in these conditions and work with them.”

The study authors and Dr. VanElzakker reported no relevant financial relationships. Dr. Bonilla consults for United Health and Resverlogix.
 

A version of this article appeared on Medscape.com.

Postinfectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS) is a distinct, centrally mediated condition, with evidence of autonomic, immune, and metabolic dysfunction, new "deep phenotyping" data suggested.

The study was initiated in 2016 at the US National Institutes of Health. Its aim was to better elucidate the underlying pathophysiology of ME/CFS, a multisystem disorder characterized by persistent and disabling fatigue, post-exertional malaise, cognitive complaints, and other physical symptoms. A total of 17 carefully selected individuals with PI-ME/CFS onset within the prior 5 years were compared with 21 healthy volunteers on a more extensive set of biologic measurements than has been examined in any prior study of the condition.

Overall, the findings suggested that ME/CFS is “a distinct entity characterized by somatic and cognitive complaints that are centrally mediated,” with fatigue that is “defined by effort preferences and central autonomic dysfunction,” Brian T. Walitt, MD, of the National Institute of Neurological Disorders and Stroke (NINDS), Bethesda, Maryland, and colleagues wrote in the paper, published on February 21 in Nature Communications.

In addition, “there are distinct sex signatures of immune and metabolic dysregulation which suggest persistent antigenic stimulation.” Physical deconditioning over time, while not the source of the condition, “is an important consequence,” the authors added.

Asked to comment, Hector Bonilla, MD, director of the ME/CFS Clinic and codirector of the Stanford Post-Acute COVID-19 Syndrome Clinic, Atherton, California, pointed out that the sample was small and the study was cross-sectional and therefore likely missed dynamic changes in the patients.

Nonetheless, Dr. Bonilla told this news organization, “they have shown clear objective changes in patients with ME/CFS not seen in the controls. These are present in the microbiome, in the immune system, and in metabolites, especially in spinal fluid, that lead to a neuroinflammatory condition. And these are linked with autonomic dysfunction that can explain many of the symptoms that patients experience ... The symptoms are not manufactured by them.”

Thus far, the only treatments for ME/CFS are symptomatic. Understanding the pathophysiology is essential to identifying disease-modifying therapy, study lead author Avindra Nath, MD, Senior Investigator and Clinical Director of Intramural Research at NINDS, told this news organization.

“The disease is real. But our medical profession is limited in what they can do to diagnose or impact them ... The first thing we need to do is try to understand the pathophysiology. So that’s why the study was put together,” Dr. Nath said.

Postinfectious syndromes including ME/CFS have been given many names, including post-Lyme disease, Gulf War illness, and more recently, long COVID. With ME/CFS, the Epstein-Barr virus has historically been one of the most commonly associated triggers, although several other viral, bacterial, and environmental toxins have been implicated.

“There are a whole host of these things that have very similar symptoms or overlapping symptoms ... It’s quite possible that the underlying pathophysiology overlaps between all these syndromes,” Dr. Nath noted.

Another ME/CFS expert not involved in the study, researcher Michael VanElzakker, PhD, of the Neurotherapeutics Division at Harvard Medical School and Massachusetts General Hospital, Boston, said that the possibility of antigen persistence of the infectious pathogen arising from the immune system profiling conducted in the study is noteworthy and merits further study.

“To me, the obvious next step would be techniques like tissue-based assays and T-cell sequencing to try and understand what exactly those antigens are and what their source might be. Importantly, it is probably not the same antigen or pathogen source in all patients, but that’s a question that needs an answer,” Dr. VanElzakker said.

Of note, the 17 study participants had been adjudicated by an expert panel from an initial 484 inquiries and 217 who underwent detailed case reviews. They had to meet at least one of three published ME/CFS criteria and to have moderate to severe clinical symptom severity as determined by several fatigue scores. None met the criteria for psychiatric diagnoses.

Yet, even in the cases that met study criteria, underlying causes emerged in 20% of the participants over time, suggesting diagnostic misattribution. “This misclassification bias has important ramifications on the interpretation of the existing ME/CFS research literature,” the authors wrote.

Dr. VanElzakker noted, “The fact that this research study was probably the most detailed workup many of these patients had ever gotten is a serious indictment of our current profit-based healthcare system’s prioritization of 15-minute doctor’s appointments. It is almost certain that other patients would also benefit from an intensive detailed workup.”
 

Multiple Abnormalities Identified

There were no differences between the PI-ME/CFS and control groups in ventilatory function, muscle oxygenation, mechanical efficiency, resting energy expenditure, basal mitochondrial function of immune cells, muscle fiber composition, or body composition, suggesting the absence of a resting low-energy state, the authors said.

In 40-minute head-up tilt-table testing, there were no differences between the ME/CFS and control groups in frequency or orthostatic hypotension or extensive orthostatic tachycardia. However, a 24-hour ambulatory electrocardiogram showed that the patients with PI-ME/CFS had diminished heart rate variability. They also showed increased heart rate throughout the day, suggesting increased sympathetic activity, and a diminished drop in nighttime heart rate, suggesting decreased parasympathetic activity.

“Considered together, these data suggest that there is an alteration in autonomic tone, implying central nervous system regulatory change,” Dr. Walitt and colleagues wrote.

On the “Effort-Expenditure for Rewards Task,” the participants with PI-ME/CFS showed significant differences in “effort preference,” or a tendency to avoid the harder tasks, as well as a slowing of button-pushing over time, compared with the controls, even with easier tasks. This pattern suggests that those with PI-ME/CFS were “pacing to limit exertion and associated feelings of discomfort,” the authors wrote.

Dr. Nath describes this behavior as akin to “if you develop a flu, you feel that you just want to lay down in bed and not hurt yourself. It’s not that you’re not capable of doing [the task], but your body tells you don’t do it. Your body just wants to fight the infection ... these people just never bounce back.”

Compared with the controls, the participants with PI-ME/CFS failed to maintain a moderate grip force even though there was no difference in maximum grip strength or arm muscle mass. This performance difference correlated with decreased activity of the right temporal-parietal junction, a novel observation suggesting that the fatigue in the PI-ME/CFS group “is due to dysfunction of integrative brain regions that drive the motor cortex, the cause of which needs to be further explored,” Dr. Walitt and colleagues wrote.

On cardiopulmonary testing, peak power, peak respiratory rate, peak heart rate, and peak VO₂ were all lower in the PI-ME/CFS group, correlating to a difference of approximately 3.3 metabolic equivalent of task units. The differential cardiorespiratory performance relates to “autonomic function, hypothalamic-pituitary-adrenal axis hyporesponsiveness, and muscular deconditioning from disuse that clinically impacts activities of daily life,” they said.

In the participants with PI-ME/CFS, catechol levels in cerebrospinal fluid correlated with grip strength and effort preference, and several metabolites of the dopamine pathway correlated with several cognitive symptoms.

“This suggests that central nervous system catechol pathways are dysregulated in PI-ME/CFS and may play a role in effort preference and cognitive complaints,” as well as decreased central catecholamine biosynthesis. Similar findings have been seen in patients with long COVID, the authors noted.

