MDedge Neurology

DENVER – Taking ozanimod for relapsing multiple sclerosis (MS) at the same time as taking antidepressants that increase serotonin levels does not appear to increase the risk for hypertension or any other adverse events related to serotonin toxicity, according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“Depression and anxiety are prevalent comorbidities occurring in up to 54% of patients with multiple sclerosis, and selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line treatments for depression and anxiety disorders,” Robert T. Naismith, MD, of Washington University in St. Louis, and his colleagues reported.

“Coadministration of ozanimod with drugs that increase serotonin could hypothetically lead to serotonin accumulation,” which can increase the likelihood of hypertension. U.S. prescribing information recommends that patients taking both ozanimod and medications that increase norepinephrine or serotonin be monitored for hypertension, an adverse reaction reported in 3.9% of patients receiving ozanimod in the phase 3 trials for relapsing MS.
 

Clarifying the risk

“It’s important to be aware of potential drug interactions and risks from MS disease modifying therapies,” Lauren Gluck, MD, an assistant professor and director of the division of multiple sclerosis at Montefiore Medical Center/Albert Einstein College of Medicine, New York, said in an interview. Dr. Gluck was not involved in this study but described some of the history that revealed the value of this type of research. For example, the first sphingosine-1-phosphate receptor (S1PR) modulator approved for MS, fingolimod (Gilenya), has a risk of cardiac conduction dysfunction with QTc prolongation, so people taking fingolimod with other medications that prolong QTc, such as SSRIs, need additional monitoring.

“Ozanimod is a newer, more selective S1PR modulator that initially raised concerns about interaction with serotonin-increasing drugs based on in vitro studies,” Dr. Gluck said. “This could mean that people on ozanimod and other serotonin-increasing medicine could be at risk for dangerous events like serotonin syndrome. However, in vitro studies do not always translate to how something affects the human body, so it is not clear how much risk truly exists.”
 

Examining open-label extension trial data

The researchers therefore evaluated the safety of taking ozanimod and SSRIs or SNRIs in a subset of patients with relapsing MS who participated in the DAYBREAK open-label extension trial. The phase 3 parent trials compared 30 mcg once weekly of intramuscular interferon beta-1a with 0.92 mg of once-daily oral ozanimod and 0.46 mg of once-daily oral ozanimod. In the DAYBREAK open-label extension, 2,256 participants underwent a dose escalation over one week until all reached 0.92 mg of ozanimod, where they remained for an average of just under 5 years of follow-up. Nearly all the participants (99.4%) were White, and two-thirds (66.5%) were female.

The researchers searched the study data for terms related to serotonin toxicity and compared the rates of adverse events related with those terms and the rates of hypertension in the 274 participants who were and the 2,032 participant who were not taking antidepressants at the same time as ozanimod.

They found that 13.9% of patients taking SSRIs or SNRIs experienced at least one treatment-emergent adverse event related to their search criteria, compared with 17.7% of patients not taking SSRIs or SNRIs. Similarly, 9.2% of trial participants not taking SSRIs or SNRIs had hypertension, compared with 4.7% of participants who were taking antidepressants. The authors further noted that “similar trends were observed when 6 weeks after the end date of concomitant SSRIs/SNRI use were included in the ‘on SSRI/SNRI’ analysis period.”

When the researchers searched specifically for three terms directly related to serotonin toxicity – “serotonin syndrome,” “neuroleptic malignant syndrome,” and “hyperthermia malignant” – they did not find any patients who had treatment-emergent adverse events related to those terms.

“SSRIs/SNRIs were freely allowed as concomitant medications in the DAYBREAK open-label extension, and among the patients from SUNBEAM or RADIANCE who were followed for up to 6 years, there have been no reported safety concerns during the concurrent administration of serotonergic antidepressants and ozanimod in patients with relapsing MS as of the data cutoff,” concluded the authors, though they also noted that the overall rate of SSRI and SNRI use was low in the extension trial.
 

A reassuring finding for clinicians and patients alike

“It is reassuring, if not unexpected, that there were no clinically significant rates of symptoms associated with excess serotonin in patients on ozanimod and SSRI/SNRIs,” Dr. Gluck commented. “These findings are important for both clinicians and patients – they can help [both] feel comfortable considering ozanimod if SSRI/SNRIs are already being used. There is also freedom to use SSRI/SNRIs for symptom management in patients already on ozanimod.”

The research was funded by Bristol Myers Squibb. Dr. Naismith reported consulting for Abata Therapeutics, Banner Life Sciences, BeiGene, Biogen, Bristol Myers Squibb, Celltrion, Genentech, Genzyme, GW Therapeutics, Janssen, Horizon Therapeutics, Lundbeck, NervGen, and TG Therapeutics. Six other authors reported disclosures for various pharmaceutical companies, and six other authors are employees and/or shareholders of Bristol Myers Squibb. Dr. Gluck has served on advisory boards with Genentech and EMD Serono.
 

DENVER – Taking ozanimod for relapsing multiple sclerosis (MS) at the same time as taking antidepressants that increase serotonin levels does not appear to increase the risk for hypertension or any other adverse events related to serotonin toxicity, according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“Depression and anxiety are prevalent comorbidities occurring in up to 54% of patients with multiple sclerosis, and selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line treatments for depression and anxiety disorders,” Robert T. Naismith, MD, of Washington University in St. Louis, and his colleagues reported.

“Coadministration of ozanimod with drugs that increase serotonin could hypothetically lead to serotonin accumulation,” which can increase the likelihood of hypertension. U.S. prescribing information recommends that patients taking both ozanimod and medications that increase norepinephrine or serotonin be monitored for hypertension, an adverse reaction reported in 3.9% of patients receiving ozanimod in the phase 3 trials for relapsing MS.
 

Clarifying the risk

“It’s important to be aware of potential drug interactions and risks from MS disease modifying therapies,” Lauren Gluck, MD, an assistant professor and director of the division of multiple sclerosis at Montefiore Medical Center/Albert Einstein College of Medicine, New York, said in an interview. Dr. Gluck was not involved in this study but described some of the history that revealed the value of this type of research. For example, the first sphingosine-1-phosphate receptor (S1PR) modulator approved for MS, fingolimod (Gilenya), has a risk of cardiac conduction dysfunction with QTc prolongation, so people taking fingolimod with other medications that prolong QTc, such as SSRIs, need additional monitoring.

“Ozanimod is a newer, more selective S1PR modulator that initially raised concerns about interaction with serotonin-increasing drugs based on in vitro studies,” Dr. Gluck said. “This could mean that people on ozanimod and other serotonin-increasing medicine could be at risk for dangerous events like serotonin syndrome. However, in vitro studies do not always translate to how something affects the human body, so it is not clear how much risk truly exists.”
 

Examining open-label extension trial data

The researchers therefore evaluated the safety of taking ozanimod and SSRIs or SNRIs in a subset of patients with relapsing MS who participated in the DAYBREAK open-label extension trial. The phase 3 parent trials compared 30 mcg once weekly of intramuscular interferon beta-1a with 0.92 mg of once-daily oral ozanimod and 0.46 mg of once-daily oral ozanimod. In the DAYBREAK open-label extension, 2,256 participants underwent a dose escalation over one week until all reached 0.92 mg of ozanimod, where they remained for an average of just under 5 years of follow-up. Nearly all the participants (99.4%) were White, and two-thirds (66.5%) were female.

The researchers searched the study data for terms related to serotonin toxicity and compared the rates of adverse events related with those terms and the rates of hypertension in the 274 participants who were and the 2,032 participant who were not taking antidepressants at the same time as ozanimod.

They found that 13.9% of patients taking SSRIs or SNRIs experienced at least one treatment-emergent adverse event related to their search criteria, compared with 17.7% of patients not taking SSRIs or SNRIs. Similarly, 9.2% of trial participants not taking SSRIs or SNRIs had hypertension, compared with 4.7% of participants who were taking antidepressants. The authors further noted that “similar trends were observed when 6 weeks after the end date of concomitant SSRIs/SNRI use were included in the ‘on SSRI/SNRI’ analysis period.”

When the researchers searched specifically for three terms directly related to serotonin toxicity – “serotonin syndrome,” “neuroleptic malignant syndrome,” and “hyperthermia malignant” – they did not find any patients who had treatment-emergent adverse events related to those terms.

“SSRIs/SNRIs were freely allowed as concomitant medications in the DAYBREAK open-label extension, and among the patients from SUNBEAM or RADIANCE who were followed for up to 6 years, there have been no reported safety concerns during the concurrent administration of serotonergic antidepressants and ozanimod in patients with relapsing MS as of the data cutoff,” concluded the authors, though they also noted that the overall rate of SSRI and SNRI use was low in the extension trial.
 

A reassuring finding for clinicians and patients alike

“It is reassuring, if not unexpected, that there were no clinically significant rates of symptoms associated with excess serotonin in patients on ozanimod and SSRI/SNRIs,” Dr. Gluck commented. “These findings are important for both clinicians and patients – they can help [both] feel comfortable considering ozanimod if SSRI/SNRIs are already being used. There is also freedom to use SSRI/SNRIs for symptom management in patients already on ozanimod.”

The research was funded by Bristol Myers Squibb. Dr. Naismith reported consulting for Abata Therapeutics, Banner Life Sciences, BeiGene, Biogen, Bristol Myers Squibb, Celltrion, Genentech, Genzyme, GW Therapeutics, Janssen, Horizon Therapeutics, Lundbeck, NervGen, and TG Therapeutics. Six other authors reported disclosures for various pharmaceutical companies, and six other authors are employees and/or shareholders of Bristol Myers Squibb. Dr. Gluck has served on advisory boards with Genentech and EMD Serono.
 

DENVER – Taking ozanimod for relapsing multiple sclerosis (MS) at the same time as taking antidepressants that increase serotonin levels does not appear to increase the risk for hypertension or any other adverse events related to serotonin toxicity, according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“Depression and anxiety are prevalent comorbidities occurring in up to 54% of patients with multiple sclerosis, and selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line treatments for depression and anxiety disorders,” Robert T. Naismith, MD, of Washington University in St. Louis, and his colleagues reported.

“Coadministration of ozanimod with drugs that increase serotonin could hypothetically lead to serotonin accumulation,” which can increase the likelihood of hypertension. U.S. prescribing information recommends that patients taking both ozanimod and medications that increase norepinephrine or serotonin be monitored for hypertension, an adverse reaction reported in 3.9% of patients receiving ozanimod in the phase 3 trials for relapsing MS.
 

Clarifying the risk

“It’s important to be aware of potential drug interactions and risks from MS disease modifying therapies,” Lauren Gluck, MD, an assistant professor and director of the division of multiple sclerosis at Montefiore Medical Center/Albert Einstein College of Medicine, New York, said in an interview. Dr. Gluck was not involved in this study but described some of the history that revealed the value of this type of research. For example, the first sphingosine-1-phosphate receptor (S1PR) modulator approved for MS, fingolimod (Gilenya), has a risk of cardiac conduction dysfunction with QTc prolongation, so people taking fingolimod with other medications that prolong QTc, such as SSRIs, need additional monitoring.

“Ozanimod is a newer, more selective S1PR modulator that initially raised concerns about interaction with serotonin-increasing drugs based on in vitro studies,” Dr. Gluck said. “This could mean that people on ozanimod and other serotonin-increasing medicine could be at risk for dangerous events like serotonin syndrome. However, in vitro studies do not always translate to how something affects the human body, so it is not clear how much risk truly exists.”
 

Examining open-label extension trial data

The researchers therefore evaluated the safety of taking ozanimod and SSRIs or SNRIs in a subset of patients with relapsing MS who participated in the DAYBREAK open-label extension trial. The phase 3 parent trials compared 30 mcg once weekly of intramuscular interferon beta-1a with 0.92 mg of once-daily oral ozanimod and 0.46 mg of once-daily oral ozanimod. In the DAYBREAK open-label extension, 2,256 participants underwent a dose escalation over one week until all reached 0.92 mg of ozanimod, where they remained for an average of just under 5 years of follow-up. Nearly all the participants (99.4%) were White, and two-thirds (66.5%) were female.

The researchers searched the study data for terms related to serotonin toxicity and compared the rates of adverse events related with those terms and the rates of hypertension in the 274 participants who were and the 2,032 participant who were not taking antidepressants at the same time as ozanimod.

They found that 13.9% of patients taking SSRIs or SNRIs experienced at least one treatment-emergent adverse event related to their search criteria, compared with 17.7% of patients not taking SSRIs or SNRIs. Similarly, 9.2% of trial participants not taking SSRIs or SNRIs had hypertension, compared with 4.7% of participants who were taking antidepressants. The authors further noted that “similar trends were observed when 6 weeks after the end date of concomitant SSRIs/SNRI use were included in the ‘on SSRI/SNRI’ analysis period.”

When the researchers searched specifically for three terms directly related to serotonin toxicity – “serotonin syndrome,” “neuroleptic malignant syndrome,” and “hyperthermia malignant” – they did not find any patients who had treatment-emergent adverse events related to those terms.

“SSRIs/SNRIs were freely allowed as concomitant medications in the DAYBREAK open-label extension, and among the patients from SUNBEAM or RADIANCE who were followed for up to 6 years, there have been no reported safety concerns during the concurrent administration of serotonergic antidepressants and ozanimod in patients with relapsing MS as of the data cutoff,” concluded the authors, though they also noted that the overall rate of SSRI and SNRI use was low in the extension trial.
 

A reassuring finding for clinicians and patients alike

“It is reassuring, if not unexpected, that there were no clinically significant rates of symptoms associated with excess serotonin in patients on ozanimod and SSRI/SNRIs,” Dr. Gluck commented. “These findings are important for both clinicians and patients – they can help [both] feel comfortable considering ozanimod if SSRI/SNRIs are already being used. There is also freedom to use SSRI/SNRIs for symptom management in patients already on ozanimod.”

The research was funded by Bristol Myers Squibb. Dr. Naismith reported consulting for Abata Therapeutics, Banner Life Sciences, BeiGene, Biogen, Bristol Myers Squibb, Celltrion, Genentech, Genzyme, GW Therapeutics, Janssen, Horizon Therapeutics, Lundbeck, NervGen, and TG Therapeutics. Six other authors reported disclosures for various pharmaceutical companies, and six other authors are employees and/or shareholders of Bristol Myers Squibb. Dr. Gluck has served on advisory boards with Genentech and EMD Serono.
 

This little fellow greets you at my office. He’s been there for 25 years.

Dr. Block

I don’t know where he came from originally. When I started out he was up front with the physician I subleased from and when he retired he passed him on to me (thanks, Fran!).

From the beginning he’s been the first thing I see when I arrive each morning. Because of my suprachiasmatic nucleus kicking me out of bed between 4 and 5 each morning, I’m always the first one in the office and so I update him. At this point he’s as much a part of my morning ritual as coffee and tea. I juggle the cubes to change the day (12 times a year I change the month) and once this is done I don’t think of him again until the next morning.

Over time this whimsical character and the calendar blocks he holds have taken on a bigger significance, quietly counting out the days of my career and life. When I started setting him each morning I didn’t have kids. Now I have three, all grown. Patients, years, drug reps, and even a pandemic have all been marked by the clicking of his cubes when I change them each morning.

Now two-thirds of the way through my career, he’s taken on a different meaning. He’s counting down the days until I walk away and leave neurology in the hands of another generation. I don’t have a date for doing that, nor a plan to do so anytime soon, but sooner or later I’ll be changing his cubes for the last office day of my life as a neurologist.

What will happen to him then? Seems like a strange question to ask about an inanimate object, but after this much time I’ve gotten attached to the little guy. He’s come to symbolize more than just the date – he’s the passage of time. Maybe he’ll stay on a shelf at home, giving me something to do each morning of my retirement. Maybe one of my kids will want him.

Inevitably, he’ll probably end up at a charity store, awaiting a new owner. When that happens I hope he gives them something to pause, smile, and think about each day, like he did with me, as we travel around the sun together.

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

This little fellow greets you at my office. He’s been there for 25 years.

Dr. Block

I don’t know where he came from originally. When I started out he was up front with the physician I subleased from and when he retired he passed him on to me (thanks, Fran!).

From the beginning he’s been the first thing I see when I arrive each morning. Because of my suprachiasmatic nucleus kicking me out of bed between 4 and 5 each morning, I’m always the first one in the office and so I update him. At this point he’s as much a part of my morning ritual as coffee and tea. I juggle the cubes to change the day (12 times a year I change the month) and once this is done I don’t think of him again until the next morning.

Over time this whimsical character and the calendar blocks he holds have taken on a bigger significance, quietly counting out the days of my career and life. When I started setting him each morning I didn’t have kids. Now I have three, all grown. Patients, years, drug reps, and even a pandemic have all been marked by the clicking of his cubes when I change them each morning.

