Clinician Reviews

PCSK9 inhibitors, which are among the most effective therapies for reducing LDL cholesterol (LDL-C), are associated with a neutral effect on cognitive function, according to a genetics-based Mendelian randomization study intended to sort out through the complexity of confounders.

The same study linked HMG-Co A reductase inhibitors (statins) with the potential for modest adverse neurocognitive effects, although these are likely to be outweighed by cardiovascular benefits, according to a collaborating team of investigators from the U.S. National Institutes of Health and the University of Oxford (England).

For clinicians and patients who continue to harbor concerns that cognitive function is threatened by very low LDL-C, this novel approach to evaluating risk is “reassuring,” according to the authors.

Early in clinical testing of PCSK9 inhibitors, a potential signal for adverse effects on cognitive function was reported but unconfirmed. This signal raised concern that extremely low levels of LDL-C, such as < 25 mg/dL, achieved with PCSK9 inhibitors might pose a risk to neurocognitive function.

Of several factors that provided a basis for concern, the PCSK9 enzyme is known to participate in brain development, according to the authors of this newly published study.
 

Mendelian randomization addresses complex issue

The objective of this Mendelian randomization analysis was to evaluate the relationship of PCSK9 inhibitors and statins on long-term neurocognitive function. Used previously to address other clinical issues, a drug-effect Mendelian randomization analysis evaluates genetic variants to determine whether there is a causal relationship between a risk, which in this case was lipid-lowering drugs, to a specific outcome, which was cognitive performance.

By looking directly at genetic variants that simulate the pharmacological inhibition of drug gene targets, the bias of confounders of clinical effects, such as baseline cognitive function, are avoided, according to the authors.

The message from this drug-effect Mendelian analysis was simple, according to the senior author of the study, Falk W. Lohoff, MD, chief of the section on clinical genomics and experimental therapeutics, National Institute of Alcohol Abuse and Alcoholism.

“Based on our data, we do not see a significant cognitive risk profile with PCSK9 inhibition associated with low LDL-C,” Dr. Lohoff said in an interview. He cautioned that “future long-term clinical studies are needed to confirm the absence of this effect,” but he and his coauthors noted that these data concur with the clinical studies.

From genome-wide association studies, single-nucleotide polymorphisms in PCSK9 and HMG-Co A reductase were extracted from a sample of more than 700,000 individuals of predominantly European ancestry. In the analysis, the investigators evaluated whether inhibition of PCSK9 or HMG-Co A reductase had an effect on seven clinical outcomes that relate to neurocognitive function, including memory, verbal intelligence, and reaction time, as well as biomarkers of cognitive function, such as cortical surface area.

The genetic effect of PCSK9 inhibition was “null for every cognitive-related outcome evaluated,” the investigators reported. The genetic effect of HMG-Co A reductase inhibition had a statistically significant but modest effect on cognitive performance (P = .03) and cortical surface area (P = .03). While the impact of HMG-Co A reductase inhibition on reaction time was stronger on a statistical basis (P = .0002), the investigators reported that it translated into a decrease of only 0.067 milliseconds per 38.7 mg/dL. They characterized this as a “small impact” unlikely to outweigh clinical benefits.

In an editorial that accompanied publication of this study, Brian A. Ference, MD, MPhil, provided context for the suitability of a Mendelian randomization analysis to address this or other questions regarding the impact of lipid-lowering therapies on clinical outcomes, and he ultimately concurred with the major conclusions

Ultimately, this analysis is consistent with other evidence that PCSK9 inhibition does not pose a risk of impaired cognitive function, he wrote. For statins, he concluded that this study “does not provide compelling evidence” to challenge their current clinical use.


 

Data do not support low LDL-C as cognitive risk factor

Moreover, this study – as well as other evidence – argues strongly against very low levels of LDL-C, regardless of how they are achieved, as a risk factor for diminished cognitive function, Dr. Ference, director of research in the division of translational therapeutics, University of Cambridge (England), said in an interview.

“There is no evidence from Mendelian randomization studies that lifelong exposure to lower LDL-C increases the risk of cognitive impairment,” he said. “This is true when evaluating lifelong exposure to lower LDL-C due to genetic variants in a wide variety of different genes or the genes that encode the target PCKS9 inhibitors, statins, or other lipid-lowering therapies.”

In other words, this study “adds to the accumulating evidence” that LDL-C lowering by itself does not contribute to an adverse impact on cognitive function despite persistent concern. This should not be surprising. Dr. Ference emphasized that there has never been strong evidence for an association.

“As I point out in the editorial, there is no biologically plausible mechanism by which reducing peripheral LDL-C should impact neurological function in any way, because the therapies do not cross the blood brain barrier, and because the nervous system produces its own cholesterol to maintain the integrity of membranes in nervous system cells,” he explained.

Dr. Lohoff reports no potential conflicts of interest. Dr. Ference has financial relationships with numerous pharmaceutical companies including those that make lipid-lowering therapies.

PCSK9 inhibitors, which are among the most effective therapies for reducing LDL cholesterol (LDL-C), are associated with a neutral effect on cognitive function, according to a genetics-based Mendelian randomization study intended to sort out through the complexity of confounders.

The same study linked HMG-Co A reductase inhibitors (statins) with the potential for modest adverse neurocognitive effects, although these are likely to be outweighed by cardiovascular benefits, according to a collaborating team of investigators from the U.S. National Institutes of Health and the University of Oxford (England).

For clinicians and patients who continue to harbor concerns that cognitive function is threatened by very low LDL-C, this novel approach to evaluating risk is “reassuring,” according to the authors.

Early in clinical testing of PCSK9 inhibitors, a potential signal for adverse effects on cognitive function was reported but unconfirmed. This signal raised concern that extremely low levels of LDL-C, such as < 25 mg/dL, achieved with PCSK9 inhibitors might pose a risk to neurocognitive function.

Of several factors that provided a basis for concern, the PCSK9 enzyme is known to participate in brain development, according to the authors of this newly published study.
 

Mendelian randomization addresses complex issue

The objective of this Mendelian randomization analysis was to evaluate the relationship of PCSK9 inhibitors and statins on long-term neurocognitive function. Used previously to address other clinical issues, a drug-effect Mendelian randomization analysis evaluates genetic variants to determine whether there is a causal relationship between a risk, which in this case was lipid-lowering drugs, to a specific outcome, which was cognitive performance.

By looking directly at genetic variants that simulate the pharmacological inhibition of drug gene targets, the bias of confounders of clinical effects, such as baseline cognitive function, are avoided, according to the authors.

The message from this drug-effect Mendelian analysis was simple, according to the senior author of the study, Falk W. Lohoff, MD, chief of the section on clinical genomics and experimental therapeutics, National Institute of Alcohol Abuse and Alcoholism.

“Based on our data, we do not see a significant cognitive risk profile with PCSK9 inhibition associated with low LDL-C,” Dr. Lohoff said in an interview. He cautioned that “future long-term clinical studies are needed to confirm the absence of this effect,” but he and his coauthors noted that these data concur with the clinical studies.

From genome-wide association studies, single-nucleotide polymorphisms in PCSK9 and HMG-Co A reductase were extracted from a sample of more than 700,000 individuals of predominantly European ancestry. In the analysis, the investigators evaluated whether inhibition of PCSK9 or HMG-Co A reductase had an effect on seven clinical outcomes that relate to neurocognitive function, including memory, verbal intelligence, and reaction time, as well as biomarkers of cognitive function, such as cortical surface area.

The genetic effect of PCSK9 inhibition was “null for every cognitive-related outcome evaluated,” the investigators reported. The genetic effect of HMG-Co A reductase inhibition had a statistically significant but modest effect on cognitive performance (P = .03) and cortical surface area (P = .03). While the impact of HMG-Co A reductase inhibition on reaction time was stronger on a statistical basis (P = .0002), the investigators reported that it translated into a decrease of only 0.067 milliseconds per 38.7 mg/dL. They characterized this as a “small impact” unlikely to outweigh clinical benefits.

In an editorial that accompanied publication of this study, Brian A. Ference, MD, MPhil, provided context for the suitability of a Mendelian randomization analysis to address this or other questions regarding the impact of lipid-lowering therapies on clinical outcomes, and he ultimately concurred with the major conclusions

Ultimately, this analysis is consistent with other evidence that PCSK9 inhibition does not pose a risk of impaired cognitive function, he wrote. For statins, he concluded that this study “does not provide compelling evidence” to challenge their current clinical use.


 

Data do not support low LDL-C as cognitive risk factor

Moreover, this study – as well as other evidence – argues strongly against very low levels of LDL-C, regardless of how they are achieved, as a risk factor for diminished cognitive function, Dr. Ference, director of research in the division of translational therapeutics, University of Cambridge (England), said in an interview.

“There is no evidence from Mendelian randomization studies that lifelong exposure to lower LDL-C increases the risk of cognitive impairment,” he said. “This is true when evaluating lifelong exposure to lower LDL-C due to genetic variants in a wide variety of different genes or the genes that encode the target PCKS9 inhibitors, statins, or other lipid-lowering therapies.”

In other words, this study “adds to the accumulating evidence” that LDL-C lowering by itself does not contribute to an adverse impact on cognitive function despite persistent concern. This should not be surprising. Dr. Ference emphasized that there has never been strong evidence for an association.

“As I point out in the editorial, there is no biologically plausible mechanism by which reducing peripheral LDL-C should impact neurological function in any way, because the therapies do not cross the blood brain barrier, and because the nervous system produces its own cholesterol to maintain the integrity of membranes in nervous system cells,” he explained.

Dr. Lohoff reports no potential conflicts of interest. Dr. Ference has financial relationships with numerous pharmaceutical companies including those that make lipid-lowering therapies.

PCSK9 inhibitors, which are among the most effective therapies for reducing LDL cholesterol (LDL-C), are associated with a neutral effect on cognitive function, according to a genetics-based Mendelian randomization study intended to sort out through the complexity of confounders.

The same study linked HMG-Co A reductase inhibitors (statins) with the potential for modest adverse neurocognitive effects, although these are likely to be outweighed by cardiovascular benefits, according to a collaborating team of investigators from the U.S. National Institutes of Health and the University of Oxford (England).

For clinicians and patients who continue to harbor concerns that cognitive function is threatened by very low LDL-C, this novel approach to evaluating risk is “reassuring,” according to the authors.

Early in clinical testing of PCSK9 inhibitors, a potential signal for adverse effects on cognitive function was reported but unconfirmed. This signal raised concern that extremely low levels of LDL-C, such as < 25 mg/dL, achieved with PCSK9 inhibitors might pose a risk to neurocognitive function.

Of several factors that provided a basis for concern, the PCSK9 enzyme is known to participate in brain development, according to the authors of this newly published study.
 

Mendelian randomization addresses complex issue

The objective of this Mendelian randomization analysis was to evaluate the relationship of PCSK9 inhibitors and statins on long-term neurocognitive function. Used previously to address other clinical issues, a drug-effect Mendelian randomization analysis evaluates genetic variants to determine whether there is a causal relationship between a risk, which in this case was lipid-lowering drugs, to a specific outcome, which was cognitive performance.

By looking directly at genetic variants that simulate the pharmacological inhibition of drug gene targets, the bias of confounders of clinical effects, such as baseline cognitive function, are avoided, according to the authors.

The message from this drug-effect Mendelian analysis was simple, according to the senior author of the study, Falk W. Lohoff, MD, chief of the section on clinical genomics and experimental therapeutics, National Institute of Alcohol Abuse and Alcoholism.

“Based on our data, we do not see a significant cognitive risk profile with PCSK9 inhibition associated with low LDL-C,” Dr. Lohoff said in an interview. He cautioned that “future long-term clinical studies are needed to confirm the absence of this effect,” but he and his coauthors noted that these data concur with the clinical studies.

From genome-wide association studies, single-nucleotide polymorphisms in PCSK9 and HMG-Co A reductase were extracted from a sample of more than 700,000 individuals of predominantly European ancestry. In the analysis, the investigators evaluated whether inhibition of PCSK9 or HMG-Co A reductase had an effect on seven clinical outcomes that relate to neurocognitive function, including memory, verbal intelligence, and reaction time, as well as biomarkers of cognitive function, such as cortical surface area.

The genetic effect of PCSK9 inhibition was “null for every cognitive-related outcome evaluated,” the investigators reported. The genetic effect of HMG-Co A reductase inhibition had a statistically significant but modest effect on cognitive performance (P = .03) and cortical surface area (P = .03). While the impact of HMG-Co A reductase inhibition on reaction time was stronger on a statistical basis (P = .0002), the investigators reported that it translated into a decrease of only 0.067 milliseconds per 38.7 mg/dL. They characterized this as a “small impact” unlikely to outweigh clinical benefits.

In an editorial that accompanied publication of this study, Brian A. Ference, MD, MPhil, provided context for the suitability of a Mendelian randomization analysis to address this or other questions regarding the impact of lipid-lowering therapies on clinical outcomes, and he ultimately concurred with the major conclusions

Ultimately, this analysis is consistent with other evidence that PCSK9 inhibition does not pose a risk of impaired cognitive function, he wrote. For statins, he concluded that this study “does not provide compelling evidence” to challenge their current clinical use.


 

Data do not support low LDL-C as cognitive risk factor

Moreover, this study – as well as other evidence – argues strongly against very low levels of LDL-C, regardless of how they are achieved, as a risk factor for diminished cognitive function, Dr. Ference, director of research in the division of translational therapeutics, University of Cambridge (England), said in an interview.

“There is no evidence from Mendelian randomization studies that lifelong exposure to lower LDL-C increases the risk of cognitive impairment,” he said. “This is true when evaluating lifelong exposure to lower LDL-C due to genetic variants in a wide variety of different genes or the genes that encode the target PCKS9 inhibitors, statins, or other lipid-lowering therapies.”

In other words, this study “adds to the accumulating evidence” that LDL-C lowering by itself does not contribute to an adverse impact on cognitive function despite persistent concern. This should not be surprising. Dr. Ference emphasized that there has never been strong evidence for an association.

“As I point out in the editorial, there is no biologically plausible mechanism by which reducing peripheral LDL-C should impact neurological function in any way, because the therapies do not cross the blood brain barrier, and because the nervous system produces its own cholesterol to maintain the integrity of membranes in nervous system cells,” he explained.

Dr. Lohoff reports no potential conflicts of interest. Dr. Ference has financial relationships with numerous pharmaceutical companies including those that make lipid-lowering therapies.

People with elevated levels of protein prostasin seem to have a higher risk of developing diabetes and dying from cancer, according to a large, prospective, population-based study. The finding may provide new insights into why people with diabetes have an increased risk of cancer.

The study claims to be the first to investigate the link between plasma prostasin levels and cancer mortality, the study authors wrote in Diabetologia. The study analyzed plasma prostasin samples from 4,297 older adults (average age, 57.5 years) from the Malmö (Sweden) Diet and Cancer Study Cardiovascular Cohort.

“This study from the general population shows that prostasin, a protein that could be measured in blood, is associated with increased risk of developing diabetes,” senior author Gunnar Engström, MD, PhD, professor of epidemiology at Lund University in Malmö, Sweden, said in a comment. “Furthermore, it was associated with increased risk of death from cancer, especially in individuals with elevated glucose levels in the prediabetic range.

“The relationship between diabetes and cancer is poorly understood,” Dr. Engström said. “To our knowledge, this is the first big population study of prostasin and risk of diabetes.”

He noted previous studies have found a relationship between prostasin and cancer outcomes. “Prostasin could be a possible shared link between  the two diseases and the results could help us understand why individuals with diabetes have increased risk of cancer.”

Patients in the study were assigned to quartiles based on prostasin levels. Those in the highest quartile had almost twice the risk of prevalent diabetes than did those in the lowest quartile (adjusted odds ratio, 1.95; 95% confidence interval, 1.39-2.76; P < .0001).

During the follow-up periods of 21.9 years for diabetes and 23.5 years for cancer, on average, 702 participants developed diabetes and 651 died from cancer. Again, the analysis found a significantly higher adjusted hazard ratio for participants in the fourth quartile: about 75% higher for diabetes (HR, 1.76; 95% CI, 1.41-2.19; P < .0001), and, after multivariable analysis, about 40% higher for death from cancer (HR, 1.43; 95% CI, 1.14-1.8; P = .0008).
 

Potential diabetes-cancer ‘interaction’

The study also identified what it called “a significant interaction” between prostasin and fasting blood glucose for cancer mortality risk (P = .022). In patients with impaired fasting blood glucose levels at baseline, the risk for cancer mortality was about 50% greater with each standard deviation increase in prostasin (HR, 1.52; 95% CI, 1.07-2.16; P = .019). Those with normal fasting blood glucose at baseline had a significantly lower risk with each SD increase in prostasin (HR, 1.11; 95% CI, 1.01-1.21; P = .025).

Further research is needed to validate the potential of prostasin as a biomarker for diabetes and cancer risks, Dr. Engström said. “The results need to be replicated in other studies. A study of cancer mortality in a big cohort of diabetes patients would be of great interest. We also need to examine whether prostasin is causally related to cancer and/or diabetes, or whether prostasin could act as a valuable risk marker in clinical settings. If causal, there could a possible molecular target for treatment.”

He added: “Biomarkers of diabetes and cancer are of great interest in the era of personalized medicine, both for disease prevention and for treatment of those with established disease.”

Li-Mei Chen, MD, PhD, a research associate professor at the University of Central Florida, Orlando, has studied the role of prostasin in epidemiology. She noted that one of the challenges of using prostasin in clinical or research settings is the lack of a standardized assay, which the Malmö study acknowledged. Dr. Engström and colleagues wrote that “prostasin levels were measured in arbitrary units (NPX values), and thus could not be compared directly with absolute values.”

Dr. Chen pointed out that the study reported a lower range of 0.24 pg/mL and an upper range of 7,800 pg/mL.

This means that, “in different groups that measure prostasin, the absolute quantity could have a difference in the thousands or tens of thousands,” she said. “That makes the judgment difficult of whether for this person you have a high level of prostasin in the blood and the other one you don’t if the difference is over a thousandfold.”

The Malmö study used the Proseek Multiplex Oncology I panel to determine plasma prostasin concentration, but Dr. Chen noted that she couldn’t find any data validating the panel for measuring prostasin. “It’s really hard for me to say whether this is of value or not because if the method that generated the data is not verified by another method, you don’t really know what you’re measuring.

“If the data are questionable, it’s really hard to say whether it means whether it’s a marker for cancer or diabetes,” Dr. Chen added. “That’s the biggest question I have, but actually the authors realize that.”

Dr. Engström confirmed that, “if prostasin is used to identify patients with increased risk of diabetes and cancer mortality, we also need to develop standardized assays for clinical use.”

Dr. Engström and coauthors had no disclosures. The study received funding from the Swedish Heart Lung Foundation, the National Natural Science Foundation of China, and the Natural Science Foundation of Jiangsu Province. The Malmö Diet and Cancer study received grants from the Swedish Cancer Society, the Swedish Medical Research Council, AFA Insurance, the Albert Påhlsson and Gunnar Nilsson Foundations, Malmö City Council, and Lund University. Dr. Chen had no relevant disclosures.
 

People with elevated levels of protein prostasin seem to have a higher risk of developing diabetes and dying from cancer, according to a large, prospective, population-based study. The finding may provide new insights into why people with diabetes have an increased risk of cancer.

The study claims to be the first to investigate the link between plasma prostasin levels and cancer mortality, the study authors wrote in Diabetologia. The study analyzed plasma prostasin samples from 4,297 older adults (average age, 57.5 years) from the Malmö (Sweden) Diet and Cancer Study Cardiovascular Cohort.

“This study from the general population shows that prostasin, a protein that could be measured in blood, is associated with increased risk of developing diabetes,” senior author Gunnar Engström, MD, PhD, professor of epidemiology at Lund University in Malmö, Sweden, said in a comment. “Furthermore, it was associated with increased risk of death from cancer, especially in individuals with elevated glucose levels in the prediabetic range.

“The relationship between diabetes and cancer is poorly understood,” Dr. Engström said. “To our knowledge, this is the first big population study of prostasin and risk of diabetes.”

He noted previous studies have found a relationship between prostasin and cancer outcomes. “Prostasin could be a possible shared link between  the two diseases and the results could help us understand why individuals with diabetes have increased risk of cancer.”

Patients in the study were assigned to quartiles based on prostasin levels. Those in the highest quartile had almost twice the risk of prevalent diabetes than did those in the lowest quartile (adjusted odds ratio, 1.95; 95% confidence interval, 1.39-2.76; P < .0001).

During the follow-up periods of 21.9 years for diabetes and 23.5 years for cancer, on average, 702 participants developed diabetes and 651 died from cancer. Again, the analysis found a significantly higher adjusted hazard ratio for participants in the fourth quartile: about 75% higher for diabetes (HR, 1.76; 95% CI, 1.41-2.19; P < .0001), and, after multivariable analysis, about 40% higher for death from cancer (HR, 1.43; 95% CI, 1.14-1.8; P = .0008).
 

Potential diabetes-cancer ‘interaction’

The study also identified what it called “a significant interaction” between prostasin and fasting blood glucose for cancer mortality risk (P = .022). In patients with impaired fasting blood glucose levels at baseline, the risk for cancer mortality was about 50% greater with each standard deviation increase in prostasin (HR, 1.52; 95% CI, 1.07-2.16; P = .019). Those with normal fasting blood glucose at baseline had a significantly lower risk with each SD increase in prostasin (HR, 1.11; 95% CI, 1.01-1.21; P = .025).

Further research is needed to validate the potential of prostasin as a biomarker for diabetes and cancer risks, Dr. Engström said. “The results need to be replicated in other studies. A study of cancer mortality in a big cohort of diabetes patients would be of great interest. We also need to examine whether prostasin is causally related to cancer and/or diabetes, or whether prostasin could act as a valuable risk marker in clinical settings. If causal, there could a possible molecular target for treatment.”

He added: “Biomarkers of diabetes and cancer are of great interest in the era of personalized medicine, both for disease prevention and for treatment of those with established disease.”

