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Nondopamine antipsychotic shows clinical signal in Parkinson’s disease psychosis
according to results of a proof-of-principle study presented at the 2021 annual meeting of the American Academy of Neurology.
In presenting study results, Stuart H. Isaacson, MD, of the Parkinson’s Disease and Movement Disorders Center in Boca Raton, Fla., noted the one potential advantage of SEP-363856 is that it does not require blood monitoring, unlike clozapine, often used as an alternative to pimavanserin, the only Food and Drug Administration–approved treatment for Parkinson’s disease psychosis.* Quetiapine has also been used off label for Parkinson’s disease psychosis, but Dr. Isaacson said this lacks the evidence supporting the other two options and has side effects including sedation and orthostatic hypotension.
“Other non–FDA-approved treatment options are limited due to their lack of efficacy, safety concerns, and exacerbation of motor symptoms,” he said.
The study involved 38 patients, 24 of whom received SEP-363856 and the rest placebo, and evaluated total scores for the novel Scale for the Assessment of Positive Symptoms for Parkinson’s Disease Psychosis (SAPS-PD) after 6 weeks of treatment. The treatment group was given one of three doses: 25 mg (n = 11), 50 mg (n = 9), and 75 mg (n = 10).
Dr. Isaacson described SEP-363856 as a novel molecule that has agonist activity at TARR1, which regulates dopamine, norepinephrine, and serotonin, as well as serotonin receptor 5-HT1A, but has no activity at the dopamine receptor D2.
“There did appear to be improvement with this medication in patients’ psychosis symptoms, using the SAPS-PD subscale to identify the frequency and severity of hallucinations and delusions, but there was also improvement in the placebo group in this small study,” Dr. Isaacson said. “That did not demonstrate significance.” The improvement was maintained through the study period.
But the gap between the treatment and placebo groups widened as the degree of response increased. The rates were identical for the 30% or above response and the 50% or above response subgroups: 27.3% and 37.5% for placebo and treatment groups, respectively. However, 25% of patients taking SEP-363856 had a 100% response in terms of SAPS-PD score versus 0% in the placebo group, Dr. Isaacson said.
The study also found Mini-Mental State Examination (MMSE) scores improved more in the treatment group, with the gap wider in those with baseline MMSE scores below 24 versus scores above 24: –5.2 (standard deviation, 2.81) versus –2.1 (SD, 3.00; P = .460).
“The scope of daytime and nighttime sleep both showed improvement, with the score for daytime sleep being significant,” Dr. Isaacson said of the treatment group. “Importantly, UPDRS [Unified Parkinson’s Disease Rating Scale] Part III motor scores showed no difference from placebo. Indeed, there was a trend toward improvement, but this again was not significant.” That’s noteworthy, he said, because other antipsychotics, with the exception of clozapine – which requires blood monitoring – are contraindicated in PDP because of their effect on motor function.
During question-and-answer, Dr. Isaacson noted that the complete response rate of 25% with SEP-363856 compared favorably with the 14% complete response rate reported with pimavanserin in the pivotal trial.
“Hopefully greater-powered studies will be performed to further identify and determine the safety and efficacy and tolerably of SEP-363856 in Parkinson’s psychosis, aiming to minimize the placebo effect and to try to hopefully identify its efficacy in relationship to other treatments,” Dr. Isaacson said.
“Right now with only one approved treatment, one that has efficacy but requires blood monitoring, and another treatment that may be fraught sometimes with sleepiness and other side effects, we need other alternatives for our patients as many of them resort to lowering and lowering their dopaminergic therapies with the consequence [of] worsening motor activity,” Dr. Isaacson said.
“This study further supports the concept that Parkinson’s disease psychosis involves much more than simply dopamine,” said Daniel E. Kremens, MD, codirector of the Parkinson’s disease and movement disorders division at Thomas Jefferson University, Philadelphia. “Targeting nondopaminergic targets allows us to treat the psychosis without worsening motor symptoms. By targeting TAAR-1 along with 5HT1A, SEP-363856 is a novel compound that appears to be well tolerated and may treat PDP without worsening motor symptoms,”
Sunovion Pharmaceuticals provided funding for the study. Dr. Isaacson has no financial relationships to disclose. Three study coauthors are employees of Sunovion. Dr. Kremens reported serving as a consultant to Sunovion.
*Correction, 5/17/21: An earlier version of this article misstated the blood monitoring requirements for pimavanserin.
according to results of a proof-of-principle study presented at the 2021 annual meeting of the American Academy of Neurology.
In presenting study results, Stuart H. Isaacson, MD, of the Parkinson’s Disease and Movement Disorders Center in Boca Raton, Fla., noted the one potential advantage of SEP-363856 is that it does not require blood monitoring, unlike clozapine, often used as an alternative to pimavanserin, the only Food and Drug Administration–approved treatment for Parkinson’s disease psychosis.* Quetiapine has also been used off label for Parkinson’s disease psychosis, but Dr. Isaacson said this lacks the evidence supporting the other two options and has side effects including sedation and orthostatic hypotension.
“Other non–FDA-approved treatment options are limited due to their lack of efficacy, safety concerns, and exacerbation of motor symptoms,” he said.
The study involved 38 patients, 24 of whom received SEP-363856 and the rest placebo, and evaluated total scores for the novel Scale for the Assessment of Positive Symptoms for Parkinson’s Disease Psychosis (SAPS-PD) after 6 weeks of treatment. The treatment group was given one of three doses: 25 mg (n = 11), 50 mg (n = 9), and 75 mg (n = 10).
Dr. Isaacson described SEP-363856 as a novel molecule that has agonist activity at TARR1, which regulates dopamine, norepinephrine, and serotonin, as well as serotonin receptor 5-HT1A, but has no activity at the dopamine receptor D2.
“There did appear to be improvement with this medication in patients’ psychosis symptoms, using the SAPS-PD subscale to identify the frequency and severity of hallucinations and delusions, but there was also improvement in the placebo group in this small study,” Dr. Isaacson said. “That did not demonstrate significance.” The improvement was maintained through the study period.
But the gap between the treatment and placebo groups widened as the degree of response increased. The rates were identical for the 30% or above response and the 50% or above response subgroups: 27.3% and 37.5% for placebo and treatment groups, respectively. However, 25% of patients taking SEP-363856 had a 100% response in terms of SAPS-PD score versus 0% in the placebo group, Dr. Isaacson said.
The study also found Mini-Mental State Examination (MMSE) scores improved more in the treatment group, with the gap wider in those with baseline MMSE scores below 24 versus scores above 24: –5.2 (standard deviation, 2.81) versus –2.1 (SD, 3.00; P = .460).
“The scope of daytime and nighttime sleep both showed improvement, with the score for daytime sleep being significant,” Dr. Isaacson said of the treatment group. “Importantly, UPDRS [Unified Parkinson’s Disease Rating Scale] Part III motor scores showed no difference from placebo. Indeed, there was a trend toward improvement, but this again was not significant.” That’s noteworthy, he said, because other antipsychotics, with the exception of clozapine – which requires blood monitoring – are contraindicated in PDP because of their effect on motor function.
During question-and-answer, Dr. Isaacson noted that the complete response rate of 25% with SEP-363856 compared favorably with the 14% complete response rate reported with pimavanserin in the pivotal trial.
“Hopefully greater-powered studies will be performed to further identify and determine the safety and efficacy and tolerably of SEP-363856 in Parkinson’s psychosis, aiming to minimize the placebo effect and to try to hopefully identify its efficacy in relationship to other treatments,” Dr. Isaacson said.
“Right now with only one approved treatment, one that has efficacy but requires blood monitoring, and another treatment that may be fraught sometimes with sleepiness and other side effects, we need other alternatives for our patients as many of them resort to lowering and lowering their dopaminergic therapies with the consequence [of] worsening motor activity,” Dr. Isaacson said.
“This study further supports the concept that Parkinson’s disease psychosis involves much more than simply dopamine,” said Daniel E. Kremens, MD, codirector of the Parkinson’s disease and movement disorders division at Thomas Jefferson University, Philadelphia. “Targeting nondopaminergic targets allows us to treat the psychosis without worsening motor symptoms. By targeting TAAR-1 along with 5HT1A, SEP-363856 is a novel compound that appears to be well tolerated and may treat PDP without worsening motor symptoms,”
Sunovion Pharmaceuticals provided funding for the study. Dr. Isaacson has no financial relationships to disclose. Three study coauthors are employees of Sunovion. Dr. Kremens reported serving as a consultant to Sunovion.
*Correction, 5/17/21: An earlier version of this article misstated the blood monitoring requirements for pimavanserin.
according to results of a proof-of-principle study presented at the 2021 annual meeting of the American Academy of Neurology.
In presenting study results, Stuart H. Isaacson, MD, of the Parkinson’s Disease and Movement Disorders Center in Boca Raton, Fla., noted the one potential advantage of SEP-363856 is that it does not require blood monitoring, unlike clozapine, often used as an alternative to pimavanserin, the only Food and Drug Administration–approved treatment for Parkinson’s disease psychosis.* Quetiapine has also been used off label for Parkinson’s disease psychosis, but Dr. Isaacson said this lacks the evidence supporting the other two options and has side effects including sedation and orthostatic hypotension.
“Other non–FDA-approved treatment options are limited due to their lack of efficacy, safety concerns, and exacerbation of motor symptoms,” he said.
The study involved 38 patients, 24 of whom received SEP-363856 and the rest placebo, and evaluated total scores for the novel Scale for the Assessment of Positive Symptoms for Parkinson’s Disease Psychosis (SAPS-PD) after 6 weeks of treatment. The treatment group was given one of three doses: 25 mg (n = 11), 50 mg (n = 9), and 75 mg (n = 10).
Dr. Isaacson described SEP-363856 as a novel molecule that has agonist activity at TARR1, which regulates dopamine, norepinephrine, and serotonin, as well as serotonin receptor 5-HT1A, but has no activity at the dopamine receptor D2.
“There did appear to be improvement with this medication in patients’ psychosis symptoms, using the SAPS-PD subscale to identify the frequency and severity of hallucinations and delusions, but there was also improvement in the placebo group in this small study,” Dr. Isaacson said. “That did not demonstrate significance.” The improvement was maintained through the study period.
But the gap between the treatment and placebo groups widened as the degree of response increased. The rates were identical for the 30% or above response and the 50% or above response subgroups: 27.3% and 37.5% for placebo and treatment groups, respectively. However, 25% of patients taking SEP-363856 had a 100% response in terms of SAPS-PD score versus 0% in the placebo group, Dr. Isaacson said.
The study also found Mini-Mental State Examination (MMSE) scores improved more in the treatment group, with the gap wider in those with baseline MMSE scores below 24 versus scores above 24: –5.2 (standard deviation, 2.81) versus –2.1 (SD, 3.00; P = .460).
“The scope of daytime and nighttime sleep both showed improvement, with the score for daytime sleep being significant,” Dr. Isaacson said of the treatment group. “Importantly, UPDRS [Unified Parkinson’s Disease Rating Scale] Part III motor scores showed no difference from placebo. Indeed, there was a trend toward improvement, but this again was not significant.” That’s noteworthy, he said, because other antipsychotics, with the exception of clozapine – which requires blood monitoring – are contraindicated in PDP because of their effect on motor function.
During question-and-answer, Dr. Isaacson noted that the complete response rate of 25% with SEP-363856 compared favorably with the 14% complete response rate reported with pimavanserin in the pivotal trial.
“Hopefully greater-powered studies will be performed to further identify and determine the safety and efficacy and tolerably of SEP-363856 in Parkinson’s psychosis, aiming to minimize the placebo effect and to try to hopefully identify its efficacy in relationship to other treatments,” Dr. Isaacson said.
“Right now with only one approved treatment, one that has efficacy but requires blood monitoring, and another treatment that may be fraught sometimes with sleepiness and other side effects, we need other alternatives for our patients as many of them resort to lowering and lowering their dopaminergic therapies with the consequence [of] worsening motor activity,” Dr. Isaacson said.
“This study further supports the concept that Parkinson’s disease psychosis involves much more than simply dopamine,” said Daniel E. Kremens, MD, codirector of the Parkinson’s disease and movement disorders division at Thomas Jefferson University, Philadelphia. “Targeting nondopaminergic targets allows us to treat the psychosis without worsening motor symptoms. By targeting TAAR-1 along with 5HT1A, SEP-363856 is a novel compound that appears to be well tolerated and may treat PDP without worsening motor symptoms,”
Sunovion Pharmaceuticals provided funding for the study. Dr. Isaacson has no financial relationships to disclose. Three study coauthors are employees of Sunovion. Dr. Kremens reported serving as a consultant to Sunovion.
*Correction, 5/17/21: An earlier version of this article misstated the blood monitoring requirements for pimavanserin.
FROM AAN 2021
Helpful giant rodents and our old friend, the hookworm
Rat-ting out coronavirus
Did you know there is a possibility that giant rodents could rat out coronavirus? Not many people are keen on the presence of a 3-foot-long African giant pouched rat, but they have already been trained to sniff out diseases that are dangerous to humans, such as brucellosis and tuberculosis, according to researchers at the University of Glasgow.
Professor Dan Haydon and his associates believe there is a good possibility that the rats can be trained to sniff out COVID-19. Dogs have been helpful in sniffing for COVID-19 at airports and are being trained to detect it through armpit sweat, making detection of the virus easier for travelers and staff. Even robots have gotten into the COVID-19 detecting act.
Since African giant pouched rats can grow to be the size of a small dog and “are easily tamed as companion animals,” it seems likely that they have the potential to do the same. That is, sniffing for COVID-19, not appearing at your local airport. That’s still gross.
Stay healthy, get a parasite bestie
The key to health could actually be swimming around in your gut. Researchers from University College London have found that a parasitic worm could be the answer to longevity and avoidance of chronic diseases.
The seeming immunity from inflammatory diseases such as arthritis, diabetes, and multiple sclerosis may come from helminth parasites, or hookworms – parasites that have been coexisting harmlessly with the human body for thousands of years. The investigators went so far as to call them “old friends,” but the kind that you rarely see at reunions or call up for a favor.
As a result of modern sanitation and improved hygiene, humans and hookworms are seeing much less of each other, which may be a factor in the rise of “aging-associated inflammation” such as COVID-19 symptoms, they suggested. So is there a way to get these old friends back?
“Restorative hookworm treatments” could help with heart disease or dementia, according to the investigators, but maybe you’re not totally on board with getting an actual parasite in your system. We get it. There are helminth-derived proteins that have already been tested to get the job done.
Maybe old friends really do make the best friends.
I love the smell of microbe-infected aerosols in the morning
Have you gone into a public restroom and just stood around for a while appreciating the fine aromas? No? You haven’t? You do your business and get out? Well, it’s a good thing you act like a normal person, because the aerosols released when toilets flush can contain all sorts of nasty bacteria and viruses.
The authors of a new study published in Physics of Fluids came to this groundbreaking conclusion by going to a public bathroom, sticking particle counters above a urinal and a toilet, and letting them sit for a while. After 3 hours and 100 flushes, the ambient level of particles 0.3-3 mcm in diameter had increased dramatically, with particles sized 0.5-1 mcm particularly prone to lingering. For those particles, the level from baseline increased by over 200%.
This is a major concern, the researchers said, because the sort of microbes that are expelled through feces, urine, and vomit can include some pretty nasty things. Ebola, noroviruses that can cause food poisoning, and even good old SARS-CoV-2 can be expelled from the body but remain viable for a time in these aerosols. The researchers recommended improving the ventilation systems in restrooms so that aerosols don’t hang around for hours at a time. Plus, it might make the place not smell like a, uh, public restroom.
Not to question the research and the people behind it, but we’re not sure how necessary it was to give people another reason not to hang out in a place where hundreds, if not thousands, of people come to relieve themselves. There’s a reason we’re supposed to “stop and smell the roses” and not “stop and smell the public bathroom.”
World ends not with a bang but with a cheeseburger
Speaking of old sayings, one of our favorites, “You are what you eat,” may offer a culinary explanation for those who do enjoy the ambiance of a fine, aerosol-infested public restroom.
That explanation involves the high-calorie, high-fat smorgasbord known as the Western diet and some mice who were forced to consume it. Those mice, it turns out, were more anxious and less cognitively advanced than their counterparts who were not eating “highly palatable, energy dense foods (e.g., high saturated fat, high sugar) that are commonly consumed by humans,” according to the authors of a recent literature review.
“Consumption of a Western diet is related to poorer cognitive performance across the lifespan,” the investigators said, adding that consumption of a Western diet “during critical early life stages of development has negative consequences on various cognitive abilities later in adulthood.”
To show their appreciation for the sacrifices these brave test subjects had made in the name of science, the scientists released the Western diet–addled rodents from captivity. Not only did they survive and thrive in the wilds of darkest suburbia, but within 6 months almost half of them were running for Congress.
Rat-ting out coronavirus
Did you know there is a possibility that giant rodents could rat out coronavirus? Not many people are keen on the presence of a 3-foot-long African giant pouched rat, but they have already been trained to sniff out diseases that are dangerous to humans, such as brucellosis and tuberculosis, according to researchers at the University of Glasgow.
Professor Dan Haydon and his associates believe there is a good possibility that the rats can be trained to sniff out COVID-19. Dogs have been helpful in sniffing for COVID-19 at airports and are being trained to detect it through armpit sweat, making detection of the virus easier for travelers and staff. Even robots have gotten into the COVID-19 detecting act.
Since African giant pouched rats can grow to be the size of a small dog and “are easily tamed as companion animals,” it seems likely that they have the potential to do the same. That is, sniffing for COVID-19, not appearing at your local airport. That’s still gross.
Stay healthy, get a parasite bestie
The key to health could actually be swimming around in your gut. Researchers from University College London have found that a parasitic worm could be the answer to longevity and avoidance of chronic diseases.
The seeming immunity from inflammatory diseases such as arthritis, diabetes, and multiple sclerosis may come from helminth parasites, or hookworms – parasites that have been coexisting harmlessly with the human body for thousands of years. The investigators went so far as to call them “old friends,” but the kind that you rarely see at reunions or call up for a favor.
As a result of modern sanitation and improved hygiene, humans and hookworms are seeing much less of each other, which may be a factor in the rise of “aging-associated inflammation” such as COVID-19 symptoms, they suggested. So is there a way to get these old friends back?
“Restorative hookworm treatments” could help with heart disease or dementia, according to the investigators, but maybe you’re not totally on board with getting an actual parasite in your system. We get it. There are helminth-derived proteins that have already been tested to get the job done.
