Neurology Reviews

It’s time to renew two of my three narcotic prescribing licenses. For the first time in my career, I’ve waffled on whether the financial outlay to the US Drug Enforcement Agency (DEA) is worth it. 

At $888 each, I’ve considered letting two licenses lapse because I only work part-time in Montana. But several friends advised me to keep a “spare” in case I transfer to a new location. 

I thought about just paying the fees until I could do a little more research, but there is no mechanism for a refund unless I die within the first year of the 3-year cycle, provide incorrect credit card digits, or accidentally duplicate payments.

The renewal fee is just part of the issue.
 

Mandatory 8-Hour Training

I also received an alert about the requirement for more “narcotics prescribing education” thanks to the Medication Access and Training Expansion Act (MATE). 

The requirement seems counterintuitive because opioid prescribing has decreased for the 10th consecutive year, according to the AMA Overdose Epidemic Report. The continuing rise in overdose deaths is largely due to illegitimate manufacturing of synthetic opioids. 

I’ve written zero outpatient narcotics prescriptions in the past 6 years, and I’ve written very few in my 33 years of practice. My use is limited to intravenous morphine for flash pulmonary edema or refractory angina, but unless you graduated from a training program within 5 years of the June 2023 mandate or are boarded in addiction medicine, there is no way to escape the 8-hour education requirement.

The problem is that these courses are never just 8 hours in duration. After signing up for one such CME course that cost $150, I was still dying of boredom and at risk for DVT 4 days later. That’s how long it took to sit through.

Instead of the 30 seconds it should have taken to review the simple instructions to deliver Narcan, there were scores of screens followed by juvenile quizlets and cartoons. All but about 2 hours out of the 4 days is now relegated to that category of “hours of my life that I can never get back.” Additionally, none of that mandatory “education” will change my prescribing habits one whit. 

And beware the penalty. 

Changes Needed

The only good thing that came of those 4 long days of opioid education was a motivation to drive change in our current licensing and educational experience. Why not use this opportunity to reform the DEA-physician/prescriber relationship? 

The educational requirements should be curtailed for those of us who do not provide outpatient narcotic prescriptions even if we use inpatient opioids. Meds with low abuse potential should be rescheduled to minimize who gets caught in the broad net of the education requirement. 

We should reduce overregulation of the legitimate prescribers by lowering, instead of increasing, licensing fees. We should change to a single license number that covers every state. In this digital age, there is no legitimate excuse to prevent this from happening. 

After all, the settlements from opioid manufacturers and distributors will in time total $50 billion. It seems that at least some of the responsibilities of the DEA could shift to states, cities, and towns. 

My friend Siamak Karimian, MD, who provides locum services in multiple states, pays for seven active DEA licenses every 3 years. He pointed out the hypocrisy in the current regulatory system: “It’s funny that you can have only one DEA or state license and work for the government in all other states or territories with no limits, including the VA, Indian healthcare systems, or prison systems.”

All other prescribers require a separate DEA number for every state. Ultimately, you’d think tracking prescriptions for a single DEA number should be far simpler than tracking someone with seven. 

Competent physicians not guilty of criminal overprescribing seem to be the last to be considered in nearly every healthcare endeavor these days. It would be refreshing if they would reduce our fees and prevent this waste of our time. 

And while we are at it, perhaps a more fitting punishment is due for Richard Sackler and all the Purdue Pharma–affiliated family members. The Sacklers will pay out $6 billion in exchange for immunity against civil litigation. That doesn’t seem like much when they are worth $11 billion. 

Perhaps they should be made to take an 8-hour course on opioid prescribing, annually and in perpetuity. Let’s see them complete a few quizlets and sit through screens of instruction on how to administer Naloxone. Of course, that would be a mild punishment for those who manufactured a drug that killed hundreds of thousands. But it would be a start. 
 

Dr. Walton-Shirley, a clinical cardiologist in Nashville, Tennessee, has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

It’s time to renew two of my three narcotic prescribing licenses. For the first time in my career, I’ve waffled on whether the financial outlay to the US Drug Enforcement Agency (DEA) is worth it. 

At $888 each, I’ve considered letting two licenses lapse because I only work part-time in Montana. But several friends advised me to keep a “spare” in case I transfer to a new location. 

I thought about just paying the fees until I could do a little more research, but there is no mechanism for a refund unless I die within the first year of the 3-year cycle, provide incorrect credit card digits, or accidentally duplicate payments.

The renewal fee is just part of the issue.
 

Mandatory 8-Hour Training

I also received an alert about the requirement for more “narcotics prescribing education” thanks to the Medication Access and Training Expansion Act (MATE). 

The requirement seems counterintuitive because opioid prescribing has decreased for the 10th consecutive year, according to the AMA Overdose Epidemic Report. The continuing rise in overdose deaths is largely due to illegitimate manufacturing of synthetic opioids. 

I’ve written zero outpatient narcotics prescriptions in the past 6 years, and I’ve written very few in my 33 years of practice. My use is limited to intravenous morphine for flash pulmonary edema or refractory angina, but unless you graduated from a training program within 5 years of the June 2023 mandate or are boarded in addiction medicine, there is no way to escape the 8-hour education requirement.

The problem is that these courses are never just 8 hours in duration. After signing up for one such CME course that cost $150, I was still dying of boredom and at risk for DVT 4 days later. That’s how long it took to sit through.

Instead of the 30 seconds it should have taken to review the simple instructions to deliver Narcan, there were scores of screens followed by juvenile quizlets and cartoons. All but about 2 hours out of the 4 days is now relegated to that category of “hours of my life that I can never get back.” Additionally, none of that mandatory “education” will change my prescribing habits one whit. 

And beware the penalty. 

Changes Needed

The only good thing that came of those 4 long days of opioid education was a motivation to drive change in our current licensing and educational experience. Why not use this opportunity to reform the DEA-physician/prescriber relationship? 

The educational requirements should be curtailed for those of us who do not provide outpatient narcotic prescriptions even if we use inpatient opioids. Meds with low abuse potential should be rescheduled to minimize who gets caught in the broad net of the education requirement. 

We should reduce overregulation of the legitimate prescribers by lowering, instead of increasing, licensing fees. We should change to a single license number that covers every state. In this digital age, there is no legitimate excuse to prevent this from happening. 

After all, the settlements from opioid manufacturers and distributors will in time total $50 billion. It seems that at least some of the responsibilities of the DEA could shift to states, cities, and towns. 

My friend Siamak Karimian, MD, who provides locum services in multiple states, pays for seven active DEA licenses every 3 years. He pointed out the hypocrisy in the current regulatory system: “It’s funny that you can have only one DEA or state license and work for the government in all other states or territories with no limits, including the VA, Indian healthcare systems, or prison systems.”

All other prescribers require a separate DEA number for every state. Ultimately, you’d think tracking prescriptions for a single DEA number should be far simpler than tracking someone with seven. 

Competent physicians not guilty of criminal overprescribing seem to be the last to be considered in nearly every healthcare endeavor these days. It would be refreshing if they would reduce our fees and prevent this waste of our time. 

And while we are at it, perhaps a more fitting punishment is due for Richard Sackler and all the Purdue Pharma–affiliated family members. The Sacklers will pay out $6 billion in exchange for immunity against civil litigation. That doesn’t seem like much when they are worth $11 billion. 

Perhaps they should be made to take an 8-hour course on opioid prescribing, annually and in perpetuity. Let’s see them complete a few quizlets and sit through screens of instruction on how to administer Naloxone. Of course, that would be a mild punishment for those who manufactured a drug that killed hundreds of thousands. But it would be a start. 
 

Dr. Walton-Shirley, a clinical cardiologist in Nashville, Tennessee, has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

It’s time to renew two of my three narcotic prescribing licenses. For the first time in my career, I’ve waffled on whether the financial outlay to the US Drug Enforcement Agency (DEA) is worth it. 

At $888 each, I’ve considered letting two licenses lapse because I only work part-time in Montana. But several friends advised me to keep a “spare” in case I transfer to a new location. 

I thought about just paying the fees until I could do a little more research, but there is no mechanism for a refund unless I die within the first year of the 3-year cycle, provide incorrect credit card digits, or accidentally duplicate payments.

The renewal fee is just part of the issue.
 

Mandatory 8-Hour Training

I also received an alert about the requirement for more “narcotics prescribing education” thanks to the Medication Access and Training Expansion Act (MATE). 

The requirement seems counterintuitive because opioid prescribing has decreased for the 10th consecutive year, according to the AMA Overdose Epidemic Report. The continuing rise in overdose deaths is largely due to illegitimate manufacturing of synthetic opioids. 

I’ve written zero outpatient narcotics prescriptions in the past 6 years, and I’ve written very few in my 33 years of practice. My use is limited to intravenous morphine for flash pulmonary edema or refractory angina, but unless you graduated from a training program within 5 years of the June 2023 mandate or are boarded in addiction medicine, there is no way to escape the 8-hour education requirement.

The problem is that these courses are never just 8 hours in duration. After signing up for one such CME course that cost $150, I was still dying of boredom and at risk for DVT 4 days later. That’s how long it took to sit through.

Instead of the 30 seconds it should have taken to review the simple instructions to deliver Narcan, there were scores of screens followed by juvenile quizlets and cartoons. All but about 2 hours out of the 4 days is now relegated to that category of “hours of my life that I can never get back.” Additionally, none of that mandatory “education” will change my prescribing habits one whit. 

And beware the penalty. 

Changes Needed

The only good thing that came of those 4 long days of opioid education was a motivation to drive change in our current licensing and educational experience. Why not use this opportunity to reform the DEA-physician/prescriber relationship? 

The educational requirements should be curtailed for those of us who do not provide outpatient narcotic prescriptions even if we use inpatient opioids. Meds with low abuse potential should be rescheduled to minimize who gets caught in the broad net of the education requirement. 

We should reduce overregulation of the legitimate prescribers by lowering, instead of increasing, licensing fees. We should change to a single license number that covers every state. In this digital age, there is no legitimate excuse to prevent this from happening. 

After all, the settlements from opioid manufacturers and distributors will in time total $50 billion. It seems that at least some of the responsibilities of the DEA could shift to states, cities, and towns. 

My friend Siamak Karimian, MD, who provides locum services in multiple states, pays for seven active DEA licenses every 3 years. He pointed out the hypocrisy in the current regulatory system: “It’s funny that you can have only one DEA or state license and work for the government in all other states or territories with no limits, including the VA, Indian healthcare systems, or prison systems.”

All other prescribers require a separate DEA number for every state. Ultimately, you’d think tracking prescriptions for a single DEA number should be far simpler than tracking someone with seven. 

Competent physicians not guilty of criminal overprescribing seem to be the last to be considered in nearly every healthcare endeavor these days. It would be refreshing if they would reduce our fees and prevent this waste of our time. 

And while we are at it, perhaps a more fitting punishment is due for Richard Sackler and all the Purdue Pharma–affiliated family members. The Sacklers will pay out $6 billion in exchange for immunity against civil litigation. That doesn’t seem like much when they are worth $11 billion. 

Perhaps they should be made to take an 8-hour course on opioid prescribing, annually and in perpetuity. Let’s see them complete a few quizlets and sit through screens of instruction on how to administer Naloxone. Of course, that would be a mild punishment for those who manufactured a drug that killed hundreds of thousands. But it would be a start. 
 

Dr. Walton-Shirley, a clinical cardiologist in Nashville, Tennessee, has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

For decades, scientists have been trying to unravel the mysteries of restless legs syndrome (RLS), a poorly understood and underdiagnosed neurological disorder causing itching, crawling, and aching sensations in the limbs that can only be relieved with movement.

A sweeping new genetic study, coauthored by an international team of 70 — including the world’s leading RLS experts — marks a significant advance in that pursuit. Published in Nature Genetics, it is the largest genetic study of the disease to date.

“It’s a huge step forward for patients as well as the scientific community,” said lead author Juliane Winkelmann, MD, a neurologist and geneticist with the Technical University of Munich, Munich, Germany, who’s been studying and treating patients with RLS for 30 years. “We believe it will allow us to better predict the likelihood of developing RLS and investigate new ways to prevent and modify it.”

The common condition, affecting about 1 in 10 adults, was first described centuries ago — by English physician Thomas Willis in the late 1600s. And while we know a lot more about it today — it’s familial in about half of all patients and has been linked to iron deficiency, among other conditions — its exact cause remains unknown.

With preferred drugs long prescribed to quell symptoms shown in recent years to actually worsen the disorder over time, doctors and patients are hungry for alternatives to treat or prevent the sleep-sabotaging condition.

“The main treatments that everybody continues to use are actually making people worse,” said Andrew Berkowski, MD, a Michigan-based neurologist and RLS specialist not involved in the study. These drugs — dopamine agonists such as levodopa and pramipexole — can also potentially cause drug dependence, Dr. Berkowski said.
 

How This Could Lead to New Treatments

In the new study, the group analyzed three genome-wide association studies, collectively including genetic information from 116,647 patients with RLS and more than 1.5 million people without it.

They identified 161 gene regions believed to contribute to RLS, about a dozen of which are already targets for existing drugs for other conditions. Previously, scientists knew of only 22 associated genes.

“It’s useful in that it identifies new genes we haven’t looked at yet and reinforces the science behind some of the older genes,” said Dr. Berkowski. “It’s given us some ideas for different things we should look into more closely.”

Among the top candidates are genes that influence glutamate — a key chemical messenger that helps move signals between nerve cells in the brain.

Several anticonvulsant and antiseizure drugs, including perampanel, lamotrigine, and gabapentin, target glutamate receptors. And at least one small study has shown perampanel prescribed off-label can improve RLS symptoms.

“Compared to starting at the beginning and developing an entirely new chemical entity, we could run clinical trials using these alternatives in RLS patients,” said the study’s first author, Steven Bell, PhD, an epidemiologist with the University of Cambridge, Cambridge, England.

The study also confirmed the MIES1 gene, which is related to dopamine expression and iron homeostasis, as a key genetic contributor to RLS risk. Low levels of iron in the blood have long been thought to trigger RLS.
 

The Role of Gene-Environment Interactions

Through additional data analysis, the team confirmed that many of the genes associated with RLS play a role in development of the central nervous system.

“This strongly supports the hypothesis that restless legs syndrome is a neurodevelopmental disorder that develops during the embryo stage but doesn’t clinically manifest until later in life,” said Dr. Winkelmann.

About half of people with RLS report some family history of it.

But not all with a genetic predisposition will develop symptoms.

For instance, the study found that while the same gene regions seem to be associated with risk in both men and women, in practice, RLS is twice as common among women. This suggests that something about women’s lives — menstruation, childbirth, metabolism — may switch a preexisting risk into a reality.

“We know that genetic factors play an important role in making people susceptible to the disease,” said Dr. Winkelmann, “but in the end, it is the interaction between genetic and environmental factors that may lead to its manifestation.”

The study also found associations between RLS and depression and suggests that RLS may increase the risk for type 2 diabetes.
 

Improving RLS Care

A potentially useful tool coming out of the study was a “polygenic risk score,” which the researchers developed based on the genes identified. When they tested how accurately the score could predict whether someone would develop RLS within the next 5 years, the model got it right about 90% of the time.

Dr. Winkelmann imagines a day when someone could use such a polygenic risk score to flag the high risk for RLS early enough to take action to try to prevent it. More research is necessary to determine precisely what that action would be.

As for treatments, Dr. Berkowski thinks it’s unlikely that doctors will suddenly begin using existing, glutamate-targeting drugs off-label to treat RLS, as many are prohibitively expensive and wouldn’t be covered by insurance. But he’s optimistic that the study can spawn new research that could ultimately help fill the treatment gap.

Shalini Paruthi, MD, an adjunct professor at Saint Louis University, St. Louis, Missouri, and chair of the Restless Legs Syndrome Foundation’s board of directors, sees another benefit.

“The associations found in this study between RLS and other medical disorders may help patients and their physicians take RLS more seriously,” Dr. Paruthi said, “as treating RLS can lead to multiple other downstream improvements in their health.”

A version of this article appeared on Medscape.com.

For decades, scientists have been trying to unravel the mysteries of restless legs syndrome (RLS), a poorly understood and underdiagnosed neurological disorder causing itching, crawling, and aching sensations in the limbs that can only be relieved with movement.