Li-Mei Chen, MD, PhD, a research associate professor at the University of Central Florida, Orlando, has studied the role of prostasin in epidemiology. She noted that one of the challenges of using prostasin in clinical or research settings is the lack of a standardized assay, which the Malmö study acknowledged. Dr. Engström and colleagues wrote that “prostasin levels were measured in arbitrary units (NPX values), and thus could not be compared directly with absolute values.”

Dr. Chen pointed out that the study reported a lower range of 0.24 pg/mL and an upper range of 7,800 pg/mL.

This means that, “in different groups that measure prostasin, the absolute quantity could have a difference in the thousands or tens of thousands,” she said. “That makes the judgment difficult of whether for this person you have a high level of prostasin in the blood and the other one you don’t if the difference is over a thousandfold.”

The Malmö study used the Proseek Multiplex Oncology I panel to determine plasma prostasin concentration, but Dr. Chen noted that she couldn’t find any data validating the panel for measuring prostasin. “It’s really hard for me to say whether this is of value or not because if the method that generated the data is not verified by another method, you don’t really know what you’re measuring.

“If the data are questionable, it’s really hard to say whether it means whether it’s a marker for cancer or diabetes,” Dr. Chen added. “That’s the biggest question I have, but actually the authors realize that.”

Dr. Engström confirmed that, “if prostasin is used to identify patients with increased risk of diabetes and cancer mortality, we also need to develop standardized assays for clinical use.”

Dr. Engström and coauthors had no disclosures. The study received funding from the Swedish Heart Lung Foundation, the National Natural Science Foundation of China, and the Natural Science Foundation of Jiangsu Province. The Malmö Diet and Cancer study received grants from the Swedish Cancer Society, the Swedish Medical Research Council, AFA Insurance, the Albert Påhlsson and Gunnar Nilsson Foundations, Malmö City Council, and Lund University. Dr. Chen had no relevant disclosures.
 

People with elevated levels of protein prostasin seem to have a higher risk of developing diabetes and dying from cancer, according to a large, prospective, population-based study. The finding may provide new insights into why people with diabetes have an increased risk of cancer.

The study claims to be the first to investigate the link between plasma prostasin levels and cancer mortality, the study authors wrote in Diabetologia. The study analyzed plasma prostasin samples from 4,297 older adults (average age, 57.5 years) from the Malmö (Sweden) Diet and Cancer Study Cardiovascular Cohort.

“This study from the general population shows that prostasin, a protein that could be measured in blood, is associated with increased risk of developing diabetes,” senior author Gunnar Engström, MD, PhD, professor of epidemiology at Lund University in Malmö, Sweden, said in a comment. “Furthermore, it was associated with increased risk of death from cancer, especially in individuals with elevated glucose levels in the prediabetic range.

“The relationship between diabetes and cancer is poorly understood,” Dr. Engström said. “To our knowledge, this is the first big population study of prostasin and risk of diabetes.”

He noted previous studies have found a relationship between prostasin and cancer outcomes. “Prostasin could be a possible shared link between  the two diseases and the results could help us understand why individuals with diabetes have increased risk of cancer.”

Patients in the study were assigned to quartiles based on prostasin levels. Those in the highest quartile had almost twice the risk of prevalent diabetes than did those in the lowest quartile (adjusted odds ratio, 1.95; 95% confidence interval, 1.39-2.76; P < .0001).

During the follow-up periods of 21.9 years for diabetes and 23.5 years for cancer, on average, 702 participants developed diabetes and 651 died from cancer. Again, the analysis found a significantly higher adjusted hazard ratio for participants in the fourth quartile: about 75% higher for diabetes (HR, 1.76; 95% CI, 1.41-2.19; P < .0001), and, after multivariable analysis, about 40% higher for death from cancer (HR, 1.43; 95% CI, 1.14-1.8; P = .0008).
 

Potential diabetes-cancer ‘interaction’

The study also identified what it called “a significant interaction” between prostasin and fasting blood glucose for cancer mortality risk (P = .022). In patients with impaired fasting blood glucose levels at baseline, the risk for cancer mortality was about 50% greater with each standard deviation increase in prostasin (HR, 1.52; 95% CI, 1.07-2.16; P = .019). Those with normal fasting blood glucose at baseline had a significantly lower risk with each SD increase in prostasin (HR, 1.11; 95% CI, 1.01-1.21; P = .025).

Further research is needed to validate the potential of prostasin as a biomarker for diabetes and cancer risks, Dr. Engström said. “The results need to be replicated in other studies. A study of cancer mortality in a big cohort of diabetes patients would be of great interest. We also need to examine whether prostasin is causally related to cancer and/or diabetes, or whether prostasin could act as a valuable risk marker in clinical settings. If causal, there could a possible molecular target for treatment.”

He added: “Biomarkers of diabetes and cancer are of great interest in the era of personalized medicine, both for disease prevention and for treatment of those with established disease.”

Li-Mei Chen, MD, PhD, a research associate professor at the University of Central Florida, Orlando, has studied the role of prostasin in epidemiology. She noted that one of the challenges of using prostasin in clinical or research settings is the lack of a standardized assay, which the Malmö study acknowledged. Dr. Engström and colleagues wrote that “prostasin levels were measured in arbitrary units (NPX values), and thus could not be compared directly with absolute values.”

Dr. Chen pointed out that the study reported a lower range of 0.24 pg/mL and an upper range of 7,800 pg/mL.

This means that, “in different groups that measure prostasin, the absolute quantity could have a difference in the thousands or tens of thousands,” she said. “That makes the judgment difficult of whether for this person you have a high level of prostasin in the blood and the other one you don’t if the difference is over a thousandfold.”

The Malmö study used the Proseek Multiplex Oncology I panel to determine plasma prostasin concentration, but Dr. Chen noted that she couldn’t find any data validating the panel for measuring prostasin. “It’s really hard for me to say whether this is of value or not because if the method that generated the data is not verified by another method, you don’t really know what you’re measuring.

“If the data are questionable, it’s really hard to say whether it means whether it’s a marker for cancer or diabetes,” Dr. Chen added. “That’s the biggest question I have, but actually the authors realize that.”

Dr. Engström confirmed that, “if prostasin is used to identify patients with increased risk of diabetes and cancer mortality, we also need to develop standardized assays for clinical use.”

Dr. Engström and coauthors had no disclosures. The study received funding from the Swedish Heart Lung Foundation, the National Natural Science Foundation of China, and the Natural Science Foundation of Jiangsu Province. The Malmö Diet and Cancer study received grants from the Swedish Cancer Society, the Swedish Medical Research Council, AFA Insurance, the Albert Påhlsson and Gunnar Nilsson Foundations, Malmö City Council, and Lund University. Dr. Chen had no relevant disclosures.
 

Emerging evidence is shedding light on the common underlying mechanisms contributing to the overlapping clinical phenomena of “long COVID,” myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and dysautonomia.

At the virtual annual meeting of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (IACFSME), speakers presented data showing similar pathophysiologic abnormalities in people with systemic symptoms associated with ME/CFS who had a prior SARS-CoV-2 infection and those who did not, including individuals whose illness preceded the COVID-19 pandemic.

Core clinical diagnostic criteria for ME/CFS established by the Institute of Medicine in 2015 include substantial decrement in functioning for 6 months or longer, postexertional malaise, or a worsening of symptoms following even minor exertion (often described by patients as “crashes”), unrefreshing sleep, and cognitive dysfunction and/or orthostatic intolerance that are frequent and severe.

Long COVID has been defined in several different ways using different terminology. The U.S. Centers for Disease Control and Prevention, for example, defines “post-COVID conditions” as those continuing four or more weeks beyond first symptoms. The World Health Organization’s clinical case definition of “post COVID-19 condition” includes otherwise unexplained symptoms 3 months from COVID-19 onset and lasting longer than 2 months.

Both ME/CFS and long COVID commonly involve numerous symptoms beyond the defining ones, affecting nearly every organ system in the body, including systemic, neurocognitive, endocrine, cardiovascular, pulmonary, musculoskeletal, and gastrointestinal, with wide variation among individuals. Autonomic dysfunction is common to both conditions, particularly postural orthostatic tachycardia syndrome (POTS).

“My way of understanding these illnesses is that they’re not just multisystem illnesses, but all these interactive systems that lean on each other are dysregulated. … I would say that a very common underlying mediator of both ME/CFS and long COVID is autonomic dysfunction, and it presents as POTS,” Nancy Klimas, MD, director of the Institute for Neuro-Immune Medicine at Nova Southeastern University, Fort Lauderdale, Fla., told this news organization.

Dr. Klimas, who is also director of Clinical Immunology Research at the Miami Veterans Affairs Medical Center, added that “if basic bioenergetics are disrupted and in an oxidative-stress state [then] they have downregulated energy production at the cellular level, which seems to be the case in ME/CFS and now in long COVID.”
 

New ICD-10 codes better characterize the syndromes

New ICD-10 codes for 2023, being implemented on Oct. 1, will enable clinicians to better document all of these interrelated conditions.

Under the existing G93.3, Postviral and related fatigue syndromes, there will now be:

• G93.31 – Postviral fatigue syndrome.
• G93.32 – Myalgic encephalomyelitis/chronic fatigue syndrome (and the separate terms).
• G93.39 – Other postinfection and related fatigue syndromes.

The old R53.82, “Chronic fatigue, unspecified” code now excludes all of the above conditions.

The additional code U09.9 for “post COVID-19 condition, unspecified,” may also be used if applicable.

In addition, a new code for POTS, G90.A, which wasn’t previously mentioned in ICD-10, may also be used starting Oct. 1.

Lucinda Bateman, MD, founder and director of the Bateman Horne Center, Salt Lake City, advises using all applicable codes for a given patient. “If a patient came into my office with long COVID and met criteria for ME/CFS, we would code both, and also any other syndrome criteria that they may meet, such as POTS or fibromyalgia.

“If people use the codes appropriately, then you can understand the overlap better. It increases the likelihood of reimbursement, creates a more accurate medical record for the patient, and provides them with a better tool should they require disability benefits.”

Dr. Bateman advises in-office orthostatic evaluation for all patients with this symptom constellation, using a passive standing evaluation such as the 10-minute NASA Lean test.

“Clinicians should take the time to do orthostatic testing in these patients because it provides objective markers and will help lead us to potential interventions to help improve people’s function.”

The Bateman Horne center offers clinician resources on management of ME/CFS and related conditions.
 

How common is ME/CFS after COVID-19?

According to one published meta-analysis, the global prevalence of “post-acute sequelae of SARS-CoV-2,” defined by any symptom, is about 43% of patients overall following infection, and 49% at 120 days. Fatigue was the most commonly reported symptom, followed by memory problems. As of March 22, the World Health Organization estimated that there have been more than 470 million COVID-19 cases, which would give a figure of about 200 million people who are experiencing a wide range of long-COVID symptoms. 

On the final day of the IACFSME conference, Luis Nacul, MD, of the University of British Columbia, Vancouver, presented several sets of data from his group and others aiming to determine the proportion of individuals who develop symptoms suggestive of ME/CFS following a COVID-19 infection.   

Among a cohort of 88 adults hospitalized with confirmed SARS-CoV-2 infections during the first pandemic wave in 2020 and followed up in the respiratory clinic, rates of reported generalized fatigue were 67% at 3 months and 59.5% at 6 months. Substantial fatigue (that is, present most days and affecting activity levels) were reported by 16% at 3 months and 7% at 6 months. “This should represent in principle the maximum prevalence of cases who would meet the criteria for ME/CFS,” Dr. Nacul said.

Baseline age was indirectly associated with fatigue at 3 and 6 months, while the number of comorbidities a patient had was directly associated. Comorbidities also predicted severe fatigue at 3 months, but the numbers were too small for assessment at 6 months.

Studies involving nonhospitalized patients suggested lower rates. One meta-analysis showed 1-year rates of fatigue in 32% and cognitive impairment in 22%. Another showed very similar rates, reporting fatigue in 28% and memory/concentration difficulties in 18%-19%.   

Dr. Nacul cautioned that these figures are likely overestimates since many of the study populations are taken from respiratory or long-COVID clinics. “The evidence on ‘post-COVID fatigue syndrome’ or ME/CFS following COVID is still evolving. There is a huge need for studies looking more closely at cases meeting well-defined ME/CFS criteria. This unfortunately hasn’t been done for most studies.”
 

Immune system dysfunction appears to underlie many cases

In a keynote address during the conference, Akiko Iwasaki, PhD, of Yale University, New Haven, Conn., pointed out that long COVID and ME/CFS are among many unexplained postacute infection syndromes associated with a long list of viral pathogens, including Ebola, the prior SARS viruses, Epstein-Barr virus, and Dengue, as well as nonviral pathogens such as Coxiella burnetii (Q fever syndrome) and Borrelia (posttreatment Lyme disease syndrome).

Dr. Iwasaki cited a recent Nature Medicine review article that she coauthored on this topic with an ME/CFS patient, noting: “We really need to understand why some people are failing to recover from these types of diseases.”

Emerging evidence supports four different hypotheses regarding pathogenesis: viral reservoir/viral pathogen-associated molecular pattern molecules, autoimmunity, dysbiosis/viral reactivation, and tissue damage

“Right now, it’s too early to exclude or make any conclusions about these. We need to have an open mind to dissect these various possibilities,” she said.

Two speakers reported findings of immune dysregulation in both ME/CFS and long COVID. Wakiro Sato, MD, PhD, of the National Center of Neurology and Psychiatry, Tokyo, reported that anti–G-protein coupled receptor antibodies were found in 33 (55%) of 60 patients with long COVID, and more than 40% had peripheral immune cell profile abnormalities. These findings were similar to those found in patients with ME/CFS, published by Sato’s team (Brain Behav Immun. 2021 Mar 29. doi: 10.1016/j.bbi.2021.03.023) and other researchers in Germany.  

Liisa K. Selin, MD, PhD, professor of pathology at the University of Massachusetts, Worcester, presented data for an analysis of peripheral blood mononuclear cells from 26 donors with ME/CFS (8 with long COVID) and 24 healthy controls. In both patient groups, they found altered expression of inflammatory markers and decreases in CD8 T-cell number and function. The patients with long COVID showed evidence of sustained activation of both T-cell populations with increased CD38 and HLA-DR, associated with a compensatory increased frequency of activated CD4+CD8+ T cells.

“These results are consistent with immune dysregulation associated with overactivation and exhaustion of CD8 T cells, as observed in chronic viral infections and tumor environments,” Dr. Selin said.
 

ME/CFS and long COVID ‘frighteningly similar, if not identical’

Data for a different system derangement in long COVID and ME/CFS, the pathophysiology of exercise intolerance, were presented in another keynote talk by David M. Systrom, MD, a pulmonary and critical care medicine specialist at Brigham and Women’s Hospital and director of the Massachusetts General Hospital cardiopulmonary laboratory, both in Boston. He has conducted invasive cardiopulmonary exercise testing in patients with ME/CFS and patients with long COVID.

Previously, Dr. Systrom and his team found that patients with ME/CFS have distinct defects in both ventricular filling pressure and oxygen extraction from the muscles. Neither of those are features of deconditioning, which is often blamed for exercise intolerance in people with ME/CFS. Rather, the major defect in deconditioning is decreased stroke volume and cardiac output. In ME/CFS patients, he found supranormal pulmonary blood flow, compared with VO₂ max, suggesting peripheral left-to-right shunting.

In addition, Dr. Systrom and colleagues found that a large proportion of ME/CFS patients with these peripheral vascular defects also have biopsy-demonstrated small-fiber neuropathy, suggesting that acute exercise intolerance is related to underlying autonomic nervous system dysfunction.

In Dr. Systrom and colleagues’ long COVID study, invasive cardiopulmonary exercise testing in 10 patients who had recovered from COVID-19 at least 6 months prior and did not have cardiopulmonary disease had significantly revealed reduced peak exercise aerobic capacity (VO₂ max), compared with 10 age- and sex-matched controls. The reduction in peak VO₂ was associated with impaired systemic oxygen extraction, compared with the controls, despite a preserved peak cardiac index.

The long-COVID patients also showed greater ventilatory inefficiency, which “is entirely related to hyperventilation, not intrinsic lung disease,” Dr. Systrom said, adding that while there may be subsets of patients with interstitial lung disease after acute respiratory distress syndrome, these patients didn’t have that. “This for all the world looks like ME/CFS. We think they are frighteningly similar, if not identical,” Dr. Systrom said.  

In a third study for which Dr. Systrom was a coauthor, published in Annals of Neurology, multisystem involvement was found in nine patients following mild COVID-19 infection, using standardized autonomic assessments including Valsalva maneuver, sudomotor and tilt tests, and skin biopsies for small-fiber neuropathy. The findings included cerebrovascular dysregulation with persistent cerebral arteriolar vasoconstriction, small-fiber neuropathy and related dysautonomia, respiratory dysregulation, and chronic inflammation.

Dr. Systrom’s conclusion: “Dyspnea and hyperventilation are common in ME/CFS and long COVID and there is significant overlap with POTS.”

Dr. Bateman disclosed that she is conducting research for Terra Biological. Dr. Systrom said he is conducting research for Astellas.

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

Emerging evidence is shedding light on the common underlying mechanisms contributing to the overlapping clinical phenomena of “long COVID,” myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and dysautonomia.

At the virtual annual meeting of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (IACFSME), speakers presented data showing similar pathophysiologic abnormalities in people with systemic symptoms associated with ME/CFS who had a prior SARS-CoV-2 infection and those who did not, including individuals whose illness preceded the COVID-19 pandemic.

Core clinical diagnostic criteria for ME/CFS established by the Institute of Medicine in 2015 include substantial decrement in functioning for 6 months or longer, postexertional malaise, or a worsening of symptoms following even minor exertion (often described by patients as “crashes”), unrefreshing sleep, and cognitive dysfunction and/or orthostatic intolerance that are frequent and severe.

Long COVID has been defined in several different ways using different terminology. The U.S. Centers for Disease Control and Prevention, for example, defines “post-COVID conditions” as those continuing four or more weeks beyond first symptoms. The World Health Organization’s clinical case definition of “post COVID-19 condition” includes otherwise unexplained symptoms 3 months from COVID-19 onset and lasting longer than 2 months.

Both ME/CFS and long COVID commonly involve numerous symptoms beyond the defining ones, affecting nearly every organ system in the body, including systemic, neurocognitive, endocrine, cardiovascular, pulmonary, musculoskeletal, and gastrointestinal, with wide variation among individuals. Autonomic dysfunction is common to both conditions, particularly postural orthostatic tachycardia syndrome (POTS).

“My way of understanding these illnesses is that they’re not just multisystem illnesses, but all these interactive systems that lean on each other are dysregulated. … I would say that a very common underlying mediator of both ME/CFS and long COVID is autonomic dysfunction, and it presents as POTS,” Nancy Klimas, MD, director of the Institute for Neuro-Immune Medicine at Nova Southeastern University, Fort Lauderdale, Fla., told this news organization.

Dr. Klimas, who is also director of Clinical Immunology Research at the Miami Veterans Affairs Medical Center, added that “if basic bioenergetics are disrupted and in an oxidative-stress state [then] they have downregulated energy production at the cellular level, which seems to be the case in ME/CFS and now in long COVID.”
 

New ICD-10 codes better characterize the syndromes

New ICD-10 codes for 2023, being implemented on Oct. 1, will enable clinicians to better document all of these interrelated conditions.

Under the existing G93.3, Postviral and related fatigue syndromes, there will now be:

• G93.31 – Postviral fatigue syndrome.
• G93.32 – Myalgic encephalomyelitis/chronic fatigue syndrome (and the separate terms).
• G93.39 – Other postinfection and related fatigue syndromes.

The old R53.82, “Chronic fatigue, unspecified” code now excludes all of the above conditions.

The additional code U09.9 for “post COVID-19 condition, unspecified,” may also be used if applicable.

In addition, a new code for POTS, G90.A, which wasn’t previously mentioned in ICD-10, may also be used starting Oct. 1.

Lucinda Bateman, MD, founder and director of the Bateman Horne Center, Salt Lake City, advises using all applicable codes for a given patient. “If a patient came into my office with long COVID and met criteria for ME/CFS, we would code both, and also any other syndrome criteria that they may meet, such as POTS or fibromyalgia.

“If people use the codes appropriately, then you can understand the overlap better. It increases the likelihood of reimbursement, creates a more accurate medical record for the patient, and provides them with a better tool should they require disability benefits.”

Dr. Bateman advises in-office orthostatic evaluation for all patients with this symptom constellation, using a passive standing evaluation such as the 10-minute NASA Lean test.

“Clinicians should take the time to do orthostatic testing in these patients because it provides objective markers and will help lead us to potential interventions to help improve people’s function.”

The Bateman Horne center offers clinician resources on management of ME/CFS and related conditions.
 

How common is ME/CFS after COVID-19?

According to one published meta-analysis, the global prevalence of “post-acute sequelae of SARS-CoV-2,” defined by any symptom, is about 43% of patients overall following infection, and 49% at 120 days. Fatigue was the most commonly reported symptom, followed by memory problems. As of March 22, the World Health Organization estimated that there have been more than 470 million COVID-19 cases, which would give a figure of about 200 million people who are experiencing a wide range of long-COVID symptoms. 

On the final day of the IACFSME conference, Luis Nacul, MD, of the University of British Columbia, Vancouver, presented several sets of data from his group and others aiming to determine the proportion of individuals who develop symptoms suggestive of ME/CFS following a COVID-19 infection.   

Among a cohort of 88 adults hospitalized with confirmed SARS-CoV-2 infections during the first pandemic wave in 2020 and followed up in the respiratory clinic, rates of reported generalized fatigue were 67% at 3 months and 59.5% at 6 months. Substantial fatigue (that is, present most days and affecting activity levels) were reported by 16% at 3 months and 7% at 6 months. “This should represent in principle the maximum prevalence of cases who would meet the criteria for ME/CFS,” Dr. Nacul said.