Maybe old friends really do make the best friends.
I love the smell of microbe-infected aerosols in the morning
Have you gone into a public restroom and just stood around for a while appreciating the fine aromas? No? You haven’t? You do your business and get out? Well, it’s a good thing you act like a normal person, because the aerosols released when toilets flush can contain all sorts of nasty bacteria and viruses.
The authors of a new study published in Physics of Fluids came to this groundbreaking conclusion by going to a public bathroom, sticking particle counters above a urinal and a toilet, and letting them sit for a while. After 3 hours and 100 flushes, the ambient level of particles 0.3-3 mcm in diameter had increased dramatically, with particles sized 0.5-1 mcm particularly prone to lingering. For those particles, the level from baseline increased by over 200%.
This is a major concern, the researchers said, because the sort of microbes that are expelled through feces, urine, and vomit can include some pretty nasty things. Ebola, noroviruses that can cause food poisoning, and even good old SARS-CoV-2 can be expelled from the body but remain viable for a time in these aerosols. The researchers recommended improving the ventilation systems in restrooms so that aerosols don’t hang around for hours at a time. Plus, it might make the place not smell like a, uh, public restroom.
Not to question the research and the people behind it, but we’re not sure how necessary it was to give people another reason not to hang out in a place where hundreds, if not thousands, of people come to relieve themselves. There’s a reason we’re supposed to “stop and smell the roses” and not “stop and smell the public bathroom.”
World ends not with a bang but with a cheeseburger
Speaking of old sayings, one of our favorites, “You are what you eat,” may offer a culinary explanation for those who do enjoy the ambiance of a fine, aerosol-infested public restroom.
That explanation involves the high-calorie, high-fat smorgasbord known as the Western diet and some mice who were forced to consume it. Those mice, it turns out, were more anxious and less cognitively advanced than their counterparts who were not eating “highly palatable, energy dense foods (e.g., high saturated fat, high sugar) that are commonly consumed by humans,” according to the authors of a recent literature review.
“Consumption of a Western diet is related to poorer cognitive performance across the lifespan,” the investigators said, adding that consumption of a Western diet “during critical early life stages of development has negative consequences on various cognitive abilities later in adulthood.”
To show their appreciation for the sacrifices these brave test subjects had made in the name of science, the scientists released the Western diet–addled rodents from captivity. Not only did they survive and thrive in the wilds of darkest suburbia, but within 6 months almost half of them were running for Congress.
Rat-ting out coronavirus
Did you know there is a possibility that giant rodents could rat out coronavirus? Not many people are keen on the presence of a 3-foot-long African giant pouched rat, but they have already been trained to sniff out diseases that are dangerous to humans, such as brucellosis and tuberculosis, according to researchers at the University of Glasgow.
Professor Dan Haydon and his associates believe there is a good possibility that the rats can be trained to sniff out COVID-19. Dogs have been helpful in sniffing for COVID-19 at airports and are being trained to detect it through armpit sweat, making detection of the virus easier for travelers and staff. Even robots have gotten into the COVID-19 detecting act.
Since African giant pouched rats can grow to be the size of a small dog and “are easily tamed as companion animals,” it seems likely that they have the potential to do the same. That is, sniffing for COVID-19, not appearing at your local airport. That’s still gross.
Stay healthy, get a parasite bestie
The key to health could actually be swimming around in your gut. Researchers from University College London have found that a parasitic worm could be the answer to longevity and avoidance of chronic diseases.
The seeming immunity from inflammatory diseases such as arthritis, diabetes, and multiple sclerosis may come from helminth parasites, or hookworms – parasites that have been coexisting harmlessly with the human body for thousands of years. The investigators went so far as to call them “old friends,” but the kind that you rarely see at reunions or call up for a favor.
As a result of modern sanitation and improved hygiene, humans and hookworms are seeing much less of each other, which may be a factor in the rise of “aging-associated inflammation” such as COVID-19 symptoms, they suggested. So is there a way to get these old friends back?
“Restorative hookworm treatments” could help with heart disease or dementia, according to the investigators, but maybe you’re not totally on board with getting an actual parasite in your system. We get it. There are helminth-derived proteins that have already been tested to get the job done.
Maybe old friends really do make the best friends.
I love the smell of microbe-infected aerosols in the morning
Have you gone into a public restroom and just stood around for a while appreciating the fine aromas? No? You haven’t? You do your business and get out? Well, it’s a good thing you act like a normal person, because the aerosols released when toilets flush can contain all sorts of nasty bacteria and viruses.
The authors of a new study published in Physics of Fluids came to this groundbreaking conclusion by going to a public bathroom, sticking particle counters above a urinal and a toilet, and letting them sit for a while. After 3 hours and 100 flushes, the ambient level of particles 0.3-3 mcm in diameter had increased dramatically, with particles sized 0.5-1 mcm particularly prone to lingering. For those particles, the level from baseline increased by over 200%.
This is a major concern, the researchers said, because the sort of microbes that are expelled through feces, urine, and vomit can include some pretty nasty things. Ebola, noroviruses that can cause food poisoning, and even good old SARS-CoV-2 can be expelled from the body but remain viable for a time in these aerosols. The researchers recommended improving the ventilation systems in restrooms so that aerosols don’t hang around for hours at a time. Plus, it might make the place not smell like a, uh, public restroom.
Not to question the research and the people behind it, but we’re not sure how necessary it was to give people another reason not to hang out in a place where hundreds, if not thousands, of people come to relieve themselves. There’s a reason we’re supposed to “stop and smell the roses” and not “stop and smell the public bathroom.”
World ends not with a bang but with a cheeseburger
Speaking of old sayings, one of our favorites, “You are what you eat,” may offer a culinary explanation for those who do enjoy the ambiance of a fine, aerosol-infested public restroom.
That explanation involves the high-calorie, high-fat smorgasbord known as the Western diet and some mice who were forced to consume it. Those mice, it turns out, were more anxious and less cognitively advanced than their counterparts who were not eating “highly palatable, energy dense foods (e.g., high saturated fat, high sugar) that are commonly consumed by humans,” according to the authors of a recent literature review.
“Consumption of a Western diet is related to poorer cognitive performance across the lifespan,” the investigators said, adding that consumption of a Western diet “during critical early life stages of development has negative consequences on various cognitive abilities later in adulthood.”
To show their appreciation for the sacrifices these brave test subjects had made in the name of science, the scientists released the Western diet–addled rodents from captivity. Not only did they survive and thrive in the wilds of darkest suburbia, but within 6 months almost half of them were running for Congress.
Gene therapy shows promise for Sanfilippo syndrome
. Most of the benefit from the treatment came in patients who began treatment at younger age, but comparisons to natural history controls showed profound improvement among many recipients, some of whom attained normal developmental trajectories.
The study was presented at the American Academy of Neurology’s 2021 annual meeting by Kevin Flanigan, MD, an attending neurologist at Nationwide Children’s Hospital in Columbus, Ohio. He highlighted the improved developmental outcomes. “There’s been nothing shown to change the cognitive pathway of the disease. This is the first time it’s been seen as a treatment effect,” Dr. Flanigan said during a follow-up Q&A session.
The therapy was delivered using an adeno-associated virus-9 (AAV-9) vector, which led one questioner to ask about potential safety concerns, since AAV-associated risks date back to the death of Jesse Gelsinger in 1999. “There is concern about AAV therapies related to immune responses to potentially complement-mediated activation and thrombocytopenic syndrome, which has led to clinical holds on some other AAV-9 products related to muscular dystrophies. We’ve not seen signals of anything reminiscent of that, and we’re at AAV-9 dosages that are quite similar to what’s been used elsewhere in the field,” said Dr. Flanigan.
The results have him optimistic about the therapy. “I do think if it continues to be increasing divergent from the natural history, it will be questionable as to whether a subsequent trial will be necessary for this. That’s a decision for the [Food and Drug Administration] and the company to decide. Each observation point that goes by, each patient treated, and each time we get more data, I get more and more confident. It’s really gratifying to watch,” said Dr. Flanigan.
The study confirms the potential of gene replacement therapy autosomal recessive conditions, according to Nicholas Johnson, MD, associate professor of neurology at Virginia Commonwealth University, Richmond, as well as a fellow of the American Academy of Neurology. “Where the genetic problem is loss of gene function, the ability to replace that gene using a viral approach is going to be transformative across the board for many of these different conditions, including Sanfilippo syndrome,” said Dr. Johnson, who attended the session but was not involved in the research.
Toxicity could remain an issue, even in the absence of AAV-based safety concerns. “The rate limiting step in terms of gene replacement therapy development likely relates to the ability to provide those therapies to larger adults, because many approaches are weight based and it’s unclear what the upper limit of toxicity would be for adults,” said Dr. Johnson.
Transpher A study results
Dr. Flanigan presented results from Transpher A, a phase 1/2 clinical trial that has enrolled 20 patients to date in three cohorts: Cohort 1, with 3 patients, received 5 x 1,012 vg/kg, and had a mean follow-up of 58 months; cohort 2, with 3 patients, received 1 x 1,013 vg/kg, and had a mean follow-up of 49 months; and cohort 3, with 14 patients, received 3 x 1,013 vg/kg, with a mean follow-up of 24 months. Included patients ranged from birth to age 2, or older than age 2 with a development quotient of 60 or higher on the Bayley Scale.
Dr. Flanigan showed a plot of developmental progress compared with natural history controls, which showed that patients treated before age 2 or with a developmental quotient of 60 or higher had improved outcomes compared to other patients in the high dose cohort. They continued to show normal developmental progression at 30-36 months post treatment, at a time when the natural history data suggested they would suffer cognitive decline. Two years after administration, this group had cerebral spinal fluid levels of heparan sulfate that fell below the lower limit of detection. Patients in the high-dose cohort had normalized CSF levels of GM2 and GM3 gangliosides, and there were reductions in plasma heparan sulfate and urinary glycosaminoglycans. There was also a sustained decrease in liver volume.
The highest dose group was originally given to older patients, and most were similar to the natural history cohort, though some did stabilize. “More compellingly, patients (in the high-dose group) who were treated younger actually showed continued increase in development. One individual follows the normal development quotient line, and we would say that these are really quite distinct from what we typically see in patients,” said Dr. Flanigan.
The treatment was well tolerated. There were no deaths or treatment-related serious adverse events, and no clinically-significant adverse events within the first 5 years of follow-up.
The study was funded by Abeona Therapeutics. Dr. Flanigan has been on advisory boards for Apic Bio and 4D Molecular Therapeutics, consulted for Encoded Therapeutics, and has received royalties from Audentes Therapeutics. Dr. Flanigan has received funding from and been a consultant for Avidity.
. Most of the benefit from the treatment came in patients who began treatment at younger age, but comparisons to natural history controls showed profound improvement among many recipients, some of whom attained normal developmental trajectories.
The study was presented at the American Academy of Neurology’s 2021 annual meeting by Kevin Flanigan, MD, an attending neurologist at Nationwide Children’s Hospital in Columbus, Ohio. He highlighted the improved developmental outcomes. “There’s been nothing shown to change the cognitive pathway of the disease. This is the first time it’s been seen as a treatment effect,” Dr. Flanigan said during a follow-up Q&A session.
The therapy was delivered using an adeno-associated virus-9 (AAV-9) vector, which led one questioner to ask about potential safety concerns, since AAV-associated risks date back to the death of Jesse Gelsinger in 1999. “There is concern about AAV therapies related to immune responses to potentially complement-mediated activation and thrombocytopenic syndrome, which has led to clinical holds on some other AAV-9 products related to muscular dystrophies. We’ve not seen signals of anything reminiscent of that, and we’re at AAV-9 dosages that are quite similar to what’s been used elsewhere in the field,” said Dr. Flanigan.
The results have him optimistic about the therapy. “I do think if it continues to be increasing divergent from the natural history, it will be questionable as to whether a subsequent trial will be necessary for this. That’s a decision for the [Food and Drug Administration] and the company to decide. Each observation point that goes by, each patient treated, and each time we get more data, I get more and more confident. It’s really gratifying to watch,” said Dr. Flanigan.
The study confirms the potential of gene replacement therapy autosomal recessive conditions, according to Nicholas Johnson, MD, associate professor of neurology at Virginia Commonwealth University, Richmond, as well as a fellow of the American Academy of Neurology. “Where the genetic problem is loss of gene function, the ability to replace that gene using a viral approach is going to be transformative across the board for many of these different conditions, including Sanfilippo syndrome,” said Dr. Johnson, who attended the session but was not involved in the research.
Toxicity could remain an issue, even in the absence of AAV-based safety concerns. “The rate limiting step in terms of gene replacement therapy development likely relates to the ability to provide those therapies to larger adults, because many approaches are weight based and it’s unclear what the upper limit of toxicity would be for adults,” said Dr. Johnson.
Transpher A study results
Dr. Flanigan presented results from Transpher A, a phase 1/2 clinical trial that has enrolled 20 patients to date in three cohorts: Cohort 1, with 3 patients, received 5 x 1,012 vg/kg, and had a mean follow-up of 58 months; cohort 2, with 3 patients, received 1 x 1,013 vg/kg, and had a mean follow-up of 49 months; and cohort 3, with 14 patients, received 3 x 1,013 vg/kg, with a mean follow-up of 24 months. Included patients ranged from birth to age 2, or older than age 2 with a development quotient of 60 or higher on the Bayley Scale.
Dr. Flanigan showed a plot of developmental progress compared with natural history controls, which showed that patients treated before age 2 or with a developmental quotient of 60 or higher had improved outcomes compared to other patients in the high dose cohort. They continued to show normal developmental progression at 30-36 months post treatment, at a time when the natural history data suggested they would suffer cognitive decline. Two years after administration, this group had cerebral spinal fluid levels of heparan sulfate that fell below the lower limit of detection. Patients in the high-dose cohort had normalized CSF levels of GM2 and GM3 gangliosides, and there were reductions in plasma heparan sulfate and urinary glycosaminoglycans. There was also a sustained decrease in liver volume.
The highest dose group was originally given to older patients, and most were similar to the natural history cohort, though some did stabilize. “More compellingly, patients (in the high-dose group) who were treated younger actually showed continued increase in development. One individual follows the normal development quotient line, and we would say that these are really quite distinct from what we typically see in patients,” said Dr. Flanigan.
The treatment was well tolerated. There were no deaths or treatment-related serious adverse events, and no clinically-significant adverse events within the first 5 years of follow-up.
The study was funded by Abeona Therapeutics. Dr. Flanigan has been on advisory boards for Apic Bio and 4D Molecular Therapeutics, consulted for Encoded Therapeutics, and has received royalties from Audentes Therapeutics. Dr. Flanigan has received funding from and been a consultant for Avidity.
. Most of the benefit from the treatment came in patients who began treatment at younger age, but comparisons to natural history controls showed profound improvement among many recipients, some of whom attained normal developmental trajectories.
The study was presented at the American Academy of Neurology’s 2021 annual meeting by Kevin Flanigan, MD, an attending neurologist at Nationwide Children’s Hospital in Columbus, Ohio. He highlighted the improved developmental outcomes. “There’s been nothing shown to change the cognitive pathway of the disease. This is the first time it’s been seen as a treatment effect,” Dr. Flanigan said during a follow-up Q&A session.
The therapy was delivered using an adeno-associated virus-9 (AAV-9) vector, which led one questioner to ask about potential safety concerns, since AAV-associated risks date back to the death of Jesse Gelsinger in 1999. “There is concern about AAV therapies related to immune responses to potentially complement-mediated activation and thrombocytopenic syndrome, which has led to clinical holds on some other AAV-9 products related to muscular dystrophies. We’ve not seen signals of anything reminiscent of that, and we’re at AAV-9 dosages that are quite similar to what’s been used elsewhere in the field,” said Dr. Flanigan.
The results have him optimistic about the therapy. “I do think if it continues to be increasing divergent from the natural history, it will be questionable as to whether a subsequent trial will be necessary for this. That’s a decision for the [Food and Drug Administration] and the company to decide. Each observation point that goes by, each patient treated, and each time we get more data, I get more and more confident. It’s really gratifying to watch,” said Dr. Flanigan.
The study confirms the potential of gene replacement therapy autosomal recessive conditions, according to Nicholas Johnson, MD, associate professor of neurology at Virginia Commonwealth University, Richmond, as well as a fellow of the American Academy of Neurology. “Where the genetic problem is loss of gene function, the ability to replace that gene using a viral approach is going to be transformative across the board for many of these different conditions, including Sanfilippo syndrome,” said Dr. Johnson, who attended the session but was not involved in the research.
Toxicity could remain an issue, even in the absence of AAV-based safety concerns. “The rate limiting step in terms of gene replacement therapy development likely relates to the ability to provide those therapies to larger adults, because many approaches are weight based and it’s unclear what the upper limit of toxicity would be for adults,” said Dr. Johnson.
Transpher A study results
Dr. Flanigan presented results from Transpher A, a phase 1/2 clinical trial that has enrolled 20 patients to date in three cohorts: Cohort 1, with 3 patients, received 5 x 1,012 vg/kg, and had a mean follow-up of 58 months; cohort 2, with 3 patients, received 1 x 1,013 vg/kg, and had a mean follow-up of 49 months; and cohort 3, with 14 patients, received 3 x 1,013 vg/kg, with a mean follow-up of 24 months. Included patients ranged from birth to age 2, or older than age 2 with a development quotient of 60 or higher on the Bayley Scale.
Dr. Flanigan showed a plot of developmental progress compared with natural history controls, which showed that patients treated before age 2 or with a developmental quotient of 60 or higher had improved outcomes compared to other patients in the high dose cohort. They continued to show normal developmental progression at 30-36 months post treatment, at a time when the natural history data suggested they would suffer cognitive decline. Two years after administration, this group had cerebral spinal fluid levels of heparan sulfate that fell below the lower limit of detection. Patients in the high-dose cohort had normalized CSF levels of GM2 and GM3 gangliosides, and there were reductions in plasma heparan sulfate and urinary glycosaminoglycans. There was also a sustained decrease in liver volume.
The highest dose group was originally given to older patients, and most were similar to the natural history cohort, though some did stabilize. “More compellingly, patients (in the high-dose group) who were treated younger actually showed continued increase in development. One individual follows the normal development quotient line, and we would say that these are really quite distinct from what we typically see in patients,” said Dr. Flanigan.
The treatment was well tolerated. There were no deaths or treatment-related serious adverse events, and no clinically-significant adverse events within the first 5 years of follow-up.