Now two-thirds of the way through my career, he’s taken on a different meaning. He’s counting down the days until I walk away and leave neurology in the hands of another generation. I don’t have a date for doing that, nor a plan to do so anytime soon, but sooner or later I’ll be changing his cubes for the last office day of my life as a neurologist.

What will happen to him then? Seems like a strange question to ask about an inanimate object, but after this much time I’ve gotten attached to the little guy. He’s come to symbolize more than just the date – he’s the passage of time. Maybe he’ll stay on a shelf at home, giving me something to do each morning of my retirement. Maybe one of my kids will want him.

Inevitably, he’ll probably end up at a charity store, awaiting a new owner. When that happens I hope he gives them something to pause, smile, and think about each day, like he did with me, as we travel around the sun together.

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

This little fellow greets you at my office. He’s been there for 25 years.

Dr. Block

I don’t know where he came from originally. When I started out he was up front with the physician I subleased from and when he retired he passed him on to me (thanks, Fran!).

From the beginning he’s been the first thing I see when I arrive each morning. Because of my suprachiasmatic nucleus kicking me out of bed between 4 and 5 each morning, I’m always the first one in the office and so I update him. At this point he’s as much a part of my morning ritual as coffee and tea. I juggle the cubes to change the day (12 times a year I change the month) and once this is done I don’t think of him again until the next morning.

Over time this whimsical character and the calendar blocks he holds have taken on a bigger significance, quietly counting out the days of my career and life. When I started setting him each morning I didn’t have kids. Now I have three, all grown. Patients, years, drug reps, and even a pandemic have all been marked by the clicking of his cubes when I change them each morning.

Now two-thirds of the way through my career, he’s taken on a different meaning. He’s counting down the days until I walk away and leave neurology in the hands of another generation. I don’t have a date for doing that, nor a plan to do so anytime soon, but sooner or later I’ll be changing his cubes for the last office day of my life as a neurologist.

What will happen to him then? Seems like a strange question to ask about an inanimate object, but after this much time I’ve gotten attached to the little guy. He’s come to symbolize more than just the date – he’s the passage of time. Maybe he’ll stay on a shelf at home, giving me something to do each morning of my retirement. Maybe one of my kids will want him.

Inevitably, he’ll probably end up at a charity store, awaiting a new owner. When that happens I hope he gives them something to pause, smile, and think about each day, like he did with me, as we travel around the sun together.

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

MUNICH, GERMANY – Giving intensive statin therapy to patients with acute mild ischemic stroke or with high-risk for transient ischemic attack (TIA) immediately after onset significantly reduces the risk for a poor functional outcome compared with delaying treatment, without compromising safety, results of the INSPIRES trial show.

The research, presented at the annual European Stroke Organisation Conference, also showed that intensive antiplatelet therapy reduced the risk for recurrent stroke albeit at an increased in bleeding risk versus standard treatment.

The study involved more than 6,000 patients with acute mild ischemic stroke or TIA and intracranial or extracranial atherosclerosis (ICAS/ECAS), who were randomly assigned in a 2 x 2 factorial design to compare intensive versus standard antiplatelet therapy and intensive statin therapy within 24 hours versus waiting up to 72 hours after onset.

Intensive antiplatelet therapy with clopidogrel plus aspirin reduced the risk for recurrent stroke within 90 days by 21% versus standard single-agent therapy, although it also doubled the risk for moderate to severe bleeding.

Starting intensive statin therapy with atorvastatin within 24 hours of onset had no impact on recurrent stroke risk but did reduce the risk for a poor functional outcome versus waiting up to 72 hours by 16%.

Moreover, it was “safe, with no increased risk of bleeding, hepatotoxicity, or muscle toxicity,” said study presenter Yilong Wang, MD, department of neurology, Beijing Tiantan Hospital, National Clinical Research Center.

There was, however, a suggestion of an interaction between intensive antiplatelet therapy and immediate intensive statin therapy, he noted, with a trend toward increased bleeding vs delaying the start of statin therapy.

Approached for comment, session cochair Carlos Molina, MD, director of the stroke unit and brain hemodynamics in Hospital Universitari Vall d’Hebron, Barcelona, said that the study is “important because when we look at studies of minor stroke and TIA, they are just focused on long-term outcomes in terms of recurrent stroke.”

He said in an interview that “putting statins in the equation and looking at their impact on long-term outcomes, the study demonstrates that statins are associated ... in particular with reductions in disabling stoke, and that’s good.”
 

Recurrence and progression

Dr. Wang began by highlighting that acute mild stroke and high-risk TIA are common and underestimated, with a relatively high risk for recurrence and progression, often caused by ICAS/ECAS.

Numerous guidelines recommend intensive antiplatelet therapy in the first 24 hours after the event, but Wang pointed out that there is little evidence to support this, and a meta-analysis suggested the window for effective treatment may be up to 72 hours.

In addition, intense statin therapy appears to be beneficial for the secondary prevention of atherosclerotic stroke in the nonacute phase, although there is no evidence for any neuroprotective effects in the acute phase nor for the optimal timing of starting the drugs.

Dr. Wang also noted that there is the potential for an interaction between intensive antiplatelet and statin therapy that could increase the risk for bleeding.

To investigate further, the researchers conducted a multicenter study involving patients aged 35-80 years with acute ischemic stroke or TIA.

The former was defined as an acute single infarction with 50% or greater stenosis of a major intracranial or extracranial artery that “probably account for the infarction and symptoms,” or multiple infarctions of large artery origin, including nonstenotic vulnerable plaques.

Patients were required to have a National Institutes of Health Stroke Scale score of 4-5 24 hours or less from acute stoke onset or 0-5 between 24 and 72 hours of onset.

TIA was defined as 50% or more stenosis of major intracranial or extracranial arteries that probably account for the symptoms, and an ABCD2 score for stroke risk of 4 or more within 24-72 hours of onset.

Patients were excluded if they had received dual antiplatelet therapy with aspirin and clopidogrel or high-intensity statin therapy within 14 days of random assignment or had intravenous thrombolysis or endovascular therapy after acute stroke or TIA onset.

Those included in the trial were randomly assigned in a 2 x 2 factorial design to receive:

• Intensive or dual antiplatelet therapy with clopidogrel and aspirin plus immediate high-intensity statin therapy with atorvastatin
• Intensive antiplatelet therapy plus delayed high-intensity statin therapy
• Standard antiplatelet therapy with aspirin alone plus immediate high-intensity statin therapy
• Standard antiplatelet therapy plus delayed high-intensity statin therapy

In all, 6,100 patients were enrolled from 222 hospitals in 99 cities across 25 provinces in China. The mean age was 65 years, and 34.6%-37.0% were women. TIA was recorded in 12.2%-14.1% of patients; 19.5%-19.7% had a single acute infarction, and 66.4%-68.1% had acute multiple infarctions.

The time to randomization was 24 hours or less after event onset in 12.5%-13.2% of cases versus 24-48 hours in 41.2%-42.5% and 48 hours or more in 44.9%-45.7% of patients.

The primary efficacy outcome, defined as stroke at 90 days, was significantly less common with intensive versus standard antiplatelet therapy, at a cumulative probability of 9.2% versus 7.3% (hazard ratio, 0.79; 95% confidence interval, 0.66-0.94; P = .007).

Clopidogrel plus aspirin was also associated with a significant reduction in a composite vascular event of stroke, myocardial infarction, or vascular death versus aspirin alone, at 7.5% versus 9.3% (HR, 0.80; 95% CI, 0.67-0.95, P = .01), as well as a reduction in rates of ischemic stroke (P = .002), and TIA (P = .02).

The primary safety outcome, defined as moderate to severe bleeding on the GUSTO criteria, was increased with intensive antiplatelet therapy, at 0.9% versus 0.4% for aspirin alone (HR, 2.08; 95% CI, 1.07-4.03; P = .02).

Turning to statin use, Dr. Wang showed that there was no significant difference in rates of stroke at 90 days between delayed and immediate intensive therapy, at a cumulative probability of 8.4% versus 8.1% (HR, 0.95; P = .58).

There was also no difference in rates of moderate to severe bleeding, at 0.8% with immediate versus 0.6% for delayed intensive statin therapy (HR, 1.36; 95% CI, 0.73-2.54; P = .34).

Dr. Wang reported that there were no significant differences in key secondary efficacy and safety outcomes.

Analysis of the distribution of modified Rankin Scale scores at 90 days, however, indicated that there was a significant reduction in the risk for poor functional outcome, defined as a score of 2-6, with immediate versus delayed statin therapy (odds ratio, 0.84; 95% CI, 0.72-0.99; P = .04).

Finally, it was found that combining dual antiplatelet therapy with immediate intensive statin therapy was associated with an increase in moderate to severe bleeding versus delayed statin therapy, affecting 1.1% versus 0.7% of patients. The association nonetheless did not reach statistical significance (HR, 1.70; 95% CI, 0.78-3.71; P = .18).

The study was funded by the National Natural Science Foundation of China, the National Key R&D Program of China, the Beijing Outstanding Young Scientist Program, the Beijing Youth Scholar Program, and the Beijing Talent Project. The drug was provided by Sanofi and Jialin Pharmaceutical. No relevant financial relationships were declared.

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

MUNICH, GERMANY – Giving intensive statin therapy to patients with acute mild ischemic stroke or with high-risk for transient ischemic attack (TIA) immediately after onset significantly reduces the risk for a poor functional outcome compared with delaying treatment, without compromising safety, results of the INSPIRES trial show.

The research, presented at the annual European Stroke Organisation Conference, also showed that intensive antiplatelet therapy reduced the risk for recurrent stroke albeit at an increased in bleeding risk versus standard treatment.

The study involved more than 6,000 patients with acute mild ischemic stroke or TIA and intracranial or extracranial atherosclerosis (ICAS/ECAS), who were randomly assigned in a 2 x 2 factorial design to compare intensive versus standard antiplatelet therapy and intensive statin therapy within 24 hours versus waiting up to 72 hours after onset.

Intensive antiplatelet therapy with clopidogrel plus aspirin reduced the risk for recurrent stroke within 90 days by 21% versus standard single-agent therapy, although it also doubled the risk for moderate to severe bleeding.

Starting intensive statin therapy with atorvastatin within 24 hours of onset had no impact on recurrent stroke risk but did reduce the risk for a poor functional outcome versus waiting up to 72 hours by 16%.

Moreover, it was “safe, with no increased risk of bleeding, hepatotoxicity, or muscle toxicity,” said study presenter Yilong Wang, MD, department of neurology, Beijing Tiantan Hospital, National Clinical Research Center.

There was, however, a suggestion of an interaction between intensive antiplatelet therapy and immediate intensive statin therapy, he noted, with a trend toward increased bleeding vs delaying the start of statin therapy.

Approached for comment, session cochair Carlos Molina, MD, director of the stroke unit and brain hemodynamics in Hospital Universitari Vall d’Hebron, Barcelona, said that the study is “important because when we look at studies of minor stroke and TIA, they are just focused on long-term outcomes in terms of recurrent stroke.”

He said in an interview that “putting statins in the equation and looking at their impact on long-term outcomes, the study demonstrates that statins are associated ... in particular with reductions in disabling stoke, and that’s good.”
 

Recurrence and progression

Dr. Wang began by highlighting that acute mild stroke and high-risk TIA are common and underestimated, with a relatively high risk for recurrence and progression, often caused by ICAS/ECAS.

Numerous guidelines recommend intensive antiplatelet therapy in the first 24 hours after the event, but Wang pointed out that there is little evidence to support this, and a meta-analysis suggested the window for effective treatment may be up to 72 hours.

In addition, intense statin therapy appears to be beneficial for the secondary prevention of atherosclerotic stroke in the nonacute phase, although there is no evidence for any neuroprotective effects in the acute phase nor for the optimal timing of starting the drugs.

Dr. Wang also noted that there is the potential for an interaction between intensive antiplatelet and statin therapy that could increase the risk for bleeding.

To investigate further, the researchers conducted a multicenter study involving patients aged 35-80 years with acute ischemic stroke or TIA.

The former was defined as an acute single infarction with 50% or greater stenosis of a major intracranial or extracranial artery that “probably account for the infarction and symptoms,” or multiple infarctions of large artery origin, including nonstenotic vulnerable plaques.

Patients were required to have a National Institutes of Health Stroke Scale score of 4-5 24 hours or less from acute stoke onset or 0-5 between 24 and 72 hours of onset.

TIA was defined as 50% or more stenosis of major intracranial or extracranial arteries that probably account for the symptoms, and an ABCD2 score for stroke risk of 4 or more within 24-72 hours of onset.

Patients were excluded if they had received dual antiplatelet therapy with aspirin and clopidogrel or high-intensity statin therapy within 14 days of random assignment or had intravenous thrombolysis or endovascular therapy after acute stroke or TIA onset.

Those included in the trial were randomly assigned in a 2 x 2 factorial design to receive:

• Intensive or dual antiplatelet therapy with clopidogrel and aspirin plus immediate high-intensity statin therapy with atorvastatin
• Intensive antiplatelet therapy plus delayed high-intensity statin therapy
• Standard antiplatelet therapy with aspirin alone plus immediate high-intensity statin therapy
• Standard antiplatelet therapy plus delayed high-intensity statin therapy

In all, 6,100 patients were enrolled from 222 hospitals in 99 cities across 25 provinces in China. The mean age was 65 years, and 34.6%-37.0% were women. TIA was recorded in 12.2%-14.1% of patients; 19.5%-19.7% had a single acute infarction, and 66.4%-68.1% had acute multiple infarctions.

The time to randomization was 24 hours or less after event onset in 12.5%-13.2% of cases versus 24-48 hours in 41.2%-42.5% and 48 hours or more in 44.9%-45.7% of patients.

The primary efficacy outcome, defined as stroke at 90 days, was significantly less common with intensive versus standard antiplatelet therapy, at a cumulative probability of 9.2% versus 7.3% (hazard ratio, 0.79; 95% confidence interval, 0.66-0.94; P = .007).

Clopidogrel plus aspirin was also associated with a significant reduction in a composite vascular event of stroke, myocardial infarction, or vascular death versus aspirin alone, at 7.5% versus 9.3% (HR, 0.80; 95% CI, 0.67-0.95, P = .01), as well as a reduction in rates of ischemic stroke (P = .002), and TIA (P = .02).

The primary safety outcome, defined as moderate to severe bleeding on the GUSTO criteria, was increased with intensive antiplatelet therapy, at 0.9% versus 0.4% for aspirin alone (HR, 2.08; 95% CI, 1.07-4.03; P = .02).

Turning to statin use, Dr. Wang showed that there was no significant difference in rates of stroke at 90 days between delayed and immediate intensive therapy, at a cumulative probability of 8.4% versus 8.1% (HR, 0.95; P = .58).

There was also no difference in rates of moderate to severe bleeding, at 0.8% with immediate versus 0.6% for delayed intensive statin therapy (HR, 1.36; 95% CI, 0.73-2.54; P = .34).

Dr. Wang reported that there were no significant differences in key secondary efficacy and safety outcomes.

Analysis of the distribution of modified Rankin Scale scores at 90 days, however, indicated that there was a significant reduction in the risk for poor functional outcome, defined as a score of 2-6, with immediate versus delayed statin therapy (odds ratio, 0.84; 95% CI, 0.72-0.99; P = .04).

Finally, it was found that combining dual antiplatelet therapy with immediate intensive statin therapy was associated with an increase in moderate to severe bleeding versus delayed statin therapy, affecting 1.1% versus 0.7% of patients. The association nonetheless did not reach statistical significance (HR, 1.70; 95% CI, 0.78-3.71; P = .18).

The study was funded by the National Natural Science Foundation of China, the National Key R&D Program of China, the Beijing Outstanding Young Scientist Program, the Beijing Youth Scholar Program, and the Beijing Talent Project. The drug was provided by Sanofi and Jialin Pharmaceutical. No relevant financial relationships were declared.

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

MUNICH, GERMANY – Giving intensive statin therapy to patients with acute mild ischemic stroke or with high-risk for transient ischemic attack (TIA) immediately after onset significantly reduces the risk for a poor functional outcome compared with delaying treatment, without compromising safety, results of the INSPIRES trial show.

The research, presented at the annual European Stroke Organisation Conference, also showed that intensive antiplatelet therapy reduced the risk for recurrent stroke albeit at an increased in bleeding risk versus standard treatment.

The study involved more than 6,000 patients with acute mild ischemic stroke or TIA and intracranial or extracranial atherosclerosis (ICAS/ECAS), who were randomly assigned in a 2 x 2 factorial design to compare intensive versus standard antiplatelet therapy and intensive statin therapy within 24 hours versus waiting up to 72 hours after onset.

Intensive antiplatelet therapy with clopidogrel plus aspirin reduced the risk for recurrent stroke within 90 days by 21% versus standard single-agent therapy, although it also doubled the risk for moderate to severe bleeding.

