A new prognostic tool may help identify infants with cerebral palsy (CP) earlier, allowing them to receive therapies to improve later outcomes.
 

Researchers from Canada used 12 clinical variables to predict the condition. The tool accurately predicted 75% of CP cases. The study was published in JAMA Pediatrics.

The prevalence of CP in the United States is 2-3 children per 1,000, a rate that has been relatively unchanged for decades. Although recent innovations in diagnosis using motor scores and MRI scans have aided in diagnosis, these techniques have historically been reserved only for infants who were cared for in neonatal intensive care units, were born prematurely, or who had other neurologic risk factors, such as birth defects.

The tool identified 2.4 times more children with CP than would have been detected using current diagnostic methods, according to the researchers.

“We developed the prediction tool to try to make these findings accessible to any health care provider, which will hopefully help break down the long-held perception that CP is usually related to prematurity or a difficult delivery,” said Mary Dunbar, MD, an author of the study. “We know that about half of children with CP aren’t premature and didn’t have a particularly difficult birth.”

The bedside tool weighs factors such as the use by mothers of illicit drugs and tobacco; the presence of diabetes and preeclampsia during pregnancy; whether the infant is male; birth weight; and the number of miscarriages the mother had prior to the birth. The tool also factors in results from a test that measures how well the infant is adjusting to life outside the womb.

Dr. Dunbar and colleagues compared 1,265 infants with CP from the Canadian Cerebral Palsy Registry from 2003 to 2019 with a control group of 1,985 children without CP from the Alberta Pregnancy Outcomes and Nutrition longitudinal study.

The study authors hope that the prognostic tool can be integrated into existing newborn screenings and completed by nurses or physicians as part of routine care.

“Its cost is low especially in comparison to MRI and specialized neurological assessments,” said Sarah Taylor, MD, section chief of neonatal-perinatal medicine at Yale New Haven Children’s Hospital in New Haven, Conn. Health systems and doctors may be more apt to adopt the tool, since it does not require specialized equipment or training.
 

Surprising findings

Several clinical variables independently increased the risk of CP, including independent 5-minute Apgar test scores of <6, chorioamnionitis, and illicit drug use during the pregnancy. Dr. Dunbar and colleagues recommend that primary care clinicians provide enhanced surveillance for these infants.

“I think there are also really important public health implications to address maternal and reproductive health to support pregnant people, since this study shows that common pregnancy conditions that are potentially treatable may additively contribute to cerebral palsy risk,” said Dr. Dunbar, a pediatric neurologist and assistant professor at the University of Calgary (Alta.)

For infants identified as being at risk, the study authors also suggest that doctors conduct focused examinations for CP at 3-, 6- and 12-month well-baby visits. If results of an examination are abnormal, doctors can advise the caregiver to conduct an early expert evaluation for a general movements assessment. Interventions for children with CP usually start in the first few years of life and can include occupational therapy, use of orthotic devices, and medication.

Dr. Dunbar and colleagues acknowledge that the test is not perfect and that additional work is needed.

“As helpful as the prediction tool may be to identify cases of CP early, we know there are still a minority of CP cases that it won’t catch because they don’t have any of the known risk factors,” Dr. Dunbar said. “We’re currently working on further research about this unique group.”

The researchers cited several limitations to the dataset used in the study, including a control group that was skewed toward older patients and persons of higher socioeconomic status. In addition, the data included a greater proportion of White women than the average Canadian population.

The Canadian Cerebral Palsy Registry was supported by the NeuroDevNet, KidsBrainHealth, the Harvey Guyda Chair of McGill University, Montreal Children’s Hospital, and the Public Health Agency of Canada. The authors disclosed no relevant financial relationships.

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

A new prognostic tool may help identify infants with cerebral palsy (CP) earlier, allowing them to receive therapies to improve later outcomes.
 

Researchers from Canada used 12 clinical variables to predict the condition. The tool accurately predicted 75% of CP cases. The study was published in JAMA Pediatrics.

The prevalence of CP in the United States is 2-3 children per 1,000, a rate that has been relatively unchanged for decades. Although recent innovations in diagnosis using motor scores and MRI scans have aided in diagnosis, these techniques have historically been reserved only for infants who were cared for in neonatal intensive care units, were born prematurely, or who had other neurologic risk factors, such as birth defects.

The tool identified 2.4 times more children with CP than would have been detected using current diagnostic methods, according to the researchers.

“We developed the prediction tool to try to make these findings accessible to any health care provider, which will hopefully help break down the long-held perception that CP is usually related to prematurity or a difficult delivery,” said Mary Dunbar, MD, an author of the study. “We know that about half of children with CP aren’t premature and didn’t have a particularly difficult birth.”

The bedside tool weighs factors such as the use by mothers of illicit drugs and tobacco; the presence of diabetes and preeclampsia during pregnancy; whether the infant is male; birth weight; and the number of miscarriages the mother had prior to the birth. The tool also factors in results from a test that measures how well the infant is adjusting to life outside the womb.

Dr. Dunbar and colleagues compared 1,265 infants with CP from the Canadian Cerebral Palsy Registry from 2003 to 2019 with a control group of 1,985 children without CP from the Alberta Pregnancy Outcomes and Nutrition longitudinal study.

The study authors hope that the prognostic tool can be integrated into existing newborn screenings and completed by nurses or physicians as part of routine care.

“Its cost is low especially in comparison to MRI and specialized neurological assessments,” said Sarah Taylor, MD, section chief of neonatal-perinatal medicine at Yale New Haven Children’s Hospital in New Haven, Conn. Health systems and doctors may be more apt to adopt the tool, since it does not require specialized equipment or training.
 

Surprising findings

Several clinical variables independently increased the risk of CP, including independent 5-minute Apgar test scores of <6, chorioamnionitis, and illicit drug use during the pregnancy. Dr. Dunbar and colleagues recommend that primary care clinicians provide enhanced surveillance for these infants.

“I think there are also really important public health implications to address maternal and reproductive health to support pregnant people, since this study shows that common pregnancy conditions that are potentially treatable may additively contribute to cerebral palsy risk,” said Dr. Dunbar, a pediatric neurologist and assistant professor at the University of Calgary (Alta.)

For infants identified as being at risk, the study authors also suggest that doctors conduct focused examinations for CP at 3-, 6- and 12-month well-baby visits. If results of an examination are abnormal, doctors can advise the caregiver to conduct an early expert evaluation for a general movements assessment. Interventions for children with CP usually start in the first few years of life and can include occupational therapy, use of orthotic devices, and medication.

Dr. Dunbar and colleagues acknowledge that the test is not perfect and that additional work is needed.

“As helpful as the prediction tool may be to identify cases of CP early, we know there are still a minority of CP cases that it won’t catch because they don’t have any of the known risk factors,” Dr. Dunbar said. “We’re currently working on further research about this unique group.”

The researchers cited several limitations to the dataset used in the study, including a control group that was skewed toward older patients and persons of higher socioeconomic status. In addition, the data included a greater proportion of White women than the average Canadian population.

The Canadian Cerebral Palsy Registry was supported by the NeuroDevNet, KidsBrainHealth, the Harvey Guyda Chair of McGill University, Montreal Children’s Hospital, and the Public Health Agency of Canada. The authors disclosed no relevant financial relationships.

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

A new prognostic tool may help identify infants with cerebral palsy (CP) earlier, allowing them to receive therapies to improve later outcomes.
 

Researchers from Canada used 12 clinical variables to predict the condition. The tool accurately predicted 75% of CP cases. The study was published in JAMA Pediatrics.

The prevalence of CP in the United States is 2-3 children per 1,000, a rate that has been relatively unchanged for decades. Although recent innovations in diagnosis using motor scores and MRI scans have aided in diagnosis, these techniques have historically been reserved only for infants who were cared for in neonatal intensive care units, were born prematurely, or who had other neurologic risk factors, such as birth defects.

The tool identified 2.4 times more children with CP than would have been detected using current diagnostic methods, according to the researchers.

“We developed the prediction tool to try to make these findings accessible to any health care provider, which will hopefully help break down the long-held perception that CP is usually related to prematurity or a difficult delivery,” said Mary Dunbar, MD, an author of the study. “We know that about half of children with CP aren’t premature and didn’t have a particularly difficult birth.”

The bedside tool weighs factors such as the use by mothers of illicit drugs and tobacco; the presence of diabetes and preeclampsia during pregnancy; whether the infant is male; birth weight; and the number of miscarriages the mother had prior to the birth. The tool also factors in results from a test that measures how well the infant is adjusting to life outside the womb.

Dr. Dunbar and colleagues compared 1,265 infants with CP from the Canadian Cerebral Palsy Registry from 2003 to 2019 with a control group of 1,985 children without CP from the Alberta Pregnancy Outcomes and Nutrition longitudinal study.

The study authors hope that the prognostic tool can be integrated into existing newborn screenings and completed by nurses or physicians as part of routine care.

“Its cost is low especially in comparison to MRI and specialized neurological assessments,” said Sarah Taylor, MD, section chief of neonatal-perinatal medicine at Yale New Haven Children’s Hospital in New Haven, Conn. Health systems and doctors may be more apt to adopt the tool, since it does not require specialized equipment or training.
 

Surprising findings

Several clinical variables independently increased the risk of CP, including independent 5-minute Apgar test scores of <6, chorioamnionitis, and illicit drug use during the pregnancy. Dr. Dunbar and colleagues recommend that primary care clinicians provide enhanced surveillance for these infants.

“I think there are also really important public health implications to address maternal and reproductive health to support pregnant people, since this study shows that common pregnancy conditions that are potentially treatable may additively contribute to cerebral palsy risk,” said Dr. Dunbar, a pediatric neurologist and assistant professor at the University of Calgary (Alta.)

For infants identified as being at risk, the study authors also suggest that doctors conduct focused examinations for CP at 3-, 6- and 12-month well-baby visits. If results of an examination are abnormal, doctors can advise the caregiver to conduct an early expert evaluation for a general movements assessment. Interventions for children with CP usually start in the first few years of life and can include occupational therapy, use of orthotic devices, and medication.

Dr. Dunbar and colleagues acknowledge that the test is not perfect and that additional work is needed.

“As helpful as the prediction tool may be to identify cases of CP early, we know there are still a minority of CP cases that it won’t catch because they don’t have any of the known risk factors,” Dr. Dunbar said. “We’re currently working on further research about this unique group.”

The researchers cited several limitations to the dataset used in the study, including a control group that was skewed toward older patients and persons of higher socioeconomic status. In addition, the data included a greater proportion of White women than the average Canadian population.

The Canadian Cerebral Palsy Registry was supported by the NeuroDevNet, KidsBrainHealth, the Harvey Guyda Chair of McGill University, Montreal Children’s Hospital, and the Public Health Agency of Canada. The authors disclosed no relevant financial relationships.

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

How many of you hadn’t heard of ambroxol until the last few weeks?

How many of you have gotten at least one call asking for a prescription for it in that time?

I’ll raise my hand on both accounts.

Ambroxol seems relatively innocuous – an over-the-counter cold medication commonly used on planet Earth (though not approved in the U.S. for whatever reason). But in the last few years some interesting data have cropped up that it may help with Parkinson’s disease.

“May” being the key word here.

Now, I’m not saying it will or won’t do something. The trials that are being started will show that. It would be totally awesome if it did.

But we’ve been here before: The hope that some old, inexpensive, and widely available medication would turn out to have an amazing benefit we didn’t anticipate. We saw this with hydroxychloroquine and ivermectin during the pandemic. Before that we saw all kinds of speculative ideas that statins would be effective for diseases from multiple sclerosis to Alzheimer’s disease.

And, as with many incurable diseases, patients and their families are hoping for a breakthrough. We have plenty of treatments for Parkinson’s disease, but no cures yet. So any potentially effective drug news makes the rounds quickly on news sites, patient advocacy sites, Facebook, and others.

Like the childrens’ telephone game, each time the story is repeated it changes a bit. We’ve gone from an article saying the drug is starting clinical trials to see if it works, to it being a cure now on the marketplace.

Which is when people start calling my office. Most are disappointed to learn that its benefit (if any) is unknown and that it’s not even available. A few get confrontational, accusing me of withholding treatment, when “everyone knows” the drug works.

Believe me, if I had a cure I’d be thrilled to be able to offer it.

I understand that patients and families want a cure.

I understand hope.

I want ambroxol to work for Parkinson’s disease and make a huge difference in the lives of those affected by it. Maybe it will. Or maybe it won’t.

But these things take time to figure out. None of the amazing medications and hi-tech toys we have came about overnight. They were all years in the making.

That’s how science works, and medicine is as much a science as an art.

The art is being able to explain this to patients, and still allow them to hope.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

How many of you hadn’t heard of ambroxol until the last few weeks?

How many of you have gotten at least one call asking for a prescription for it in that time?

I’ll raise my hand on both accounts.

Ambroxol seems relatively innocuous – an over-the-counter cold medication commonly used on planet Earth (though not approved in the U.S. for whatever reason). But in the last few years some interesting data have cropped up that it may help with Parkinson’s disease.

“May” being the key word here.

Now, I’m not saying it will or won’t do something. The trials that are being started will show that. It would be totally awesome if it did.

But we’ve been here before: The hope that some old, inexpensive, and widely available medication would turn out to have an amazing benefit we didn’t anticipate. We saw this with hydroxychloroquine and ivermectin during the pandemic. Before that we saw all kinds of speculative ideas that statins would be effective for diseases from multiple sclerosis to Alzheimer’s disease.

And, as with many incurable diseases, patients and their families are hoping for a breakthrough. We have plenty of treatments for Parkinson’s disease, but no cures yet. So any potentially effective drug news makes the rounds quickly on news sites, patient advocacy sites, Facebook, and others.

Like the childrens’ telephone game, each time the story is repeated it changes a bit. We’ve gone from an article saying the drug is starting clinical trials to see if it works, to it being a cure now on the marketplace.

Which is when people start calling my office. Most are disappointed to learn that its benefit (if any) is unknown and that it’s not even available. A few get confrontational, accusing me of withholding treatment, when “everyone knows” the drug works.

Believe me, if I had a cure I’d be thrilled to be able to offer it.

I understand that patients and families want a cure.

I understand hope.

I want ambroxol to work for Parkinson’s disease and make a huge difference in the lives of those affected by it. Maybe it will. Or maybe it won’t.

But these things take time to figure out. None of the amazing medications and hi-tech toys we have came about overnight. They were all years in the making.

That’s how science works, and medicine is as much a science as an art.

The art is being able to explain this to patients, and still allow them to hope.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

How many of you hadn’t heard of ambroxol until the last few weeks?

How many of you have gotten at least one call asking for a prescription for it in that time?

I’ll raise my hand on both accounts.

Ambroxol seems relatively innocuous – an over-the-counter cold medication commonly used on planet Earth (though not approved in the U.S. for whatever reason). But in the last few years some interesting data have cropped up that it may help with Parkinson’s disease.

“May” being the key word here.

Now, I’m not saying it will or won’t do something. The trials that are being started will show that. It would be totally awesome if it did.

But we’ve been here before: The hope that some old, inexpensive, and widely available medication would turn out to have an amazing benefit we didn’t anticipate. We saw this with hydroxychloroquine and ivermectin during the pandemic. Before that we saw all kinds of speculative ideas that statins would be effective for diseases from multiple sclerosis to Alzheimer’s disease.

And, as with many incurable diseases, patients and their families are hoping for a breakthrough. We have plenty of treatments for Parkinson’s disease, but no cures yet. So any potentially effective drug news makes the rounds quickly on news sites, patient advocacy sites, Facebook, and others.

Like the childrens’ telephone game, each time the story is repeated it changes a bit. We’ve gone from an article saying the drug is starting clinical trials to see if it works, to it being a cure now on the marketplace.

Which is when people start calling my office. Most are disappointed to learn that its benefit (if any) is unknown and that it’s not even available. A few get confrontational, accusing me of withholding treatment, when “everyone knows” the drug works.

Believe me, if I had a cure I’d be thrilled to be able to offer it.

I understand that patients and families want a cure.

I understand hope.

I want ambroxol to work for Parkinson’s disease and make a huge difference in the lives of those affected by it. Maybe it will. Or maybe it won’t.

But these things take time to figure out. None of the amazing medications and hi-tech toys we have came about overnight. They were all years in the making.

That’s how science works, and medicine is as much a science as an art.

The art is being able to explain this to patients, and still allow them to hope.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Few pediatricians have warm, fuzzy memories about taking their initial board exam.

But many reacted strongly when they read a recent post on Twitter by Bryan Carmody, MD, who noted that the passing rate for first-time test takers had dipped to its lowest level in 5 years – hitting 81% in 2021, down from 91% 3 years earlier.

“It’s literally an awfully written exam,” replied one person who posted. Another asked: “At what point is the exam just not reflective of clinical practice?” And, inevitably, the question of the effect of COVID-19 surfaced: “Is any of this attributable to pulling early career physicians into the pandemic?”

But Dr. Carmody, an associate professor of pediatrics at the University of Eastern Virginia Medical School, Norfolk, isn’t buying that explanation. He researched board scores for internal medicine, general surgery, and family medicine for 2021. All were stable during the same period, he said, leading him to dismiss the idea that the pandemic drove the decline. “It’s not really clear to me why other specialties wouldn’t have seen similar drops,” Dr. Carmody said.

The slip has caught the attention of the American Board of Pediatrics, according to Judy Schaechter, MD, MBA, who was chair of the department of pediatrics at the University of Miami before taking her post as president and CEO of the American Board of Pediatrics in 2021.

“So, our first question was, was this within the range of what one might expect?” Dr. Schaechter said. “Were there other factors that might have come into play?”

The board performs an extensive analysis every year before releasing scores, and it didn’t uncover any changes in the difficulty or content of the test in 2021, nor did the score that was needed to pass increase. Dr. Schaechter pointed out that the passing rate that year was not unprecedented – in 2016, it also dipped to 81%.

Dr. Schaechter said COVID-19 might have affected test takers. “Remember, pediatrics was different from any other specialty during the pandemic,” she said. The census in pediatric wards around the country dropped dramatically in the first two winters of the pandemic, leaving residents with less hands-on experience with patients and mentorship from attendings – both of which can help test-takers pass the exam.

Eyal Ben-Isaac, MD, an associate professor of the department of pediatrics at the Keck School of Medicine at the University of Southern California, Los Angeles, said residents likely suffered during the pandemic, when noon lectures and grand rounds became virtual events.

“I’m sure that clearly affected a person’s ability to sit and listen and really learn the material, as opposed to either doing it hands on or learning the material from a faculty member face to face,” Dr. Ben-Isaac said.

But how much do the didactic experiences of residency programs contribute to residents’ readiness to take the boards? Thomas Welch, MD, professor and chair emeritus of the department of pediatrics at SUNY Upstate Medical University, Syracuse, credits his own success in advancing through college, medical school, pediatric residency, and nephrology fellowship to his skill as a test taker.

He confirmed his suspicions by conducting a study that evaluated correlations between residents’ performance on the United States Medical Licensing Exam (USMLE) taken during medical school and their board scores after completing residency.

Dr. Welch said he wasn’t surprised to find that “the best predictor of one’s passing the pediatric boards was not the training program in which one worked. It was their performance on Step 2 [taken during the fourth year of medical school] of the USMLE.”

Although Dr. Ben-Isaac felt that changes in residency training opportunities might have partially explained the drop in passing rates, he agreed that other factors contribute to success on boards. As director of the pediatric residency program at Children’s Hospital of Los Angeles from 1994 to 2019, one of his first goals was to increase the pass rate of graduates. He developed a board review course for residents, revising it over time on the basis of resident feedback and adding individual coaching for residents who wanted more help.

“Without a question, it raised our board pass rate to being one of the highest in the country,” he said.

Dr. Welch said that while “being up all night with a sick child teaches you a lot about medicine and certainly makes you a better doctor, it doesn’t do anything to improve your board scores.”

None of the pediatricians was too worried about a 1-year drop in scores, and the consensus was that supporting residents with review courses and coaching on how to take multiple choice tests would raise passing rates.

“There are definitely people who are amazing clinicians who did not pass the boards on their first attempt,” Dr. Ben-Isaac said.

But Dr. Schaechter defended the importance of the examination. “Our first obligation is really to the public,” she said. The ABP’s role is to ensure that pediatricians “provide the care that parents want their kids to have.”

As Dr. Welch put it, “Would I trust someone who didn’t pass the board exam to take care of my own kid? Probably not.”

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

Few pediatricians have warm, fuzzy memories about taking their initial board exam.

But many reacted strongly when they read a recent post on Twitter by Bryan Carmody, MD, who noted that the passing rate for first-time test takers had dipped to its lowest level in 5 years – hitting 81% in 2021, down from 91% 3 years earlier.

“It’s literally an awfully written exam,” replied one person who posted. Another asked: “At what point is the exam just not reflective of clinical practice?” And, inevitably, the question of the effect of COVID-19 surfaced: “Is any of this attributable to pulling early career physicians into the pandemic?”

But Dr. Carmody, an associate professor of pediatrics at the University of Eastern Virginia Medical School, Norfolk, isn’t buying that explanation. He researched board scores for internal medicine, general surgery, and family medicine for 2021. All were stable during the same period, he said, leading him to dismiss the idea that the pandemic drove the decline. “It’s not really clear to me why other specialties wouldn’t have seen similar drops,” Dr. Carmody said.

The slip has caught the attention of the American Board of Pediatrics, according to Judy Schaechter, MD, MBA, who was chair of the department of pediatrics at the University of Miami before taking her post as president and CEO of the American Board of Pediatrics in 2021.

“So, our first question was, was this within the range of what one might expect?” Dr. Schaechter said. “Were there other factors that might have come into play?”

The board performs an extensive analysis every year before releasing scores, and it didn’t uncover any changes in the difficulty or content of the test in 2021, nor did the score that was needed to pass increase. Dr. Schaechter pointed out that the passing rate that year was not unprecedented – in 2016, it also dipped to 81%.

Dr. Schaechter said COVID-19 might have affected test takers. “Remember, pediatrics was different from any other specialty during the pandemic,” she said. The census in pediatric wards around the country dropped dramatically in the first two winters of the pandemic, leaving residents with less hands-on experience with patients and mentorship from attendings – both of which can help test-takers pass the exam.

Eyal Ben-Isaac, MD, an associate professor of the department of pediatrics at the Keck School of Medicine at the University of Southern California, Los Angeles, said residents likely suffered during the pandemic, when noon lectures and grand rounds became virtual events.

“I’m sure that clearly affected a person’s ability to sit and listen and really learn the material, as opposed to either doing it hands on or learning the material from a faculty member face to face,” Dr. Ben-Isaac said.

But how much do the didactic experiences of residency programs contribute to residents’ readiness to take the boards? Thomas Welch, MD, professor and chair emeritus of the department of pediatrics at SUNY Upstate Medical University, Syracuse, credits his own success in advancing through college, medical school, pediatric residency, and nephrology fellowship to his skill as a test taker.

He confirmed his suspicions by conducting a study that evaluated correlations between residents’ performance on the United States Medical Licensing Exam (USMLE) taken during medical school and their board scores after completing residency.

Dr. Welch said he wasn’t surprised to find that “the best predictor of one’s passing the pediatric boards was not the training program in which one worked. It was their performance on Step 2 [taken during the fourth year of medical school] of the USMLE.”

Although Dr. Ben-Isaac felt that changes in residency training opportunities might have partially explained the drop in passing rates, he agreed that other factors contribute to success on boards. As director of the pediatric residency program at Children’s Hospital of Los Angeles from 1994 to 2019, one of his first goals was to increase the pass rate of graduates. He developed a board review course for residents, revising it over time on the basis of resident feedback and adding individual coaching for residents who wanted more help.

“Without a question, it raised our board pass rate to being one of the highest in the country,” he said.

Dr. Welch said that while “being up all night with a sick child teaches you a lot about medicine and certainly makes you a better doctor, it doesn’t do anything to improve your board scores.”