The study was funded by Abeona Therapeutics. Dr. Flanigan has been on advisory boards for Apic Bio and 4D Molecular Therapeutics, consulted for Encoded Therapeutics, and has received royalties from Audentes Therapeutics. Dr. Flanigan has received funding from and been a consultant for Avidity.
FROM AAN 2021
Investigative gepant liver profile comparable with standard of care
according to results of a multicenter, open-label trial presented at the 2021 annual meeting of the American Academy of Neurology.
The trial included 739 patients, 543 of whom were randomized to daily oral atogepant with the remainder assigned to the existing standard of care oral migraine prevention medication, said Messoud Ashina, MD, PhD, of the Danish Headache Center at the University of Copenhagen. Initially, 67% (n = 364) of the atogepant patients reported treatment-emergent adverse events (TEAEs). However, he noted, the rate of TEAEs related to treatment was actually 18% (n = 98), and the rate of serious AEs was 4.4% (n = 24); 31 patients (5.7%) discontinued therapy because of TEAEs.
Those rates compared favorably with the standard of care group, Dr. Ashina said. In that group, the rate of TEAEs was 78.6% (154/196), and the rate of treatment-related TEAEs was 36.2% (n = 71).
In the atogepant group, the most common TEAEs were upper respiratory tract infection (10.3%, n = 56), constipation (7.2%, n = 39) and nausea (6.3%, n = 34). “With constipation in particular most cases were mild to moderate,” Dr. Ashina said. “Only one case was considered severe and it resolved before the end of the trial.” One patient discontinued treatment because of constipation.
Most significantly, said Dr. Ashina, “No hepatic safety issues were identified.” In the atogepant group, 2.4% of patients (n = 13) had ALT/AST levels at three times the upper limit of normal versus 3.2% (n = 6) in the standard of care group.
During question-and-answer, Dr. Ashina was pressed on the rate or urinary tract infections in the atogepant patients – 5.2% (n = 28), a measure not reported in the standard of care group – but he said there was no indication the UTIs resulted from atogepant itself. “I assume if there was some problems with urinary tract infections because of the kidneys then you would expect to see the lab data showing that,” he added in an interview. “There were no differences in lab abnormalities between the two groups.”
While Dr. Ashina said “I don’t think it’s something of concern” with regard to the UTI risk, he added: “It doesn’t mean that we don’t have to be careful. As physicians, we have to exhibit pharmacovigilance all the time, especially with the new drugs coming out over the next 5 years. But don’t panic.”
Stephen D. Silberstein, MD, director of the headache center at Thomas Jefferson University, Philadelphia, agreed that the hepatic values reported in the open-label trial are important. “What’s really nice about this study is the fact that we now know that this particular gepant when given on a regular basis for 1 year has no problem with liver or kidney function,” he said in an interview.
Dr. Ashina said once-daily oral atogepant could potentially be a desirable alternative migraine preventive treatment to monoclonal antibodies and their quarterly injections and a second-line therapy when other treatments don’t work. However, Dr. Silverstein noted that patients typically aren’t as compliant with self-administered oral medications as they are with periodic injections.
Allergan/AbbVie sponsored the trial. Dr. Ashina reported financial relationships with Allergan/AbbVie, Amgen, Eli Lilly, Lundbeck, Novartis, and Teva. Dr. Silberstein is a trial investigator.
according to results of a multicenter, open-label trial presented at the 2021 annual meeting of the American Academy of Neurology.
The trial included 739 patients, 543 of whom were randomized to daily oral atogepant with the remainder assigned to the existing standard of care oral migraine prevention medication, said Messoud Ashina, MD, PhD, of the Danish Headache Center at the University of Copenhagen. Initially, 67% (n = 364) of the atogepant patients reported treatment-emergent adverse events (TEAEs). However, he noted, the rate of TEAEs related to treatment was actually 18% (n = 98), and the rate of serious AEs was 4.4% (n = 24); 31 patients (5.7%) discontinued therapy because of TEAEs.
Those rates compared favorably with the standard of care group, Dr. Ashina said. In that group, the rate of TEAEs was 78.6% (154/196), and the rate of treatment-related TEAEs was 36.2% (n = 71).
In the atogepant group, the most common TEAEs were upper respiratory tract infection (10.3%, n = 56), constipation (7.2%, n = 39) and nausea (6.3%, n = 34). “With constipation in particular most cases were mild to moderate,” Dr. Ashina said. “Only one case was considered severe and it resolved before the end of the trial.” One patient discontinued treatment because of constipation.
Most significantly, said Dr. Ashina, “No hepatic safety issues were identified.” In the atogepant group, 2.4% of patients (n = 13) had ALT/AST levels at three times the upper limit of normal versus 3.2% (n = 6) in the standard of care group.
During question-and-answer, Dr. Ashina was pressed on the rate or urinary tract infections in the atogepant patients – 5.2% (n = 28), a measure not reported in the standard of care group – but he said there was no indication the UTIs resulted from atogepant itself. “I assume if there was some problems with urinary tract infections because of the kidneys then you would expect to see the lab data showing that,” he added in an interview. “There were no differences in lab abnormalities between the two groups.”
While Dr. Ashina said “I don’t think it’s something of concern” with regard to the UTI risk, he added: “It doesn’t mean that we don’t have to be careful. As physicians, we have to exhibit pharmacovigilance all the time, especially with the new drugs coming out over the next 5 years. But don’t panic.”
Stephen D. Silberstein, MD, director of the headache center at Thomas Jefferson University, Philadelphia, agreed that the hepatic values reported in the open-label trial are important. “What’s really nice about this study is the fact that we now know that this particular gepant when given on a regular basis for 1 year has no problem with liver or kidney function,” he said in an interview.
Dr. Ashina said once-daily oral atogepant could potentially be a desirable alternative migraine preventive treatment to monoclonal antibodies and their quarterly injections and a second-line therapy when other treatments don’t work. However, Dr. Silverstein noted that patients typically aren’t as compliant with self-administered oral medications as they are with periodic injections.
Allergan/AbbVie sponsored the trial. Dr. Ashina reported financial relationships with Allergan/AbbVie, Amgen, Eli Lilly, Lundbeck, Novartis, and Teva. Dr. Silberstein is a trial investigator.
according to results of a multicenter, open-label trial presented at the 2021 annual meeting of the American Academy of Neurology.
The trial included 739 patients, 543 of whom were randomized to daily oral atogepant with the remainder assigned to the existing standard of care oral migraine prevention medication, said Messoud Ashina, MD, PhD, of the Danish Headache Center at the University of Copenhagen. Initially, 67% (n = 364) of the atogepant patients reported treatment-emergent adverse events (TEAEs). However, he noted, the rate of TEAEs related to treatment was actually 18% (n = 98), and the rate of serious AEs was 4.4% (n = 24); 31 patients (5.7%) discontinued therapy because of TEAEs.
Those rates compared favorably with the standard of care group, Dr. Ashina said. In that group, the rate of TEAEs was 78.6% (154/196), and the rate of treatment-related TEAEs was 36.2% (n = 71).
In the atogepant group, the most common TEAEs were upper respiratory tract infection (10.3%, n = 56), constipation (7.2%, n = 39) and nausea (6.3%, n = 34). “With constipation in particular most cases were mild to moderate,” Dr. Ashina said. “Only one case was considered severe and it resolved before the end of the trial.” One patient discontinued treatment because of constipation.
Most significantly, said Dr. Ashina, “No hepatic safety issues were identified.” In the atogepant group, 2.4% of patients (n = 13) had ALT/AST levels at three times the upper limit of normal versus 3.2% (n = 6) in the standard of care group.
During question-and-answer, Dr. Ashina was pressed on the rate or urinary tract infections in the atogepant patients – 5.2% (n = 28), a measure not reported in the standard of care group – but he said there was no indication the UTIs resulted from atogepant itself. “I assume if there was some problems with urinary tract infections because of the kidneys then you would expect to see the lab data showing that,” he added in an interview. “There were no differences in lab abnormalities between the two groups.”
While Dr. Ashina said “I don’t think it’s something of concern” with regard to the UTI risk, he added: “It doesn’t mean that we don’t have to be careful. As physicians, we have to exhibit pharmacovigilance all the time, especially with the new drugs coming out over the next 5 years. But don’t panic.”
Stephen D. Silberstein, MD, director of the headache center at Thomas Jefferson University, Philadelphia, agreed that the hepatic values reported in the open-label trial are important. “What’s really nice about this study is the fact that we now know that this particular gepant when given on a regular basis for 1 year has no problem with liver or kidney function,” he said in an interview.
Dr. Ashina said once-daily oral atogepant could potentially be a desirable alternative migraine preventive treatment to monoclonal antibodies and their quarterly injections and a second-line therapy when other treatments don’t work. However, Dr. Silverstein noted that patients typically aren’t as compliant with self-administered oral medications as they are with periodic injections.
Allergan/AbbVie sponsored the trial. Dr. Ashina reported financial relationships with Allergan/AbbVie, Amgen, Eli Lilly, Lundbeck, Novartis, and Teva. Dr. Silberstein is a trial investigator.
FROM AAN 2021
The neurology of long-haul COVID-19
Long-haul neurologic symptoms of COVID-19 seem to be distinct from neurologic conditions found in acute disease. Much work remains to be done to understand the biological mechanisms behind these problems, but inflammation and autoimmune responses may play a role in some cases.
Those were some of the takeaways from a talk by Serena Spudich, MD, who presented her research at the 2021 annual meeting of the American Academy of Neurology. Dr. Spudich is the division chief of neurologic infections and global neurology and codirector of the Center for Neuroepidemiology and Clinical Neurological Research at Yale University, New Haven, Conn.
Examining the nervous system’s involvement in COVID-19
Even early on in the pandemic, it became clear that there were lingering complaints of neuromuscular problems, cognitive dysfunction, and mood and psychiatric issues. Breathing and heart rate problems also can arise. “There seems to be a preponderance of syndromes that reflect involvement of the nervous system,” said Dr. Spudich.
To try to understand the etiology of these persistent problems, Dr. Spudich said it’s important to examine the nervous system’s involvement in acute COVID-19. She has been involved in these efforts since early in the pandemic, when she ran an inpatient consult service at Yale dedicated to neurologic effects of acute COVID-19. She witnessed complications including stroke, encephalopathy, and seizures, among others.
Stroke during acute COVID-19 seemed to be associated with inflammation and endothelial activation or endotheliopathy. SARS-CoV-2 has been undetectable in the cerebrospinal fluid (CSF) of patients with acute COVID-19 and neurologic symptoms, but inflammatory cytokines can be present along with increased frequency of B cells. Anti–SARS-CoV-2 antibodies have also been found in CSF, some of which were auto reactive to brain tissue. The immune response was altered, compared with healthy controls, and in the CNS, compared with in the blood, “raising the question of whether inflammation and autoimmunity may be underlying causes of these syndromes,” said Dr. Spudich.
She also pointed to an MRI study of autopsied brain tissue of patients with COVID-19 and neurologic complications, which showed indications of both hemorrhagic and ischemic microvascular injury. “It’s just a reminder that, during acute COVID-19, there may be inflammation in the brain, there may be autoimmune reactions, and there may be vascular changes that underlie some of the neurologic syndromes that are seen,” said Dr. Spudich.
A panoply of different syndromes
In October, Yale set up a post-COVID neurologic clinic that brought together pulmonary, cardiology, and psychiatric specialists, many of whom saw the same patients, about 60% of whom had cognitive impairment, more than 40% had neuromuscular problems, and over 30% headache. “There’s not a single entity of a post-COVID neurologic syndrome. There’s a panoply of different syndromes that may have similar or distinct etiologies,” said Dr. Spudich.
Most patients were in their 30s, 40s, or 50s. That doesn’t necessarily mean this is the most common age range for these issues, though. There could be some bias if these individuals are seeking specialty care because they expected to recover from COVID-19 quickly. But it could be that there is something biologically unique among this age group that predisposes them to complications. Regardless, two out of three patients were never hospitalized, “suggesting that even mild COVID-19 can lead to some long-term sequelae,” said Dr. Spudich.
One potential explanation for long-term neurologic syndromes is that they are an extension of the inflammation, autoimmunity, and immune perturbation occurring during acute disease. One study looked at 18 cancer patients who had neurologic complications with COVID-19. Two months after onset, they had elevated markers of neuroinflammation and neuronal injury in the cerebral spinal fluid compared to cancer patients with no history of COVID-19.
Looking for biologic markers
An Italian study looked at patients who were evaluated during acute hospitalization and again 3 months later, and found that some markers of inflation in the blood were associated with later cognitive impairment. The patients were more severely ill, so it’s not clear what the findings mean for patients who present with neurologic symptoms after milder illness.
A PET scan study of 35 patients with persistent neurologic symptoms found patterns of reduced fluorodeoxyglucose uptake in some regions of the brain that are believed to be associated with some symptoms. Lower values were associated with greater severity for symptoms like memory dysfunction, and anosmia. “Why there might be hypometabolism in these regions I think needs to be assessed and used as a biomarker to associate hypometabolism with other kinds of processes in blood and spinal fluid,” said Dr. Spudich.
Along with colleagues at Yale, Dr. Spudich is conducting the MIND study, which is using PET and MRI imaging along with blood and CSF biomarkers to track the progress of patients after COVID-19. There are few results to discuss since only 20 patients have been recruited so far, except that brain imaging and blood values are generally normal despite neurologic complaints. Most were not hospitalized for COVID-19. Dr. Spudich highlighted one man in his 30s who developed new-onset psychosis, despite no previous history. Although clinical tests were all negative, a novel autoantibody detection method revealed a previously unknown autoreactive antibody in his spinal fluid. “This may suggest that there is autoantibody production in some individuals with post–COVID-19 psychosis, and potentially other syndromes,” said Dr. Spudich.
The research task ahead
The case illustrates the task ahead for neurology. “There’s a real research mandate to understand the biological substrates of these diverse disorders, not only to address the emergent public health concern and reduce the stigma in our patients, but to develop targeted therapeutic interventions,” said Dr. Spudich.
Anna Cervantes-Arslanian, MD, an associate professor of neurology at Boston University who also treats and studies patients with post-COVID neurologic symptoms, agreed with that assessment. “It’s not like every patient that has muscle aches and fatigue also has brain fog. It’s really hard to parse them out into specific phenotypes that are pretty classic. Some people will have all of those things, some will have very few of them,” said Dr. Cervantes-Arslanian. “We need to be able to identify them sand see if there is clustering of symptoms so we can better look into what the biological underpinnings are. That’s the first step to thinking about a therapeutic target.”
Dr. Spudich and Dr. Cervantes-Arslanian had no relevant financial disclosures.
Long-haul neurologic symptoms of COVID-19 seem to be distinct from neurologic conditions found in acute disease. Much work remains to be done to understand the biological mechanisms behind these problems, but inflammation and autoimmune responses may play a role in some cases.
Those were some of the takeaways from a talk by Serena Spudich, MD, who presented her research at the 2021 annual meeting of the American Academy of Neurology. Dr. Spudich is the division chief of neurologic infections and global neurology and codirector of the Center for Neuroepidemiology and Clinical Neurological Research at Yale University, New Haven, Conn.
Examining the nervous system’s involvement in COVID-19
Even early on in the pandemic, it became clear that there were lingering complaints of neuromuscular problems, cognitive dysfunction, and mood and psychiatric issues. Breathing and heart rate problems also can arise. “There seems to be a preponderance of syndromes that reflect involvement of the nervous system,” said Dr. Spudich.
To try to understand the etiology of these persistent problems, Dr. Spudich said it’s important to examine the nervous system’s involvement in acute COVID-19. She has been involved in these efforts since early in the pandemic, when she ran an inpatient consult service at Yale dedicated to neurologic effects of acute COVID-19. She witnessed complications including stroke, encephalopathy, and seizures, among others.
Stroke during acute COVID-19 seemed to be associated with inflammation and endothelial activation or endotheliopathy. SARS-CoV-2 has been undetectable in the cerebrospinal fluid (CSF) of patients with acute COVID-19 and neurologic symptoms, but inflammatory cytokines can be present along with increased frequency of B cells. Anti–SARS-CoV-2 antibodies have also been found in CSF, some of which were auto reactive to brain tissue. The immune response was altered, compared with healthy controls, and in the CNS, compared with in the blood, “raising the question of whether inflammation and autoimmunity may be underlying causes of these syndromes,” said Dr. Spudich.
She also pointed to an MRI study of autopsied brain tissue of patients with COVID-19 and neurologic complications, which showed indications of both hemorrhagic and ischemic microvascular injury. “It’s just a reminder that, during acute COVID-19, there may be inflammation in the brain, there may be autoimmune reactions, and there may be vascular changes that underlie some of the neurologic syndromes that are seen,” said Dr. Spudich.
A panoply of different syndromes
In October, Yale set up a post-COVID neurologic clinic that brought together pulmonary, cardiology, and psychiatric specialists, many of whom saw the same patients, about 60% of whom had cognitive impairment, more than 40% had neuromuscular problems, and over 30% headache. “There’s not a single entity of a post-COVID neurologic syndrome. There’s a panoply of different syndromes that may have similar or distinct etiologies,” said Dr. Spudich.
Most patients were in their 30s, 40s, or 50s. That doesn’t necessarily mean this is the most common age range for these issues, though. There could be some bias if these individuals are seeking specialty care because they expected to recover from COVID-19 quickly. But it could be that there is something biologically unique among this age group that predisposes them to complications. Regardless, two out of three patients were never hospitalized, “suggesting that even mild COVID-19 can lead to some long-term sequelae,” said Dr. Spudich.
One potential explanation for long-term neurologic syndromes is that they are an extension of the inflammation, autoimmunity, and immune perturbation occurring during acute disease. One study looked at 18 cancer patients who had neurologic complications with COVID-19. Two months after onset, they had elevated markers of neuroinflammation and neuronal injury in the cerebral spinal fluid compared to cancer patients with no history of COVID-19.
Looking for biologic markers
An Italian study looked at patients who were evaluated during acute hospitalization and again 3 months later, and found that some markers of inflation in the blood were associated with later cognitive impairment. The patients were more severely ill, so it’s not clear what the findings mean for patients who present with neurologic symptoms after milder illness.