A sweeping new genetic study, coauthored by an international team of 70 — including the world’s leading RLS experts — marks a significant advance in that pursuit. Published in Nature Genetics, it is the largest genetic study of the disease to date.

“It’s a huge step forward for patients as well as the scientific community,” said lead author Juliane Winkelmann, MD, a neurologist and geneticist with the Technical University of Munich, Munich, Germany, who’s been studying and treating patients with RLS for 30 years. “We believe it will allow us to better predict the likelihood of developing RLS and investigate new ways to prevent and modify it.”

The common condition, affecting about 1 in 10 adults, was first described centuries ago — by English physician Thomas Willis in the late 1600s. And while we know a lot more about it today — it’s familial in about half of all patients and has been linked to iron deficiency, among other conditions — its exact cause remains unknown.

With preferred drugs long prescribed to quell symptoms shown in recent years to actually worsen the disorder over time, doctors and patients are hungry for alternatives to treat or prevent the sleep-sabotaging condition.

“The main treatments that everybody continues to use are actually making people worse,” said Andrew Berkowski, MD, a Michigan-based neurologist and RLS specialist not involved in the study. These drugs — dopamine agonists such as levodopa and pramipexole — can also potentially cause drug dependence, Dr. Berkowski said.
 

How This Could Lead to New Treatments

In the new study, the group analyzed three genome-wide association studies, collectively including genetic information from 116,647 patients with RLS and more than 1.5 million people without it.

They identified 161 gene regions believed to contribute to RLS, about a dozen of which are already targets for existing drugs for other conditions. Previously, scientists knew of only 22 associated genes.

“It’s useful in that it identifies new genes we haven’t looked at yet and reinforces the science behind some of the older genes,” said Dr. Berkowski. “It’s given us some ideas for different things we should look into more closely.”

Among the top candidates are genes that influence glutamate — a key chemical messenger that helps move signals between nerve cells in the brain.

Several anticonvulsant and antiseizure drugs, including perampanel, lamotrigine, and gabapentin, target glutamate receptors. And at least one small study has shown perampanel prescribed off-label can improve RLS symptoms.

“Compared to starting at the beginning and developing an entirely new chemical entity, we could run clinical trials using these alternatives in RLS patients,” said the study’s first author, Steven Bell, PhD, an epidemiologist with the University of Cambridge, Cambridge, England.

The study also confirmed the MIES1 gene, which is related to dopamine expression and iron homeostasis, as a key genetic contributor to RLS risk. Low levels of iron in the blood have long been thought to trigger RLS.
 

The Role of Gene-Environment Interactions

Through additional data analysis, the team confirmed that many of the genes associated with RLS play a role in development of the central nervous system.

“This strongly supports the hypothesis that restless legs syndrome is a neurodevelopmental disorder that develops during the embryo stage but doesn’t clinically manifest until later in life,” said Dr. Winkelmann.

About half of people with RLS report some family history of it.

But not all with a genetic predisposition will develop symptoms.

For instance, the study found that while the same gene regions seem to be associated with risk in both men and women, in practice, RLS is twice as common among women. This suggests that something about women’s lives — menstruation, childbirth, metabolism — may switch a preexisting risk into a reality.

“We know that genetic factors play an important role in making people susceptible to the disease,” said Dr. Winkelmann, “but in the end, it is the interaction between genetic and environmental factors that may lead to its manifestation.”

The study also found associations between RLS and depression and suggests that RLS may increase the risk for type 2 diabetes.
 

Improving RLS Care

A potentially useful tool coming out of the study was a “polygenic risk score,” which the researchers developed based on the genes identified. When they tested how accurately the score could predict whether someone would develop RLS within the next 5 years, the model got it right about 90% of the time.

Dr. Winkelmann imagines a day when someone could use such a polygenic risk score to flag the high risk for RLS early enough to take action to try to prevent it. More research is necessary to determine precisely what that action would be.

As for treatments, Dr. Berkowski thinks it’s unlikely that doctors will suddenly begin using existing, glutamate-targeting drugs off-label to treat RLS, as many are prohibitively expensive and wouldn’t be covered by insurance. But he’s optimistic that the study can spawn new research that could ultimately help fill the treatment gap.

Shalini Paruthi, MD, an adjunct professor at Saint Louis University, St. Louis, Missouri, and chair of the Restless Legs Syndrome Foundation’s board of directors, sees another benefit.

“The associations found in this study between RLS and other medical disorders may help patients and their physicians take RLS more seriously,” Dr. Paruthi said, “as treating RLS can lead to multiple other downstream improvements in their health.”

A version of this article appeared on Medscape.com.

For decades, scientists have been trying to unravel the mysteries of restless legs syndrome (RLS), a poorly understood and underdiagnosed neurological disorder causing itching, crawling, and aching sensations in the limbs that can only be relieved with movement.

A sweeping new genetic study, coauthored by an international team of 70 — including the world’s leading RLS experts — marks a significant advance in that pursuit. Published in Nature Genetics, it is the largest genetic study of the disease to date.

“It’s a huge step forward for patients as well as the scientific community,” said lead author Juliane Winkelmann, MD, a neurologist and geneticist with the Technical University of Munich, Munich, Germany, who’s been studying and treating patients with RLS for 30 years. “We believe it will allow us to better predict the likelihood of developing RLS and investigate new ways to prevent and modify it.”

The common condition, affecting about 1 in 10 adults, was first described centuries ago — by English physician Thomas Willis in the late 1600s. And while we know a lot more about it today — it’s familial in about half of all patients and has been linked to iron deficiency, among other conditions — its exact cause remains unknown.

With preferred drugs long prescribed to quell symptoms shown in recent years to actually worsen the disorder over time, doctors and patients are hungry for alternatives to treat or prevent the sleep-sabotaging condition.

“The main treatments that everybody continues to use are actually making people worse,” said Andrew Berkowski, MD, a Michigan-based neurologist and RLS specialist not involved in the study. These drugs — dopamine agonists such as levodopa and pramipexole — can also potentially cause drug dependence, Dr. Berkowski said.
 

How This Could Lead to New Treatments

In the new study, the group analyzed three genome-wide association studies, collectively including genetic information from 116,647 patients with RLS and more than 1.5 million people without it.

They identified 161 gene regions believed to contribute to RLS, about a dozen of which are already targets for existing drugs for other conditions. Previously, scientists knew of only 22 associated genes.

“It’s useful in that it identifies new genes we haven’t looked at yet and reinforces the science behind some of the older genes,” said Dr. Berkowski. “It’s given us some ideas for different things we should look into more closely.”

Among the top candidates are genes that influence glutamate — a key chemical messenger that helps move signals between nerve cells in the brain.

Several anticonvulsant and antiseizure drugs, including perampanel, lamotrigine, and gabapentin, target glutamate receptors. And at least one small study has shown perampanel prescribed off-label can improve RLS symptoms.

“Compared to starting at the beginning and developing an entirely new chemical entity, we could run clinical trials using these alternatives in RLS patients,” said the study’s first author, Steven Bell, PhD, an epidemiologist with the University of Cambridge, Cambridge, England.

The study also confirmed the MIES1 gene, which is related to dopamine expression and iron homeostasis, as a key genetic contributor to RLS risk. Low levels of iron in the blood have long been thought to trigger RLS.
 

The Role of Gene-Environment Interactions

Through additional data analysis, the team confirmed that many of the genes associated with RLS play a role in development of the central nervous system.

“This strongly supports the hypothesis that restless legs syndrome is a neurodevelopmental disorder that develops during the embryo stage but doesn’t clinically manifest until later in life,” said Dr. Winkelmann.

About half of people with RLS report some family history of it.

But not all with a genetic predisposition will develop symptoms.

For instance, the study found that while the same gene regions seem to be associated with risk in both men and women, in practice, RLS is twice as common among women. This suggests that something about women’s lives — menstruation, childbirth, metabolism — may switch a preexisting risk into a reality.

“We know that genetic factors play an important role in making people susceptible to the disease,” said Dr. Winkelmann, “but in the end, it is the interaction between genetic and environmental factors that may lead to its manifestation.”

The study also found associations between RLS and depression and suggests that RLS may increase the risk for type 2 diabetes.
 

Improving RLS Care

A potentially useful tool coming out of the study was a “polygenic risk score,” which the researchers developed based on the genes identified. When they tested how accurately the score could predict whether someone would develop RLS within the next 5 years, the model got it right about 90% of the time.

Dr. Winkelmann imagines a day when someone could use such a polygenic risk score to flag the high risk for RLS early enough to take action to try to prevent it. More research is necessary to determine precisely what that action would be.

As for treatments, Dr. Berkowski thinks it’s unlikely that doctors will suddenly begin using existing, glutamate-targeting drugs off-label to treat RLS, as many are prohibitively expensive and wouldn’t be covered by insurance. But he’s optimistic that the study can spawn new research that could ultimately help fill the treatment gap.

Shalini Paruthi, MD, an adjunct professor at Saint Louis University, St. Louis, Missouri, and chair of the Restless Legs Syndrome Foundation’s board of directors, sees another benefit.

“The associations found in this study between RLS and other medical disorders may help patients and their physicians take RLS more seriously,” Dr. Paruthi said, “as treating RLS can lead to multiple other downstream improvements in their health.”

A version of this article appeared on Medscape.com.

VIENNA — Results from the phase 3 SELECT-GCA study showed that the Janus kinase (JAK) inhibitor upadacitinib (Rinvoq) induces significant and sustained remission in people with new-onset or relapsing giant cell arteritis (GCA).

The primary endpoint of sustained remission — the absence of GCA signs or symptoms from weeks 12 to 52 together with adherence to a steroid-tapering regimen — occurred in 46% of 210 individuals randomly assigned to treatment treated with a once-daily 15-mg dose of upadacitinib and 29% of 105 randomly assigned to placebo (P = .0019).

Nine of the 11 secondary endpoints were also positive for upadacitinib 15 mg vs placebo, and no new safety concerns were identified in a late-breaking abstract presented at the at the annual European Congress of Rheumatology.
 

First JAK Trial in GCA

This is the first trial to look at the use of a JAK inhibitor for the treatment of GCA, and it is addressing a real unmet need, the presenting study investigator Daniel Blockmans, MD, PhD, of University Hospitals Leuven in Belgium, told this news organization.

Glucocorticoids remain the mainstay of treatment, and tocilizumab has been licensed for use, but people don’t always get better or can relapse, he explained.

“I have the impression that these only suppress the disease but do not cure it,” Dr. Blockmans said, adding that “patients get very well soon after these treatments are started, but there are more and more reports that there is a kind of smoldering vasculitis that exists, and this can lead to dilatation of the aorta.”

Upadacitinib inhibits two JAK-dependent cytokines, interleukin 6 and interferon gamma, which have been implicated in the pathogenesis of GCA. The latter could be particularly important, Dr. Blockmans suggested.
 

Study Details

SELECT-GCA is an ongoing multicenter, randomized, double-blind, placebo-controlled study designed to evaluate the safety and efficacy of upadacitinib vs placebo in patients with GCA.

A total of 428 patients have been included: 210 were randomly allocated to treatment with upadacitinib 15 mg, 105 to upadacitinib 7.5 mg, and 105 to placebo. The inclusion of the lower “minimally effective” upadacitinib dose was a requirement of the regulatory authorities, Dr. Blockmans said; the licensed dose in rheumatoid arthritis (RA) is 15 mg.

Dr. Blockmans reported data from the first 52 weeks of the trial during which all patients underwent glucocorticoid tapering — 26 weeks for upadacitinib and 52 weeks for placebo.

No imaging was done in this trial, which Dr. Blockmans said should be considered for future studies.
 

Secondary Endpoints

One of the key secondary endpoints was sustained complete remission, defined as sustained remission plus a normalized erythrocyte sedimentation rate to ≤ 30 mm/h and reducing high-sensitivity C-reactive protein to < 1 mg/dL.

Sustained complete remission occurred in 37% and 16% of patients treated with upadacitinib 15 mg and placebo, respectively (P < .0001).

Additionally, a significantly lower proportion of upadacitinib 15 mg- than placebo-treated patients experienced at least one disease flare through week 52 (34% vs 56%, P = .0014).

Other positive secondary endpoints for upadacitinib 15 mg vs placebo out to week 52 were the number of disease flares per patient, cumulative glucocorticoid exposure, and complete remission (also at week 24).

And significant changes in SF-36 and FACIT-Fatigue from baseline to week 52 were seen for upadacitinib 15 mg.

The only secondary endpoints not showing a clear benefit for upadacitinib 15 mg were the changes in the Treatment Satisfaction Questionnaire for Medication at 52 weeks and the rate of glucocorticoid-related adverse events through week 52.

As for the 7.5-mg dose of upadacitinib, neither the primary nor secondary endpoints were significantly better vs placebo.
 

‘Life-Changing’

The study’s findings could be “really life-changing” for patients with this type of vasculitis if upadacitinib gets approval for use in this indication, Milena Bond, MD, PhD, of Brunico Hospital in Italy, told this news organization at the meeting.

“Unfortunately, nowadays, we still have only a few options for treating these patients,” she said. “So, this drug could be really, really important.”

Dr. Bond added: “The data ... also shows there is a very good safety profile, which was a main concern given the class of the drug. So, I’m very positive about this treatment and very excited to see the preliminary results.”

After his presentation, Dr. Blockmans said, “Of course, if we already had an ideal treatment for GCA, there would be no need for a JAK inhibitor, but I don’t think that steroid treatment or tocilizumab treatment is the ideal treatment.”
 

Judicious Use Still Warranted

Upadacitinib still needs to be used cautiously, following appropriate guidance from the European Medicines Agency (EMA) and the US Food and Drug Administration.

Dr. Bond said: “It is not advised to use to the drug when people are older than 65 years old,” according to the EMA, for example, and “given the rules that we have, I would not use this drug as a first-line treatment. We do not do that for rheumatoid arthritis.”

But, she added, “As for arthritis, when you fail treating patients with the other alternatives, you could use this drug, and you have to discuss risks with the patients.”

Dr. Blockmans reported there had been no increased risk for major adverse cardiovascular events or venous thromboembolism associated with upadacitinib relative to placebo in the population of patients studied, and he pointed out that they had a much higher risk for these events than perhaps an RA population.

He said: “It’s effective, and it’s apparently safe in these older people, despite what we heard about tofacitinib in the ORAL [Surveillance] study; we didn’t see these problems here in this elderly population.”

The SELECT-GCA trial was funded by AbbVie, and the company participated in all aspects of the study, including its design, conduct, interpretation of data, and reporting. Dr. Blockmans received no funding or other honoraria from the company but reported a research grant from Roche and consulting fees from GlaxoSmithKline. Most of his coauthors reported financial relationships with AbbVie, and some are employees of the company. Dr. Bond reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

VIENNA — Results from the phase 3 SELECT-GCA study showed that the Janus kinase (JAK) inhibitor upadacitinib (Rinvoq) induces significant and sustained remission in people with new-onset or relapsing giant cell arteritis (GCA).

The primary endpoint of sustained remission — the absence of GCA signs or symptoms from weeks 12 to 52 together with adherence to a steroid-tapering regimen — occurred in 46% of 210 individuals randomly assigned to treatment treated with a once-daily 15-mg dose of upadacitinib and 29% of 105 randomly assigned to placebo (P = .0019).

Nine of the 11 secondary endpoints were also positive for upadacitinib 15 mg vs placebo, and no new safety concerns were identified in a late-breaking abstract presented at the at the annual European Congress of Rheumatology.
 

First JAK Trial in GCA

This is the first trial to look at the use of a JAK inhibitor for the treatment of GCA, and it is addressing a real unmet need, the presenting study investigator Daniel Blockmans, MD, PhD, of University Hospitals Leuven in Belgium, told this news organization.

Glucocorticoids remain the mainstay of treatment, and tocilizumab has been licensed for use, but people don’t always get better or can relapse, he explained.

“I have the impression that these only suppress the disease but do not cure it,” Dr. Blockmans said, adding that “patients get very well soon after these treatments are started, but there are more and more reports that there is a kind of smoldering vasculitis that exists, and this can lead to dilatation of the aorta.”

Upadacitinib inhibits two JAK-dependent cytokines, interleukin 6 and interferon gamma, which have been implicated in the pathogenesis of GCA. The latter could be particularly important, Dr. Blockmans suggested.
 

