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TOPLINE:

Adults aged 50 years who were born preterm have a higher risk for hypertension but lower risk for cardiovascular events than those born at term, with similar risks for diabetes, prediabetes, and dyslipidemia between groups.

METHODOLOGY:

• The researchers conducted a prospective cohort study of the Auckland Steroid Trial — the first randomized trial of antenatal corticosteroids (betamethasone) for women who were at risk for preterm birth, conducted in Auckland, New Zealand, between December 1969 and February 1974.
• They analyzed 470 participants, including 424 survivors recruited between January 2020 and May 2022 and 46 participants who died after infancy.
• The outcomes for 326 participants born preterm (mean age, 49.4 years) and 144 participants born at term (mean age, 49.2 years) were assessed using either a questionnaire, administrative datasets, or both.
• The primary outcome was a composite of cardiovascular events or risk factors, defined as a history of a major adverse cardiovascular event or the presence of at least one cardiovascular risk factor, including diabetes mellitus, prediabetes, treated dyslipidemia, and treated hypertension.
• The secondary outcomes included respiratory, mental health, educational, and other health outcomes, as well as components of the primary outcomes.

TAKEAWAY:

• The composite of cardiovascular events or risk factors occurred in 34.5% of participants born preterm and 29.9% of participants born at term, with no differences in the risk factor components.
• The risk for cardiovascular events was lower in participants born preterm than in those born at term (adjusted relative risk [aRR], 0.33; P = .013).
• The participants born preterm had a higher risk for high blood pressure (aRR, 1.74; P = .007) and the composite of treated hypertension or self-reported diagnosis of high blood pressure (aRR, 1.63; P = .010) than those born at term.
• From randomization to the 50-year follow-up, death from any cause was more common in those born preterm than in those born at term (aRR, 2.29; P < .0001), whereas the diagnosis or treatment of a mental health disorder was less common (P = .007); no differences were observed between the groups for other outcomes.

IN PRACTICE:

“Those aware of being born preterm also may be more likely to seek preventive treatments, potentially resulting in a reduced risk of cardiovascular disease but a greater prevalence of risk factors if defined by a treatment such as treated dyslipidemia or treated hypertension,” the authors wrote.

“In this cohort, the survival advantage of the term-born control group abated after infancy, with a higher all-cause mortality rate, compared with that of the group born preterm,” wrote Jonathan S. Litt, MD, MPH, ScD, and Henning Tiemeier, MD, PhD, in a related commentary published in Pediatrics.

SOURCE:

The study was led by Anthony G. B. Walters, MBChB, Liggins Institute, Auckland, New Zealand. It was published online on December 16, 2024, in Pediatrics .

LIMITATIONS:

The small sample size limited the ability to detect subtle differences between groups and the validity of subgroup analyses. Attrition bias may have occurred because of low follow-up rates among presumed survivors. Bias could have been introduced because of lack of consent for access to the administrative dataset or from missing data from the participants in the questionnaire. The lack of in-person assessments for blood pressure and blood tests, resulting from geographical dispersion over 50 years, may have led to underestimation of some outcomes. Additionally, as most participants were born moderately or late preterm, with a median gestational age of 34.1 weeks, findings may not be generalizable to those born preterm at earlier gestational ages.

DISCLOSURES:

The study was supported in part by the Aotearoa Foundation, the Auckland Medical Research Foundation, Cure Kids New Zealand, and the Health Research Council of New Zealand. The authors of both the study and the commentary reported no conflicts of interest.

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

TOPLINE:

Adults aged 50 years who were born preterm have a higher risk for hypertension but lower risk for cardiovascular events than those born at term, with similar risks for diabetes, prediabetes, and dyslipidemia between groups.

METHODOLOGY:

• The researchers conducted a prospective cohort study of the Auckland Steroid Trial — the first randomized trial of antenatal corticosteroids (betamethasone) for women who were at risk for preterm birth, conducted in Auckland, New Zealand, between December 1969 and February 1974.
• They analyzed 470 participants, including 424 survivors recruited between January 2020 and May 2022 and 46 participants who died after infancy.
• The outcomes for 326 participants born preterm (mean age, 49.4 years) and 144 participants born at term (mean age, 49.2 years) were assessed using either a questionnaire, administrative datasets, or both.
• The primary outcome was a composite of cardiovascular events or risk factors, defined as a history of a major adverse cardiovascular event or the presence of at least one cardiovascular risk factor, including diabetes mellitus, prediabetes, treated dyslipidemia, and treated hypertension.
• The secondary outcomes included respiratory, mental health, educational, and other health outcomes, as well as components of the primary outcomes.

TAKEAWAY:

• The composite of cardiovascular events or risk factors occurred in 34.5% of participants born preterm and 29.9% of participants born at term, with no differences in the risk factor components.
• The risk for cardiovascular events was lower in participants born preterm than in those born at term (adjusted relative risk [aRR], 0.33; P = .013).
• The participants born preterm had a higher risk for high blood pressure (aRR, 1.74; P = .007) and the composite of treated hypertension or self-reported diagnosis of high blood pressure (aRR, 1.63; P = .010) than those born at term.
• From randomization to the 50-year follow-up, death from any cause was more common in those born preterm than in those born at term (aRR, 2.29; P < .0001), whereas the diagnosis or treatment of a mental health disorder was less common (P = .007); no differences were observed between the groups for other outcomes.

IN PRACTICE:

“Those aware of being born preterm also may be more likely to seek preventive treatments, potentially resulting in a reduced risk of cardiovascular disease but a greater prevalence of risk factors if defined by a treatment such as treated dyslipidemia or treated hypertension,” the authors wrote.

“In this cohort, the survival advantage of the term-born control group abated after infancy, with a higher all-cause mortality rate, compared with that of the group born preterm,” wrote Jonathan S. Litt, MD, MPH, ScD, and Henning Tiemeier, MD, PhD, in a related commentary published in Pediatrics.

SOURCE:

The study was led by Anthony G. B. Walters, MBChB, Liggins Institute, Auckland, New Zealand. It was published online on December 16, 2024, in Pediatrics .

LIMITATIONS:

The small sample size limited the ability to detect subtle differences between groups and the validity of subgroup analyses. Attrition bias may have occurred because of low follow-up rates among presumed survivors. Bias could have been introduced because of lack of consent for access to the administrative dataset or from missing data from the participants in the questionnaire. The lack of in-person assessments for blood pressure and blood tests, resulting from geographical dispersion over 50 years, may have led to underestimation of some outcomes. Additionally, as most participants were born moderately or late preterm, with a median gestational age of 34.1 weeks, findings may not be generalizable to those born preterm at earlier gestational ages.

DISCLOSURES:

The study was supported in part by the Aotearoa Foundation, the Auckland Medical Research Foundation, Cure Kids New Zealand, and the Health Research Council of New Zealand. The authors of both the study and the commentary reported no conflicts of interest.

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

TOPLINE:

Adults aged 50 years who were born preterm have a higher risk for hypertension but lower risk for cardiovascular events than those born at term, with similar risks for diabetes, prediabetes, and dyslipidemia between groups.

METHODOLOGY:

• The researchers conducted a prospective cohort study of the Auckland Steroid Trial — the first randomized trial of antenatal corticosteroids (betamethasone) for women who were at risk for preterm birth, conducted in Auckland, New Zealand, between December 1969 and February 1974.
• They analyzed 470 participants, including 424 survivors recruited between January 2020 and May 2022 and 46 participants who died after infancy.
• The outcomes for 326 participants born preterm (mean age, 49.4 years) and 144 participants born at term (mean age, 49.2 years) were assessed using either a questionnaire, administrative datasets, or both.
• The primary outcome was a composite of cardiovascular events or risk factors, defined as a history of a major adverse cardiovascular event or the presence of at least one cardiovascular risk factor, including diabetes mellitus, prediabetes, treated dyslipidemia, and treated hypertension.
• The secondary outcomes included respiratory, mental health, educational, and other health outcomes, as well as components of the primary outcomes.

TAKEAWAY:

• The composite of cardiovascular events or risk factors occurred in 34.5% of participants born preterm and 29.9% of participants born at term, with no differences in the risk factor components.
• The risk for cardiovascular events was lower in participants born preterm than in those born at term (adjusted relative risk [aRR], 0.33; P = .013).
• The participants born preterm had a higher risk for high blood pressure (aRR, 1.74; P = .007) and the composite of treated hypertension or self-reported diagnosis of high blood pressure (aRR, 1.63; P = .010) than those born at term.
• From randomization to the 50-year follow-up, death from any cause was more common in those born preterm than in those born at term (aRR, 2.29; P < .0001), whereas the diagnosis or treatment of a mental health disorder was less common (P = .007); no differences were observed between the groups for other outcomes.

IN PRACTICE:

“Those aware of being born preterm also may be more likely to seek preventive treatments, potentially resulting in a reduced risk of cardiovascular disease but a greater prevalence of risk factors if defined by a treatment such as treated dyslipidemia or treated hypertension,” the authors wrote.

“In this cohort, the survival advantage of the term-born control group abated after infancy, with a higher all-cause mortality rate, compared with that of the group born preterm,” wrote Jonathan S. Litt, MD, MPH, ScD, and Henning Tiemeier, MD, PhD, in a related commentary published in Pediatrics.

SOURCE:

The study was led by Anthony G. B. Walters, MBChB, Liggins Institute, Auckland, New Zealand. It was published online on December 16, 2024, in Pediatrics .

LIMITATIONS:

The small sample size limited the ability to detect subtle differences between groups and the validity of subgroup analyses. Attrition bias may have occurred because of low follow-up rates among presumed survivors. Bias could have been introduced because of lack of consent for access to the administrative dataset or from missing data from the participants in the questionnaire. The lack of in-person assessments for blood pressure and blood tests, resulting from geographical dispersion over 50 years, may have led to underestimation of some outcomes. Additionally, as most participants were born moderately or late preterm, with a median gestational age of 34.1 weeks, findings may not be generalizable to those born preterm at earlier gestational ages.

DISCLOSURES:

The study was supported in part by the Aotearoa Foundation, the Auckland Medical Research Foundation, Cure Kids New Zealand, and the Health Research Council of New Zealand. The authors of both the study and the commentary reported no conflicts of interest.

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

Children aged 5-12 years with concussion have similar recovery trajectories, regardless of whether the injury is linked to sports or to other causes, such as falls, new data indicated. 

“With that result, it means we don’t need to change management protocols” depending on the cause of the concussion, study author Andrée-Anne Ledoux, PhD, a scientist at Children’s Hospital of Eastern Ontario Research Institute in Ottawa, Ontario, Canada, said in an interview. “That’s kind of good news. We’re applying the right management protocols with them.”

The data were published on December 4 in JAMA Network Open.

 

Secondary Analysis

The results stem from a planned secondary analysis of the prospective Predicting and Preventing Postconcussive Problems in Pediatrics study. Conducted from August 2013 to June 2015 at nine pediatric emergency departments in Canada, it included children of different ages (5 to < 18 years), genders, demographic characteristics, and comorbidities. All participants had a concussion.

The secondary analysis focused on study participants who were aged 5-12 years and had presented within 48 hours of injury. The primary outcome was symptom change, which was defined as current ratings minus preinjury ratings, across time (1, 2, 4, 8, and 12 weeks), measured using the Post-Concussion Symptom Inventory.

No significant differences in postinjury recovery curves were found between participants with sport-related concussions (SRC) and those with non-SRC. The latter injuries resulted from causes such as falls and objects dropped on heads. SRC and non-SRC showed a nonlinear association with time, with symptoms decreasing over time.

Perhaps surprisingly, the researchers also reported a higher rate of persisting symptoms after concussion (PSAC) following limited contact sports than following contact sports such as hockey, soccer, rugby, lacrosse, and football. Limited contact sports include activities such as bicycling, horseback riding, tobogganing, gymnastics, and cheerleading.

This finding suggests that the management of SRC may not require distinct strategies based on sports classification, the researchers wrote. “Instead, it may be more appropriate for clinicians to consider the specific dynamics of the activity, such as velocity and risk of falls from heights. This nuanced perspective can aid in assessing the likelihood of persisting symptoms.” The researchers urged more investigation of this question. “A larger sample with more information on injury height and velocity would be required to confirm whether an association exists.”

In addition, the researchers cited guidelines that include a recommendation for a gradual return to low to moderate physical and cognitive activity starting 24-48 hours after a concussion at a level that does not result in recurrence or exacerbation of symptoms.

“Children do need to return to their lives. They need to return to school,” said Ledoux. “They can have accommodations while they return to school, but just returning to school has huge benefits because you’re reintegrating the child into their typical lifestyle and socialization as well.”

A potential limitation of the study was its reliance on participants who had been seen in emergency departments and thus may have been experiencing more intense symptoms than those seen elsewhere.

The researchers also excluded cases of concussion resulting from assaults and motor vehicle crashes. This decision may explain why they didn’t reproduce the previous observation that patients with SRC tended to recover faster than those with concussions from other causes.

Injuries resulting from assaults and motor vehicle crashes can involve damage beyond concussions, Ledoux said. Including these cases would not allow for an apples-to-apples comparison of SRC and non-SRC.

 

‘Don’t Cocoon Kids’

The authors of an accompanying editorial wrote that the researchers had done “a beautiful job highlighting this important nuance.” Noncontact sports with seemingly little risk “actually carry substantial risks when one imagines the high-impact forces that can occur with a fall from height, albeit rare,” Scott Zuckerman, MD, MPH, assistant professor of neurological surgery at Vanderbilt University Medical Center, Nashville, Tennessee, and colleagues wrote.

The new analysis suggests a need to rethink a “somewhat archaic way of classifying sport risk, which may oversimplify how we categorize risk of brain and spine injuries.”

The commentary also noted how the researchers used the term PSAC to describe lingering symptoms instead of more widely used terms like “persistent postconcussive symptoms” or “postconcussive syndrome.”

“These traditional terms often connote a permanent syndrome or assumption that the concussion itself is solely responsible for 100% of symptoms, which can be harmful to a patient’s recovery,” the editorialists wrote. “Conversely, PSAC offers room for the clinician to discuss how other causes may be maintaining, magnifying, or mimicking concussion symptoms.”

Commenting on the findings, Richard Figler, MD, an orthopedic surgeon at the Cleveland Clinic, Cleveland, praised the researchers for addressing concussion in younger children, a field in which little research has been conducted. The research supports the current approaches to treatment. The approach has shifted toward easing children quickly and safely back into normal routines. “We don’t cocoon kids. We don’t send them to dark rooms,” Figler added.

He also commended the researchers’ decision to examine data about concussions linked to limited contact sports. In contact sports, participants may be more likely to anticipate and prepare for a hit. That’s not the case with injuries sustained in limited contact sports.

“Dodgeball is basically a sucker punch. That’s why these kids have so many concussions,” said Figler. “They typically don’t see the ball coming, or they can’t get out of the way, and they can’t tense themselves to take that blow.”

The Predicting and Preventing Postconcussive Problems in Pediatrics study was funded by the Canadian Institutes of Health Research and the Canadian Institutes of Health Research-Ontario Neurotrauma Foundation Mild Traumatic Brain Injury Team. Ledoux reported receiving grants from the Children’s Hospital of Eastern Ontario Foundation, Ontario Brain Institute, and University of Ottawa Brain and Mind Research Institute. She received nonfinancial support from Mobio Interactive outside the submitted work. Zuckerman reported receiving personal fees from the National Football League and Medtronic outside the submitted work. Figler had no relevant financial disclosures.

A version of this article appeared on Medscape.com.

Children aged 5-12 years with concussion have similar recovery trajectories, regardless of whether the injury is linked to sports or to other causes, such as falls, new data indicated. 

“With that result, it means we don’t need to change management protocols” depending on the cause of the concussion, study author Andrée-Anne Ledoux, PhD, a scientist at Children’s Hospital of Eastern Ontario Research Institute in Ottawa, Ontario, Canada, said in an interview. “That’s kind of good news. We’re applying the right management protocols with them.”

The data were published on December 4 in JAMA Network Open.

 

Secondary Analysis

The results stem from a planned secondary analysis of the prospective Predicting and Preventing Postconcussive Problems in Pediatrics study. Conducted from August 2013 to June 2015 at nine pediatric emergency departments in Canada, it included children of different ages (5 to < 18 years), genders, demographic characteristics, and comorbidities. All participants had a concussion.