A PET scan study of 35 patients with persistent neurologic symptoms found patterns of reduced fluorodeoxyglucose uptake in some regions of the brain that are believed to be associated with some symptoms. Lower values were associated with greater severity for symptoms like memory dysfunction, and anosmia. “Why there might be hypometabolism in these regions I think needs to be assessed and used as a biomarker to associate hypometabolism with other kinds of processes in blood and spinal fluid,” said Dr. Spudich.
Along with colleagues at Yale, Dr. Spudich is conducting the MIND study, which is using PET and MRI imaging along with blood and CSF biomarkers to track the progress of patients after COVID-19. There are few results to discuss since only 20 patients have been recruited so far, except that brain imaging and blood values are generally normal despite neurologic complaints. Most were not hospitalized for COVID-19. Dr. Spudich highlighted one man in his 30s who developed new-onset psychosis, despite no previous history. Although clinical tests were all negative, a novel autoantibody detection method revealed a previously unknown autoreactive antibody in his spinal fluid. “This may suggest that there is autoantibody production in some individuals with post–COVID-19 psychosis, and potentially other syndromes,” said Dr. Spudich.
The research task ahead
The case illustrates the task ahead for neurology. “There’s a real research mandate to understand the biological substrates of these diverse disorders, not only to address the emergent public health concern and reduce the stigma in our patients, but to develop targeted therapeutic interventions,” said Dr. Spudich.
Anna Cervantes-Arslanian, MD, an associate professor of neurology at Boston University who also treats and studies patients with post-COVID neurologic symptoms, agreed with that assessment. “It’s not like every patient that has muscle aches and fatigue also has brain fog. It’s really hard to parse them out into specific phenotypes that are pretty classic. Some people will have all of those things, some will have very few of them,” said Dr. Cervantes-Arslanian. “We need to be able to identify them sand see if there is clustering of symptoms so we can better look into what the biological underpinnings are. That’s the first step to thinking about a therapeutic target.”
Dr. Spudich and Dr. Cervantes-Arslanian had no relevant financial disclosures.
Long-haul neurologic symptoms of COVID-19 seem to be distinct from neurologic conditions found in acute disease. Much work remains to be done to understand the biological mechanisms behind these problems, but inflammation and autoimmune responses may play a role in some cases.
Those were some of the takeaways from a talk by Serena Spudich, MD, who presented her research at the 2021 annual meeting of the American Academy of Neurology. Dr. Spudich is the division chief of neurologic infections and global neurology and codirector of the Center for Neuroepidemiology and Clinical Neurological Research at Yale University, New Haven, Conn.
Examining the nervous system’s involvement in COVID-19
Even early on in the pandemic, it became clear that there were lingering complaints of neuromuscular problems, cognitive dysfunction, and mood and psychiatric issues. Breathing and heart rate problems also can arise. “There seems to be a preponderance of syndromes that reflect involvement of the nervous system,” said Dr. Spudich.
To try to understand the etiology of these persistent problems, Dr. Spudich said it’s important to examine the nervous system’s involvement in acute COVID-19. She has been involved in these efforts since early in the pandemic, when she ran an inpatient consult service at Yale dedicated to neurologic effects of acute COVID-19. She witnessed complications including stroke, encephalopathy, and seizures, among others.
Stroke during acute COVID-19 seemed to be associated with inflammation and endothelial activation or endotheliopathy. SARS-CoV-2 has been undetectable in the cerebrospinal fluid (CSF) of patients with acute COVID-19 and neurologic symptoms, but inflammatory cytokines can be present along with increased frequency of B cells. Anti–SARS-CoV-2 antibodies have also been found in CSF, some of which were auto reactive to brain tissue. The immune response was altered, compared with healthy controls, and in the CNS, compared with in the blood, “raising the question of whether inflammation and autoimmunity may be underlying causes of these syndromes,” said Dr. Spudich.
She also pointed to an MRI study of autopsied brain tissue of patients with COVID-19 and neurologic complications, which showed indications of both hemorrhagic and ischemic microvascular injury. “It’s just a reminder that, during acute COVID-19, there may be inflammation in the brain, there may be autoimmune reactions, and there may be vascular changes that underlie some of the neurologic syndromes that are seen,” said Dr. Spudich.
A panoply of different syndromes
In October, Yale set up a post-COVID neurologic clinic that brought together pulmonary, cardiology, and psychiatric specialists, many of whom saw the same patients, about 60% of whom had cognitive impairment, more than 40% had neuromuscular problems, and over 30% headache. “There’s not a single entity of a post-COVID neurologic syndrome. There’s a panoply of different syndromes that may have similar or distinct etiologies,” said Dr. Spudich.
Most patients were in their 30s, 40s, or 50s. That doesn’t necessarily mean this is the most common age range for these issues, though. There could be some bias if these individuals are seeking specialty care because they expected to recover from COVID-19 quickly. But it could be that there is something biologically unique among this age group that predisposes them to complications. Regardless, two out of three patients were never hospitalized, “suggesting that even mild COVID-19 can lead to some long-term sequelae,” said Dr. Spudich.
One potential explanation for long-term neurologic syndromes is that they are an extension of the inflammation, autoimmunity, and immune perturbation occurring during acute disease. One study looked at 18 cancer patients who had neurologic complications with COVID-19. Two months after onset, they had elevated markers of neuroinflammation and neuronal injury in the cerebral spinal fluid compared to cancer patients with no history of COVID-19.
Looking for biologic markers
An Italian study looked at patients who were evaluated during acute hospitalization and again 3 months later, and found that some markers of inflation in the blood were associated with later cognitive impairment. The patients were more severely ill, so it’s not clear what the findings mean for patients who present with neurologic symptoms after milder illness.
A PET scan study of 35 patients with persistent neurologic symptoms found patterns of reduced fluorodeoxyglucose uptake in some regions of the brain that are believed to be associated with some symptoms. Lower values were associated with greater severity for symptoms like memory dysfunction, and anosmia. “Why there might be hypometabolism in these regions I think needs to be assessed and used as a biomarker to associate hypometabolism with other kinds of processes in blood and spinal fluid,” said Dr. Spudich.
Along with colleagues at Yale, Dr. Spudich is conducting the MIND study, which is using PET and MRI imaging along with blood and CSF biomarkers to track the progress of patients after COVID-19. There are few results to discuss since only 20 patients have been recruited so far, except that brain imaging and blood values are generally normal despite neurologic complaints. Most were not hospitalized for COVID-19. Dr. Spudich highlighted one man in his 30s who developed new-onset psychosis, despite no previous history. Although clinical tests were all negative, a novel autoantibody detection method revealed a previously unknown autoreactive antibody in his spinal fluid. “This may suggest that there is autoantibody production in some individuals with post–COVID-19 psychosis, and potentially other syndromes,” said Dr. Spudich.
The research task ahead
The case illustrates the task ahead for neurology. “There’s a real research mandate to understand the biological substrates of these diverse disorders, not only to address the emergent public health concern and reduce the stigma in our patients, but to develop targeted therapeutic interventions,” said Dr. Spudich.
Anna Cervantes-Arslanian, MD, an associate professor of neurology at Boston University who also treats and studies patients with post-COVID neurologic symptoms, agreed with that assessment. “It’s not like every patient that has muscle aches and fatigue also has brain fog. It’s really hard to parse them out into specific phenotypes that are pretty classic. Some people will have all of those things, some will have very few of them,” said Dr. Cervantes-Arslanian. “We need to be able to identify them sand see if there is clustering of symptoms so we can better look into what the biological underpinnings are. That’s the first step to thinking about a therapeutic target.”
Dr. Spudich and Dr. Cervantes-Arslanian had no relevant financial disclosures.
FROM AAN 2021
AHA statement on obesity emphasizes abdominal fat, AFib
An updated American Heart Association scientific statement on the role of obesity in cardiovascular disease provides the first new guidance in 15 years, drawing on evidence that’s emerged in that time to clarify the potential of newer drug therapies and interventions like bariatric surgery and lifestyle modifications to curtail cardiovascular disease risks.
“The timing of this information is important because the obesity epidemic contributes significantly to the global burden of cardiovascular disease and numerous chronic health conditions that also impact heart disease,” said Tiffany Powell-Wiley, MD, MPH, chair of the volunteer statement writing group.
“One of the big takeaways that I hope people get from the statement is really making it clear that obesity is a complex disease, and that it is multifactorial,” Dr. Powell-Wiley said in an interview. “There are not just biological reasons why individuals have obesity, but there are environmental, psychosocial, and really multilevel factors that contribute to the development and course of obesity.”
Most significantly, Dr. Powell-Wiley said, “we want to emphasize that we really want to have cardiologists think about and focus on abdominal obesity in particular.”
A metric for cardiovascular risk that seems to gain credibility in the statement is the relationship of waist circumference to height regardless of overall weight. “That is a very important finding that we can now really think of waist circumference as an important measure in our clinical practice,” said Dr. Powell-Wiley, chief of the Social Determinants of Obesity and Cardiovascular Risk Laboratory in the division of intramural research at the National Heart, Lung, and Blood Institute. “We want to get across to providers that this is something that should be measured and should be followed over time, based on data from the last 15 years that waist circumference and abdominal obesity are associated with higher cardiovascular risk regardless of body mass index.”
The statement provides potentially groundbreaking advice on atrial fibrillation as a consequence of weight, noted Dr. Powell-Wiley. “Up until recently, we haven’t really thought about weight management as a part of managing Afib [atrial fibrillation],” she said. “This statement highlights the need to think about weight management in addition to anticoagulation as part of the pieces for managing Afib.”
Evidence on interventions
The statement, published in Circulation, also dives into the evidence surrounding the varied interventions for managing weight.
“The biggest area where there’s much more data is bariatric surgery,” said Dr. Powell-Wiley. “There’s clear evidence that bariatric surgery lowers cardio mortality and all-cause mortality for patients, but we’ve also seen data around lifestyle interventions, with the Look AHEAD trial, which showed that while there were improvements in CV [cardiovascular] risk factors, we didn’t see the reduction in CV mortality that we wanted to see.”
The statement noted that the Look AHEAD trial (for Action for Health in Diabetes) of people with type 2 diabetes failed to show a significant reduction in major adverse cardiac events or CV mortality after almost 10 years of an intensive weight-loss intervention. Dr. Powell-Wiley added that the result seemed to be related more to the lack of weight loss with lifestyle interventions when compared with bariatric surgery.
The statement also addressed the effectiveness of drug treatments for weight control in managing CV risk, and while the evidence supporting pharmacotherapy specifically for weight loss has been mixed, emerging treatments have shown promise, Dr. Powell-Wiley said. “I think we now have some bright spots with new therapies that have been developed for diabetes and heart failure, such as the SGLT2 inhibitors as well as the GLP-1 agonists, and how they can also appear to improve weight and likely will improve CV mortality in patients with obesity.”
The “obesity paradox,” which Dr. Powell-Wiley noted is “definitely a controversial topic,” is also addressed in the statement. “We try to explain what it is and what we know about it right now,” she said. “We know for instance that patients with obesity, particularly those who have class 1 obesity or patients who are overweight, seem to do better in the short term in relation to coronary artery disease and heart failure, but the reasons for that are not necessarily clear.”
The statement also provides evidence-based insights on the use of diagnostic tools, including stress echocardiography and cardiac MRI as well as coronary angiography, and the clinical significance of specific echocardiographic changes in obese patients.
The writing committee also identified areas that need future research. “It’s really important to emphasize what we learned about the complexity of obesity over this time period,” Dr. Powell-Wiley said. “But again, we don’t have all the answers; there’s a lot more work to be done to understand what type of lifestyle intervention might be most beneficial, especially with addressing abdominal obesity, and how these new therapeutics around heart failure and diabetes may be useful in patients with obesity.
Obesity in adolescents is another area that needs further research, Dr. Powell-Wiley said. “How do we prevent obesity in those populations when we know they’re at risk for so much as they get older? Once you have obesity it’s hard to change that trajectory.”
The scientific statement was prepared by the volunteer writing group on behalf of the AHA’s Council on Lifestyle and Cardiometabolic Health, the Council on Cardiovascular and Stroke Nursing, the Council on Clinical Cardiology, the Council on Epidemiology and Prevention, and the Stroke Council. Committee vice chair Paul Poirier, MD, PhD, reported financial relationships with Abbott, Amgen, AstraZeneca, Bausch Health, Bayer, Boehringer Ingelheim, Eli Lilly, Janssen, Novartis, Novo Nordisk, Sanofi, Servier, and HLS Therapeutics. One committee member disclosed a financial relationship with AstraZeneca. Dr. Powell-Wiley and the other committee members have no relationships to disclose.
An updated American Heart Association scientific statement on the role of obesity in cardiovascular disease provides the first new guidance in 15 years, drawing on evidence that’s emerged in that time to clarify the potential of newer drug therapies and interventions like bariatric surgery and lifestyle modifications to curtail cardiovascular disease risks.
“The timing of this information is important because the obesity epidemic contributes significantly to the global burden of cardiovascular disease and numerous chronic health conditions that also impact heart disease,” said Tiffany Powell-Wiley, MD, MPH, chair of the volunteer statement writing group.
“One of the big takeaways that I hope people get from the statement is really making it clear that obesity is a complex disease, and that it is multifactorial,” Dr. Powell-Wiley said in an interview. “There are not just biological reasons why individuals have obesity, but there are environmental, psychosocial, and really multilevel factors that contribute to the development and course of obesity.”
Most significantly, Dr. Powell-Wiley said, “we want to emphasize that we really want to have cardiologists think about and focus on abdominal obesity in particular.”
A metric for cardiovascular risk that seems to gain credibility in the statement is the relationship of waist circumference to height regardless of overall weight. “That is a very important finding that we can now really think of waist circumference as an important measure in our clinical practice,” said Dr. Powell-Wiley, chief of the Social Determinants of Obesity and Cardiovascular Risk Laboratory in the division of intramural research at the National Heart, Lung, and Blood Institute. “We want to get across to providers that this is something that should be measured and should be followed over time, based on data from the last 15 years that waist circumference and abdominal obesity are associated with higher cardiovascular risk regardless of body mass index.”
The statement provides potentially groundbreaking advice on atrial fibrillation as a consequence of weight, noted Dr. Powell-Wiley. “Up until recently, we haven’t really thought about weight management as a part of managing Afib [atrial fibrillation],” she said. “This statement highlights the need to think about weight management in addition to anticoagulation as part of the pieces for managing Afib.”
Evidence on interventions
The statement, published in Circulation, also dives into the evidence surrounding the varied interventions for managing weight.
“The biggest area where there’s much more data is bariatric surgery,” said Dr. Powell-Wiley. “There’s clear evidence that bariatric surgery lowers cardio mortality and all-cause mortality for patients, but we’ve also seen data around lifestyle interventions, with the Look AHEAD trial, which showed that while there were improvements in CV [cardiovascular] risk factors, we didn’t see the reduction in CV mortality that we wanted to see.”
The statement noted that the Look AHEAD trial (for Action for Health in Diabetes) of people with type 2 diabetes failed to show a significant reduction in major adverse cardiac events or CV mortality after almost 10 years of an intensive weight-loss intervention. Dr. Powell-Wiley added that the result seemed to be related more to the lack of weight loss with lifestyle interventions when compared with bariatric surgery.
The statement also addressed the effectiveness of drug treatments for weight control in managing CV risk, and while the evidence supporting pharmacotherapy specifically for weight loss has been mixed, emerging treatments have shown promise, Dr. Powell-Wiley said. “I think we now have some bright spots with new therapies that have been developed for diabetes and heart failure, such as the SGLT2 inhibitors as well as the GLP-1 agonists, and how they can also appear to improve weight and likely will improve CV mortality in patients with obesity.”
The “obesity paradox,” which Dr. Powell-Wiley noted is “definitely a controversial topic,” is also addressed in the statement. “We try to explain what it is and what we know about it right now,” she said. “We know for instance that patients with obesity, particularly those who have class 1 obesity or patients who are overweight, seem to do better in the short term in relation to coronary artery disease and heart failure, but the reasons for that are not necessarily clear.”
The statement also provides evidence-based insights on the use of diagnostic tools, including stress echocardiography and cardiac MRI as well as coronary angiography, and the clinical significance of specific echocardiographic changes in obese patients.
The writing committee also identified areas that need future research. “It’s really important to emphasize what we learned about the complexity of obesity over this time period,” Dr. Powell-Wiley said. “But again, we don’t have all the answers; there’s a lot more work to be done to understand what type of lifestyle intervention might be most beneficial, especially with addressing abdominal obesity, and how these new therapeutics around heart failure and diabetes may be useful in patients with obesity.
Obesity in adolescents is another area that needs further research, Dr. Powell-Wiley said. “How do we prevent obesity in those populations when we know they’re at risk for so much as they get older? Once you have obesity it’s hard to change that trajectory.”
The scientific statement was prepared by the volunteer writing group on behalf of the AHA’s Council on Lifestyle and Cardiometabolic Health, the Council on Cardiovascular and Stroke Nursing, the Council on Clinical Cardiology, the Council on Epidemiology and Prevention, and the Stroke Council. Committee vice chair Paul Poirier, MD, PhD, reported financial relationships with Abbott, Amgen, AstraZeneca, Bausch Health, Bayer, Boehringer Ingelheim, Eli Lilly, Janssen, Novartis, Novo Nordisk, Sanofi, Servier, and HLS Therapeutics. One committee member disclosed a financial relationship with AstraZeneca. Dr. Powell-Wiley and the other committee members have no relationships to disclose.
An updated American Heart Association scientific statement on the role of obesity in cardiovascular disease provides the first new guidance in 15 years, drawing on evidence that’s emerged in that time to clarify the potential of newer drug therapies and interventions like bariatric surgery and lifestyle modifications to curtail cardiovascular disease risks.
“The timing of this information is important because the obesity epidemic contributes significantly to the global burden of cardiovascular disease and numerous chronic health conditions that also impact heart disease,” said Tiffany Powell-Wiley, MD, MPH, chair of the volunteer statement writing group.
“One of the big takeaways that I hope people get from the statement is really making it clear that obesity is a complex disease, and that it is multifactorial,” Dr. Powell-Wiley said in an interview. “There are not just biological reasons why individuals have obesity, but there are environmental, psychosocial, and really multilevel factors that contribute to the development and course of obesity.”
Most significantly, Dr. Powell-Wiley said, “we want to emphasize that we really want to have cardiologists think about and focus on abdominal obesity in particular.”