Study Details

SELECT-GCA is an ongoing multicenter, randomized, double-blind, placebo-controlled study designed to evaluate the safety and efficacy of upadacitinib vs placebo in patients with GCA.

A total of 428 patients have been included: 210 were randomly allocated to treatment with upadacitinib 15 mg, 105 to upadacitinib 7.5 mg, and 105 to placebo. The inclusion of the lower “minimally effective” upadacitinib dose was a requirement of the regulatory authorities, Dr. Blockmans said; the licensed dose in rheumatoid arthritis (RA) is 15 mg.

Dr. Blockmans reported data from the first 52 weeks of the trial during which all patients underwent glucocorticoid tapering — 26 weeks for upadacitinib and 52 weeks for placebo.

No imaging was done in this trial, which Dr. Blockmans said should be considered for future studies.
 

Secondary Endpoints

One of the key secondary endpoints was sustained complete remission, defined as sustained remission plus a normalized erythrocyte sedimentation rate to ≤ 30 mm/h and reducing high-sensitivity C-reactive protein to < 1 mg/dL.

Sustained complete remission occurred in 37% and 16% of patients treated with upadacitinib 15 mg and placebo, respectively (P < .0001).

Additionally, a significantly lower proportion of upadacitinib 15 mg- than placebo-treated patients experienced at least one disease flare through week 52 (34% vs 56%, P = .0014).

Other positive secondary endpoints for upadacitinib 15 mg vs placebo out to week 52 were the number of disease flares per patient, cumulative glucocorticoid exposure, and complete remission (also at week 24).

And significant changes in SF-36 and FACIT-Fatigue from baseline to week 52 were seen for upadacitinib 15 mg.

The only secondary endpoints not showing a clear benefit for upadacitinib 15 mg were the changes in the Treatment Satisfaction Questionnaire for Medication at 52 weeks and the rate of glucocorticoid-related adverse events through week 52.

As for the 7.5-mg dose of upadacitinib, neither the primary nor secondary endpoints were significantly better vs placebo.
 

‘Life-Changing’

The study’s findings could be “really life-changing” for patients with this type of vasculitis if upadacitinib gets approval for use in this indication, Milena Bond, MD, PhD, of Brunico Hospital in Italy, told this news organization at the meeting.

“Unfortunately, nowadays, we still have only a few options for treating these patients,” she said. “So, this drug could be really, really important.”

Dr. Bond added: “The data ... also shows there is a very good safety profile, which was a main concern given the class of the drug. So, I’m very positive about this treatment and very excited to see the preliminary results.”

After his presentation, Dr. Blockmans said, “Of course, if we already had an ideal treatment for GCA, there would be no need for a JAK inhibitor, but I don’t think that steroid treatment or tocilizumab treatment is the ideal treatment.”
 

Judicious Use Still Warranted

Upadacitinib still needs to be used cautiously, following appropriate guidance from the European Medicines Agency (EMA) and the US Food and Drug Administration.

Dr. Bond said: “It is not advised to use to the drug when people are older than 65 years old,” according to the EMA, for example, and “given the rules that we have, I would not use this drug as a first-line treatment. We do not do that for rheumatoid arthritis.”

But, she added, “As for arthritis, when you fail treating patients with the other alternatives, you could use this drug, and you have to discuss risks with the patients.”

Dr. Blockmans reported there had been no increased risk for major adverse cardiovascular events or venous thromboembolism associated with upadacitinib relative to placebo in the population of patients studied, and he pointed out that they had a much higher risk for these events than perhaps an RA population.

He said: “It’s effective, and it’s apparently safe in these older people, despite what we heard about tofacitinib in the ORAL [Surveillance] study; we didn’t see these problems here in this elderly population.”

The SELECT-GCA trial was funded by AbbVie, and the company participated in all aspects of the study, including its design, conduct, interpretation of data, and reporting. Dr. Blockmans received no funding or other honoraria from the company but reported a research grant from Roche and consulting fees from GlaxoSmithKline. Most of his coauthors reported financial relationships with AbbVie, and some are employees of the company. Dr. Bond reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

VIENNA — Results from the phase 3 SELECT-GCA study showed that the Janus kinase (JAK) inhibitor upadacitinib (Rinvoq) induces significant and sustained remission in people with new-onset or relapsing giant cell arteritis (GCA).

The primary endpoint of sustained remission — the absence of GCA signs or symptoms from weeks 12 to 52 together with adherence to a steroid-tapering regimen — occurred in 46% of 210 individuals randomly assigned to treatment treated with a once-daily 15-mg dose of upadacitinib and 29% of 105 randomly assigned to placebo (P = .0019).

Nine of the 11 secondary endpoints were also positive for upadacitinib 15 mg vs placebo, and no new safety concerns were identified in a late-breaking abstract presented at the at the annual European Congress of Rheumatology.
 

First JAK Trial in GCA

This is the first trial to look at the use of a JAK inhibitor for the treatment of GCA, and it is addressing a real unmet need, the presenting study investigator Daniel Blockmans, MD, PhD, of University Hospitals Leuven in Belgium, told this news organization.

Glucocorticoids remain the mainstay of treatment, and tocilizumab has been licensed for use, but people don’t always get better or can relapse, he explained.

“I have the impression that these only suppress the disease but do not cure it,” Dr. Blockmans said, adding that “patients get very well soon after these treatments are started, but there are more and more reports that there is a kind of smoldering vasculitis that exists, and this can lead to dilatation of the aorta.”

Upadacitinib inhibits two JAK-dependent cytokines, interleukin 6 and interferon gamma, which have been implicated in the pathogenesis of GCA. The latter could be particularly important, Dr. Blockmans suggested.
 

Study Details

SELECT-GCA is an ongoing multicenter, randomized, double-blind, placebo-controlled study designed to evaluate the safety and efficacy of upadacitinib vs placebo in patients with GCA.

A total of 428 patients have been included: 210 were randomly allocated to treatment with upadacitinib 15 mg, 105 to upadacitinib 7.5 mg, and 105 to placebo. The inclusion of the lower “minimally effective” upadacitinib dose was a requirement of the regulatory authorities, Dr. Blockmans said; the licensed dose in rheumatoid arthritis (RA) is 15 mg.

Dr. Blockmans reported data from the first 52 weeks of the trial during which all patients underwent glucocorticoid tapering — 26 weeks for upadacitinib and 52 weeks for placebo.

No imaging was done in this trial, which Dr. Blockmans said should be considered for future studies.
 

Secondary Endpoints

One of the key secondary endpoints was sustained complete remission, defined as sustained remission plus a normalized erythrocyte sedimentation rate to ≤ 30 mm/h and reducing high-sensitivity C-reactive protein to < 1 mg/dL.

Sustained complete remission occurred in 37% and 16% of patients treated with upadacitinib 15 mg and placebo, respectively (P < .0001).

Additionally, a significantly lower proportion of upadacitinib 15 mg- than placebo-treated patients experienced at least one disease flare through week 52 (34% vs 56%, P = .0014).

Other positive secondary endpoints for upadacitinib 15 mg vs placebo out to week 52 were the number of disease flares per patient, cumulative glucocorticoid exposure, and complete remission (also at week 24).

And significant changes in SF-36 and FACIT-Fatigue from baseline to week 52 were seen for upadacitinib 15 mg.

The only secondary endpoints not showing a clear benefit for upadacitinib 15 mg were the changes in the Treatment Satisfaction Questionnaire for Medication at 52 weeks and the rate of glucocorticoid-related adverse events through week 52.

As for the 7.5-mg dose of upadacitinib, neither the primary nor secondary endpoints were significantly better vs placebo.
 

‘Life-Changing’

The study’s findings could be “really life-changing” for patients with this type of vasculitis if upadacitinib gets approval for use in this indication, Milena Bond, MD, PhD, of Brunico Hospital in Italy, told this news organization at the meeting.

“Unfortunately, nowadays, we still have only a few options for treating these patients,” she said. “So, this drug could be really, really important.”

Dr. Bond added: “The data ... also shows there is a very good safety profile, which was a main concern given the class of the drug. So, I’m very positive about this treatment and very excited to see the preliminary results.”

After his presentation, Dr. Blockmans said, “Of course, if we already had an ideal treatment for GCA, there would be no need for a JAK inhibitor, but I don’t think that steroid treatment or tocilizumab treatment is the ideal treatment.”
 

Judicious Use Still Warranted

Upadacitinib still needs to be used cautiously, following appropriate guidance from the European Medicines Agency (EMA) and the US Food and Drug Administration.

Dr. Bond said: “It is not advised to use to the drug when people are older than 65 years old,” according to the EMA, for example, and “given the rules that we have, I would not use this drug as a first-line treatment. We do not do that for rheumatoid arthritis.”

But, she added, “As for arthritis, when you fail treating patients with the other alternatives, you could use this drug, and you have to discuss risks with the patients.”

Dr. Blockmans reported there had been no increased risk for major adverse cardiovascular events or venous thromboembolism associated with upadacitinib relative to placebo in the population of patients studied, and he pointed out that they had a much higher risk for these events than perhaps an RA population.

He said: “It’s effective, and it’s apparently safe in these older people, despite what we heard about tofacitinib in the ORAL [Surveillance] study; we didn’t see these problems here in this elderly population.”

The SELECT-GCA trial was funded by AbbVie, and the company participated in all aspects of the study, including its design, conduct, interpretation of data, and reporting. Dr. Blockmans received no funding or other honoraria from the company but reported a research grant from Roche and consulting fees from GlaxoSmithKline. Most of his coauthors reported financial relationships with AbbVie, and some are employees of the company. Dr. Bond reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

TOPLINE:

Nearly 13% of older adults in the United States were treated for traumatic brain injury (TBI) over an 18-year period, a new study showed.

METHODOLOGY:

• Researchers analyzed data from approximately 9200 Medicare enrollees who were part of the Health and Retirement Study (HRS), aged 65 years and older, from 2000 to 2018.
• The baseline date was the date of the first age eligible HRS core interview in the community in 2000 or later.
• Incident TBI cases came from an updated list of the International Classification of Diseases (ICD), 9th and 10th edition codes, from the Defense and Veterans Brain Injury Center and the Armed Forces Health Surveillance Branch for TBI surveillance.
• Codes corresponded with emergency department, CT, and/or fMRI visits.

TAKEAWAY:

• Almost 13% of older individuals (n = 797) experienced TBI during the study, highlighting its significant prevalence in this population.
• Older adults (mean age at baseline, 75 years) who experienced TBI during the study period were more likely to be women and White individuals as well as individuals having higher levels of education and normal cognition (P < .001), challenging previous assumptions about risk factors.
• The study underscored the need for targeted interventions and research focused on TBI prevention and postdischarge care in older adults.

IN PRACTICE:

“The number of people 65 and older with TBI is shockingly high,” senior author Raquel Gardner, MD, said in a press release. “We need evidence-based guidelines to inform postdischarge care of this very large Medicare population and more research on post-TBI dementia prevention and repeat injury prevention.”

SOURCE:

The study was led by Erica Kornblith, PhD, of the University of California, San Francisco. It was published online in JAMA Network Open.

LIMITATIONS:

The study’s reliance on ICD codes for TBI identification may not capture the full spectrum of TBI severity. Self-reported data on sociodemographic factors may have introduced bias, affecting the accuracy of associations with TBI incidence. In addition, the findings’ generalizability may be limited due to the study’s focus on Medicare enrollees, potentially excluding those from diverse socioeconomic backgrounds.

DISCLOSURES:

The study was funded by the Alzheimer’s Association, the US Department of Veterans Affairs, the National Institute on Aging, and the Department of Defense. Disclosures are noted in the original study.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article appeared on Medscape.com.

TOPLINE:

Nearly 13% of older adults in the United States were treated for traumatic brain injury (TBI) over an 18-year period, a new study showed.

METHODOLOGY:

• Researchers analyzed data from approximately 9200 Medicare enrollees who were part of the Health and Retirement Study (HRS), aged 65 years and older, from 2000 to 2018.
• The baseline date was the date of the first age eligible HRS core interview in the community in 2000 or later.
• Incident TBI cases came from an updated list of the International Classification of Diseases (ICD), 9th and 10th edition codes, from the Defense and Veterans Brain Injury Center and the Armed Forces Health Surveillance Branch for TBI surveillance.
• Codes corresponded with emergency department, CT, and/or fMRI visits.

TAKEAWAY:

• Almost 13% of older individuals (n = 797) experienced TBI during the study, highlighting its significant prevalence in this population.
• Older adults (mean age at baseline, 75 years) who experienced TBI during the study period were more likely to be women and White individuals as well as individuals having higher levels of education and normal cognition (P < .001), challenging previous assumptions about risk factors.
• The study underscored the need for targeted interventions and research focused on TBI prevention and postdischarge care in older adults.

IN PRACTICE:

“The number of people 65 and older with TBI is shockingly high,” senior author Raquel Gardner, MD, said in a press release. “We need evidence-based guidelines to inform postdischarge care of this very large Medicare population and more research on post-TBI dementia prevention and repeat injury prevention.”

SOURCE:

The study was led by Erica Kornblith, PhD, of the University of California, San Francisco. It was published online in JAMA Network Open.

LIMITATIONS:

The study’s reliance on ICD codes for TBI identification may not capture the full spectrum of TBI severity. Self-reported data on sociodemographic factors may have introduced bias, affecting the accuracy of associations with TBI incidence. In addition, the findings’ generalizability may be limited due to the study’s focus on Medicare enrollees, potentially excluding those from diverse socioeconomic backgrounds.

DISCLOSURES:

The study was funded by the Alzheimer’s Association, the US Department of Veterans Affairs, the National Institute on Aging, and the Department of Defense. Disclosures are noted in the original study.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article appeared on Medscape.com.

TOPLINE:

Nearly 13% of older adults in the United States were treated for traumatic brain injury (TBI) over an 18-year period, a new study showed.

METHODOLOGY:

• Researchers analyzed data from approximately 9200 Medicare enrollees who were part of the Health and Retirement Study (HRS), aged 65 years and older, from 2000 to 2018.
• The baseline date was the date of the first age eligible HRS core interview in the community in 2000 or later.
• Incident TBI cases came from an updated list of the International Classification of Diseases (ICD), 9th and 10th edition codes, from the Defense and Veterans Brain Injury Center and the Armed Forces Health Surveillance Branch for TBI surveillance.
• Codes corresponded with emergency department, CT, and/or fMRI visits.

TAKEAWAY:

• Almost 13% of older individuals (n = 797) experienced TBI during the study, highlighting its significant prevalence in this population.
• Older adults (mean age at baseline, 75 years) who experienced TBI during the study period were more likely to be women and White individuals as well as individuals having higher levels of education and normal cognition (P < .001), challenging previous assumptions about risk factors.
• The study underscored the need for targeted interventions and research focused on TBI prevention and postdischarge care in older adults.

IN PRACTICE:

“The number of people 65 and older with TBI is shockingly high,” senior author Raquel Gardner, MD, said in a press release. “We need evidence-based guidelines to inform postdischarge care of this very large Medicare population and more research on post-TBI dementia prevention and repeat injury prevention.”

SOURCE:

The study was led by Erica Kornblith, PhD, of the University of California, San Francisco. It was published online in JAMA Network Open.

LIMITATIONS:

The study’s reliance on ICD codes for TBI identification may not capture the full spectrum of TBI severity. Self-reported data on sociodemographic factors may have introduced bias, affecting the accuracy of associations with TBI incidence. In addition, the findings’ generalizability may be limited due to the study’s focus on Medicare enrollees, potentially excluding those from diverse socioeconomic backgrounds.

DISCLOSURES:

The study was funded by the Alzheimer’s Association, the US Department of Veterans Affairs, the National Institute on Aging, and the Department of Defense. Disclosures are noted in the original study.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article appeared on Medscape.com.

The US Food and Drug Administration has granted accelerated approval to repotrectinib (Augtyro, Bristol Myers Squibb) for all locally advanced, unresectable, or metastatic solid tumors with an NTRK gene fusion that have progressed after initial treatment or that have no satisfactory alternative therapies.

The approval is a label expansion for the tyrosine kinase inhibitor (TKI), which received initial clearance in November 2023 for locally advanced or metastatic ROS1-positive non–small cell lung cancer. 

NTRK gene fusions are genetic abnormalities wherein part of the NTRK gene fuses with an unrelated gene. The abnormal gene can then produce an oncogenic protein. Although rare, these mutations are found in many cancer types.