The secondary analysis focused on study participants who were aged 5-12 years and had presented within 48 hours of injury. The primary outcome was symptom change, which was defined as current ratings minus preinjury ratings, across time (1, 2, 4, 8, and 12 weeks), measured using the Post-Concussion Symptom Inventory.

No significant differences in postinjury recovery curves were found between participants with sport-related concussions (SRC) and those with non-SRC. The latter injuries resulted from causes such as falls and objects dropped on heads. SRC and non-SRC showed a nonlinear association with time, with symptoms decreasing over time.

Perhaps surprisingly, the researchers also reported a higher rate of persisting symptoms after concussion (PSAC) following limited contact sports than following contact sports such as hockey, soccer, rugby, lacrosse, and football. Limited contact sports include activities such as bicycling, horseback riding, tobogganing, gymnastics, and cheerleading.

This finding suggests that the management of SRC may not require distinct strategies based on sports classification, the researchers wrote. “Instead, it may be more appropriate for clinicians to consider the specific dynamics of the activity, such as velocity and risk of falls from heights. This nuanced perspective can aid in assessing the likelihood of persisting symptoms.” The researchers urged more investigation of this question. “A larger sample with more information on injury height and velocity would be required to confirm whether an association exists.”

In addition, the researchers cited guidelines that include a recommendation for a gradual return to low to moderate physical and cognitive activity starting 24-48 hours after a concussion at a level that does not result in recurrence or exacerbation of symptoms.

“Children do need to return to their lives. They need to return to school,” said Ledoux. “They can have accommodations while they return to school, but just returning to school has huge benefits because you’re reintegrating the child into their typical lifestyle and socialization as well.”

A potential limitation of the study was its reliance on participants who had been seen in emergency departments and thus may have been experiencing more intense symptoms than those seen elsewhere.

The researchers also excluded cases of concussion resulting from assaults and motor vehicle crashes. This decision may explain why they didn’t reproduce the previous observation that patients with SRC tended to recover faster than those with concussions from other causes.

Injuries resulting from assaults and motor vehicle crashes can involve damage beyond concussions, Ledoux said. Including these cases would not allow for an apples-to-apples comparison of SRC and non-SRC.

 

‘Don’t Cocoon Kids’

The authors of an accompanying editorial wrote that the researchers had done “a beautiful job highlighting this important nuance.” Noncontact sports with seemingly little risk “actually carry substantial risks when one imagines the high-impact forces that can occur with a fall from height, albeit rare,” Scott Zuckerman, MD, MPH, assistant professor of neurological surgery at Vanderbilt University Medical Center, Nashville, Tennessee, and colleagues wrote.

The new analysis suggests a need to rethink a “somewhat archaic way of classifying sport risk, which may oversimplify how we categorize risk of brain and spine injuries.”

The commentary also noted how the researchers used the term PSAC to describe lingering symptoms instead of more widely used terms like “persistent postconcussive symptoms” or “postconcussive syndrome.”

“These traditional terms often connote a permanent syndrome or assumption that the concussion itself is solely responsible for 100% of symptoms, which can be harmful to a patient’s recovery,” the editorialists wrote. “Conversely, PSAC offers room for the clinician to discuss how other causes may be maintaining, magnifying, or mimicking concussion symptoms.”

Commenting on the findings, Richard Figler, MD, an orthopedic surgeon at the Cleveland Clinic, Cleveland, praised the researchers for addressing concussion in younger children, a field in which little research has been conducted. The research supports the current approaches to treatment. The approach has shifted toward easing children quickly and safely back into normal routines. “We don’t cocoon kids. We don’t send them to dark rooms,” Figler added.

He also commended the researchers’ decision to examine data about concussions linked to limited contact sports. In contact sports, participants may be more likely to anticipate and prepare for a hit. That’s not the case with injuries sustained in limited contact sports.

“Dodgeball is basically a sucker punch. That’s why these kids have so many concussions,” said Figler. “They typically don’t see the ball coming, or they can’t get out of the way, and they can’t tense themselves to take that blow.”

The Predicting and Preventing Postconcussive Problems in Pediatrics study was funded by the Canadian Institutes of Health Research and the Canadian Institutes of Health Research-Ontario Neurotrauma Foundation Mild Traumatic Brain Injury Team. Ledoux reported receiving grants from the Children’s Hospital of Eastern Ontario Foundation, Ontario Brain Institute, and University of Ottawa Brain and Mind Research Institute. She received nonfinancial support from Mobio Interactive outside the submitted work. Zuckerman reported receiving personal fees from the National Football League and Medtronic outside the submitted work. Figler had no relevant financial disclosures.

A version of this article appeared on Medscape.com.

Children aged 5-12 years with concussion have similar recovery trajectories, regardless of whether the injury is linked to sports or to other causes, such as falls, new data indicated. 

“With that result, it means we don’t need to change management protocols” depending on the cause of the concussion, study author Andrée-Anne Ledoux, PhD, a scientist at Children’s Hospital of Eastern Ontario Research Institute in Ottawa, Ontario, Canada, said in an interview. “That’s kind of good news. We’re applying the right management protocols with them.”

The data were published on December 4 in JAMA Network Open.

 

Secondary Analysis

The results stem from a planned secondary analysis of the prospective Predicting and Preventing Postconcussive Problems in Pediatrics study. Conducted from August 2013 to June 2015 at nine pediatric emergency departments in Canada, it included children of different ages (5 to < 18 years), genders, demographic characteristics, and comorbidities. All participants had a concussion.

The secondary analysis focused on study participants who were aged 5-12 years and had presented within 48 hours of injury. The primary outcome was symptom change, which was defined as current ratings minus preinjury ratings, across time (1, 2, 4, 8, and 12 weeks), measured using the Post-Concussion Symptom Inventory.

No significant differences in postinjury recovery curves were found between participants with sport-related concussions (SRC) and those with non-SRC. The latter injuries resulted from causes such as falls and objects dropped on heads. SRC and non-SRC showed a nonlinear association with time, with symptoms decreasing over time.

Perhaps surprisingly, the researchers also reported a higher rate of persisting symptoms after concussion (PSAC) following limited contact sports than following contact sports such as hockey, soccer, rugby, lacrosse, and football. Limited contact sports include activities such as bicycling, horseback riding, tobogganing, gymnastics, and cheerleading.

This finding suggests that the management of SRC may not require distinct strategies based on sports classification, the researchers wrote. “Instead, it may be more appropriate for clinicians to consider the specific dynamics of the activity, such as velocity and risk of falls from heights. This nuanced perspective can aid in assessing the likelihood of persisting symptoms.” The researchers urged more investigation of this question. “A larger sample with more information on injury height and velocity would be required to confirm whether an association exists.”

In addition, the researchers cited guidelines that include a recommendation for a gradual return to low to moderate physical and cognitive activity starting 24-48 hours after a concussion at a level that does not result in recurrence or exacerbation of symptoms.

“Children do need to return to their lives. They need to return to school,” said Ledoux. “They can have accommodations while they return to school, but just returning to school has huge benefits because you’re reintegrating the child into their typical lifestyle and socialization as well.”

A potential limitation of the study was its reliance on participants who had been seen in emergency departments and thus may have been experiencing more intense symptoms than those seen elsewhere.

The researchers also excluded cases of concussion resulting from assaults and motor vehicle crashes. This decision may explain why they didn’t reproduce the previous observation that patients with SRC tended to recover faster than those with concussions from other causes.

Injuries resulting from assaults and motor vehicle crashes can involve damage beyond concussions, Ledoux said. Including these cases would not allow for an apples-to-apples comparison of SRC and non-SRC.

 

‘Don’t Cocoon Kids’

The authors of an accompanying editorial wrote that the researchers had done “a beautiful job highlighting this important nuance.” Noncontact sports with seemingly little risk “actually carry substantial risks when one imagines the high-impact forces that can occur with a fall from height, albeit rare,” Scott Zuckerman, MD, MPH, assistant professor of neurological surgery at Vanderbilt University Medical Center, Nashville, Tennessee, and colleagues wrote.

The new analysis suggests a need to rethink a “somewhat archaic way of classifying sport risk, which may oversimplify how we categorize risk of brain and spine injuries.”

The commentary also noted how the researchers used the term PSAC to describe lingering symptoms instead of more widely used terms like “persistent postconcussive symptoms” or “postconcussive syndrome.”

“These traditional terms often connote a permanent syndrome or assumption that the concussion itself is solely responsible for 100% of symptoms, which can be harmful to a patient’s recovery,” the editorialists wrote. “Conversely, PSAC offers room for the clinician to discuss how other causes may be maintaining, magnifying, or mimicking concussion symptoms.”

Commenting on the findings, Richard Figler, MD, an orthopedic surgeon at the Cleveland Clinic, Cleveland, praised the researchers for addressing concussion in younger children, a field in which little research has been conducted. The research supports the current approaches to treatment. The approach has shifted toward easing children quickly and safely back into normal routines. “We don’t cocoon kids. We don’t send them to dark rooms,” Figler added.

He also commended the researchers’ decision to examine data about concussions linked to limited contact sports. In contact sports, participants may be more likely to anticipate and prepare for a hit. That’s not the case with injuries sustained in limited contact sports.

“Dodgeball is basically a sucker punch. That’s why these kids have so many concussions,” said Figler. “They typically don’t see the ball coming, or they can’t get out of the way, and they can’t tense themselves to take that blow.”

The Predicting and Preventing Postconcussive Problems in Pediatrics study was funded by the Canadian Institutes of Health Research and the Canadian Institutes of Health Research-Ontario Neurotrauma Foundation Mild Traumatic Brain Injury Team. Ledoux reported receiving grants from the Children’s Hospital of Eastern Ontario Foundation, Ontario Brain Institute, and University of Ottawa Brain and Mind Research Institute. She received nonfinancial support from Mobio Interactive outside the submitted work. Zuckerman reported receiving personal fees from the National Football League and Medtronic outside the submitted work. Figler had no relevant financial disclosures.

A version of this article appeared on Medscape.com.

A new US Department of Veterans Affairs (VA) outreach campaign is encouraging all eligible veterans to enroll in VA health care, aiming to connect the roughly 1 million unenrolled veterans to care.  
 

The campaign was prompted following reports of concerns from veterans about health issues—including mental health hurdles and thoughts of suicide—potentially related to repeated low-level artillery blasts, improvised explosive devices, missile launches, heavy fire, and other blast exposures.  
 

Veterans enrolled in VA health care have access to specialty screenings and services to address issues related to blast exposure. Those who served in Vietnam, the Gulf War, Iraq, Afghanistan, and other specific locations are eligible for these benefits based on their deployments. They do not need to have any health conditions specifically associated with their service to be eligible. 
 

“We take veteran concerns about repeated blast exposure very seriously, and we are studying this matter urgently to learn more about potential health impacts,” VA Secretary Denis McDonough said. “While we do that, we don’t want veterans to wait—they should enroll in VA health care today to get full access to primary care, mental health care, regular screenings, specialty care, and more. That’s what this outreach effort is all about: getting veterans in our care, because veterans who come to VA are proven to do better.”  
 

The campaign will consist of text messages and emails sent directly to veterans, in addition to thousands of nationwide events, advertising, and social media campaigns. It is the latest effort to appeal to more veterans and is part of the largest outreach campaign in VA history, which began when President Joseph R. Biden signed the PACT Act into law in 2022. As a result > 835,000 veterans have enrolled in VA health care (a 37% increase), > 900,000 veterans have upgraded their priority groups, making them eligible for health care with fewer copays (a record), and > 4.4 million veterans and survivors have applied for disability compensation benefits (another record).  
 

Increased enrollment benefits not only the individuals enrolled in VA health care, but those who come after.

"[W]e are constantly looking for ways to improve that care as science and research tells us about new concerns," said VA Under Secretary for Health Shereef Elnahal, MD. "The more veterans who enroll, the more we can learn about the impact of blast exposure—and the better care we can ultimately provide those who served."

A new US Department of Veterans Affairs (VA) outreach campaign is encouraging all eligible veterans to enroll in VA health care, aiming to connect the roughly 1 million unenrolled veterans to care.  
 

The campaign was prompted following reports of concerns from veterans about health issues—including mental health hurdles and thoughts of suicide—potentially related to repeated low-level artillery blasts, improvised explosive devices, missile launches, heavy fire, and other blast exposures.  
 

Veterans enrolled in VA health care have access to specialty screenings and services to address issues related to blast exposure. Those who served in Vietnam, the Gulf War, Iraq, Afghanistan, and other specific locations are eligible for these benefits based on their deployments. They do not need to have any health conditions specifically associated with their service to be eligible. 
 

“We take veteran concerns about repeated blast exposure very seriously, and we are studying this matter urgently to learn more about potential health impacts,” VA Secretary Denis McDonough said. “While we do that, we don’t want veterans to wait—they should enroll in VA health care today to get full access to primary care, mental health care, regular screenings, specialty care, and more. That’s what this outreach effort is all about: getting veterans in our care, because veterans who come to VA are proven to do better.”  
 

The campaign will consist of text messages and emails sent directly to veterans, in addition to thousands of nationwide events, advertising, and social media campaigns. It is the latest effort to appeal to more veterans and is part of the largest outreach campaign in VA history, which began when President Joseph R. Biden signed the PACT Act into law in 2022. As a result > 835,000 veterans have enrolled in VA health care (a 37% increase), > 900,000 veterans have upgraded their priority groups, making them eligible for health care with fewer copays (a record), and > 4.4 million veterans and survivors have applied for disability compensation benefits (another record).  
 

Increased enrollment benefits not only the individuals enrolled in VA health care, but those who come after.

"[W]e are constantly looking for ways to improve that care as science and research tells us about new concerns," said VA Under Secretary for Health Shereef Elnahal, MD. "The more veterans who enroll, the more we can learn about the impact of blast exposure—and the better care we can ultimately provide those who served."

A new US Department of Veterans Affairs (VA) outreach campaign is encouraging all eligible veterans to enroll in VA health care, aiming to connect the roughly 1 million unenrolled veterans to care.  
 

The campaign was prompted following reports of concerns from veterans about health issues—including mental health hurdles and thoughts of suicide—potentially related to repeated low-level artillery blasts, improvised explosive devices, missile launches, heavy fire, and other blast exposures.  
 

Veterans enrolled in VA health care have access to specialty screenings and services to address issues related to blast exposure. Those who served in Vietnam, the Gulf War, Iraq, Afghanistan, and other specific locations are eligible for these benefits based on their deployments. They do not need to have any health conditions specifically associated with their service to be eligible. 
 

“We take veteran concerns about repeated blast exposure very seriously, and we are studying this matter urgently to learn more about potential health impacts,” VA Secretary Denis McDonough said. “While we do that, we don’t want veterans to wait—they should enroll in VA health care today to get full access to primary care, mental health care, regular screenings, specialty care, and more. That’s what this outreach effort is all about: getting veterans in our care, because veterans who come to VA are proven to do better.”  
 

The campaign will consist of text messages and emails sent directly to veterans, in addition to thousands of nationwide events, advertising, and social media campaigns. It is the latest effort to appeal to more veterans and is part of the largest outreach campaign in VA history, which began when President Joseph R. Biden signed the PACT Act into law in 2022. As a result > 835,000 veterans have enrolled in VA health care (a 37% increase), > 900,000 veterans have upgraded their priority groups, making them eligible for health care with fewer copays (a record), and > 4.4 million veterans and survivors have applied for disability compensation benefits (another record).  
 

Increased enrollment benefits not only the individuals enrolled in VA health care, but those who come after.

"[W]e are constantly looking for ways to improve that care as science and research tells us about new concerns," said VA Under Secretary for Health Shereef Elnahal, MD. "The more veterans who enroll, the more we can learn about the impact of blast exposure—and the better care we can ultimately provide those who served."

Identifying the phenomenon of post-exertional malaise (PEM) in patients with fatiguing conditions is critical because it necessitates a far more cautious approach to exercise, experts said.

PEM is a defining feature of the condition myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and it is present in many people with long COVID. It is characterized by a worsening of fatigue and of other symptoms after previously tolerated physical or mental exertion, typically emerging 24-72 hours after the exertion and lasting days or weeks thereafter. The experience is often called a “crash.”

In a study presented at the American College of Rheumatology (ACR) 2024 Annual Meeting, PEM was also identified in people with various rheumatologic conditions, ranging from 4% in those with osteoarthritis to 20% in those with fibromyalgia. The presence of PEM was also associated with worse pain, sleep, cognition, and other symptoms that are also characteristic of ME/CFS and many cases of long COVID.