Starting intensive statin therapy with atorvastatin within 24 hours of onset had no impact on recurrent stroke risk but did reduce the risk for a poor functional outcome versus waiting up to 72 hours by 16%.

Moreover, it was “safe, with no increased risk of bleeding, hepatotoxicity, or muscle toxicity,” said study presenter Yilong Wang, MD, department of neurology, Beijing Tiantan Hospital, National Clinical Research Center.

There was, however, a suggestion of an interaction between intensive antiplatelet therapy and immediate intensive statin therapy, he noted, with a trend toward increased bleeding vs delaying the start of statin therapy.

Approached for comment, session cochair Carlos Molina, MD, director of the stroke unit and brain hemodynamics in Hospital Universitari Vall d’Hebron, Barcelona, said that the study is “important because when we look at studies of minor stroke and TIA, they are just focused on long-term outcomes in terms of recurrent stroke.”

He said in an interview that “putting statins in the equation and looking at their impact on long-term outcomes, the study demonstrates that statins are associated ... in particular with reductions in disabling stoke, and that’s good.”
 

Recurrence and progression

Dr. Wang began by highlighting that acute mild stroke and high-risk TIA are common and underestimated, with a relatively high risk for recurrence and progression, often caused by ICAS/ECAS.

Numerous guidelines recommend intensive antiplatelet therapy in the first 24 hours after the event, but Wang pointed out that there is little evidence to support this, and a meta-analysis suggested the window for effective treatment may be up to 72 hours.

In addition, intense statin therapy appears to be beneficial for the secondary prevention of atherosclerotic stroke in the nonacute phase, although there is no evidence for any neuroprotective effects in the acute phase nor for the optimal timing of starting the drugs.

Dr. Wang also noted that there is the potential for an interaction between intensive antiplatelet and statin therapy that could increase the risk for bleeding.

To investigate further, the researchers conducted a multicenter study involving patients aged 35-80 years with acute ischemic stroke or TIA.

The former was defined as an acute single infarction with 50% or greater stenosis of a major intracranial or extracranial artery that “probably account for the infarction and symptoms,” or multiple infarctions of large artery origin, including nonstenotic vulnerable plaques.

Patients were required to have a National Institutes of Health Stroke Scale score of 4-5 24 hours or less from acute stoke onset or 0-5 between 24 and 72 hours of onset.

TIA was defined as 50% or more stenosis of major intracranial or extracranial arteries that probably account for the symptoms, and an ABCD2 score for stroke risk of 4 or more within 24-72 hours of onset.

Patients were excluded if they had received dual antiplatelet therapy with aspirin and clopidogrel or high-intensity statin therapy within 14 days of random assignment or had intravenous thrombolysis or endovascular therapy after acute stroke or TIA onset.

Those included in the trial were randomly assigned in a 2 x 2 factorial design to receive:

• Intensive or dual antiplatelet therapy with clopidogrel and aspirin plus immediate high-intensity statin therapy with atorvastatin
• Intensive antiplatelet therapy plus delayed high-intensity statin therapy
• Standard antiplatelet therapy with aspirin alone plus immediate high-intensity statin therapy
• Standard antiplatelet therapy plus delayed high-intensity statin therapy

In all, 6,100 patients were enrolled from 222 hospitals in 99 cities across 25 provinces in China. The mean age was 65 years, and 34.6%-37.0% were women. TIA was recorded in 12.2%-14.1% of patients; 19.5%-19.7% had a single acute infarction, and 66.4%-68.1% had acute multiple infarctions.

The time to randomization was 24 hours or less after event onset in 12.5%-13.2% of cases versus 24-48 hours in 41.2%-42.5% and 48 hours or more in 44.9%-45.7% of patients.

The primary efficacy outcome, defined as stroke at 90 days, was significantly less common with intensive versus standard antiplatelet therapy, at a cumulative probability of 9.2% versus 7.3% (hazard ratio, 0.79; 95% confidence interval, 0.66-0.94; P = .007).

Clopidogrel plus aspirin was also associated with a significant reduction in a composite vascular event of stroke, myocardial infarction, or vascular death versus aspirin alone, at 7.5% versus 9.3% (HR, 0.80; 95% CI, 0.67-0.95, P = .01), as well as a reduction in rates of ischemic stroke (P = .002), and TIA (P = .02).

The primary safety outcome, defined as moderate to severe bleeding on the GUSTO criteria, was increased with intensive antiplatelet therapy, at 0.9% versus 0.4% for aspirin alone (HR, 2.08; 95% CI, 1.07-4.03; P = .02).

Turning to statin use, Dr. Wang showed that there was no significant difference in rates of stroke at 90 days between delayed and immediate intensive therapy, at a cumulative probability of 8.4% versus 8.1% (HR, 0.95; P = .58).

There was also no difference in rates of moderate to severe bleeding, at 0.8% with immediate versus 0.6% for delayed intensive statin therapy (HR, 1.36; 95% CI, 0.73-2.54; P = .34).

Dr. Wang reported that there were no significant differences in key secondary efficacy and safety outcomes.

Analysis of the distribution of modified Rankin Scale scores at 90 days, however, indicated that there was a significant reduction in the risk for poor functional outcome, defined as a score of 2-6, with immediate versus delayed statin therapy (odds ratio, 0.84; 95% CI, 0.72-0.99; P = .04).

Finally, it was found that combining dual antiplatelet therapy with immediate intensive statin therapy was associated with an increase in moderate to severe bleeding versus delayed statin therapy, affecting 1.1% versus 0.7% of patients. The association nonetheless did not reach statistical significance (HR, 1.70; 95% CI, 0.78-3.71; P = .18).

The study was funded by the National Natural Science Foundation of China, the National Key R&D Program of China, the Beijing Outstanding Young Scientist Program, the Beijing Youth Scholar Program, and the Beijing Talent Project. The drug was provided by Sanofi and Jialin Pharmaceutical. No relevant financial relationships were declared.

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

Members of a Food and Drug Administration advisory committee have unanimously concluded that a postmarketing study confirms the benefit of the Alzheimer’s drug lecanemab (Leqembi, Eisai), paving the way for traditional approval.

“Overall, the study demonstrated clearly that this is an effective treatment,” said acting chair Robert C. Alexander, MD, chief scientific officer, Alzheimer’s Prevention Initiative, Banner Alzheimer’s Institute, and research professor, department of psychiatry, University of Arizona, Phoenix, during the meeting.

An intravenous infusion targeting amyloid-beta, lecanemab received accelerated FDA approved earlier in 2023 for the treatment of early Alzheimer’s disease (AD). The company was required to complete a confirmatory study to verify and describe the product’s clinical benefit.

The Peripheral and Central Nervous System Drugs Advisory Committee met to discuss this phase 3 study (CLARITY-AD). The multicenter, double-blind study included 1,795 patients (mean age, 71 years) who had mild cognitive impairment caused by AD or mild AD dementia.
 

Delayed progression

Study participants had a broad range of comorbidities, and many were concomitantly receiving other medications. Black people were underrepresented in the study at just 3% of the total cohort.

Patients were randomly assigned to receive placebo or lecanemab 10 mg/kg biweekly. In addition to a placebo-controlled period and safety follow-up, the study has an ongoing extension phase of up to 4 years.

The study met its primary endpoint, showing a highly statistically significant 27% less decline on the Clinical Dementia Rating-Sum of Boxes at 18 months (difference in adjusted mean, –0.45; 95% CI, –0.67 to –0.23; P = .00005).

This was supported by a significant 26% difference on the AD Assessment Scale–Cognitive Subscale with 14 tasks (ADAS-Cog 14).

The drug also affected function, with a 37% decrease, compared with placebo, on the AD Cooperative Study–Activities of Daily Living Scale for Mild Cognitive Impairment.

Committee members heard that the results signal delays in disease progression by about 5 months, giving patients more time to live independently and participate in hobbies and interests.

Patients who received the active drug also experienced quality of life benefits. Compared with patients who received placebo, those who took lecanemab had 49% less decline as measured with the European Quality of Life–5 Dimensions scale and 56% less decline as measured by the Quality of Life in AD scale, and caregivers reported less burden.

Lecanemab also affected biomarkers of amyloid, tau, and neurodegeneration, providing a biological basis for the treatment effects consistent with slowing of disease progression.
 

Unanimous support

All six committee members agreed by vote that the study provides evidence of clinical benefit. They variously descried the study and results as “robust,” “compelling,” “well conducted,” “clear and consistent,” and “clinically meaningful.”

In the active treatment group, there was a higher incidence of amyloid-related imaging abnormalities (ARIAs), which can be serious and life-threatening but are usually asymptomatic. In this study, most ARIAs had resolved by 3 months.

Deaths occurred in 0.8% of the placebo and 0.7% of the treatment group. Dean Follmann, PhD, assistant director for biostatistics, National Institute of Allergy and Infectious Diseases, Bethesda, Md., noted that the numbers of deaths and serious adverse events were “quite similar” in the two groups.

“And for serious ARIA, there was an imbalance favoring placebo, but overall, these were pretty rare,” he said.
 

Subgroup concerns

Committee members discussed the risk/benefit profile for three subgroups of patients – those with apolipoprotein E4 (apo E4) allele, patients taking an anticoagulant, and those with cerebral amyloid angiopathy (CAA).

In the apo E4 group, the study’s primary endpoint did not favor the drug, but secondary endpoints did.

“I think the general feeling [for apo E4 status] is that the risk/benefit still remains favorable, especially when looking across multiple endpoints,” said Dr. Alexander.

However, some members supported recommending genetic testing before initiating the drug.

The views were more diverse for the use of lecanemab in the presence of an anticoagulant, which may increase the risk for cerebral hemorrhage. Some committee members strongly recommended that these patients not receive lecanemab, while others highlighted the need for more information, owing to uncertainties about the risks.

With respect to CAA, most members supported the idea of considering use of the drug in the presence of this condition, but only after discussing the risks with patients and their families and in the presence of a robust reporting system.

An Alzheimer’s Association representative was in attendance during the public hearing portion of the meeting to express support for traditional approval of lecanemab for people with early AD.

The association strongly favors full Medicare coverage for FDA-approved AD treatments. The Centers for Medicare & Medicaid Services has determined that AD treatments receiving traditional FDA approval will be covered if clinicians register and enter data in a registry.

“While this is an important signal that CMS wants to improve access to FDA-approved treatments, registry as a condition of coverage is an unnecessary and potentially harmful barrier,” said the Alzheimer’s Association in a press release following the meeting.

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

Members of a Food and Drug Administration advisory committee have unanimously concluded that a postmarketing study confirms the benefit of the Alzheimer’s drug lecanemab (Leqembi, Eisai), paving the way for traditional approval.

“Overall, the study demonstrated clearly that this is an effective treatment,” said acting chair Robert C. Alexander, MD, chief scientific officer, Alzheimer’s Prevention Initiative, Banner Alzheimer’s Institute, and research professor, department of psychiatry, University of Arizona, Phoenix, during the meeting.

An intravenous infusion targeting amyloid-beta, lecanemab received accelerated FDA approved earlier in 2023 for the treatment of early Alzheimer’s disease (AD). The company was required to complete a confirmatory study to verify and describe the product’s clinical benefit.

The Peripheral and Central Nervous System Drugs Advisory Committee met to discuss this phase 3 study (CLARITY-AD). The multicenter, double-blind study included 1,795 patients (mean age, 71 years) who had mild cognitive impairment caused by AD or mild AD dementia.
 

Delayed progression

Study participants had a broad range of comorbidities, and many were concomitantly receiving other medications. Black people were underrepresented in the study at just 3% of the total cohort.

Patients were randomly assigned to receive placebo or lecanemab 10 mg/kg biweekly. In addition to a placebo-controlled period and safety follow-up, the study has an ongoing extension phase of up to 4 years.

The study met its primary endpoint, showing a highly statistically significant 27% less decline on the Clinical Dementia Rating-Sum of Boxes at 18 months (difference in adjusted mean, –0.45; 95% CI, –0.67 to –0.23; P = .00005).

This was supported by a significant 26% difference on the AD Assessment Scale–Cognitive Subscale with 14 tasks (ADAS-Cog 14).

The drug also affected function, with a 37% decrease, compared with placebo, on the AD Cooperative Study–Activities of Daily Living Scale for Mild Cognitive Impairment.

Committee members heard that the results signal delays in disease progression by about 5 months, giving patients more time to live independently and participate in hobbies and interests.

Patients who received the active drug also experienced quality of life benefits. Compared with patients who received placebo, those who took lecanemab had 49% less decline as measured with the European Quality of Life–5 Dimensions scale and 56% less decline as measured by the Quality of Life in AD scale, and caregivers reported less burden.

Lecanemab also affected biomarkers of amyloid, tau, and neurodegeneration, providing a biological basis for the treatment effects consistent with slowing of disease progression.
 

Unanimous support

All six committee members agreed by vote that the study provides evidence of clinical benefit. They variously descried the study and results as “robust,” “compelling,” “well conducted,” “clear and consistent,” and “clinically meaningful.”

In the active treatment group, there was a higher incidence of amyloid-related imaging abnormalities (ARIAs), which can be serious and life-threatening but are usually asymptomatic. In this study, most ARIAs had resolved by 3 months.

Deaths occurred in 0.8% of the placebo and 0.7% of the treatment group. Dean Follmann, PhD, assistant director for biostatistics, National Institute of Allergy and Infectious Diseases, Bethesda, Md., noted that the numbers of deaths and serious adverse events were “quite similar” in the two groups.

“And for serious ARIA, there was an imbalance favoring placebo, but overall, these were pretty rare,” he said.
 

Subgroup concerns

Committee members discussed the risk/benefit profile for three subgroups of patients – those with apolipoprotein E4 (apo E4) allele, patients taking an anticoagulant, and those with cerebral amyloid angiopathy (CAA).

In the apo E4 group, the study’s primary endpoint did not favor the drug, but secondary endpoints did.

“I think the general feeling [for apo E4 status] is that the risk/benefit still remains favorable, especially when looking across multiple endpoints,” said Dr. Alexander.

However, some members supported recommending genetic testing before initiating the drug.

The views were more diverse for the use of lecanemab in the presence of an anticoagulant, which may increase the risk for cerebral hemorrhage. Some committee members strongly recommended that these patients not receive lecanemab, while others highlighted the need for more information, owing to uncertainties about the risks.

With respect to CAA, most members supported the idea of considering use of the drug in the presence of this condition, but only after discussing the risks with patients and their families and in the presence of a robust reporting system.

An Alzheimer’s Association representative was in attendance during the public hearing portion of the meeting to express support for traditional approval of lecanemab for people with early AD.

The association strongly favors full Medicare coverage for FDA-approved AD treatments. The Centers for Medicare & Medicaid Services has determined that AD treatments receiving traditional FDA approval will be covered if clinicians register and enter data in a registry.

“While this is an important signal that CMS wants to improve access to FDA-approved treatments, registry as a condition of coverage is an unnecessary and potentially harmful barrier,” said the Alzheimer’s Association in a press release following the meeting.

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

Members of a Food and Drug Administration advisory committee have unanimously concluded that a postmarketing study confirms the benefit of the Alzheimer’s drug lecanemab (Leqembi, Eisai), paving the way for traditional approval.

“Overall, the study demonstrated clearly that this is an effective treatment,” said acting chair Robert C. Alexander, MD, chief scientific officer, Alzheimer’s Prevention Initiative, Banner Alzheimer’s Institute, and research professor, department of psychiatry, University of Arizona, Phoenix, during the meeting.

An intravenous infusion targeting amyloid-beta, lecanemab received accelerated FDA approved earlier in 2023 for the treatment of early Alzheimer’s disease (AD). The company was required to complete a confirmatory study to verify and describe the product’s clinical benefit.

The Peripheral and Central Nervous System Drugs Advisory Committee met to discuss this phase 3 study (CLARITY-AD). The multicenter, double-blind study included 1,795 patients (mean age, 71 years) who had mild cognitive impairment caused by AD or mild AD dementia.
 

Delayed progression

Study participants had a broad range of comorbidities, and many were concomitantly receiving other medications. Black people were underrepresented in the study at just 3% of the total cohort.

Patients were randomly assigned to receive placebo or lecanemab 10 mg/kg biweekly. In addition to a placebo-controlled period and safety follow-up, the study has an ongoing extension phase of up to 4 years.

The study met its primary endpoint, showing a highly statistically significant 27% less decline on the Clinical Dementia Rating-Sum of Boxes at 18 months (difference in adjusted mean, –0.45; 95% CI, –0.67 to –0.23; P = .00005).

This was supported by a significant 26% difference on the AD Assessment Scale–Cognitive Subscale with 14 tasks (ADAS-Cog 14).