There were increased naive B cells and decreased switched memory B cells in blood of participants with PI-ME/CFS. Contrary to prior studies, there was no consistent pattern of autoimmunity across all participants with PI-ME/CFS, and no previously undescribed antibodies were identified.

However, programmed cell death protein 1, a marker of T-cell exhaustion and activation, was elevated in the cerebrospinal fluid of the patients with PI-ME/CFS.

Several sex-based differences were noted, including in immune cell expression in cerebrospinal fluid, peripheral blood mononuclear cell gene expression, and muscle gene expression. Males and females also differed in the cerebrospinal metabolomics that distinguished the participants with PI-ME/CFS from controls.
 

What Do These Findings Suggest About Treatment?

The data point to several treatment implications. For one, the finding of possible immune exhaustion suggests that immune checkpoint inhibitors may be therapeutic by promoting clearance of foreign antigens. Immune dysfunction leads to neurochemical alterations that affect neuronal circuits, which may be another point of intervention, the authors suggested.

On the other hand, “attempting to target downstream mechanisms with exercise, cognitive behavioral therapy, or autonomic directed therapies may have limited impact on symptom burden, as it would not address the root cause of PI-ME/CFS,” they noted.

Combination therapy targeting multiple pathways along with a personalized medicine approach should be considered, they said.

“I think the most important thing is not to discount these patients,” Dr. Nath told this news organization. “They have a real disease, and we need to be empathetic towards them. We also need to make sure that they don’t have something underlying that is treatable, and then treat them symptomatically the best that you can. If not, then refer them to ME/CFS studies or clinics where people specialize in these conditions and work with them.”

The study authors and Dr. VanElzakker reported no relevant financial relationships. Dr. Bonilla consults for United Health and Resverlogix.
 

A version of this article appeared on Medscape.com.

Women may gain greater health benefits from regular physical activity at equivalent or lower doses of activity, compared with men, according to data from more than 400,000 US adults. 

Over two decades, with any regular physical activity, all-cause mortality risk was reduced by 24% in women vs 15% in men, and cardiovascular mortality risk was reduced by 36% and 14%, respectively, compared with inactivity, researchers found. 

Participating in strength training exercises (vs not) was associated with a reduced risk for all-cause death of 19% in women and 11% men and reductions in cardiovascular death of 30% and 11%, respectively.

“Women have historically and statistically lagged behind men in engaging in meaningful exercise,” co–lead author Martha Gulati, MD, with the Smidt Heart Institute at Cedars-Sinai, Los Angeles, said in a statement. “The beauty of this study is learning that women can get more out of each minute of moderate to vigorous activity than men do. It’s an incentivizing notion that we hope women will take to heart.”

The study was published online February 19 in the Journal of the American College of Cardiology. 
 

Sex-Specific Exercise Advice? 

The findings are based on leisure-time physical activity data collected over roughly 20 years via the National Health Interview Survey for 412,413 US adults aged 27-61 years. During roughly 4.9 million person-years of follow-up, there were 39,935 all-cause deaths and 11,670 cardiovascular deaths.

Both men and women achieved a peak survival benefit at 300 minutes of weekly moderate to vigorous aerobic physical activity. But the mortality reduction was substantially greater in women than in men for the same amount of regular exercise (24% vs 18%). 

Similarly, for any given dose of physical activity leading up to 300 minutes per week, women derived proportionately greater survival benefits than did men, the authors reported. 

“Importantly, the greater magnitude of physical activity-related survival benefit in women than men was consistently found across varied measures and types of physical activity including frequency, duration per session, and intensity of aerobic physical activity, as well as frequency of muscle strengthening activities,” they wrote. 

They say multiple factors, including variations in anatomy and physiology, may account for the differences in outcomes between men and women. For example, compared with men, women may use more respiratory, metabolic, and strength demands to conduct the same movement and in turn, reap greater health benefits.

The study also showed only 33% of women and 43% of men regularly engaged in aerobic physical activity, whereas only 20% of women and 28% of men completed a weekly strength training session.

“We hope this study will help everyone, especially women, understand they are poised to gain tremendous benefits from exercise,” senior author Susan Cheng, MD, with the Smidt Heart Institute at Cedars-Sinai, Los Angeles, said in a statement.

In an accompanying editorial, Wael A. Jaber, MD, and Erika Hutt, MD, from Cleveland Clinic Ohio, wrote that this analysis “brings us one step farther in gaining insights into the role and influence of physiological responses to exercise with a sex-specific lens.” 

The study is “well designed and adds important information to the body of literature that can potentially close the gender gap and optimize sex-specific physical activity recommendations by policy makers and societal guidelines,” they wrote. 

“This study emphasizes that there is no singular approach for exercise. A person’s physical activity needs and goals may change based on their age, health status, and schedule — but the value of any type of exercise is irrefutable,” Eric J. Shiroma, ScD, with the National Heart, Lung, and Blood Institute, said in a statement. 

The study was supported in part by grants from the National Institutes of Health. The authors and editorial writers have declared no relevant conflicts of interest.
 

A version of this article appeared on Medscape.com.

Women may gain greater health benefits from regular physical activity at equivalent or lower doses of activity, compared with men, according to data from more than 400,000 US adults. 

Over two decades, with any regular physical activity, all-cause mortality risk was reduced by 24% in women vs 15% in men, and cardiovascular mortality risk was reduced by 36% and 14%, respectively, compared with inactivity, researchers found. 

Participating in strength training exercises (vs not) was associated with a reduced risk for all-cause death of 19% in women and 11% men and reductions in cardiovascular death of 30% and 11%, respectively.

“Women have historically and statistically lagged behind men in engaging in meaningful exercise,” co–lead author Martha Gulati, MD, with the Smidt Heart Institute at Cedars-Sinai, Los Angeles, said in a statement. “The beauty of this study is learning that women can get more out of each minute of moderate to vigorous activity than men do. It’s an incentivizing notion that we hope women will take to heart.”

The study was published online February 19 in the Journal of the American College of Cardiology. 
 

Sex-Specific Exercise Advice? 

The findings are based on leisure-time physical activity data collected over roughly 20 years via the National Health Interview Survey for 412,413 US adults aged 27-61 years. During roughly 4.9 million person-years of follow-up, there were 39,935 all-cause deaths and 11,670 cardiovascular deaths.

Both men and women achieved a peak survival benefit at 300 minutes of weekly moderate to vigorous aerobic physical activity. But the mortality reduction was substantially greater in women than in men for the same amount of regular exercise (24% vs 18%). 

Similarly, for any given dose of physical activity leading up to 300 minutes per week, women derived proportionately greater survival benefits than did men, the authors reported. 

“Importantly, the greater magnitude of physical activity-related survival benefit in women than men was consistently found across varied measures and types of physical activity including frequency, duration per session, and intensity of aerobic physical activity, as well as frequency of muscle strengthening activities,” they wrote. 

They say multiple factors, including variations in anatomy and physiology, may account for the differences in outcomes between men and women. For example, compared with men, women may use more respiratory, metabolic, and strength demands to conduct the same movement and in turn, reap greater health benefits.

The study also showed only 33% of women and 43% of men regularly engaged in aerobic physical activity, whereas only 20% of women and 28% of men completed a weekly strength training session.