Baseline age was indirectly associated with fatigue at 3 and 6 months, while the number of comorbidities a patient had was directly associated. Comorbidities also predicted severe fatigue at 3 months, but the numbers were too small for assessment at 6 months.

Studies involving nonhospitalized patients suggested lower rates. One meta-analysis showed 1-year rates of fatigue in 32% and cognitive impairment in 22%. Another showed very similar rates, reporting fatigue in 28% and memory/concentration difficulties in 18%-19%.   

Dr. Nacul cautioned that these figures are likely overestimates since many of the study populations are taken from respiratory or long-COVID clinics. “The evidence on ‘post-COVID fatigue syndrome’ or ME/CFS following COVID is still evolving. There is a huge need for studies looking more closely at cases meeting well-defined ME/CFS criteria. This unfortunately hasn’t been done for most studies.”
 

Immune system dysfunction appears to underlie many cases

In a keynote address during the conference, Akiko Iwasaki, PhD, of Yale University, New Haven, Conn., pointed out that long COVID and ME/CFS are among many unexplained postacute infection syndromes associated with a long list of viral pathogens, including Ebola, the prior SARS viruses, Epstein-Barr virus, and Dengue, as well as nonviral pathogens such as Coxiella burnetii (Q fever syndrome) and Borrelia (posttreatment Lyme disease syndrome).

Dr. Iwasaki cited a recent Nature Medicine review article that she coauthored on this topic with an ME/CFS patient, noting: “We really need to understand why some people are failing to recover from these types of diseases.”

Emerging evidence supports four different hypotheses regarding pathogenesis: viral reservoir/viral pathogen-associated molecular pattern molecules, autoimmunity, dysbiosis/viral reactivation, and tissue damage

“Right now, it’s too early to exclude or make any conclusions about these. We need to have an open mind to dissect these various possibilities,” she said.

Two speakers reported findings of immune dysregulation in both ME/CFS and long COVID. Wakiro Sato, MD, PhD, of the National Center of Neurology and Psychiatry, Tokyo, reported that anti–G-protein coupled receptor antibodies were found in 33 (55%) of 60 patients with long COVID, and more than 40% had peripheral immune cell profile abnormalities. These findings were similar to those found in patients with ME/CFS, published by Sato’s team (Brain Behav Immun. 2021 Mar 29. doi: 10.1016/j.bbi.2021.03.023) and other researchers in Germany.  

Liisa K. Selin, MD, PhD, professor of pathology at the University of Massachusetts, Worcester, presented data for an analysis of peripheral blood mononuclear cells from 26 donors with ME/CFS (8 with long COVID) and 24 healthy controls. In both patient groups, they found altered expression of inflammatory markers and decreases in CD8 T-cell number and function. The patients with long COVID showed evidence of sustained activation of both T-cell populations with increased CD38 and HLA-DR, associated with a compensatory increased frequency of activated CD4+CD8+ T cells.

“These results are consistent with immune dysregulation associated with overactivation and exhaustion of CD8 T cells, as observed in chronic viral infections and tumor environments,” Dr. Selin said.
 

ME/CFS and long COVID ‘frighteningly similar, if not identical’

Data for a different system derangement in long COVID and ME/CFS, the pathophysiology of exercise intolerance, were presented in another keynote talk by David M. Systrom, MD, a pulmonary and critical care medicine specialist at Brigham and Women’s Hospital and director of the Massachusetts General Hospital cardiopulmonary laboratory, both in Boston. He has conducted invasive cardiopulmonary exercise testing in patients with ME/CFS and patients with long COVID.

Previously, Dr. Systrom and his team found that patients with ME/CFS have distinct defects in both ventricular filling pressure and oxygen extraction from the muscles. Neither of those are features of deconditioning, which is often blamed for exercise intolerance in people with ME/CFS. Rather, the major defect in deconditioning is decreased stroke volume and cardiac output. In ME/CFS patients, he found supranormal pulmonary blood flow, compared with VO₂ max, suggesting peripheral left-to-right shunting.

In addition, Dr. Systrom and colleagues found that a large proportion of ME/CFS patients with these peripheral vascular defects also have biopsy-demonstrated small-fiber neuropathy, suggesting that acute exercise intolerance is related to underlying autonomic nervous system dysfunction.

In Dr. Systrom and colleagues’ long COVID study, invasive cardiopulmonary exercise testing in 10 patients who had recovered from COVID-19 at least 6 months prior and did not have cardiopulmonary disease had significantly revealed reduced peak exercise aerobic capacity (VO₂ max), compared with 10 age- and sex-matched controls. The reduction in peak VO₂ was associated with impaired systemic oxygen extraction, compared with the controls, despite a preserved peak cardiac index.

The long-COVID patients also showed greater ventilatory inefficiency, which “is entirely related to hyperventilation, not intrinsic lung disease,” Dr. Systrom said, adding that while there may be subsets of patients with interstitial lung disease after acute respiratory distress syndrome, these patients didn’t have that. “This for all the world looks like ME/CFS. We think they are frighteningly similar, if not identical,” Dr. Systrom said.  

In a third study for which Dr. Systrom was a coauthor, published in Annals of Neurology, multisystem involvement was found in nine patients following mild COVID-19 infection, using standardized autonomic assessments including Valsalva maneuver, sudomotor and tilt tests, and skin biopsies for small-fiber neuropathy. The findings included cerebrovascular dysregulation with persistent cerebral arteriolar vasoconstriction, small-fiber neuropathy and related dysautonomia, respiratory dysregulation, and chronic inflammation.

Dr. Systrom’s conclusion: “Dyspnea and hyperventilation are common in ME/CFS and long COVID and there is significant overlap with POTS.”

Dr. Bateman disclosed that she is conducting research for Terra Biological. Dr. Systrom said he is conducting research for Astellas.

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

Emerging evidence is shedding light on the common underlying mechanisms contributing to the overlapping clinical phenomena of “long COVID,” myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and dysautonomia.

At the virtual annual meeting of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (IACFSME), speakers presented data showing similar pathophysiologic abnormalities in people with systemic symptoms associated with ME/CFS who had a prior SARS-CoV-2 infection and those who did not, including individuals whose illness preceded the COVID-19 pandemic.

Core clinical diagnostic criteria for ME/CFS established by the Institute of Medicine in 2015 include substantial decrement in functioning for 6 months or longer, postexertional malaise, or a worsening of symptoms following even minor exertion (often described by patients as “crashes”), unrefreshing sleep, and cognitive dysfunction and/or orthostatic intolerance that are frequent and severe.

Long COVID has been defined in several different ways using different terminology. The U.S. Centers for Disease Control and Prevention, for example, defines “post-COVID conditions” as those continuing four or more weeks beyond first symptoms. The World Health Organization’s clinical case definition of “post COVID-19 condition” includes otherwise unexplained symptoms 3 months from COVID-19 onset and lasting longer than 2 months.

Both ME/CFS and long COVID commonly involve numerous symptoms beyond the defining ones, affecting nearly every organ system in the body, including systemic, neurocognitive, endocrine, cardiovascular, pulmonary, musculoskeletal, and gastrointestinal, with wide variation among individuals. Autonomic dysfunction is common to both conditions, particularly postural orthostatic tachycardia syndrome (POTS).

“My way of understanding these illnesses is that they’re not just multisystem illnesses, but all these interactive systems that lean on each other are dysregulated. … I would say that a very common underlying mediator of both ME/CFS and long COVID is autonomic dysfunction, and it presents as POTS,” Nancy Klimas, MD, director of the Institute for Neuro-Immune Medicine at Nova Southeastern University, Fort Lauderdale, Fla., told this news organization.

Dr. Klimas, who is also director of Clinical Immunology Research at the Miami Veterans Affairs Medical Center, added that “if basic bioenergetics are disrupted and in an oxidative-stress state [then] they have downregulated energy production at the cellular level, which seems to be the case in ME/CFS and now in long COVID.”
 

New ICD-10 codes better characterize the syndromes

New ICD-10 codes for 2023, being implemented on Oct. 1, will enable clinicians to better document all of these interrelated conditions.

Under the existing G93.3, Postviral and related fatigue syndromes, there will now be:

• G93.31 – Postviral fatigue syndrome.
• G93.32 – Myalgic encephalomyelitis/chronic fatigue syndrome (and the separate terms).
• G93.39 – Other postinfection and related fatigue syndromes.

The old R53.82, “Chronic fatigue, unspecified” code now excludes all of the above conditions.

The additional code U09.9 for “post COVID-19 condition, unspecified,” may also be used if applicable.

In addition, a new code for POTS, G90.A, which wasn’t previously mentioned in ICD-10, may also be used starting Oct. 1.

Lucinda Bateman, MD, founder and director of the Bateman Horne Center, Salt Lake City, advises using all applicable codes for a given patient. “If a patient came into my office with long COVID and met criteria for ME/CFS, we would code both, and also any other syndrome criteria that they may meet, such as POTS or fibromyalgia.

“If people use the codes appropriately, then you can understand the overlap better. It increases the likelihood of reimbursement, creates a more accurate medical record for the patient, and provides them with a better tool should they require disability benefits.”

Dr. Bateman advises in-office orthostatic evaluation for all patients with this symptom constellation, using a passive standing evaluation such as the 10-minute NASA Lean test.

“Clinicians should take the time to do orthostatic testing in these patients because it provides objective markers and will help lead us to potential interventions to help improve people’s function.”

The Bateman Horne center offers clinician resources on management of ME/CFS and related conditions.
 

How common is ME/CFS after COVID-19?

According to one published meta-analysis, the global prevalence of “post-acute sequelae of SARS-CoV-2,” defined by any symptom, is about 43% of patients overall following infection, and 49% at 120 days. Fatigue was the most commonly reported symptom, followed by memory problems. As of March 22, the World Health Organization estimated that there have been more than 470 million COVID-19 cases, which would give a figure of about 200 million people who are experiencing a wide range of long-COVID symptoms. 

On the final day of the IACFSME conference, Luis Nacul, MD, of the University of British Columbia, Vancouver, presented several sets of data from his group and others aiming to determine the proportion of individuals who develop symptoms suggestive of ME/CFS following a COVID-19 infection.   

Among a cohort of 88 adults hospitalized with confirmed SARS-CoV-2 infections during the first pandemic wave in 2020 and followed up in the respiratory clinic, rates of reported generalized fatigue were 67% at 3 months and 59.5% at 6 months. Substantial fatigue (that is, present most days and affecting activity levels) were reported by 16% at 3 months and 7% at 6 months. “This should represent in principle the maximum prevalence of cases who would meet the criteria for ME/CFS,” Dr. Nacul said.

Baseline age was indirectly associated with fatigue at 3 and 6 months, while the number of comorbidities a patient had was directly associated. Comorbidities also predicted severe fatigue at 3 months, but the numbers were too small for assessment at 6 months.

Studies involving nonhospitalized patients suggested lower rates. One meta-analysis showed 1-year rates of fatigue in 32% and cognitive impairment in 22%. Another showed very similar rates, reporting fatigue in 28% and memory/concentration difficulties in 18%-19%.   

Dr. Nacul cautioned that these figures are likely overestimates since many of the study populations are taken from respiratory or long-COVID clinics. “The evidence on ‘post-COVID fatigue syndrome’ or ME/CFS following COVID is still evolving. There is a huge need for studies looking more closely at cases meeting well-defined ME/CFS criteria. This unfortunately hasn’t been done for most studies.”
 

Immune system dysfunction appears to underlie many cases

In a keynote address during the conference, Akiko Iwasaki, PhD, of Yale University, New Haven, Conn., pointed out that long COVID and ME/CFS are among many unexplained postacute infection syndromes associated with a long list of viral pathogens, including Ebola, the prior SARS viruses, Epstein-Barr virus, and Dengue, as well as nonviral pathogens such as Coxiella burnetii (Q fever syndrome) and Borrelia (posttreatment Lyme disease syndrome).

Dr. Iwasaki cited a recent Nature Medicine review article that she coauthored on this topic with an ME/CFS patient, noting: “We really need to understand why some people are failing to recover from these types of diseases.”

Emerging evidence supports four different hypotheses regarding pathogenesis: viral reservoir/viral pathogen-associated molecular pattern molecules, autoimmunity, dysbiosis/viral reactivation, and tissue damage

“Right now, it’s too early to exclude or make any conclusions about these. We need to have an open mind to dissect these various possibilities,” she said.

Two speakers reported findings of immune dysregulation in both ME/CFS and long COVID. Wakiro Sato, MD, PhD, of the National Center of Neurology and Psychiatry, Tokyo, reported that anti–G-protein coupled receptor antibodies were found in 33 (55%) of 60 patients with long COVID, and more than 40% had peripheral immune cell profile abnormalities. These findings were similar to those found in patients with ME/CFS, published by Sato’s team (Brain Behav Immun. 2021 Mar 29. doi: 10.1016/j.bbi.2021.03.023) and other researchers in Germany.  

Liisa K. Selin, MD, PhD, professor of pathology at the University of Massachusetts, Worcester, presented data for an analysis of peripheral blood mononuclear cells from 26 donors with ME/CFS (8 with long COVID) and 24 healthy controls. In both patient groups, they found altered expression of inflammatory markers and decreases in CD8 T-cell number and function. The patients with long COVID showed evidence of sustained activation of both T-cell populations with increased CD38 and HLA-DR, associated with a compensatory increased frequency of activated CD4+CD8+ T cells.

“These results are consistent with immune dysregulation associated with overactivation and exhaustion of CD8 T cells, as observed in chronic viral infections and tumor environments,” Dr. Selin said.
 

ME/CFS and long COVID ‘frighteningly similar, if not identical’

Data for a different system derangement in long COVID and ME/CFS, the pathophysiology of exercise intolerance, were presented in another keynote talk by David M. Systrom, MD, a pulmonary and critical care medicine specialist at Brigham and Women’s Hospital and director of the Massachusetts General Hospital cardiopulmonary laboratory, both in Boston. He has conducted invasive cardiopulmonary exercise testing in patients with ME/CFS and patients with long COVID.

Previously, Dr. Systrom and his team found that patients with ME/CFS have distinct defects in both ventricular filling pressure and oxygen extraction from the muscles. Neither of those are features of deconditioning, which is often blamed for exercise intolerance in people with ME/CFS. Rather, the major defect in deconditioning is decreased stroke volume and cardiac output. In ME/CFS patients, he found supranormal pulmonary blood flow, compared with VO₂ max, suggesting peripheral left-to-right shunting.

In addition, Dr. Systrom and colleagues found that a large proportion of ME/CFS patients with these peripheral vascular defects also have biopsy-demonstrated small-fiber neuropathy, suggesting that acute exercise intolerance is related to underlying autonomic nervous system dysfunction.

In Dr. Systrom and colleagues’ long COVID study, invasive cardiopulmonary exercise testing in 10 patients who had recovered from COVID-19 at least 6 months prior and did not have cardiopulmonary disease had significantly revealed reduced peak exercise aerobic capacity (VO₂ max), compared with 10 age- and sex-matched controls. The reduction in peak VO₂ was associated with impaired systemic oxygen extraction, compared with the controls, despite a preserved peak cardiac index.

The long-COVID patients also showed greater ventilatory inefficiency, which “is entirely related to hyperventilation, not intrinsic lung disease,” Dr. Systrom said, adding that while there may be subsets of patients with interstitial lung disease after acute respiratory distress syndrome, these patients didn’t have that. “This for all the world looks like ME/CFS. We think they are frighteningly similar, if not identical,” Dr. Systrom said.  

In a third study for which Dr. Systrom was a coauthor, published in Annals of Neurology, multisystem involvement was found in nine patients following mild COVID-19 infection, using standardized autonomic assessments including Valsalva maneuver, sudomotor and tilt tests, and skin biopsies for small-fiber neuropathy. The findings included cerebrovascular dysregulation with persistent cerebral arteriolar vasoconstriction, small-fiber neuropathy and related dysautonomia, respiratory dysregulation, and chronic inflammation.

Dr. Systrom’s conclusion: “Dyspnea and hyperventilation are common in ME/CFS and long COVID and there is significant overlap with POTS.”

Dr. Bateman disclosed that she is conducting research for Terra Biological. Dr. Systrom said he is conducting research for Astellas.

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

A variety of treatments, most already commercially available, are under investigation for treating the constellation of overlapping symptoms associated with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), “long COVID,” and dysautonomia.

At the virtual annual meeting of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis, speakers presented data for a variety of approaches to ease symptoms common across postviral conditions, such as extreme fatigue, postexertional malaise (“crash”), cognitive dysfunction (“brain fog”), orthostatic intolerance including postural orthostatic tachycardia syndrome (POTS), and chronic pain. Most of the modalities are already commercially available for other indications, although some are costly and not covered by payers for these conditions.

“Both post–acute COVID-19 syndrome and ME/CFS are forms of postinfectious viral syndromes and they have overlapping symptoms. ... In the past, patients were told ‘you have chronic fatigue syndrome but there’s nothing we can do for it.’ That certainly is not the case. There aren’t cures, but there are many management techniques to improve symptoms,” Charles W. Lapp, MD, medical director of the Hunter-Hopkins Center, Charlotte, N.C., said in an interview.

A current mainstay of treatment for ME/CFS – including that triggered by COVID-19 – is activity pacing, in which patients learn to stay within their “energy envelopes” in order to avoid postexertional malaise, a worsening of all symptoms with exertion. The use of “graded exercise” is no longer recommended, per U.K. and U.S. guidelines.

Data for the following approaches were presented at the IACFS/ME conference:
 

Pyridostigmine (mestinon, others)

Pyridostigmine, an acetylcholinesterase inhibitor, is approved for the treatment of muscle weakness resulting from myasthenia gravis and is available in generic form. It has previously been shown to produce significant improvement in both symptom burden and heart rate response in POTS.

At the IACFS/ME conference, David M. Systrom, MD, a pulmonary and critical care medicine specialist at Brigham and Women’s Hospital and director of the Massachusetts General Hospital Cardiopulmonary laboratory, both in Boston, summarized his group’s study in patients with ME/CFS using pyridostigmine as both a potential treatment for improving exercise capacity and a proof-of-concept that neurovascular dysregulation underlies exertional intolerance in the condition.

A total of 45 patients were randomized to 60 mg oral pyridostigmine or placebo after an invasive cardiopulmonary exercise test, and a second test performed 50 minutes later. Peak VO₂ increased after pyridostigmine but decreased after placebo (+13.3 mL/min vs. –40.2 mL/min, P < .05). Cardiac output and right atrial pressure were also significantly improved with pyridostigmine and worse with placebo.

“We suggest that treatable neurovascular dysregulation underlies acute exercise intolerance in ME/CFS. ... Pyridostigmine may be a useful repurposed off-label treatment [for] a subset of patients with exercise intolerance,” Dr. Systrom said.

Asked to comment, Dr. Lapp said: “We’ve used Mestinon for years because it helps with POTS and also with neurally mediated hypotension. Systrom is taking it to a new level because he’s shown that it increases preload to the heart.” However, he noted that it’s unclear whether the drug will help patients who don’t have POTS specifically. On the other hand, patients rarely experience side effects from the drug.

Since the generic tablets come only in 60-mg doses, and the starting dose is 30 mg three times a day, he advised cutting the tablets in half during titration up to 60 mg three times a day.
 

Oxaloacetate (benaGene)

David Lyons Kaufman, MD, of the Center for Complex Diseases, Mountain View, Calif., summarized data from his group’s recently published open-label, nonrandomized, “proof-of-concept” study on use of the commercially available nutritional supplement anhydrous enol-oxaloacetate for treating mental and physical fatigue in 76 patients with longstanding ME/CFS and 43 with long-COVID fatigue.

Oxaloacetate is a major step in the Krebs cycle within the mitochondria that are depleted in patients with ME/CFS. It is also an energy metabolite that has multiple effects in cells and mitochondria, Dr. Kaufman explained.

Doses ranging from 500 mg twice daily up to 1,000 mg three times a day were given for 6 weeks. Up to 33% of the patients with ME/CFS and up to 46.8% of the long-COVID group achieved clinical efficacy as measured by physical and mental fatigue scores, compared with just 5.9% of historical ME/CFS controls. All doses showed highly significant improvements.

The only adverse effects were occasional dyspepsia, which was avoided by taking the supplement with food, and insomnia, resolved by having them dose at breakfast and lunch, Dr. Kaufman said.

Following those preliminary data, there is now an ongoing 90-day, randomized, placebo-controlled clinical trial of 80 patients with ME/CFS using 2,000 mg anhydrous enol-oxaloacetate per day. Endpoints include multiple objective measures.

“We have a health care crisis with long COVID, and we’ve had this smoldering crisis with ME/CFS for decades that’s never been addressed. ME/CFS and long COVID, if not identical, are certainly overlapping. ... We have to pursue these translational medicine pilot studies as rapidly as possible,” Dr. Kaufman remarked.

Dr. Lapp told this news organization that it makes sense to use constituents of the Krebs cycle to improve mitochondrial function, but the problem with oxaloacetate is its cost. Dr. Kaufman mentioned that based on the preliminary trial, the therapeutic “sweet spot” appeared to be 1,000 mg twice daily. The manufacturer’s website lists the price for a single bottle of 30 250-mg capsules at $49, or $42 if purchased via a monthly subscription.

“It’s a benign drug, and it’s over the counter. I would give it to any patient who’s got a big wallet,” Dr. Lapp quipped, adding: “If they’ve got the money, they can order it tonight.”
 

Inspiritol

Inspiritol is an investigational “nebulized, inhaled, multimechanism medication designed to treat the major symptoms of respiratory distress with antioxidant, anti-inflammatory, and broad-spectrum antiviral and antibacterial properties. Inspiritol is composed of both endogenously produced and naturally occurring, well-tolerated biochemicals,” according to the company website.

The hypothesis, Liisa K. Selin, MD, PhD, professor of pathology at the University of Massachusetts, Worcester, said at the meeting, is that “ME/CFS and long COVID-19 result from an aberrant response to an immunological trigger like infection, which results in a permanently dysregulated immune system as a result of overactivation of CD8 T cells and subsequent exhaustion.”