“PEM assessment is becoming more important in those with long COVID, as we are assisting more of those with long durations of this condition. ... This is the first study we know of presenting PEM rates in a rheumatologic disease population,” Kaleb Michaud, PhD, director of FORWARD — The National Databank for Rheumatic Diseases and professor of rheumatology and immunology, University of Nebraska Medical Center, Omaha, said at the meeting.

During the discussion period, study investigator Leonard H. Calabrese, DO, head of the Section of Clinical Immunology, Cleveland Clinic, Ohio, commented, “PEM is seen with numerous post-acute infectious sequelae. It segregates with that population of patients who meet the diagnostic criteria for ME/CFS, of which 50%-70% of people will also meet criteria for fibromyalgia…This is a first step, but it has big ramifications regarding exercise.”

In an interview with this news organization, Calabrese said, “We recommend exercise to virtually everyone with fibromyalgia who doesn’t have ME/CFS,” but that the assessment tool used in the study, the 5-item DePaul Symptoms Questionnaire, isn’t adequate for assessing true PEM that would preclude exercise, despite being validated. “That instrument is inexact and lacks specificity. ... It just shows where the field is. We need better biomarkers.”

 

In Those With PEM, Exercise May Harm

Asked to comment, Brayden P. Yellman, MD, a rheumatologist at the Bateman Horne Center, Salt Lake City, Utah, told this news organization, “if there is an infection-associated chronic condition that meets criteria for what we would call ME/CFS or long COVID, and if there’s true post-exertional malaise, any graded exercise that ultimately leads to post-exertional malaise is harmful. ... There is a subset of people who have milder disease, who can sometimes do very mild exercise that does not trigger PEM, and they do see benefits over time very slowly with really carefully curated, carefully monitored exercise. But we have to be really careful.”

For the majority, however, the approach is to teach patients to pace their activities in order to avoid PEM, also referred to as staying within their “energy envelope.” Clinician resources are available on the Bateman Horne Center’s website.

This isn’t typically included in rheumatology training, Yellman noted. “Having completed an entire rheumatology fellowship and working in rheumatology, I was not taught at all about [then-termed] chronic fatigue syndrome. It was lumped under fibromyalgia. And of course, they teach about fibromyalgia because it’s a great mimic of a lot of inflammatory, rheumatologic conditions, but the idea of [PEM], that pathognomonic feature that we see in infection-associated chronic conditions, was not once mentioned when I trained, in 2014 to 2016.”

Nonetheless, he added, “rheumatologists are definitely seeing this in their fibromyalgia patients and some of their other patients at a high rate, and I’m sure that they’re missing it, along with other comorbidities like orthostatic hypotension.”

Another expert asked to weigh in, Todd Davenport, PT, DPT, PhD, professor and chair of the Department of Physical Therapy at the University of the Pacific, Stockton, California, told this news organization: “Our experience is that the body’s responses to short bouts of exercise are abnormal, and graded exercise is unsuccessful and makes people worse. ... Clinicians should be particularly on the lookout for PEM in patients who are already reporting fatigue, such as with fibromyalgia and rheumatologic conditions that can have some diagnostic overlaps with ME/CFS, because you can get fooled into thinking that your well-meaning exercise program intended to help give them a little more juice during their daily activities actually might be harmful.”

There are several lines of evidence for abnormal responses to exercise in people with PEM, Davenport said. These include muscle worsening, cardiac preload failure and impaired systemic oxygen extraction, metabolic dysregulation, and abnormal immunologic and neurologic changes.

Several studies show impaired recovery after 2-day cardiopulmonary exercise testing, with the largest to date published in July 2024. Patients with PEM have also reported harm from prescribed exercise.

Yellman commented: “We think of PEM like an injury, where you need to recover. If you keep stacking injuries on top of it, that injury is never going to heal the same way again…We are still trying to understand the pathophysiology of ME/CFS in general, and of PEM. But if you think of it as a neuroinflammatory injury, and there’s some evidence suggesting neuroinflammation, you can kind of understand the approach of needing to heal and to recover.”

 

How Prevalent Is PEM in Rheumatologic Conditions?

For the study presented at the ACR meeting, data of people with confirmed rheumatic diseases were taken from the ongoing longitudinal US-based research database FORWARD. Participants completed biannual self-reported questionnaires during January–June 2024 that included the 5-item PEM subscale from the validated DePaul Symptoms Questionnaire.

Questions relate to frequency and severity of each of the five items: “Dead, heavy feeling after starting to exercise,” “next-day soreness or fatigue after nonstrenuous, everyday activities,” “mentally tired after the slightest effort,” “minimum exercise makes you physically tired,” and “physically drained or sick after mild activity.” Participants are asked to rate each item on a scale from 0 if not present to 1 (mild/a little of the time) up to 4 (very severe/all of the time).

A positive PEM result was defined as a frequency of at least two and simultaneous severity of at least two on any survey item. Additional questions asked about recent and previous SARS-CoV-2 infections, long COVID diagnoses, and comorbidities.

Of 1158 individuals who completed the PEM questionnaire, 7.5% overall met PEM criteria. By individual condition, the proportions were 4.4% with osteoarthritis, 7.4% with rheumatoid arthritis, 12.2% with systemic lupus erythematosus, 13.8% with fibromyalgia diagnosed by rheumatologists, and 20.3% with fibromyalgia based on the 2016 revised ACR criteria.

The overall PEM prevalence was 8.3% among those reporting ever having COVID-19 and 9.5% among those who had COVID-19 during July–December 2023. The PEM prevalence increased more dramatically with more severe COVID-19 — 17.2% among those who had been hospitalized for COVID-19, 22.0% of those ever diagnosed with long COVID, and 28.1% with a long COVID diagnosis in January 2024.

By diagnosis, 50% of individuals who met the ACR’s 2016 fibromyalgia criteria and currently had long COVID scored positively for PEM.

Measures of pain, fatigue, sleep, patient global assessment, activity score, polysymptomatic distress, disability, depression, anxiety, and other functional scores were all significantly worse among those scoring positive for PEM (P < .001), Michaud reported.

 

Better Tools Are Available

The developer of the DePaul questionnaire, Leonard Jason, PhD, director of the Center for Community Research and professor of psychology at DePaul College of Science and Health, Chicago, Illinois, told this news organization that an updated 10-item screening tool specifically designed to screen for PEM adds some important elements missing from the 5-item version.

Here, patients are initially asked two questions: “Do you experience a worsening of your fatigue/energy related illness after engaging in minimal physical effort?” and “Do you experience a worsening of your fatigue/energy related illness after engaging in mental effort?” If they answer “yes” to either, the next question is “If you feel worse after activities, how long does this last?” Answers are coded from 0 to 6 (24 hours or more).

The fourth additional question then asks how quickly patients recover, while a fifth question asks whether the person is avoiding activity because it makes them feel worse (thereby potentially creating a false negative).

For those scoring positive on the 10-item screen, a more comprehensive measure could be used, such as this online screening tool, Jason said.

Yellman said that the Bateman Horne Center uses a “good day, bad day” questionnaire to tease out some of the same information. In addition, he noted that it’s important to capture the timeframe between the exertion and the onset of symptoms because PEM doesn’t start during or immediately after activity. “If somebody is mowing the lawn and they start feeling symptoms immediately, they’re probably, at least in ME/CFS, experiencing orthostatic intolerance. Post-exertional malaise occurs 12-72 hours later, when their function is severely reduced as compared to baseline.” 

And of course, Davenport noted, listening to patients is key. “Patients will tell you wildly unusual responses to activity before you even do the work of trying to figure out what the activity was. They’ll tell you things like they can’t think as well, that they have to be in bed for 3 days to a week to 2 weeks, depending on the level of exertion.”

Yellman, Davenport, and several other colleagues are currently working on a paper that will explain the differences between pacing and graded exercise, define PEM, and provide guidelines. They aim to submit it in time for publication early in 2025. In the meantime, the Bateman Horne Center’s website provides numerous resources for healthcare professionals and patients.

Yellman is also working to define minimum quality of care standards for infection-associated chronic conditions for state medical boards and to provide continuing medical education for clinicians on those standards. These would include recognizing and evaluating patients for PEM, as well as orthostatic intolerance, cognitive impairment, and other associated comorbidities.

Importantly, he said, the standards will include the principles of teaching people with PEM how to pace and will emphasize not prescribing them graded exercise as first- or even second-line therapy. “We need people to do some basic things. And the first thing is do no harm.”

None of the individuals quoted for this article had relevant financial disclosures.

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

Identifying the phenomenon of post-exertional malaise (PEM) in patients with fatiguing conditions is critical because it necessitates a far more cautious approach to exercise, experts said.

PEM is a defining feature of the condition myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and it is present in many people with long COVID. It is characterized by a worsening of fatigue and of other symptoms after previously tolerated physical or mental exertion, typically emerging 24-72 hours after the exertion and lasting days or weeks thereafter. The experience is often called a “crash.”

In a study presented at the American College of Rheumatology (ACR) 2024 Annual Meeting, PEM was also identified in people with various rheumatologic conditions, ranging from 4% in those with osteoarthritis to 20% in those with fibromyalgia. The presence of PEM was also associated with worse pain, sleep, cognition, and other symptoms that are also characteristic of ME/CFS and many cases of long COVID.

“PEM assessment is becoming more important in those with long COVID, as we are assisting more of those with long durations of this condition. ... This is the first study we know of presenting PEM rates in a rheumatologic disease population,” Kaleb Michaud, PhD, director of FORWARD — The National Databank for Rheumatic Diseases and professor of rheumatology and immunology, University of Nebraska Medical Center, Omaha, said at the meeting.

During the discussion period, study investigator Leonard H. Calabrese, DO, head of the Section of Clinical Immunology, Cleveland Clinic, Ohio, commented, “PEM is seen with numerous post-acute infectious sequelae. It segregates with that population of patients who meet the diagnostic criteria for ME/CFS, of which 50%-70% of people will also meet criteria for fibromyalgia…This is a first step, but it has big ramifications regarding exercise.”

In an interview with this news organization, Calabrese said, “We recommend exercise to virtually everyone with fibromyalgia who doesn’t have ME/CFS,” but that the assessment tool used in the study, the 5-item DePaul Symptoms Questionnaire, isn’t adequate for assessing true PEM that would preclude exercise, despite being validated. “That instrument is inexact and lacks specificity. ... It just shows where the field is. We need better biomarkers.”

 

In Those With PEM, Exercise May Harm

Asked to comment, Brayden P. Yellman, MD, a rheumatologist at the Bateman Horne Center, Salt Lake City, Utah, told this news organization, “if there is an infection-associated chronic condition that meets criteria for what we would call ME/CFS or long COVID, and if there’s true post-exertional malaise, any graded exercise that ultimately leads to post-exertional malaise is harmful. ... There is a subset of people who have milder disease, who can sometimes do very mild exercise that does not trigger PEM, and they do see benefits over time very slowly with really carefully curated, carefully monitored exercise. But we have to be really careful.”

For the majority, however, the approach is to teach patients to pace their activities in order to avoid PEM, also referred to as staying within their “energy envelope.” Clinician resources are available on the Bateman Horne Center’s website.

This isn’t typically included in rheumatology training, Yellman noted. “Having completed an entire rheumatology fellowship and working in rheumatology, I was not taught at all about [then-termed] chronic fatigue syndrome. It was lumped under fibromyalgia. And of course, they teach about fibromyalgia because it’s a great mimic of a lot of inflammatory, rheumatologic conditions, but the idea of [PEM], that pathognomonic feature that we see in infection-associated chronic conditions, was not once mentioned when I trained, in 2014 to 2016.”

Nonetheless, he added, “rheumatologists are definitely seeing this in their fibromyalgia patients and some of their other patients at a high rate, and I’m sure that they’re missing it, along with other comorbidities like orthostatic hypotension.”

Another expert asked to weigh in, Todd Davenport, PT, DPT, PhD, professor and chair of the Department of Physical Therapy at the University of the Pacific, Stockton, California, told this news organization: “Our experience is that the body’s responses to short bouts of exercise are abnormal, and graded exercise is unsuccessful and makes people worse. ... Clinicians should be particularly on the lookout for PEM in patients who are already reporting fatigue, such as with fibromyalgia and rheumatologic conditions that can have some diagnostic overlaps with ME/CFS, because you can get fooled into thinking that your well-meaning exercise program intended to help give them a little more juice during their daily activities actually might be harmful.”

There are several lines of evidence for abnormal responses to exercise in people with PEM, Davenport said. These include muscle worsening, cardiac preload failure and impaired systemic oxygen extraction, metabolic dysregulation, and abnormal immunologic and neurologic changes.

Several studies show impaired recovery after 2-day cardiopulmonary exercise testing, with the largest to date published in July 2024. Patients with PEM have also reported harm from prescribed exercise.

Yellman commented: “We think of PEM like an injury, where you need to recover. If you keep stacking injuries on top of it, that injury is never going to heal the same way again…We are still trying to understand the pathophysiology of ME/CFS in general, and of PEM. But if you think of it as a neuroinflammatory injury, and there’s some evidence suggesting neuroinflammation, you can kind of understand the approach of needing to heal and to recover.”

 

How Prevalent Is PEM in Rheumatologic Conditions?

For the study presented at the ACR meeting, data of people with confirmed rheumatic diseases were taken from the ongoing longitudinal US-based research database FORWARD. Participants completed biannual self-reported questionnaires during January–June 2024 that included the 5-item PEM subscale from the validated DePaul Symptoms Questionnaire.

Questions relate to frequency and severity of each of the five items: “Dead, heavy feeling after starting to exercise,” “next-day soreness or fatigue after nonstrenuous, everyday activities,” “mentally tired after the slightest effort,” “minimum exercise makes you physically tired,” and “physically drained or sick after mild activity.” Participants are asked to rate each item on a scale from 0 if not present to 1 (mild/a little of the time) up to 4 (very severe/all of the time).

A positive PEM result was defined as a frequency of at least two and simultaneous severity of at least two on any survey item. Additional questions asked about recent and previous SARS-CoV-2 infections, long COVID diagnoses, and comorbidities.

Of 1158 individuals who completed the PEM questionnaire, 7.5% overall met PEM criteria. By individual condition, the proportions were 4.4% with osteoarthritis, 7.4% with rheumatoid arthritis, 12.2% with systemic lupus erythematosus, 13.8% with fibromyalgia diagnosed by rheumatologists, and 20.3% with fibromyalgia based on the 2016 revised ACR criteria.

The overall PEM prevalence was 8.3% among those reporting ever having COVID-19 and 9.5% among those who had COVID-19 during July–December 2023. The PEM prevalence increased more dramatically with more severe COVID-19 — 17.2% among those who had been hospitalized for COVID-19, 22.0% of those ever diagnosed with long COVID, and 28.1% with a long COVID diagnosis in January 2024.

By diagnosis, 50% of individuals who met the ACR’s 2016 fibromyalgia criteria and currently had long COVID scored positively for PEM.

Measures of pain, fatigue, sleep, patient global assessment, activity score, polysymptomatic distress, disability, depression, anxiety, and other functional scores were all significantly worse among those scoring positive for PEM (P < .001), Michaud reported.

 

Better Tools Are Available

The developer of the DePaul questionnaire, Leonard Jason, PhD, director of the Center for Community Research and professor of psychology at DePaul College of Science and Health, Chicago, Illinois, told this news organization that an updated 10-item screening tool specifically designed to screen for PEM adds some important elements missing from the 5-item version.

Here, patients are initially asked two questions: “Do you experience a worsening of your fatigue/energy related illness after engaging in minimal physical effort?” and “Do you experience a worsening of your fatigue/energy related illness after engaging in mental effort?” If they answer “yes” to either, the next question is “If you feel worse after activities, how long does this last?” Answers are coded from 0 to 6 (24 hours or more).

The fourth additional question then asks how quickly patients recover, while a fifth question asks whether the person is avoiding activity because it makes them feel worse (thereby potentially creating a false negative).

For those scoring positive on the 10-item screen, a more comprehensive measure could be used, such as this online screening tool, Jason said.

Yellman said that the Bateman Horne Center uses a “good day, bad day” questionnaire to tease out some of the same information. In addition, he noted that it’s important to capture the timeframe between the exertion and the onset of symptoms because PEM doesn’t start during or immediately after activity. “If somebody is mowing the lawn and they start feeling symptoms immediately, they’re probably, at least in ME/CFS, experiencing orthostatic intolerance. Post-exertional malaise occurs 12-72 hours later, when their function is severely reduced as compared to baseline.” 

