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Older people with high levels of stress are nearly 40% more likely to have cognitive impairment than those with low stress, a new study shows.

Individuals with elevated stress levels also had higher rates of diabetes, hypertension, and other cardiovascular disease (CVD) risk factors. But even after controlling for those risk factors, stress remained an independent predictor of cognitive decline.

The national cohort study showed that the association between stress and cognition was similar between Black and White individuals and that those with controlled stress were less likely to have cognitive impairment than those with uncontrolled or new stress.

“We have known for a while that excess levels of stress can be harmful for the human body and the heart, but we are now adding more evidence that excess levels of stress can be harmful for cognition,” said lead investigator Ambar Kulshreshtha, MD, PhD, associate professor of family and preventive medicine and epidemiology at Emory University, Atlanta. “We were able to see that regardless of race or gender, stress is bad.”

The findings were published online  in JAMA Network Open.
 

Independent risk factor

For the study, investigators analyzed data from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a national population-based cohort of Black and White participants aged 45 years or older, sampled from the U.S. population.

Participants completed a questionnaire designed to evaluate stress levels when they were enrolled in the study between 2003 and 2007 and again about 11 years after enrollment.

Of the 24,448 participants (41.6% Black) in the study, 22.9% reported elevated stress levels.

Those with high stress were more likely to be younger, female, Black, smokers, and have a higher body mass index and less likely to have a college degree and to be physically active. They also had a lower family income and were more likely to have cardiovascular disease risk factors, such as hypertension, diabetes, and dyslipidemia.

Participants with elevated levels of perceived stress were 37% more likely to have poor cognition after adjustment for sociodemographic variables, cardiovascular risk factors, and depression (adjusted odds ratio, 1.37; 95% confidence interval, 1.22-1.53).

There was no significant difference between Black and White participants.
 

Damaging consequences

Researchers also found a dose-response relationship, with the greatest cognitive decline found in people who reported high stress at both time points and those who had new stress at follow up (aOR, 1.16; 95% CI, 0.92-1.45), compared with those with resolved stress (aOR, 1.03; 95% CI, 0.81-1.32) or no stress (aOR, 0.81; 95% CI, 0.68-0.97).

A change in perceived stress by 1 unit was associated with 4% increased risk of cognitive impairment after adjusting for sociodemographic variables, CVD risk factors, lifestyle factors, and depressive symptoms (aOR, 1.04; 95% CI, 1.02-1.06).

Although the study didn’t reveal the mechanisms that might link stress and cognition, it does point to stress as a potentially modifiable risk factor for cognitive decline, Dr. Kulshreshtha said.

“One in three of my patients have had to deal with extra levels of stress and anxiety over the past few years,” said Dr. Kulshreshtha. “We as clinicians are aware that stress can have damaging consequences to the heart and other organs, and when we see patients who have these complaints, especially elderly patients, we should spend some time asking people about their stress and how they are managing it.”
 

Additional screening

Gregory Day, MD, a neurologist at the Mayo Clinic, Jacksonville, Fla., said that the findings help fill a void in the research about stress and cognition.

“It’s a potentially important association that’s easy for us to miss in clinical practice,” said Dr. Day, who was not a part of the study. “It’s one of those things that we can all recognize impacts health, but we have very few large, well thought out studies that give us the data we need to inform its place in clinical decision-making.”

In addition to its large sample size, the overrepresentation of diverse populations is a strength of the study and a contribution to the field, Dr. Day said.

“One question they don’t directly ask is, is this association maybe due to some differences in stress? And the answer from the paper is probably not, because it looks like when we control for these things, we don’t see big differences incident risk factors between race,” he added.

The findings also point to the need for clinicians, especially primary care physicians, to screen patients for stress during routine examinations.

“Every visit is an opportunity to screen for risk factors that are going to set people up for future brain health,” Dr. Day said. “In addition to screening for all of these other risk factors for brain health, maybe it’s worth including some more global assessment of stress in a standard screener.”

The study was funded by the National Institute of Neurological Disorders and Stroke, the National Institutes of Health, and the National Institute on Aging. Dr. Kulshreshtha and Dr. Day report no relevant financial relationships.

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

Older people with high levels of stress are nearly 40% more likely to have cognitive impairment than those with low stress, a new study shows.

Individuals with elevated stress levels also had higher rates of diabetes, hypertension, and other cardiovascular disease (CVD) risk factors. But even after controlling for those risk factors, stress remained an independent predictor of cognitive decline.

The national cohort study showed that the association between stress and cognition was similar between Black and White individuals and that those with controlled stress were less likely to have cognitive impairment than those with uncontrolled or new stress.

“We have known for a while that excess levels of stress can be harmful for the human body and the heart, but we are now adding more evidence that excess levels of stress can be harmful for cognition,” said lead investigator Ambar Kulshreshtha, MD, PhD, associate professor of family and preventive medicine and epidemiology at Emory University, Atlanta. “We were able to see that regardless of race or gender, stress is bad.”

The findings were published online  in JAMA Network Open.
 

Independent risk factor

For the study, investigators analyzed data from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a national population-based cohort of Black and White participants aged 45 years or older, sampled from the U.S. population.

Participants completed a questionnaire designed to evaluate stress levels when they were enrolled in the study between 2003 and 2007 and again about 11 years after enrollment.

Of the 24,448 participants (41.6% Black) in the study, 22.9% reported elevated stress levels.

Those with high stress were more likely to be younger, female, Black, smokers, and have a higher body mass index and less likely to have a college degree and to be physically active. They also had a lower family income and were more likely to have cardiovascular disease risk factors, such as hypertension, diabetes, and dyslipidemia.

Participants with elevated levels of perceived stress were 37% more likely to have poor cognition after adjustment for sociodemographic variables, cardiovascular risk factors, and depression (adjusted odds ratio, 1.37; 95% confidence interval, 1.22-1.53).

There was no significant difference between Black and White participants.
 

Damaging consequences

Researchers also found a dose-response relationship, with the greatest cognitive decline found in people who reported high stress at both time points and those who had new stress at follow up (aOR, 1.16; 95% CI, 0.92-1.45), compared with those with resolved stress (aOR, 1.03; 95% CI, 0.81-1.32) or no stress (aOR, 0.81; 95% CI, 0.68-0.97).

A change in perceived stress by 1 unit was associated with 4% increased risk of cognitive impairment after adjusting for sociodemographic variables, CVD risk factors, lifestyle factors, and depressive symptoms (aOR, 1.04; 95% CI, 1.02-1.06).

Although the study didn’t reveal the mechanisms that might link stress and cognition, it does point to stress as a potentially modifiable risk factor for cognitive decline, Dr. Kulshreshtha said.

“One in three of my patients have had to deal with extra levels of stress and anxiety over the past few years,” said Dr. Kulshreshtha. “We as clinicians are aware that stress can have damaging consequences to the heart and other organs, and when we see patients who have these complaints, especially elderly patients, we should spend some time asking people about their stress and how they are managing it.”
 

Additional screening

Gregory Day, MD, a neurologist at the Mayo Clinic, Jacksonville, Fla., said that the findings help fill a void in the research about stress and cognition.

“It’s a potentially important association that’s easy for us to miss in clinical practice,” said Dr. Day, who was not a part of the study. “It’s one of those things that we can all recognize impacts health, but we have very few large, well thought out studies that give us the data we need to inform its place in clinical decision-making.”

In addition to its large sample size, the overrepresentation of diverse populations is a strength of the study and a contribution to the field, Dr. Day said.

“One question they don’t directly ask is, is this association maybe due to some differences in stress? And the answer from the paper is probably not, because it looks like when we control for these things, we don’t see big differences incident risk factors between race,” he added.

The findings also point to the need for clinicians, especially primary care physicians, to screen patients for stress during routine examinations.

“Every visit is an opportunity to screen for risk factors that are going to set people up for future brain health,” Dr. Day said. “In addition to screening for all of these other risk factors for brain health, maybe it’s worth including some more global assessment of stress in a standard screener.”

The study was funded by the National Institute of Neurological Disorders and Stroke, the National Institutes of Health, and the National Institute on Aging. Dr. Kulshreshtha and Dr. Day report no relevant financial relationships.

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

Older people with high levels of stress are nearly 40% more likely to have cognitive impairment than those with low stress, a new study shows.

Individuals with elevated stress levels also had higher rates of diabetes, hypertension, and other cardiovascular disease (CVD) risk factors. But even after controlling for those risk factors, stress remained an independent predictor of cognitive decline.

The national cohort study showed that the association between stress and cognition was similar between Black and White individuals and that those with controlled stress were less likely to have cognitive impairment than those with uncontrolled or new stress.

“We have known for a while that excess levels of stress can be harmful for the human body and the heart, but we are now adding more evidence that excess levels of stress can be harmful for cognition,” said lead investigator Ambar Kulshreshtha, MD, PhD, associate professor of family and preventive medicine and epidemiology at Emory University, Atlanta. “We were able to see that regardless of race or gender, stress is bad.”

The findings were published online  in JAMA Network Open.
 

Independent risk factor

For the study, investigators analyzed data from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a national population-based cohort of Black and White participants aged 45 years or older, sampled from the U.S. population.

Participants completed a questionnaire designed to evaluate stress levels when they were enrolled in the study between 2003 and 2007 and again about 11 years after enrollment.

Of the 24,448 participants (41.6% Black) in the study, 22.9% reported elevated stress levels.

Those with high stress were more likely to be younger, female, Black, smokers, and have a higher body mass index and less likely to have a college degree and to be physically active. They also had a lower family income and were more likely to have cardiovascular disease risk factors, such as hypertension, diabetes, and dyslipidemia.

Participants with elevated levels of perceived stress were 37% more likely to have poor cognition after adjustment for sociodemographic variables, cardiovascular risk factors, and depression (adjusted odds ratio, 1.37; 95% confidence interval, 1.22-1.53).

There was no significant difference between Black and White participants.
 

Damaging consequences

Researchers also found a dose-response relationship, with the greatest cognitive decline found in people who reported high stress at both time points and those who had new stress at follow up (aOR, 1.16; 95% CI, 0.92-1.45), compared with those with resolved stress (aOR, 1.03; 95% CI, 0.81-1.32) or no stress (aOR, 0.81; 95% CI, 0.68-0.97).

A change in perceived stress by 1 unit was associated with 4% increased risk of cognitive impairment after adjusting for sociodemographic variables, CVD risk factors, lifestyle factors, and depressive symptoms (aOR, 1.04; 95% CI, 1.02-1.06).

Although the study didn’t reveal the mechanisms that might link stress and cognition, it does point to stress as a potentially modifiable risk factor for cognitive decline, Dr. Kulshreshtha said.

“One in three of my patients have had to deal with extra levels of stress and anxiety over the past few years,” said Dr. Kulshreshtha. “We as clinicians are aware that stress can have damaging consequences to the heart and other organs, and when we see patients who have these complaints, especially elderly patients, we should spend some time asking people about their stress and how they are managing it.”
 

Additional screening

Gregory Day, MD, a neurologist at the Mayo Clinic, Jacksonville, Fla., said that the findings help fill a void in the research about stress and cognition.

“It’s a potentially important association that’s easy for us to miss in clinical practice,” said Dr. Day, who was not a part of the study. “It’s one of those things that we can all recognize impacts health, but we have very few large, well thought out studies that give us the data we need to inform its place in clinical decision-making.”

In addition to its large sample size, the overrepresentation of diverse populations is a strength of the study and a contribution to the field, Dr. Day said.

“One question they don’t directly ask is, is this association maybe due to some differences in stress? And the answer from the paper is probably not, because it looks like when we control for these things, we don’t see big differences incident risk factors between race,” he added.

The findings also point to the need for clinicians, especially primary care physicians, to screen patients for stress during routine examinations.

“Every visit is an opportunity to screen for risk factors that are going to set people up for future brain health,” Dr. Day said. “In addition to screening for all of these other risk factors for brain health, maybe it’s worth including some more global assessment of stress in a standard screener.”

The study was funded by the National Institute of Neurological Disorders and Stroke, the National Institutes of Health, and the National Institute on Aging. Dr. Kulshreshtha and Dr. Day report no relevant financial relationships.

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

Digital rectal examination (DRE) is neither helpful nor useful as a solitary prostate cancer screening tool in middle-aged men, say investigators reporting the PROBASE study.

The study compared risk-adapted screening measures in men who had prostate-specific antigen (PSA) measured at age 45 with those who had PSA measurements plus DRE at age 50.

The results show that as a solitary screening tool, 99% of DREs did not raise suspicion for prostate cancer, and among the 57 cases where DRE did raise suspicion, only three men were found to have cancer, all of which were low-grade, reported Agne Krilaviciute, PhD, from the German Cancer Research Center in Heidelberg, and colleagues.

“We also see that the cancer detection rate by PSA is four times higher compared to the DRE detection. Around 18% of the tumors are located in the part of the prostate where DRE cannot detect them,” she said in an oral presentation at the European Association of Urology Congress.

The investigators found that the majority of prostate cancers that occurred in this relatively young population were International Society of Urological Pathology grade 1 (Gleason score 3 + 3 = 6) or grade 2 (Gleason 3 + 4 = 7). DRE yields positive results in only about 12% of cases of ISUP grade 1 or 2, they noted.

“We conclude that DRE as a solitary screening test does not lead to a significant PCa [prostate cancer] detection rate in young men,” Dr. Krilaviciute said.
 

Falling by the wayside

The study adds to the growing body of evidence that DRE may not be especially helpful as either a screening tool or when used in active surveillance of men with prostate cancer.

An international consensus panel found that DRE could be safely skipped for active surveillance when MRI and other more accurate and objective measures, such as biomarkers, are available.

A prostate cancer expert who was not involved in the PROBASE study told this news organization that when he was in medical school, it would have been considered a serious lapse of practice not to perform a DRE, but that things have changed considerably over the past several years.

“We have PSA now, we have technology with MRI, and the yield of digital rectal examination is very low,” commented Julio Pow-Sang, MD, chief of the genitourinary oncology program at Moffitt Cancer Center in Tampa, Fla.

“Empirically, it’s very rare to find positive cancer through rectal exam in this day and age of PSA,” he said, adding that the examination itself is highly subjective, with varying results depending on the skills of the particular examiner.

“I think that in time, with good studies like this, digital rectal exam specifically for prostate cancer is going to slowly fade away,” Dr. Pow-Sang said.
 

PROBASE results

PROBASE was a randomized screening study enrolling men at age 45 to test a risk-adapted screening strategy using a baseline PSA value with the additional offer of DRE in a large subcohort of participants.

The study was conducted in Germany, and the authors note that the “German statutory early detection program recommends DRE as a stand-alone screening test starting annually at age 45.”

The PROBASE investigators enrolled 46,495 men from February 2014 through December 2019.

Among the first 23,194 men enrolled, 6,537 underwent DRE at enrollment without a study PSA test.

In this group, 6,480 DREs (99%) were not suspicious for cancer, and 57 (1%) were. Of those with suspected prostate cancer, 37 underwent biopsy and 20 did not. Of those biopsied, only two were found to have prostate cancer. This translated into a cancer detection rate of 0.03% for DRE.

After a median of 6.6 years of follow-up, only one additional case of ISUP grade 2 prostate cancer was detected among the 6,357 men who had DREs at enrollment, translating into a prostate cancer detection rate of .05%.

The investigators also looked at men who suspicious DRE findings at baseline. They assumed that a DRE-detectable tumor at age 45 would still be manifest 5 years later and should be detectable with PSA at age 50. Of the 57 men with initially suspicious findings, 11 returned for PSA screening but refused biopsy, and of this group only one had an elevated PSA level. He then underwent biopsy, but the findings were negative.

Of those who underwent biopsy on the basis of DRE, 16 had prostatitis, 14 had benign prostatic hyperplasia, 1 had high-grade prostatic intraepithelial neoplasia, 1 had atypical small acinar proliferation, and 3 had equivocal findings.

In total, the investigators found 24 tumors among men screened with DRE. Of these, 3 occurred in men with results deemed suspicious and 21 were in men with unsuspicious digital exams. All of the tumors were ISUP grade 1, 2, or 3 tumors.

Among 245 men who had biopsies for a PSA level equal to or higher than 3 ng/mL, primarily Prostate Imaging Reporting and Data System (PI-RADS) 3-5 tumors, DRE findings at the time of biopsy were unsuspicious in about 82% of cases, Dr. Krilaviciute said.

“We also used MRI data to determine what proportion of tumors would be potentially detectable by DRE. We estimated that around 18% of tumors are located in the upper part of the prostate, which is not detectable by DRE,” she said. “Even excluding those tumors, still the DRE detection rate is low in palpable tumors.”

Although DRE performed better in higher-grade tumors, 80% of the tumors in the PROBASE participants were ISUP grade 1 or 2 and were likely to be undetected by DRE, she added.

“In Germany, the recommendations for the screening still include 45-year-olds to go with annual DRE. The PROBASE trial allowed us to evaluate for the first time what was the diagnostic performance for DRE at such a young age, and we see that 99% of men undergoing DRE have no suspicious findings, and among the 1% of suspicious findings having cancers extremely unlikely,” she said.

The study was supported by Deutsche Krebshilfe (German Cancer Aid). Dr. Krilaviciute and Dr. Pow-Sang reported having no relevant conflicts of interest.

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

Digital rectal examination (DRE) is neither helpful nor useful as a solitary prostate cancer screening tool in middle-aged men, say investigators reporting the PROBASE study.

The study compared risk-adapted screening measures in men who had prostate-specific antigen (PSA) measured at age 45 with those who had PSA measurements plus DRE at age 50.

The results show that as a solitary screening tool, 99% of DREs did not raise suspicion for prostate cancer, and among the 57 cases where DRE did raise suspicion, only three men were found to have cancer, all of which were low-grade, reported Agne Krilaviciute, PhD, from the German Cancer Research Center in Heidelberg, and colleagues.

“We also see that the cancer detection rate by PSA is four times higher compared to the DRE detection. Around 18% of the tumors are located in the part of the prostate where DRE cannot detect them,” she said in an oral presentation at the European Association of Urology Congress.

The investigators found that the majority of prostate cancers that occurred in this relatively young population were International Society of Urological Pathology grade 1 (Gleason score 3 + 3 = 6) or grade 2 (Gleason 3 + 4 = 7). DRE yields positive results in only about 12% of cases of ISUP grade 1 or 2, they noted.

“We conclude that DRE as a solitary screening test does not lead to a significant PCa [prostate cancer] detection rate in young men,” Dr. Krilaviciute said.
 

Falling by the wayside

The study adds to the growing body of evidence that DRE may not be especially helpful as either a screening tool or when used in active surveillance of men with prostate cancer.

An international consensus panel found that DRE could be safely skipped for active surveillance when MRI and other more accurate and objective measures, such as biomarkers, are available.

