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Napping and AFib risk: The long and the short of it
Napping for more than half an hour during the day was associated with a 90% increased risk of atrial fibrillation (AFib), but shorter naps were linked to a reduced risk, based on data from more than 20,000 individuals.
“Short daytime napping is a common, healthy habit, especially in Mediterranean countries,” Jesus Diaz-Gutierrez, MD, of Juan Ramon Jimenez University Hospital, Huelva, Spain, said in a presentation at the annual congress of the European Association of Preventive Cardiology (EAPC).
Previous studies have shown a potential link between sleep patterns and AFib risk, but the association between specific duration of daytime naps and AFib risk has not been explored, he said.
Dr. Diaz-Gutierrez and colleagues used data from the University of Navarra Follow-up (SUN) Project, a prospective cohort of Spanish university graduates, to explore the possible link between naps and AFib. The study population included 20,348 individuals without AFib at baseline who were followed for a median of 13.8 years. The average age of participants at baseline was 38 years; 61% were women.
Daytime napping patterns were assessed at baseline, and participants were divided into nap groups of short nappers (defined as less than 30 minutes per day), and longer nappers (30 minutes or more per day), and those who reported no napping.
The researchers identified 131 incident cases of AFib during the follow-up period. Overall, the relative risk of incident AFib was significantly higher for the long nappers (adjusted hazard ratio 1.90) compared with short nappers in a multivariate analysis, while no significant risk appeared among non-nappers compared to short nappers (aHR 1.26).
The researchers then excluded the non-nappers in a secondary analysis to explore the impact of more specific daily nap duration on AFib risk. In a multivariate analysis, they found a 42% reduced risk of AF among those who napped for less than 15 minutes, and a 56% reduced risk for those who napped for 15-30 minutes, compared with those who napped for more than 30 minutes (aHR 0.56 and 0.42, respectively).
Potential explanations for the associations include the role of circadian rhythms, Dr. Diaz-Gutierrez said in a press release accompanying the presentation at the meeting. “Long daytime naps may disrupt the body’s internal clock (circadian rhythm), leading to shorter nighttime sleep, more nocturnal awakening, and reduced physical activity. In contrast, short daytime napping may improve circadian rhythm, lower blood pressure levels, and reduce stress.” More research is needed to validate the findings and the optimum nap duration, and whether a short nap is more advantageous than not napping in terms of AFib risk reduction, he said.
The study results suggest that naps of 15-30 minutes represent “a potential novel healthy lifestyle habit in the primary prevention of AFib,” Dr. Diaz-Gutierrez said in his presentation. However, the results also suggest that daily naps be limited to less than 30 minutes, he concluded.
Sleep habits may serve as red flag
“As we age, most if not all of us will develop sleep disturbances, such as insomnia, obstructive sleep apnea (OSA), and other sleep issues,” Lawrence S. Rosenthal, MD, of the University of Massachusetts, Worcester, said in an interview.
Therefore, “this study is near and dear to most people, and most would agree that poor sleeping habits affect our health.” In particular, OSA has been linked to AFib, although that was not measured in the current study, he added.
Dr. Rosenthal said he was not surprised by the current study findings. “It seems that a quick recharge of your ‘battery’ during the day is healthier than a long, deep sleep daytime nap,” he said. In addition, “Longer naps may be a marker of OSA,” he noted.
For clinicians, the take-home message of the current study is the need to consider underlying medical conditions in patients who regularly take long afternoon naps, and to consider these longer naps as a potential marker for AFib, said Dr. Rosenthal.
Looking ahead, a “deeper dive into the makeup of the populations studied” would be useful as a foundation for additional research, he said.
The SUN Project disclosed funding from the Spanish Government-Instituto de Salud Carlos III and the European Regional Development Fund (FEDER), the Navarra Regional Government, Plan Nacional Sobre Drogas, the University of Navarra, and the European Research Council. The researchers, and Dr. Rosenthal, had no financial conflicts to disclose.
Napping for more than half an hour during the day was associated with a 90% increased risk of atrial fibrillation (AFib), but shorter naps were linked to a reduced risk, based on data from more than 20,000 individuals.
