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Can an Algorithm Optimize Caffeine Dosing Strategies?
Adjusting the timing of caffeine intake may improve psychomotor vigilance without increasing total caffeine consumption.
BALTIMORE—A new algorithm may be key to optimizing alertness with caffeine, a study suggests. Caffeine is the most widely used stimulant to counter the effects of sleep loss on neurobehavioral performance, but no tools exist to guide the timing and amount of caffeine consumption to optimize its benefits, said Jaques Reifman, PhD, and colleagues. “By using our algorithm, which determines when and how much caffeine a subject should consume, we can improve alertness by up to 64% while consuming the same total amount of caffeine” as in previous studies of caffeine use during chronic sleep restriction, said Dr. Reifman. “Alternatively, a subject can reduce caffeine consumption by up to 65% and still achieve equivalent improvements in alertness.” 
The study was presented at the 32nd Annual Meeting of the Associated Professional Sleep Societies and published online ahead of print in the Journal of Sleep Research. Dr. Reifman is a senior research scientist and Director of the Department of Defense Biotechnology High Performance Computing Software Applications Institute and the Telemedicine and Advanced Technology Research Center at the US Army Medical Research and Materiel Command in Fort Detrick, Maryland.
The researchers used a validated mathematical model that predicts the effects of sleep loss and caffeine on psychomotor vigilance task (PVT) performance and combined it with a computationally efficient optimization algorithm to determine when and how much caffeine should be consumed to safely maximize alertness during sleep loss. They used the algorithm to determine ideal dosing strategies for four previously published experimental studies of chronic sleep restriction. The researchers computed dosing strategies that enhanced the predicted PVT performance using the same total amount of caffeine as in the original studies, as well as strategies that achieved an equivalent level of performance, but used less caffeine overall.
The algorithm tailored the timing and amount of caffeine to the sleep–wake schedule of each study condition to maximize caffeine’s benefits, such as by postponing the first dose on certain days, prescribing more caffeine during longer periods of wakefulness, and allocating doses near the end of the day.
The algorithm is designed to predict caffeine’s effects on simple tasks, so dosing strategies for other tasks may differ, the researchers noted. In addition, the algorithm does not account for the effects of sleep debt on caffeine’s benefits or individual differences in caffeine sensitivity.
Suggested Reading
Vital-Lopez FG, Ramakrishnan S, Doty TJ, et al. Caffeine dosing strategies to optimize alertness during sleep loss. J Sleep Res. 2018 May 28 [Epub ahead of print].
Adjusting the timing of caffeine intake may improve psychomotor vigilance without increasing total caffeine consumption.
Adjusting the timing of caffeine intake may improve psychomotor vigilance without increasing total caffeine consumption.
BALTIMORE—A new algorithm may be key to optimizing alertness with caffeine, a study suggests. Caffeine is the most widely used stimulant to counter the effects of sleep loss on neurobehavioral performance, but no tools exist to guide the timing and amount of caffeine consumption to optimize its benefits, said Jaques Reifman, PhD, and colleagues. “By using our algorithm, which determines when and how much caffeine a subject should consume, we can improve alertness by up to 64% while consuming the same total amount of caffeine” as in previous studies of caffeine use during chronic sleep restriction, said Dr. Reifman. “Alternatively, a subject can reduce caffeine consumption by up to 65% and still achieve equivalent improvements in alertness.”
The study was presented at the 32nd Annual Meeting of the Associated Professional Sleep Societies and published online ahead of print in the Journal of Sleep Research. Dr. Reifman is a senior research scientist and Director of the Department of Defense Biotechnology High Performance Computing Software Applications Institute and the Telemedicine and Advanced Technology Research Center at the US Army Medical Research and Materiel Command in Fort Detrick, Maryland.
The researchers used a validated mathematical model that predicts the effects of sleep loss and caffeine on psychomotor vigilance task (PVT) performance and combined it with a computationally efficient optimization algorithm to determine when and how much caffeine should be consumed to safely maximize alertness during sleep loss. They used the algorithm to determine ideal dosing strategies for four previously published experimental studies of chronic sleep restriction. The researchers computed dosing strategies that enhanced the predicted PVT performance using the same total amount of caffeine as in the original studies, as well as strategies that achieved an equivalent level of performance, but used less caffeine overall.
The algorithm tailored the timing and amount of caffeine to the sleep–wake schedule of each study condition to maximize caffeine’s benefits, such as by postponing the first dose on certain days, prescribing more caffeine during longer periods of wakefulness, and allocating doses near the end of the day.
The algorithm is designed to predict caffeine’s effects on simple tasks, so dosing strategies for other tasks may differ, the researchers noted. In addition, the algorithm does not account for the effects of sleep debt on caffeine’s benefits or individual differences in caffeine sensitivity.
Suggested Reading
Vital-Lopez FG, Ramakrishnan S, Doty TJ, et al. Caffeine dosing strategies to optimize alertness during sleep loss. J Sleep Res. 2018 May 28 [Epub ahead of print].
BALTIMORE—A new algorithm may be key to optimizing alertness with caffeine, a study suggests. Caffeine is the most widely used stimulant to counter the effects of sleep loss on neurobehavioral performance, but no tools exist to guide the timing and amount of caffeine consumption to optimize its benefits, said Jaques Reifman, PhD, and colleagues. “By using our algorithm, which determines when and how much caffeine a subject should consume, we can improve alertness by up to 64% while consuming the same total amount of caffeine” as in previous studies of caffeine use during chronic sleep restriction, said Dr. Reifman. “Alternatively, a subject can reduce caffeine consumption by up to 65% and still achieve equivalent improvements in alertness.”
The study was presented at the 32nd Annual Meeting of the Associated Professional Sleep Societies and published online ahead of print in the Journal of Sleep Research. Dr. Reifman is a senior research scientist and Director of the Department of Defense Biotechnology High Performance Computing Software Applications Institute and the Telemedicine and Advanced Technology Research Center at the US Army Medical Research and Materiel Command in Fort Detrick, Maryland.
The researchers used a validated mathematical model that predicts the effects of sleep loss and caffeine on psychomotor vigilance task (PVT) performance and combined it with a computationally efficient optimization algorithm to determine when and how much caffeine should be consumed to safely maximize alertness during sleep loss. They used the algorithm to determine ideal dosing strategies for four previously published experimental studies of chronic sleep restriction. The researchers computed dosing strategies that enhanced the predicted PVT performance using the same total amount of caffeine as in the original studies, as well as strategies that achieved an equivalent level of performance, but used less caffeine overall.
The algorithm tailored the timing and amount of caffeine to the sleep–wake schedule of each study condition to maximize caffeine’s benefits, such as by postponing the first dose on certain days, prescribing more caffeine during longer periods of wakefulness, and allocating doses near the end of the day.
The algorithm is designed to predict caffeine’s effects on simple tasks, so dosing strategies for other tasks may differ, the researchers noted. In addition, the algorithm does not account for the effects of sleep debt on caffeine’s benefits or individual differences in caffeine sensitivity.
Suggested Reading
Vital-Lopez FG, Ramakrishnan S, Doty TJ, et al. Caffeine dosing strategies to optimize alertness during sleep loss. J Sleep Res. 2018 May 28 [Epub ahead of print].
‘Reverse transitions’ from injecting to noninjecting drug use studied
SAN DIEGO – The transition from noninjecting to injecting drug use can be a reversible process, results from a long-term study suggest.
“There’s a common stereotype in popular culture and in academic research that once people start injecting drugs, that will be their dominant route of administration for the rest of their lives,” lead study author Don C. Des Jarlais, PhD, said in an interview at the annual meeting of the College on Problems of Drug Dependence. “We found that people who started injecting injected for several years, but then went back to noninjecting drug use. That so-called ‘reverse transition’ leads to a very big difference in infection with hepatitis C virus as well as reduced risk of overdose and reduced risk of other bacterial infections. Even though these people continued to use drugs, they were doing it in a way that was much safer.”
In an effort to examine the prevalence and characteristics of reverse transitions, Dr. Des Jarlais and his associates recruited injecting and noninjecting drug users aged 18 years and older from the Mount Sinai Beth Israel detoxification and methadone maintenance programs in New York City from 2000 to 2017. The researchers obtained informed consent and conducted a structured interview that included questions on why former injectors had ceased injecting drugs, along with testing for HIV and HCV.
People who were currently injecting were defined as those whose first injection was in 2000 or later and who had injected heroin or cocaine during the 6 months prior to treatment entry. People who formerly injected drugs were defined as those whose first injection was in 2000 or later but who had used heroin or cocaine without injecting drugs during the 6 months prior to treatment entry.
Dr. Des Jarlais, professor of psychiatry at the Icahn School of Medicine at Mount Sinai, New York, reported results from 937 current and 104 former injection drug users. Compared with current injection drug users, former users were older (a mean age of 41 vs. 35, respectively), more likely to be African American (28% vs. 12%), more likely to have received previous methadone treatment (68% vs. 54%), and less likely to be HCV positive (30% vs. 47%; P less than 0.05 for all associations).
The researchers found that 11% of former injection drug users had reverse transitioned to noninjection drug use. Among former injection drug users, the most common reasons for ceasing to inject were “don’t like needles” (30%), “got tired of injecting” (29%), “afraid of overdose” (17%), “concerns about stigma” (16%), and other health concerns (14%).
Dr. Des Jarlais said. “Injecting is messy and it requires private space; it’s not a pleasant way of using drugs compared to just sniffing it. If we’re going to control hepatitis C, we need to find ways of encouraging people that if they’re going to continue to use drugs, they should try to stop injecting.”
The next step in this research area is to develop a more complete understanding of reverse transitions. “These are people doing it on their own, but we don’t have any programs to help them,” he said. “We have needle exchange programs for people to inject safely, but we don’t have any programs where people go from injecting to noninjecting.”
The study received funding support from the National Institute on Drug Abuse. Dr. Des Jarlais reported having no financial disclosures.
SAN DIEGO – The transition from noninjecting to injecting drug use can be a reversible process, results from a long-term study suggest.
“There’s a common stereotype in popular culture and in academic research that once people start injecting drugs, that will be their dominant route of administration for the rest of their lives,” lead study author Don C. Des Jarlais, PhD, said in an interview at the annual meeting of the College on Problems of Drug Dependence. “We found that people who started injecting injected for several years, but then went back to noninjecting drug use. That so-called ‘reverse transition’ leads to a very big difference in infection with hepatitis C virus as well as reduced risk of overdose and reduced risk of other bacterial infections. Even though these people continued to use drugs, they were doing it in a way that was much safer.”
In an effort to examine the prevalence and characteristics of reverse transitions, Dr. Des Jarlais and his associates recruited injecting and noninjecting drug users aged 18 years and older from the Mount Sinai Beth Israel detoxification and methadone maintenance programs in New York City from 2000 to 2017. The researchers obtained informed consent and conducted a structured interview that included questions on why former injectors had ceased injecting drugs, along with testing for HIV and HCV.
People who were currently injecting were defined as those whose first injection was in 2000 or later and who had injected heroin or cocaine during the 6 months prior to treatment entry. People who formerly injected drugs were defined as those whose first injection was in 2000 or later but who had used heroin or cocaine without injecting drugs during the 6 months prior to treatment entry.
Dr. Des Jarlais, professor of psychiatry at the Icahn School of Medicine at Mount Sinai, New York, reported results from 937 current and 104 former injection drug users. Compared with current injection drug users, former users were older (a mean age of 41 vs. 35, respectively), more likely to be African American (28% vs. 12%), more likely to have received previous methadone treatment (68% vs. 54%), and less likely to be HCV positive (30% vs. 47%; P less than 0.05 for all associations).
The researchers found that 11% of former injection drug users had reverse transitioned to noninjection drug use. Among former injection drug users, the most common reasons for ceasing to inject were “don’t like needles” (30%), “got tired of injecting” (29%), “afraid of overdose” (17%), “concerns about stigma” (16%), and other health concerns (14%).
Dr. Des Jarlais said. “Injecting is messy and it requires private space; it’s not a pleasant way of using drugs compared to just sniffing it. If we’re going to control hepatitis C, we need to find ways of encouraging people that if they’re going to continue to use drugs, they should try to stop injecting.”
The next step in this research area is to develop a more complete understanding of reverse transitions. “These are people doing it on their own, but we don’t have any programs to help them,” he said. “We have needle exchange programs for people to inject safely, but we don’t have any programs where people go from injecting to noninjecting.”
The study received funding support from the National Institute on Drug Abuse. Dr. Des Jarlais reported having no financial disclosures.
SAN DIEGO – The transition from noninjecting to injecting drug use can be a reversible process, results from a long-term study suggest.
“There’s a common stereotype in popular culture and in academic research that once people start injecting drugs, that will be their dominant route of administration for the rest of their lives,” lead study author Don C. Des Jarlais, PhD, said in an interview at the annual meeting of the College on Problems of Drug Dependence. “We found that people who started injecting injected for several years, but then went back to noninjecting drug use. That so-called ‘reverse transition’ leads to a very big difference in infection with hepatitis C virus as well as reduced risk of overdose and reduced risk of other bacterial infections. Even though these people continued to use drugs, they were doing it in a way that was much safer.”
In an effort to examine the prevalence and characteristics of reverse transitions, Dr. Des Jarlais and his associates recruited injecting and noninjecting drug users aged 18 years and older from the Mount Sinai Beth Israel detoxification and methadone maintenance programs in New York City from 2000 to 2017. The researchers obtained informed consent and conducted a structured interview that included questions on why former injectors had ceased injecting drugs, along with testing for HIV and HCV.
People who were currently injecting were defined as those whose first injection was in 2000 or later and who had injected heroin or cocaine during the 6 months prior to treatment entry. People who formerly injected drugs were defined as those whose first injection was in 2000 or later but who had used heroin or cocaine without injecting drugs during the 6 months prior to treatment entry.
Dr. Des Jarlais, professor of psychiatry at the Icahn School of Medicine at Mount Sinai, New York, reported results from 937 current and 104 former injection drug users. Compared with current injection drug users, former users were older (a mean age of 41 vs. 35, respectively), more likely to be African American (28% vs. 12%), more likely to have received previous methadone treatment (68% vs. 54%), and less likely to be HCV positive (30% vs. 47%; P less than 0.05 for all associations).
