Miriam E. Tucker

A Lancet Commission has redefined obesity by classifying it as either “clinical obesity,” a disease, or “preclinical,” a health risk factor, with the distinction based on factors beyond body mass index (BMI).

“We propose a radical overhaul of the actual diagnosis of obesity to improve global healthcare and practices and policies. The specific aims were to facilitate individualized assessment and care of people living with obesity while preserving resources by reducing overdiagnosis and unnecessary or inadequate interventions,” Professor Louise Baur, chair of Child & Adolescent Health at the University of Sydney, Australia, said during a UK Science Media Centre (SMC) news briefing.

The report calls first for a diagnosis of obesity via confirmation of excess adiposity using measures such as waist circumference or waist-to-hip ratio in addition to BMI. Next, a clinical assessment of signs and symptoms of organ dysfunction due to obesity and/or functional limitations determines whether the individual has the disease “clinical obesity,” or “preclinical obesity,” a condition of health risk but not an illness itself.

Published on January 14, 2025, in The Lancet Diabetes & Endocrinology, the document also provides broad guidance on management for the two obesity conditions, emphasizing a personalized and stigma-free approach. The Lancet Commission on Obesity comprised 56 experts in relevant fields including endocrinology, surgery, nutrition, and public health, along with people living with obesity.

The report has been endorsed by more than 75 medical organizations, including the Association of British Clinical Diabetologists, the American Association of Clinical Endocrinologists, the American Diabetes Association, the American Heart Association, the Obesity Society, the World Obesity Federation, and obesity and endocrinology societies from countries in Europe, Latin America, Asia, and South Africa.

In recent years, many in the field have found fault with the current BMI-based definition of obesity (> 30 for people of European descent or other cutoffs for specific ethnic groups), primarily because BMI alone doesn’t reflect a person’s fat vs lean mass, fat distribution, or overall health. The new definition aims to overcome these limitations, as well as settle the debate about whether obesity is a “disease.”

“We now have a clinical diagnosis for obesity, which has been lacking. ... The traditional classification based on BMI ... reflects simply whether or not there is excess adiposity, and sometimes not even precise in that regard, either…It has never been a classification that was meant to diagnose a specific illness with its own clinical characteristics in the same way we diagnose any other illness,” Commission Chair Francesco Rubino, MD, professor and chair of Metabolic and Bariatric Surgery at King’s College London, England, said in an interview.

He added, “The fact that now we have a clinical diagnosis allows recognition of the nuance that obesity is generally a risk and for some can be an illness. There are some who have risk but don’t have the illness here and now. And it’s crucially important for clinical decision-making, but also for policies to have a distinction between those two things because the treatment strategy for one and the other are substantially different.”

Asked to comment, obesity specialist Michael A. Weintraub, MD, clinical assistant professor of endocrinology at New York University Langone Health, said in an interview, “I wholeheartedly agree with modifying the definition of obesity in this more accurate way. ... There has already been a lot of talk about the fallibility of BMI and that BMI over 30 does not equal obesity. ... So a major Commission article like this I think can really move those discussions even more into the forefront and start changing practice.” 

However, Weintraub added, “I think there needs to be another step here of more practical guidance on how to actually implement this ... including how to measure waist circumference and to put it into a patient flow.” 

Asked to comment, obesity expert Luca Busetto, MD, associate professor of internal medicine at the Department of Medicine of the University of Padova, Italy, said in an interview that he agrees with the general concept of moving beyond BMI in defining obesity. That view was expressed in a proposed “framework” from the European Association for the Study of Obesity (EASO), for which Busetto was the lead author.

Busetto also agrees with the emphasis on the need for a complete clinical evaluation of patients to define their health status. “The precise definition of the symptoms defining clinical obesity in adults and children is extremely important, emphasizing the fact that obesity is a severe and disabling disease by itself, even without or before the occurrence of obesity-related complications,” he said.

However, he takes issue with the Commission’s designation that “preclinical” obesity is not a disease. “The critical point of disagreement for me is the message that obesity is a disease only if it is clinical or only if it presents functional impairment or clinical symptoms. This remains, in my opinion, an oversimplification, not taking into account the fact that the pathophysiological mechanisms that lead to fat accumulation and ‘adipose tissue-based chronic disease’ usually start well before the occurrence of symptoms.”

Busetto pointed to examples such as type 2 diabetes and chronic kidney disease, both of which can be asymptomatic in their early phases yet are still considered diseases at those points. “I have no problem in accepting a distinction between preclinical and clinical stages of the disease, and I like the definition of clinical obesity, but why should this imply the fact that obesity is NOT a disease since its beginning?”

The Commission does state that preclinical obesity should be addressed, mostly with preventive approaches but in some cases with more intensive management. “This is highly relevant, but the risk of an undertreatment of obesity in its asymptomatic state remains in place. This could delay appropriate management for a progressive disease that certainly should not be treated only when presenting symptoms. It would be too late,” Busetto said.

And EASO framework coauthor Gijs Goossens, PhD, professor of cardiometabolic physiology of obesity at Maastricht University Medical Centre, the Netherlands, added a concern that those with excess adiposity but lower BMI might be missed entirely, noting “Since abdominal fat accumulation better predicts chronic cardiometabolic diseases and can also be accompanied by clinical manifestations in individuals with overweight as a consequence of compromised adipose tissue function, the proposed model may lead to underdiagnosis or undertreatment in individuals with BMI 25-30 who have excess abdominal fat.”

 

Diagnosis and Management Beyond BMI

The Commission advises the use of BMI solely as a marker to screen for potential obesity. Those with a BMI > 40 can be assumed to have excess body fat. For others with a BMI at or near the threshold for obesity in a specific country or ethnic group or for whom there is the clinical judgment of the potential for clinical obesity, confirmation of excess or abnormal adiposity is needed by one of the following:

• At least one measurement of body size and BMI
• At least two measures of body size, regardless of BMI
• Direct body fat measurement, such as a dual-energy x-ray absorptiometry (DEXA) scan

Measurement of body size can be assessed in three ways: 

• Waist circumference ≥ 102 cm for men and ≥ 88 cm for women
• Waist-to-hip ratio > 0.90 for men and > 0.50 for women
• Waist-to-height ratio > 0.50 for all.

Weintraub noted, “Telemedicine is a useful tool used by many patients and providers but may also make it challenging to accurately assess someone’s body size. Having technology like an iPhone app to measure body size would circumvent this challenge but this type of tool has not yet been validated.” 

If the person does not have excess adiposity, they don’t have obesity. Those with excess adiposity do have obesity. Further assessment is then needed to establish whether the person has an illness, that is, clinical obesity, indicated by signs/symptoms of organ dysfunction, and/or limitations of daily activities. If not, they have “preclinical” obesity.

The document provides a list of 18 obesity-related organ, tissue, and body system criteria for diagnosing “clinical” obesity in adults, including upper airways (eg, apneas/hypopneas), respiratory (breathlessness), cardiovascular (hypertension, heart failure), liver (fatty liver disease with hepatic fibrosis), reproductive (polycystic ovary syndrome, hypogonadism), and metabolism (hyperglycemia, hypertriglyceridemia, low high-density lipoprotein cholesterol). A list of 13 such criteria is also provided for children. “Limitations of day-to-day activities” are included on both lists.

 

Management Differs by Designation

For preclinical obesity, management should focus on risk reduction and prevention of progression to clinical obesity or other obesity-related diseases. Such approaches include health counseling for weight loss or prevention of weight gain, monitoring over time, and active weight loss interventions in people at higher risk of developing clinical obesity and other obesity-related diseases.

Management for clinical obesity focuses on improvements or reversal of the organ dysfunction. The type of evidence-based treatment and management should be informed by individual risk-benefit assessments and decided via “active discussion” with the patient. Success is determined by improvement in the signs and symptoms rather than measures of weight loss.

In response to a reporter’s question at the SMC briefing about the implications for the use of weight-loss medications, Rubino noted that this wasn’t the focus of the report, but nonetheless said that this new obesity definition could help with their targeted use. “The strategy and intent by which you use the drugs is different in clinical and preclinical obesity. ... Pharmacological interventions could be used for patients with high-risk preclinical obesity, with the intent of reducing risk, but we ... would use the same medication at a different intensity, dose, and maybe in combination therapies.”

As for clinical obesity, “It could be more or less severe and could affect more than one organ, and so clinical obesity might require drugs, might require surgery, or may require, in some cases, a combination of both of them, to achieve the best possible outcomes. ... We want to make sure that the person is restoring health ... with whatever it takes.”

Rubino believes this new definition will convince the remaining clinicians who haven’t yet accepted the concept of obesity as a disease. “When they see clinical obesity, I think it will be much harder to say that a biological process that is capable of causing a dysfunction in the heart or the lungs is less of a disease than another biological process that causes similar dysfunction in the heart of the lungs. ... It’s going to be objective. Obesity is a spectrum of different situations. ... When it’s an illness, clinical obesity, it’s not a matter of if or when. It’s a matter of fact.”

There were no industrial grants or other funding for this initiative. King’s Health Partners hosted the initiative and provided logistical and personnel support to facilitate administrative work and the Delphi-like consensus-development process. Rubino declared receiving research grants from Ethicon (Johnson & Johnson), Novo Nordisk, and Medtronic; consulting fees from Morphic Medical; speaking honoraria from Medtronic, Ethicon, Novo Nordisk, Eli Lilly, and Amgen. Rubino has served (unpaid) as a member of the scientific advisory board for Keyron and a member of the data safety and monitoring board for GI Metabolic Solutions; is president of the Metabolic Health Institute (non-profit); and is the sole director of Metabolic Health International and London Metabolic and Bariatric Surgery (private practice). Baur declared serving on the scientific advisory board for Novo Nordisk (for the ACTION Teens study) and Eli Lilly and receiving speaker fees (paid to the institution) from Novo Nordisk.

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

A Lancet Commission has redefined obesity by classifying it as either “clinical obesity,” a disease, or “preclinical,” a health risk factor, with the distinction based on factors beyond body mass index (BMI).

“We propose a radical overhaul of the actual diagnosis of obesity to improve global healthcare and practices and policies. The specific aims were to facilitate individualized assessment and care of people living with obesity while preserving resources by reducing overdiagnosis and unnecessary or inadequate interventions,” Professor Louise Baur, chair of Child & Adolescent Health at the University of Sydney, Australia, said during a UK Science Media Centre (SMC) news briefing.

The report calls first for a diagnosis of obesity via confirmation of excess adiposity using measures such as waist circumference or waist-to-hip ratio in addition to BMI. Next, a clinical assessment of signs and symptoms of organ dysfunction due to obesity and/or functional limitations determines whether the individual has the disease “clinical obesity,” or “preclinical obesity,” a condition of health risk but not an illness itself.

Published on January 14, 2025, in The Lancet Diabetes & Endocrinology, the document also provides broad guidance on management for the two obesity conditions, emphasizing a personalized and stigma-free approach. The Lancet Commission on Obesity comprised 56 experts in relevant fields including endocrinology, surgery, nutrition, and public health, along with people living with obesity.

The report has been endorsed by more than 75 medical organizations, including the Association of British Clinical Diabetologists, the American Association of Clinical Endocrinologists, the American Diabetes Association, the American Heart Association, the Obesity Society, the World Obesity Federation, and obesity and endocrinology societies from countries in Europe, Latin America, Asia, and South Africa.

In recent years, many in the field have found fault with the current BMI-based definition of obesity (> 30 for people of European descent or other cutoffs for specific ethnic groups), primarily because BMI alone doesn’t reflect a person’s fat vs lean mass, fat distribution, or overall health. The new definition aims to overcome these limitations, as well as settle the debate about whether obesity is a “disease.”

“We now have a clinical diagnosis for obesity, which has been lacking. ... The traditional classification based on BMI ... reflects simply whether or not there is excess adiposity, and sometimes not even precise in that regard, either…It has never been a classification that was meant to diagnose a specific illness with its own clinical characteristics in the same way we diagnose any other illness,” Commission Chair Francesco Rubino, MD, professor and chair of Metabolic and Bariatric Surgery at King’s College London, England, said in an interview.

He added, “The fact that now we have a clinical diagnosis allows recognition of the nuance that obesity is generally a risk and for some can be an illness. There are some who have risk but don’t have the illness here and now. And it’s crucially important for clinical decision-making, but also for policies to have a distinction between those two things because the treatment strategy for one and the other are substantially different.”

Asked to comment, obesity specialist Michael A. Weintraub, MD, clinical assistant professor of endocrinology at New York University Langone Health, said in an interview, “I wholeheartedly agree with modifying the definition of obesity in this more accurate way. ... There has already been a lot of talk about the fallibility of BMI and that BMI over 30 does not equal obesity. ... So a major Commission article like this I think can really move those discussions even more into the forefront and start changing practice.” 

However, Weintraub added, “I think there needs to be another step here of more practical guidance on how to actually implement this ... including how to measure waist circumference and to put it into a patient flow.” 

Asked to comment, obesity expert Luca Busetto, MD, associate professor of internal medicine at the Department of Medicine of the University of Padova, Italy, said in an interview that he agrees with the general concept of moving beyond BMI in defining obesity. That view was expressed in a proposed “framework” from the European Association for the Study of Obesity (EASO), for which Busetto was the lead author.

Busetto also agrees with the emphasis on the need for a complete clinical evaluation of patients to define their health status. “The precise definition of the symptoms defining clinical obesity in adults and children is extremely important, emphasizing the fact that obesity is a severe and disabling disease by itself, even without or before the occurrence of obesity-related complications,” he said.

However, he takes issue with the Commission’s designation that “preclinical” obesity is not a disease. “The critical point of disagreement for me is the message that obesity is a disease only if it is clinical or only if it presents functional impairment or clinical symptoms. This remains, in my opinion, an oversimplification, not taking into account the fact that the pathophysiological mechanisms that lead to fat accumulation and ‘adipose tissue-based chronic disease’ usually start well before the occurrence of symptoms.”

Busetto pointed to examples such as type 2 diabetes and chronic kidney disease, both of which can be asymptomatic in their early phases yet are still considered diseases at those points. “I have no problem in accepting a distinction between preclinical and clinical stages of the disease, and I like the definition of clinical obesity, but why should this imply the fact that obesity is NOT a disease since its beginning?”

The Commission does state that preclinical obesity should be addressed, mostly with preventive approaches but in some cases with more intensive management. “This is highly relevant, but the risk of an undertreatment of obesity in its asymptomatic state remains in place. This could delay appropriate management for a progressive disease that certainly should not be treated only when presenting symptoms. It would be too late,” Busetto said.

And EASO framework coauthor Gijs Goossens, PhD, professor of cardiometabolic physiology of obesity at Maastricht University Medical Centre, the Netherlands, added a concern that those with excess adiposity but lower BMI might be missed entirely, noting “Since abdominal fat accumulation better predicts chronic cardiometabolic diseases and can also be accompanied by clinical manifestations in individuals with overweight as a consequence of compromised adipose tissue function, the proposed model may lead to underdiagnosis or undertreatment in individuals with BMI 25-30 who have excess abdominal fat.”

 

Diagnosis and Management Beyond BMI

The Commission advises the use of BMI solely as a marker to screen for potential obesity. Those with a BMI > 40 can be assumed to have excess body fat. For others with a BMI at or near the threshold for obesity in a specific country or ethnic group or for whom there is the clinical judgment of the potential for clinical obesity, confirmation of excess or abnormal adiposity is needed by one of the following:

• At least one measurement of body size and BMI
• At least two measures of body size, regardless of BMI
• Direct body fat measurement, such as a dual-energy x-ray absorptiometry (DEXA) scan

Measurement of body size can be assessed in three ways: 

• Waist circumference ≥ 102 cm for men and ≥ 88 cm for women
• Waist-to-hip ratio > 0.90 for men and > 0.50 for women
• Waist-to-height ratio > 0.50 for all.

Weintraub noted, “Telemedicine is a useful tool used by many patients and providers but may also make it challenging to accurately assess someone’s body size. Having technology like an iPhone app to measure body size would circumvent this challenge but this type of tool has not yet been validated.” 

If the person does not have excess adiposity, they don’t have obesity. Those with excess adiposity do have obesity. Further assessment is then needed to establish whether the person has an illness, that is, clinical obesity, indicated by signs/symptoms of organ dysfunction, and/or limitations of daily activities. If not, they have “preclinical” obesity.