“Short daytime napping is a common, healthy habit, especially in Mediterranean countries,” Jesus Diaz-Gutierrez, MD, of Juan Ramon Jimenez University Hospital, Huelva, Spain, said in a presentation at the annual congress of the European Association of Preventive Cardiology (EAPC).
Previous studies have shown a potential link between sleep patterns and AFib risk, but the association between specific duration of daytime naps and AFib risk has not been explored, he said.
Dr. Diaz-Gutierrez and colleagues used data from the University of Navarra Follow-up (SUN) Project, a prospective cohort of Spanish university graduates, to explore the possible link between naps and AFib. The study population included 20,348 individuals without AFib at baseline who were followed for a median of 13.8 years. The average age of participants at baseline was 38 years; 61% were women.
Daytime napping patterns were assessed at baseline, and participants were divided into nap groups of short nappers (defined as less than 30 minutes per day), and longer nappers (30 minutes or more per day), and those who reported no napping.
The researchers identified 131 incident cases of AFib during the follow-up period. Overall, the relative risk of incident AFib was significantly higher for the long nappers (adjusted hazard ratio 1.90) compared with short nappers in a multivariate analysis, while no significant risk appeared among non-nappers compared to short nappers (aHR 1.26).
The researchers then excluded the non-nappers in a secondary analysis to explore the impact of more specific daily nap duration on AFib risk. In a multivariate analysis, they found a 42% reduced risk of AF among those who napped for less than 15 minutes, and a 56% reduced risk for those who napped for 15-30 minutes, compared with those who napped for more than 30 minutes (aHR 0.56 and 0.42, respectively).
Potential explanations for the associations include the role of circadian rhythms, Dr. Diaz-Gutierrez said in a press release accompanying the presentation at the meeting. “Long daytime naps may disrupt the body’s internal clock (circadian rhythm), leading to shorter nighttime sleep, more nocturnal awakening, and reduced physical activity. In contrast, short daytime napping may improve circadian rhythm, lower blood pressure levels, and reduce stress.” More research is needed to validate the findings and the optimum nap duration, and whether a short nap is more advantageous than not napping in terms of AFib risk reduction, he said.
The study results suggest that naps of 15-30 minutes represent “a potential novel healthy lifestyle habit in the primary prevention of AFib,” Dr. Diaz-Gutierrez said in his presentation. However, the results also suggest that daily naps be limited to less than 30 minutes, he concluded.
Sleep habits may serve as red flag
“As we age, most if not all of us will develop sleep disturbances, such as insomnia, obstructive sleep apnea (OSA), and other sleep issues,” Lawrence S. Rosenthal, MD, of the University of Massachusetts, Worcester, said in an interview.
Therefore, “this study is near and dear to most people, and most would agree that poor sleeping habits affect our health.” In particular, OSA has been linked to AFib, although that was not measured in the current study, he added.
Dr. Rosenthal said he was not surprised by the current study findings. “It seems that a quick recharge of your ‘battery’ during the day is healthier than a long, deep sleep daytime nap,” he said. In addition, “Longer naps may be a marker of OSA,” he noted.
For clinicians, the take-home message of the current study is the need to consider underlying medical conditions in patients who regularly take long afternoon naps, and to consider these longer naps as a potential marker for AFib, said Dr. Rosenthal.
Looking ahead, a “deeper dive into the makeup of the populations studied” would be useful as a foundation for additional research, he said.
The SUN Project disclosed funding from the Spanish Government-Instituto de Salud Carlos III and the European Regional Development Fund (FEDER), the Navarra Regional Government, Plan Nacional Sobre Drogas, the University of Navarra, and the European Research Council. The researchers, and Dr. Rosenthal, had no financial conflicts to disclose.
Napping for more than half an hour during the day was associated with a 90% increased risk of atrial fibrillation (AFib), but shorter naps were linked to a reduced risk, based on data from more than 20,000 individuals.
“Short daytime napping is a common, healthy habit, especially in Mediterranean countries,” Jesus Diaz-Gutierrez, MD, of Juan Ramon Jimenez University Hospital, Huelva, Spain, said in a presentation at the annual congress of the European Association of Preventive Cardiology (EAPC).
Previous studies have shown a potential link between sleep patterns and AFib risk, but the association between specific duration of daytime naps and AFib risk has not been explored, he said.