The researchers found that 11% of former injection drug users had reverse transitioned to noninjection drug use. Among former injection drug users, the most common reasons for ceasing to inject were “don’t like needles” (30%), “got tired of injecting” (29%), “afraid of overdose” (17%), “concerns about stigma” (16%), and other health concerns (14%).
Dr. Des Jarlais said. “Injecting is messy and it requires private space; it’s not a pleasant way of using drugs compared to just sniffing it. If we’re going to control hepatitis C, we need to find ways of encouraging people that if they’re going to continue to use drugs, they should try to stop injecting.”
The next step in this research area is to develop a more complete understanding of reverse transitions. “These are people doing it on their own, but we don’t have any programs to help them,” he said. “We have needle exchange programs for people to inject safely, but we don’t have any programs where people go from injecting to noninjecting.”
The study received funding support from the National Institute on Drug Abuse. Dr. Des Jarlais reported having no financial disclosures.
AT CPDD 2018
Key clinical point: To control hepatitis C, patients who continue to use drugs should be encouraged to stop injecting.
Major finding: Among former injection drug users, 11% had reverse transitioned to noninjection drug use.
Study details: A study of 937 current and 104 former injection drug users between 2000 and 2017.
Disclosures: The study received funding support from the National Institute on Drug Abuse. Dr. Des Jarlais reported having no financial disclosures.
Explore Ultrasound Corner
The use of ultrasound is often overlooked when it could very well aid in the diagnosis of a critical illness in a shorter amount of time, while eliminating potential risks that come with many of the usually administered tests.
In 2013, Seth Koenig, MD, FCCP, of Hofstra School of Medicine in New Hyde Park, New York, noticed the need to educate providers about the use of ultrasound in the ICU. Dr. Koenig approached Richard Irwin, MD, Master FCCP, and Editor in Chief of the journal CHEST, with an idea for a new section in the journal. So began “Ultrasound Corner,” an online, video-based series in the journal that provides readers with real cases where ultrasound has played a large role in diagnostic patient care.
Each month, the journal receives two to four submissions from chest medicine clinicians who want to share their critical care ultrasound patient stories. One to two stories are selected and published monthly with real video images that are explained in the manuscript and in a narration done by Dr. Koenig.
“This creates a section where clinicians worldwide can share their experiences so that others may incorporate different methods of diagnosis into their practice,” said Dr. Koenig. “This method of learning challenges the readers to interpret images and integrate the results into a patient management plan.”
Dr. Koenig recommends that clinicians who have experienced benefit using ultrasound in critical care situations submit their cases so that viewers can learn from each other. Share the knowledge you’ve gained from your patient cases. Visit https://mc.manuscriptcentral.com/chest, log in to your account, and click “Start a New Submission” under the “Author” section.
More importantly, Dr. Koenig encourages the journal readership to explore Ultrasound Corner (https://journal.chestnet.org/ultrasound) every month in CHEST to learn of different courses of diagnosis and treatment being used to strengthen patient diagnostic and management plans in new, evolving ways.
The use of ultrasound is often overlooked when it could very well aid in the diagnosis of a critical illness in a shorter amount of time, while eliminating potential risks that come with many of the usually administered tests.
In 2013, Seth Koenig, MD, FCCP, of Hofstra School of Medicine in New Hyde Park, New York, noticed the need to educate providers about the use of ultrasound in the ICU. Dr. Koenig approached Richard Irwin, MD, Master FCCP, and Editor in Chief of the journal CHEST, with an idea for a new section in the journal. So began “Ultrasound Corner,” an online, video-based series in the journal that provides readers with real cases where ultrasound has played a large role in diagnostic patient care.
Each month, the journal receives two to four submissions from chest medicine clinicians who want to share their critical care ultrasound patient stories. One to two stories are selected and published monthly with real video images that are explained in the manuscript and in a narration done by Dr. Koenig.
“This creates a section where clinicians worldwide can share their experiences so that others may incorporate different methods of diagnosis into their practice,” said Dr. Koenig. “This method of learning challenges the readers to interpret images and integrate the results into a patient management plan.”
Dr. Koenig recommends that clinicians who have experienced benefit using ultrasound in critical care situations submit their cases so that viewers can learn from each other. Share the knowledge you’ve gained from your patient cases. Visit https://mc.manuscriptcentral.com/chest, log in to your account, and click “Start a New Submission” under the “Author” section.
More importantly, Dr. Koenig encourages the journal readership to explore Ultrasound Corner (https://journal.chestnet.org/ultrasound) every month in CHEST to learn of different courses of diagnosis and treatment being used to strengthen patient diagnostic and management plans in new, evolving ways.
The use of ultrasound is often overlooked when it could very well aid in the diagnosis of a critical illness in a shorter amount of time, while eliminating potential risks that come with many of the usually administered tests.
In 2013, Seth Koenig, MD, FCCP, of Hofstra School of Medicine in New Hyde Park, New York, noticed the need to educate providers about the use of ultrasound in the ICU. Dr. Koenig approached Richard Irwin, MD, Master FCCP, and Editor in Chief of the journal CHEST, with an idea for a new section in the journal. So began “Ultrasound Corner,” an online, video-based series in the journal that provides readers with real cases where ultrasound has played a large role in diagnostic patient care.
Each month, the journal receives two to four submissions from chest medicine clinicians who want to share their critical care ultrasound patient stories. One to two stories are selected and published monthly with real video images that are explained in the manuscript and in a narration done by Dr. Koenig.
“This creates a section where clinicians worldwide can share their experiences so that others may incorporate different methods of diagnosis into their practice,” said Dr. Koenig. “This method of learning challenges the readers to interpret images and integrate the results into a patient management plan.”
Dr. Koenig recommends that clinicians who have experienced benefit using ultrasound in critical care situations submit their cases so that viewers can learn from each other. Share the knowledge you’ve gained from your patient cases. Visit https://mc.manuscriptcentral.com/chest, log in to your account, and click “Start a New Submission” under the “Author” section.
More importantly, Dr. Koenig encourages the journal readership to explore Ultrasound Corner (https://journal.chestnet.org/ultrasound) every month in CHEST to learn of different courses of diagnosis and treatment being used to strengthen patient diagnostic and management plans in new, evolving ways.
Zolpidem does not boost cannabis abstinence during treatment
SAN DIEGO – Disturbed sleep is one of the symptoms of withdrawal from marijuana, and it can wreak havoc on the lives of people with cannabis use disorder who are trying to quit. Now, a new study provides more evidence about the problem and suggests that the sleep aid zolpidem is not a solution on its own.
Zolpidem seemed to help subjects sleep better, but the effect lasted only as long as they took the drug. And .
“Zolpidem or other hypnotics may have some efficacy as a pharmacotherapy to relieve short-term sleep disruption in the treatment of cannabis use disorder. But they should only be used in cases where abstinence-induced insomnia is a significant barrier to cessation and only in combination with other evidence-based interventions to address key aspects of cannabis use disorder,” study coauthor Dustin C. Lee, PhD, of Johns Hopkins University, Baltimore, said in an interview. He presented the study findings at the annual meeting of the College on Problems of Drug Dependence.
Previous research, including studies by some of the authors of the new report, suggests that people trying to withdraw from cannabis often suffer from sleep disturbances.
In a 2010 study, for instance, researchers interviewed 469 adult cannabis users in the Baltimore area who had tried to quit outside of treatment programs. Nearly half reported trouble falling asleep, while 20%-36% reported sleep-related symptoms, such as sleeping more or less than usual, having unusual dreams, and waking during the night (Drug Alcohol Depend. 2010 Sep 1;111[1-2]:120-7).
Another factor could be at play: Cannabis users may sleep better while they use the drug, then lose the benefit when they try to withdraw.
“Studies have demonstrated that acute use of cannabis reduces sleep latency and increases stage 3 sleep, informally referred to as ‘deep’ or ‘slow-wave’ sleep, which means individuals fall asleep faster and remain in deep sleep longer after using cannabis,” Dr. Lee said.
Whatever the explanation, the sleep problems during withdrawal are not helpful to users who are trying to quit. “Research indicates that cannabis cessation results in sleep problems that are a barrier to quitting,” Dr. Lee said.
For the new study, Dr. Lee and his colleagues randomly assigned 127 adults – all in a 12-week clinical trial of cannabis use disorder treatment – to receive extended-release zolpidem or placebo.
Participants underwent urine screens to test for drug use and ambulatory polysomnography to measure sleep.
A preliminary analysis found that those who received zolpidem had higher rates of cannabis abstinence during the 12 weeks and at end of treatment. But analysis showed that the differences were not statistically significant, Dr. Lee said, “which suggests that sleep is not the predominant factor driving successful cessation attempts.”
Researchers also found that sleep efficiency and sleep onset latency deteriorated to a clinically significant degree in week 1 of the study for those who took the placebo (mean sleep efficiency fell from 82% to 74%, while sleep onset latency increased from 28 to 82 minutes).
The zolpidem group did not see any significant change in sleep efficiency or sleep onset latency. However, those participants showed signs of rebound insomnia after they stopped taking zolpidem.
As for the risk of abuse of zolpidem, Dr. Lee said: “We did not see any indication of abuse among the individuals who participated in our study. We monitored this via quantitative urine toxicology testing and remote medication adherence monitoring.”
Moving forward, he said, zolpidem “may have some efficacy as a short-term therapy for sleep disruption in a subset of cannabis users. More research is needed to further evaluate the efficacy of zolpidem or other hypnotic medications in individuals who differ in withdrawal severity or demographics.”
Dr. Lee said evaluating behavioral sleep treatments would be a logical next-step in light of his team’s data.
The National Institute on Drug Abuse funded the study. Three of the authors reported no relevant disclosures, and one reported consulting/advisory links to several drug companies and several state-licensed medical cannabis cultivation or dispensary businesses.
SAN DIEGO – Disturbed sleep is one of the symptoms of withdrawal from marijuana, and it can wreak havoc on the lives of people with cannabis use disorder who are trying to quit. Now, a new study provides more evidence about the problem and suggests that the sleep aid zolpidem is not a solution on its own.
Zolpidem seemed to help subjects sleep better, but the effect lasted only as long as they took the drug. And .
“Zolpidem or other hypnotics may have some efficacy as a pharmacotherapy to relieve short-term sleep disruption in the treatment of cannabis use disorder. But they should only be used in cases where abstinence-induced insomnia is a significant barrier to cessation and only in combination with other evidence-based interventions to address key aspects of cannabis use disorder,” study coauthor Dustin C. Lee, PhD, of Johns Hopkins University, Baltimore, said in an interview. He presented the study findings at the annual meeting of the College on Problems of Drug Dependence.
Previous research, including studies by some of the authors of the new report, suggests that people trying to withdraw from cannabis often suffer from sleep disturbances.
In a 2010 study, for instance, researchers interviewed 469 adult cannabis users in the Baltimore area who had tried to quit outside of treatment programs. Nearly half reported trouble falling asleep, while 20%-36% reported sleep-related symptoms, such as sleeping more or less than usual, having unusual dreams, and waking during the night (Drug Alcohol Depend. 2010 Sep 1;111[1-2]:120-7).
Another factor could be at play: Cannabis users may sleep better while they use the drug, then lose the benefit when they try to withdraw.
“Studies have demonstrated that acute use of cannabis reduces sleep latency and increases stage 3 sleep, informally referred to as ‘deep’ or ‘slow-wave’ sleep, which means individuals fall asleep faster and remain in deep sleep longer after using cannabis,” Dr. Lee said.
Whatever the explanation, the sleep problems during withdrawal are not helpful to users who are trying to quit. “Research indicates that cannabis cessation results in sleep problems that are a barrier to quitting,” Dr. Lee said.
For the new study, Dr. Lee and his colleagues randomly assigned 127 adults – all in a 12-week clinical trial of cannabis use disorder treatment – to receive extended-release zolpidem or placebo.
Participants underwent urine screens to test for drug use and ambulatory polysomnography to measure sleep.
A preliminary analysis found that those who received zolpidem had higher rates of cannabis abstinence during the 12 weeks and at end of treatment. But analysis showed that the differences were not statistically significant, Dr. Lee said, “which suggests that sleep is not the predominant factor driving successful cessation attempts.”
Researchers also found that sleep efficiency and sleep onset latency deteriorated to a clinically significant degree in week 1 of the study for those who took the placebo (mean sleep efficiency fell from 82% to 74%, while sleep onset latency increased from 28 to 82 minutes).
The zolpidem group did not see any significant change in sleep efficiency or sleep onset latency. However, those participants showed signs of rebound insomnia after they stopped taking zolpidem.
As for the risk of abuse of zolpidem, Dr. Lee said: “We did not see any indication of abuse among the individuals who participated in our study. We monitored this via quantitative urine toxicology testing and remote medication adherence monitoring.”
Moving forward, he said, zolpidem “may have some efficacy as a short-term therapy for sleep disruption in a subset of cannabis users. More research is needed to further evaluate the efficacy of zolpidem or other hypnotic medications in individuals who differ in withdrawal severity or demographics.”
Dr. Lee said evaluating behavioral sleep treatments would be a logical next-step in light of his team’s data.
The National Institute on Drug Abuse funded the study. Three of the authors reported no relevant disclosures, and one reported consulting/advisory links to several drug companies and several state-licensed medical cannabis cultivation or dispensary businesses.
SAN DIEGO – Disturbed sleep is one of the symptoms of withdrawal from marijuana, and it can wreak havoc on the lives of people with cannabis use disorder who are trying to quit. Now, a new study provides more evidence about the problem and suggests that the sleep aid zolpidem is not a solution on its own.
Zolpidem seemed to help subjects sleep better, but the effect lasted only as long as they took the drug. And .
“Zolpidem or other hypnotics may have some efficacy as a pharmacotherapy to relieve short-term sleep disruption in the treatment of cannabis use disorder. But they should only be used in cases where abstinence-induced insomnia is a significant barrier to cessation and only in combination with other evidence-based interventions to address key aspects of cannabis use disorder,” study coauthor Dustin C. Lee, PhD, of Johns Hopkins University, Baltimore, said in an interview. He presented the study findings at the annual meeting of the College on Problems of Drug Dependence.