And of course, Davenport noted, listening to patients is key. “Patients will tell you wildly unusual responses to activity before you even do the work of trying to figure out what the activity was. They’ll tell you things like they can’t think as well, that they have to be in bed for 3 days to a week to 2 weeks, depending on the level of exertion.”

Yellman, Davenport, and several other colleagues are currently working on a paper that will explain the differences between pacing and graded exercise, define PEM, and provide guidelines. They aim to submit it in time for publication early in 2025. In the meantime, the Bateman Horne Center’s website provides numerous resources for healthcare professionals and patients.

Yellman is also working to define minimum quality of care standards for infection-associated chronic conditions for state medical boards and to provide continuing medical education for clinicians on those standards. These would include recognizing and evaluating patients for PEM, as well as orthostatic intolerance, cognitive impairment, and other associated comorbidities.

Importantly, he said, the standards will include the principles of teaching people with PEM how to pace and will emphasize not prescribing them graded exercise as first- or even second-line therapy. “We need people to do some basic things. And the first thing is do no harm.”

None of the individuals quoted for this article had relevant financial disclosures.

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

Identifying the phenomenon of post-exertional malaise (PEM) in patients with fatiguing conditions is critical because it necessitates a far more cautious approach to exercise, experts said.

PEM is a defining feature of the condition myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and it is present in many people with long COVID. It is characterized by a worsening of fatigue and of other symptoms after previously tolerated physical or mental exertion, typically emerging 24-72 hours after the exertion and lasting days or weeks thereafter. The experience is often called a “crash.”

In a study presented at the American College of Rheumatology (ACR) 2024 Annual Meeting, PEM was also identified in people with various rheumatologic conditions, ranging from 4% in those with osteoarthritis to 20% in those with fibromyalgia. The presence of PEM was also associated with worse pain, sleep, cognition, and other symptoms that are also characteristic of ME/CFS and many cases of long COVID.

“PEM assessment is becoming more important in those with long COVID, as we are assisting more of those with long durations of this condition. ... This is the first study we know of presenting PEM rates in a rheumatologic disease population,” Kaleb Michaud, PhD, director of FORWARD — The National Databank for Rheumatic Diseases and professor of rheumatology and immunology, University of Nebraska Medical Center, Omaha, said at the meeting.

During the discussion period, study investigator Leonard H. Calabrese, DO, head of the Section of Clinical Immunology, Cleveland Clinic, Ohio, commented, “PEM is seen with numerous post-acute infectious sequelae. It segregates with that population of patients who meet the diagnostic criteria for ME/CFS, of which 50%-70% of people will also meet criteria for fibromyalgia…This is a first step, but it has big ramifications regarding exercise.”

In an interview with this news organization, Calabrese said, “We recommend exercise to virtually everyone with fibromyalgia who doesn’t have ME/CFS,” but that the assessment tool used in the study, the 5-item DePaul Symptoms Questionnaire, isn’t adequate for assessing true PEM that would preclude exercise, despite being validated. “That instrument is inexact and lacks specificity. ... It just shows where the field is. We need better biomarkers.”

 

In Those With PEM, Exercise May Harm

Asked to comment, Brayden P. Yellman, MD, a rheumatologist at the Bateman Horne Center, Salt Lake City, Utah, told this news organization, “if there is an infection-associated chronic condition that meets criteria for what we would call ME/CFS or long COVID, and if there’s true post-exertional malaise, any graded exercise that ultimately leads to post-exertional malaise is harmful. ... There is a subset of people who have milder disease, who can sometimes do very mild exercise that does not trigger PEM, and they do see benefits over time very slowly with really carefully curated, carefully monitored exercise. But we have to be really careful.”

For the majority, however, the approach is to teach patients to pace their activities in order to avoid PEM, also referred to as staying within their “energy envelope.” Clinician resources are available on the Bateman Horne Center’s website.

This isn’t typically included in rheumatology training, Yellman noted. “Having completed an entire rheumatology fellowship and working in rheumatology, I was not taught at all about [then-termed] chronic fatigue syndrome. It was lumped under fibromyalgia. And of course, they teach about fibromyalgia because it’s a great mimic of a lot of inflammatory, rheumatologic conditions, but the idea of [PEM], that pathognomonic feature that we see in infection-associated chronic conditions, was not once mentioned when I trained, in 2014 to 2016.”

Nonetheless, he added, “rheumatologists are definitely seeing this in their fibromyalgia patients and some of their other patients at a high rate, and I’m sure that they’re missing it, along with other comorbidities like orthostatic hypotension.”

Another expert asked to weigh in, Todd Davenport, PT, DPT, PhD, professor and chair of the Department of Physical Therapy at the University of the Pacific, Stockton, California, told this news organization: “Our experience is that the body’s responses to short bouts of exercise are abnormal, and graded exercise is unsuccessful and makes people worse. ... Clinicians should be particularly on the lookout for PEM in patients who are already reporting fatigue, such as with fibromyalgia and rheumatologic conditions that can have some diagnostic overlaps with ME/CFS, because you can get fooled into thinking that your well-meaning exercise program intended to help give them a little more juice during their daily activities actually might be harmful.”

There are several lines of evidence for abnormal responses to exercise in people with PEM, Davenport said. These include muscle worsening, cardiac preload failure and impaired systemic oxygen extraction, metabolic dysregulation, and abnormal immunologic and neurologic changes.

Several studies show impaired recovery after 2-day cardiopulmonary exercise testing, with the largest to date published in July 2024. Patients with PEM have also reported harm from prescribed exercise.

Yellman commented: “We think of PEM like an injury, where you need to recover. If you keep stacking injuries on top of it, that injury is never going to heal the same way again…We are still trying to understand the pathophysiology of ME/CFS in general, and of PEM. But if you think of it as a neuroinflammatory injury, and there’s some evidence suggesting neuroinflammation, you can kind of understand the approach of needing to heal and to recover.”

 

How Prevalent Is PEM in Rheumatologic Conditions?

For the study presented at the ACR meeting, data of people with confirmed rheumatic diseases were taken from the ongoing longitudinal US-based research database FORWARD. Participants completed biannual self-reported questionnaires during January–June 2024 that included the 5-item PEM subscale from the validated DePaul Symptoms Questionnaire.

Questions relate to frequency and severity of each of the five items: “Dead, heavy feeling after starting to exercise,” “next-day soreness or fatigue after nonstrenuous, everyday activities,” “mentally tired after the slightest effort,” “minimum exercise makes you physically tired,” and “physically drained or sick after mild activity.” Participants are asked to rate each item on a scale from 0 if not present to 1 (mild/a little of the time) up to 4 (very severe/all of the time).

A positive PEM result was defined as a frequency of at least two and simultaneous severity of at least two on any survey item. Additional questions asked about recent and previous SARS-CoV-2 infections, long COVID diagnoses, and comorbidities.

Of 1158 individuals who completed the PEM questionnaire, 7.5% overall met PEM criteria. By individual condition, the proportions were 4.4% with osteoarthritis, 7.4% with rheumatoid arthritis, 12.2% with systemic lupus erythematosus, 13.8% with fibromyalgia diagnosed by rheumatologists, and 20.3% with fibromyalgia based on the 2016 revised ACR criteria.

The overall PEM prevalence was 8.3% among those reporting ever having COVID-19 and 9.5% among those who had COVID-19 during July–December 2023. The PEM prevalence increased more dramatically with more severe COVID-19 — 17.2% among those who had been hospitalized for COVID-19, 22.0% of those ever diagnosed with long COVID, and 28.1% with a long COVID diagnosis in January 2024.

By diagnosis, 50% of individuals who met the ACR’s 2016 fibromyalgia criteria and currently had long COVID scored positively for PEM.

Measures of pain, fatigue, sleep, patient global assessment, activity score, polysymptomatic distress, disability, depression, anxiety, and other functional scores were all significantly worse among those scoring positive for PEM (P < .001), Michaud reported.

 

Better Tools Are Available

The developer of the DePaul questionnaire, Leonard Jason, PhD, director of the Center for Community Research and professor of psychology at DePaul College of Science and Health, Chicago, Illinois, told this news organization that an updated 10-item screening tool specifically designed to screen for PEM adds some important elements missing from the 5-item version.

Here, patients are initially asked two questions: “Do you experience a worsening of your fatigue/energy related illness after engaging in minimal physical effort?” and “Do you experience a worsening of your fatigue/energy related illness after engaging in mental effort?” If they answer “yes” to either, the next question is “If you feel worse after activities, how long does this last?” Answers are coded from 0 to 6 (24 hours or more).

The fourth additional question then asks how quickly patients recover, while a fifth question asks whether the person is avoiding activity because it makes them feel worse (thereby potentially creating a false negative).

For those scoring positive on the 10-item screen, a more comprehensive measure could be used, such as this online screening tool, Jason said.

Yellman said that the Bateman Horne Center uses a “good day, bad day” questionnaire to tease out some of the same information. In addition, he noted that it’s important to capture the timeframe between the exertion and the onset of symptoms because PEM doesn’t start during or immediately after activity. “If somebody is mowing the lawn and they start feeling symptoms immediately, they’re probably, at least in ME/CFS, experiencing orthostatic intolerance. Post-exertional malaise occurs 12-72 hours later, when their function is severely reduced as compared to baseline.” 

And of course, Davenport noted, listening to patients is key. “Patients will tell you wildly unusual responses to activity before you even do the work of trying to figure out what the activity was. They’ll tell you things like they can’t think as well, that they have to be in bed for 3 days to a week to 2 weeks, depending on the level of exertion.”

Yellman, Davenport, and several other colleagues are currently working on a paper that will explain the differences between pacing and graded exercise, define PEM, and provide guidelines. They aim to submit it in time for publication early in 2025. In the meantime, the Bateman Horne Center’s website provides numerous resources for healthcare professionals and patients.

Yellman is also working to define minimum quality of care standards for infection-associated chronic conditions for state medical boards and to provide continuing medical education for clinicians on those standards. These would include recognizing and evaluating patients for PEM, as well as orthostatic intolerance, cognitive impairment, and other associated comorbidities.

Importantly, he said, the standards will include the principles of teaching people with PEM how to pace and will emphasize not prescribing them graded exercise as first- or even second-line therapy. “We need people to do some basic things. And the first thing is do no harm.”

None of the individuals quoted for this article had relevant financial disclosures.

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

TOPLINE:

Patients with anorexia nervosa are at significantly increased risk for cardiovascular conditions such as heart failure and cardiac arrest, compared with people without an eating disorder, researchers found. The risk for many of these conditions declines after 5 years of follow-up, whereas the risk for ischemic heart disease rises only after that period.

METHODOLOGY:

• Researchers conducted a longitudinal cohort study by analyzing the data from Taiwan’s National Health Insurance database to investigate the incidences and risk for cardiovascular conditions in patients with anorexia.
• They included 22,891 participants (mean age, 24.9 years; 91.3% women), of whom 2081 were diagnosed with anorexia between January 2010 and December 2021 and 20,810 were matched control participants without any eating disorder.
• The mean follow-up duration of this study was 5 years; investigators also assessed the risk for individual cardiovascular conditions during three periods after the diagnosis of anorexia: 0-24 months, between 24 and 60 months, and greater than 60 months.
• The primary outcomes were the occurrence of major adverse cardiovascular events (MACE) and any cardiovascular condition, including heart failure, stroke, ischemic heart diseases, conduction disorder, inflammatory heart disease, valve disease, cardiomyopathy, atherosclerosis, and cardiac arrest.

TAKEAWAY:

• At the 5-year follow-up, the incidence and risk for MACE were higher in patients with anorexia than in those without (4.82% vs 0.85% and adjusted hazard ratio [aHR], 3.78; 95% CI, 2.83-5.05, respectively).
• Similarly, the incidence of any cardiovascular condition was higher in patients with anorexia than in those without (6.19% vs 2.27%), which translated to a nearly twofold increased risk (aHR, 1.93; 95% CI, 1.54-2.41).
• Patients with anorexia showed elevated risks for individual cardiovascular conditions such as cardiac arrest, structural heart disease, conduction disorder, and heart failure, but not stroke, atherosclerosis, ischemic heart disease, or inflammatory heart disease.
• The risks for congestive heart failure, structural heart disease, and conduction disorder increased in the first 24 months after the diagnosis of anorexia and disappeared after 5 years of follow-up, whereas the risk for ischemic heart disease increased only after 5 years of follow-up.

IN PRACTICE:

“Clinicians should monitor comorbid cardiovascular conditions among patients with [anorexia] at initial presentation, during treatment, and at follow-up,” the authors of the study wrote.

“In this study, most cardiovascular conditions were in remission after 5 years except ischemic heart disease,” the researchers noted. “This finding is corroborated by the recovery rate of 50%-70% in patients with [anorexia] after 4 years of follow-up in a recent meta-analysis, and in previous studies, most of the cardiac complications improved with weight restoration. Similarly, genome-wide association studies did not support elevated cardiovascular risk in patients with [anorexia] due to shared genetic mechanisms between [anorexia] and cardiovascular diseases, but they suggested that cardiovascular diseases were a downstream consequence” of the eating disorder.
 

SOURCE:

The study was led by Mei-Chih Meg Tseng, MD, PhD, of the Department of Psychiatry at Taipei Medical University in Taipei, Taiwan. It was published online on December 19, 2024, in JAMA Network Open.

LIMITATIONS:

The cardiovascular outcomes relied on the clinical diagnoses, and the validity of anorexia or its subtype was not confirmed. The study population was limited to patients seeking medical treatment, which may have led to the inclusion of patients with more severe symptoms. Key potential confounders such as body weight, nutritional status, lifestyle, drug use, and family history were unavailable in the claims dataset and could not be adjusted. The generalizability of the study may be limited as it involved only participants from a single ethnic group.

DISCLOSURES:

This study was supported by grants from the National Science and Technology Council, Taiwan, and Taipei Medical University. The authors reported no conflicts of interest.

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

TOPLINE:

Patients with anorexia nervosa are at significantly increased risk for cardiovascular conditions such as heart failure and cardiac arrest, compared with people without an eating disorder, researchers found. The risk for many of these conditions declines after 5 years of follow-up, whereas the risk for ischemic heart disease rises only after that period.

METHODOLOGY:

• Researchers conducted a longitudinal cohort study by analyzing the data from Taiwan’s National Health Insurance database to investigate the incidences and risk for cardiovascular conditions in patients with anorexia.
• They included 22,891 participants (mean age, 24.9 years; 91.3% women), of whom 2081 were diagnosed with anorexia between January 2010 and December 2021 and 20,810 were matched control participants without any eating disorder.
• The mean follow-up duration of this study was 5 years; investigators also assessed the risk for individual cardiovascular conditions during three periods after the diagnosis of anorexia: 0-24 months, between 24 and 60 months, and greater than 60 months.
• The primary outcomes were the occurrence of major adverse cardiovascular events (MACE) and any cardiovascular condition, including heart failure, stroke, ischemic heart diseases, conduction disorder, inflammatory heart disease, valve disease, cardiomyopathy, atherosclerosis, and cardiac arrest.

TAKEAWAY:

• At the 5-year follow-up, the incidence and risk for MACE were higher in patients with anorexia than in those without (4.82% vs 0.85% and adjusted hazard ratio [aHR], 3.78; 95% CI, 2.83-5.05, respectively).
• Similarly, the incidence of any cardiovascular condition was higher in patients with anorexia than in those without (6.19% vs 2.27%), which translated to a nearly twofold increased risk (aHR, 1.93; 95% CI, 1.54-2.41).
• Patients with anorexia showed elevated risks for individual cardiovascular conditions such as cardiac arrest, structural heart disease, conduction disorder, and heart failure, but not stroke, atherosclerosis, ischemic heart disease, or inflammatory heart disease.
• The risks for congestive heart failure, structural heart disease, and conduction disorder increased in the first 24 months after the diagnosis of anorexia and disappeared after 5 years of follow-up, whereas the risk for ischemic heart disease increased only after 5 years of follow-up.

IN PRACTICE:

“Clinicians should monitor comorbid cardiovascular conditions among patients with [anorexia] at initial presentation, during treatment, and at follow-up,” the authors of the study wrote.

“In this study, most cardiovascular conditions were in remission after 5 years except ischemic heart disease,” the researchers noted. “This finding is corroborated by the recovery rate of 50%-70% in patients with [anorexia] after 4 years of follow-up in a recent meta-analysis, and in previous studies, most of the cardiac complications improved with weight restoration. Similarly, genome-wide association studies did not support elevated cardiovascular risk in patients with [anorexia] due to shared genetic mechanisms between [anorexia] and cardiovascular diseases, but they suggested that cardiovascular diseases were a downstream consequence” of the eating disorder.
 