The approval, for adult and pediatric patients aged 12 years or older, was based on the single-arm open-label TRIDENT-1 trial in 88 adults with locally advanced or metastatic NTRK gene fusion solid tumors.

In the 40 patients who were TKI-naive, the overall response rate was 58%, and the median duration of response was not estimable. In the 48 patients who had a TKI previously, the overall response rate was 50% and median duration of response was 9.9 months.

In 20% or more of participants, treatment caused dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, fatigue, ataxia, cognitive impairment, muscular weakness, and nausea.

Labeling warns of central nervous system reactions, interstitial lung disease/pneumonitis, hepatotoxicity, myalgia with creatine phosphokinase elevation, hyperuricemia, bone fractures, and embryo-fetal toxicity.

The recommended dose is 160 mg orally once daily for 14 days then increased to 160 mg twice daily until disease progression or unacceptable toxicity.

Sixty 40-mg capsules cost around $7,644, according to drugs.com. 
 

A version of this article appeared on Medscape.com.

The US Food and Drug Administration has granted accelerated approval to repotrectinib (Augtyro, Bristol Myers Squibb) for all locally advanced, unresectable, or metastatic solid tumors with an NTRK gene fusion that have progressed after initial treatment or that have no satisfactory alternative therapies.

The approval is a label expansion for the tyrosine kinase inhibitor (TKI), which received initial clearance in November 2023 for locally advanced or metastatic ROS1-positive non–small cell lung cancer. 

NTRK gene fusions are genetic abnormalities wherein part of the NTRK gene fuses with an unrelated gene. The abnormal gene can then produce an oncogenic protein. Although rare, these mutations are found in many cancer types.

The approval, for adult and pediatric patients aged 12 years or older, was based on the single-arm open-label TRIDENT-1 trial in 88 adults with locally advanced or metastatic NTRK gene fusion solid tumors.

In the 40 patients who were TKI-naive, the overall response rate was 58%, and the median duration of response was not estimable. In the 48 patients who had a TKI previously, the overall response rate was 50% and median duration of response was 9.9 months.

In 20% or more of participants, treatment caused dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, fatigue, ataxia, cognitive impairment, muscular weakness, and nausea.

Labeling warns of central nervous system reactions, interstitial lung disease/pneumonitis, hepatotoxicity, myalgia with creatine phosphokinase elevation, hyperuricemia, bone fractures, and embryo-fetal toxicity.

The recommended dose is 160 mg orally once daily for 14 days then increased to 160 mg twice daily until disease progression or unacceptable toxicity.

Sixty 40-mg capsules cost around $7,644, according to drugs.com. 
 

A version of this article appeared on Medscape.com.

The US Food and Drug Administration has granted accelerated approval to repotrectinib (Augtyro, Bristol Myers Squibb) for all locally advanced, unresectable, or metastatic solid tumors with an NTRK gene fusion that have progressed after initial treatment or that have no satisfactory alternative therapies.

The approval is a label expansion for the tyrosine kinase inhibitor (TKI), which received initial clearance in November 2023 for locally advanced or metastatic ROS1-positive non–small cell lung cancer. 

NTRK gene fusions are genetic abnormalities wherein part of the NTRK gene fuses with an unrelated gene. The abnormal gene can then produce an oncogenic protein. Although rare, these mutations are found in many cancer types.

The approval, for adult and pediatric patients aged 12 years or older, was based on the single-arm open-label TRIDENT-1 trial in 88 adults with locally advanced or metastatic NTRK gene fusion solid tumors.

In the 40 patients who were TKI-naive, the overall response rate was 58%, and the median duration of response was not estimable. In the 48 patients who had a TKI previously, the overall response rate was 50% and median duration of response was 9.9 months.

In 20% or more of participants, treatment caused dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, fatigue, ataxia, cognitive impairment, muscular weakness, and nausea.

Labeling warns of central nervous system reactions, interstitial lung disease/pneumonitis, hepatotoxicity, myalgia with creatine phosphokinase elevation, hyperuricemia, bone fractures, and embryo-fetal toxicity.

The recommended dose is 160 mg orally once daily for 14 days then increased to 160 mg twice daily until disease progression or unacceptable toxicity.

Sixty 40-mg capsules cost around $7,644, according to drugs.com. 
 

A version of this article appeared on Medscape.com.

The largest US physician organization wrestled with the professional risks and rewards of artificial intelligence (AI) at its annual meeting, delaying action even as it adopted new policies on prior authorization and other concerns for clinicians and patients.

Physicians and medical students at the annual meeting of the American Medical Association (AMA) House of Delegates in Chicago intensely debated a report and two key resolutions on AI but could not reach consensus, pushing off decision-making until a future meeting in November.

One resolution would establish “augmented intelligence” as the preferred term for AI, reflecting the desired role of these tools in supporting — not making — physicians’ decisions. The other resolution focused on insurers’ use of AI in determining medical necessity.

(See specific policies adopted at the meeting, held June 8-12, below.)

A comprehensive AMA trustees’ report on AI considered additional issues including requirements for disclosing AI use, liability for harms due to flawed application of AI, data privacy, and cybersecurity.

The AMA intends to “continue to methodically assess these issues and make informed recommendations in proposing new policy,” said Bobby Mukkamala, MD, an otolaryngologist from Flint, Michigan, who became the AMA’s new president-elect.

AMA members at the meeting largely applauded the aim of these AI proposals, but some objected to parts of the trustees’ report.

They raised questions about what, exactly, constitutes an AI-powered service and whether all AI tools need the kind of guardrails the AMA may seek. There also were concerns about calls to make AI use more transparent.

While transparency might be an admirable goal, it might prove too hard to achieve given that AI-powered tools and products are already woven into medical practice in ways that physicians may not know or understand, said Christopher Libby, MD, MPH, a clinical informaticist and emergency physician at Cedars Sinai Medical Center in Los Angeles.

“It’s hard for the practicing clinician to know how every piece of technology works in order to describe it to the patient,” Dr. Libby said at the meeting. “How many people here can identify when algorithms are used in their EHR today?”

He suggested asking for more transparency from the companies that make and sell AI-powered software and tools to insurers and healthcare systems.

Steven H. Kroft, MD, the editor of the American Journal of Clinical Pathology, raised concerns about the unintended harm that unchecked use of AI may pose to scientific research.

He asked the AMA to address “a significant omission in an otherwise comprehensive report” — the need to protect the integrity of study results that can direct patient care.

“While sham science is not a new issue, large language models make it far easier for authors to generate fake papers and far harder for editors, reviewers, and publishers to identify them,” Dr. Kroft said. “This is a rapidly growing phenomenon that is threatening the integrity of the literature. These papers become embedded in the evidence bases that drive clinical decision-making.”

AMA has been working with specialty societies and outside AI experts to refine an effective set of recommendations. The new policies, once finalized, are intended to build on steps AMA already has taken, including last year releasing principles for AI development, deployment, and use.
 

Congress Mulling

The AMA delegates are far from alone in facing AI policy challenges.

Leaders in Congress also are examining AI guardrails, with influential panels such as the Senate Finance and House Energy and Commerce committees holding hearings.

A key congressional AI effort to watch is the expected implementation of a bipartisan Senate “road map,” which Senate Majority Leader Chuck Schumer (D-NY) and colleagues released in May, said Miranda A. Franco, a senior policy advisor at the law firm Holland & Knight.

The product of many months of deliberation, this Senate road map identifies priorities for future legislation, including:

• Creating appropriate guardrails and safety measures to protect patients.
• Making healthcare and biomedical data available for machine learning and data science research while carefully addressing privacy issues.
• Providing transparency for clinicians and the public about the use of AI in medical products and clinical support services, including the data used to train models.
• Examining the Centers for Medicare & Medicaid Services’ reimbursement mechanisms as well as guardrails to ensure accountability, appropriate use, and broad application of AI across all populations.

Congress likely will address issues of AI in healthcare in piecemeal fashion, taking on different aspects of these challenges at different times, Ms. Franco said. The Senate road map gives the key committees directions on where to proceed in their efforts to develop new laws.

“I think this is all going to be slow and rolling, not big and sweeping,” Ms. Franco told this news organization. “I don’t think we’re going to see an encompassing AI bill.”
 

AMA Policies Adopted on Other Issues

At the June meeting, AMA delegates adopted the following policies aiming to:

• Increase oversight and accountability of health insurers’ use of prior authorization controls on patient access to care.
• Encourage policy changes allowing physicians to receive loan forgiveness when they practice in an Indian Health Service, Tribal, or Urban Indian Health Program, similar to physicians practicing in a Veterans Administration facility.
• Advocate for federal policy that limits a patient’s out-of-pocket cost to be the same or less than the amount that a patient with traditional Medicare plus a Medigap plan would pay.
• Oppose state or national legislation that could criminalize in vitro fertilization.
• Limit what the AMA calls the “expensive” cost for Medicare Advantage enrollees who need physician-administered drugs or biologics.
• Help physicians address the handling of de-identified patient data in a rapidly changing digital health ecosystem.
• Support efforts to decriminalize the possession of non-prescribed buprenorphine for personal use by individuals who lack access to a physician for the treatment of opioid use disorder.
• Expand access to hearing, vision, and dental care. The new AMA policy advocates working with state medical associations to support coverage of hearing exams, hearing aids, cochlear implants, and vision exams and aids. The revised AMA policy also supports working with the American Dental Association and other national organizations to improve access to dental care for people enrolled in Medicare, Medicaid, and CHIP programs.
• Increase enrollment of more women and sexual and gender minority populations in clinical trials.

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

The largest US physician organization wrestled with the professional risks and rewards of artificial intelligence (AI) at its annual meeting, delaying action even as it adopted new policies on prior authorization and other concerns for clinicians and patients.

Physicians and medical students at the annual meeting of the American Medical Association (AMA) House of Delegates in Chicago intensely debated a report and two key resolutions on AI but could not reach consensus, pushing off decision-making until a future meeting in November.

One resolution would establish “augmented intelligence” as the preferred term for AI, reflecting the desired role of these tools in supporting — not making — physicians’ decisions. The other resolution focused on insurers’ use of AI in determining medical necessity.

(See specific policies adopted at the meeting, held June 8-12, below.)

A comprehensive AMA trustees’ report on AI considered additional issues including requirements for disclosing AI use, liability for harms due to flawed application of AI, data privacy, and cybersecurity.

The AMA intends to “continue to methodically assess these issues and make informed recommendations in proposing new policy,” said Bobby Mukkamala, MD, an otolaryngologist from Flint, Michigan, who became the AMA’s new president-elect.

AMA members at the meeting largely applauded the aim of these AI proposals, but some objected to parts of the trustees’ report.

They raised questions about what, exactly, constitutes an AI-powered service and whether all AI tools need the kind of guardrails the AMA may seek. There also were concerns about calls to make AI use more transparent.

While transparency might be an admirable goal, it might prove too hard to achieve given that AI-powered tools and products are already woven into medical practice in ways that physicians may not know or understand, said Christopher Libby, MD, MPH, a clinical informaticist and emergency physician at Cedars Sinai Medical Center in Los Angeles.

“It’s hard for the practicing clinician to know how every piece of technology works in order to describe it to the patient,” Dr. Libby said at the meeting. “How many people here can identify when algorithms are used in their EHR today?”

He suggested asking for more transparency from the companies that make and sell AI-powered software and tools to insurers and healthcare systems.

Steven H. Kroft, MD, the editor of the American Journal of Clinical Pathology, raised concerns about the unintended harm that unchecked use of AI may pose to scientific research.

He asked the AMA to address “a significant omission in an otherwise comprehensive report” — the need to protect the integrity of study results that can direct patient care.

“While sham science is not a new issue, large language models make it far easier for authors to generate fake papers and far harder for editors, reviewers, and publishers to identify them,” Dr. Kroft said. “This is a rapidly growing phenomenon that is threatening the integrity of the literature. These papers become embedded in the evidence bases that drive clinical decision-making.”

AMA has been working with specialty societies and outside AI experts to refine an effective set of recommendations. The new policies, once finalized, are intended to build on steps AMA already has taken, including last year releasing principles for AI development, deployment, and use.
 

Congress Mulling

The AMA delegates are far from alone in facing AI policy challenges.

Leaders in Congress also are examining AI guardrails, with influential panels such as the Senate Finance and House Energy and Commerce committees holding hearings.

A key congressional AI effort to watch is the expected implementation of a bipartisan Senate “road map,” which Senate Majority Leader Chuck Schumer (D-NY) and colleagues released in May, said Miranda A. Franco, a senior policy advisor at the law firm Holland & Knight.

The product of many months of deliberation, this Senate road map identifies priorities for future legislation, including:

• Creating appropriate guardrails and safety measures to protect patients.
• Making healthcare and biomedical data available for machine learning and data science research while carefully addressing privacy issues.
• Providing transparency for clinicians and the public about the use of AI in medical products and clinical support services, including the data used to train models.
• Examining the Centers for Medicare & Medicaid Services’ reimbursement mechanisms as well as guardrails to ensure accountability, appropriate use, and broad application of AI across all populations.

Congress likely will address issues of AI in healthcare in piecemeal fashion, taking on different aspects of these challenges at different times, Ms. Franco said. The Senate road map gives the key committees directions on where to proceed in their efforts to develop new laws.

“I think this is all going to be slow and rolling, not big and sweeping,” Ms. Franco told this news organization. “I don’t think we’re going to see an encompassing AI bill.”
 

AMA Policies Adopted on Other Issues

At the June meeting, AMA delegates adopted the following policies aiming to:

• Increase oversight and accountability of health insurers’ use of prior authorization controls on patient access to care.
• Encourage policy changes allowing physicians to receive loan forgiveness when they practice in an Indian Health Service, Tribal, or Urban Indian Health Program, similar to physicians practicing in a Veterans Administration facility.
• Advocate for federal policy that limits a patient’s out-of-pocket cost to be the same or less than the amount that a patient with traditional Medicare plus a Medigap plan would pay.
• Oppose state or national legislation that could criminalize in vitro fertilization.
• Limit what the AMA calls the “expensive” cost for Medicare Advantage enrollees who need physician-administered drugs or biologics.
• Help physicians address the handling of de-identified patient data in a rapidly changing digital health ecosystem.
• Support efforts to decriminalize the possession of non-prescribed buprenorphine for personal use by individuals who lack access to a physician for the treatment of opioid use disorder.
• Expand access to hearing, vision, and dental care. The new AMA policy advocates working with state medical associations to support coverage of hearing exams, hearing aids, cochlear implants, and vision exams and aids. The revised AMA policy also supports working with the American Dental Association and other national organizations to improve access to dental care for people enrolled in Medicare, Medicaid, and CHIP programs.
• Increase enrollment of more women and sexual and gender minority populations in clinical trials.

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

The largest US physician organization wrestled with the professional risks and rewards of artificial intelligence (AI) at its annual meeting, delaying action even as it adopted new policies on prior authorization and other concerns for clinicians and patients.

Physicians and medical students at the annual meeting of the American Medical Association (AMA) House of Delegates in Chicago intensely debated a report and two key resolutions on AI but could not reach consensus, pushing off decision-making until a future meeting in November.

One resolution would establish “augmented intelligence” as the preferred term for AI, reflecting the desired role of these tools in supporting — not making — physicians’ decisions. The other resolution focused on insurers’ use of AI in determining medical necessity.

(See specific policies adopted at the meeting, held June 8-12, below.)

A comprehensive AMA trustees’ report on AI considered additional issues including requirements for disclosing AI use, liability for harms due to flawed application of AI, data privacy, and cybersecurity.

The AMA intends to “continue to methodically assess these issues and make informed recommendations in proposing new policy,” said Bobby Mukkamala, MD, an otolaryngologist from Flint, Michigan, who became the AMA’s new president-elect.

AMA members at the meeting largely applauded the aim of these AI proposals, but some objected to parts of the trustees’ report.

They raised questions about what, exactly, constitutes an AI-powered service and whether all AI tools need the kind of guardrails the AMA may seek. There also were concerns about calls to make AI use more transparent.

While transparency might be an admirable goal, it might prove too hard to achieve given that AI-powered tools and products are already woven into medical practice in ways that physicians may not know or understand, said Christopher Libby, MD, MPH, a clinical informaticist and emergency physician at Cedars Sinai Medical Center in Los Angeles.