Dr. Diaz-Gutierrez and colleagues used data from the University of Navarra Follow-up (SUN) Project, a prospective cohort of Spanish university graduates, to explore the possible link between naps and AFib. The study population included 20,348 individuals without AFib at baseline who were followed for a median of 13.8 years. The average age of participants at baseline was 38 years; 61% were women.
Daytime napping patterns were assessed at baseline, and participants were divided into nap groups of short nappers (defined as less than 30 minutes per day), and longer nappers (30 minutes or more per day), and those who reported no napping.
The researchers identified 131 incident cases of AFib during the follow-up period. Overall, the relative risk of incident AFib was significantly higher for the long nappers (adjusted hazard ratio 1.90) compared with short nappers in a multivariate analysis, while no significant risk appeared among non-nappers compared to short nappers (aHR 1.26).
The researchers then excluded the non-nappers in a secondary analysis to explore the impact of more specific daily nap duration on AFib risk. In a multivariate analysis, they found a 42% reduced risk of AF among those who napped for less than 15 minutes, and a 56% reduced risk for those who napped for 15-30 minutes, compared with those who napped for more than 30 minutes (aHR 0.56 and 0.42, respectively).
Potential explanations for the associations include the role of circadian rhythms, Dr. Diaz-Gutierrez said in a press release accompanying the presentation at the meeting. “Long daytime naps may disrupt the body’s internal clock (circadian rhythm), leading to shorter nighttime sleep, more nocturnal awakening, and reduced physical activity. In contrast, short daytime napping may improve circadian rhythm, lower blood pressure levels, and reduce stress.” More research is needed to validate the findings and the optimum nap duration, and whether a short nap is more advantageous than not napping in terms of AFib risk reduction, he said.
The study results suggest that naps of 15-30 minutes represent “a potential novel healthy lifestyle habit in the primary prevention of AFib,” Dr. Diaz-Gutierrez said in his presentation. However, the results also suggest that daily naps be limited to less than 30 minutes, he concluded.
Sleep habits may serve as red flag
“As we age, most if not all of us will develop sleep disturbances, such as insomnia, obstructive sleep apnea (OSA), and other sleep issues,” Lawrence S. Rosenthal, MD, of the University of Massachusetts, Worcester, said in an interview.
Therefore, “this study is near and dear to most people, and most would agree that poor sleeping habits affect our health.” In particular, OSA has been linked to AFib, although that was not measured in the current study, he added.
Dr. Rosenthal said he was not surprised by the current study findings. “It seems that a quick recharge of your ‘battery’ during the day is healthier than a long, deep sleep daytime nap,” he said. In addition, “Longer naps may be a marker of OSA,” he noted.
For clinicians, the take-home message of the current study is the need to consider underlying medical conditions in patients who regularly take long afternoon naps, and to consider these longer naps as a potential marker for AFib, said Dr. Rosenthal.
Looking ahead, a “deeper dive into the makeup of the populations studied” would be useful as a foundation for additional research, he said.
The SUN Project disclosed funding from the Spanish Government-Instituto de Salud Carlos III and the European Regional Development Fund (FEDER), the Navarra Regional Government, Plan Nacional Sobre Drogas, the University of Navarra, and the European Research Council. The researchers, and Dr. Rosenthal, had no financial conflicts to disclose.
FROM ESC PREVENTIVE CARDIOLOGY 2023
Sleep disturbances linked to post-COVID dyspnea
according to data from the U.K.’s CircCOVID study.
The researchers, led by John Blaikley, MRCP, PhD, respiratory physician and clinical scientist from the University of Manchester (England), found that sleep disturbance is a common problem after hospital admission for COVID-19 and may last for at least 1 year.
The study also showed that sleep disturbance after COVID hospitalization was associated with dyspnea and lower lung function. Further in-depth analysis revealed that the effects of sleep disturbance on dyspnea were partially mediated through both anxiety and muscle weakness; however, “this does not fully explain the association, suggesting other pathways are involved,” said Dr. Blaikley.
The study was jointly conducted by researchers from the University of Leicester (England), as well as 20 other U.K. institutes and the University of Helsinki. It was presented at the European Congress of Clinical Microbiology & Infectious Diseases and was simultaneously published in The Lancet Respiratory Medicine.