Previous research, including studies by some of the authors of the new report, suggests that people trying to withdraw from cannabis often suffer from sleep disturbances.
In a 2010 study, for instance, researchers interviewed 469 adult cannabis users in the Baltimore area who had tried to quit outside of treatment programs. Nearly half reported trouble falling asleep, while 20%-36% reported sleep-related symptoms, such as sleeping more or less than usual, having unusual dreams, and waking during the night (Drug Alcohol Depend. 2010 Sep 1;111[1-2]:120-7).
Another factor could be at play: Cannabis users may sleep better while they use the drug, then lose the benefit when they try to withdraw.
“Studies have demonstrated that acute use of cannabis reduces sleep latency and increases stage 3 sleep, informally referred to as ‘deep’ or ‘slow-wave’ sleep, which means individuals fall asleep faster and remain in deep sleep longer after using cannabis,” Dr. Lee said.
Whatever the explanation, the sleep problems during withdrawal are not helpful to users who are trying to quit. “Research indicates that cannabis cessation results in sleep problems that are a barrier to quitting,” Dr. Lee said.
For the new study, Dr. Lee and his colleagues randomly assigned 127 adults – all in a 12-week clinical trial of cannabis use disorder treatment – to receive extended-release zolpidem or placebo.
Participants underwent urine screens to test for drug use and ambulatory polysomnography to measure sleep.
A preliminary analysis found that those who received zolpidem had higher rates of cannabis abstinence during the 12 weeks and at end of treatment. But analysis showed that the differences were not statistically significant, Dr. Lee said, “which suggests that sleep is not the predominant factor driving successful cessation attempts.”
Researchers also found that sleep efficiency and sleep onset latency deteriorated to a clinically significant degree in week 1 of the study for those who took the placebo (mean sleep efficiency fell from 82% to 74%, while sleep onset latency increased from 28 to 82 minutes).
The zolpidem group did not see any significant change in sleep efficiency or sleep onset latency. However, those participants showed signs of rebound insomnia after they stopped taking zolpidem.
As for the risk of abuse of zolpidem, Dr. Lee said: “We did not see any indication of abuse among the individuals who participated in our study. We monitored this via quantitative urine toxicology testing and remote medication adherence monitoring.”
Moving forward, he said, zolpidem “may have some efficacy as a short-term therapy for sleep disruption in a subset of cannabis users. More research is needed to further evaluate the efficacy of zolpidem or other hypnotic medications in individuals who differ in withdrawal severity or demographics.”
Dr. Lee said evaluating behavioral sleep treatments would be a logical next-step in light of his team’s data.
The National Institute on Drug Abuse funded the study. Three of the authors reported no relevant disclosures, and one reported consulting/advisory links to several drug companies and several state-licensed medical cannabis cultivation or dispensary businesses.
REPORTING FROM CPDD 2018
Key clinical point: Zolpidem does not boost rates of abstinence during treatment for cannabis use disorder.
Major finding: Researchers did not find a statistically significant difference in cannabis abstinence rates between subjects who took zolpidem during treatment and those who did not.
Study details: Randomized, placebo-controlled trial of 127 adults with cannabis use disorder, all in a 12-week clinical trial of a treatment program, who received extended-release zolpidem or placebo.
Disclosures: Three of the authors reported no relevant disclosures, and one reported consulting/advisory links to several drug companies and several state-licensed medical cannabis cultivation or dispensary businesses.
Fetal exposure to folic acid may reduce youth psychosis risk
Gestational exposure to grain products fortified with folic acid resulted in delayed thinning of the cerebral cortex, and thus may protect against later psychosis, according to results published in JAMA Psychiatry.
In a retrospective, observational cohort study of 292 patients aged 8-18 years, increases in cortical thickness were associated with folic acid exposure in the bilateral frontal and temporal regions of the brain (9.9%-11.6%; corrected P less than .001 to P = .03). Delayed, age-associated thinning in temporal and parietal regions was also observed (beta = –11.1 to –13.9; corrected P = .002), reported Hamdi Eryilmaz, PhD, of the department of psychiatry at Massachusetts General Hospital, Boston, and his coauthors.
The study authors first observed MRI scans in the Massachusetts General Hospital (MGH) cohort, which included the 292 patients aged 8-18 years, and then conducted subsequent analyses on two additional cohorts – the Philadelphia Neurodevelopmental Cohort (PNC) and the National Institutes of Health MRI Study of Normal Brain Development (NIH) cohort – to test the reliability and specificity of cortical development associations and the relevance of MRI changes to psychopathological characteristics, the authors wrote.
Using the U.S. implementation of folic acid fortification in grain foods in 1996 and 1997 to define exposure status, the investigators identified MRI scans of 97 prerollout (not exposed), 96 rollout (partly exposed), and 99 postrollout (fully exposed) unique individuals in the MGH group between January 2005 and March 2015, for patients born between January 1993 and December 2001. They also collected information on demographics; reason for MRI scan; and prior use of psychotropic medications, folic acid, or multivitamins.
The PNC cohort consisted of 861 patients, also aged 8-18 years, from community health settings in Philadelphia who had an MRI assessment and a clinical assessment of psychiatric symptoms. The NIH comparison cohort included 217 patients recruited from six health sites across the United States and born before the fortification rollout.
The MGH analysis contrasted mean cortical thickness and linear and quadratic models of age-associated change in cortical thickness within the fully exposed and nonexposed groups. PNC and NIH analyses evaluated quadratic associations of age with cortical thickness.
In the MGH cohort, increases in cortical thickness were associated with folic acid exposure in the bilateral frontal and temporal regions of the brain (9.9%-11.6%; corrected P less than .001 to P = .03), and delayed, age-associated thinning in the temporal and parietal regions was observed (corrected P = .002). Thickness was higher in the fully exposed group, compared with those in the nonexposed group. The effect was intermediate in the partly exposed group, Dr. Eryilmaz and his coauthors wrote.
In the PNC cohort, delayed, age-related thinning was observed in four clusters overlapping with the MGH analysis: left frontal, right inferior temporal, left inferior parietal, and right inferior parietal. In addition, onset of cortical thinning was found to be between 13.0 and 14.3 years of age in least-square regression analysis. In the comparison NIH cohort, though, only the left frontal cortex demonstrated significant quadratic thinning; the break point occurred at a significantly younger age, compared with those in the PNC group (P less than .001).
In the PNC group, 248 of the 861 patients included in the MRI analysis were typically developing, 199 had a psychosis diagnosis, 105 had attenuated psychotic symptoms, and 309 had various other psychiatric conditions. Best-fit local thinning slopes were calculated for each participant for each region with postfortification thinning, and in three of four regions, less-negative local slopes were associated with significantly reduced adjusted odds of psychosis spectrum diagnosis (odds ratio, 0.37-0.59; P less than .001 to P = .02), the authors reported.
The findings confirm that “fetal exposure to population-wide folic acid fortification was associated with subsequent alterations in cortical development among school-aged youths,” Dr. Eryilmaz and his coauthors wrote. “These cortical changes were associated with reduced risk of psychosis.”
The results also suggest that the protective effects of folic acid in gestation “may extend beyond prevention of neural tube defects and span neurodevelopment during childhood and adolescence,” they concluded.
The study was funded by MQ: Transforming Mental Health, with support from grants from several additional sources, including the National Institutes of Health.
SOURCE: Eryilmaz H et al. JAMA Psychiatry. 2018 Jul 3. doi: 10.1001/jamapsychiatry.2018.1381.
The results of this study complement previous studies in the Netherlands “addressing similar questions using plasma levels of folate in maternal blood during pregnancy,” Tomáš Paus, MD, PhD, wrote in an editorial (JAMA Psychiatry. 2018 Jul 3. doi: 10.1001/jamapsychiatry.2018.1255) published with the study. However, he added, “it is unfortunate that the authors did not report values of cortical surface area in the different groups of individuals studied.”
Previous studies have shown that the children of mothers with high folic acid levels during pregnancy showed greater head growth and larger brain volumes at 6-8 years of age, Dr. Paus wrote, adding that future research should explore the possibility that exposure to folic acid induces effects such as DNA methylation, that may persist over time.
“This folate-methylation hypothesis needs to be tested empirically in large data sets, ideally in conjunction with relevant brain phenotypes, to replicate and expand the initial findings reported” in this study, he concluded.
Dr. Paus is affiliated with the department of psychology at the Rotman Research Institute, Toronto. He reported no conflicts of interest.
The results of this study complement previous studies in the Netherlands “addressing similar questions using plasma levels of folate in maternal blood during pregnancy,” Tomáš Paus, MD, PhD, wrote in an editorial (JAMA Psychiatry. 2018 Jul 3. doi: 10.1001/jamapsychiatry.2018.1255) published with the study. However, he added, “it is unfortunate that the authors did not report values of cortical surface area in the different groups of individuals studied.”
Previous studies have shown that the children of mothers with high folic acid levels during pregnancy showed greater head growth and larger brain volumes at 6-8 years of age, Dr. Paus wrote, adding that future research should explore the possibility that exposure to folic acid induces effects such as DNA methylation, that may persist over time.
“This folate-methylation hypothesis needs to be tested empirically in large data sets, ideally in conjunction with relevant brain phenotypes, to replicate and expand the initial findings reported” in this study, he concluded.
Dr. Paus is affiliated with the department of psychology at the Rotman Research Institute, Toronto. He reported no conflicts of interest.
The results of this study complement previous studies in the Netherlands “addressing similar questions using plasma levels of folate in maternal blood during pregnancy,” Tomáš Paus, MD, PhD, wrote in an editorial (JAMA Psychiatry. 2018 Jul 3. doi: 10.1001/jamapsychiatry.2018.1255) published with the study. However, he added, “it is unfortunate that the authors did not report values of cortical surface area in the different groups of individuals studied.”
Previous studies have shown that the children of mothers with high folic acid levels during pregnancy showed greater head growth and larger brain volumes at 6-8 years of age, Dr. Paus wrote, adding that future research should explore the possibility that exposure to folic acid induces effects such as DNA methylation, that may persist over time.
“This folate-methylation hypothesis needs to be tested empirically in large data sets, ideally in conjunction with relevant brain phenotypes, to replicate and expand the initial findings reported” in this study, he concluded.
Dr. Paus is affiliated with the department of psychology at the Rotman Research Institute, Toronto. He reported no conflicts of interest.
Gestational exposure to grain products fortified with folic acid resulted in delayed thinning of the cerebral cortex, and thus may protect against later psychosis, according to results published in JAMA Psychiatry.
In a retrospective, observational cohort study of 292 patients aged 8-18 years, increases in cortical thickness were associated with folic acid exposure in the bilateral frontal and temporal regions of the brain (9.9%-11.6%; corrected P less than .001 to P = .03). Delayed, age-associated thinning in temporal and parietal regions was also observed (beta = –11.1 to –13.9; corrected P = .002), reported Hamdi Eryilmaz, PhD, of the department of psychiatry at Massachusetts General Hospital, Boston, and his coauthors.
The study authors first observed MRI scans in the Massachusetts General Hospital (MGH) cohort, which included the 292 patients aged 8-18 years, and then conducted subsequent analyses on two additional cohorts – the Philadelphia Neurodevelopmental Cohort (PNC) and the National Institutes of Health MRI Study of Normal Brain Development (NIH) cohort – to test the reliability and specificity of cortical development associations and the relevance of MRI changes to psychopathological characteristics, the authors wrote.
Using the U.S. implementation of folic acid fortification in grain foods in 1996 and 1997 to define exposure status, the investigators identified MRI scans of 97 prerollout (not exposed), 96 rollout (partly exposed), and 99 postrollout (fully exposed) unique individuals in the MGH group between January 2005 and March 2015, for patients born between January 1993 and December 2001. They also collected information on demographics; reason for MRI scan; and prior use of psychotropic medications, folic acid, or multivitamins.
The PNC cohort consisted of 861 patients, also aged 8-18 years, from community health settings in Philadelphia who had an MRI assessment and a clinical assessment of psychiatric symptoms. The NIH comparison cohort included 217 patients recruited from six health sites across the United States and born before the fortification rollout.
The MGH analysis contrasted mean cortical thickness and linear and quadratic models of age-associated change in cortical thickness within the fully exposed and nonexposed groups. PNC and NIH analyses evaluated quadratic associations of age with cortical thickness.
In the MGH cohort, increases in cortical thickness were associated with folic acid exposure in the bilateral frontal and temporal regions of the brain (9.9%-11.6%; corrected P less than .001 to P = .03), and delayed, age-associated thinning in the temporal and parietal regions was observed (corrected P = .002). Thickness was higher in the fully exposed group, compared with those in the nonexposed group. The effect was intermediate in the partly exposed group, Dr. Eryilmaz and his coauthors wrote.
In the PNC cohort, delayed, age-related thinning was observed in four clusters overlapping with the MGH analysis: left frontal, right inferior temporal, left inferior parietal, and right inferior parietal. In addition, onset of cortical thinning was found to be between 13.0 and 14.3 years of age in least-square regression analysis. In the comparison NIH cohort, though, only the left frontal cortex demonstrated significant quadratic thinning; the break point occurred at a significantly younger age, compared with those in the PNC group (P less than .001).
In the PNC group, 248 of the 861 patients included in the MRI analysis were typically developing, 199 had a psychosis diagnosis, 105 had attenuated psychotic symptoms, and 309 had various other psychiatric conditions. Best-fit local thinning slopes were calculated for each participant for each region with postfortification thinning, and in three of four regions, less-negative local slopes were associated with significantly reduced adjusted odds of psychosis spectrum diagnosis (odds ratio, 0.37-0.59; P less than .001 to P = .02), the authors reported.
The findings confirm that “fetal exposure to population-wide folic acid fortification was associated with subsequent alterations in cortical development among school-aged youths,” Dr. Eryilmaz and his coauthors wrote. “These cortical changes were associated with reduced risk of psychosis.”