A metric for cardiovascular risk that seems to gain credibility in the statement is the relationship of waist circumference to height regardless of overall weight. “That is a very important finding that we can now really think of waist circumference as an important measure in our clinical practice,” said Dr. Powell-Wiley, chief of the Social Determinants of Obesity and Cardiovascular Risk Laboratory in the division of intramural research at the National Heart, Lung, and Blood Institute. “We want to get across to providers that this is something that should be measured and should be followed over time, based on data from the last 15 years that waist circumference and abdominal obesity are associated with higher cardiovascular risk regardless of body mass index.”
The statement provides potentially groundbreaking advice on atrial fibrillation as a consequence of weight, noted Dr. Powell-Wiley. “Up until recently, we haven’t really thought about weight management as a part of managing Afib [atrial fibrillation],” she said. “This statement highlights the need to think about weight management in addition to anticoagulation as part of the pieces for managing Afib.”
Evidence on interventions
The statement, published in Circulation, also dives into the evidence surrounding the varied interventions for managing weight.
“The biggest area where there’s much more data is bariatric surgery,” said Dr. Powell-Wiley. “There’s clear evidence that bariatric surgery lowers cardio mortality and all-cause mortality for patients, but we’ve also seen data around lifestyle interventions, with the Look AHEAD trial, which showed that while there were improvements in CV [cardiovascular] risk factors, we didn’t see the reduction in CV mortality that we wanted to see.”
The statement noted that the Look AHEAD trial (for Action for Health in Diabetes) of people with type 2 diabetes failed to show a significant reduction in major adverse cardiac events or CV mortality after almost 10 years of an intensive weight-loss intervention. Dr. Powell-Wiley added that the result seemed to be related more to the lack of weight loss with lifestyle interventions when compared with bariatric surgery.
The statement also addressed the effectiveness of drug treatments for weight control in managing CV risk, and while the evidence supporting pharmacotherapy specifically for weight loss has been mixed, emerging treatments have shown promise, Dr. Powell-Wiley said. “I think we now have some bright spots with new therapies that have been developed for diabetes and heart failure, such as the SGLT2 inhibitors as well as the GLP-1 agonists, and how they can also appear to improve weight and likely will improve CV mortality in patients with obesity.”
The “obesity paradox,” which Dr. Powell-Wiley noted is “definitely a controversial topic,” is also addressed in the statement. “We try to explain what it is and what we know about it right now,” she said. “We know for instance that patients with obesity, particularly those who have class 1 obesity or patients who are overweight, seem to do better in the short term in relation to coronary artery disease and heart failure, but the reasons for that are not necessarily clear.”
The statement also provides evidence-based insights on the use of diagnostic tools, including stress echocardiography and cardiac MRI as well as coronary angiography, and the clinical significance of specific echocardiographic changes in obese patients.
The writing committee also identified areas that need future research. “It’s really important to emphasize what we learned about the complexity of obesity over this time period,” Dr. Powell-Wiley said. “But again, we don’t have all the answers; there’s a lot more work to be done to understand what type of lifestyle intervention might be most beneficial, especially with addressing abdominal obesity, and how these new therapeutics around heart failure and diabetes may be useful in patients with obesity.
Obesity in adolescents is another area that needs further research, Dr. Powell-Wiley said. “How do we prevent obesity in those populations when we know they’re at risk for so much as they get older? Once you have obesity it’s hard to change that trajectory.”
The scientific statement was prepared by the volunteer writing group on behalf of the AHA’s Council on Lifestyle and Cardiometabolic Health, the Council on Cardiovascular and Stroke Nursing, the Council on Clinical Cardiology, the Council on Epidemiology and Prevention, and the Stroke Council. Committee vice chair Paul Poirier, MD, PhD, reported financial relationships with Abbott, Amgen, AstraZeneca, Bausch Health, Bayer, Boehringer Ingelheim, Eli Lilly, Janssen, Novartis, Novo Nordisk, Sanofi, Servier, and HLS Therapeutics. One committee member disclosed a financial relationship with AstraZeneca. Dr. Powell-Wiley and the other committee members have no relationships to disclose.
FROM CIRCULATION
Pigmented palmar lesions
Fortunately, the dermoscopy images of these 2 small palmar lesions showed a pattern of pigmentation that aligned in the furrows and was consistent with benign palmar nevi.
It is not uncommon to have nevi on the palms or soles of the feet, so it is important to distinguish between acral lentiginous melanoma (ALM) and benign nevi. ALM is the least common form of melanoma. In contrast to other types of melanoma, it is not considered secondary to excessive sun exposure. Clinically, ALM presents with irregular, enlarging pigmentation that follows, or crosses, the raised ridges of the palms or soles.1 The pigmented areas can progress to ulcerated or bleeding lesions. As with other melanomas, early diagnosis and removal is important to optimize prognosis.
Removal of lesions suspicious for ALM can be achieved in several ways: deep shave biopsy, punch excision if the lesion is small, excision with narrow margins, or, if the lesion is large, by a selective punch biopsy of the most suspicious portion of the lesion (typically the thickest and most irregular area). Larger diameter lesions that are raised and irregular are more worrisome than this patient’s 2-mm macular lesions.
In this case, the patient was reassured that the lesions did not require excision. She was advised to continue to monitor her lesions for growth or changes over time and to return for evaluation, as needed. She was also counseled regarding the American Cancer Society’s ABCDE rules (Asymmetry, Border irregularity, Color, Diameter, Elevation or Evolving) regarding melanomas.
Photo and text courtesy of Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque
1. Hall KH, Rapini RP. Acral lentiginous melanoma. In: StatPearls [Internet]. StatPearls Publishing; 2020. Accessed April 5, 2021. https://www.ncbi.nlm.nih.gov/books/NBK559113/
Fortunately, the dermoscopy images of these 2 small palmar lesions showed a pattern of pigmentation that aligned in the furrows and was consistent with benign palmar nevi.
It is not uncommon to have nevi on the palms or soles of the feet, so it is important to distinguish between acral lentiginous melanoma (ALM) and benign nevi. ALM is the least common form of melanoma. In contrast to other types of melanoma, it is not considered secondary to excessive sun exposure. Clinically, ALM presents with irregular, enlarging pigmentation that follows, or crosses, the raised ridges of the palms or soles.1 The pigmented areas can progress to ulcerated or bleeding lesions. As with other melanomas, early diagnosis and removal is important to optimize prognosis.
Removal of lesions suspicious for ALM can be achieved in several ways: deep shave biopsy, punch excision if the lesion is small, excision with narrow margins, or, if the lesion is large, by a selective punch biopsy of the most suspicious portion of the lesion (typically the thickest and most irregular area). Larger diameter lesions that are raised and irregular are more worrisome than this patient’s 2-mm macular lesions.
In this case, the patient was reassured that the lesions did not require excision. She was advised to continue to monitor her lesions for growth or changes over time and to return for evaluation, as needed. She was also counseled regarding the American Cancer Society’s ABCDE rules (Asymmetry, Border irregularity, Color, Diameter, Elevation or Evolving) regarding melanomas.
Photo and text courtesy of Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque
Fortunately, the dermoscopy images of these 2 small palmar lesions showed a pattern of pigmentation that aligned in the furrows and was consistent with benign palmar nevi.
It is not uncommon to have nevi on the palms or soles of the feet, so it is important to distinguish between acral lentiginous melanoma (ALM) and benign nevi. ALM is the least common form of melanoma. In contrast to other types of melanoma, it is not considered secondary to excessive sun exposure. Clinically, ALM presents with irregular, enlarging pigmentation that follows, or crosses, the raised ridges of the palms or soles.1 The pigmented areas can progress to ulcerated or bleeding lesions. As with other melanomas, early diagnosis and removal is important to optimize prognosis.
Removal of lesions suspicious for ALM can be achieved in several ways: deep shave biopsy, punch excision if the lesion is small, excision with narrow margins, or, if the lesion is large, by a selective punch biopsy of the most suspicious portion of the lesion (typically the thickest and most irregular area). Larger diameter lesions that are raised and irregular are more worrisome than this patient’s 2-mm macular lesions.
In this case, the patient was reassured that the lesions did not require excision. She was advised to continue to monitor her lesions for growth or changes over time and to return for evaluation, as needed. She was also counseled regarding the American Cancer Society’s ABCDE rules (Asymmetry, Border irregularity, Color, Diameter, Elevation or Evolving) regarding melanomas.
Photo and text courtesy of Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque
1. Hall KH, Rapini RP. Acral lentiginous melanoma. In: StatPearls [Internet]. StatPearls Publishing; 2020. Accessed April 5, 2021. https://www.ncbi.nlm.nih.gov/books/NBK559113/
1. Hall KH, Rapini RP. Acral lentiginous melanoma. In: StatPearls [Internet]. StatPearls Publishing; 2020. Accessed April 5, 2021. https://www.ncbi.nlm.nih.gov/books/NBK559113/
Cushing’s death rate ‘unacceptable,’ triple that of general population
Excess mortality among people with endogenous Cushing’s syndrome (CS) has declined in the past 20 years yet remains three times higher than in the general population, new research finds.
Among more than 90,000 individuals with endogenous CS, the overall proportion of mortality – defined as the ratio of the number of deaths from CS divided by the total number of CS patients – was 0.05, and the standardized mortality rate was an “unacceptable” three times that of the general population, Padiporn Limumpornpetch, MD, reported on March 20 at ENDO 2021: The Endocrine Society Annual Meeting.
Excess deaths were higher among those with adrenal CS, compared with those with Cushing’s disease. The most common causes of death among those with CS were cardiovascular diseases, cerebrovascular accident, infection, and malignancy, noted Dr. Limumpornpetch, of Songkla University, Hat Yai, Thailand, who is also a PhD student at the University of Leeds, United Kingdom.
“While mortality has improved since 2000, it is still significantly compromised compared to the background population ... The causes of death highlight the need for aggressive management of cardiovascular risk, prevention of thromboembolism, infection control, and a normalized cortisol level,” she said.
Asked to comment, Maria Fleseriu, MD, told this news organization that the new data show “we are making improvements in the care of patients with CS and thus outcomes, but we are not there yet ... This meta-analysis highlights the whole spectrum of acute and life-threatening complications in CS and their high prevalence, even before disease diagnosis and after successful surgery.”
She noted that although she wasn’t surprised by the overall results, “the improvement over time was indeed lower than I expected. However, interestingly here, the risk of mortality in adrenal Cushing’s was unexpectedly high despite patients with adrenal cancer being excluded.”
Dr. Fleseriu, who is director of the Pituitary Center at Oregon Health and Science University, Portland, advised, “Management of hyperglycemia and diabetes, hypertension, hypokalemia, hyperlipidemia, and other cardiovascular risk factors is generally undertaken in accordance with standard of clinical care.”
“But we should focus more on optimizing more aggressively this care in addition to the specific Cushing’s treatment,” she stressed.
In addition, she noted, “Medical therapy for CS may be needed even prior to surgery in severe and/or prolonged hypercortisolism to decrease complications ... We definitely need a multidisciplinary approach to address complications and etiologic treatment as well as the reduced long-term quality of life in patients with CS.”
Largest study in scale and scope of Cushing’s syndrome mortality
Endogenous Cushing’s syndrome occurs when the body overproduces cortisol. The most common cause of the latter is a tumor of the pituitary gland (Cushing’s disease), but another cause is a usually benign tumor of the adrenal glands (adrenal Cushing’s syndrome). Surgery is the mainstay of initial treatment of Cushing’s syndrome. If an operation to remove the tumor fails to cause remission, medications are available.
Prior to this new meta-analysis, there had been limited data on mortality among patients with endogenous CS. Research has mostly been limited to single-cohort studies. A previous systematic review/meta-analysis comprised only seven articles with 780 patients. All the studies were conducted prior to 2012, and most were limited to Cushing’s disease.
“In 2021, we lacked a detailed understanding of patient outcomes and mortality because of the rarity of Cushing’s syndrome,” Dr. Limumpornpetch noted.
The current meta-analysis included 91 articles that reported mortality among patients with endogenous CS. There was a total of 19,181 patients from 92 study cohorts, including 49 studies on CD (n = 14,971), 24 studies on adrenal CS (n = 2304), and 19 studies that included both (n = 1906).
Among 21 studies that reported standardized mortality rate (SMR) data, including 13 CD studies (n = 2160) and seven on adrenal CS (n = 1531), the overall increase in mortality compared to the background population was a significant 3.00 (range, 1.15-7.84).
This SMR was higher among patients with adrenal Cushing’s syndrome (3.3) versus Cushing’s disease (2.8) (P = .003) and among patients who had active disease (5.7) versus those whose disease was in remission (2.3) (P < .001).
The SMR was also worse among patients with Cushing’s disease with larger tumors (macroadenomas), at 7.4, than among patients with very small tumors (microadenomas), at 1.9 (P = .004).
The proportion of death was 0.05 for CS overall, with 0.04 for CD and 0.02 for adrenal adenomas.
Compared to studies published prior to the year 2000, more recent studies seem to reflect advances in treatment and care. The overall proportion of death for all CS cohorts dropped from 0.10 to 0.03 (P < .001); for all CD cohorts, it dropped from 0.14 to 0.03; and for adrenal CS cohorts, it dropped from 0.09 to 0.03 (P = .04).
Causes of death were cardiovascular diseases (29.5% of cases), cerebrovascular accident (11.5%), infection (10.5%), and malignancy (10.1%). Less common causes of death were gastrointestinal bleeding and acute pancreatitis (3.7%), active CS (3.5%), adrenal insufficiency (2.5%), suicide (2.5%), and surgery (1.6%).
Overall, in the CS groups, the proportion of deaths within 30 days of surgery dropped from 0.04 prior to 2000 to 0.01 since (P = .07). For CD, the proportion dropped from 0.02 to 0.01 (P = .25).
Preventing perioperative mortality: Consider thromboprophylaxis
Dr. Fleseriu told this news organization that she believes hypercoagulability is “the least recognized complication with a big role in mortality.” Because most of the perioperative mortality is due to venous thromboembolism and infections, “thromboprophylaxis should be considered for CS patients with severe hypercortisolism and/or postoperatively, based on individual risk factors of thromboembolism and bleeding.”
Recently, Dr. Fleseriu’s group showed in a single retrospective study that the risk for arterial and venous thromboembolic events among patients with CS was approximately 20%. Many patients experienced more than one event. Risk was higher 30 to 60 days postoperatively.
The odds ratio of venous thromoboembolism among patients with CS was 18 times higher than in the normal population.
“Due to the additional thrombotic risk of surgery or any invasive procedure, anticoagulation prophylaxis should be at least considered in all patients with Cushing’s syndrome and balanced with individual bleeding risk,” Dr. Fleseriu advised.
A recent Pituitary Society workshop discussed the management of complications of CS at length; proceedings will be published soon, she noted.
Dr. Limumpornpetch commented, “We look forward to the day when our interdisciplinary approach to managing these challenging patients can deliver outcomes similar to the background population.”
Dr. Limumpornpetch has disclosed no relevant financial relationships. Dr. Fleseriu has been a scientific consultant to Recordati, Sparrow, and Strongbridge and has received grants (inst) from Novartis and Strongbridge.
A version of this article first appeared on Medscape.com.
Excess mortality among people with endogenous Cushing’s syndrome (CS) has declined in the past 20 years yet remains three times higher than in the general population, new research finds.
Among more than 90,000 individuals with endogenous CS, the overall proportion of mortality – defined as the ratio of the number of deaths from CS divided by the total number of CS patients – was 0.05, and the standardized mortality rate was an “unacceptable” three times that of the general population, Padiporn Limumpornpetch, MD, reported on March 20 at ENDO 2021: The Endocrine Society Annual Meeting.
Excess deaths were higher among those with adrenal CS, compared with those with Cushing’s disease. The most common causes of death among those with CS were cardiovascular diseases, cerebrovascular accident, infection, and malignancy, noted Dr. Limumpornpetch, of Songkla University, Hat Yai, Thailand, who is also a PhD student at the University of Leeds, United Kingdom.
“While mortality has improved since 2000, it is still significantly compromised compared to the background population ... The causes of death highlight the need for aggressive management of cardiovascular risk, prevention of thromboembolism, infection control, and a normalized cortisol level,” she said.
Asked to comment, Maria Fleseriu, MD, told this news organization that the new data show “we are making improvements in the care of patients with CS and thus outcomes, but we are not there yet ... This meta-analysis highlights the whole spectrum of acute and life-threatening complications in CS and their high prevalence, even before disease diagnosis and after successful surgery.”
She noted that although she wasn’t surprised by the overall results, “the improvement over time was indeed lower than I expected. However, interestingly here, the risk of mortality in adrenal Cushing’s was unexpectedly high despite patients with adrenal cancer being excluded.”
Dr. Fleseriu, who is director of the Pituitary Center at Oregon Health and Science University, Portland, advised, “Management of hyperglycemia and diabetes, hypertension, hypokalemia, hyperlipidemia, and other cardiovascular risk factors is generally undertaken in accordance with standard of clinical care.”
“But we should focus more on optimizing more aggressively this care in addition to the specific Cushing’s treatment,” she stressed.
In addition, she noted, “Medical therapy for CS may be needed even prior to surgery in severe and/or prolonged hypercortisolism to decrease complications ... We definitely need a multidisciplinary approach to address complications and etiologic treatment as well as the reduced long-term quality of life in patients with CS.”
Largest study in scale and scope of Cushing’s syndrome mortality
Endogenous Cushing’s syndrome occurs when the body overproduces cortisol. The most common cause of the latter is a tumor of the pituitary gland (Cushing’s disease), but another cause is a usually benign tumor of the adrenal glands (adrenal Cushing’s syndrome). Surgery is the mainstay of initial treatment of Cushing’s syndrome. If an operation to remove the tumor fails to cause remission, medications are available.
Prior to this new meta-analysis, there had been limited data on mortality among patients with endogenous CS. Research has mostly been limited to single-cohort studies. A previous systematic review/meta-analysis comprised only seven articles with 780 patients. All the studies were conducted prior to 2012, and most were limited to Cushing’s disease.
“In 2021, we lacked a detailed understanding of patient outcomes and mortality because of the rarity of Cushing’s syndrome,” Dr. Limumpornpetch noted.
The current meta-analysis included 91 articles that reported mortality among patients with endogenous CS. There was a total of 19,181 patients from 92 study cohorts, including 49 studies on CD (n = 14,971), 24 studies on adrenal CS (n = 2304), and 19 studies that included both (n = 1906).
Among 21 studies that reported standardized mortality rate (SMR) data, including 13 CD studies (n = 2160) and seven on adrenal CS (n = 1531), the overall increase in mortality compared to the background population was a significant 3.00 (range, 1.15-7.84).