“Sleep disturbance is a common problem after hospitalization for COVID-19 and is associated with several symptoms in the post-COVID syndrome,” said Dr. Blaikley. “Clinicians should be aware of this association in their post-COVID syndrome clinics.”
He added that further work needs to be done to define the mechanism and to see whether the links are causal. “However, if they are, then treating sleep disturbance could have beneficial effects beyond improving sleep quality,” he said in an interview.
A large study recently showed that 4 in 10 people with post-COVID syndrome had moderate to severe sleep problems. Black people were at least three times more likely than White people to experience sleep problems. A total of 59% of all participants with long COVID reported having normal sleep or mild sleep disturbances, and 41% reported having moderate to severe sleep disturbances.
Unlike prior studies that evaluated sleep quality after COVID-19, which used either objective or subjective measures of sleep disturbance, the current study used both. “Using both measures revealed previously poorly described associations between sleep disturbance, breathlessness, reduced lung function, anxiety, and muscle weakness,” Dr. Blaikley pointed out.
Subjective and objective measures of sleep
The multicenter CircCOVID cohort study aimed to shed light on the prevalence and nature of sleep disturbance after patients are discharged from hospital for COVID-19 and to assess whether this was associated with dyspnea.
The study recruited a total of 2,320 participants who were part of a larger parent PHOSP-COVID study. After attending an early follow-up visit (at a median of 5 months after discharge from 83 U.K. hospitals for COVID-19), 638 participants provided data for analysis as measured by the Pittsburgh Sleep Quality Index (a subjective measure of sleep quality); 729 participants provided data for analysis as measured by actigraphy (an objective, wrist-worn, device-based measure of sleep quality) at a median of 7 months.
Breathlessness, the primary outcome, was assessed using the Dyspnea-12 validated questionnaire.
Actigraphy measurements were compared with an age-matched, sex-matched, body mass index (BMI)–matched, and time from discharge–matched cohort from the UK Biobank (a prepandemic comparator longitudinal cohort of 502,540 individuals, one-fifth of whom wore actigraphy devices). Sleep regularity was found to be 19% less in previously hospitalized patients with post-COVID syndrome, compared with matched controls who had been hospitalized for other reasons.
This “revealed that the actigraphy changes may be, in part, due to COVID-19 rather than hospitalization alone,” said Dr. Blaikley.
Data were collected at two time points after hospital discharge: 2-7 months (early), and 10-14 months (late). At the early time point, participants were clinically assessed with respect to anxiety, muscle function, and dyspnea, and lung function.
After discharge from hospital, the majority (62%) of post–COVID-19 participants reported poor sleep quality on the Pittsburgh Sleep Quality Index questionnaire. A “comparable” proportion (53%) felt that their quality of sleep had deteriorated following hospital discharge according to the numerical rating scale (subjective measure).
Also, sleep disturbance was found likely to persist for at least 12 months, since subjective sleep quality hardly changed between the early and late time points after hospital discharge.
Both subjective metrics (sleep quality and sleep quality deterioration after hospital discharge) and objective, device-based metrics (sleep regularity) were found to be associated with dyspnea and reduced lung function in patients with post-COVID syndrome.
“One of the striking findings in our study is the consistency with breathlessness and reduced lung function across different methods used to evaluate sleep,” highlighted Dr. Blaikley.
“The other striking finding was that participants following COVID-19 hospitalization actually slept longer [65 min; 95% confidence interval, 59-71 min] than participants hospitalized for non-COVID; however, their bedtimes were irregular, and it was this irregularity that was associated with breathlessness,” he added.
In comparison with nonhospitalized controls, also from the UK Biobank, study participants with lower sleep regularity had higher Dyspnea-12 scores (unadjusted effect estimate, 4.38; 95%: CI, 2.10-6.65). Those with poor sleep quality overall also had higher Dyspnea-12 scores (unadjusted effect estimate, 3.94; 95% CI, 2.78-5.10), and those who reported sleep quality deterioration had higher Dyspnea-12 scores (unadjusted effect estimate, 3,00; 95% CI, 1.82-4.28).
In comparison with hospitalized controls, CircCOVID participants had lower sleep regularity index (–19%; 95% CI, –20 to –16) and lower sleep efficiency (3.83 percentage points; 95% CI, 3.40-4.26).