The results also suggest that the protective effects of folic acid in gestation “may extend beyond prevention of neural tube defects and span neurodevelopment during childhood and adolescence,” they concluded.
The study was funded by MQ: Transforming Mental Health, with support from grants from several additional sources, including the National Institutes of Health.
SOURCE: Eryilmaz H et al. JAMA Psychiatry. 2018 Jul 3. doi: 10.1001/jamapsychiatry.2018.1381.
Gestational exposure to grain products fortified with folic acid resulted in delayed thinning of the cerebral cortex, and thus may protect against later psychosis, according to results published in JAMA Psychiatry.
In a retrospective, observational cohort study of 292 patients aged 8-18 years, increases in cortical thickness were associated with folic acid exposure in the bilateral frontal and temporal regions of the brain (9.9%-11.6%; corrected P less than .001 to P = .03). Delayed, age-associated thinning in temporal and parietal regions was also observed (beta = –11.1 to –13.9; corrected P = .002), reported Hamdi Eryilmaz, PhD, of the department of psychiatry at Massachusetts General Hospital, Boston, and his coauthors.
The study authors first observed MRI scans in the Massachusetts General Hospital (MGH) cohort, which included the 292 patients aged 8-18 years, and then conducted subsequent analyses on two additional cohorts – the Philadelphia Neurodevelopmental Cohort (PNC) and the National Institutes of Health MRI Study of Normal Brain Development (NIH) cohort – to test the reliability and specificity of cortical development associations and the relevance of MRI changes to psychopathological characteristics, the authors wrote.
Using the U.S. implementation of folic acid fortification in grain foods in 1996 and 1997 to define exposure status, the investigators identified MRI scans of 97 prerollout (not exposed), 96 rollout (partly exposed), and 99 postrollout (fully exposed) unique individuals in the MGH group between January 2005 and March 2015, for patients born between January 1993 and December 2001. They also collected information on demographics; reason for MRI scan; and prior use of psychotropic medications, folic acid, or multivitamins.
The PNC cohort consisted of 861 patients, also aged 8-18 years, from community health settings in Philadelphia who had an MRI assessment and a clinical assessment of psychiatric symptoms. The NIH comparison cohort included 217 patients recruited from six health sites across the United States and born before the fortification rollout.
The MGH analysis contrasted mean cortical thickness and linear and quadratic models of age-associated change in cortical thickness within the fully exposed and nonexposed groups. PNC and NIH analyses evaluated quadratic associations of age with cortical thickness.
In the MGH cohort, increases in cortical thickness were associated with folic acid exposure in the bilateral frontal and temporal regions of the brain (9.9%-11.6%; corrected P less than .001 to P = .03), and delayed, age-associated thinning in the temporal and parietal regions was observed (corrected P = .002). Thickness was higher in the fully exposed group, compared with those in the nonexposed group. The effect was intermediate in the partly exposed group, Dr. Eryilmaz and his coauthors wrote.
In the PNC cohort, delayed, age-related thinning was observed in four clusters overlapping with the MGH analysis: left frontal, right inferior temporal, left inferior parietal, and right inferior parietal. In addition, onset of cortical thinning was found to be between 13.0 and 14.3 years of age in least-square regression analysis. In the comparison NIH cohort, though, only the left frontal cortex demonstrated significant quadratic thinning; the break point occurred at a significantly younger age, compared with those in the PNC group (P less than .001).
In the PNC group, 248 of the 861 patients included in the MRI analysis were typically developing, 199 had a psychosis diagnosis, 105 had attenuated psychotic symptoms, and 309 had various other psychiatric conditions. Best-fit local thinning slopes were calculated for each participant for each region with postfortification thinning, and in three of four regions, less-negative local slopes were associated with significantly reduced adjusted odds of psychosis spectrum diagnosis (odds ratio, 0.37-0.59; P less than .001 to P = .02), the authors reported.
The findings confirm that “fetal exposure to population-wide folic acid fortification was associated with subsequent alterations in cortical development among school-aged youths,” Dr. Eryilmaz and his coauthors wrote. “These cortical changes were associated with reduced risk of psychosis.”
The results also suggest that the protective effects of folic acid in gestation “may extend beyond prevention of neural tube defects and span neurodevelopment during childhood and adolescence,” they concluded.
The study was funded by MQ: Transforming Mental Health, with support from grants from several additional sources, including the National Institutes of Health.
SOURCE: Eryilmaz H et al. JAMA Psychiatry. 2018 Jul 3. doi: 10.1001/jamapsychiatry.2018.1381.
FROM JAMA PSYCHIATRY
Key clinical point: Gestational exposure to grain products fortified with folic acid resulted in delayed thinning of the cerebral cortex, and thus may protect against later psychosis.
Major finding: Increases in cortical thickness were associated with folic acid exposure in the bilateral frontal and temporal regions of the brain (9.9%-11.6%; corrected P less than .001 to P = .03).
Study details: A retrospective, observational cohort study of 292 patients aged 8-18 years.
Disclosures: The study was funded by MQ: Transforming Mental Health, with support from grants from several additional sources, including the National Institutes of Health.
Source: Eryilmaz H et al. JAMA Psychiatry. 2018 Jul 3. doi: 10.1001/jamapsychiatry.2018.1381.
Patient survey results highlight disease burden in atopic dermatitis
More than half of the patients with moderate to severe atopic dermatitis (AD) had inadequately controlled disease, which was associated with a higher patient-reported disease burden compared with those who had adequately controlled disease, in a cross-sectional study of adults with AD.
Disease control aside, patient-reported burden was generally higher in those with moderate to severe AD versus patients with mild AD, according to Eric L. Simpson, MD, professor of dermatology, Oregon Health & Science University, Portland, and his coauthors.
“These results highlight beyond using measures of disease activity,” the researchers wrote. The study, published in JAMA Dermatology, was conducted before the introduction of dupilumab (Dupixent), the first biologic approved by the Food and Drug Administration for treatment of moderate to severe AD, the authors noted. (The study was supported by the manufacturers of dupilumab.)
The patients were in the Adults With Atopic Dermatitis Reporting on Their Experience (AD-AWARE) study, a cross-sectional analysis of burden of illness in adults with AD in clinical practices at six U.S. academic medical centers. The 1,519 patients completed a self-administered, Internet-based questionnaire during 2013-2014. Among these patients, 830 (54.6%) had moderate to severe AD.
A total of 185 patients with moderate to severe disease received systemic immunomodulators or phototherapy, and of those, more than half (103, or 55.7%) reported inadequate disease control, according to the survey results.
Regardless of disease control, the patients with moderate to severe AD had a greater burden of disease compared with patients with mild AD, according to the investigators. Those burdens included more severe pain and itching, sleep effects, anxiety and depression, and impairment of health-related quality of life, they reported.
Those with moderate to severe disease had a mean of 5.7 days per week with itchy skin, and 22.8% reported itch lasting for more than half a day, compared with a mean of 2.7 days and 2.9%, respectively, for those with mild disease, all significant differences.
Those with moderate to severe disease also reported more trouble sleeping, along with more frequent sleep disturbances, longer time transitioning into sleep, and more use of nonprescription sleep medications than those with mild disease.
Among those with moderate to severe disease, those who were inadequately controlled had a higher level of itch intensity and more frequent itching (a mean of 6.3 days per week), compared with those who were controlled (a mean of 5.7 days per week).
In a previous study looking at patient burden in a phase 2b clinical trial of dupilumab, Dr. Simpson and his coinvestigators found that adults with moderate to severe AD reported a “multidimensional burden” of disease that included disease activity, patient-reported symptoms, quality-of-life impact, and comorbidities (J Am Acad Dermatol. 2016 Mar;74[3]:491-8).
The current analysis based on the AD-AWARE study was supported by dupilumab manufacturers Regeneron Pharmaceuticals and Sanofi. Dr. Simpson reported disclosures related to Amgen, Anacor, Asubio, Celgene, Chugai, Galderma, Genentech, Medicis, Merck, and Regeneron; five of the 15 authors were employees of Sanofi or Regeneron. Other authors reported disclosures related to these and other companies.
SOURCE: Simpson EL et al. JAMA Dermatol. 2018 Jul 3. doi: 10.1001/jamadermatol.2018.1572.
More than half of the patients with moderate to severe atopic dermatitis (AD) had inadequately controlled disease, which was associated with a higher patient-reported disease burden compared with those who had adequately controlled disease, in a cross-sectional study of adults with AD.
Disease control aside, patient-reported burden was generally higher in those with moderate to severe AD versus patients with mild AD, according to Eric L. Simpson, MD, professor of dermatology, Oregon Health & Science University, Portland, and his coauthors.
“These results highlight beyond using measures of disease activity,” the researchers wrote. The study, published in JAMA Dermatology, was conducted before the introduction of dupilumab (Dupixent), the first biologic approved by the Food and Drug Administration for treatment of moderate to severe AD, the authors noted. (The study was supported by the manufacturers of dupilumab.)
The patients were in the Adults With Atopic Dermatitis Reporting on Their Experience (AD-AWARE) study, a cross-sectional analysis of burden of illness in adults with AD in clinical practices at six U.S. academic medical centers. The 1,519 patients completed a self-administered, Internet-based questionnaire during 2013-2014. Among these patients, 830 (54.6%) had moderate to severe AD.
A total of 185 patients with moderate to severe disease received systemic immunomodulators or phototherapy, and of those, more than half (103, or 55.7%) reported inadequate disease control, according to the survey results.
Regardless of disease control, the patients with moderate to severe AD had a greater burden of disease compared with patients with mild AD, according to the investigators. Those burdens included more severe pain and itching, sleep effects, anxiety and depression, and impairment of health-related quality of life, they reported.
Those with moderate to severe disease had a mean of 5.7 days per week with itchy skin, and 22.8% reported itch lasting for more than half a day, compared with a mean of 2.7 days and 2.9%, respectively, for those with mild disease, all significant differences.
Those with moderate to severe disease also reported more trouble sleeping, along with more frequent sleep disturbances, longer time transitioning into sleep, and more use of nonprescription sleep medications than those with mild disease.
Among those with moderate to severe disease, those who were inadequately controlled had a higher level of itch intensity and more frequent itching (a mean of 6.3 days per week), compared with those who were controlled (a mean of 5.7 days per week).
In a previous study looking at patient burden in a phase 2b clinical trial of dupilumab, Dr. Simpson and his coinvestigators found that adults with moderate to severe AD reported a “multidimensional burden” of disease that included disease activity, patient-reported symptoms, quality-of-life impact, and comorbidities (J Am Acad Dermatol. 2016 Mar;74[3]:491-8).
The current analysis based on the AD-AWARE study was supported by dupilumab manufacturers Regeneron Pharmaceuticals and Sanofi. Dr. Simpson reported disclosures related to Amgen, Anacor, Asubio, Celgene, Chugai, Galderma, Genentech, Medicis, Merck, and Regeneron; five of the 15 authors were employees of Sanofi or Regeneron. Other authors reported disclosures related to these and other companies.
SOURCE: Simpson EL et al. JAMA Dermatol. 2018 Jul 3. doi: 10.1001/jamadermatol.2018.1572.
More than half of the patients with moderate to severe atopic dermatitis (AD) had inadequately controlled disease, which was associated with a higher patient-reported disease burden compared with those who had adequately controlled disease, in a cross-sectional study of adults with AD.
Disease control aside, patient-reported burden was generally higher in those with moderate to severe AD versus patients with mild AD, according to Eric L. Simpson, MD, professor of dermatology, Oregon Health & Science University, Portland, and his coauthors.
“These results highlight beyond using measures of disease activity,” the researchers wrote. The study, published in JAMA Dermatology, was conducted before the introduction of dupilumab (Dupixent), the first biologic approved by the Food and Drug Administration for treatment of moderate to severe AD, the authors noted. (The study was supported by the manufacturers of dupilumab.)
The patients were in the Adults With Atopic Dermatitis Reporting on Their Experience (AD-AWARE) study, a cross-sectional analysis of burden of illness in adults with AD in clinical practices at six U.S. academic medical centers. The 1,519 patients completed a self-administered, Internet-based questionnaire during 2013-2014. Among these patients, 830 (54.6%) had moderate to severe AD.
A total of 185 patients with moderate to severe disease received systemic immunomodulators or phototherapy, and of those, more than half (103, or 55.7%) reported inadequate disease control, according to the survey results.
Regardless of disease control, the patients with moderate to severe AD had a greater burden of disease compared with patients with mild AD, according to the investigators. Those burdens included more severe pain and itching, sleep effects, anxiety and depression, and impairment of health-related quality of life, they reported.
Those with moderate to severe disease had a mean of 5.7 days per week with itchy skin, and 22.8% reported itch lasting for more than half a day, compared with a mean of 2.7 days and 2.9%, respectively, for those with mild disease, all significant differences.
Those with moderate to severe disease also reported more trouble sleeping, along with more frequent sleep disturbances, longer time transitioning into sleep, and more use of nonprescription sleep medications than those with mild disease.
Among those with moderate to severe disease, those who were inadequately controlled had a higher level of itch intensity and more frequent itching (a mean of 6.3 days per week), compared with those who were controlled (a mean of 5.7 days per week).
In a previous study looking at patient burden in a phase 2b clinical trial of dupilumab, Dr. Simpson and his coinvestigators found that adults with moderate to severe AD reported a “multidimensional burden” of disease that included disease activity, patient-reported symptoms, quality-of-life impact, and comorbidities (J Am Acad Dermatol. 2016 Mar;74[3]:491-8).
The current analysis based on the AD-AWARE study was supported by dupilumab manufacturers Regeneron Pharmaceuticals and Sanofi. Dr. Simpson reported disclosures related to Amgen, Anacor, Asubio, Celgene, Chugai, Galderma, Genentech, Medicis, Merck, and Regeneron; five of the 15 authors were employees of Sanofi or Regeneron. Other authors reported disclosures related to these and other companies.
SOURCE: Simpson EL et al. JAMA Dermatol. 2018 Jul 3. doi: 10.1001/jamadermatol.2018.1572.