The drug also affected function, with a 37% decrease, compared with placebo, on the AD Cooperative Study–Activities of Daily Living Scale for Mild Cognitive Impairment.

Committee members heard that the results signal delays in disease progression by about 5 months, giving patients more time to live independently and participate in hobbies and interests.

Patients who received the active drug also experienced quality of life benefits. Compared with patients who received placebo, those who took lecanemab had 49% less decline as measured with the European Quality of Life–5 Dimensions scale and 56% less decline as measured by the Quality of Life in AD scale, and caregivers reported less burden.

Lecanemab also affected biomarkers of amyloid, tau, and neurodegeneration, providing a biological basis for the treatment effects consistent with slowing of disease progression.
 

Unanimous support

All six committee members agreed by vote that the study provides evidence of clinical benefit. They variously descried the study and results as “robust,” “compelling,” “well conducted,” “clear and consistent,” and “clinically meaningful.”

In the active treatment group, there was a higher incidence of amyloid-related imaging abnormalities (ARIAs), which can be serious and life-threatening but are usually asymptomatic. In this study, most ARIAs had resolved by 3 months.

Deaths occurred in 0.8% of the placebo and 0.7% of the treatment group. Dean Follmann, PhD, assistant director for biostatistics, National Institute of Allergy and Infectious Diseases, Bethesda, Md., noted that the numbers of deaths and serious adverse events were “quite similar” in the two groups.

“And for serious ARIA, there was an imbalance favoring placebo, but overall, these were pretty rare,” he said.
 

Subgroup concerns

Committee members discussed the risk/benefit profile for three subgroups of patients – those with apolipoprotein E4 (apo E4) allele, patients taking an anticoagulant, and those with cerebral amyloid angiopathy (CAA).

In the apo E4 group, the study’s primary endpoint did not favor the drug, but secondary endpoints did.

“I think the general feeling [for apo E4 status] is that the risk/benefit still remains favorable, especially when looking across multiple endpoints,” said Dr. Alexander.

However, some members supported recommending genetic testing before initiating the drug.

The views were more diverse for the use of lecanemab in the presence of an anticoagulant, which may increase the risk for cerebral hemorrhage. Some committee members strongly recommended that these patients not receive lecanemab, while others highlighted the need for more information, owing to uncertainties about the risks.

With respect to CAA, most members supported the idea of considering use of the drug in the presence of this condition, but only after discussing the risks with patients and their families and in the presence of a robust reporting system.

An Alzheimer’s Association representative was in attendance during the public hearing portion of the meeting to express support for traditional approval of lecanemab for people with early AD.

The association strongly favors full Medicare coverage for FDA-approved AD treatments. The Centers for Medicare & Medicaid Services has determined that AD treatments receiving traditional FDA approval will be covered if clinicians register and enter data in a registry.

“While this is an important signal that CMS wants to improve access to FDA-approved treatments, registry as a condition of coverage is an unnecessary and potentially harmful barrier,” said the Alzheimer’s Association in a press release following the meeting.

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

AURORA, COLO. – Frexalimab, a novel, second-generation anti-CD40L antibody, shows “strikingly positive” effects in the treatment of relapsing multiple sclerosis (MS), significantly reducing disease activity.

“We should be very excited about these results, which are better than expected and fundamentally tackle autoimmunity,” said study investigator Gavin Giovannoni, MD, PhD, chair of neurology at the Blizard Institute of Barts, London, and the London School of Medicine and Dentistry. “It will be interesting to see if this treatment reestablishes immune tolerance and induces long-term remission,” he said.

The late-breaking study was presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
 

Significant lesion reduction

With a variety of disease-modifying therapies available for MS, frexalimab would be unique as a novel second-generation monoclonal antibody designed to block the costimulatory CD40/CD40L cellular pathway. Importantly, the mechanism is believed to potentially modify T- and B-cell activation and innate immune cell function, for an effect of reducing inflammation without depleting B cells.

To investigate the drug’s efficacy and safety, Dr. Giovannoni and his colleagues conducted the phase 2, multicenter trial, in which 129 participants with relapsing MS were randomized to one of four groups – high-dose frexalimab (n = 52); low-dose frexalimab (n = 51); or placebo (n = 12 high-dose, n = 14 low-dose), for the 12-week placebo-controlled period, followed by an open-label extension period that is currently ongoing.

Among 125 participants who completed the study’s 12-week double-blind period, those receiving high-dose frexalimab had an 89% greater reduction in the number of new gadolinium-enhancing T1-lesions, compared with the pooled placebo group (P = .0004), meeting the study’s primary endpoint. After 24 weeks, as many as 96% of those in the high-dose frexalimab arm were free of gadolinium-enhanced T1 lesions.

The frexalimab low-dose group also had a lower, but significant, reduction in the number of new gadolinium-enhanced T1-lesions of 79% versus the pooled placebo group (P = .0021).

Both of the frexalimab groups also had reductions in enlarging T2-lesions and total gadolinium-enhanced T1-lesions.

In the high-dose group, data on 38 participants with open-label data from week 37 showed no new gadolinium-enhanced lesions.

In terms of safety, frexalimab was well tolerated over the 12-week study, with headache and COVID-19 reported among 4% or fewer participants. No serious adverse events were reported.

Looking ahead at safety, Dr. Giovannoni noted that “a known unknown is infections, but this is a problem with all therapies that work via immunosuppressive mechanisms, not only therapies targeting CD40L.” That said, “we didn’t see a big infection signal in the trial, which is reassuring. It also shows the immune system has built-in redundancy and many mechanisms to fight infections,” he added.

In his newsletter, Dr. Giovannoni characterized the study’s results as “strikingly positive,” adding that they “are the most exciting to emerge in MS in the last 12-24 months.”

Overall, “these are the first randomized controlled phase 2 data for a CD40L inhibitor in MS and indicate potential for further development of frexalimab as a high-efficacy therapy,” the investigators noted. “Frexalimab led to a pronounced reduction of new gadolinium-enhancing lesions by 3 months and was well-tolerated,” they added.
 

An intriguing mechanism

Commenting on the study, Salim Chahin, MD, an assistant professor of neurology in the John L. Trotter MS Center in the department of neurology at Washington University, St. Louis, said that frexalimab represents an intriguing mechanistic approach to MS.

“In the world of MS and neuroimmunology, this is indeed a unique mechanism that has not been explored before,” Dr. Chahin said.

“Therapies targeting CD40 and CD40L are not new but were previously associated with unfavorable side effects, mainly thromboembolic events that halted their development,” he said, noting that the drug appears to avoid these side effects, providing good phase 2 efficacy data.

Dr. Chahin agreed that the phase 3 data will be watched closely for further safety and efficacy issues. “Indeed, it is difficult to interpret the occurrence of COVID-19 infections, given the timing of the phase 2 study, or their severity, but based on the mechanism of action, it is possible that this drug will be associated with a more favorable safety profile than some of the currently approved MS treatments,” Dr. Chahin said.

“But phase 3 trial data are much needed to clarify the immunosuppressive risk.”

The study received funding from Sanofi. Dr. Giovannoni’s disclosures include current or recent relationships with AbbVie, Aslan, Atara Bio, Biogen, BMS-Celgene, GlaxoSmithKline, Janssen/J&J, Japanese Tobacco, Jazz Pharmaceuticals, LifNano, Merck & Co, Merck KGaA/EMD, Moderna, Serono, Moderna, Novartis, Sandoz, Sanofi, and Roche/Genentech. Dr. Chahin reports no relevant financial relationships.

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

AURORA, COLO. – Frexalimab, a novel, second-generation anti-CD40L antibody, shows “strikingly positive” effects in the treatment of relapsing multiple sclerosis (MS), significantly reducing disease activity.

“We should be very excited about these results, which are better than expected and fundamentally tackle autoimmunity,” said study investigator Gavin Giovannoni, MD, PhD, chair of neurology at the Blizard Institute of Barts, London, and the London School of Medicine and Dentistry. “It will be interesting to see if this treatment reestablishes immune tolerance and induces long-term remission,” he said.

The late-breaking study was presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
 

Significant lesion reduction

With a variety of disease-modifying therapies available for MS, frexalimab would be unique as a novel second-generation monoclonal antibody designed to block the costimulatory CD40/CD40L cellular pathway. Importantly, the mechanism is believed to potentially modify T- and B-cell activation and innate immune cell function, for an effect of reducing inflammation without depleting B cells.

To investigate the drug’s efficacy and safety, Dr. Giovannoni and his colleagues conducted the phase 2, multicenter trial, in which 129 participants with relapsing MS were randomized to one of four groups – high-dose frexalimab (n = 52); low-dose frexalimab (n = 51); or placebo (n = 12 high-dose, n = 14 low-dose), for the 12-week placebo-controlled period, followed by an open-label extension period that is currently ongoing.

Among 125 participants who completed the study’s 12-week double-blind period, those receiving high-dose frexalimab had an 89% greater reduction in the number of new gadolinium-enhancing T1-lesions, compared with the pooled placebo group (P = .0004), meeting the study’s primary endpoint. After 24 weeks, as many as 96% of those in the high-dose frexalimab arm were free of gadolinium-enhanced T1 lesions.

The frexalimab low-dose group also had a lower, but significant, reduction in the number of new gadolinium-enhanced T1-lesions of 79% versus the pooled placebo group (P = .0021).

Both of the frexalimab groups also had reductions in enlarging T2-lesions and total gadolinium-enhanced T1-lesions.

In the high-dose group, data on 38 participants with open-label data from week 37 showed no new gadolinium-enhanced lesions.

In terms of safety, frexalimab was well tolerated over the 12-week study, with headache and COVID-19 reported among 4% or fewer participants. No serious adverse events were reported.

Looking ahead at safety, Dr. Giovannoni noted that “a known unknown is infections, but this is a problem with all therapies that work via immunosuppressive mechanisms, not only therapies targeting CD40L.” That said, “we didn’t see a big infection signal in the trial, which is reassuring. It also shows the immune system has built-in redundancy and many mechanisms to fight infections,” he added.

In his newsletter, Dr. Giovannoni characterized the study’s results as “strikingly positive,” adding that they “are the most exciting to emerge in MS in the last 12-24 months.”

Overall, “these are the first randomized controlled phase 2 data for a CD40L inhibitor in MS and indicate potential for further development of frexalimab as a high-efficacy therapy,” the investigators noted. “Frexalimab led to a pronounced reduction of new gadolinium-enhancing lesions by 3 months and was well-tolerated,” they added.
 

An intriguing mechanism

Commenting on the study, Salim Chahin, MD, an assistant professor of neurology in the John L. Trotter MS Center in the department of neurology at Washington University, St. Louis, said that frexalimab represents an intriguing mechanistic approach to MS.

“In the world of MS and neuroimmunology, this is indeed a unique mechanism that has not been explored before,” Dr. Chahin said.

“Therapies targeting CD40 and CD40L are not new but were previously associated with unfavorable side effects, mainly thromboembolic events that halted their development,” he said, noting that the drug appears to avoid these side effects, providing good phase 2 efficacy data.

Dr. Chahin agreed that the phase 3 data will be watched closely for further safety and efficacy issues. “Indeed, it is difficult to interpret the occurrence of COVID-19 infections, given the timing of the phase 2 study, or their severity, but based on the mechanism of action, it is possible that this drug will be associated with a more favorable safety profile than some of the currently approved MS treatments,” Dr. Chahin said.

“But phase 3 trial data are much needed to clarify the immunosuppressive risk.”

The study received funding from Sanofi. Dr. Giovannoni’s disclosures include current or recent relationships with AbbVie, Aslan, Atara Bio, Biogen, BMS-Celgene, GlaxoSmithKline, Janssen/J&J, Japanese Tobacco, Jazz Pharmaceuticals, LifNano, Merck & Co, Merck KGaA/EMD, Moderna, Serono, Moderna, Novartis, Sandoz, Sanofi, and Roche/Genentech. Dr. Chahin reports no relevant financial relationships.

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

AURORA, COLO. – Frexalimab, a novel, second-generation anti-CD40L antibody, shows “strikingly positive” effects in the treatment of relapsing multiple sclerosis (MS), significantly reducing disease activity.

“We should be very excited about these results, which are better than expected and fundamentally tackle autoimmunity,” said study investigator Gavin Giovannoni, MD, PhD, chair of neurology at the Blizard Institute of Barts, London, and the London School of Medicine and Dentistry. “It will be interesting to see if this treatment reestablishes immune tolerance and induces long-term remission,” he said.

The late-breaking study was presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
 

Significant lesion reduction

With a variety of disease-modifying therapies available for MS, frexalimab would be unique as a novel second-generation monoclonal antibody designed to block the costimulatory CD40/CD40L cellular pathway. Importantly, the mechanism is believed to potentially modify T- and B-cell activation and innate immune cell function, for an effect of reducing inflammation without depleting B cells.

To investigate the drug’s efficacy and safety, Dr. Giovannoni and his colleagues conducted the phase 2, multicenter trial, in which 129 participants with relapsing MS were randomized to one of four groups – high-dose frexalimab (n = 52); low-dose frexalimab (n = 51); or placebo (n = 12 high-dose, n = 14 low-dose), for the 12-week placebo-controlled period, followed by an open-label extension period that is currently ongoing.

Among 125 participants who completed the study’s 12-week double-blind period, those receiving high-dose frexalimab had an 89% greater reduction in the number of new gadolinium-enhancing T1-lesions, compared with the pooled placebo group (P = .0004), meeting the study’s primary endpoint. After 24 weeks, as many as 96% of those in the high-dose frexalimab arm were free of gadolinium-enhanced T1 lesions.

The frexalimab low-dose group also had a lower, but significant, reduction in the number of new gadolinium-enhanced T1-lesions of 79% versus the pooled placebo group (P = .0021).

Both of the frexalimab groups also had reductions in enlarging T2-lesions and total gadolinium-enhanced T1-lesions.

In the high-dose group, data on 38 participants with open-label data from week 37 showed no new gadolinium-enhanced lesions.

In terms of safety, frexalimab was well tolerated over the 12-week study, with headache and COVID-19 reported among 4% or fewer participants. No serious adverse events were reported.

Looking ahead at safety, Dr. Giovannoni noted that “a known unknown is infections, but this is a problem with all therapies that work via immunosuppressive mechanisms, not only therapies targeting CD40L.” That said, “we didn’t see a big infection signal in the trial, which is reassuring. It also shows the immune system has built-in redundancy and many mechanisms to fight infections,” he added.

In his newsletter, Dr. Giovannoni characterized the study’s results as “strikingly positive,” adding that they “are the most exciting to emerge in MS in the last 12-24 months.”

Overall, “these are the first randomized controlled phase 2 data for a CD40L inhibitor in MS and indicate potential for further development of frexalimab as a high-efficacy therapy,” the investigators noted. “Frexalimab led to a pronounced reduction of new gadolinium-enhancing lesions by 3 months and was well-tolerated,” they added.
 

An intriguing mechanism

Commenting on the study, Salim Chahin, MD, an assistant professor of neurology in the John L. Trotter MS Center in the department of neurology at Washington University, St. Louis, said that frexalimab represents an intriguing mechanistic approach to MS.

“In the world of MS and neuroimmunology, this is indeed a unique mechanism that has not been explored before,” Dr. Chahin said.

“Therapies targeting CD40 and CD40L are not new but were previously associated with unfavorable side effects, mainly thromboembolic events that halted their development,” he said, noting that the drug appears to avoid these side effects, providing good phase 2 efficacy data.

Dr. Chahin agreed that the phase 3 data will be watched closely for further safety and efficacy issues. “Indeed, it is difficult to interpret the occurrence of COVID-19 infections, given the timing of the phase 2 study, or their severity, but based on the mechanism of action, it is possible that this drug will be associated with a more favorable safety profile than some of the currently approved MS treatments,” Dr. Chahin said.

“But phase 3 trial data are much needed to clarify the immunosuppressive risk.”

The study received funding from Sanofi. Dr. Giovannoni’s disclosures include current or recent relationships with AbbVie, Aslan, Atara Bio, Biogen, BMS-Celgene, GlaxoSmithKline, Janssen/J&J, Japanese Tobacco, Jazz Pharmaceuticals, LifNano, Merck & Co, Merck KGaA/EMD, Moderna, Serono, Moderna, Novartis, Sandoz, Sanofi, and Roche/Genentech. Dr. Chahin reports no relevant financial relationships.

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

DENVER – Patients with multiple sclerosis (MS) who switched from anti-CD20 monoclonal antibody therapy to fumarates showed no significant differences in relapse rates or total health care encounters, compared with those who remained on anti-CD20 mAbs, according to a retrospective study presented at the annual meeting of the Consortium of Multiple Sclerosis Centers. Those who switched did, however, experience a lower rate of inpatient infection-related health care visits per year than those who continued anti-CD20 mAbs.