Inspiritol, containing five antioxidants, acts as an immune modulator to reverse the CD8 T cell exhaustion and improve symptoms. Administration by inhaler delivers it directly to the brain from the lung. It was originally designed for use in chronic obstructive pulmonary disease and asthma and has shown efficacy for acute COVID-19, Dr. Selin said.

In a preliminary study, four patients with ME/CFS and five with long COVID have been treated with Inspiritol for 2-15 months, and all have self-reported improved symptoms. Cough has been the only reported side effect.

The company is pursuing an Investigational New Drug Application for the product with the Food and Drug Administration and has several patents pending. Dr. Lapp called Inspiritol “very interesting,” and said that reversal of CD8 “exhaustion” also would appear to be a promising approach. However, he noted, “the problem is that we don’t know what’s in it.”
 

Stellate ganglion block

Injection of local anesthetic near the stellate ganglion to block activity of the entire cervical sympathetic chain has been used for nearly a century to treat a variety of sympathetically mediated conditions, including complex regional pain syndrome (CRPS), shingles, and phantom-limb pain. More recently, it has been used in a variety of other conditions, including PTSD, Raynaud’s disease, menopausal hot flashes, and hyperhidrosis.

Insurance companies typically cover it for CRPS, neuropathic upper-extremity pain, hyperhidrosis, and Raynaud’s, said Luke Liu, MD, an anesthesiologist who is founder and chief executive officer of Alaska-based pain management company Neuroversion.

Deborah Duricka, PhD, also with Neuroversion, presented results from a now-published case series of 11 patients with long COVID who underwent stellate ganglion block by a board-certified anesthesiologist, first on one side at the level of C6, then on the contralateral side the following day.

Clinically meaningful benefits were seen in at least five of the patients in fatigue, memory problems, problems concentrating, rapid heartbeat, orthostatic intolerance, sleep problems, postexertional malaise, anxiety, and depression.

The hypothetical mechanism, she said, is that “sympathetic block prevents sympathetically driven vasoconstriction in carotid and vertebral arteries.”

Dr. Liu presented another case series of five patients with ME/CFS who underwent the procedure with ultrasound guidance, again on one side and the other side the next day. All had upper-limb autonomic issues such as Raynaud’s and/or neuropathic pain that had been refractory to more conventional treatments.

All five patients reported improvements in symptoms of ME/CFS, including energy level, cognition, pain, and postexertional malaise. One patient reported “feeling well for the first time in decades.” However, that patient relapsed after a mild viral illness 3.5 months after treatment. Some of the patients have required further treatments.

Dr. Lapp commented that, although the procedure is generally safe when performed by an experienced clinician, “Any time you do an injection like that, there’s a high risk that you could nick an artery or a vein or hit an essential nerve in the neck. That’s why it has to be done under fluoroscopy or ultrasound.”

He said he’s had a few patients undergo the procedure, mostly for CRPS, and they seem to have benefited from it. “It might increase cerebral blood flow and preload to the heart, so it might decrease ME/CFS symptoms and help with POTS as well.”

Nonetheless, Dr. Lapp said he wouldn’t consider stellate ganglion block as first-line treatment for ME/CFS or long COVID. “I think it would be for the treatment-resistant patient, when you’ve gone through all the treatments that we know and addressed all the comorbidities and they’re still not getting better.”

But, he added, it is a standard procedure. “Any pain clinic can do a stellate block.”
 

Transcutaneous auricular vagus nerve stimulation

Nicola Clague-Baker, PhD, a physiotherapist at the University of Liverpool (England), presented findings from an international survey of people with ME/CFS regarding their experience with transcutaneous auricular vagus nerve stimulation (taVNS) to manage their autonomic symptoms. The technique involves stimulation of the autonomic nervous system via the vagus nerve using electrodes applied to part of the ear. The theory is that the technique stimulates the parasympathetic nervous system and improves autonomic balance.

Two small previous trials showing benefit of vagus nerve stimulation for people with ME/CFS used more invasive and less comfortable methods of applying the stimulation rather than to the ear, Dr. Clague-Baker and colleagues noted in a poster. It has also been used successfully in treating POTS, another conference speaker noted.

A total of 131 people with ME/CFS (called simply “ME” in the United Kingdom) responded to a survey advertised on social media and websites. The majority (60%) were from the United Kingdom while the rest were from Europe, Australia, and North America. Most were female, and slightly more than half had lived with ME for 10 or more years.

The majority (72%) were still using taVNS, while 28% had stopped using it. Only 9% had used the modality for longer than a year. Respondents identified more than 30 benefits in symptoms and activities, with improvements in postexertional malaise (39%) and brain fog (37%) being the most common. One reported significant reduction in constipation.

However, respondents also mentioned more than 20 short- and long-term negatives, including headaches (15%) and long-term irritation at the site (9%). One participant reported a “big improvement in neuropathic pain, but not so much for muscles and joints.”

Overall, 80% reported that they would continue using taVNS and 67% said they would recommend it to others with ME, and 56% said that the system was mildly to very beneficial.

Dr. Lapp noted that several types of transcutaneous electrical nerve stimulation units with ear clips are sold online, and he’s seen them work well for migraine treatment. However, he cautioned that some patients have had side effects from the treatment, such as headaches and dizziness. “It’s putting an electrical current through your brain. In my mind, it’s another last-ditch measure.”

Dr. Lapp reported no financial disclosures.

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

A variety of treatments, most already commercially available, are under investigation for treating the constellation of overlapping symptoms associated with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), “long COVID,” and dysautonomia.

At the virtual annual meeting of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis, speakers presented data for a variety of approaches to ease symptoms common across postviral conditions, such as extreme fatigue, postexertional malaise (“crash”), cognitive dysfunction (“brain fog”), orthostatic intolerance including postural orthostatic tachycardia syndrome (POTS), and chronic pain. Most of the modalities are already commercially available for other indications, although some are costly and not covered by payers for these conditions.

“Both post–acute COVID-19 syndrome and ME/CFS are forms of postinfectious viral syndromes and they have overlapping symptoms. ... In the past, patients were told ‘you have chronic fatigue syndrome but there’s nothing we can do for it.’ That certainly is not the case. There aren’t cures, but there are many management techniques to improve symptoms,” Charles W. Lapp, MD, medical director of the Hunter-Hopkins Center, Charlotte, N.C., said in an interview.

A current mainstay of treatment for ME/CFS – including that triggered by COVID-19 – is activity pacing, in which patients learn to stay within their “energy envelopes” in order to avoid postexertional malaise, a worsening of all symptoms with exertion. The use of “graded exercise” is no longer recommended, per U.K. and U.S. guidelines.

Data for the following approaches were presented at the IACFS/ME conference:
 

Pyridostigmine (mestinon, others)

Pyridostigmine, an acetylcholinesterase inhibitor, is approved for the treatment of muscle weakness resulting from myasthenia gravis and is available in generic form. It has previously been shown to produce significant improvement in both symptom burden and heart rate response in POTS.

At the IACFS/ME conference, David M. Systrom, MD, a pulmonary and critical care medicine specialist at Brigham and Women’s Hospital and director of the Massachusetts General Hospital Cardiopulmonary laboratory, both in Boston, summarized his group’s study in patients with ME/CFS using pyridostigmine as both a potential treatment for improving exercise capacity and a proof-of-concept that neurovascular dysregulation underlies exertional intolerance in the condition.

A total of 45 patients were randomized to 60 mg oral pyridostigmine or placebo after an invasive cardiopulmonary exercise test, and a second test performed 50 minutes later. Peak VO₂ increased after pyridostigmine but decreased after placebo (+13.3 mL/min vs. –40.2 mL/min, P < .05). Cardiac output and right atrial pressure were also significantly improved with pyridostigmine and worse with placebo.

“We suggest that treatable neurovascular dysregulation underlies acute exercise intolerance in ME/CFS. ... Pyridostigmine may be a useful repurposed off-label treatment [for] a subset of patients with exercise intolerance,” Dr. Systrom said.

Asked to comment, Dr. Lapp said: “We’ve used Mestinon for years because it helps with POTS and also with neurally mediated hypotension. Systrom is taking it to a new level because he’s shown that it increases preload to the heart.” However, he noted that it’s unclear whether the drug will help patients who don’t have POTS specifically. On the other hand, patients rarely experience side effects from the drug.

Since the generic tablets come only in 60-mg doses, and the starting dose is 30 mg three times a day, he advised cutting the tablets in half during titration up to 60 mg three times a day.
 

Oxaloacetate (benaGene)

David Lyons Kaufman, MD, of the Center for Complex Diseases, Mountain View, Calif., summarized data from his group’s recently published open-label, nonrandomized, “proof-of-concept” study on use of the commercially available nutritional supplement anhydrous enol-oxaloacetate for treating mental and physical fatigue in 76 patients with longstanding ME/CFS and 43 with long-COVID fatigue.

Oxaloacetate is a major step in the Krebs cycle within the mitochondria that are depleted in patients with ME/CFS. It is also an energy metabolite that has multiple effects in cells and mitochondria, Dr. Kaufman explained.

Doses ranging from 500 mg twice daily up to 1,000 mg three times a day were given for 6 weeks. Up to 33% of the patients with ME/CFS and up to 46.8% of the long-COVID group achieved clinical efficacy as measured by physical and mental fatigue scores, compared with just 5.9% of historical ME/CFS controls. All doses showed highly significant improvements.

The only adverse effects were occasional dyspepsia, which was avoided by taking the supplement with food, and insomnia, resolved by having them dose at breakfast and lunch, Dr. Kaufman said.

Following those preliminary data, there is now an ongoing 90-day, randomized, placebo-controlled clinical trial of 80 patients with ME/CFS using 2,000 mg anhydrous enol-oxaloacetate per day. Endpoints include multiple objective measures.

“We have a health care crisis with long COVID, and we’ve had this smoldering crisis with ME/CFS for decades that’s never been addressed. ME/CFS and long COVID, if not identical, are certainly overlapping. ... We have to pursue these translational medicine pilot studies as rapidly as possible,” Dr. Kaufman remarked.

Dr. Lapp told this news organization that it makes sense to use constituents of the Krebs cycle to improve mitochondrial function, but the problem with oxaloacetate is its cost. Dr. Kaufman mentioned that based on the preliminary trial, the therapeutic “sweet spot” appeared to be 1,000 mg twice daily. The manufacturer’s website lists the price for a single bottle of 30 250-mg capsules at $49, or $42 if purchased via a monthly subscription.

“It’s a benign drug, and it’s over the counter. I would give it to any patient who’s got a big wallet,” Dr. Lapp quipped, adding: “If they’ve got the money, they can order it tonight.”
 

Inspiritol

Inspiritol is an investigational “nebulized, inhaled, multimechanism medication designed to treat the major symptoms of respiratory distress with antioxidant, anti-inflammatory, and broad-spectrum antiviral and antibacterial properties. Inspiritol is composed of both endogenously produced and naturally occurring, well-tolerated biochemicals,” according to the company website.

The hypothesis, Liisa K. Selin, MD, PhD, professor of pathology at the University of Massachusetts, Worcester, said at the meeting, is that “ME/CFS and long COVID-19 result from an aberrant response to an immunological trigger like infection, which results in a permanently dysregulated immune system as a result of overactivation of CD8 T cells and subsequent exhaustion.”

Inspiritol, containing five antioxidants, acts as an immune modulator to reverse the CD8 T cell exhaustion and improve symptoms. Administration by inhaler delivers it directly to the brain from the lung. It was originally designed for use in chronic obstructive pulmonary disease and asthma and has shown efficacy for acute COVID-19, Dr. Selin said.

In a preliminary study, four patients with ME/CFS and five with long COVID have been treated with Inspiritol for 2-15 months, and all have self-reported improved symptoms. Cough has been the only reported side effect.

The company is pursuing an Investigational New Drug Application for the product with the Food and Drug Administration and has several patents pending. Dr. Lapp called Inspiritol “very interesting,” and said that reversal of CD8 “exhaustion” also would appear to be a promising approach. However, he noted, “the problem is that we don’t know what’s in it.”
 

Stellate ganglion block

Injection of local anesthetic near the stellate ganglion to block activity of the entire cervical sympathetic chain has been used for nearly a century to treat a variety of sympathetically mediated conditions, including complex regional pain syndrome (CRPS), shingles, and phantom-limb pain. More recently, it has been used in a variety of other conditions, including PTSD, Raynaud’s disease, menopausal hot flashes, and hyperhidrosis.

Insurance companies typically cover it for CRPS, neuropathic upper-extremity pain, hyperhidrosis, and Raynaud’s, said Luke Liu, MD, an anesthesiologist who is founder and chief executive officer of Alaska-based pain management company Neuroversion.

Deborah Duricka, PhD, also with Neuroversion, presented results from a now-published case series of 11 patients with long COVID who underwent stellate ganglion block by a board-certified anesthesiologist, first on one side at the level of C6, then on the contralateral side the following day.

Clinically meaningful benefits were seen in at least five of the patients in fatigue, memory problems, problems concentrating, rapid heartbeat, orthostatic intolerance, sleep problems, postexertional malaise, anxiety, and depression.

The hypothetical mechanism, she said, is that “sympathetic block prevents sympathetically driven vasoconstriction in carotid and vertebral arteries.”

Dr. Liu presented another case series of five patients with ME/CFS who underwent the procedure with ultrasound guidance, again on one side and the other side the next day. All had upper-limb autonomic issues such as Raynaud’s and/or neuropathic pain that had been refractory to more conventional treatments.

All five patients reported improvements in symptoms of ME/CFS, including energy level, cognition, pain, and postexertional malaise. One patient reported “feeling well for the first time in decades.” However, that patient relapsed after a mild viral illness 3.5 months after treatment. Some of the patients have required further treatments.

Dr. Lapp commented that, although the procedure is generally safe when performed by an experienced clinician, “Any time you do an injection like that, there’s a high risk that you could nick an artery or a vein or hit an essential nerve in the neck. That’s why it has to be done under fluoroscopy or ultrasound.”

He said he’s had a few patients undergo the procedure, mostly for CRPS, and they seem to have benefited from it. “It might increase cerebral blood flow and preload to the heart, so it might decrease ME/CFS symptoms and help with POTS as well.”

Nonetheless, Dr. Lapp said he wouldn’t consider stellate ganglion block as first-line treatment for ME/CFS or long COVID. “I think it would be for the treatment-resistant patient, when you’ve gone through all the treatments that we know and addressed all the comorbidities and they’re still not getting better.”

But, he added, it is a standard procedure. “Any pain clinic can do a stellate block.”
 

Transcutaneous auricular vagus nerve stimulation

Nicola Clague-Baker, PhD, a physiotherapist at the University of Liverpool (England), presented findings from an international survey of people with ME/CFS regarding their experience with transcutaneous auricular vagus nerve stimulation (taVNS) to manage their autonomic symptoms. The technique involves stimulation of the autonomic nervous system via the vagus nerve using electrodes applied to part of the ear. The theory is that the technique stimulates the parasympathetic nervous system and improves autonomic balance.

Two small previous trials showing benefit of vagus nerve stimulation for people with ME/CFS used more invasive and less comfortable methods of applying the stimulation rather than to the ear, Dr. Clague-Baker and colleagues noted in a poster. It has also been used successfully in treating POTS, another conference speaker noted.

A total of 131 people with ME/CFS (called simply “ME” in the United Kingdom) responded to a survey advertised on social media and websites. The majority (60%) were from the United Kingdom while the rest were from Europe, Australia, and North America. Most were female, and slightly more than half had lived with ME for 10 or more years.

The majority (72%) were still using taVNS, while 28% had stopped using it. Only 9% had used the modality for longer than a year. Respondents identified more than 30 benefits in symptoms and activities, with improvements in postexertional malaise (39%) and brain fog (37%) being the most common. One reported significant reduction in constipation.

However, respondents also mentioned more than 20 short- and long-term negatives, including headaches (15%) and long-term irritation at the site (9%). One participant reported a “big improvement in neuropathic pain, but not so much for muscles and joints.”

Overall, 80% reported that they would continue using taVNS and 67% said they would recommend it to others with ME, and 56% said that the system was mildly to very beneficial.

Dr. Lapp noted that several types of transcutaneous electrical nerve stimulation units with ear clips are sold online, and he’s seen them work well for migraine treatment. However, he cautioned that some patients have had side effects from the treatment, such as headaches and dizziness. “It’s putting an electrical current through your brain. In my mind, it’s another last-ditch measure.”

Dr. Lapp reported no financial disclosures.

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

A variety of treatments, most already commercially available, are under investigation for treating the constellation of overlapping symptoms associated with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), “long COVID,” and dysautonomia.

At the virtual annual meeting of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis, speakers presented data for a variety of approaches to ease symptoms common across postviral conditions, such as extreme fatigue, postexertional malaise (“crash”), cognitive dysfunction (“brain fog”), orthostatic intolerance including postural orthostatic tachycardia syndrome (POTS), and chronic pain. Most of the modalities are already commercially available for other indications, although some are costly and not covered by payers for these conditions.

“Both post–acute COVID-19 syndrome and ME/CFS are forms of postinfectious viral syndromes and they have overlapping symptoms. ... In the past, patients were told ‘you have chronic fatigue syndrome but there’s nothing we can do for it.’ That certainly is not the case. There aren’t cures, but there are many management techniques to improve symptoms,” Charles W. Lapp, MD, medical director of the Hunter-Hopkins Center, Charlotte, N.C., said in an interview.

A current mainstay of treatment for ME/CFS – including that triggered by COVID-19 – is activity pacing, in which patients learn to stay within their “energy envelopes” in order to avoid postexertional malaise, a worsening of all symptoms with exertion. The use of “graded exercise” is no longer recommended, per U.K. and U.S. guidelines.

Data for the following approaches were presented at the IACFS/ME conference:
 

Pyridostigmine (mestinon, others)

Pyridostigmine, an acetylcholinesterase inhibitor, is approved for the treatment of muscle weakness resulting from myasthenia gravis and is available in generic form. It has previously been shown to produce significant improvement in both symptom burden and heart rate response in POTS.

At the IACFS/ME conference, David M. Systrom, MD, a pulmonary and critical care medicine specialist at Brigham and Women’s Hospital and director of the Massachusetts General Hospital Cardiopulmonary laboratory, both in Boston, summarized his group’s study in patients with ME/CFS using pyridostigmine as both a potential treatment for improving exercise capacity and a proof-of-concept that neurovascular dysregulation underlies exertional intolerance in the condition.

A total of 45 patients were randomized to 60 mg oral pyridostigmine or placebo after an invasive cardiopulmonary exercise test, and a second test performed 50 minutes later. Peak VO₂ increased after pyridostigmine but decreased after placebo (+13.3 mL/min vs. –40.2 mL/min, P < .05). Cardiac output and right atrial pressure were also significantly improved with pyridostigmine and worse with placebo.

“We suggest that treatable neurovascular dysregulation underlies acute exercise intolerance in ME/CFS. ... Pyridostigmine may be a useful repurposed off-label treatment [for] a subset of patients with exercise intolerance,” Dr. Systrom said.

Asked to comment, Dr. Lapp said: “We’ve used Mestinon for years because it helps with POTS and also with neurally mediated hypotension. Systrom is taking it to a new level because he’s shown that it increases preload to the heart.” However, he noted that it’s unclear whether the drug will help patients who don’t have POTS specifically. On the other hand, patients rarely experience side effects from the drug.

Since the generic tablets come only in 60-mg doses, and the starting dose is 30 mg three times a day, he advised cutting the tablets in half during titration up to 60 mg three times a day.
 

Oxaloacetate (benaGene)

David Lyons Kaufman, MD, of the Center for Complex Diseases, Mountain View, Calif., summarized data from his group’s recently published open-label, nonrandomized, “proof-of-concept” study on use of the commercially available nutritional supplement anhydrous enol-oxaloacetate for treating mental and physical fatigue in 76 patients with longstanding ME/CFS and 43 with long-COVID fatigue.

Oxaloacetate is a major step in the Krebs cycle within the mitochondria that are depleted in patients with ME/CFS. It is also an energy metabolite that has multiple effects in cells and mitochondria, Dr. Kaufman explained.

Doses ranging from 500 mg twice daily up to 1,000 mg three times a day were given for 6 weeks. Up to 33% of the patients with ME/CFS and up to 46.8% of the long-COVID group achieved clinical efficacy as measured by physical and mental fatigue scores, compared with just 5.9% of historical ME/CFS controls. All doses showed highly significant improvements.

The only adverse effects were occasional dyspepsia, which was avoided by taking the supplement with food, and insomnia, resolved by having them dose at breakfast and lunch, Dr. Kaufman said.

Following those preliminary data, there is now an ongoing 90-day, randomized, placebo-controlled clinical trial of 80 patients with ME/CFS using 2,000 mg anhydrous enol-oxaloacetate per day. Endpoints include multiple objective measures.

“We have a health care crisis with long COVID, and we’ve had this smoldering crisis with ME/CFS for decades that’s never been addressed. ME/CFS and long COVID, if not identical, are certainly overlapping. ... We have to pursue these translational medicine pilot studies as rapidly as possible,” Dr. Kaufman remarked.

Dr. Lapp told this news organization that it makes sense to use constituents of the Krebs cycle to improve mitochondrial function, but the problem with oxaloacetate is its cost. Dr. Kaufman mentioned that based on the preliminary trial, the therapeutic “sweet spot” appeared to be 1,000 mg twice daily. The manufacturer’s website lists the price for a single bottle of 30 250-mg capsules at $49, or $42 if purchased via a monthly subscription.

“It’s a benign drug, and it’s over the counter. I would give it to any patient who’s got a big wallet,” Dr. Lapp quipped, adding: “If they’ve got the money, they can order it tonight.”
 

Inspiritol

Inspiritol is an investigational “nebulized, inhaled, multimechanism medication designed to treat the major symptoms of respiratory distress with antioxidant, anti-inflammatory, and broad-spectrum antiviral and antibacterial properties. Inspiritol is composed of both endogenously produced and naturally occurring, well-tolerated biochemicals,” according to the company website.