None of the pediatricians was too worried about a 1-year drop in scores, and the consensus was that supporting residents with review courses and coaching on how to take multiple choice tests would raise passing rates.

“There are definitely people who are amazing clinicians who did not pass the boards on their first attempt,” Dr. Ben-Isaac said.

But Dr. Schaechter defended the importance of the examination. “Our first obligation is really to the public,” she said. The ABP’s role is to ensure that pediatricians “provide the care that parents want their kids to have.”

As Dr. Welch put it, “Would I trust someone who didn’t pass the board exam to take care of my own kid? Probably not.”

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

Few pediatricians have warm, fuzzy memories about taking their initial board exam.

But many reacted strongly when they read a recent post on Twitter by Bryan Carmody, MD, who noted that the passing rate for first-time test takers had dipped to its lowest level in 5 years – hitting 81% in 2021, down from 91% 3 years earlier.

“It’s literally an awfully written exam,” replied one person who posted. Another asked: “At what point is the exam just not reflective of clinical practice?” And, inevitably, the question of the effect of COVID-19 surfaced: “Is any of this attributable to pulling early career physicians into the pandemic?”

But Dr. Carmody, an associate professor of pediatrics at the University of Eastern Virginia Medical School, Norfolk, isn’t buying that explanation. He researched board scores for internal medicine, general surgery, and family medicine for 2021. All were stable during the same period, he said, leading him to dismiss the idea that the pandemic drove the decline. “It’s not really clear to me why other specialties wouldn’t have seen similar drops,” Dr. Carmody said.

The slip has caught the attention of the American Board of Pediatrics, according to Judy Schaechter, MD, MBA, who was chair of the department of pediatrics at the University of Miami before taking her post as president and CEO of the American Board of Pediatrics in 2021.

“So, our first question was, was this within the range of what one might expect?” Dr. Schaechter said. “Were there other factors that might have come into play?”

The board performs an extensive analysis every year before releasing scores, and it didn’t uncover any changes in the difficulty or content of the test in 2021, nor did the score that was needed to pass increase. Dr. Schaechter pointed out that the passing rate that year was not unprecedented – in 2016, it also dipped to 81%.

Dr. Schaechter said COVID-19 might have affected test takers. “Remember, pediatrics was different from any other specialty during the pandemic,” she said. The census in pediatric wards around the country dropped dramatically in the first two winters of the pandemic, leaving residents with less hands-on experience with patients and mentorship from attendings – both of which can help test-takers pass the exam.

Eyal Ben-Isaac, MD, an associate professor of the department of pediatrics at the Keck School of Medicine at the University of Southern California, Los Angeles, said residents likely suffered during the pandemic, when noon lectures and grand rounds became virtual events.

“I’m sure that clearly affected a person’s ability to sit and listen and really learn the material, as opposed to either doing it hands on or learning the material from a faculty member face to face,” Dr. Ben-Isaac said.

But how much do the didactic experiences of residency programs contribute to residents’ readiness to take the boards? Thomas Welch, MD, professor and chair emeritus of the department of pediatrics at SUNY Upstate Medical University, Syracuse, credits his own success in advancing through college, medical school, pediatric residency, and nephrology fellowship to his skill as a test taker.

He confirmed his suspicions by conducting a study that evaluated correlations between residents’ performance on the United States Medical Licensing Exam (USMLE) taken during medical school and their board scores after completing residency.

Dr. Welch said he wasn’t surprised to find that “the best predictor of one’s passing the pediatric boards was not the training program in which one worked. It was their performance on Step 2 [taken during the fourth year of medical school] of the USMLE.”

Although Dr. Ben-Isaac felt that changes in residency training opportunities might have partially explained the drop in passing rates, he agreed that other factors contribute to success on boards. As director of the pediatric residency program at Children’s Hospital of Los Angeles from 1994 to 2019, one of his first goals was to increase the pass rate of graduates. He developed a board review course for residents, revising it over time on the basis of resident feedback and adding individual coaching for residents who wanted more help.

“Without a question, it raised our board pass rate to being one of the highest in the country,” he said.

Dr. Welch said that while “being up all night with a sick child teaches you a lot about medicine and certainly makes you a better doctor, it doesn’t do anything to improve your board scores.”

None of the pediatricians was too worried about a 1-year drop in scores, and the consensus was that supporting residents with review courses and coaching on how to take multiple choice tests would raise passing rates.

“There are definitely people who are amazing clinicians who did not pass the boards on their first attempt,” Dr. Ben-Isaac said.

But Dr. Schaechter defended the importance of the examination. “Our first obligation is really to the public,” she said. The ABP’s role is to ensure that pediatricians “provide the care that parents want their kids to have.”

As Dr. Welch put it, “Would I trust someone who didn’t pass the board exam to take care of my own kid? Probably not.”

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

Clinical cardiologist Heba Wassif, MD, MPH, knows the value of working with her fellow rheumatologists, surgeons, and other clinicians to establish a care plan for her patients with cardiac conditions and autoimmune diseases.

She is the cofounder of the Cleveland Clinic’s new cardio-rheumatology program, which places an emphasis on multidisciplinary care. In her role, Dr. Wassif closely follows her patients, and if she sees any inflammation or any other condition that requires the rheumatologist, she reaches out to her colleagues to adjust medications if needed.

Collaboration with a rheumatologist was important when a patient with valvular disease was prepping for surgery. The patient was on significant immunosuppressants and the surgery had to be timed appropriately, accounting for any decreases in her immunosuppression, explained Dr. Wassif, director of inpatient clinical cardiology at Cleveland Clinic in Ohio.

Cardio-rheumatology programs are “the newest child” in a series of cardiology offshoots focusing on different populations. Cardio-oncology and cardio-obstetrics took off about 6 years ago, with cardio-rheumatology clinics and interested physicians rising in number over the last several years, Dr. Wassif noted.

The relationship between cardiovascular diseases and rheumatologic conditions is certainly recognized more often, “which means more literature is being published to discuss the link,” according to Rekha Mankad, MD, a trailblazer of this model of care. She directs the Women’s Heart Clinic at Mayo Clinic in Rochester, Minn., which was one of the earliest adopters of a cardio-rheumatology clinic.

Challenges of treating cardiac, rheumatologic conditions

The rise in clinics addresses the longstanding connection between autoimmune disorders and cardiac conditions.

Cardiologists have known that there is an element of inflammation that contributes to atherosclerosis, said Dr. Wassif, who has researched this topic extensively. A recent study she led found a strong association between rheumatic immune-mediated inflammatory diseases (IMIDs) and high risk of acute coronary syndrome in Medicare patients.

“This particular population has a very clear increased risk for cardiovascular conditions, including valve disease and heart failure,” she emphasized.

Patients with rheumatoid arthritis and lupus have up to a twofold and eightfold higher risk of heart disease, respectively, noted Michael S. Garshick, MD, a cardiovascular disease specialist who directs the cardio-rheumatology program at NYU-Langone Health, in New York. Cardiologists “have really developed an understanding that the immune system can impact the heart, and that there’s a need for people to understand the nuance behind how the immune system can affect them and what to do about it,” Dr. Garshick said.

Courtesy Rob Lisak

‘Reading the tea leaves’

Each program has its own unique story. For the Cleveland Clinic, the concept of a cardio-rheumatology program began during the COVID-19 pandemic in 2020. Developing such a concept and gaining institutional acceptance is always a work in process, Dr. Wassif said. “It’s not that you decide one day that you’re going to build a center, and that center is going to come into fruition overnight. You first gauge interest within your division. Who are the individuals that are interested in this area?”

Cleveland Clinic’s center is seeking to build relations between medical disciplines while spotlighting the concept of cardio-rheumatology, said Dr. Wassif, who has been providing education within the clinic and at other health institutions to ensure that patients receive appropriate attention early.

NYU-Langone launched its program amid this heightened awareness that the immune system could affect atherosclerosis, “kind of reading of the tea leaves, so to speak,” Dr. Garshick said.

Several clinical trials served as a catalyst for this movement. “A lot of clinical cardiologists were never 100% convinced that targeting the immune system reduced cardiovascular disease,” he said. Then the CANTOS clinical trial came along and showed for the first time that a therapeutic monoclonal antibody targeting interleukin-1beta, a cytokine central to inflammatory response, could in fact reduce cardiovascular disease.

Trials like this, along with epidemiologic literature connecting the rheumatologic and the autoimmune conditions with cardiovascular disease, pushed this concept to the forefront, Dr. Garshick said.

The notion that a clinic could successfully address cardiac problems in patients with rheumatic diseases yielded promising returns at Women’s College Hospital in Toronto, according to a report presented at the 2018 American College of Rheumatology annual meeting. Researchers reported that patients with rheumatologic conditions who attended a cardio-rheumatology clinic at this center saw improvements in care. The clinic identified increased cardiovascular risk and early atherosclerosis, and 53.8% of patients altered their medications after being seen in the clinic.

A total of 39.7% and 32.1% received lipid lowering and antiplatelet therapies, respectively, and 14% received antihypertensive therapy. A small percentage were treated for heart failure or placed on lifelong anticoagulation therapy for atrial fibrillation, and one patient received a percutaneous coronary stent.
 

Ins and outs of the referral process

Initially designed for preventive cardiac risk assessment, Yale’s program evolved into a multidisciplinary, patient-centered approach for the management of complex cardiovascular conditions in patients with autoimmune rheumatologic diseases.

The program is open to anyone who carries a diagnosis of rheumatologic disease or has elevated inflammatory markers. “Every patient, regardless of the reason for the referral, receives a cardiovascular risk assessment,” Dr. Furman said.

Harold Shapiro

A personalized assessment to reduce cardiac risk

NYU-Langone’s program offers opportunities to educate patients about the link between cardiac and rheumatologic disease.

“Their rheumatologist or their dermatologist will say, ‘Hey, have you heard about the connection between psoriasis, psoriatic or rheumatoid arthritis, and heart disease and the risk of heart attack or stroke?’ ” Dr. Garshick said.

The patients will often say they know nothing about these connections and want to learn more about how to treat it.

“We’ll say, ‘we have someone here that can help you.’ They’ll send them to myself or other colleagues like me across the country. We’ll assess blood pressure, weight, lipids, hemoglobin A1c, and other serologic and oftentimes imaging biomarkers of cardiovascular risk.” The patients will receive a personalized assessment, listing things they can do to lower their risk, whether it’s diet, exercise, or lifestyle. “Many times it can involve medications to reduce heart disease risk,” said Dr. Garshick.

In some instances, a rheumatologist or dermatologist may be concerned about starting a patient on a specific medication for the disease such as a JAK inhibitor. “We’ll help assess their risk because there’s been a lot of literature out in the rheumatology world about the risk of JAK inhibitors and heart disease and blood clots,” said Dr. Garshick.

Dr. Garshick also sees patients with rheumatologic conditions who have a specific cardiovascular concern or complaint such as shortness of breath or chest pain. “We’ll work that up with a specific knowledge of the underlying immune condition and how that may impact their heart,” he said.
 

Advances in research

As they continue to see patients and devise specific care plans, developers of cardio-rheumatology programs have been supplementing their work with ongoing research.

Yale’s clinic is expanding this year to include a new attending physician, Attila Feher, MD, PhD, who has conducted research in autoimmunity and microcirculation using molecular imaging and multimodality imaging techniques. Prevalence of coronary microvascular dysfunction appears to be increased in this patient population, Dr. Furman said.

Dr. Wassif recently coauthored a paper that examined patients with underlying rheumatologic conditions who undergo valvular and aortic valve replacement. “To our surprise, there was really no difference between patients with autoimmune conditions and others with nonautoimmune conditions,” she said, adding that the study had its limitations.

Other work includes data on Medicare patients with ST- and non-ST-elevation myocardial infarctions who have an underlying autoimmune disorder. Dr. Wassif and her colleagues found that their long-term outcomes are worse than those of patients without these conditions. “It’s unclear if worse outcomes are related to complications of autoimmunity versus the extent of their underlying disease. This is a work in progress and certainly an area that is ripe for research.”

Dr. Garshick and other collaborators at NYU have been focusing on the endothelium, specifically platelet biology in patients with psoriasis, psoriatic arthritis, and lupus. “We’re about to start the same research with gout as well,” he said.

“The process we’re most interested in is understanding how these diseases impact the early stages of cholesterol. And the way we’re doing that is evaluating the vasculature, specifically the endothelium,” he said.

He has finished two clinical trials that evaluate how standard heart disease medications such as aspirin and statins impact or can potentially benefit patients with psoriasis and/or psoriatic arthritis. “We have a whole list of other trials in the pipeline with other institutions across the country.”

Through a grant, Dr. Mankad is assessing whether a PET scan could detect inflammation in the hearts of rheumatoid arthritis patients. “We’re looking to see if the reason these patients have heart failure later in life is because their heart muscle actually shows evidence of inflammation, even when they have no symptoms,” she explained.

Other tests such as echocardiogram and CT scans will be used to evaluate coronary disease in about 40-50 patients. The goal of using these multiple imaging tools is to find markers indicating that the heart is affected by rheumatoid arthritis, which may indicate a higher likelihood of developing heart failure, she said.
 

Clinics are popping up

Through these new clinics, some collaborations have emerged. Dr. Garshick works closely with Brigham and Women’s Hospital, which has a similar cardio-rheumatology program, run by Brittany Weber, MD, to exchange ideas, discuss challenging cases, and collaborate.

“There are a lot of clinics like us popping up across the country,” he observed. Every so often, he hears from other institutions that are interested in starting their own cardio-rheumatology programs. “They ask us: How do you start, what should we look for?”

It’s an education process for both patients and providers, Dr. Garshick emphasized. “I also think it’s a bandwidth issue. Many of our rheumatology and dermatology colleagues are acutely aware of the connection, but there may not be enough time at a clinic visit to really go in depth” with these dual conditions, he said.

NYU-Langone Health for the past several years has been holding a symposium to educate people on the cardio-rheumatology connection and treating inflammation in cardiovascular disease. This year’s symposium, held in conjunction with Brigham and Women’s Hospital, is scheduled for April 28. For more information, visit the course website: nyulmc.org/cvinflammationcme.

“What we’re trying to do is help [other institutions] get that bandwidth” to adequately help and serve these patients, he said.

Dr. Garshick has received consultant fees from Abbvie and Horizon therapeutics and an unrestricted research grant from Pfizer. No other sources had relevant financial disclosures.

Clinical cardiologist Heba Wassif, MD, MPH, knows the value of working with her fellow rheumatologists, surgeons, and other clinicians to establish a care plan for her patients with cardiac conditions and autoimmune diseases.

She is the cofounder of the Cleveland Clinic’s new cardio-rheumatology program, which places an emphasis on multidisciplinary care. In her role, Dr. Wassif closely follows her patients, and if she sees any inflammation or any other condition that requires the rheumatologist, she reaches out to her colleagues to adjust medications if needed.

Collaboration with a rheumatologist was important when a patient with valvular disease was prepping for surgery. The patient was on significant immunosuppressants and the surgery had to be timed appropriately, accounting for any decreases in her immunosuppression, explained Dr. Wassif, director of inpatient clinical cardiology at Cleveland Clinic in Ohio.

Cardio-rheumatology programs are “the newest child” in a series of cardiology offshoots focusing on different populations. Cardio-oncology and cardio-obstetrics took off about 6 years ago, with cardio-rheumatology clinics and interested physicians rising in number over the last several years, Dr. Wassif noted.

The relationship between cardiovascular diseases and rheumatologic conditions is certainly recognized more often, “which means more literature is being published to discuss the link,” according to Rekha Mankad, MD, a trailblazer of this model of care. She directs the Women’s Heart Clinic at Mayo Clinic in Rochester, Minn., which was one of the earliest adopters of a cardio-rheumatology clinic.

Challenges of treating cardiac, rheumatologic conditions

The rise in clinics addresses the longstanding connection between autoimmune disorders and cardiac conditions.

Cardiologists have known that there is an element of inflammation that contributes to atherosclerosis, said Dr. Wassif, who has researched this topic extensively. A recent study she led found a strong association between rheumatic immune-mediated inflammatory diseases (IMIDs) and high risk of acute coronary syndrome in Medicare patients.

“This particular population has a very clear increased risk for cardiovascular conditions, including valve disease and heart failure,” she emphasized.

Patients with rheumatoid arthritis and lupus have up to a twofold and eightfold higher risk of heart disease, respectively, noted Michael S. Garshick, MD, a cardiovascular disease specialist who directs the cardio-rheumatology program at NYU-Langone Health, in New York. Cardiologists “have really developed an understanding that the immune system can impact the heart, and that there’s a need for people to understand the nuance behind how the immune system can affect them and what to do about it,” Dr. Garshick said.

Courtesy Rob Lisak

‘Reading the tea leaves’

Each program has its own unique story. For the Cleveland Clinic, the concept of a cardio-rheumatology program began during the COVID-19 pandemic in 2020. Developing such a concept and gaining institutional acceptance is always a work in process, Dr. Wassif said. “It’s not that you decide one day that you’re going to build a center, and that center is going to come into fruition overnight. You first gauge interest within your division. Who are the individuals that are interested in this area?”

Cleveland Clinic’s center is seeking to build relations between medical disciplines while spotlighting the concept of cardio-rheumatology, said Dr. Wassif, who has been providing education within the clinic and at other health institutions to ensure that patients receive appropriate attention early.

NYU-Langone launched its program amid this heightened awareness that the immune system could affect atherosclerosis, “kind of reading of the tea leaves, so to speak,” Dr. Garshick said.

Several clinical trials served as a catalyst for this movement. “A lot of clinical cardiologists were never 100% convinced that targeting the immune system reduced cardiovascular disease,” he said. Then the CANTOS clinical trial came along and showed for the first time that a therapeutic monoclonal antibody targeting interleukin-1beta, a cytokine central to inflammatory response, could in fact reduce cardiovascular disease.

Trials like this, along with epidemiologic literature connecting the rheumatologic and the autoimmune conditions with cardiovascular disease, pushed this concept to the forefront, Dr. Garshick said.

The notion that a clinic could successfully address cardiac problems in patients with rheumatic diseases yielded promising returns at Women’s College Hospital in Toronto, according to a report presented at the 2018 American College of Rheumatology annual meeting. Researchers reported that patients with rheumatologic conditions who attended a cardio-rheumatology clinic at this center saw improvements in care. The clinic identified increased cardiovascular risk and early atherosclerosis, and 53.8% of patients altered their medications after being seen in the clinic.

A total of 39.7% and 32.1% received lipid lowering and antiplatelet therapies, respectively, and 14% received antihypertensive therapy. A small percentage were treated for heart failure or placed on lifelong anticoagulation therapy for atrial fibrillation, and one patient received a percutaneous coronary stent.
 

Ins and outs of the referral process

Initially designed for preventive cardiac risk assessment, Yale’s program evolved into a multidisciplinary, patient-centered approach for the management of complex cardiovascular conditions in patients with autoimmune rheumatologic diseases.

The program is open to anyone who carries a diagnosis of rheumatologic disease or has elevated inflammatory markers. “Every patient, regardless of the reason for the referral, receives a cardiovascular risk assessment,” Dr. Furman said.

Harold Shapiro

A personalized assessment to reduce cardiac risk

NYU-Langone’s program offers opportunities to educate patients about the link between cardiac and rheumatologic disease.

“Their rheumatologist or their dermatologist will say, ‘Hey, have you heard about the connection between psoriasis, psoriatic or rheumatoid arthritis, and heart disease and the risk of heart attack or stroke?’ ” Dr. Garshick said.

The patients will often say they know nothing about these connections and want to learn more about how to treat it.

“We’ll say, ‘we have someone here that can help you.’ They’ll send them to myself or other colleagues like me across the country. We’ll assess blood pressure, weight, lipids, hemoglobin A1c, and other serologic and oftentimes imaging biomarkers of cardiovascular risk.” The patients will receive a personalized assessment, listing things they can do to lower their risk, whether it’s diet, exercise, or lifestyle. “Many times it can involve medications to reduce heart disease risk,” said Dr. Garshick.

In some instances, a rheumatologist or dermatologist may be concerned about starting a patient on a specific medication for the disease such as a JAK inhibitor. “We’ll help assess their risk because there’s been a lot of literature out in the rheumatology world about the risk of JAK inhibitors and heart disease and blood clots,” said Dr. Garshick.

Dr. Garshick also sees patients with rheumatologic conditions who have a specific cardiovascular concern or complaint such as shortness of breath or chest pain. “We’ll work that up with a specific knowledge of the underlying immune condition and how that may impact their heart,” he said.
 

Advances in research

As they continue to see patients and devise specific care plans, developers of cardio-rheumatology programs have been supplementing their work with ongoing research.

Yale’s clinic is expanding this year to include a new attending physician, Attila Feher, MD, PhD, who has conducted research in autoimmunity and microcirculation using molecular imaging and multimodality imaging techniques. Prevalence of coronary microvascular dysfunction appears to be increased in this patient population, Dr. Furman said.

Dr. Wassif recently coauthored a paper that examined patients with underlying rheumatologic conditions who undergo valvular and aortic valve replacement. “To our surprise, there was really no difference between patients with autoimmune conditions and others with nonautoimmune conditions,” she said, adding that the study had its limitations.

Other work includes data on Medicare patients with ST- and non-ST-elevation myocardial infarctions who have an underlying autoimmune disorder. Dr. Wassif and her colleagues found that their long-term outcomes are worse than those of patients without these conditions. “It’s unclear if worse outcomes are related to complications of autoimmunity versus the extent of their underlying disease. This is a work in progress and certainly an area that is ripe for research.”

Dr. Garshick and other collaborators at NYU have been focusing on the endothelium, specifically platelet biology in patients with psoriasis, psoriatic arthritis, and lupus. “We’re about to start the same research with gout as well,” he said.

“The process we’re most interested in is understanding how these diseases impact the early stages of cholesterol. And the way we’re doing that is evaluating the vasculature, specifically the endothelium,” he said.

He has finished two clinical trials that evaluate how standard heart disease medications such as aspirin and statins impact or can potentially benefit patients with psoriasis and/or psoriatic arthritis. “We have a whole list of other trials in the pipeline with other institutions across the country.”

Through a grant, Dr. Mankad is assessing whether a PET scan could detect inflammation in the hearts of rheumatoid arthritis patients. “We’re looking to see if the reason these patients have heart failure later in life is because their heart muscle actually shows evidence of inflammation, even when they have no symptoms,” she explained.

Other tests such as echocardiogram and CT scans will be used to evaluate coronary disease in about 40-50 patients. The goal of using these multiple imaging tools is to find markers indicating that the heart is affected by rheumatoid arthritis, which may indicate a higher likelihood of developing heart failure, she said.
 

Clinics are popping up

Through these new clinics, some collaborations have emerged. Dr. Garshick works closely with Brigham and Women’s Hospital, which has a similar cardio-rheumatology program, run by Brittany Weber, MD, to exchange ideas, discuss challenging cases, and collaborate.

“There are a lot of clinics like us popping up across the country,” he observed. Every so often, he hears from other institutions that are interested in starting their own cardio-rheumatology programs. “They ask us: How do you start, what should we look for?”

It’s an education process for both patients and providers, Dr. Garshick emphasized. “I also think it’s a bandwidth issue. Many of our rheumatology and dermatology colleagues are acutely aware of the connection, but there may not be enough time at a clinic visit to really go in depth” with these dual conditions, he said.

NYU-Langone Health for the past several years has been holding a symposium to educate people on the cardio-rheumatology connection and treating inflammation in cardiovascular disease. This year’s symposium, held in conjunction with Brigham and Women’s Hospital, is scheduled for April 28. For more information, visit the course website: nyulmc.org/cvinflammationcme.

“What we’re trying to do is help [other institutions] get that bandwidth” to adequately help and serve these patients, he said.

Dr. Garshick has received consultant fees from Abbvie and Horizon therapeutics and an unrestricted research grant from Pfizer. No other sources had relevant financial disclosures.