FROM JAMA DERMATOLOGY
Key clinical point: Consider the burden of disease in patients, in addition to severity, when evaluating patients with atopic dermatitis.
Major finding: Patients with moderate to severe AD experienced itchy skin a mean of 5.7 days per week, with 22.8% reporting itch lasting for more than half a day, vs. a mean of 2.7 days and 2.9%, respectively, among those with mild disease (P less than .001 for both measures).
Study details: A cross-sectional study of 1,519 adult patients with AD, who answered a questionnaire related to disease burden.
Disclosures: Dr. Simpson reported disclosures related to Amgen, Anacor, Asubio, Celgene, Chugai, Galderma, Genentech, Medicis, Merck, and Regeneron. Five of the 15 authors were employees of Sanofi or Regeneron. Other authors reported disclosures related to these and/or other companies.
Source: Simpson EL et al. JAMA Dermatol. 2018 Jul 3. doi: 10.1001/jamadermatol.2018.1572.
HPV vaccine: New therapeutic option for SCC?
A patient with an aggressive form of squamous cell carcinoma (SCC) experienced complete resolution of tumors following administration of human papillomavirus (HPV) vaccine, a recent case report shows.
The patient, an immunocompetent woman, aged in her 90s, with multiple inoperable cutaneous basaloid SCCs, was treated with a combination of systemic and intratumoral delivery of 9-valent HPV vaccine, authors of the case report wrote in JAMA Dermatology.
All tumors resolved within 11 months of the first intratumoral injection, according to Anna J. Nichols, MD, PhD, department of dermatology and cutaneous surgery, University of Miami, and her coauthors.
‘These findings suggest that the 9-valent HPV vaccine can provide a therapeutic option for inoperable cutaneous SCCs, in addition to its approved use to prevent anogenital HPV infection,” they wrote.
Previously, Dr. Nichols and her coinvestigators reported a reduction in SCCs and basal cell carcinoma in 2 immunocompetent patients who had received quadrivalent HPV vaccine. Those results suggested development of these keratinocyte carcinomas in immunocompetent patients may be driven in part by HPV, the investigators said at the time.
The patient in the current report was treated with 9-valent HPV vaccine in a university-based outpatient clinic between March 2016 and February 2017.
She initially received two doses of intramuscular vaccine 6 weeks apart; 3 weeks later, she received intratumoral administration of the vaccine diluted with sterile saline, followed by three additional intratumoral doses over the next 8 months.
“The marked regression of numerous SCCs after initiation of the intratumoral injections eliminated the need for additional treatment,” Dr. Nichols and her coauthors said in the report.
A reduction in tumor size and number was seen 2 weeks after the second intratumoral dose of the 9-valent HPV vaccine, and within 11 months of the first intratumoral dose, there was no clinical or histologic evidence of SCC, they said.
The patient was left with small, violet-colored scars, along with a small pink papule, histopathologic analysis of which showed mild cellular atypia of basal keratinocytes with hyperkeratosis, according to published details of the case report.
The patient experienced mild pain in some of the tumors on days of intratumoral treatment, but no other side effects were seen, according to the authors.
The patient remained tumor free at the end of follow-up in May 2018, and there was no clinical evidence of SCC recurrence at the patient’s most recent follow-up visit, 24 months after the first intratumoral HPV dose, the researchers wrote.
It’s not clear what role the systemic vaccine doses played in the therapeutic benefit the patient experienced, authors said, noting that tumors not injected directly may have regressed because of either local vaccine dispersion or systemic, immune-mediated mechanisms.
“The potent therapeutic benefit may reflect a combination of immunologic, antiviral, and antitumor effects of 9-valent HPV vaccine,” they concluded.
Dr. Nichols had no disclosures. Study coauthors Tim Ioannides, MD, and Evangelos V. Badiavas, MD, PhD, have a patent pending for the application of human papillomavirus vaccine described in the study.
SOURCE: Nichols AJ et al. JAMA Dermatol. 2018 Jul 3. doi: 10.1001/jamadermatol.2016.5703.
A patient with an aggressive form of squamous cell carcinoma (SCC) experienced complete resolution of tumors following administration of human papillomavirus (HPV) vaccine, a recent case report shows.
The patient, an immunocompetent woman, aged in her 90s, with multiple inoperable cutaneous basaloid SCCs, was treated with a combination of systemic and intratumoral delivery of 9-valent HPV vaccine, authors of the case report wrote in JAMA Dermatology.
All tumors resolved within 11 months of the first intratumoral injection, according to Anna J. Nichols, MD, PhD, department of dermatology and cutaneous surgery, University of Miami, and her coauthors.
‘These findings suggest that the 9-valent HPV vaccine can provide a therapeutic option for inoperable cutaneous SCCs, in addition to its approved use to prevent anogenital HPV infection,” they wrote.
Previously, Dr. Nichols and her coinvestigators reported a reduction in SCCs and basal cell carcinoma in 2 immunocompetent patients who had received quadrivalent HPV vaccine. Those results suggested development of these keratinocyte carcinomas in immunocompetent patients may be driven in part by HPV, the investigators said at the time.
The patient in the current report was treated with 9-valent HPV vaccine in a university-based outpatient clinic between March 2016 and February 2017.
She initially received two doses of intramuscular vaccine 6 weeks apart; 3 weeks later, she received intratumoral administration of the vaccine diluted with sterile saline, followed by three additional intratumoral doses over the next 8 months.
“The marked regression of numerous SCCs after initiation of the intratumoral injections eliminated the need for additional treatment,” Dr. Nichols and her coauthors said in the report.
A reduction in tumor size and number was seen 2 weeks after the second intratumoral dose of the 9-valent HPV vaccine, and within 11 months of the first intratumoral dose, there was no clinical or histologic evidence of SCC, they said.
The patient was left with small, violet-colored scars, along with a small pink papule, histopathologic analysis of which showed mild cellular atypia of basal keratinocytes with hyperkeratosis, according to published details of the case report.
The patient experienced mild pain in some of the tumors on days of intratumoral treatment, but no other side effects were seen, according to the authors.
The patient remained tumor free at the end of follow-up in May 2018, and there was no clinical evidence of SCC recurrence at the patient’s most recent follow-up visit, 24 months after the first intratumoral HPV dose, the researchers wrote.
It’s not clear what role the systemic vaccine doses played in the therapeutic benefit the patient experienced, authors said, noting that tumors not injected directly may have regressed because of either local vaccine dispersion or systemic, immune-mediated mechanisms.
“The potent therapeutic benefit may reflect a combination of immunologic, antiviral, and antitumor effects of 9-valent HPV vaccine,” they concluded.
Dr. Nichols had no disclosures. Study coauthors Tim Ioannides, MD, and Evangelos V. Badiavas, MD, PhD, have a patent pending for the application of human papillomavirus vaccine described in the study.
SOURCE: Nichols AJ et al. JAMA Dermatol. 2018 Jul 3. doi: 10.1001/jamadermatol.2016.5703.
A patient with an aggressive form of squamous cell carcinoma (SCC) experienced complete resolution of tumors following administration of human papillomavirus (HPV) vaccine, a recent case report shows.
The patient, an immunocompetent woman, aged in her 90s, with multiple inoperable cutaneous basaloid SCCs, was treated with a combination of systemic and intratumoral delivery of 9-valent HPV vaccine, authors of the case report wrote in JAMA Dermatology.
All tumors resolved within 11 months of the first intratumoral injection, according to Anna J. Nichols, MD, PhD, department of dermatology and cutaneous surgery, University of Miami, and her coauthors.
‘These findings suggest that the 9-valent HPV vaccine can provide a therapeutic option for inoperable cutaneous SCCs, in addition to its approved use to prevent anogenital HPV infection,” they wrote.
Previously, Dr. Nichols and her coinvestigators reported a reduction in SCCs and basal cell carcinoma in 2 immunocompetent patients who had received quadrivalent HPV vaccine. Those results suggested development of these keratinocyte carcinomas in immunocompetent patients may be driven in part by HPV, the investigators said at the time.
The patient in the current report was treated with 9-valent HPV vaccine in a university-based outpatient clinic between March 2016 and February 2017.
She initially received two doses of intramuscular vaccine 6 weeks apart; 3 weeks later, she received intratumoral administration of the vaccine diluted with sterile saline, followed by three additional intratumoral doses over the next 8 months.
“The marked regression of numerous SCCs after initiation of the intratumoral injections eliminated the need for additional treatment,” Dr. Nichols and her coauthors said in the report.
A reduction in tumor size and number was seen 2 weeks after the second intratumoral dose of the 9-valent HPV vaccine, and within 11 months of the first intratumoral dose, there was no clinical or histologic evidence of SCC, they said.
The patient was left with small, violet-colored scars, along with a small pink papule, histopathologic analysis of which showed mild cellular atypia of basal keratinocytes with hyperkeratosis, according to published details of the case report.
The patient experienced mild pain in some of the tumors on days of intratumoral treatment, but no other side effects were seen, according to the authors.
The patient remained tumor free at the end of follow-up in May 2018, and there was no clinical evidence of SCC recurrence at the patient’s most recent follow-up visit, 24 months after the first intratumoral HPV dose, the researchers wrote.
It’s not clear what role the systemic vaccine doses played in the therapeutic benefit the patient experienced, authors said, noting that tumors not injected directly may have regressed because of either local vaccine dispersion or systemic, immune-mediated mechanisms.
“The potent therapeutic benefit may reflect a combination of immunologic, antiviral, and antitumor effects of 9-valent HPV vaccine,” they concluded.
Dr. Nichols had no disclosures. Study coauthors Tim Ioannides, MD, and Evangelos V. Badiavas, MD, PhD, have a patent pending for the application of human papillomavirus vaccine described in the study.
SOURCE: Nichols AJ et al. JAMA Dermatol. 2018 Jul 3. doi: 10.1001/jamadermatol.2016.5703.
FROM JAMA DERMATOLOGY
Key clinical point: Human papillomavirus (HPV) vaccine may provide a therapeutic option for inoperable cutaneous squamous cell carcinoma (SCC).
Major finding: One patient experienced complete resolution of tumors after systemic and intratumoral delivery of 9-valent HPV vaccine.
Study details: A case report of an immunocompetent woman in her 90s with multiple inoperable cutaneous basaloid SCCs.
Disclosures: Study coauthors Tim Ioannides, MD, and Evangelos V. Badiavas, MD, PhD, have a patent pending for the application of human papillomavirus vaccine described in the study.
Source: Nichols AJ et al. JAMA Dermatol. 2018 Jul 3. doi: 10.1001/jamadermatol.2016.5703.
Ozanimod May Provide Better MS Outcomes Than Interferon Beta
NASHVILLE—Two doses of ozanimod provide greater benefits on annualized relapse rate and MRI end points than interferon beta-1a does, according to research described at the 2018 CMSC Annual Meeting. Together with safety and tolerability results, the data indicate that oral ozanimod has a favorable risk–benefit profile in patients with relapsing-remitting multiple sclerosis (MS), said the investigators.
Ozanimod is an oral immunomodulator that selectively targets sphingosine 1-phosphate receptors 1 and 5. The drug is administered once daily. Bruce A. C. Cree, MD, PhD, Associate Professor of Neurology at the University of California, San Francisco, and colleagues examined data for patients with relapsing-remitting MS in the SUNBEAM and RADIANCE Part B trials to compare the efficacy and safety of ozanimod with those of interferon beta-1a. Patients received 1 mg or 0.5 mg of ozanimod HCl (with a seven-day dose escalation) or 30 μg of interferon beta-1a.
Ozanimod Decreased Annualized Relapse Rate
Dr. Cree and colleagues analyzed 12-month efficacy data from SUNBEAM, 24-month efficacy data from RADIANCE, and pooled safety data. 
In all, 1,346 patients were treated in SUNBEAM, and 1,313 patients were treated in RADIANCE. Ozanimod 1 mg and 0.5 mg reduced participants’ adjusted annualized relapse rate by 48% (0.181) and 31% (0.241), respectively, versus interferon beta-1a (0.350) in SUNBEAM, and by 38% (0.172) and 21% (0.218), respectively, versus interferon beta-1a (0.276) in RADIANCE.
The adjusted mean number of new or enlarging T2 lesions was reduced by 48% and 25% versus interferon beta-1a for ozanimod 1 mg and 0.5 mg, respectively, in SUNBEAM, and by 42% and 34%, respectively, in RADIANCE. The adjusted mean number of gadolinium-enhancing lesions was reduced by 63% for the 1-mg dose of ozanimod and by 34% for the 0.5-mg dose of ozanimod versus interferon beta-1a in SUNBEAM. In RADIANCE, ozanimod 1 mg reduced this outcome by 53% and ozanimod 0.5 mg reduced this outcome by 47%, compared with interferon beta-1a.
Fewer Adverse Events With Ozanimod
Confirmed three-month pooled disability progression was low in the ozanimod 1 mg (0.102), ozanimod 0.5 mg (0.080), and interferon beta-1a (0.099) groups. In SUNBEAM, whole brain volume loss was 33% lower with ozanimod 1 mg and 12% lower with ozanimod 0.5 mg, compared with interferon beta-1a. In RADIANCE, whole brain volume loss was 27% lower with ozanimod 1 mg and 25% lower with ozanimod 0.5 mg, compared with interferon beta-1a. Ozanimod was associated with greater slowing of cortical gray matter and thalamic volume loss in both studies, c
Compared with interferon beta-1a, ozanimod-treated patients had fewer adverse events (ozanimod 1 mg, 67.1%; ozanimod 0.5 mg, 65.6%; interferon beta-1a, 79.2%) and adverse events leading to study drug discontinuation (ozanimod 1 mg, 2.9%; ozanimod 0.5 mg, 2.4%; interferon beta-1a, 3.8%). Serious adverse events, including infections, were balanced and infrequent across groups (ozanimod 1 mg, 4.6%; ozanimod 0.5 mg, 5.3%; interferon beta-1a, 4.4%); no serious opportunistic infections were reported.
No second degree or higher atrioventricular block was observed. Researchers observed one death due to drowning (ozanimod 0.5 mg) deemed unrelated to the study drug.