Sleep disturbance after COVID hospitalization was also associated with lower lung function, from a 7% to a 14% reduction in predicted forced vital capacity, depending on which sleep measure used.
In an analysis of mediating factors active in the relationship between sleep disturbance and dyspnea/decreased lung function, the researchers found that reduced muscle function and anxiety, which are both recognized causes of dyspnea, could partially contribute to the association.
Regarding anxiety, and depending on the sleep metric, anxiety mediated 18%-39% of the effect of sleep disturbance on dyspnea, while muscle weakness mediated 27%-41% of this effect, reported Dr. Blaikley. Those with poor sleep quality were more likely to have mild, moderate, or severe anxiety, compared with participants who reported good-quality sleep.
A similar association was observed between anxiety and sleep quality deterioration.
“Two key questions are raised by our study: Do sleep interventions have a beneficial effect in post–COVID-19 syndrome, and are the associations causal?” asked Dr. Blaikley. “We hope to do a sleep intervention trial to answer these questions to explore if this is an effective treatment for post–COVID-19 syndrome.”
‘Underlying mechanisms remain unclear’
Amitava Banerjee, MD, professor of clinical data science and honorary consultant cardiologist, Institute of Health Informatics, UCL, London, welcomed the study but noted that it did not include nonhospitalized post-COVID patients.
“The majority of people with long COVID were not hospitalized for COVID, so the results may not be generalizable to this larger group,” she said in an interview. “Good-quality sleep is important for health and reduces risk of chronic diseases; quality of sleep is therefore likely to be important for those with long COVID in reducing their risk of chronic disease, but the role of sleep in the mechanism of long COVID needs further research.”
In a commentary also published in The Lancet Respiratory Medicine, W. Cameron McGuire, MD, pulmonary and critical care specialist from San Diego, California, and colleagues wrote: “These findings suggest that sleep disturbance, dyspnea, and anxiety are common after COVID-19 and are associated with one another, although the underlying mechanisms remain unclear.”
The commentators “applauded” the work overall but noted that the findings represent correlation rather than causation. “It is unclear whether sleep disturbance is causing anxiety or whether anxiety is contributing to poor sleep. ... For the sleep disturbances, increased BMI in the cohort reporting poor sleep, compared with those reporting good sleep might suggest underlying obstructive sleep apnea,” they wrote.
Dr. McGuire and colleagues added that many questions remain for researchers and clinicians, including “whether anxiety and dyspnoea are contributing to a low arousal threshold [disrupting sleep] ... whether the observed abnormalities (e.g., in dyspnea score) are clinically significant,” and “whether therapies such as glucocorticoids, anticoagulants, or previous vaccinations mitigate the observed abnormalities during COVID-19 recovery.”
Dr. Blaikley has received support to his institute from an MRC Transition Fellowship, Asthma + Lung UK, NIHR Manchester BRC, and UKRI; grants to his institution from the Small Business Research Initiative Home Spirometer and the National Institute of Academic Anaesthesia; and support from TEVA and Therakos for attending meetings. He is a committee member of the Royal Society of Medicine. A coauthor received funding from the National Institutes of Health and income for medical education from Zoll, Livanova, Jazz, and Eli Lilly. Dr. Banerjee is the chief investigator of STIMULATE-ICP (an NIHR-funded study) and has received research funding from AstraZeneca.
A version of this article first appeared on Medscape.com.
according to data from the U.K.’s CircCOVID study.
The researchers, led by John Blaikley, MRCP, PhD, respiratory physician and clinical scientist from the University of Manchester (England), found that sleep disturbance is a common problem after hospital admission for COVID-19 and may last for at least 1 year.
The study also showed that sleep disturbance after COVID hospitalization was associated with dyspnea and lower lung function. Further in-depth analysis revealed that the effects of sleep disturbance on dyspnea were partially mediated through both anxiety and muscle weakness; however, “this does not fully explain the association, suggesting other pathways are involved,” said Dr. Blaikley.
The study was jointly conducted by researchers from the University of Leicester (England), as well as 20 other U.K. institutes and the University of Helsinki. It was presented at the European Congress of Clinical Microbiology & Infectious Diseases and was simultaneously published in The Lancet Respiratory Medicine.