SOURCE:

The study was led by Mei-Chih Meg Tseng, MD, PhD, of the Department of Psychiatry at Taipei Medical University in Taipei, Taiwan. It was published online on December 19, 2024, in JAMA Network Open.

LIMITATIONS:

The cardiovascular outcomes relied on the clinical diagnoses, and the validity of anorexia or its subtype was not confirmed. The study population was limited to patients seeking medical treatment, which may have led to the inclusion of patients with more severe symptoms. Key potential confounders such as body weight, nutritional status, lifestyle, drug use, and family history were unavailable in the claims dataset and could not be adjusted. The generalizability of the study may be limited as it involved only participants from a single ethnic group.

DISCLOSURES:

This study was supported by grants from the National Science and Technology Council, Taiwan, and Taipei Medical University. The authors reported no conflicts of interest.

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

TOPLINE:

Patients with anorexia nervosa are at significantly increased risk for cardiovascular conditions such as heart failure and cardiac arrest, compared with people without an eating disorder, researchers found. The risk for many of these conditions declines after 5 years of follow-up, whereas the risk for ischemic heart disease rises only after that period.

METHODOLOGY:

• Researchers conducted a longitudinal cohort study by analyzing the data from Taiwan’s National Health Insurance database to investigate the incidences and risk for cardiovascular conditions in patients with anorexia.
• They included 22,891 participants (mean age, 24.9 years; 91.3% women), of whom 2081 were diagnosed with anorexia between January 2010 and December 2021 and 20,810 were matched control participants without any eating disorder.
• The mean follow-up duration of this study was 5 years; investigators also assessed the risk for individual cardiovascular conditions during three periods after the diagnosis of anorexia: 0-24 months, between 24 and 60 months, and greater than 60 months.
• The primary outcomes were the occurrence of major adverse cardiovascular events (MACE) and any cardiovascular condition, including heart failure, stroke, ischemic heart diseases, conduction disorder, inflammatory heart disease, valve disease, cardiomyopathy, atherosclerosis, and cardiac arrest.

TAKEAWAY:

• At the 5-year follow-up, the incidence and risk for MACE were higher in patients with anorexia than in those without (4.82% vs 0.85% and adjusted hazard ratio [aHR], 3.78; 95% CI, 2.83-5.05, respectively).
• Similarly, the incidence of any cardiovascular condition was higher in patients with anorexia than in those without (6.19% vs 2.27%), which translated to a nearly twofold increased risk (aHR, 1.93; 95% CI, 1.54-2.41).
• Patients with anorexia showed elevated risks for individual cardiovascular conditions such as cardiac arrest, structural heart disease, conduction disorder, and heart failure, but not stroke, atherosclerosis, ischemic heart disease, or inflammatory heart disease.
• The risks for congestive heart failure, structural heart disease, and conduction disorder increased in the first 24 months after the diagnosis of anorexia and disappeared after 5 years of follow-up, whereas the risk for ischemic heart disease increased only after 5 years of follow-up.

IN PRACTICE:

“Clinicians should monitor comorbid cardiovascular conditions among patients with [anorexia] at initial presentation, during treatment, and at follow-up,” the authors of the study wrote.

“In this study, most cardiovascular conditions were in remission after 5 years except ischemic heart disease,” the researchers noted. “This finding is corroborated by the recovery rate of 50%-70% in patients with [anorexia] after 4 years of follow-up in a recent meta-analysis, and in previous studies, most of the cardiac complications improved with weight restoration. Similarly, genome-wide association studies did not support elevated cardiovascular risk in patients with [anorexia] due to shared genetic mechanisms between [anorexia] and cardiovascular diseases, but they suggested that cardiovascular diseases were a downstream consequence” of the eating disorder.
 

SOURCE:

The study was led by Mei-Chih Meg Tseng, MD, PhD, of the Department of Psychiatry at Taipei Medical University in Taipei, Taiwan. It was published online on December 19, 2024, in JAMA Network Open.

LIMITATIONS:

The cardiovascular outcomes relied on the clinical diagnoses, and the validity of anorexia or its subtype was not confirmed. The study population was limited to patients seeking medical treatment, which may have led to the inclusion of patients with more severe symptoms. Key potential confounders such as body weight, nutritional status, lifestyle, drug use, and family history were unavailable in the claims dataset and could not be adjusted. The generalizability of the study may be limited as it involved only participants from a single ethnic group.

DISCLOSURES:

This study was supported by grants from the National Science and Technology Council, Taiwan, and Taipei Medical University. The authors reported no conflicts of interest.

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

The World Health Organization Regional Office for Europe (WHO/Europe) and the European Association for the Study of the Liver held a symposium on December 11 to establish the European Alcohol Health Alliance to reduce alcohol-related harms across Europe. 

Europe has the highest levels of alcohol consumption in the world. Alcohol is the continent’s leading cause of death, accounting for almost 800,000 deaths per year, or 1 in 11 deaths in the region. 

This news organization spoke with Frank Murray, MBBCh, a consultant gastroenterologist and hepatologist at Bon Secours Hospital and Beaumont Private Clinic in Dublin, Ireland, who attended the symposium. The intention is to launch the European Alcohol Health Alliance in 2025. 

“We’d like to see evidence-based policies to reduce alcohol harm, which we think would be good for individual citizens and the economy,” said Murray. 

The symposium brought together multiple professional societies to discuss problems related to alcohol use, possible solutions, and their willingness to collaborate. Murray noted that attendees were enthusiastic about forming an alliance. 

Among the alliance’s first priorities, he noted, are changing the pricing and availability of alcohol, implementing restrictions in marketing and advertising, protecting children from alcohol harm, and labeling products with health warnings. 

“It’s interesting that the most dangerous product in the supermarket is sold without any nutrition or content information and without any warnings,” he said. 

 

‘David and Goliath’ 

This news organization also spoke with Barbara Broers, MD, professor of addiction medicine at the University of Geneva in Switzerland, who did not attend the meeting. 

She noted that although methods for reducing alcohol intake are well known, little action is taken to implement them. The alcohol industry is a major reason for this, she said, because it will “do everything to keep its business going.” 

One tactic, according to Broers and Murray, is heavy governmental lobbying. The industry’s resources for lobbying and advocating greatly outweigh any counterforce in what Murray described as a “bit of a David and Goliath” situation. 

“The alcohol industry should not have any role in policy making for alcohol, because it has a conflict of interest that clearly gets in the way of giving public health advice. It wants to maximize profits, while public health requires policies to reduce alcohol consumption,” he noted. 

Among the aims of the European Alcohol Health Alliance is “to rebalance the battle between those advocating for and against alcohol,” he continued.

 

Public Misperceptions

Although alcohol’s harmful effects on the liver are well known, Broers and Murray noted that its other effects are less known. 

A 2024 study found that whereas 90% of Europeans are aware of alcohol’s causal role in liver disease, just 68% are aware of a causal role for heart diseases and 53% for cancer. And only 15% were aware of a causal link with female breast cancer, even though drinking alcohol causes up to 1 in 10 cases of breast cancer.

Adding to a general lack of public awareness, methodologically flawed research may have generated a false impression that moderate drinking is beneficial for health, according to a s ystematic review and meta-analysis of 107 longitudinal studies. 

Broers noted that more work must be done to increase public knowledge about the harmful effects of alcohol, and especially its link to cancer. “We now know that a person’s risk of cancer increases right from the first drink, but I think the people don’t know this,” she said. 

“Local context and culture have a significant impact on the prevalence of alcohol consumption within a population, as well as the pattern of alcohol consumption,” Andrew Smyth, MBBCh, PhD, professor of clinical epidemiology at the University of Galway in Ireland, told this news organization. 

“Each country, region, and area are likely to need culturally appropriate and socially acceptable solutions to overcome their own hurdles,” he added.

 

Normalizing Abstinence

“Alcohol is involved in our social lives in so many ways. Reducing it would be Sisyphus’s work,” said Bernhard Maisch, MD, professor at Philipps University of Marburg, Germany. 

Jelena Šarić Posavec, a former PhD student at the University of Ljubljana in Slovenia, said that, while numerous obstacles make addressing alcohol-related harms difficult in Europe, solutions exist, too. 

Broers noted, for example, that Germany is working to change social perceptions around not drinking. “No alcohol should be the norm and should be considered positive. People should know that they might feel much better if they don’t drink at all.” 

Short-term improvements from abstaining from alcohol may be felt in sleep and energy levels, with long-term health effects ranging from weight to liver health and cancer risk, she noted. The problem, she said, however, lies in how to communicate this message. 

Murray, Broers, Smyth, Maisch, and Posavec reported having no relevant financial relationships.

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

The World Health Organization Regional Office for Europe (WHO/Europe) and the European Association for the Study of the Liver held a symposium on December 11 to establish the European Alcohol Health Alliance to reduce alcohol-related harms across Europe. 

Europe has the highest levels of alcohol consumption in the world. Alcohol is the continent’s leading cause of death, accounting for almost 800,000 deaths per year, or 1 in 11 deaths in the region. 

This news organization spoke with Frank Murray, MBBCh, a consultant gastroenterologist and hepatologist at Bon Secours Hospital and Beaumont Private Clinic in Dublin, Ireland, who attended the symposium. The intention is to launch the European Alcohol Health Alliance in 2025. 

“We’d like to see evidence-based policies to reduce alcohol harm, which we think would be good for individual citizens and the economy,” said Murray. 

The symposium brought together multiple professional societies to discuss problems related to alcohol use, possible solutions, and their willingness to collaborate. Murray noted that attendees were enthusiastic about forming an alliance. 

Among the alliance’s first priorities, he noted, are changing the pricing and availability of alcohol, implementing restrictions in marketing and advertising, protecting children from alcohol harm, and labeling products with health warnings. 

“It’s interesting that the most dangerous product in the supermarket is sold without any nutrition or content information and without any warnings,” he said. 

 

‘David and Goliath’ 

This news organization also spoke with Barbara Broers, MD, professor of addiction medicine at the University of Geneva in Switzerland, who did not attend the meeting. 

She noted that although methods for reducing alcohol intake are well known, little action is taken to implement them. The alcohol industry is a major reason for this, she said, because it will “do everything to keep its business going.” 

One tactic, according to Broers and Murray, is heavy governmental lobbying. The industry’s resources for lobbying and advocating greatly outweigh any counterforce in what Murray described as a “bit of a David and Goliath” situation. 

“The alcohol industry should not have any role in policy making for alcohol, because it has a conflict of interest that clearly gets in the way of giving public health advice. It wants to maximize profits, while public health requires policies to reduce alcohol consumption,” he noted. 

Among the aims of the European Alcohol Health Alliance is “to rebalance the battle between those advocating for and against alcohol,” he continued.

 

Public Misperceptions

Although alcohol’s harmful effects on the liver are well known, Broers and Murray noted that its other effects are less known. 

A 2024 study found that whereas 90% of Europeans are aware of alcohol’s causal role in liver disease, just 68% are aware of a causal role for heart diseases and 53% for cancer. And only 15% were aware of a causal link with female breast cancer, even though drinking alcohol causes up to 1 in 10 cases of breast cancer.

Adding to a general lack of public awareness, methodologically flawed research may have generated a false impression that moderate drinking is beneficial for health, according to a s ystematic review and meta-analysis of 107 longitudinal studies. 

Broers noted that more work must be done to increase public knowledge about the harmful effects of alcohol, and especially its link to cancer. “We now know that a person’s risk of cancer increases right from the first drink, but I think the people don’t know this,” she said. 

“Local context and culture have a significant impact on the prevalence of alcohol consumption within a population, as well as the pattern of alcohol consumption,” Andrew Smyth, MBBCh, PhD, professor of clinical epidemiology at the University of Galway in Ireland, told this news organization. 

“Each country, region, and area are likely to need culturally appropriate and socially acceptable solutions to overcome their own hurdles,” he added.

 

Normalizing Abstinence

“Alcohol is involved in our social lives in so many ways. Reducing it would be Sisyphus’s work,” said Bernhard Maisch, MD, professor at Philipps University of Marburg, Germany. 

Jelena Šarić Posavec, a former PhD student at the University of Ljubljana in Slovenia, said that, while numerous obstacles make addressing alcohol-related harms difficult in Europe, solutions exist, too. 

Broers noted, for example, that Germany is working to change social perceptions around not drinking. “No alcohol should be the norm and should be considered positive. People should know that they might feel much better if they don’t drink at all.” 

Short-term improvements from abstaining from alcohol may be felt in sleep and energy levels, with long-term health effects ranging from weight to liver health and cancer risk, she noted. The problem, she said, however, lies in how to communicate this message. 

Murray, Broers, Smyth, Maisch, and Posavec reported having no relevant financial relationships.

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

The World Health Organization Regional Office for Europe (WHO/Europe) and the European Association for the Study of the Liver held a symposium on December 11 to establish the European Alcohol Health Alliance to reduce alcohol-related harms across Europe. 

Europe has the highest levels of alcohol consumption in the world. Alcohol is the continent’s leading cause of death, accounting for almost 800,000 deaths per year, or 1 in 11 deaths in the region. 

This news organization spoke with Frank Murray, MBBCh, a consultant gastroenterologist and hepatologist at Bon Secours Hospital and Beaumont Private Clinic in Dublin, Ireland, who attended the symposium. The intention is to launch the European Alcohol Health Alliance in 2025. 

“We’d like to see evidence-based policies to reduce alcohol harm, which we think would be good for individual citizens and the economy,” said Murray. 

The symposium brought together multiple professional societies to discuss problems related to alcohol use, possible solutions, and their willingness to collaborate. Murray noted that attendees were enthusiastic about forming an alliance. 

Among the alliance’s first priorities, he noted, are changing the pricing and availability of alcohol, implementing restrictions in marketing and advertising, protecting children from alcohol harm, and labeling products with health warnings. 

“It’s interesting that the most dangerous product in the supermarket is sold without any nutrition or content information and without any warnings,” he said. 

 

‘David and Goliath’ 

This news organization also spoke with Barbara Broers, MD, professor of addiction medicine at the University of Geneva in Switzerland, who did not attend the meeting. 

She noted that although methods for reducing alcohol intake are well known, little action is taken to implement them. The alcohol industry is a major reason for this, she said, because it will “do everything to keep its business going.” 

One tactic, according to Broers and Murray, is heavy governmental lobbying. The industry’s resources for lobbying and advocating greatly outweigh any counterforce in what Murray described as a “bit of a David and Goliath” situation. 

“The alcohol industry should not have any role in policy making for alcohol, because it has a conflict of interest that clearly gets in the way of giving public health advice. It wants to maximize profits, while public health requires policies to reduce alcohol consumption,” he noted. 

Among the aims of the European Alcohol Health Alliance is “to rebalance the battle between those advocating for and against alcohol,” he continued.

 

Public Misperceptions

Although alcohol’s harmful effects on the liver are well known, Broers and Murray noted that its other effects are less known. 

A 2024 study found that whereas 90% of Europeans are aware of alcohol’s causal role in liver disease, just 68% are aware of a causal role for heart diseases and 53% for cancer. And only 15% were aware of a causal link with female breast cancer, even though drinking alcohol causes up to 1 in 10 cases of breast cancer.

Adding to a general lack of public awareness, methodologically flawed research may have generated a false impression that moderate drinking is beneficial for health, according to a s ystematic review and meta-analysis of 107 longitudinal studies. 

Broers noted that more work must be done to increase public knowledge about the harmful effects of alcohol, and especially its link to cancer. “We now know that a person’s risk of cancer increases right from the first drink, but I think the people don’t know this,” she said. 

“Local context and culture have a significant impact on the prevalence of alcohol consumption within a population, as well as the pattern of alcohol consumption,” Andrew Smyth, MBBCh, PhD, professor of clinical epidemiology at the University of Galway in Ireland, told this news organization. 

“Each country, region, and area are likely to need culturally appropriate and socially acceptable solutions to overcome their own hurdles,” he added.

 

Normalizing Abstinence

“Alcohol is involved in our social lives in so many ways. Reducing it would be Sisyphus’s work,” said Bernhard Maisch, MD, professor at Philipps University of Marburg, Germany. 

Jelena Šarić Posavec, a former PhD student at the University of Ljubljana in Slovenia, said that, while numerous obstacles make addressing alcohol-related harms difficult in Europe, solutions exist, too. 