Clinical cardiologist Heba Wassif, MD, MPH, knows the value of working with her fellow rheumatologists, surgeons, and other clinicians to establish a care plan for her patients with cardiac conditions and autoimmune diseases.

She is the cofounder of the Cleveland Clinic’s new cardio-rheumatology program, which places an emphasis on multidisciplinary care. In her role, Dr. Wassif closely follows her patients, and if she sees any inflammation or any other condition that requires the rheumatologist, she reaches out to her colleagues to adjust medications if needed.

Collaboration with a rheumatologist was important when a patient with valvular disease was prepping for surgery. The patient was on significant immunosuppressants and the surgery had to be timed appropriately, accounting for any decreases in her immunosuppression, explained Dr. Wassif, director of inpatient clinical cardiology at Cleveland Clinic in Ohio.

Cardio-rheumatology programs are “the newest child” in a series of cardiology offshoots focusing on different populations. Cardio-oncology and cardio-obstetrics took off about 6 years ago, with cardio-rheumatology clinics and interested physicians rising in number over the last several years, Dr. Wassif noted.

The relationship between cardiovascular diseases and rheumatologic conditions is certainly recognized more often, “which means more literature is being published to discuss the link,” according to Rekha Mankad, MD, a trailblazer of this model of care. She directs the Women’s Heart Clinic at Mayo Clinic in Rochester, Minn., which was one of the earliest adopters of a cardio-rheumatology clinic.

Challenges of treating cardiac, rheumatologic conditions

The rise in clinics addresses the longstanding connection between autoimmune disorders and cardiac conditions.

Cardiologists have known that there is an element of inflammation that contributes to atherosclerosis, said Dr. Wassif, who has researched this topic extensively. A recent study she led found a strong association between rheumatic immune-mediated inflammatory diseases (IMIDs) and high risk of acute coronary syndrome in Medicare patients.

“This particular population has a very clear increased risk for cardiovascular conditions, including valve disease and heart failure,” she emphasized.

Patients with rheumatoid arthritis and lupus have up to a twofold and eightfold higher risk of heart disease, respectively, noted Michael S. Garshick, MD, a cardiovascular disease specialist who directs the cardio-rheumatology program at NYU-Langone Health, in New York. Cardiologists “have really developed an understanding that the immune system can impact the heart, and that there’s a need for people to understand the nuance behind how the immune system can affect them and what to do about it,” Dr. Garshick said.

Courtesy Rob Lisak

‘Reading the tea leaves’

Each program has its own unique story. For the Cleveland Clinic, the concept of a cardio-rheumatology program began during the COVID-19 pandemic in 2020. Developing such a concept and gaining institutional acceptance is always a work in process, Dr. Wassif said. “It’s not that you decide one day that you’re going to build a center, and that center is going to come into fruition overnight. You first gauge interest within your division. Who are the individuals that are interested in this area?”

Cleveland Clinic’s center is seeking to build relations between medical disciplines while spotlighting the concept of cardio-rheumatology, said Dr. Wassif, who has been providing education within the clinic and at other health institutions to ensure that patients receive appropriate attention early.

NYU-Langone launched its program amid this heightened awareness that the immune system could affect atherosclerosis, “kind of reading of the tea leaves, so to speak,” Dr. Garshick said.

Several clinical trials served as a catalyst for this movement. “A lot of clinical cardiologists were never 100% convinced that targeting the immune system reduced cardiovascular disease,” he said. Then the CANTOS clinical trial came along and showed for the first time that a therapeutic monoclonal antibody targeting interleukin-1beta, a cytokine central to inflammatory response, could in fact reduce cardiovascular disease.

Trials like this, along with epidemiologic literature connecting the rheumatologic and the autoimmune conditions with cardiovascular disease, pushed this concept to the forefront, Dr. Garshick said.

The notion that a clinic could successfully address cardiac problems in patients with rheumatic diseases yielded promising returns at Women’s College Hospital in Toronto, according to a report presented at the 2018 American College of Rheumatology annual meeting. Researchers reported that patients with rheumatologic conditions who attended a cardio-rheumatology clinic at this center saw improvements in care. The clinic identified increased cardiovascular risk and early atherosclerosis, and 53.8% of patients altered their medications after being seen in the clinic.

A total of 39.7% and 32.1% received lipid lowering and antiplatelet therapies, respectively, and 14% received antihypertensive therapy. A small percentage were treated for heart failure or placed on lifelong anticoagulation therapy for atrial fibrillation, and one patient received a percutaneous coronary stent.
 

Ins and outs of the referral process

Initially designed for preventive cardiac risk assessment, Yale’s program evolved into a multidisciplinary, patient-centered approach for the management of complex cardiovascular conditions in patients with autoimmune rheumatologic diseases.

The program is open to anyone who carries a diagnosis of rheumatologic disease or has elevated inflammatory markers. “Every patient, regardless of the reason for the referral, receives a cardiovascular risk assessment,” Dr. Furman said.

Harold Shapiro

A personalized assessment to reduce cardiac risk

NYU-Langone’s program offers opportunities to educate patients about the link between cardiac and rheumatologic disease.

“Their rheumatologist or their dermatologist will say, ‘Hey, have you heard about the connection between psoriasis, psoriatic or rheumatoid arthritis, and heart disease and the risk of heart attack or stroke?’ ” Dr. Garshick said.

The patients will often say they know nothing about these connections and want to learn more about how to treat it.

“We’ll say, ‘we have someone here that can help you.’ They’ll send them to myself or other colleagues like me across the country. We’ll assess blood pressure, weight, lipids, hemoglobin A1c, and other serologic and oftentimes imaging biomarkers of cardiovascular risk.” The patients will receive a personalized assessment, listing things they can do to lower their risk, whether it’s diet, exercise, or lifestyle. “Many times it can involve medications to reduce heart disease risk,” said Dr. Garshick.

In some instances, a rheumatologist or dermatologist may be concerned about starting a patient on a specific medication for the disease such as a JAK inhibitor. “We’ll help assess their risk because there’s been a lot of literature out in the rheumatology world about the risk of JAK inhibitors and heart disease and blood clots,” said Dr. Garshick.

Dr. Garshick also sees patients with rheumatologic conditions who have a specific cardiovascular concern or complaint such as shortness of breath or chest pain. “We’ll work that up with a specific knowledge of the underlying immune condition and how that may impact their heart,” he said.
 

Advances in research

As they continue to see patients and devise specific care plans, developers of cardio-rheumatology programs have been supplementing their work with ongoing research.

Yale’s clinic is expanding this year to include a new attending physician, Attila Feher, MD, PhD, who has conducted research in autoimmunity and microcirculation using molecular imaging and multimodality imaging techniques. Prevalence of coronary microvascular dysfunction appears to be increased in this patient population, Dr. Furman said.

Dr. Wassif recently coauthored a paper that examined patients with underlying rheumatologic conditions who undergo valvular and aortic valve replacement. “To our surprise, there was really no difference between patients with autoimmune conditions and others with nonautoimmune conditions,” she said, adding that the study had its limitations.

Other work includes data on Medicare patients with ST- and non-ST-elevation myocardial infarctions who have an underlying autoimmune disorder. Dr. Wassif and her colleagues found that their long-term outcomes are worse than those of patients without these conditions. “It’s unclear if worse outcomes are related to complications of autoimmunity versus the extent of their underlying disease. This is a work in progress and certainly an area that is ripe for research.”

Dr. Garshick and other collaborators at NYU have been focusing on the endothelium, specifically platelet biology in patients with psoriasis, psoriatic arthritis, and lupus. “We’re about to start the same research with gout as well,” he said.

“The process we’re most interested in is understanding how these diseases impact the early stages of cholesterol. And the way we’re doing that is evaluating the vasculature, specifically the endothelium,” he said.

He has finished two clinical trials that evaluate how standard heart disease medications such as aspirin and statins impact or can potentially benefit patients with psoriasis and/or psoriatic arthritis. “We have a whole list of other trials in the pipeline with other institutions across the country.”

Through a grant, Dr. Mankad is assessing whether a PET scan could detect inflammation in the hearts of rheumatoid arthritis patients. “We’re looking to see if the reason these patients have heart failure later in life is because their heart muscle actually shows evidence of inflammation, even when they have no symptoms,” she explained.

Other tests such as echocardiogram and CT scans will be used to evaluate coronary disease in about 40-50 patients. The goal of using these multiple imaging tools is to find markers indicating that the heart is affected by rheumatoid arthritis, which may indicate a higher likelihood of developing heart failure, she said.
 

Clinics are popping up

Through these new clinics, some collaborations have emerged. Dr. Garshick works closely with Brigham and Women’s Hospital, which has a similar cardio-rheumatology program, run by Brittany Weber, MD, to exchange ideas, discuss challenging cases, and collaborate.

“There are a lot of clinics like us popping up across the country,” he observed. Every so often, he hears from other institutions that are interested in starting their own cardio-rheumatology programs. “They ask us: How do you start, what should we look for?”

It’s an education process for both patients and providers, Dr. Garshick emphasized. “I also think it’s a bandwidth issue. Many of our rheumatology and dermatology colleagues are acutely aware of the connection, but there may not be enough time at a clinic visit to really go in depth” with these dual conditions, he said.

NYU-Langone Health for the past several years has been holding a symposium to educate people on the cardio-rheumatology connection and treating inflammation in cardiovascular disease. This year’s symposium, held in conjunction with Brigham and Women’s Hospital, is scheduled for April 28. For more information, visit the course website: nyulmc.org/cvinflammationcme.

“What we’re trying to do is help [other institutions] get that bandwidth” to adequately help and serve these patients, he said.

Dr. Garshick has received consultant fees from Abbvie and Horizon therapeutics and an unrestricted research grant from Pfizer. No other sources had relevant financial disclosures.

SAN DIEGO – After Arisa E. Ortiz, MD, and colleagues published results of a multicenter study reporting that one treatment with the long-pulsed 1,064-nm Nd:YAG laser cleared nonaggressive basal cell carcinoma (BCC) on the trunk and extremities in 90% of patients, she heard from colleagues who were skeptical of the approach.

Maybe it’s just the biopsy alone that’s clearing these tumors, some told her. Others postulated that since the energy was delivered with a 5- to 6-mm spot size at a fluence of 125-140 J/cm² and a 7- to 10-ms pulse duration, bulk heating likely disrupted the tumors. However, treatments were generally well tolerated, required no anesthesia, and caused no significant adverse events.

“It’s almost scarless,” Dr. Ortiz, director of laser and cosmetic dermatology at the University of California, San Diego, said at the annual Masters of Aesthetics Symposium. “Sometimes the treatment does leave a mark, but I think the scars are always acceptable. We do have good histologic evidence that we can penetrate 2.15 mm, which is a lot deeper than what the pulsed-dye laser or other superficial wavelengths are able to penetrate.”

Data is well powered to reject the null hypothesis that laser treatment does not have an effect on nodular and superficial BCC lesions, she continued, noting that it is at least comparable if not superior with clearance rates reported for methyl aminolevulinate–PDT (73%), imiquimod cream (83%), and fluorouracil cream (80%). “Maybe we’re not specifically targeting the vasculature [with this approach], but we did some optical coherence tomography imaging and saw that the blood vessels in the tumor were coagulated while the vasculature in the surrounding normal skin were spared,” said Dr. Ortiz, who is also vice president of the American Society for Laser Medicine and Surgery.

In a more recent analysis, she and her colleagues retrospectively analyzed long-term outcomes in 11 patients with BCC who had 16 lesions treated with the 1,064-nm Nd:YAG laser. At a mean of 9 months, 100% of lesions remained clear as determined by clinical observation.

In a subsequent, as yet unpublished study, she and her collaborators followed 34 patients with BCC one year following laser treatment. “Of these, 33 had no recurrence at 1-year follow-up,” Dr. Ortiz said, noting that the one patient with a recurrence was on a biologic agent for Crohn’s disease.

One key advantage of using the long-pulsed 1,064-nm Nd:YAG laser for nonaggressive BCC is the potential for one treatment visit. “They don’t have to come back for suture removal,” she said. “It’s a quick procedure, takes only about 5 minutes. There’s no limitation on activity and there’s minimal wound care, light ointment, and a band-aid; that’s it.”

In addition, she said, there is a lower risk of complications, infections, and bleeding, and there is minimal scarring. It is “also an alternative for treating patients with multiple tumors or those who are poor surgical candidates, such as the elderly and those with Gorlin syndrome.”

Dr. Ortiz avoids treating aggressive subtypes “because we don’t know what margin to treat,” she added. “Avoid the face. I do make some exceptions for patients if they’re elderly or if they’ve had multiple tumors. Monitor for recurrence like you would using any other modality.”

She uses lidocaine without epinephrine to avoid vasoconstriction and treats with the 1,064-nm Nd:YAG laser as follows: a 5-mm spot size, a fluence of 140 J/cm², and a pulse duration of 8 ms, with no cooling, which are the settings for the Excel V Laser System, she noted. “If you’re using a different Nd:YAG laser, your pulse duration may vary. I do let the device cool in between pulses to avoid bulk heating.”

The immediate endpoint to strive for is slight greying and slight contraction, and the procedure is covered by insurance, billed as malignant destruction/EDC (CPT codes 17260-17266 trunk and 17280-17283 face). “I do biopsy prior to treatment,” she said. “I like the biopsy to be healed when I’m using the laser, so I’ll treat them about a month later.”

As for future directions, Dr. Ortiz and colleagues plan to evaluate the use of gold nanoparticles to more selectively target BCC during treatment with the 1,064-nm Nd:YAG laser. For now, she sees no downside of the procedure for proper candidates. “I do think that patients really like it,” she said. “It’s effective and easy.”

Dr. Ortiz disclosed having financial relationships with several pharmaceutical and device companies. She is also cochair of the MOAS.





 

SAN DIEGO – After Arisa E. Ortiz, MD, and colleagues published results of a multicenter study reporting that one treatment with the long-pulsed 1,064-nm Nd:YAG laser cleared nonaggressive basal cell carcinoma (BCC) on the trunk and extremities in 90% of patients, she heard from colleagues who were skeptical of the approach.

Maybe it’s just the biopsy alone that’s clearing these tumors, some told her. Others postulated that since the energy was delivered with a 5- to 6-mm spot size at a fluence of 125-140 J/cm² and a 7- to 10-ms pulse duration, bulk heating likely disrupted the tumors. However, treatments were generally well tolerated, required no anesthesia, and caused no significant adverse events.

“It’s almost scarless,” Dr. Ortiz, director of laser and cosmetic dermatology at the University of California, San Diego, said at the annual Masters of Aesthetics Symposium. “Sometimes the treatment does leave a mark, but I think the scars are always acceptable. We do have good histologic evidence that we can penetrate 2.15 mm, which is a lot deeper than what the pulsed-dye laser or other superficial wavelengths are able to penetrate.”

Data is well powered to reject the null hypothesis that laser treatment does not have an effect on nodular and superficial BCC lesions, she continued, noting that it is at least comparable if not superior with clearance rates reported for methyl aminolevulinate–PDT (73%), imiquimod cream (83%), and fluorouracil cream (80%). “Maybe we’re not specifically targeting the vasculature [with this approach], but we did some optical coherence tomography imaging and saw that the blood vessels in the tumor were coagulated while the vasculature in the surrounding normal skin were spared,” said Dr. Ortiz, who is also vice president of the American Society for Laser Medicine and Surgery.

In a more recent analysis, she and her colleagues retrospectively analyzed long-term outcomes in 11 patients with BCC who had 16 lesions treated with the 1,064-nm Nd:YAG laser. At a mean of 9 months, 100% of lesions remained clear as determined by clinical observation.

In a subsequent, as yet unpublished study, she and her collaborators followed 34 patients with BCC one year following laser treatment. “Of these, 33 had no recurrence at 1-year follow-up,” Dr. Ortiz said, noting that the one patient with a recurrence was on a biologic agent for Crohn’s disease.

One key advantage of using the long-pulsed 1,064-nm Nd:YAG laser for nonaggressive BCC is the potential for one treatment visit. “They don’t have to come back for suture removal,” she said. “It’s a quick procedure, takes only about 5 minutes. There’s no limitation on activity and there’s minimal wound care, light ointment, and a band-aid; that’s it.”

In addition, she said, there is a lower risk of complications, infections, and bleeding, and there is minimal scarring. It is “also an alternative for treating patients with multiple tumors or those who are poor surgical candidates, such as the elderly and those with Gorlin syndrome.”

Dr. Ortiz avoids treating aggressive subtypes “because we don’t know what margin to treat,” she added. “Avoid the face. I do make some exceptions for patients if they’re elderly or if they’ve had multiple tumors. Monitor for recurrence like you would using any other modality.”

She uses lidocaine without epinephrine to avoid vasoconstriction and treats with the 1,064-nm Nd:YAG laser as follows: a 5-mm spot size, a fluence of 140 J/cm², and a pulse duration of 8 ms, with no cooling, which are the settings for the Excel V Laser System, she noted. “If you’re using a different Nd:YAG laser, your pulse duration may vary. I do let the device cool in between pulses to avoid bulk heating.”

The immediate endpoint to strive for is slight greying and slight contraction, and the procedure is covered by insurance, billed as malignant destruction/EDC (CPT codes 17260-17266 trunk and 17280-17283 face). “I do biopsy prior to treatment,” she said. “I like the biopsy to be healed when I’m using the laser, so I’ll treat them about a month later.”

As for future directions, Dr. Ortiz and colleagues plan to evaluate the use of gold nanoparticles to more selectively target BCC during treatment with the 1,064-nm Nd:YAG laser. For now, she sees no downside of the procedure for proper candidates. “I do think that patients really like it,” she said. “It’s effective and easy.”

Dr. Ortiz disclosed having financial relationships with several pharmaceutical and device companies. She is also cochair of the MOAS.





 

SAN DIEGO – After Arisa E. Ortiz, MD, and colleagues published results of a multicenter study reporting that one treatment with the long-pulsed 1,064-nm Nd:YAG laser cleared nonaggressive basal cell carcinoma (BCC) on the trunk and extremities in 90% of patients, she heard from colleagues who were skeptical of the approach.

Maybe it’s just the biopsy alone that’s clearing these tumors, some told her. Others postulated that since the energy was delivered with a 5- to 6-mm spot size at a fluence of 125-140 J/cm² and a 7- to 10-ms pulse duration, bulk heating likely disrupted the tumors. However, treatments were generally well tolerated, required no anesthesia, and caused no significant adverse events.

“It’s almost scarless,” Dr. Ortiz, director of laser and cosmetic dermatology at the University of California, San Diego, said at the annual Masters of Aesthetics Symposium. “Sometimes the treatment does leave a mark, but I think the scars are always acceptable. We do have good histologic evidence that we can penetrate 2.15 mm, which is a lot deeper than what the pulsed-dye laser or other superficial wavelengths are able to penetrate.”

Data is well powered to reject the null hypothesis that laser treatment does not have an effect on nodular and superficial BCC lesions, she continued, noting that it is at least comparable if not superior with clearance rates reported for methyl aminolevulinate–PDT (73%), imiquimod cream (83%), and fluorouracil cream (80%). “Maybe we’re not specifically targeting the vasculature [with this approach], but we did some optical coherence tomography imaging and saw that the blood vessels in the tumor were coagulated while the vasculature in the surrounding normal skin were spared,” said Dr. Ortiz, who is also vice president of the American Society for Laser Medicine and Surgery.

In a more recent analysis, she and her colleagues retrospectively analyzed long-term outcomes in 11 patients with BCC who had 16 lesions treated with the 1,064-nm Nd:YAG laser. At a mean of 9 months, 100% of lesions remained clear as determined by clinical observation.

In a subsequent, as yet unpublished study, she and her collaborators followed 34 patients with BCC one year following laser treatment. “Of these, 33 had no recurrence at 1-year follow-up,” Dr. Ortiz said, noting that the one patient with a recurrence was on a biologic agent for Crohn’s disease.

One key advantage of using the long-pulsed 1,064-nm Nd:YAG laser for nonaggressive BCC is the potential for one treatment visit. “They don’t have to come back for suture removal,” she said. “It’s a quick procedure, takes only about 5 minutes. There’s no limitation on activity and there’s minimal wound care, light ointment, and a band-aid; that’s it.”

In addition, she said, there is a lower risk of complications, infections, and bleeding, and there is minimal scarring. It is “also an alternative for treating patients with multiple tumors or those who are poor surgical candidates, such as the elderly and those with Gorlin syndrome.”

Dr. Ortiz avoids treating aggressive subtypes “because we don’t know what margin to treat,” she added. “Avoid the face. I do make some exceptions for patients if they’re elderly or if they’ve had multiple tumors. Monitor for recurrence like you would using any other modality.”

She uses lidocaine without epinephrine to avoid vasoconstriction and treats with the 1,064-nm Nd:YAG laser as follows: a 5-mm spot size, a fluence of 140 J/cm², and a pulse duration of 8 ms, with no cooling, which are the settings for the Excel V Laser System, she noted. “If you’re using a different Nd:YAG laser, your pulse duration may vary. I do let the device cool in between pulses to avoid bulk heating.”

The immediate endpoint to strive for is slight greying and slight contraction, and the procedure is covered by insurance, billed as malignant destruction/EDC (CPT codes 17260-17266 trunk and 17280-17283 face). “I do biopsy prior to treatment,” she said. “I like the biopsy to be healed when I’m using the laser, so I’ll treat them about a month later.”

As for future directions, Dr. Ortiz and colleagues plan to evaluate the use of gold nanoparticles to more selectively target BCC during treatment with the 1,064-nm Nd:YAG laser. For now, she sees no downside of the procedure for proper candidates. “I do think that patients really like it,” she said. “It’s effective and easy.”

Dr. Ortiz disclosed having financial relationships with several pharmaceutical and device companies. She is also cochair of the MOAS.





 

Data from a dermatology monkeypox (mpox) registry reveal that patients struck during the 2022 worldwide outbreak experienced two nontraditional findings: Skin lesions that frequently appeared before systemic illness and a much lower overall numbers of lesions.

“Just these two findings alone show how important it is to remain clinically vigilant as dermatologists,” Esther Freeman, MD, PhD, director of global health dermatology at Massachusetts General Hospital, Boston, said in an interview. She is the corresponding author of the study, which analyzed 101 mpox cases from 13 countries and was published online on in the Journal of the American Academy of Dermatology.

NIAID

“Mpox appeared to manifest differently than in previous outbreaks with morphologic and clinical evolutions much different than previously reported in endemic and prior outbreaks,” added Dr. Freeman. “Dermatologists should continue to keep mpox on the differential as it continues to circulate at low levels in the population and is a mimicker of many other common skin diseases.”

According to the Centers for Disease Control and Prevention, as of Jan. 20, 2023, there have been 30,061 cases of mpox in the United States during the outbreak that began in 2022; 23 people died. Worldwide, the number of cases neared 85,000.

In contrast to past outbreaks where patients may have had dozens or hundreds of lesions, 20% had only 1 lesion, while 52% had 2-5 lesions, and 20% had 6-20 lesions. “There may be only a few lesions, so index of suspicion needs to be high,” Dr. Freeman said.

According to the study, “the most common skin lesion morphologies and secondary characteristics reported included papules, vesicles/blisters, pustules, erosions/ulcers and crust/scabs.” Dr. Freeman cautioned that “lesions may not go through the ‘typical’ progression from papule to pustule. The initial lesion could even be an ulceration or a crust. For dermatologists, this means you need to have a high index of suspicion, especially if you see a new onset lesion in the groin or perianal area, though they can also start elsewhere.”

She added that “the lesion you see on exam could be a classic pustule/pseudopustule, but it might not be – it could be a small perianal erosion or ulceration. If you have any concern it could be mpox, it’s a good idea to test by PCR.”