“It’s hard for the practicing clinician to know how every piece of technology works in order to describe it to the patient,” Dr. Libby said at the meeting. “How many people here can identify when algorithms are used in their EHR today?”

He suggested asking for more transparency from the companies that make and sell AI-powered software and tools to insurers and healthcare systems.

Steven H. Kroft, MD, the editor of the American Journal of Clinical Pathology, raised concerns about the unintended harm that unchecked use of AI may pose to scientific research.

He asked the AMA to address “a significant omission in an otherwise comprehensive report” — the need to protect the integrity of study results that can direct patient care.

“While sham science is not a new issue, large language models make it far easier for authors to generate fake papers and far harder for editors, reviewers, and publishers to identify them,” Dr. Kroft said. “This is a rapidly growing phenomenon that is threatening the integrity of the literature. These papers become embedded in the evidence bases that drive clinical decision-making.”

AMA has been working with specialty societies and outside AI experts to refine an effective set of recommendations. The new policies, once finalized, are intended to build on steps AMA already has taken, including last year releasing principles for AI development, deployment, and use.
 

Congress Mulling

The AMA delegates are far from alone in facing AI policy challenges.

Leaders in Congress also are examining AI guardrails, with influential panels such as the Senate Finance and House Energy and Commerce committees holding hearings.

A key congressional AI effort to watch is the expected implementation of a bipartisan Senate “road map,” which Senate Majority Leader Chuck Schumer (D-NY) and colleagues released in May, said Miranda A. Franco, a senior policy advisor at the law firm Holland & Knight.

The product of many months of deliberation, this Senate road map identifies priorities for future legislation, including:

• Creating appropriate guardrails and safety measures to protect patients.
• Making healthcare and biomedical data available for machine learning and data science research while carefully addressing privacy issues.
• Providing transparency for clinicians and the public about the use of AI in medical products and clinical support services, including the data used to train models.
• Examining the Centers for Medicare & Medicaid Services’ reimbursement mechanisms as well as guardrails to ensure accountability, appropriate use, and broad application of AI across all populations.

Congress likely will address issues of AI in healthcare in piecemeal fashion, taking on different aspects of these challenges at different times, Ms. Franco said. The Senate road map gives the key committees directions on where to proceed in their efforts to develop new laws.

“I think this is all going to be slow and rolling, not big and sweeping,” Ms. Franco told this news organization. “I don’t think we’re going to see an encompassing AI bill.”
 

AMA Policies Adopted on Other Issues

At the June meeting, AMA delegates adopted the following policies aiming to:

• Increase oversight and accountability of health insurers’ use of prior authorization controls on patient access to care.
• Encourage policy changes allowing physicians to receive loan forgiveness when they practice in an Indian Health Service, Tribal, or Urban Indian Health Program, similar to physicians practicing in a Veterans Administration facility.
• Advocate for federal policy that limits a patient’s out-of-pocket cost to be the same or less than the amount that a patient with traditional Medicare plus a Medigap plan would pay.
• Oppose state or national legislation that could criminalize in vitro fertilization.
• Limit what the AMA calls the “expensive” cost for Medicare Advantage enrollees who need physician-administered drugs or biologics.
• Help physicians address the handling of de-identified patient data in a rapidly changing digital health ecosystem.
• Support efforts to decriminalize the possession of non-prescribed buprenorphine for personal use by individuals who lack access to a physician for the treatment of opioid use disorder.
• Expand access to hearing, vision, and dental care. The new AMA policy advocates working with state medical associations to support coverage of hearing exams, hearing aids, cochlear implants, and vision exams and aids. The revised AMA policy also supports working with the American Dental Association and other national organizations to improve access to dental care for people enrolled in Medicare, Medicaid, and CHIP programs.
• Increase enrollment of more women and sexual and gender minority populations in clinical trials.

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

Women who had overweight or obesity as teens or young adults had more than a twofold increased risk for stroke before age 55, new research suggested.

An analysis of more than five decades of health data on 10,000 adults revealed that close to 5% experienced a stroke during the follow-up period, with the risk for ischemic stroke being more than twice as high in women who had obesity as teens or young adults. The risk was even higher for hemorrhagic stroke in both men and women with a history of obesity in youth.

“Our findings suggest that being overweight may have long-term health effects, even if the excess weight is temporary,” lead author Ursula Mikkola, BM, an investigator in the Research Unit of Population Health at the University of Oulu, Oulu, Finland, said in a news release.

Gender Differences

Childhood obesity has been associated with a heightened risk for cerebrovascular disease later in life, but most studies have focused on body mass index (BMI) at a single time point without considering its fluctuations throughout life, the investigators noted.

For the study, investigators used data from the Northern Finland Birth Cohort 1966, a prospective, general population-based birth cohort that followed 10,491 individuals (5185 women) until 2020 or the first stroke, death, or moving abroad, whichever came first.

Mean (SD) follow-up for each participant was 39 years from age 14 onward and 23 years from age 31 onward. The analysis was conducted between 1980 and 2020.

BMI data were collected from participants at the age of 14 and 31 years. Age 14 covariates included smoking, parental socioeconomic status, and age at menarche (for girls). Age 31 covariates included smoking and participants’ educational level.

During the follow-up period, 4.7% of participants experienced stroke. Of these events, 31% were ischemic strokes and 40% were transient ischemic attacks. The remainder were hemorrhagic or other cerebrovascular events.

Using normal weight as a reference, researchers found that the risk for ischemic stroke was over twice as high for women who had been overweight at ages 14 (hazard ratio [HR], 2.49; 95% confidence interval [CI], 1.44-4.31) and 31 (HR, 2.13; 95% CI, 1.14-3.97) years. The risk was also considerably higher for women who had obesity at ages 14 (HR, 1.87; 95% CI, 0.76-4.58) and 31 (HR, 2.67; 95% CI, 1.26-5.65) years.

The risk for hemorrhagic stroke was even higher, both among women (HR, 3.49; 95% CI, 1.13-10.7) and men (HR, 5.75; 95% CI, 1.43-23.1) who had obesity at age 31.

No similar associations were found among men, and the findings were independent of earlier or later BMI.

The risk for any cerebrovascular disease related to overweight at age 14 was twice as high among girls vs boys (HR, 2.09; 95% CI, 1.06-4.15), and the risk for ischemic stroke related to obesity at age 31 was nearly seven times higher among women vs men (HR, 6.96; 95% CI, 1.36-35.7).

“Stroke at a young age is rare, so the difference of just a few strokes could have an outsized impact on the risk estimates,” the study authors said. “Also, BMI relies solely on a person’s height and weight; therefore, a high BMI may be a misleading way to define obesity, especially in muscular people who may carry little fat even while weighing more.”
 

Caveats

In an accompanying editorial, Larry Goldstein, MD, chair of the Department of Neurology, University of Kentucky, Lexington, Kentucky, and codirector of the Kentucky Neuroscience Institute, said the study “provides additional evidence of an association between overweight/obesity and stroke in young adults.”

However, Dr. Goldstein added that “while it is tempting to assume that reductions in overweight/obesity in younger populations would translate to lower stroke rates in young adults, this remains to be proven.”

Moreover, it is “always important to acknowledge that associations found in observational studies may not reflect causality.”

This study was supported by Orion Research Foundation, Päivikki and Sakari Sohlberg Foundation, and Paulo Foundation. Dr. Mikkola reported no relevant financial relationships. The other authors’ disclosures are listed on the original paper. Dr. Goldstein reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Women who had overweight or obesity as teens or young adults had more than a twofold increased risk for stroke before age 55, new research suggested.

An analysis of more than five decades of health data on 10,000 adults revealed that close to 5% experienced a stroke during the follow-up period, with the risk for ischemic stroke being more than twice as high in women who had obesity as teens or young adults. The risk was even higher for hemorrhagic stroke in both men and women with a history of obesity in youth.

“Our findings suggest that being overweight may have long-term health effects, even if the excess weight is temporary,” lead author Ursula Mikkola, BM, an investigator in the Research Unit of Population Health at the University of Oulu, Oulu, Finland, said in a news release.

Gender Differences

Childhood obesity has been associated with a heightened risk for cerebrovascular disease later in life, but most studies have focused on body mass index (BMI) at a single time point without considering its fluctuations throughout life, the investigators noted.

For the study, investigators used data from the Northern Finland Birth Cohort 1966, a prospective, general population-based birth cohort that followed 10,491 individuals (5185 women) until 2020 or the first stroke, death, or moving abroad, whichever came first.

Mean (SD) follow-up for each participant was 39 years from age 14 onward and 23 years from age 31 onward. The analysis was conducted between 1980 and 2020.

BMI data were collected from participants at the age of 14 and 31 years. Age 14 covariates included smoking, parental socioeconomic status, and age at menarche (for girls). Age 31 covariates included smoking and participants’ educational level.

During the follow-up period, 4.7% of participants experienced stroke. Of these events, 31% were ischemic strokes and 40% were transient ischemic attacks. The remainder were hemorrhagic or other cerebrovascular events.

Using normal weight as a reference, researchers found that the risk for ischemic stroke was over twice as high for women who had been overweight at ages 14 (hazard ratio [HR], 2.49; 95% confidence interval [CI], 1.44-4.31) and 31 (HR, 2.13; 95% CI, 1.14-3.97) years. The risk was also considerably higher for women who had obesity at ages 14 (HR, 1.87; 95% CI, 0.76-4.58) and 31 (HR, 2.67; 95% CI, 1.26-5.65) years.

The risk for hemorrhagic stroke was even higher, both among women (HR, 3.49; 95% CI, 1.13-10.7) and men (HR, 5.75; 95% CI, 1.43-23.1) who had obesity at age 31.

No similar associations were found among men, and the findings were independent of earlier or later BMI.

The risk for any cerebrovascular disease related to overweight at age 14 was twice as high among girls vs boys (HR, 2.09; 95% CI, 1.06-4.15), and the risk for ischemic stroke related to obesity at age 31 was nearly seven times higher among women vs men (HR, 6.96; 95% CI, 1.36-35.7).

“Stroke at a young age is rare, so the difference of just a few strokes could have an outsized impact on the risk estimates,” the study authors said. “Also, BMI relies solely on a person’s height and weight; therefore, a high BMI may be a misleading way to define obesity, especially in muscular people who may carry little fat even while weighing more.”
 

Caveats

In an accompanying editorial, Larry Goldstein, MD, chair of the Department of Neurology, University of Kentucky, Lexington, Kentucky, and codirector of the Kentucky Neuroscience Institute, said the study “provides additional evidence of an association between overweight/obesity and stroke in young adults.”

However, Dr. Goldstein added that “while it is tempting to assume that reductions in overweight/obesity in younger populations would translate to lower stroke rates in young adults, this remains to be proven.”

Moreover, it is “always important to acknowledge that associations found in observational studies may not reflect causality.”

This study was supported by Orion Research Foundation, Päivikki and Sakari Sohlberg Foundation, and Paulo Foundation. Dr. Mikkola reported no relevant financial relationships. The other authors’ disclosures are listed on the original paper. Dr. Goldstein reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Women who had overweight or obesity as teens or young adults had more than a twofold increased risk for stroke before age 55, new research suggested.

An analysis of more than five decades of health data on 10,000 adults revealed that close to 5% experienced a stroke during the follow-up period, with the risk for ischemic stroke being more than twice as high in women who had obesity as teens or young adults. The risk was even higher for hemorrhagic stroke in both men and women with a history of obesity in youth.

“Our findings suggest that being overweight may have long-term health effects, even if the excess weight is temporary,” lead author Ursula Mikkola, BM, an investigator in the Research Unit of Population Health at the University of Oulu, Oulu, Finland, said in a news release.

Gender Differences

Childhood obesity has been associated with a heightened risk for cerebrovascular disease later in life, but most studies have focused on body mass index (BMI) at a single time point without considering its fluctuations throughout life, the investigators noted.

For the study, investigators used data from the Northern Finland Birth Cohort 1966, a prospective, general population-based birth cohort that followed 10,491 individuals (5185 women) until 2020 or the first stroke, death, or moving abroad, whichever came first.

Mean (SD) follow-up for each participant was 39 years from age 14 onward and 23 years from age 31 onward. The analysis was conducted between 1980 and 2020.

BMI data were collected from participants at the age of 14 and 31 years. Age 14 covariates included smoking, parental socioeconomic status, and age at menarche (for girls). Age 31 covariates included smoking and participants’ educational level.

During the follow-up period, 4.7% of participants experienced stroke. Of these events, 31% were ischemic strokes and 40% were transient ischemic attacks. The remainder were hemorrhagic or other cerebrovascular events.

Using normal weight as a reference, researchers found that the risk for ischemic stroke was over twice as high for women who had been overweight at ages 14 (hazard ratio [HR], 2.49; 95% confidence interval [CI], 1.44-4.31) and 31 (HR, 2.13; 95% CI, 1.14-3.97) years. The risk was also considerably higher for women who had obesity at ages 14 (HR, 1.87; 95% CI, 0.76-4.58) and 31 (HR, 2.67; 95% CI, 1.26-5.65) years.

The risk for hemorrhagic stroke was even higher, both among women (HR, 3.49; 95% CI, 1.13-10.7) and men (HR, 5.75; 95% CI, 1.43-23.1) who had obesity at age 31.

No similar associations were found among men, and the findings were independent of earlier or later BMI.

The risk for any cerebrovascular disease related to overweight at age 14 was twice as high among girls vs boys (HR, 2.09; 95% CI, 1.06-4.15), and the risk for ischemic stroke related to obesity at age 31 was nearly seven times higher among women vs men (HR, 6.96; 95% CI, 1.36-35.7).

“Stroke at a young age is rare, so the difference of just a few strokes could have an outsized impact on the risk estimates,” the study authors said. “Also, BMI relies solely on a person’s height and weight; therefore, a high BMI may be a misleading way to define obesity, especially in muscular people who may carry little fat even while weighing more.”
 

Caveats

In an accompanying editorial, Larry Goldstein, MD, chair of the Department of Neurology, University of Kentucky, Lexington, Kentucky, and codirector of the Kentucky Neuroscience Institute, said the study “provides additional evidence of an association between overweight/obesity and stroke in young adults.”

However, Dr. Goldstein added that “while it is tempting to assume that reductions in overweight/obesity in younger populations would translate to lower stroke rates in young adults, this remains to be proven.”

Moreover, it is “always important to acknowledge that associations found in observational studies may not reflect causality.”

This study was supported by Orion Research Foundation, Päivikki and Sakari Sohlberg Foundation, and Paulo Foundation. Dr. Mikkola reported no relevant financial relationships. The other authors’ disclosures are listed on the original paper. Dr. Goldstein reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

NASHVILLE, Tennessee — In a population of Black/African American and Hispanic/Latino patients with multiple sclerosis (MS), ocrelizumab had high efficacy and an acceptable safety profile, according to the results of a 1-year analysis of the CHIMES trial. The study is the first-ever prospective study of an MS disease-modifying therapy (DMT) exclusively performed in under-represented populations, and offers lessons to researchers aiming to design more inclusive clinical trials to bolster participation by under-represented populations.

“The goal was to better understand efficacy of therapy in under-represented populations because we typically have very low numbers of these patients in our clinical trials, although there are multiple studies over the past decades suggesting that there may be poorer outcomes in Black and Hispanic individuals, particularly in the United States, and that there also may be more aggressive disease,” said Mitzi Williams, MD, who presented the study in a poster session at the annual meeting of the Consortium of Multiple Sclerosis Centers.

The team recruited 113 Black participants and 69 Hispanic participants, and, in fact, over-recruited the target number by 25%, and did so 2 months before the launch of the study in July 2020, which just happened to be in the midst of a global pandemic.

After 48 weeks of ocrelizumab treatment, 46.0% of Black participants and 58.0% of Hispanic participants achieved no evidence of disease activity in three components (NEDA-3), while 94.7% and 95.7% were free from relapses, respectively, and 94.7% and 94.2% were free from disease worsening. Serious adverse events occurred in 6.2% and 4.3% of each group, respectively, and there were no new safety signals in either group.

“The good news is that the efficacy and safety was very similar to what we saw in other clinical trials. I don’t think we really expected it to be much different, because when we think about race, it’s a social construct, not a biologic construct. What we do hope to find out is more about some of the interplay of social determinants of health, and how getting on high efficacy treatment can improve and increase productivity and outcomes in the long term,” said Dr. Williams, who is medical director of Joi Life Wellness Group, Smyrna, Georgia.