“Sleep disturbance is a common problem after hospitalization for COVID-19 and is associated with several symptoms in the post-COVID syndrome,” said Dr. Blaikley. “Clinicians should be aware of this association in their post-COVID syndrome clinics.”
He added that further work needs to be done to define the mechanism and to see whether the links are causal. “However, if they are, then treating sleep disturbance could have beneficial effects beyond improving sleep quality,” he said in an interview.
A large study recently showed that 4 in 10 people with post-COVID syndrome had moderate to severe sleep problems. Black people were at least three times more likely than White people to experience sleep problems. A total of 59% of all participants with long COVID reported having normal sleep or mild sleep disturbances, and 41% reported having moderate to severe sleep disturbances.
Unlike prior studies that evaluated sleep quality after COVID-19, which used either objective or subjective measures of sleep disturbance, the current study used both. “Using both measures revealed previously poorly described associations between sleep disturbance, breathlessness, reduced lung function, anxiety, and muscle weakness,” Dr. Blaikley pointed out.
Subjective and objective measures of sleep
The multicenter CircCOVID cohort study aimed to shed light on the prevalence and nature of sleep disturbance after patients are discharged from hospital for COVID-19 and to assess whether this was associated with dyspnea.
The study recruited a total of 2,320 participants who were part of a larger parent PHOSP-COVID study. After attending an early follow-up visit (at a median of 5 months after discharge from 83 U.K. hospitals for COVID-19), 638 participants provided data for analysis as measured by the Pittsburgh Sleep Quality Index (a subjective measure of sleep quality); 729 participants provided data for analysis as measured by actigraphy (an objective, wrist-worn, device-based measure of sleep quality) at a median of 7 months.
Breathlessness, the primary outcome, was assessed using the Dyspnea-12 validated questionnaire.
Actigraphy measurements were compared with an age-matched, sex-matched, body mass index (BMI)–matched, and time from discharge–matched cohort from the UK Biobank (a prepandemic comparator longitudinal cohort of 502,540 individuals, one-fifth of whom wore actigraphy devices). Sleep regularity was found to be 19% less in previously hospitalized patients with post-COVID syndrome, compared with matched controls who had been hospitalized for other reasons.
This “revealed that the actigraphy changes may be, in part, due to COVID-19 rather than hospitalization alone,” said Dr. Blaikley.
Data were collected at two time points after hospital discharge: 2-7 months (early), and 10-14 months (late). At the early time point, participants were clinically assessed with respect to anxiety, muscle function, and dyspnea, and lung function.
After discharge from hospital, the majority (62%) of post–COVID-19 participants reported poor sleep quality on the Pittsburgh Sleep Quality Index questionnaire. A “comparable” proportion (53%) felt that their quality of sleep had deteriorated following hospital discharge according to the numerical rating scale (subjective measure).
Also, sleep disturbance was found likely to persist for at least 12 months, since subjective sleep quality hardly changed between the early and late time points after hospital discharge.
Both subjective metrics (sleep quality and sleep quality deterioration after hospital discharge) and objective, device-based metrics (sleep regularity) were found to be associated with dyspnea and reduced lung function in patients with post-COVID syndrome.
“One of the striking findings in our study is the consistency with breathlessness and reduced lung function across different methods used to evaluate sleep,” highlighted Dr. Blaikley.
“The other striking finding was that participants following COVID-19 hospitalization actually slept longer [65 min; 95% confidence interval, 59-71 min] than participants hospitalized for non-COVID; however, their bedtimes were irregular, and it was this irregularity that was associated with breathlessness,” he added.
In comparison with nonhospitalized controls, also from the UK Biobank, study participants with lower sleep regularity had higher Dyspnea-12 scores (unadjusted effect estimate, 4.38; 95%: CI, 2.10-6.65). Those with poor sleep quality overall also had higher Dyspnea-12 scores (unadjusted effect estimate, 3.94; 95% CI, 2.78-5.10), and those who reported sleep quality deterioration had higher Dyspnea-12 scores (unadjusted effect estimate, 3,00; 95% CI, 1.82-4.28).