 

Morbilliform rash, scarring reported

The study also highlighted 10 cases of morbilliform rash. “A morbilliform exanthem is pretty nonspecific, and usually cases of mpox have more specific features,” dermatologist and study coauthor Misha Rosenbach, MD, of the University of Pennsylvania, Philadelphia, said in an interview.

“Given the current low rates of mpox, I do not think most dermatologists need to worry about mpox when evaluating morbilliform exanthems. However, in high-risk patients or patients with other morphologies, it is worth noting that there’s a chance that this may be related.”

Emory University dermatologist Howa Yeung, MD, MSc, who wasn’t involved with the study, said in an interview that morbilliform rashes in the mouth/tongue area, mostly on days 1-5, should be considered a possible sign of mpox. “While I didn’t typically think of monkeypox virus as a cause of viral exanthems, I will now add it to my differential diagnoses.”

Data from a dermatology monkeypox (mpox) registry reveal that patients struck during the 2022 worldwide outbreak experienced two nontraditional findings: Skin lesions that frequently appeared before systemic illness and a much lower overall numbers of lesions.

“Just these two findings alone show how important it is to remain clinically vigilant as dermatologists,” Esther Freeman, MD, PhD, director of global health dermatology at Massachusetts General Hospital, Boston, said in an interview. She is the corresponding author of the study, which analyzed 101 mpox cases from 13 countries and was published online on in the Journal of the American Academy of Dermatology.

NIAID

“Mpox appeared to manifest differently than in previous outbreaks with morphologic and clinical evolutions much different than previously reported in endemic and prior outbreaks,” added Dr. Freeman. “Dermatologists should continue to keep mpox on the differential as it continues to circulate at low levels in the population and is a mimicker of many other common skin diseases.”

According to the Centers for Disease Control and Prevention, as of Jan. 20, 2023, there have been 30,061 cases of mpox in the United States during the outbreak that began in 2022; 23 people died. Worldwide, the number of cases neared 85,000.

In contrast to past outbreaks where patients may have had dozens or hundreds of lesions, 20% had only 1 lesion, while 52% had 2-5 lesions, and 20% had 6-20 lesions. “There may be only a few lesions, so index of suspicion needs to be high,” Dr. Freeman said.

According to the study, “the most common skin lesion morphologies and secondary characteristics reported included papules, vesicles/blisters, pustules, erosions/ulcers and crust/scabs.” Dr. Freeman cautioned that “lesions may not go through the ‘typical’ progression from papule to pustule. The initial lesion could even be an ulceration or a crust. For dermatologists, this means you need to have a high index of suspicion, especially if you see a new onset lesion in the groin or perianal area, though they can also start elsewhere.”

She added that “the lesion you see on exam could be a classic pustule/pseudopustule, but it might not be – it could be a small perianal erosion or ulceration. If you have any concern it could be mpox, it’s a good idea to test by PCR.”

 

Morbilliform rash, scarring reported

The study also highlighted 10 cases of morbilliform rash. “A morbilliform exanthem is pretty nonspecific, and usually cases of mpox have more specific features,” dermatologist and study coauthor Misha Rosenbach, MD, of the University of Pennsylvania, Philadelphia, said in an interview.

“Given the current low rates of mpox, I do not think most dermatologists need to worry about mpox when evaluating morbilliform exanthems. However, in high-risk patients or patients with other morphologies, it is worth noting that there’s a chance that this may be related.”

Emory University dermatologist Howa Yeung, MD, MSc, who wasn’t involved with the study, said in an interview that morbilliform rashes in the mouth/tongue area, mostly on days 1-5, should be considered a possible sign of mpox. “While I didn’t typically think of monkeypox virus as a cause of viral exanthems, I will now add it to my differential diagnoses.”

Data from a dermatology monkeypox (mpox) registry reveal that patients struck during the 2022 worldwide outbreak experienced two nontraditional findings: Skin lesions that frequently appeared before systemic illness and a much lower overall numbers of lesions.

“Just these two findings alone show how important it is to remain clinically vigilant as dermatologists,” Esther Freeman, MD, PhD, director of global health dermatology at Massachusetts General Hospital, Boston, said in an interview. She is the corresponding author of the study, which analyzed 101 mpox cases from 13 countries and was published online on in the Journal of the American Academy of Dermatology.

NIAID

“Mpox appeared to manifest differently than in previous outbreaks with morphologic and clinical evolutions much different than previously reported in endemic and prior outbreaks,” added Dr. Freeman. “Dermatologists should continue to keep mpox on the differential as it continues to circulate at low levels in the population and is a mimicker of many other common skin diseases.”

According to the Centers for Disease Control and Prevention, as of Jan. 20, 2023, there have been 30,061 cases of mpox in the United States during the outbreak that began in 2022; 23 people died. Worldwide, the number of cases neared 85,000.

In contrast to past outbreaks where patients may have had dozens or hundreds of lesions, 20% had only 1 lesion, while 52% had 2-5 lesions, and 20% had 6-20 lesions. “There may be only a few lesions, so index of suspicion needs to be high,” Dr. Freeman said.

According to the study, “the most common skin lesion morphologies and secondary characteristics reported included papules, vesicles/blisters, pustules, erosions/ulcers and crust/scabs.” Dr. Freeman cautioned that “lesions may not go through the ‘typical’ progression from papule to pustule. The initial lesion could even be an ulceration or a crust. For dermatologists, this means you need to have a high index of suspicion, especially if you see a new onset lesion in the groin or perianal area, though they can also start elsewhere.”

She added that “the lesion you see on exam could be a classic pustule/pseudopustule, but it might not be – it could be a small perianal erosion or ulceration. If you have any concern it could be mpox, it’s a good idea to test by PCR.”

 

Morbilliform rash, scarring reported

The study also highlighted 10 cases of morbilliform rash. “A morbilliform exanthem is pretty nonspecific, and usually cases of mpox have more specific features,” dermatologist and study coauthor Misha Rosenbach, MD, of the University of Pennsylvania, Philadelphia, said in an interview.

“Given the current low rates of mpox, I do not think most dermatologists need to worry about mpox when evaluating morbilliform exanthems. However, in high-risk patients or patients with other morphologies, it is worth noting that there’s a chance that this may be related.”

Emory University dermatologist Howa Yeung, MD, MSc, who wasn’t involved with the study, said in an interview that morbilliform rashes in the mouth/tongue area, mostly on days 1-5, should be considered a possible sign of mpox. “While I didn’t typically think of monkeypox virus as a cause of viral exanthems, I will now add it to my differential diagnoses.”

1. The treatment of multiple myeloma has evolved significantly in recent years. What are some of the most important things you consider in the treatment of your newly diagnosed, transplant-ineligible patients?

We’ve seen great progress in the treatment of multiple myeloma over the last decade, and outcomes continue to improve for many patients.¹ Still, it is important to keep in mind that more than 34,000 patients will be diagnosed and more than 12,000 people will die from the disease this year.² We may have the greatest opportunity to impact the course of disease in the treatment of newly diagnosed patients due to the nature of this cancer:

• Multiple myeloma is characterized by relapse, and we know the length of remission generally decreases with each relapse and subsequent line of therapy.³
• Patients often become refractory to treatment over time.

When I meet with a patient who has been diagnosed with multiple myeloma, the first thing I consider is their eligibility for autologous stem cell transplant (ASCT). In my opinion, the introduction of ASCT is one of the biggest advancements in the last few decades, and we’ve found that ASCT followed by maintenance therapy with targeted tools improves progression-free survival (PFS).⁴

Unfortunately, many newly diagnosed patients are not eligible for ASCT–either because of comorbidities or other complexities related to the presentation of their disease.  

For patients who are transplant-ineligible (TIE), it is important to have treatment options that are proven effective in extending PFS and overall survival (OS), and capable of producing deep and durable responses.

2. What are the challenges associated with treating newly diagnosed patients who are not eligible for ASCT?

We still consider multiple myeloma to be an incurable disease but, in my opinion, the treatment of TIE patients is less challenging today than a decade ago due to the emergence of novel therapies. That said, TIE patients are typically older and present with more advanced disease and comorbidities, including diabetes or cardiovascular events.⁵ 

A retrospective analysis published in 2020 by Rafael Fonseca examined frontline treatment patterns and attrition rates by line of therapy among newly diagnosed multiple myeloma (NDMM) patients who are TIE. More than 22,000 patients were identified from three patient-level databases between 2000 and 2018 - the OPTUM Commercial Claims database, the OPTUM Electronic Medical Records database, and the Surveillance, Epidemiology, and End Results-Meidcare Linked database. Patients included had to have a multiple myeloma diagnosis on or after January 1, 2007. Results showed that attrition rates among newly diagnosed, TIE patients with multiple myeloma increase with each line of therapy, with the proportion of patients who receive a second line of therapy decreasing by 50 percent with each subsequent line.³ 

3. Can you provide more detail on the goals of therapy for newly diagnosed, transplant-ineligible patients?

When I discuss treatment goals with TIE patients, I feel it is important to emphasize managing side effects and achieving deep and durable responses. I have the benefit of being in an academic setting, where I regularly exchange information with my colleagues about what we’re learning from the clinical studies in which we participate. Choosing which treatment to administer is complex and involves other considerations. For example, if two regimens have comparable efficacy, I may recommend the regimen with a more established safety profile or more robust evidence so I can properly anticipate and manage toxicities in my patients. Overall survival is one of the most important endpoints I consider, in addition to depth of response and PFS. In recent years, we’ve seen increasing evidence pointing to the importance of  using a proven effective treatment in frontline patients that are ineligible for transplant. 

4. A key study in newly-diagnosed, transplant-ineligible multiple myeloma is the Phase 3 MAIA study. Can you share the key takeaways from this study and discuss how the results have shaped treatment for this patient population?

Of course. The MAIA study is a randomized Phase 3 study evaluating DARZALEX^® (daratumumab) intravenous injection in combination with lenalidomide and dexamethasone (D-Rd) compared with Rd in 737 adult patients with newly diagnosed, transplant-ineligible multiple myeloma. The median age of patients participating in the MAIA study was 73 (range 45-90), an important consideration since the median age for multiple myeloma diagnosis is approximately 66-70 years of age.⁶ The study evaluated PFS as the primary endpoint, and overall survival as a key secondary endpoint, and supported the FDA approval of DARZALEX^® in combination with lenalidomide and dexamethasone for adult patients with newly diagnosed, multiple myeloma who are ineligible for ASCT.

MAIA study design⁷

The baseline demographic and disease characteristics were similar between the 2 treatment groups. Forty-four percent of the patients were  ≥75 years of age. Fifty-two percent (52%) of patients were male, 92% White, 4% Black or African American, and 1% Asian. Three percent (3%) of patients reported an ethnicity of Hispanic or Latino. Thirty-four (34%) had an Eastern Cooperative Oncology Group (ECOG) performance score of 0, 50% had an ECOG performance score of 1, and 17% had an ECOG performance score of ≥2. Twenty-seven percent had International Staging System (ISS) Stage I, 43% had ISS Stage II, and 29% had ISS Stage III disease. 

Select Important Safety Information: 

CONTRAINDICATIONS

DARZALEX^® is contraindicated in patients with a history of severe hypersensitivity (eg, anaphylactic reactions) to daratumumab or any of the components of the formulation.

WARNINGS AND PRECAUTIONS
Infusion-Related Reactions: DARZALEX^® can cause severe and/or serious infusion-related reactions including anaphylactic reactions.
These reactions can be life-threatening, and fatal outcomes have been reported. Please scroll down to read Important Safety Information for DARZALEX^®. 

Primary findings from the study, which were published in 2019, showed an improvement in PFS in patients receiving D-Rd compared with those receiving Rd alone.⁷ The median PFS was not reached in the D-Rd arm and was reached at 31.9 months in the Rd arm (HR 0.56; 95% CI 0.43-0.73; P<0.0001).⁷ At a median of 30 months of follow-up, the data showed the clinical benefit of D-Rd therapy, with a 44% reduction in the risk of disease progression or death in patients receiving D-Rd compared with Rd alone.⁷ 

Progression-free survival in TIE NDMM after ~30 months of treatment with D-Rd^7,8

Additionally, 70.6% of patients (95% CI, 65.0-75.4) had no progressive disease with D-Rd treatment at median 30 months of follow-up, compared with 55.6% (95% CI, 49.5-61.3) of patients in the Rd group.⁷

In terms of depth of response, the percentage of patients with a complete response or better was 47.6% in patients receiving D-Rd compared with 24.9% in the Rd group.⁷

Overall response rate with D-Rd in TIE NDMM at ~30 months of follow-up⁸

An overview of the most frequent adverse events at 30-months of follow-up are provided below. The most frequent adverse reactions were reported in ≥20% of patients, with at least a 5% greater frequency in the D-Rd arm compared with Rd alone.⁸ 

Most frequent adverse events at ~30 months of follow-up with D-Rd in TIE NDMM⁸

Most frequent hematologic laboratory abnormalities with D-Rd in TIE NDMM at ~30 months⁸

Serious adverse reactions with a 2% greater incidence in the D-Rd arm compared with the Rd arm were pneumonia (D-Rd 15% vs Rd 8%), bronchitis (D-Rd 4% vs Rd 2%), and dehydration (D-Rd 2% vs Rd <1).
• Discontinuation rates due to any adverse event: 7% with D-Rd vs 16% with Rd
• Infusion-related reactions (IRRs) with D-Rd occurred in 41% of patients; 2% were Grade 3 and <1% were Grade 4
• IRRs of any grade or severity may require management by interruption, modification, and/or discontinuation of the infusion
• Most IRRs occurred during first infusion

5. Thanks for that overview. In addition to these results, The Lancet Oncology has published updated overall survival data from a 5-year follow-up on the MAIA study. Can you provide an overview of these data and insights on their potential for patients?  

The MAIA trial was an important study, and for me, the results were practice changing. We see that after a median of nearly 5 years of follow-up, D-Rd significantly improved OS in TIE NDMM patients who were treated to progression compared with Rd alone (66.3% vs. 53.1% [HR=0.68; 95% CI, 0.53-0.86; P=0.0013]).⁹ This equates to approximately a 32% reduction in death when DARZALEX^® was added to a two-drug regimen, which is a meaningful consideration when selecting the most appropriate regimens for my newly diagnosed, transplant-ineligible patients.⁹

Overall survival data at ~5 years with D-Rd compared to Rd alone in TIE NDMM⁹

Importantly, efficacy that resulted from longer treatment with D-Rd is also supported by approximately 5 years of safety evaluation. Below is information from a follow-up analysis of the MAIA study. This information is not included in the current Prescribing Information and has not been evaluated by the FDA. Treatment-emergent adverse events are reported as observed. These analyses have not been adjusted for multiple comparisons and no conclusions should be drawn. In what I’ve observed through published data and in my practice, longer treatment has not revealed new safety signals.

Most frequent treatment-emergent adverse events (any grade reported in ≥30% of patients and/or Grade 3/4 reported in ≥10% of patients) at ~5 years⁹

Select Important Safety Information: 

DARZALEX^® can cause severe and/or serious infusion-related reactions including anaphylactic reactions. These reactions can be life threatening, and fatal outcomes have been reported. In clinical trials (monotherapy and combination: N=2066), infusion-related reactions occurred in 37% of patients with the Week 1 (16 mg/kg) infusion, 2% with the Week 2 infusion, and cumulatively 6% with subsequent infusions. Less than 1% of patients had a Grade 3/4 infusion-related reaction at Week 2 or subsequent infusions. The median time to onset was 1.5 hours (range: 0 to 73 hours). Nearly all reactions occurred during infusion or within 4 hours of completing DARZALEX^®. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, tachycardia, headache, laryngeal edema, pulmonary edema, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting, and nausea. Less common signs and symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, hypotension and blurred vision. Please scroll down to see Important Safety Information for DARZALEX^®.

6. Does the availability of OS data influence your decisions on treatment selection in TIE NDMM?

Overall survival absolutely remains the gold standard and informs my practice. Prior to OS data being available, I will often look at other efficacy endpoints that are available sooner. In MAIA, I was encouraged by efficacy endpoints in earlier data, which were later confirmed by the latest data on OS.

7. The MAIA study shows that treating to disease progression or unacceptable toxicity is important. How does that impact your approach to treatment?

It's important to keep in mind that the MAIA trial was designed to evaluate treatment until progression or unacceptable toxicity. The results revealed a significant difference between the DR-d and Rd treatment arms, but results observed in this study are contingent on this treatment approach. From a clinical perspective, unless there is considerable toxicity, I advocate for treating with D-Rd to progression.

In the clinic, we also see that TIE patients who have higher frailty scores are more likely to discontinue treatment prior to progression.¹⁰ There can be other reasons too – such as a patient simply wanting to have a break from treatment. These conversations are not always easy, but it is important to have an honest dialogue with patients.

8. What can we learn from studies like the MAIA trial that included a wide range of patient populations including patients who are elderly, frail, or had high cytogenetic risk? 

Several patient subgroups were analyzed as part of the MAIA study. It is important to note that these subgroup analyses are not included in the Prescribing Information for DARZALEX^®. These analyses were not adjusted for multiple comparisons, and there are insufficient numbers of patients per subgroup to make definitive conclusions of efficacy among the subgroups.

As mentioned above, the MAIA study evaluated a wide range of patients (n=737). The baseline demographic and disease characteristics were similar between the D-Rd and Rd treatment groups and the median age was 73 (range: 45-90) years, with 44% of the patients ≥75 years of age.

In the various patient subgroups that were analyzed as part of the MAIA study, it was found that at ~3-years of follow-up the PFS numerically favored DRd compared with Rd alone in most subgroups (see table below).

Median progression-free survival by sub-population at ~3 year follow-up⁸

The MAIA trial also included patients who were frail and a post hoc analysis was conducted in this subgroup of patients. These analyses are not included in the Prescribing Information for DARZALEX^®. These analyses were conducted post hoc and there are insufficient numbers of patients per subgroup to make definitive conclusions of efficacy among the subgroups.

A frailty assessment was performed retrospectively using age, the Charlson Comorbidity Index (CCI) – which is calculated based on a retrospective review of the patient’s medical history to predict the 10-year mortality – and the baseline Eastern Cooperative Oncology Group (ECOG) performance status score, used to measure a patient’s level of functioning in terms of their ability to care for themselves, daily activity, and physical activity. The frailty scores were then added up to classify patients into fit (0), intermediate (1), or frail (≥2). Frailty status was further simplified into 2 categories: non-frail (0-1) and frail (≥2). The median age in the frail subgroup was 77 years (range: 57-80 years), with 88% of patients having ECOG performance score ≥1. CCI was calculated based on retrospective review of each patient’s medical history.¹²

The charts below illustrate the frailty scoring system with an overview of the patient population included in the 3-year post hoc analysis, PFS rate, and adverse events.

MAIA post hoc subgroup analysis by frailty status score¹²

The retrospective assessment of frailty score was a limitation of this study. Retrospective CCI calculations were based on reported medical history, which may contain missing data and result in underestimating or overestimating the number of patients in each frailty subgroup. The ECOG PS score parameter used for frailty score calculations in the study is more subjective, with susceptibility to intra- and inter-observer bias, compared with the ADL (activities of daily living) and IADL (instrumental activities of daily living) scales used in the IMWG scoring system. While the frailty scale used in the study is based on parameters that are routinely assessed in clinical practice for clinical use, the use of comprehensive frailty assessments that more accurately reflect biological or functional frailty will remain important for the further optimization of treatment strategies for frail patients. Patients with an ECOG PS score ≥3 and patients with comorbidities that may interfere with the study procedures were excluded from MAIA; the inclusion and exclusion criteria for the study limits the generalizability of these results to more frail patients seen in clinical practice.

Progression-free survival in a ~3-year subgroup analysis of frail patients following treatment with D-Rd in TIE NDMM¹²

Most frequent Grade 3/4 treatment-emergent adverse events (≥10%) in frail patients at ~3 year follow-up of MAIA trial¹²

Please see additional Important Safety Information for DARZALEX^® below.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

DARZALEX^® is contraindicated in patients with a history of severe hypersensitivity (eg, anaphylactic reactions) to daratumumab or any of the components of the formulation.

WARNINGS AND PRECAUTIONS

Infusion-Related Reactions

DARZALEX^® can cause severe and/or serious infusion-related reactions including anaphylactic reactions. These reactions can be life‑threatening, and fatal outcomes have been reported. In clinical trials (monotherapy and combination: N=2066), infusion-related reactions occurred in 37% of patients with the Week 1 (16 mg/kg) infusion, 2% with the Week 2 infusion, and cumulatively 6% with subsequent infusions. Less than 1% of patients had a Grade 3/4 infusion-related reaction at Week 2 or subsequent infusions. The median time to onset was 1.5 hours (range: 0 to 73 hours). Nearly all reactions occurred during infusion or within 4 hours of completing DARZALEX^®. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, tachycardia, headache, laryngeal edema, pulmonary edema, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting, and nausea. Less common signs and symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, hypotension and blurred vision.

When DARZALEX^® dosing was interrupted in the setting of ASCT (CASSIOPEIA) for a median of 3.75 months (range: 2.4 to 6.9 months), upon re-initiation of DARZALEX^®, the incidence of infusion-related reactions was 11% for the first infusion following ASCT. Infusion-related reactions occurring at re-initiation of DARZALEX^® following ASCT were consistent in terms of symptoms and severity (Grade 3 or 4: <1%) with those reported in previous studies at Week 2 or subsequent infusions. In EQUULEUS, patients receiving combination treatment (n=97) were administered the first 16 mg/kg dose at Week 1 split over two days, ie, 8 mg/kg on Day 1 and Day 2, respectively. The incidence of any grade infusion-related reactions was 42%, with 36% of patients experiencing infusion-related reactions on Day 1 of Week 1, 4% on Day 2 of Week 1, and 8% with subsequent infusions.

Pre-medicate patients with antihistamines, antipyretics, and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt DARZALEX^® infusion for reactions of any severity and institute medical management as needed. Permanently discontinue DARZALEX^® therapy if an anaphylactic reaction or life-threatening (Grade 4) reaction occurs and institute appropriate emergency care. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion.

To reduce the risk of delayed infusion-related reactions, administer oral corticosteroids to all patients following DARZALEX^® infusions. Patients with a history of chronic obstructive pulmonary disease may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease.

Ocular adverse reactions, including acute myopia and narrowing of the anterior chamber angle due to ciliochoroidal effusions with potential for increased intraocular pressure or glaucoma, have occurred with DARZALEX infusion. If ocular symptoms occur, interrupt DARZALEX infusion and seek immediate ophthalmologic evaluation prior to restarting DARZALEX.

Interference With Serological Testing

Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive indirect antiglobulin test (indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab infusion. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient’s serum. The determination of a patient’s ABO and Rh blood type is not impacted. Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX^®. Type and screen patients prior to starting DARZALEX^®.

Neutropenia and Thrombocytopenia

DARZALEX^® may increase neutropenia and thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. Consider withholding DARZALEX^® until recovery of neutrophils or for recovery of platelets.

Interference With Determination of Complete Response

Daratumumab is a human immunoglobulin G (IgG) kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein.

Embryo-Fetal Toxicity

Based on the mechanism of action, DARZALEX^® can cause fetal harm when administered to a pregnant woman. DARZALEX^® may cause depletion of fetal immune cells and decreased bone density. Advise pregnant women of the potential risk to a fetus. Advise females with reproductive potential to use effective contraception during treatment with DARZALEX^® and for 3 months after the last dose.

The combination of DARZALEX^® with lenalidomide, pomalidomide, or thalidomide is contraindicated in pregnant women because lenalidomide, pomalidomide, and thalidomide may cause birth defects and death of the unborn child. Refer to the lenalidomide, pomalidomide, or thalidomide prescribing information on use during pregnancy.

ADVERSE REACTIONS

The most frequently reported adverse reactions (incidence ≥20%) were: upper respiratory infection, neutropenia, infusion‑related reactions, thrombocytopenia, diarrhea, constipation, anemia, peripheral sensory neuropathy, fatigue, peripheral edema, nausea, cough, pyrexia, dyspnea, and asthenia. The most common hematologic laboratory abnormalities (≥40%) with DARZALEX^® are: neutropenia, lymphopenia, thrombocytopenia, leukopenia, and anemia.