A prostate cancer expert who was not involved in the PROBASE study told this news organization that when he was in medical school, it would have been considered a serious lapse of practice not to perform a DRE, but that things have changed considerably over the past several years.

“We have PSA now, we have technology with MRI, and the yield of digital rectal examination is very low,” commented Julio Pow-Sang, MD, chief of the genitourinary oncology program at Moffitt Cancer Center in Tampa, Fla.

“Empirically, it’s very rare to find positive cancer through rectal exam in this day and age of PSA,” he said, adding that the examination itself is highly subjective, with varying results depending on the skills of the particular examiner.

“I think that in time, with good studies like this, digital rectal exam specifically for prostate cancer is going to slowly fade away,” Dr. Pow-Sang said.
 

PROBASE results

PROBASE was a randomized screening study enrolling men at age 45 to test a risk-adapted screening strategy using a baseline PSA value with the additional offer of DRE in a large subcohort of participants.

The study was conducted in Germany, and the authors note that the “German statutory early detection program recommends DRE as a stand-alone screening test starting annually at age 45.”

The PROBASE investigators enrolled 46,495 men from February 2014 through December 2019.

Among the first 23,194 men enrolled, 6,537 underwent DRE at enrollment without a study PSA test.

In this group, 6,480 DREs (99%) were not suspicious for cancer, and 57 (1%) were. Of those with suspected prostate cancer, 37 underwent biopsy and 20 did not. Of those biopsied, only two were found to have prostate cancer. This translated into a cancer detection rate of 0.03% for DRE.

After a median of 6.6 years of follow-up, only one additional case of ISUP grade 2 prostate cancer was detected among the 6,357 men who had DREs at enrollment, translating into a prostate cancer detection rate of .05%.

The investigators also looked at men who suspicious DRE findings at baseline. They assumed that a DRE-detectable tumor at age 45 would still be manifest 5 years later and should be detectable with PSA at age 50. Of the 57 men with initially suspicious findings, 11 returned for PSA screening but refused biopsy, and of this group only one had an elevated PSA level. He then underwent biopsy, but the findings were negative.

Of those who underwent biopsy on the basis of DRE, 16 had prostatitis, 14 had benign prostatic hyperplasia, 1 had high-grade prostatic intraepithelial neoplasia, 1 had atypical small acinar proliferation, and 3 had equivocal findings.

In total, the investigators found 24 tumors among men screened with DRE. Of these, 3 occurred in men with results deemed suspicious and 21 were in men with unsuspicious digital exams. All of the tumors were ISUP grade 1, 2, or 3 tumors.

Among 245 men who had biopsies for a PSA level equal to or higher than 3 ng/mL, primarily Prostate Imaging Reporting and Data System (PI-RADS) 3-5 tumors, DRE findings at the time of biopsy were unsuspicious in about 82% of cases, Dr. Krilaviciute said.

“We also used MRI data to determine what proportion of tumors would be potentially detectable by DRE. We estimated that around 18% of tumors are located in the upper part of the prostate, which is not detectable by DRE,” she said. “Even excluding those tumors, still the DRE detection rate is low in palpable tumors.”

Although DRE performed better in higher-grade tumors, 80% of the tumors in the PROBASE participants were ISUP grade 1 or 2 and were likely to be undetected by DRE, she added.

“In Germany, the recommendations for the screening still include 45-year-olds to go with annual DRE. The PROBASE trial allowed us to evaluate for the first time what was the diagnostic performance for DRE at such a young age, and we see that 99% of men undergoing DRE have no suspicious findings, and among the 1% of suspicious findings having cancers extremely unlikely,” she said.

The study was supported by Deutsche Krebshilfe (German Cancer Aid). Dr. Krilaviciute and Dr. Pow-Sang reported having no relevant conflicts of interest.

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

Digital rectal examination (DRE) is neither helpful nor useful as a solitary prostate cancer screening tool in middle-aged men, say investigators reporting the PROBASE study.

The study compared risk-adapted screening measures in men who had prostate-specific antigen (PSA) measured at age 45 with those who had PSA measurements plus DRE at age 50.

The results show that as a solitary screening tool, 99% of DREs did not raise suspicion for prostate cancer, and among the 57 cases where DRE did raise suspicion, only three men were found to have cancer, all of which were low-grade, reported Agne Krilaviciute, PhD, from the German Cancer Research Center in Heidelberg, and colleagues.

“We also see that the cancer detection rate by PSA is four times higher compared to the DRE detection. Around 18% of the tumors are located in the part of the prostate where DRE cannot detect them,” she said in an oral presentation at the European Association of Urology Congress.

The investigators found that the majority of prostate cancers that occurred in this relatively young population were International Society of Urological Pathology grade 1 (Gleason score 3 + 3 = 6) or grade 2 (Gleason 3 + 4 = 7). DRE yields positive results in only about 12% of cases of ISUP grade 1 or 2, they noted.

“We conclude that DRE as a solitary screening test does not lead to a significant PCa [prostate cancer] detection rate in young men,” Dr. Krilaviciute said.
 

Falling by the wayside

The study adds to the growing body of evidence that DRE may not be especially helpful as either a screening tool or when used in active surveillance of men with prostate cancer.

An international consensus panel found that DRE could be safely skipped for active surveillance when MRI and other more accurate and objective measures, such as biomarkers, are available.

A prostate cancer expert who was not involved in the PROBASE study told this news organization that when he was in medical school, it would have been considered a serious lapse of practice not to perform a DRE, but that things have changed considerably over the past several years.

“We have PSA now, we have technology with MRI, and the yield of digital rectal examination is very low,” commented Julio Pow-Sang, MD, chief of the genitourinary oncology program at Moffitt Cancer Center in Tampa, Fla.

“Empirically, it’s very rare to find positive cancer through rectal exam in this day and age of PSA,” he said, adding that the examination itself is highly subjective, with varying results depending on the skills of the particular examiner.

“I think that in time, with good studies like this, digital rectal exam specifically for prostate cancer is going to slowly fade away,” Dr. Pow-Sang said.
 

PROBASE results

PROBASE was a randomized screening study enrolling men at age 45 to test a risk-adapted screening strategy using a baseline PSA value with the additional offer of DRE in a large subcohort of participants.

The study was conducted in Germany, and the authors note that the “German statutory early detection program recommends DRE as a stand-alone screening test starting annually at age 45.”

The PROBASE investigators enrolled 46,495 men from February 2014 through December 2019.

Among the first 23,194 men enrolled, 6,537 underwent DRE at enrollment without a study PSA test.

In this group, 6,480 DREs (99%) were not suspicious for cancer, and 57 (1%) were. Of those with suspected prostate cancer, 37 underwent biopsy and 20 did not. Of those biopsied, only two were found to have prostate cancer. This translated into a cancer detection rate of 0.03% for DRE.

After a median of 6.6 years of follow-up, only one additional case of ISUP grade 2 prostate cancer was detected among the 6,357 men who had DREs at enrollment, translating into a prostate cancer detection rate of .05%.

The investigators also looked at men who suspicious DRE findings at baseline. They assumed that a DRE-detectable tumor at age 45 would still be manifest 5 years later and should be detectable with PSA at age 50. Of the 57 men with initially suspicious findings, 11 returned for PSA screening but refused biopsy, and of this group only one had an elevated PSA level. He then underwent biopsy, but the findings were negative.

Of those who underwent biopsy on the basis of DRE, 16 had prostatitis, 14 had benign prostatic hyperplasia, 1 had high-grade prostatic intraepithelial neoplasia, 1 had atypical small acinar proliferation, and 3 had equivocal findings.

In total, the investigators found 24 tumors among men screened with DRE. Of these, 3 occurred in men with results deemed suspicious and 21 were in men with unsuspicious digital exams. All of the tumors were ISUP grade 1, 2, or 3 tumors.

Among 245 men who had biopsies for a PSA level equal to or higher than 3 ng/mL, primarily Prostate Imaging Reporting and Data System (PI-RADS) 3-5 tumors, DRE findings at the time of biopsy were unsuspicious in about 82% of cases, Dr. Krilaviciute said.

“We also used MRI data to determine what proportion of tumors would be potentially detectable by DRE. We estimated that around 18% of tumors are located in the upper part of the prostate, which is not detectable by DRE,” she said. “Even excluding those tumors, still the DRE detection rate is low in palpable tumors.”

Although DRE performed better in higher-grade tumors, 80% of the tumors in the PROBASE participants were ISUP grade 1 or 2 and were likely to be undetected by DRE, she added.

“In Germany, the recommendations for the screening still include 45-year-olds to go with annual DRE. The PROBASE trial allowed us to evaluate for the first time what was the diagnostic performance for DRE at such a young age, and we see that 99% of men undergoing DRE have no suspicious findings, and among the 1% of suspicious findings having cancers extremely unlikely,” she said.

The study was supported by Deutsche Krebshilfe (German Cancer Aid). Dr. Krilaviciute and Dr. Pow-Sang reported having no relevant conflicts of interest.

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

Lung development in the fetus may be adversely affected by a mother’s gestational diabetes, based on data from in vivo, in vitro, and ex vivo studies.

Gestational diabetes mellitus (GDM) has recently been associated with fetal lung underdevelopment (FLUD) and delayed lung maturation that may lead to immediate respiratory distress in newborns and later chronic lung disease, Pengzheng Chen, PhD, of Shandong University, Jinan, China, and colleagues wrote.

Antenatal corticosteroids are considered an effective treatment for gestational fetal lung underdevelopment, but recent studies have shown adverse effects of these medications, and therefore more research is needed to identify the etiology and pathogenesis of FLUD induced by GDM, they said.

In a study published in the International Journal of Nanomedicine, the researchers collected umbilical cord blood samples from patients with GDM and matched controls at a single hospital in China.

“Using an ex vivo exosome exposure model of fetal lung explants, we observed the morphological alteration of lung explants and evaluated the expression of molecules involved in lung development,” the researchers wrote.

Fetal lung underdevelopment was more common after exposure to exosomes from the umbilical cord plasma of individuals with gestational diabetes mellitus, compared with exosomes from healthy controls.

The researchers also used mouse models to examine the effects of exosomes on fetal lung development in vivo. They found that exosomes associated with GDM impeded the growth, branching morphogenesis, and maturation of fetal lungs in mouse models. In addition, the expression of the apoptotic biomarkers known as BAX, BIM, and cleaved CASPASE-3 was up-regulated in GDMUB-exosomes and HG-exos groups, but the antiapoptotic protein BCL-2 was down-regulated; this further supported the negative impact of GDM exomes on fetal lung development, the researchers said.

The researchers then conducted miRNA sequencing, which showed that the miRNA in placenta-derived exosomes from GDM pregnancies were distinct from the miRNA in exosomes from healthy control pregnancies.

The study findings were limited by several factors including the impurity of the isolated placenta-derived exosomes from the umbilical cord blood plasma, which were not placenta specific, the researchers noted. Other limitations included the lack of data on different stages of lung development, and more research is needed to validate miRNAs and to explore the signally pathways involved in fetal lung development.

However, the study is the first known to demonstrate an adverse effect of GDM on fetal lung development via in vitro, ex vivo, and in vitro models, they said.

“These data highlight an emerging role of placenta-derived exosomes in the pathogenesis of fetal lung underdevelopment in GDM pregnancies, and provide a novel strategy for maternal-fetal communication,” they concluded.

The study received no outside funding. The researchers had no financial conflicts to disclose.

Lung development in the fetus may be adversely affected by a mother’s gestational diabetes, based on data from in vivo, in vitro, and ex vivo studies.

Gestational diabetes mellitus (GDM) has recently been associated with fetal lung underdevelopment (FLUD) and delayed lung maturation that may lead to immediate respiratory distress in newborns and later chronic lung disease, Pengzheng Chen, PhD, of Shandong University, Jinan, China, and colleagues wrote.

Antenatal corticosteroids are considered an effective treatment for gestational fetal lung underdevelopment, but recent studies have shown adverse effects of these medications, and therefore more research is needed to identify the etiology and pathogenesis of FLUD induced by GDM, they said.

In a study published in the International Journal of Nanomedicine, the researchers collected umbilical cord blood samples from patients with GDM and matched controls at a single hospital in China.

“Using an ex vivo exosome exposure model of fetal lung explants, we observed the morphological alteration of lung explants and evaluated the expression of molecules involved in lung development,” the researchers wrote.

Fetal lung underdevelopment was more common after exposure to exosomes from the umbilical cord plasma of individuals with gestational diabetes mellitus, compared with exosomes from healthy controls.

The researchers also used mouse models to examine the effects of exosomes on fetal lung development in vivo. They found that exosomes associated with GDM impeded the growth, branching morphogenesis, and maturation of fetal lungs in mouse models. In addition, the expression of the apoptotic biomarkers known as BAX, BIM, and cleaved CASPASE-3 was up-regulated in GDMUB-exosomes and HG-exos groups, but the antiapoptotic protein BCL-2 was down-regulated; this further supported the negative impact of GDM exomes on fetal lung development, the researchers said.

The researchers then conducted miRNA sequencing, which showed that the miRNA in placenta-derived exosomes from GDM pregnancies were distinct from the miRNA in exosomes from healthy control pregnancies.

The study findings were limited by several factors including the impurity of the isolated placenta-derived exosomes from the umbilical cord blood plasma, which were not placenta specific, the researchers noted. Other limitations included the lack of data on different stages of lung development, and more research is needed to validate miRNAs and to explore the signally pathways involved in fetal lung development.

However, the study is the first known to demonstrate an adverse effect of GDM on fetal lung development via in vitro, ex vivo, and in vitro models, they said.

“These data highlight an emerging role of placenta-derived exosomes in the pathogenesis of fetal lung underdevelopment in GDM pregnancies, and provide a novel strategy for maternal-fetal communication,” they concluded.

The study received no outside funding. The researchers had no financial conflicts to disclose.

Lung development in the fetus may be adversely affected by a mother’s gestational diabetes, based on data from in vivo, in vitro, and ex vivo studies.

Gestational diabetes mellitus (GDM) has recently been associated with fetal lung underdevelopment (FLUD) and delayed lung maturation that may lead to immediate respiratory distress in newborns and later chronic lung disease, Pengzheng Chen, PhD, of Shandong University, Jinan, China, and colleagues wrote.

Antenatal corticosteroids are considered an effective treatment for gestational fetal lung underdevelopment, but recent studies have shown adverse effects of these medications, and therefore more research is needed to identify the etiology and pathogenesis of FLUD induced by GDM, they said.

In a study published in the International Journal of Nanomedicine, the researchers collected umbilical cord blood samples from patients with GDM and matched controls at a single hospital in China.

“Using an ex vivo exosome exposure model of fetal lung explants, we observed the morphological alteration of lung explants and evaluated the expression of molecules involved in lung development,” the researchers wrote.

Fetal lung underdevelopment was more common after exposure to exosomes from the umbilical cord plasma of individuals with gestational diabetes mellitus, compared with exosomes from healthy controls.

The researchers also used mouse models to examine the effects of exosomes on fetal lung development in vivo. They found that exosomes associated with GDM impeded the growth, branching morphogenesis, and maturation of fetal lungs in mouse models. In addition, the expression of the apoptotic biomarkers known as BAX, BIM, and cleaved CASPASE-3 was up-regulated in GDMUB-exosomes and HG-exos groups, but the antiapoptotic protein BCL-2 was down-regulated; this further supported the negative impact of GDM exomes on fetal lung development, the researchers said.

The researchers then conducted miRNA sequencing, which showed that the miRNA in placenta-derived exosomes from GDM pregnancies were distinct from the miRNA in exosomes from healthy control pregnancies.

The study findings were limited by several factors including the impurity of the isolated placenta-derived exosomes from the umbilical cord blood plasma, which were not placenta specific, the researchers noted. Other limitations included the lack of data on different stages of lung development, and more research is needed to validate miRNAs and to explore the signally pathways involved in fetal lung development.

However, the study is the first known to demonstrate an adverse effect of GDM on fetal lung development via in vitro, ex vivo, and in vitro models, they said.

“These data highlight an emerging role of placenta-derived exosomes in the pathogenesis of fetal lung underdevelopment in GDM pregnancies, and provide a novel strategy for maternal-fetal communication,” they concluded.

The study received no outside funding. The researchers had no financial conflicts to disclose.

A simple urine test for genetic mutations in urine-derived DNA can predict urothelial cancer up to 12 years before patients develop symptoms, an international team of researchers claims.

The test, if validated in further studies, has the potential to serve as a cancer screening tool for individuals at elevated risk for bladder cancer due to genetics, smoking, or from environmental exposures to known carcinogens, and it could help to reduce the frequency of unnecessary cystoscopies, say urologists who were not involved in the research.

The test involved was performed using a next-generation sequencing assay (UroAmp, Convergent Genomics, based in San Francisco) that identifies mutations in 60 genes associated with bladder cancer. New research reported at the annual congress of the European Association of Urology described the screening model that focused on 10 key genes covered in the assay.

In training and validation cohorts, the urinary comprehensive genomic profiling test accurately predicted future bladder cancer in 66% of patient urine samples, including some that had been collected more than a decade prior to being tested, reported Florence Le Calvez-Kelm, PhD, MSc, from the International Agency for Research on Cancer, Lyon, France.

“Our results provide first evidence from a population-based cohort study of preclinical urothelial cancer detection with urinary comprehensive genomic profiling,” she told the meeting.

The results were consistent both in individuals with known risk factors for bladder cancer who were undergoing cystoscopy and in those with no evidence of disease, she said.

“Research of this nature is very encouraging, as it shows that our ability to identify molecular alterations in liquid biopsies such as urine that might indicate cancer is constantly improving,” commented Joost Boormans, MD, PhD, a urologist at the Erasmus University Medical Center, Rotterdam, Netherlands, and a member of the EAU Scientific Congress Office.

“While we do need to develop more accurate diagnostics, it’s unlikely that we’ll have a mass screening program for bladder cancer in the near future,” he continued. “Where a urine test for genetic mutations could show its value is in reducing cystoscopies and scans in bladder cancer patients who are being monitored for recurrence, as well as those referred for blood in their urine. A simple urine test would be far easier for patients to undergo than invasive procedures or scans, as well as being less costly for health services.”

Dr. Le Calvez-Kelm and colleagues had previously shown that promoter mutations in the gene encoding for the enzyme telomerase reverse transcriptase (TERT) identified in urine were “promising noninvasive biomarkers” for early detection of bladder cancer.

They found that TERT mutations in urine could predict which patients were likely to develop urothelial cancer with 48% sensitivity and 100% specificity.

In the study presented at EAU23, they hypothesized that uCGP of DNA in urine could offer enhanced sensitivity for early detection of urothelial cancer.

They first used the 60-gene assay to create a training set using urine samples from 46 patients with de novo urothelial cancer, 40 with recurrent cancer, and 140 healthy controls.