In comparison with hospitalized controls, CircCOVID participants had lower sleep regularity index (–19%; 95% CI, –20 to –16) and lower sleep efficiency (3.83 percentage points; 95% CI, 3.40-4.26).
Sleep disturbance after COVID hospitalization was also associated with lower lung function, from a 7% to a 14% reduction in predicted forced vital capacity, depending on which sleep measure used.
In an analysis of mediating factors active in the relationship between sleep disturbance and dyspnea/decreased lung function, the researchers found that reduced muscle function and anxiety, which are both recognized causes of dyspnea, could partially contribute to the association.
Regarding anxiety, and depending on the sleep metric, anxiety mediated 18%-39% of the effect of sleep disturbance on dyspnea, while muscle weakness mediated 27%-41% of this effect, reported Dr. Blaikley. Those with poor sleep quality were more likely to have mild, moderate, or severe anxiety, compared with participants who reported good-quality sleep.
A similar association was observed between anxiety and sleep quality deterioration.
“Two key questions are raised by our study: Do sleep interventions have a beneficial effect in post–COVID-19 syndrome, and are the associations causal?” asked Dr. Blaikley. “We hope to do a sleep intervention trial to answer these questions to explore if this is an effective treatment for post–COVID-19 syndrome.”
‘Underlying mechanisms remain unclear’
Amitava Banerjee, MD, professor of clinical data science and honorary consultant cardiologist, Institute of Health Informatics, UCL, London, welcomed the study but noted that it did not include nonhospitalized post-COVID patients.
“The majority of people with long COVID were not hospitalized for COVID, so the results may not be generalizable to this larger group,” she said in an interview. “Good-quality sleep is important for health and reduces risk of chronic diseases; quality of sleep is therefore likely to be important for those with long COVID in reducing their risk of chronic disease, but the role of sleep in the mechanism of long COVID needs further research.”
In a commentary also published in The Lancet Respiratory Medicine, W. Cameron McGuire, MD, pulmonary and critical care specialist from San Diego, California, and colleagues wrote: “These findings suggest that sleep disturbance, dyspnea, and anxiety are common after COVID-19 and are associated with one another, although the underlying mechanisms remain unclear.”
The commentators “applauded” the work overall but noted that the findings represent correlation rather than causation. “It is unclear whether sleep disturbance is causing anxiety or whether anxiety is contributing to poor sleep. ... For the sleep disturbances, increased BMI in the cohort reporting poor sleep, compared with those reporting good sleep might suggest underlying obstructive sleep apnea,” they wrote.
Dr. McGuire and colleagues added that many questions remain for researchers and clinicians, including “whether anxiety and dyspnoea are contributing to a low arousal threshold [disrupting sleep] ... whether the observed abnormalities (e.g., in dyspnea score) are clinically significant,” and “whether therapies such as glucocorticoids, anticoagulants, or previous vaccinations mitigate the observed abnormalities during COVID-19 recovery.”
Dr. Blaikley has received support to his institute from an MRC Transition Fellowship, Asthma + Lung UK, NIHR Manchester BRC, and UKRI; grants to his institution from the Small Business Research Initiative Home Spirometer and the National Institute of Academic Anaesthesia; and support from TEVA and Therakos for attending meetings. He is a committee member of the Royal Society of Medicine. A coauthor received funding from the National Institutes of Health and income for medical education from Zoll, Livanova, Jazz, and Eli Lilly. Dr. Banerjee is the chief investigator of STIMULATE-ICP (an NIHR-funded study) and has received research funding from AstraZeneca.
A version of this article first appeared on Medscape.com.
according to data from the U.K.’s CircCOVID study.
The researchers, led by John Blaikley, MRCP, PhD, respiratory physician and clinical scientist from the University of Manchester (England), found that sleep disturbance is a common problem after hospital admission for COVID-19 and may last for at least 1 year.
The study also showed that sleep disturbance after COVID hospitalization was associated with dyspnea and lower lung function. Further in-depth analysis revealed that the effects of sleep disturbance on dyspnea were partially mediated through both anxiety and muscle weakness; however, “this does not fully explain the association, suggesting other pathways are involved,” said Dr. Blaikley.
The study was jointly conducted by researchers from the University of Leicester (England), as well as 20 other U.K. institutes and the University of Helsinki. It was presented at the European Congress of Clinical Microbiology & Infectious Diseases and was simultaneously published in The Lancet Respiratory Medicine.