INDICATIONS

DARZALEX^® (daratumumab) is indicated for the treatment of adult patients with multiple myeloma:

• In combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy
• In combination with bortezomib, melphalan, and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant
• In combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant
• In combination with bortezomib and dexamethasone in patients who have received at least one prior therapy
• In combination with carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy
• In combination with pomalidomide and dexamethasone in patients who have received at least two prior therapies including lenalidomide and a proteasome inhibitor
• As monotherapy in patients who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent

Please click here to see the full Prescribing Information.

1. The treatment of multiple myeloma has evolved significantly in recent years. What are some of the most important things you consider in the treatment of your newly diagnosed, transplant-ineligible patients?

We’ve seen great progress in the treatment of multiple myeloma over the last decade, and outcomes continue to improve for many patients.¹ Still, it is important to keep in mind that more than 34,000 patients will be diagnosed and more than 12,000 people will die from the disease this year.² We may have the greatest opportunity to impact the course of disease in the treatment of newly diagnosed patients due to the nature of this cancer:

• Multiple myeloma is characterized by relapse, and we know the length of remission generally decreases with each relapse and subsequent line of therapy.³
• Patients often become refractory to treatment over time.

When I meet with a patient who has been diagnosed with multiple myeloma, the first thing I consider is their eligibility for autologous stem cell transplant (ASCT). In my opinion, the introduction of ASCT is one of the biggest advancements in the last few decades, and we’ve found that ASCT followed by maintenance therapy with targeted tools improves progression-free survival (PFS).⁴

Unfortunately, many newly diagnosed patients are not eligible for ASCT–either because of comorbidities or other complexities related to the presentation of their disease.  

For patients who are transplant-ineligible (TIE), it is important to have treatment options that are proven effective in extending PFS and overall survival (OS), and capable of producing deep and durable responses.

2. What are the challenges associated with treating newly diagnosed patients who are not eligible for ASCT?

We still consider multiple myeloma to be an incurable disease but, in my opinion, the treatment of TIE patients is less challenging today than a decade ago due to the emergence of novel therapies. That said, TIE patients are typically older and present with more advanced disease and comorbidities, including diabetes or cardiovascular events.⁵ 

A retrospective analysis published in 2020 by Rafael Fonseca examined frontline treatment patterns and attrition rates by line of therapy among newly diagnosed multiple myeloma (NDMM) patients who are TIE. More than 22,000 patients were identified from three patient-level databases between 2000 and 2018 - the OPTUM Commercial Claims database, the OPTUM Electronic Medical Records database, and the Surveillance, Epidemiology, and End Results-Meidcare Linked database. Patients included had to have a multiple myeloma diagnosis on or after January 1, 2007. Results showed that attrition rates among newly diagnosed, TIE patients with multiple myeloma increase with each line of therapy, with the proportion of patients who receive a second line of therapy decreasing by 50 percent with each subsequent line.³ 

3. Can you provide more detail on the goals of therapy for newly diagnosed, transplant-ineligible patients?

When I discuss treatment goals with TIE patients, I feel it is important to emphasize managing side effects and achieving deep and durable responses. I have the benefit of being in an academic setting, where I regularly exchange information with my colleagues about what we’re learning from the clinical studies in which we participate. Choosing which treatment to administer is complex and involves other considerations. For example, if two regimens have comparable efficacy, I may recommend the regimen with a more established safety profile or more robust evidence so I can properly anticipate and manage toxicities in my patients. Overall survival is one of the most important endpoints I consider, in addition to depth of response and PFS. In recent years, we’ve seen increasing evidence pointing to the importance of  using a proven effective treatment in frontline patients that are ineligible for transplant. 

4. A key study in newly-diagnosed, transplant-ineligible multiple myeloma is the Phase 3 MAIA study. Can you share the key takeaways from this study and discuss how the results have shaped treatment for this patient population?

Of course. The MAIA study is a randomized Phase 3 study evaluating DARZALEX^® (daratumumab) intravenous injection in combination with lenalidomide and dexamethasone (D-Rd) compared with Rd in 737 adult patients with newly diagnosed, transplant-ineligible multiple myeloma. The median age of patients participating in the MAIA study was 73 (range 45-90), an important consideration since the median age for multiple myeloma diagnosis is approximately 66-70 years of age.⁶ The study evaluated PFS as the primary endpoint, and overall survival as a key secondary endpoint, and supported the FDA approval of DARZALEX^® in combination with lenalidomide and dexamethasone for adult patients with newly diagnosed, multiple myeloma who are ineligible for ASCT.

MAIA study design⁷

The baseline demographic and disease characteristics were similar between the 2 treatment groups. Forty-four percent of the patients were  ≥75 years of age. Fifty-two percent (52%) of patients were male, 92% White, 4% Black or African American, and 1% Asian. Three percent (3%) of patients reported an ethnicity of Hispanic or Latino. Thirty-four (34%) had an Eastern Cooperative Oncology Group (ECOG) performance score of 0, 50% had an ECOG performance score of 1, and 17% had an ECOG performance score of ≥2. Twenty-seven percent had International Staging System (ISS) Stage I, 43% had ISS Stage II, and 29% had ISS Stage III disease. 

Select Important Safety Information: 

CONTRAINDICATIONS

DARZALEX^® is contraindicated in patients with a history of severe hypersensitivity (eg, anaphylactic reactions) to daratumumab or any of the components of the formulation.

WARNINGS AND PRECAUTIONS
Infusion-Related Reactions: DARZALEX^® can cause severe and/or serious infusion-related reactions including anaphylactic reactions.
These reactions can be life-threatening, and fatal outcomes have been reported. Please scroll down to read Important Safety Information for DARZALEX^®. 

Primary findings from the study, which were published in 2019, showed an improvement in PFS in patients receiving D-Rd compared with those receiving Rd alone.⁷ The median PFS was not reached in the D-Rd arm and was reached at 31.9 months in the Rd arm (HR 0.56; 95% CI 0.43-0.73; P<0.0001).⁷ At a median of 30 months of follow-up, the data showed the clinical benefit of D-Rd therapy, with a 44% reduction in the risk of disease progression or death in patients receiving D-Rd compared with Rd alone.⁷ 

Progression-free survival in TIE NDMM after ~30 months of treatment with D-Rd^7,8

Additionally, 70.6% of patients (95% CI, 65.0-75.4) had no progressive disease with D-Rd treatment at median 30 months of follow-up, compared with 55.6% (95% CI, 49.5-61.3) of patients in the Rd group.⁷

In terms of depth of response, the percentage of patients with a complete response or better was 47.6% in patients receiving D-Rd compared with 24.9% in the Rd group.⁷

Overall response rate with D-Rd in TIE NDMM at ~30 months of follow-up⁸

An overview of the most frequent adverse events at 30-months of follow-up are provided below. The most frequent adverse reactions were reported in ≥20% of patients, with at least a 5% greater frequency in the D-Rd arm compared with Rd alone.⁸ 

Most frequent adverse events at ~30 months of follow-up with D-Rd in TIE NDMM⁸

Most frequent hematologic laboratory abnormalities with D-Rd in TIE NDMM at ~30 months⁸

Serious adverse reactions with a 2% greater incidence in the D-Rd arm compared with the Rd arm were pneumonia (D-Rd 15% vs Rd 8%), bronchitis (D-Rd 4% vs Rd 2%), and dehydration (D-Rd 2% vs Rd <1).
• Discontinuation rates due to any adverse event: 7% with D-Rd vs 16% with Rd
• Infusion-related reactions (IRRs) with D-Rd occurred in 41% of patients; 2% were Grade 3 and <1% were Grade 4
• IRRs of any grade or severity may require management by interruption, modification, and/or discontinuation of the infusion
• Most IRRs occurred during first infusion

5. Thanks for that overview. In addition to these results, The Lancet Oncology has published updated overall survival data from a 5-year follow-up on the MAIA study. Can you provide an overview of these data and insights on their potential for patients?  

The MAIA trial was an important study, and for me, the results were practice changing. We see that after a median of nearly 5 years of follow-up, D-Rd significantly improved OS in TIE NDMM patients who were treated to progression compared with Rd alone (66.3% vs. 53.1% [HR=0.68; 95% CI, 0.53-0.86; P=0.0013]).⁹ This equates to approximately a 32% reduction in death when DARZALEX^® was added to a two-drug regimen, which is a meaningful consideration when selecting the most appropriate regimens for my newly diagnosed, transplant-ineligible patients.⁹

Overall survival data at ~5 years with D-Rd compared to Rd alone in TIE NDMM⁹

Importantly, efficacy that resulted from longer treatment with D-Rd is also supported by approximately 5 years of safety evaluation. Below is information from a follow-up analysis of the MAIA study. This information is not included in the current Prescribing Information and has not been evaluated by the FDA. Treatment-emergent adverse events are reported as observed. These analyses have not been adjusted for multiple comparisons and no conclusions should be drawn. In what I’ve observed through published data and in my practice, longer treatment has not revealed new safety signals.

Most frequent treatment-emergent adverse events (any grade reported in ≥30% of patients and/or Grade 3/4 reported in ≥10% of patients) at ~5 years⁹

Select Important Safety Information: 

DARZALEX^® can cause severe and/or serious infusion-related reactions including anaphylactic reactions. These reactions can be life threatening, and fatal outcomes have been reported. In clinical trials (monotherapy and combination: N=2066), infusion-related reactions occurred in 37% of patients with the Week 1 (16 mg/kg) infusion, 2% with the Week 2 infusion, and cumulatively 6% with subsequent infusions. Less than 1% of patients had a Grade 3/4 infusion-related reaction at Week 2 or subsequent infusions. The median time to onset was 1.5 hours (range: 0 to 73 hours). Nearly all reactions occurred during infusion or within 4 hours of completing DARZALEX^®. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, tachycardia, headache, laryngeal edema, pulmonary edema, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting, and nausea. Less common signs and symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, hypotension and blurred vision. Please scroll down to see Important Safety Information for DARZALEX^®.

6. Does the availability of OS data influence your decisions on treatment selection in TIE NDMM?

Overall survival absolutely remains the gold standard and informs my practice. Prior to OS data being available, I will often look at other efficacy endpoints that are available sooner. In MAIA, I was encouraged by efficacy endpoints in earlier data, which were later confirmed by the latest data on OS.

7. The MAIA study shows that treating to disease progression or unacceptable toxicity is important. How does that impact your approach to treatment?

It's important to keep in mind that the MAIA trial was designed to evaluate treatment until progression or unacceptable toxicity. The results revealed a significant difference between the DR-d and Rd treatment arms, but results observed in this study are contingent on this treatment approach. From a clinical perspective, unless there is considerable toxicity, I advocate for treating with D-Rd to progression.

In the clinic, we also see that TIE patients who have higher frailty scores are more likely to discontinue treatment prior to progression.¹⁰ There can be other reasons too – such as a patient simply wanting to have a break from treatment. These conversations are not always easy, but it is important to have an honest dialogue with patients.

8. What can we learn from studies like the MAIA trial that included a wide range of patient populations including patients who are elderly, frail, or had high cytogenetic risk? 

Several patient subgroups were analyzed as part of the MAIA study. It is important to note that these subgroup analyses are not included in the Prescribing Information for DARZALEX^®. These analyses were not adjusted for multiple comparisons, and there are insufficient numbers of patients per subgroup to make definitive conclusions of efficacy among the subgroups.

As mentioned above, the MAIA study evaluated a wide range of patients (n=737). The baseline demographic and disease characteristics were similar between the D-Rd and Rd treatment groups and the median age was 73 (range: 45-90) years, with 44% of the patients ≥75 years of age.

In the various patient subgroups that were analyzed as part of the MAIA study, it was found that at ~3-years of follow-up the PFS numerically favored DRd compared with Rd alone in most subgroups (see table below).

Median progression-free survival by sub-population at ~3 year follow-up⁸

The MAIA trial also included patients who were frail and a post hoc analysis was conducted in this subgroup of patients. These analyses are not included in the Prescribing Information for DARZALEX^®. These analyses were conducted post hoc and there are insufficient numbers of patients per subgroup to make definitive conclusions of efficacy among the subgroups.

A frailty assessment was performed retrospectively using age, the Charlson Comorbidity Index (CCI) – which is calculated based on a retrospective review of the patient’s medical history to predict the 10-year mortality – and the baseline Eastern Cooperative Oncology Group (ECOG) performance status score, used to measure a patient’s level of functioning in terms of their ability to care for themselves, daily activity, and physical activity. The frailty scores were then added up to classify patients into fit (0), intermediate (1), or frail (≥2). Frailty status was further simplified into 2 categories: non-frail (0-1) and frail (≥2). The median age in the frail subgroup was 77 years (range: 57-80 years), with 88% of patients having ECOG performance score ≥1. CCI was calculated based on retrospective review of each patient’s medical history.¹²

The charts below illustrate the frailty scoring system with an overview of the patient population included in the 3-year post hoc analysis, PFS rate, and adverse events.

MAIA post hoc subgroup analysis by frailty status score¹²

The retrospective assessment of frailty score was a limitation of this study. Retrospective CCI calculations were based on reported medical history, which may contain missing data and result in underestimating or overestimating the number of patients in each frailty subgroup. The ECOG PS score parameter used for frailty score calculations in the study is more subjective, with susceptibility to intra- and inter-observer bias, compared with the ADL (activities of daily living) and IADL (instrumental activities of daily living) scales used in the IMWG scoring system. While the frailty scale used in the study is based on parameters that are routinely assessed in clinical practice for clinical use, the use of comprehensive frailty assessments that more accurately reflect biological or functional frailty will remain important for the further optimization of treatment strategies for frail patients. Patients with an ECOG PS score ≥3 and patients with comorbidities that may interfere with the study procedures were excluded from MAIA; the inclusion and exclusion criteria for the study limits the generalizability of these results to more frail patients seen in clinical practice.

Progression-free survival in a ~3-year subgroup analysis of frail patients following treatment with D-Rd in TIE NDMM¹²

Most frequent Grade 3/4 treatment-emergent adverse events (≥10%) in frail patients at ~3 year follow-up of MAIA trial¹²

Please see additional Important Safety Information for DARZALEX^® below.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

DARZALEX^® is contraindicated in patients with a history of severe hypersensitivity (eg, anaphylactic reactions) to daratumumab or any of the components of the formulation.

WARNINGS AND PRECAUTIONS

Infusion-Related Reactions

DARZALEX^® can cause severe and/or serious infusion-related reactions including anaphylactic reactions. These reactions can be life‑threatening, and fatal outcomes have been reported. In clinical trials (monotherapy and combination: N=2066), infusion-related reactions occurred in 37% of patients with the Week 1 (16 mg/kg) infusion, 2% with the Week 2 infusion, and cumulatively 6% with subsequent infusions. Less than 1% of patients had a Grade 3/4 infusion-related reaction at Week 2 or subsequent infusions. The median time to onset was 1.5 hours (range: 0 to 73 hours). Nearly all reactions occurred during infusion or within 4 hours of completing DARZALEX^®. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, tachycardia, headache, laryngeal edema, pulmonary edema, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting, and nausea. Less common signs and symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, hypotension and blurred vision.

When DARZALEX^® dosing was interrupted in the setting of ASCT (CASSIOPEIA) for a median of 3.75 months (range: 2.4 to 6.9 months), upon re-initiation of DARZALEX^®, the incidence of infusion-related reactions was 11% for the first infusion following ASCT. Infusion-related reactions occurring at re-initiation of DARZALEX^® following ASCT were consistent in terms of symptoms and severity (Grade 3 or 4: <1%) with those reported in previous studies at Week 2 or subsequent infusions. In EQUULEUS, patients receiving combination treatment (n=97) were administered the first 16 mg/kg dose at Week 1 split over two days, ie, 8 mg/kg on Day 1 and Day 2, respectively. The incidence of any grade infusion-related reactions was 42%, with 36% of patients experiencing infusion-related reactions on Day 1 of Week 1, 4% on Day 2 of Week 1, and 8% with subsequent infusions.

Pre-medicate patients with antihistamines, antipyretics, and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt DARZALEX^® infusion for reactions of any severity and institute medical management as needed. Permanently discontinue DARZALEX^® therapy if an anaphylactic reaction or life-threatening (Grade 4) reaction occurs and institute appropriate emergency care. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion.

To reduce the risk of delayed infusion-related reactions, administer oral corticosteroids to all patients following DARZALEX^® infusions. Patients with a history of chronic obstructive pulmonary disease may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease.

Ocular adverse reactions, including acute myopia and narrowing of the anterior chamber angle due to ciliochoroidal effusions with potential for increased intraocular pressure or glaucoma, have occurred with DARZALEX infusion. If ocular symptoms occur, interrupt DARZALEX infusion and seek immediate ophthalmologic evaluation prior to restarting DARZALEX.

Interference With Serological Testing

Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive indirect antiglobulin test (indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab infusion. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient’s serum. The determination of a patient’s ABO and Rh blood type is not impacted. Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX^®. Type and screen patients prior to starting DARZALEX^®.

Neutropenia and Thrombocytopenia

DARZALEX^® may increase neutropenia and thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. Consider withholding DARZALEX^® until recovery of neutrophils or for recovery of platelets.

Interference With Determination of Complete Response

Daratumumab is a human immunoglobulin G (IgG) kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein.

Embryo-Fetal Toxicity

Based on the mechanism of action, DARZALEX^® can cause fetal harm when administered to a pregnant woman. DARZALEX^® may cause depletion of fetal immune cells and decreased bone density. Advise pregnant women of the potential risk to a fetus. Advise females with reproductive potential to use effective contraception during treatment with DARZALEX^® and for 3 months after the last dose.

The combination of DARZALEX^® with lenalidomide, pomalidomide, or thalidomide is contraindicated in pregnant women because lenalidomide, pomalidomide, and thalidomide may cause birth defects and death of the unborn child. Refer to the lenalidomide, pomalidomide, or thalidomide prescribing information on use during pregnancy.

ADVERSE REACTIONS

The most frequently reported adverse reactions (incidence ≥20%) were: upper respiratory infection, neutropenia, infusion‑related reactions, thrombocytopenia, diarrhea, constipation, anemia, peripheral sensory neuropathy, fatigue, peripheral edema, nausea, cough, pyrexia, dyspnea, and asthenia. The most common hematologic laboratory abnormalities (≥40%) with DARZALEX^® are: neutropenia, lymphopenia, thrombocytopenia, leukopenia, and anemia.

INDICATIONS

DARZALEX^® (daratumumab) is indicated for the treatment of adult patients with multiple myeloma:

• In combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy
• In combination with bortezomib, melphalan, and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant
• In combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant
• In combination with bortezomib and dexamethasone in patients who have received at least one prior therapy
• In combination with carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy
• In combination with pomalidomide and dexamethasone in patients who have received at least two prior therapies including lenalidomide and a proteasome inhibitor
• As monotherapy in patients who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent

Please click here to see the full Prescribing Information.

1. The treatment of multiple myeloma has evolved significantly in recent years. What are some of the most important things you consider in the treatment of your newly diagnosed, transplant-ineligible patients?

We’ve seen great progress in the treatment of multiple myeloma over the last decade, and outcomes continue to improve for many patients.¹ Still, it is important to keep in mind that more than 34,000 patients will be diagnosed and more than 12,000 people will die from the disease this year.² We may have the greatest opportunity to impact the course of disease in the treatment of newly diagnosed patients due to the nature of this cancer:

• Multiple myeloma is characterized by relapse, and we know the length of remission generally decreases with each relapse and subsequent line of therapy.³
• Patients often become refractory to treatment over time.

When I meet with a patient who has been diagnosed with multiple myeloma, the first thing I consider is their eligibility for autologous stem cell transplant (ASCT). In my opinion, the introduction of ASCT is one of the biggest advancements in the last few decades, and we’ve found that ASCT followed by maintenance therapy with targeted tools improves progression-free survival (PFS).⁴

Unfortunately, many newly diagnosed patients are not eligible for ASCT–either because of comorbidities or other complexities related to the presentation of their disease.  

For patients who are transplant-ineligible (TIE), it is important to have treatment options that are proven effective in extending PFS and overall survival (OS), and capable of producing deep and durable responses.

2. What are the challenges associated with treating newly diagnosed patients who are not eligible for ASCT?

We still consider multiple myeloma to be an incurable disease but, in my opinion, the treatment of TIE patients is less challenging today than a decade ago due to the emergence of novel therapies. That said, TIE patients are typically older and present with more advanced disease and comorbidities, including diabetes or cardiovascular events.⁵ 

A retrospective analysis published in 2020 by Rafael Fonseca examined frontline treatment patterns and attrition rates by line of therapy among newly diagnosed multiple myeloma (NDMM) patients who are TIE. More than 22,000 patients were identified from three patient-level databases between 2000 and 2018 - the OPTUM Commercial Claims database, the OPTUM Electronic Medical Records database, and the Surveillance, Epidemiology, and End Results-Meidcare Linked database. Patients included had to have a multiple myeloma diagnosis on or after January 1, 2007. Results showed that attrition rates among newly diagnosed, TIE patients with multiple myeloma increase with each line of therapy, with the proportion of patients who receive a second line of therapy decreasing by 50 percent with each subsequent line.³ 

3. Can you provide more detail on the goals of therapy for newly diagnosed, transplant-ineligible patients?

When I discuss treatment goals with TIE patients, I feel it is important to emphasize managing side effects and achieving deep and durable responses. I have the benefit of being in an academic setting, where I regularly exchange information with my colleagues about what we’re learning from the clinical studies in which we participate. Choosing which treatment to administer is complex and involves other considerations. For example, if two regimens have comparable efficacy, I may recommend the regimen with a more established safety profile or more robust evidence so I can properly anticipate and manage toxicities in my patients. Overall survival is one of the most important endpoints I consider, in addition to depth of response and PFS. In recent years, we’ve seen increasing evidence pointing to the importance of  using a proven effective treatment in frontline patients that are ineligible for transplant. 

4. A key study in newly-diagnosed, transplant-ineligible multiple myeloma is the Phase 3 MAIA study. Can you share the key takeaways from this study and discuss how the results have shaped treatment for this patient population?

Of course. The MAIA study is a randomized Phase 3 study evaluating DARZALEX^® (daratumumab) intravenous injection in combination with lenalidomide and dexamethasone (D-Rd) compared with Rd in 737 adult patients with newly diagnosed, transplant-ineligible multiple myeloma. The median age of patients participating in the MAIA study was 73 (range 45-90), an important consideration since the median age for multiple myeloma diagnosis is approximately 66-70 years of age.⁶ The study evaluated PFS as the primary endpoint, and overall survival as a key secondary endpoint, and supported the FDA approval of DARZALEX^® in combination with lenalidomide and dexamethasone for adult patients with newly diagnosed, multiple myeloma who are ineligible for ASCT.

MAIA study design⁷

The baseline demographic and disease characteristics were similar between the 2 treatment groups. Forty-four percent of the patients were  ≥75 years of age. Fifty-two percent (52%) of patients were male, 92% White, 4% Black or African American, and 1% Asian. Three percent (3%) of patients reported an ethnicity of Hispanic or Latino. Thirty-four (34%) had an Eastern Cooperative Oncology Group (ECOG) performance score of 0, 50% had an ECOG performance score of 1, and 17% had an ECOG performance score of ≥2. Twenty-seven percent had International Staging System (ISS) Stage I, 43% had ISS Stage II, and 29% had ISS Stage III disease. 

Select Important Safety Information: 

CONTRAINDICATIONS

DARZALEX^® is contraindicated in patients with a history of severe hypersensitivity (eg, anaphylactic reactions) to daratumumab or any of the components of the formulation.