“We hope this study will help everyone, especially women, understand they are poised to gain tremendous benefits from exercise,” senior author Susan Cheng, MD, with the Smidt Heart Institute at Cedars-Sinai, Los Angeles, said in a statement.

In an accompanying editorial, Wael A. Jaber, MD, and Erika Hutt, MD, from Cleveland Clinic Ohio, wrote that this analysis “brings us one step farther in gaining insights into the role and influence of physiological responses to exercise with a sex-specific lens.” 

The study is “well designed and adds important information to the body of literature that can potentially close the gender gap and optimize sex-specific physical activity recommendations by policy makers and societal guidelines,” they wrote. 

“This study emphasizes that there is no singular approach for exercise. A person’s physical activity needs and goals may change based on their age, health status, and schedule — but the value of any type of exercise is irrefutable,” Eric J. Shiroma, ScD, with the National Heart, Lung, and Blood Institute, said in a statement. 

The study was supported in part by grants from the National Institutes of Health. The authors and editorial writers have declared no relevant conflicts of interest.
 

A version of this article appeared on Medscape.com.

Women may gain greater health benefits from regular physical activity at equivalent or lower doses of activity, compared with men, according to data from more than 400,000 US adults. 

Over two decades, with any regular physical activity, all-cause mortality risk was reduced by 24% in women vs 15% in men, and cardiovascular mortality risk was reduced by 36% and 14%, respectively, compared with inactivity, researchers found. 

Participating in strength training exercises (vs not) was associated with a reduced risk for all-cause death of 19% in women and 11% men and reductions in cardiovascular death of 30% and 11%, respectively.

“Women have historically and statistically lagged behind men in engaging in meaningful exercise,” co–lead author Martha Gulati, MD, with the Smidt Heart Institute at Cedars-Sinai, Los Angeles, said in a statement. “The beauty of this study is learning that women can get more out of each minute of moderate to vigorous activity than men do. It’s an incentivizing notion that we hope women will take to heart.”

The study was published online February 19 in the Journal of the American College of Cardiology. 
 

Sex-Specific Exercise Advice? 

The findings are based on leisure-time physical activity data collected over roughly 20 years via the National Health Interview Survey for 412,413 US adults aged 27-61 years. During roughly 4.9 million person-years of follow-up, there were 39,935 all-cause deaths and 11,670 cardiovascular deaths.

Both men and women achieved a peak survival benefit at 300 minutes of weekly moderate to vigorous aerobic physical activity. But the mortality reduction was substantially greater in women than in men for the same amount of regular exercise (24% vs 18%). 

Similarly, for any given dose of physical activity leading up to 300 minutes per week, women derived proportionately greater survival benefits than did men, the authors reported. 

“Importantly, the greater magnitude of physical activity-related survival benefit in women than men was consistently found across varied measures and types of physical activity including frequency, duration per session, and intensity of aerobic physical activity, as well as frequency of muscle strengthening activities,” they wrote. 

They say multiple factors, including variations in anatomy and physiology, may account for the differences in outcomes between men and women. For example, compared with men, women may use more respiratory, metabolic, and strength demands to conduct the same movement and in turn, reap greater health benefits.

The study also showed only 33% of women and 43% of men regularly engaged in aerobic physical activity, whereas only 20% of women and 28% of men completed a weekly strength training session.

“We hope this study will help everyone, especially women, understand they are poised to gain tremendous benefits from exercise,” senior author Susan Cheng, MD, with the Smidt Heart Institute at Cedars-Sinai, Los Angeles, said in a statement.

In an accompanying editorial, Wael A. Jaber, MD, and Erika Hutt, MD, from Cleveland Clinic Ohio, wrote that this analysis “brings us one step farther in gaining insights into the role and influence of physiological responses to exercise with a sex-specific lens.” 

The study is “well designed and adds important information to the body of literature that can potentially close the gender gap and optimize sex-specific physical activity recommendations by policy makers and societal guidelines,” they wrote. 

“This study emphasizes that there is no singular approach for exercise. A person’s physical activity needs and goals may change based on their age, health status, and schedule — but the value of any type of exercise is irrefutable,” Eric J. Shiroma, ScD, with the National Heart, Lung, and Blood Institute, said in a statement. 

The study was supported in part by grants from the National Institutes of Health. The authors and editorial writers have declared no relevant conflicts of interest.
 

A version of this article appeared on Medscape.com.

In January 2024, the American Academy of Dermatology released updated clinical guidelines for the treatment of acne. These guidelines include 18 evidence-based recommendations.

As primary care physicians, we commonly encounter acne vulgaris in our practices. While it may not be a life-threatening condition, it deeply affects the quality of life for many who suffer from it. It can be accompanied by stigmatization and bullying and can affect a person’s self-esteem; it can lead to suicidal ideation. It is important to treat it and know when to refer to a dermatologist.

According to the AAD, acne is the most common skin condition, affecting 50 million Americans annually. It can occur at any stage in life, often starting during puberty. It is so common that at least 85% of people between the ages of 12 and 24 experience at least mild acne.

The guidelines stress using multimodal therapies combining multiple mechanisms of action. For example, they show strong evidence for using topical retinoids with topical benzoyl peroxide or topical retinoids with topical antibiotics. They recommend against using oral antibiotics, except in severe cases, to prevent antibiotic resistance. The strongest evidence regarding antibiotics shows doxycycline or minocycline to be the most effective for treating acne and these can be combined with topical medications.

These guidelines also include isotretinoin to be used for severe acne patients, who are defined as “patients with psychosocial burden or scarring.” They recommend monitoring liver function and lipids as good practice and mandatory pregnancy prevention. These guidelines find no conclusive evidence for physical modalities such as lesion extraction, chemical peels, use of laser and light-based devices, microneedling, use of radiofrequency devices, and photodynamic therapy.

A conditional recommendation is given for the use of combined oral contraception pills and spironolactone. The AAD advises considering the risks of these agents along with other conditions present that they may be useful for.

In primary care, we see many complicated patients and often acne is not considered a serious condition. However, it can be as life-altering to the patient as other chronic diseases such as rheumatoid arthritis. We need to know the appropriate management of acne and start following the evidence-based guidelines. Acne needs follow-up as close as for other chronic diseases. We need to be able to assess the severity of disease and the effectiveness of treatments we have prescribed.

Some patients may be embarrassed to start the discussion about acne. If the patient doesn’t initiate the discussion, we should in an empathetic way. Acne is one of those diseases that doesn’t need any diagnostic tests to discover as it is readily apparent right in front of us.

Some patients may not be bothered by it, but for others, it may be ruining their lives, and they just don’t feel comfortable starting the conversation. Offering them a treatment will alleviate their disease but may also change their lives for the better.

Acne is also one of those conditions that has a host of misinformation and myths surrounding it. These myths range from dietary recommendations to hygiene and many others. As physicians, we need to educate ourselves about these myths and misconceptions. Patients will have questions regarding them and we need to be able to give them answers to their questions. We also shouldn’t give out misinformation ourselves. The evidence around acne treatment is readily available.

Given the availability of multiple acne therapies, shared-decision making is important. We need to discuss options with the patients and devise the best treatment regimen for them. If our therapies are not getting the results we would like, we need to consider referring the patient to a dermatologist.