The hypothesis, Liisa K. Selin, MD, PhD, professor of pathology at the University of Massachusetts, Worcester, said at the meeting, is that “ME/CFS and long COVID-19 result from an aberrant response to an immunological trigger like infection, which results in a permanently dysregulated immune system as a result of overactivation of CD8 T cells and subsequent exhaustion.”

Inspiritol, containing five antioxidants, acts as an immune modulator to reverse the CD8 T cell exhaustion and improve symptoms. Administration by inhaler delivers it directly to the brain from the lung. It was originally designed for use in chronic obstructive pulmonary disease and asthma and has shown efficacy for acute COVID-19, Dr. Selin said.

In a preliminary study, four patients with ME/CFS and five with long COVID have been treated with Inspiritol for 2-15 months, and all have self-reported improved symptoms. Cough has been the only reported side effect.

The company is pursuing an Investigational New Drug Application for the product with the Food and Drug Administration and has several patents pending. Dr. Lapp called Inspiritol “very interesting,” and said that reversal of CD8 “exhaustion” also would appear to be a promising approach. However, he noted, “the problem is that we don’t know what’s in it.”
 

Stellate ganglion block

Injection of local anesthetic near the stellate ganglion to block activity of the entire cervical sympathetic chain has been used for nearly a century to treat a variety of sympathetically mediated conditions, including complex regional pain syndrome (CRPS), shingles, and phantom-limb pain. More recently, it has been used in a variety of other conditions, including PTSD, Raynaud’s disease, menopausal hot flashes, and hyperhidrosis.

Insurance companies typically cover it for CRPS, neuropathic upper-extremity pain, hyperhidrosis, and Raynaud’s, said Luke Liu, MD, an anesthesiologist who is founder and chief executive officer of Alaska-based pain management company Neuroversion.

Deborah Duricka, PhD, also with Neuroversion, presented results from a now-published case series of 11 patients with long COVID who underwent stellate ganglion block by a board-certified anesthesiologist, first on one side at the level of C6, then on the contralateral side the following day.

Clinically meaningful benefits were seen in at least five of the patients in fatigue, memory problems, problems concentrating, rapid heartbeat, orthostatic intolerance, sleep problems, postexertional malaise, anxiety, and depression.

The hypothetical mechanism, she said, is that “sympathetic block prevents sympathetically driven vasoconstriction in carotid and vertebral arteries.”

Dr. Liu presented another case series of five patients with ME/CFS who underwent the procedure with ultrasound guidance, again on one side and the other side the next day. All had upper-limb autonomic issues such as Raynaud’s and/or neuropathic pain that had been refractory to more conventional treatments.

All five patients reported improvements in symptoms of ME/CFS, including energy level, cognition, pain, and postexertional malaise. One patient reported “feeling well for the first time in decades.” However, that patient relapsed after a mild viral illness 3.5 months after treatment. Some of the patients have required further treatments.

Dr. Lapp commented that, although the procedure is generally safe when performed by an experienced clinician, “Any time you do an injection like that, there’s a high risk that you could nick an artery or a vein or hit an essential nerve in the neck. That’s why it has to be done under fluoroscopy or ultrasound.”

He said he’s had a few patients undergo the procedure, mostly for CRPS, and they seem to have benefited from it. “It might increase cerebral blood flow and preload to the heart, so it might decrease ME/CFS symptoms and help with POTS as well.”

Nonetheless, Dr. Lapp said he wouldn’t consider stellate ganglion block as first-line treatment for ME/CFS or long COVID. “I think it would be for the treatment-resistant patient, when you’ve gone through all the treatments that we know and addressed all the comorbidities and they’re still not getting better.”

But, he added, it is a standard procedure. “Any pain clinic can do a stellate block.”
 

Transcutaneous auricular vagus nerve stimulation

Nicola Clague-Baker, PhD, a physiotherapist at the University of Liverpool (England), presented findings from an international survey of people with ME/CFS regarding their experience with transcutaneous auricular vagus nerve stimulation (taVNS) to manage their autonomic symptoms. The technique involves stimulation of the autonomic nervous system via the vagus nerve using electrodes applied to part of the ear. The theory is that the technique stimulates the parasympathetic nervous system and improves autonomic balance.

Two small previous trials showing benefit of vagus nerve stimulation for people with ME/CFS used more invasive and less comfortable methods of applying the stimulation rather than to the ear, Dr. Clague-Baker and colleagues noted in a poster. It has also been used successfully in treating POTS, another conference speaker noted.

A total of 131 people with ME/CFS (called simply “ME” in the United Kingdom) responded to a survey advertised on social media and websites. The majority (60%) were from the United Kingdom while the rest were from Europe, Australia, and North America. Most were female, and slightly more than half had lived with ME for 10 or more years.

The majority (72%) were still using taVNS, while 28% had stopped using it. Only 9% had used the modality for longer than a year. Respondents identified more than 30 benefits in symptoms and activities, with improvements in postexertional malaise (39%) and brain fog (37%) being the most common. One reported significant reduction in constipation.

However, respondents also mentioned more than 20 short- and long-term negatives, including headaches (15%) and long-term irritation at the site (9%). One participant reported a “big improvement in neuropathic pain, but not so much for muscles and joints.”

Overall, 80% reported that they would continue using taVNS and 67% said they would recommend it to others with ME, and 56% said that the system was mildly to very beneficial.

Dr. Lapp noted that several types of transcutaneous electrical nerve stimulation units with ear clips are sold online, and he’s seen them work well for migraine treatment. However, he cautioned that some patients have had side effects from the treatment, such as headaches and dizziness. “It’s putting an electrical current through your brain. In my mind, it’s another last-ditch measure.”

Dr. Lapp reported no financial disclosures.

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

Are you among the hundreds of millions of people worldwide with low back pain? If so, you may be familiar with standard treatments like surgery, shots, medications, and spinal manipulations. But new research suggests the solution for the world’s leading cause of disability may lie in fixing how the brain and the body communicate.

Setting out to challenge traditional treatments for chronic back pain, scientists across Australia, Europe, and the United States came together to test the effectiveness of altering how neural networks recognize pain for new research published this week in JAMA.

The randomized clinical trial recruited two groups of 138 participants with chronic low back pain, testing one group with a novel method called graded sensorimotor retraining intervention (RESOLVE) and the other with things like mock laser therapy and noninvasive brain stimulation.

The researchers found the RESOLVE 12-week training course resulted in a statistically significant improvement in pain intensity at 18 weeks.

“What we observed in our trial was a clinically meaningful effect on pain intensity and a clinically meaningful effect on disability. People were happier, they reported their backs felt better, and their quality of life was better,” the study’s lead author, James McAuley, PhD, said in a statement. “This is the first new treatment of its kind for back pain.”
 

Brainy talk

Communication between your brain and back changes over time when you have chronic lower back pain, leading the brain to interpret signals from the back differently and change how you move. It is thought that these neural changes make recovery from pain slower and more complicated , according to Neuroscience Research Australia (NeuRA), a nonprofit research institute in Sydney.

“Over time, the back becomes less fit, and the way the back and brain communicate is disrupted in ways that seem to reinforce the notion that the back is vulnerable and needs protecting,” said Dr. McAuley, a professor at the University of New South Wales, Sydney, and a NeuRA senior research scientist. “The treatment we devised aims to break this self-sustaining cycle.”

RESOLVE treatment focuses on improving this transformed brain-back communication by slowly retraining the body and the brain without the use of opioids or surgery. People in the study have reported improved quality of life 1 year later, according to Dr. McAuley.

The researchers said the pain improvement was “modest,” and the method will need to be tested on other patients and conditions. They hope to introduce this new treatment to doctors and physiotherapists within the next 6-9 months and have already enlisted partner organizations to start this process, according to NeuRA.

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

Are you among the hundreds of millions of people worldwide with low back pain? If so, you may be familiar with standard treatments like surgery, shots, medications, and spinal manipulations. But new research suggests the solution for the world’s leading cause of disability may lie in fixing how the brain and the body communicate.

Setting out to challenge traditional treatments for chronic back pain, scientists across Australia, Europe, and the United States came together to test the effectiveness of altering how neural networks recognize pain for new research published this week in JAMA.

The randomized clinical trial recruited two groups of 138 participants with chronic low back pain, testing one group with a novel method called graded sensorimotor retraining intervention (RESOLVE) and the other with things like mock laser therapy and noninvasive brain stimulation.

The researchers found the RESOLVE 12-week training course resulted in a statistically significant improvement in pain intensity at 18 weeks.

“What we observed in our trial was a clinically meaningful effect on pain intensity and a clinically meaningful effect on disability. People were happier, they reported their backs felt better, and their quality of life was better,” the study’s lead author, James McAuley, PhD, said in a statement. “This is the first new treatment of its kind for back pain.”
 

Brainy talk

Communication between your brain and back changes over time when you have chronic lower back pain, leading the brain to interpret signals from the back differently and change how you move. It is thought that these neural changes make recovery from pain slower and more complicated , according to Neuroscience Research Australia (NeuRA), a nonprofit research institute in Sydney.

“Over time, the back becomes less fit, and the way the back and brain communicate is disrupted in ways that seem to reinforce the notion that the back is vulnerable and needs protecting,” said Dr. McAuley, a professor at the University of New South Wales, Sydney, and a NeuRA senior research scientist. “The treatment we devised aims to break this self-sustaining cycle.”

RESOLVE treatment focuses on improving this transformed brain-back communication by slowly retraining the body and the brain without the use of opioids or surgery. People in the study have reported improved quality of life 1 year later, according to Dr. McAuley.

The researchers said the pain improvement was “modest,” and the method will need to be tested on other patients and conditions. They hope to introduce this new treatment to doctors and physiotherapists within the next 6-9 months and have already enlisted partner organizations to start this process, according to NeuRA.

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

Are you among the hundreds of millions of people worldwide with low back pain? If so, you may be familiar with standard treatments like surgery, shots, medications, and spinal manipulations. But new research suggests the solution for the world’s leading cause of disability may lie in fixing how the brain and the body communicate.

Setting out to challenge traditional treatments for chronic back pain, scientists across Australia, Europe, and the United States came together to test the effectiveness of altering how neural networks recognize pain for new research published this week in JAMA.

The randomized clinical trial recruited two groups of 138 participants with chronic low back pain, testing one group with a novel method called graded sensorimotor retraining intervention (RESOLVE) and the other with things like mock laser therapy and noninvasive brain stimulation.

The researchers found the RESOLVE 12-week training course resulted in a statistically significant improvement in pain intensity at 18 weeks.

“What we observed in our trial was a clinically meaningful effect on pain intensity and a clinically meaningful effect on disability. People were happier, they reported their backs felt better, and their quality of life was better,” the study’s lead author, James McAuley, PhD, said in a statement. “This is the first new treatment of its kind for back pain.”
 

Brainy talk

Communication between your brain and back changes over time when you have chronic lower back pain, leading the brain to interpret signals from the back differently and change how you move. It is thought that these neural changes make recovery from pain slower and more complicated , according to Neuroscience Research Australia (NeuRA), a nonprofit research institute in Sydney.

“Over time, the back becomes less fit, and the way the back and brain communicate is disrupted in ways that seem to reinforce the notion that the back is vulnerable and needs protecting,” said Dr. McAuley, a professor at the University of New South Wales, Sydney, and a NeuRA senior research scientist. “The treatment we devised aims to break this self-sustaining cycle.”

RESOLVE treatment focuses on improving this transformed brain-back communication by slowly retraining the body and the brain without the use of opioids or surgery. People in the study have reported improved quality of life 1 year later, according to Dr. McAuley.

The researchers said the pain improvement was “modest,” and the method will need to be tested on other patients and conditions. They hope to introduce this new treatment to doctors and physiotherapists within the next 6-9 months and have already enlisted partner organizations to start this process, according to NeuRA.

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

A simple blood test that looks for a combination of specific RNA snippets may become a novel way to screen for early-onset colorectal cancer, suggests a new study published online in Gastroenterology.

Researchers identified four microRNAs that together comprise a signature biomarker that can be used to detect and diagnose the presence of colorectal cancer from a liquid biopsy in a younger population.

MicroRNAs, or miRNAs, are small RNA molecules that do not encode proteins but are used instead to regulate gene expression. The study authors developed and validated a panel that detects four miRNAs occurring at higher levels in plasma samples from patients with early-onset colorectal cancer, with high sensitivity and specificity.

“The point would be to use this test as a routine part of annual healthcare, or for people in high-risk families every 6 months,” study senior author Ajay Goel, PhD, MS, chair of the department of molecular diagnostics and experimental therapeutics at the City of Hope Comprehensive Cancer Center, Duarte, Calif., said in an interview.

“It’s affordable, it can be done easily from a small tube of blood, and as long as that test stays negative, you’re good,” Dr. Goel said, because even if patients miss a test, the next one, whether it’s 6 months or a year later, will catch any potential cancer.

“Colon cancer is not going to kill somebody overnight, so this should be used as a precursor to colonoscopy. As long as that test is negative, you can postpone a colonoscopy,” he said.

Andrew T. Chan, MD, MPH, a professor of medicine at Harvard Medical School and vice chair of gastroenterology at Massachusetts General Hospital, both in Boston, who was not involved in the research, said in an interview that the findings are exciting.

“It would be really value-added to have a blood-based screening test,” Dr. Chan said, adding that researchers have pursued multiple different avenues in pursuit of one. “It’s very nice to see that area progress and to actually have some evidence that microRNAs could be a potential biomarker for colorectal cancer.”
 

Screening now insufficient for early-onset disease

The U.S. Preventive Services Task Force recently lowered the recommended age to 45 years to begin screening for colorectal cancer. Part of the rationale for the change came from the rising rates of early-onset colorectal cancer, a distinct clinical and molecular entity that tends to have poorer survival than late-onset disease, the authors noted.

Early-onset disease, occurring primarily in people under 50 without a family or genetic history of colorectal cancer, now makes up about 10%-15% of all new cases and continues to rise, they write.

“Early-onset colorectal cancer patients are more likely to exhibit an advanced stage tumor at initial presentation, distal tumor localization, signet ring histology, and a disease presentation with concurrent metastasis,” the authors wrote. “This raises the logistical clinical concern that, since the tumors in early-onset colorectal cancer patients are often more aggressive than those with late-onset colorectal cancer, a delayed diagnosis could have a significant adverse impact and can lead to early death.”

Yet current screening strategies are insufficient for detecting enough early-onset cases, the authors assert.

Colonoscopies are invasive, carry a risk for complications, and are cost- and time-prohibitive for people at average risk. Meanwhile, existing fecal and blood tests “lack adequate diagnostic performance for the early detection of colorectal cancer, especially early-onset colorectal cancer, as these assays have yet to be explored or developed in this population,” they wrote.

The ideal “diagnostic modality should preferably be acceptable to healthy individuals, inexpensive, rapid, and preferably noninvasive,” they note.
 

Finding and validating miRNA

The researchers therefore turned to the concept of a liquid biopsy, focusing on identifying miRNAs associated with colorectal cancer, because their expression tends to be stable in tissues, blood, stool, and other body fluids.

They first analyzed an miRNA expression profiling dataset from 1,061 individuals to look for miRNAs whose expression was higher in colorectal cancer patients. The dataset included 42 patients with stage 1-2 early-onset colorectal cancer, 370 patients with stage 1-2 late-onset colorectal cancer, 62 patients younger than 50 years without cancer, and 587 patients aged 50 years or older without cancer.

The researchers found 28 miRNAs that were significantly unregulated in early-onset colorectal cancer tissue samples, compared with cancer-free samples and 11 miRNAs unregulated specifically in only the early-onset colorectal cancer samples. Four of these 11 miRNAs were adequately distinct from one another and were detectable in the plasma samples that the researchers would use to train and validate them as a combination biomarker.

The researchers used 117 plasma samples from Japan, including 72 from people with early-onset colorectal cancer and 45 from healthy donors, to develop and train an assay detecting the four miRNAs. They then validated the assay using 142 plasma samples from Spain, including 77 with early-onset colorectal cancer and 65 healthy donors.

In the Japan cohort, the four-miRNA assay had a sensitivity of 90% and a specificity of 80%, with a positive predictive value (PPV) of 88% and a negative predictive value (NPV) of 84%. In the Spain cohort used for validation, the assay performed with a sensitivity of 82%, a specificity of 86%, a PPV of 88%, and an NPV of 80%.

“Taken together, the genome-wide transcriptomic profiling approach was indeed robust, as it identified the biomarkers that were successfully trained and validated in plasma specimens from independent cohorts of patients with early-onset colorectal cancer, hence highlighting their translational potential in the clinic for the detection of this malignancy in early stages,” the authors wrote.

By disease stage, the four-miRNA panel identified both early-stage (stage 1-2; sensitivity, 92%; specificity, 80%) and late-stage (stage 3-4; sensitivity, 79%; specificity, 86%) early-onset colorectal cancer in the validation cohort.
 

Clinical benefit of blood test

The researchers also assessed the benefit-harm trade-off of this liquid biopsy assay compared with other screening modalities, taking into consideration the risk for false positives and false negatives.

A decision curve analysis “revealed that the miRNA panel achieved a higher net benefit regardless of threshold probability in comparison to intervention for all patients or none of the patients,” the researchers reported. “These findings suggest that this miRNA panel might offer more clinical benefit with regards to the avoidance of physical harm and misdiagnosis.”

They also found that expression levels of these four miRNAs significantly decreased after surgical removal of the colorectal cancer, strongly suggesting that the miRNAs do originate with the tumor.

“To have a relatively inexpensive and noninvasive means of screening a younger population is a very important unmet need,” said Dr. Chan.

It’s not feasible to recommend colonoscopies in people younger than 45 years because of resource constraints, he said, so “this is a wonderful new development to actually have the possibility of a blood-based screening test for younger individuals, especially given that rising incidence of young-onset colorectal cancer.”

Dr. Goel pointed out that only half of those recommended to get screened for colorectal cancer actually undergo screening, and a large reason for that is the desire to avoid colonoscopy, a concern echoed in the findings of a recent study by Christopher V. Almario, MD, MSHPM, and colleagues.

Dr. Goel expects that this strategy would increase compliance with screening because it’s less invasive and more affordable, particularly for younger patients. He estimates that a commercial assay using this panel, if approved by the Food and Drug Administration, should cost less than $100.

Dr. Almario, an assistant professor of medicine at the Cedars-Sinai Karsh Division of Gastroenterology and Hepatology in Los Angeles, agreed that an FDA-approved blood-based screening test would be a “game-changer,” as long as it’s accurate and effective.

Though Dr. Almario did not review the data in Goel’s study, he said in an interview that a blood test for colorectal cancer screening would be “the holy grail, so to speak, in terms of really moving the needle on screening uptake.”
 

Next steps

Dr. Chan noted that one caveat to consider with this study is that it was done in a relatively small population of individuals, even though the test was validated in a second set of plasma samples.

“Additional validation needs to be done in larger numbers of patients to really understand the performance characteristics because it is possible that some of these signatures may, when they’re using a broader group of individuals, not perform as well,” Dr. Chan said.

Dr. Goel said he is working with several companies right now to develop and further test a commercial product. He anticipates it may be shelf-ready in 2-5 years.

“The take-home message is that clinicians need to be more cognizant of the fact that incidence of this disease is rising, and we need to do something about it,” Dr. Goel said, particularly for those younger than 45 years who currently don’t have a screening option.

“Now we have at least a sliver of hope for those who might be suffering from this disease, for those for whom we have zero screening or diagnostic tests,” he said.

The research was funded by the National Cancer Institute and Fundación MAPFRE Guanarteme. Dr. Goel, Dr. Chan, and Dr. Almario reported no conflicts of interest.

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

A simple blood test that looks for a combination of specific RNA snippets may become a novel way to screen for early-onset colorectal cancer, suggests a new study published online in Gastroenterology.

Researchers identified four microRNAs that together comprise a signature biomarker that can be used to detect and diagnose the presence of colorectal cancer from a liquid biopsy in a younger population.

MicroRNAs, or miRNAs, are small RNA molecules that do not encode proteins but are used instead to regulate gene expression. The study authors developed and validated a panel that detects four miRNAs occurring at higher levels in plasma samples from patients with early-onset colorectal cancer, with high sensitivity and specificity.

“The point would be to use this test as a routine part of annual healthcare, or for people in high-risk families every 6 months,” study senior author Ajay Goel, PhD, MS, chair of the department of molecular diagnostics and experimental therapeutics at the City of Hope Comprehensive Cancer Center, Duarte, Calif., said in an interview.

“It’s affordable, it can be done easily from a small tube of blood, and as long as that test stays negative, you’re good,” Dr. Goel said, because even if patients miss a test, the next one, whether it’s 6 months or a year later, will catch any potential cancer.

“Colon cancer is not going to kill somebody overnight, so this should be used as a precursor to colonoscopy. As long as that test is negative, you can postpone a colonoscopy,” he said.

Andrew T. Chan, MD, MPH, a professor of medicine at Harvard Medical School and vice chair of gastroenterology at Massachusetts General Hospital, both in Boston, who was not involved in the research, said in an interview that the findings are exciting.

“It would be really value-added to have a blood-based screening test,” Dr. Chan said, adding that researchers have pursued multiple different avenues in pursuit of one. “It’s very nice to see that area progress and to actually have some evidence that microRNAs could be a potential biomarker for colorectal cancer.”
 

Screening now insufficient for early-onset disease

The U.S. Preventive Services Task Force recently lowered the recommended age to 45 years to begin screening for colorectal cancer. Part of the rationale for the change came from the rising rates of early-onset colorectal cancer, a distinct clinical and molecular entity that tends to have poorer survival than late-onset disease, the authors noted.

Early-onset disease, occurring primarily in people under 50 without a family or genetic history of colorectal cancer, now makes up about 10%-15% of all new cases and continues to rise, they write.