“As MS is a chronic disease requiring long-term treatment, switching between disease-modifying therapies [DMTs] is a common clinical strategy to optimize individual patient outcomes,” lead author Aliza Ben-Zacharia, PhD, DNP, RN, an assistant professor at the Phillips School of Nursing at Mount Sinai and Hunter College, both in New York, and colleagues reported. They noted that anti-CD20 mAbs are considered high-efficacy DMTs while fumarates are considered moderate-efficacy DMTs.

The researchers used data from the Komodo Health Sentinel Claims Database to track and compare 108 patients who were clinically stable on anti-CD20 mAbs and then switched to fumarates with 540 patients who remained on anti-CD20 mAbs for a follow-up period of approximately 1 year.

The study included adults with a diagnosis of MS between January 2015 and August 2022, and only those with a gap of no more than 9 months between anti-CD20 mAbs and fumarates were included as switchers. The researchers also required that switchers had not had any relapses in the previous year on anti-CD20 mAbs before switching, and had to have been on fumarates for at least 3 months after switching.

Women made up 70% of both groups, and both had an average age of 49 years. The racial/ethnic demographics were similar in both groups, and the average MS severity score was 5.5 in the switching group and 5.6 in the staying group. Most patients had been taking or remained on ocrelizumab (93.5%) with a smaller proportion on rituximab (5.6%). Just over a third of those who switched therapy took diroximel fumarate while 64% took dimethyl fumarate.

The researchers noted that patients who stayed on anti-CD20 mAbs had “slightly higher use of other mAbs prior to anti-CD20 mAbs.” Further, “a higher proportion of patients were DMT naive prior to anti-CD20 mAb initiation, compared with those in the switchers group.”

Patients who switched had been on anti-CD20 mAbs an average 730 days before switching to fumarates, and the average time between their last anti-CD20 mAbs dose and starting fumarates was 274 days. Average exposure to fumarates was 341 days.

The 10.2% of patients who relapsed during follow-up after switching to fumarates was not significantly statistically different than the 6.7% of patients who relapsed while remaining on anti-CD20 mAbs (P = .17). A relapse was considered “an MS-related inpatient claim with a primary diagnosis of MS or an outpatient MS-related diagnosis and a prescription claim for an intravenous steroid, adrenocorticotropic hormone, total plasma exchange, or a high-dose oral corticosteroid 7 days or sooner after the outpatient visit,” the researchers explained. The researchers could not track mild relapses that didn’t involve a health care interaction.

There was also no significant difference in overall average health care encounters between those who switched (7.85 encounters) and those who stayed (8.08; P = .57). Further, average health care costs were statistically similar between those who switched ($22,512) and those who stayed ($20,634; P = 0.59).

The likelihood of having more than one infection-related health care encounter was greater for those who remained on anti-CD20 mAbs, but the difference was not statistically significant. The annual rate of infection-related health care encounters was also not statistically different for outpatient and ED visits, but those who switched did have a statistically lower rate of annual infection-related inpatient visits (P = .03).

Among those who switched, 2.8% were hospitalized for infections, compared with 6.5% who stayed on anti-CD20 mAbs. Urinary tract infections, sepsis, and Escherichia coli were the most common infections among those who switched to fumarates, compared with COVID-19, sepsis, and pneumonia, among those who stayed on anti-CD20 mAbs.

The research was sponsored by and funded by Biogen. Six of the authors are Biogen employees who hold stock options in the company. The other three authors reported combined consulting fees from Biogen, EMD Serono, Greenwich Biosciences, TG Therapeutics, Bristol-Myers Squibb, Horizon, and Novartis; research funding from Genentech and Novartis; and stock options in Pfizer.

DENVER – Patients with multiple sclerosis (MS) who switched from anti-CD20 monoclonal antibody therapy to fumarates showed no significant differences in relapse rates or total health care encounters, compared with those who remained on anti-CD20 mAbs, according to a retrospective study presented at the annual meeting of the Consortium of Multiple Sclerosis Centers. Those who switched did, however, experience a lower rate of inpatient infection-related health care visits per year than those who continued anti-CD20 mAbs.

“As MS is a chronic disease requiring long-term treatment, switching between disease-modifying therapies [DMTs] is a common clinical strategy to optimize individual patient outcomes,” lead author Aliza Ben-Zacharia, PhD, DNP, RN, an assistant professor at the Phillips School of Nursing at Mount Sinai and Hunter College, both in New York, and colleagues reported. They noted that anti-CD20 mAbs are considered high-efficacy DMTs while fumarates are considered moderate-efficacy DMTs.

The researchers used data from the Komodo Health Sentinel Claims Database to track and compare 108 patients who were clinically stable on anti-CD20 mAbs and then switched to fumarates with 540 patients who remained on anti-CD20 mAbs for a follow-up period of approximately 1 year.

The study included adults with a diagnosis of MS between January 2015 and August 2022, and only those with a gap of no more than 9 months between anti-CD20 mAbs and fumarates were included as switchers. The researchers also required that switchers had not had any relapses in the previous year on anti-CD20 mAbs before switching, and had to have been on fumarates for at least 3 months after switching.

Women made up 70% of both groups, and both had an average age of 49 years. The racial/ethnic demographics were similar in both groups, and the average MS severity score was 5.5 in the switching group and 5.6 in the staying group. Most patients had been taking or remained on ocrelizumab (93.5%) with a smaller proportion on rituximab (5.6%). Just over a third of those who switched therapy took diroximel fumarate while 64% took dimethyl fumarate.

The researchers noted that patients who stayed on anti-CD20 mAbs had “slightly higher use of other mAbs prior to anti-CD20 mAbs.” Further, “a higher proportion of patients were DMT naive prior to anti-CD20 mAb initiation, compared with those in the switchers group.”

Patients who switched had been on anti-CD20 mAbs an average 730 days before switching to fumarates, and the average time between their last anti-CD20 mAbs dose and starting fumarates was 274 days. Average exposure to fumarates was 341 days.

The 10.2% of patients who relapsed during follow-up after switching to fumarates was not significantly statistically different than the 6.7% of patients who relapsed while remaining on anti-CD20 mAbs (P = .17). A relapse was considered “an MS-related inpatient claim with a primary diagnosis of MS or an outpatient MS-related diagnosis and a prescription claim for an intravenous steroid, adrenocorticotropic hormone, total plasma exchange, or a high-dose oral corticosteroid 7 days or sooner after the outpatient visit,” the researchers explained. The researchers could not track mild relapses that didn’t involve a health care interaction.

There was also no significant difference in overall average health care encounters between those who switched (7.85 encounters) and those who stayed (8.08; P = .57). Further, average health care costs were statistically similar between those who switched ($22,512) and those who stayed ($20,634; P = 0.59).

The likelihood of having more than one infection-related health care encounter was greater for those who remained on anti-CD20 mAbs, but the difference was not statistically significant. The annual rate of infection-related health care encounters was also not statistically different for outpatient and ED visits, but those who switched did have a statistically lower rate of annual infection-related inpatient visits (P = .03).

Among those who switched, 2.8% were hospitalized for infections, compared with 6.5% who stayed on anti-CD20 mAbs. Urinary tract infections, sepsis, and Escherichia coli were the most common infections among those who switched to fumarates, compared with COVID-19, sepsis, and pneumonia, among those who stayed on anti-CD20 mAbs.

The research was sponsored by and funded by Biogen. Six of the authors are Biogen employees who hold stock options in the company. The other three authors reported combined consulting fees from Biogen, EMD Serono, Greenwich Biosciences, TG Therapeutics, Bristol-Myers Squibb, Horizon, and Novartis; research funding from Genentech and Novartis; and stock options in Pfizer.

DENVER – Patients with multiple sclerosis (MS) who switched from anti-CD20 monoclonal antibody therapy to fumarates showed no significant differences in relapse rates or total health care encounters, compared with those who remained on anti-CD20 mAbs, according to a retrospective study presented at the annual meeting of the Consortium of Multiple Sclerosis Centers. Those who switched did, however, experience a lower rate of inpatient infection-related health care visits per year than those who continued anti-CD20 mAbs.

“As MS is a chronic disease requiring long-term treatment, switching between disease-modifying therapies [DMTs] is a common clinical strategy to optimize individual patient outcomes,” lead author Aliza Ben-Zacharia, PhD, DNP, RN, an assistant professor at the Phillips School of Nursing at Mount Sinai and Hunter College, both in New York, and colleagues reported. They noted that anti-CD20 mAbs are considered high-efficacy DMTs while fumarates are considered moderate-efficacy DMTs.

The researchers used data from the Komodo Health Sentinel Claims Database to track and compare 108 patients who were clinically stable on anti-CD20 mAbs and then switched to fumarates with 540 patients who remained on anti-CD20 mAbs for a follow-up period of approximately 1 year.

The study included adults with a diagnosis of MS between January 2015 and August 2022, and only those with a gap of no more than 9 months between anti-CD20 mAbs and fumarates were included as switchers. The researchers also required that switchers had not had any relapses in the previous year on anti-CD20 mAbs before switching, and had to have been on fumarates for at least 3 months after switching.

Women made up 70% of both groups, and both had an average age of 49 years. The racial/ethnic demographics were similar in both groups, and the average MS severity score was 5.5 in the switching group and 5.6 in the staying group. Most patients had been taking or remained on ocrelizumab (93.5%) with a smaller proportion on rituximab (5.6%). Just over a third of those who switched therapy took diroximel fumarate while 64% took dimethyl fumarate.

The researchers noted that patients who stayed on anti-CD20 mAbs had “slightly higher use of other mAbs prior to anti-CD20 mAbs.” Further, “a higher proportion of patients were DMT naive prior to anti-CD20 mAb initiation, compared with those in the switchers group.”

Patients who switched had been on anti-CD20 mAbs an average 730 days before switching to fumarates, and the average time between their last anti-CD20 mAbs dose and starting fumarates was 274 days. Average exposure to fumarates was 341 days.

The 10.2% of patients who relapsed during follow-up after switching to fumarates was not significantly statistically different than the 6.7% of patients who relapsed while remaining on anti-CD20 mAbs (P = .17). A relapse was considered “an MS-related inpatient claim with a primary diagnosis of MS or an outpatient MS-related diagnosis and a prescription claim for an intravenous steroid, adrenocorticotropic hormone, total plasma exchange, or a high-dose oral corticosteroid 7 days or sooner after the outpatient visit,” the researchers explained. The researchers could not track mild relapses that didn’t involve a health care interaction.

There was also no significant difference in overall average health care encounters between those who switched (7.85 encounters) and those who stayed (8.08; P = .57). Further, average health care costs were statistically similar between those who switched ($22,512) and those who stayed ($20,634; P = 0.59).

The likelihood of having more than one infection-related health care encounter was greater for those who remained on anti-CD20 mAbs, but the difference was not statistically significant. The annual rate of infection-related health care encounters was also not statistically different for outpatient and ED visits, but those who switched did have a statistically lower rate of annual infection-related inpatient visits (P = .03).

Among those who switched, 2.8% were hospitalized for infections, compared with 6.5% who stayed on anti-CD20 mAbs. Urinary tract infections, sepsis, and Escherichia coli were the most common infections among those who switched to fumarates, compared with COVID-19, sepsis, and pneumonia, among those who stayed on anti-CD20 mAbs.

The research was sponsored by and funded by Biogen. Six of the authors are Biogen employees who hold stock options in the company. The other three authors reported combined consulting fees from Biogen, EMD Serono, Greenwich Biosciences, TG Therapeutics, Bristol-Myers Squibb, Horizon, and Novartis; research funding from Genentech and Novartis; and stock options in Pfizer.

Adult survivors of childhood cancer have an elevated risk of developing cognitive impairment years after their cancer diagnosis and treatment, new research shows.

Among more than 2,300 adult survivors of childhood cancer and their siblings, who served as controls, new-onset memory impairment emerged more often in survivors decades later.

The increased risk was associated with the cancer treatment that was provided as well as modifiable health behaviors and chronic health conditions.

Even 35 years after being diagnosed, cancer survivors who never received chemotherapies or radiation therapies known to damage the brain reported far greater memory impairment than did their siblings, first author Nicholas Phillips, MD, told this news organization.

What the findings suggest is that “we need to educate oncologists and primary care providers on the risks our survivors face long after completion of therapy,” said Dr. Phillips, of the epidemiology and cancer control department at St. Jude Children’s Research Hospital, Memphis, Tenn.

The study was published online in JAMA Network Open.

Cancer survivors face an elevated risk for severe neurocognitive effects that can emerge 5-10 years following their diagnosis and treatment. However, it’s unclear whether new-onset neurocognitive problems can still develop a decade or more following diagnosis.

Over a long-term follow-up, Dr. Phillips and colleagues explored this question in 2,375 adult survivors of childhood cancer from the Childhood Cancer Survivor Study and 232 of their siblings.

Among the cancer cohort, 1,316 patients were survivors of acute lymphoblastic leukemia (ALL), 488 were survivors of central nervous system (CNS) tumors, and 571 had survived Hodgkin lymphoma.

The researchers determined the prevalence of new-onset neurocognitive impairment between baseline (23 years after diagnosis) and follow-up (35 years after diagnosis). New-onset neurocognitive impairment – present at follow-up but not at baseline – was defined as having a score in the worst 10% of the sibling cohort.

A higher proportion of survivors had new-onset memory impairment at follow-up compared with siblings. Specifically, about 8% of siblings had new-onset memory trouble, compared with 14% of ALL survivors treated with chemotherapy only, 26% of ALL survivors treated with cranial radiation, 35% of CNS tumor survivors, and 17% of Hodgkin lymphoma survivors.

New-onset memory impairment was associated with cranial radiation among CNS tumor survivors (relative risk [RR], 1.97) and alkylator chemotherapy at or above 8,000 mg/m² among survivors of ALL who were treated without cranial radiation (RR, 2.80). The authors also found that smoking, low educational attainment, and low physical activity were associated with an elevated risk for new-onset memory impairment.

Dr. Phillips noted that current guidelines emphasize the importance of short-term monitoring of a survivor’s neurocognitive status on the basis of that person’s chemotherapy and radiation exposures.

However, “our study suggests that all survivors, regardless of their therapy, should be screened regularly for new-onset neurocognitive problems. And this screening should be done regularly for decades after diagnosis,” he said in an interview.

Dr. Phillips also noted the importance of communicating lifestyle modifications, such as not smoking and maintaining an active lifestyle.

“We need to start early and use the power of repetition when communicating with our survivors and their families,” Dr. Phillips said. “When our families and survivors hear the word ‘exercise,’ they think of gym memberships, lifting weights, and running on treadmills. But what we really want our survivors to do is stay active.”

What this means is engaging for about 2.5 hours a week in a range of activities, such as ballet, basketball, volleyball, bicycling, or swimming.

“And if our kids want to quit after 3 months, let them know that this is okay. They just need to replace that activity with another activity,” said Dr. Phillips. “We want them to find a fun hobby that they will enjoy that will keep them active.”

The study was supported by the National Cancer Institute. Dr. Phillips has disclosed no relevant financial relationships.

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

Adult survivors of childhood cancer have an elevated risk of developing cognitive impairment years after their cancer diagnosis and treatment, new research shows.

Among more than 2,300 adult survivors of childhood cancer and their siblings, who served as controls, new-onset memory impairment emerged more often in survivors decades later.

The increased risk was associated with the cancer treatment that was provided as well as modifiable health behaviors and chronic health conditions.

Even 35 years after being diagnosed, cancer survivors who never received chemotherapies or radiation therapies known to damage the brain reported far greater memory impairment than did their siblings, first author Nicholas Phillips, MD, told this news organization.

What the findings suggest is that “we need to educate oncologists and primary care providers on the risks our survivors face long after completion of therapy,” said Dr. Phillips, of the epidemiology and cancer control department at St. Jude Children’s Research Hospital, Memphis, Tenn.

The study was published online in JAMA Network Open.

Cancer survivors face an elevated risk for severe neurocognitive effects that can emerge 5-10 years following their diagnosis and treatment. However, it’s unclear whether new-onset neurocognitive problems can still develop a decade or more following diagnosis.

Over a long-term follow-up, Dr. Phillips and colleagues explored this question in 2,375 adult survivors of childhood cancer from the Childhood Cancer Survivor Study and 232 of their siblings.

Among the cancer cohort, 1,316 patients were survivors of acute lymphoblastic leukemia (ALL), 488 were survivors of central nervous system (CNS) tumors, and 571 had survived Hodgkin lymphoma.

The researchers determined the prevalence of new-onset neurocognitive impairment between baseline (23 years after diagnosis) and follow-up (35 years after diagnosis). New-onset neurocognitive impairment – present at follow-up but not at baseline – was defined as having a score in the worst 10% of the sibling cohort.