We need to remember that acne is not just a cosmetic disease. It affects the lives of those suffering from it and we need to address it like any other chronic disease.
 

Dr. Girgis practices family medicine in South River, N.J., and is a clinical assistant professor of family medicine at Robert Wood Johnson Medical School, New Brunswick, N.J.

In January 2024, the American Academy of Dermatology released updated clinical guidelines for the treatment of acne. These guidelines include 18 evidence-based recommendations.

As primary care physicians, we commonly encounter acne vulgaris in our practices. While it may not be a life-threatening condition, it deeply affects the quality of life for many who suffer from it. It can be accompanied by stigmatization and bullying and can affect a person’s self-esteem; it can lead to suicidal ideation. It is important to treat it and know when to refer to a dermatologist.

According to the AAD, acne is the most common skin condition, affecting 50 million Americans annually. It can occur at any stage in life, often starting during puberty. It is so common that at least 85% of people between the ages of 12 and 24 experience at least mild acne.

The guidelines stress using multimodal therapies combining multiple mechanisms of action. For example, they show strong evidence for using topical retinoids with topical benzoyl peroxide or topical retinoids with topical antibiotics. They recommend against using oral antibiotics, except in severe cases, to prevent antibiotic resistance. The strongest evidence regarding antibiotics shows doxycycline or minocycline to be the most effective for treating acne and these can be combined with topical medications.

These guidelines also include isotretinoin to be used for severe acne patients, who are defined as “patients with psychosocial burden or scarring.” They recommend monitoring liver function and lipids as good practice and mandatory pregnancy prevention. These guidelines find no conclusive evidence for physical modalities such as lesion extraction, chemical peels, use of laser and light-based devices, microneedling, use of radiofrequency devices, and photodynamic therapy.

A conditional recommendation is given for the use of combined oral contraception pills and spironolactone. The AAD advises considering the risks of these agents along with other conditions present that they may be useful for.

In primary care, we see many complicated patients and often acne is not considered a serious condition. However, it can be as life-altering to the patient as other chronic diseases such as rheumatoid arthritis. We need to know the appropriate management of acne and start following the evidence-based guidelines. Acne needs follow-up as close as for other chronic diseases. We need to be able to assess the severity of disease and the effectiveness of treatments we have prescribed.

Some patients may be embarrassed to start the discussion about acne. If the patient doesn’t initiate the discussion, we should in an empathetic way. Acne is one of those diseases that doesn’t need any diagnostic tests to discover as it is readily apparent right in front of us.

Some patients may not be bothered by it, but for others, it may be ruining their lives, and they just don’t feel comfortable starting the conversation. Offering them a treatment will alleviate their disease but may also change their lives for the better.

Acne is also one of those conditions that has a host of misinformation and myths surrounding it. These myths range from dietary recommendations to hygiene and many others. As physicians, we need to educate ourselves about these myths and misconceptions. Patients will have questions regarding them and we need to be able to give them answers to their questions. We also shouldn’t give out misinformation ourselves. The evidence around acne treatment is readily available.

Given the availability of multiple acne therapies, shared-decision making is important. We need to discuss options with the patients and devise the best treatment regimen for them. If our therapies are not getting the results we would like, we need to consider referring the patient to a dermatologist.

We need to remember that acne is not just a cosmetic disease. It affects the lives of those suffering from it and we need to address it like any other chronic disease.
 

Dr. Girgis practices family medicine in South River, N.J., and is a clinical assistant professor of family medicine at Robert Wood Johnson Medical School, New Brunswick, N.J.

In January 2024, the American Academy of Dermatology released updated clinical guidelines for the treatment of acne. These guidelines include 18 evidence-based recommendations.

As primary care physicians, we commonly encounter acne vulgaris in our practices. While it may not be a life-threatening condition, it deeply affects the quality of life for many who suffer from it. It can be accompanied by stigmatization and bullying and can affect a person’s self-esteem; it can lead to suicidal ideation. It is important to treat it and know when to refer to a dermatologist.

According to the AAD, acne is the most common skin condition, affecting 50 million Americans annually. It can occur at any stage in life, often starting during puberty. It is so common that at least 85% of people between the ages of 12 and 24 experience at least mild acne.

The guidelines stress using multimodal therapies combining multiple mechanisms of action. For example, they show strong evidence for using topical retinoids with topical benzoyl peroxide or topical retinoids with topical antibiotics. They recommend against using oral antibiotics, except in severe cases, to prevent antibiotic resistance. The strongest evidence regarding antibiotics shows doxycycline or minocycline to be the most effective for treating acne and these can be combined with topical medications.

These guidelines also include isotretinoin to be used for severe acne patients, who are defined as “patients with psychosocial burden or scarring.” They recommend monitoring liver function and lipids as good practice and mandatory pregnancy prevention. These guidelines find no conclusive evidence for physical modalities such as lesion extraction, chemical peels, use of laser and light-based devices, microneedling, use of radiofrequency devices, and photodynamic therapy.

A conditional recommendation is given for the use of combined oral contraception pills and spironolactone. The AAD advises considering the risks of these agents along with other conditions present that they may be useful for.

In primary care, we see many complicated patients and often acne is not considered a serious condition. However, it can be as life-altering to the patient as other chronic diseases such as rheumatoid arthritis. We need to know the appropriate management of acne and start following the evidence-based guidelines. Acne needs follow-up as close as for other chronic diseases. We need to be able to assess the severity of disease and the effectiveness of treatments we have prescribed.

Some patients may be embarrassed to start the discussion about acne. If the patient doesn’t initiate the discussion, we should in an empathetic way. Acne is one of those diseases that doesn’t need any diagnostic tests to discover as it is readily apparent right in front of us.

Some patients may not be bothered by it, but for others, it may be ruining their lives, and they just don’t feel comfortable starting the conversation. Offering them a treatment will alleviate their disease but may also change their lives for the better.

Acne is also one of those conditions that has a host of misinformation and myths surrounding it. These myths range from dietary recommendations to hygiene and many others. As physicians, we need to educate ourselves about these myths and misconceptions. Patients will have questions regarding them and we need to be able to give them answers to their questions. We also shouldn’t give out misinformation ourselves. The evidence around acne treatment is readily available.

Given the availability of multiple acne therapies, shared-decision making is important. We need to discuss options with the patients and devise the best treatment regimen for them. If our therapies are not getting the results we would like, we need to consider referring the patient to a dermatologist.

We need to remember that acne is not just a cosmetic disease. It affects the lives of those suffering from it and we need to address it like any other chronic disease.
 

Dr. Girgis practices family medicine in South River, N.J., and is a clinical assistant professor of family medicine at Robert Wood Johnson Medical School, New Brunswick, N.J.

TOPLINE:

Gargling with mouthwash two to three times a day can reduce periodontopathic bacteria and possibly improve glycemic control in people with type 2 diabetes (T2D), especially younger adults.

METHODOLOGY:

• A total of 173 patients with T2D who had at least six total periodontopathic bacteria in their mouths and  ≥ 6.5% were instructed to gargle with water three times a day for 6 months, followed by gargling with chlorhexidine gluconate mouthwash three times a day for the next 6 months.
• Saliva specimens were collected every 1-2 months at clinic visits totaling 6-12 samples per study period and bacterial DNA examined for three red complex species, namely, Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia.