They then tested the model in two validation cohorts. The first validation cohort consisted of samples from 22 patients with de novo cancer, 48 with recurrent urothelial cancer, and 96 controls from a case-control study conducted at Massachusetts General Hospital, Boston, and Ohio State University, Columbus.

The second validation cohort included 29 patients from the prospective Golestan Cohort Study who subsequently developed urothelial cancer, with 98 controls.

In all, 10 genes were identified as optimal for inclusion in a screening model, which was trained to an overall sensitivity of 88% and a 97% sensitivity for high-grade tumors, with a specificity of 94%.

In the MGH/OSU validation cohort the sensitivity of the models was 71%, and the specificity was 94%. In the Golestan cohort, the sensitivity was 66%, with a specificity of 94%. This compared favorably with the performance of the TERT-only screening model, which, as noted before, had a sensitivity of 48%, albeit with 100% specificity.

“Interestingly, when we broke down the analysis according to the lag time between urine collection and diagnosis, sensitivity increased as the time to diagnosis decreased, so the closer we got to the diagnosis, the higher was the sensitivity,” Dr. Le Calvez-Kelm said.

When the analysis was limited to urothelial cancers diagnosed within 7 years of sample collection, the sensitivity for detecting preclinical cancer improved to 86%, compared with 57% for a test of TERT promoter mutations alone. 

Among the patients in the Golestan cohort, uCGP-predicted positive results were associated with a more than eightfold higher risk for worse cancer-free survival, compared with uCGP-predicted negatives (hazard ratio 8.5, P < .0001).

“Of course, further studies are needed to validate this finding and to assess the clinical utility in other longitudinal cohorts,” Dr. Le Calvez-Kelm concluded.

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

A simple urine test for genetic mutations in urine-derived DNA can predict urothelial cancer up to 12 years before patients develop symptoms, an international team of researchers claims.

The test, if validated in further studies, has the potential to serve as a cancer screening tool for individuals at elevated risk for bladder cancer due to genetics, smoking, or from environmental exposures to known carcinogens, and it could help to reduce the frequency of unnecessary cystoscopies, say urologists who were not involved in the research.

The test involved was performed using a next-generation sequencing assay (UroAmp, Convergent Genomics, based in San Francisco) that identifies mutations in 60 genes associated with bladder cancer. New research reported at the annual congress of the European Association of Urology described the screening model that focused on 10 key genes covered in the assay.

In training and validation cohorts, the urinary comprehensive genomic profiling test accurately predicted future bladder cancer in 66% of patient urine samples, including some that had been collected more than a decade prior to being tested, reported Florence Le Calvez-Kelm, PhD, MSc, from the International Agency for Research on Cancer, Lyon, France.

“Our results provide first evidence from a population-based cohort study of preclinical urothelial cancer detection with urinary comprehensive genomic profiling,” she told the meeting.

The results were consistent both in individuals with known risk factors for bladder cancer who were undergoing cystoscopy and in those with no evidence of disease, she said.

“Research of this nature is very encouraging, as it shows that our ability to identify molecular alterations in liquid biopsies such as urine that might indicate cancer is constantly improving,” commented Joost Boormans, MD, PhD, a urologist at the Erasmus University Medical Center, Rotterdam, Netherlands, and a member of the EAU Scientific Congress Office.

“While we do need to develop more accurate diagnostics, it’s unlikely that we’ll have a mass screening program for bladder cancer in the near future,” he continued. “Where a urine test for genetic mutations could show its value is in reducing cystoscopies and scans in bladder cancer patients who are being monitored for recurrence, as well as those referred for blood in their urine. A simple urine test would be far easier for patients to undergo than invasive procedures or scans, as well as being less costly for health services.”

Dr. Le Calvez-Kelm and colleagues had previously shown that promoter mutations in the gene encoding for the enzyme telomerase reverse transcriptase (TERT) identified in urine were “promising noninvasive biomarkers” for early detection of bladder cancer.

They found that TERT mutations in urine could predict which patients were likely to develop urothelial cancer with 48% sensitivity and 100% specificity.

In the study presented at EAU23, they hypothesized that uCGP of DNA in urine could offer enhanced sensitivity for early detection of urothelial cancer.

They first used the 60-gene assay to create a training set using urine samples from 46 patients with de novo urothelial cancer, 40 with recurrent cancer, and 140 healthy controls.

They then tested the model in two validation cohorts. The first validation cohort consisted of samples from 22 patients with de novo cancer, 48 with recurrent urothelial cancer, and 96 controls from a case-control study conducted at Massachusetts General Hospital, Boston, and Ohio State University, Columbus.

The second validation cohort included 29 patients from the prospective Golestan Cohort Study who subsequently developed urothelial cancer, with 98 controls.

In all, 10 genes were identified as optimal for inclusion in a screening model, which was trained to an overall sensitivity of 88% and a 97% sensitivity for high-grade tumors, with a specificity of 94%.

In the MGH/OSU validation cohort the sensitivity of the models was 71%, and the specificity was 94%. In the Golestan cohort, the sensitivity was 66%, with a specificity of 94%. This compared favorably with the performance of the TERT-only screening model, which, as noted before, had a sensitivity of 48%, albeit with 100% specificity.

“Interestingly, when we broke down the analysis according to the lag time between urine collection and diagnosis, sensitivity increased as the time to diagnosis decreased, so the closer we got to the diagnosis, the higher was the sensitivity,” Dr. Le Calvez-Kelm said.

When the analysis was limited to urothelial cancers diagnosed within 7 years of sample collection, the sensitivity for detecting preclinical cancer improved to 86%, compared with 57% for a test of TERT promoter mutations alone. 

Among the patients in the Golestan cohort, uCGP-predicted positive results were associated with a more than eightfold higher risk for worse cancer-free survival, compared with uCGP-predicted negatives (hazard ratio 8.5, P < .0001).

“Of course, further studies are needed to validate this finding and to assess the clinical utility in other longitudinal cohorts,” Dr. Le Calvez-Kelm concluded.

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

A simple urine test for genetic mutations in urine-derived DNA can predict urothelial cancer up to 12 years before patients develop symptoms, an international team of researchers claims.

The test, if validated in further studies, has the potential to serve as a cancer screening tool for individuals at elevated risk for bladder cancer due to genetics, smoking, or from environmental exposures to known carcinogens, and it could help to reduce the frequency of unnecessary cystoscopies, say urologists who were not involved in the research.

The test involved was performed using a next-generation sequencing assay (UroAmp, Convergent Genomics, based in San Francisco) that identifies mutations in 60 genes associated with bladder cancer. New research reported at the annual congress of the European Association of Urology described the screening model that focused on 10 key genes covered in the assay.

In training and validation cohorts, the urinary comprehensive genomic profiling test accurately predicted future bladder cancer in 66% of patient urine samples, including some that had been collected more than a decade prior to being tested, reported Florence Le Calvez-Kelm, PhD, MSc, from the International Agency for Research on Cancer, Lyon, France.

“Our results provide first evidence from a population-based cohort study of preclinical urothelial cancer detection with urinary comprehensive genomic profiling,” she told the meeting.

The results were consistent both in individuals with known risk factors for bladder cancer who were undergoing cystoscopy and in those with no evidence of disease, she said.

“Research of this nature is very encouraging, as it shows that our ability to identify molecular alterations in liquid biopsies such as urine that might indicate cancer is constantly improving,” commented Joost Boormans, MD, PhD, a urologist at the Erasmus University Medical Center, Rotterdam, Netherlands, and a member of the EAU Scientific Congress Office.

“While we do need to develop more accurate diagnostics, it’s unlikely that we’ll have a mass screening program for bladder cancer in the near future,” he continued. “Where a urine test for genetic mutations could show its value is in reducing cystoscopies and scans in bladder cancer patients who are being monitored for recurrence, as well as those referred for blood in their urine. A simple urine test would be far easier for patients to undergo than invasive procedures or scans, as well as being less costly for health services.”

Dr. Le Calvez-Kelm and colleagues had previously shown that promoter mutations in the gene encoding for the enzyme telomerase reverse transcriptase (TERT) identified in urine were “promising noninvasive biomarkers” for early detection of bladder cancer.

They found that TERT mutations in urine could predict which patients were likely to develop urothelial cancer with 48% sensitivity and 100% specificity.

In the study presented at EAU23, they hypothesized that uCGP of DNA in urine could offer enhanced sensitivity for early detection of urothelial cancer.

They first used the 60-gene assay to create a training set using urine samples from 46 patients with de novo urothelial cancer, 40 with recurrent cancer, and 140 healthy controls.

They then tested the model in two validation cohorts. The first validation cohort consisted of samples from 22 patients with de novo cancer, 48 with recurrent urothelial cancer, and 96 controls from a case-control study conducted at Massachusetts General Hospital, Boston, and Ohio State University, Columbus.

The second validation cohort included 29 patients from the prospective Golestan Cohort Study who subsequently developed urothelial cancer, with 98 controls.

In all, 10 genes were identified as optimal for inclusion in a screening model, which was trained to an overall sensitivity of 88% and a 97% sensitivity for high-grade tumors, with a specificity of 94%.

In the MGH/OSU validation cohort the sensitivity of the models was 71%, and the specificity was 94%. In the Golestan cohort, the sensitivity was 66%, with a specificity of 94%. This compared favorably with the performance of the TERT-only screening model, which, as noted before, had a sensitivity of 48%, albeit with 100% specificity.

“Interestingly, when we broke down the analysis according to the lag time between urine collection and diagnosis, sensitivity increased as the time to diagnosis decreased, so the closer we got to the diagnosis, the higher was the sensitivity,” Dr. Le Calvez-Kelm said.

When the analysis was limited to urothelial cancers diagnosed within 7 years of sample collection, the sensitivity for detecting preclinical cancer improved to 86%, compared with 57% for a test of TERT promoter mutations alone. 

Among the patients in the Golestan cohort, uCGP-predicted positive results were associated with a more than eightfold higher risk for worse cancer-free survival, compared with uCGP-predicted negatives (hazard ratio 8.5, P < .0001).

“Of course, further studies are needed to validate this finding and to assess the clinical utility in other longitudinal cohorts,” Dr. Le Calvez-Kelm concluded.

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

MARSEILLE, France – It is well known that viral infections, especially respiratory syncytial virus (RSV) and rhinovirus (RV), exacerbate symptoms of asthma. But could they also play a part in triggering the onset of asthma?

The link between RSV and RV infections in early childhood and the development of asthma symptoms is well established, said Camille Taillé, MD, PhD, of the department of respiratory medicine and the rare diseases center of excellence at Bichat Hospital, Paris. But getting asthma is probably not just a matter of having a viral infection at a young age or of having a severe form of it. Gene polymorphisms, immune system disorders, and preexisting atopy are also associated with the risk of asthma. This was the focus of the 27th French-language respiratory medicine conference, held in Marseille, France.
 

RV and RSV

Persons with asthma are vulnerable to certain viral respiratory infections, in particular the flu and RV, which can exacerbate asthma symptoms. Inhaled corticosteroids have an overall protective effect against viral-induced exacerbations. For worsening asthma symptoms during an epidemic or pandemic, there is no contraindication to inhaled or oral corticosteroids.

Young children from the time of birth to 4 years of age are particularly susceptible to viral respiratory infections. According to data from France’s clinical surveillance network, Sentinelles, from the period covering winter 2021-2022, the rate of incidence per 100,000 inhabitants was systematically greater for the 0 to 4-year age range than for older age ranges.

Of the most common viruses that infect young children, RV, the virus that causes the common cold, is a nonenveloped RNA virus from the enterovirus family. There are 160 types, which are classified into three strains (A, B, and C). Of those strains, A and C confer the most severe infections. The virus is highly variable, which makes developing a vaccine challenging. The virus circulates year round, usually peaking in the fall and at the end of spring. RSV is an RNA virus that is classed as a respiratory virus. It comprises two serotypes: type A and B. Almost all children will have been infected with RSV by the time they are 2 years old. Epidemics occur each year during winter or in early spring in temperate climates. Vaccines are currently being developed and will soon be marketed. A monoclonal antibody (palivizumab), which targets fusion proteins of the virus, is available as prophylactic treatment for at-risk children.
 

RSV infection

During an RSV infection, the severe inflammation of the bronchial and alveolar wall causes acute respiratory distress. “But not all infants will develop severe forms of bronchiolitis,” said Dr. Taillé. “The risk factors for the severe form of the illness are well known: being under 6 months of age, prematurity, comorbidities (neurovascular, cardiovascular, respiratory, etc.), history of a stay in a neonatal intensive care unit at birth, living in low socioeconomic status towns, and exposure to smoking.”

Asthma development

The issue of whether or not viral diseases cause asthma has been the subject of intense debate. The studies are starting to stack up, however. They seem to show that RSV or RV infections are associated with the risk of subsequent asthma development. “For example, in a study published in 2022,” said Dr. Taillé, “in children admitted with an RSV infection, 60% of those who had been admitted to neonatal intensive care presented with symptoms of asthma between 3 and 6 years of age, compared with 18% of those who had had a milder case of RSV (admitted to nonintensive care settings). A serious RSV infection is a risk factor for later development of asthma.”

However, the link between RSV and later onset of asthma is also seen in milder cases of the infection. The American COAST study was designed to examine the effect of childhood respiratory infections on the risk of developing asthma. Researchers followed 259 newborns prospectively for 1, 3, and 6 years. To qualify, at least one parent was required to have respiratory allergies (defined as one or more positive aeroallergen skin tests) or a history of physician-diagnosed asthma. Regular samples taken during infectious episodes identified a virus in 90% of cases.

“We now know that RSV is not the only pathogen responsible for bronchiolitis. RV is often found, now that it can routinely be detected by PCR tests,” said Dr. Taillé. In the COAST study, the onset of wheezing during an RSV or RV infection in children aged 0-3 years was associated with an increased risk of asthma at 6 years of age. Globally, 28% of children infected by either virus were deemed to have asthma at 6 years of age. “There is clearly a link between having had a respiratory virus like RV or RSV and getting asthma symptoms at 6 years of age,” said Dr. Taillé. “What’s more, the effect of RV is not changed in this study by allergic sensitization.”

Many articles have been published on this topic. The results of cohort studies, from Japan to Finland and the United States, Italy, and Australia, are consistent with each other. Persons who have contracted RV or RSV are more likely to suffer from recurrent wheezing or asthma, especially if the infection is contracted in infancy or if it is severe. “Some studies even suggest that viral-induced asthma is more severe,” said Dr. Taillé. “For example, a Scottish study ... showed that children with a previous history of RSV infection had more hospital admissions and required more medication than asthmatics with no history of an RSV infection, suggesting the link between a previous history of RSV infection and the development of a more severe form of asthma.”
 

Reaching adulthood

Few longitudinal cohorts explore this issue in adulthood. A relatively old study reported an increased rate of asthma among adults who had required hospital admission for bronchiolitis in early childhood, as well as the effect on respiratory function. A 2023 study of the effects of respiratory illnesses in childhood reported similar findings. The authors evaluated lung structure and function via CT scans of 39 patients aged 26 years and concluded that participants who had been infected with RSV in childhood presented with increased air trapping, which is suggestive of airway abnormalities, possibly linked to a direct effect of viruses on lung development.

Mechanisms of action

“The real question is understanding if it’s the virus itself that causes asthma, or if the virus is simply uncovering underlying asthma in predisposed children,” said Dr. Taillé. From 30% to 40% of children who have had RSV will go on to develop wheezing or asthma in childhood. This observation suggests that there are factors favoring the development of asthma after infection with RSV. It has been shown that there is a genetic predisposition for RV. The roles of cigarette smoke, air pollution, environmental exposures to allergens, rapid urbanization, low vitamin D levels, low maternal omega-3 long-chain polyunsaturated fatty acid levels, maternal stress, and depression have also been highlighted.

It would seem that RSV and RV are a bit different. RV is thought to be associated with the development of asthma and wheezing, especially in people with a preexisting atopy or a reduced interferon immune response, while RSV, which occurs at a younger age and among the most vulnerable populations, seems to act independently of a person’s predisposition to allergies. RV stands out from other viral factors, owing to its tendency to create a Th2-biased inflammatory environment and its association with specific risk genes in people predisposed to asthma development (CDHR3).

Dr. Taillé has disclosed no relevant financial relationships.

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

MARSEILLE, France – It is well known that viral infections, especially respiratory syncytial virus (RSV) and rhinovirus (RV), exacerbate symptoms of asthma. But could they also play a part in triggering the onset of asthma?

The link between RSV and RV infections in early childhood and the development of asthma symptoms is well established, said Camille Taillé, MD, PhD, of the department of respiratory medicine and the rare diseases center of excellence at Bichat Hospital, Paris. But getting asthma is probably not just a matter of having a viral infection at a young age or of having a severe form of it. Gene polymorphisms, immune system disorders, and preexisting atopy are also associated with the risk of asthma. This was the focus of the 27th French-language respiratory medicine conference, held in Marseille, France.
 

RV and RSV

Persons with asthma are vulnerable to certain viral respiratory infections, in particular the flu and RV, which can exacerbate asthma symptoms. Inhaled corticosteroids have an overall protective effect against viral-induced exacerbations. For worsening asthma symptoms during an epidemic or pandemic, there is no contraindication to inhaled or oral corticosteroids.

Young children from the time of birth to 4 years of age are particularly susceptible to viral respiratory infections. According to data from France’s clinical surveillance network, Sentinelles, from the period covering winter 2021-2022, the rate of incidence per 100,000 inhabitants was systematically greater for the 0 to 4-year age range than for older age ranges.

Of the most common viruses that infect young children, RV, the virus that causes the common cold, is a nonenveloped RNA virus from the enterovirus family. There are 160 types, which are classified into three strains (A, B, and C). Of those strains, A and C confer the most severe infections. The virus is highly variable, which makes developing a vaccine challenging. The virus circulates year round, usually peaking in the fall and at the end of spring. RSV is an RNA virus that is classed as a respiratory virus. It comprises two serotypes: type A and B. Almost all children will have been infected with RSV by the time they are 2 years old. Epidemics occur each year during winter or in early spring in temperate climates. Vaccines are currently being developed and will soon be marketed. A monoclonal antibody (palivizumab), which targets fusion proteins of the virus, is available as prophylactic treatment for at-risk children.
 

RSV infection

During an RSV infection, the severe inflammation of the bronchial and alveolar wall causes acute respiratory distress. “But not all infants will develop severe forms of bronchiolitis,” said Dr. Taillé. “The risk factors for the severe form of the illness are well known: being under 6 months of age, prematurity, comorbidities (neurovascular, cardiovascular, respiratory, etc.), history of a stay in a neonatal intensive care unit at birth, living in low socioeconomic status towns, and exposure to smoking.”