NASHVILLE—Two doses of ozanimod provide greater benefits on annualized relapse rate and MRI end points than interferon beta-1a does, according to research described at the 2018 CMSC Annual Meeting. Together with safety and tolerability results, the data indicate that oral ozanimod has a favorable risk–benefit profile in patients with relapsing-remitting multiple sclerosis (MS), said the investigators.
Ozanimod is an oral immunomodulator that selectively targets sphingosine 1-phosphate receptors 1 and 5. The drug is administered once daily. Bruce A. C. Cree, MD, PhD, Associate Professor of Neurology at the University of California, San Francisco, and colleagues examined data for patients with relapsing-remitting MS in the SUNBEAM and RADIANCE Part B trials to compare the efficacy and safety of ozanimod with those of interferon beta-1a. Patients received 1 mg or 0.5 mg of ozanimod HCl (with a seven-day dose escalation) or 30 μg of interferon beta-1a.
Ozanimod Decreased Annualized Relapse Rate
Dr. Cree and colleagues analyzed 12-month efficacy data from SUNBEAM, 24-month efficacy data from RADIANCE, and pooled safety data.
In all, 1,346 patients were treated in SUNBEAM, and 1,313 patients were treated in RADIANCE. Ozanimod 1 mg and 0.5 mg reduced participants’ adjusted annualized relapse rate by 48% (0.181) and 31% (0.241), respectively, versus interferon beta-1a (0.350) in SUNBEAM, and by 38% (0.172) and 21% (0.218), respectively, versus interferon beta-1a (0.276) in RADIANCE.
The adjusted mean number of new or enlarging T2 lesions was reduced by 48% and 25% versus interferon beta-1a for ozanimod 1 mg and 0.5 mg, respectively, in SUNBEAM, and by 42% and 34%, respectively, in RADIANCE. The adjusted mean number of gadolinium-enhancing lesions was reduced by 63% for the 1-mg dose of ozanimod and by 34% for the 0.5-mg dose of ozanimod versus interferon beta-1a in SUNBEAM. In RADIANCE, ozanimod 1 mg reduced this outcome by 53% and ozanimod 0.5 mg reduced this outcome by 47%, compared with interferon beta-1a.
Fewer Adverse Events With Ozanimod
Confirmed three-month pooled disability progression was low in the ozanimod 1 mg (0.102), ozanimod 0.5 mg (0.080), and interferon beta-1a (0.099) groups. In SUNBEAM, whole brain volume loss was 33% lower with ozanimod 1 mg and 12% lower with ozanimod 0.5 mg, compared with interferon beta-1a. In RADIANCE, whole brain volume loss was 27% lower with ozanimod 1 mg and 25% lower with ozanimod 0.5 mg, compared with interferon beta-1a. Ozanimod was associated with greater slowing of cortical gray matter and thalamic volume loss in both studies, c
Compared with interferon beta-1a, ozanimod-treated patients had fewer adverse events (ozanimod 1 mg, 67.1%; ozanimod 0.5 mg, 65.6%; interferon beta-1a, 79.2%) and adverse events leading to study drug discontinuation (ozanimod 1 mg, 2.9%; ozanimod 0.5 mg, 2.4%; interferon beta-1a, 3.8%). Serious adverse events, including infections, were balanced and infrequent across groups (ozanimod 1 mg, 4.6%; ozanimod 0.5 mg, 5.3%; interferon beta-1a, 4.4%); no serious opportunistic infections were reported.
No second degree or higher atrioventricular block was observed. Researchers observed one death due to drowning (ozanimod 0.5 mg) deemed unrelated to the study drug.
NASHVILLE—Two doses of ozanimod provide greater benefits on annualized relapse rate and MRI end points than interferon beta-1a does, according to research described at the 2018 CMSC Annual Meeting. Together with safety and tolerability results, the data indicate that oral ozanimod has a favorable risk–benefit profile in patients with relapsing-remitting multiple sclerosis (MS), said the investigators.
Ozanimod is an oral immunomodulator that selectively targets sphingosine 1-phosphate receptors 1 and 5. The drug is administered once daily. Bruce A. C. Cree, MD, PhD, Associate Professor of Neurology at the University of California, San Francisco, and colleagues examined data for patients with relapsing-remitting MS in the SUNBEAM and RADIANCE Part B trials to compare the efficacy and safety of ozanimod with those of interferon beta-1a. Patients received 1 mg or 0.5 mg of ozanimod HCl (with a seven-day dose escalation) or 30 μg of interferon beta-1a.
Ozanimod Decreased Annualized Relapse Rate
Dr. Cree and colleagues analyzed 12-month efficacy data from SUNBEAM, 24-month efficacy data from RADIANCE, and pooled safety data.
In all, 1,346 patients were treated in SUNBEAM, and 1,313 patients were treated in RADIANCE. Ozanimod 1 mg and 0.5 mg reduced participants’ adjusted annualized relapse rate by 48% (0.181) and 31% (0.241), respectively, versus interferon beta-1a (0.350) in SUNBEAM, and by 38% (0.172) and 21% (0.218), respectively, versus interferon beta-1a (0.276) in RADIANCE.
The adjusted mean number of new or enlarging T2 lesions was reduced by 48% and 25% versus interferon beta-1a for ozanimod 1 mg and 0.5 mg, respectively, in SUNBEAM, and by 42% and 34%, respectively, in RADIANCE. The adjusted mean number of gadolinium-enhancing lesions was reduced by 63% for the 1-mg dose of ozanimod and by 34% for the 0.5-mg dose of ozanimod versus interferon beta-1a in SUNBEAM. In RADIANCE, ozanimod 1 mg reduced this outcome by 53% and ozanimod 0.5 mg reduced this outcome by 47%, compared with interferon beta-1a.
Fewer Adverse Events With Ozanimod
Confirmed three-month pooled disability progression was low in the ozanimod 1 mg (0.102), ozanimod 0.5 mg (0.080), and interferon beta-1a (0.099) groups. In SUNBEAM, whole brain volume loss was 33% lower with ozanimod 1 mg and 12% lower with ozanimod 0.5 mg, compared with interferon beta-1a. In RADIANCE, whole brain volume loss was 27% lower with ozanimod 1 mg and 25% lower with ozanimod 0.5 mg, compared with interferon beta-1a. Ozanimod was associated with greater slowing of cortical gray matter and thalamic volume loss in both studies, c
Compared with interferon beta-1a, ozanimod-treated patients had fewer adverse events (ozanimod 1 mg, 67.1%; ozanimod 0.5 mg, 65.6%; interferon beta-1a, 79.2%) and adverse events leading to study drug discontinuation (ozanimod 1 mg, 2.9%; ozanimod 0.5 mg, 2.4%; interferon beta-1a, 3.8%). Serious adverse events, including infections, were balanced and infrequent across groups (ozanimod 1 mg, 4.6%; ozanimod 0.5 mg, 5.3%; interferon beta-1a, 4.4%); no serious opportunistic infections were reported.
No second degree or higher atrioventricular block was observed. Researchers observed one death due to drowning (ozanimod 0.5 mg) deemed unrelated to the study drug.
Which Clinical Scenarios Warrant Amyloid PET?
LOS ANGELES—Amyloid PET scans may play an important role in neurologists’ management of patients with cognitive impairment. For the moment, clinical use should be restricted to cases that can be summarized with the mnemonic MAY—Mild, Atypical, and Young, said Gil D. Rabinovici, MD. “Those are the people who are most likely to benefit,” he said.
Although amyloid PET scans may affect diagnostic certainty and influence treatment in these scenarios, most patients do not get the scans. “They cost thousands of dollars, and most insurance will not pay for them,” Dr. Rabinovici said in a lecture at the 70th Annual Meeting of the American Academy of Neurology. 
Looking to the future, amyloid PET may play a larger role in clinical practice if insurance providers more readily cover the cost of the scans and if the definition of Alzheimer’s disease shifts from a clinical basis to a biologic one. Someday, neurologists may be able to offer interventions to delay or prevent the onset of dementia in patients at risk of Alzheimer’s disease, Dr. Rabinovici said.“During the coming decade, we are going to see a real paradigm shift,” he said, “from the current status quo where we are diagnosing and treating clinical dementia to a paradigm where we are doing early screening with biomarkers.” Dr. Rabinovici is the Edward Fein and Pearl Landrith Distinguished Professor in the Memory and Aging Center at the University of California, San Francisco.
Three FDA-Approved Tracers
Three amyloid-beta tracers are FDA approved for clinical use in cognitively impaired patients—18F-florbetapir (Amyvid, approved in 2012), 18F-flutemetamol (Vizamyl, approved in 2013), and 18F-florbetaben (Neuraceq, approved in 2014).
The agents were approved on the basis of studies that found that blinded visual reads of amyloid PET scans during life accurately predicted postmortem burden of amyloid pathology in the same individuals. The scans distinguish patients with moderate or frequent neuritic plaques from those with absent or sparse neuritic plaques with a sensitivity and specificity of 80% or greater. Many scans can be categorized as positive or negative, and neurologists can quickly learn to read them, Dr. Rabinovici said.
Scans have the potential to improve the accuracy of Alzheimer’s disease diagnosis. Compared with postmortem findings, the clinical diagnosis of probable Alzheimer’s disease was accurate only 70% of the time in one study. Conversely, another study found that approximately 40% of patients with a diagnosis of non-Alzheimer’s disease dementia turned out to have Alzheimer’s disease as the primary causative pathology at autopsy.
Real-Life Ramifications
To illustrate amyloid PET’s potential usefulness in clinical practice, Dr. Rabinovici described a case of a 57-year-old internist. The patient had progressive trouble finding words, but otherwise did not have major symptoms or concerns. He did poorly on repeating sentences, but the rest of his examination was normal. MRI revealed nothing remarkable.
“That is the typical standard of care that is meant for someone with a cognitive complaint,” Dr. Rabinovici said. An FDG-PET scan was suspicious but not definitive. The patient’s amyloid PET scan, however, was clearly positive and showed amyloid throughout the neocortex. “With the scans, I could diagnose him. He had mild cognitive impairment, but I thought with high likelihood due to Alzheimer’s disease.”
As a result, Dr. Rabinovici started the patient on a cholinesterase inhibitor, and the patient decided to retire early due to medical disability. In addition, the patient enrolled in a clinical trial of an investigational antiamyloid therapy.
“I was not able to cure or modify the course of his Alzheimer’s disease, but amyloid PET did have real ramifications for his life,” he said.
Consider the Clinical Context
As with any diagnostic agent, clinical context is critical for interpreting the significance of positive and negative amyloid scans, Dr. Rabinovici said.
Among patients with dementia, amyloid PET can distinguish Alzheimer’s disease from conditions that do not involve amyloid-beta deposition, such as frontotemporal dementia or pure vascular dementia. It is not useful, however, in distinguishing Alzheimer’s disease from other conditions in which amyloid is deposited in the brain, such as cerebral amyloid angiopathy or dementia with Lewy bodies.
“It is important to consider the patient’s age when you think about the meaning of a positive scan,” he said. “A negative scan is always helpful in ruling out Alzheimer’s disease,” but a positive scan is less meaningful in older patients. Approximately 25% of cognitively normal older individuals have positive amyloid PET scans. The prevalence of amyloid positivity is about 10% at age 60 and more than 50% at age 90.
Not everyone with amyloid deposition has or develops Alzheimer’s disease dementia or mild cognitive impairment, but amyloid is a risk factor, said Dr. Rabinovici. “To summarize 15 years of research in one bullet point, it is not good to have amyloid in your brain even if you are cognitively normal,” he said. “Amyloid-positive normal controls are already showing Alzheimer’s-disease-like structural and functional changes in their brains. Over time, they are likely to decline cognitively. And they have an increased risk of cognitive impairment,” compared with people who are amyloid negative.
Research indicates that the deposition of amyloid plaques begins at least 15 years before the onset of cognitive symptoms, which may represent a window for early intervention, Dr. Rabinovici said.
When to Scan and When Not To
To guide clinicians in the appropriate use of amyloid PET, the Society for Nuclear Medicine and Molecular Imaging and the Alzheimer’s Association in 2013 published appropriate use criteria for the technology. Given amyloid PET’s cost and need for nuanced interpretation, the authors determined that it should not be a first-line test in the evaluation of cognitive complaints, Dr. Rabinovici said. Rather, it should be an ancillary test ordered by subspecialists in patients who meet the following criteria:
- Have a cognitive complaint with objectively confirmed impairment.
- Have an uncertain diagnosis, with Alzheimer’s disease as a possibility, after comprehensive evaluation by a dementia expert.
- Knowledge of their amyloid-beta status is expected to increase diagnostic certainty and alter management.
The three main clinical scenarios in which amyloid imaging may be most useful include the following:
- Cases with persistent and progressive unexplained mild cognitive impairment.
- Cases with possible (rather than probable) Alzheimer’s disease who have an atypical or mixed course or significant comorbidities (eg, vascular, psychiatric, or substance abuse disorders).
- Cases with an atypically early age of onset (ie, younger than 65).
The appropriate use criteria also highlight the following scenarios in which clinical amyloid PET is considered inappropriate:
- For the initial evaluation of cognitive complaints.
- To screen cognitively normal individuals outside the context of research or clinical trials.
- When requested solely based on a family history of dementia or the presence of other Alzheimer’s disease risk factors, such as the ApoE4 gene.
- As a substitute for genetic testing for mutations that cause Alzheimer’s disease.
- For nonmedical reasons, such as insurance, legal, or employment decisions.
Finally, the criteria identify scenarios where amyloid imaging is unlikely to be useful, including as a means of determining the severity of dementia, straightforward clinical cases, and to differentiate Alzheimer’s disease from other diseases that involve the deposition of amyloid-beta.