The document provides a list of 18 obesity-related organ, tissue, and body system criteria for diagnosing “clinical” obesity in adults, including upper airways (eg, apneas/hypopneas), respiratory (breathlessness), cardiovascular (hypertension, heart failure), liver (fatty liver disease with hepatic fibrosis), reproductive (polycystic ovary syndrome, hypogonadism), and metabolism (hyperglycemia, hypertriglyceridemia, low high-density lipoprotein cholesterol). A list of 13 such criteria is also provided for children. “Limitations of day-to-day activities” are included on both lists.

 

Management Differs by Designation

For preclinical obesity, management should focus on risk reduction and prevention of progression to clinical obesity or other obesity-related diseases. Such approaches include health counseling for weight loss or prevention of weight gain, monitoring over time, and active weight loss interventions in people at higher risk of developing clinical obesity and other obesity-related diseases.

Management for clinical obesity focuses on improvements or reversal of the organ dysfunction. The type of evidence-based treatment and management should be informed by individual risk-benefit assessments and decided via “active discussion” with the patient. Success is determined by improvement in the signs and symptoms rather than measures of weight loss.

In response to a reporter’s question at the SMC briefing about the implications for the use of weight-loss medications, Rubino noted that this wasn’t the focus of the report, but nonetheless said that this new obesity definition could help with their targeted use. “The strategy and intent by which you use the drugs is different in clinical and preclinical obesity. ... Pharmacological interventions could be used for patients with high-risk preclinical obesity, with the intent of reducing risk, but we ... would use the same medication at a different intensity, dose, and maybe in combination therapies.”

As for clinical obesity, “It could be more or less severe and could affect more than one organ, and so clinical obesity might require drugs, might require surgery, or may require, in some cases, a combination of both of them, to achieve the best possible outcomes. ... We want to make sure that the person is restoring health ... with whatever it takes.”

Rubino believes this new definition will convince the remaining clinicians who haven’t yet accepted the concept of obesity as a disease. “When they see clinical obesity, I think it will be much harder to say that a biological process that is capable of causing a dysfunction in the heart or the lungs is less of a disease than another biological process that causes similar dysfunction in the heart of the lungs. ... It’s going to be objective. Obesity is a spectrum of different situations. ... When it’s an illness, clinical obesity, it’s not a matter of if or when. It’s a matter of fact.”

There were no industrial grants or other funding for this initiative. King’s Health Partners hosted the initiative and provided logistical and personnel support to facilitate administrative work and the Delphi-like consensus-development process. Rubino declared receiving research grants from Ethicon (Johnson & Johnson), Novo Nordisk, and Medtronic; consulting fees from Morphic Medical; speaking honoraria from Medtronic, Ethicon, Novo Nordisk, Eli Lilly, and Amgen. Rubino has served (unpaid) as a member of the scientific advisory board for Keyron and a member of the data safety and monitoring board for GI Metabolic Solutions; is president of the Metabolic Health Institute (non-profit); and is the sole director of Metabolic Health International and London Metabolic and Bariatric Surgery (private practice). Baur declared serving on the scientific advisory board for Novo Nordisk (for the ACTION Teens study) and Eli Lilly and receiving speaker fees (paid to the institution) from Novo Nordisk.

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

A Lancet Commission has redefined obesity by classifying it as either “clinical obesity,” a disease, or “preclinical,” a health risk factor, with the distinction based on factors beyond body mass index (BMI).

“We propose a radical overhaul of the actual diagnosis of obesity to improve global healthcare and practices and policies. The specific aims were to facilitate individualized assessment and care of people living with obesity while preserving resources by reducing overdiagnosis and unnecessary or inadequate interventions,” Professor Louise Baur, chair of Child & Adolescent Health at the University of Sydney, Australia, said during a UK Science Media Centre (SMC) news briefing.

The report calls first for a diagnosis of obesity via confirmation of excess adiposity using measures such as waist circumference or waist-to-hip ratio in addition to BMI. Next, a clinical assessment of signs and symptoms of organ dysfunction due to obesity and/or functional limitations determines whether the individual has the disease “clinical obesity,” or “preclinical obesity,” a condition of health risk but not an illness itself.

Published on January 14, 2025, in The Lancet Diabetes & Endocrinology, the document also provides broad guidance on management for the two obesity conditions, emphasizing a personalized and stigma-free approach. The Lancet Commission on Obesity comprised 56 experts in relevant fields including endocrinology, surgery, nutrition, and public health, along with people living with obesity.

The report has been endorsed by more than 75 medical organizations, including the Association of British Clinical Diabetologists, the American Association of Clinical Endocrinologists, the American Diabetes Association, the American Heart Association, the Obesity Society, the World Obesity Federation, and obesity and endocrinology societies from countries in Europe, Latin America, Asia, and South Africa.

In recent years, many in the field have found fault with the current BMI-based definition of obesity (> 30 for people of European descent or other cutoffs for specific ethnic groups), primarily because BMI alone doesn’t reflect a person’s fat vs lean mass, fat distribution, or overall health. The new definition aims to overcome these limitations, as well as settle the debate about whether obesity is a “disease.”

“We now have a clinical diagnosis for obesity, which has been lacking. ... The traditional classification based on BMI ... reflects simply whether or not there is excess adiposity, and sometimes not even precise in that regard, either…It has never been a classification that was meant to diagnose a specific illness with its own clinical characteristics in the same way we diagnose any other illness,” Commission Chair Francesco Rubino, MD, professor and chair of Metabolic and Bariatric Surgery at King’s College London, England, said in an interview.

He added, “The fact that now we have a clinical diagnosis allows recognition of the nuance that obesity is generally a risk and for some can be an illness. There are some who have risk but don’t have the illness here and now. And it’s crucially important for clinical decision-making, but also for policies to have a distinction between those two things because the treatment strategy for one and the other are substantially different.”

Asked to comment, obesity specialist Michael A. Weintraub, MD, clinical assistant professor of endocrinology at New York University Langone Health, said in an interview, “I wholeheartedly agree with modifying the definition of obesity in this more accurate way. ... There has already been a lot of talk about the fallibility of BMI and that BMI over 30 does not equal obesity. ... So a major Commission article like this I think can really move those discussions even more into the forefront and start changing practice.” 

However, Weintraub added, “I think there needs to be another step here of more practical guidance on how to actually implement this ... including how to measure waist circumference and to put it into a patient flow.” 

Asked to comment, obesity expert Luca Busetto, MD, associate professor of internal medicine at the Department of Medicine of the University of Padova, Italy, said in an interview that he agrees with the general concept of moving beyond BMI in defining obesity. That view was expressed in a proposed “framework” from the European Association for the Study of Obesity (EASO), for which Busetto was the lead author.

Busetto also agrees with the emphasis on the need for a complete clinical evaluation of patients to define their health status. “The precise definition of the symptoms defining clinical obesity in adults and children is extremely important, emphasizing the fact that obesity is a severe and disabling disease by itself, even without or before the occurrence of obesity-related complications,” he said.

However, he takes issue with the Commission’s designation that “preclinical” obesity is not a disease. “The critical point of disagreement for me is the message that obesity is a disease only if it is clinical or only if it presents functional impairment or clinical symptoms. This remains, in my opinion, an oversimplification, not taking into account the fact that the pathophysiological mechanisms that lead to fat accumulation and ‘adipose tissue-based chronic disease’ usually start well before the occurrence of symptoms.”

Busetto pointed to examples such as type 2 diabetes and chronic kidney disease, both of which can be asymptomatic in their early phases yet are still considered diseases at those points. “I have no problem in accepting a distinction between preclinical and clinical stages of the disease, and I like the definition of clinical obesity, but why should this imply the fact that obesity is NOT a disease since its beginning?”

The Commission does state that preclinical obesity should be addressed, mostly with preventive approaches but in some cases with more intensive management. “This is highly relevant, but the risk of an undertreatment of obesity in its asymptomatic state remains in place. This could delay appropriate management for a progressive disease that certainly should not be treated only when presenting symptoms. It would be too late,” Busetto said.

And EASO framework coauthor Gijs Goossens, PhD, professor of cardiometabolic physiology of obesity at Maastricht University Medical Centre, the Netherlands, added a concern that those with excess adiposity but lower BMI might be missed entirely, noting “Since abdominal fat accumulation better predicts chronic cardiometabolic diseases and can also be accompanied by clinical manifestations in individuals with overweight as a consequence of compromised adipose tissue function, the proposed model may lead to underdiagnosis or undertreatment in individuals with BMI 25-30 who have excess abdominal fat.”

 

Diagnosis and Management Beyond BMI

The Commission advises the use of BMI solely as a marker to screen for potential obesity. Those with a BMI > 40 can be assumed to have excess body fat. For others with a BMI at or near the threshold for obesity in a specific country or ethnic group or for whom there is the clinical judgment of the potential for clinical obesity, confirmation of excess or abnormal adiposity is needed by one of the following:

• At least one measurement of body size and BMI
• At least two measures of body size, regardless of BMI
• Direct body fat measurement, such as a dual-energy x-ray absorptiometry (DEXA) scan

Measurement of body size can be assessed in three ways: 

• Waist circumference ≥ 102 cm for men and ≥ 88 cm for women
• Waist-to-hip ratio > 0.90 for men and > 0.50 for women
• Waist-to-height ratio > 0.50 for all.

Weintraub noted, “Telemedicine is a useful tool used by many patients and providers but may also make it challenging to accurately assess someone’s body size. Having technology like an iPhone app to measure body size would circumvent this challenge but this type of tool has not yet been validated.” 

If the person does not have excess adiposity, they don’t have obesity. Those with excess adiposity do have obesity. Further assessment is then needed to establish whether the person has an illness, that is, clinical obesity, indicated by signs/symptoms of organ dysfunction, and/or limitations of daily activities. If not, they have “preclinical” obesity.

The document provides a list of 18 obesity-related organ, tissue, and body system criteria for diagnosing “clinical” obesity in adults, including upper airways (eg, apneas/hypopneas), respiratory (breathlessness), cardiovascular (hypertension, heart failure), liver (fatty liver disease with hepatic fibrosis), reproductive (polycystic ovary syndrome, hypogonadism), and metabolism (hyperglycemia, hypertriglyceridemia, low high-density lipoprotein cholesterol). A list of 13 such criteria is also provided for children. “Limitations of day-to-day activities” are included on both lists.

 

Management Differs by Designation

For preclinical obesity, management should focus on risk reduction and prevention of progression to clinical obesity or other obesity-related diseases. Such approaches include health counseling for weight loss or prevention of weight gain, monitoring over time, and active weight loss interventions in people at higher risk of developing clinical obesity and other obesity-related diseases.

Management for clinical obesity focuses on improvements or reversal of the organ dysfunction. The type of evidence-based treatment and management should be informed by individual risk-benefit assessments and decided via “active discussion” with the patient. Success is determined by improvement in the signs and symptoms rather than measures of weight loss.

In response to a reporter’s question at the SMC briefing about the implications for the use of weight-loss medications, Rubino noted that this wasn’t the focus of the report, but nonetheless said that this new obesity definition could help with their targeted use. “The strategy and intent by which you use the drugs is different in clinical and preclinical obesity. ... Pharmacological interventions could be used for patients with high-risk preclinical obesity, with the intent of reducing risk, but we ... would use the same medication at a different intensity, dose, and maybe in combination therapies.”

As for clinical obesity, “It could be more or less severe and could affect more than one organ, and so clinical obesity might require drugs, might require surgery, or may require, in some cases, a combination of both of them, to achieve the best possible outcomes. ... We want to make sure that the person is restoring health ... with whatever it takes.”

Rubino believes this new definition will convince the remaining clinicians who haven’t yet accepted the concept of obesity as a disease. “When they see clinical obesity, I think it will be much harder to say that a biological process that is capable of causing a dysfunction in the heart or the lungs is less of a disease than another biological process that causes similar dysfunction in the heart of the lungs. ... It’s going to be objective. Obesity is a spectrum of different situations. ... When it’s an illness, clinical obesity, it’s not a matter of if or when. It’s a matter of fact.”

There were no industrial grants or other funding for this initiative. King’s Health Partners hosted the initiative and provided logistical and personnel support to facilitate administrative work and the Delphi-like consensus-development process. Rubino declared receiving research grants from Ethicon (Johnson & Johnson), Novo Nordisk, and Medtronic; consulting fees from Morphic Medical; speaking honoraria from Medtronic, Ethicon, Novo Nordisk, Eli Lilly, and Amgen. Rubino has served (unpaid) as a member of the scientific advisory board for Keyron and a member of the data safety and monitoring board for GI Metabolic Solutions; is president of the Metabolic Health Institute (non-profit); and is the sole director of Metabolic Health International and London Metabolic and Bariatric Surgery (private practice). Baur declared serving on the scientific advisory board for Novo Nordisk (for the ACTION Teens study) and Eli Lilly and receiving speaker fees (paid to the institution) from Novo Nordisk.

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

The Food and Drug Administration (FDA) has approved the obesity treatment tirzepatide (Zepbound, Eli Lilly) for treating moderate to severe obstructive sleep apnea (OSA) in adults with obesity.

The new indication is for use in combination with reduced-calorie diet and increased physical activity. The once-weekly injectable is the first-ever drug treatment for OSA. Until now, OSA treatment has focused on mechanical support during sleep in the form of positive airway pressure (PAP) therapy. 

“Today’s approval marks the first drug treatment option for certain patients with obstructive sleep apnea,” said Sally Seymour, MD, director of the Division of Pulmonology, Allergy, and Critical Care in the FDA’s Center for Drug Evaluation and Research. “This is a major step forward for patients with obstructive sleep apnea.”

Excess weight is a major risk factor for OSA, in which the upper airways become blocked multiple times during sleep and obstruct breathing. The condition causes loud snoring, recurrent awakenings, and daytime sleepiness. It is also associated with cardiovascular disease.

Tirzepatide, a dual glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide receptor agonist, was initially approved with brand name Mounjaro in May 2022 for the treatment of type 2 diabetes, and as Zepbound for weight loss in November 2023.

The new OSA approval was based on two phase 3, double-blind randomized controlled trials, SURMOUNT-OSA, in patients with obesity and moderate to severe OSA, conducted at 60 sites in nine countries. Results from both were presented in June 2024 at the annual Scientific Sessions of the American Diabetes Association and were simultaneously published in The New England Journal of Medicine.

The first trial enrolled 469 participants who were unable or unwilling to use PAP therapy, while the second included 234 who had been using PAP for at least 3 months and planned to continue during the trial. In both, the participants randomly received either 10 mg or 15 mg of tirzepatide or placebo once weekly for 52 weeks.

At baseline, 65%-70% of participants had severe OSA, with more than 30 events/h on the apnea-hypopnea index (AHI) and a mean of 51.5 events/h. By 52 weeks, those randomized to tirzepatide had 27-30 fewer events/h, compared with 4-6 fewer events/h for those taking placebo. In addition, significantly more of those on tirzepatide achieved OSA remission or severity reduction to mild.

Those randomized to tirzepatide also averaged up to 20% weight loss, significantly more than with placebo. “The improvement in AHI in participants with OSA is likely related to body weight reduction with Zepbound,” according to an FDA statement.

Side effects of tirzepatide include nausea, diarrhea, vomiting, constipation, abdominal discomfort and pain, injection site reactions, fatigue, hypersensitivity reactions (typically fever and rash), burping, hair loss, and gastroesophageal reflux disease.

In an editorial accompanying The New England Journal of Medicine publication of the SURMOUNT-OSA results, Sanjay R. Patel, MD, wrote: “The potential incorporation of tirzepatide into treatment algorithms for obstructive sleep apnea should include consideration of the challenges of adherence to treatment and the imperative to address racial disparities in medical care.”

Patel, who is professor of medicine and epidemiology at the University of Pittsburgh in Pennsylvania, and medical director of the University of Pittsburgh Medical Center’s Comprehensive Sleep Disorders program, pointed out that suboptimal adherence to continuous PAP therapy has been a major limitation, but that adherence to the GLP-1 drug class has also been suboptimal.

“Although adherence to tirzepatide therapy in the SURMOUNT-OSA trial was high, real-world evidence suggests that nearly 50% of patients who begin treatment with a GLP-1 receptor agonist for obesity discontinue therapy within 12 months. Thus, it is likely that any incorporation of tirzepatide into treatment pathways for obstructive sleep apnea will not diminish the importance of long-term strategies to optimize adherence to treatment.”