“Early-onset colorectal cancer patients are more likely to exhibit an advanced stage tumor at initial presentation, distal tumor localization, signet ring histology, and a disease presentation with concurrent metastasis,” the authors wrote. “This raises the logistical clinical concern that, since the tumors in early-onset colorectal cancer patients are often more aggressive than those with late-onset colorectal cancer, a delayed diagnosis could have a significant adverse impact and can lead to early death.”

Yet current screening strategies are insufficient for detecting enough early-onset cases, the authors assert.

Colonoscopies are invasive, carry a risk for complications, and are cost- and time-prohibitive for people at average risk. Meanwhile, existing fecal and blood tests “lack adequate diagnostic performance for the early detection of colorectal cancer, especially early-onset colorectal cancer, as these assays have yet to be explored or developed in this population,” they wrote.

The ideal “diagnostic modality should preferably be acceptable to healthy individuals, inexpensive, rapid, and preferably noninvasive,” they note.
 

Finding and validating miRNA

The researchers therefore turned to the concept of a liquid biopsy, focusing on identifying miRNAs associated with colorectal cancer, because their expression tends to be stable in tissues, blood, stool, and other body fluids.

They first analyzed an miRNA expression profiling dataset from 1,061 individuals to look for miRNAs whose expression was higher in colorectal cancer patients. The dataset included 42 patients with stage 1-2 early-onset colorectal cancer, 370 patients with stage 1-2 late-onset colorectal cancer, 62 patients younger than 50 years without cancer, and 587 patients aged 50 years or older without cancer.

The researchers found 28 miRNAs that were significantly unregulated in early-onset colorectal cancer tissue samples, compared with cancer-free samples and 11 miRNAs unregulated specifically in only the early-onset colorectal cancer samples. Four of these 11 miRNAs were adequately distinct from one another and were detectable in the plasma samples that the researchers would use to train and validate them as a combination biomarker.

The researchers used 117 plasma samples from Japan, including 72 from people with early-onset colorectal cancer and 45 from healthy donors, to develop and train an assay detecting the four miRNAs. They then validated the assay using 142 plasma samples from Spain, including 77 with early-onset colorectal cancer and 65 healthy donors.

In the Japan cohort, the four-miRNA assay had a sensitivity of 90% and a specificity of 80%, with a positive predictive value (PPV) of 88% and a negative predictive value (NPV) of 84%. In the Spain cohort used for validation, the assay performed with a sensitivity of 82%, a specificity of 86%, a PPV of 88%, and an NPV of 80%.

“Taken together, the genome-wide transcriptomic profiling approach was indeed robust, as it identified the biomarkers that were successfully trained and validated in plasma specimens from independent cohorts of patients with early-onset colorectal cancer, hence highlighting their translational potential in the clinic for the detection of this malignancy in early stages,” the authors wrote.

By disease stage, the four-miRNA panel identified both early-stage (stage 1-2; sensitivity, 92%; specificity, 80%) and late-stage (stage 3-4; sensitivity, 79%; specificity, 86%) early-onset colorectal cancer in the validation cohort.
 

Clinical benefit of blood test

The researchers also assessed the benefit-harm trade-off of this liquid biopsy assay compared with other screening modalities, taking into consideration the risk for false positives and false negatives.

A decision curve analysis “revealed that the miRNA panel achieved a higher net benefit regardless of threshold probability in comparison to intervention for all patients or none of the patients,” the researchers reported. “These findings suggest that this miRNA panel might offer more clinical benefit with regards to the avoidance of physical harm and misdiagnosis.”

They also found that expression levels of these four miRNAs significantly decreased after surgical removal of the colorectal cancer, strongly suggesting that the miRNAs do originate with the tumor.

“To have a relatively inexpensive and noninvasive means of screening a younger population is a very important unmet need,” said Dr. Chan.

It’s not feasible to recommend colonoscopies in people younger than 45 years because of resource constraints, he said, so “this is a wonderful new development to actually have the possibility of a blood-based screening test for younger individuals, especially given that rising incidence of young-onset colorectal cancer.”

Dr. Goel pointed out that only half of those recommended to get screened for colorectal cancer actually undergo screening, and a large reason for that is the desire to avoid colonoscopy, a concern echoed in the findings of a recent study by Christopher V. Almario, MD, MSHPM, and colleagues.

Dr. Goel expects that this strategy would increase compliance with screening because it’s less invasive and more affordable, particularly for younger patients. He estimates that a commercial assay using this panel, if approved by the Food and Drug Administration, should cost less than $100.

Dr. Almario, an assistant professor of medicine at the Cedars-Sinai Karsh Division of Gastroenterology and Hepatology in Los Angeles, agreed that an FDA-approved blood-based screening test would be a “game-changer,” as long as it’s accurate and effective.

Though Dr. Almario did not review the data in Goel’s study, he said in an interview that a blood test for colorectal cancer screening would be “the holy grail, so to speak, in terms of really moving the needle on screening uptake.”
 

Next steps

Dr. Chan noted that one caveat to consider with this study is that it was done in a relatively small population of individuals, even though the test was validated in a second set of plasma samples.

“Additional validation needs to be done in larger numbers of patients to really understand the performance characteristics because it is possible that some of these signatures may, when they’re using a broader group of individuals, not perform as well,” Dr. Chan said.

Dr. Goel said he is working with several companies right now to develop and further test a commercial product. He anticipates it may be shelf-ready in 2-5 years.

“The take-home message is that clinicians need to be more cognizant of the fact that incidence of this disease is rising, and we need to do something about it,” Dr. Goel said, particularly for those younger than 45 years who currently don’t have a screening option.

“Now we have at least a sliver of hope for those who might be suffering from this disease, for those for whom we have zero screening or diagnostic tests,” he said.

The research was funded by the National Cancer Institute and Fundación MAPFRE Guanarteme. Dr. Goel, Dr. Chan, and Dr. Almario reported no conflicts of interest.

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

A simple blood test that looks for a combination of specific RNA snippets may become a novel way to screen for early-onset colorectal cancer, suggests a new study published online in Gastroenterology.

Researchers identified four microRNAs that together comprise a signature biomarker that can be used to detect and diagnose the presence of colorectal cancer from a liquid biopsy in a younger population.

MicroRNAs, or miRNAs, are small RNA molecules that do not encode proteins but are used instead to regulate gene expression. The study authors developed and validated a panel that detects four miRNAs occurring at higher levels in plasma samples from patients with early-onset colorectal cancer, with high sensitivity and specificity.

“The point would be to use this test as a routine part of annual healthcare, or for people in high-risk families every 6 months,” study senior author Ajay Goel, PhD, MS, chair of the department of molecular diagnostics and experimental therapeutics at the City of Hope Comprehensive Cancer Center, Duarte, Calif., said in an interview.

“It’s affordable, it can be done easily from a small tube of blood, and as long as that test stays negative, you’re good,” Dr. Goel said, because even if patients miss a test, the next one, whether it’s 6 months or a year later, will catch any potential cancer.

“Colon cancer is not going to kill somebody overnight, so this should be used as a precursor to colonoscopy. As long as that test is negative, you can postpone a colonoscopy,” he said.

Andrew T. Chan, MD, MPH, a professor of medicine at Harvard Medical School and vice chair of gastroenterology at Massachusetts General Hospital, both in Boston, who was not involved in the research, said in an interview that the findings are exciting.

“It would be really value-added to have a blood-based screening test,” Dr. Chan said, adding that researchers have pursued multiple different avenues in pursuit of one. “It’s very nice to see that area progress and to actually have some evidence that microRNAs could be a potential biomarker for colorectal cancer.”
 

Screening now insufficient for early-onset disease

The U.S. Preventive Services Task Force recently lowered the recommended age to 45 years to begin screening for colorectal cancer. Part of the rationale for the change came from the rising rates of early-onset colorectal cancer, a distinct clinical and molecular entity that tends to have poorer survival than late-onset disease, the authors noted.

Early-onset disease, occurring primarily in people under 50 without a family or genetic history of colorectal cancer, now makes up about 10%-15% of all new cases and continues to rise, they write.

“Early-onset colorectal cancer patients are more likely to exhibit an advanced stage tumor at initial presentation, distal tumor localization, signet ring histology, and a disease presentation with concurrent metastasis,” the authors wrote. “This raises the logistical clinical concern that, since the tumors in early-onset colorectal cancer patients are often more aggressive than those with late-onset colorectal cancer, a delayed diagnosis could have a significant adverse impact and can lead to early death.”

Yet current screening strategies are insufficient for detecting enough early-onset cases, the authors assert.

Colonoscopies are invasive, carry a risk for complications, and are cost- and time-prohibitive for people at average risk. Meanwhile, existing fecal and blood tests “lack adequate diagnostic performance for the early detection of colorectal cancer, especially early-onset colorectal cancer, as these assays have yet to be explored or developed in this population,” they wrote.

The ideal “diagnostic modality should preferably be acceptable to healthy individuals, inexpensive, rapid, and preferably noninvasive,” they note.
 

Finding and validating miRNA

The researchers therefore turned to the concept of a liquid biopsy, focusing on identifying miRNAs associated with colorectal cancer, because their expression tends to be stable in tissues, blood, stool, and other body fluids.

They first analyzed an miRNA expression profiling dataset from 1,061 individuals to look for miRNAs whose expression was higher in colorectal cancer patients. The dataset included 42 patients with stage 1-2 early-onset colorectal cancer, 370 patients with stage 1-2 late-onset colorectal cancer, 62 patients younger than 50 years without cancer, and 587 patients aged 50 years or older without cancer.

The researchers found 28 miRNAs that were significantly unregulated in early-onset colorectal cancer tissue samples, compared with cancer-free samples and 11 miRNAs unregulated specifically in only the early-onset colorectal cancer samples. Four of these 11 miRNAs were adequately distinct from one another and were detectable in the plasma samples that the researchers would use to train and validate them as a combination biomarker.

The researchers used 117 plasma samples from Japan, including 72 from people with early-onset colorectal cancer and 45 from healthy donors, to develop and train an assay detecting the four miRNAs. They then validated the assay using 142 plasma samples from Spain, including 77 with early-onset colorectal cancer and 65 healthy donors.

In the Japan cohort, the four-miRNA assay had a sensitivity of 90% and a specificity of 80%, with a positive predictive value (PPV) of 88% and a negative predictive value (NPV) of 84%. In the Spain cohort used for validation, the assay performed with a sensitivity of 82%, a specificity of 86%, a PPV of 88%, and an NPV of 80%.

“Taken together, the genome-wide transcriptomic profiling approach was indeed robust, as it identified the biomarkers that were successfully trained and validated in plasma specimens from independent cohorts of patients with early-onset colorectal cancer, hence highlighting their translational potential in the clinic for the detection of this malignancy in early stages,” the authors wrote.

By disease stage, the four-miRNA panel identified both early-stage (stage 1-2; sensitivity, 92%; specificity, 80%) and late-stage (stage 3-4; sensitivity, 79%; specificity, 86%) early-onset colorectal cancer in the validation cohort.
 

Clinical benefit of blood test

The researchers also assessed the benefit-harm trade-off of this liquid biopsy assay compared with other screening modalities, taking into consideration the risk for false positives and false negatives.

A decision curve analysis “revealed that the miRNA panel achieved a higher net benefit regardless of threshold probability in comparison to intervention for all patients or none of the patients,” the researchers reported. “These findings suggest that this miRNA panel might offer more clinical benefit with regards to the avoidance of physical harm and misdiagnosis.”

They also found that expression levels of these four miRNAs significantly decreased after surgical removal of the colorectal cancer, strongly suggesting that the miRNAs do originate with the tumor.

“To have a relatively inexpensive and noninvasive means of screening a younger population is a very important unmet need,” said Dr. Chan.

It’s not feasible to recommend colonoscopies in people younger than 45 years because of resource constraints, he said, so “this is a wonderful new development to actually have the possibility of a blood-based screening test for younger individuals, especially given that rising incidence of young-onset colorectal cancer.”

Dr. Goel pointed out that only half of those recommended to get screened for colorectal cancer actually undergo screening, and a large reason for that is the desire to avoid colonoscopy, a concern echoed in the findings of a recent study by Christopher V. Almario, MD, MSHPM, and colleagues.

Dr. Goel expects that this strategy would increase compliance with screening because it’s less invasive and more affordable, particularly for younger patients. He estimates that a commercial assay using this panel, if approved by the Food and Drug Administration, should cost less than $100.

Dr. Almario, an assistant professor of medicine at the Cedars-Sinai Karsh Division of Gastroenterology and Hepatology in Los Angeles, agreed that an FDA-approved blood-based screening test would be a “game-changer,” as long as it’s accurate and effective.

Though Dr. Almario did not review the data in Goel’s study, he said in an interview that a blood test for colorectal cancer screening would be “the holy grail, so to speak, in terms of really moving the needle on screening uptake.”
 

Next steps

Dr. Chan noted that one caveat to consider with this study is that it was done in a relatively small population of individuals, even though the test was validated in a second set of plasma samples.

“Additional validation needs to be done in larger numbers of patients to really understand the performance characteristics because it is possible that some of these signatures may, when they’re using a broader group of individuals, not perform as well,” Dr. Chan said.

Dr. Goel said he is working with several companies right now to develop and further test a commercial product. He anticipates it may be shelf-ready in 2-5 years.

“The take-home message is that clinicians need to be more cognizant of the fact that incidence of this disease is rising, and we need to do something about it,” Dr. Goel said, particularly for those younger than 45 years who currently don’t have a screening option.

“Now we have at least a sliver of hope for those who might be suffering from this disease, for those for whom we have zero screening or diagnostic tests,” he said.

The research was funded by the National Cancer Institute and Fundación MAPFRE Guanarteme. Dr. Goel, Dr. Chan, and Dr. Almario reported no conflicts of interest.

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

People who are socially isolated or lonely have an increased risk for myocardial infarction, stroke, and death, independent of other factors, the American Heart Association concludes in a new scientific statement.

More than 4 decades of research have “clearly demonstrated that social isolation and loneliness are both associated with adverse health outcomes,” writing group chair Crystal Wiley Cené, MD, University of California San Diego Health, said in a news release.

“Given the prevalence of social disconnectedness across the United States, the public health impact is quite significant,” Dr. Cené added.

The writing group says more research is needed to develop, implement, and test interventions to improve cardiovascular (CV) and brain health in people who are socially isolated or lonely.

The scientific statement was published online in the Journal of the American Heart Association.
 

Common and potentially deadly

Social isolation is defined as having infrequent in-person contact with people and loneliness is when a person feels he or she is alone or has less connection with others than desired.

It’s estimated that one-quarter of community-dwelling Americans 65 years and older are socially isolated, with even more experiencing loneliness.

The problem is not limited to older adults, however. Research suggests that younger adults also experience social isolation and loneliness, which might be attributed to more social media use and less frequent in-person activities.

Dr. Cené and colleagues reviewed observational and intervention research on social isolation published through July 2021 to examine the impact of social isolation and loneliness on CV and brain health.

The evidence is most consistent for a direct association between social isolation, loneliness, and death from coronary heart disease (CHD) and stroke, they reported.

For example, one meta-analysis of 19 studies showed that social isolation and loneliness increase the risk for CHD by 29%; most of these studies focused on acute MI and/or CHD death as the measure of CHD.

A meta-analysis of eight longitudinal observational studies showed social isolation and loneliness were associated with a 32% increased risk for stroke, after adjustment for age, sex, and socioeconomic status.

The literature also suggests social isolation and loneliness are associated with worse prognoses in adults with existing CHD or history of stroke.

One systematic review showed that socially isolated people with CHD had a two- to threefold increase in illness and death over 6 years, independent of cardiac risk factors.

Other research suggests that socially isolated adults with three or fewer social contacts per month have a 40% increased risk for recurrent stroke or MI.

There are fewer and less robust data on the association between social isolation and loneliness with heart failure (HF), dementia, and cognitive impairment, the writing group noted.

It’s also unclear whether actually being isolated (social isolation) or feeling isolated (loneliness) matters most for cardiovascular and brain health, because only a few studies have examined both in the same sample, they pointed out.

However, a study published in Neurology in June showed that older adults who reported feeling socially isolated had worse cognitive function at baseline than did those who did not report social isolation, and were 26% more likely to have dementia at follow-up, as reported by this news organization.
 

Urgent need for interventions

“There is an urgent need to develop, implement, and evaluate programs and strategies to reduce the negative effects of social isolation and loneliness on cardiovascular and brain health, particularly for at-risk populations,” Dr. Cené said in the news release. 

She encourages clinicians to ask patients about their social life and whether they are satisfied with their level of interactions with friends and family, and to be prepared to refer patients who are socially isolated or lonely, especially those with a history of CHD or stroke, to community resources to help them connect with others.

Fitness programs and recreational activities at senior centers, as well as interventions that address negative thoughts of self-worth and other negative thinking, have shown promise in reducing isolation and loneliness, the writing group said.

This scientific statement was prepared by the volunteer writing group on behalf of the AHA Social Determinants of Health Committee of the Council on Epidemiology and Prevention and the Council on Quality of Care and Outcomes Research; the Prevention Science Committee of the Council on Epidemiology and Prevention and the Council on Quality of Care and Outcomes Research; the Prevention Science Committee of the Council on Epidemiology and Prevention and the Council on Cardiovascular and Stroke Nursing; the Council on Arteriosclerosis, Thrombosis, and Vascular Biology; and the Stroke Council.

This research had no commercial funding. Members of the writing group have disclosed no relevant conflicts of interest.

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

People who are socially isolated or lonely have an increased risk for myocardial infarction, stroke, and death, independent of other factors, the American Heart Association concludes in a new scientific statement.

More than 4 decades of research have “clearly demonstrated that social isolation and loneliness are both associated with adverse health outcomes,” writing group chair Crystal Wiley Cené, MD, University of California San Diego Health, said in a news release.

“Given the prevalence of social disconnectedness across the United States, the public health impact is quite significant,” Dr. Cené added.

The writing group says more research is needed to develop, implement, and test interventions to improve cardiovascular (CV) and brain health in people who are socially isolated or lonely.

The scientific statement was published online in the Journal of the American Heart Association.
 

Common and potentially deadly

Social isolation is defined as having infrequent in-person contact with people and loneliness is when a person feels he or she is alone or has less connection with others than desired.

It’s estimated that one-quarter of community-dwelling Americans 65 years and older are socially isolated, with even more experiencing loneliness.

The problem is not limited to older adults, however. Research suggests that younger adults also experience social isolation and loneliness, which might be attributed to more social media use and less frequent in-person activities.

Dr. Cené and colleagues reviewed observational and intervention research on social isolation published through July 2021 to examine the impact of social isolation and loneliness on CV and brain health.

The evidence is most consistent for a direct association between social isolation, loneliness, and death from coronary heart disease (CHD) and stroke, they reported.

For example, one meta-analysis of 19 studies showed that social isolation and loneliness increase the risk for CHD by 29%; most of these studies focused on acute MI and/or CHD death as the measure of CHD.

A meta-analysis of eight longitudinal observational studies showed social isolation and loneliness were associated with a 32% increased risk for stroke, after adjustment for age, sex, and socioeconomic status.

The literature also suggests social isolation and loneliness are associated with worse prognoses in adults with existing CHD or history of stroke.

One systematic review showed that socially isolated people with CHD had a two- to threefold increase in illness and death over 6 years, independent of cardiac risk factors.

Other research suggests that socially isolated adults with three or fewer social contacts per month have a 40% increased risk for recurrent stroke or MI.

There are fewer and less robust data on the association between social isolation and loneliness with heart failure (HF), dementia, and cognitive impairment, the writing group noted.

It’s also unclear whether actually being isolated (social isolation) or feeling isolated (loneliness) matters most for cardiovascular and brain health, because only a few studies have examined both in the same sample, they pointed out.

However, a study published in Neurology in June showed that older adults who reported feeling socially isolated had worse cognitive function at baseline than did those who did not report social isolation, and were 26% more likely to have dementia at follow-up, as reported by this news organization.
 

Urgent need for interventions

“There is an urgent need to develop, implement, and evaluate programs and strategies to reduce the negative effects of social isolation and loneliness on cardiovascular and brain health, particularly for at-risk populations,” Dr. Cené said in the news release. 

She encourages clinicians to ask patients about their social life and whether they are satisfied with their level of interactions with friends and family, and to be prepared to refer patients who are socially isolated or lonely, especially those with a history of CHD or stroke, to community resources to help them connect with others.

Fitness programs and recreational activities at senior centers, as well as interventions that address negative thoughts of self-worth and other negative thinking, have shown promise in reducing isolation and loneliness, the writing group said.

This scientific statement was prepared by the volunteer writing group on behalf of the AHA Social Determinants of Health Committee of the Council on Epidemiology and Prevention and the Council on Quality of Care and Outcomes Research; the Prevention Science Committee of the Council on Epidemiology and Prevention and the Council on Quality of Care and Outcomes Research; the Prevention Science Committee of the Council on Epidemiology and Prevention and the Council on Cardiovascular and Stroke Nursing; the Council on Arteriosclerosis, Thrombosis, and Vascular Biology; and the Stroke Council.

This research had no commercial funding. Members of the writing group have disclosed no relevant conflicts of interest.

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

People who are socially isolated or lonely have an increased risk for myocardial infarction, stroke, and death, independent of other factors, the American Heart Association concludes in a new scientific statement.

More than 4 decades of research have “clearly demonstrated that social isolation and loneliness are both associated with adverse health outcomes,” writing group chair Crystal Wiley Cené, MD, University of California San Diego Health, said in a news release.

“Given the prevalence of social disconnectedness across the United States, the public health impact is quite significant,” Dr. Cené added.

The writing group says more research is needed to develop, implement, and test interventions to improve cardiovascular (CV) and brain health in people who are socially isolated or lonely.

The scientific statement was published online in the Journal of the American Heart Association.
 

Common and potentially deadly

Social isolation is defined as having infrequent in-person contact with people and loneliness is when a person feels he or she is alone or has less connection with others than desired.

It’s estimated that one-quarter of community-dwelling Americans 65 years and older are socially isolated, with even more experiencing loneliness.