TAKEAWAY:

• Twelve individuals who gargled once a day or less showed no significant reductions in red complex species after mouthwash or water gargling.
• By contrast, significant decreases in red complex bacteria were seen after 6 months of mouthwash gargling (P < .001) in the 80 who gargled twice a day and the 81 who did so three times a day compared with no changes after water gargling.
• Among the 161 individuals who gargled at least twice a day, the decrease in red species with mouthwash vs water gargling was highly significant (P < .0001).
• After adjustment for A1c seasonal variation, neither water gargling nor mouthwash gargling led to significant overall reduction in A1c levels.
• However, A1c levels were significantly lower in the 83 individuals aged ≤ 68 years than among the 78 aged ≥ 69 years after gargling with mouthwash (P < .05), with no change in either group after water gargling.
• Similarly, A1c levels were significantly reduced (P < .05) after mouthwash in the 69 with baseline A1c ≥ 7.5% compared with the 92 whose baseline A1c levels were ≤ 7.4%, with no changes in either after water.

IN PRACTICE:

“A bidirectional relationship between periodontitis and T2D has been reported. Patients with T2D are more susceptible to severe periodontitis than subjects without diabetes, and inflammatory periodontitis aggravates hyperglycemia, leading to inadequate glycemic control.” “Recently, it has been reported that patients with T2D treated for periodontitis have reduced periodontopathic bacteria and improved glycemic control. Patients with T2D complicated by periodontitis have more red complex species, and poor glycemic control is thought to be associated with increased levels of red complex species in the oral cavity.” “Further studies should be planned, taking into account various patient factors to determine the effect of mouthwash gargling on the amount of red complex species and A1c levels in patients with T2D.”

SOURCE:

This study was conducted by Saaya Matayoshi, of the Joint Research Laboratory of Science for Oral and Systemic Connection, Osaka University Graduate School of Dentistry, Osaka, Japan, and colleagues and published in Scientific Reports.

LIMITATIONS:

Only polymerase chain reaction used to detect periodontopathic bacteria so not quantified. No assessment of periodontal pocket depth. Saliva sampling conditions not standardized. Study conducted during COVID-19 pandemic; all patients wore masks. Heterogeneity in patient responses to the mouthwash.

DISCLOSURES:

This work was supported by the Fund for Scientific Promotion of Weltec Corp, Osaka, Japan. The authors declared no competing interests.

A version of this article appeared on Medscape.com.

TOPLINE:

Gargling with mouthwash two to three times a day can reduce periodontopathic bacteria and possibly improve glycemic control in people with type 2 diabetes (T2D), especially younger adults.

METHODOLOGY:

• A total of 173 patients with T2D who had at least six total periodontopathic bacteria in their mouths and  ≥ 6.5% were instructed to gargle with water three times a day for 6 months, followed by gargling with chlorhexidine gluconate mouthwash three times a day for the next 6 months.
• Saliva specimens were collected every 1-2 months at clinic visits totaling 6-12 samples per study period and bacterial DNA examined for three red complex species, namely, Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia.

TAKEAWAY:

• Twelve individuals who gargled once a day or less showed no significant reductions in red complex species after mouthwash or water gargling.
• By contrast, significant decreases in red complex bacteria were seen after 6 months of mouthwash gargling (P < .001) in the 80 who gargled twice a day and the 81 who did so three times a day compared with no changes after water gargling.
• Among the 161 individuals who gargled at least twice a day, the decrease in red species with mouthwash vs water gargling was highly significant (P < .0001).
• After adjustment for A1c seasonal variation, neither water gargling nor mouthwash gargling led to significant overall reduction in A1c levels.
• However, A1c levels were significantly lower in the 83 individuals aged ≤ 68 years than among the 78 aged ≥ 69 years after gargling with mouthwash (P < .05), with no change in either group after water gargling.
• Similarly, A1c levels were significantly reduced (P < .05) after mouthwash in the 69 with baseline A1c ≥ 7.5% compared with the 92 whose baseline A1c levels were ≤ 7.4%, with no changes in either after water.

IN PRACTICE:

“A bidirectional relationship between periodontitis and T2D has been reported. Patients with T2D are more susceptible to severe periodontitis than subjects without diabetes, and inflammatory periodontitis aggravates hyperglycemia, leading to inadequate glycemic control.” “Recently, it has been reported that patients with T2D treated for periodontitis have reduced periodontopathic bacteria and improved glycemic control. Patients with T2D complicated by periodontitis have more red complex species, and poor glycemic control is thought to be associated with increased levels of red complex species in the oral cavity.” “Further studies should be planned, taking into account various patient factors to determine the effect of mouthwash gargling on the amount of red complex species and A1c levels in patients with T2D.”

SOURCE:

This study was conducted by Saaya Matayoshi, of the Joint Research Laboratory of Science for Oral and Systemic Connection, Osaka University Graduate School of Dentistry, Osaka, Japan, and colleagues and published in Scientific Reports.

LIMITATIONS:

Only polymerase chain reaction used to detect periodontopathic bacteria so not quantified. No assessment of periodontal pocket depth. Saliva sampling conditions not standardized. Study conducted during COVID-19 pandemic; all patients wore masks. Heterogeneity in patient responses to the mouthwash.

DISCLOSURES:

This work was supported by the Fund for Scientific Promotion of Weltec Corp, Osaka, Japan. The authors declared no competing interests.

A version of this article appeared on Medscape.com.

TOPLINE:

Gargling with mouthwash two to three times a day can reduce periodontopathic bacteria and possibly improve glycemic control in people with type 2 diabetes (T2D), especially younger adults.

METHODOLOGY:

• A total of 173 patients with T2D who had at least six total periodontopathic bacteria in their mouths and  ≥ 6.5% were instructed to gargle with water three times a day for 6 months, followed by gargling with chlorhexidine gluconate mouthwash three times a day for the next 6 months.
• Saliva specimens were collected every 1-2 months at clinic visits totaling 6-12 samples per study period and bacterial DNA examined for three red complex species, namely, Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia.

TAKEAWAY:

• Twelve individuals who gargled once a day or less showed no significant reductions in red complex species after mouthwash or water gargling.
• By contrast, significant decreases in red complex bacteria were seen after 6 months of mouthwash gargling (P < .001) in the 80 who gargled twice a day and the 81 who did so three times a day compared with no changes after water gargling.
• Among the 161 individuals who gargled at least twice a day, the decrease in red species with mouthwash vs water gargling was highly significant (P < .0001).
• After adjustment for A1c seasonal variation, neither water gargling nor mouthwash gargling led to significant overall reduction in A1c levels.
• However, A1c levels were significantly lower in the 83 individuals aged ≤ 68 years than among the 78 aged ≥ 69 years after gargling with mouthwash (P < .05), with no change in either group after water gargling.
• Similarly, A1c levels were significantly reduced (P < .05) after mouthwash in the 69 with baseline A1c ≥ 7.5% compared with the 92 whose baseline A1c levels were ≤ 7.4%, with no changes in either after water.