Moreover, Patel noted, “racial disparities in the use of GLP-1 receptor agonists among patients with diabetes arouse concern that the addition of tirzepatide as a treatment option for obstructive sleep apnea without directly addressing policies relative to coverage of care will only further exacerbate already pervasive disparities in clinical care for obstructive sleep apnea.”

Patel reported consulting for Apnimed, Bayer Pharmaceuticals, Lilly USA, NovaResp Technologies, Philips Respironics, and Powell Mansfield. He is a fiduciary officer of BreathPA.

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

The Food and Drug Administration (FDA) has approved the obesity treatment tirzepatide (Zepbound, Eli Lilly) for treating moderate to severe obstructive sleep apnea (OSA) in adults with obesity.

The new indication is for use in combination with reduced-calorie diet and increased physical activity. The once-weekly injectable is the first-ever drug treatment for OSA. Until now, OSA treatment has focused on mechanical support during sleep in the form of positive airway pressure (PAP) therapy. 

“Today’s approval marks the first drug treatment option for certain patients with obstructive sleep apnea,” said Sally Seymour, MD, director of the Division of Pulmonology, Allergy, and Critical Care in the FDA’s Center for Drug Evaluation and Research. “This is a major step forward for patients with obstructive sleep apnea.”

Excess weight is a major risk factor for OSA, in which the upper airways become blocked multiple times during sleep and obstruct breathing. The condition causes loud snoring, recurrent awakenings, and daytime sleepiness. It is also associated with cardiovascular disease.

Tirzepatide, a dual glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide receptor agonist, was initially approved with brand name Mounjaro in May 2022 for the treatment of type 2 diabetes, and as Zepbound for weight loss in November 2023.

The new OSA approval was based on two phase 3, double-blind randomized controlled trials, SURMOUNT-OSA, in patients with obesity and moderate to severe OSA, conducted at 60 sites in nine countries. Results from both were presented in June 2024 at the annual Scientific Sessions of the American Diabetes Association and were simultaneously published in The New England Journal of Medicine.

The first trial enrolled 469 participants who were unable or unwilling to use PAP therapy, while the second included 234 who had been using PAP for at least 3 months and planned to continue during the trial. In both, the participants randomly received either 10 mg or 15 mg of tirzepatide or placebo once weekly for 52 weeks.

At baseline, 65%-70% of participants had severe OSA, with more than 30 events/h on the apnea-hypopnea index (AHI) and a mean of 51.5 events/h. By 52 weeks, those randomized to tirzepatide had 27-30 fewer events/h, compared with 4-6 fewer events/h for those taking placebo. In addition, significantly more of those on tirzepatide achieved OSA remission or severity reduction to mild.

Those randomized to tirzepatide also averaged up to 20% weight loss, significantly more than with placebo. “The improvement in AHI in participants with OSA is likely related to body weight reduction with Zepbound,” according to an FDA statement.

Side effects of tirzepatide include nausea, diarrhea, vomiting, constipation, abdominal discomfort and pain, injection site reactions, fatigue, hypersensitivity reactions (typically fever and rash), burping, hair loss, and gastroesophageal reflux disease.

In an editorial accompanying The New England Journal of Medicine publication of the SURMOUNT-OSA results, Sanjay R. Patel, MD, wrote: “The potential incorporation of tirzepatide into treatment algorithms for obstructive sleep apnea should include consideration of the challenges of adherence to treatment and the imperative to address racial disparities in medical care.”

Patel, who is professor of medicine and epidemiology at the University of Pittsburgh in Pennsylvania, and medical director of the University of Pittsburgh Medical Center’s Comprehensive Sleep Disorders program, pointed out that suboptimal adherence to continuous PAP therapy has been a major limitation, but that adherence to the GLP-1 drug class has also been suboptimal.

“Although adherence to tirzepatide therapy in the SURMOUNT-OSA trial was high, real-world evidence suggests that nearly 50% of patients who begin treatment with a GLP-1 receptor agonist for obesity discontinue therapy within 12 months. Thus, it is likely that any incorporation of tirzepatide into treatment pathways for obstructive sleep apnea will not diminish the importance of long-term strategies to optimize adherence to treatment.”

Moreover, Patel noted, “racial disparities in the use of GLP-1 receptor agonists among patients with diabetes arouse concern that the addition of tirzepatide as a treatment option for obstructive sleep apnea without directly addressing policies relative to coverage of care will only further exacerbate already pervasive disparities in clinical care for obstructive sleep apnea.”

Patel reported consulting for Apnimed, Bayer Pharmaceuticals, Lilly USA, NovaResp Technologies, Philips Respironics, and Powell Mansfield. He is a fiduciary officer of BreathPA.

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

The Food and Drug Administration (FDA) has approved the obesity treatment tirzepatide (Zepbound, Eli Lilly) for treating moderate to severe obstructive sleep apnea (OSA) in adults with obesity.

The new indication is for use in combination with reduced-calorie diet and increased physical activity. The once-weekly injectable is the first-ever drug treatment for OSA. Until now, OSA treatment has focused on mechanical support during sleep in the form of positive airway pressure (PAP) therapy. 

“Today’s approval marks the first drug treatment option for certain patients with obstructive sleep apnea,” said Sally Seymour, MD, director of the Division of Pulmonology, Allergy, and Critical Care in the FDA’s Center for Drug Evaluation and Research. “This is a major step forward for patients with obstructive sleep apnea.”

Excess weight is a major risk factor for OSA, in which the upper airways become blocked multiple times during sleep and obstruct breathing. The condition causes loud snoring, recurrent awakenings, and daytime sleepiness. It is also associated with cardiovascular disease.

Tirzepatide, a dual glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide receptor agonist, was initially approved with brand name Mounjaro in May 2022 for the treatment of type 2 diabetes, and as Zepbound for weight loss in November 2023.

The new OSA approval was based on two phase 3, double-blind randomized controlled trials, SURMOUNT-OSA, in patients with obesity and moderate to severe OSA, conducted at 60 sites in nine countries. Results from both were presented in June 2024 at the annual Scientific Sessions of the American Diabetes Association and were simultaneously published in The New England Journal of Medicine.

The first trial enrolled 469 participants who were unable or unwilling to use PAP therapy, while the second included 234 who had been using PAP for at least 3 months and planned to continue during the trial. In both, the participants randomly received either 10 mg or 15 mg of tirzepatide or placebo once weekly for 52 weeks.

At baseline, 65%-70% of participants had severe OSA, with more than 30 events/h on the apnea-hypopnea index (AHI) and a mean of 51.5 events/h. By 52 weeks, those randomized to tirzepatide had 27-30 fewer events/h, compared with 4-6 fewer events/h for those taking placebo. In addition, significantly more of those on tirzepatide achieved OSA remission or severity reduction to mild.

Those randomized to tirzepatide also averaged up to 20% weight loss, significantly more than with placebo. “The improvement in AHI in participants with OSA is likely related to body weight reduction with Zepbound,” according to an FDA statement.

Side effects of tirzepatide include nausea, diarrhea, vomiting, constipation, abdominal discomfort and pain, injection site reactions, fatigue, hypersensitivity reactions (typically fever and rash), burping, hair loss, and gastroesophageal reflux disease.

In an editorial accompanying The New England Journal of Medicine publication of the SURMOUNT-OSA results, Sanjay R. Patel, MD, wrote: “The potential incorporation of tirzepatide into treatment algorithms for obstructive sleep apnea should include consideration of the challenges of adherence to treatment and the imperative to address racial disparities in medical care.”

Patel, who is professor of medicine and epidemiology at the University of Pittsburgh in Pennsylvania, and medical director of the University of Pittsburgh Medical Center’s Comprehensive Sleep Disorders program, pointed out that suboptimal adherence to continuous PAP therapy has been a major limitation, but that adherence to the GLP-1 drug class has also been suboptimal.

“Although adherence to tirzepatide therapy in the SURMOUNT-OSA trial was high, real-world evidence suggests that nearly 50% of patients who begin treatment with a GLP-1 receptor agonist for obesity discontinue therapy within 12 months. Thus, it is likely that any incorporation of tirzepatide into treatment pathways for obstructive sleep apnea will not diminish the importance of long-term strategies to optimize adherence to treatment.”

Moreover, Patel noted, “racial disparities in the use of GLP-1 receptor agonists among patients with diabetes arouse concern that the addition of tirzepatide as a treatment option for obstructive sleep apnea without directly addressing policies relative to coverage of care will only further exacerbate already pervasive disparities in clinical care for obstructive sleep apnea.”

Patel reported consulting for Apnimed, Bayer Pharmaceuticals, Lilly USA, NovaResp Technologies, Philips Respironics, and Powell Mansfield. He is a fiduciary officer of BreathPA.

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.

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:

Mannkind expects to submit a request for a supplemental new drug application meeting to the Food and Drug Administration (FDA) for its inhaled human insulin (Afrezza Inhalation Powder). Currently indicated to improve glycemic control in adults with diabetes, the company announced 6-month results from its phase 3 INHALE-1 study of inhaled human insulin in children and adolescents aged 4-17.

METHODOLOGY:

• INHALE-1 is a 26-week, open-label clinical trial that randomized 230 subjects aged 4-17 years with type 1 or type 2 diabetes to either inhaled pre-meal insulin or multiple daily injections (MDI) of rapid-acting insulin analog, both in combination with basal insulin.
• The primary endpoint was a noninferior change in hemoglobin A1c levels, compared with MDI after 26 weeks.
• A 26-week extension phase in which all remaining MDI patients were switched to inhaled insulin is ongoing.

TAKEAWAY:

• In the full intent-to-treat (ITT) population analysis, the between-group difference in mean A1c change over 26 weeks exceeded the prespecified non-inferiority margin of 0.4% (0.435%), but this was largely driven by the variability of a single patient who didn’t adhere to the study protocol.
• A modified ITT analysis excluding that person did not exceed the predetermined threshold of 0.4% (0.370%), thereby establishing noninferiority of inhaled insulin with MDI.
• Over 26 weeks of treatment, there were no differences in lung function parameters between the treatment groups, with mean forced expiratory volume at 1 second (FEV1) at baseline vs 26 weeks of 2.901 liters (99.6% of predicted) vs 2.934 L (96.6%) in the inhaled insulin group and 2.948 L (102.3%) vs 2.957 (98%), respectively, in the MDI group.
• There were no differences between groups or concerns in other safety measures, including hypoglycemia.

IN PRACTICE:

“It was exciting to partner with MannKind and help lead this study to potentially expand the use of inhaled insulin, which is currently used successfully by many adults with diabetes, to a population that hasn’t had a treatment option other than injectable insulin in the history of their care,” said INHALE-1 investigator Roy W. Beck, MD, PhD, founder of the Jaeb Center for Health Research, Tampa, Florida.

“The 6-month results are clinically meaningful and show Afrezza as a potential future treatment option for a growing pediatric population living with type 1 and type 2 diabetes,” Beck added.

 

SOURCE:

The results of the study were announced at a Mannkind press release on December 16, 2024.

SAFETY INFORMATION:

Inhaled insulin is not recommended for the treatment of diabetic ketoacidosis or in patients who smoke or have recently stopped smoking.

Warning: Risk for acute bronchospasm in patients with chronic lung disease

• Acute bronchospasm has been observed in Afrezza-treated patients with asthma and chronic obstructive pulmonary disease (COPD)
• Afrezza is contraindicated in patients with chronic lung disease such as asthma or COPD
• Before initiating Afrezza, perform a detailed medical history, physical examination, and spirometry (FEV1) to identify potential lung disease in all patients
• Most common adverse reactions are hypoglycemia, cough, and throat pain or irritation.
•  

DISCLOSURES:

This study was funded by MannKind.

A version of this article appeared on Medscape.com.

TOPLINE:

Mannkind expects to submit a request for a supplemental new drug application meeting to the Food and Drug Administration (FDA) for its inhaled human insulin (Afrezza Inhalation Powder). Currently indicated to improve glycemic control in adults with diabetes, the company announced 6-month results from its phase 3 INHALE-1 study of inhaled human insulin in children and adolescents aged 4-17.

METHODOLOGY:

• INHALE-1 is a 26-week, open-label clinical trial that randomized 230 subjects aged 4-17 years with type 1 or type 2 diabetes to either inhaled pre-meal insulin or multiple daily injections (MDI) of rapid-acting insulin analog, both in combination with basal insulin.
• The primary endpoint was a noninferior change in hemoglobin A1c levels, compared with MDI after 26 weeks.
• A 26-week extension phase in which all remaining MDI patients were switched to inhaled insulin is ongoing.

TAKEAWAY:

• In the full intent-to-treat (ITT) population analysis, the between-group difference in mean A1c change over 26 weeks exceeded the prespecified non-inferiority margin of 0.4% (0.435%), but this was largely driven by the variability of a single patient who didn’t adhere to the study protocol.
• A modified ITT analysis excluding that person did not exceed the predetermined threshold of 0.4% (0.370%), thereby establishing noninferiority of inhaled insulin with MDI.
• Over 26 weeks of treatment, there were no differences in lung function parameters between the treatment groups, with mean forced expiratory volume at 1 second (FEV1) at baseline vs 26 weeks of 2.901 liters (99.6% of predicted) vs 2.934 L (96.6%) in the inhaled insulin group and 2.948 L (102.3%) vs 2.957 (98%), respectively, in the MDI group.
• There were no differences between groups or concerns in other safety measures, including hypoglycemia.

IN PRACTICE:

“It was exciting to partner with MannKind and help lead this study to potentially expand the use of inhaled insulin, which is currently used successfully by many adults with diabetes, to a population that hasn’t had a treatment option other than injectable insulin in the history of their care,” said INHALE-1 investigator Roy W. Beck, MD, PhD, founder of the Jaeb Center for Health Research, Tampa, Florida.

“The 6-month results are clinically meaningful and show Afrezza as a potential future treatment option for a growing pediatric population living with type 1 and type 2 diabetes,” Beck added.

 

SOURCE:

The results of the study were announced at a Mannkind press release on December 16, 2024.

SAFETY INFORMATION:

Inhaled insulin is not recommended for the treatment of diabetic ketoacidosis or in patients who smoke or have recently stopped smoking.

Warning: Risk for acute bronchospasm in patients with chronic lung disease

• Acute bronchospasm has been observed in Afrezza-treated patients with asthma and chronic obstructive pulmonary disease (COPD)
• Afrezza is contraindicated in patients with chronic lung disease such as asthma or COPD
• Before initiating Afrezza, perform a detailed medical history, physical examination, and spirometry (FEV1) to identify potential lung disease in all patients
• Most common adverse reactions are hypoglycemia, cough, and throat pain or irritation.
•  

DISCLOSURES:

This study was funded by MannKind.

A version of this article appeared on Medscape.com.

TOPLINE:

Mannkind expects to submit a request for a supplemental new drug application meeting to the Food and Drug Administration (FDA) for its inhaled human insulin (Afrezza Inhalation Powder). Currently indicated to improve glycemic control in adults with diabetes, the company announced 6-month results from its phase 3 INHALE-1 study of inhaled human insulin in children and adolescents aged 4-17.

METHODOLOGY:

• INHALE-1 is a 26-week, open-label clinical trial that randomized 230 subjects aged 4-17 years with type 1 or type 2 diabetes to either inhaled pre-meal insulin or multiple daily injections (MDI) of rapid-acting insulin analog, both in combination with basal insulin.
• The primary endpoint was a noninferior change in hemoglobin A1c levels, compared with MDI after 26 weeks.
• A 26-week extension phase in which all remaining MDI patients were switched to inhaled insulin is ongoing.

TAKEAWAY:

• In the full intent-to-treat (ITT) population analysis, the between-group difference in mean A1c change over 26 weeks exceeded the prespecified non-inferiority margin of 0.4% (0.435%), but this was largely driven by the variability of a single patient who didn’t adhere to the study protocol.
• A modified ITT analysis excluding that person did not exceed the predetermined threshold of 0.4% (0.370%), thereby establishing noninferiority of inhaled insulin with MDI.
• Over 26 weeks of treatment, there were no differences in lung function parameters between the treatment groups, with mean forced expiratory volume at 1 second (FEV1) at baseline vs 26 weeks of 2.901 liters (99.6% of predicted) vs 2.934 L (96.6%) in the inhaled insulin group and 2.948 L (102.3%) vs 2.957 (98%), respectively, in the MDI group.
• There were no differences between groups or concerns in other safety measures, including hypoglycemia.