This SMR was higher among patients with adrenal Cushing’s syndrome (3.3) versus Cushing’s disease (2.8) (P = .003) and among patients who had active disease (5.7) versus those whose disease was in remission (2.3) (P < .001).
The SMR was also worse among patients with Cushing’s disease with larger tumors (macroadenomas), at 7.4, than among patients with very small tumors (microadenomas), at 1.9 (P = .004).
The proportion of death was 0.05 for CS overall, with 0.04 for CD and 0.02 for adrenal adenomas.
Compared to studies published prior to the year 2000, more recent studies seem to reflect advances in treatment and care. The overall proportion of death for all CS cohorts dropped from 0.10 to 0.03 (P < .001); for all CD cohorts, it dropped from 0.14 to 0.03; and for adrenal CS cohorts, it dropped from 0.09 to 0.03 (P = .04).
Causes of death were cardiovascular diseases (29.5% of cases), cerebrovascular accident (11.5%), infection (10.5%), and malignancy (10.1%). Less common causes of death were gastrointestinal bleeding and acute pancreatitis (3.7%), active CS (3.5%), adrenal insufficiency (2.5%), suicide (2.5%), and surgery (1.6%).
Overall, in the CS groups, the proportion of deaths within 30 days of surgery dropped from 0.04 prior to 2000 to 0.01 since (P = .07). For CD, the proportion dropped from 0.02 to 0.01 (P = .25).
Preventing perioperative mortality: Consider thromboprophylaxis
Dr. Fleseriu told this news organization that she believes hypercoagulability is “the least recognized complication with a big role in mortality.” Because most of the perioperative mortality is due to venous thromboembolism and infections, “thromboprophylaxis should be considered for CS patients with severe hypercortisolism and/or postoperatively, based on individual risk factors of thromboembolism and bleeding.”
Recently, Dr. Fleseriu’s group showed in a single retrospective study that the risk for arterial and venous thromboembolic events among patients with CS was approximately 20%. Many patients experienced more than one event. Risk was higher 30 to 60 days postoperatively.
The odds ratio of venous thromoboembolism among patients with CS was 18 times higher than in the normal population.
“Due to the additional thrombotic risk of surgery or any invasive procedure, anticoagulation prophylaxis should be at least considered in all patients with Cushing’s syndrome and balanced with individual bleeding risk,” Dr. Fleseriu advised.
A recent Pituitary Society workshop discussed the management of complications of CS at length; proceedings will be published soon, she noted.
Dr. Limumpornpetch commented, “We look forward to the day when our interdisciplinary approach to managing these challenging patients can deliver outcomes similar to the background population.”
Dr. Limumpornpetch has disclosed no relevant financial relationships. Dr. Fleseriu has been a scientific consultant to Recordati, Sparrow, and Strongbridge and has received grants (inst) from Novartis and Strongbridge.
A version of this article first appeared on Medscape.com.
Excess mortality among people with endogenous Cushing’s syndrome (CS) has declined in the past 20 years yet remains three times higher than in the general population, new research finds.
Among more than 90,000 individuals with endogenous CS, the overall proportion of mortality – defined as the ratio of the number of deaths from CS divided by the total number of CS patients – was 0.05, and the standardized mortality rate was an “unacceptable” three times that of the general population, Padiporn Limumpornpetch, MD, reported on March 20 at ENDO 2021: The Endocrine Society Annual Meeting.
Excess deaths were higher among those with adrenal CS, compared with those with Cushing’s disease. The most common causes of death among those with CS were cardiovascular diseases, cerebrovascular accident, infection, and malignancy, noted Dr. Limumpornpetch, of Songkla University, Hat Yai, Thailand, who is also a PhD student at the University of Leeds, United Kingdom.
“While mortality has improved since 2000, it is still significantly compromised compared to the background population ... The causes of death highlight the need for aggressive management of cardiovascular risk, prevention of thromboembolism, infection control, and a normalized cortisol level,” she said.
Asked to comment, Maria Fleseriu, MD, told this news organization that the new data show “we are making improvements in the care of patients with CS and thus outcomes, but we are not there yet ... This meta-analysis highlights the whole spectrum of acute and life-threatening complications in CS and their high prevalence, even before disease diagnosis and after successful surgery.”
She noted that although she wasn’t surprised by the overall results, “the improvement over time was indeed lower than I expected. However, interestingly here, the risk of mortality in adrenal Cushing’s was unexpectedly high despite patients with adrenal cancer being excluded.”
Dr. Fleseriu, who is director of the Pituitary Center at Oregon Health and Science University, Portland, advised, “Management of hyperglycemia and diabetes, hypertension, hypokalemia, hyperlipidemia, and other cardiovascular risk factors is generally undertaken in accordance with standard of clinical care.”
“But we should focus more on optimizing more aggressively this care in addition to the specific Cushing’s treatment,” she stressed.
In addition, she noted, “Medical therapy for CS may be needed even prior to surgery in severe and/or prolonged hypercortisolism to decrease complications ... We definitely need a multidisciplinary approach to address complications and etiologic treatment as well as the reduced long-term quality of life in patients with CS.”
Largest study in scale and scope of Cushing’s syndrome mortality
Endogenous Cushing’s syndrome occurs when the body overproduces cortisol. The most common cause of the latter is a tumor of the pituitary gland (Cushing’s disease), but another cause is a usually benign tumor of the adrenal glands (adrenal Cushing’s syndrome). Surgery is the mainstay of initial treatment of Cushing’s syndrome. If an operation to remove the tumor fails to cause remission, medications are available.
Prior to this new meta-analysis, there had been limited data on mortality among patients with endogenous CS. Research has mostly been limited to single-cohort studies. A previous systematic review/meta-analysis comprised only seven articles with 780 patients. All the studies were conducted prior to 2012, and most were limited to Cushing’s disease.
“In 2021, we lacked a detailed understanding of patient outcomes and mortality because of the rarity of Cushing’s syndrome,” Dr. Limumpornpetch noted.
The current meta-analysis included 91 articles that reported mortality among patients with endogenous CS. There was a total of 19,181 patients from 92 study cohorts, including 49 studies on CD (n = 14,971), 24 studies on adrenal CS (n = 2304), and 19 studies that included both (n = 1906).
Among 21 studies that reported standardized mortality rate (SMR) data, including 13 CD studies (n = 2160) and seven on adrenal CS (n = 1531), the overall increase in mortality compared to the background population was a significant 3.00 (range, 1.15-7.84).
This SMR was higher among patients with adrenal Cushing’s syndrome (3.3) versus Cushing’s disease (2.8) (P = .003) and among patients who had active disease (5.7) versus those whose disease was in remission (2.3) (P < .001).
The SMR was also worse among patients with Cushing’s disease with larger tumors (macroadenomas), at 7.4, than among patients with very small tumors (microadenomas), at 1.9 (P = .004).
The proportion of death was 0.05 for CS overall, with 0.04 for CD and 0.02 for adrenal adenomas.
Compared to studies published prior to the year 2000, more recent studies seem to reflect advances in treatment and care. The overall proportion of death for all CS cohorts dropped from 0.10 to 0.03 (P < .001); for all CD cohorts, it dropped from 0.14 to 0.03; and for adrenal CS cohorts, it dropped from 0.09 to 0.03 (P = .04).
Causes of death were cardiovascular diseases (29.5% of cases), cerebrovascular accident (11.5%), infection (10.5%), and malignancy (10.1%). Less common causes of death were gastrointestinal bleeding and acute pancreatitis (3.7%), active CS (3.5%), adrenal insufficiency (2.5%), suicide (2.5%), and surgery (1.6%).
Overall, in the CS groups, the proportion of deaths within 30 days of surgery dropped from 0.04 prior to 2000 to 0.01 since (P = .07). For CD, the proportion dropped from 0.02 to 0.01 (P = .25).
Preventing perioperative mortality: Consider thromboprophylaxis
Dr. Fleseriu told this news organization that she believes hypercoagulability is “the least recognized complication with a big role in mortality.” Because most of the perioperative mortality is due to venous thromboembolism and infections, “thromboprophylaxis should be considered for CS patients with severe hypercortisolism and/or postoperatively, based on individual risk factors of thromboembolism and bleeding.”
Recently, Dr. Fleseriu’s group showed in a single retrospective study that the risk for arterial and venous thromboembolic events among patients with CS was approximately 20%. Many patients experienced more than one event. Risk was higher 30 to 60 days postoperatively.
The odds ratio of venous thromoboembolism among patients with CS was 18 times higher than in the normal population.
“Due to the additional thrombotic risk of surgery or any invasive procedure, anticoagulation prophylaxis should be at least considered in all patients with Cushing’s syndrome and balanced with individual bleeding risk,” Dr. Fleseriu advised.
A recent Pituitary Society workshop discussed the management of complications of CS at length; proceedings will be published soon, she noted.
Dr. Limumpornpetch commented, “We look forward to the day when our interdisciplinary approach to managing these challenging patients can deliver outcomes similar to the background population.”
Dr. Limumpornpetch has disclosed no relevant financial relationships. Dr. Fleseriu has been a scientific consultant to Recordati, Sparrow, and Strongbridge and has received grants (inst) from Novartis and Strongbridge.
A version of this article first appeared on Medscape.com.
Boosting the presence of darker skin in rheumatology education
Studies are flagging racial and ethnic disparities in rheumatology training materials, pointing to a need to boost representation of darker skin tones and better educate physicians in evaluating this cohort.
Not enough is known about these disparities in rheumatology education, despite the fact that minorities make up 40% of the population in the United States.
The problem starts with books and references used in medical schools, Lynn McKinley-Grant, MD, immediate past president of the Skin of Color Society and associate professor of dermatology at Howard University, Washington, said in an interview. “In the medical literature there has been a dearth of images in skin of color in all specialties,” she said. With an increased diversity in the U.S. population, there is a need for health care providers to be able to recognize disease patterns in all skin types.” If a physician is training at an institution where there are not many patients of color in the community, the rheumatologists are even more limited in terms of their clinical experience.
This lack of training in diagnosis of disease has serious clinical repercussions, as seen in COVID cases, Dr. McKinley-Grant noted. “You end up not being able to recognize early erythema, jaundice, anemia, or hypoxemia because those conditions are a different color or pattern in the darker skin types. This can lead to errors in treatment, diagnosis, and medical care, resulting in increased morbidity and mortality.”
Studies point to education gaps
A team of researchers from Washington University in St. Louis called attention to this issue at the American College of Rhematology’s Convergence 2020 conference.
“Patients of color with lupus are especially vulnerable as they often carry a greater disease burden, yet studies show that individuals with darker skin tones are underrepresented in medical educational materials,” Vijay Kannuthurai, MD, and colleagues wrote in their study abstract. The team surveyed 132 providers in St. Louis, Mo., on their confidence in evaluating any rash, and rashes in patients with lupus and varied skin tones.
Participating clinicians, mostly rheumatologists, dermatologists, or internists, had a higher confidence level in diagnosing any rash versus lupus rashes, but were considerably less confident in diagnosing lupus rash on darker skin, compared with those on fair skin. This represents “a disparity between provider confidence and the patient population lupus traditionally affects,” the investigators concluded.
Another recent study found evidence of disparities in clinical education resources. “The lack of dark skin representation among rheumatology educational materials contributes to the implicit bias and structural racism present in medical education by promoting White-only models of disease,” lead author Adrienne Strait, a medical student at the University of California, San Francisco, said in an interview. “Given that rheumatic diseases disproportionately impact racial and ethnic minorities, we felt it was important to examine the representation of these groups within rheumatology training resources.”
She and her colleagues gathered images of rheumatic diseases from four major databases: the American College of Rheumatology’s Image Library, UpToDate, the New England Journal of Medicine Images in Clinical Medicine and Clinical Cases filtered by “Rheumatology,” and the 9th edition of Kelley’s Textbook of Rheumatology. They used Fitzpatrick’s skin phototypes to independently code images depicting skin as “light” (skin types I-IV), “dark” (skin types V-VI), or “indeterminate,” focusing on systemic lupus erythematosus (SLE) and rheumatoid arthritis, two conditions with a known connection to racial and ethnic health disparities.
Taking into account the high incidence of sarcoidosis and SLE in Black patients when compared with White patients, the investigators did a secondary analysis that excluded these cases.
Among 1,043 patient images studied, just 13.4% represented dark skin, compared with 84% that represented light skin. More than 2% represented an indeterminate skin color. Comparing dark-skin representation in the clinical images and SLE images with the representation of Asian, Native American, and Black individuals in the United States and within lupus cases nationally, the investigators found significant underrepresentation of dark skin.
Only 4.2% of RA images had dark-skin representation, making RA one of the diseases with the lowest representation in the study, along with juvenile idiopathic arthritis, the spondyloarthropathies, and Kawasaki disease. “Representation of dark skin in SLE was also lower than the proportion of Black individuals in SLE studies,” the investigators noted. Overall, representation of dark skin in SLE images was just 22.6%. Sarcoidosis comparatively had the largest representation of dark-skin images (69.6%, n = 32).
“Excluding sarcoidosis and SLE images, the overall representation of dark skin was 9.4% (n = 84), which was significantly lower than the proportion of Asian, Native American, and Black individuals within the U.S. Census population,” according to Ms. Strait and her associates. UpToDate contained the largest proportion of images of dark skin respective to other databases, whereas Kelley’s Textbook had the smallest.
Actionable steps
Many physicians are willing to improve upon their skills in identifying conditions on darker skin, as the study by Dr. Kannuthurai and associates suggests. Overall, 93% of the survey’s participants wanted to learn more about rashes in patients of color. “Future educational interventions may help practitioners improve their confidence when diagnosing rashes in lupus patients” with darker skin, they suggested.
Ms. Strait and her colleagues recommended a series of actionable steps to improve diversity and equity of dark skin tone representation in rheumatology curricula.
Editors of educational resources, for example, should make image diversity a priority for those diseases that are most commonly associated with cutaneous manifestations, such as SLE, vasculitis, inflammatory myopathies, systemic sclerosis, sarcoidosis, and psoriasis. They also called for educators in academic rheumatology programs to collaborate to improve diversity in resources used at the undergraduate and graduate medical education level.
Efforts should take place at the local, regional, and national level to publicly discuss and educate clinicians about rheumatic diseases in individuals of color. Speakers at rheumatology conferences should strive to educate learners about presentations of rheumatic diseases in individuals of color. The ACR in the meantime could establish a task force to enhance racial and ethnic diversity in their image library and other published resources.
“These steps may improve provider recognition and diagnosis of rheumatic disease manifestations in skin of color, which may in turn reduce health disparities among racial and ethnic minority groups,” Ms. Strait said.
Beth L. Jonas, MD, chair of the ACR’s Committee on Rheumatology Training and Workforce Issues, called the findings of this study “timely and important.” The researchers highlighted a deficiency in rheumatology training materials that needs addressing, she said in an interview. “I definitely agree that ACR needs to be mindful of this. There’s no doubt that we need to take these recommendations and move along these lines.”
The ACR took a first step in 2020 with the creation of a diversity, equity, and inclusion committee. “We are undergoing a college-wide look at what we do, with an eye toward inclusion. There is a strong interest in addressing health disparities and being an equitable and inclusive community of rheumatology health care professionals,” said Dr. Jonas, chief of the University of North Carolina at Chapel Hill’s division of rheumatology, allergy, and immunology.
The American Academy of Dermatology is also working to improve the image library with images of disease in skin of color. “Everyone’s jumping on this now,” Dr. McKinley-Grant observed. The medical profession can’t afford not to. It’s a life-threatening issue when rheumatoid arthritis and other diseases in people of color aren’t diagnosed early and correctly, she added.
Technologies seek to reduce bias
While many organizations are taking steps to improve representation of darker skin images, VisualDx has taken the lead on this, she said. “They’ve been doing this for years now. There are over 14,000 images of disease in skin of color, including all the rheumatologic diseases. There’s a mobile app and desktop decision support system, and it is very popular. A majority of medical schools have this as a library resource, and hospital systems license it for EHR integration.” Doctors can also get it individually. This enables them to share images and handouts of a diagnosis and select images of patients of color, said Dr. McKinley-Grant, who uses the VisualDx smartphone app DermExpert, which is an app for nondermatologists that features an image library of skin lesions, including darker-skin images.
ProjectIMPACT, powered by VisualDx, is another effort to support reducing health care bias in darker skin. The project is a collaboration between the New England Journal of Medicine Group and the Skin Of Color Society. According to Dr. McKinley-Grant, the organizers are building awareness of the importance of reducing the educational and clinical gaps in diagnosing patients of color and trying to get students and educators to pledge to take meaningful steps and to have real-world impact.
This isn’t just exclusive to dermatology and rheumatology – it involves all medical specialties, she stressed.
ProjectIMPACT isn’t just a resource for physicians, she continued. Librarians can also use it to develop more resources on skin of color.
The Skin Of Color Society and VisualDx have also partnered with the NEJM Group to develop a comprehensive virtual series on the impact of skin color and ethnicity on clinical research. The four-part series addresses structural racism and racial bias in medicine, hair disorders in people of color, pigmentary disorders, keloids, COVID-19 comorbidities, and cutaneous manifestations of systemic diseases in children and adults.
Nuances of recognizing disease
As a medical student, Dr. McKinley-Grant said she was fortunate to attend the Albert Schweitzer Hospital in Lambarene, Gabon, on a fellowship. For 3 months, she gained a wealth of experience examining only African patients with brown skin.
In her other training in medicine, “I’ve been at institutions with diverse populations, in Boston, New York, and Washington,” learning more about all different skin pigments.
This type of training should be more widely available, especially now, with COVID-19 producing new manifestations of skin lesions, she emphasized. Such efforts involve a diversification of images physicians are being trained on so that they can recognize the same disease in a person of color.
“Doctors have to be able to recognize different colors, different shades of brown and shades of white. Not all white skin is the same color,” she noted. In looking at a rash or lesion, “you have to learn how to discern differences in the background color of the skin, which is determined by melanin in the skin (Fitzpatrick skin types I-VI) and by what’s going on in the blood, such as how much oxygen and hemoglobin the patient has in their blood.” Inflammation and infection (erythema) will appear more violaceous in IV-VI skin types, for example.
At the University of North Carolina at Chapel Hill, a group of students and faculty have created a dermatology image library to address the deficiency in the availability of images for teaching purposes. “Our medical students recognized the gap and started this,” Dr. Jonas said. Julie Mervak, MD, assistant professor of dermatology, is spearheading this effort, with students Linnea Westerkam and Anuj Pranav Sanghvi.