A higher proportion of survivors had new-onset memory impairment at follow-up compared with siblings. Specifically, about 8% of siblings had new-onset memory trouble, compared with 14% of ALL survivors treated with chemotherapy only, 26% of ALL survivors treated with cranial radiation, 35% of CNS tumor survivors, and 17% of Hodgkin lymphoma survivors.

New-onset memory impairment was associated with cranial radiation among CNS tumor survivors (relative risk [RR], 1.97) and alkylator chemotherapy at or above 8,000 mg/m² among survivors of ALL who were treated without cranial radiation (RR, 2.80). The authors also found that smoking, low educational attainment, and low physical activity were associated with an elevated risk for new-onset memory impairment.

Dr. Phillips noted that current guidelines emphasize the importance of short-term monitoring of a survivor’s neurocognitive status on the basis of that person’s chemotherapy and radiation exposures.

However, “our study suggests that all survivors, regardless of their therapy, should be screened regularly for new-onset neurocognitive problems. And this screening should be done regularly for decades after diagnosis,” he said in an interview.

Dr. Phillips also noted the importance of communicating lifestyle modifications, such as not smoking and maintaining an active lifestyle.

“We need to start early and use the power of repetition when communicating with our survivors and their families,” Dr. Phillips said. “When our families and survivors hear the word ‘exercise,’ they think of gym memberships, lifting weights, and running on treadmills. But what we really want our survivors to do is stay active.”

What this means is engaging for about 2.5 hours a week in a range of activities, such as ballet, basketball, volleyball, bicycling, or swimming.

“And if our kids want to quit after 3 months, let them know that this is okay. They just need to replace that activity with another activity,” said Dr. Phillips. “We want them to find a fun hobby that they will enjoy that will keep them active.”

The study was supported by the National Cancer Institute. Dr. Phillips has disclosed no relevant financial relationships.

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

Adult survivors of childhood cancer have an elevated risk of developing cognitive impairment years after their cancer diagnosis and treatment, new research shows.

Among more than 2,300 adult survivors of childhood cancer and their siblings, who served as controls, new-onset memory impairment emerged more often in survivors decades later.

The increased risk was associated with the cancer treatment that was provided as well as modifiable health behaviors and chronic health conditions.

Even 35 years after being diagnosed, cancer survivors who never received chemotherapies or radiation therapies known to damage the brain reported far greater memory impairment than did their siblings, first author Nicholas Phillips, MD, told this news organization.

What the findings suggest is that “we need to educate oncologists and primary care providers on the risks our survivors face long after completion of therapy,” said Dr. Phillips, of the epidemiology and cancer control department at St. Jude Children’s Research Hospital, Memphis, Tenn.

The study was published online in JAMA Network Open.

Cancer survivors face an elevated risk for severe neurocognitive effects that can emerge 5-10 years following their diagnosis and treatment. However, it’s unclear whether new-onset neurocognitive problems can still develop a decade or more following diagnosis.

Over a long-term follow-up, Dr. Phillips and colleagues explored this question in 2,375 adult survivors of childhood cancer from the Childhood Cancer Survivor Study and 232 of their siblings.

Among the cancer cohort, 1,316 patients were survivors of acute lymphoblastic leukemia (ALL), 488 were survivors of central nervous system (CNS) tumors, and 571 had survived Hodgkin lymphoma.

The researchers determined the prevalence of new-onset neurocognitive impairment between baseline (23 years after diagnosis) and follow-up (35 years after diagnosis). New-onset neurocognitive impairment – present at follow-up but not at baseline – was defined as having a score in the worst 10% of the sibling cohort.

A higher proportion of survivors had new-onset memory impairment at follow-up compared with siblings. Specifically, about 8% of siblings had new-onset memory trouble, compared with 14% of ALL survivors treated with chemotherapy only, 26% of ALL survivors treated with cranial radiation, 35% of CNS tumor survivors, and 17% of Hodgkin lymphoma survivors.

New-onset memory impairment was associated with cranial radiation among CNS tumor survivors (relative risk [RR], 1.97) and alkylator chemotherapy at or above 8,000 mg/m² among survivors of ALL who were treated without cranial radiation (RR, 2.80). The authors also found that smoking, low educational attainment, and low physical activity were associated with an elevated risk for new-onset memory impairment.

Dr. Phillips noted that current guidelines emphasize the importance of short-term monitoring of a survivor’s neurocognitive status on the basis of that person’s chemotherapy and radiation exposures.

However, “our study suggests that all survivors, regardless of their therapy, should be screened regularly for new-onset neurocognitive problems. And this screening should be done regularly for decades after diagnosis,” he said in an interview.

Dr. Phillips also noted the importance of communicating lifestyle modifications, such as not smoking and maintaining an active lifestyle.

“We need to start early and use the power of repetition when communicating with our survivors and their families,” Dr. Phillips said. “When our families and survivors hear the word ‘exercise,’ they think of gym memberships, lifting weights, and running on treadmills. But what we really want our survivors to do is stay active.”

What this means is engaging for about 2.5 hours a week in a range of activities, such as ballet, basketball, volleyball, bicycling, or swimming.

“And if our kids want to quit after 3 months, let them know that this is okay. They just need to replace that activity with another activity,” said Dr. Phillips. “We want them to find a fun hobby that they will enjoy that will keep them active.”

The study was supported by the National Cancer Institute. Dr. Phillips has disclosed no relevant financial relationships.

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

Researchers may use artificial intelligence (AI) language models such as ChatGPT to write and revise scientific manuscripts, according to a new announcement from the International Committee of Medical Journal Editors. These tools should not be listed as authors, and researchers must denote how AI-assisted technologies were used, the committee said.

These new guidelines are the latest effort for medical journals to define policies for using these large-scale language models (LLMs) in scientific publication. While these AI-assisted tools can help with tasks such as writing, analyzing data, catching mistakes, and much more, they are also prone to errors, noted Casey Greene, PhD, a professor of biomedical informatics at the University of Colorado at Denver, Aurora. It is also not totally clear how information is stored and processed in these kinds of tools, and who has access to that information, he noted.

At the same time, experts argue that these AI tools could have a positive impact on the field by limiting some of the linguistic disparities in scientific publishing as well as alleviating the burden of some monotonous or mechanical tasks that come along with manuscript writing.

What experts can agree on, though, is that the use of AI tools is here to stay. “This is going to become a common tool,” Dr. Greene said. “I don’t think there’s a way out of that at this point.”
 

A change in medical publishing

OpenAI released ChatGPT in November 2022. In its own words, ChatGPT is “a deep learning model that has been trained on a massive amount of text data to understand and generate humanlike text.” Enter a question or a prompt, and it will respond. For example, when asked how the AI tool can be used in scientific publishing, ChatGPT responded:

“ChatGPT can aid scientific publishing by generating ideas, clarifying concepts, conducting preliminary literature reviews, providing proofreading and editing suggestions, and assisting with outlining and organizing scientific papers. However, it should be used as a supportive tool alongside domain expertise and validation from trusted scientific sources.”

Just a few months after ChatGPT became available, researchers began using this tool in their own work. One individual, Som Biswas, MD, a radiologist at the University of Tennessee Health Science Center in Memphis, reportedly used ChatGPT to author 16 scientific articles in just 4 months, according to the Daily Beast. Five of these articles have been published in four different journals. Dr. Biswas declined to be interviewed for this article.

There were also reports of papers with ChatGPT as one of the listed authors, which sparked backlash. In response, JAMA, Nature, and Science all published editorials in January outlining their policies for using ChatGPT and other large language models in the scientific authoring process. Editors from the journals of the American College of Cardiology and the American College of Rheumatology also updated their policies to reflect the influence of AI authoring tools.

The consensus is that AI has no place on the author byline.

“We think that’s not appropriate, because coauthorship means that you are taking responsibility for the analysis and the generation of data that are included in a manuscript. A machine that is dictated by AI can’t take responsibility,” said Daniel Solomon, MD, MPH, a rheumatologist at Brigham and Women’s Hospital, Boston, and the editor in chief of the ACR journal Arthritis & Rheumatology.
 

Issues with AI

One of the big concerns around using AI in writing is that it can generate text that seems plausible but is untrue or not supported by data. For example, Dr. Greene and colleague Milton Pividori, PhD, also of the University of Colorado, were writing a journal article about new software they developed that uses a large language model to revise scientific manuscripts.

“We used the same software to revise that article and at one point, it added a line that noted that the large language model had been fine-tuned on a data set of manuscripts from within the same field. This makes a lot of sense, and is absolutely something you could do, but was not something that we did,” Dr. Greene said. “Without a really careful review of the content, it becomes possible to invent things that were not actually done.”

In another case, ChatGPT falsely stated that a prominent law professor had been accused of sexual assault, citing a Washington Post article that did not exist.

“We live in a society where we are extremely concerned about fake news,” Dr. Pividori added, “and [these kinds of errors] could certainly exacerbate that in the scientific community, which is very concerning because science informs public policy.”

Another issue is the lack of transparency around how large language models like ChatGPT process and store data used to make queries.

“We have no idea how they are recording all the prompts and things that we input into ChatGPT and their systems,” Dr. Pividori said.

OpenAI recently addressed some privacy concerns by allowing users to turn off their chat history with the AI chatbot, so conversations cannot be used to train or improve the company’s models. But Dr. Greene noted that the terms of service “still remain pretty nebulous.”

Dr. Solomon is also concerned with researchers using these AI tools in authoring without knowing how they work. “The thing we are really concerned about is that fact that [LLMs] are a bit of a black box – people don’t really understand the methodologies,” he said.
 

A positive tool?

But despite these concerns, many think that these types of AI-assisted tools could have a positive impact on medical publishing, particularly for researchers for whom English is not their first language, noted Catherine Gao, MD, a pulmonary and critical care instructor at Northwestern University, Chicago. She recently led research comparing scientific abstracts written by ChatGPT and real abstracts and discovered that reviewers found it “surprisingly difficult” to differentiate the two.

“The majority of research is published in English,” she said in an email. “Responsible use of LLMs can potentially reduce the burden of writing for busy scientists and improve equity for those who are not native English speakers.”

Dr. Pividori agreed, adding that as a non-native English speaker, he spends much more time working on the structure and grammar of sentences when authoring a manuscript, compared with people who speak English as a first language. He noted that these tools can also be used to automate some of the more monotonous tasks that come along with writing manuscripts and allow researchers to focus on the more creative aspects.

In the future, “I want to focus more on the things that only a human can do and let these tools do all the rest of it,” he said.
 

New rules

But despite how individual researchers feel about LLMs, they agree that these AI tools are here to stay.

“I think that we should anticipate that they will become part of the medical research establishment over time, when we figure out how to use them appropriately,” Dr. Solomon said.

While the debate of how to best use AI in medical publications will continue, journal editors agree that all authors of a manuscript are solely responsible for content in articles that used AI-assisted technology.

“Authors should carefully review and edit the result because AI can generate authoritative-sounding output that can be incorrect, incomplete, or biased,” the ICMJE guidelines state. “Authors should be able to assert that there is no plagiarism in their paper, including in text and images produced by the AI.” This includes appropriate attribution of all cited materials.

The committee also recommends that authors write in both the cover letter and submitted work how AI was used in the manuscript writing process. Recently updated guidelines from the World Association of Medical Editors recommend that all prompts used to generate new text or analytical work should be provided in submitted work. Dr. Greene also noted that if authors used an AI tool to revise their work, they can include a version of the manuscript untouched by LLMs.

It is similar to a preprint, he said, but rather than publishing a version of a paper prior to peer review, someone is showing a version of a manuscript before it was reviewed and revised by AI. “This type of practice could be a path that lets us benefit from these models,” he said, “without having the drawbacks that many are concerned about.”

Dr. Solomon has financial relationships with AbbVie, Amgen, Janssen, CorEvitas, and Moderna. Both Dr. Greene and Dr. Pividori are inventors in the U.S. Provisional Patent Application No. 63/486,706 that the University of Colorado has filed for the “Publishing Infrastructure For AI-Assisted Academic Authoring” invention with the U.S. Patent and Trademark Office. Dr. Greene and Dr. Pividori also received a grant from the Alfred P. Sloan Foundation to improve their AI-based manuscript revision tool. Dr. Gao reported no relevant financial relationships.

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

Researchers may use artificial intelligence (AI) language models such as ChatGPT to write and revise scientific manuscripts, according to a new announcement from the International Committee of Medical Journal Editors. These tools should not be listed as authors, and researchers must denote how AI-assisted technologies were used, the committee said.

These new guidelines are the latest effort for medical journals to define policies for using these large-scale language models (LLMs) in scientific publication. While these AI-assisted tools can help with tasks such as writing, analyzing data, catching mistakes, and much more, they are also prone to errors, noted Casey Greene, PhD, a professor of biomedical informatics at the University of Colorado at Denver, Aurora. It is also not totally clear how information is stored and processed in these kinds of tools, and who has access to that information, he noted.

At the same time, experts argue that these AI tools could have a positive impact on the field by limiting some of the linguistic disparities in scientific publishing as well as alleviating the burden of some monotonous or mechanical tasks that come along with manuscript writing.

What experts can agree on, though, is that the use of AI tools is here to stay. “This is going to become a common tool,” Dr. Greene said. “I don’t think there’s a way out of that at this point.”
 

A change in medical publishing

OpenAI released ChatGPT in November 2022. In its own words, ChatGPT is “a deep learning model that has been trained on a massive amount of text data to understand and generate humanlike text.” Enter a question or a prompt, and it will respond. For example, when asked how the AI tool can be used in scientific publishing, ChatGPT responded:

“ChatGPT can aid scientific publishing by generating ideas, clarifying concepts, conducting preliminary literature reviews, providing proofreading and editing suggestions, and assisting with outlining and organizing scientific papers. However, it should be used as a supportive tool alongside domain expertise and validation from trusted scientific sources.”

Just a few months after ChatGPT became available, researchers began using this tool in their own work. One individual, Som Biswas, MD, a radiologist at the University of Tennessee Health Science Center in Memphis, reportedly used ChatGPT to author 16 scientific articles in just 4 months, according to the Daily Beast. Five of these articles have been published in four different journals. Dr. Biswas declined to be interviewed for this article.

There were also reports of papers with ChatGPT as one of the listed authors, which sparked backlash. In response, JAMA, Nature, and Science all published editorials in January outlining their policies for using ChatGPT and other large language models in the scientific authoring process. Editors from the journals of the American College of Cardiology and the American College of Rheumatology also updated their policies to reflect the influence of AI authoring tools.

The consensus is that AI has no place on the author byline.

“We think that’s not appropriate, because coauthorship means that you are taking responsibility for the analysis and the generation of data that are included in a manuscript. A machine that is dictated by AI can’t take responsibility,” said Daniel Solomon, MD, MPH, a rheumatologist at Brigham and Women’s Hospital, Boston, and the editor in chief of the ACR journal Arthritis & Rheumatology.
 

Issues with AI

One of the big concerns around using AI in writing is that it can generate text that seems plausible but is untrue or not supported by data. For example, Dr. Greene and colleague Milton Pividori, PhD, also of the University of Colorado, were writing a journal article about new software they developed that uses a large language model to revise scientific manuscripts.

“We used the same software to revise that article and at one point, it added a line that noted that the large language model had been fine-tuned on a data set of manuscripts from within the same field. This makes a lot of sense, and is absolutely something you could do, but was not something that we did,” Dr. Greene said. “Without a really careful review of the content, it becomes possible to invent things that were not actually done.”

In another case, ChatGPT falsely stated that a prominent law professor had been accused of sexual assault, citing a Washington Post article that did not exist.

“We live in a society where we are extremely concerned about fake news,” Dr. Pividori added, “and [these kinds of errors] could certainly exacerbate that in the scientific community, which is very concerning because science informs public policy.”

Another issue is the lack of transparency around how large language models like ChatGPT process and store data used to make queries.

“We have no idea how they are recording all the prompts and things that we input into ChatGPT and their systems,” Dr. Pividori said.

OpenAI recently addressed some privacy concerns by allowing users to turn off their chat history with the AI chatbot, so conversations cannot be used to train or improve the company’s models. But Dr. Greene noted that the terms of service “still remain pretty nebulous.”

Dr. Solomon is also concerned with researchers using these AI tools in authoring without knowing how they work. “The thing we are really concerned about is that fact that [LLMs] are a bit of a black box – people don’t really understand the methodologies,” he said.
 

A positive tool?

But despite these concerns, many think that these types of AI-assisted tools could have a positive impact on medical publishing, particularly for researchers for whom English is not their first language, noted Catherine Gao, MD, a pulmonary and critical care instructor at Northwestern University, Chicago. She recently led research comparing scientific abstracts written by ChatGPT and real abstracts and discovered that reviewers found it “surprisingly difficult” to differentiate the two.

“The majority of research is published in English,” she said in an email. “Responsible use of LLMs can potentially reduce the burden of writing for busy scientists and improve equity for those who are not native English speakers.”