IN PRACTICE:

“A bidirectional relationship between periodontitis and T2D has been reported. Patients with T2D are more susceptible to severe periodontitis than subjects without diabetes, and inflammatory periodontitis aggravates hyperglycemia, leading to inadequate glycemic control.” “Recently, it has been reported that patients with T2D treated for periodontitis have reduced periodontopathic bacteria and improved glycemic control. Patients with T2D complicated by periodontitis have more red complex species, and poor glycemic control is thought to be associated with increased levels of red complex species in the oral cavity.” “Further studies should be planned, taking into account various patient factors to determine the effect of mouthwash gargling on the amount of red complex species and A1c levels in patients with T2D.”

SOURCE:

This study was conducted by Saaya Matayoshi, of the Joint Research Laboratory of Science for Oral and Systemic Connection, Osaka University Graduate School of Dentistry, Osaka, Japan, and colleagues and published in Scientific Reports.

LIMITATIONS:

Only polymerase chain reaction used to detect periodontopathic bacteria so not quantified. No assessment of periodontal pocket depth. Saliva sampling conditions not standardized. Study conducted during COVID-19 pandemic; all patients wore masks. Heterogeneity in patient responses to the mouthwash.

DISCLOSURES:

This work was supported by the Fund for Scientific Promotion of Weltec Corp, Osaka, Japan. The authors declared no competing interests.

A version of this article appeared on Medscape.com.

TOPLINE:

A value-based medication plan that lowers out-of-pocket costs for antidiabetic medications reduces health complications in commercially insured individuals with diabetes, especially those living in lower-income areas.

METHODOLOGY: 

• Researchers assessed the 1-year impact on type 2 diabetes outcomes from a preventive drug list (PDL), which employers can add to plans to reduce out-of-pocket costs (copayments or deductibles) for high-value preventive medications.
• Using data from a national insurer, they identified 10,588 members with diabetes newly enrolled in PDL plans between January 2004 and June 2017 (age, 12-64 years; 44.8% women; 45.5% from the South; 33.4% from employers with < 100 enrollees).
• The members with diabetes on a PDL plan for a full follow-up year were matched and weighted against 690,075 control participants whose employers did not offer PDL.
• In a subgroup analysis, health outcomes for members with diabetes residing in lower-income neighborhoods (53.1%) were evaluated.
• The primary outcome was acute, preventable diabetes complications, such as bacterial infections, neurovascular events, acute coronary disease, and diabetic ketoacidosis, measured as complication days per 1000 members per year.

TAKEAWAY: 

• Out-of-pocket costs for noninsulin antidiabetic agents and insulin declined by 30.7% and 38.6%, respectively, in the PDL group vs controls. 
• The 30-day prescription fills for noninsulin and insulin antidiabetic medication increased by 7.1% (95% CI, 5.0%-9.3%) and 5.3% (95% CI, 2.2%-8.4%), respectively, among PDL members and was slightly higher among PDL members residing in low-income areas. 
• The PDL transition was associated with an 8.4% relative reduction (95% CI, −13.9% to −2.8%) in complication days overall (absolute reduction, −20.2 days per 1000 members per year). 
• Among members from lower-income areas, PDL transition was associated with a 10.2% relative reduction (95% CI, −17.4% to −3.0%) in complication days (absolute reduction, −26.1 per 1000 members per year) compared with controls. 

IN PRACTICE:

“Targeting out-of-pocket cost reductions to specific populations, in this case patients with diabetes from lower-income areas, might enhance health outcomes,” wrote the authors.

SOURCE: 

The study was conducted by J. Franklin Wharam, MD, MPH, Department of Medicine, Duke University, Durham, North Carolina. It was published online in JAMA Health Forum. 

LIMITATIONS: 

The findings may be generalized only to patients with diabetes enrolled in commercial health plans. Instead of being randomized, the PDL coverage was chosen by certain employers. Moreover, only outcomes associated with new PDL enrollment over a single year were evaluated.

DISCLOSURES: 

The study was funded by grants from the Centers for Disease Control and Prevention and National Institute of Diabetes and Digestive and Kidney Diseases. One of the authors reported receiving postmarket safety study stipends from Pfizer and GlaxoSmithKline outside the submitted work.

A version of this article appeared on Medscape.com.

TOPLINE:

A value-based medication plan that lowers out-of-pocket costs for antidiabetic medications reduces health complications in commercially insured individuals with diabetes, especially those living in lower-income areas.

METHODOLOGY: 

• Researchers assessed the 1-year impact on type 2 diabetes outcomes from a preventive drug list (PDL), which employers can add to plans to reduce out-of-pocket costs (copayments or deductibles) for high-value preventive medications.
• Using data from a national insurer, they identified 10,588 members with diabetes newly enrolled in PDL plans between January 2004 and June 2017 (age, 12-64 years; 44.8% women; 45.5% from the South; 33.4% from employers with < 100 enrollees).
• The members with diabetes on a PDL plan for a full follow-up year were matched and weighted against 690,075 control participants whose employers did not offer PDL.
• In a subgroup analysis, health outcomes for members with diabetes residing in lower-income neighborhoods (53.1%) were evaluated.
• The primary outcome was acute, preventable diabetes complications, such as bacterial infections, neurovascular events, acute coronary disease, and diabetic ketoacidosis, measured as complication days per 1000 members per year.

TAKEAWAY: 

• Out-of-pocket costs for noninsulin antidiabetic agents and insulin declined by 30.7% and 38.6%, respectively, in the PDL group vs controls. 
• The 30-day prescription fills for noninsulin and insulin antidiabetic medication increased by 7.1% (95% CI, 5.0%-9.3%) and 5.3% (95% CI, 2.2%-8.4%), respectively, among PDL members and was slightly higher among PDL members residing in low-income areas. 
• The PDL transition was associated with an 8.4% relative reduction (95% CI, −13.9% to −2.8%) in complication days overall (absolute reduction, −20.2 days per 1000 members per year). 
• Among members from lower-income areas, PDL transition was associated with a 10.2% relative reduction (95% CI, −17.4% to −3.0%) in complication days (absolute reduction, −26.1 per 1000 members per year) compared with controls. 

IN PRACTICE:

“Targeting out-of-pocket cost reductions to specific populations, in this case patients with diabetes from lower-income areas, might enhance health outcomes,” wrote the authors.

SOURCE: 

The study was conducted by J. Franklin Wharam, MD, MPH, Department of Medicine, Duke University, Durham, North Carolina. It was published online in JAMA Health Forum. 

LIMITATIONS: 

The findings may be generalized only to patients with diabetes enrolled in commercial health plans. Instead of being randomized, the PDL coverage was chosen by certain employers. Moreover, only outcomes associated with new PDL enrollment over a single year were evaluated.

DISCLOSURES: 

The study was funded by grants from the Centers for Disease Control and Prevention and National Institute of Diabetes and Digestive and Kidney Diseases. One of the authors reported receiving postmarket safety study stipends from Pfizer and GlaxoSmithKline outside the submitted work.

A version of this article appeared on Medscape.com.