Broers noted, for example, that Germany is working to change social perceptions around not drinking. “No alcohol should be the norm and should be considered positive. People should know that they might feel much better if they don’t drink at all.” 

Short-term improvements from abstaining from alcohol may be felt in sleep and energy levels, with long-term health effects ranging from weight to liver health and cancer risk, she noted. The problem, she said, however, lies in how to communicate this message. 

Murray, Broers, Smyth, Maisch, and Posavec reported having no relevant financial relationships.

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

While fewer than 10% of US physicians are unionized, the number of official union drives among private-sector doctors have skyrocketed in the last 2 years, compared with 2 decades prior, according to a new study. 

Researchers counted 21 union drives in 2023 and 12 in the first 5 months of 2024, compared with 0-6 drives each year between 2000 and 2022. 

If the 2023 and 2024 drives succeed, unions will represent 3523 new physicians — nearly equal to the 3541 doctors who sought unionization between 2000 and 2022.

“We were able to document a significant uptick in union petitions and success in certification drives,” said corresponding author Hayden Rooke-Ley, JD, of the Center for Advancing Health Policy Through Research, Brown University School of Public Health, Providence, Rhode Island. “We were surprised to see such a marked shift in 2023.”

About 72,000 physicians, an estimated 8% of all US doctors, are covered by unions, including some in the public sector. Physicians who are self-employed, now comprising less than a fifth of all doctors, are not eligible to join labor unions.

The study authors launched their research to better understand trends in physician unionization in light of high-profile union drives, especially among residents. Rooke-Ley said: “We suspected that declining morale and increased corporate employment for physicians were leading them to consider unionization.”

The researchers gathered data from the National Labor Relations Board about union drives by potential bargaining units that included physicians. From 2000 to 2022, 44 union petitions were filed. The number jumped to 33 from 2023-2024. 

 

“Tip of the Iceberg”

“This is the tip of the iceberg,” said ethicist Joseph F. Kras, MD, DDS, MA, an associate professor of anesthesiology at Washington University in St. Louis, Missouri, and corresponding author of a recent Anesthesia & Analgesia report about physician unionization.

“We are independent by nature,” Kras said. “But when you put us in an employed environment and start treating us as widgets, then we will act like employees of Amazon, Starbucks, and other companies and join together to push back against the increasing emphasis on profit over all at the expense of our independent judgment on what’s best for the patient.”

Of the 66 unionization efforts between 2000 and 2024 that were decided, 62% were certified, according to the JAMA study. The drives targeted hospitals (49%), community health centers (38%), and nonhospital corporate owners (13%).

The researchers only analyzed private-sector unionization and did not include physicians who are unionized at public institutions. 

 

What’s Behind Union Drives?

Alyssa Burgart, MD, MA, an ethicist and clinical associate professor of anesthesiology and pediatrics at Stanford University in California, told this news organization that physician unionization “is a big topic with a lot of really strong opinions.” 

Many doctors wrongly assume they can’t unionize because they’re physicians, said Burgart, a coauthor of the Anesthesia & Analgesia report.

Supporters of unionization believe it’s a strategy to be “recognized not as simply as a single physician with a concern,” she said. “When you’re among clinicians who can speak as a more unified group, organizations are more likely to take that seriously.”

A union may also be able to hold employers to account in areas such as the gender wage gap, sexual harassment, and bias in hiring and firing, Burgart said. And union supporters believe they’ll make more money if they collectively bargain. 

Other factors driving interest in unions include “increasing physician burnout, increasing physician exhaustion, and immense frustration with the ways that private equity is influencing how physicians need to work in order to practice,” she said. 

Earlier in 2024, physicians in Delaware’s ChristianaCare health system voted 288-130 to be represented by Doctors Council/Service Employees International, according to the union. 

“We have still not been able to staff up enough to where us physicians can get back to just focusing on taking care of patients,” a unionization leader told WHYY. 

The JAMA study examined news reports regarding most of the 2023-2024 union drives and found that supporters claimed they were motivated by working conditions (85%), lack of voice in management (81%), patient care concerns (54%), and pay (4%).

 

Critics Worry They’ll Lose Pay Because of Unions

Skeptics of unionization worry about whether “I’m going to be required to stand by some union stance that is actually out of alignment with my values as a physician,” Burgart said. And, she said, critics such as highly paid surgeons fear that adjustments to salaries because of union contracts could cause them to lose income.

In regard to compensation, a 2024 study surveyed unionized residents — along with faculty and staff — at general surgery programs and found evidence that unionization didn’t improve resident well-being or benefits, although it “provided a mechanism for resident voice and agency.”

“It is critical to study the outcomes of those who unionized to ensure that the reasons for unionizing were realized over time,” said that study’s coauthor Karl Bilimoria, MD, MS, chair of surgery at Indiana University School of Medicine, Indianapolis. “The unintended consequences of unionization must be examined along with the potential improvements.”

Rooke-Ley discloses consulting fees from the American Economic Liberties Project, National Academy of State Health Policy, and 32BJ Funds. Kras and Burgart disclose previous union membership. Bilimoria has no disclosures.

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

While fewer than 10% of US physicians are unionized, the number of official union drives among private-sector doctors have skyrocketed in the last 2 years, compared with 2 decades prior, according to a new study. 

Researchers counted 21 union drives in 2023 and 12 in the first 5 months of 2024, compared with 0-6 drives each year between 2000 and 2022. 

If the 2023 and 2024 drives succeed, unions will represent 3523 new physicians — nearly equal to the 3541 doctors who sought unionization between 2000 and 2022.

“We were able to document a significant uptick in union petitions and success in certification drives,” said corresponding author Hayden Rooke-Ley, JD, of the Center for Advancing Health Policy Through Research, Brown University School of Public Health, Providence, Rhode Island. “We were surprised to see such a marked shift in 2023.”

About 72,000 physicians, an estimated 8% of all US doctors, are covered by unions, including some in the public sector. Physicians who are self-employed, now comprising less than a fifth of all doctors, are not eligible to join labor unions.

The study authors launched their research to better understand trends in physician unionization in light of high-profile union drives, especially among residents. Rooke-Ley said: “We suspected that declining morale and increased corporate employment for physicians were leading them to consider unionization.”

The researchers gathered data from the National Labor Relations Board about union drives by potential bargaining units that included physicians. From 2000 to 2022, 44 union petitions were filed. The number jumped to 33 from 2023-2024. 

 

“Tip of the Iceberg”

“This is the tip of the iceberg,” said ethicist Joseph F. Kras, MD, DDS, MA, an associate professor of anesthesiology at Washington University in St. Louis, Missouri, and corresponding author of a recent Anesthesia & Analgesia report about physician unionization.

“We are independent by nature,” Kras said. “But when you put us in an employed environment and start treating us as widgets, then we will act like employees of Amazon, Starbucks, and other companies and join together to push back against the increasing emphasis on profit over all at the expense of our independent judgment on what’s best for the patient.”

Of the 66 unionization efforts between 2000 and 2024 that were decided, 62% were certified, according to the JAMA study. The drives targeted hospitals (49%), community health centers (38%), and nonhospital corporate owners (13%).

The researchers only analyzed private-sector unionization and did not include physicians who are unionized at public institutions. 

 

What’s Behind Union Drives?

Alyssa Burgart, MD, MA, an ethicist and clinical associate professor of anesthesiology and pediatrics at Stanford University in California, told this news organization that physician unionization “is a big topic with a lot of really strong opinions.” 

Many doctors wrongly assume they can’t unionize because they’re physicians, said Burgart, a coauthor of the Anesthesia & Analgesia report.

Supporters of unionization believe it’s a strategy to be “recognized not as simply as a single physician with a concern,” she said. “When you’re among clinicians who can speak as a more unified group, organizations are more likely to take that seriously.”

A union may also be able to hold employers to account in areas such as the gender wage gap, sexual harassment, and bias in hiring and firing, Burgart said. And union supporters believe they’ll make more money if they collectively bargain. 

Other factors driving interest in unions include “increasing physician burnout, increasing physician exhaustion, and immense frustration with the ways that private equity is influencing how physicians need to work in order to practice,” she said. 

Earlier in 2024, physicians in Delaware’s ChristianaCare health system voted 288-130 to be represented by Doctors Council/Service Employees International, according to the union. 

“We have still not been able to staff up enough to where us physicians can get back to just focusing on taking care of patients,” a unionization leader told WHYY. 

The JAMA study examined news reports regarding most of the 2023-2024 union drives and found that supporters claimed they were motivated by working conditions (85%), lack of voice in management (81%), patient care concerns (54%), and pay (4%).

 

Critics Worry They’ll Lose Pay Because of Unions

Skeptics of unionization worry about whether “I’m going to be required to stand by some union stance that is actually out of alignment with my values as a physician,” Burgart said. And, she said, critics such as highly paid surgeons fear that adjustments to salaries because of union contracts could cause them to lose income.

In regard to compensation, a 2024 study surveyed unionized residents — along with faculty and staff — at general surgery programs and found evidence that unionization didn’t improve resident well-being or benefits, although it “provided a mechanism for resident voice and agency.”

“It is critical to study the outcomes of those who unionized to ensure that the reasons for unionizing were realized over time,” said that study’s coauthor Karl Bilimoria, MD, MS, chair of surgery at Indiana University School of Medicine, Indianapolis. “The unintended consequences of unionization must be examined along with the potential improvements.”

Rooke-Ley discloses consulting fees from the American Economic Liberties Project, National Academy of State Health Policy, and 32BJ Funds. Kras and Burgart disclose previous union membership. Bilimoria has no disclosures.

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

While fewer than 10% of US physicians are unionized, the number of official union drives among private-sector doctors have skyrocketed in the last 2 years, compared with 2 decades prior, according to a new study. 

Researchers counted 21 union drives in 2023 and 12 in the first 5 months of 2024, compared with 0-6 drives each year between 2000 and 2022. 

If the 2023 and 2024 drives succeed, unions will represent 3523 new physicians — nearly equal to the 3541 doctors who sought unionization between 2000 and 2022.

“We were able to document a significant uptick in union petitions and success in certification drives,” said corresponding author Hayden Rooke-Ley, JD, of the Center for Advancing Health Policy Through Research, Brown University School of Public Health, Providence, Rhode Island. “We were surprised to see such a marked shift in 2023.”

About 72,000 physicians, an estimated 8% of all US doctors, are covered by unions, including some in the public sector. Physicians who are self-employed, now comprising less than a fifth of all doctors, are not eligible to join labor unions.

The study authors launched their research to better understand trends in physician unionization in light of high-profile union drives, especially among residents. Rooke-Ley said: “We suspected that declining morale and increased corporate employment for physicians were leading them to consider unionization.”

The researchers gathered data from the National Labor Relations Board about union drives by potential bargaining units that included physicians. From 2000 to 2022, 44 union petitions were filed. The number jumped to 33 from 2023-2024. 

 

“Tip of the Iceberg”

“This is the tip of the iceberg,” said ethicist Joseph F. Kras, MD, DDS, MA, an associate professor of anesthesiology at Washington University in St. Louis, Missouri, and corresponding author of a recent Anesthesia & Analgesia report about physician unionization.

“We are independent by nature,” Kras said. “But when you put us in an employed environment and start treating us as widgets, then we will act like employees of Amazon, Starbucks, and other companies and join together to push back against the increasing emphasis on profit over all at the expense of our independent judgment on what’s best for the patient.”

Of the 66 unionization efforts between 2000 and 2024 that were decided, 62% were certified, according to the JAMA study. The drives targeted hospitals (49%), community health centers (38%), and nonhospital corporate owners (13%).

The researchers only analyzed private-sector unionization and did not include physicians who are unionized at public institutions. 

 

What’s Behind Union Drives?

Alyssa Burgart, MD, MA, an ethicist and clinical associate professor of anesthesiology and pediatrics at Stanford University in California, told this news organization that physician unionization “is a big topic with a lot of really strong opinions.” 

Many doctors wrongly assume they can’t unionize because they’re physicians, said Burgart, a coauthor of the Anesthesia & Analgesia report.

Supporters of unionization believe it’s a strategy to be “recognized not as simply as a single physician with a concern,” she said. “When you’re among clinicians who can speak as a more unified group, organizations are more likely to take that seriously.”

A union may also be able to hold employers to account in areas such as the gender wage gap, sexual harassment, and bias in hiring and firing, Burgart said. And union supporters believe they’ll make more money if they collectively bargain. 

Other factors driving interest in unions include “increasing physician burnout, increasing physician exhaustion, and immense frustration with the ways that private equity is influencing how physicians need to work in order to practice,” she said. 

Earlier in 2024, physicians in Delaware’s ChristianaCare health system voted 288-130 to be represented by Doctors Council/Service Employees International, according to the union. 

“We have still not been able to staff up enough to where us physicians can get back to just focusing on taking care of patients,” a unionization leader told WHYY. 

The JAMA study examined news reports regarding most of the 2023-2024 union drives and found that supporters claimed they were motivated by working conditions (85%), lack of voice in management (81%), patient care concerns (54%), and pay (4%).

 

Critics Worry They’ll Lose Pay Because of Unions

Skeptics of unionization worry about whether “I’m going to be required to stand by some union stance that is actually out of alignment with my values as a physician,” Burgart said. And, she said, critics such as highly paid surgeons fear that adjustments to salaries because of union contracts could cause them to lose income.

In regard to compensation, a 2024 study surveyed unionized residents — along with faculty and staff — at general surgery programs and found evidence that unionization didn’t improve resident well-being or benefits, although it “provided a mechanism for resident voice and agency.”

“It is critical to study the outcomes of those who unionized to ensure that the reasons for unionizing were realized over time,” said that study’s coauthor Karl Bilimoria, MD, MS, chair of surgery at Indiana University School of Medicine, Indianapolis. “The unintended consequences of unionization must be examined along with the potential improvements.”

Rooke-Ley discloses consulting fees from the American Economic Liberties Project, National Academy of State Health Policy, and 32BJ Funds. Kras and Burgart disclose previous union membership. Bilimoria has no disclosures.

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

Interleukin-6 receptor (IL-6r) inhibition is a promising approach for the treatment of calcium pyrophosphate deposition disease (CPPD), although no prospective studies have been conducted to date. Nevertheless, a retrospective analysis of patients treated with the IL-6r inhibitor tocilizumab, presented at American College of Rheumatology (ACR) 2024 Annual Meeting, showed improved CPPD control in more than two thirds of patients who had failed or could not tolerate usual therapies.

Both the monosodium urate (MSU) crystals associated with gout and CPP crystals induce inflammation dependent on IL-1 beta, but IL-1 beta inhibitors have been investigated more as treatments for gout than for CPPD, and they are recommended by both ACR and European Alliance of Associations for Rheumatology (EULAR) guidelines for patients with gout who have flares despite efforts to treat with colchicine, nonsteroidal anti-inflammatory drugs, and corticosteroids. However, IL-1 beta inhibitors are sometimes used off label in CPPD.

There are similarities among the various crystal types that induce arthritis, typically producing similar clinical features of acute arthritis and severe pain and local inflammation and tending to self-resolve within days to weeks. Those shared clinical features suggest common inflammatory mechanisms, likely stemming from the innate immune system, said Augustin Latourte, MD, PhD, of Lariboisière Hospital, Paris, France, during a talk on the topic at the annual research symposium of the Gout Hyperuricemia and Crystal-Associated Disease Network (G-CAN).

CPPD management is generally derived from strategies developed for gout, but there is little evidence supporting IL-1 beta inhibitors outside of case reports, he said. One clinical trial published in 2020 showed efficacy of the IL-1 inhibitor anakinra, but the study was halted due to low patient recruitment, resulting in a small study population. In that study, “anakinra seems to have a faster onset of action than prednisone and could be useful in specific situations regarding acute CPPD arthritis. But it’s not relevant for chronic CPPD arthritis when you have persistent polyarthritis requiring chronic treatment. Anakinra requires daily injections and may not be appropriate in this situation,” he said.

IL-6r inhibition has been studied since IL-6 was first discovered in 1989 as a mediator of inflammatory responses in gout and CPPD, when it was shown that both CPP and MSU crystals can stimulate its production. In monocytes, IL-6 is expressed at higher levels than IL-1 beta in response to both CPP and MSU crystals. IL-6 production in monocytes in response to crystals is dependent on IL-1, and IL-1 inhibition reduces IL-6 production. “So the hypothesis is that IL-1 beta is the first event, and the production of IL-6 and the amplification of crystal inflammation occurs downstream before the self-limitation of the crystal-induced arthritis. IL-6 may be a very important event in the onset of crystal-induced inflammation,” Latourte said.