“I understand that others around the country are working on similar initiatives,” Dr. Jonas said.
None of the sources for this story had any relevant disclosures.
Studies are flagging racial and ethnic disparities in rheumatology training materials, pointing to a need to boost representation of darker skin tones and better educate physicians in evaluating this cohort.
Not enough is known about these disparities in rheumatology education, despite the fact that minorities make up 40% of the population in the United States.
The problem starts with books and references used in medical schools, Lynn McKinley-Grant, MD, immediate past president of the Skin of Color Society and associate professor of dermatology at Howard University, Washington, said in an interview. “In the medical literature there has been a dearth of images in skin of color in all specialties,” she said. With an increased diversity in the U.S. population, there is a need for health care providers to be able to recognize disease patterns in all skin types.” If a physician is training at an institution where there are not many patients of color in the community, the rheumatologists are even more limited in terms of their clinical experience.
This lack of training in diagnosis of disease has serious clinical repercussions, as seen in COVID cases, Dr. McKinley-Grant noted. “You end up not being able to recognize early erythema, jaundice, anemia, or hypoxemia because those conditions are a different color or pattern in the darker skin types. This can lead to errors in treatment, diagnosis, and medical care, resulting in increased morbidity and mortality.”
Studies point to education gaps
A team of researchers from Washington University in St. Louis called attention to this issue at the American College of Rhematology’s Convergence 2020 conference.
“Patients of color with lupus are especially vulnerable as they often carry a greater disease burden, yet studies show that individuals with darker skin tones are underrepresented in medical educational materials,” Vijay Kannuthurai, MD, and colleagues wrote in their study abstract. The team surveyed 132 providers in St. Louis, Mo., on their confidence in evaluating any rash, and rashes in patients with lupus and varied skin tones.
Participating clinicians, mostly rheumatologists, dermatologists, or internists, had a higher confidence level in diagnosing any rash versus lupus rashes, but were considerably less confident in diagnosing lupus rash on darker skin, compared with those on fair skin. This represents “a disparity between provider confidence and the patient population lupus traditionally affects,” the investigators concluded.
Another recent study found evidence of disparities in clinical education resources. “The lack of dark skin representation among rheumatology educational materials contributes to the implicit bias and structural racism present in medical education by promoting White-only models of disease,” lead author Adrienne Strait, a medical student at the University of California, San Francisco, said in an interview. “Given that rheumatic diseases disproportionately impact racial and ethnic minorities, we felt it was important to examine the representation of these groups within rheumatology training resources.”
She and her colleagues gathered images of rheumatic diseases from four major databases: the American College of Rheumatology’s Image Library, UpToDate, the New England Journal of Medicine Images in Clinical Medicine and Clinical Cases filtered by “Rheumatology,” and the 9th edition of Kelley’s Textbook of Rheumatology. They used Fitzpatrick’s skin phototypes to independently code images depicting skin as “light” (skin types I-IV), “dark” (skin types V-VI), or “indeterminate,” focusing on systemic lupus erythematosus (SLE) and rheumatoid arthritis, two conditions with a known connection to racial and ethnic health disparities.
Taking into account the high incidence of sarcoidosis and SLE in Black patients when compared with White patients, the investigators did a secondary analysis that excluded these cases.
Among 1,043 patient images studied, just 13.4% represented dark skin, compared with 84% that represented light skin. More than 2% represented an indeterminate skin color. Comparing dark-skin representation in the clinical images and SLE images with the representation of Asian, Native American, and Black individuals in the United States and within lupus cases nationally, the investigators found significant underrepresentation of dark skin.
Only 4.2% of RA images had dark-skin representation, making RA one of the diseases with the lowest representation in the study, along with juvenile idiopathic arthritis, the spondyloarthropathies, and Kawasaki disease. “Representation of dark skin in SLE was also lower than the proportion of Black individuals in SLE studies,” the investigators noted. Overall, representation of dark skin in SLE images was just 22.6%. Sarcoidosis comparatively had the largest representation of dark-skin images (69.6%, n = 32).
“Excluding sarcoidosis and SLE images, the overall representation of dark skin was 9.4% (n = 84), which was significantly lower than the proportion of Asian, Native American, and Black individuals within the U.S. Census population,” according to Ms. Strait and her associates. UpToDate contained the largest proportion of images of dark skin respective to other databases, whereas Kelley’s Textbook had the smallest.
Actionable steps
Many physicians are willing to improve upon their skills in identifying conditions on darker skin, as the study by Dr. Kannuthurai and associates suggests. Overall, 93% of the survey’s participants wanted to learn more about rashes in patients of color. “Future educational interventions may help practitioners improve their confidence when diagnosing rashes in lupus patients” with darker skin, they suggested.
Ms. Strait and her colleagues recommended a series of actionable steps to improve diversity and equity of dark skin tone representation in rheumatology curricula.
Editors of educational resources, for example, should make image diversity a priority for those diseases that are most commonly associated with cutaneous manifestations, such as SLE, vasculitis, inflammatory myopathies, systemic sclerosis, sarcoidosis, and psoriasis. They also called for educators in academic rheumatology programs to collaborate to improve diversity in resources used at the undergraduate and graduate medical education level.
Efforts should take place at the local, regional, and national level to publicly discuss and educate clinicians about rheumatic diseases in individuals of color. Speakers at rheumatology conferences should strive to educate learners about presentations of rheumatic diseases in individuals of color. The ACR in the meantime could establish a task force to enhance racial and ethnic diversity in their image library and other published resources.
“These steps may improve provider recognition and diagnosis of rheumatic disease manifestations in skin of color, which may in turn reduce health disparities among racial and ethnic minority groups,” Ms. Strait said.
Beth L. Jonas, MD, chair of the ACR’s Committee on Rheumatology Training and Workforce Issues, called the findings of this study “timely and important.” The researchers highlighted a deficiency in rheumatology training materials that needs addressing, she said in an interview. “I definitely agree that ACR needs to be mindful of this. There’s no doubt that we need to take these recommendations and move along these lines.”
The ACR took a first step in 2020 with the creation of a diversity, equity, and inclusion committee. “We are undergoing a college-wide look at what we do, with an eye toward inclusion. There is a strong interest in addressing health disparities and being an equitable and inclusive community of rheumatology health care professionals,” said Dr. Jonas, chief of the University of North Carolina at Chapel Hill’s division of rheumatology, allergy, and immunology.
The American Academy of Dermatology is also working to improve the image library with images of disease in skin of color. “Everyone’s jumping on this now,” Dr. McKinley-Grant observed. The medical profession can’t afford not to. It’s a life-threatening issue when rheumatoid arthritis and other diseases in people of color aren’t diagnosed early and correctly, she added.
Technologies seek to reduce bias
While many organizations are taking steps to improve representation of darker skin images, VisualDx has taken the lead on this, she said. “They’ve been doing this for years now. There are over 14,000 images of disease in skin of color, including all the rheumatologic diseases. There’s a mobile app and desktop decision support system, and it is very popular. A majority of medical schools have this as a library resource, and hospital systems license it for EHR integration.” Doctors can also get it individually. This enables them to share images and handouts of a diagnosis and select images of patients of color, said Dr. McKinley-Grant, who uses the VisualDx smartphone app DermExpert, which is an app for nondermatologists that features an image library of skin lesions, including darker-skin images.
ProjectIMPACT, powered by VisualDx, is another effort to support reducing health care bias in darker skin. The project is a collaboration between the New England Journal of Medicine Group and the Skin Of Color Society. According to Dr. McKinley-Grant, the organizers are building awareness of the importance of reducing the educational and clinical gaps in diagnosing patients of color and trying to get students and educators to pledge to take meaningful steps and to have real-world impact.
This isn’t just exclusive to dermatology and rheumatology – it involves all medical specialties, she stressed.
ProjectIMPACT isn’t just a resource for physicians, she continued. Librarians can also use it to develop more resources on skin of color.
The Skin Of Color Society and VisualDx have also partnered with the NEJM Group to develop a comprehensive virtual series on the impact of skin color and ethnicity on clinical research. The four-part series addresses structural racism and racial bias in medicine, hair disorders in people of color, pigmentary disorders, keloids, COVID-19 comorbidities, and cutaneous manifestations of systemic diseases in children and adults.
Nuances of recognizing disease
As a medical student, Dr. McKinley-Grant said she was fortunate to attend the Albert Schweitzer Hospital in Lambarene, Gabon, on a fellowship. For 3 months, she gained a wealth of experience examining only African patients with brown skin.
In her other training in medicine, “I’ve been at institutions with diverse populations, in Boston, New York, and Washington,” learning more about all different skin pigments.
This type of training should be more widely available, especially now, with COVID-19 producing new manifestations of skin lesions, she emphasized. Such efforts involve a diversification of images physicians are being trained on so that they can recognize the same disease in a person of color.
“Doctors have to be able to recognize different colors, different shades of brown and shades of white. Not all white skin is the same color,” she noted. In looking at a rash or lesion, “you have to learn how to discern differences in the background color of the skin, which is determined by melanin in the skin (Fitzpatrick skin types I-VI) and by what’s going on in the blood, such as how much oxygen and hemoglobin the patient has in their blood.” Inflammation and infection (erythema) will appear more violaceous in IV-VI skin types, for example.
At the University of North Carolina at Chapel Hill, a group of students and faculty have created a dermatology image library to address the deficiency in the availability of images for teaching purposes. “Our medical students recognized the gap and started this,” Dr. Jonas said. Julie Mervak, MD, assistant professor of dermatology, is spearheading this effort, with students Linnea Westerkam and Anuj Pranav Sanghvi.
“I understand that others around the country are working on similar initiatives,” Dr. Jonas said.
None of the sources for this story had any relevant disclosures.
Studies are flagging racial and ethnic disparities in rheumatology training materials, pointing to a need to boost representation of darker skin tones and better educate physicians in evaluating this cohort.
Not enough is known about these disparities in rheumatology education, despite the fact that minorities make up 40% of the population in the United States.
The problem starts with books and references used in medical schools, Lynn McKinley-Grant, MD, immediate past president of the Skin of Color Society and associate professor of dermatology at Howard University, Washington, said in an interview. “In the medical literature there has been a dearth of images in skin of color in all specialties,” she said. With an increased diversity in the U.S. population, there is a need for health care providers to be able to recognize disease patterns in all skin types.” If a physician is training at an institution where there are not many patients of color in the community, the rheumatologists are even more limited in terms of their clinical experience.
This lack of training in diagnosis of disease has serious clinical repercussions, as seen in COVID cases, Dr. McKinley-Grant noted. “You end up not being able to recognize early erythema, jaundice, anemia, or hypoxemia because those conditions are a different color or pattern in the darker skin types. This can lead to errors in treatment, diagnosis, and medical care, resulting in increased morbidity and mortality.”
Studies point to education gaps
A team of researchers from Washington University in St. Louis called attention to this issue at the American College of Rhematology’s Convergence 2020 conference.
“Patients of color with lupus are especially vulnerable as they often carry a greater disease burden, yet studies show that individuals with darker skin tones are underrepresented in medical educational materials,” Vijay Kannuthurai, MD, and colleagues wrote in their study abstract. The team surveyed 132 providers in St. Louis, Mo., on their confidence in evaluating any rash, and rashes in patients with lupus and varied skin tones.
Participating clinicians, mostly rheumatologists, dermatologists, or internists, had a higher confidence level in diagnosing any rash versus lupus rashes, but were considerably less confident in diagnosing lupus rash on darker skin, compared with those on fair skin. This represents “a disparity between provider confidence and the patient population lupus traditionally affects,” the investigators concluded.
Another recent study found evidence of disparities in clinical education resources. “The lack of dark skin representation among rheumatology educational materials contributes to the implicit bias and structural racism present in medical education by promoting White-only models of disease,” lead author Adrienne Strait, a medical student at the University of California, San Francisco, said in an interview. “Given that rheumatic diseases disproportionately impact racial and ethnic minorities, we felt it was important to examine the representation of these groups within rheumatology training resources.”
She and her colleagues gathered images of rheumatic diseases from four major databases: the American College of Rheumatology’s Image Library, UpToDate, the New England Journal of Medicine Images in Clinical Medicine and Clinical Cases filtered by “Rheumatology,” and the 9th edition of Kelley’s Textbook of Rheumatology. They used Fitzpatrick’s skin phototypes to independently code images depicting skin as “light” (skin types I-IV), “dark” (skin types V-VI), or “indeterminate,” focusing on systemic lupus erythematosus (SLE) and rheumatoid arthritis, two conditions with a known connection to racial and ethnic health disparities.
Taking into account the high incidence of sarcoidosis and SLE in Black patients when compared with White patients, the investigators did a secondary analysis that excluded these cases.
Among 1,043 patient images studied, just 13.4% represented dark skin, compared with 84% that represented light skin. More than 2% represented an indeterminate skin color. Comparing dark-skin representation in the clinical images and SLE images with the representation of Asian, Native American, and Black individuals in the United States and within lupus cases nationally, the investigators found significant underrepresentation of dark skin.
Only 4.2% of RA images had dark-skin representation, making RA one of the diseases with the lowest representation in the study, along with juvenile idiopathic arthritis, the spondyloarthropathies, and Kawasaki disease. “Representation of dark skin in SLE was also lower than the proportion of Black individuals in SLE studies,” the investigators noted. Overall, representation of dark skin in SLE images was just 22.6%. Sarcoidosis comparatively had the largest representation of dark-skin images (69.6%, n = 32).
“Excluding sarcoidosis and SLE images, the overall representation of dark skin was 9.4% (n = 84), which was significantly lower than the proportion of Asian, Native American, and Black individuals within the U.S. Census population,” according to Ms. Strait and her associates. UpToDate contained the largest proportion of images of dark skin respective to other databases, whereas Kelley’s Textbook had the smallest.
Actionable steps
Many physicians are willing to improve upon their skills in identifying conditions on darker skin, as the study by Dr. Kannuthurai and associates suggests. Overall, 93% of the survey’s participants wanted to learn more about rashes in patients of color. “Future educational interventions may help practitioners improve their confidence when diagnosing rashes in lupus patients” with darker skin, they suggested.
Ms. Strait and her colleagues recommended a series of actionable steps to improve diversity and equity of dark skin tone representation in rheumatology curricula.
Editors of educational resources, for example, should make image diversity a priority for those diseases that are most commonly associated with cutaneous manifestations, such as SLE, vasculitis, inflammatory myopathies, systemic sclerosis, sarcoidosis, and psoriasis. They also called for educators in academic rheumatology programs to collaborate to improve diversity in resources used at the undergraduate and graduate medical education level.
Efforts should take place at the local, regional, and national level to publicly discuss and educate clinicians about rheumatic diseases in individuals of color. Speakers at rheumatology conferences should strive to educate learners about presentations of rheumatic diseases in individuals of color. The ACR in the meantime could establish a task force to enhance racial and ethnic diversity in their image library and other published resources.
“These steps may improve provider recognition and diagnosis of rheumatic disease manifestations in skin of color, which may in turn reduce health disparities among racial and ethnic minority groups,” Ms. Strait said.
Beth L. Jonas, MD, chair of the ACR’s Committee on Rheumatology Training and Workforce Issues, called the findings of this study “timely and important.” The researchers highlighted a deficiency in rheumatology training materials that needs addressing, she said in an interview. “I definitely agree that ACR needs to be mindful of this. There’s no doubt that we need to take these recommendations and move along these lines.”
The ACR took a first step in 2020 with the creation of a diversity, equity, and inclusion committee. “We are undergoing a college-wide look at what we do, with an eye toward inclusion. There is a strong interest in addressing health disparities and being an equitable and inclusive community of rheumatology health care professionals,” said Dr. Jonas, chief of the University of North Carolina at Chapel Hill’s division of rheumatology, allergy, and immunology.
The American Academy of Dermatology is also working to improve the image library with images of disease in skin of color. “Everyone’s jumping on this now,” Dr. McKinley-Grant observed. The medical profession can’t afford not to. It’s a life-threatening issue when rheumatoid arthritis and other diseases in people of color aren’t diagnosed early and correctly, she added.
Technologies seek to reduce bias
While many organizations are taking steps to improve representation of darker skin images, VisualDx has taken the lead on this, she said. “They’ve been doing this for years now. There are over 14,000 images of disease in skin of color, including all the rheumatologic diseases. There’s a mobile app and desktop decision support system, and it is very popular. A majority of medical schools have this as a library resource, and hospital systems license it for EHR integration.” Doctors can also get it individually. This enables them to share images and handouts of a diagnosis and select images of patients of color, said Dr. McKinley-Grant, who uses the VisualDx smartphone app DermExpert, which is an app for nondermatologists that features an image library of skin lesions, including darker-skin images.
ProjectIMPACT, powered by VisualDx, is another effort to support reducing health care bias in darker skin. The project is a collaboration between the New England Journal of Medicine Group and the Skin Of Color Society. According to Dr. McKinley-Grant, the organizers are building awareness of the importance of reducing the educational and clinical gaps in diagnosing patients of color and trying to get students and educators to pledge to take meaningful steps and to have real-world impact.
This isn’t just exclusive to dermatology and rheumatology – it involves all medical specialties, she stressed.
ProjectIMPACT isn’t just a resource for physicians, she continued. Librarians can also use it to develop more resources on skin of color.
The Skin Of Color Society and VisualDx have also partnered with the NEJM Group to develop a comprehensive virtual series on the impact of skin color and ethnicity on clinical research. The four-part series addresses structural racism and racial bias in medicine, hair disorders in people of color, pigmentary disorders, keloids, COVID-19 comorbidities, and cutaneous manifestations of systemic diseases in children and adults.
Nuances of recognizing disease
As a medical student, Dr. McKinley-Grant said she was fortunate to attend the Albert Schweitzer Hospital in Lambarene, Gabon, on a fellowship. For 3 months, she gained a wealth of experience examining only African patients with brown skin.
In her other training in medicine, “I’ve been at institutions with diverse populations, in Boston, New York, and Washington,” learning more about all different skin pigments.
This type of training should be more widely available, especially now, with COVID-19 producing new manifestations of skin lesions, she emphasized. Such efforts involve a diversification of images physicians are being trained on so that they can recognize the same disease in a person of color.