IN PRACTICE:

“It was exciting to partner with MannKind and help lead this study to potentially expand the use of inhaled insulin, which is currently used successfully by many adults with diabetes, to a population that hasn’t had a treatment option other than injectable insulin in the history of their care,” said INHALE-1 investigator Roy W. Beck, MD, PhD, founder of the Jaeb Center for Health Research, Tampa, Florida.

“The 6-month results are clinically meaningful and show Afrezza as a potential future treatment option for a growing pediatric population living with type 1 and type 2 diabetes,” Beck added.

 

SOURCE:

The results of the study were announced at a Mannkind press release on December 16, 2024.

SAFETY INFORMATION:

Inhaled insulin is not recommended for the treatment of diabetic ketoacidosis or in patients who smoke or have recently stopped smoking.

Warning: Risk for acute bronchospasm in patients with chronic lung disease

• Acute bronchospasm has been observed in Afrezza-treated patients with asthma and chronic obstructive pulmonary disease (COPD)
• Afrezza is contraindicated in patients with chronic lung disease such as asthma or COPD
• Before initiating Afrezza, perform a detailed medical history, physical examination, and spirometry (FEV1) to identify potential lung disease in all patients
• Most common adverse reactions are hypoglycemia, cough, and throat pain or irritation.
•  

DISCLOSURES:

This study was funded by MannKind.

A version of this article appeared on Medscape.com.

The American Diabetes Association (ADA)’s Standards of Care — 2025 offer new guidance on broader use of continuous glucose monitoring (CGM), use of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) beyond weight loss, management of metabolic dysfunction-associated liver disease (MAFLD), plus a strong endorsement for drinking water and much more. 

The Standards of Care — 2025 were published December 9 as a supplement to Diabetes Care. The standards “incorporate the latest information from clinical trial data and knowledge of diabetes management into a comprehensive guidelines document that will assist physicians in managing patients with diabetes in their practices,” said Mandeep Bajaj, MBBS, ADA’s President, Medicine & Science.

In an interview, Bajaj highlighted some of the most important of the clinical updates in 2024, including the following: 

• Consideration of the use of continuous glucose monitoring devices in adults with type 2 diabetes (T2D) who don’t use insulin. Medicare and many other payers currently only cover CGM for people who use insulin or are otherwise at risk for hypoglycemia. However, some CGMs are now available over the counter, Bajaj pointed out.
• Actions to be taken in the event of medication shortages. The ADA published guidance for this in the case of GLP-1 RAs on December 2. Essentially ADA advised substituting a different GLP-1 RA if possible. Nonapproved products aren’t recommended, but guidance is provided for people who choose to use them.
• Use of GLP-1 RAs for heart and kidney health. Recommendations were revised to explicitly advise on choice of pharmacotherapy for individuals with T2D, based on new data on those with established or high risk for atherosclerotic cardiovascular disease, heart failure with preserved ejection fraction, and chronic kidney disease.
• Treatment of MAFLD with moderate or advanced liver fibrosis. A new recommendation for use of a thyroid hormone receptor–beta agonist is based on trial data for resmetirom. Moreover, Bajaj noted, “we’ve adopted the new nomenclature, which was previously NAFLD and NASH, and now is MAFLD and MASH [metabolic-associated steatohepatitis].”
• Advice to continue weight management therapy beyond achieving weight loss goals. This is based on a large amount of evidence that “stopping these therapies are associated with weight regain and increased cardiovascular risk,” Bajaj said, adding that this recommendation was made in collaboration with the Obesity Society.
• Antibody-based screening for presymptomatic T1D in family members of people with T2D and others who may be at risk. “Individuals who test autoantibody positive should be provided with or referred for counseling about the risk of developing diabetes, diabetes symptoms, and [diabetic ketoacidosis] prevention and should be given consideration for referral to a specialized center for further evaluation and/or consideration of a clinical trial or approved therapy to potentially delay development of clinical diabetes,” the document says.
• Screen for psychosocial issues. People with diabetes should be screened for concerns including diabetes distress, depression, anxiety, fear of hypoglycemia, and disordered eating behaviors. “People on insulin or sulfonylureas may have fear of hypoglycemia, but diabetes distress can happen to anyone with diabetes,” Bajaj pointed out. Caregivers and family members should be screened as well, the document advises.
• Drink water, not soda. In the nutrition section, a new recommendation strongly advises drinking water instead of nutritive or nonnutritive sweetened beverages. “This is an important recommendation. So, when patients ask what’s the best thing to drink, our answer is drink water rather than Coca Cola or Diet Coke,” Bajaj said. But, what about people with diabetes who can’t quit their diet soda habit? “We’ve said that the nonnutritive sweetener is preferred over sugar sweetener, provided it’s in moderation and short term ... but the best is water.”

Bajaj has received grant support from ADA. He had no further disclosures.

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

The American Diabetes Association (ADA)’s Standards of Care — 2025 offer new guidance on broader use of continuous glucose monitoring (CGM), use of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) beyond weight loss, management of metabolic dysfunction-associated liver disease (MAFLD), plus a strong endorsement for drinking water and much more. 

The Standards of Care — 2025 were published December 9 as a supplement to Diabetes Care. The standards “incorporate the latest information from clinical trial data and knowledge of diabetes management into a comprehensive guidelines document that will assist physicians in managing patients with diabetes in their practices,” said Mandeep Bajaj, MBBS, ADA’s President, Medicine & Science.

In an interview, Bajaj highlighted some of the most important of the clinical updates in 2024, including the following: 

• Consideration of the use of continuous glucose monitoring devices in adults with type 2 diabetes (T2D) who don’t use insulin. Medicare and many other payers currently only cover CGM for people who use insulin or are otherwise at risk for hypoglycemia. However, some CGMs are now available over the counter, Bajaj pointed out.
• Actions to be taken in the event of medication shortages. The ADA published guidance for this in the case of GLP-1 RAs on December 2. Essentially ADA advised substituting a different GLP-1 RA if possible. Nonapproved products aren’t recommended, but guidance is provided for people who choose to use them.
• Use of GLP-1 RAs for heart and kidney health. Recommendations were revised to explicitly advise on choice of pharmacotherapy for individuals with T2D, based on new data on those with established or high risk for atherosclerotic cardiovascular disease, heart failure with preserved ejection fraction, and chronic kidney disease.
• Treatment of MAFLD with moderate or advanced liver fibrosis. A new recommendation for use of a thyroid hormone receptor–beta agonist is based on trial data for resmetirom. Moreover, Bajaj noted, “we’ve adopted the new nomenclature, which was previously NAFLD and NASH, and now is MAFLD and MASH [metabolic-associated steatohepatitis].”
• Advice to continue weight management therapy beyond achieving weight loss goals. This is based on a large amount of evidence that “stopping these therapies are associated with weight regain and increased cardiovascular risk,” Bajaj said, adding that this recommendation was made in collaboration with the Obesity Society.
• Antibody-based screening for presymptomatic T1D in family members of people with T2D and others who may be at risk. “Individuals who test autoantibody positive should be provided with or referred for counseling about the risk of developing diabetes, diabetes symptoms, and [diabetic ketoacidosis] prevention and should be given consideration for referral to a specialized center for further evaluation and/or consideration of a clinical trial or approved therapy to potentially delay development of clinical diabetes,” the document says.
• Screen for psychosocial issues. People with diabetes should be screened for concerns including diabetes distress, depression, anxiety, fear of hypoglycemia, and disordered eating behaviors. “People on insulin or sulfonylureas may have fear of hypoglycemia, but diabetes distress can happen to anyone with diabetes,” Bajaj pointed out. Caregivers and family members should be screened as well, the document advises.
• Drink water, not soda. In the nutrition section, a new recommendation strongly advises drinking water instead of nutritive or nonnutritive sweetened beverages. “This is an important recommendation. So, when patients ask what’s the best thing to drink, our answer is drink water rather than Coca Cola or Diet Coke,” Bajaj said. But, what about people with diabetes who can’t quit their diet soda habit? “We’ve said that the nonnutritive sweetener is preferred over sugar sweetener, provided it’s in moderation and short term ... but the best is water.”

Bajaj has received grant support from ADA. He had no further disclosures.

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

The American Diabetes Association (ADA)’s Standards of Care — 2025 offer new guidance on broader use of continuous glucose monitoring (CGM), use of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) beyond weight loss, management of metabolic dysfunction-associated liver disease (MAFLD), plus a strong endorsement for drinking water and much more. 

The Standards of Care — 2025 were published December 9 as a supplement to Diabetes Care. The standards “incorporate the latest information from clinical trial data and knowledge of diabetes management into a comprehensive guidelines document that will assist physicians in managing patients with diabetes in their practices,” said Mandeep Bajaj, MBBS, ADA’s President, Medicine & Science.

In an interview, Bajaj highlighted some of the most important of the clinical updates in 2024, including the following: 

• Consideration of the use of continuous glucose monitoring devices in adults with type 2 diabetes (T2D) who don’t use insulin. Medicare and many other payers currently only cover CGM for people who use insulin or are otherwise at risk for hypoglycemia. However, some CGMs are now available over the counter, Bajaj pointed out.
• Actions to be taken in the event of medication shortages. The ADA published guidance for this in the case of GLP-1 RAs on December 2. Essentially ADA advised substituting a different GLP-1 RA if possible. Nonapproved products aren’t recommended, but guidance is provided for people who choose to use them.
• Use of GLP-1 RAs for heart and kidney health. Recommendations were revised to explicitly advise on choice of pharmacotherapy for individuals with T2D, based on new data on those with established or high risk for atherosclerotic cardiovascular disease, heart failure with preserved ejection fraction, and chronic kidney disease.
• Treatment of MAFLD with moderate or advanced liver fibrosis. A new recommendation for use of a thyroid hormone receptor–beta agonist is based on trial data for resmetirom. Moreover, Bajaj noted, “we’ve adopted the new nomenclature, which was previously NAFLD and NASH, and now is MAFLD and MASH [metabolic-associated steatohepatitis].”
• Advice to continue weight management therapy beyond achieving weight loss goals. This is based on a large amount of evidence that “stopping these therapies are associated with weight regain and increased cardiovascular risk,” Bajaj said, adding that this recommendation was made in collaboration with the Obesity Society.
• Antibody-based screening for presymptomatic T1D in family members of people with T2D and others who may be at risk. “Individuals who test autoantibody positive should be provided with or referred for counseling about the risk of developing diabetes, diabetes symptoms, and [diabetic ketoacidosis] prevention and should be given consideration for referral to a specialized center for further evaluation and/or consideration of a clinical trial or approved therapy to potentially delay development of clinical diabetes,” the document says.
• Screen for psychosocial issues. People with diabetes should be screened for concerns including diabetes distress, depression, anxiety, fear of hypoglycemia, and disordered eating behaviors. “People on insulin or sulfonylureas may have fear of hypoglycemia, but diabetes distress can happen to anyone with diabetes,” Bajaj pointed out. Caregivers and family members should be screened as well, the document advises.
• Drink water, not soda. In the nutrition section, a new recommendation strongly advises drinking water instead of nutritive or nonnutritive sweetened beverages. “This is an important recommendation. So, when patients ask what’s the best thing to drink, our answer is drink water rather than Coca Cola or Diet Coke,” Bajaj said. But, what about people with diabetes who can’t quit their diet soda habit? “We’ve said that the nonnutritive sweetener is preferred over sugar sweetener, provided it’s in moderation and short term ... but the best is water.”

Bajaj has received grant support from ADA. He had no further disclosures.

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

In a new statement, the American Diabetes Association (ADA) has advised against the use of compounded glucagon-like peptide 1 receptor agonist (GLP-1 RA) and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RA medication classes.

The ADA recommends GLP-1 RA and GIP/GLP-1 RA medications approved by the Food and Drug Administration (FDA) for the treatment of type 2 diabetes, cardiovascular and kidney disease risk reduction, and weight management. The new ADA statement pertains to the unapproved, unregulated versions that have emerged as the demand for these medications for weight loss increases. These are often marketed directly to consumers.

“Compounded GLP-1 RA and dual GIP/GLP-1 RA products have been associated with clinically important dosing errors and adverse events. More concerning to individuals’ safety are counterfeit products that have made their way into the US drug supply chain and those advertised online and by unregulated sources,” the ADA said in the statement, published online on December 2, 2024, in Diabetes Care.

The statement, authored by Joshua J. Neumiller, PharmD, CDCES, of the Department of Pharmacotherapy, Washington State University, Spokane, and colleagues, states the following:

• Non–FDA-approved compounded incretin products are not recommended for use due to uncertainty about their content and resulting concerns about safety, quality, and effectiveness.
• If an incretin medication is unavailable (eg, in shortage), switching to a different FDA-approved medication is recommended as clinically appropriate to achieve and maintain individualized glucose-lowering, weight management, and/or cardiovascular and kidney risk reduction goals.
• Upon resolution of incretin product unavailability, reassess the appropriateness of resuming the original FDA-approved incretin medication.

The document points out that compounded products are not identical to the FDA-approved versions, may be distributed in nonstandard dosing devices, and may not provide sufficient user instructions.

However, “the ADA also recognizes that individuals and clinicians may still elect to use or recommend compounded products for financial or other reasons,” and therefore offers additional advice for the public, including the following:

• Discuss product use with their usual healthcare providers.
• Only use products that include dosing guidance.
• Verify that the compounding pharmacy is registered with FDA.

In addition, report any adverse events or medication errors to the FDA’s Medwatch.

A version of this article appeared on Medscape.com.

In a new statement, the American Diabetes Association (ADA) has advised against the use of compounded glucagon-like peptide 1 receptor agonist (GLP-1 RA) and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RA medication classes.

The ADA recommends GLP-1 RA and GIP/GLP-1 RA medications approved by the Food and Drug Administration (FDA) for the treatment of type 2 diabetes, cardiovascular and kidney disease risk reduction, and weight management. The new ADA statement pertains to the unapproved, unregulated versions that have emerged as the demand for these medications for weight loss increases. These are often marketed directly to consumers.

“Compounded GLP-1 RA and dual GIP/GLP-1 RA products have been associated with clinically important dosing errors and adverse events. More concerning to individuals’ safety are counterfeit products that have made their way into the US drug supply chain and those advertised online and by unregulated sources,” the ADA said in the statement, published online on December 2, 2024, in Diabetes Care.

The statement, authored by Joshua J. Neumiller, PharmD, CDCES, of the Department of Pharmacotherapy, Washington State University, Spokane, and colleagues, states the following:

• Non–FDA-approved compounded incretin products are not recommended for use due to uncertainty about their content and resulting concerns about safety, quality, and effectiveness.
• If an incretin medication is unavailable (eg, in shortage), switching to a different FDA-approved medication is recommended as clinically appropriate to achieve and maintain individualized glucose-lowering, weight management, and/or cardiovascular and kidney risk reduction goals.
• Upon resolution of incretin product unavailability, reassess the appropriateness of resuming the original FDA-approved incretin medication.

The document points out that compounded products are not identical to the FDA-approved versions, may be distributed in nonstandard dosing devices, and may not provide sufficient user instructions.

However, “the ADA also recognizes that individuals and clinicians may still elect to use or recommend compounded products for financial or other reasons,” and therefore offers additional advice for the public, including the following:

• Discuss product use with their usual healthcare providers.
• Only use products that include dosing guidance.
• Verify that the compounding pharmacy is registered with FDA.

In addition, report any adverse events or medication errors to the FDA’s Medwatch.

A version of this article appeared on Medscape.com.

In a new statement, the American Diabetes Association (ADA) has advised against the use of compounded glucagon-like peptide 1 receptor agonist (GLP-1 RA) and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RA medication classes.

The ADA recommends GLP-1 RA and GIP/GLP-1 RA medications approved by the Food and Drug Administration (FDA) for the treatment of type 2 diabetes, cardiovascular and kidney disease risk reduction, and weight management. The new ADA statement pertains to the unapproved, unregulated versions that have emerged as the demand for these medications for weight loss increases. These are often marketed directly to consumers.