The researchers succeeded by involving patient advocates and advocacy organizations at the very earliest stages of the trial design. “We were very intentional about looking at things like social determinants of health, childcare, transportation, and things like that to ease some of the burden of participating in the trial, obviously in a legal and compliant way,” said Dr. Williams. The team also ensured complete and accurate translation of patient materials into Spanish.

The study was also a phase 4 trial, which may have simplified recruitment. “So it’s a therapy that’s already approved, which may make people feel more comfortable, but obviously the goal is for our phase 3 trials to make sure that we are recruiting represented populations. We’re taking these learnings and applying them to the broader clinical trial population so that hopefully we won’t have to come back and do phase 4 studies like this,” said Dr. Williams.

She noted that the results of more inclusive studies don’t just benefit underserved populations. “You have groups of people that are suffering and having more disability from a condition, and you need to understand why. When we broaden the population to understand those that are most vulnerable and underserved and [having the worst outcomes], it really helps us to better treat everybody. Because if we can get a hold of those factors that make us do the worst, then we can also better understand the factors that make us do the best,” said Dr. Williams.
 

Inclusive Recruitment in Clinical Trials

Asked for comment, Ahmed Obeidat, MD, PhD, highlighted the importance of inclusive recruitment. “The study is very important because historically and even in most recent clinical trials, these groups were markedly under-represented and most completed clinical trials derive conclusions based on the study of a nondiverse, White-non-Hispanic predominant population,” said Dr. Obeidat, who is an associate professor at the Medical College of Wisconsin, Milwaukee. He pointed to a systematic review showing that the median percentage of White participants in MS clinical trials was 93% and ranged from 86% to 98%.

“Several factors may contribute to the disparity in clinical trial participation, and solutions must be explored and developed. CHIMES is a first step in this direction where the study itself is designed to address disparity in MS clinical trial participation,” said Dr. Obeidat.

Dr. Obeidat also pointed to the need to consider other forms of diversity in clinical trials, such as older patients and those with advanced disability. “Investigators, coordinators, and other staff should all strive to be as inclusive as possible in clinical trials,” he said.

Dr. Williams has received consulting fees from Alexion, Biogen, Bristol Myers Squibb, EMD Serono, Genentech Inc., Janssen, Novartis, Sanofi, and TG Therapeutics, and serves on speakers bureaus for Biogen, Bristol Myers Squibb, EMD Serono, Janssen, Genentech, and TG Therapeutics. Dr. Ahmed Z. Obeidat has financial relationships with Alexion Pharmaceuticals, Banner Life Sciences, BD Biosciences, Biogen, Biologix Solutions, Bristol Myers Squibb, Celgene, EMD Serono, Genentech, GW Pharmaceuticals, Horizon Therapeutics, Jazz Pharmaceuticals, Novartis, Sandoz, Sanofi Genzyme, TG Therapeutics, and Viela Bio.

NASHVILLE, Tennessee — In a population of Black/African American and Hispanic/Latino patients with multiple sclerosis (MS), ocrelizumab had high efficacy and an acceptable safety profile, according to the results of a 1-year analysis of the CHIMES trial. The study is the first-ever prospective study of an MS disease-modifying therapy (DMT) exclusively performed in under-represented populations, and offers lessons to researchers aiming to design more inclusive clinical trials to bolster participation by under-represented populations.

“The goal was to better understand efficacy of therapy in under-represented populations because we typically have very low numbers of these patients in our clinical trials, although there are multiple studies over the past decades suggesting that there may be poorer outcomes in Black and Hispanic individuals, particularly in the United States, and that there also may be more aggressive disease,” said Mitzi Williams, MD, who presented the study in a poster session at the annual meeting of the Consortium of Multiple Sclerosis Centers.

The team recruited 113 Black participants and 69 Hispanic participants, and, in fact, over-recruited the target number by 25%, and did so 2 months before the launch of the study in July 2020, which just happened to be in the midst of a global pandemic.

After 48 weeks of ocrelizumab treatment, 46.0% of Black participants and 58.0% of Hispanic participants achieved no evidence of disease activity in three components (NEDA-3), while 94.7% and 95.7% were free from relapses, respectively, and 94.7% and 94.2% were free from disease worsening. Serious adverse events occurred in 6.2% and 4.3% of each group, respectively, and there were no new safety signals in either group.

“The good news is that the efficacy and safety was very similar to what we saw in other clinical trials. I don’t think we really expected it to be much different, because when we think about race, it’s a social construct, not a biologic construct. What we do hope to find out is more about some of the interplay of social determinants of health, and how getting on high efficacy treatment can improve and increase productivity and outcomes in the long term,” said Dr. Williams, who is medical director of Joi Life Wellness Group, Smyrna, Georgia.

The researchers succeeded by involving patient advocates and advocacy organizations at the very earliest stages of the trial design. “We were very intentional about looking at things like social determinants of health, childcare, transportation, and things like that to ease some of the burden of participating in the trial, obviously in a legal and compliant way,” said Dr. Williams. The team also ensured complete and accurate translation of patient materials into Spanish.

The study was also a phase 4 trial, which may have simplified recruitment. “So it’s a therapy that’s already approved, which may make people feel more comfortable, but obviously the goal is for our phase 3 trials to make sure that we are recruiting represented populations. We’re taking these learnings and applying them to the broader clinical trial population so that hopefully we won’t have to come back and do phase 4 studies like this,” said Dr. Williams.

She noted that the results of more inclusive studies don’t just benefit underserved populations. “You have groups of people that are suffering and having more disability from a condition, and you need to understand why. When we broaden the population to understand those that are most vulnerable and underserved and [having the worst outcomes], it really helps us to better treat everybody. Because if we can get a hold of those factors that make us do the worst, then we can also better understand the factors that make us do the best,” said Dr. Williams.
 

Inclusive Recruitment in Clinical Trials

Asked for comment, Ahmed Obeidat, MD, PhD, highlighted the importance of inclusive recruitment. “The study is very important because historically and even in most recent clinical trials, these groups were markedly under-represented and most completed clinical trials derive conclusions based on the study of a nondiverse, White-non-Hispanic predominant population,” said Dr. Obeidat, who is an associate professor at the Medical College of Wisconsin, Milwaukee. He pointed to a systematic review showing that the median percentage of White participants in MS clinical trials was 93% and ranged from 86% to 98%.

“Several factors may contribute to the disparity in clinical trial participation, and solutions must be explored and developed. CHIMES is a first step in this direction where the study itself is designed to address disparity in MS clinical trial participation,” said Dr. Obeidat.

Dr. Obeidat also pointed to the need to consider other forms of diversity in clinical trials, such as older patients and those with advanced disability. “Investigators, coordinators, and other staff should all strive to be as inclusive as possible in clinical trials,” he said.

Dr. Williams has received consulting fees from Alexion, Biogen, Bristol Myers Squibb, EMD Serono, Genentech Inc., Janssen, Novartis, Sanofi, and TG Therapeutics, and serves on speakers bureaus for Biogen, Bristol Myers Squibb, EMD Serono, Janssen, Genentech, and TG Therapeutics. Dr. Ahmed Z. Obeidat has financial relationships with Alexion Pharmaceuticals, Banner Life Sciences, BD Biosciences, Biogen, Biologix Solutions, Bristol Myers Squibb, Celgene, EMD Serono, Genentech, GW Pharmaceuticals, Horizon Therapeutics, Jazz Pharmaceuticals, Novartis, Sandoz, Sanofi Genzyme, TG Therapeutics, and Viela Bio.

NASHVILLE, Tennessee — In a population of Black/African American and Hispanic/Latino patients with multiple sclerosis (MS), ocrelizumab had high efficacy and an acceptable safety profile, according to the results of a 1-year analysis of the CHIMES trial. The study is the first-ever prospective study of an MS disease-modifying therapy (DMT) exclusively performed in under-represented populations, and offers lessons to researchers aiming to design more inclusive clinical trials to bolster participation by under-represented populations.

“The goal was to better understand efficacy of therapy in under-represented populations because we typically have very low numbers of these patients in our clinical trials, although there are multiple studies over the past decades suggesting that there may be poorer outcomes in Black and Hispanic individuals, particularly in the United States, and that there also may be more aggressive disease,” said Mitzi Williams, MD, who presented the study in a poster session at the annual meeting of the Consortium of Multiple Sclerosis Centers.

The team recruited 113 Black participants and 69 Hispanic participants, and, in fact, over-recruited the target number by 25%, and did so 2 months before the launch of the study in July 2020, which just happened to be in the midst of a global pandemic.

After 48 weeks of ocrelizumab treatment, 46.0% of Black participants and 58.0% of Hispanic participants achieved no evidence of disease activity in three components (NEDA-3), while 94.7% and 95.7% were free from relapses, respectively, and 94.7% and 94.2% were free from disease worsening. Serious adverse events occurred in 6.2% and 4.3% of each group, respectively, and there were no new safety signals in either group.

“The good news is that the efficacy and safety was very similar to what we saw in other clinical trials. I don’t think we really expected it to be much different, because when we think about race, it’s a social construct, not a biologic construct. What we do hope to find out is more about some of the interplay of social determinants of health, and how getting on high efficacy treatment can improve and increase productivity and outcomes in the long term,” said Dr. Williams, who is medical director of Joi Life Wellness Group, Smyrna, Georgia.

The researchers succeeded by involving patient advocates and advocacy organizations at the very earliest stages of the trial design. “We were very intentional about looking at things like social determinants of health, childcare, transportation, and things like that to ease some of the burden of participating in the trial, obviously in a legal and compliant way,” said Dr. Williams. The team also ensured complete and accurate translation of patient materials into Spanish.

The study was also a phase 4 trial, which may have simplified recruitment. “So it’s a therapy that’s already approved, which may make people feel more comfortable, but obviously the goal is for our phase 3 trials to make sure that we are recruiting represented populations. We’re taking these learnings and applying them to the broader clinical trial population so that hopefully we won’t have to come back and do phase 4 studies like this,” said Dr. Williams.

She noted that the results of more inclusive studies don’t just benefit underserved populations. “You have groups of people that are suffering and having more disability from a condition, and you need to understand why. When we broaden the population to understand those that are most vulnerable and underserved and [having the worst outcomes], it really helps us to better treat everybody. Because if we can get a hold of those factors that make us do the worst, then we can also better understand the factors that make us do the best,” said Dr. Williams.
 

Inclusive Recruitment in Clinical Trials

Asked for comment, Ahmed Obeidat, MD, PhD, highlighted the importance of inclusive recruitment. “The study is very important because historically and even in most recent clinical trials, these groups were markedly under-represented and most completed clinical trials derive conclusions based on the study of a nondiverse, White-non-Hispanic predominant population,” said Dr. Obeidat, who is an associate professor at the Medical College of Wisconsin, Milwaukee. He pointed to a systematic review showing that the median percentage of White participants in MS clinical trials was 93% and ranged from 86% to 98%.

“Several factors may contribute to the disparity in clinical trial participation, and solutions must be explored and developed. CHIMES is a first step in this direction where the study itself is designed to address disparity in MS clinical trial participation,” said Dr. Obeidat.

Dr. Obeidat also pointed to the need to consider other forms of diversity in clinical trials, such as older patients and those with advanced disability. “Investigators, coordinators, and other staff should all strive to be as inclusive as possible in clinical trials,” he said.

Dr. Williams has received consulting fees from Alexion, Biogen, Bristol Myers Squibb, EMD Serono, Genentech Inc., Janssen, Novartis, Sanofi, and TG Therapeutics, and serves on speakers bureaus for Biogen, Bristol Myers Squibb, EMD Serono, Janssen, Genentech, and TG Therapeutics. Dr. Ahmed Z. Obeidat has financial relationships with Alexion Pharmaceuticals, Banner Life Sciences, BD Biosciences, Biogen, Biologix Solutions, Bristol Myers Squibb, Celgene, EMD Serono, Genentech, GW Pharmaceuticals, Horizon Therapeutics, Jazz Pharmaceuticals, Novartis, Sandoz, Sanofi Genzyme, TG Therapeutics, and Viela Bio.

NASHVILLE, Tennessee — In pediatric multiple sclerosis (MS), the optimal dose of ocrelizumab is the same as the 600 mg adult dose for patients weighing more than 35 kg, according to pharmacokinetic/pharmacodynamic (PK/PD) data from the OPERETTA 1 phase 2 clinical trial. The safety profile was similar to adult patients.

“While we believe the disease to be the same in children and adolescents, [MS] is distinguished by its very inflammatory nature, oftentimes causing two to three times the number of relapses per year as their adult-onset colleagues,” said Teri Schreiner, MD, during a presentation of the results at the annual meeting of the Consortium of Multiple Sclerosis Centers.

Approved therapies for pediatric MS include fingolimod in the United States and Europe, as well as dimethyl fumarate in Europe. “There’s a real need for high-efficacy treatment [in pediatric patients], again referring back to this disease being very inflammatory in children and adolescents. We oftentimes will use medications off label but this is clearly suboptimal as we lack safety data, and oftentimes run into difficulty with insurance approval of off-label use of medicine,” said Dr. Schreiner, who is an associate professor of neurology at University of Colorado School of Medicine, Aurora.

To determine the dose in pediatric patients that would produce comparable PK and PD to adults, the researchers dosed six patients aged 10-18 with 300 mg ocrelizumab, and 17 such patients with 600 mg ocrelizumab during a 24-week dose-exploration period, followed by a 264-week optional extension period. The cohorts were separated based on weight of less than or more than 40 kg. The mean ages were 11.2 years (mean weight, 34.9 kg) and 15.3 years (mean weight, 62.3 kg), respectively.

During the dose-exploration period, seven blood draws were performed to characterize PK. “When the PK data was analyzed, we saw that the proper cut-off point was 35 kilos. At less than 35 kilos, the appropriate dose was half of that adult dose, so 300 milligrams every 6 months, whereas above 35 kilos, the proper dose was actually 600, or the adult dose. Given the rarity of pediatric-onset MS patients less than 35 kilos, most patients will benefit from the adult dose of 600 milligrams twice yearly,” said Dr. Schreiner.

PD data were also encouraging. “The primary PD was the absence of CD-19 B cells, and that was tracked over time. While there were a few patients in both cohorts that had modest reconstitution, there was no patient in our study that crossed the retreatment threshold, and all blood samples were negative for anti-drug antibodies,” said Dr. Schreiner.

Adverse events occurred in five of six patients in the 300 mg group (83%; 4 grade 2, 1 grade 3) and 100% of patients in the 600 mg group (1 grade 1, 9 grade 2, 6 grade 3, 1 grade 4). There was one serious adverse event in the 300 mg group (16.7%) and four serious adverse events in the 600 mg group (23.5%). None led to treatment discontinuation. “This is largely consistent with what was seen in the adult studies of ocrelizumab,” said Dr. Schreiner.

Roche is now recruiting for the phase 3 OPERETTA 2 trial, which will use the 600 mg dose and compare outcomes to a fingolimod arm.
 

Establishing Safety in the Pediatric Population

“In [pediatric onset MS] it’s an important piece of information to design OPERETTA 2 and to dose ocrelizumab in pediatric-onset MS in general,” said Jeffrey A Cohen, MD, professor of neurology at the Cleveland Clinic, who was asked for comment.

During the Q&A period, Dr. Schreiner was asked whether it is possible to extrapolate experience from rituximab to the pediatric population. “They’re very similar molecules, and we know the mechanisms of action, but I think part of the importance of doing these studies is to get the safety data so that we actually can say with certainty, we are giving you a drug that has this list of side effects and we know about them definitively. We all use other high-efficacy medications, but I don’t think we can exactly extrapolate,” said Dr. Schreiner.

Session moderator Amy Perrin Ross, APN, noted the lack of approved pediatric therapies for MS. “This is an extremely important study, because we at least in the lower 48 are quite limited in our resources for approved pediatric cases. Information like this will make it easier for a potential pediatric indication, which would then make it easier on us to go after [treatment of the disease in this population]. The weight-based dosing, I think, is really a good thing. Patients have been asking for weight-based dosing on everything for many years,” she said.