WARNINGS AND PRECAUTIONS
Infusion-Related Reactions: DARZALEX^® can cause severe and/or serious infusion-related reactions including anaphylactic reactions.
These reactions can be life-threatening, and fatal outcomes have been reported. Please scroll down to read Important Safety Information for DARZALEX^®. 

Primary findings from the study, which were published in 2019, showed an improvement in PFS in patients receiving D-Rd compared with those receiving Rd alone.⁷ The median PFS was not reached in the D-Rd arm and was reached at 31.9 months in the Rd arm (HR 0.56; 95% CI 0.43-0.73; P<0.0001).⁷ At a median of 30 months of follow-up, the data showed the clinical benefit of D-Rd therapy, with a 44% reduction in the risk of disease progression or death in patients receiving D-Rd compared with Rd alone.⁷ 

Progression-free survival in TIE NDMM after ~30 months of treatment with D-Rd^7,8

Additionally, 70.6% of patients (95% CI, 65.0-75.4) had no progressive disease with D-Rd treatment at median 30 months of follow-up, compared with 55.6% (95% CI, 49.5-61.3) of patients in the Rd group.⁷

In terms of depth of response, the percentage of patients with a complete response or better was 47.6% in patients receiving D-Rd compared with 24.9% in the Rd group.⁷

Overall response rate with D-Rd in TIE NDMM at ~30 months of follow-up⁸

An overview of the most frequent adverse events at 30-months of follow-up are provided below. The most frequent adverse reactions were reported in ≥20% of patients, with at least a 5% greater frequency in the D-Rd arm compared with Rd alone.⁸ 

Most frequent adverse events at ~30 months of follow-up with D-Rd in TIE NDMM⁸

Most frequent hematologic laboratory abnormalities with D-Rd in TIE NDMM at ~30 months⁸

Serious adverse reactions with a 2% greater incidence in the D-Rd arm compared with the Rd arm were pneumonia (D-Rd 15% vs Rd 8%), bronchitis (D-Rd 4% vs Rd 2%), and dehydration (D-Rd 2% vs Rd <1).
• Discontinuation rates due to any adverse event: 7% with D-Rd vs 16% with Rd
• Infusion-related reactions (IRRs) with D-Rd occurred in 41% of patients; 2% were Grade 3 and <1% were Grade 4
• IRRs of any grade or severity may require management by interruption, modification, and/or discontinuation of the infusion
• Most IRRs occurred during first infusion

5. Thanks for that overview. In addition to these results, The Lancet Oncology has published updated overall survival data from a 5-year follow-up on the MAIA study. Can you provide an overview of these data and insights on their potential for patients?  

The MAIA trial was an important study, and for me, the results were practice changing. We see that after a median of nearly 5 years of follow-up, D-Rd significantly improved OS in TIE NDMM patients who were treated to progression compared with Rd alone (66.3% vs. 53.1% [HR=0.68; 95% CI, 0.53-0.86; P=0.0013]).⁹ This equates to approximately a 32% reduction in death when DARZALEX^® was added to a two-drug regimen, which is a meaningful consideration when selecting the most appropriate regimens for my newly diagnosed, transplant-ineligible patients.⁹

Overall survival data at ~5 years with D-Rd compared to Rd alone in TIE NDMM⁹

Importantly, efficacy that resulted from longer treatment with D-Rd is also supported by approximately 5 years of safety evaluation. Below is information from a follow-up analysis of the MAIA study. This information is not included in the current Prescribing Information and has not been evaluated by the FDA. Treatment-emergent adverse events are reported as observed. These analyses have not been adjusted for multiple comparisons and no conclusions should be drawn. In what I’ve observed through published data and in my practice, longer treatment has not revealed new safety signals.

Most frequent treatment-emergent adverse events (any grade reported in ≥30% of patients and/or Grade 3/4 reported in ≥10% of patients) at ~5 years⁹

Select Important Safety Information: 

DARZALEX^® can cause severe and/or serious infusion-related reactions including anaphylactic reactions. These reactions can be life threatening, and fatal outcomes have been reported. In clinical trials (monotherapy and combination: N=2066), infusion-related reactions occurred in 37% of patients with the Week 1 (16 mg/kg) infusion, 2% with the Week 2 infusion, and cumulatively 6% with subsequent infusions. Less than 1% of patients had a Grade 3/4 infusion-related reaction at Week 2 or subsequent infusions. The median time to onset was 1.5 hours (range: 0 to 73 hours). Nearly all reactions occurred during infusion or within 4 hours of completing DARZALEX^®. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, tachycardia, headache, laryngeal edema, pulmonary edema, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting, and nausea. Less common signs and symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, hypotension and blurred vision. Please scroll down to see Important Safety Information for DARZALEX^®.

6. Does the availability of OS data influence your decisions on treatment selection in TIE NDMM?

Overall survival absolutely remains the gold standard and informs my practice. Prior to OS data being available, I will often look at other efficacy endpoints that are available sooner. In MAIA, I was encouraged by efficacy endpoints in earlier data, which were later confirmed by the latest data on OS.

7. The MAIA study shows that treating to disease progression or unacceptable toxicity is important. How does that impact your approach to treatment?

It's important to keep in mind that the MAIA trial was designed to evaluate treatment until progression or unacceptable toxicity. The results revealed a significant difference between the DR-d and Rd treatment arms, but results observed in this study are contingent on this treatment approach. From a clinical perspective, unless there is considerable toxicity, I advocate for treating with D-Rd to progression.

In the clinic, we also see that TIE patients who have higher frailty scores are more likely to discontinue treatment prior to progression.¹⁰ There can be other reasons too – such as a patient simply wanting to have a break from treatment. These conversations are not always easy, but it is important to have an honest dialogue with patients.

8. What can we learn from studies like the MAIA trial that included a wide range of patient populations including patients who are elderly, frail, or had high cytogenetic risk? 

Several patient subgroups were analyzed as part of the MAIA study. It is important to note that these subgroup analyses are not included in the Prescribing Information for DARZALEX^®. These analyses were not adjusted for multiple comparisons, and there are insufficient numbers of patients per subgroup to make definitive conclusions of efficacy among the subgroups.

As mentioned above, the MAIA study evaluated a wide range of patients (n=737). The baseline demographic and disease characteristics were similar between the D-Rd and Rd treatment groups and the median age was 73 (range: 45-90) years, with 44% of the patients ≥75 years of age.

In the various patient subgroups that were analyzed as part of the MAIA study, it was found that at ~3-years of follow-up the PFS numerically favored DRd compared with Rd alone in most subgroups (see table below).

Median progression-free survival by sub-population at ~3 year follow-up⁸

The MAIA trial also included patients who were frail and a post hoc analysis was conducted in this subgroup of patients. These analyses are not included in the Prescribing Information for DARZALEX^®. These analyses were conducted post hoc and there are insufficient numbers of patients per subgroup to make definitive conclusions of efficacy among the subgroups.

A frailty assessment was performed retrospectively using age, the Charlson Comorbidity Index (CCI) – which is calculated based on a retrospective review of the patient’s medical history to predict the 10-year mortality – and the baseline Eastern Cooperative Oncology Group (ECOG) performance status score, used to measure a patient’s level of functioning in terms of their ability to care for themselves, daily activity, and physical activity. The frailty scores were then added up to classify patients into fit (0), intermediate (1), or frail (≥2). Frailty status was further simplified into 2 categories: non-frail (0-1) and frail (≥2). The median age in the frail subgroup was 77 years (range: 57-80 years), with 88% of patients having ECOG performance score ≥1. CCI was calculated based on retrospective review of each patient’s medical history.¹²

The charts below illustrate the frailty scoring system with an overview of the patient population included in the 3-year post hoc analysis, PFS rate, and adverse events.

MAIA post hoc subgroup analysis by frailty status score¹²

The retrospective assessment of frailty score was a limitation of this study. Retrospective CCI calculations were based on reported medical history, which may contain missing data and result in underestimating or overestimating the number of patients in each frailty subgroup. The ECOG PS score parameter used for frailty score calculations in the study is more subjective, with susceptibility to intra- and inter-observer bias, compared with the ADL (activities of daily living) and IADL (instrumental activities of daily living) scales used in the IMWG scoring system. While the frailty scale used in the study is based on parameters that are routinely assessed in clinical practice for clinical use, the use of comprehensive frailty assessments that more accurately reflect biological or functional frailty will remain important for the further optimization of treatment strategies for frail patients. Patients with an ECOG PS score ≥3 and patients with comorbidities that may interfere with the study procedures were excluded from MAIA; the inclusion and exclusion criteria for the study limits the generalizability of these results to more frail patients seen in clinical practice.

Progression-free survival in a ~3-year subgroup analysis of frail patients following treatment with D-Rd in TIE NDMM¹²

Most frequent Grade 3/4 treatment-emergent adverse events (≥10%) in frail patients at ~3 year follow-up of MAIA trial¹²

Please see additional Important Safety Information for DARZALEX^® below.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

DARZALEX^® is contraindicated in patients with a history of severe hypersensitivity (eg, anaphylactic reactions) to daratumumab or any of the components of the formulation.

WARNINGS AND PRECAUTIONS

Infusion-Related Reactions

DARZALEX^® can cause severe and/or serious infusion-related reactions including anaphylactic reactions. These reactions can be life‑threatening, and fatal outcomes have been reported. In clinical trials (monotherapy and combination: N=2066), infusion-related reactions occurred in 37% of patients with the Week 1 (16 mg/kg) infusion, 2% with the Week 2 infusion, and cumulatively 6% with subsequent infusions. Less than 1% of patients had a Grade 3/4 infusion-related reaction at Week 2 or subsequent infusions. The median time to onset was 1.5 hours (range: 0 to 73 hours). Nearly all reactions occurred during infusion or within 4 hours of completing DARZALEX^®. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, tachycardia, headache, laryngeal edema, pulmonary edema, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting, and nausea. Less common signs and symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, hypotension and blurred vision.

When DARZALEX^® dosing was interrupted in the setting of ASCT (CASSIOPEIA) for a median of 3.75 months (range: 2.4 to 6.9 months), upon re-initiation of DARZALEX^®, the incidence of infusion-related reactions was 11% for the first infusion following ASCT. Infusion-related reactions occurring at re-initiation of DARZALEX^® following ASCT were consistent in terms of symptoms and severity (Grade 3 or 4: <1%) with those reported in previous studies at Week 2 or subsequent infusions. In EQUULEUS, patients receiving combination treatment (n=97) were administered the first 16 mg/kg dose at Week 1 split over two days, ie, 8 mg/kg on Day 1 and Day 2, respectively. The incidence of any grade infusion-related reactions was 42%, with 36% of patients experiencing infusion-related reactions on Day 1 of Week 1, 4% on Day 2 of Week 1, and 8% with subsequent infusions.

Pre-medicate patients with antihistamines, antipyretics, and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt DARZALEX^® infusion for reactions of any severity and institute medical management as needed. Permanently discontinue DARZALEX^® therapy if an anaphylactic reaction or life-threatening (Grade 4) reaction occurs and institute appropriate emergency care. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion.

To reduce the risk of delayed infusion-related reactions, administer oral corticosteroids to all patients following DARZALEX^® infusions. Patients with a history of chronic obstructive pulmonary disease may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease.

Ocular adverse reactions, including acute myopia and narrowing of the anterior chamber angle due to ciliochoroidal effusions with potential for increased intraocular pressure or glaucoma, have occurred with DARZALEX infusion. If ocular symptoms occur, interrupt DARZALEX infusion and seek immediate ophthalmologic evaluation prior to restarting DARZALEX.

Interference With Serological Testing

Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive indirect antiglobulin test (indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab infusion. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient’s serum. The determination of a patient’s ABO and Rh blood type is not impacted. Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX^®. Type and screen patients prior to starting DARZALEX^®.

Neutropenia and Thrombocytopenia

DARZALEX^® may increase neutropenia and thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. Consider withholding DARZALEX^® until recovery of neutrophils or for recovery of platelets.

Interference With Determination of Complete Response

Daratumumab is a human immunoglobulin G (IgG) kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein.

Embryo-Fetal Toxicity

Based on the mechanism of action, DARZALEX^® can cause fetal harm when administered to a pregnant woman. DARZALEX^® may cause depletion of fetal immune cells and decreased bone density. Advise pregnant women of the potential risk to a fetus. Advise females with reproductive potential to use effective contraception during treatment with DARZALEX^® and for 3 months after the last dose.

The combination of DARZALEX^® with lenalidomide, pomalidomide, or thalidomide is contraindicated in pregnant women because lenalidomide, pomalidomide, and thalidomide may cause birth defects and death of the unborn child. Refer to the lenalidomide, pomalidomide, or thalidomide prescribing information on use during pregnancy.

ADVERSE REACTIONS

The most frequently reported adverse reactions (incidence ≥20%) were: upper respiratory infection, neutropenia, infusion‑related reactions, thrombocytopenia, diarrhea, constipation, anemia, peripheral sensory neuropathy, fatigue, peripheral edema, nausea, cough, pyrexia, dyspnea, and asthenia. The most common hematologic laboratory abnormalities (≥40%) with DARZALEX^® are: neutropenia, lymphopenia, thrombocytopenia, leukopenia, and anemia.

INDICATIONS

DARZALEX^® (daratumumab) is indicated for the treatment of adult patients with multiple myeloma:

• In combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy
• In combination with bortezomib, melphalan, and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant
• In combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant
• In combination with bortezomib and dexamethasone in patients who have received at least one prior therapy
• In combination with carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy
• In combination with pomalidomide and dexamethasone in patients who have received at least two prior therapies including lenalidomide and a proteasome inhibitor
• As monotherapy in patients who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent

Please click here to see the full Prescribing Information.

Photo: Shutterstock

Six months after the Supreme Court decision that overturned the constitutional right to abortion, trainees across the United States are asking a critical question in the current resident recruitment season: How will the restrictions on abortion access affect my training as an obstetrician-gynecologist, and will they impact my ability to be the kind of provider I want to be in the future?

Among the myriad of downstream effects to patient care, the Dobbs decision will indisputably impact the scope of residency training for those that provide reproductive health services. Almost half of ObGyn residents train in states that have abortion restrictions in place.¹ New educational milestones for abortion training, which are a requirement by the Accreditation Council for Graduate Medical Education (ACGME), were proposed quickly after Dobbs, guiding programs to offer opportunities for training in nonrestricted areas or the “combination of didactic activities, including simulation” to meet the training requirement in abortion care.²

Like many providers, residents already are grappling with precarious and risky circumstances, balancing patient safety and patient-driven care amidst pre-existing and newly enforced abortion restrictions. Whether managing a patient with an undesired pregnancy, severe medical comorbidities, unexpected pregnancy complications such as preterm premature rupture of membranes, or bleeding, or substantial fetal anomalies, ObGyn residents cannot gain the experience of providing the full scope of reproductive health care without the ability to offer all possible management options. While some enacted abortion restrictions have exceptions for the health of or life-saving measures for the mother, there is no standard guidance for timing of interventions, leaving providers confused and in fear of legal retribution. At a time when trainees should be learning to provide patient-centered, evidence-based care, they are instead paralyzed by the legal or professional consequences they may face for offering their best medical judgements.

Furthermore, the lack of exposure to dilation and evacuation procedures for residents in restricted practice areas will undoubtably decrease their confidence in managing acute complications, which is one of the critical facets of residency training. In a surgical field where repetition is crucial for technical competence, highlighted by ACGME minimum case requirements, the decreased volume of abortion procedures is a disadvantage for trainees and a disservice for patients. While anti-choice promoters may argue that involvement in surgical management of early pregnancy loss should suffice for ObGyn training in family planning, this piecemeal approach will leave gaps in technical skills.

The fear of legal ramifications, moral injury, and inadequate surgical training may lead to the siphoning of talented trainees to areas in the country with fewer restrictions.³Dobbs already has demonstrated how limiting abortion access will deepen inequities in reproductive health care service delivery. Approximately 55% of ObGyn trainees and nearly two-thirds of maternal-fetal medicine graduates join the workforce in the state where they received their training.⁴ Medical students will seek opportunities for high-quality ObGyn training in areas that will help them to be well-prepared, competent physicians—and more often than not, stay in the area or region that they trained in. This will lead to provider shortages in areas where access to reproductive health care and subspecialist providers already is limited, further exacerbating existing health disparities.

During this recruitment season, trainees and residency programs alike will need to reckon with how the ramifications of Dobbs will alter both the immediate and long-term training in comprehensive reproductive health care for the ObGyn workforce. ObGyn trainees have taken a stand in response to the Dobbs decision, and nearly 750 current residents signed onto the statement below as a commitment to high-quality training and patient-centered care. Clinical experience in performing abortions is essential to the provision of comprehensive evidence-based reproductive health care, and access to these procedures is as important for physicians-in-training as it is for patients.

Actions to take to ensure high-quality abortion training in ObGyn residencies include the following:

• Connect with and stay involved with organizations such as the American College of Obstetricians and Gynecologists (ACOG), Physicians for Reproductive Health (PRH), and Medical Students for Choice (MSFC) for initiatives, toolkits, and resources for training at your institutions.
• Seek specific abortion training opportunities through the Leadership Training Academy (offered through PRH) or the Abortion Training Institute (offered through MSFC).
• Ensure that your residency program meets the ACGME criteria of providing opportunities for clinical experiences for abortion care and work with program leadership at a program, state, or regional level to enforce these competencies.
• Reach out to your local American Civil Liberties Union or other local reproductive legal rights organizations if you want to be involved with advocacy around abortion access and training but have concerns about legal protections.
• Have a voice at the table for empowering training opportunities by seeking leadership positions through ACOG, ACGME, Council on Resident Education in Obstetrics and Gynecology and the Association of Professors of Gynecology and Obstetrics, American Medical Association, Student National Medical Association, and subspecialty organizations.
• Vote in every election and promote voting registration and access to your patients, colleagues, and communities. ●

Continue to: The implications of the Dobbs v Jackson Women’s Health Organization decision on the health care and wellbeing of our patients...

Photo: Shutterstock

Six months after the Supreme Court decision that overturned the constitutional right to abortion, trainees across the United States are asking a critical question in the current resident recruitment season: How will the restrictions on abortion access affect my training as an obstetrician-gynecologist, and will they impact my ability to be the kind of provider I want to be in the future?

Among the myriad of downstream effects to patient care, the Dobbs decision will indisputably impact the scope of residency training for those that provide reproductive health services. Almost half of ObGyn residents train in states that have abortion restrictions in place.¹ New educational milestones for abortion training, which are a requirement by the Accreditation Council for Graduate Medical Education (ACGME), were proposed quickly after Dobbs, guiding programs to offer opportunities for training in nonrestricted areas or the “combination of didactic activities, including simulation” to meet the training requirement in abortion care.²

Like many providers, residents already are grappling with precarious and risky circumstances, balancing patient safety and patient-driven care amidst pre-existing and newly enforced abortion restrictions. Whether managing a patient with an undesired pregnancy, severe medical comorbidities, unexpected pregnancy complications such as preterm premature rupture of membranes, or bleeding, or substantial fetal anomalies, ObGyn residents cannot gain the experience of providing the full scope of reproductive health care without the ability to offer all possible management options. While some enacted abortion restrictions have exceptions for the health of or life-saving measures for the mother, there is no standard guidance for timing of interventions, leaving providers confused and in fear of legal retribution. At a time when trainees should be learning to provide patient-centered, evidence-based care, they are instead paralyzed by the legal or professional consequences they may face for offering their best medical judgements.

Furthermore, the lack of exposure to dilation and evacuation procedures for residents in restricted practice areas will undoubtably decrease their confidence in managing acute complications, which is one of the critical facets of residency training. In a surgical field where repetition is crucial for technical competence, highlighted by ACGME minimum case requirements, the decreased volume of abortion procedures is a disadvantage for trainees and a disservice for patients. While anti-choice promoters may argue that involvement in surgical management of early pregnancy loss should suffice for ObGyn training in family planning, this piecemeal approach will leave gaps in technical skills.

The fear of legal ramifications, moral injury, and inadequate surgical training may lead to the siphoning of talented trainees to areas in the country with fewer restrictions.³Dobbs already has demonstrated how limiting abortion access will deepen inequities in reproductive health care service delivery. Approximately 55% of ObGyn trainees and nearly two-thirds of maternal-fetal medicine graduates join the workforce in the state where they received their training.⁴ Medical students will seek opportunities for high-quality ObGyn training in areas that will help them to be well-prepared, competent physicians—and more often than not, stay in the area or region that they trained in. This will lead to provider shortages in areas where access to reproductive health care and subspecialist providers already is limited, further exacerbating existing health disparities.

During this recruitment season, trainees and residency programs alike will need to reckon with how the ramifications of Dobbs will alter both the immediate and long-term training in comprehensive reproductive health care for the ObGyn workforce. ObGyn trainees have taken a stand in response to the Dobbs decision, and nearly 750 current residents signed onto the statement below as a commitment to high-quality training and patient-centered care. Clinical experience in performing abortions is essential to the provision of comprehensive evidence-based reproductive health care, and access to these procedures is as important for physicians-in-training as it is for patients.

Actions to take to ensure high-quality abortion training in ObGyn residencies include the following:

• Connect with and stay involved with organizations such as the American College of Obstetricians and Gynecologists (ACOG), Physicians for Reproductive Health (PRH), and Medical Students for Choice (MSFC) for initiatives, toolkits, and resources for training at your institutions.
• Seek specific abortion training opportunities through the Leadership Training Academy (offered through PRH) or the Abortion Training Institute (offered through MSFC).
• Ensure that your residency program meets the ACGME criteria of providing opportunities for clinical experiences for abortion care and work with program leadership at a program, state, or regional level to enforce these competencies.
• Reach out to your local American Civil Liberties Union or other local reproductive legal rights organizations if you want to be involved with advocacy around abortion access and training but have concerns about legal protections.
• Have a voice at the table for empowering training opportunities by seeking leadership positions through ACOG, ACGME, Council on Resident Education in Obstetrics and Gynecology and the Association of Professors of Gynecology and Obstetrics, American Medical Association, Student National Medical Association, and subspecialty organizations.
• Vote in every election and promote voting registration and access to your patients, colleagues, and communities. ●

Continue to: The implications of the Dobbs v Jackson Women’s Health Organization decision on the health care and wellbeing of our patients...

Photo: Shutterstock

Six months after the Supreme Court decision that overturned the constitutional right to abortion, trainees across the United States are asking a critical question in the current resident recruitment season: How will the restrictions on abortion access affect my training as an obstetrician-gynecologist, and will they impact my ability to be the kind of provider I want to be in the future?

Among the myriad of downstream effects to patient care, the Dobbs decision will indisputably impact the scope of residency training for those that provide reproductive health services. Almost half of ObGyn residents train in states that have abortion restrictions in place.¹ New educational milestones for abortion training, which are a requirement by the Accreditation Council for Graduate Medical Education (ACGME), were proposed quickly after Dobbs, guiding programs to offer opportunities for training in nonrestricted areas or the “combination of didactic activities, including simulation” to meet the training requirement in abortion care.²

Like many providers, residents already are grappling with precarious and risky circumstances, balancing patient safety and patient-driven care amidst pre-existing and newly enforced abortion restrictions. Whether managing a patient with an undesired pregnancy, severe medical comorbidities, unexpected pregnancy complications such as preterm premature rupture of membranes, or bleeding, or substantial fetal anomalies, ObGyn residents cannot gain the experience of providing the full scope of reproductive health care without the ability to offer all possible management options. While some enacted abortion restrictions have exceptions for the health of or life-saving measures for the mother, there is no standard guidance for timing of interventions, leaving providers confused and in fear of legal retribution. At a time when trainees should be learning to provide patient-centered, evidence-based care, they are instead paralyzed by the legal or professional consequences they may face for offering their best medical judgements.