 

Building on Mechanistic Insights to Test Off-Label Use of Tocilizumab

Inspired by this insight, Latourte’s group tested tocilizumab in a 28-year-old man with a familial ANKH mutation who had not responded to anakinra and other conventional treatments. The patient experienced a reduction in flare intensity in the first month after the initial treatment and no flares after the second tocilizumab infusion. The group went on to test tocilizumab in 10 additional patients with CPPD (median age, 62.5 years), including 6 with idiopathic CPPD, 3 with Gitelman syndrome, and 1 with ANKH mutation. The clinical presentation included four with recurrent acute arthritis and six with chronic polyarthritis, and all had x-ray–proven disease, with a median visual analog scale (VAS) of 60 mm out of 100 mm. Tocilizumab was administered intravenously or subcutaneously. At 3 months, there was a median improvement of 30 mm in the VAS. Treatment efficacy continued for a median follow-up of 5.5 months at the time of publication, and the researchers have noted ongoing efficacy out to 50 months for some patients.

Tocilizumab has gone on to more frequent use in Europe as a second- or third-line therapy for CPPD, which led Latourte and his colleagues to perform the retrospective analysis that they presented at the ACR meeting. It included 55 patients who received tocilizumab for chronic inflammatory CPPD at two university hospitals. Participants had a median age of 72 years, and 67.3% were women. The patient group included 39 with chronic CPPD, 14 with recurrent acute CPPD (who experienced 0-4 attacks per month), and two patients with mixed CPPD. All participants had been treated with colchicine, and 20 had been treated also with prednisone and 24 with anakinra. Patients had stopped anakinra because it was either ineffective (n = 13) or poorly tolerated (n = 11).

Tocilizumab was administered intravenously in 46 patients and subcutaneously in nine patients for a median duration of 16.5 months (range, 0.8-76.4 months). The median VAS for pain (0- to 100-mm scale) dropped from 60 mm at baseline to 40 mm at 3 months and 30 mm at 6 months. There were 21 adverse events, including 8 cytopenias, 6 transaminase elevations, 4 infections (two severe), and 3 injection-site reactions. After a median of 7.8 months, 26 patients discontinued tocilizumab because of lack of efficacy in 15 patients and intolerance in 11. Among those who continued on tocilizumab, the median length of treatment was 26.0 months (range, 3-76.5 months).

 

Comments on the Study

The study population had some unusual characteristics, according to G-CAN President Robert Terkeltaub, MD, who was asked to comment on the study. “Almost half the patients had received anakinra and then, basically, they failed. In about half of the people who got anakinra, it didn’t work, and in the other half, it wasn’t well tolerated. It’s just rather odd. I find anakinra reasonably well tolerated by people, but we’re dealing with an older population of patients, and the subcutaneous administration of anakinra sometimes can give you injection site reactions, but people started off with a pain level that was close to what we register as severe pain, and the pain level decreased,” he said.

Treatment decisions can be difficult in patients with chronic or acute recurrent CPPD, said Terkeltaub, professor of medicine at the University of California, San Diego. “What’s the lesser evil? Putting people on chronic prednisone is really hard on patients or using a biologic that’s more of an immunologic scalpel here, and more selective, and trying to get people through a long course of therapy. If you have chronic arthritis, it took a while for it to get chronic, and it generally doesn’t go away overnight.”

Terkeltaub also pointed out the gastrointestinal side effects of IL-6r inhibitors, which can include diverticulitis, but there are also concerns over infections and lipid and liver abnormalities. Subcutaneously injected tocilizumab also has a longer half-life than something like anakinra.

Beyond the retrospective nature of the study and the limits it imposes on conclusions that can be drawn, Terkeltaub noted a lack of data on the number of “inflamed joints [in each patient] and what the functioning of the patients was.”

Still, the findings are encouraging. “What I can glean from this study is that the first biologic drug might be an IL-6 inhibitor, but you really need prospective, controlled, blinded clinical trials to know, and it’s hard. It’s just hard to do those trials” because patients tend to be of advanced age, Terkeltaub said.

Latourte said a randomized controlled trial of tocilizumab vs placebo, called TociCCAre, is planned to begin in France in 2025.

Latourte has financial relationships with Fresenius Kabi, Roche Chugai, AbbVie, Arsylab, Celltrion, Janssen, Nordic, Pfizer, UCB, Amgen, Biogen, Galapagos, and Eli Lilly. Terkeltaub had no relevant financial disclosures.

A version of this article appeared on Medscape.com.

Interleukin-6 receptor (IL-6r) inhibition is a promising approach for the treatment of calcium pyrophosphate deposition disease (CPPD), although no prospective studies have been conducted to date. Nevertheless, a retrospective analysis of patients treated with the IL-6r inhibitor tocilizumab, presented at American College of Rheumatology (ACR) 2024 Annual Meeting, showed improved CPPD control in more than two thirds of patients who had failed or could not tolerate usual therapies.

Both the monosodium urate (MSU) crystals associated with gout and CPP crystals induce inflammation dependent on IL-1 beta, but IL-1 beta inhibitors have been investigated more as treatments for gout than for CPPD, and they are recommended by both ACR and European Alliance of Associations for Rheumatology (EULAR) guidelines for patients with gout who have flares despite efforts to treat with colchicine, nonsteroidal anti-inflammatory drugs, and corticosteroids. However, IL-1 beta inhibitors are sometimes used off label in CPPD.

There are similarities among the various crystal types that induce arthritis, typically producing similar clinical features of acute arthritis and severe pain and local inflammation and tending to self-resolve within days to weeks. Those shared clinical features suggest common inflammatory mechanisms, likely stemming from the innate immune system, said Augustin Latourte, MD, PhD, of Lariboisière Hospital, Paris, France, during a talk on the topic at the annual research symposium of the Gout Hyperuricemia and Crystal-Associated Disease Network (G-CAN).

CPPD management is generally derived from strategies developed for gout, but there is little evidence supporting IL-1 beta inhibitors outside of case reports, he said. One clinical trial published in 2020 showed efficacy of the IL-1 inhibitor anakinra, but the study was halted due to low patient recruitment, resulting in a small study population. In that study, “anakinra seems to have a faster onset of action than prednisone and could be useful in specific situations regarding acute CPPD arthritis. But it’s not relevant for chronic CPPD arthritis when you have persistent polyarthritis requiring chronic treatment. Anakinra requires daily injections and may not be appropriate in this situation,” he said.

IL-6r inhibition has been studied since IL-6 was first discovered in 1989 as a mediator of inflammatory responses in gout and CPPD, when it was shown that both CPP and MSU crystals can stimulate its production. In monocytes, IL-6 is expressed at higher levels than IL-1 beta in response to both CPP and MSU crystals. IL-6 production in monocytes in response to crystals is dependent on IL-1, and IL-1 inhibition reduces IL-6 production. “So the hypothesis is that IL-1 beta is the first event, and the production of IL-6 and the amplification of crystal inflammation occurs downstream before the self-limitation of the crystal-induced arthritis. IL-6 may be a very important event in the onset of crystal-induced inflammation,” Latourte said.

 

Building on Mechanistic Insights to Test Off-Label Use of Tocilizumab

Inspired by this insight, Latourte’s group tested tocilizumab in a 28-year-old man with a familial ANKH mutation who had not responded to anakinra and other conventional treatments. The patient experienced a reduction in flare intensity in the first month after the initial treatment and no flares after the second tocilizumab infusion. The group went on to test tocilizumab in 10 additional patients with CPPD (median age, 62.5 years), including 6 with idiopathic CPPD, 3 with Gitelman syndrome, and 1 with ANKH mutation. The clinical presentation included four with recurrent acute arthritis and six with chronic polyarthritis, and all had x-ray–proven disease, with a median visual analog scale (VAS) of 60 mm out of 100 mm. Tocilizumab was administered intravenously or subcutaneously. At 3 months, there was a median improvement of 30 mm in the VAS. Treatment efficacy continued for a median follow-up of 5.5 months at the time of publication, and the researchers have noted ongoing efficacy out to 50 months for some patients.

Tocilizumab has gone on to more frequent use in Europe as a second- or third-line therapy for CPPD, which led Latourte and his colleagues to perform the retrospective analysis that they presented at the ACR meeting. It included 55 patients who received tocilizumab for chronic inflammatory CPPD at two university hospitals. Participants had a median age of 72 years, and 67.3% were women. The patient group included 39 with chronic CPPD, 14 with recurrent acute CPPD (who experienced 0-4 attacks per month), and two patients with mixed CPPD. All participants had been treated with colchicine, and 20 had been treated also with prednisone and 24 with anakinra. Patients had stopped anakinra because it was either ineffective (n = 13) or poorly tolerated (n = 11).

Tocilizumab was administered intravenously in 46 patients and subcutaneously in nine patients for a median duration of 16.5 months (range, 0.8-76.4 months). The median VAS for pain (0- to 100-mm scale) dropped from 60 mm at baseline to 40 mm at 3 months and 30 mm at 6 months. There were 21 adverse events, including 8 cytopenias, 6 transaminase elevations, 4 infections (two severe), and 3 injection-site reactions. After a median of 7.8 months, 26 patients discontinued tocilizumab because of lack of efficacy in 15 patients and intolerance in 11. Among those who continued on tocilizumab, the median length of treatment was 26.0 months (range, 3-76.5 months).

 

Comments on the Study

The study population had some unusual characteristics, according to G-CAN President Robert Terkeltaub, MD, who was asked to comment on the study. “Almost half the patients had received anakinra and then, basically, they failed. In about half of the people who got anakinra, it didn’t work, and in the other half, it wasn’t well tolerated. It’s just rather odd. I find anakinra reasonably well tolerated by people, but we’re dealing with an older population of patients, and the subcutaneous administration of anakinra sometimes can give you injection site reactions, but people started off with a pain level that was close to what we register as severe pain, and the pain level decreased,” he said.

Treatment decisions can be difficult in patients with chronic or acute recurrent CPPD, said Terkeltaub, professor of medicine at the University of California, San Diego. “What’s the lesser evil? Putting people on chronic prednisone is really hard on patients or using a biologic that’s more of an immunologic scalpel here, and more selective, and trying to get people through a long course of therapy. If you have chronic arthritis, it took a while for it to get chronic, and it generally doesn’t go away overnight.”

Terkeltaub also pointed out the gastrointestinal side effects of IL-6r inhibitors, which can include diverticulitis, but there are also concerns over infections and lipid and liver abnormalities. Subcutaneously injected tocilizumab also has a longer half-life than something like anakinra.

Beyond the retrospective nature of the study and the limits it imposes on conclusions that can be drawn, Terkeltaub noted a lack of data on the number of “inflamed joints [in each patient] and what the functioning of the patients was.”

Still, the findings are encouraging. “What I can glean from this study is that the first biologic drug might be an IL-6 inhibitor, but you really need prospective, controlled, blinded clinical trials to know, and it’s hard. It’s just hard to do those trials” because patients tend to be of advanced age, Terkeltaub said.

Latourte said a randomized controlled trial of tocilizumab vs placebo, called TociCCAre, is planned to begin in France in 2025.

Latourte has financial relationships with Fresenius Kabi, Roche Chugai, AbbVie, Arsylab, Celltrion, Janssen, Nordic, Pfizer, UCB, Amgen, Biogen, Galapagos, and Eli Lilly. Terkeltaub had no relevant financial disclosures.

A version of this article appeared on Medscape.com.

Interleukin-6 receptor (IL-6r) inhibition is a promising approach for the treatment of calcium pyrophosphate deposition disease (CPPD), although no prospective studies have been conducted to date. Nevertheless, a retrospective analysis of patients treated with the IL-6r inhibitor tocilizumab, presented at American College of Rheumatology (ACR) 2024 Annual Meeting, showed improved CPPD control in more than two thirds of patients who had failed or could not tolerate usual therapies.

Both the monosodium urate (MSU) crystals associated with gout and CPP crystals induce inflammation dependent on IL-1 beta, but IL-1 beta inhibitors have been investigated more as treatments for gout than for CPPD, and they are recommended by both ACR and European Alliance of Associations for Rheumatology (EULAR) guidelines for patients with gout who have flares despite efforts to treat with colchicine, nonsteroidal anti-inflammatory drugs, and corticosteroids. However, IL-1 beta inhibitors are sometimes used off label in CPPD.

There are similarities among the various crystal types that induce arthritis, typically producing similar clinical features of acute arthritis and severe pain and local inflammation and tending to self-resolve within days to weeks. Those shared clinical features suggest common inflammatory mechanisms, likely stemming from the innate immune system, said Augustin Latourte, MD, PhD, of Lariboisière Hospital, Paris, France, during a talk on the topic at the annual research symposium of the Gout Hyperuricemia and Crystal-Associated Disease Network (G-CAN).

CPPD management is generally derived from strategies developed for gout, but there is little evidence supporting IL-1 beta inhibitors outside of case reports, he said. One clinical trial published in 2020 showed efficacy of the IL-1 inhibitor anakinra, but the study was halted due to low patient recruitment, resulting in a small study population. In that study, “anakinra seems to have a faster onset of action than prednisone and could be useful in specific situations regarding acute CPPD arthritis. But it’s not relevant for chronic CPPD arthritis when you have persistent polyarthritis requiring chronic treatment. Anakinra requires daily injections and may not be appropriate in this situation,” he said.

IL-6r inhibition has been studied since IL-6 was first discovered in 1989 as a mediator of inflammatory responses in gout and CPPD, when it was shown that both CPP and MSU crystals can stimulate its production. In monocytes, IL-6 is expressed at higher levels than IL-1 beta in response to both CPP and MSU crystals. IL-6 production in monocytes in response to crystals is dependent on IL-1, and IL-1 inhibition reduces IL-6 production. “So the hypothesis is that IL-1 beta is the first event, and the production of IL-6 and the amplification of crystal inflammation occurs downstream before the self-limitation of the crystal-induced arthritis. IL-6 may be a very important event in the onset of crystal-induced inflammation,” Latourte said.

 

Building on Mechanistic Insights to Test Off-Label Use of Tocilizumab

Inspired by this insight, Latourte’s group tested tocilizumab in a 28-year-old man with a familial ANKH mutation who had not responded to anakinra and other conventional treatments. The patient experienced a reduction in flare intensity in the first month after the initial treatment and no flares after the second tocilizumab infusion. The group went on to test tocilizumab in 10 additional patients with CPPD (median age, 62.5 years), including 6 with idiopathic CPPD, 3 with Gitelman syndrome, and 1 with ANKH mutation. The clinical presentation included four with recurrent acute arthritis and six with chronic polyarthritis, and all had x-ray–proven disease, with a median visual analog scale (VAS) of 60 mm out of 100 mm. Tocilizumab was administered intravenously or subcutaneously. At 3 months, there was a median improvement of 30 mm in the VAS. Treatment efficacy continued for a median follow-up of 5.5 months at the time of publication, and the researchers have noted ongoing efficacy out to 50 months for some patients.

Tocilizumab has gone on to more frequent use in Europe as a second- or third-line therapy for CPPD, which led Latourte and his colleagues to perform the retrospective analysis that they presented at the ACR meeting. It included 55 patients who received tocilizumab for chronic inflammatory CPPD at two university hospitals. Participants had a median age of 72 years, and 67.3% were women. The patient group included 39 with chronic CPPD, 14 with recurrent acute CPPD (who experienced 0-4 attacks per month), and two patients with mixed CPPD. All participants had been treated with colchicine, and 20 had been treated also with prednisone and 24 with anakinra. Patients had stopped anakinra because it was either ineffective (n = 13) or poorly tolerated (n = 11).

Tocilizumab was administered intravenously in 46 patients and subcutaneously in nine patients for a median duration of 16.5 months (range, 0.8-76.4 months). The median VAS for pain (0- to 100-mm scale) dropped from 60 mm at baseline to 40 mm at 3 months and 30 mm at 6 months. There were 21 adverse events, including 8 cytopenias, 6 transaminase elevations, 4 infections (two severe), and 3 injection-site reactions. After a median of 7.8 months, 26 patients discontinued tocilizumab because of lack of efficacy in 15 patients and intolerance in 11. Among those who continued on tocilizumab, the median length of treatment was 26.0 months (range, 3-76.5 months).