TOPLINE:

A value-based medication plan that lowers out-of-pocket costs for antidiabetic medications reduces health complications in commercially insured individuals with diabetes, especially those living in lower-income areas.

METHODOLOGY: 

• Researchers assessed the 1-year impact on type 2 diabetes outcomes from a preventive drug list (PDL), which employers can add to plans to reduce out-of-pocket costs (copayments or deductibles) for high-value preventive medications.
• Using data from a national insurer, they identified 10,588 members with diabetes newly enrolled in PDL plans between January 2004 and June 2017 (age, 12-64 years; 44.8% women; 45.5% from the South; 33.4% from employers with < 100 enrollees).
• The members with diabetes on a PDL plan for a full follow-up year were matched and weighted against 690,075 control participants whose employers did not offer PDL.
• In a subgroup analysis, health outcomes for members with diabetes residing in lower-income neighborhoods (53.1%) were evaluated.
• The primary outcome was acute, preventable diabetes complications, such as bacterial infections, neurovascular events, acute coronary disease, and diabetic ketoacidosis, measured as complication days per 1000 members per year.

TAKEAWAY: 

• Out-of-pocket costs for noninsulin antidiabetic agents and insulin declined by 30.7% and 38.6%, respectively, in the PDL group vs controls. 
• The 30-day prescription fills for noninsulin and insulin antidiabetic medication increased by 7.1% (95% CI, 5.0%-9.3%) and 5.3% (95% CI, 2.2%-8.4%), respectively, among PDL members and was slightly higher among PDL members residing in low-income areas. 
• The PDL transition was associated with an 8.4% relative reduction (95% CI, −13.9% to −2.8%) in complication days overall (absolute reduction, −20.2 days per 1000 members per year). 
• Among members from lower-income areas, PDL transition was associated with a 10.2% relative reduction (95% CI, −17.4% to −3.0%) in complication days (absolute reduction, −26.1 per 1000 members per year) compared with controls. 

IN PRACTICE:

“Targeting out-of-pocket cost reductions to specific populations, in this case patients with diabetes from lower-income areas, might enhance health outcomes,” wrote the authors.

SOURCE: 

The study was conducted by J. Franklin Wharam, MD, MPH, Department of Medicine, Duke University, Durham, North Carolina. It was published online in JAMA Health Forum. 

LIMITATIONS: 

The findings may be generalized only to patients with diabetes enrolled in commercial health plans. Instead of being randomized, the PDL coverage was chosen by certain employers. Moreover, only outcomes associated with new PDL enrollment over a single year were evaluated.

DISCLOSURES: 

The study was funded by grants from the Centers for Disease Control and Prevention and National Institute of Diabetes and Digestive and Kidney Diseases. One of the authors reported receiving postmarket safety study stipends from Pfizer and GlaxoSmithKline outside the submitted work.

A version of this article appeared on Medscape.com.

TOPLINE:

Two breakdown products from excess niacin, called 2PY and 4PY, were strongly associated with myocardial infarction, stroke, and other adverse cardiac events, suggesting that niacin supplementation may require a more “nuanced, titrated approach,” researchers said.

METHODOLOGY:

• Investigators performed an untargeted metabolomics analysis of fasting plasma from stable cardiac patients in a prospective discovery cohort of 1162 individuals (36% women).
• Additional analyses were performed in a US validation cohort, including measurement of soluble vascular adhesion molecule-1 (sVCAM-1), and on archival fasting samples from patients in a European validation cohort undergoing diagnostic coronary angiography.
• Genetic analyses of samples from the UK Biobank were used to test the association with sVCAM-1 levels of a genetic variant, rs10496731, which was significantly associated with both N1-methyl-2-pyridone-5-carboxamide (2 PY) and N1-methyl-4-pyridone-3-carboxamide (4PY) levels.

TAKEAWAY:

• Niacin metabolism was associated with incident major adverse cardiovascular events (MACE).
• Plasma levels of the terminal metabolites of excess niacin, 2PY and 4PY, were associated with increased 3-year MACE risk in two validation cohorts (US: 2331 total, 33% women; European: 832 total, 30% women), with adjusted hazard ratios for 2PY of 1.64 and 2.02, respectively, and for 4PY, 1.89 and 1.99.
• The genetic variant rs10496731 was significantly associated with levels of sVCAM-1.
• Treatment with physiological levels of 4PY, but not 2PY, induced expression of VCAM-1 and leukocyte adherence to vascular endothelium in mice, suggesting an inflammation-dependent mechanism underlying the clinical association of 4PY, in particular, with MACE.
• In functional testing, a physiological level of 4PY, but not 2PY, provoked messenger RNA and protein expression of VCAM-1 on human endothelial cells.

IN PRACTICE:

“Total niacin consumption in the US averaged 48 mg/d from 2017 to 2020 — more than triple the Recommended Daily Allowance — and 2PY and 4PY were also increased by nicotinamideriboside and nicotinamide mononucleotide, both of which are commonly sold supplements with claimed antiaging benefits,” the authors noted.

“The present studies suggest that niacin pool supplementation may optimally require a more nuanced, titrated approach to achieve intended health benefits,” while not fostering excess 4PY generation.

SOURCE:

Stanley Hazen, MD, PhD, of Cleveland Clinic, Cleveland, Ohio, was the principal author of the study, published online in Nature Medicine.

LIMITATIONS:

Measurement of 2PY and 4PY in the validation cohorts was performed only once, whereas serial measures might have provided enhanced prognostic value for incident cardiovascular disease (CVD) risks. Cohorts were recruited at quaternary referral centers and showed a high prevalence of CVD and cardiometabolic disease risk factors. Although the meta-analysis of the community-based genomic (Biobank) studies showed a link between 4PY and VCAM-1 expression in multiple ethnic groups, the clinical studies linking 4PY to CVD events were based on high-risk European ancestry populations in the US and European cohorts.

DISCLOSURES:

The study was supported by grants from the National Institutes of Health (NIH; both the National Heart, Lung, and Blood Institute and the Office of Dietary Supplements: A), Pilot Project Programs of the USC Center for Genetic Epidemiology and Southern California Environmental Health Sciences Center, and the Deutsche Forschungsgemeinschaft. One co-author was supported, in part, by NIH training grants; another was a participant in the BIH-Charité Advanced Clinician Scientist Program funded by Charité – Universitätsmedizin Berlin and the Berlin Institute of Health. The LipidCardio study [validation cohort] was partially supported by Sanofi-Aventis Deutschland GmbH. The UK Biobank Resource provided access to their data. Dr. Hazen and a co-author reported being coinventors on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics and therapeutics, and Dr. Hazen and two co-authors received funds from industry.

A version of the article appeared on Medscape.com.

TOPLINE:

Two breakdown products from excess niacin, called 2PY and 4PY, were strongly associated with myocardial infarction, stroke, and other adverse cardiac events, suggesting that niacin supplementation may require a more “nuanced, titrated approach,” researchers said.