Asthma development

The issue of whether or not viral diseases cause asthma has been the subject of intense debate. The studies are starting to stack up, however. They seem to show that RSV or RV infections are associated with the risk of subsequent asthma development. “For example, in a study published in 2022,” said Dr. Taillé, “in children admitted with an RSV infection, 60% of those who had been admitted to neonatal intensive care presented with symptoms of asthma between 3 and 6 years of age, compared with 18% of those who had had a milder case of RSV (admitted to nonintensive care settings). A serious RSV infection is a risk factor for later development of asthma.”

However, the link between RSV and later onset of asthma is also seen in milder cases of the infection. The American COAST study was designed to examine the effect of childhood respiratory infections on the risk of developing asthma. Researchers followed 259 newborns prospectively for 1, 3, and 6 years. To qualify, at least one parent was required to have respiratory allergies (defined as one or more positive aeroallergen skin tests) or a history of physician-diagnosed asthma. Regular samples taken during infectious episodes identified a virus in 90% of cases.

“We now know that RSV is not the only pathogen responsible for bronchiolitis. RV is often found, now that it can routinely be detected by PCR tests,” said Dr. Taillé. In the COAST study, the onset of wheezing during an RSV or RV infection in children aged 0-3 years was associated with an increased risk of asthma at 6 years of age. Globally, 28% of children infected by either virus were deemed to have asthma at 6 years of age. “There is clearly a link between having had a respiratory virus like RV or RSV and getting asthma symptoms at 6 years of age,” said Dr. Taillé. “What’s more, the effect of RV is not changed in this study by allergic sensitization.”

Many articles have been published on this topic. The results of cohort studies, from Japan to Finland and the United States, Italy, and Australia, are consistent with each other. Persons who have contracted RV or RSV are more likely to suffer from recurrent wheezing or asthma, especially if the infection is contracted in infancy or if it is severe. “Some studies even suggest that viral-induced asthma is more severe,” said Dr. Taillé. “For example, a Scottish study ... showed that children with a previous history of RSV infection had more hospital admissions and required more medication than asthmatics with no history of an RSV infection, suggesting the link between a previous history of RSV infection and the development of a more severe form of asthma.”
 

Reaching adulthood

Few longitudinal cohorts explore this issue in adulthood. A relatively old study reported an increased rate of asthma among adults who had required hospital admission for bronchiolitis in early childhood, as well as the effect on respiratory function. A 2023 study of the effects of respiratory illnesses in childhood reported similar findings. The authors evaluated lung structure and function via CT scans of 39 patients aged 26 years and concluded that participants who had been infected with RSV in childhood presented with increased air trapping, which is suggestive of airway abnormalities, possibly linked to a direct effect of viruses on lung development.

Mechanisms of action

“The real question is understanding if it’s the virus itself that causes asthma, or if the virus is simply uncovering underlying asthma in predisposed children,” said Dr. Taillé. From 30% to 40% of children who have had RSV will go on to develop wheezing or asthma in childhood. This observation suggests that there are factors favoring the development of asthma after infection with RSV. It has been shown that there is a genetic predisposition for RV. The roles of cigarette smoke, air pollution, environmental exposures to allergens, rapid urbanization, low vitamin D levels, low maternal omega-3 long-chain polyunsaturated fatty acid levels, maternal stress, and depression have also been highlighted.

It would seem that RSV and RV are a bit different. RV is thought to be associated with the development of asthma and wheezing, especially in people with a preexisting atopy or a reduced interferon immune response, while RSV, which occurs at a younger age and among the most vulnerable populations, seems to act independently of a person’s predisposition to allergies. RV stands out from other viral factors, owing to its tendency to create a Th2-biased inflammatory environment and its association with specific risk genes in people predisposed to asthma development (CDHR3).

Dr. Taillé has disclosed no relevant financial relationships.

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

MARSEILLE, France – It is well known that viral infections, especially respiratory syncytial virus (RSV) and rhinovirus (RV), exacerbate symptoms of asthma. But could they also play a part in triggering the onset of asthma?

The link between RSV and RV infections in early childhood and the development of asthma symptoms is well established, said Camille Taillé, MD, PhD, of the department of respiratory medicine and the rare diseases center of excellence at Bichat Hospital, Paris. But getting asthma is probably not just a matter of having a viral infection at a young age or of having a severe form of it. Gene polymorphisms, immune system disorders, and preexisting atopy are also associated with the risk of asthma. This was the focus of the 27th French-language respiratory medicine conference, held in Marseille, France.
 

RV and RSV

Persons with asthma are vulnerable to certain viral respiratory infections, in particular the flu and RV, which can exacerbate asthma symptoms. Inhaled corticosteroids have an overall protective effect against viral-induced exacerbations. For worsening asthma symptoms during an epidemic or pandemic, there is no contraindication to inhaled or oral corticosteroids.

Young children from the time of birth to 4 years of age are particularly susceptible to viral respiratory infections. According to data from France’s clinical surveillance network, Sentinelles, from the period covering winter 2021-2022, the rate of incidence per 100,000 inhabitants was systematically greater for the 0 to 4-year age range than for older age ranges.

Of the most common viruses that infect young children, RV, the virus that causes the common cold, is a nonenveloped RNA virus from the enterovirus family. There are 160 types, which are classified into three strains (A, B, and C). Of those strains, A and C confer the most severe infections. The virus is highly variable, which makes developing a vaccine challenging. The virus circulates year round, usually peaking in the fall and at the end of spring. RSV is an RNA virus that is classed as a respiratory virus. It comprises two serotypes: type A and B. Almost all children will have been infected with RSV by the time they are 2 years old. Epidemics occur each year during winter or in early spring in temperate climates. Vaccines are currently being developed and will soon be marketed. A monoclonal antibody (palivizumab), which targets fusion proteins of the virus, is available as prophylactic treatment for at-risk children.
 

RSV infection

During an RSV infection, the severe inflammation of the bronchial and alveolar wall causes acute respiratory distress. “But not all infants will develop severe forms of bronchiolitis,” said Dr. Taillé. “The risk factors for the severe form of the illness are well known: being under 6 months of age, prematurity, comorbidities (neurovascular, cardiovascular, respiratory, etc.), history of a stay in a neonatal intensive care unit at birth, living in low socioeconomic status towns, and exposure to smoking.”

Asthma development

The issue of whether or not viral diseases cause asthma has been the subject of intense debate. The studies are starting to stack up, however. They seem to show that RSV or RV infections are associated with the risk of subsequent asthma development. “For example, in a study published in 2022,” said Dr. Taillé, “in children admitted with an RSV infection, 60% of those who had been admitted to neonatal intensive care presented with symptoms of asthma between 3 and 6 years of age, compared with 18% of those who had had a milder case of RSV (admitted to nonintensive care settings). A serious RSV infection is a risk factor for later development of asthma.”

However, the link between RSV and later onset of asthma is also seen in milder cases of the infection. The American COAST study was designed to examine the effect of childhood respiratory infections on the risk of developing asthma. Researchers followed 259 newborns prospectively for 1, 3, and 6 years. To qualify, at least one parent was required to have respiratory allergies (defined as one or more positive aeroallergen skin tests) or a history of physician-diagnosed asthma. Regular samples taken during infectious episodes identified a virus in 90% of cases.

“We now know that RSV is not the only pathogen responsible for bronchiolitis. RV is often found, now that it can routinely be detected by PCR tests,” said Dr. Taillé. In the COAST study, the onset of wheezing during an RSV or RV infection in children aged 0-3 years was associated with an increased risk of asthma at 6 years of age. Globally, 28% of children infected by either virus were deemed to have asthma at 6 years of age. “There is clearly a link between having had a respiratory virus like RV or RSV and getting asthma symptoms at 6 years of age,” said Dr. Taillé. “What’s more, the effect of RV is not changed in this study by allergic sensitization.”

Many articles have been published on this topic. The results of cohort studies, from Japan to Finland and the United States, Italy, and Australia, are consistent with each other. Persons who have contracted RV or RSV are more likely to suffer from recurrent wheezing or asthma, especially if the infection is contracted in infancy or if it is severe. “Some studies even suggest that viral-induced asthma is more severe,” said Dr. Taillé. “For example, a Scottish study ... showed that children with a previous history of RSV infection had more hospital admissions and required more medication than asthmatics with no history of an RSV infection, suggesting the link between a previous history of RSV infection and the development of a more severe form of asthma.”
 

Reaching adulthood

Few longitudinal cohorts explore this issue in adulthood. A relatively old study reported an increased rate of asthma among adults who had required hospital admission for bronchiolitis in early childhood, as well as the effect on respiratory function. A 2023 study of the effects of respiratory illnesses in childhood reported similar findings. The authors evaluated lung structure and function via CT scans of 39 patients aged 26 years and concluded that participants who had been infected with RSV in childhood presented with increased air trapping, which is suggestive of airway abnormalities, possibly linked to a direct effect of viruses on lung development.

Mechanisms of action

“The real question is understanding if it’s the virus itself that causes asthma, or if the virus is simply uncovering underlying asthma in predisposed children,” said Dr. Taillé. From 30% to 40% of children who have had RSV will go on to develop wheezing or asthma in childhood. This observation suggests that there are factors favoring the development of asthma after infection with RSV. It has been shown that there is a genetic predisposition for RV. The roles of cigarette smoke, air pollution, environmental exposures to allergens, rapid urbanization, low vitamin D levels, low maternal omega-3 long-chain polyunsaturated fatty acid levels, maternal stress, and depression have also been highlighted.

It would seem that RSV and RV are a bit different. RV is thought to be associated with the development of asthma and wheezing, especially in people with a preexisting atopy or a reduced interferon immune response, while RSV, which occurs at a younger age and among the most vulnerable populations, seems to act independently of a person’s predisposition to allergies. RV stands out from other viral factors, owing to its tendency to create a Th2-biased inflammatory environment and its association with specific risk genes in people predisposed to asthma development (CDHR3).

Dr. Taillé has disclosed no relevant financial relationships.

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

Opioid overdose and other preventable causes are important contributors to postpartum death rates, Medicaid claims data show, particularly in women who have a recent history of opioid use disorder (OUD), according to research published in Obstetrics and Gynecology.

Opioid overdose deaths account for up to 10% of pregnancy-associated deaths in the United States, and 75% of the deliveries of women with OUD are covered by Medicaid, according to lead author Elizabeth Suarez, PhD, MPH, with the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital and Harvard Medical School in Boston, and colleagues.
 

Nearly 5 million deliveries studied

Researchers studied claims data from Medicaid and the National Death Index database in the United States from 2006 to 2013 for 4,972,061 deliveries. They also identified a subgroup of women with a documented history of OUD in the 3 months before delivery.

They found the incidence of postpartum opioid overdose deaths was 5.4 per 100,000 deliveries (95% confidence interval, 4.5-6.4) among all in the study and 118 per 100,000 (95% CI, 84-163) among individuals with OUD.

Incidence of all-cause postpartum death was six times higher in women with OUD than in all the women studied. Common causes of death of those with OUD were other drug- and alcohol-related deaths (47/100,000); suicide (26/100,000); and other injuries, including accidents and falls (33/100,000).

Risk factors strongly linked with postpartum opioid overdose death included mental health and other substance use disorders.
 

Medication significantly lowers death risk

The authors also documented the benefit of buprenorphine or methadone for OUD.

For women with OUD who used medication to treat OUD post partum, odds of opioid overdose death were 60% lower (odds ratio, 0.4; 95% CI 0.1-0.9).

As important as use of medication, Marcela Smid, MD, MS, writes in an accompanying editorial, is noting that 80% of the women in this study who died of opioid overdoses had contact with a health care provider before death.

“Both of these results indicate that we have the means and opportunity to prevent these deaths,” writes Dr. Smid, with the division of maternal fetal medicine, University of Utah Health in Salt Lake City.
 

Dismal numbers on ob.gyns. trained to prescribe medications

She points out some barriers, however. Most clinicians, she notes, lack time and training to prescribe buprenorphine, and in 2019, fewer than 2% of ob.gyns. who accept Medicaid were able to prescribe it.

Her charge to ob.gyns.: “We need to help identify individuals who are at high risk of OUD or opioid overdose by screening.” A validated screening tool should be used at prenatal and postpartum appointments.

On a bigger scale, she urges Medicaid to be expanded for a full year post partum through the American Rescue Act’s State Plan Amendment, something only 28 states and Washington, D.C., have done so far.

Dr. Smid points out some good news, however: President Joe Biden signed the Consolidated Appropriations Act 2023, which eliminated the “X” waiver.

Now all clinicians who have a Drug Enforcement Administration registration that includes Schedule III authority can prescribe buprenorphine for OUD if applicable state law allows it.

But that calls for medical schools and residency programs to prioritize addiction medicine as a core competency, Dr. Smid says.
 

Getting naloxone to patients, families

One of the potential interventions the study authors suggest is providing naloxone prescriptions and training to pregnant and postpartum women who have a substance use history and to their partners and significant others.

However, Mishka Terplan, MD, MPH, told this publication, “It’s one thing to write a prescription; it’s another thing for the person to actually get the medication.” He is medical director of the Friends Research Institute in Baltimore, an ob.gyn. who specializes in addiction medicine.

“What can we do?” We can think about how to get naloxone into people’s hands at discharge from the hospital after they give birth, instead of prescribing. That would mean that health systems need to prioritize this, he said. “We give people discharge medications all the time.”

Still, naloxone can’t be seen as the answer, he said.

He compares it to defibrillators in public places, which are for rescues, not reversing a population problem.

“Some people think that naloxone reversals are doing something about OUD. It’s doing about as much about OUD as defibrillators do for cardiovascular disease,” he said.

The best help, he says, will be continuation of treatment.

“Addiction is a chronic condition,” he says, “but often we only provide episodic care. We see that particularly in pregnancy. Once the pregnancy is finished, there’s not categorical continuation of insurance.”

Even if you do have insurance, it’s hard to find a clinic that’s family friendly, he notes. “You might not feel comfortable taking your newborn and standing in line in the morning to get your daily methodone dose. We have to make those environments more welcoming.”
 

Problem probably understated

He also says that though the study was well done given the data available, he’s frustrated that researchers still have to depend on billing data and can’t capture factors such as child care availability, living wages, and continuation of health insurance. Additionally, not everyone is coded correctly for OUD.

“It’s all Medicaid, so it’s only people who continued with care,” he pointed out. That means these numbers may actually underrepresent the problem.

Still, he says it’s important to realize the magnitude of deaths this study does highlight in this population.

In people with OUD in the postpartum period, the deaths are more than 1 in 1,000.

“That should be alarming,” Dr. Terplan said. “That’s a very big number from a public health perspective.”

Coauthor Kathryn J. Gray received payment from Aetion Inc., Roche, and BillionToOne. Funds were paid to the University of Utah for Dr. Smid from Alydia Inc. for being the site principal investigator for a study of the JADA device, and from Gilead for Dr. Smid’s study of hepatitis C in pregnancy; she was also a consultant for Organon and Rhia Ventures. Dr. Terplan reports no relevant financial relationships.
 

Opioid overdose and other preventable causes are important contributors to postpartum death rates, Medicaid claims data show, particularly in women who have a recent history of opioid use disorder (OUD), according to research published in Obstetrics and Gynecology.

Opioid overdose deaths account for up to 10% of pregnancy-associated deaths in the United States, and 75% of the deliveries of women with OUD are covered by Medicaid, according to lead author Elizabeth Suarez, PhD, MPH, with the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital and Harvard Medical School in Boston, and colleagues.
 

Nearly 5 million deliveries studied

Researchers studied claims data from Medicaid and the National Death Index database in the United States from 2006 to 2013 for 4,972,061 deliveries. They also identified a subgroup of women with a documented history of OUD in the 3 months before delivery.

They found the incidence of postpartum opioid overdose deaths was 5.4 per 100,000 deliveries (95% confidence interval, 4.5-6.4) among all in the study and 118 per 100,000 (95% CI, 84-163) among individuals with OUD.

Incidence of all-cause postpartum death was six times higher in women with OUD than in all the women studied. Common causes of death of those with OUD were other drug- and alcohol-related deaths (47/100,000); suicide (26/100,000); and other injuries, including accidents and falls (33/100,000).

Risk factors strongly linked with postpartum opioid overdose death included mental health and other substance use disorders.
 

Medication significantly lowers death risk

The authors also documented the benefit of buprenorphine or methadone for OUD.

For women with OUD who used medication to treat OUD post partum, odds of opioid overdose death were 60% lower (odds ratio, 0.4; 95% CI 0.1-0.9).

As important as use of medication, Marcela Smid, MD, MS, writes in an accompanying editorial, is noting that 80% of the women in this study who died of opioid overdoses had contact with a health care provider before death.

“Both of these results indicate that we have the means and opportunity to prevent these deaths,” writes Dr. Smid, with the division of maternal fetal medicine, University of Utah Health in Salt Lake City.
 

Dismal numbers on ob.gyns. trained to prescribe medications

She points out some barriers, however. Most clinicians, she notes, lack time and training to prescribe buprenorphine, and in 2019, fewer than 2% of ob.gyns. who accept Medicaid were able to prescribe it.

Her charge to ob.gyns.: “We need to help identify individuals who are at high risk of OUD or opioid overdose by screening.” A validated screening tool should be used at prenatal and postpartum appointments.

On a bigger scale, she urges Medicaid to be expanded for a full year post partum through the American Rescue Act’s State Plan Amendment, something only 28 states and Washington, D.C., have done so far.

Dr. Smid points out some good news, however: President Joe Biden signed the Consolidated Appropriations Act 2023, which eliminated the “X” waiver.

Now all clinicians who have a Drug Enforcement Administration registration that includes Schedule III authority can prescribe buprenorphine for OUD if applicable state law allows it.

But that calls for medical schools and residency programs to prioritize addiction medicine as a core competency, Dr. Smid says.
 

Getting naloxone to patients, families

One of the potential interventions the study authors suggest is providing naloxone prescriptions and training to pregnant and postpartum women who have a substance use history and to their partners and significant others.

However, Mishka Terplan, MD, MPH, told this publication, “It’s one thing to write a prescription; it’s another thing for the person to actually get the medication.” He is medical director of the Friends Research Institute in Baltimore, an ob.gyn. who specializes in addiction medicine.

“What can we do?” We can think about how to get naloxone into people’s hands at discharge from the hospital after they give birth, instead of prescribing. That would mean that health systems need to prioritize this, he said. “We give people discharge medications all the time.”

Still, naloxone can’t be seen as the answer, he said.

He compares it to defibrillators in public places, which are for rescues, not reversing a population problem.

“Some people think that naloxone reversals are doing something about OUD. It’s doing about as much about OUD as defibrillators do for cardiovascular disease,” he said.

The best help, he says, will be continuation of treatment.