“Compounded GLP-1 RA and dual GIP/GLP-1 RA products have been associated with clinically important dosing errors and adverse events. More concerning to individuals’ safety are counterfeit products that have made their way into the US drug supply chain and those advertised online and by unregulated sources,” the ADA said in the statement, published online on December 2, 2024, in Diabetes Care.

The statement, authored by Joshua J. Neumiller, PharmD, CDCES, of the Department of Pharmacotherapy, Washington State University, Spokane, and colleagues, states the following:

• Non–FDA-approved compounded incretin products are not recommended for use due to uncertainty about their content and resulting concerns about safety, quality, and effectiveness.
• If an incretin medication is unavailable (eg, in shortage), switching to a different FDA-approved medication is recommended as clinically appropriate to achieve and maintain individualized glucose-lowering, weight management, and/or cardiovascular and kidney risk reduction goals.
• Upon resolution of incretin product unavailability, reassess the appropriateness of resuming the original FDA-approved incretin medication.

The document points out that compounded products are not identical to the FDA-approved versions, may be distributed in nonstandard dosing devices, and may not provide sufficient user instructions.

However, “the ADA also recognizes that individuals and clinicians may still elect to use or recommend compounded products for financial or other reasons,” and therefore offers additional advice for the public, including the following:

• Discuss product use with their usual healthcare providers.
• Only use products that include dosing guidance.
• Verify that the compounding pharmacy is registered with FDA.

In addition, report any adverse events or medication errors to the FDA’s Medwatch.

A version of this article appeared on Medscape.com.

WASHINGTON — Investigational treatments aimed specifically at reducing pain in knee osteoarthritis (OA) are moving forward in parallel with disease-modifying approaches.

“We still have very few treatments for the pain of osteoarthritis…It worries me that people think the only way forward is structure modification. I think while we’re waiting for some drugs to be structure modifying, we still need more pain relief. About 70% of people can’t tolerate or shouldn’t be on a [nonsteroidal anti-inflammatory drug], and that leaves a large number of people with pain,” Philip Conaghan, MBBS, PhD, Chair of Musculoskeletal Medicine at the University of Leeds in England, said in an interview.

At the annual meeting of the American College of Rheumatology, Conaghan, who is also honorary consultant rheumatologist for the Leeds Teaching Hospitals NHS Trust, presented new data for two novel approaches, both targeting peripheral nociceptive pain signaling.

In a late-breaking poster, he presented phase 2 trial data on RTX-GRT7039 (resiniferatoxin [RTX]), an agonist of the transient receptor potential vanilloid 1 that is a driver of OA pain. The trial investigated the efficacy and safety of a single intra-articular injection of RTX-GRT7039 in people with knee OA.

And separately, in a late-breaking oral abstract session, Conaghan presented phase 2 trial safety and efficacy data for another investigational agent called LEVI-04, a first-in-class neurotrophin receptor fusion protein (p75NTR-Fc) that supplements the endogenous protein and provides analgesia via inhibition of NT-3 activity.

“I think both have potential to provide good pain relief, through slightly different mechanisms,” Conaghan said in an interview.

Asked to comment, session moderator Gregory C. Gardner, MD, emeritus professor in the Division of Rheumatology at the University of Washington, Seattle, said in an interview: “I think the results are really exciting terms of the ability to control pain to a significant degree in patients with osteoarthritis.”

However, Gardner also said, “The molecules can be very expensive ... so who do we give them to? Will insurance companies pay for this simply for OA pain? They improve function ... so clearly, [they] will be a boon to treating osteoarthritis, but do we give them to people with only more advanced forms of osteoarthritis or earlier on?”

Moreover, Gardner said, “One of my concerns about treating osteoarthritis is I don’t want to do too good of a job treating pain in somebody who has a biomechanically abnormal joint. ... You’ve got a knee that’s worn out some of the cartilage, and now you feel like you can go out and play soccer again. That’s not a good thing. That joint will wear out very quickly, even though it doesn’t feel pain.”

Another OA expert, Matlock Jeffries, MD, director of the Arthritis Research Unit at the Oklahoma Medical Research Foundation, Oklahoma City, said in an interview, “I think we don’t focus nearly enough on pain, and that’s [partly] because the [Food and Drug Administration] has defined endpoints for knee OA trials that are radiographic. ... Patients do not care what their joint space narrowing is. They care what their pain is. And joint space changes and pain do not correlate in knee OA. ... About 20% or 30% of patients who have completely normal x-rays have a lot of pain…I hope that we’ll have some new OA pain therapeutics in the future because that’s what patients actually care about.”

But Jeffries noted that it will be very important to ensure that these agents don’t produce significant side effects, as had been seen previously in several large industry-sponsored trials of drugs targeting nerve growth factors.

“The big concern that we have in the field ... is that the nerve growth factor antibody trials were all stopped because there was a low but persistent risk of rapidly progressive OA in a small percent of patients. I think one of the questions in the field is whether targeting other things having to do with OA pain is going to result in similar bad outcomes. I think the answer is probably not, but that’s one thing that people do worry about, and they never really figured out why the [rapidly progressive OA] was happening.”

 

‘Potential to Provide Meaningful and Sustained Analgesia’

The phase 2 trial of RTX-GRT7039, funded by manufacturer Grünenthal, enrolled 40 patients with a baseline visual analog pain score (VAS) of > 40 mm on motion for average joint pain in the target knee over the past 2 days with or without analgesic medication and Kellgren-Lawrence grades 2-4.

They were randomized to receive a single intra-articular injection of 2 mg or 4 mg RTX-GRT7039 within 1 minute after receiving 5 mL ropivacaine (0.5%) or 4 mg or 8 mg RTX-GRT7039 administered 15 minutes after 5 mL ropivacaine pretreatment, or equivalent placebo treatments plus ropivacaine.

Plasma samples were collected for up to 2 hours, and VAS pain scores were collected for up to 3 hours post injection.

Reductions in VAS scores from baseline in the treated knee were seen in all RTX treatment groups as early as day 8 post injection and were maintained up to 6 months, while no reductions in VAS pain on motion scores were seen in the placebo group.

At 3 months, the absolute baseline-adjusted reductions in VAS scores were similar for RTX 2 mg (–39.75), RTX 4 mg (–40.20), and RTX 8 mg (–30.25), while the reduction in the placebo group was just –8.50. At 6 months, the mean absolute reduction in VAS score was numerically greater in the RTX 2-mg (–46.49), RTX 4-mg (–43.40), and RTX 8-mg (–38.60) groups vs the group that received RTX 4 mg within 1 minute after receiving ropivacaine (–22.00).

At both 3 and 6 months, a higher proportion of patients receiving any dose of RTX-GRT7039 achieved ≥ 50% and ≥ 70% reduction in pain on motion, compared with those who received placebo. All RTX-GRT7039 treatment groups reported a greater improvement in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score than the placebo group at both 3 and 6 months.

Rates of treatment-emergent adverse events were similar between the RTX groups (85.7%-90.9%) and placebo (85.7%) and slightly lower in the group that received RTX 4 mg within 1 minute of receiving ropivacaine (60.0%).

There was a trend toward greater procedural/injection site pain in the RTX treatment groups, compared with placebo, most commonly arthralgia (37.5%), headache (17.5%), and back pain (10%). This tended to peak around 0.5 hours post injection and resolve by 1.5-3.0 hours.

No treatment-related serious adverse events occurred, and no treatment-emergent adverse events led to discontinuation or death.

“This early-phase trial indicates that RTX-GRT7039 has the potential to provide meaningful and sustained analgesia for patients with knee OA pain,” Conaghan and colleagues wrote in their poster.

The drug is now being evaluated in three phase 3 trials (NCT05248386, NCT05449132, and NCT05377489).

 

LEVI-04: Modulation of NT-3 Appears to Work Safely

LEVI-04 was evaluated in a phase 2, 20-week, 13-center (Europe and Hong Kong) randomized, double-blind, placebo-controlled trial in 518 people with knee OA who had WOMAC pain subscale scores ≥ 20, mean average daily pain numeric rating scale score of 4-9, and radiographic Kellgren-Lawrence grade ≥ 2.

They were randomized to a total of five infusions of placebo or 0.3 mg/kg, 0.1 mg/kg, or 2 mg/kg LEVI-04 from baseline through week 16, with safety follow-up to week 30.

The primary endpoint, change in WOMAC pain from baseline to weeks 5 and 17, was met for all three doses. At 17 weeks, those were –2.79, –2.89, and –3.08 for 0.3 mg, 1.0 mg, and 2 mg, respectively, vs –2.28 for placebo (all P < .05).

Secondary endpoints, including WOMAC physical function, WOMAC stiffness, and Patient Global Assessment, and > 50% pain responders, were also all met at weeks 5 and 17. More than 50% of the LEVI-04–treated patients reported ≥ 50% reduction in pain, and > 25% reported ≥ 75% reduction at weeks 5 and 17.

“So, this modulation of NT-3 is working,” Conaghan commented.

There were no increased incidences of severe adverse events, treatment-emergent adverse events, or joint pathologies, including rapidly progressive OA, compared with placebo.

There were more paresthesias reported with the active drug, 2-4 vs 1 with placebo. “That says to me that the drug is working and that it’s having an effect on peripheral nerves, but luckily these were all mild or moderate and didn’t lead to any study withdrawal or discontinuation,” Conaghan said.

Phase 3 trials are in the planning stages, he noted.

 

Other Approaches to Treating OA Pain

Other approaches to treating OA pain have included methotrexate, for which Conaghan was also a coauthor on one paper that came out earlier in 2024. “This presumably works by treating inflammation, but it’s not clear if that is within-joint inflammation or systemic inflammation,” he said in an interview.

Another approach, using the weight loss drug semaglutide, was presented in April 2024 at the 2024 World Congress on Osteoarthritis annual meeting and published in October 2024 in The New England Journal of Medicine

The trial involving RTX-GRT7039 was funded by Grünenthal, and some study coauthors are employees of the company. The trial involving LEVI-04 was funded by Levicept, and some study coauthors are employees of the company. Conaghan is a consultant and/or speaker for Eli Lilly, Eupraxia Pharmaceuticals, Formation Bio, Galapagos, Genascence, GlaxoSmithKline, Grünenthal, Janssen Pharmaceuticals, Kolon TissueGene, Levicept, Medipost, Moebius, Novartis, Pacira, Sandoz, Stryker Corporation, and Takeda. Gardner and Jeffries had no disclosures.

A version of this article appeared on Medscape.com.

WASHINGTON — Investigational treatments aimed specifically at reducing pain in knee osteoarthritis (OA) are moving forward in parallel with disease-modifying approaches.

“We still have very few treatments for the pain of osteoarthritis…It worries me that people think the only way forward is structure modification. I think while we’re waiting for some drugs to be structure modifying, we still need more pain relief. About 70% of people can’t tolerate or shouldn’t be on a [nonsteroidal anti-inflammatory drug], and that leaves a large number of people with pain,” Philip Conaghan, MBBS, PhD, Chair of Musculoskeletal Medicine at the University of Leeds in England, said in an interview.

At the annual meeting of the American College of Rheumatology, Conaghan, who is also honorary consultant rheumatologist for the Leeds Teaching Hospitals NHS Trust, presented new data for two novel approaches, both targeting peripheral nociceptive pain signaling.

In a late-breaking poster, he presented phase 2 trial data on RTX-GRT7039 (resiniferatoxin [RTX]), an agonist of the transient receptor potential vanilloid 1 that is a driver of OA pain. The trial investigated the efficacy and safety of a single intra-articular injection of RTX-GRT7039 in people with knee OA.

And separately, in a late-breaking oral abstract session, Conaghan presented phase 2 trial safety and efficacy data for another investigational agent called LEVI-04, a first-in-class neurotrophin receptor fusion protein (p75NTR-Fc) that supplements the endogenous protein and provides analgesia via inhibition of NT-3 activity.

“I think both have potential to provide good pain relief, through slightly different mechanisms,” Conaghan said in an interview.

Asked to comment, session moderator Gregory C. Gardner, MD, emeritus professor in the Division of Rheumatology at the University of Washington, Seattle, said in an interview: “I think the results are really exciting terms of the ability to control pain to a significant degree in patients with osteoarthritis.”

However, Gardner also said, “The molecules can be very expensive ... so who do we give them to? Will insurance companies pay for this simply for OA pain? They improve function ... so clearly, [they] will be a boon to treating osteoarthritis, but do we give them to people with only more advanced forms of osteoarthritis or earlier on?”

Moreover, Gardner said, “One of my concerns about treating osteoarthritis is I don’t want to do too good of a job treating pain in somebody who has a biomechanically abnormal joint. ... You’ve got a knee that’s worn out some of the cartilage, and now you feel like you can go out and play soccer again. That’s not a good thing. That joint will wear out very quickly, even though it doesn’t feel pain.”

Another OA expert, Matlock Jeffries, MD, director of the Arthritis Research Unit at the Oklahoma Medical Research Foundation, Oklahoma City, said in an interview, “I think we don’t focus nearly enough on pain, and that’s [partly] because the [Food and Drug Administration] has defined endpoints for knee OA trials that are radiographic. ... Patients do not care what their joint space narrowing is. They care what their pain is. And joint space changes and pain do not correlate in knee OA. ... About 20% or 30% of patients who have completely normal x-rays have a lot of pain…I hope that we’ll have some new OA pain therapeutics in the future because that’s what patients actually care about.”

But Jeffries noted that it will be very important to ensure that these agents don’t produce significant side effects, as had been seen previously in several large industry-sponsored trials of drugs targeting nerve growth factors.

“The big concern that we have in the field ... is that the nerve growth factor antibody trials were all stopped because there was a low but persistent risk of rapidly progressive OA in a small percent of patients. I think one of the questions in the field is whether targeting other things having to do with OA pain is going to result in similar bad outcomes. I think the answer is probably not, but that’s one thing that people do worry about, and they never really figured out why the [rapidly progressive OA] was happening.”

 

‘Potential to Provide Meaningful and Sustained Analgesia’

The phase 2 trial of RTX-GRT7039, funded by manufacturer Grünenthal, enrolled 40 patients with a baseline visual analog pain score (VAS) of > 40 mm on motion for average joint pain in the target knee over the past 2 days with or without analgesic medication and Kellgren-Lawrence grades 2-4.

They were randomized to receive a single intra-articular injection of 2 mg or 4 mg RTX-GRT7039 within 1 minute after receiving 5 mL ropivacaine (0.5%) or 4 mg or 8 mg RTX-GRT7039 administered 15 minutes after 5 mL ropivacaine pretreatment, or equivalent placebo treatments plus ropivacaine.

Plasma samples were collected for up to 2 hours, and VAS pain scores were collected for up to 3 hours post injection.

Reductions in VAS scores from baseline in the treated knee were seen in all RTX treatment groups as early as day 8 post injection and were maintained up to 6 months, while no reductions in VAS pain on motion scores were seen in the placebo group.

At 3 months, the absolute baseline-adjusted reductions in VAS scores were similar for RTX 2 mg (–39.75), RTX 4 mg (–40.20), and RTX 8 mg (–30.25), while the reduction in the placebo group was just –8.50. At 6 months, the mean absolute reduction in VAS score was numerically greater in the RTX 2-mg (–46.49), RTX 4-mg (–43.40), and RTX 8-mg (–38.60) groups vs the group that received RTX 4 mg within 1 minute after receiving ropivacaine (–22.00).

At both 3 and 6 months, a higher proportion of patients receiving any dose of RTX-GRT7039 achieved ≥ 50% and ≥ 70% reduction in pain on motion, compared with those who received placebo. All RTX-GRT7039 treatment groups reported a greater improvement in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score than the placebo group at both 3 and 6 months.

Rates of treatment-emergent adverse events were similar between the RTX groups (85.7%-90.9%) and placebo (85.7%) and slightly lower in the group that received RTX 4 mg within 1 minute of receiving ropivacaine (60.0%).

There was a trend toward greater procedural/injection site pain in the RTX treatment groups, compared with placebo, most commonly arthralgia (37.5%), headache (17.5%), and back pain (10%). This tended to peak around 0.5 hours post injection and resolve by 1.5-3.0 hours.

No treatment-related serious adverse events occurred, and no treatment-emergent adverse events led to discontinuation or death.

“This early-phase trial indicates that RTX-GRT7039 has the potential to provide meaningful and sustained analgesia for patients with knee OA pain,” Conaghan and colleagues wrote in their poster.