“Doctors have to be able to recognize different colors, different shades of brown and shades of white. Not all white skin is the same color,” she noted. In looking at a rash or lesion, “you have to learn how to discern differences in the background color of the skin, which is determined by melanin in the skin (Fitzpatrick skin types I-VI) and by what’s going on in the blood, such as how much oxygen and hemoglobin the patient has in their blood.” Inflammation and infection (erythema) will appear more violaceous in IV-VI skin types, for example.
At the University of North Carolina at Chapel Hill, a group of students and faculty have created a dermatology image library to address the deficiency in the availability of images for teaching purposes. “Our medical students recognized the gap and started this,” Dr. Jonas said. Julie Mervak, MD, assistant professor of dermatology, is spearheading this effort, with students Linnea Westerkam and Anuj Pranav Sanghvi.
“I understand that others around the country are working on similar initiatives,” Dr. Jonas said.
None of the sources for this story had any relevant disclosures.
Early pediatric rheumatology residency exposure key to solving workforce shortages
The biggest factors that attract medical students to enter pediatric rheumatology are interest in disease pathology, the patient-physician relationship, and clinical exposure in residency, according to preliminary research shared at the annual scientific meeting of the Childhood Arthritis and Rheumatology Research Alliance.
A shortage in pediatric rheumatology already exists and is expected to worsen to 61% by 2030, noted the authors. About one-third (32%) of current pediatric rheumatologists will retire in the next decade, and less than two-thirds of fellowship slots have filled in the past 5 years.
Katherine Schultz, MD, a clinical fellow in the division of rheumatology at Cincinnati Children’s Medical Center, led the study and said she was surprised that medical school exposure did not play a bigger role in attracting people to the field, but perhaps that’s because too few people received that early exposure.
“If we had earlier exposure, maybe that wouldn’t be definitive for saying, ‘yes, I want to do this subspecialty of pediatric rheumatology,’ but it would open the door, so when you hit residency, you can explore it further,” Dr. Schultz said in an interview.
Dr. Schultz and her colleagues conducted a survey using the CARRA registry during September-December 2020. Respondents included pediatric rheumatology clinical fellows, early-career pediatric rheumatology faculty with less than 7 years practice experience, and mid- to late-career pediatric rheumatology faculty – those with more than 7 years of practice. They are currently in the process of analyzing additional qualitative data.
Of the 428 clinicians recruited to complete the study, 92 did so, for a response rate of 21%. Most respondents were female and non-Hispanic White. A total of 40% were clinical fellows, 41% were early-career faculty, and 18% were mid- to late-career faculty.
Positive factors for choosing the field
More than 80% of respondents across all three experience levels cited disease pathology as a positive attribute of pediatric rheumatology, something that Dr. Schultz mentioned as well.
“The rewarding part of pediatric rheumatology is we take these complex diseases and we help give kids their life back,” she said.
Nearly all the clinical fellows who responded said the patient-physician relationship was important, which early- and mid- and late-career faculty mentioned as well, although to a slightly lesser extent.
Other factors following closely behind disease pathology, patient-physician relationship, and clinical exposure in residency were having a role model in the field – cited by more than three-quarters of clinical fellows and early-career faculty – and having mentorship during residency.
“One of the strengths of our field and one of the things I love about pediatric rheumatology is our community is so close-knit, so kind, and so welcoming,” Dr. Schultz said. “If students can have that exposure and they can see the kind of people who are in this field, that’s our greatest power to draw people to our field.”
Low compensation is a deterrent
The least frequently mentioned positive factors were research opportunities and income. In fact, income was by far the most commonly cited negative attribute of pediatric rheumatology, reported by nearly half of clinical fellows and more than a quarter of early- and mid- and late-career faculty.
“We are one of the lowest paid specialties in pediatrics. We often make [income] comparable to or less than a general pediatrician,” Dr. Schultz said. One reason for that is the difficulty of doing pediatric rheumatology in private practice. Most positions are at academic institutions, which will nearly always involve lower pay scales, she said. The field is also not a procedure-based one, which makes billing more difficult to quantify.
“If I spend an hour thinking about a patient’s diagnosis and interpreting their labs, how do we quantify that?” she asked. “Our field is so cognitive that it makes it hard to bill in the same manner” as fields who bill more procedures, she said.
Colleen Correll, MD, MPH, an assistant professor of pediatric rheumatology at the University of Minnesota in Minneapolis, was also not surprised to see salary listed as the biggest deterrent to the field.
“Unfortunately, compared to other specialties, our compensation is lower, and this can be a real barrier for people who have large medical student loans to repay and for those providing for their families,” Dr. Correll said in an interview. She and Dr. Schultz both said that workforce advocacy groups are working on ways to compensate for that difference, including loan repayment programs.
The other specialties that respondents considered before choosing pediatric rheumatology varied by generation, but allergy and immunology and endocrinology were among the most cited by early-, mid-, and late-career faculty. Clinical fellows’ responses were more evenly distributed across a range of different subspecialties.
Early exposure is key
A large proportion of all three groups, including almost 90% of early-career faculty and clinical fellows, said they received exposure to pediatric rheumatology during residency. However, only a little more than two-thirds of clinical fellows had exposure to the field in medical school, and fewer than that reported medical school exposure among both faculty groups.
Both Dr. Correll and Dr. Schultz said that early exposure to pediatric rheumatology was key to bringing more people into the workforce.
“I believe that once a medical student or resident has an opportunity to work with a pediatric rheumatologist, they are able to see the many reasons for which this is a great career choice,” Dr. Correll said. “Pediatric rheumatologists are seen as positive role models. We love what we do, we have great patient-physician relationships, and we see interesting disease pathophysiology on a regular basis.”
Although earlier exposure to the field is primarily an institutional issue, clinicians can play a role as well.
“For the individual practitioners, the biggest way they can make an impact is to make themselves visible,” Dr. Schultz said. Although the subspecialty is stretched thin, she encouraged pediatric rheumatologists to do med school and resident lectures, volunteer to do feedback sessions, offer residents opportunities to rotate with them, and generally make themselves more visible. “It’s going to take the community to really make the change we need,” she said.
She and Dr. Correll both cited the American College of Rheumatology and CARRA pediatric residency programs as helpful, but there’s more to do. Other ways to increase exposure to the field include creating medical student rotations in pediatric rheumatology, working on case reports or small research projects with new learners, and requesting that pediatric rheumatology be a mandatory rotation in pediatrics training, Dr. Correll said.
“We absolutely have a responsibility to promote our field because if we don’t, the workforce supply issue will continue to worsen,” Dr. Correll said. “We already have a workforce shortage, and models show this shortage will only worsen if we don’t improve recruitment into the field, especially with many pediatric rheumatologists coming up on retirement. Once we are able to expose medical students and residents to the field, I think they easily see our passion and our love for the field, and it’s easy to recruit them.”
The research was funded by CARRA, which receives funding from the Arthritis Foundation. Dr. Schultz and Dr. Correll had no disclosures.
The biggest factors that attract medical students to enter pediatric rheumatology are interest in disease pathology, the patient-physician relationship, and clinical exposure in residency, according to preliminary research shared at the annual scientific meeting of the Childhood Arthritis and Rheumatology Research Alliance.
A shortage in pediatric rheumatology already exists and is expected to worsen to 61% by 2030, noted the authors. About one-third (32%) of current pediatric rheumatologists will retire in the next decade, and less than two-thirds of fellowship slots have filled in the past 5 years.
Katherine Schultz, MD, a clinical fellow in the division of rheumatology at Cincinnati Children’s Medical Center, led the study and said she was surprised that medical school exposure did not play a bigger role in attracting people to the field, but perhaps that’s because too few people received that early exposure.
“If we had earlier exposure, maybe that wouldn’t be definitive for saying, ‘yes, I want to do this subspecialty of pediatric rheumatology,’ but it would open the door, so when you hit residency, you can explore it further,” Dr. Schultz said in an interview.
Dr. Schultz and her colleagues conducted a survey using the CARRA registry during September-December 2020. Respondents included pediatric rheumatology clinical fellows, early-career pediatric rheumatology faculty with less than 7 years practice experience, and mid- to late-career pediatric rheumatology faculty – those with more than 7 years of practice. They are currently in the process of analyzing additional qualitative data.
Of the 428 clinicians recruited to complete the study, 92 did so, for a response rate of 21%. Most respondents were female and non-Hispanic White. A total of 40% were clinical fellows, 41% were early-career faculty, and 18% were mid- to late-career faculty.
Positive factors for choosing the field
More than 80% of respondents across all three experience levels cited disease pathology as a positive attribute of pediatric rheumatology, something that Dr. Schultz mentioned as well.
“The rewarding part of pediatric rheumatology is we take these complex diseases and we help give kids their life back,” she said.
Nearly all the clinical fellows who responded said the patient-physician relationship was important, which early- and mid- and late-career faculty mentioned as well, although to a slightly lesser extent.
Other factors following closely behind disease pathology, patient-physician relationship, and clinical exposure in residency were having a role model in the field – cited by more than three-quarters of clinical fellows and early-career faculty – and having mentorship during residency.
“One of the strengths of our field and one of the things I love about pediatric rheumatology is our community is so close-knit, so kind, and so welcoming,” Dr. Schultz said. “If students can have that exposure and they can see the kind of people who are in this field, that’s our greatest power to draw people to our field.”
Low compensation is a deterrent
The least frequently mentioned positive factors were research opportunities and income. In fact, income was by far the most commonly cited negative attribute of pediatric rheumatology, reported by nearly half of clinical fellows and more than a quarter of early- and mid- and late-career faculty.
“We are one of the lowest paid specialties in pediatrics. We often make [income] comparable to or less than a general pediatrician,” Dr. Schultz said. One reason for that is the difficulty of doing pediatric rheumatology in private practice. Most positions are at academic institutions, which will nearly always involve lower pay scales, she said. The field is also not a procedure-based one, which makes billing more difficult to quantify.
“If I spend an hour thinking about a patient’s diagnosis and interpreting their labs, how do we quantify that?” she asked. “Our field is so cognitive that it makes it hard to bill in the same manner” as fields who bill more procedures, she said.
Colleen Correll, MD, MPH, an assistant professor of pediatric rheumatology at the University of Minnesota in Minneapolis, was also not surprised to see salary listed as the biggest deterrent to the field.
“Unfortunately, compared to other specialties, our compensation is lower, and this can be a real barrier for people who have large medical student loans to repay and for those providing for their families,” Dr. Correll said in an interview. She and Dr. Schultz both said that workforce advocacy groups are working on ways to compensate for that difference, including loan repayment programs.
The other specialties that respondents considered before choosing pediatric rheumatology varied by generation, but allergy and immunology and endocrinology were among the most cited by early-, mid-, and late-career faculty. Clinical fellows’ responses were more evenly distributed across a range of different subspecialties.
Early exposure is key
A large proportion of all three groups, including almost 90% of early-career faculty and clinical fellows, said they received exposure to pediatric rheumatology during residency. However, only a little more than two-thirds of clinical fellows had exposure to the field in medical school, and fewer than that reported medical school exposure among both faculty groups.
Both Dr. Correll and Dr. Schultz said that early exposure to pediatric rheumatology was key to bringing more people into the workforce.
“I believe that once a medical student or resident has an opportunity to work with a pediatric rheumatologist, they are able to see the many reasons for which this is a great career choice,” Dr. Correll said. “Pediatric rheumatologists are seen as positive role models. We love what we do, we have great patient-physician relationships, and we see interesting disease pathophysiology on a regular basis.”
Although earlier exposure to the field is primarily an institutional issue, clinicians can play a role as well.
“For the individual practitioners, the biggest way they can make an impact is to make themselves visible,” Dr. Schultz said. Although the subspecialty is stretched thin, she encouraged pediatric rheumatologists to do med school and resident lectures, volunteer to do feedback sessions, offer residents opportunities to rotate with them, and generally make themselves more visible. “It’s going to take the community to really make the change we need,” she said.
She and Dr. Correll both cited the American College of Rheumatology and CARRA pediatric residency programs as helpful, but there’s more to do. Other ways to increase exposure to the field include creating medical student rotations in pediatric rheumatology, working on case reports or small research projects with new learners, and requesting that pediatric rheumatology be a mandatory rotation in pediatrics training, Dr. Correll said.
“We absolutely have a responsibility to promote our field because if we don’t, the workforce supply issue will continue to worsen,” Dr. Correll said. “We already have a workforce shortage, and models show this shortage will only worsen if we don’t improve recruitment into the field, especially with many pediatric rheumatologists coming up on retirement. Once we are able to expose medical students and residents to the field, I think they easily see our passion and our love for the field, and it’s easy to recruit them.”
The research was funded by CARRA, which receives funding from the Arthritis Foundation. Dr. Schultz and Dr. Correll had no disclosures.
The biggest factors that attract medical students to enter pediatric rheumatology are interest in disease pathology, the patient-physician relationship, and clinical exposure in residency, according to preliminary research shared at the annual scientific meeting of the Childhood Arthritis and Rheumatology Research Alliance.
A shortage in pediatric rheumatology already exists and is expected to worsen to 61% by 2030, noted the authors. About one-third (32%) of current pediatric rheumatologists will retire in the next decade, and less than two-thirds of fellowship slots have filled in the past 5 years.
Katherine Schultz, MD, a clinical fellow in the division of rheumatology at Cincinnati Children’s Medical Center, led the study and said she was surprised that medical school exposure did not play a bigger role in attracting people to the field, but perhaps that’s because too few people received that early exposure.
“If we had earlier exposure, maybe that wouldn’t be definitive for saying, ‘yes, I want to do this subspecialty of pediatric rheumatology,’ but it would open the door, so when you hit residency, you can explore it further,” Dr. Schultz said in an interview.
Dr. Schultz and her colleagues conducted a survey using the CARRA registry during September-December 2020. Respondents included pediatric rheumatology clinical fellows, early-career pediatric rheumatology faculty with less than 7 years practice experience, and mid- to late-career pediatric rheumatology faculty – those with more than 7 years of practice. They are currently in the process of analyzing additional qualitative data.
Of the 428 clinicians recruited to complete the study, 92 did so, for a response rate of 21%. Most respondents were female and non-Hispanic White. A total of 40% were clinical fellows, 41% were early-career faculty, and 18% were mid- to late-career faculty.
Positive factors for choosing the field
More than 80% of respondents across all three experience levels cited disease pathology as a positive attribute of pediatric rheumatology, something that Dr. Schultz mentioned as well.
“The rewarding part of pediatric rheumatology is we take these complex diseases and we help give kids their life back,” she said.
Nearly all the clinical fellows who responded said the patient-physician relationship was important, which early- and mid- and late-career faculty mentioned as well, although to a slightly lesser extent.
Other factors following closely behind disease pathology, patient-physician relationship, and clinical exposure in residency were having a role model in the field – cited by more than three-quarters of clinical fellows and early-career faculty – and having mentorship during residency.
“One of the strengths of our field and one of the things I love about pediatric rheumatology is our community is so close-knit, so kind, and so welcoming,” Dr. Schultz said. “If students can have that exposure and they can see the kind of people who are in this field, that’s our greatest power to draw people to our field.”
Low compensation is a deterrent
The least frequently mentioned positive factors were research opportunities and income. In fact, income was by far the most commonly cited negative attribute of pediatric rheumatology, reported by nearly half of clinical fellows and more than a quarter of early- and mid- and late-career faculty.
“We are one of the lowest paid specialties in pediatrics. We often make [income] comparable to or less than a general pediatrician,” Dr. Schultz said. One reason for that is the difficulty of doing pediatric rheumatology in private practice. Most positions are at academic institutions, which will nearly always involve lower pay scales, she said. The field is also not a procedure-based one, which makes billing more difficult to quantify.
“If I spend an hour thinking about a patient’s diagnosis and interpreting their labs, how do we quantify that?” she asked. “Our field is so cognitive that it makes it hard to bill in the same manner” as fields who bill more procedures, she said.
Colleen Correll, MD, MPH, an assistant professor of pediatric rheumatology at the University of Minnesota in Minneapolis, was also not surprised to see salary listed as the biggest deterrent to the field.
“Unfortunately, compared to other specialties, our compensation is lower, and this can be a real barrier for people who have large medical student loans to repay and for those providing for their families,” Dr. Correll said in an interview. She and Dr. Schultz both said that workforce advocacy groups are working on ways to compensate for that difference, including loan repayment programs.
The other specialties that respondents considered before choosing pediatric rheumatology varied by generation, but allergy and immunology and endocrinology were among the most cited by early-, mid-, and late-career faculty. Clinical fellows’ responses were more evenly distributed across a range of different subspecialties.
Early exposure is key
A large proportion of all three groups, including almost 90% of early-career faculty and clinical fellows, said they received exposure to pediatric rheumatology during residency. However, only a little more than two-thirds of clinical fellows had exposure to the field in medical school, and fewer than that reported medical school exposure among both faculty groups.
Both Dr. Correll and Dr. Schultz said that early exposure to pediatric rheumatology was key to bringing more people into the workforce.
“I believe that once a medical student or resident has an opportunity to work with a pediatric rheumatologist, they are able to see the many reasons for which this is a great career choice,” Dr. Correll said. “Pediatric rheumatologists are seen as positive role models. We love what we do, we have great patient-physician relationships, and we see interesting disease pathophysiology on a regular basis.”
Although earlier exposure to the field is primarily an institutional issue, clinicians can play a role as well.
“For the individual practitioners, the biggest way they can make an impact is to make themselves visible,” Dr. Schultz said. Although the subspecialty is stretched thin, she encouraged pediatric rheumatologists to do med school and resident lectures, volunteer to do feedback sessions, offer residents opportunities to rotate with them, and generally make themselves more visible. “It’s going to take the community to really make the change we need,” she said.
She and Dr. Correll both cited the American College of Rheumatology and CARRA pediatric residency programs as helpful, but there’s more to do. Other ways to increase exposure to the field include creating medical student rotations in pediatric rheumatology, working on case reports or small research projects with new learners, and requesting that pediatric rheumatology be a mandatory rotation in pediatrics training, Dr. Correll said.
“We absolutely have a responsibility to promote our field because if we don’t, the workforce supply issue will continue to worsen,” Dr. Correll said. “We already have a workforce shortage, and models show this shortage will only worsen if we don’t improve recruitment into the field, especially with many pediatric rheumatologists coming up on retirement. Once we are able to expose medical students and residents to the field, I think they easily see our passion and our love for the field, and it’s easy to recruit them.”
The research was funded by CARRA, which receives funding from the Arthritis Foundation. Dr. Schultz and Dr. Correll had no disclosures.
FROM CARRA 2021