“Addiction is a chronic condition,” he says, “but often we only provide episodic care. We see that particularly in pregnancy. Once the pregnancy is finished, there’s not categorical continuation of insurance.”

Even if you do have insurance, it’s hard to find a clinic that’s family friendly, he notes. “You might not feel comfortable taking your newborn and standing in line in the morning to get your daily methodone dose. We have to make those environments more welcoming.”
 

Problem probably understated

He also says that though the study was well done given the data available, he’s frustrated that researchers still have to depend on billing data and can’t capture factors such as child care availability, living wages, and continuation of health insurance. Additionally, not everyone is coded correctly for OUD.

“It’s all Medicaid, so it’s only people who continued with care,” he pointed out. That means these numbers may actually underrepresent the problem.

Still, he says it’s important to realize the magnitude of deaths this study does highlight in this population.

In people with OUD in the postpartum period, the deaths are more than 1 in 1,000.

“That should be alarming,” Dr. Terplan said. “That’s a very big number from a public health perspective.”

Coauthor Kathryn J. Gray received payment from Aetion Inc., Roche, and BillionToOne. Funds were paid to the University of Utah for Dr. Smid from Alydia Inc. for being the site principal investigator for a study of the JADA device, and from Gilead for Dr. Smid’s study of hepatitis C in pregnancy; she was also a consultant for Organon and Rhia Ventures. Dr. Terplan reports no relevant financial relationships.
 

Opioid overdose and other preventable causes are important contributors to postpartum death rates, Medicaid claims data show, particularly in women who have a recent history of opioid use disorder (OUD), according to research published in Obstetrics and Gynecology.

Opioid overdose deaths account for up to 10% of pregnancy-associated deaths in the United States, and 75% of the deliveries of women with OUD are covered by Medicaid, according to lead author Elizabeth Suarez, PhD, MPH, with the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital and Harvard Medical School in Boston, and colleagues.
 

Nearly 5 million deliveries studied

Researchers studied claims data from Medicaid and the National Death Index database in the United States from 2006 to 2013 for 4,972,061 deliveries. They also identified a subgroup of women with a documented history of OUD in the 3 months before delivery.

They found the incidence of postpartum opioid overdose deaths was 5.4 per 100,000 deliveries (95% confidence interval, 4.5-6.4) among all in the study and 118 per 100,000 (95% CI, 84-163) among individuals with OUD.

Incidence of all-cause postpartum death was six times higher in women with OUD than in all the women studied. Common causes of death of those with OUD were other drug- and alcohol-related deaths (47/100,000); suicide (26/100,000); and other injuries, including accidents and falls (33/100,000).

Risk factors strongly linked with postpartum opioid overdose death included mental health and other substance use disorders.
 

Medication significantly lowers death risk

The authors also documented the benefit of buprenorphine or methadone for OUD.

For women with OUD who used medication to treat OUD post partum, odds of opioid overdose death were 60% lower (odds ratio, 0.4; 95% CI 0.1-0.9).

As important as use of medication, Marcela Smid, MD, MS, writes in an accompanying editorial, is noting that 80% of the women in this study who died of opioid overdoses had contact with a health care provider before death.

“Both of these results indicate that we have the means and opportunity to prevent these deaths,” writes Dr. Smid, with the division of maternal fetal medicine, University of Utah Health in Salt Lake City.
 

Dismal numbers on ob.gyns. trained to prescribe medications

She points out some barriers, however. Most clinicians, she notes, lack time and training to prescribe buprenorphine, and in 2019, fewer than 2% of ob.gyns. who accept Medicaid were able to prescribe it.

Her charge to ob.gyns.: “We need to help identify individuals who are at high risk of OUD or opioid overdose by screening.” A validated screening tool should be used at prenatal and postpartum appointments.

On a bigger scale, she urges Medicaid to be expanded for a full year post partum through the American Rescue Act’s State Plan Amendment, something only 28 states and Washington, D.C., have done so far.

Dr. Smid points out some good news, however: President Joe Biden signed the Consolidated Appropriations Act 2023, which eliminated the “X” waiver.

Now all clinicians who have a Drug Enforcement Administration registration that includes Schedule III authority can prescribe buprenorphine for OUD if applicable state law allows it.

But that calls for medical schools and residency programs to prioritize addiction medicine as a core competency, Dr. Smid says.
 

Getting naloxone to patients, families

One of the potential interventions the study authors suggest is providing naloxone prescriptions and training to pregnant and postpartum women who have a substance use history and to their partners and significant others.

However, Mishka Terplan, MD, MPH, told this publication, “It’s one thing to write a prescription; it’s another thing for the person to actually get the medication.” He is medical director of the Friends Research Institute in Baltimore, an ob.gyn. who specializes in addiction medicine.

“What can we do?” We can think about how to get naloxone into people’s hands at discharge from the hospital after they give birth, instead of prescribing. That would mean that health systems need to prioritize this, he said. “We give people discharge medications all the time.”

Still, naloxone can’t be seen as the answer, he said.

He compares it to defibrillators in public places, which are for rescues, not reversing a population problem.

“Some people think that naloxone reversals are doing something about OUD. It’s doing about as much about OUD as defibrillators do for cardiovascular disease,” he said.

The best help, he says, will be continuation of treatment.

“Addiction is a chronic condition,” he says, “but often we only provide episodic care. We see that particularly in pregnancy. Once the pregnancy is finished, there’s not categorical continuation of insurance.”

Even if you do have insurance, it’s hard to find a clinic that’s family friendly, he notes. “You might not feel comfortable taking your newborn and standing in line in the morning to get your daily methodone dose. We have to make those environments more welcoming.”
 

Problem probably understated

He also says that though the study was well done given the data available, he’s frustrated that researchers still have to depend on billing data and can’t capture factors such as child care availability, living wages, and continuation of health insurance. Additionally, not everyone is coded correctly for OUD.

“It’s all Medicaid, so it’s only people who continued with care,” he pointed out. That means these numbers may actually underrepresent the problem.

Still, he says it’s important to realize the magnitude of deaths this study does highlight in this population.

In people with OUD in the postpartum period, the deaths are more than 1 in 1,000.

“That should be alarming,” Dr. Terplan said. “That’s a very big number from a public health perspective.”

Coauthor Kathryn J. Gray received payment from Aetion Inc., Roche, and BillionToOne. Funds were paid to the University of Utah for Dr. Smid from Alydia Inc. for being the site principal investigator for a study of the JADA device, and from Gilead for Dr. Smid’s study of hepatitis C in pregnancy; she was also a consultant for Organon and Rhia Ventures. Dr. Terplan reports no relevant financial relationships.
 

When the Food and Drug Administration approved avacopan (Tavneos) as an adjunctive treatment for severe, active antineutrophil cytoplasmic autoantibody (ANCA)–associated vasculitis (AAV) in October 2021, the oral complement C5a receptor inhibitor was hailed by its developer, ChemoCentryx, as a “new hope” for patients with the disease.

But avacopan’s novelty as a new drug for the rare diseases granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), coupled with its approval as an adjunctive to standard therapy, including glucocorticoids, rather than strictly as a glucocorticoid-sparing agent as it was tested, has so far led to little reported real-world experience with the drug.

M. Alexander Otto

In the phase 3 ADVOCATE trial, the pivotal trial that served as the basis for avacopan’s approval, 331 patients with active newly diagnosed or relapsing GPA or MPA received either avacopan or an oral prednisone taper over 20 weeks on a background of cyclophosphamide followed by azathioprine or rituximab. The results of the trial showed avacopan was noninferior to the group that received prednisone taper for remission at 26 weeks and superior to prednisone taper for sustained remission at 52 weeks, but the FDA was concerned that its complex design made it difficult to define the clinically meaningful benefit of avacopan and its role in the management of AAV.

The FDA noted that, in the avacopan arm of the trial, 86% of patients received glucocorticoids outside of the study protocol. Despite this, avacopan reduced the cumulative glucocorticoid dose over the trial’s 52 weeks by nearly two-thirds, compared with the prednisone group (1,349 mg vs. 3,655 mg).

The data also indicate a higher sustained remission rate at 52 weeks in patients who received induction with rituximab, compared with cyclophosphamide. But trial did not include a maintenance therapy dose of rituximab and is thereby not a good comparison against the standard of care, the FDA said. (ADVOCATE began enrolling patients prior to the FDA's 2018 approval of an expanded indication for patients with GPA or MPA who have achieved disease control after induction treatment.)

At the FDA’s Arthritis Advisory Committee meeting in May 2021, committee members were split on whether to recommend avacopan for approval. The committee voted 9-9 on whether the ADVOCATE trial showed efficacy supporting approval of avacopan, 10-8 in favor of whether the drug’s safety profile supported approval, and 10-8 in favor of the overall benefit-risk profile of avacopan for approval. But rather than give an indication to avacopan to reduce the use of glucocorticoids in adults with GPA or MPA, the agency approved avacopan as an adjunctive treatment for severe, active disease, noting in particular that avacopan “does not eliminate glucocorticoid use.”

The European Union’s marketing authorization for avacopan states its indication for use in combination with a rituximab or cyclophosphamide regimen for the treatment of adult patients with severe, active GPA or MPA and does not mention a role for reducing glucocorticoids. Avacopan will appear in forthcoming guidelines on management of AAV released by the European Alliance of Associations for Rheumatology.

In North America, the Canadian Vasculitis Research Network recently released an addendum to their guidelines on AAV specifically for avacopan, which includes recommendations to consider adding oral avacopan (30 mg twice daily) for induction of remission in patients with new or relapsing GPA or MPA who are also receiving cyclophosphamide or rituximab. The guidelines also recommend clinicians consider a glucocorticoid tapering schedule that aims for discontinuation at 4 weeks, and continuing avacopan for at least 1 year after induction therapy. The American College of Rheumatology guideline for AAV management, updated in 2021, acknowledges avacopan but did not consider its inclusion prior to FDA approval.

There have been few real-world studies of how patients with AAV are responding to avacopan, but recent studies from researchers in the Netherlands and in France have evaluated prednisone tapering and clinical outcomes.

Anisha B. Dua, MD, an associate professor of rheumatology at Northwestern University, Chicago, said those real-world studies “seemed to re-enforce the findings from the ADVOCATE study demonstrating the efficacy of avacopan in severe disease with steroid-sparing effects.”

However, Carol Langford, MD, MHS, director of the Center for Vasculitis Care and Research at the Cleveland Clinic, emphasized caution is needed when drawing conclusions about avacopan use outside formal studies.

“We are all interested in what other settings this might be used. I think those are things that really require formal investigation to really try and understand better as far as through a study process,” she said.
 

Prescribing experience with avacopan

A spokesperson from Amgen, which recently acquired ChemoCentryx, said in an interview that over 800 physicians in the United States have prescribed avacopan to patients with new or relapsing ANCA-associated vasculitis as induction or maintenance treatment, and physicians have reported outcomes consistent with the ADVOCATE trial.

Many rheumatologists are likely familiar with avacopan but are not used to prescribing it, said Lindsay S. Lally, MD, a rheumatologist with Hospital for Special Surgery in New York.

“Rituximab was approved for GPA and MPA a decade ago at this point. It was a drug that we as rheumatologists were used to using. We used it for other indications. Avacopan is a totally new drug, a new mechanism of action, so there’s not a lot of extractable data that we have in terms of comfort with the drug, and so I think that’s one of the biggest hurdles,” she said.

Mehrnaz Hojjati, MD, a rheumatologist with Loma Linda (Calif.) University Health, said that, when the FDA approved avacopan, it was an “exciting time” in her practice. “I have used avacopan now in a handful of my patients with severe ANCA-associated vasculitis, and the results are similar to what [was] reported in the ADVOCATE trial.”

Amgen offers help for clinicians in obtaining avacopan for patients, financial assistance for patients, and support in navigating insurance, which several rheumatologists noted was important for patients. Dr. Langford said the process of working with the manufacturer to get avacopan while insurance information is being processed has been “fairly smooth.”

“Certainly, the ability to get a very rapid 30-day supply with the goal of trying to initiate this as early as possible in the disease process has been helpful,” she said.

In Dr. Dua’s experience, while there were “some glitches or difficulty for providers early on” in how to access and prescribe avacopan, since then “it has been much easier to obtain the medication with the first month being provided to patients free while the authorization process is managed.”

Prescribing avacopan from inpatient pharmacies has been more challenging, she said. “The inpatient side is trickier because each hospital system has their own pharmacy system and regulations that have to be navigated. For outpatients, all the provider needs to do is fill out the start form available on their website, have the patients sign it, and then have it sent in.”
 

Concerns about affordability, insurance approval

Another consideration is cost, with avacopan having an estimated price of $150,000-$200,000 per patient per year.

Dr. Hojjati noted that, while it is easy to prescribe, avacopan is hard to get approved through insurance. “We face the same challenge every time a new medication comes to the market on how to convince the payers to pay for it given higher prices,” she said.

Rheumatologist Michael Putman, MD, MSCI, assistant professor of medicine at the Medical College of Wisconsin, Milwaukee, also acknowledged some difficulties in prescribing the medication. “The insurance companies have no interest in spending $150,000 on a drug that they know nothing about, and patients are a little hesitant to take it because it’s just so new,” he said.

While Dr. Lally said avacopan has not been difficult to get for patients with commercial insurance, reimbursement through Medicare has been problematic. “In many of the Medicare patients it has not really been a feasible option for them to be on the drug for the year of therapy.”
 

Patient response

Dr. Dua said almost all her patients with new or relapsing AAV who require induction are being prescribed avacopan, and that the medication is well tolerated. “The remission and ability to wean prednisone has really paralleled the findings from the clinical trial.”

In her practice, Dr. Hojjati starts patients on avacopan immediately after discharge from the hospital after a major vasculitis flare requiring high-dose glucocorticoids. “Avacopan does not eliminate/replace GC [glucocorticoid] use but has a notable GC-sparing effect and assists in rapid tapering of the GC while treating our severe ANCA-associated vasculitis patients,” she said.

Dr. Lally said her patients are tolerating avacopan well and hasn’t seen any of the safety signals seen in the trial, including liver function abnormalities. She has treated about 20-25 patients with avacopan.

Dr. Putman noted that he has treated about five patients with avacopan but hasn’t seen dramatic efficacy or side effects in his practice, compared with standard therapy.

Unanswered questions about avacopan

A key unanswered question with avacopan is the timeline for tapering glucocorticoids once patients start treatment. “I would like to see much more data on how prednisone is being tapered in clinical practice as well as outcomes in patients who are treated with the standard of care second dose of rituximab at 6 months,” Dr. Dua said.

Dr. Lally noted she has tried to expedite the steroid taper in her patients. “That’s really where I feel this drug is going to have most relevance, is getting it started early in active disease and getting patients off of the reliance on high doses of oral steroids. I have been able to see that in practice, and I do think ultimately that’s going to lead to better outcomes and quality of life for these patients.”

Of the rheumatologists Dr. Lally has spoken to about avacopan, there is “some confusion about what type of patients are appropriate, [and] how sick or not sick the patient needs to be.”

Dr. Putman noted he is unsure which of his patients should be receiving avacopan. “I don’t totally have a sense for where avacopan stands and how often we should be using it” outside of patients with severe disease. He added that the drug is still trying to find a niche because most patients with AAV who take rituximab and steroids get better without additional treatments.

“I think we do a pretty good job treating these diseases even in the preavacopan era. But it’s really a matter of how to really optimize these outcomes, reduce damage, reduce steroid-related and treatment-related toxicity for our patients,” Dr. Lally said.

Dr. Dua reported being a consultant and serving on advisory boards for ChemoCentryx; she was also a site principal investigator for the ADVOCATE trial. Dr. Hojjati reported being on the speaker’s bureau for Amgen. Dr. Langford reported being an investigator in the ADVOCATE trial, and her institution received funding to conduct the trial. Dr. Lally reported being a consultant for Amgen on avacopan. Dr. Putman reported no relevant financial disclosures.

*This story was updated 3/15/2023.

When the Food and Drug Administration approved avacopan (Tavneos) as an adjunctive treatment for severe, active antineutrophil cytoplasmic autoantibody (ANCA)–associated vasculitis (AAV) in October 2021, the oral complement C5a receptor inhibitor was hailed by its developer, ChemoCentryx, as a “new hope” for patients with the disease.

But avacopan’s novelty as a new drug for the rare diseases granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), coupled with its approval as an adjunctive to standard therapy, including glucocorticoids, rather than strictly as a glucocorticoid-sparing agent as it was tested, has so far led to little reported real-world experience with the drug.

M. Alexander Otto

In the phase 3 ADVOCATE trial, the pivotal trial that served as the basis for avacopan’s approval, 331 patients with active newly diagnosed or relapsing GPA or MPA received either avacopan or an oral prednisone taper over 20 weeks on a background of cyclophosphamide followed by azathioprine or rituximab. The results of the trial showed avacopan was noninferior to the group that received prednisone taper for remission at 26 weeks and superior to prednisone taper for sustained remission at 52 weeks, but the FDA was concerned that its complex design made it difficult to define the clinically meaningful benefit of avacopan and its role in the management of AAV.

The FDA noted that, in the avacopan arm of the trial, 86% of patients received glucocorticoids outside of the study protocol. Despite this, avacopan reduced the cumulative glucocorticoid dose over the trial’s 52 weeks by nearly two-thirds, compared with the prednisone group (1,349 mg vs. 3,655 mg).

The data also indicate a higher sustained remission rate at 52 weeks in patients who received induction with rituximab, compared with cyclophosphamide. But trial did not include a maintenance therapy dose of rituximab and is thereby not a good comparison against the standard of care, the FDA said. (ADVOCATE began enrolling patients prior to the FDA's 2018 approval of an expanded indication for patients with GPA or MPA who have achieved disease control after induction treatment.)

At the FDA’s Arthritis Advisory Committee meeting in May 2021, committee members were split on whether to recommend avacopan for approval. The committee voted 9-9 on whether the ADVOCATE trial showed efficacy supporting approval of avacopan, 10-8 in favor of whether the drug’s safety profile supported approval, and 10-8 in favor of the overall benefit-risk profile of avacopan for approval. But rather than give an indication to avacopan to reduce the use of glucocorticoids in adults with GPA or MPA, the agency approved avacopan as an adjunctive treatment for severe, active disease, noting in particular that avacopan “does not eliminate glucocorticoid use.”

The European Union’s marketing authorization for avacopan states its indication for use in combination with a rituximab or cyclophosphamide regimen for the treatment of adult patients with severe, active GPA or MPA and does not mention a role for reducing glucocorticoids. Avacopan will appear in forthcoming guidelines on management of AAV released by the European Alliance of Associations for Rheumatology.