The drug is now being evaluated in three phase 3 trials (NCT05248386, NCT05449132, and NCT05377489).

 

LEVI-04: Modulation of NT-3 Appears to Work Safely

LEVI-04 was evaluated in a phase 2, 20-week, 13-center (Europe and Hong Kong) randomized, double-blind, placebo-controlled trial in 518 people with knee OA who had WOMAC pain subscale scores ≥ 20, mean average daily pain numeric rating scale score of 4-9, and radiographic Kellgren-Lawrence grade ≥ 2.

They were randomized to a total of five infusions of placebo or 0.3 mg/kg, 0.1 mg/kg, or 2 mg/kg LEVI-04 from baseline through week 16, with safety follow-up to week 30.

The primary endpoint, change in WOMAC pain from baseline to weeks 5 and 17, was met for all three doses. At 17 weeks, those were –2.79, –2.89, and –3.08 for 0.3 mg, 1.0 mg, and 2 mg, respectively, vs –2.28 for placebo (all P < .05).

Secondary endpoints, including WOMAC physical function, WOMAC stiffness, and Patient Global Assessment, and > 50% pain responders, were also all met at weeks 5 and 17. More than 50% of the LEVI-04–treated patients reported ≥ 50% reduction in pain, and > 25% reported ≥ 75% reduction at weeks 5 and 17.

“So, this modulation of NT-3 is working,” Conaghan commented.

There were no increased incidences of severe adverse events, treatment-emergent adverse events, or joint pathologies, including rapidly progressive OA, compared with placebo.

There were more paresthesias reported with the active drug, 2-4 vs 1 with placebo. “That says to me that the drug is working and that it’s having an effect on peripheral nerves, but luckily these were all mild or moderate and didn’t lead to any study withdrawal or discontinuation,” Conaghan said.

Phase 3 trials are in the planning stages, he noted.

 

Other Approaches to Treating OA Pain

Other approaches to treating OA pain have included methotrexate, for which Conaghan was also a coauthor on one paper that came out earlier in 2024. “This presumably works by treating inflammation, but it’s not clear if that is within-joint inflammation or systemic inflammation,” he said in an interview.

Another approach, using the weight loss drug semaglutide, was presented in April 2024 at the 2024 World Congress on Osteoarthritis annual meeting and published in October 2024 in The New England Journal of Medicine

The trial involving RTX-GRT7039 was funded by Grünenthal, and some study coauthors are employees of the company. The trial involving LEVI-04 was funded by Levicept, and some study coauthors are employees of the company. Conaghan is a consultant and/or speaker for Eli Lilly, Eupraxia Pharmaceuticals, Formation Bio, Galapagos, Genascence, GlaxoSmithKline, Grünenthal, Janssen Pharmaceuticals, Kolon TissueGene, Levicept, Medipost, Moebius, Novartis, Pacira, Sandoz, Stryker Corporation, and Takeda. Gardner and Jeffries had no disclosures.

A version of this article appeared on Medscape.com.

WASHINGTON — Investigational treatments aimed specifically at reducing pain in knee osteoarthritis (OA) are moving forward in parallel with disease-modifying approaches.

“We still have very few treatments for the pain of osteoarthritis…It worries me that people think the only way forward is structure modification. I think while we’re waiting for some drugs to be structure modifying, we still need more pain relief. About 70% of people can’t tolerate or shouldn’t be on a [nonsteroidal anti-inflammatory drug], and that leaves a large number of people with pain,” Philip Conaghan, MBBS, PhD, Chair of Musculoskeletal Medicine at the University of Leeds in England, said in an interview.

At the annual meeting of the American College of Rheumatology, Conaghan, who is also honorary consultant rheumatologist for the Leeds Teaching Hospitals NHS Trust, presented new data for two novel approaches, both targeting peripheral nociceptive pain signaling.

In a late-breaking poster, he presented phase 2 trial data on RTX-GRT7039 (resiniferatoxin [RTX]), an agonist of the transient receptor potential vanilloid 1 that is a driver of OA pain. The trial investigated the efficacy and safety of a single intra-articular injection of RTX-GRT7039 in people with knee OA.

And separately, in a late-breaking oral abstract session, Conaghan presented phase 2 trial safety and efficacy data for another investigational agent called LEVI-04, a first-in-class neurotrophin receptor fusion protein (p75NTR-Fc) that supplements the endogenous protein and provides analgesia via inhibition of NT-3 activity.

“I think both have potential to provide good pain relief, through slightly different mechanisms,” Conaghan said in an interview.

Asked to comment, session moderator Gregory C. Gardner, MD, emeritus professor in the Division of Rheumatology at the University of Washington, Seattle, said in an interview: “I think the results are really exciting terms of the ability to control pain to a significant degree in patients with osteoarthritis.”

However, Gardner also said, “The molecules can be very expensive ... so who do we give them to? Will insurance companies pay for this simply for OA pain? They improve function ... so clearly, [they] will be a boon to treating osteoarthritis, but do we give them to people with only more advanced forms of osteoarthritis or earlier on?”

Moreover, Gardner said, “One of my concerns about treating osteoarthritis is I don’t want to do too good of a job treating pain in somebody who has a biomechanically abnormal joint. ... You’ve got a knee that’s worn out some of the cartilage, and now you feel like you can go out and play soccer again. That’s not a good thing. That joint will wear out very quickly, even though it doesn’t feel pain.”

Another OA expert, Matlock Jeffries, MD, director of the Arthritis Research Unit at the Oklahoma Medical Research Foundation, Oklahoma City, said in an interview, “I think we don’t focus nearly enough on pain, and that’s [partly] because the [Food and Drug Administration] has defined endpoints for knee OA trials that are radiographic. ... Patients do not care what their joint space narrowing is. They care what their pain is. And joint space changes and pain do not correlate in knee OA. ... About 20% or 30% of patients who have completely normal x-rays have a lot of pain…I hope that we’ll have some new OA pain therapeutics in the future because that’s what patients actually care about.”

But Jeffries noted that it will be very important to ensure that these agents don’t produce significant side effects, as had been seen previously in several large industry-sponsored trials of drugs targeting nerve growth factors.

“The big concern that we have in the field ... is that the nerve growth factor antibody trials were all stopped because there was a low but persistent risk of rapidly progressive OA in a small percent of patients. I think one of the questions in the field is whether targeting other things having to do with OA pain is going to result in similar bad outcomes. I think the answer is probably not, but that’s one thing that people do worry about, and they never really figured out why the [rapidly progressive OA] was happening.”

 

‘Potential to Provide Meaningful and Sustained Analgesia’

The phase 2 trial of RTX-GRT7039, funded by manufacturer Grünenthal, enrolled 40 patients with a baseline visual analog pain score (VAS) of > 40 mm on motion for average joint pain in the target knee over the past 2 days with or without analgesic medication and Kellgren-Lawrence grades 2-4.

They were randomized to receive a single intra-articular injection of 2 mg or 4 mg RTX-GRT7039 within 1 minute after receiving 5 mL ropivacaine (0.5%) or 4 mg or 8 mg RTX-GRT7039 administered 15 minutes after 5 mL ropivacaine pretreatment, or equivalent placebo treatments plus ropivacaine.

Plasma samples were collected for up to 2 hours, and VAS pain scores were collected for up to 3 hours post injection.

Reductions in VAS scores from baseline in the treated knee were seen in all RTX treatment groups as early as day 8 post injection and were maintained up to 6 months, while no reductions in VAS pain on motion scores were seen in the placebo group.

At 3 months, the absolute baseline-adjusted reductions in VAS scores were similar for RTX 2 mg (–39.75), RTX 4 mg (–40.20), and RTX 8 mg (–30.25), while the reduction in the placebo group was just –8.50. At 6 months, the mean absolute reduction in VAS score was numerically greater in the RTX 2-mg (–46.49), RTX 4-mg (–43.40), and RTX 8-mg (–38.60) groups vs the group that received RTX 4 mg within 1 minute after receiving ropivacaine (–22.00).

At both 3 and 6 months, a higher proportion of patients receiving any dose of RTX-GRT7039 achieved ≥ 50% and ≥ 70% reduction in pain on motion, compared with those who received placebo. All RTX-GRT7039 treatment groups reported a greater improvement in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score than the placebo group at both 3 and 6 months.

Rates of treatment-emergent adverse events were similar between the RTX groups (85.7%-90.9%) and placebo (85.7%) and slightly lower in the group that received RTX 4 mg within 1 minute of receiving ropivacaine (60.0%).

There was a trend toward greater procedural/injection site pain in the RTX treatment groups, compared with placebo, most commonly arthralgia (37.5%), headache (17.5%), and back pain (10%). This tended to peak around 0.5 hours post injection and resolve by 1.5-3.0 hours.

No treatment-related serious adverse events occurred, and no treatment-emergent adverse events led to discontinuation or death.

“This early-phase trial indicates that RTX-GRT7039 has the potential to provide meaningful and sustained analgesia for patients with knee OA pain,” Conaghan and colleagues wrote in their poster.

The drug is now being evaluated in three phase 3 trials (NCT05248386, NCT05449132, and NCT05377489).

 

LEVI-04: Modulation of NT-3 Appears to Work Safely

LEVI-04 was evaluated in a phase 2, 20-week, 13-center (Europe and Hong Kong) randomized, double-blind, placebo-controlled trial in 518 people with knee OA who had WOMAC pain subscale scores ≥ 20, mean average daily pain numeric rating scale score of 4-9, and radiographic Kellgren-Lawrence grade ≥ 2.

They were randomized to a total of five infusions of placebo or 0.3 mg/kg, 0.1 mg/kg, or 2 mg/kg LEVI-04 from baseline through week 16, with safety follow-up to week 30.

The primary endpoint, change in WOMAC pain from baseline to weeks 5 and 17, was met for all three doses. At 17 weeks, those were –2.79, –2.89, and –3.08 for 0.3 mg, 1.0 mg, and 2 mg, respectively, vs –2.28 for placebo (all P < .05).

Secondary endpoints, including WOMAC physical function, WOMAC stiffness, and Patient Global Assessment, and > 50% pain responders, were also all met at weeks 5 and 17. More than 50% of the LEVI-04–treated patients reported ≥ 50% reduction in pain, and > 25% reported ≥ 75% reduction at weeks 5 and 17.

“So, this modulation of NT-3 is working,” Conaghan commented.

There were no increased incidences of severe adverse events, treatment-emergent adverse events, or joint pathologies, including rapidly progressive OA, compared with placebo.

There were more paresthesias reported with the active drug, 2-4 vs 1 with placebo. “That says to me that the drug is working and that it’s having an effect on peripheral nerves, but luckily these were all mild or moderate and didn’t lead to any study withdrawal or discontinuation,” Conaghan said.

Phase 3 trials are in the planning stages, he noted.

 

Other Approaches to Treating OA Pain

Other approaches to treating OA pain have included methotrexate, for which Conaghan was also a coauthor on one paper that came out earlier in 2024. “This presumably works by treating inflammation, but it’s not clear if that is within-joint inflammation or systemic inflammation,” he said in an interview.

Another approach, using the weight loss drug semaglutide, was presented in April 2024 at the 2024 World Congress on Osteoarthritis annual meeting and published in October 2024 in The New England Journal of Medicine

The trial involving RTX-GRT7039 was funded by Grünenthal, and some study coauthors are employees of the company. The trial involving LEVI-04 was funded by Levicept, and some study coauthors are employees of the company. Conaghan is a consultant and/or speaker for Eli Lilly, Eupraxia Pharmaceuticals, Formation Bio, Galapagos, Genascence, GlaxoSmithKline, Grünenthal, Janssen Pharmaceuticals, Kolon TissueGene, Levicept, Medipost, Moebius, Novartis, Pacira, Sandoz, Stryker Corporation, and Takeda. Gardner and Jeffries had no disclosures.

A version of this article appeared on Medscape.com.

WASHINGTON — Glucagon-like peptide 1 receptor agonist (GLP-1 RA) medications appear beneficial for people with systemic lupus erythematosus (SLE) and lupus nephritis, two new studies suggest. 

“The risk of cardiovascular disease is thought to be at least double that for people with lupus ... and we know the risk of progressing to end-stage renal disease [ESKD] for patients with lupus nephritis can be as high as 10%-30%, so there’s clearly a major unmet need for new treatments and approaches to improve these outcomes, perhaps with adjunctive treatment beyond our typical immunosuppressive therapy,” April Jorge, MD, of Massachusetts General Hospital, Boston, said at the annual meeting of the American College of Rheumatology (ACR). 

The GLP-1 RAs are approved for the treatment of type 2 diabetes (T2D) and obesity. They also have proven cardiovascular benefit, along with emerging data suggesting kidney protection independent of glucose lowering. Jorge presented findings from a study using data from the US multicenter electronic health record database TriNetX, showing that, among patients who had both T2D and SLE, those using GLP-1 RAs had lower risks for major adverse cardiac events (MACE), venous thrombosis, kidney disease progression, and all-cause mortality, compared with those using a different class of T2D medication. 

A second study using TriNetX, presented at the same ACR meeting session by Anna-Kay Palmer, MD, a third-year internal medicine resident at Jefferson Einstein Hospital, Philadelphia, Pennsylvania, showed that GLP-1 RAs reduced the risk of progression to ESKD in patients with lupus nephritis, possibly caused by reductions in pro-inflammatory mediators.

Asked to comment, session moderator Diane L. Kamen, MD, professor of medicine at the Medical University of South Carolina Division of Rheumatology, Charleston, said in an interview that she definitely supports the use of GLP-1 RAs for patients who have SLE and/or lupus nephritis and also a drug label indication, either T2D or obesity. “[The GLP-1 RA prescriber] will usually run it by rheumatology to make sure that it doesn’t conflict with any of their other medical treatment, and it’s very reassuring to know that they could actually get a win-win.” 

But as far as prescribing off-label for those with SLE/lupus nephritis who don’t have other GLP-1 RA indications, Kamen said, “that’s a black hole at this point. We need to do those prospective studies. But if they have another indication, yes.”

 

Cardiovascular, Kidney Benefits of GLP-1 RAs

Jorge noted that patients with lupus were excluded from the randomized clinical trials of GLP-1 RAs, so the current study was designed to investigate the potential impact of these medications on cardiovascular and kidney outcomes in patients with SLE and lupus nephritis. 

From TriNetX data for 46 healthcare organizations nationwide, a total of 96,511 patients with both SLE and T2D but not ESKD had initiated either a GLP-1 RA or another diabetes drug class, dipeptidyl peptidase 4 inhibitors (DPP4i), between October 2006 and August 2021. Of those, 29,177 had lupus nephritis. 

Propensity score matching for factors such as demographics, lupus severity, comorbidities, and medication use was used to emulate a randomized trial. This yielded 25,838 with SLE and T2D, of whom 910 initiated a GLP-1 RA and 1004 started a DPP4i, and 12,387 with lupus nephritis and T2D, including 267 on a GLP-1 RA and 324 on a DPP4i. After matching, the mean age was 55 years, more than 90% were women, and just under half were White individuals. About one third had chronic kidney disease stages ≥ 3, and about 15% had heart failure. 

Over an average follow-up time of 1.2-1.4 years among those with SLE, the hazard ratio (HR) for MACE (a composite of myocardial infarction, stroke, and heart failure) for those taking a GLP-1 RA vs a DPP4i was 0.66, a significant difference. And for venous thrombosis, the HR was also significant at 0.49.

Kidney disease progression, defined as an estimated glomerular filtration rate decline of 30% or more or new ESKD, was significantly less likely in the GLP-1 RA group, with a HR of 0.77. All-cause mortality also was dramatically reduced (HR, 0.26). As expected, there was no difference in control outcome, genital infections (HR, 1.02). 

In the subgroup with lupus nephritis, there were also lower risks for both MACE (HR, 0.64) and for renal progression (HR, 0.70). “The findings suggest similar cardiac and kidney benefits among patients with SLE and lupus nephritis as have been observed in other populations,” Jorge concluded. 

Kamen commented that the study design “was pretty brilliant, because you wouldn’t be able to do a placebo-controlled trial since the indication was diabetes ... but the fact is you do see that the GLP-1 RA gets the benefit whereas the other drug does not.”