The problem is not limited to older adults, however. Research suggests that younger adults also experience social isolation and loneliness, which might be attributed to more social media use and less frequent in-person activities.

Dr. Cené and colleagues reviewed observational and intervention research on social isolation published through July 2021 to examine the impact of social isolation and loneliness on CV and brain health.

The evidence is most consistent for a direct association between social isolation, loneliness, and death from coronary heart disease (CHD) and stroke, they reported.

For example, one meta-analysis of 19 studies showed that social isolation and loneliness increase the risk for CHD by 29%; most of these studies focused on acute MI and/or CHD death as the measure of CHD.

A meta-analysis of eight longitudinal observational studies showed social isolation and loneliness were associated with a 32% increased risk for stroke, after adjustment for age, sex, and socioeconomic status.

The literature also suggests social isolation and loneliness are associated with worse prognoses in adults with existing CHD or history of stroke.

One systematic review showed that socially isolated people with CHD had a two- to threefold increase in illness and death over 6 years, independent of cardiac risk factors.

Other research suggests that socially isolated adults with three or fewer social contacts per month have a 40% increased risk for recurrent stroke or MI.

There are fewer and less robust data on the association between social isolation and loneliness with heart failure (HF), dementia, and cognitive impairment, the writing group noted.

It’s also unclear whether actually being isolated (social isolation) or feeling isolated (loneliness) matters most for cardiovascular and brain health, because only a few studies have examined both in the same sample, they pointed out.

However, a study published in Neurology in June showed that older adults who reported feeling socially isolated had worse cognitive function at baseline than did those who did not report social isolation, and were 26% more likely to have dementia at follow-up, as reported by this news organization.
 

Urgent need for interventions

“There is an urgent need to develop, implement, and evaluate programs and strategies to reduce the negative effects of social isolation and loneliness on cardiovascular and brain health, particularly for at-risk populations,” Dr. Cené said in the news release. 

She encourages clinicians to ask patients about their social life and whether they are satisfied with their level of interactions with friends and family, and to be prepared to refer patients who are socially isolated or lonely, especially those with a history of CHD or stroke, to community resources to help them connect with others.

Fitness programs and recreational activities at senior centers, as well as interventions that address negative thoughts of self-worth and other negative thinking, have shown promise in reducing isolation and loneliness, the writing group said.

This scientific statement was prepared by the volunteer writing group on behalf of the AHA Social Determinants of Health Committee of the Council on Epidemiology and Prevention and the Council on Quality of Care and Outcomes Research; the Prevention Science Committee of the Council on Epidemiology and Prevention and the Council on Quality of Care and Outcomes Research; the Prevention Science Committee of the Council on Epidemiology and Prevention and the Council on Cardiovascular and Stroke Nursing; the Council on Arteriosclerosis, Thrombosis, and Vascular Biology; and the Stroke Council.

This research had no commercial funding. Members of the writing group have disclosed no relevant conflicts of interest.

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

Patients who take beta-blockers or antiplatelet agents are lowering their risk for cardiovascular events, but the protection may fall short for those who spend time outdoors on hot summer days, hints a limited analysis published as a letter in Nature Cardiovascular Research.

Patients taking either a beta-blocker or antiplatelet, or both medications together, appeared at elevated risk for nonfatal acute MI specifically on days when the weather turned hot, suggests the registry cohort study that covered 14 years of clinical and meteorologic data.

rottadana/Thinkstock

“The take-away message is not that patients should stop using these two medications, by no means. We’re raising cautions for patients taking them, to watch out for themselves during high-heat days,” lead author Kai Chen, PhD, Yale University, New Haven, Conn., said in an interview.

“We’re not giving the message that these drugs have harmful effects” because the nature of the links between the medications and MI in the study, with its potential for confounding, remain unknown, said Dr. Chen, from the department of environmental health sciences and Yale Center on Climate Change and Health.

For example, patients who take beta-blockers or antiplatelets tend to be sicker than patients not on the drugs, which could make heat-related MI more likely, and the drugs wrongly appear to be culprits, he observed. The analysis contained signals that could support either scenario.

The study is based on cases of nonfatal MI in Augsburg, Germany, that are part of the MONICA-KORA MI registry. The odds of a heat-related nonfatal MI, it suggests, were increased 63% among patients taking antiplatelets and by 65% among those on beta-blockers, compared with those not on these drugs. The odds went up by 75% among those on both drug classes, but the risks weren’t raised in patients not taking them.
 

Rising heat-related MI

Chen said analysis was inspired by a 2019 report – also based on MONICA-KORA, from many of the same authors and using similar methods to track events by daily air temperature – that showed a rising trend for heat-related MI and declining rate for MI related to cold weather from 1987 to 2014. A next step, he figured, would be to determine whether the MI risk trends were associated with any cardiovascular medications.

The current study’s signal of risk related to antiplatelets and beta-blockers did not emerge for ACE inhibitors, calcium-channel blockers, or diuretics. Statins showed a link to increased nonfatal MI risk, but solely among participants aged younger than 60 years, who were also far less likely to have pre-existing coronary heart disease (CHD). He and his colleagues chose not to highlight that finding, Dr. Chen said, because the age subgroup analysis was grossly underpowered.

The overall analysis involved 2,494 cases of nonfatal MI that occurred during the warmer months – May to September – from 2001 to 2014. It was limited to nonfatal cases – those with at least a month of survival after hospital admission – because of insufficient data on medication use associated with fatal MIs, the report states.

Nonfatal MIs were defined as heat-related if they struck on days reaching the 95th percentile for temperature across the 14 years, in this case 24.2 °C (about 75.6 °F), relative to the average temperature of lowest nonfatal MI risk across the cohort, 7.5 °C (about 45.5 °F).

Patients served as both cases and their own controls, in that air temperature exposures on the day of their MI (case day) were compared with the remaining same days of the week in the same calendar month (control days). That approach, the report stated, “automatically controls for long-term time trends, seasonality, day of the week, and time-invariant confounders (for example, pre-existing cardiovascular disease).”

The odds ratio for heat-related MI for patients on antiplatelets was 1.63 (95% confidence interval, 1.07-2.46), and for antiplatelet nonusers was 0.94 (95% CI, 0.68-1.29). The difference between the two ratios was significant (P = .04).

The corresponding OR for patients taking beta-blockers was 1.65 (95% CI, 1.11-2.45), and for nonusers of beta-blockers was 0.90 (95% CI, 0.64-1.26). Again, the OR difference was significant (P = .02).

The ORs for users of both medication classes and nonusers of either med class, respectively, were 1.75 (95% CI, 1.12-2.73) and 0.84 (95% CI, 0.59-1.19). The latter OR was significantly lower than former (P = .01).

In a sign that antiplatelet and beta-blocker use might have been just a marker for sicker patients who were more vulnerable to heat-related MI, Chen said, the nonfatal MI risk was significantly elevated (OR, 2.17; 95% CI, 1.40-3.38) among patients with pre-existing CHD, but not among those free of pre-existing CHD (OR, 0.88; 95% CI, 0.65-1.20); the odds difference was P < .01.

That signal of confounding by indication is somewhat countered, the report states, by variations in nonfatal MI risk by age group. The increased chances of an event seen overall in relation to beta-blockers and antiplatelets were more pronounced among the 39% of patients aged 25-59 years (P < .01). That’s in spite that group’s lower CHD prevalence. The risk elevation solely among the older patients was attenuated and rendered nonsignificant, even with their greater CHD burden, the report noted.

The report speculates on a potential mechanism by which beta-blockers, at least, might conceivably raise the risk for heat-related MI. “Beta-receptor blockers inhibit skin vasodilation, resulting in reduced heat dissipation through convection and, at the same time, could intensify the blood-pressure-lowering effect of other antihypertensive drugs, which then could lead to syncope.”

Beta-blockers, Dr. Chen said, “can mechanistically make people more vulnerable to heat. That’s one potential explanation. Or it could be that these people taking the medications are just sicker. Whatever the reasons, the phenomenon we observed is that these patients taking these two medications are at higher risk during high-temperature days.”

Dr. Chen and the other authors declare no competing interests.

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

Patients who take beta-blockers or antiplatelet agents are lowering their risk for cardiovascular events, but the protection may fall short for those who spend time outdoors on hot summer days, hints a limited analysis published as a letter in Nature Cardiovascular Research.

Patients taking either a beta-blocker or antiplatelet, or both medications together, appeared at elevated risk for nonfatal acute MI specifically on days when the weather turned hot, suggests the registry cohort study that covered 14 years of clinical and meteorologic data.

rottadana/Thinkstock

“The take-away message is not that patients should stop using these two medications, by no means. We’re raising cautions for patients taking them, to watch out for themselves during high-heat days,” lead author Kai Chen, PhD, Yale University, New Haven, Conn., said in an interview.

“We’re not giving the message that these drugs have harmful effects” because the nature of the links between the medications and MI in the study, with its potential for confounding, remain unknown, said Dr. Chen, from the department of environmental health sciences and Yale Center on Climate Change and Health.

For example, patients who take beta-blockers or antiplatelets tend to be sicker than patients not on the drugs, which could make heat-related MI more likely, and the drugs wrongly appear to be culprits, he observed. The analysis contained signals that could support either scenario.

The study is based on cases of nonfatal MI in Augsburg, Germany, that are part of the MONICA-KORA MI registry. The odds of a heat-related nonfatal MI, it suggests, were increased 63% among patients taking antiplatelets and by 65% among those on beta-blockers, compared with those not on these drugs. The odds went up by 75% among those on both drug classes, but the risks weren’t raised in patients not taking them.
 

Rising heat-related MI

Chen said analysis was inspired by a 2019 report – also based on MONICA-KORA, from many of the same authors and using similar methods to track events by daily air temperature – that showed a rising trend for heat-related MI and declining rate for MI related to cold weather from 1987 to 2014. A next step, he figured, would be to determine whether the MI risk trends were associated with any cardiovascular medications.

The current study’s signal of risk related to antiplatelets and beta-blockers did not emerge for ACE inhibitors, calcium-channel blockers, or diuretics. Statins showed a link to increased nonfatal MI risk, but solely among participants aged younger than 60 years, who were also far less likely to have pre-existing coronary heart disease (CHD). He and his colleagues chose not to highlight that finding, Dr. Chen said, because the age subgroup analysis was grossly underpowered.

The overall analysis involved 2,494 cases of nonfatal MI that occurred during the warmer months – May to September – from 2001 to 2014. It was limited to nonfatal cases – those with at least a month of survival after hospital admission – because of insufficient data on medication use associated with fatal MIs, the report states.

Nonfatal MIs were defined as heat-related if they struck on days reaching the 95th percentile for temperature across the 14 years, in this case 24.2 °C (about 75.6 °F), relative to the average temperature of lowest nonfatal MI risk across the cohort, 7.5 °C (about 45.5 °F).

Patients served as both cases and their own controls, in that air temperature exposures on the day of their MI (case day) were compared with the remaining same days of the week in the same calendar month (control days). That approach, the report stated, “automatically controls for long-term time trends, seasonality, day of the week, and time-invariant confounders (for example, pre-existing cardiovascular disease).”

The odds ratio for heat-related MI for patients on antiplatelets was 1.63 (95% confidence interval, 1.07-2.46), and for antiplatelet nonusers was 0.94 (95% CI, 0.68-1.29). The difference between the two ratios was significant (P = .04).

The corresponding OR for patients taking beta-blockers was 1.65 (95% CI, 1.11-2.45), and for nonusers of beta-blockers was 0.90 (95% CI, 0.64-1.26). Again, the OR difference was significant (P = .02).

The ORs for users of both medication classes and nonusers of either med class, respectively, were 1.75 (95% CI, 1.12-2.73) and 0.84 (95% CI, 0.59-1.19). The latter OR was significantly lower than former (P = .01).

In a sign that antiplatelet and beta-blocker use might have been just a marker for sicker patients who were more vulnerable to heat-related MI, Chen said, the nonfatal MI risk was significantly elevated (OR, 2.17; 95% CI, 1.40-3.38) among patients with pre-existing CHD, but not among those free of pre-existing CHD (OR, 0.88; 95% CI, 0.65-1.20); the odds difference was P < .01.

That signal of confounding by indication is somewhat countered, the report states, by variations in nonfatal MI risk by age group. The increased chances of an event seen overall in relation to beta-blockers and antiplatelets were more pronounced among the 39% of patients aged 25-59 years (P < .01). That’s in spite that group’s lower CHD prevalence. The risk elevation solely among the older patients was attenuated and rendered nonsignificant, even with their greater CHD burden, the report noted.

The report speculates on a potential mechanism by which beta-blockers, at least, might conceivably raise the risk for heat-related MI. “Beta-receptor blockers inhibit skin vasodilation, resulting in reduced heat dissipation through convection and, at the same time, could intensify the blood-pressure-lowering effect of other antihypertensive drugs, which then could lead to syncope.”

Beta-blockers, Dr. Chen said, “can mechanistically make people more vulnerable to heat. That’s one potential explanation. Or it could be that these people taking the medications are just sicker. Whatever the reasons, the phenomenon we observed is that these patients taking these two medications are at higher risk during high-temperature days.”

Dr. Chen and the other authors declare no competing interests.

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

Patients who take beta-blockers or antiplatelet agents are lowering their risk for cardiovascular events, but the protection may fall short for those who spend time outdoors on hot summer days, hints a limited analysis published as a letter in Nature Cardiovascular Research.

Patients taking either a beta-blocker or antiplatelet, or both medications together, appeared at elevated risk for nonfatal acute MI specifically on days when the weather turned hot, suggests the registry cohort study that covered 14 years of clinical and meteorologic data.

rottadana/Thinkstock

“The take-away message is not that patients should stop using these two medications, by no means. We’re raising cautions for patients taking them, to watch out for themselves during high-heat days,” lead author Kai Chen, PhD, Yale University, New Haven, Conn., said in an interview.

“We’re not giving the message that these drugs have harmful effects” because the nature of the links between the medications and MI in the study, with its potential for confounding, remain unknown, said Dr. Chen, from the department of environmental health sciences and Yale Center on Climate Change and Health.

For example, patients who take beta-blockers or antiplatelets tend to be sicker than patients not on the drugs, which could make heat-related MI more likely, and the drugs wrongly appear to be culprits, he observed. The analysis contained signals that could support either scenario.

The study is based on cases of nonfatal MI in Augsburg, Germany, that are part of the MONICA-KORA MI registry. The odds of a heat-related nonfatal MI, it suggests, were increased 63% among patients taking antiplatelets and by 65% among those on beta-blockers, compared with those not on these drugs. The odds went up by 75% among those on both drug classes, but the risks weren’t raised in patients not taking them.
 

Rising heat-related MI

Chen said analysis was inspired by a 2019 report – also based on MONICA-KORA, from many of the same authors and using similar methods to track events by daily air temperature – that showed a rising trend for heat-related MI and declining rate for MI related to cold weather from 1987 to 2014. A next step, he figured, would be to determine whether the MI risk trends were associated with any cardiovascular medications.

The current study’s signal of risk related to antiplatelets and beta-blockers did not emerge for ACE inhibitors, calcium-channel blockers, or diuretics. Statins showed a link to increased nonfatal MI risk, but solely among participants aged younger than 60 years, who were also far less likely to have pre-existing coronary heart disease (CHD). He and his colleagues chose not to highlight that finding, Dr. Chen said, because the age subgroup analysis was grossly underpowered.

The overall analysis involved 2,494 cases of nonfatal MI that occurred during the warmer months – May to September – from 2001 to 2014. It was limited to nonfatal cases – those with at least a month of survival after hospital admission – because of insufficient data on medication use associated with fatal MIs, the report states.

Nonfatal MIs were defined as heat-related if they struck on days reaching the 95th percentile for temperature across the 14 years, in this case 24.2 °C (about 75.6 °F), relative to the average temperature of lowest nonfatal MI risk across the cohort, 7.5 °C (about 45.5 °F).

Patients served as both cases and their own controls, in that air temperature exposures on the day of their MI (case day) were compared with the remaining same days of the week in the same calendar month (control days). That approach, the report stated, “automatically controls for long-term time trends, seasonality, day of the week, and time-invariant confounders (for example, pre-existing cardiovascular disease).”

The odds ratio for heat-related MI for patients on antiplatelets was 1.63 (95% confidence interval, 1.07-2.46), and for antiplatelet nonusers was 0.94 (95% CI, 0.68-1.29). The difference between the two ratios was significant (P = .04).

The corresponding OR for patients taking beta-blockers was 1.65 (95% CI, 1.11-2.45), and for nonusers of beta-blockers was 0.90 (95% CI, 0.64-1.26). Again, the OR difference was significant (P = .02).

The ORs for users of both medication classes and nonusers of either med class, respectively, were 1.75 (95% CI, 1.12-2.73) and 0.84 (95% CI, 0.59-1.19). The latter OR was significantly lower than former (P = .01).

In a sign that antiplatelet and beta-blocker use might have been just a marker for sicker patients who were more vulnerable to heat-related MI, Chen said, the nonfatal MI risk was significantly elevated (OR, 2.17; 95% CI, 1.40-3.38) among patients with pre-existing CHD, but not among those free of pre-existing CHD (OR, 0.88; 95% CI, 0.65-1.20); the odds difference was P < .01.

That signal of confounding by indication is somewhat countered, the report states, by variations in nonfatal MI risk by age group. The increased chances of an event seen overall in relation to beta-blockers and antiplatelets were more pronounced among the 39% of patients aged 25-59 years (P < .01). That’s in spite that group’s lower CHD prevalence. The risk elevation solely among the older patients was attenuated and rendered nonsignificant, even with their greater CHD burden, the report noted.

The report speculates on a potential mechanism by which beta-blockers, at least, might conceivably raise the risk for heat-related MI. “Beta-receptor blockers inhibit skin vasodilation, resulting in reduced heat dissipation through convection and, at the same time, could intensify the blood-pressure-lowering effect of other antihypertensive drugs, which then could lead to syncope.”

Beta-blockers, Dr. Chen said, “can mechanistically make people more vulnerable to heat. That’s one potential explanation. Or it could be that these people taking the medications are just sicker. Whatever the reasons, the phenomenon we observed is that these patients taking these two medications are at higher risk during high-temperature days.”

Dr. Chen and the other authors declare no competing interests.

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

Researchers published the study covered in this summary on researchsquare.com as a preprint that has not yet been peer reviewed.

Key takeaways

• In Japanese adults with type 1 diabetes insulin-pump treatment (continuous subcutaneous insulin infusion) and higher problem-solving perception appear protective against impaired awareness of hypoglycemia (IAH), while diabetic peripheral neuropathy (DPN) is associated with increased risk.
• Diabetes distress and fear of hypoglycemia are common in people with IAH.

Why this matters

• Adults with type 1 diabetes and IAH have a reduced ability to perceive hypoglycemic symptoms and are at risk of severe hypoglycemic events because they are unable to take immediate corrective action.
• This is the first study to identify protective factors and risk factors of IAH in Japanese adults with type 1 diabetes.
• People with IAH may plan to loosen tight glucose management and intentionally omit insulin injection to prevent severe hypoglycemia.
• The information in this report may help improve the management of people with problematic hypoglycemia, the authors suggested. Treatment with an insulin pump and structured education aimed at improving problem-solving skills may be useful interventions for adults with type 1 diabetes and IAH, they suggested.

Study design

• The study involved a cross-sectional analysis of 288 Japanese adults with type 1 diabetes who averaged 50 years old, had diabetes for an average of about 18 years, had an average hemoglobin A1c at baseline of 7.7%, and included about 37% men and 63% women.
• The cohort included 55 people with IAH (19%) and 233 with no impairment of their hypoglycemia awareness, based on their score on the .

Key results

• DPN was significantly more prevalent in the IAH group than in the control group (12.0% vs. 26.5%). A logistic regression analysis showed that the odds ratio for DPN was 2.63-fold higher among people with IAH, compared with those without IAH, but there were no differences in other complications or by HbA1c levels.
• Treatment with continuous subcutaneous insulin therapy (an insulin pump) was significantly less prevalent in the IAH group, compared with those without IAH (23.6% vs 39.5%), with an adjusted odds ratio of 0.48. The two subgroups showed no differences in use of continuous glucose monitoring, used by 56% of the people in each of the two subgroups.
• The two subgroups showed no differences in their healthy lifestyle score, sleep debt, or rates of excessive drinking.
• Mean autonomic symptom scores for both sweating and shaking were significantly reduced in the IAH group, but no between-group differences appeared for palpations or hunger.
• All mean neuroglycopenic symptom scores were significantly lower in those without IAH, including confusion and speech difficulty.
• Scores for measures of diabetes distress and for the worry component of the fear of hypoglycemia were significantly higher in the IAH group, but there were no differences in other psychological measures.
• Higher were significantly associated with decreased IAH risk with a calculated odds ratio of 0.54, but other aspects of hypoglycemia problem-solving such as detection control, goal setting, and strategy evaluation showed no significant links.

Limitations

• The study used a cross-sectional design, which is not suited to making causal inferences.
• The authors characterized DPN as either present or absent. They did not evaluate or analyze the severity of peripheral neuropathy.
• The authors evaluated diabetic cardiac autonomic neuropathy (DCAN) by a person’s coefficient of variation of R-R intervals, and definitive diagnosis of DCAN required at least two positive results on a cardiac autonomic test. More vigorous evaluation using a more definitive assessment of DCAN is needed to relate DCAN and IAH status.

Disclosures

• The study received no commercial funding.
• The authors have disclosed no relevant financial relationships.

This is a summary of a preprint research study, “Protective and risk factors of impaired awareness of hypoglycemia in patients with type 1 diabetes: a cross- sectional analysis of baseline data from the PR-IAH study,” written by researchers at several hospitals in Japan, all affiliated with the National Hospital Organization, on Research Square. The study has not yet been peer reviewed. The full text of the study can be found on researchsquare.com.

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

Researchers published the study covered in this summary on researchsquare.com as a preprint that has not yet been peer reviewed.