In North America, the Canadian Vasculitis Research Network recently released an addendum to their guidelines on AAV specifically for avacopan, which includes recommendations to consider adding oral avacopan (30 mg twice daily) for induction of remission in patients with new or relapsing GPA or MPA who are also receiving cyclophosphamide or rituximab. The guidelines also recommend clinicians consider a glucocorticoid tapering schedule that aims for discontinuation at 4 weeks, and continuing avacopan for at least 1 year after induction therapy. The American College of Rheumatology guideline for AAV management, updated in 2021, acknowledges avacopan but did not consider its inclusion prior to FDA approval.

There have been few real-world studies of how patients with AAV are responding to avacopan, but recent studies from researchers in the Netherlands and in France have evaluated prednisone tapering and clinical outcomes.

Anisha B. Dua, MD, an associate professor of rheumatology at Northwestern University, Chicago, said those real-world studies “seemed to re-enforce the findings from the ADVOCATE study demonstrating the efficacy of avacopan in severe disease with steroid-sparing effects.”

However, Carol Langford, MD, MHS, director of the Center for Vasculitis Care and Research at the Cleveland Clinic, emphasized caution is needed when drawing conclusions about avacopan use outside formal studies.

“We are all interested in what other settings this might be used. I think those are things that really require formal investigation to really try and understand better as far as through a study process,” she said.
 

Prescribing experience with avacopan

A spokesperson from Amgen, which recently acquired ChemoCentryx, said in an interview that over 800 physicians in the United States have prescribed avacopan to patients with new or relapsing ANCA-associated vasculitis as induction or maintenance treatment, and physicians have reported outcomes consistent with the ADVOCATE trial.

Many rheumatologists are likely familiar with avacopan but are not used to prescribing it, said Lindsay S. Lally, MD, a rheumatologist with Hospital for Special Surgery in New York.

“Rituximab was approved for GPA and MPA a decade ago at this point. It was a drug that we as rheumatologists were used to using. We used it for other indications. Avacopan is a totally new drug, a new mechanism of action, so there’s not a lot of extractable data that we have in terms of comfort with the drug, and so I think that’s one of the biggest hurdles,” she said.

Mehrnaz Hojjati, MD, a rheumatologist with Loma Linda (Calif.) University Health, said that, when the FDA approved avacopan, it was an “exciting time” in her practice. “I have used avacopan now in a handful of my patients with severe ANCA-associated vasculitis, and the results are similar to what [was] reported in the ADVOCATE trial.”

Amgen offers help for clinicians in obtaining avacopan for patients, financial assistance for patients, and support in navigating insurance, which several rheumatologists noted was important for patients. Dr. Langford said the process of working with the manufacturer to get avacopan while insurance information is being processed has been “fairly smooth.”

“Certainly, the ability to get a very rapid 30-day supply with the goal of trying to initiate this as early as possible in the disease process has been helpful,” she said.

In Dr. Dua’s experience, while there were “some glitches or difficulty for providers early on” in how to access and prescribe avacopan, since then “it has been much easier to obtain the medication with the first month being provided to patients free while the authorization process is managed.”

Prescribing avacopan from inpatient pharmacies has been more challenging, she said. “The inpatient side is trickier because each hospital system has their own pharmacy system and regulations that have to be navigated. For outpatients, all the provider needs to do is fill out the start form available on their website, have the patients sign it, and then have it sent in.”
 

Concerns about affordability, insurance approval

Another consideration is cost, with avacopan having an estimated price of $150,000-$200,000 per patient per year.

Dr. Hojjati noted that, while it is easy to prescribe, avacopan is hard to get approved through insurance. “We face the same challenge every time a new medication comes to the market on how to convince the payers to pay for it given higher prices,” she said.

Rheumatologist Michael Putman, MD, MSCI, assistant professor of medicine at the Medical College of Wisconsin, Milwaukee, also acknowledged some difficulties in prescribing the medication. “The insurance companies have no interest in spending $150,000 on a drug that they know nothing about, and patients are a little hesitant to take it because it’s just so new,” he said.

While Dr. Lally said avacopan has not been difficult to get for patients with commercial insurance, reimbursement through Medicare has been problematic. “In many of the Medicare patients it has not really been a feasible option for them to be on the drug for the year of therapy.”
 

Patient response

Dr. Dua said almost all her patients with new or relapsing AAV who require induction are being prescribed avacopan, and that the medication is well tolerated. “The remission and ability to wean prednisone has really paralleled the findings from the clinical trial.”

In her practice, Dr. Hojjati starts patients on avacopan immediately after discharge from the hospital after a major vasculitis flare requiring high-dose glucocorticoids. “Avacopan does not eliminate/replace GC [glucocorticoid] use but has a notable GC-sparing effect and assists in rapid tapering of the GC while treating our severe ANCA-associated vasculitis patients,” she said.

Dr. Lally said her patients are tolerating avacopan well and hasn’t seen any of the safety signals seen in the trial, including liver function abnormalities. She has treated about 20-25 patients with avacopan.

Dr. Putman noted that he has treated about five patients with avacopan but hasn’t seen dramatic efficacy or side effects in his practice, compared with standard therapy.

Unanswered questions about avacopan

A key unanswered question with avacopan is the timeline for tapering glucocorticoids once patients start treatment. “I would like to see much more data on how prednisone is being tapered in clinical practice as well as outcomes in patients who are treated with the standard of care second dose of rituximab at 6 months,” Dr. Dua said.

Dr. Lally noted she has tried to expedite the steroid taper in her patients. “That’s really where I feel this drug is going to have most relevance, is getting it started early in active disease and getting patients off of the reliance on high doses of oral steroids. I have been able to see that in practice, and I do think ultimately that’s going to lead to better outcomes and quality of life for these patients.”

Of the rheumatologists Dr. Lally has spoken to about avacopan, there is “some confusion about what type of patients are appropriate, [and] how sick or not sick the patient needs to be.”

Dr. Putman noted he is unsure which of his patients should be receiving avacopan. “I don’t totally have a sense for where avacopan stands and how often we should be using it” outside of patients with severe disease. He added that the drug is still trying to find a niche because most patients with AAV who take rituximab and steroids get better without additional treatments.

“I think we do a pretty good job treating these diseases even in the preavacopan era. But it’s really a matter of how to really optimize these outcomes, reduce damage, reduce steroid-related and treatment-related toxicity for our patients,” Dr. Lally said.

Dr. Dua reported being a consultant and serving on advisory boards for ChemoCentryx; she was also a site principal investigator for the ADVOCATE trial. Dr. Hojjati reported being on the speaker’s bureau for Amgen. Dr. Langford reported being an investigator in the ADVOCATE trial, and her institution received funding to conduct the trial. Dr. Lally reported being a consultant for Amgen on avacopan. Dr. Putman reported no relevant financial disclosures.

*This story was updated 3/15/2023.

When the Food and Drug Administration approved avacopan (Tavneos) as an adjunctive treatment for severe, active antineutrophil cytoplasmic autoantibody (ANCA)–associated vasculitis (AAV) in October 2021, the oral complement C5a receptor inhibitor was hailed by its developer, ChemoCentryx, as a “new hope” for patients with the disease.

But avacopan’s novelty as a new drug for the rare diseases granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), coupled with its approval as an adjunctive to standard therapy, including glucocorticoids, rather than strictly as a glucocorticoid-sparing agent as it was tested, has so far led to little reported real-world experience with the drug.

M. Alexander Otto

In the phase 3 ADVOCATE trial, the pivotal trial that served as the basis for avacopan’s approval, 331 patients with active newly diagnosed or relapsing GPA or MPA received either avacopan or an oral prednisone taper over 20 weeks on a background of cyclophosphamide followed by azathioprine or rituximab. The results of the trial showed avacopan was noninferior to the group that received prednisone taper for remission at 26 weeks and superior to prednisone taper for sustained remission at 52 weeks, but the FDA was concerned that its complex design made it difficult to define the clinically meaningful benefit of avacopan and its role in the management of AAV.

The FDA noted that, in the avacopan arm of the trial, 86% of patients received glucocorticoids outside of the study protocol. Despite this, avacopan reduced the cumulative glucocorticoid dose over the trial’s 52 weeks by nearly two-thirds, compared with the prednisone group (1,349 mg vs. 3,655 mg).

The data also indicate a higher sustained remission rate at 52 weeks in patients who received induction with rituximab, compared with cyclophosphamide. But trial did not include a maintenance therapy dose of rituximab and is thereby not a good comparison against the standard of care, the FDA said. (ADVOCATE began enrolling patients prior to the FDA's 2018 approval of an expanded indication for patients with GPA or MPA who have achieved disease control after induction treatment.)

At the FDA’s Arthritis Advisory Committee meeting in May 2021, committee members were split on whether to recommend avacopan for approval. The committee voted 9-9 on whether the ADVOCATE trial showed efficacy supporting approval of avacopan, 10-8 in favor of whether the drug’s safety profile supported approval, and 10-8 in favor of the overall benefit-risk profile of avacopan for approval. But rather than give an indication to avacopan to reduce the use of glucocorticoids in adults with GPA or MPA, the agency approved avacopan as an adjunctive treatment for severe, active disease, noting in particular that avacopan “does not eliminate glucocorticoid use.”

The European Union’s marketing authorization for avacopan states its indication for use in combination with a rituximab or cyclophosphamide regimen for the treatment of adult patients with severe, active GPA or MPA and does not mention a role for reducing glucocorticoids. Avacopan will appear in forthcoming guidelines on management of AAV released by the European Alliance of Associations for Rheumatology.

In North America, the Canadian Vasculitis Research Network recently released an addendum to their guidelines on AAV specifically for avacopan, which includes recommendations to consider adding oral avacopan (30 mg twice daily) for induction of remission in patients with new or relapsing GPA or MPA who are also receiving cyclophosphamide or rituximab. The guidelines also recommend clinicians consider a glucocorticoid tapering schedule that aims for discontinuation at 4 weeks, and continuing avacopan for at least 1 year after induction therapy. The American College of Rheumatology guideline for AAV management, updated in 2021, acknowledges avacopan but did not consider its inclusion prior to FDA approval.

There have been few real-world studies of how patients with AAV are responding to avacopan, but recent studies from researchers in the Netherlands and in France have evaluated prednisone tapering and clinical outcomes.

Anisha B. Dua, MD, an associate professor of rheumatology at Northwestern University, Chicago, said those real-world studies “seemed to re-enforce the findings from the ADVOCATE study demonstrating the efficacy of avacopan in severe disease with steroid-sparing effects.”

However, Carol Langford, MD, MHS, director of the Center for Vasculitis Care and Research at the Cleveland Clinic, emphasized caution is needed when drawing conclusions about avacopan use outside formal studies.

“We are all interested in what other settings this might be used. I think those are things that really require formal investigation to really try and understand better as far as through a study process,” she said.
 

Prescribing experience with avacopan

A spokesperson from Amgen, which recently acquired ChemoCentryx, said in an interview that over 800 physicians in the United States have prescribed avacopan to patients with new or relapsing ANCA-associated vasculitis as induction or maintenance treatment, and physicians have reported outcomes consistent with the ADVOCATE trial.

Many rheumatologists are likely familiar with avacopan but are not used to prescribing it, said Lindsay S. Lally, MD, a rheumatologist with Hospital for Special Surgery in New York.

“Rituximab was approved for GPA and MPA a decade ago at this point. It was a drug that we as rheumatologists were used to using. We used it for other indications. Avacopan is a totally new drug, a new mechanism of action, so there’s not a lot of extractable data that we have in terms of comfort with the drug, and so I think that’s one of the biggest hurdles,” she said.

Mehrnaz Hojjati, MD, a rheumatologist with Loma Linda (Calif.) University Health, said that, when the FDA approved avacopan, it was an “exciting time” in her practice. “I have used avacopan now in a handful of my patients with severe ANCA-associated vasculitis, and the results are similar to what [was] reported in the ADVOCATE trial.”

Amgen offers help for clinicians in obtaining avacopan for patients, financial assistance for patients, and support in navigating insurance, which several rheumatologists noted was important for patients. Dr. Langford said the process of working with the manufacturer to get avacopan while insurance information is being processed has been “fairly smooth.”

“Certainly, the ability to get a very rapid 30-day supply with the goal of trying to initiate this as early as possible in the disease process has been helpful,” she said.

In Dr. Dua’s experience, while there were “some glitches or difficulty for providers early on” in how to access and prescribe avacopan, since then “it has been much easier to obtain the medication with the first month being provided to patients free while the authorization process is managed.”

Prescribing avacopan from inpatient pharmacies has been more challenging, she said. “The inpatient side is trickier because each hospital system has their own pharmacy system and regulations that have to be navigated. For outpatients, all the provider needs to do is fill out the start form available on their website, have the patients sign it, and then have it sent in.”
 

Concerns about affordability, insurance approval

Another consideration is cost, with avacopan having an estimated price of $150,000-$200,000 per patient per year.

Dr. Hojjati noted that, while it is easy to prescribe, avacopan is hard to get approved through insurance. “We face the same challenge every time a new medication comes to the market on how to convince the payers to pay for it given higher prices,” she said.

Rheumatologist Michael Putman, MD, MSCI, assistant professor of medicine at the Medical College of Wisconsin, Milwaukee, also acknowledged some difficulties in prescribing the medication. “The insurance companies have no interest in spending $150,000 on a drug that they know nothing about, and patients are a little hesitant to take it because it’s just so new,” he said.

While Dr. Lally said avacopan has not been difficult to get for patients with commercial insurance, reimbursement through Medicare has been problematic. “In many of the Medicare patients it has not really been a feasible option for them to be on the drug for the year of therapy.”
 

Patient response

Dr. Dua said almost all her patients with new or relapsing AAV who require induction are being prescribed avacopan, and that the medication is well tolerated. “The remission and ability to wean prednisone has really paralleled the findings from the clinical trial.”

In her practice, Dr. Hojjati starts patients on avacopan immediately after discharge from the hospital after a major vasculitis flare requiring high-dose glucocorticoids. “Avacopan does not eliminate/replace GC [glucocorticoid] use but has a notable GC-sparing effect and assists in rapid tapering of the GC while treating our severe ANCA-associated vasculitis patients,” she said.

Dr. Lally said her patients are tolerating avacopan well and hasn’t seen any of the safety signals seen in the trial, including liver function abnormalities. She has treated about 20-25 patients with avacopan.

Dr. Putman noted that he has treated about five patients with avacopan but hasn’t seen dramatic efficacy or side effects in his practice, compared with standard therapy.

Unanswered questions about avacopan

A key unanswered question with avacopan is the timeline for tapering glucocorticoids once patients start treatment. “I would like to see much more data on how prednisone is being tapered in clinical practice as well as outcomes in patients who are treated with the standard of care second dose of rituximab at 6 months,” Dr. Dua said.

Dr. Lally noted she has tried to expedite the steroid taper in her patients. “That’s really where I feel this drug is going to have most relevance, is getting it started early in active disease and getting patients off of the reliance on high doses of oral steroids. I have been able to see that in practice, and I do think ultimately that’s going to lead to better outcomes and quality of life for these patients.”

Of the rheumatologists Dr. Lally has spoken to about avacopan, there is “some confusion about what type of patients are appropriate, [and] how sick or not sick the patient needs to be.”

Dr. Putman noted he is unsure which of his patients should be receiving avacopan. “I don’t totally have a sense for where avacopan stands and how often we should be using it” outside of patients with severe disease. He added that the drug is still trying to find a niche because most patients with AAV who take rituximab and steroids get better without additional treatments.

“I think we do a pretty good job treating these diseases even in the preavacopan era. But it’s really a matter of how to really optimize these outcomes, reduce damage, reduce steroid-related and treatment-related toxicity for our patients,” Dr. Lally said.

Dr. Dua reported being a consultant and serving on advisory boards for ChemoCentryx; she was also a site principal investigator for the ADVOCATE trial. Dr. Hojjati reported being on the speaker’s bureau for Amgen. Dr. Langford reported being an investigator in the ADVOCATE trial, and her institution received funding to conduct the trial. Dr. Lally reported being a consultant for Amgen on avacopan. Dr. Putman reported no relevant financial disclosures.

*This story was updated 3/15/2023.

To defend the gut from microbes and pathogens, Paneth cells rely on TMEM16A, a calcium-activated chloride channel, and TMEM16F, a phospholipid scramblase, according to a new study published in Gastro Hep Advances.

The Paneth cells in mice missing TMEM16A or TMEM16F showed defects in signaling and release of secretary factors, researchers reported.

Inhibiting or activating TMEM16A and TMEM16F is likely to affect microbial content and immune functions in the small intestine, concluded Rainer Schreiber, Dr. rer. nat., of the Institute of Physiology at Universität Regensburg, Germany, and colleagues.

“Many small molecules and numerous natural or herbal compounds have been identified that either inhibit or activate TMEM16A or TMEM16F,” they wrote. “Some of these compounds may turn out to be useful therapeutics in inflammatory bowel disease, intestinal allergies, or abnormal colonization of the gut.”

Paneth cells play a central role in intestinal innate immune response, the authors wrote. Located at the base of small intestinal crypts and occasionally found in the proximal colon, these cells have defensive functions, such as protecting stem cells in response to invading microbes and eradicating ingested pathogens from intestinal crypts. Through secretion, they also regulate the composition and number of commensal intestinal bacteria. In inflammatory bowel disease, the Paneth cell zone expands due to an increase in cell size and cell number.

In previous studies, cholinergic stimulation provided enhanced protection in animals orally infected with virulent Salmonella enterica. However, the mechanisms of luminal stimulation of Paneth cell secretion in response to bacteria or lipopolysaccharide are unclear. Recent reports show that TMEM16A (also known as anoctamin 1, or ANO1) and TMEM16F (anoctamin 6, or ANO6) control intracellular calcium (Ca2+) signaling and that high local Ca2+ levels support exocytosis in intestinal cells.

The researchers analyzed the roles of the two molecules in Paneth cell secretion using mice with intestinal epithelial-specific knockout of TMEM16A or TMEM16F. They examined tissue structures and Paneth cells in the mice, as well as Paneth cell exocytosis in small intestinal organoids in vitro. They also compared Ca2+ signals between wild-type and knockout mice and analyzed bacterial colonization and intestinal apoptosis.

In wild-type mice, TMEM16A was detected at the apical pole of crypt epithelial cells, while TMEM16F was located predominantly at the basolateral side. Notably, TMEM16A was also located in intestinal smooth muscle cells.

Compared with wild-type mice, the TMEM16 knockout mice had pronounced accumulation of lysozyme in jejunal Paneth cells. This suggests a defect in Paneth cell secretion in the absence of TMEM16A and TMEM16F, the authors wrote.