Ahmed Obeidat, MD, PhD, associate professor at the Medical College of Wisconsin, also praised the study. “While pediatric MS is rare, it is an area of unmet need when it comes to disease-modifying therapies as only fingolimod is FDA-approved, and many use B cell–depleting therapy, such as rituximab, off label to treat children with MS with good outcomes. The need for guidance on the dosing of B cell–depleting therapy is a main priority for research in pediatric MS,” he said.

The study was funded by Roche. Dr. Schreiner has consulted for Roche and Cycle Pharmaceuticals. Dr. Cohen has consulted for Astoria, Bristol Myers Squibb, Convelo, EMD Serono Inc, FiND, INMune, and Sandoz. Dr. Obeidat has financial relationships with Alexion Pharmaceuticals, Banner Life Sciences, BD Biosciences, Biogen, Biologix Solutions, Bristol Myers Squibb, Celgene, EMD Serono, Genentech, GW Pharmaceuticals, Horizon Therapeutics, Jazz Pharmaceuticals, Novartis, Sandoz, Sanofi Genzyme, TG Therapeutics, and Viela Bio. Ms. Ross has consulted for EMD Serono, BMS, Horizon, Alexion, TG Therapeutics, Novartis, Roche, and Sanofi.

NASHVILLE, Tennessee — In pediatric multiple sclerosis (MS), the optimal dose of ocrelizumab is the same as the 600 mg adult dose for patients weighing more than 35 kg, according to pharmacokinetic/pharmacodynamic (PK/PD) data from the OPERETTA 1 phase 2 clinical trial. The safety profile was similar to adult patients.

“While we believe the disease to be the same in children and adolescents, [MS] is distinguished by its very inflammatory nature, oftentimes causing two to three times the number of relapses per year as their adult-onset colleagues,” said Teri Schreiner, MD, during a presentation of the results at the annual meeting of the Consortium of Multiple Sclerosis Centers.

Approved therapies for pediatric MS include fingolimod in the United States and Europe, as well as dimethyl fumarate in Europe. “There’s a real need for high-efficacy treatment [in pediatric patients], again referring back to this disease being very inflammatory in children and adolescents. We oftentimes will use medications off label but this is clearly suboptimal as we lack safety data, and oftentimes run into difficulty with insurance approval of off-label use of medicine,” said Dr. Schreiner, who is an associate professor of neurology at University of Colorado School of Medicine, Aurora.

To determine the dose in pediatric patients that would produce comparable PK and PD to adults, the researchers dosed six patients aged 10-18 with 300 mg ocrelizumab, and 17 such patients with 600 mg ocrelizumab during a 24-week dose-exploration period, followed by a 264-week optional extension period. The cohorts were separated based on weight of less than or more than 40 kg. The mean ages were 11.2 years (mean weight, 34.9 kg) and 15.3 years (mean weight, 62.3 kg), respectively.

During the dose-exploration period, seven blood draws were performed to characterize PK. “When the PK data was analyzed, we saw that the proper cut-off point was 35 kilos. At less than 35 kilos, the appropriate dose was half of that adult dose, so 300 milligrams every 6 months, whereas above 35 kilos, the proper dose was actually 600, or the adult dose. Given the rarity of pediatric-onset MS patients less than 35 kilos, most patients will benefit from the adult dose of 600 milligrams twice yearly,” said Dr. Schreiner.

PD data were also encouraging. “The primary PD was the absence of CD-19 B cells, and that was tracked over time. While there were a few patients in both cohorts that had modest reconstitution, there was no patient in our study that crossed the retreatment threshold, and all blood samples were negative for anti-drug antibodies,” said Dr. Schreiner.

Adverse events occurred in five of six patients in the 300 mg group (83%; 4 grade 2, 1 grade 3) and 100% of patients in the 600 mg group (1 grade 1, 9 grade 2, 6 grade 3, 1 grade 4). There was one serious adverse event in the 300 mg group (16.7%) and four serious adverse events in the 600 mg group (23.5%). None led to treatment discontinuation. “This is largely consistent with what was seen in the adult studies of ocrelizumab,” said Dr. Schreiner.

Roche is now recruiting for the phase 3 OPERETTA 2 trial, which will use the 600 mg dose and compare outcomes to a fingolimod arm.
 

Establishing Safety in the Pediatric Population

“In [pediatric onset MS] it’s an important piece of information to design OPERETTA 2 and to dose ocrelizumab in pediatric-onset MS in general,” said Jeffrey A Cohen, MD, professor of neurology at the Cleveland Clinic, who was asked for comment.

During the Q&A period, Dr. Schreiner was asked whether it is possible to extrapolate experience from rituximab to the pediatric population. “They’re very similar molecules, and we know the mechanisms of action, but I think part of the importance of doing these studies is to get the safety data so that we actually can say with certainty, we are giving you a drug that has this list of side effects and we know about them definitively. We all use other high-efficacy medications, but I don’t think we can exactly extrapolate,” said Dr. Schreiner.

Session moderator Amy Perrin Ross, APN, noted the lack of approved pediatric therapies for MS. “This is an extremely important study, because we at least in the lower 48 are quite limited in our resources for approved pediatric cases. Information like this will make it easier for a potential pediatric indication, which would then make it easier on us to go after [treatment of the disease in this population]. The weight-based dosing, I think, is really a good thing. Patients have been asking for weight-based dosing on everything for many years,” she said.

Ahmed Obeidat, MD, PhD, associate professor at the Medical College of Wisconsin, also praised the study. “While pediatric MS is rare, it is an area of unmet need when it comes to disease-modifying therapies as only fingolimod is FDA-approved, and many use B cell–depleting therapy, such as rituximab, off label to treat children with MS with good outcomes. The need for guidance on the dosing of B cell–depleting therapy is a main priority for research in pediatric MS,” he said.

The study was funded by Roche. Dr. Schreiner has consulted for Roche and Cycle Pharmaceuticals. Dr. Cohen has consulted for Astoria, Bristol Myers Squibb, Convelo, EMD Serono Inc, FiND, INMune, and Sandoz. Dr. Obeidat has financial relationships with Alexion Pharmaceuticals, Banner Life Sciences, BD Biosciences, Biogen, Biologix Solutions, Bristol Myers Squibb, Celgene, EMD Serono, Genentech, GW Pharmaceuticals, Horizon Therapeutics, Jazz Pharmaceuticals, Novartis, Sandoz, Sanofi Genzyme, TG Therapeutics, and Viela Bio. Ms. Ross has consulted for EMD Serono, BMS, Horizon, Alexion, TG Therapeutics, Novartis, Roche, and Sanofi.

NASHVILLE, Tennessee — In pediatric multiple sclerosis (MS), the optimal dose of ocrelizumab is the same as the 600 mg adult dose for patients weighing more than 35 kg, according to pharmacokinetic/pharmacodynamic (PK/PD) data from the OPERETTA 1 phase 2 clinical trial. The safety profile was similar to adult patients.

“While we believe the disease to be the same in children and adolescents, [MS] is distinguished by its very inflammatory nature, oftentimes causing two to three times the number of relapses per year as their adult-onset colleagues,” said Teri Schreiner, MD, during a presentation of the results at the annual meeting of the Consortium of Multiple Sclerosis Centers.

Approved therapies for pediatric MS include fingolimod in the United States and Europe, as well as dimethyl fumarate in Europe. “There’s a real need for high-efficacy treatment [in pediatric patients], again referring back to this disease being very inflammatory in children and adolescents. We oftentimes will use medications off label but this is clearly suboptimal as we lack safety data, and oftentimes run into difficulty with insurance approval of off-label use of medicine,” said Dr. Schreiner, who is an associate professor of neurology at University of Colorado School of Medicine, Aurora.

To determine the dose in pediatric patients that would produce comparable PK and PD to adults, the researchers dosed six patients aged 10-18 with 300 mg ocrelizumab, and 17 such patients with 600 mg ocrelizumab during a 24-week dose-exploration period, followed by a 264-week optional extension period. The cohorts were separated based on weight of less than or more than 40 kg. The mean ages were 11.2 years (mean weight, 34.9 kg) and 15.3 years (mean weight, 62.3 kg), respectively.

During the dose-exploration period, seven blood draws were performed to characterize PK. “When the PK data was analyzed, we saw that the proper cut-off point was 35 kilos. At less than 35 kilos, the appropriate dose was half of that adult dose, so 300 milligrams every 6 months, whereas above 35 kilos, the proper dose was actually 600, or the adult dose. Given the rarity of pediatric-onset MS patients less than 35 kilos, most patients will benefit from the adult dose of 600 milligrams twice yearly,” said Dr. Schreiner.

PD data were also encouraging. “The primary PD was the absence of CD-19 B cells, and that was tracked over time. While there were a few patients in both cohorts that had modest reconstitution, there was no patient in our study that crossed the retreatment threshold, and all blood samples were negative for anti-drug antibodies,” said Dr. Schreiner.

Adverse events occurred in five of six patients in the 300 mg group (83%; 4 grade 2, 1 grade 3) and 100% of patients in the 600 mg group (1 grade 1, 9 grade 2, 6 grade 3, 1 grade 4). There was one serious adverse event in the 300 mg group (16.7%) and four serious adverse events in the 600 mg group (23.5%). None led to treatment discontinuation. “This is largely consistent with what was seen in the adult studies of ocrelizumab,” said Dr. Schreiner.

Roche is now recruiting for the phase 3 OPERETTA 2 trial, which will use the 600 mg dose and compare outcomes to a fingolimod arm.
 

Establishing Safety in the Pediatric Population

“In [pediatric onset MS] it’s an important piece of information to design OPERETTA 2 and to dose ocrelizumab in pediatric-onset MS in general,” said Jeffrey A Cohen, MD, professor of neurology at the Cleveland Clinic, who was asked for comment.

During the Q&A period, Dr. Schreiner was asked whether it is possible to extrapolate experience from rituximab to the pediatric population. “They’re very similar molecules, and we know the mechanisms of action, but I think part of the importance of doing these studies is to get the safety data so that we actually can say with certainty, we are giving you a drug that has this list of side effects and we know about them definitively. We all use other high-efficacy medications, but I don’t think we can exactly extrapolate,” said Dr. Schreiner.

Session moderator Amy Perrin Ross, APN, noted the lack of approved pediatric therapies for MS. “This is an extremely important study, because we at least in the lower 48 are quite limited in our resources for approved pediatric cases. Information like this will make it easier for a potential pediatric indication, which would then make it easier on us to go after [treatment of the disease in this population]. The weight-based dosing, I think, is really a good thing. Patients have been asking for weight-based dosing on everything for many years,” she said.

Ahmed Obeidat, MD, PhD, associate professor at the Medical College of Wisconsin, also praised the study. “While pediatric MS is rare, it is an area of unmet need when it comes to disease-modifying therapies as only fingolimod is FDA-approved, and many use B cell–depleting therapy, such as rituximab, off label to treat children with MS with good outcomes. The need for guidance on the dosing of B cell–depleting therapy is a main priority for research in pediatric MS,” he said.

The study was funded by Roche. Dr. Schreiner has consulted for Roche and Cycle Pharmaceuticals. Dr. Cohen has consulted for Astoria, Bristol Myers Squibb, Convelo, EMD Serono Inc, FiND, INMune, and Sandoz. Dr. Obeidat has financial relationships with Alexion Pharmaceuticals, Banner Life Sciences, BD Biosciences, Biogen, Biologix Solutions, Bristol Myers Squibb, Celgene, EMD Serono, Genentech, GW Pharmaceuticals, Horizon Therapeutics, Jazz Pharmaceuticals, Novartis, Sandoz, Sanofi Genzyme, TG Therapeutics, and Viela Bio. Ms. Ross has consulted for EMD Serono, BMS, Horizon, Alexion, TG Therapeutics, Novartis, Roche, and Sanofi.

Novel, noninvasive testing is able to predict dementia onset with 80% accuracy up to 9 years before clinical diagnosis.

The results suggest resting-state functional MRI (rs-fMRI) could be used to identify a neural network signature of dementia risk early in the pathological course of the disease, an important advance as disease-modifying drugs such as those targeting amyloid beta are now becoming available.

“The brain has been changing for a long time before people get symptoms of dementia, and if we’re very precise about how we do it, we can actually, in principle, detect those changes, which could be really exciting,” study investigator Charles R. Marshall, PhD, professor of clinical neurology, Centre for Preventive Neurology, Wolfson Institute of Population Health, Queen Mary University of London, London, England, told this news organization.

“This could become a platform for screening people for risk status in the future, and it could one day make all the difference in terms of being able to prevent dementia,” he added.

The findings were published online in Nature Mental Health.

The rs-fMRI measures fluctuations in blood oxygen level–dependent signals across the brain, which reflect functional connectivity.

Brain regions commonly implicated in altered functional connectivity in Alzheimer’s disease (AD) are within the default-mode network (DMN). This is the group of regions “connecting with each other and communicating with each other when someone is just lying in an MRI scanner doing nothing, which is how it came to be called the default-mode network,” explained Dr. Marshall.

The DMN encompasses the medial prefrontal cortex, posterior cingulate cortex or precuneus, and bilateral inferior parietal cortices, as well as supplementary brain regions including the medial temporal lobes and temporal poles.

This network is believed to be selectively vulnerable to AD neuropathology. “Something about that network starts to be disrupted in the very earliest stages of Alzheimer’s disease,” said Dr. Marshall.

While this has been known for some time, “what we’ve not been able to do before is build a precise enough model of how the network is connected to be able to tell whether individual participants were going to get dementia or not,” he added.

The investigators used data from the UK Biobank, a large-scale biomedical database and research resource containing genetic and health information from about a half a million UK volunteer participants.

The analysis included 103 individuals with dementia (22 with prevalent dementia and 81 later diagnosed with dementia over a median of 3.7 years) and 1030 matched participants without dementia. All participants had MRI imaging between 2006 and 2010.

The total sample had a mean age of 70.4 years at the time of MRI data acquisition. For each participant, researchers extracted relevant data from 10 predefined regions of interest in the brain, which together defined their DMN. This included two midline regions and four regions in each hemisphere.
 

Greater Predictive Power

Researchers built a model using an approach related to how brain regions communicate with each other. “The model sort of incorporates what we know about how the changes that you see on a functional MRI scan relate to changes in the firing of brain cells, in a very precise way,” said Dr. Marshall.

The researchers then used a machine learning approach to develop a model for effective connectivity, which describes the causal influence of one brain region over another. “We trained a machine learning tool to recognize what a dementia-like pattern of connectivity looks like,” said Dr. Marshall.

Investigators controlled for potential confounders, including age, sex, handedness, in-scanner head motion, and geographical location of data acquisition.

The model was able to determine the difference in brain connectivity patterns between those who would go on to develop dementia and those who would not, with an accuracy of 82% up to 9 years before an official diagnosis was made.

When the researchers trained a model to use brain connections to predict time to diagnosis, the predicted time to diagnosis and actual time to diagnosis were within about 2 years.

This effective connectivity approach has much more predictive power than memory test scores or brain structural measures, said Dr. Marshall. “We looked at brain volumes and they performed very poorly, only just better than tossing a coin, and the same with cognitive test scores, which were only just better than chance.”

As for markers of amyloid beta and tau in the brain, these are “very useful diagnostically” but only when someone has symptoms, said Dr. Marshall. He noted people live for years with these proteins without developing dementia symptoms.

“We wouldn’t necessarily want to expose somebody who has a brain full of amyloid but was not going to get symptoms for the next 20 years to a treatment, but if we knew that person was highly likely to develop symptoms of dementia in the next 5 years, then we probably would,” he said.

Dr. Marshall believes the predictive power of all these diagnostic tools could be boosted if they were used together.
 

Potential for Early Detection, Treatment

Researchers examined a number of modifiable dementia risk factors, including hearing loss, depression, hypertension, and physical inactivity. They found self-reported social isolation was the only variable that showed a significant association with effective connectivity, meaning those who are socially isolated were more likely to have a “dementia-like” pattern of DMN effective connectivity. This finding suggests social isolation is a cause, rather than a consequence, of dementia.

The study also revealed associations between DMN effective connectivity and AD polygenic risk score, derived from meta-analysis of multiple external genome-wide association study sources.

A predictive tool that uses rs-fMRI could also help select participants at a high risk for dementia to investigate potential treatments. “There’s good reason to think that if we could go in earlier with, for example, anti-amyloid treatments, they’re more likely to be effective,” said Dr. Marshall.