Effects on Management and Outcomes
Relatively few studies have assessed amyloid PET’s impact on clinical decision making and patient outcomes, Dr. Rabinovici said. In 2013, the US Centers for Medicare and Medicaid Services (CMS) determined that there was insufficient evidence to justify reimbursement of amyloid PET and said that it would reimburse the scans for patients who enroll in studies to assess amyloid PET’s clinical utility, under a mechanism called coverage with evidence development. For CMS to reconsider its coverage decision, studies must demonstrate that amyloid PET changes patient management in the short term and improves dementia outcomes long term. The Imaging Dementia—Evidence for Amyloid Scanning (IDEAS) study, which Dr. Rabinovici chairs, is a multisite study to assess the utility of amyloid PET in Medicare beneficiaries age 65 and older who meet appropriate use criteria for amyloid imaging.
The IDEAS study enrolled more than 18,000 participants and finished recruiting patients this year. It aims to examine how the scans affect patient management plans at three months and medical outcomes at 12 months. “The primary hypothesis is that, in these diagnostically uncertain cases, knowing the amyloid result will change management, and that will translate into better outcomes,” Dr. Rabinovici said.
Results regarding amyloid PET’s influence on patient management at three months will be presented soon, and 12-month outcome data are expected to be presented in 2019.
An interim analysis of the first 3,979 patients found that, three months after the amyloid PET scans, patients’ management plans had changed from the pre-PET management plan in about 67% of cases. Changes included starting or stopping Alzheimer’s-disease-specific medications and other neurologic therapies and changes in patient counseling.
Matched With Controls
To assess 12-month outcomes, investigators plan to use Medicare claims data to compare medical outcomes for patients enrolled in the study with those for matched controls who did not undergo amyloid PET. The primary objective is to determine whether amyloid PET is associated with a 10% or greater reduction in hospitalizations and emergency room visits. The researchers plan to use an algorithm to match each IDEAS study participant with a control with a similar dementia diagnosis, pre-scan dementia-related resource utilization, age, race, gender, ethnicity, geographic location, and comorbid chronic conditions.
Further imaging advances, such as tau PET tracers, are in development but have not yet received regulatory approval from the FDA, Dr. Rabinovici said. Tau PET has the potential to detect pathology in tauopathies such as progressive supranuclear palsy, corticobasal degeneration, chronic traumatic encephalopathy, and subtypes of frontotemporal dementia, as well as Alzheimer’s disease, he said.
—Jake Remaly
Suggested Reading
Jack CR Jr, Bennett DA, Blennow K, et al. NIA-AA Research Framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14(4):535-562.
Johnson KA, Minoshima S, Bohnen NI, et al. Appropriate use criteria for amyloid PET: a report of the Amyloid Imaging Task Force, the Society of Nuclear Medicine and Molecular Imaging, and the Alzheimer’s Association. Alzheimers Dement. 2013;9(1):e1-e16.
LOS ANGELES—Amyloid PET scans may play an important role in neurologists’ management of patients with cognitive impairment. For the moment, clinical use should be restricted to cases that can be summarized with the mnemonic MAY—Mild, Atypical, and Young, said Gil D. Rabinovici, MD. “Those are the people who are most likely to benefit,” he said.
Although amyloid PET scans may affect diagnostic certainty and influence treatment in these scenarios, most patients do not get the scans. “They cost thousands of dollars, and most insurance will not pay for them,” Dr. Rabinovici said in a lecture at the 70th Annual Meeting of the American Academy of Neurology.
Looking to the future, amyloid PET may play a larger role in clinical practice if insurance providers more readily cover the cost of the scans and if the definition of Alzheimer’s disease shifts from a clinical basis to a biologic one. Someday, neurologists may be able to offer interventions to delay or prevent the onset of dementia in patients at risk of Alzheimer’s disease, Dr. Rabinovici said.“During the coming decade, we are going to see a real paradigm shift,” he said, “from the current status quo where we are diagnosing and treating clinical dementia to a paradigm where we are doing early screening with biomarkers.” Dr. Rabinovici is the Edward Fein and Pearl Landrith Distinguished Professor in the Memory and Aging Center at the University of California, San Francisco.
Three FDA-Approved Tracers
Three amyloid-beta tracers are FDA approved for clinical use in cognitively impaired patients—18F-florbetapir (Amyvid, approved in 2012), 18F-flutemetamol (Vizamyl, approved in 2013), and 18F-florbetaben (Neuraceq, approved in 2014).
The agents were approved on the basis of studies that found that blinded visual reads of amyloid PET scans during life accurately predicted postmortem burden of amyloid pathology in the same individuals. The scans distinguish patients with moderate or frequent neuritic plaques from those with absent or sparse neuritic plaques with a sensitivity and specificity of 80% or greater. Many scans can be categorized as positive or negative, and neurologists can quickly learn to read them, Dr. Rabinovici said.
Scans have the potential to improve the accuracy of Alzheimer’s disease diagnosis. Compared with postmortem findings, the clinical diagnosis of probable Alzheimer’s disease was accurate only 70% of the time in one study. Conversely, another study found that approximately 40% of patients with a diagnosis of non-Alzheimer’s disease dementia turned out to have Alzheimer’s disease as the primary causative pathology at autopsy.
Real-Life Ramifications
To illustrate amyloid PET’s potential usefulness in clinical practice, Dr. Rabinovici described a case of a 57-year-old internist. The patient had progressive trouble finding words, but otherwise did not have major symptoms or concerns. He did poorly on repeating sentences, but the rest of his examination was normal. MRI revealed nothing remarkable.
“That is the typical standard of care that is meant for someone with a cognitive complaint,” Dr. Rabinovici said. An FDG-PET scan was suspicious but not definitive. The patient’s amyloid PET scan, however, was clearly positive and showed amyloid throughout the neocortex. “With the scans, I could diagnose him. He had mild cognitive impairment, but I thought with high likelihood due to Alzheimer’s disease.”
As a result, Dr. Rabinovici started the patient on a cholinesterase inhibitor, and the patient decided to retire early due to medical disability. In addition, the patient enrolled in a clinical trial of an investigational antiamyloid therapy.
“I was not able to cure or modify the course of his Alzheimer’s disease, but amyloid PET did have real ramifications for his life,” he said.
Consider the Clinical Context
As with any diagnostic agent, clinical context is critical for interpreting the significance of positive and negative amyloid scans, Dr. Rabinovici said.
Among patients with dementia, amyloid PET can distinguish Alzheimer’s disease from conditions that do not involve amyloid-beta deposition, such as frontotemporal dementia or pure vascular dementia. It is not useful, however, in distinguishing Alzheimer’s disease from other conditions in which amyloid is deposited in the brain, such as cerebral amyloid angiopathy or dementia with Lewy bodies.
“It is important to consider the patient’s age when you think about the meaning of a positive scan,” he said. “A negative scan is always helpful in ruling out Alzheimer’s disease,” but a positive scan is less meaningful in older patients. Approximately 25% of cognitively normal older individuals have positive amyloid PET scans. The prevalence of amyloid positivity is about 10% at age 60 and more than 50% at age 90.
Not everyone with amyloid deposition has or develops Alzheimer’s disease dementia or mild cognitive impairment, but amyloid is a risk factor, said Dr. Rabinovici. “To summarize 15 years of research in one bullet point, it is not good to have amyloid in your brain even if you are cognitively normal,” he said. “Amyloid-positive normal controls are already showing Alzheimer’s-disease-like structural and functional changes in their brains. Over time, they are likely to decline cognitively. And they have an increased risk of cognitive impairment,” compared with people who are amyloid negative.
Research indicates that the deposition of amyloid plaques begins at least 15 years before the onset of cognitive symptoms, which may represent a window for early intervention, Dr. Rabinovici said.
When to Scan and When Not To
To guide clinicians in the appropriate use of amyloid PET, the Society for Nuclear Medicine and Molecular Imaging and the Alzheimer’s Association in 2013 published appropriate use criteria for the technology. Given amyloid PET’s cost and need for nuanced interpretation, the authors determined that it should not be a first-line test in the evaluation of cognitive complaints, Dr. Rabinovici said. Rather, it should be an ancillary test ordered by subspecialists in patients who meet the following criteria:
- Have a cognitive complaint with objectively confirmed impairment.
- Have an uncertain diagnosis, with Alzheimer’s disease as a possibility, after comprehensive evaluation by a dementia expert.
- Knowledge of their amyloid-beta status is expected to increase diagnostic certainty and alter management.
The three main clinical scenarios in which amyloid imaging may be most useful include the following:
- Cases with persistent and progressive unexplained mild cognitive impairment.
- Cases with possible (rather than probable) Alzheimer’s disease who have an atypical or mixed course or significant comorbidities (eg, vascular, psychiatric, or substance abuse disorders).
- Cases with an atypically early age of onset (ie, younger than 65).
The appropriate use criteria also highlight the following scenarios in which clinical amyloid PET is considered inappropriate:
- For the initial evaluation of cognitive complaints.
- To screen cognitively normal individuals outside the context of research or clinical trials.
- When requested solely based on a family history of dementia or the presence of other Alzheimer’s disease risk factors, such as the ApoE4 gene.
- As a substitute for genetic testing for mutations that cause Alzheimer’s disease.
- For nonmedical reasons, such as insurance, legal, or employment decisions.
Finally, the criteria identify scenarios where amyloid imaging is unlikely to be useful, including as a means of determining the severity of dementia, straightforward clinical cases, and to differentiate Alzheimer’s disease from other diseases that involve the deposition of amyloid-beta.
Effects on Management and Outcomes
Relatively few studies have assessed amyloid PET’s impact on clinical decision making and patient outcomes, Dr. Rabinovici said. In 2013, the US Centers for Medicare and Medicaid Services (CMS) determined that there was insufficient evidence to justify reimbursement of amyloid PET and said that it would reimburse the scans for patients who enroll in studies to assess amyloid PET’s clinical utility, under a mechanism called coverage with evidence development. For CMS to reconsider its coverage decision, studies must demonstrate that amyloid PET changes patient management in the short term and improves dementia outcomes long term. The Imaging Dementia—Evidence for Amyloid Scanning (IDEAS) study, which Dr. Rabinovici chairs, is a multisite study to assess the utility of amyloid PET in Medicare beneficiaries age 65 and older who meet appropriate use criteria for amyloid imaging.
The IDEAS study enrolled more than 18,000 participants and finished recruiting patients this year. It aims to examine how the scans affect patient management plans at three months and medical outcomes at 12 months. “The primary hypothesis is that, in these diagnostically uncertain cases, knowing the amyloid result will change management, and that will translate into better outcomes,” Dr. Rabinovici said.
Results regarding amyloid PET’s influence on patient management at three months will be presented soon, and 12-month outcome data are expected to be presented in 2019.
An interim analysis of the first 3,979 patients found that, three months after the amyloid PET scans, patients’ management plans had changed from the pre-PET management plan in about 67% of cases. Changes included starting or stopping Alzheimer’s-disease-specific medications and other neurologic therapies and changes in patient counseling.
Matched With Controls
To assess 12-month outcomes, investigators plan to use Medicare claims data to compare medical outcomes for patients enrolled in the study with those for matched controls who did not undergo amyloid PET. The primary objective is to determine whether amyloid PET is associated with a 10% or greater reduction in hospitalizations and emergency room visits. The researchers plan to use an algorithm to match each IDEAS study participant with a control with a similar dementia diagnosis, pre-scan dementia-related resource utilization, age, race, gender, ethnicity, geographic location, and comorbid chronic conditions.
Further imaging advances, such as tau PET tracers, are in development but have not yet received regulatory approval from the FDA, Dr. Rabinovici said. Tau PET has the potential to detect pathology in tauopathies such as progressive supranuclear palsy, corticobasal degeneration, chronic traumatic encephalopathy, and subtypes of frontotemporal dementia, as well as Alzheimer’s disease, he said.
—Jake Remaly
Suggested Reading
Jack CR Jr, Bennett DA, Blennow K, et al. NIA-AA Research Framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14(4):535-562.
Johnson KA, Minoshima S, Bohnen NI, et al. Appropriate use criteria for amyloid PET: a report of the Amyloid Imaging Task Force, the Society of Nuclear Medicine and Molecular Imaging, and the Alzheimer’s Association. Alzheimers Dement. 2013;9(1):e1-e16.
LOS ANGELES—Amyloid PET scans may play an important role in neurologists’ management of patients with cognitive impairment. For the moment, clinical use should be restricted to cases that can be summarized with the mnemonic MAY—Mild, Atypical, and Young, said Gil D. Rabinovici, MD. “Those are the people who are most likely to benefit,” he said.
Although amyloid PET scans may affect diagnostic certainty and influence treatment in these scenarios, most patients do not get the scans. “They cost thousands of dollars, and most insurance will not pay for them,” Dr. Rabinovici said in a lecture at the 70th Annual Meeting of the American Academy of Neurology.
Looking to the future, amyloid PET may play a larger role in clinical practice if insurance providers more readily cover the cost of the scans and if the definition of Alzheimer’s disease shifts from a clinical basis to a biologic one. Someday, neurologists may be able to offer interventions to delay or prevent the onset of dementia in patients at risk of Alzheimer’s disease, Dr. Rabinovici said.“During the coming decade, we are going to see a real paradigm shift,” he said, “from the current status quo where we are diagnosing and treating clinical dementia to a paradigm where we are doing early screening with biomarkers.” Dr. Rabinovici is the Edward Fein and Pearl Landrith Distinguished Professor in the Memory and Aging Center at the University of California, San Francisco.
Three FDA-Approved Tracers
Three amyloid-beta tracers are FDA approved for clinical use in cognitively impaired patients—18F-florbetapir (Amyvid, approved in 2012), 18F-flutemetamol (Vizamyl, approved in 2013), and 18F-florbetaben (Neuraceq, approved in 2014).
The agents were approved on the basis of studies that found that blinded visual reads of amyloid PET scans during life accurately predicted postmortem burden of amyloid pathology in the same individuals. The scans distinguish patients with moderate or frequent neuritic plaques from those with absent or sparse neuritic plaques with a sensitivity and specificity of 80% or greater. Many scans can be categorized as positive or negative, and neurologists can quickly learn to read them, Dr. Rabinovici said.
Scans have the potential to improve the accuracy of Alzheimer’s disease diagnosis. Compared with postmortem findings, the clinical diagnosis of probable Alzheimer’s disease was accurate only 70% of the time in one study. Conversely, another study found that approximately 40% of patients with a diagnosis of non-Alzheimer’s disease dementia turned out to have Alzheimer’s disease as the primary causative pathology at autopsy.