Furthermore, the lack of exposure to dilation and evacuation procedures for residents in restricted practice areas will undoubtably decrease their confidence in managing acute complications, which is one of the critical facets of residency training. In a surgical field where repetition is crucial for technical competence, highlighted by ACGME minimum case requirements, the decreased volume of abortion procedures is a disadvantage for trainees and a disservice for patients. While anti-choice promoters may argue that involvement in surgical management of early pregnancy loss should suffice for ObGyn training in family planning, this piecemeal approach will leave gaps in technical skills.

The fear of legal ramifications, moral injury, and inadequate surgical training may lead to the siphoning of talented trainees to areas in the country with fewer restrictions.³Dobbs already has demonstrated how limiting abortion access will deepen inequities in reproductive health care service delivery. Approximately 55% of ObGyn trainees and nearly two-thirds of maternal-fetal medicine graduates join the workforce in the state where they received their training.⁴ Medical students will seek opportunities for high-quality ObGyn training in areas that will help them to be well-prepared, competent physicians—and more often than not, stay in the area or region that they trained in. This will lead to provider shortages in areas where access to reproductive health care and subspecialist providers already is limited, further exacerbating existing health disparities.

During this recruitment season, trainees and residency programs alike will need to reckon with how the ramifications of Dobbs will alter both the immediate and long-term training in comprehensive reproductive health care for the ObGyn workforce. ObGyn trainees have taken a stand in response to the Dobbs decision, and nearly 750 current residents signed onto the statement below as a commitment to high-quality training and patient-centered care. Clinical experience in performing abortions is essential to the provision of comprehensive evidence-based reproductive health care, and access to these procedures is as important for physicians-in-training as it is for patients.

Actions to take to ensure high-quality abortion training in ObGyn residencies include the following:

• Connect with and stay involved with organizations such as the American College of Obstetricians and Gynecologists (ACOG), Physicians for Reproductive Health (PRH), and Medical Students for Choice (MSFC) for initiatives, toolkits, and resources for training at your institutions.
• Seek specific abortion training opportunities through the Leadership Training Academy (offered through PRH) or the Abortion Training Institute (offered through MSFC).
• Ensure that your residency program meets the ACGME criteria of providing opportunities for clinical experiences for abortion care and work with program leadership at a program, state, or regional level to enforce these competencies.
• Reach out to your local American Civil Liberties Union or other local reproductive legal rights organizations if you want to be involved with advocacy around abortion access and training but have concerns about legal protections.
• Have a voice at the table for empowering training opportunities by seeking leadership positions through ACOG, ACGME, Council on Resident Education in Obstetrics and Gynecology and the Association of Professors of Gynecology and Obstetrics, American Medical Association, Student National Medical Association, and subspecialty organizations.
• Vote in every election and promote voting registration and access to your patients, colleagues, and communities. ●

Continue to: The implications of the Dobbs v Jackson Women’s Health Organization decision on the health care and wellbeing of our patients...

Thadhani R, Lemoine E, Rana S, et al. Circulating angiogenic factor levels in hypertensive disorders of pregnancy. N Engl J Med. 2022;1. DOI: 10.1056/EVIDoa2200161

EXPERT COMMENTARY
 

The standard core lecture on preeclampsia given to all medical students frequently begins with an epic, if not potentially apocryphal, statement regarding how this disease has been noted in the annals of medical history since the time of the Ancients. Although contemporary diagnostic criteria for preeclampsia are not that far out of date, they are close. The increased urinary protein loss and hypertension preceding eclamptic seizures was first noted at the end of the 19th century. The blood pressure and proteinuria criteria used for diagnosis was codified in its contemporary form in the late 1940s. Since then, “tweak” rather than “overhaul” probably best describes the updates of the obstetrical community to the definition of preeclampsia. This has just changed.

Details of the study

Thadhani and colleagues prospectively recruited a nationally representative observational cohort of patients hospitalized for hypertension during pregnancy, then followed the patients until either the diagnosis of preeclampsia with severe features or for 2 weeks, whichever came first. At enrollment, circulating levels of the soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF) were measured. In a 2-phased design, the first 219 participants were used to define a sFlt-1/PlGF ratio that would predict progression to severe preeclampsia within 2 weeks. The next 556 enrollees served to validate the predictive properties of the ratio. The authors found that a sFlt-1/PlGF ratio of ≥40 predicted progression to preeclampsia with severe features with an area under the curve (AUC) of 0.92.

As products of the trophoblasts, both sFlt-1 and PlGF have been mooted for almost 2 decades as potential predictive, if not diagnostic, aids with respect to preeclampsia. Indeed, both analytes are commercially available in Europe for specifically this purpose and many maternal-fetal medicine practitioners working in the European equivalent American tertiary referral centers use an sFlt-1/PlGF ratio as their primary criteria for a diagnosis of preeclampsia. Within the United States, there was an initial flurry of interest in and an infusion of corporate and federal research support for sFlt-1 and PlGF as diagnostic aids for preeclampsia in the mid-2000s. However, at present, the US Food and Drug Administration (FDA) has not sanctioned these (or any) biomarkers to aid in the diagnosis of preeclampsia. As Thermo-Fisher Scientific (Waltham, Massachusetts) is a supporting partner in this study, it is almost certain that these data will be submitted for review by the FDA as part of an application for a preeclampsia diagnostic. At some point in the near future, American practitioners will potentially be able to join their European colleagues in utilizing these biomarkers in the diagnosis of preeclampsia with severe features. ●

Thadhani R, Lemoine E, Rana S, et al. Circulating angiogenic factor levels in hypertensive disorders of pregnancy. N Engl J Med. 2022;1. DOI: 10.1056/EVIDoa2200161

EXPERT COMMENTARY
 

The standard core lecture on preeclampsia given to all medical students frequently begins with an epic, if not potentially apocryphal, statement regarding how this disease has been noted in the annals of medical history since the time of the Ancients. Although contemporary diagnostic criteria for preeclampsia are not that far out of date, they are close. The increased urinary protein loss and hypertension preceding eclamptic seizures was first noted at the end of the 19th century. The blood pressure and proteinuria criteria used for diagnosis was codified in its contemporary form in the late 1940s. Since then, “tweak” rather than “overhaul” probably best describes the updates of the obstetrical community to the definition of preeclampsia. This has just changed.

Details of the study

Thadhani and colleagues prospectively recruited a nationally representative observational cohort of patients hospitalized for hypertension during pregnancy, then followed the patients until either the diagnosis of preeclampsia with severe features or for 2 weeks, whichever came first. At enrollment, circulating levels of the soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF) were measured. In a 2-phased design, the first 219 participants were used to define a sFlt-1/PlGF ratio that would predict progression to severe preeclampsia within 2 weeks. The next 556 enrollees served to validate the predictive properties of the ratio. The authors found that a sFlt-1/PlGF ratio of ≥40 predicted progression to preeclampsia with severe features with an area under the curve (AUC) of 0.92.

As products of the trophoblasts, both sFlt-1 and PlGF have been mooted for almost 2 decades as potential predictive, if not diagnostic, aids with respect to preeclampsia. Indeed, both analytes are commercially available in Europe for specifically this purpose and many maternal-fetal medicine practitioners working in the European equivalent American tertiary referral centers use an sFlt-1/PlGF ratio as their primary criteria for a diagnosis of preeclampsia. Within the United States, there was an initial flurry of interest in and an infusion of corporate and federal research support for sFlt-1 and PlGF as diagnostic aids for preeclampsia in the mid-2000s. However, at present, the US Food and Drug Administration (FDA) has not sanctioned these (or any) biomarkers to aid in the diagnosis of preeclampsia. As Thermo-Fisher Scientific (Waltham, Massachusetts) is a supporting partner in this study, it is almost certain that these data will be submitted for review by the FDA as part of an application for a preeclampsia diagnostic. At some point in the near future, American practitioners will potentially be able to join their European colleagues in utilizing these biomarkers in the diagnosis of preeclampsia with severe features. ●

Thadhani R, Lemoine E, Rana S, et al. Circulating angiogenic factor levels in hypertensive disorders of pregnancy. N Engl J Med. 2022;1. DOI: 10.1056/EVIDoa2200161

EXPERT COMMENTARY
 

The standard core lecture on preeclampsia given to all medical students frequently begins with an epic, if not potentially apocryphal, statement regarding how this disease has been noted in the annals of medical history since the time of the Ancients. Although contemporary diagnostic criteria for preeclampsia are not that far out of date, they are close. The increased urinary protein loss and hypertension preceding eclamptic seizures was first noted at the end of the 19th century. The blood pressure and proteinuria criteria used for diagnosis was codified in its contemporary form in the late 1940s. Since then, “tweak” rather than “overhaul” probably best describes the updates of the obstetrical community to the definition of preeclampsia. This has just changed.

Details of the study

Thadhani and colleagues prospectively recruited a nationally representative observational cohort of patients hospitalized for hypertension during pregnancy, then followed the patients until either the diagnosis of preeclampsia with severe features or for 2 weeks, whichever came first. At enrollment, circulating levels of the soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF) were measured. In a 2-phased design, the first 219 participants were used to define a sFlt-1/PlGF ratio that would predict progression to severe preeclampsia within 2 weeks. The next 556 enrollees served to validate the predictive properties of the ratio. The authors found that a sFlt-1/PlGF ratio of ≥40 predicted progression to preeclampsia with severe features with an area under the curve (AUC) of 0.92.

As products of the trophoblasts, both sFlt-1 and PlGF have been mooted for almost 2 decades as potential predictive, if not diagnostic, aids with respect to preeclampsia. Indeed, both analytes are commercially available in Europe for specifically this purpose and many maternal-fetal medicine practitioners working in the European equivalent American tertiary referral centers use an sFlt-1/PlGF ratio as their primary criteria for a diagnosis of preeclampsia. Within the United States, there was an initial flurry of interest in and an infusion of corporate and federal research support for sFlt-1 and PlGF as diagnostic aids for preeclampsia in the mid-2000s. However, at present, the US Food and Drug Administration (FDA) has not sanctioned these (or any) biomarkers to aid in the diagnosis of preeclampsia. As Thermo-Fisher Scientific (Waltham, Massachusetts) is a supporting partner in this study, it is almost certain that these data will be submitted for review by the FDA as part of an application for a preeclampsia diagnostic. At some point in the near future, American practitioners will potentially be able to join their European colleagues in utilizing these biomarkers in the diagnosis of preeclampsia with severe features. ●

In the musical Hamilton, there is a line from the song “The Election of 1800” in which, after a tumultuous time, Thomas Jefferson pleads for a sense of normalcy with, “Can we get back to politics?”

Trying to get back to “normal,” whatever that is, characterized the year 2022. Peeking out from under the constant shadow of the COVID-19 pandemic (not really gone, definitely not forgotten) were some blockbuster obstetrical headlines, including those on the CHAP (Chronic Hypertension and Pregnancy) trial and the impact of the Dobbs v Jackson Supreme Court decision. As these have been extensively covered in both OBG Management and other publications, in this Update we simply ask, “Can we get back to obstetrics?” as we focus on some straightforward patient care guidelines.

Thus, we offer updated information on the use of progesterone for preterm birth prevention, management of pregnancies that result from in vitro fertilization (IVF), and headache management in pregnant and postpartum patients.

Society guidance and FDA  advisement on the use of  progesterone for the prevention  of spontaneous preterm birth

American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins–Obstetrics. Prediction and prevention of spontaneous preterm birth. ACOG practice bulletin no. 234. Obstet Gynecol. 2021;138:e65-e90.

EPPPIC Group. Evaluating Progestogens for Preventing Preterm birth International Collaborative (EPPPIC): meta-analysis of individual participant data from randomised controlled trials. Lancet. 2021;397:1183-1194.

This is not déjà vu! Progesterone and spontaneous preterm birth (sPTB) is a hot topic again. If you wonder what to tell your patients, you are not alone. Preterm birth (PTB) continues to pose a challenge in obstetrics, with a most recently reported overall rate of 10.49%¹ in the United States—a 4% increase from 2019. Preterm birth accounts for approximately 75% of perinatal mortality and more than half of neonatal morbidity.²

What has not changed

A recent practice bulletin from the American College of Obstetricians and Gynecologists (ACOG) notes that some risk factors and screening assessments for PTB remain unchanged, including²:

• A history of PTB increases the risk for subsequent PTB. Risk increases with the number of prior preterm deliveries.
• A short cervix (<25 mm between 16 and  24 weeks’ gestation) is a risk factor for sPTB.
• The cervix should be visualized during the anatomy ultrasound exam (18 0/7 to 22 6/7 weeks’ gestation) in all pregnant patients regardless of prior birth history. If the cervix length (CL) appears shortened on transabdominal imaging, transvaginal (TV) imaging should be performed.
• Patients with a current singleton pregnancy and history of sPTB should have serial TV cervical measurements between 16 0/7 and 24 0/7 weeks’ gestation.²

EPPPIC changes and key takeaway points

In a meta-analysis of data from 31 randomized controlled trials, the EPPPIC (Evaluating Progestogens for Preventing Preterm birth International Collaborative) investigators compared vaginal progesterone, intramuscular 17-hydroxyprogesterone caproate  (17-OHPC), or oral progesterone with control or with each other in women at risk for PTB.³ Outcomes included PTB and the associated adverse neonatal and maternal outcomes.

The EPPPIC study’s main findings were:

• Singleton pregnancies at high risk for PTB due to prior sPTB or short cervix who received 17-OHPC or vaginal progesterone were less likely to deliver before  34 weeks’ gestation compared with those who received no treatment.
• There is a benefit to both 17-OHPC and vaginal progesterone in reducing the risk of PTB, with no clear evidence to support one intervention’s effectiveness over the other.
• There is benefit to either 17-OHPC or vaginal progesterone for CL less than 25 mm. The shorter the CL, the greater the absolute risk reduction on PTB.
• In multifetal pregnancies, use of 17-OHPC, when compared with placebo, was shown to increase the risk of preterm premature rupture of membranes. Neither 17-OHPC nor vaginal progesterone was found to reduce the risk of sPTB in multifetal pregnancies.³

What continues to change

While the March 30, 2021, statement from the Society for Maternal-Fetal Medicine (SMFM), “Response to EPPPIC and consideration for the use of progestogens for the prevention of preterm birth” (https://www .smfm.org/publications/383-smfm-stat ement-response-to-epppic-and-consider ations-of-the-use-of-progestogens-for-the -prevention-of-preterm-birth), stands, ACOG has withdrawn its accompanying Practice Advisory on guidance for integrating the EPPPIC findings.

In August 2022, the US Food and Drug Administration (FDA) granted a hearing on the Center for Drug Evaluation and Research’s proposal to withdraw approval for Makena (hydroxyprogesterone caproate injection, 250 mg/mL, once weekly) on the basis that available evidence does not demonstrate that it is effective for its approved indication to reduce the risk of PTB in women with a singleton pregnancy with a history of singleton sPTB.⁴

The key takeaway points from the FDA hearing (October 17–19, 2022) were:

• A better designed randomized controlled confirmatory trial is needed in the most at-risk patients to determine if Makena is effective for its approved indication.
• Makena and its approved generic equivalents remain on the market until the FDA makes its final decision regarding approval.⁴

Continue to: Managing pregnancies that result from IVF...

Society for Maternal-Fetal Medicine (SMFM); Ghidini A, Gandhi M, McCoy J, et al; Publications Committee. Society for Maternal-Fetal Medicine consult series #60: management of pregnancies resulting from in vitro fertilization. Am J Obstet Gynecol. 2022;226:B2-B12.

Assisted reproductive technology contributes to 1.6% of all infant births, and although most pregnancies are uncomplicated, some specific risks alter management.^5–7 For example, IVF is associated with increased rates of prematurity and its complications, fetal growth restriction, low birth weight, congenital anomalies, genetic abnormalities, and placental abnormalities. In addition, there is doubling of the risk of morbidities to the pregnant IVF patient, including but not limited to hypertensive disorders and diabetes. These complications are thought to be related to both the process of IVF itself as well as to conditions that contribute to subfertility and infertility in the first place.

Genetic screening and diagnostic testing options

IVF pregnancies have a documented increase in chromosomal abnormalities compared with spontaneously conceived pregnancies due to the following factors:

• karyotypic abnormalities in couples with infertility
• microdeletions on the Y chromosome in patients with oligospermia or azoospermia
• de novo chromosomal abnormalities in IVF pregnancies that utilize intracytoplasmic sperm injection (ICSI)
• fragile X mutations in patients with reduced ovarian reserve
• imprinting disorders in patients with fertility issues.

A common misconception is that preimplantation genetic testing renders prenatal genetic screening or testing unnecessary. However, preimplantation testing can be anywhere from 43% to 84% concordant with prenatal diagnostic testing due to biologic and technical factors. Therefore, all pregnancies should be offered the same options of aneuploidy screening as well as diagnostic testing. Pretest counseling should include an increased risk in IVF pregnancies of false-positives for the first-trimester screen and “no-call” results for cell-free fetal DNA. Additionally, diagnostic testing is recommended specifically in cases where mosaic embryos are transferred when euploid embryos are not available.

Counseling on fetal reduction for multifetal pregnancies

The risks of multifetal pregnancies (particularly higher order multiples) are significant and well documented for both the patient and the fetuses. It is therefore recommended that the option of multifetal pregnancy reduction be discussed, including the risks and benefits of reduction versus pregnancy continuation, timing, procedural considerations, and genetic testing options.^5,8

Detailed anatomic survey and fetal echocardiogram are indicated

Fetal anomalies, including congenital cardiac defects, occur at a higher rate in IVF pregnancies compared with spontaneously conceived pregnancies (475/10,000 live births vs 317/10,000 live births). Placental anomalies (such as placenta previa, vasa previa, and velamentous cord insertion) are also more common in this population. A detailed anatomic survey is therefore recommended for all IVF pregnancies and it is suggested that a fetal echocardiogram is offered these patients as well.

Pregnancy management and delivery considerations

Despite an increased risk of preterm birth, preeclampsia, and fetal growth restriction in IVF pregnancies (odds ratios range, 1.4–2), serial cervical lengths, serial growth ultrasound exams, and low-dose aspirin are not recommended for the sole indication of IVF. Due to lack of data on the utility of serial exams, a single screening cervical length at the time of anatomic survey and a third-trimester growth assessment are recommended. For aspirin, IVF qualifies as a “moderate” risk factor for preeclampsia; it is therefore recommended if another moderate risk factor is present (for example, nulliparity, obesity, or family history of preeclampsia).⁹

There is a 2- to 3-fold increased risk of stillbirth in IVF pregnancies; therefore, antenatal surveillance in the third trimester is recommended (weekly starting at 36 weeks for the sole indication of IVF).¹⁰ As no specific studies have evaluated the timing of delivery in IVF pregnancies, delivery recommendations include the option of 39-week delivery with shared decision-making with the patient.

Continue to: Evaluating and treating headaches in pregnancy and postpartum...

Evaluating and treating headaches in pregnancy and postpartum

American College of Obstetricians and Gynecologists. Clinical practice guideline no. 3: headaches in pregnancy and postpartum. Obstet Gynecol. 2022;139:944-972.

For obstetricians, headaches are a common and often frustrating condition to treat, as many of the available diagnostic tools and medications are either not recommended or have no data on use in pregnancy and lactation. Additionally, a headache is not always just a headache but could be a sign of a time-sensitive serious complication. An updated guideline from the American College of Obstetricians and Gynecologists approaches the topic of headaches in a stepwise algorithm that promotes efficiency and efficacy in diagnosis  and treatment.¹¹

Types of headaches

The primary headache types—migraine, cluster, and tension—are distinguished from each other by patient characteristics, quality, duration, location, and related symptoms. Reassuringly, headache frequency decreases by 30% to 80% during pregnancy, which allows for the option to decrease, change, or stop current medications, ideally prior to pregnancy. Prevention via use of calcium channel blockers, antihistamines, or β-blockers is recommended, as requiring acute treatments more than 2 days per week increases the risk of medication overuse headaches.

Treating acute headache

For patients who present with an acute headache consistent with their usual type, treatment starts with known medications that are compatible with pregnancy and proceeds in a stepwise fashion:

1. Acetaminophen 1,000 mg orally with or without caffeine 130 mg orally (maximum dose, acetaminophen < 3.25–4 g per day, caffeine 200 mg per day)

2. Metoclopramide 10 mg intravenously with or without diphenhydramine 25 mg intravenously (for nausea and to counteract restlessness and offer sedation)

3. If headache continues after steps 1 and 2, consider the following secondary treatment options: magnesium sulfate 1–2 g intravenously, sumatriptan 6 mg subcutaneously or 20-mg nasal spray, ibuprofen 600 mg orally once, or ketorolac 30 mg intravenously once (second trimester only)

4. If continued treatment and/or hospitalization is required after step 3, steroids can be used: prednisone 20 mg 4 times a day for 2 days or methylprednisolone 4-mg dose pack over 6 days

5. Do not use butalbital, opioids, or ergotamines due to lack of efficacy in providing additional pain relief, potential for addiction, risk of medication overuse headaches, and association with fetal/ pregnancy abnormalities.

Consider secondary headache

An acute headache discordant from the patient’s usual type or with concerning symptoms (“red flags”) requires consideration of secondary headaches as well as a comprehensive symptom evaluation, imaging, and consultation as needed. While secondary headaches postpartum are most likely musculoskeletal in nature, the following symptoms need to be evaluated immediately:

• rapid onset/change from baseline
• “thunderclap” nature
• hypertension
• fever
• focal neurologic deficits (blurry vision or blindness, confusion, seizures)
• altered consciousness
• laboratory abnormalities.

The differential diagnosis includes preeclampsia, reversible cerebral vasoconstriction syndrome (RCVS), posterior reversible encephalopathy syndrome (PRES), infection, cerebral venous sinus thrombosis (CVST), post–dural puncture (PDP) headache, idiopathic intracranial hypertension (IIH), and less likely, carotid dissection, subarachnoid hemorrhage, intracranial hemorrhage, pituitary apoplexy, or neoplasm.

Treatment. Individualized treatment depends on the diagnosis. Preeclampsia with severe features is treated with antihypertensive medication, magnesium sulfate, and delivery planning. PDP headache is treated with epidural blood patch, sphenopalatine block, or occipital block with an anesthesiology consultation. If preeclampsia and PDP are ruled out, or if there are more concerning neurologic features, imaging is essential, as 25% of pregnant patients with acute headaches will have a secondary etiology. Magnetic resonance imaging without contrast is preferred due to concerns about gadolinium crossing the placenta and the lack of data on long-term accumulation in fetal  tissues. Once diagnosed on imaging, PRES and RCVS are treated with antihypertensives and delivery. CVST is treated with anticoagulation and a thrombophilia workup. IIH may be treated with acetazolamide after 20 weeks or serial lumbar punctures. Intracranial vascular abnormalities may be treated with endoscopic resection and steroids. ●

In the musical Hamilton, there is a line from the song “The Election of 1800” in which, after a tumultuous time, Thomas Jefferson pleads for a sense of normalcy with, “Can we get back to politics?”

Trying to get back to “normal,” whatever that is, characterized the year 2022. Peeking out from under the constant shadow of the COVID-19 pandemic (not really gone, definitely not forgotten) were some blockbuster obstetrical headlines, including those on the CHAP (Chronic Hypertension and Pregnancy) trial and the impact of the Dobbs v Jackson Supreme Court decision. As these have been extensively covered in both OBG Management and other publications, in this Update we simply ask, “Can we get back to obstetrics?” as we focus on some straightforward patient care guidelines.

Thus, we offer updated information on the use of progesterone for preterm birth prevention, management of pregnancies that result from in vitro fertilization (IVF), and headache management in pregnant and postpartum patients.

Society guidance and FDA  advisement on the use of  progesterone for the prevention  of spontaneous preterm birth

American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins–Obstetrics. Prediction and prevention of spontaneous preterm birth. ACOG practice bulletin no. 234. Obstet Gynecol. 2021;138:e65-e90.