The new test might eventually have value as a population screening tool, something akin to colon cancer screening, he added. “We don’t send everyone for a colonoscopy; you do a kind of pre-screening test at home, and if that’s positive, then you get called in for a colonoscopy.”

The researchers looked at all-cause dementia and not just AD because dementia subtype diagnoses in the UK Biobank “are not at all reliable,” said Dr. Marshall.

Study limitations included the fact that UK Biobank participants are healthier and less socioeconomically deprived than the general population and are predominantly White. Another study limitation was that labeling of cases and controls depended on clinician coding rather than on standardized diagnostic criteria.
 

Kudos, Caveats

In a release from the Science Media Center, a nonprofit organization promoting voices and views of the scientific community, Sebastian Walsh, National Institute for Health and Care Research doctoral fellow in Public Health Medicine, University of Cambridge, Cambridge, England, said the results are “potentially exciting,” and he praised the way the team conducted the study.

However, he noted some caveats, including the small sample size, with only about 100 people with dementia, and the relatively short time between the brain scan and diagnosis (an average of 3.7 years).

Dr. Walsh emphasized the importance of replicating the findings “in bigger samples with a much longer delay between scan and onset of cognitive symptoms.”

He also noted the average age of study participants was 70 years, whereas the average age at which individuals in the United Kingdom develop dementia is mid to late 80s, “so we need to see these results repeated for more diverse and older samples.”

He also noted that MRI scans are expensive, and the approach used in the study needs “a high-quality scan which requires people to keep their head still.”

Also commenting, Andrew Doig, PhD, professor, Division of Neuroscience, the University of Manchester, Manchester, England, said the MRI connectivity method used in the study might form part of a broader diagnostic approach.

“Dementia is a complex condition, and it is unlikely that we will ever find one simple test that can accurately diagnose it,” Dr. Doig noted. “Within a few years, however, there is good reason to believe that we will be routinely testing for dementia in middle-aged people, using a combination of methods, such as a blood test, followed by imaging.”

“The MRI connectivity method described here could form part of this diagnostic platform. We will then have an excellent understanding of which people are likely to benefit most from the new generation of dementia drugs,” he said.

Dr. Marshall and Dr. Walsh reported no relevant disclosures. Dr. Doig reported that he is a founder, shareholder, and consultant for PharmaKure Ltd, which is developing new diagnostics for neurodegenerative diseases using blood biomarkers.

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

Novel, noninvasive testing is able to predict dementia onset with 80% accuracy up to 9 years before clinical diagnosis.

The results suggest resting-state functional MRI (rs-fMRI) could be used to identify a neural network signature of dementia risk early in the pathological course of the disease, an important advance as disease-modifying drugs such as those targeting amyloid beta are now becoming available.

“The brain has been changing for a long time before people get symptoms of dementia, and if we’re very precise about how we do it, we can actually, in principle, detect those changes, which could be really exciting,” study investigator Charles R. Marshall, PhD, professor of clinical neurology, Centre for Preventive Neurology, Wolfson Institute of Population Health, Queen Mary University of London, London, England, told this news organization.

“This could become a platform for screening people for risk status in the future, and it could one day make all the difference in terms of being able to prevent dementia,” he added.

The findings were published online in Nature Mental Health.

The rs-fMRI measures fluctuations in blood oxygen level–dependent signals across the brain, which reflect functional connectivity.

Brain regions commonly implicated in altered functional connectivity in Alzheimer’s disease (AD) are within the default-mode network (DMN). This is the group of regions “connecting with each other and communicating with each other when someone is just lying in an MRI scanner doing nothing, which is how it came to be called the default-mode network,” explained Dr. Marshall.

The DMN encompasses the medial prefrontal cortex, posterior cingulate cortex or precuneus, and bilateral inferior parietal cortices, as well as supplementary brain regions including the medial temporal lobes and temporal poles.

This network is believed to be selectively vulnerable to AD neuropathology. “Something about that network starts to be disrupted in the very earliest stages of Alzheimer’s disease,” said Dr. Marshall.

While this has been known for some time, “what we’ve not been able to do before is build a precise enough model of how the network is connected to be able to tell whether individual participants were going to get dementia or not,” he added.

The investigators used data from the UK Biobank, a large-scale biomedical database and research resource containing genetic and health information from about a half a million UK volunteer participants.

The analysis included 103 individuals with dementia (22 with prevalent dementia and 81 later diagnosed with dementia over a median of 3.7 years) and 1030 matched participants without dementia. All participants had MRI imaging between 2006 and 2010.

The total sample had a mean age of 70.4 years at the time of MRI data acquisition. For each participant, researchers extracted relevant data from 10 predefined regions of interest in the brain, which together defined their DMN. This included two midline regions and four regions in each hemisphere.
 

Greater Predictive Power

Researchers built a model using an approach related to how brain regions communicate with each other. “The model sort of incorporates what we know about how the changes that you see on a functional MRI scan relate to changes in the firing of brain cells, in a very precise way,” said Dr. Marshall.

The researchers then used a machine learning approach to develop a model for effective connectivity, which describes the causal influence of one brain region over another. “We trained a machine learning tool to recognize what a dementia-like pattern of connectivity looks like,” said Dr. Marshall.

Investigators controlled for potential confounders, including age, sex, handedness, in-scanner head motion, and geographical location of data acquisition.

The model was able to determine the difference in brain connectivity patterns between those who would go on to develop dementia and those who would not, with an accuracy of 82% up to 9 years before an official diagnosis was made.

When the researchers trained a model to use brain connections to predict time to diagnosis, the predicted time to diagnosis and actual time to diagnosis were within about 2 years.

This effective connectivity approach has much more predictive power than memory test scores or brain structural measures, said Dr. Marshall. “We looked at brain volumes and they performed very poorly, only just better than tossing a coin, and the same with cognitive test scores, which were only just better than chance.”

As for markers of amyloid beta and tau in the brain, these are “very useful diagnostically” but only when someone has symptoms, said Dr. Marshall. He noted people live for years with these proteins without developing dementia symptoms.

“We wouldn’t necessarily want to expose somebody who has a brain full of amyloid but was not going to get symptoms for the next 20 years to a treatment, but if we knew that person was highly likely to develop symptoms of dementia in the next 5 years, then we probably would,” he said.

Dr. Marshall believes the predictive power of all these diagnostic tools could be boosted if they were used together.
 

Potential for Early Detection, Treatment

Researchers examined a number of modifiable dementia risk factors, including hearing loss, depression, hypertension, and physical inactivity. They found self-reported social isolation was the only variable that showed a significant association with effective connectivity, meaning those who are socially isolated were more likely to have a “dementia-like” pattern of DMN effective connectivity. This finding suggests social isolation is a cause, rather than a consequence, of dementia.

The study also revealed associations between DMN effective connectivity and AD polygenic risk score, derived from meta-analysis of multiple external genome-wide association study sources.

A predictive tool that uses rs-fMRI could also help select participants at a high risk for dementia to investigate potential treatments. “There’s good reason to think that if we could go in earlier with, for example, anti-amyloid treatments, they’re more likely to be effective,” said Dr. Marshall.

The new test might eventually have value as a population screening tool, something akin to colon cancer screening, he added. “We don’t send everyone for a colonoscopy; you do a kind of pre-screening test at home, and if that’s positive, then you get called in for a colonoscopy.”

The researchers looked at all-cause dementia and not just AD because dementia subtype diagnoses in the UK Biobank “are not at all reliable,” said Dr. Marshall.

Study limitations included the fact that UK Biobank participants are healthier and less socioeconomically deprived than the general population and are predominantly White. Another study limitation was that labeling of cases and controls depended on clinician coding rather than on standardized diagnostic criteria.
 

Kudos, Caveats

In a release from the Science Media Center, a nonprofit organization promoting voices and views of the scientific community, Sebastian Walsh, National Institute for Health and Care Research doctoral fellow in Public Health Medicine, University of Cambridge, Cambridge, England, said the results are “potentially exciting,” and he praised the way the team conducted the study.

However, he noted some caveats, including the small sample size, with only about 100 people with dementia, and the relatively short time between the brain scan and diagnosis (an average of 3.7 years).

Dr. Walsh emphasized the importance of replicating the findings “in bigger samples with a much longer delay between scan and onset of cognitive symptoms.”

He also noted the average age of study participants was 70 years, whereas the average age at which individuals in the United Kingdom develop dementia is mid to late 80s, “so we need to see these results repeated for more diverse and older samples.”

He also noted that MRI scans are expensive, and the approach used in the study needs “a high-quality scan which requires people to keep their head still.”

Also commenting, Andrew Doig, PhD, professor, Division of Neuroscience, the University of Manchester, Manchester, England, said the MRI connectivity method used in the study might form part of a broader diagnostic approach.

“Dementia is a complex condition, and it is unlikely that we will ever find one simple test that can accurately diagnose it,” Dr. Doig noted. “Within a few years, however, there is good reason to believe that we will be routinely testing for dementia in middle-aged people, using a combination of methods, such as a blood test, followed by imaging.”

“The MRI connectivity method described here could form part of this diagnostic platform. We will then have an excellent understanding of which people are likely to benefit most from the new generation of dementia drugs,” he said.

Dr. Marshall and Dr. Walsh reported no relevant disclosures. Dr. Doig reported that he is a founder, shareholder, and consultant for PharmaKure Ltd, which is developing new diagnostics for neurodegenerative diseases using blood biomarkers.

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

Novel, noninvasive testing is able to predict dementia onset with 80% accuracy up to 9 years before clinical diagnosis.

The results suggest resting-state functional MRI (rs-fMRI) could be used to identify a neural network signature of dementia risk early in the pathological course of the disease, an important advance as disease-modifying drugs such as those targeting amyloid beta are now becoming available.

“The brain has been changing for a long time before people get symptoms of dementia, and if we’re very precise about how we do it, we can actually, in principle, detect those changes, which could be really exciting,” study investigator Charles R. Marshall, PhD, professor of clinical neurology, Centre for Preventive Neurology, Wolfson Institute of Population Health, Queen Mary University of London, London, England, told this news organization.

“This could become a platform for screening people for risk status in the future, and it could one day make all the difference in terms of being able to prevent dementia,” he added.

The findings were published online in Nature Mental Health.

The rs-fMRI measures fluctuations in blood oxygen level–dependent signals across the brain, which reflect functional connectivity.

Brain regions commonly implicated in altered functional connectivity in Alzheimer’s disease (AD) are within the default-mode network (DMN). This is the group of regions “connecting with each other and communicating with each other when someone is just lying in an MRI scanner doing nothing, which is how it came to be called the default-mode network,” explained Dr. Marshall.

The DMN encompasses the medial prefrontal cortex, posterior cingulate cortex or precuneus, and bilateral inferior parietal cortices, as well as supplementary brain regions including the medial temporal lobes and temporal poles.

This network is believed to be selectively vulnerable to AD neuropathology. “Something about that network starts to be disrupted in the very earliest stages of Alzheimer’s disease,” said Dr. Marshall.

While this has been known for some time, “what we’ve not been able to do before is build a precise enough model of how the network is connected to be able to tell whether individual participants were going to get dementia or not,” he added.

The investigators used data from the UK Biobank, a large-scale biomedical database and research resource containing genetic and health information from about a half a million UK volunteer participants.

The analysis included 103 individuals with dementia (22 with prevalent dementia and 81 later diagnosed with dementia over a median of 3.7 years) and 1030 matched participants without dementia. All participants had MRI imaging between 2006 and 2010.

The total sample had a mean age of 70.4 years at the time of MRI data acquisition. For each participant, researchers extracted relevant data from 10 predefined regions of interest in the brain, which together defined their DMN. This included two midline regions and four regions in each hemisphere.
 

Greater Predictive Power

Researchers built a model using an approach related to how brain regions communicate with each other. “The model sort of incorporates what we know about how the changes that you see on a functional MRI scan relate to changes in the firing of brain cells, in a very precise way,” said Dr. Marshall.

The researchers then used a machine learning approach to develop a model for effective connectivity, which describes the causal influence of one brain region over another. “We trained a machine learning tool to recognize what a dementia-like pattern of connectivity looks like,” said Dr. Marshall.

Investigators controlled for potential confounders, including age, sex, handedness, in-scanner head motion, and geographical location of data acquisition.

The model was able to determine the difference in brain connectivity patterns between those who would go on to develop dementia and those who would not, with an accuracy of 82% up to 9 years before an official diagnosis was made.

When the researchers trained a model to use brain connections to predict time to diagnosis, the predicted time to diagnosis and actual time to diagnosis were within about 2 years.

This effective connectivity approach has much more predictive power than memory test scores or brain structural measures, said Dr. Marshall. “We looked at brain volumes and they performed very poorly, only just better than tossing a coin, and the same with cognitive test scores, which were only just better than chance.”

As for markers of amyloid beta and tau in the brain, these are “very useful diagnostically” but only when someone has symptoms, said Dr. Marshall. He noted people live for years with these proteins without developing dementia symptoms.

“We wouldn’t necessarily want to expose somebody who has a brain full of amyloid but was not going to get symptoms for the next 20 years to a treatment, but if we knew that person was highly likely to develop symptoms of dementia in the next 5 years, then we probably would,” he said.

Dr. Marshall believes the predictive power of all these diagnostic tools could be boosted if they were used together.
 

Potential for Early Detection, Treatment

Researchers examined a number of modifiable dementia risk factors, including hearing loss, depression, hypertension, and physical inactivity. They found self-reported social isolation was the only variable that showed a significant association with effective connectivity, meaning those who are socially isolated were more likely to have a “dementia-like” pattern of DMN effective connectivity. This finding suggests social isolation is a cause, rather than a consequence, of dementia.

The study also revealed associations between DMN effective connectivity and AD polygenic risk score, derived from meta-analysis of multiple external genome-wide association study sources.

A predictive tool that uses rs-fMRI could also help select participants at a high risk for dementia to investigate potential treatments. “There’s good reason to think that if we could go in earlier with, for example, anti-amyloid treatments, they’re more likely to be effective,” said Dr. Marshall.

The new test might eventually have value as a population screening tool, something akin to colon cancer screening, he added. “We don’t send everyone for a colonoscopy; you do a kind of pre-screening test at home, and if that’s positive, then you get called in for a colonoscopy.”

The researchers looked at all-cause dementia and not just AD because dementia subtype diagnoses in the UK Biobank “are not at all reliable,” said Dr. Marshall.

Study limitations included the fact that UK Biobank participants are healthier and less socioeconomically deprived than the general population and are predominantly White. Another study limitation was that labeling of cases and controls depended on clinician coding rather than on standardized diagnostic criteria.
 

Kudos, Caveats

In a release from the Science Media Center, a nonprofit organization promoting voices and views of the scientific community, Sebastian Walsh, National Institute for Health and Care Research doctoral fellow in Public Health Medicine, University of Cambridge, Cambridge, England, said the results are “potentially exciting,” and he praised the way the team conducted the study.

However, he noted some caveats, including the small sample size, with only about 100 people with dementia, and the relatively short time between the brain scan and diagnosis (an average of 3.7 years).

Dr. Walsh emphasized the importance of replicating the findings “in bigger samples with a much longer delay between scan and onset of cognitive symptoms.”

He also noted the average age of study participants was 70 years, whereas the average age at which individuals in the United Kingdom develop dementia is mid to late 80s, “so we need to see these results repeated for more diverse and older samples.”

He also noted that MRI scans are expensive, and the approach used in the study needs “a high-quality scan which requires people to keep their head still.”

Also commenting, Andrew Doig, PhD, professor, Division of Neuroscience, the University of Manchester, Manchester, England, said the MRI connectivity method used in the study might form part of a broader diagnostic approach.

“Dementia is a complex condition, and it is unlikely that we will ever find one simple test that can accurately diagnose it,” Dr. Doig noted. “Within a few years, however, there is good reason to believe that we will be routinely testing for dementia in middle-aged people, using a combination of methods, such as a blood test, followed by imaging.”

“The MRI connectivity method described here could form part of this diagnostic platform. We will then have an excellent understanding of which people are likely to benefit most from the new generation of dementia drugs,” he said.

Dr. Marshall and Dr. Walsh reported no relevant disclosures. Dr. Doig reported that he is a founder, shareholder, and consultant for PharmaKure Ltd, which is developing new diagnostics for neurodegenerative diseases using blood biomarkers.

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