Real-Life Ramifications
To illustrate amyloid PET’s potential usefulness in clinical practice, Dr. Rabinovici described a case of a 57-year-old internist. The patient had progressive trouble finding words, but otherwise did not have major symptoms or concerns. He did poorly on repeating sentences, but the rest of his examination was normal. MRI revealed nothing remarkable.
“That is the typical standard of care that is meant for someone with a cognitive complaint,” Dr. Rabinovici said. An FDG-PET scan was suspicious but not definitive. The patient’s amyloid PET scan, however, was clearly positive and showed amyloid throughout the neocortex. “With the scans, I could diagnose him. He had mild cognitive impairment, but I thought with high likelihood due to Alzheimer’s disease.”
As a result, Dr. Rabinovici started the patient on a cholinesterase inhibitor, and the patient decided to retire early due to medical disability. In addition, the patient enrolled in a clinical trial of an investigational antiamyloid therapy.
“I was not able to cure or modify the course of his Alzheimer’s disease, but amyloid PET did have real ramifications for his life,” he said.
Consider the Clinical Context
As with any diagnostic agent, clinical context is critical for interpreting the significance of positive and negative amyloid scans, Dr. Rabinovici said.
Among patients with dementia, amyloid PET can distinguish Alzheimer’s disease from conditions that do not involve amyloid-beta deposition, such as frontotemporal dementia or pure vascular dementia. It is not useful, however, in distinguishing Alzheimer’s disease from other conditions in which amyloid is deposited in the brain, such as cerebral amyloid angiopathy or dementia with Lewy bodies.
“It is important to consider the patient’s age when you think about the meaning of a positive scan,” he said. “A negative scan is always helpful in ruling out Alzheimer’s disease,” but a positive scan is less meaningful in older patients. Approximately 25% of cognitively normal older individuals have positive amyloid PET scans. The prevalence of amyloid positivity is about 10% at age 60 and more than 50% at age 90.
Not everyone with amyloid deposition has or develops Alzheimer’s disease dementia or mild cognitive impairment, but amyloid is a risk factor, said Dr. Rabinovici. “To summarize 15 years of research in one bullet point, it is not good to have amyloid in your brain even if you are cognitively normal,” he said. “Amyloid-positive normal controls are already showing Alzheimer’s-disease-like structural and functional changes in their brains. Over time, they are likely to decline cognitively. And they have an increased risk of cognitive impairment,” compared with people who are amyloid negative.
Research indicates that the deposition of amyloid plaques begins at least 15 years before the onset of cognitive symptoms, which may represent a window for early intervention, Dr. Rabinovici said.
When to Scan and When Not To
To guide clinicians in the appropriate use of amyloid PET, the Society for Nuclear Medicine and Molecular Imaging and the Alzheimer’s Association in 2013 published appropriate use criteria for the technology. Given amyloid PET’s cost and need for nuanced interpretation, the authors determined that it should not be a first-line test in the evaluation of cognitive complaints, Dr. Rabinovici said. Rather, it should be an ancillary test ordered by subspecialists in patients who meet the following criteria:
- Have a cognitive complaint with objectively confirmed impairment.
- Have an uncertain diagnosis, with Alzheimer’s disease as a possibility, after comprehensive evaluation by a dementia expert.
- Knowledge of their amyloid-beta status is expected to increase diagnostic certainty and alter management.
The three main clinical scenarios in which amyloid imaging may be most useful include the following:
- Cases with persistent and progressive unexplained mild cognitive impairment.
- Cases with possible (rather than probable) Alzheimer’s disease who have an atypical or mixed course or significant comorbidities (eg, vascular, psychiatric, or substance abuse disorders).
- Cases with an atypically early age of onset (ie, younger than 65).
The appropriate use criteria also highlight the following scenarios in which clinical amyloid PET is considered inappropriate:
- For the initial evaluation of cognitive complaints.
- To screen cognitively normal individuals outside the context of research or clinical trials.
- When requested solely based on a family history of dementia or the presence of other Alzheimer’s disease risk factors, such as the ApoE4 gene.
- As a substitute for genetic testing for mutations that cause Alzheimer’s disease.
- For nonmedical reasons, such as insurance, legal, or employment decisions.
Finally, the criteria identify scenarios where amyloid imaging is unlikely to be useful, including as a means of determining the severity of dementia, straightforward clinical cases, and to differentiate Alzheimer’s disease from other diseases that involve the deposition of amyloid-beta.
Effects on Management and Outcomes
Relatively few studies have assessed amyloid PET’s impact on clinical decision making and patient outcomes, Dr. Rabinovici said. In 2013, the US Centers for Medicare and Medicaid Services (CMS) determined that there was insufficient evidence to justify reimbursement of amyloid PET and said that it would reimburse the scans for patients who enroll in studies to assess amyloid PET’s clinical utility, under a mechanism called coverage with evidence development. For CMS to reconsider its coverage decision, studies must demonstrate that amyloid PET changes patient management in the short term and improves dementia outcomes long term. The Imaging Dementia—Evidence for Amyloid Scanning (IDEAS) study, which Dr. Rabinovici chairs, is a multisite study to assess the utility of amyloid PET in Medicare beneficiaries age 65 and older who meet appropriate use criteria for amyloid imaging.
The IDEAS study enrolled more than 18,000 participants and finished recruiting patients this year. It aims to examine how the scans affect patient management plans at three months and medical outcomes at 12 months. “The primary hypothesis is that, in these diagnostically uncertain cases, knowing the amyloid result will change management, and that will translate into better outcomes,” Dr. Rabinovici said.
Results regarding amyloid PET’s influence on patient management at three months will be presented soon, and 12-month outcome data are expected to be presented in 2019.
An interim analysis of the first 3,979 patients found that, three months after the amyloid PET scans, patients’ management plans had changed from the pre-PET management plan in about 67% of cases. Changes included starting or stopping Alzheimer’s-disease-specific medications and other neurologic therapies and changes in patient counseling.
Matched With Controls
To assess 12-month outcomes, investigators plan to use Medicare claims data to compare medical outcomes for patients enrolled in the study with those for matched controls who did not undergo amyloid PET. The primary objective is to determine whether amyloid PET is associated with a 10% or greater reduction in hospitalizations and emergency room visits. The researchers plan to use an algorithm to match each IDEAS study participant with a control with a similar dementia diagnosis, pre-scan dementia-related resource utilization, age, race, gender, ethnicity, geographic location, and comorbid chronic conditions.
Further imaging advances, such as tau PET tracers, are in development but have not yet received regulatory approval from the FDA, Dr. Rabinovici said. Tau PET has the potential to detect pathology in tauopathies such as progressive supranuclear palsy, corticobasal degeneration, chronic traumatic encephalopathy, and subtypes of frontotemporal dementia, as well as Alzheimer’s disease, he said.
—Jake Remaly
Suggested Reading
Jack CR Jr, Bennett DA, Blennow K, et al. NIA-AA Research Framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14(4):535-562.
Johnson KA, Minoshima S, Bohnen NI, et al. Appropriate use criteria for amyloid PET: a report of the Amyloid Imaging Task Force, the Society of Nuclear Medicine and Molecular Imaging, and the Alzheimer’s Association. Alzheimers Dement. 2013;9(1):e1-e16.
CMSC Guideline Re-Examines Use of Gadolinium-Based Contrast Agents
Standard high-quality MRI without contrast can adequately identify the majority of MS lesions over time, say the authors.
NASHVILLE—Gadolinium-based contrast agents (GBCAs) are necessary for the accurate initial diagnosis of patients experiencing a first clinical attack of symptoms consistent with multiple sclerosis (MS) and for following patients with highly active disease or sudden, unexpected declines, according to a guideline issued by the Consortium of MS Centers (CMSC).
GBCAs are optional, although helpful, in many other clinical scenarios, especially when noncontrast MRI can provide answers.
“The key is that there is an optional role for gadolinium,” said David Li, MD, Professor of Radiology and Associate Member in Neurology at the University of British Columbia in Vancouver, at the 2018 CMSC Annual Meeting. 
Although a GBCA is still “essential” for some clinical scenarios in clinically isolated syndrome and MS, standard, high-quality MRI without contrast can adequately identify the majority of new MS lesions over time, the new guideline suggests. If a neurologist needs to monitor ongoing, current activity in settings of acute change, then gadolinium is still necessary, said Dr. Li.
The guideline, which was described at the meeting, is an update of the CMSC’s 2015 document, which endorsed a more liberal use of GBCAs. This more conservative stance reflects new research on the agents and an update in 2017 from the FDA that required a class-wide warning about gadolinium retention.
The agency began investigating gadolinium in 2015. In May 2017, it issued a statement confirming that gadolinium accumulates in neural tissue and can be retained for an extended period. In reviewing the evidence, however, the FDA found no concerning safety signals. Despite the presumed lack of toxicity, the agency issued the warning and recommended limiting the contrast agents’ use. The CMSC’s new MRI protocol guideline reflects these regulatory actions.
“While there is no known CNS toxicity, these agents should be used judiciously, recognizing that gadolinium continues to play an invaluable role in specific circumstances related to the diagnosis and follow-up of individuals with MS,” the document noted.
“It remains indispensable in patients presenting with their first clinical attack, as [its] use allows for an earlier diagnosis by demonstrating lesion dissemination in time in addition to lesion dissemination in space, which are the hallmarks of the diagnosis of MS. Early diagnosis leads to early treatment, which may help in preventing disease progression and improve long-term prognosis,” said Dr. Li. He had no disclosures relevant to gadolinium.
—Michele G. Sullivan
Standard high-quality MRI without contrast can adequately identify the majority of MS lesions over time, say the authors.
Standard high-quality MRI without contrast can adequately identify the majority of MS lesions over time, say the authors.
NASHVILLE—Gadolinium-based contrast agents (GBCAs) are necessary for the accurate initial diagnosis of patients experiencing a first clinical attack of symptoms consistent with multiple sclerosis (MS) and for following patients with highly active disease or sudden, unexpected declines, according to a guideline issued by the Consortium of MS Centers (CMSC).
GBCAs are optional, although helpful, in many other clinical scenarios, especially when noncontrast MRI can provide answers.
“The key is that there is an optional role for gadolinium,” said David Li, MD, Professor of Radiology and Associate Member in Neurology at the University of British Columbia in Vancouver, at the 2018 CMSC Annual Meeting.
Although a GBCA is still “essential” for some clinical scenarios in clinically isolated syndrome and MS, standard, high-quality MRI without contrast can adequately identify the majority of new MS lesions over time, the new guideline suggests. If a neurologist needs to monitor ongoing, current activity in settings of acute change, then gadolinium is still necessary, said Dr. Li.
The guideline, which was described at the meeting, is an update of the CMSC’s 2015 document, which endorsed a more liberal use of GBCAs. This more conservative stance reflects new research on the agents and an update in 2017 from the FDA that required a class-wide warning about gadolinium retention.
The agency began investigating gadolinium in 2015. In May 2017, it issued a statement confirming that gadolinium accumulates in neural tissue and can be retained for an extended period. In reviewing the evidence, however, the FDA found no concerning safety signals. Despite the presumed lack of toxicity, the agency issued the warning and recommended limiting the contrast agents’ use. The CMSC’s new MRI protocol guideline reflects these regulatory actions.
“While there is no known CNS toxicity, these agents should be used judiciously, recognizing that gadolinium continues to play an invaluable role in specific circumstances related to the diagnosis and follow-up of individuals with MS,” the document noted.
“It remains indispensable in patients presenting with their first clinical attack, as [its] use allows for an earlier diagnosis by demonstrating lesion dissemination in time in addition to lesion dissemination in space, which are the hallmarks of the diagnosis of MS. Early diagnosis leads to early treatment, which may help in preventing disease progression and improve long-term prognosis,” said Dr. Li. He had no disclosures relevant to gadolinium.
—Michele G. Sullivan
NASHVILLE—Gadolinium-based contrast agents (GBCAs) are necessary for the accurate initial diagnosis of patients experiencing a first clinical attack of symptoms consistent with multiple sclerosis (MS) and for following patients with highly active disease or sudden, unexpected declines, according to a guideline issued by the Consortium of MS Centers (CMSC).
GBCAs are optional, although helpful, in many other clinical scenarios, especially when noncontrast MRI can provide answers.
“The key is that there is an optional role for gadolinium,” said David Li, MD, Professor of Radiology and Associate Member in Neurology at the University of British Columbia in Vancouver, at the 2018 CMSC Annual Meeting.
Although a GBCA is still “essential” for some clinical scenarios in clinically isolated syndrome and MS, standard, high-quality MRI without contrast can adequately identify the majority of new MS lesions over time, the new guideline suggests. If a neurologist needs to monitor ongoing, current activity in settings of acute change, then gadolinium is still necessary, said Dr. Li.
The guideline, which was described at the meeting, is an update of the CMSC’s 2015 document, which endorsed a more liberal use of GBCAs. This more conservative stance reflects new research on the agents and an update in 2017 from the FDA that required a class-wide warning about gadolinium retention.
The agency began investigating gadolinium in 2015. In May 2017, it issued a statement confirming that gadolinium accumulates in neural tissue and can be retained for an extended period. In reviewing the evidence, however, the FDA found no concerning safety signals. Despite the presumed lack of toxicity, the agency issued the warning and recommended limiting the contrast agents’ use. The CMSC’s new MRI protocol guideline reflects these regulatory actions.
“While there is no known CNS toxicity, these agents should be used judiciously, recognizing that gadolinium continues to play an invaluable role in specific circumstances related to the diagnosis and follow-up of individuals with MS,” the document noted.
“It remains indispensable in patients presenting with their first clinical attack, as [its] use allows for an earlier diagnosis by demonstrating lesion dissemination in time in addition to lesion dissemination in space, which are the hallmarks of the diagnosis of MS. Early diagnosis leads to early treatment, which may help in preventing disease progression and improve long-term prognosis,” said Dr. Li. He had no disclosures relevant to gadolinium.
—Michele G. Sullivan