Next steps, Jorge said, will be mechanistic studies to better understand the effects of GLP-1 RAs in lupus and other rheumatic diseases, prospective studies of GLP-1 RAs in SLE and lupus nephritis without diabetes, and clarification of ideal timing for GLP-1 RA use in SLE and lupus nephritis. 

“Ideally, with our prospective studies with these patients we can try to isolate the effect on patients with lupus and also better understand whether there might be an impact on disease activity through the anti-inflammatory effects of these medications, rather than just the cardioprotective and nephroprotective benefits,” she said. 

 

In Those With Lupus Nephritis, Kidney Protection Seen

In her presentation, Palmer noted that, despite immunosuppressive therapies for SLE, 10%-20% of patients who develop lupus nephritis will progress to ESKD within 5 years of diagnosis. 

She added that GLP-1 RAs have been shown to reduce albuminuria in people with diabetes and have been hypothesized to reduce inflammation through multiple pathways, thereby potentially reducing kidney disease independently of the presence of diabetes or weight loss. These pathways include modulating immune cell signaling and reducing pro-inflammatory cytokines. 

Based on all this, Palmer and colleagues used International Classification of Diseases – 10th edition diagnostic codes in TriNetX to identify 839 patients who had been diagnosed with lupus nephritis between 2014 and 2024 and who were prescribed liraglutide, dulaglutide, semaglutide, or exenatide for any time after the lupus nephritis diagnosis. Another 29,840 patients with lupus nephritis had not used GLP-1 RAs. 

After 1:1 propensity score matching for age, sex, race, ethnicity, presence of hypertension, diabetes, use of immunosuppressive and diabetes medication, smoking, obesity, and statin use, there were 735 individuals in each group. About two thirds in each had diabetes, whereas the rest had been prescribed the GLP-1 RAs for other indications. 

Patients who were not on GLP-1 RAs were twice as likely to develop ESKD or dialysis (8.88% vs 3.971%; odds ratio, 2.35; P = .001). 

Kamen pointed out that not including the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers was a study flaw. On the other hand, the fact that not everyone in this study had diabetes was an advantage.

Jorge received grant/research support from Bristol-Myers Squibb, Cabaletta Bio, and the Lupus Clinical Investigator Network. Kamen is an adviser/review panel member for Alpine Immune Sciences. Palmer had no disclosures.

A version of this article appeared on Medscape.com.

WASHINGTON — Glucagon-like peptide 1 receptor agonist (GLP-1 RA) medications appear beneficial for people with systemic lupus erythematosus (SLE) and lupus nephritis, two new studies suggest. 

“The risk of cardiovascular disease is thought to be at least double that for people with lupus ... and we know the risk of progressing to end-stage renal disease [ESKD] for patients with lupus nephritis can be as high as 10%-30%, so there’s clearly a major unmet need for new treatments and approaches to improve these outcomes, perhaps with adjunctive treatment beyond our typical immunosuppressive therapy,” April Jorge, MD, of Massachusetts General Hospital, Boston, said at the annual meeting of the American College of Rheumatology (ACR). 

The GLP-1 RAs are approved for the treatment of type 2 diabetes (T2D) and obesity. They also have proven cardiovascular benefit, along with emerging data suggesting kidney protection independent of glucose lowering. Jorge presented findings from a study using data from the US multicenter electronic health record database TriNetX, showing that, among patients who had both T2D and SLE, those using GLP-1 RAs had lower risks for major adverse cardiac events (MACE), venous thrombosis, kidney disease progression, and all-cause mortality, compared with those using a different class of T2D medication. 

A second study using TriNetX, presented at the same ACR meeting session by Anna-Kay Palmer, MD, a third-year internal medicine resident at Jefferson Einstein Hospital, Philadelphia, Pennsylvania, showed that GLP-1 RAs reduced the risk of progression to ESKD in patients with lupus nephritis, possibly caused by reductions in pro-inflammatory mediators.

Asked to comment, session moderator Diane L. Kamen, MD, professor of medicine at the Medical University of South Carolina Division of Rheumatology, Charleston, said in an interview that she definitely supports the use of GLP-1 RAs for patients who have SLE and/or lupus nephritis and also a drug label indication, either T2D or obesity. “[The GLP-1 RA prescriber] will usually run it by rheumatology to make sure that it doesn’t conflict with any of their other medical treatment, and it’s very reassuring to know that they could actually get a win-win.” 

But as far as prescribing off-label for those with SLE/lupus nephritis who don’t have other GLP-1 RA indications, Kamen said, “that’s a black hole at this point. We need to do those prospective studies. But if they have another indication, yes.”

 

Cardiovascular, Kidney Benefits of GLP-1 RAs

Jorge noted that patients with lupus were excluded from the randomized clinical trials of GLP-1 RAs, so the current study was designed to investigate the potential impact of these medications on cardiovascular and kidney outcomes in patients with SLE and lupus nephritis. 

From TriNetX data for 46 healthcare organizations nationwide, a total of 96,511 patients with both SLE and T2D but not ESKD had initiated either a GLP-1 RA or another diabetes drug class, dipeptidyl peptidase 4 inhibitors (DPP4i), between October 2006 and August 2021. Of those, 29,177 had lupus nephritis. 

Propensity score matching for factors such as demographics, lupus severity, comorbidities, and medication use was used to emulate a randomized trial. This yielded 25,838 with SLE and T2D, of whom 910 initiated a GLP-1 RA and 1004 started a DPP4i, and 12,387 with lupus nephritis and T2D, including 267 on a GLP-1 RA and 324 on a DPP4i. After matching, the mean age was 55 years, more than 90% were women, and just under half were White individuals. About one third had chronic kidney disease stages ≥ 3, and about 15% had heart failure. 

Over an average follow-up time of 1.2-1.4 years among those with SLE, the hazard ratio (HR) for MACE (a composite of myocardial infarction, stroke, and heart failure) for those taking a GLP-1 RA vs a DPP4i was 0.66, a significant difference. And for venous thrombosis, the HR was also significant at 0.49.

Kidney disease progression, defined as an estimated glomerular filtration rate decline of 30% or more or new ESKD, was significantly less likely in the GLP-1 RA group, with a HR of 0.77. All-cause mortality also was dramatically reduced (HR, 0.26). As expected, there was no difference in control outcome, genital infections (HR, 1.02). 

In the subgroup with lupus nephritis, there were also lower risks for both MACE (HR, 0.64) and for renal progression (HR, 0.70). “The findings suggest similar cardiac and kidney benefits among patients with SLE and lupus nephritis as have been observed in other populations,” Jorge concluded. 

Kamen commented that the study design “was pretty brilliant, because you wouldn’t be able to do a placebo-controlled trial since the indication was diabetes ... but the fact is you do see that the GLP-1 RA gets the benefit whereas the other drug does not.”

Next steps, Jorge said, will be mechanistic studies to better understand the effects of GLP-1 RAs in lupus and other rheumatic diseases, prospective studies of GLP-1 RAs in SLE and lupus nephritis without diabetes, and clarification of ideal timing for GLP-1 RA use in SLE and lupus nephritis. 

“Ideally, with our prospective studies with these patients we can try to isolate the effect on patients with lupus and also better understand whether there might be an impact on disease activity through the anti-inflammatory effects of these medications, rather than just the cardioprotective and nephroprotective benefits,” she said. 

 

In Those With Lupus Nephritis, Kidney Protection Seen

In her presentation, Palmer noted that, despite immunosuppressive therapies for SLE, 10%-20% of patients who develop lupus nephritis will progress to ESKD within 5 years of diagnosis. 

She added that GLP-1 RAs have been shown to reduce albuminuria in people with diabetes and have been hypothesized to reduce inflammation through multiple pathways, thereby potentially reducing kidney disease independently of the presence of diabetes or weight loss. These pathways include modulating immune cell signaling and reducing pro-inflammatory cytokines. 

Based on all this, Palmer and colleagues used International Classification of Diseases – 10th edition diagnostic codes in TriNetX to identify 839 patients who had been diagnosed with lupus nephritis between 2014 and 2024 and who were prescribed liraglutide, dulaglutide, semaglutide, or exenatide for any time after the lupus nephritis diagnosis. Another 29,840 patients with lupus nephritis had not used GLP-1 RAs. 

After 1:1 propensity score matching for age, sex, race, ethnicity, presence of hypertension, diabetes, use of immunosuppressive and diabetes medication, smoking, obesity, and statin use, there were 735 individuals in each group. About two thirds in each had diabetes, whereas the rest had been prescribed the GLP-1 RAs for other indications. 

Patients who were not on GLP-1 RAs were twice as likely to develop ESKD or dialysis (8.88% vs 3.971%; odds ratio, 2.35; P = .001). 

Kamen pointed out that not including the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers was a study flaw. On the other hand, the fact that not everyone in this study had diabetes was an advantage.

Jorge received grant/research support from Bristol-Myers Squibb, Cabaletta Bio, and the Lupus Clinical Investigator Network. Kamen is an adviser/review panel member for Alpine Immune Sciences. Palmer had no disclosures.

A version of this article appeared on Medscape.com.

WASHINGTON — Glucagon-like peptide 1 receptor agonist (GLP-1 RA) medications appear beneficial for people with systemic lupus erythematosus (SLE) and lupus nephritis, two new studies suggest. 

“The risk of cardiovascular disease is thought to be at least double that for people with lupus ... and we know the risk of progressing to end-stage renal disease [ESKD] for patients with lupus nephritis can be as high as 10%-30%, so there’s clearly a major unmet need for new treatments and approaches to improve these outcomes, perhaps with adjunctive treatment beyond our typical immunosuppressive therapy,” April Jorge, MD, of Massachusetts General Hospital, Boston, said at the annual meeting of the American College of Rheumatology (ACR). 

The GLP-1 RAs are approved for the treatment of type 2 diabetes (T2D) and obesity. They also have proven cardiovascular benefit, along with emerging data suggesting kidney protection independent of glucose lowering. Jorge presented findings from a study using data from the US multicenter electronic health record database TriNetX, showing that, among patients who had both T2D and SLE, those using GLP-1 RAs had lower risks for major adverse cardiac events (MACE), venous thrombosis, kidney disease progression, and all-cause mortality, compared with those using a different class of T2D medication. 

A second study using TriNetX, presented at the same ACR meeting session by Anna-Kay Palmer, MD, a third-year internal medicine resident at Jefferson Einstein Hospital, Philadelphia, Pennsylvania, showed that GLP-1 RAs reduced the risk of progression to ESKD in patients with lupus nephritis, possibly caused by reductions in pro-inflammatory mediators.

Asked to comment, session moderator Diane L. Kamen, MD, professor of medicine at the Medical University of South Carolina Division of Rheumatology, Charleston, said in an interview that she definitely supports the use of GLP-1 RAs for patients who have SLE and/or lupus nephritis and also a drug label indication, either T2D or obesity. “[The GLP-1 RA prescriber] will usually run it by rheumatology to make sure that it doesn’t conflict with any of their other medical treatment, and it’s very reassuring to know that they could actually get a win-win.” 

But as far as prescribing off-label for those with SLE/lupus nephritis who don’t have other GLP-1 RA indications, Kamen said, “that’s a black hole at this point. We need to do those prospective studies. But if they have another indication, yes.”

 

Cardiovascular, Kidney Benefits of GLP-1 RAs

Jorge noted that patients with lupus were excluded from the randomized clinical trials of GLP-1 RAs, so the current study was designed to investigate the potential impact of these medications on cardiovascular and kidney outcomes in patients with SLE and lupus nephritis. 

From TriNetX data for 46 healthcare organizations nationwide, a total of 96,511 patients with both SLE and T2D but not ESKD had initiated either a GLP-1 RA or another diabetes drug class, dipeptidyl peptidase 4 inhibitors (DPP4i), between October 2006 and August 2021. Of those, 29,177 had lupus nephritis. 

Propensity score matching for factors such as demographics, lupus severity, comorbidities, and medication use was used to emulate a randomized trial. This yielded 25,838 with SLE and T2D, of whom 910 initiated a GLP-1 RA and 1004 started a DPP4i, and 12,387 with lupus nephritis and T2D, including 267 on a GLP-1 RA and 324 on a DPP4i. After matching, the mean age was 55 years, more than 90% were women, and just under half were White individuals. About one third had chronic kidney disease stages ≥ 3, and about 15% had heart failure. 

Over an average follow-up time of 1.2-1.4 years among those with SLE, the hazard ratio (HR) for MACE (a composite of myocardial infarction, stroke, and heart failure) for those taking a GLP-1 RA vs a DPP4i was 0.66, a significant difference. And for venous thrombosis, the HR was also significant at 0.49.

Kidney disease progression, defined as an estimated glomerular filtration rate decline of 30% or more or new ESKD, was significantly less likely in the GLP-1 RA group, with a HR of 0.77. All-cause mortality also was dramatically reduced (HR, 0.26). As expected, there was no difference in control outcome, genital infections (HR, 1.02). 

In the subgroup with lupus nephritis, there were also lower risks for both MACE (HR, 0.64) and for renal progression (HR, 0.70). “The findings suggest similar cardiac and kidney benefits among patients with SLE and lupus nephritis as have been observed in other populations,” Jorge concluded. 

Kamen commented that the study design “was pretty brilliant, because you wouldn’t be able to do a placebo-controlled trial since the indication was diabetes ... but the fact is you do see that the GLP-1 RA gets the benefit whereas the other drug does not.”

Next steps, Jorge said, will be mechanistic studies to better understand the effects of GLP-1 RAs in lupus and other rheumatic diseases, prospective studies of GLP-1 RAs in SLE and lupus nephritis without diabetes, and clarification of ideal timing for GLP-1 RA use in SLE and lupus nephritis. 

“Ideally, with our prospective studies with these patients we can try to isolate the effect on patients with lupus and also better understand whether there might be an impact on disease activity through the anti-inflammatory effects of these medications, rather than just the cardioprotective and nephroprotective benefits,” she said. 

 

In Those With Lupus Nephritis, Kidney Protection Seen

In her presentation, Palmer noted that, despite immunosuppressive therapies for SLE, 10%-20% of patients who develop lupus nephritis will progress to ESKD within 5 years of diagnosis. 

She added that GLP-1 RAs have been shown to reduce albuminuria in people with diabetes and have been hypothesized to reduce inflammation through multiple pathways, thereby potentially reducing kidney disease independently of the presence of diabetes or weight loss. These pathways include modulating immune cell signaling and reducing pro-inflammatory cytokines. 

Based on all this, Palmer and colleagues used International Classification of Diseases – 10th edition diagnostic codes in TriNetX to identify 839 patients who had been diagnosed with lupus nephritis between 2014 and 2024 and who were prescribed liraglutide, dulaglutide, semaglutide, or exenatide for any time after the lupus nephritis diagnosis. Another 29,840 patients with lupus nephritis had not used GLP-1 RAs. 

After 1:1 propensity score matching for age, sex, race, ethnicity, presence of hypertension, diabetes, use of immunosuppressive and diabetes medication, smoking, obesity, and statin use, there were 735 individuals in each group. About two thirds in each had diabetes, whereas the rest had been prescribed the GLP-1 RAs for other indications. 

Patients who were not on GLP-1 RAs were twice as likely to develop ESKD or dialysis (8.88% vs 3.971%; odds ratio, 2.35; P = .001). 

Kamen pointed out that not including the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers was a study flaw. On the other hand, the fact that not everyone in this study had diabetes was an advantage.

Jorge received grant/research support from Bristol-Myers Squibb, Cabaletta Bio, and the Lupus Clinical Investigator Network. Kamen is an adviser/review panel member for Alpine Immune Sciences. Palmer had no disclosures.

A version of this article appeared on Medscape.com.

WASHINGTON — A fully automated ultrasound scanning system combined with artificial intelligence–based disease activity scoring performed as well as expert rheumatologists in hand joint assessment of patients with rheumatoid arthritis (RA), new research found.

The system, made by a Danish company called ROPCA, comprises an ultrasound scanner called ARTHUR (RA Ultrasound Robot) that interacts directly with the patient and scans 11 joints per hand and a neural network–based software system, DIANA (Diagnosis Aid Network for RA), that evaluates the images and monitors RA activity.

 

The combined system classifies the degree of RA according to the joint European Alliance of Associations for Rheumatology (EULAR)–Outcome Measures in Rheumatology (OMERACT) standards for RA diagnosis. It received a CE Mark in Europe in 2022 and is currently in use in six rheumatology clinics in Denmark, Germany, Switzerland, and Austria, with more to come, ROPCA Co-founder and Chief Medical Officer Søren A. Just, MD, said in an interview.