EPPPIC Group. Evaluating Progestogens for Preventing Preterm birth International Collaborative (EPPPIC): meta-analysis of individual participant data from randomised controlled trials. Lancet. 2021;397:1183-1194.

This is not déjà vu! Progesterone and spontaneous preterm birth (sPTB) is a hot topic again. If you wonder what to tell your patients, you are not alone. Preterm birth (PTB) continues to pose a challenge in obstetrics, with a most recently reported overall rate of 10.49%¹ in the United States—a 4% increase from 2019. Preterm birth accounts for approximately 75% of perinatal mortality and more than half of neonatal morbidity.²

What has not changed

A recent practice bulletin from the American College of Obstetricians and Gynecologists (ACOG) notes that some risk factors and screening assessments for PTB remain unchanged, including²:

• A history of PTB increases the risk for subsequent PTB. Risk increases with the number of prior preterm deliveries.
• A short cervix (<25 mm between 16 and  24 weeks’ gestation) is a risk factor for sPTB.
• The cervix should be visualized during the anatomy ultrasound exam (18 0/7 to 22 6/7 weeks’ gestation) in all pregnant patients regardless of prior birth history. If the cervix length (CL) appears shortened on transabdominal imaging, transvaginal (TV) imaging should be performed.
• Patients with a current singleton pregnancy and history of sPTB should have serial TV cervical measurements between 16 0/7 and 24 0/7 weeks’ gestation.²

EPPPIC changes and key takeaway points

In a meta-analysis of data from 31 randomized controlled trials, the EPPPIC (Evaluating Progestogens for Preventing Preterm birth International Collaborative) investigators compared vaginal progesterone, intramuscular 17-hydroxyprogesterone caproate  (17-OHPC), or oral progesterone with control or with each other in women at risk for PTB.³ Outcomes included PTB and the associated adverse neonatal and maternal outcomes.

The EPPPIC study’s main findings were:

• Singleton pregnancies at high risk for PTB due to prior sPTB or short cervix who received 17-OHPC or vaginal progesterone were less likely to deliver before  34 weeks’ gestation compared with those who received no treatment.
• There is a benefit to both 17-OHPC and vaginal progesterone in reducing the risk of PTB, with no clear evidence to support one intervention’s effectiveness over the other.
• There is benefit to either 17-OHPC or vaginal progesterone for CL less than 25 mm. The shorter the CL, the greater the absolute risk reduction on PTB.
• In multifetal pregnancies, use of 17-OHPC, when compared with placebo, was shown to increase the risk of preterm premature rupture of membranes. Neither 17-OHPC nor vaginal progesterone was found to reduce the risk of sPTB in multifetal pregnancies.³

What continues to change

While the March 30, 2021, statement from the Society for Maternal-Fetal Medicine (SMFM), “Response to EPPPIC and consideration for the use of progestogens for the prevention of preterm birth” (https://www .smfm.org/publications/383-smfm-stat ement-response-to-epppic-and-consider ations-of-the-use-of-progestogens-for-the -prevention-of-preterm-birth), stands, ACOG has withdrawn its accompanying Practice Advisory on guidance for integrating the EPPPIC findings.

In August 2022, the US Food and Drug Administration (FDA) granted a hearing on the Center for Drug Evaluation and Research’s proposal to withdraw approval for Makena (hydroxyprogesterone caproate injection, 250 mg/mL, once weekly) on the basis that available evidence does not demonstrate that it is effective for its approved indication to reduce the risk of PTB in women with a singleton pregnancy with a history of singleton sPTB.⁴

The key takeaway points from the FDA hearing (October 17–19, 2022) were:

• A better designed randomized controlled confirmatory trial is needed in the most at-risk patients to determine if Makena is effective for its approved indication.
• Makena and its approved generic equivalents remain on the market until the FDA makes its final decision regarding approval.⁴

Continue to: Managing pregnancies that result from IVF...

Society for Maternal-Fetal Medicine (SMFM); Ghidini A, Gandhi M, McCoy J, et al; Publications Committee. Society for Maternal-Fetal Medicine consult series #60: management of pregnancies resulting from in vitro fertilization. Am J Obstet Gynecol. 2022;226:B2-B12.

Assisted reproductive technology contributes to 1.6% of all infant births, and although most pregnancies are uncomplicated, some specific risks alter management.^5–7 For example, IVF is associated with increased rates of prematurity and its complications, fetal growth restriction, low birth weight, congenital anomalies, genetic abnormalities, and placental abnormalities. In addition, there is doubling of the risk of morbidities to the pregnant IVF patient, including but not limited to hypertensive disorders and diabetes. These complications are thought to be related to both the process of IVF itself as well as to conditions that contribute to subfertility and infertility in the first place.

Genetic screening and diagnostic testing options

IVF pregnancies have a documented increase in chromosomal abnormalities compared with spontaneously conceived pregnancies due to the following factors:

• karyotypic abnormalities in couples with infertility
• microdeletions on the Y chromosome in patients with oligospermia or azoospermia
• de novo chromosomal abnormalities in IVF pregnancies that utilize intracytoplasmic sperm injection (ICSI)
• fragile X mutations in patients with reduced ovarian reserve
• imprinting disorders in patients with fertility issues.

A common misconception is that preimplantation genetic testing renders prenatal genetic screening or testing unnecessary. However, preimplantation testing can be anywhere from 43% to 84% concordant with prenatal diagnostic testing due to biologic and technical factors. Therefore, all pregnancies should be offered the same options of aneuploidy screening as well as diagnostic testing. Pretest counseling should include an increased risk in IVF pregnancies of false-positives for the first-trimester screen and “no-call” results for cell-free fetal DNA. Additionally, diagnostic testing is recommended specifically in cases where mosaic embryos are transferred when euploid embryos are not available.

Counseling on fetal reduction for multifetal pregnancies

The risks of multifetal pregnancies (particularly higher order multiples) are significant and well documented for both the patient and the fetuses. It is therefore recommended that the option of multifetal pregnancy reduction be discussed, including the risks and benefits of reduction versus pregnancy continuation, timing, procedural considerations, and genetic testing options.^5,8

Detailed anatomic survey and fetal echocardiogram are indicated

Fetal anomalies, including congenital cardiac defects, occur at a higher rate in IVF pregnancies compared with spontaneously conceived pregnancies (475/10,000 live births vs 317/10,000 live births). Placental anomalies (such as placenta previa, vasa previa, and velamentous cord insertion) are also more common in this population. A detailed anatomic survey is therefore recommended for all IVF pregnancies and it is suggested that a fetal echocardiogram is offered these patients as well.

Pregnancy management and delivery considerations

Despite an increased risk of preterm birth, preeclampsia, and fetal growth restriction in IVF pregnancies (odds ratios range, 1.4–2), serial cervical lengths, serial growth ultrasound exams, and low-dose aspirin are not recommended for the sole indication of IVF. Due to lack of data on the utility of serial exams, a single screening cervical length at the time of anatomic survey and a third-trimester growth assessment are recommended. For aspirin, IVF qualifies as a “moderate” risk factor for preeclampsia; it is therefore recommended if another moderate risk factor is present (for example, nulliparity, obesity, or family history of preeclampsia).⁹

There is a 2- to 3-fold increased risk of stillbirth in IVF pregnancies; therefore, antenatal surveillance in the third trimester is recommended (weekly starting at 36 weeks for the sole indication of IVF).¹⁰ As no specific studies have evaluated the timing of delivery in IVF pregnancies, delivery recommendations include the option of 39-week delivery with shared decision-making with the patient.

Continue to: Evaluating and treating headaches in pregnancy and postpartum...

Evaluating and treating headaches in pregnancy and postpartum

American College of Obstetricians and Gynecologists. Clinical practice guideline no. 3: headaches in pregnancy and postpartum. Obstet Gynecol. 2022;139:944-972.

For obstetricians, headaches are a common and often frustrating condition to treat, as many of the available diagnostic tools and medications are either not recommended or have no data on use in pregnancy and lactation. Additionally, a headache is not always just a headache but could be a sign of a time-sensitive serious complication. An updated guideline from the American College of Obstetricians and Gynecologists approaches the topic of headaches in a stepwise algorithm that promotes efficiency and efficacy in diagnosis  and treatment.¹¹

Types of headaches

The primary headache types—migraine, cluster, and tension—are distinguished from each other by patient characteristics, quality, duration, location, and related symptoms. Reassuringly, headache frequency decreases by 30% to 80% during pregnancy, which allows for the option to decrease, change, or stop current medications, ideally prior to pregnancy. Prevention via use of calcium channel blockers, antihistamines, or β-blockers is recommended, as requiring acute treatments more than 2 days per week increases the risk of medication overuse headaches.

Treating acute headache

For patients who present with an acute headache consistent with their usual type, treatment starts with known medications that are compatible with pregnancy and proceeds in a stepwise fashion:

1. Acetaminophen 1,000 mg orally with or without caffeine 130 mg orally (maximum dose, acetaminophen < 3.25–4 g per day, caffeine 200 mg per day)

2. Metoclopramide 10 mg intravenously with or without diphenhydramine 25 mg intravenously (for nausea and to counteract restlessness and offer sedation)

3. If headache continues after steps 1 and 2, consider the following secondary treatment options: magnesium sulfate 1–2 g intravenously, sumatriptan 6 mg subcutaneously or 20-mg nasal spray, ibuprofen 600 mg orally once, or ketorolac 30 mg intravenously once (second trimester only)

4. If continued treatment and/or hospitalization is required after step 3, steroids can be used: prednisone 20 mg 4 times a day for 2 days or methylprednisolone 4-mg dose pack over 6 days

5. Do not use butalbital, opioids, or ergotamines due to lack of efficacy in providing additional pain relief, potential for addiction, risk of medication overuse headaches, and association with fetal/ pregnancy abnormalities.

Consider secondary headache

An acute headache discordant from the patient’s usual type or with concerning symptoms (“red flags”) requires consideration of secondary headaches as well as a comprehensive symptom evaluation, imaging, and consultation as needed. While secondary headaches postpartum are most likely musculoskeletal in nature, the following symptoms need to be evaluated immediately:

• rapid onset/change from baseline
• “thunderclap” nature
• hypertension
• fever
• focal neurologic deficits (blurry vision or blindness, confusion, seizures)
• altered consciousness
• laboratory abnormalities.

The differential diagnosis includes preeclampsia, reversible cerebral vasoconstriction syndrome (RCVS), posterior reversible encephalopathy syndrome (PRES), infection, cerebral venous sinus thrombosis (CVST), post–dural puncture (PDP) headache, idiopathic intracranial hypertension (IIH), and less likely, carotid dissection, subarachnoid hemorrhage, intracranial hemorrhage, pituitary apoplexy, or neoplasm.

Treatment. Individualized treatment depends on the diagnosis. Preeclampsia with severe features is treated with antihypertensive medication, magnesium sulfate, and delivery planning. PDP headache is treated with epidural blood patch, sphenopalatine block, or occipital block with an anesthesiology consultation. If preeclampsia and PDP are ruled out, or if there are more concerning neurologic features, imaging is essential, as 25% of pregnant patients with acute headaches will have a secondary etiology. Magnetic resonance imaging without contrast is preferred due to concerns about gadolinium crossing the placenta and the lack of data on long-term accumulation in fetal  tissues. Once diagnosed on imaging, PRES and RCVS are treated with antihypertensives and delivery. CVST is treated with anticoagulation and a thrombophilia workup. IIH may be treated with acetazolamide after 20 weeks or serial lumbar punctures. Intracranial vascular abnormalities may be treated with endoscopic resection and steroids. ●

In the musical Hamilton, there is a line from the song “The Election of 1800” in which, after a tumultuous time, Thomas Jefferson pleads for a sense of normalcy with, “Can we get back to politics?”

Trying to get back to “normal,” whatever that is, characterized the year 2022. Peeking out from under the constant shadow of the COVID-19 pandemic (not really gone, definitely not forgotten) were some blockbuster obstetrical headlines, including those on the CHAP (Chronic Hypertension and Pregnancy) trial and the impact of the Dobbs v Jackson Supreme Court decision. As these have been extensively covered in both OBG Management and other publications, in this Update we simply ask, “Can we get back to obstetrics?” as we focus on some straightforward patient care guidelines.

Thus, we offer updated information on the use of progesterone for preterm birth prevention, management of pregnancies that result from in vitro fertilization (IVF), and headache management in pregnant and postpartum patients.

Society guidance and FDA  advisement on the use of  progesterone for the prevention  of spontaneous preterm birth

American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins–Obstetrics. Prediction and prevention of spontaneous preterm birth. ACOG practice bulletin no. 234. Obstet Gynecol. 2021;138:e65-e90.

EPPPIC Group. Evaluating Progestogens for Preventing Preterm birth International Collaborative (EPPPIC): meta-analysis of individual participant data from randomised controlled trials. Lancet. 2021;397:1183-1194.

This is not déjà vu! Progesterone and spontaneous preterm birth (sPTB) is a hot topic again. If you wonder what to tell your patients, you are not alone. Preterm birth (PTB) continues to pose a challenge in obstetrics, with a most recently reported overall rate of 10.49%¹ in the United States—a 4% increase from 2019. Preterm birth accounts for approximately 75% of perinatal mortality and more than half of neonatal morbidity.²

What has not changed

A recent practice bulletin from the American College of Obstetricians and Gynecologists (ACOG) notes that some risk factors and screening assessments for PTB remain unchanged, including²:

• A history of PTB increases the risk for subsequent PTB. Risk increases with the number of prior preterm deliveries.
• A short cervix (<25 mm between 16 and  24 weeks’ gestation) is a risk factor for sPTB.
• The cervix should be visualized during the anatomy ultrasound exam (18 0/7 to 22 6/7 weeks’ gestation) in all pregnant patients regardless of prior birth history. If the cervix length (CL) appears shortened on transabdominal imaging, transvaginal (TV) imaging should be performed.
• Patients with a current singleton pregnancy and history of sPTB should have serial TV cervical measurements between 16 0/7 and 24 0/7 weeks’ gestation.²

EPPPIC changes and key takeaway points

In a meta-analysis of data from 31 randomized controlled trials, the EPPPIC (Evaluating Progestogens for Preventing Preterm birth International Collaborative) investigators compared vaginal progesterone, intramuscular 17-hydroxyprogesterone caproate  (17-OHPC), or oral progesterone with control or with each other in women at risk for PTB.³ Outcomes included PTB and the associated adverse neonatal and maternal outcomes.

The EPPPIC study’s main findings were:

• Singleton pregnancies at high risk for PTB due to prior sPTB or short cervix who received 17-OHPC or vaginal progesterone were less likely to deliver before  34 weeks’ gestation compared with those who received no treatment.
• There is a benefit to both 17-OHPC and vaginal progesterone in reducing the risk of PTB, with no clear evidence to support one intervention’s effectiveness over the other.
• There is benefit to either 17-OHPC or vaginal progesterone for CL less than 25 mm. The shorter the CL, the greater the absolute risk reduction on PTB.
• In multifetal pregnancies, use of 17-OHPC, when compared with placebo, was shown to increase the risk of preterm premature rupture of membranes. Neither 17-OHPC nor vaginal progesterone was found to reduce the risk of sPTB in multifetal pregnancies.³

What continues to change

While the March 30, 2021, statement from the Society for Maternal-Fetal Medicine (SMFM), “Response to EPPPIC and consideration for the use of progestogens for the prevention of preterm birth” (https://www .smfm.org/publications/383-smfm-stat ement-response-to-epppic-and-consider ations-of-the-use-of-progestogens-for-the -prevention-of-preterm-birth), stands, ACOG has withdrawn its accompanying Practice Advisory on guidance for integrating the EPPPIC findings.

In August 2022, the US Food and Drug Administration (FDA) granted a hearing on the Center for Drug Evaluation and Research’s proposal to withdraw approval for Makena (hydroxyprogesterone caproate injection, 250 mg/mL, once weekly) on the basis that available evidence does not demonstrate that it is effective for its approved indication to reduce the risk of PTB in women with a singleton pregnancy with a history of singleton sPTB.⁴

The key takeaway points from the FDA hearing (October 17–19, 2022) were:

• A better designed randomized controlled confirmatory trial is needed in the most at-risk patients to determine if Makena is effective for its approved indication.
• Makena and its approved generic equivalents remain on the market until the FDA makes its final decision regarding approval.⁴

Continue to: Managing pregnancies that result from IVF...

Society for Maternal-Fetal Medicine (SMFM); Ghidini A, Gandhi M, McCoy J, et al; Publications Committee. Society for Maternal-Fetal Medicine consult series #60: management of pregnancies resulting from in vitro fertilization. Am J Obstet Gynecol. 2022;226:B2-B12.

Assisted reproductive technology contributes to 1.6% of all infant births, and although most pregnancies are uncomplicated, some specific risks alter management.^5–7 For example, IVF is associated with increased rates of prematurity and its complications, fetal growth restriction, low birth weight, congenital anomalies, genetic abnormalities, and placental abnormalities. In addition, there is doubling of the risk of morbidities to the pregnant IVF patient, including but not limited to hypertensive disorders and diabetes. These complications are thought to be related to both the process of IVF itself as well as to conditions that contribute to subfertility and infertility in the first place.

Genetic screening and diagnostic testing options

IVF pregnancies have a documented increase in chromosomal abnormalities compared with spontaneously conceived pregnancies due to the following factors:

• karyotypic abnormalities in couples with infertility
• microdeletions on the Y chromosome in patients with oligospermia or azoospermia
• de novo chromosomal abnormalities in IVF pregnancies that utilize intracytoplasmic sperm injection (ICSI)
• fragile X mutations in patients with reduced ovarian reserve
• imprinting disorders in patients with fertility issues.

A common misconception is that preimplantation genetic testing renders prenatal genetic screening or testing unnecessary. However, preimplantation testing can be anywhere from 43% to 84% concordant with prenatal diagnostic testing due to biologic and technical factors. Therefore, all pregnancies should be offered the same options of aneuploidy screening as well as diagnostic testing. Pretest counseling should include an increased risk in IVF pregnancies of false-positives for the first-trimester screen and “no-call” results for cell-free fetal DNA. Additionally, diagnostic testing is recommended specifically in cases where mosaic embryos are transferred when euploid embryos are not available.

Counseling on fetal reduction for multifetal pregnancies

The risks of multifetal pregnancies (particularly higher order multiples) are significant and well documented for both the patient and the fetuses. It is therefore recommended that the option of multifetal pregnancy reduction be discussed, including the risks and benefits of reduction versus pregnancy continuation, timing, procedural considerations, and genetic testing options.^5,8

Detailed anatomic survey and fetal echocardiogram are indicated

Fetal anomalies, including congenital cardiac defects, occur at a higher rate in IVF pregnancies compared with spontaneously conceived pregnancies (475/10,000 live births vs 317/10,000 live births). Placental anomalies (such as placenta previa, vasa previa, and velamentous cord insertion) are also more common in this population. A detailed anatomic survey is therefore recommended for all IVF pregnancies and it is suggested that a fetal echocardiogram is offered these patients as well.

Pregnancy management and delivery considerations

Despite an increased risk of preterm birth, preeclampsia, and fetal growth restriction in IVF pregnancies (odds ratios range, 1.4–2), serial cervical lengths, serial growth ultrasound exams, and low-dose aspirin are not recommended for the sole indication of IVF. Due to lack of data on the utility of serial exams, a single screening cervical length at the time of anatomic survey and a third-trimester growth assessment are recommended. For aspirin, IVF qualifies as a “moderate” risk factor for preeclampsia; it is therefore recommended if another moderate risk factor is present (for example, nulliparity, obesity, or family history of preeclampsia).⁹

There is a 2- to 3-fold increased risk of stillbirth in IVF pregnancies; therefore, antenatal surveillance in the third trimester is recommended (weekly starting at 36 weeks for the sole indication of IVF).¹⁰ As no specific studies have evaluated the timing of delivery in IVF pregnancies, delivery recommendations include the option of 39-week delivery with shared decision-making with the patient.

Continue to: Evaluating and treating headaches in pregnancy and postpartum...

Evaluating and treating headaches in pregnancy and postpartum

American College of Obstetricians and Gynecologists. Clinical practice guideline no. 3: headaches in pregnancy and postpartum. Obstet Gynecol. 2022;139:944-972.

For obstetricians, headaches are a common and often frustrating condition to treat, as many of the available diagnostic tools and medications are either not recommended or have no data on use in pregnancy and lactation. Additionally, a headache is not always just a headache but could be a sign of a time-sensitive serious complication. An updated guideline from the American College of Obstetricians and Gynecologists approaches the topic of headaches in a stepwise algorithm that promotes efficiency and efficacy in diagnosis  and treatment.¹¹

Types of headaches

The primary headache types—migraine, cluster, and tension—are distinguished from each other by patient characteristics, quality, duration, location, and related symptoms. Reassuringly, headache frequency decreases by 30% to 80% during pregnancy, which allows for the option to decrease, change, or stop current medications, ideally prior to pregnancy. Prevention via use of calcium channel blockers, antihistamines, or β-blockers is recommended, as requiring acute treatments more than 2 days per week increases the risk of medication overuse headaches.

Treating acute headache

For patients who present with an acute headache consistent with their usual type, treatment starts with known medications that are compatible with pregnancy and proceeds in a stepwise fashion:

1. Acetaminophen 1,000 mg orally with or without caffeine 130 mg orally (maximum dose, acetaminophen < 3.25–4 g per day, caffeine 200 mg per day)

2. Metoclopramide 10 mg intravenously with or without diphenhydramine 25 mg intravenously (for nausea and to counteract restlessness and offer sedation)

3. If headache continues after steps 1 and 2, consider the following secondary treatment options: magnesium sulfate 1–2 g intravenously, sumatriptan 6 mg subcutaneously or 20-mg nasal spray, ibuprofen 600 mg orally once, or ketorolac 30 mg intravenously once (second trimester only)

4. If continued treatment and/or hospitalization is required after step 3, steroids can be used: prednisone 20 mg 4 times a day for 2 days or methylprednisolone 4-mg dose pack over 6 days

5. Do not use butalbital, opioids, or ergotamines due to lack of efficacy in providing additional pain relief, potential for addiction, risk of medication overuse headaches, and association with fetal/ pregnancy abnormalities.

Consider secondary headache

An acute headache discordant from the patient’s usual type or with concerning symptoms (“red flags”) requires consideration of secondary headaches as well as a comprehensive symptom evaluation, imaging, and consultation as needed. While secondary headaches postpartum are most likely musculoskeletal in nature, the following symptoms need to be evaluated immediately:

• rapid onset/change from baseline
• “thunderclap” nature
• hypertension
• fever
• focal neurologic deficits (blurry vision or blindness, confusion, seizures)
• altered consciousness
• laboratory abnormalities.

The differential diagnosis includes preeclampsia, reversible cerebral vasoconstriction syndrome (RCVS), posterior reversible encephalopathy syndrome (PRES), infection, cerebral venous sinus thrombosis (CVST), post–dural puncture (PDP) headache, idiopathic intracranial hypertension (IIH), and less likely, carotid dissection, subarachnoid hemorrhage, intracranial hemorrhage, pituitary apoplexy, or neoplasm.

Treatment. Individualized treatment depends on the diagnosis. Preeclampsia with severe features is treated with antihypertensive medication, magnesium sulfate, and delivery planning. PDP headache is treated with epidural blood patch, sphenopalatine block, or occipital block with an anesthesiology consultation. If preeclampsia and PDP are ruled out, or if there are more concerning neurologic features, imaging is essential, as 25% of pregnant patients with acute headaches will have a secondary etiology. Magnetic resonance imaging without contrast is preferred due to concerns about gadolinium crossing the placenta and the lack of data on long-term accumulation in fetal  tissues. Once diagnosed on imaging, PRES and RCVS are treated with antihypertensives and delivery. CVST is treated with anticoagulation and a thrombophilia workup. IIH may be treated with acetazolamide after 20 weeks or serial lumbar punctures. Intracranial vascular abnormalities may be treated with endoscopic resection and steroids. ●