Dr. Pividori agreed, adding that as a non-native English speaker, he spends much more time working on the structure and grammar of sentences when authoring a manuscript, compared with people who speak English as a first language. He noted that these tools can also be used to automate some of the more monotonous tasks that come along with writing manuscripts and allow researchers to focus on the more creative aspects.

In the future, “I want to focus more on the things that only a human can do and let these tools do all the rest of it,” he said.
 

New rules

But despite how individual researchers feel about LLMs, they agree that these AI tools are here to stay.

“I think that we should anticipate that they will become part of the medical research establishment over time, when we figure out how to use them appropriately,” Dr. Solomon said.

While the debate of how to best use AI in medical publications will continue, journal editors agree that all authors of a manuscript are solely responsible for content in articles that used AI-assisted technology.

“Authors should carefully review and edit the result because AI can generate authoritative-sounding output that can be incorrect, incomplete, or biased,” the ICMJE guidelines state. “Authors should be able to assert that there is no plagiarism in their paper, including in text and images produced by the AI.” This includes appropriate attribution of all cited materials.

The committee also recommends that authors write in both the cover letter and submitted work how AI was used in the manuscript writing process. Recently updated guidelines from the World Association of Medical Editors recommend that all prompts used to generate new text or analytical work should be provided in submitted work. Dr. Greene also noted that if authors used an AI tool to revise their work, they can include a version of the manuscript untouched by LLMs.

It is similar to a preprint, he said, but rather than publishing a version of a paper prior to peer review, someone is showing a version of a manuscript before it was reviewed and revised by AI. “This type of practice could be a path that lets us benefit from these models,” he said, “without having the drawbacks that many are concerned about.”

Dr. Solomon has financial relationships with AbbVie, Amgen, Janssen, CorEvitas, and Moderna. Both Dr. Greene and Dr. Pividori are inventors in the U.S. Provisional Patent Application No. 63/486,706 that the University of Colorado has filed for the “Publishing Infrastructure For AI-Assisted Academic Authoring” invention with the U.S. Patent and Trademark Office. Dr. Greene and Dr. Pividori also received a grant from the Alfred P. Sloan Foundation to improve their AI-based manuscript revision tool. Dr. Gao reported no relevant financial relationships.

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

Researchers may use artificial intelligence (AI) language models such as ChatGPT to write and revise scientific manuscripts, according to a new announcement from the International Committee of Medical Journal Editors. These tools should not be listed as authors, and researchers must denote how AI-assisted technologies were used, the committee said.

These new guidelines are the latest effort for medical journals to define policies for using these large-scale language models (LLMs) in scientific publication. While these AI-assisted tools can help with tasks such as writing, analyzing data, catching mistakes, and much more, they are also prone to errors, noted Casey Greene, PhD, a professor of biomedical informatics at the University of Colorado at Denver, Aurora. It is also not totally clear how information is stored and processed in these kinds of tools, and who has access to that information, he noted.

At the same time, experts argue that these AI tools could have a positive impact on the field by limiting some of the linguistic disparities in scientific publishing as well as alleviating the burden of some monotonous or mechanical tasks that come along with manuscript writing.

What experts can agree on, though, is that the use of AI tools is here to stay. “This is going to become a common tool,” Dr. Greene said. “I don’t think there’s a way out of that at this point.”
 

A change in medical publishing

OpenAI released ChatGPT in November 2022. In its own words, ChatGPT is “a deep learning model that has been trained on a massive amount of text data to understand and generate humanlike text.” Enter a question or a prompt, and it will respond. For example, when asked how the AI tool can be used in scientific publishing, ChatGPT responded:

“ChatGPT can aid scientific publishing by generating ideas, clarifying concepts, conducting preliminary literature reviews, providing proofreading and editing suggestions, and assisting with outlining and organizing scientific papers. However, it should be used as a supportive tool alongside domain expertise and validation from trusted scientific sources.”

Just a few months after ChatGPT became available, researchers began using this tool in their own work. One individual, Som Biswas, MD, a radiologist at the University of Tennessee Health Science Center in Memphis, reportedly used ChatGPT to author 16 scientific articles in just 4 months, according to the Daily Beast. Five of these articles have been published in four different journals. Dr. Biswas declined to be interviewed for this article.

There were also reports of papers with ChatGPT as one of the listed authors, which sparked backlash. In response, JAMA, Nature, and Science all published editorials in January outlining their policies for using ChatGPT and other large language models in the scientific authoring process. Editors from the journals of the American College of Cardiology and the American College of Rheumatology also updated their policies to reflect the influence of AI authoring tools.

The consensus is that AI has no place on the author byline.

“We think that’s not appropriate, because coauthorship means that you are taking responsibility for the analysis and the generation of data that are included in a manuscript. A machine that is dictated by AI can’t take responsibility,” said Daniel Solomon, MD, MPH, a rheumatologist at Brigham and Women’s Hospital, Boston, and the editor in chief of the ACR journal Arthritis & Rheumatology.
 

Issues with AI

One of the big concerns around using AI in writing is that it can generate text that seems plausible but is untrue or not supported by data. For example, Dr. Greene and colleague Milton Pividori, PhD, also of the University of Colorado, were writing a journal article about new software they developed that uses a large language model to revise scientific manuscripts.

“We used the same software to revise that article and at one point, it added a line that noted that the large language model had been fine-tuned on a data set of manuscripts from within the same field. This makes a lot of sense, and is absolutely something you could do, but was not something that we did,” Dr. Greene said. “Without a really careful review of the content, it becomes possible to invent things that were not actually done.”

In another case, ChatGPT falsely stated that a prominent law professor had been accused of sexual assault, citing a Washington Post article that did not exist.

“We live in a society where we are extremely concerned about fake news,” Dr. Pividori added, “and [these kinds of errors] could certainly exacerbate that in the scientific community, which is very concerning because science informs public policy.”

Another issue is the lack of transparency around how large language models like ChatGPT process and store data used to make queries.

“We have no idea how they are recording all the prompts and things that we input into ChatGPT and their systems,” Dr. Pividori said.

OpenAI recently addressed some privacy concerns by allowing users to turn off their chat history with the AI chatbot, so conversations cannot be used to train or improve the company’s models. But Dr. Greene noted that the terms of service “still remain pretty nebulous.”

Dr. Solomon is also concerned with researchers using these AI tools in authoring without knowing how they work. “The thing we are really concerned about is that fact that [LLMs] are a bit of a black box – people don’t really understand the methodologies,” he said.
 

A positive tool?

But despite these concerns, many think that these types of AI-assisted tools could have a positive impact on medical publishing, particularly for researchers for whom English is not their first language, noted Catherine Gao, MD, a pulmonary and critical care instructor at Northwestern University, Chicago. She recently led research comparing scientific abstracts written by ChatGPT and real abstracts and discovered that reviewers found it “surprisingly difficult” to differentiate the two.

“The majority of research is published in English,” she said in an email. “Responsible use of LLMs can potentially reduce the burden of writing for busy scientists and improve equity for those who are not native English speakers.”

Dr. Pividori agreed, adding that as a non-native English speaker, he spends much more time working on the structure and grammar of sentences when authoring a manuscript, compared with people who speak English as a first language. He noted that these tools can also be used to automate some of the more monotonous tasks that come along with writing manuscripts and allow researchers to focus on the more creative aspects.

In the future, “I want to focus more on the things that only a human can do and let these tools do all the rest of it,” he said.
 

New rules

But despite how individual researchers feel about LLMs, they agree that these AI tools are here to stay.

“I think that we should anticipate that they will become part of the medical research establishment over time, when we figure out how to use them appropriately,” Dr. Solomon said.

While the debate of how to best use AI in medical publications will continue, journal editors agree that all authors of a manuscript are solely responsible for content in articles that used AI-assisted technology.

“Authors should carefully review and edit the result because AI can generate authoritative-sounding output that can be incorrect, incomplete, or biased,” the ICMJE guidelines state. “Authors should be able to assert that there is no plagiarism in their paper, including in text and images produced by the AI.” This includes appropriate attribution of all cited materials.

The committee also recommends that authors write in both the cover letter and submitted work how AI was used in the manuscript writing process. Recently updated guidelines from the World Association of Medical Editors recommend that all prompts used to generate new text or analytical work should be provided in submitted work. Dr. Greene also noted that if authors used an AI tool to revise their work, they can include a version of the manuscript untouched by LLMs.

It is similar to a preprint, he said, but rather than publishing a version of a paper prior to peer review, someone is showing a version of a manuscript before it was reviewed and revised by AI. “This type of practice could be a path that lets us benefit from these models,” he said, “without having the drawbacks that many are concerned about.”

Dr. Solomon has financial relationships with AbbVie, Amgen, Janssen, CorEvitas, and Moderna. Both Dr. Greene and Dr. Pividori are inventors in the U.S. Provisional Patent Application No. 63/486,706 that the University of Colorado has filed for the “Publishing Infrastructure For AI-Assisted Academic Authoring” invention with the U.S. Patent and Trademark Office. Dr. Greene and Dr. Pividori also received a grant from the Alfred P. Sloan Foundation to improve their AI-based manuscript revision tool. Dr. Gao reported no relevant financial relationships.

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

INDIANAPOLIS – Maintaining a regular healthy sleep schedule may help guard against premature death, new research suggests.

In a diverse group of older adults, those with regular and optimal sleep had about a 40% lower risk of dying of any cause during follow-up compared with peers who had irregular and insufficient sleep.

“If sleep were an 8-hour pill, it would be beneficial to take the full dose at regular times consistently,” lead researcher Joon Chung, PhD, of Harvard Medical School and Brigham and Women’s Hospital, Boston, said in a news release.

The findings were presented at the annual meeting of the Associated Professional Sleep Societies.
 

Broad adverse health effects

“Evidence is mounting that irregular sleep is associated with pretty broad adverse health outcomes, most prominently cardiometabolic disease, obesity, and cardiovascular disease,” Dr. Chungsaid in an interview.

JGI/Tom Grill/Getty Images

In the current study, the researchers estimated the association of regular sleep of optimal sleep duration with all-cause mortality using data from 1,759 adults the Multi-Ethnic Study of Atherosclerosis Sleep Study.

Sleep regularity and duration were classified using 7 days of data gathered by wrist actigraphy. Adults were categorized as “regular-optimal” sleepers (n = 1,015) or “irregular-insufficient” sleepers (n = 744).

During 7 years of follow-up, 176 people died. In the fully adjusted model, the regular-optimal group had a 39% lower mortality risk compared with the irregular-insufficient sleep group (hazard ratio, 0.61;95% confidence interval [CI], 0.45-0.83). The findings were robust in sensitivity analyses.

The regular and optimal duration sleep pattern maps behaviorally to regular bed and wake times, suggesting potential health benefits of adherence to recommended sleep practices, the researchers noted.

“Results suggest benefits of expanding the public conversation on getting ‘a good night’s sleep’ and broadening this goal to getting many good nights of sleep, in a row, on weekdays and weekends,” Dr. Chung said in the release.

He further said that “getting adequate, regular sleep seems to be something that is good for all. I don’t know of anyone who wouldn’t benefit.”

Fariha Abassi-Feinberg, MD, spokesperson for the American Academy of Sleep Medicine and sleep specialist with the Millennium Physician Group, Fort Myers, Fla., agreed.

“We know our bodies have an internal clock, known as the circadian rhythm, which regulates various biological processes, including sleep-wake cycles. Sticking to a consistent sleep schedule allows your body to align its natural rhythm with the external day-night cycle. This synchronization promotes better sleep quality and therefore better health,” said Dr. Abassi-Feinberg, who wasn’t involved in the study.

“The AASM recommends adults try to aim for at least 7 hours of sleep and I often tell my patients that keeping a regular routine is best for your sleep and health,” she said in an interview.

Funding for the study was provided by the American Academy of Sleep Medicine Foundation and the National Institutes of Health. Dr. Chung and Dr. Abassi-Feinberg report no relevant financial relationships.

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

INDIANAPOLIS – Maintaining a regular healthy sleep schedule may help guard against premature death, new research suggests.

In a diverse group of older adults, those with regular and optimal sleep had about a 40% lower risk of dying of any cause during follow-up compared with peers who had irregular and insufficient sleep.

“If sleep were an 8-hour pill, it would be beneficial to take the full dose at regular times consistently,” lead researcher Joon Chung, PhD, of Harvard Medical School and Brigham and Women’s Hospital, Boston, said in a news release.

The findings were presented at the annual meeting of the Associated Professional Sleep Societies.
 

Broad adverse health effects

“Evidence is mounting that irregular sleep is associated with pretty broad adverse health outcomes, most prominently cardiometabolic disease, obesity, and cardiovascular disease,” Dr. Chungsaid in an interview.

JGI/Tom Grill/Getty Images

In the current study, the researchers estimated the association of regular sleep of optimal sleep duration with all-cause mortality using data from 1,759 adults the Multi-Ethnic Study of Atherosclerosis Sleep Study.

Sleep regularity and duration were classified using 7 days of data gathered by wrist actigraphy. Adults were categorized as “regular-optimal” sleepers (n = 1,015) or “irregular-insufficient” sleepers (n = 744).

During 7 years of follow-up, 176 people died. In the fully adjusted model, the regular-optimal group had a 39% lower mortality risk compared with the irregular-insufficient sleep group (hazard ratio, 0.61;95% confidence interval [CI], 0.45-0.83). The findings were robust in sensitivity analyses.

The regular and optimal duration sleep pattern maps behaviorally to regular bed and wake times, suggesting potential health benefits of adherence to recommended sleep practices, the researchers noted.

“Results suggest benefits of expanding the public conversation on getting ‘a good night’s sleep’ and broadening this goal to getting many good nights of sleep, in a row, on weekdays and weekends,” Dr. Chung said in the release.

He further said that “getting adequate, regular sleep seems to be something that is good for all. I don’t know of anyone who wouldn’t benefit.”

Fariha Abassi-Feinberg, MD, spokesperson for the American Academy of Sleep Medicine and sleep specialist with the Millennium Physician Group, Fort Myers, Fla., agreed.

“We know our bodies have an internal clock, known as the circadian rhythm, which regulates various biological processes, including sleep-wake cycles. Sticking to a consistent sleep schedule allows your body to align its natural rhythm with the external day-night cycle. This synchronization promotes better sleep quality and therefore better health,” said Dr. Abassi-Feinberg, who wasn’t involved in the study.

“The AASM recommends adults try to aim for at least 7 hours of sleep and I often tell my patients that keeping a regular routine is best for your sleep and health,” she said in an interview.

Funding for the study was provided by the American Academy of Sleep Medicine Foundation and the National Institutes of Health. Dr. Chung and Dr. Abassi-Feinberg report no relevant financial relationships.

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

INDIANAPOLIS – Maintaining a regular healthy sleep schedule may help guard against premature death, new research suggests.

In a diverse group of older adults, those with regular and optimal sleep had about a 40% lower risk of dying of any cause during follow-up compared with peers who had irregular and insufficient sleep.

“If sleep were an 8-hour pill, it would be beneficial to take the full dose at regular times consistently,” lead researcher Joon Chung, PhD, of Harvard Medical School and Brigham and Women’s Hospital, Boston, said in a news release.

The findings were presented at the annual meeting of the Associated Professional Sleep Societies.
 

Broad adverse health effects

“Evidence is mounting that irregular sleep is associated with pretty broad adverse health outcomes, most prominently cardiometabolic disease, obesity, and cardiovascular disease,” Dr. Chungsaid in an interview.

JGI/Tom Grill/Getty Images

In the current study, the researchers estimated the association of regular sleep of optimal sleep duration with all-cause mortality using data from 1,759 adults the Multi-Ethnic Study of Atherosclerosis Sleep Study.

Sleep regularity and duration were classified using 7 days of data gathered by wrist actigraphy. Adults were categorized as “regular-optimal” sleepers (n = 1,015) or “irregular-insufficient” sleepers (n = 744).

During 7 years of follow-up, 176 people died. In the fully adjusted model, the regular-optimal group had a 39% lower mortality risk compared with the irregular-insufficient sleep group (hazard ratio, 0.61;95% confidence interval [CI], 0.45-0.83). The findings were robust in sensitivity analyses.

The regular and optimal duration sleep pattern maps behaviorally to regular bed and wake times, suggesting potential health benefits of adherence to recommended sleep practices, the researchers noted.

“Results suggest benefits of expanding the public conversation on getting ‘a good night’s sleep’ and broadening this goal to getting many good nights of sleep, in a row, on weekdays and weekends,” Dr. Chung said in the release.

He further said that “getting adequate, regular sleep seems to be something that is good for all. I don’t know of anyone who wouldn’t benefit.”

Fariha Abassi-Feinberg, MD, spokesperson for the American Academy of Sleep Medicine and sleep specialist with the Millennium Physician Group, Fort Myers, Fla., agreed.