Previous studies had found an accumulation of mucus in intestinal goblet cells in mice with tissue-specific knockout of TMEM16A and TMEM16F. In this study, a more detailed analysis of mucus using periodic acid-Schiff staining of duodenum, jejunum, and ileum confirmed those results and demonstrated enhanced mucus in the small intestine of knockout mice. This suggests that a lack of TMEM16A or TMEM16F causes a broad secretion defect in secretory cells, including Paneth cells, the authors wrote.

Because granules of Paneth cells contain antimicrobial peptides, cytokines, and other factors that control proliferation or epithelial cell death, the researchers analyzed the presence of Gram-positive and Gram-negative bacteria in the jejunum and ileum. Compared to wild-type mice, the number of bacteria was higher in the ileum of both TMEM16A and TMEM16F knockout mice and in the jejunum of TMEM16F knockout mice, suggesting reduced antimicrobial activity in the absence of TMEM16 proteins.

The researchers also compared regulated cell death of intestinal epithelial cells in jejuna of wild-type and knockout mice. They found largely reduced cell death in both TMEM16A and TMEM16F knockout mice.

“Intestinal inflammatory diseases such as Crohn’s disease, necrotizing enterocolitis, and intestinal microbiota dysbiosis have been related to abnormal Paneth cell physiology,” the authors wrote. “The present findings may therefore provide the basis for a novel anti-inflammatory therapy for intestinal diseases and may improve our understanding of the molecular mechanism of some of the currently available drugs.”

The study was supported by the Deutsche Forschungsgemeinschaft funding program. The authors disclosed no conflicts of interest.

To defend the gut from microbes and pathogens, Paneth cells rely on TMEM16A, a calcium-activated chloride channel, and TMEM16F, a phospholipid scramblase, according to a new study published in Gastro Hep Advances.

The Paneth cells in mice missing TMEM16A or TMEM16F showed defects in signaling and release of secretary factors, researchers reported.

Inhibiting or activating TMEM16A and TMEM16F is likely to affect microbial content and immune functions in the small intestine, concluded Rainer Schreiber, Dr. rer. nat., of the Institute of Physiology at Universität Regensburg, Germany, and colleagues.

“Many small molecules and numerous natural or herbal compounds have been identified that either inhibit or activate TMEM16A or TMEM16F,” they wrote. “Some of these compounds may turn out to be useful therapeutics in inflammatory bowel disease, intestinal allergies, or abnormal colonization of the gut.”

Paneth cells play a central role in intestinal innate immune response, the authors wrote. Located at the base of small intestinal crypts and occasionally found in the proximal colon, these cells have defensive functions, such as protecting stem cells in response to invading microbes and eradicating ingested pathogens from intestinal crypts. Through secretion, they also regulate the composition and number of commensal intestinal bacteria. In inflammatory bowel disease, the Paneth cell zone expands due to an increase in cell size and cell number.

In previous studies, cholinergic stimulation provided enhanced protection in animals orally infected with virulent Salmonella enterica. However, the mechanisms of luminal stimulation of Paneth cell secretion in response to bacteria or lipopolysaccharide are unclear. Recent reports show that TMEM16A (also known as anoctamin 1, or ANO1) and TMEM16F (anoctamin 6, or ANO6) control intracellular calcium (Ca2+) signaling and that high local Ca2+ levels support exocytosis in intestinal cells.

The researchers analyzed the roles of the two molecules in Paneth cell secretion using mice with intestinal epithelial-specific knockout of TMEM16A or TMEM16F. They examined tissue structures and Paneth cells in the mice, as well as Paneth cell exocytosis in small intestinal organoids in vitro. They also compared Ca2+ signals between wild-type and knockout mice and analyzed bacterial colonization and intestinal apoptosis.

In wild-type mice, TMEM16A was detected at the apical pole of crypt epithelial cells, while TMEM16F was located predominantly at the basolateral side. Notably, TMEM16A was also located in intestinal smooth muscle cells.

Compared with wild-type mice, the TMEM16 knockout mice had pronounced accumulation of lysozyme in jejunal Paneth cells. This suggests a defect in Paneth cell secretion in the absence of TMEM16A and TMEM16F, the authors wrote.

Previous studies had found an accumulation of mucus in intestinal goblet cells in mice with tissue-specific knockout of TMEM16A and TMEM16F. In this study, a more detailed analysis of mucus using periodic acid-Schiff staining of duodenum, jejunum, and ileum confirmed those results and demonstrated enhanced mucus in the small intestine of knockout mice. This suggests that a lack of TMEM16A or TMEM16F causes a broad secretion defect in secretory cells, including Paneth cells, the authors wrote.

Because granules of Paneth cells contain antimicrobial peptides, cytokines, and other factors that control proliferation or epithelial cell death, the researchers analyzed the presence of Gram-positive and Gram-negative bacteria in the jejunum and ileum. Compared to wild-type mice, the number of bacteria was higher in the ileum of both TMEM16A and TMEM16F knockout mice and in the jejunum of TMEM16F knockout mice, suggesting reduced antimicrobial activity in the absence of TMEM16 proteins.

The researchers also compared regulated cell death of intestinal epithelial cells in jejuna of wild-type and knockout mice. They found largely reduced cell death in both TMEM16A and TMEM16F knockout mice.

“Intestinal inflammatory diseases such as Crohn’s disease, necrotizing enterocolitis, and intestinal microbiota dysbiosis have been related to abnormal Paneth cell physiology,” the authors wrote. “The present findings may therefore provide the basis for a novel anti-inflammatory therapy for intestinal diseases and may improve our understanding of the molecular mechanism of some of the currently available drugs.”

The study was supported by the Deutsche Forschungsgemeinschaft funding program. The authors disclosed no conflicts of interest.

To defend the gut from microbes and pathogens, Paneth cells rely on TMEM16A, a calcium-activated chloride channel, and TMEM16F, a phospholipid scramblase, according to a new study published in Gastro Hep Advances.

The Paneth cells in mice missing TMEM16A or TMEM16F showed defects in signaling and release of secretary factors, researchers reported.

Inhibiting or activating TMEM16A and TMEM16F is likely to affect microbial content and immune functions in the small intestine, concluded Rainer Schreiber, Dr. rer. nat., of the Institute of Physiology at Universität Regensburg, Germany, and colleagues.

“Many small molecules and numerous natural or herbal compounds have been identified that either inhibit or activate TMEM16A or TMEM16F,” they wrote. “Some of these compounds may turn out to be useful therapeutics in inflammatory bowel disease, intestinal allergies, or abnormal colonization of the gut.”

Paneth cells play a central role in intestinal innate immune response, the authors wrote. Located at the base of small intestinal crypts and occasionally found in the proximal colon, these cells have defensive functions, such as protecting stem cells in response to invading microbes and eradicating ingested pathogens from intestinal crypts. Through secretion, they also regulate the composition and number of commensal intestinal bacteria. In inflammatory bowel disease, the Paneth cell zone expands due to an increase in cell size and cell number.

In previous studies, cholinergic stimulation provided enhanced protection in animals orally infected with virulent Salmonella enterica. However, the mechanisms of luminal stimulation of Paneth cell secretion in response to bacteria or lipopolysaccharide are unclear. Recent reports show that TMEM16A (also known as anoctamin 1, or ANO1) and TMEM16F (anoctamin 6, or ANO6) control intracellular calcium (Ca2+) signaling and that high local Ca2+ levels support exocytosis in intestinal cells.

The researchers analyzed the roles of the two molecules in Paneth cell secretion using mice with intestinal epithelial-specific knockout of TMEM16A or TMEM16F. They examined tissue structures and Paneth cells in the mice, as well as Paneth cell exocytosis in small intestinal organoids in vitro. They also compared Ca2+ signals between wild-type and knockout mice and analyzed bacterial colonization and intestinal apoptosis.

In wild-type mice, TMEM16A was detected at the apical pole of crypt epithelial cells, while TMEM16F was located predominantly at the basolateral side. Notably, TMEM16A was also located in intestinal smooth muscle cells.

Compared with wild-type mice, the TMEM16 knockout mice had pronounced accumulation of lysozyme in jejunal Paneth cells. This suggests a defect in Paneth cell secretion in the absence of TMEM16A and TMEM16F, the authors wrote.

Previous studies had found an accumulation of mucus in intestinal goblet cells in mice with tissue-specific knockout of TMEM16A and TMEM16F. In this study, a more detailed analysis of mucus using periodic acid-Schiff staining of duodenum, jejunum, and ileum confirmed those results and demonstrated enhanced mucus in the small intestine of knockout mice. This suggests that a lack of TMEM16A or TMEM16F causes a broad secretion defect in secretory cells, including Paneth cells, the authors wrote.

Because granules of Paneth cells contain antimicrobial peptides, cytokines, and other factors that control proliferation or epithelial cell death, the researchers analyzed the presence of Gram-positive and Gram-negative bacteria in the jejunum and ileum. Compared to wild-type mice, the number of bacteria was higher in the ileum of both TMEM16A and TMEM16F knockout mice and in the jejunum of TMEM16F knockout mice, suggesting reduced antimicrobial activity in the absence of TMEM16 proteins.

The researchers also compared regulated cell death of intestinal epithelial cells in jejuna of wild-type and knockout mice. They found largely reduced cell death in both TMEM16A and TMEM16F knockout mice.

“Intestinal inflammatory diseases such as Crohn’s disease, necrotizing enterocolitis, and intestinal microbiota dysbiosis have been related to abnormal Paneth cell physiology,” the authors wrote. “The present findings may therefore provide the basis for a novel anti-inflammatory therapy for intestinal diseases and may improve our understanding of the molecular mechanism of some of the currently available drugs.”

The study was supported by the Deutsche Forschungsgemeinschaft funding program. The authors disclosed no conflicts of interest.

A growing body of evidence shows that deeper and larger tumors can be safely removed with endoscopy instead of surgery when individual patient risk is taken into account, according to a review by Eva P.D. Verheij, a doctoral candidate at Amsterdam University Medical Center, and colleagues.

“Management of patients with superficial esophageal adenocarcinoma (EAC) is becoming less invasive and more patient-tailored,” the researchers wrote in Techniques and Innovations in Gastrointestinal Endoscopy. “In the future, watchful waiting may be a valid alternative to surgery in selected cases.”

Courtesy Eva P. D. Verheij

The investigators examined new advances that have been made in the management of superficial esophageal adenocarcinomas by endoscopy, and they address how guidelines may be falling short in light of newly published evidence.

Surgery is usually the first choice for the management of advanced esophageal adenocarcinoma. “Endoscopic treatment has become the cornerstone for early cancer confined to the mucosa,” the authors wrote.

“For low-risk submucosal EAC, which only invades the superficial submucosa (sm1, i.e. less than 500 mcm) without any other risk factors, endoscopic treatment as an alternative to surgery is gaining acceptance because multiple studies have demonstrated a very low risk of lymph node metastases (less than 2% for these lesions),” the investigators wrote. Although surgical resection with lymphadenectomy is currently the recommended treatment for cases with deep submucosal invasion, poor differentiation, or lymphovascular invasion, the investigators suggested that even these tumors may be within an endoscopist’s reach.

While the rate of lymph node metastasis for such patients has been reported to be as high as 46%, more recent endoscopic studies show a metastasis rate range of up to 20% after 23-63 months of follow-up.

“One possible explanation for the discrepancy in lymph node metastases rates between surgical and endoscopic studies could be the different preparation of slides for histopathological assessment,” the investigators wrote. “In general, the cuts in surgical specimen are made with wider intervals (±5 mm) than the cuts in endoscopic resection specimens (2-3 mm), with additional cuts in case of submucosal invasion. The hypothesis is that this wider interval may result in missing the area with the deepest tumor infiltration. This could result in an underdiagnosis of the actual invasion depth, and therefore an overestimation of the associated lymph node metastases risk.” A study published in August 2022 in Gastrointestinal Endoscopy found an annual metastases risk of 6.9% in patients with high-risk T1a EAC.

“Given its invasiveness and associated morbidity and mortality, esophagectomy may be overtreatment in those patients who will not develop lymph node metastases,” the investigators wrote. “Given the technical advances in endoscopy that enable us to radically remove large EACs, and to perform more meticulous follow-up, it might be time to swing the pendulum and only send those patients for surgery who have an indisputable indication for surgery, instead of performing esophagectomy as a prophylactic treatment.”

To truly find the limits of endoscopic resection for EAC, however, more research is needed.

“Ongoing studies are necessary to evaluate the lymph node metastases risk on an individual basis, using presence of histological risk factors. By predicting the risk of lymph node metastases, and considering patients’ wishes and condition, one might decide to perform esophagectomy or watchful waiting with strict endoscopic follow-up. In high-risk cases, we may use sentinel node navigated surgery in the future as an extra safety check before deciding on optimal management,” the authors wrote.

The investigators disclosed relationships Medtronic, C2 Therapeutics/Pentax Medical, MicroTech, and Aqua Medical.

A growing body of evidence shows that deeper and larger tumors can be safely removed with endoscopy instead of surgery when individual patient risk is taken into account, according to a review by Eva P.D. Verheij, a doctoral candidate at Amsterdam University Medical Center, and colleagues.

“Management of patients with superficial esophageal adenocarcinoma (EAC) is becoming less invasive and more patient-tailored,” the researchers wrote in Techniques and Innovations in Gastrointestinal Endoscopy. “In the future, watchful waiting may be a valid alternative to surgery in selected cases.”

Courtesy Eva P. D. Verheij

The investigators examined new advances that have been made in the management of superficial esophageal adenocarcinomas by endoscopy, and they address how guidelines may be falling short in light of newly published evidence.

Surgery is usually the first choice for the management of advanced esophageal adenocarcinoma. “Endoscopic treatment has become the cornerstone for early cancer confined to the mucosa,” the authors wrote.

“For low-risk submucosal EAC, which only invades the superficial submucosa (sm1, i.e. less than 500 mcm) without any other risk factors, endoscopic treatment as an alternative to surgery is gaining acceptance because multiple studies have demonstrated a very low risk of lymph node metastases (less than 2% for these lesions),” the investigators wrote. Although surgical resection with lymphadenectomy is currently the recommended treatment for cases with deep submucosal invasion, poor differentiation, or lymphovascular invasion, the investigators suggested that even these tumors may be within an endoscopist’s reach.

While the rate of lymph node metastasis for such patients has been reported to be as high as 46%, more recent endoscopic studies show a metastasis rate range of up to 20% after 23-63 months of follow-up.

“One possible explanation for the discrepancy in lymph node metastases rates between surgical and endoscopic studies could be the different preparation of slides for histopathological assessment,” the investigators wrote. “In general, the cuts in surgical specimen are made with wider intervals (±5 mm) than the cuts in endoscopic resection specimens (2-3 mm), with additional cuts in case of submucosal invasion. The hypothesis is that this wider interval may result in missing the area with the deepest tumor infiltration. This could result in an underdiagnosis of the actual invasion depth, and therefore an overestimation of the associated lymph node metastases risk.” A study published in August 2022 in Gastrointestinal Endoscopy found an annual metastases risk of 6.9% in patients with high-risk T1a EAC.

“Given its invasiveness and associated morbidity and mortality, esophagectomy may be overtreatment in those patients who will not develop lymph node metastases,” the investigators wrote. “Given the technical advances in endoscopy that enable us to radically remove large EACs, and to perform more meticulous follow-up, it might be time to swing the pendulum and only send those patients for surgery who have an indisputable indication for surgery, instead of performing esophagectomy as a prophylactic treatment.”

To truly find the limits of endoscopic resection for EAC, however, more research is needed.

“Ongoing studies are necessary to evaluate the lymph node metastases risk on an individual basis, using presence of histological risk factors. By predicting the risk of lymph node metastases, and considering patients’ wishes and condition, one might decide to perform esophagectomy or watchful waiting with strict endoscopic follow-up. In high-risk cases, we may use sentinel node navigated surgery in the future as an extra safety check before deciding on optimal management,” the authors wrote.

The investigators disclosed relationships Medtronic, C2 Therapeutics/Pentax Medical, MicroTech, and Aqua Medical.

A growing body of evidence shows that deeper and larger tumors can be safely removed with endoscopy instead of surgery when individual patient risk is taken into account, according to a review by Eva P.D. Verheij, a doctoral candidate at Amsterdam University Medical Center, and colleagues.

“Management of patients with superficial esophageal adenocarcinoma (EAC) is becoming less invasive and more patient-tailored,” the researchers wrote in Techniques and Innovations in Gastrointestinal Endoscopy. “In the future, watchful waiting may be a valid alternative to surgery in selected cases.”

Courtesy Eva P. D. Verheij

The investigators examined new advances that have been made in the management of superficial esophageal adenocarcinomas by endoscopy, and they address how guidelines may be falling short in light of newly published evidence.

Surgery is usually the first choice for the management of advanced esophageal adenocarcinoma. “Endoscopic treatment has become the cornerstone for early cancer confined to the mucosa,” the authors wrote.

“For low-risk submucosal EAC, which only invades the superficial submucosa (sm1, i.e. less than 500 mcm) without any other risk factors, endoscopic treatment as an alternative to surgery is gaining acceptance because multiple studies have demonstrated a very low risk of lymph node metastases (less than 2% for these lesions),” the investigators wrote. Although surgical resection with lymphadenectomy is currently the recommended treatment for cases with deep submucosal invasion, poor differentiation, or lymphovascular invasion, the investigators suggested that even these tumors may be within an endoscopist’s reach.

While the rate of lymph node metastasis for such patients has been reported to be as high as 46%, more recent endoscopic studies show a metastasis rate range of up to 20% after 23-63 months of follow-up.

“One possible explanation for the discrepancy in lymph node metastases rates between surgical and endoscopic studies could be the different preparation of slides for histopathological assessment,” the investigators wrote. “In general, the cuts in surgical specimen are made with wider intervals (±5 mm) than the cuts in endoscopic resection specimens (2-3 mm), with additional cuts in case of submucosal invasion. The hypothesis is that this wider interval may result in missing the area with the deepest tumor infiltration. This could result in an underdiagnosis of the actual invasion depth, and therefore an overestimation of the associated lymph node metastases risk.” A study published in August 2022 in Gastrointestinal Endoscopy found an annual metastases risk of 6.9% in patients with high-risk T1a EAC.

“Given its invasiveness and associated morbidity and mortality, esophagectomy may be overtreatment in those patients who will not develop lymph node metastases,” the investigators wrote. “Given the technical advances in endoscopy that enable us to radically remove large EACs, and to perform more meticulous follow-up, it might be time to swing the pendulum and only send those patients for surgery who have an indisputable indication for surgery, instead of performing esophagectomy as a prophylactic treatment.”

To truly find the limits of endoscopic resection for EAC, however, more research is needed.

“Ongoing studies are necessary to evaluate the lymph node metastases risk on an individual basis, using presence of histological risk factors. By predicting the risk of lymph node metastases, and considering patients’ wishes and condition, one might decide to perform esophagectomy or watchful waiting with strict endoscopic follow-up. In high-risk cases, we may use sentinel node navigated surgery in the future as an extra safety check before deciding on optimal management,” the authors wrote.