Key takeaways

• In Japanese adults with type 1 diabetes insulin-pump treatment (continuous subcutaneous insulin infusion) and higher problem-solving perception appear protective against impaired awareness of hypoglycemia (IAH), while diabetic peripheral neuropathy (DPN) is associated with increased risk.
• Diabetes distress and fear of hypoglycemia are common in people with IAH.

Why this matters

• Adults with type 1 diabetes and IAH have a reduced ability to perceive hypoglycemic symptoms and are at risk of severe hypoglycemic events because they are unable to take immediate corrective action.
• This is the first study to identify protective factors and risk factors of IAH in Japanese adults with type 1 diabetes.
• People with IAH may plan to loosen tight glucose management and intentionally omit insulin injection to prevent severe hypoglycemia.
• The information in this report may help improve the management of people with problematic hypoglycemia, the authors suggested. Treatment with an insulin pump and structured education aimed at improving problem-solving skills may be useful interventions for adults with type 1 diabetes and IAH, they suggested.

Study design

• The study involved a cross-sectional analysis of 288 Japanese adults with type 1 diabetes who averaged 50 years old, had diabetes for an average of about 18 years, had an average hemoglobin A1c at baseline of 7.7%, and included about 37% men and 63% women.
• The cohort included 55 people with IAH (19%) and 233 with no impairment of their hypoglycemia awareness, based on their score on the .

Key results

• DPN was significantly more prevalent in the IAH group than in the control group (12.0% vs. 26.5%). A logistic regression analysis showed that the odds ratio for DPN was 2.63-fold higher among people with IAH, compared with those without IAH, but there were no differences in other complications or by HbA1c levels.
• Treatment with continuous subcutaneous insulin therapy (an insulin pump) was significantly less prevalent in the IAH group, compared with those without IAH (23.6% vs 39.5%), with an adjusted odds ratio of 0.48. The two subgroups showed no differences in use of continuous glucose monitoring, used by 56% of the people in each of the two subgroups.
• The two subgroups showed no differences in their healthy lifestyle score, sleep debt, or rates of excessive drinking.
• Mean autonomic symptom scores for both sweating and shaking were significantly reduced in the IAH group, but no between-group differences appeared for palpations or hunger.
• All mean neuroglycopenic symptom scores were significantly lower in those without IAH, including confusion and speech difficulty.
• Scores for measures of diabetes distress and for the worry component of the fear of hypoglycemia were significantly higher in the IAH group, but there were no differences in other psychological measures.
• Higher were significantly associated with decreased IAH risk with a calculated odds ratio of 0.54, but other aspects of hypoglycemia problem-solving such as detection control, goal setting, and strategy evaluation showed no significant links.

Limitations

• The study used a cross-sectional design, which is not suited to making causal inferences.
• The authors characterized DPN as either present or absent. They did not evaluate or analyze the severity of peripheral neuropathy.
• The authors evaluated diabetic cardiac autonomic neuropathy (DCAN) by a person’s coefficient of variation of R-R intervals, and definitive diagnosis of DCAN required at least two positive results on a cardiac autonomic test. More vigorous evaluation using a more definitive assessment of DCAN is needed to relate DCAN and IAH status.

Disclosures

• The study received no commercial funding.
• The authors have disclosed no relevant financial relationships.

This is a summary of a preprint research study, “Protective and risk factors of impaired awareness of hypoglycemia in patients with type 1 diabetes: a cross- sectional analysis of baseline data from the PR-IAH study,” written by researchers at several hospitals in Japan, all affiliated with the National Hospital Organization, on Research Square. The study has not yet been peer reviewed. The full text of the study can be found on researchsquare.com.

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

Researchers published the study covered in this summary on researchsquare.com as a preprint that has not yet been peer reviewed.

Key takeaways

• In Japanese adults with type 1 diabetes insulin-pump treatment (continuous subcutaneous insulin infusion) and higher problem-solving perception appear protective against impaired awareness of hypoglycemia (IAH), while diabetic peripheral neuropathy (DPN) is associated with increased risk.
• Diabetes distress and fear of hypoglycemia are common in people with IAH.

Why this matters

• Adults with type 1 diabetes and IAH have a reduced ability to perceive hypoglycemic symptoms and are at risk of severe hypoglycemic events because they are unable to take immediate corrective action.
• This is the first study to identify protective factors and risk factors of IAH in Japanese adults with type 1 diabetes.
• People with IAH may plan to loosen tight glucose management and intentionally omit insulin injection to prevent severe hypoglycemia.
• The information in this report may help improve the management of people with problematic hypoglycemia, the authors suggested. Treatment with an insulin pump and structured education aimed at improving problem-solving skills may be useful interventions for adults with type 1 diabetes and IAH, they suggested.

Study design

• The study involved a cross-sectional analysis of 288 Japanese adults with type 1 diabetes who averaged 50 years old, had diabetes for an average of about 18 years, had an average hemoglobin A1c at baseline of 7.7%, and included about 37% men and 63% women.
• The cohort included 55 people with IAH (19%) and 233 with no impairment of their hypoglycemia awareness, based on their score on the .

Key results

• DPN was significantly more prevalent in the IAH group than in the control group (12.0% vs. 26.5%). A logistic regression analysis showed that the odds ratio for DPN was 2.63-fold higher among people with IAH, compared with those without IAH, but there were no differences in other complications or by HbA1c levels.
• Treatment with continuous subcutaneous insulin therapy (an insulin pump) was significantly less prevalent in the IAH group, compared with those without IAH (23.6% vs 39.5%), with an adjusted odds ratio of 0.48. The two subgroups showed no differences in use of continuous glucose monitoring, used by 56% of the people in each of the two subgroups.
• The two subgroups showed no differences in their healthy lifestyle score, sleep debt, or rates of excessive drinking.
• Mean autonomic symptom scores for both sweating and shaking were significantly reduced in the IAH group, but no between-group differences appeared for palpations or hunger.
• All mean neuroglycopenic symptom scores were significantly lower in those without IAH, including confusion and speech difficulty.
• Scores for measures of diabetes distress and for the worry component of the fear of hypoglycemia were significantly higher in the IAH group, but there were no differences in other psychological measures.
• Higher were significantly associated with decreased IAH risk with a calculated odds ratio of 0.54, but other aspects of hypoglycemia problem-solving such as detection control, goal setting, and strategy evaluation showed no significant links.

Limitations

• The study used a cross-sectional design, which is not suited to making causal inferences.
• The authors characterized DPN as either present or absent. They did not evaluate or analyze the severity of peripheral neuropathy.
• The authors evaluated diabetic cardiac autonomic neuropathy (DCAN) by a person’s coefficient of variation of R-R intervals, and definitive diagnosis of DCAN required at least two positive results on a cardiac autonomic test. More vigorous evaluation using a more definitive assessment of DCAN is needed to relate DCAN and IAH status.

Disclosures

• The study received no commercial funding.
• The authors have disclosed no relevant financial relationships.

This is a summary of a preprint research study, “Protective and risk factors of impaired awareness of hypoglycemia in patients with type 1 diabetes: a cross- sectional analysis of baseline data from the PR-IAH study,” written by researchers at several hospitals in Japan, all affiliated with the National Hospital Organization, on Research Square. The study has not yet been peer reviewed. The full text of the study can be found on researchsquare.com.

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

Topical ruxolitinib appears to quickly relieve itch in Black patients with atopic dermatitis (AD), an industry-sponsored analysis of pooled data from two studies suggests.

“Ruxolitinib cream monotherapy over 8 weeks was associated with rapid and considerable itch relief in Black or African American patients with AD and was well tolerated,” the study authors wrote in a poster presented at the annual meeting of the Society for Investigative Dermatology.

AD can behave differently in different racial groups and can be especially bothersome in Black patients. AD has a prevalence of about 20% in Black children and 5%-10% in Black adults. Black children are roughly twice as likely to be diagnosed with AD, and to have severe AD, than White children, according to the authors.

Lead author Lawrence F. Eichenfield, MD, professor of dermatology and pediatrics at the University of California, San Diego, and colleagues used pooled data from two identically designed phase 3 studies to describe the effects of the cream formulation of the Janus kinase (JAK) 1 and JAK 2 inhibitor ruxolitinib on itch in Black patients.

Topical ruxolitinib (Opzelura), 1.5%, was approved last September for treating AD in non-immunocompromised patients with mild to moderate AD, ages 12 years and older. In July 2022, it was approved for the treatment of nonsegmental vitiligo in the same age group.  

FDA approval for AD was based on the results of the TRuE-AD1 and TRuE-AD2 double-blind randomized trials, which enrolled about 1,200 patients over age 12 with AD. These patients included 292 Black teenagers and adults between aged 12-71 years who had AD for 2 years or longer, with an Investigator’s Global Assessment (IGA) score of 2 or 3, with 3%-20% affected body surface area, excluding the scalp.

Of the 292 patients, those in the two treatment groups (n = 231) applied ruxolitinib cream twice a day for 8 weeks (0.75% in 118 patients and 1.5% in 113 patients) and 61 applied the vehicle. They used electronic diaries to record the worst level of itch they had experienced each day, from 0 (no itch) to 10 (worst imaginable itch). The main results were as follows: 

• Mean itch numerical rating scale (NRS) scores at baseline were 5.3 and 5.4 for ruxolitinib cream 0.75% and 1.5%, respectively, and 5.7 for vehicle. Within about 12 hours of first application, mean itch NRS scores dropped –0.6 and –0.7 from baseline among those treated with ruxolitinib cream 0.75% and 1.5%, respectively, compared with –0.2 for those on the vehicle. At day 4, the decreases were –1.4 and –1.6 for ruxolitinib cream 0.75% and 1.5%, respectively, versus –0.6 for the vehicle (P = .026 and P = .005, respectively, vs. vehicle).
• At day 2, among the 187 patients with a baseline itch NRS score 4 or higher, more patients achieved 4-point or greater itch NRS improvement: 6.1% and 16.4% for ruxolitinib cream 0.75% and 1.5%, respectively versus 0% for vehicle. At day 7, the differences were 15.9% and 26.6% versus 3%, respectively. And by week 8, they increased to 30.1% and 43.2% versus 17.5% (P = .212 and P = .009), respectively.
• At week 2, 19% of patients in the 0.75% formulation group and 19.4% of patients in the 1.5% formulation group, compared with 5.3% in the vehicle group, reported no days of itch on question 1 of the Patient-Oriented Eczema Measure (POEM) questionnaire that evaluated various aspects of the disease over the previous week. By week 8, the differences grew to 34% and 30.8% versus 12.2%, respectively.
• Adverse events, reported by 14.4% and 22.1% of patients on 0.75% and 1.5% ruxolitinib, respectively, and by 32.8% of patients who received the vehicle, were headaches, upper respiratory tract infection, and application site pain.

Ruxolitinib may be an alternative to systemic immunosuppressives

Asked to comment on the results, Amy J. McMichael, MD, professor of dermatology at Wake Forest University School of Medicine, Winston-Salem, N.C., called itch “one of the major life disruptors in atopic dermatitis.”

Providers often assume that patients of different races respond similarly to treatment, but that is not always true, she noted in an email.

“This study proves ruxolitinib’s effectiveness in Black patients, who often have more severe atopic dermatitis signs and symptoms,” said Dr. McMichael, who was not involved in the study. “The fact that atopic dermatitis in patients of color has been singled out to examine efficacy is a great way to show that the findings are not just in those who have thinner plaques and potentially less longstanding thickening of the skin from scratching (lichenification),” she added.

Dr. McMichael welcomed the lack of systemic side effects and quick relief of itch with this treatment, noting that the effect on itch “is rare with other treatments and extremely rare with other topical medications.”

The effect of topical ruxolitinib on pruritus “was interesting and surprising because very few available topical medications can control itch,” she explained. “The strongest topical steroids can help with pruritus, but they have the risk for skin thinning (atrophy),” while topical ruxolitinib is not associated with skin atrophy.

“After topical steroids fail as first-line treatment, it is likely that more patients will be given this topical medication rather than be moved to immunosuppressive systemic medications,” she noted.

All study authors report relevant relationships with Incyte Corporation, which manufactures ruxolitinib and funded the study, and several authors report employment and shareholding interests in the company. Dr. McMichael reports no relevant relationship with the study.

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

Topical ruxolitinib appears to quickly relieve itch in Black patients with atopic dermatitis (AD), an industry-sponsored analysis of pooled data from two studies suggests.

“Ruxolitinib cream monotherapy over 8 weeks was associated with rapid and considerable itch relief in Black or African American patients with AD and was well tolerated,” the study authors wrote in a poster presented at the annual meeting of the Society for Investigative Dermatology.

AD can behave differently in different racial groups and can be especially bothersome in Black patients. AD has a prevalence of about 20% in Black children and 5%-10% in Black adults. Black children are roughly twice as likely to be diagnosed with AD, and to have severe AD, than White children, according to the authors.

Lead author Lawrence F. Eichenfield, MD, professor of dermatology and pediatrics at the University of California, San Diego, and colleagues used pooled data from two identically designed phase 3 studies to describe the effects of the cream formulation of the Janus kinase (JAK) 1 and JAK 2 inhibitor ruxolitinib on itch in Black patients.

Topical ruxolitinib (Opzelura), 1.5%, was approved last September for treating AD in non-immunocompromised patients with mild to moderate AD, ages 12 years and older. In July 2022, it was approved for the treatment of nonsegmental vitiligo in the same age group.  

FDA approval for AD was based on the results of the TRuE-AD1 and TRuE-AD2 double-blind randomized trials, which enrolled about 1,200 patients over age 12 with AD. These patients included 292 Black teenagers and adults between aged 12-71 years who had AD for 2 years or longer, with an Investigator’s Global Assessment (IGA) score of 2 or 3, with 3%-20% affected body surface area, excluding the scalp.

Of the 292 patients, those in the two treatment groups (n = 231) applied ruxolitinib cream twice a day for 8 weeks (0.75% in 118 patients and 1.5% in 113 patients) and 61 applied the vehicle. They used electronic diaries to record the worst level of itch they had experienced each day, from 0 (no itch) to 10 (worst imaginable itch). The main results were as follows: 

• Mean itch numerical rating scale (NRS) scores at baseline were 5.3 and 5.4 for ruxolitinib cream 0.75% and 1.5%, respectively, and 5.7 for vehicle. Within about 12 hours of first application, mean itch NRS scores dropped –0.6 and –0.7 from baseline among those treated with ruxolitinib cream 0.75% and 1.5%, respectively, compared with –0.2 for those on the vehicle. At day 4, the decreases were –1.4 and –1.6 for ruxolitinib cream 0.75% and 1.5%, respectively, versus –0.6 for the vehicle (P = .026 and P = .005, respectively, vs. vehicle).
• At day 2, among the 187 patients with a baseline itch NRS score 4 or higher, more patients achieved 4-point or greater itch NRS improvement: 6.1% and 16.4% for ruxolitinib cream 0.75% and 1.5%, respectively versus 0% for vehicle. At day 7, the differences were 15.9% and 26.6% versus 3%, respectively. And by week 8, they increased to 30.1% and 43.2% versus 17.5% (P = .212 and P = .009), respectively.
• At week 2, 19% of patients in the 0.75% formulation group and 19.4% of patients in the 1.5% formulation group, compared with 5.3% in the vehicle group, reported no days of itch on question 1 of the Patient-Oriented Eczema Measure (POEM) questionnaire that evaluated various aspects of the disease over the previous week. By week 8, the differences grew to 34% and 30.8% versus 12.2%, respectively.
• Adverse events, reported by 14.4% and 22.1% of patients on 0.75% and 1.5% ruxolitinib, respectively, and by 32.8% of patients who received the vehicle, were headaches, upper respiratory tract infection, and application site pain.

Ruxolitinib may be an alternative to systemic immunosuppressives

Asked to comment on the results, Amy J. McMichael, MD, professor of dermatology at Wake Forest University School of Medicine, Winston-Salem, N.C., called itch “one of the major life disruptors in atopic dermatitis.”

Providers often assume that patients of different races respond similarly to treatment, but that is not always true, she noted in an email.

“This study proves ruxolitinib’s effectiveness in Black patients, who often have more severe atopic dermatitis signs and symptoms,” said Dr. McMichael, who was not involved in the study. “The fact that atopic dermatitis in patients of color has been singled out to examine efficacy is a great way to show that the findings are not just in those who have thinner plaques and potentially less longstanding thickening of the skin from scratching (lichenification),” she added.

Dr. McMichael welcomed the lack of systemic side effects and quick relief of itch with this treatment, noting that the effect on itch “is rare with other treatments and extremely rare with other topical medications.”

The effect of topical ruxolitinib on pruritus “was interesting and surprising because very few available topical medications can control itch,” she explained. “The strongest topical steroids can help with pruritus, but they have the risk for skin thinning (atrophy),” while topical ruxolitinib is not associated with skin atrophy.

“After topical steroids fail as first-line treatment, it is likely that more patients will be given this topical medication rather than be moved to immunosuppressive systemic medications,” she noted.

All study authors report relevant relationships with Incyte Corporation, which manufactures ruxolitinib and funded the study, and several authors report employment and shareholding interests in the company. Dr. McMichael reports no relevant relationship with the study.

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

Topical ruxolitinib appears to quickly relieve itch in Black patients with atopic dermatitis (AD), an industry-sponsored analysis of pooled data from two studies suggests.

“Ruxolitinib cream monotherapy over 8 weeks was associated with rapid and considerable itch relief in Black or African American patients with AD and was well tolerated,” the study authors wrote in a poster presented at the annual meeting of the Society for Investigative Dermatology.

AD can behave differently in different racial groups and can be especially bothersome in Black patients. AD has a prevalence of about 20% in Black children and 5%-10% in Black adults. Black children are roughly twice as likely to be diagnosed with AD, and to have severe AD, than White children, according to the authors.

Lead author Lawrence F. Eichenfield, MD, professor of dermatology and pediatrics at the University of California, San Diego, and colleagues used pooled data from two identically designed phase 3 studies to describe the effects of the cream formulation of the Janus kinase (JAK) 1 and JAK 2 inhibitor ruxolitinib on itch in Black patients.

Topical ruxolitinib (Opzelura), 1.5%, was approved last September for treating AD in non-immunocompromised patients with mild to moderate AD, ages 12 years and older. In July 2022, it was approved for the treatment of nonsegmental vitiligo in the same age group.  

FDA approval for AD was based on the results of the TRuE-AD1 and TRuE-AD2 double-blind randomized trials, which enrolled about 1,200 patients over age 12 with AD. These patients included 292 Black teenagers and adults between aged 12-71 years who had AD for 2 years or longer, with an Investigator’s Global Assessment (IGA) score of 2 or 3, with 3%-20% affected body surface area, excluding the scalp.

Of the 292 patients, those in the two treatment groups (n = 231) applied ruxolitinib cream twice a day for 8 weeks (0.75% in 118 patients and 1.5% in 113 patients) and 61 applied the vehicle. They used electronic diaries to record the worst level of itch they had experienced each day, from 0 (no itch) to 10 (worst imaginable itch). The main results were as follows: 

• Mean itch numerical rating scale (NRS) scores at baseline were 5.3 and 5.4 for ruxolitinib cream 0.75% and 1.5%, respectively, and 5.7 for vehicle. Within about 12 hours of first application, mean itch NRS scores dropped –0.6 and –0.7 from baseline among those treated with ruxolitinib cream 0.75% and 1.5%, respectively, compared with –0.2 for those on the vehicle. At day 4, the decreases were –1.4 and –1.6 for ruxolitinib cream 0.75% and 1.5%, respectively, versus –0.6 for the vehicle (P = .026 and P = .005, respectively, vs. vehicle).
• At day 2, among the 187 patients with a baseline itch NRS score 4 or higher, more patients achieved 4-point or greater itch NRS improvement: 6.1% and 16.4% for ruxolitinib cream 0.75% and 1.5%, respectively versus 0% for vehicle. At day 7, the differences were 15.9% and 26.6% versus 3%, respectively. And by week 8, they increased to 30.1% and 43.2% versus 17.5% (P = .212 and P = .009), respectively.
• At week 2, 19% of patients in the 0.75% formulation group and 19.4% of patients in the 1.5% formulation group, compared with 5.3% in the vehicle group, reported no days of itch on question 1 of the Patient-Oriented Eczema Measure (POEM) questionnaire that evaluated various aspects of the disease over the previous week. By week 8, the differences grew to 34% and 30.8% versus 12.2%, respectively.
• Adverse events, reported by 14.4% and 22.1% of patients on 0.75% and 1.5% ruxolitinib, respectively, and by 32.8% of patients who received the vehicle, were headaches, upper respiratory tract infection, and application site pain.

Ruxolitinib may be an alternative to systemic immunosuppressives

Asked to comment on the results, Amy J. McMichael, MD, professor of dermatology at Wake Forest University School of Medicine, Winston-Salem, N.C., called itch “one of the major life disruptors in atopic dermatitis.”

Providers often assume that patients of different races respond similarly to treatment, but that is not always true, she noted in an email.

“This study proves ruxolitinib’s effectiveness in Black patients, who often have more severe atopic dermatitis signs and symptoms,” said Dr. McMichael, who was not involved in the study. “The fact that atopic dermatitis in patients of color has been singled out to examine efficacy is a great way to show that the findings are not just in those who have thinner plaques and potentially less longstanding thickening of the skin from scratching (lichenification),” she added.

Dr. McMichael welcomed the lack of systemic side effects and quick relief of itch with this treatment, noting that the effect on itch “is rare with other treatments and extremely rare with other topical medications.”

The effect of topical ruxolitinib on pruritus “was interesting and surprising because very few available topical medications can control itch,” she explained. “The strongest topical steroids can help with pruritus, but they have the risk for skin thinning (atrophy),” while topical ruxolitinib is not associated with skin atrophy.

“After topical steroids fail as first-line treatment, it is likely that more patients will be given this topical medication rather than be moved to immunosuppressive systemic medications,” she noted.

All study authors report relevant relationships with Incyte Corporation, which manufactures ruxolitinib and funded the study, and several authors report employment and shareholding interests in the company. Dr. McMichael reports no relevant relationship with the study.

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