“We know our bodies have an internal clock, known as the circadian rhythm, which regulates various biological processes, including sleep-wake cycles. Sticking to a consistent sleep schedule allows your body to align its natural rhythm with the external day-night cycle. This synchronization promotes better sleep quality and therefore better health,” said Dr. Abassi-Feinberg, who wasn’t involved in the study.

“The AASM recommends adults try to aim for at least 7 hours of sleep and I often tell my patients that keeping a regular routine is best for your sleep and health,” she said in an interview.

Funding for the study was provided by the American Academy of Sleep Medicine Foundation and the National Institutes of Health. Dr. Chung and Dr. Abassi-Feinberg report no relevant financial relationships.

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

Muscle adiposity may be a novel risk factor for cognitive decline in older adults, new research suggests.

Investigators assessed muscle fat in more than 1,600 adults in their 70s and evaluated their cognitive function over a 10-year period. They found that increases in muscle adiposity from year 1 to year 6 were associated with greater cognitive decline over time, independent of total weight, other fat deposits, muscle characteristics, and traditional dementia risk factors.

The findings were similar between Black and White people and between men and women.

“Increasing adiposity – or fat deposition – in skeletal muscles predicted faster cognitive decline, irrespective of demographics or other disease, and this effect was distinct from that of other types of fat or other muscle characteristics, such as strength or mass,” study investigator Caterina Rosano MD, MPH, professor of epidemiology at the University of Pittsburgh, said in an interview.

The study was published in the Journal of the American Geriatrics Society.
 

Biologically plausible

“There has been a growing recognition that overall adiposity and muscle measures, such as strength and mass, are individual indicators of future dementia risk and both strengthen the algorithms to predict cognitive decline,” said Dr. Rosano, associate director for clinical translation at the University of Pittsburgh’s Aging Institute. “However, adiposity in the muscle has not been examined.”

Some evidence supports a “biologically plausible link” between muscle adiposity and dementia risk. For example, muscle adiposity increases the risk for type 2 diabetes and hypertension, both of which are dementia risk factors.

Skeletal muscle adiposity increases with older age, even in older adults who lose weight, and is “highly prevalent” among older adults of African ancestry.

The researchers examined a large, biracial sample of older adults participating in the Health, Aging and Body Composition study, which enrolled men and women aged between 70 and 79 years. Participants were followed for an average of 9.0 ± 1.8 years.

During years 1 and 6, participants’ body composition was analyzed, including intermuscular adipose tissue (IMAT), visceral and subcutaneous adiposity, total fat mass, and muscle area.

In years 1, 3, 5, 8, and 10, participants’ cognition was measured using the modified Mini-Mental State (3MS) exam.

The main independent variable was 5-year change in thigh IMAT (year 6 minus year 1), and the main dependent variable was 3MS decline (from year 5 to year 10).

The researchers adjusted all the models for traditional dementia risk factors at baseline including 3MS, education, apo E4 allele, diabetes, hypertension, and physical activity and also calculated interactions between IMAT change by race or sex.

These models also accounted for change in muscle strength, muscle area, body weight, abdominal subcutaneous and visceral adiposity, and total body fat mass as well as cytokines related to adiposity.
 

‘Rich and engaging crosstalk’

The final sample included 1634 participants (mean age, 73.38 years at baseline; 48% female; 35% Black; mean baseline 3MS score, 91.6).

Thigh IMAT increased by 39.0% in all participants from year 1 to year 6, which corresponded to an increase of 4.85 cm² or 0.97 cm²/year. During the same time period, muscle strength decreased by 14.0% (P < .05), although thigh muscle area remained stable, decreasing less than 0.5%.

There were decreases in both abdominal subcutaneous and visceral adiposity of 3.92% and 6.43%, respectively (P < .05). There was a decrease of 3.3% in 3MS from year 5 to year 10.

Several variables were associated with 3MS decline, independent of any change in thigh IMAT: older age, less education, and having at least one copy of the APOe4 allele. These variables were included in the model of IMAT change predicting 3MS change.

A statistically significant association of IMAT increase with 3MS decline was found. The IMAT increase of 4.85 cm² corresponded to a 3MS decline of an additional 3.6 points (P < .0001) from year 5 to year 10, “indicating a clinically important change.”

The association between increasing thigh IMAT with declining 3MS “remained statistically significant” after adjusting for race, age, education, and apo E4 (P < .0001) and was independent of changes in thigh muscle area, muscle strength, and other adiposity measures.

In participants with increased IMAT in years 1-6, the mean 3MS score fell to approximately 87 points at year 10, compared with those without increased IMAT, with a 3MS score that dropped to approximately 89 points.

Interactions by race and sex were not statistically significant (P > .08).

“Our results suggest that adiposity in muscles can predict cognitive decline, in addition to (not instead of) other traditional dementia risk factors,” said Dr. Rosano.

There is “a rich and engaging crosstalk between muscle, adipose tissue, and the brain all throughout our lives, happening through factors released in the bloodstream that can reach the brain, however, the specific identity of the factors responsible for the crosstalk of muscle adiposity and brain in older adults has not yet been discovered,” she noted.

Although muscle adiposity is “not yet routinely measured in clinical settings, it is being measured opportunistically on clinical CT scans obtained as part of routine patient care,” she added. “These CT measurements have already been validated in many studies of older adults; thus, clinicians could have access to this novel information without additional cost, time, or radiation exposure.”
 

Causality not proven

In a comment, Bruce Albala, PhD, professor, department of environmental and occupational health, University of California, Irvine, noted that the 3MS assessment is scored on a 100-point scale, with a score less than 78 “generally regarded as indicating cognitive impairment or approaching a dementia condition.” In the current study, the mean 3MS score of participants with increased IMAT was still “well above the dementia cut-off.”

Moreover, “even if there is a relationship or correlation between IMAT and cognition, this does not prove or even suggest causality, especially from a biological mechanistic approach,” said Dr. Albaba, an adjunct professor of neurology, who was not involved in the study. “Clearly, more research is needed even to understand the relationship between these two factors.”

The study was supported by the National Institute on Aging. Dr. Rosano and coauthors and Dr. Albala declared no relevant financial relationships.

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

Muscle adiposity may be a novel risk factor for cognitive decline in older adults, new research suggests.

Investigators assessed muscle fat in more than 1,600 adults in their 70s and evaluated their cognitive function over a 10-year period. They found that increases in muscle adiposity from year 1 to year 6 were associated with greater cognitive decline over time, independent of total weight, other fat deposits, muscle characteristics, and traditional dementia risk factors.

The findings were similar between Black and White people and between men and women.

“Increasing adiposity – or fat deposition – in skeletal muscles predicted faster cognitive decline, irrespective of demographics or other disease, and this effect was distinct from that of other types of fat or other muscle characteristics, such as strength or mass,” study investigator Caterina Rosano MD, MPH, professor of epidemiology at the University of Pittsburgh, said in an interview.

The study was published in the Journal of the American Geriatrics Society.
 

Biologically plausible

“There has been a growing recognition that overall adiposity and muscle measures, such as strength and mass, are individual indicators of future dementia risk and both strengthen the algorithms to predict cognitive decline,” said Dr. Rosano, associate director for clinical translation at the University of Pittsburgh’s Aging Institute. “However, adiposity in the muscle has not been examined.”

Some evidence supports a “biologically plausible link” between muscle adiposity and dementia risk. For example, muscle adiposity increases the risk for type 2 diabetes and hypertension, both of which are dementia risk factors.

Skeletal muscle adiposity increases with older age, even in older adults who lose weight, and is “highly prevalent” among older adults of African ancestry.

The researchers examined a large, biracial sample of older adults participating in the Health, Aging and Body Composition study, which enrolled men and women aged between 70 and 79 years. Participants were followed for an average of 9.0 ± 1.8 years.

During years 1 and 6, participants’ body composition was analyzed, including intermuscular adipose tissue (IMAT), visceral and subcutaneous adiposity, total fat mass, and muscle area.

In years 1, 3, 5, 8, and 10, participants’ cognition was measured using the modified Mini-Mental State (3MS) exam.

The main independent variable was 5-year change in thigh IMAT (year 6 minus year 1), and the main dependent variable was 3MS decline (from year 5 to year 10).

The researchers adjusted all the models for traditional dementia risk factors at baseline including 3MS, education, apo E4 allele, diabetes, hypertension, and physical activity and also calculated interactions between IMAT change by race or sex.

These models also accounted for change in muscle strength, muscle area, body weight, abdominal subcutaneous and visceral adiposity, and total body fat mass as well as cytokines related to adiposity.
 

‘Rich and engaging crosstalk’

The final sample included 1634 participants (mean age, 73.38 years at baseline; 48% female; 35% Black; mean baseline 3MS score, 91.6).

Thigh IMAT increased by 39.0% in all participants from year 1 to year 6, which corresponded to an increase of 4.85 cm² or 0.97 cm²/year. During the same time period, muscle strength decreased by 14.0% (P < .05), although thigh muscle area remained stable, decreasing less than 0.5%.

There were decreases in both abdominal subcutaneous and visceral adiposity of 3.92% and 6.43%, respectively (P < .05). There was a decrease of 3.3% in 3MS from year 5 to year 10.

Several variables were associated with 3MS decline, independent of any change in thigh IMAT: older age, less education, and having at least one copy of the APOe4 allele. These variables were included in the model of IMAT change predicting 3MS change.

A statistically significant association of IMAT increase with 3MS decline was found. The IMAT increase of 4.85 cm² corresponded to a 3MS decline of an additional 3.6 points (P < .0001) from year 5 to year 10, “indicating a clinically important change.”

The association between increasing thigh IMAT with declining 3MS “remained statistically significant” after adjusting for race, age, education, and apo E4 (P < .0001) and was independent of changes in thigh muscle area, muscle strength, and other adiposity measures.

In participants with increased IMAT in years 1-6, the mean 3MS score fell to approximately 87 points at year 10, compared with those without increased IMAT, with a 3MS score that dropped to approximately 89 points.

Interactions by race and sex were not statistically significant (P > .08).

“Our results suggest that adiposity in muscles can predict cognitive decline, in addition to (not instead of) other traditional dementia risk factors,” said Dr. Rosano.

There is “a rich and engaging crosstalk between muscle, adipose tissue, and the brain all throughout our lives, happening through factors released in the bloodstream that can reach the brain, however, the specific identity of the factors responsible for the crosstalk of muscle adiposity and brain in older adults has not yet been discovered,” she noted.

Although muscle adiposity is “not yet routinely measured in clinical settings, it is being measured opportunistically on clinical CT scans obtained as part of routine patient care,” she added. “These CT measurements have already been validated in many studies of older adults; thus, clinicians could have access to this novel information without additional cost, time, or radiation exposure.”
 

Causality not proven

In a comment, Bruce Albala, PhD, professor, department of environmental and occupational health, University of California, Irvine, noted that the 3MS assessment is scored on a 100-point scale, with a score less than 78 “generally regarded as indicating cognitive impairment or approaching a dementia condition.” In the current study, the mean 3MS score of participants with increased IMAT was still “well above the dementia cut-off.”

Moreover, “even if there is a relationship or correlation between IMAT and cognition, this does not prove or even suggest causality, especially from a biological mechanistic approach,” said Dr. Albaba, an adjunct professor of neurology, who was not involved in the study. “Clearly, more research is needed even to understand the relationship between these two factors.”

The study was supported by the National Institute on Aging. Dr. Rosano and coauthors and Dr. Albala declared no relevant financial relationships.

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

Muscle adiposity may be a novel risk factor for cognitive decline in older adults, new research suggests.

Investigators assessed muscle fat in more than 1,600 adults in their 70s and evaluated their cognitive function over a 10-year period. They found that increases in muscle adiposity from year 1 to year 6 were associated with greater cognitive decline over time, independent of total weight, other fat deposits, muscle characteristics, and traditional dementia risk factors.

The findings were similar between Black and White people and between men and women.

“Increasing adiposity – or fat deposition – in skeletal muscles predicted faster cognitive decline, irrespective of demographics or other disease, and this effect was distinct from that of other types of fat or other muscle characteristics, such as strength or mass,” study investigator Caterina Rosano MD, MPH, professor of epidemiology at the University of Pittsburgh, said in an interview.

The study was published in the Journal of the American Geriatrics Society.
 

Biologically plausible

“There has been a growing recognition that overall adiposity and muscle measures, such as strength and mass, are individual indicators of future dementia risk and both strengthen the algorithms to predict cognitive decline,” said Dr. Rosano, associate director for clinical translation at the University of Pittsburgh’s Aging Institute. “However, adiposity in the muscle has not been examined.”

Some evidence supports a “biologically plausible link” between muscle adiposity and dementia risk. For example, muscle adiposity increases the risk for type 2 diabetes and hypertension, both of which are dementia risk factors.

Skeletal muscle adiposity increases with older age, even in older adults who lose weight, and is “highly prevalent” among older adults of African ancestry.

The researchers examined a large, biracial sample of older adults participating in the Health, Aging and Body Composition study, which enrolled men and women aged between 70 and 79 years. Participants were followed for an average of 9.0 ± 1.8 years.

During years 1 and 6, participants’ body composition was analyzed, including intermuscular adipose tissue (IMAT), visceral and subcutaneous adiposity, total fat mass, and muscle area.

In years 1, 3, 5, 8, and 10, participants’ cognition was measured using the modified Mini-Mental State (3MS) exam.

The main independent variable was 5-year change in thigh IMAT (year 6 minus year 1), and the main dependent variable was 3MS decline (from year 5 to year 10).

The researchers adjusted all the models for traditional dementia risk factors at baseline including 3MS, education, apo E4 allele, diabetes, hypertension, and physical activity and also calculated interactions between IMAT change by race or sex.

These models also accounted for change in muscle strength, muscle area, body weight, abdominal subcutaneous and visceral adiposity, and total body fat mass as well as cytokines related to adiposity.
 

‘Rich and engaging crosstalk’

The final sample included 1634 participants (mean age, 73.38 years at baseline; 48% female; 35% Black; mean baseline 3MS score, 91.6).

Thigh IMAT increased by 39.0% in all participants from year 1 to year 6, which corresponded to an increase of 4.85 cm² or 0.97 cm²/year. During the same time period, muscle strength decreased by 14.0% (P < .05), although thigh muscle area remained stable, decreasing less than 0.5%.

There were decreases in both abdominal subcutaneous and visceral adiposity of 3.92% and 6.43%, respectively (P < .05). There was a decrease of 3.3% in 3MS from year 5 to year 10.

Several variables were associated with 3MS decline, independent of any change in thigh IMAT: older age, less education, and having at least one copy of the APOe4 allele. These variables were included in the model of IMAT change predicting 3MS change.

A statistically significant association of IMAT increase with 3MS decline was found. The IMAT increase of 4.85 cm² corresponded to a 3MS decline of an additional 3.6 points (P < .0001) from year 5 to year 10, “indicating a clinically important change.”

The association between increasing thigh IMAT with declining 3MS “remained statistically significant” after adjusting for race, age, education, and apo E4 (P < .0001) and was independent of changes in thigh muscle area, muscle strength, and other adiposity measures.

In participants with increased IMAT in years 1-6, the mean 3MS score fell to approximately 87 points at year 10, compared with those without increased IMAT, with a 3MS score that dropped to approximately 89 points.

Interactions by race and sex were not statistically significant (P > .08).

“Our results suggest that adiposity in muscles can predict cognitive decline, in addition to (not instead of) other traditional dementia risk factors,” said Dr. Rosano.

There is “a rich and engaging crosstalk between muscle, adipose tissue, and the brain all throughout our lives, happening through factors released in the bloodstream that can reach the brain, however, the specific identity of the factors responsible for the crosstalk of muscle adiposity and brain in older adults has not yet been discovered,” she noted.

Although muscle adiposity is “not yet routinely measured in clinical settings, it is being measured opportunistically on clinical CT scans obtained as part of routine patient care,” she added. “These CT measurements have already been validated in many studies of older adults; thus, clinicians could have access to this novel information without additional cost, time, or radiation exposure.”
 

Causality not proven

In a comment, Bruce Albala, PhD, professor, department of environmental and occupational health, University of California, Irvine, noted that the 3MS assessment is scored on a 100-point scale, with a score less than 78 “generally regarded as indicating cognitive impairment or approaching a dementia condition.” In the current study, the mean 3MS score of participants with increased IMAT was still “well above the dementia cut-off.”

Moreover, “even if there is a relationship or correlation between IMAT and cognition, this does not prove or even suggest causality, especially from a biological mechanistic approach,” said Dr. Albaba, an adjunct professor of neurology, who was not involved in the study. “Clearly, more research is needed even to understand the relationship between these two factors.”

The study was supported by the National Institute on Aging. Dr. Rosano and coauthors and Dr. Albala declared no relevant financial relationships.

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