METHODOLOGY:

• Investigators performed an untargeted metabolomics analysis of fasting plasma from stable cardiac patients in a prospective discovery cohort of 1162 individuals (36% women).
• Additional analyses were performed in a US validation cohort, including measurement of soluble vascular adhesion molecule-1 (sVCAM-1), and on archival fasting samples from patients in a European validation cohort undergoing diagnostic coronary angiography.
• Genetic analyses of samples from the UK Biobank were used to test the association with sVCAM-1 levels of a genetic variant, rs10496731, which was significantly associated with both N1-methyl-2-pyridone-5-carboxamide (2 PY) and N1-methyl-4-pyridone-3-carboxamide (4PY) levels.

TAKEAWAY:

• Niacin metabolism was associated with incident major adverse cardiovascular events (MACE).
• Plasma levels of the terminal metabolites of excess niacin, 2PY and 4PY, were associated with increased 3-year MACE risk in two validation cohorts (US: 2331 total, 33% women; European: 832 total, 30% women), with adjusted hazard ratios for 2PY of 1.64 and 2.02, respectively, and for 4PY, 1.89 and 1.99.
• The genetic variant rs10496731 was significantly associated with levels of sVCAM-1.
• Treatment with physiological levels of 4PY, but not 2PY, induced expression of VCAM-1 and leukocyte adherence to vascular endothelium in mice, suggesting an inflammation-dependent mechanism underlying the clinical association of 4PY, in particular, with MACE.
• In functional testing, a physiological level of 4PY, but not 2PY, provoked messenger RNA and protein expression of VCAM-1 on human endothelial cells.

IN PRACTICE:

“Total niacin consumption in the US averaged 48 mg/d from 2017 to 2020 — more than triple the Recommended Daily Allowance — and 2PY and 4PY were also increased by nicotinamideriboside and nicotinamide mononucleotide, both of which are commonly sold supplements with claimed antiaging benefits,” the authors noted.

“The present studies suggest that niacin pool supplementation may optimally require a more nuanced, titrated approach to achieve intended health benefits,” while not fostering excess 4PY generation.

SOURCE:

Stanley Hazen, MD, PhD, of Cleveland Clinic, Cleveland, Ohio, was the principal author of the study, published online in Nature Medicine.

LIMITATIONS:

Measurement of 2PY and 4PY in the validation cohorts was performed only once, whereas serial measures might have provided enhanced prognostic value for incident cardiovascular disease (CVD) risks. Cohorts were recruited at quaternary referral centers and showed a high prevalence of CVD and cardiometabolic disease risk factors. Although the meta-analysis of the community-based genomic (Biobank) studies showed a link between 4PY and VCAM-1 expression in multiple ethnic groups, the clinical studies linking 4PY to CVD events were based on high-risk European ancestry populations in the US and European cohorts.

DISCLOSURES:

The study was supported by grants from the National Institutes of Health (NIH; both the National Heart, Lung, and Blood Institute and the Office of Dietary Supplements: A), Pilot Project Programs of the USC Center for Genetic Epidemiology and Southern California Environmental Health Sciences Center, and the Deutsche Forschungsgemeinschaft. One co-author was supported, in part, by NIH training grants; another was a participant in the BIH-Charité Advanced Clinician Scientist Program funded by Charité – Universitätsmedizin Berlin and the Berlin Institute of Health. The LipidCardio study [validation cohort] was partially supported by Sanofi-Aventis Deutschland GmbH. The UK Biobank Resource provided access to their data. Dr. Hazen and a co-author reported being coinventors on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics and therapeutics, and Dr. Hazen and two co-authors received funds from industry.

A version of the article appeared on Medscape.com.

TOPLINE:

Two breakdown products from excess niacin, called 2PY and 4PY, were strongly associated with myocardial infarction, stroke, and other adverse cardiac events, suggesting that niacin supplementation may require a more “nuanced, titrated approach,” researchers said.

METHODOLOGY:

• Investigators performed an untargeted metabolomics analysis of fasting plasma from stable cardiac patients in a prospective discovery cohort of 1162 individuals (36% women).
• Additional analyses were performed in a US validation cohort, including measurement of soluble vascular adhesion molecule-1 (sVCAM-1), and on archival fasting samples from patients in a European validation cohort undergoing diagnostic coronary angiography.
• Genetic analyses of samples from the UK Biobank were used to test the association with sVCAM-1 levels of a genetic variant, rs10496731, which was significantly associated with both N1-methyl-2-pyridone-5-carboxamide (2 PY) and N1-methyl-4-pyridone-3-carboxamide (4PY) levels.

TAKEAWAY:

• Niacin metabolism was associated with incident major adverse cardiovascular events (MACE).
• Plasma levels of the terminal metabolites of excess niacin, 2PY and 4PY, were associated with increased 3-year MACE risk in two validation cohorts (US: 2331 total, 33% women; European: 832 total, 30% women), with adjusted hazard ratios for 2PY of 1.64 and 2.02, respectively, and for 4PY, 1.89 and 1.99.
• The genetic variant rs10496731 was significantly associated with levels of sVCAM-1.
• Treatment with physiological levels of 4PY, but not 2PY, induced expression of VCAM-1 and leukocyte adherence to vascular endothelium in mice, suggesting an inflammation-dependent mechanism underlying the clinical association of 4PY, in particular, with MACE.
• In functional testing, a physiological level of 4PY, but not 2PY, provoked messenger RNA and protein expression of VCAM-1 on human endothelial cells.

IN PRACTICE:

“Total niacin consumption in the US averaged 48 mg/d from 2017 to 2020 — more than triple the Recommended Daily Allowance — and 2PY and 4PY were also increased by nicotinamideriboside and nicotinamide mononucleotide, both of which are commonly sold supplements with claimed antiaging benefits,” the authors noted.

“The present studies suggest that niacin pool supplementation may optimally require a more nuanced, titrated approach to achieve intended health benefits,” while not fostering excess 4PY generation.

SOURCE:

Stanley Hazen, MD, PhD, of Cleveland Clinic, Cleveland, Ohio, was the principal author of the study, published online in Nature Medicine.

LIMITATIONS:

Measurement of 2PY and 4PY in the validation cohorts was performed only once, whereas serial measures might have provided enhanced prognostic value for incident cardiovascular disease (CVD) risks. Cohorts were recruited at quaternary referral centers and showed a high prevalence of CVD and cardiometabolic disease risk factors. Although the meta-analysis of the community-based genomic (Biobank) studies showed a link between 4PY and VCAM-1 expression in multiple ethnic groups, the clinical studies linking 4PY to CVD events were based on high-risk European ancestry populations in the US and European cohorts.

DISCLOSURES:

The study was supported by grants from the National Institutes of Health (NIH; both the National Heart, Lung, and Blood Institute and the Office of Dietary Supplements: A), Pilot Project Programs of the USC Center for Genetic Epidemiology and Southern California Environmental Health Sciences Center, and the Deutsche Forschungsgemeinschaft. One co-author was supported, in part, by NIH training grants; another was a participant in the BIH-Charité Advanced Clinician Scientist Program funded by Charité – Universitätsmedizin Berlin and the Berlin Institute of Health. The LipidCardio study [validation cohort] was partially supported by Sanofi-Aventis Deutschland GmbH. The UK Biobank Resource provided access to their data. Dr. Hazen and a co-author reported being coinventors on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics and therapeutics, and Dr. Hazen and two co-authors received funds from industry.

A version of the article appeared on Medscape.com.