The investigators disclosed relationships Medtronic, C2 Therapeutics/Pentax Medical, MicroTech, and Aqua Medical.

NEW ORLEANS – An investigational, first-in class agent that delivers a completely new type of intervention to patients with pulmonary arterial hypertension (PAH) scored a clear win in the STELLAR trial, the first to complete among three phase 3 trials that are testing this agent.

Sotatercept, administered subcutaneously every 3 weeks for 24 weeks, improved from baseline average 6-minute walk distance (6MWD) by a significant and clinically meaningful 40.8 meters, compared with placebo, for the trial’s primary efficacy endpoint (P < .001). The treatment also “delivered broad clinical benefit across multiple domains including hemodynamics, World Health Organization functional class, disease biomarkers, risk scores and patient-reported outcomes,” Marius M. Hoeper, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Mitchel L. Zoler/MDedge News

“These results establish the clinical utility of sotatercept, administered in combination with approved PAH therapies, as a new treatment for PAH,” added Dr. Hoeper, professor and deputy director of the department of respiratory medicine at Hannover (Germany) Medical School,

“The most important aspect was the hemodynamic improvement,” with sotatercept treatment, which led to an average 235 dyn/sec per cm⁻⁵ reduction in pulmonary vascular resistance from baseline and an average cut in pulmonary artery pressure of 13.9 mm Hg from baseline, compared with placebo, a result that’s “unheard of,” Dr. Hoeper said in a press conference during the meeting.

“With other tested agents we usually see very little improvement in pulmonary artery pressure. This is a signal that we achieved some reversing of the pathological changes in the pulmonary vessels that lead to” PAH, he added.

Simultaneously with his report the findings also appeared online in the New England Journal of Medicine.
 

‘A new hope’ for patients with PAH

Based on the reported findings, sotatercept is a “very exciting boutique molecule” that will “offer patients with PAH a very exciting new treatment,” commented Rhonda Cooper-DeHoff, PharmD, a designated discussant and a researcher at the University of Florida, Gainesville.

Mitchel L. Zoler/MDedge News

“This study is a new hope for patients with PAH. Until now, they’ve had really bad outcomes, but [in this study] we see significant differences in 6MWD, hemodynamics, and risk factors. Overall, I think the benefit is greater than the risk” it may pose to patients through potential adverse effects, commented Julia Grapsa, MD, PhD, a cardiologist at St. Thomas Hospital in London, and another discussant at the meeting.

“The results are impressive” and “encouraging,” and “suggest that sotatercept may represent a new and clinically consequential addition to current medications for PAH,” wrote three clinicians from Canyons Region Intermountain Medical Center in Murray, Utah, in an editorial that accompanied the published report.

But the authors of the editorial also raised several cautions and concerns. They questioned the generalizability of the findings, noting that the patients with PAH enrolled in the study were all adults who were clinically stable and an average of more than 8 years out from their initial PAH diagnosis, and more than 90% were on stable treatment for PAH with two or three agents specific for treating the disorder. The study cohort also had a disproportionately high enrollment of patients with idiopathic (59%) or heritable (18%) forms of PAH, and the 15% of patients in the trial with connective tissue disease represented a disproportionately low prevalence of this PAH subtype.

The editorialists also called for “ongoing vigilance” for adverse effects from sotatercept treatment, although they acknowledged that the adverse effects reported to date from sotatercept are “largely reassuring.”
 

Death or clinical worsening cut by 84%

STELLAR randomized 323 patients at 91 sites in 21 countries with WHO Group 1 PAH and with WHO functional class II or III disease to receive either sotatercept or placebo for 24 weeks, with an option for treatment to continue beyond that until the last patient in the study reached 24 weeks on treatment, resulting in an overall median treatment duration of nearly 33 weeks.

In addition to the significant result for the primary endpoint, the 163 patients who received sotatercept had significant improvements, compared with 160 placebo-treated patients, for eight of nine secondary endpoints. The only secondary endpoint with a neutral result was for a measure of cognitive and emotional wellbeing, a parameter that was already at a normal level at baseline in most enrolled patients, Dr. Hoeper explained.

The incidence of either death or an event indicative of clinical worsening during the overall median follow-up of almost 33 weeks was 26.3% among the control patients and 5.5% among those who received sotatercept. This translated into a significant reduction for this endpoint of 84% with sotatercept treatment, compared with placebo.

The rates of treatment-emergent adverse events leading to discontinuation were roughly the same in the control and sotatercept arms, and the incidence of severe or serious treatment-emergent adverse events was higher among the control patients.

The most common adverse event on sotatercept was bleeding events, which occurred in 32% of those on sotatercept and in 16% of the control patients, but the events in the sotatercept arm were “mostly mild,” said Dr. Hoeper. The next most frequent adverse event during sotatercept treatment was appearance of telangiectasias, which occurred in 14% of those on sotatercept and in 4% of control patients.

“It’s an uncommon adverse event profile, but not unexpected for a drug with its mechanism of action,” he said.

Drug binds activin, a pathologic driver of PAH

Sotatercept is an engineered molecule that combines a section of a human immunoglobulin G molecule with a portion of the receptor for activin. This structure allows sotatercept to bind free activin molecules in a patient’s blood, thereby removing a key driver of the pulmonary vascular wall remodeling that is at the pathologic root of PAH.

“Hyperproliferation of blood vessel–wall cells” caused by activin signaling “is perhaps the most important driver of PAH,” Dr. Hoeper said. “Sotatercept allows us for the first time to target the underlying mechanism behind PAH.”

Still ongoing are the HYPERION and ZENITH phase 3 trials of sotatercept. HYPERION is enrolling patients with newly diagnosed or high-risk PAH and is expected to complete in 2028. ZENITH is enrolling patients with more advanced PAH and a higher mortality risk, with results expected in 2026.

Sotatercept has received “Breakthrough Therapy” designation and “Orphan Drug” designation by the Food and Drug Administration, and “Priority Medicines” designation and “Orphan Drug” designation by the European Medicines Agency for the treatment of PAH. One recent review estimated a worldwide PAH prevalence of about 3-4 cases/100,000, which for the United States translates into a total prevalence of perhaps 10,000-15,000 affected people.

STELLAR was funded by Acceleron Pharma, a subsidiary of Merck. Dr. Hoeper is a consultant to Acceleron. Dr. Cooper-DeHoff, Dr. Grapsa, and the authors of the editorial on STELLAR have no relevant disclosures.

NEW ORLEANS – An investigational, first-in class agent that delivers a completely new type of intervention to patients with pulmonary arterial hypertension (PAH) scored a clear win in the STELLAR trial, the first to complete among three phase 3 trials that are testing this agent.

Sotatercept, administered subcutaneously every 3 weeks for 24 weeks, improved from baseline average 6-minute walk distance (6MWD) by a significant and clinically meaningful 40.8 meters, compared with placebo, for the trial’s primary efficacy endpoint (P < .001). The treatment also “delivered broad clinical benefit across multiple domains including hemodynamics, World Health Organization functional class, disease biomarkers, risk scores and patient-reported outcomes,” Marius M. Hoeper, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Mitchel L. Zoler/MDedge News

“These results establish the clinical utility of sotatercept, administered in combination with approved PAH therapies, as a new treatment for PAH,” added Dr. Hoeper, professor and deputy director of the department of respiratory medicine at Hannover (Germany) Medical School,

“The most important aspect was the hemodynamic improvement,” with sotatercept treatment, which led to an average 235 dyn/sec per cm⁻⁵ reduction in pulmonary vascular resistance from baseline and an average cut in pulmonary artery pressure of 13.9 mm Hg from baseline, compared with placebo, a result that’s “unheard of,” Dr. Hoeper said in a press conference during the meeting.

“With other tested agents we usually see very little improvement in pulmonary artery pressure. This is a signal that we achieved some reversing of the pathological changes in the pulmonary vessels that lead to” PAH, he added.

Simultaneously with his report the findings also appeared online in the New England Journal of Medicine.
 

‘A new hope’ for patients with PAH

Based on the reported findings, sotatercept is a “very exciting boutique molecule” that will “offer patients with PAH a very exciting new treatment,” commented Rhonda Cooper-DeHoff, PharmD, a designated discussant and a researcher at the University of Florida, Gainesville.

Mitchel L. Zoler/MDedge News

“This study is a new hope for patients with PAH. Until now, they’ve had really bad outcomes, but [in this study] we see significant differences in 6MWD, hemodynamics, and risk factors. Overall, I think the benefit is greater than the risk” it may pose to patients through potential adverse effects, commented Julia Grapsa, MD, PhD, a cardiologist at St. Thomas Hospital in London, and another discussant at the meeting.

“The results are impressive” and “encouraging,” and “suggest that sotatercept may represent a new and clinically consequential addition to current medications for PAH,” wrote three clinicians from Canyons Region Intermountain Medical Center in Murray, Utah, in an editorial that accompanied the published report.

But the authors of the editorial also raised several cautions and concerns. They questioned the generalizability of the findings, noting that the patients with PAH enrolled in the study were all adults who were clinically stable and an average of more than 8 years out from their initial PAH diagnosis, and more than 90% were on stable treatment for PAH with two or three agents specific for treating the disorder. The study cohort also had a disproportionately high enrollment of patients with idiopathic (59%) or heritable (18%) forms of PAH, and the 15% of patients in the trial with connective tissue disease represented a disproportionately low prevalence of this PAH subtype.

The editorialists also called for “ongoing vigilance” for adverse effects from sotatercept treatment, although they acknowledged that the adverse effects reported to date from sotatercept are “largely reassuring.”
 

Death or clinical worsening cut by 84%

STELLAR randomized 323 patients at 91 sites in 21 countries with WHO Group 1 PAH and with WHO functional class II or III disease to receive either sotatercept or placebo for 24 weeks, with an option for treatment to continue beyond that until the last patient in the study reached 24 weeks on treatment, resulting in an overall median treatment duration of nearly 33 weeks.

In addition to the significant result for the primary endpoint, the 163 patients who received sotatercept had significant improvements, compared with 160 placebo-treated patients, for eight of nine secondary endpoints. The only secondary endpoint with a neutral result was for a measure of cognitive and emotional wellbeing, a parameter that was already at a normal level at baseline in most enrolled patients, Dr. Hoeper explained.

The incidence of either death or an event indicative of clinical worsening during the overall median follow-up of almost 33 weeks was 26.3% among the control patients and 5.5% among those who received sotatercept. This translated into a significant reduction for this endpoint of 84% with sotatercept treatment, compared with placebo.

The rates of treatment-emergent adverse events leading to discontinuation were roughly the same in the control and sotatercept arms, and the incidence of severe or serious treatment-emergent adverse events was higher among the control patients.

The most common adverse event on sotatercept was bleeding events, which occurred in 32% of those on sotatercept and in 16% of the control patients, but the events in the sotatercept arm were “mostly mild,” said Dr. Hoeper. The next most frequent adverse event during sotatercept treatment was appearance of telangiectasias, which occurred in 14% of those on sotatercept and in 4% of control patients.

“It’s an uncommon adverse event profile, but not unexpected for a drug with its mechanism of action,” he said.

Drug binds activin, a pathologic driver of PAH

Sotatercept is an engineered molecule that combines a section of a human immunoglobulin G molecule with a portion of the receptor for activin. This structure allows sotatercept to bind free activin molecules in a patient’s blood, thereby removing a key driver of the pulmonary vascular wall remodeling that is at the pathologic root of PAH.

“Hyperproliferation of blood vessel–wall cells” caused by activin signaling “is perhaps the most important driver of PAH,” Dr. Hoeper said. “Sotatercept allows us for the first time to target the underlying mechanism behind PAH.”

Still ongoing are the HYPERION and ZENITH phase 3 trials of sotatercept. HYPERION is enrolling patients with newly diagnosed or high-risk PAH and is expected to complete in 2028. ZENITH is enrolling patients with more advanced PAH and a higher mortality risk, with results expected in 2026.

Sotatercept has received “Breakthrough Therapy” designation and “Orphan Drug” designation by the Food and Drug Administration, and “Priority Medicines” designation and “Orphan Drug” designation by the European Medicines Agency for the treatment of PAH. One recent review estimated a worldwide PAH prevalence of about 3-4 cases/100,000, which for the United States translates into a total prevalence of perhaps 10,000-15,000 affected people.

STELLAR was funded by Acceleron Pharma, a subsidiary of Merck. Dr. Hoeper is a consultant to Acceleron. Dr. Cooper-DeHoff, Dr. Grapsa, and the authors of the editorial on STELLAR have no relevant disclosures.

NEW ORLEANS – An investigational, first-in class agent that delivers a completely new type of intervention to patients with pulmonary arterial hypertension (PAH) scored a clear win in the STELLAR trial, the first to complete among three phase 3 trials that are testing this agent.

Sotatercept, administered subcutaneously every 3 weeks for 24 weeks, improved from baseline average 6-minute walk distance (6MWD) by a significant and clinically meaningful 40.8 meters, compared with placebo, for the trial’s primary efficacy endpoint (P < .001). The treatment also “delivered broad clinical benefit across multiple domains including hemodynamics, World Health Organization functional class, disease biomarkers, risk scores and patient-reported outcomes,” Marius M. Hoeper, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Mitchel L. Zoler/MDedge News

“These results establish the clinical utility of sotatercept, administered in combination with approved PAH therapies, as a new treatment for PAH,” added Dr. Hoeper, professor and deputy director of the department of respiratory medicine at Hannover (Germany) Medical School,

“The most important aspect was the hemodynamic improvement,” with sotatercept treatment, which led to an average 235 dyn/sec per cm⁻⁵ reduction in pulmonary vascular resistance from baseline and an average cut in pulmonary artery pressure of 13.9 mm Hg from baseline, compared with placebo, a result that’s “unheard of,” Dr. Hoeper said in a press conference during the meeting.

“With other tested agents we usually see very little improvement in pulmonary artery pressure. This is a signal that we achieved some reversing of the pathological changes in the pulmonary vessels that lead to” PAH, he added.

Simultaneously with his report the findings also appeared online in the New England Journal of Medicine.
 

‘A new hope’ for patients with PAH

Based on the reported findings, sotatercept is a “very exciting boutique molecule” that will “offer patients with PAH a very exciting new treatment,” commented Rhonda Cooper-DeHoff, PharmD, a designated discussant and a researcher at the University of Florida, Gainesville.

Mitchel L. Zoler/MDedge News

“This study is a new hope for patients with PAH. Until now, they’ve had really bad outcomes, but [in this study] we see significant differences in 6MWD, hemodynamics, and risk factors. Overall, I think the benefit is greater than the risk” it may pose to patients through potential adverse effects, commented Julia Grapsa, MD, PhD, a cardiologist at St. Thomas Hospital in London, and another discussant at the meeting.

“The results are impressive” and “encouraging,” and “suggest that sotatercept may represent a new and clinically consequential addition to current medications for PAH,” wrote three clinicians from Canyons Region Intermountain Medical Center in Murray, Utah, in an editorial that accompanied the published report.

But the authors of the editorial also raised several cautions and concerns. They questioned the generalizability of the findings, noting that the patients with PAH enrolled in the study were all adults who were clinically stable and an average of more than 8 years out from their initial PAH diagnosis, and more than 90% were on stable treatment for PAH with two or three agents specific for treating the disorder. The study cohort also had a disproportionately high enrollment of patients with idiopathic (59%) or heritable (18%) forms of PAH, and the 15% of patients in the trial with connective tissue disease represented a disproportionately low prevalence of this PAH subtype.

The editorialists also called for “ongoing vigilance” for adverse effects from sotatercept treatment, although they acknowledged that the adverse effects reported to date from sotatercept are “largely reassuring.”
 

Death or clinical worsening cut by 84%

STELLAR randomized 323 patients at 91 sites in 21 countries with WHO Group 1 PAH and with WHO functional class II or III disease to receive either sotatercept or placebo for 24 weeks, with an option for treatment to continue beyond that until the last patient in the study reached 24 weeks on treatment, resulting in an overall median treatment duration of nearly 33 weeks.

In addition to the significant result for the primary endpoint, the 163 patients who received sotatercept had significant improvements, compared with 160 placebo-treated patients, for eight of nine secondary endpoints. The only secondary endpoint with a neutral result was for a measure of cognitive and emotional wellbeing, a parameter that was already at a normal level at baseline in most enrolled patients, Dr. Hoeper explained.

The incidence of either death or an event indicative of clinical worsening during the overall median follow-up of almost 33 weeks was 26.3% among the control patients and 5.5% among those who received sotatercept. This translated into a significant reduction for this endpoint of 84% with sotatercept treatment, compared with placebo.

The rates of treatment-emergent adverse events leading to discontinuation were roughly the same in the control and sotatercept arms, and the incidence of severe or serious treatment-emergent adverse events was higher among the control patients.

The most common adverse event on sotatercept was bleeding events, which occurred in 32% of those on sotatercept and in 16% of the control patients, but the events in the sotatercept arm were “mostly mild,” said Dr. Hoeper. The next most frequent adverse event during sotatercept treatment was appearance of telangiectasias, which occurred in 14% of those on sotatercept and in 4% of control patients.

“It’s an uncommon adverse event profile, but not unexpected for a drug with its mechanism of action,” he said.

Drug binds activin, a pathologic driver of PAH

Sotatercept is an engineered molecule that combines a section of a human immunoglobulin G molecule with a portion of the receptor for activin. This structure allows sotatercept to bind free activin molecules in a patient’s blood, thereby removing a key driver of the pulmonary vascular wall remodeling that is at the pathologic root of PAH.

“Hyperproliferation of blood vessel–wall cells” caused by activin signaling “is perhaps the most important driver of PAH,” Dr. Hoeper said. “Sotatercept allows us for the first time to target the underlying mechanism behind PAH.”

Still ongoing are the HYPERION and ZENITH phase 3 trials of sotatercept. HYPERION is enrolling patients with newly diagnosed or high-risk PAH and is expected to complete in 2028. ZENITH is enrolling patients with more advanced PAH and a higher mortality risk, with results expected in 2026.

Sotatercept has received “Breakthrough Therapy” designation and “Orphan Drug” designation by the Food and Drug Administration, and “Priority Medicines” designation and “Orphan Drug” designation by the European Medicines Agency for the treatment of PAH. One recent review estimated a worldwide PAH prevalence of about 3-4 cases/100,000, which for the United States translates into a total prevalence of perhaps 10,000-15,000 affected people.

STELLAR was funded by Acceleron Pharma, a subsidiary of Merck. Dr. Hoeper is a consultant to Acceleron. Dr. Cooper-DeHoff, Dr. Grapsa, and the authors of the editorial on STELLAR have no relevant disclosures.