 

Comments on the Study

The study population had some unusual characteristics, according to G-CAN President Robert Terkeltaub, MD, who was asked to comment on the study. “Almost half the patients had received anakinra and then, basically, they failed. In about half of the people who got anakinra, it didn’t work, and in the other half, it wasn’t well tolerated. It’s just rather odd. I find anakinra reasonably well tolerated by people, but we’re dealing with an older population of patients, and the subcutaneous administration of anakinra sometimes can give you injection site reactions, but people started off with a pain level that was close to what we register as severe pain, and the pain level decreased,” he said.

Treatment decisions can be difficult in patients with chronic or acute recurrent CPPD, said Terkeltaub, professor of medicine at the University of California, San Diego. “What’s the lesser evil? Putting people on chronic prednisone is really hard on patients or using a biologic that’s more of an immunologic scalpel here, and more selective, and trying to get people through a long course of therapy. If you have chronic arthritis, it took a while for it to get chronic, and it generally doesn’t go away overnight.”

Terkeltaub also pointed out the gastrointestinal side effects of IL-6r inhibitors, which can include diverticulitis, but there are also concerns over infections and lipid and liver abnormalities. Subcutaneously injected tocilizumab also has a longer half-life than something like anakinra.

Beyond the retrospective nature of the study and the limits it imposes on conclusions that can be drawn, Terkeltaub noted a lack of data on the number of “inflamed joints [in each patient] and what the functioning of the patients was.”

Still, the findings are encouraging. “What I can glean from this study is that the first biologic drug might be an IL-6 inhibitor, but you really need prospective, controlled, blinded clinical trials to know, and it’s hard. It’s just hard to do those trials” because patients tend to be of advanced age, Terkeltaub said.

Latourte said a randomized controlled trial of tocilizumab vs placebo, called TociCCAre, is planned to begin in France in 2025.

Latourte has financial relationships with Fresenius Kabi, Roche Chugai, AbbVie, Arsylab, Celltrion, Janssen, Nordic, Pfizer, UCB, Amgen, Biogen, Galapagos, and Eli Lilly. Terkeltaub had no relevant financial disclosures.

A version of this article appeared on Medscape.com.

XEN-D0501, a transient receptor potential vanilloid 1 (TRPV1) antagonist, is gaining attention for its potential as an oral tablet to treat type 2 diabetes, obesity, and cardiovascular diseases. Dorte X. Gram, PhD, founder of Pila Pharma, a Swedish pharmaceutical company investigating XEN-D0501, first noticed the connection more than 20 years ago as a researcher at Novo Nordisk. 

“In my very first experiments, I noticed that mice who would normally become diabetic didn’t get diabetes at all,” she said in an interview.

These surprising observations prompted Gram to investigate further the potential role of the TRPV1 receptor in regulating metabolism, leading her to file a patent and pursue the development of TRPV1 antagonists for obesity and related conditions. 

The company has received enough attention from investors that it witnessed a triple-digit percentage gain on the Nasdaq First North stock exchange in 2024.

While XEN-D0501 shows promise, researchers urge caution, as the drug is still in early development. “There is simply no quality human data to say anything about the possibilities for this pathway,” said John B. Dixon, PhD, professor at Iverson Health Innovation Research Institute, Swinburne University of Technology, Melbourne, Australia.

 

What Is TRPV1 and How Do TRPV1 Modulators Work? 

TRPV1 is a homotetrameric receptor with six transmembrane domains expressed primarily in sensory nerve fibers. It is responsible for detecting noxious signals, including heat and chemical irritants — particularly capsaicin, the active component of chili peppers.

TRPV1 mediates the sensation of burning pain, often associated with inflammation and heat exposure. It also helps detect and regulate body temperature and influences the release of inflammatory mediators. In the central nervous system, it affects synaptic function and plasticity.

Given TRPV1’s broad physiologic role, its modulation has potential for treating several conditions, including pain disorders, inflammation, and cardiovascular diseases. 

Studies have shown that activating TRPV1 can help counter diet-induced obesity by increasing thermogenesis in brown adipose tissue and improving metabolic activity. TRPV1 agonists such as capsaicin have been shown to reduce weight gain in high-fat-diet‒induced obese mice, with clinical trials further supporting its potential for decreasing body weight in people with overweight. 

For instance, a clinical trial showed that participants with obesity taking capsinoid supplementation for 12 weeks experienced a reduction in body weight compared with those who took a placebo. 

While TRPV1 agonists have been more commonly studied for obesity management, most studies involving antagonists have focused on pain relief, inflammation, and conditions like erythromelalgia rather than weight loss. 

However, some evidence suggests that TRPV1 antagonism may influence metabolism. For example, in one study, mice lacking TRPV1 were resistant to obesity, “but that is not sufficient [to come to any conclusion],” said Vincenzo Di Marzo, PhD, director of the Joint International Research Unit for the Chemical and Biomolecular Study of the Microbiome in Metabolic Health and Nutrition between the Consiglio Nazionale delle Ricerche, Italy, and Université Laval, Quebec City, Canada. He was not involved in the study.

Gram admits that the picture around the mechanism of action of TRPV1 modulators is unclear. “There is not a consensus in the literature about the effect of this receptor. Should it be agonized or should it be antagonized?” she said. 

 

What Is XEN-D0501?

XEN-D0501 is a novel selective TRPV1 antagonist, which Pila Pharma is developing for treating erythromelalgia, a rare condition that causes burning pain, redness, and hotness in the skin, especially the feet. It has received orphan-drug status for this indication in the United States. 

Initially, the company explored XEN-D0501 for treating overactive bladder, but the development of the drug for this condition has been discontinued. Now, attention has moved to investigating XEN-D0501 for its potential in treating type 2 diabetes, obesity, and cardiovascular disease.

Although phase 2a clinical trials showed that XEN-D0501 is generally well tolerated in healthy participants, it has been associated with several side effects, including hyperthermia and oral discomfort, thought to be due to TRPV1 antagonism at sensory nerve endings in the mouth, in addition to transient urinary retention and postvoiding residual volumes, indicating potential issues with bladder function.

Another phase 2a trial (PP-CT03) is planned to assess the maximum tolerable dose of XEN-D0501 in people with obesity and type 2 diabetes, focusing on safety and potential effects on body weight. Gram said that early data show these populations experience less hyperthermia than healthy participants. However, the mechanism behind it is still not understood. These studies also showed some positive effects on insulin sensitivity and a biomarker for heart failure.

“The company data provided so far for XEN-D0501 are promising but still too preliminary,” said Di Marzo.

The company is now planning a further 3-month-long dose-escalation study in people with obesity and diabetes. “If these studies show that the molecule is as efficacious and safe as we think it is, then it would make life a lot better for a lot of people because it is a tablet, not an injectable,” Gram said.

Also being explored by the company is the potential of the molecule for treating cardiovascular diseases, particularly abdominal aortic aneurysms, and as a potential nonopioid painkiller. 

Dixon and Di Marzo disclosed no relevant financial relationships. Gram is founder and CSO at Pila Pharma.

A version of this article appeared on Medscape.com.

XEN-D0501, a transient receptor potential vanilloid 1 (TRPV1) antagonist, is gaining attention for its potential as an oral tablet to treat type 2 diabetes, obesity, and cardiovascular diseases. Dorte X. Gram, PhD, founder of Pila Pharma, a Swedish pharmaceutical company investigating XEN-D0501, first noticed the connection more than 20 years ago as a researcher at Novo Nordisk. 

“In my very first experiments, I noticed that mice who would normally become diabetic didn’t get diabetes at all,” she said in an interview.

These surprising observations prompted Gram to investigate further the potential role of the TRPV1 receptor in regulating metabolism, leading her to file a patent and pursue the development of TRPV1 antagonists for obesity and related conditions. 

The company has received enough attention from investors that it witnessed a triple-digit percentage gain on the Nasdaq First North stock exchange in 2024.

While XEN-D0501 shows promise, researchers urge caution, as the drug is still in early development. “There is simply no quality human data to say anything about the possibilities for this pathway,” said John B. Dixon, PhD, professor at Iverson Health Innovation Research Institute, Swinburne University of Technology, Melbourne, Australia.

 

What Is TRPV1 and How Do TRPV1 Modulators Work? 

TRPV1 is a homotetrameric receptor with six transmembrane domains expressed primarily in sensory nerve fibers. It is responsible for detecting noxious signals, including heat and chemical irritants — particularly capsaicin, the active component of chili peppers.

TRPV1 mediates the sensation of burning pain, often associated with inflammation and heat exposure. It also helps detect and regulate body temperature and influences the release of inflammatory mediators. In the central nervous system, it affects synaptic function and plasticity.

Given TRPV1’s broad physiologic role, its modulation has potential for treating several conditions, including pain disorders, inflammation, and cardiovascular diseases. 

Studies have shown that activating TRPV1 can help counter diet-induced obesity by increasing thermogenesis in brown adipose tissue and improving metabolic activity. TRPV1 agonists such as capsaicin have been shown to reduce weight gain in high-fat-diet‒induced obese mice, with clinical trials further supporting its potential for decreasing body weight in people with overweight. 

For instance, a clinical trial showed that participants with obesity taking capsinoid supplementation for 12 weeks experienced a reduction in body weight compared with those who took a placebo. 

While TRPV1 agonists have been more commonly studied for obesity management, most studies involving antagonists have focused on pain relief, inflammation, and conditions like erythromelalgia rather than weight loss. 

However, some evidence suggests that TRPV1 antagonism may influence metabolism. For example, in one study, mice lacking TRPV1 were resistant to obesity, “but that is not sufficient [to come to any conclusion],” said Vincenzo Di Marzo, PhD, director of the Joint International Research Unit for the Chemical and Biomolecular Study of the Microbiome in Metabolic Health and Nutrition between the Consiglio Nazionale delle Ricerche, Italy, and Université Laval, Quebec City, Canada. He was not involved in the study.

Gram admits that the picture around the mechanism of action of TRPV1 modulators is unclear. “There is not a consensus in the literature about the effect of this receptor. Should it be agonized or should it be antagonized?” she said. 

 

What Is XEN-D0501?

XEN-D0501 is a novel selective TRPV1 antagonist, which Pila Pharma is developing for treating erythromelalgia, a rare condition that causes burning pain, redness, and hotness in the skin, especially the feet. It has received orphan-drug status for this indication in the United States. 

Initially, the company explored XEN-D0501 for treating overactive bladder, but the development of the drug for this condition has been discontinued. Now, attention has moved to investigating XEN-D0501 for its potential in treating type 2 diabetes, obesity, and cardiovascular disease.

Although phase 2a clinical trials showed that XEN-D0501 is generally well tolerated in healthy participants, it has been associated with several side effects, including hyperthermia and oral discomfort, thought to be due to TRPV1 antagonism at sensory nerve endings in the mouth, in addition to transient urinary retention and postvoiding residual volumes, indicating potential issues with bladder function.

Another phase 2a trial (PP-CT03) is planned to assess the maximum tolerable dose of XEN-D0501 in people with obesity and type 2 diabetes, focusing on safety and potential effects on body weight. Gram said that early data show these populations experience less hyperthermia than healthy participants. However, the mechanism behind it is still not understood. These studies also showed some positive effects on insulin sensitivity and a biomarker for heart failure.

“The company data provided so far for XEN-D0501 are promising but still too preliminary,” said Di Marzo.

The company is now planning a further 3-month-long dose-escalation study in people with obesity and diabetes. “If these studies show that the molecule is as efficacious and safe as we think it is, then it would make life a lot better for a lot of people because it is a tablet, not an injectable,” Gram said.

Also being explored by the company is the potential of the molecule for treating cardiovascular diseases, particularly abdominal aortic aneurysms, and as a potential nonopioid painkiller. 

Dixon and Di Marzo disclosed no relevant financial relationships. Gram is founder and CSO at Pila Pharma.

A version of this article appeared on Medscape.com.

XEN-D0501, a transient receptor potential vanilloid 1 (TRPV1) antagonist, is gaining attention for its potential as an oral tablet to treat type 2 diabetes, obesity, and cardiovascular diseases. Dorte X. Gram, PhD, founder of Pila Pharma, a Swedish pharmaceutical company investigating XEN-D0501, first noticed the connection more than 20 years ago as a researcher at Novo Nordisk. 

“In my very first experiments, I noticed that mice who would normally become diabetic didn’t get diabetes at all,” she said in an interview.

These surprising observations prompted Gram to investigate further the potential role of the TRPV1 receptor in regulating metabolism, leading her to file a patent and pursue the development of TRPV1 antagonists for obesity and related conditions. 

The company has received enough attention from investors that it witnessed a triple-digit percentage gain on the Nasdaq First North stock exchange in 2024.

While XEN-D0501 shows promise, researchers urge caution, as the drug is still in early development. “There is simply no quality human data to say anything about the possibilities for this pathway,” said John B. Dixon, PhD, professor at Iverson Health Innovation Research Institute, Swinburne University of Technology, Melbourne, Australia.

 

What Is TRPV1 and How Do TRPV1 Modulators Work? 

TRPV1 is a homotetrameric receptor with six transmembrane domains expressed primarily in sensory nerve fibers. It is responsible for detecting noxious signals, including heat and chemical irritants — particularly capsaicin, the active component of chili peppers.

TRPV1 mediates the sensation of burning pain, often associated with inflammation and heat exposure. It also helps detect and regulate body temperature and influences the release of inflammatory mediators. In the central nervous system, it affects synaptic function and plasticity.

Given TRPV1’s broad physiologic role, its modulation has potential for treating several conditions, including pain disorders, inflammation, and cardiovascular diseases. 

Studies have shown that activating TRPV1 can help counter diet-induced obesity by increasing thermogenesis in brown adipose tissue and improving metabolic activity. TRPV1 agonists such as capsaicin have been shown to reduce weight gain in high-fat-diet‒induced obese mice, with clinical trials further supporting its potential for decreasing body weight in people with overweight. 

For instance, a clinical trial showed that participants with obesity taking capsinoid supplementation for 12 weeks experienced a reduction in body weight compared with those who took a placebo. 

While TRPV1 agonists have been more commonly studied for obesity management, most studies involving antagonists have focused on pain relief, inflammation, and conditions like erythromelalgia rather than weight loss. 

However, some evidence suggests that TRPV1 antagonism may influence metabolism. For example, in one study, mice lacking TRPV1 were resistant to obesity, “but that is not sufficient [to come to any conclusion],” said Vincenzo Di Marzo, PhD, director of the Joint International Research Unit for the Chemical and Biomolecular Study of the Microbiome in Metabolic Health and Nutrition between the Consiglio Nazionale delle Ricerche, Italy, and Université Laval, Quebec City, Canada. He was not involved in the study.

Gram admits that the picture around the mechanism of action of TRPV1 modulators is unclear. “There is not a consensus in the literature about the effect of this receptor. Should it be agonized or should it be antagonized?” she said. 

 

What Is XEN-D0501?

XEN-D0501 is a novel selective TRPV1 antagonist, which Pila Pharma is developing for treating erythromelalgia, a rare condition that causes burning pain, redness, and hotness in the skin, especially the feet. It has received orphan-drug status for this indication in the United States. 

Initially, the company explored XEN-D0501 for treating overactive bladder, but the development of the drug for this condition has been discontinued. Now, attention has moved to investigating XEN-D0501 for its potential in treating type 2 diabetes, obesity, and cardiovascular disease.

Although phase 2a clinical trials showed that XEN-D0501 is generally well tolerated in healthy participants, it has been associated with several side effects, including hyperthermia and oral discomfort, thought to be due to TRPV1 antagonism at sensory nerve endings in the mouth, in addition to transient urinary retention and postvoiding residual volumes, indicating potential issues with bladder function.

Another phase 2a trial (PP-CT03) is planned to assess the maximum tolerable dose of XEN-D0501 in people with obesity and type 2 diabetes, focusing on safety and potential effects on body weight. Gram said that early data show these populations experience less hyperthermia than healthy participants. However, the mechanism behind it is still not understood. These studies also showed some positive effects on insulin sensitivity and a biomarker for heart failure.

“The company data provided so far for XEN-D0501 are promising but still too preliminary,” said Di Marzo.

The company is now planning a further 3-month-long dose-escalation study in people with obesity and diabetes. “If these studies show that the molecule is as efficacious and safe as we think it is, then it would make life a lot better for a lot of people because it is a tablet, not an injectable,” Gram said.

Also being explored by the company is the potential of the molecule for treating cardiovascular diseases, particularly abdominal aortic aneurysms, and as a potential nonopioid painkiller. 

Dixon and Di Marzo disclosed no relevant financial relationships. Gram is founder and CSO at Pila Pharma.

A version of this article appeared on Medscape.com.