“Automated systems could help rheumatologists in the early detection and monitoring of arthritis diseases. Systems can be placed or move in areas with insufficient rheumatological expertise,” Just said during a special late-breaker session presentation at the annual meeting of the American College of Rheumatology (ACR).

He said in an interview: “Currently, there are so many people referred and few and fewer rheumatologists. So we need to think differently. We need good automated assistants.” As a screening tool, the system can determine whether a person with hand pain has RA or just osteoarthritis “and also can give the patient an immediate answer, instead of waiting sometimes up to 6 months to get the information.”

Just, who is also a senior physician in the Department of Internal Medicine at Odense University Hospital in Denmark, said that his department is also using the system to assess flares in patients with established RA. “They can have a blood sample taken. They’re scanned by the robot, and you can see if there is any disease activity. But I think that screening of patients with joint pain is the beginning.”

Asked to comment, session moderator Gregory C. Gardner, MD, Emeritus Professor in the Division of Rheumatology at the University of Washington, Seattle, and a member of the ACR conference program committee, said in an interview “one of the reasons we chose to feature this abstract is because we’re interested in science at the convergence. We really thought this was a potential way to move the field forward for rheumatologists.”

Gardner said it’s an advantage that the patient could potentially have an ARTHUR scan with a DIANA report and get blood tests done prior to a visit with the rheumatologist. “It’s really time-consuming for a human to do these studies, so if you automate it, that’s a step forward in terms of having the data available for the rheumatologist to view and use sequentially to follow how patients are doing.”

When introducing Just’s presentation, Gardner called it “the coolest abstract of the meeting.”

 

Both DIANA and ARTHUR Performed At Least as Well as Human Rheumatologists

In the study, 30 patients with RA underwent two scans by ARTHUR, followed by a scan from a rheumatologist specialist in musculoskeletal ultrasound. The scans were sent to DIANA, who graded the images according to the Global OMERACT-EULAR Synovitis Score, as did the human rheumatologist.

A “ground truth” was established by another human expert who evaluated both ARTHUR’s and the other rheumatologist’s images, blinded to the scanning method. The image with the highest disease activity was deemed “ground truth,” and agreement with that was assessed for the two individual methods.

 

Just showed a video of a patient being scanned by ARTHUR. The machine verbally guided her through removing her jewelry, applying the gel, and placing her hand on the screen under the scanner. ARTHUR’s arm moved around on the patient’s hand, locating the best angles to take grayscale images and Doppler images and Doppler video. The scan takes 15-20 minutes, and the images are stored, Just said.

The study patients had a mean age of 65 years, and 23 of the 30 were men. Their average disease duration was 11 years, and mean Disease Activity Score in 28 joints using C-reactive protein was 3.86, indicating moderate disease. A majority (73%) of patients were taking disease-modifying antirheumatic drugs, and about one third were taking biologics. ARTHUR scanned a total of 660 joints, and 564 scans were successful.

For repeatability between the two ARTHUR scans, percent exact agreement was 63% for synovial hypertrophy, 75% for Doppler activity, and 60% combined. Percent close (within a point) agreements were 93%, 94%, and 92%, respectively. Binary agreements as to whether the joint was healthy vs diseased were 88%, 91%, and 85%, respectively.

At the joint level, ARTHUR and DIANA’s percent exact agreement with ground truth was 49% for synovial hypertrophy, 63% for Doppler activity, and 48% combined. Binary agreements with disease vs healthy were 80%, 88%, and 78%, respectively.

The human rheumatologists scored very similarly. Percent exact agreement with ground truth was 51% for synovial hypertrophy, 64% for Doppler activity, and 50% combined. Percent close agreements were 94%, 94%, and 92%, respectively. And binary agreements with diseased vs healthy were 83%, 91%, and 80%, respectively.

At the patient level (all joints combined), ARTHUR and DIANA’s binary disease assessment of healthy vs disease showed agreement with the ground truth of 87% for synovial hypertrophy, 83% for Doppler activity, and 87% combined. Here, the rheumatologists scored lower, at 53%, 67%, and 60%, respectively.

“In this study, we think the precision of ARTHUR and DIANA was comparable to that of an experienced rheumatologist, at both the joint and patient level,” Just said.

Gardner pointed out another advantage of the system. “DIANA doesn’t get fatigued. ... With human reading, the precision may change based on the time of day or stress level. ... But with DIANA, you’re going to get consistent information.”

Just said that the Arthritis Foundation in Germany recently put ARTHUR and DIANA on a bus and took it to cities that lacked a rheumatologist. Patients lined up, answered a questionnaire, had blood drawn, and received their scans. A rheumatologist on the bus then interpreted the data and consulted with the individuals about their RA risk. “In the last trip, we screened 800 patients in 6 days. So there are definitely possibilities here.”

Just is co-owner of ROPCA. Gardner had no disclosures.

A version of this article appeared on Medscape.com.

WASHINGTON — A fully automated ultrasound scanning system combined with artificial intelligence–based disease activity scoring performed as well as expert rheumatologists in hand joint assessment of patients with rheumatoid arthritis (RA), new research found.

The system, made by a Danish company called ROPCA, comprises an ultrasound scanner called ARTHUR (RA Ultrasound Robot) that interacts directly with the patient and scans 11 joints per hand and a neural network–based software system, DIANA (Diagnosis Aid Network for RA), that evaluates the images and monitors RA activity.

 

The combined system classifies the degree of RA according to the joint European Alliance of Associations for Rheumatology (EULAR)–Outcome Measures in Rheumatology (OMERACT) standards for RA diagnosis. It received a CE Mark in Europe in 2022 and is currently in use in six rheumatology clinics in Denmark, Germany, Switzerland, and Austria, with more to come, ROPCA Co-founder and Chief Medical Officer Søren A. Just, MD, said in an interview.

“Automated systems could help rheumatologists in the early detection and monitoring of arthritis diseases. Systems can be placed or move in areas with insufficient rheumatological expertise,” Just said during a special late-breaker session presentation at the annual meeting of the American College of Rheumatology (ACR).

He said in an interview: “Currently, there are so many people referred and few and fewer rheumatologists. So we need to think differently. We need good automated assistants.” As a screening tool, the system can determine whether a person with hand pain has RA or just osteoarthritis “and also can give the patient an immediate answer, instead of waiting sometimes up to 6 months to get the information.”

Just, who is also a senior physician in the Department of Internal Medicine at Odense University Hospital in Denmark, said that his department is also using the system to assess flares in patients with established RA. “They can have a blood sample taken. They’re scanned by the robot, and you can see if there is any disease activity. But I think that screening of patients with joint pain is the beginning.”

Asked to comment, session moderator Gregory C. Gardner, MD, Emeritus Professor in the Division of Rheumatology at the University of Washington, Seattle, and a member of the ACR conference program committee, said in an interview “one of the reasons we chose to feature this abstract is because we’re interested in science at the convergence. We really thought this was a potential way to move the field forward for rheumatologists.”

Gardner said it’s an advantage that the patient could potentially have an ARTHUR scan with a DIANA report and get blood tests done prior to a visit with the rheumatologist. “It’s really time-consuming for a human to do these studies, so if you automate it, that’s a step forward in terms of having the data available for the rheumatologist to view and use sequentially to follow how patients are doing.”

When introducing Just’s presentation, Gardner called it “the coolest abstract of the meeting.”

 

Both DIANA and ARTHUR Performed At Least as Well as Human Rheumatologists

In the study, 30 patients with RA underwent two scans by ARTHUR, followed by a scan from a rheumatologist specialist in musculoskeletal ultrasound. The scans were sent to DIANA, who graded the images according to the Global OMERACT-EULAR Synovitis Score, as did the human rheumatologist.

A “ground truth” was established by another human expert who evaluated both ARTHUR’s and the other rheumatologist’s images, blinded to the scanning method. The image with the highest disease activity was deemed “ground truth,” and agreement with that was assessed for the two individual methods.

 

Just showed a video of a patient being scanned by ARTHUR. The machine verbally guided her through removing her jewelry, applying the gel, and placing her hand on the screen under the scanner. ARTHUR’s arm moved around on the patient’s hand, locating the best angles to take grayscale images and Doppler images and Doppler video. The scan takes 15-20 minutes, and the images are stored, Just said.

The study patients had a mean age of 65 years, and 23 of the 30 were men. Their average disease duration was 11 years, and mean Disease Activity Score in 28 joints using C-reactive protein was 3.86, indicating moderate disease. A majority (73%) of patients were taking disease-modifying antirheumatic drugs, and about one third were taking biologics. ARTHUR scanned a total of 660 joints, and 564 scans were successful.

For repeatability between the two ARTHUR scans, percent exact agreement was 63% for synovial hypertrophy, 75% for Doppler activity, and 60% combined. Percent close (within a point) agreements were 93%, 94%, and 92%, respectively. Binary agreements as to whether the joint was healthy vs diseased were 88%, 91%, and 85%, respectively.

At the joint level, ARTHUR and DIANA’s percent exact agreement with ground truth was 49% for synovial hypertrophy, 63% for Doppler activity, and 48% combined. Binary agreements with disease vs healthy were 80%, 88%, and 78%, respectively.

The human rheumatologists scored very similarly. Percent exact agreement with ground truth was 51% for synovial hypertrophy, 64% for Doppler activity, and 50% combined. Percent close agreements were 94%, 94%, and 92%, respectively. And binary agreements with diseased vs healthy were 83%, 91%, and 80%, respectively.

At the patient level (all joints combined), ARTHUR and DIANA’s binary disease assessment of healthy vs disease showed agreement with the ground truth of 87% for synovial hypertrophy, 83% for Doppler activity, and 87% combined. Here, the rheumatologists scored lower, at 53%, 67%, and 60%, respectively.

“In this study, we think the precision of ARTHUR and DIANA was comparable to that of an experienced rheumatologist, at both the joint and patient level,” Just said.

Gardner pointed out another advantage of the system. “DIANA doesn’t get fatigued. ... With human reading, the precision may change based on the time of day or stress level. ... But with DIANA, you’re going to get consistent information.”

Just said that the Arthritis Foundation in Germany recently put ARTHUR and DIANA on a bus and took it to cities that lacked a rheumatologist. Patients lined up, answered a questionnaire, had blood drawn, and received their scans. A rheumatologist on the bus then interpreted the data and consulted with the individuals about their RA risk. “In the last trip, we screened 800 patients in 6 days. So there are definitely possibilities here.”

Just is co-owner of ROPCA. Gardner had no disclosures.

A version of this article appeared on Medscape.com.

WASHINGTON — A fully automated ultrasound scanning system combined with artificial intelligence–based disease activity scoring performed as well as expert rheumatologists in hand joint assessment of patients with rheumatoid arthritis (RA), new research found.

The system, made by a Danish company called ROPCA, comprises an ultrasound scanner called ARTHUR (RA Ultrasound Robot) that interacts directly with the patient and scans 11 joints per hand and a neural network–based software system, DIANA (Diagnosis Aid Network for RA), that evaluates the images and monitors RA activity.

 

The combined system classifies the degree of RA according to the joint European Alliance of Associations for Rheumatology (EULAR)–Outcome Measures in Rheumatology (OMERACT) standards for RA diagnosis. It received a CE Mark in Europe in 2022 and is currently in use in six rheumatology clinics in Denmark, Germany, Switzerland, and Austria, with more to come, ROPCA Co-founder and Chief Medical Officer Søren A. Just, MD, said in an interview.

“Automated systems could help rheumatologists in the early detection and monitoring of arthritis diseases. Systems can be placed or move in areas with insufficient rheumatological expertise,” Just said during a special late-breaker session presentation at the annual meeting of the American College of Rheumatology (ACR).

He said in an interview: “Currently, there are so many people referred and few and fewer rheumatologists. So we need to think differently. We need good automated assistants.” As a screening tool, the system can determine whether a person with hand pain has RA or just osteoarthritis “and also can give the patient an immediate answer, instead of waiting sometimes up to 6 months to get the information.”

Just, who is also a senior physician in the Department of Internal Medicine at Odense University Hospital in Denmark, said that his department is also using the system to assess flares in patients with established RA. “They can have a blood sample taken. They’re scanned by the robot, and you can see if there is any disease activity. But I think that screening of patients with joint pain is the beginning.”

Asked to comment, session moderator Gregory C. Gardner, MD, Emeritus Professor in the Division of Rheumatology at the University of Washington, Seattle, and a member of the ACR conference program committee, said in an interview “one of the reasons we chose to feature this abstract is because we’re interested in science at the convergence. We really thought this was a potential way to move the field forward for rheumatologists.”

Gardner said it’s an advantage that the patient could potentially have an ARTHUR scan with a DIANA report and get blood tests done prior to a visit with the rheumatologist. “It’s really time-consuming for a human to do these studies, so if you automate it, that’s a step forward in terms of having the data available for the rheumatologist to view and use sequentially to follow how patients are doing.”

When introducing Just’s presentation, Gardner called it “the coolest abstract of the meeting.”

 

Both DIANA and ARTHUR Performed At Least as Well as Human Rheumatologists

In the study, 30 patients with RA underwent two scans by ARTHUR, followed by a scan from a rheumatologist specialist in musculoskeletal ultrasound. The scans were sent to DIANA, who graded the images according to the Global OMERACT-EULAR Synovitis Score, as did the human rheumatologist.

A “ground truth” was established by another human expert who evaluated both ARTHUR’s and the other rheumatologist’s images, blinded to the scanning method. The image with the highest disease activity was deemed “ground truth,” and agreement with that was assessed for the two individual methods.

 

Just showed a video of a patient being scanned by ARTHUR. The machine verbally guided her through removing her jewelry, applying the gel, and placing her hand on the screen under the scanner. ARTHUR’s arm moved around on the patient’s hand, locating the best angles to take grayscale images and Doppler images and Doppler video. The scan takes 15-20 minutes, and the images are stored, Just said.

The study patients had a mean age of 65 years, and 23 of the 30 were men. Their average disease duration was 11 years, and mean Disease Activity Score in 28 joints using C-reactive protein was 3.86, indicating moderate disease. A majority (73%) of patients were taking disease-modifying antirheumatic drugs, and about one third were taking biologics. ARTHUR scanned a total of 660 joints, and 564 scans were successful.

For repeatability between the two ARTHUR scans, percent exact agreement was 63% for synovial hypertrophy, 75% for Doppler activity, and 60% combined. Percent close (within a point) agreements were 93%, 94%, and 92%, respectively. Binary agreements as to whether the joint was healthy vs diseased were 88%, 91%, and 85%, respectively.

At the joint level, ARTHUR and DIANA’s percent exact agreement with ground truth was 49% for synovial hypertrophy, 63% for Doppler activity, and 48% combined. Binary agreements with disease vs healthy were 80%, 88%, and 78%, respectively.

The human rheumatologists scored very similarly. Percent exact agreement with ground truth was 51% for synovial hypertrophy, 64% for Doppler activity, and 50% combined. Percent close agreements were 94%, 94%, and 92%, respectively. And binary agreements with diseased vs healthy were 83%, 91%, and 80%, respectively.

At the patient level (all joints combined), ARTHUR and DIANA’s binary disease assessment of healthy vs disease showed agreement with the ground truth of 87% for synovial hypertrophy, 83% for Doppler activity, and 87% combined. Here, the rheumatologists scored lower, at 53%, 67%, and 60%, respectively.

“In this study, we think the precision of ARTHUR and DIANA was comparable to that of an experienced rheumatologist, at both the joint and patient level,” Just said.

Gardner pointed out another advantage of the system. “DIANA doesn’t get fatigued. ... With human reading, the precision may change based on the time of day or stress level. ... But with DIANA, you’re going to get consistent information.”

Just said that the Arthritis Foundation in Germany recently put ARTHUR and DIANA on a bus and took it to cities that lacked a rheumatologist. Patients lined up, answered a questionnaire, had blood drawn, and received their scans. A rheumatologist on the bus then interpreted the data and consulted with the individuals about their RA risk. “In the last trip, we screened 800 patients in 6 days. So there are definitely possibilities here.”

Just is co-owner of ROPCA. Gardner had no disclosures.

A version of this article appeared on Medscape.com.