“Sleep disturbance is a common problem after hospitalization for COVID-19 and is associated with several symptoms in the post-COVID syndrome,” said Dr. Blaikley. “Clinicians should be aware of this association in their post-COVID syndrome clinics.”
He added that further work needs to be done to define the mechanism and to see whether the links are causal. “However, if they are, then treating sleep disturbance could have beneficial effects beyond improving sleep quality,” he said in an interview.
A large study recently showed that 4 in 10 people with post-COVID syndrome had moderate to severe sleep problems. Black people were at least three times more likely than White people to experience sleep problems. A total of 59% of all participants with long COVID reported having normal sleep or mild sleep disturbances, and 41% reported having moderate to severe sleep disturbances.
Unlike prior studies that evaluated sleep quality after COVID-19, which used either objective or subjective measures of sleep disturbance, the current study used both. “Using both measures revealed previously poorly described associations between sleep disturbance, breathlessness, reduced lung function, anxiety, and muscle weakness,” Dr. Blaikley pointed out.
Subjective and objective measures of sleep
The multicenter CircCOVID cohort study aimed to shed light on the prevalence and nature of sleep disturbance after patients are discharged from hospital for COVID-19 and to assess whether this was associated with dyspnea.
The study recruited a total of 2,320 participants who were part of a larger parent PHOSP-COVID study. After attending an early follow-up visit (at a median of 5 months after discharge from 83 U.K. hospitals for COVID-19), 638 participants provided data for analysis as measured by the Pittsburgh Sleep Quality Index (a subjective measure of sleep quality); 729 participants provided data for analysis as measured by actigraphy (an objective, wrist-worn, device-based measure of sleep quality) at a median of 7 months.
Breathlessness, the primary outcome, was assessed using the Dyspnea-12 validated questionnaire.
Actigraphy measurements were compared with an age-matched, sex-matched, body mass index (BMI)–matched, and time from discharge–matched cohort from the UK Biobank (a prepandemic comparator longitudinal cohort of 502,540 individuals, one-fifth of whom wore actigraphy devices). Sleep regularity was found to be 19% less in previously hospitalized patients with post-COVID syndrome, compared with matched controls who had been hospitalized for other reasons.
This “revealed that the actigraphy changes may be, in part, due to COVID-19 rather than hospitalization alone,” said Dr. Blaikley.
Data were collected at two time points after hospital discharge: 2-7 months (early), and 10-14 months (late). At the early time point, participants were clinically assessed with respect to anxiety, muscle function, and dyspnea, and lung function.
After discharge from hospital, the majority (62%) of post–COVID-19 participants reported poor sleep quality on the Pittsburgh Sleep Quality Index questionnaire. A “comparable” proportion (53%) felt that their quality of sleep had deteriorated following hospital discharge according to the numerical rating scale (subjective measure).
Also, sleep disturbance was found likely to persist for at least 12 months, since subjective sleep quality hardly changed between the early and late time points after hospital discharge.
Both subjective metrics (sleep quality and sleep quality deterioration after hospital discharge) and objective, device-based metrics (sleep regularity) were found to be associated with dyspnea and reduced lung function in patients with post-COVID syndrome.
“One of the striking findings in our study is the consistency with breathlessness and reduced lung function across different methods used to evaluate sleep,” highlighted Dr. Blaikley.
“The other striking finding was that participants following COVID-19 hospitalization actually slept longer [65 min; 95% confidence interval, 59-71 min] than participants hospitalized for non-COVID; however, their bedtimes were irregular, and it was this irregularity that was associated with breathlessness,” he added.
In comparison with nonhospitalized controls, also from the UK Biobank, study participants with lower sleep regularity had higher Dyspnea-12 scores (unadjusted effect estimate, 4.38; 95%: CI, 2.10-6.65). Those with poor sleep quality overall also had higher Dyspnea-12 scores (unadjusted effect estimate, 3.94; 95% CI, 2.78-5.10), and those who reported sleep quality deterioration had higher Dyspnea-12 scores (unadjusted effect estimate, 3,00; 95% CI, 1.82-4.28).
In comparison with hospitalized controls, CircCOVID participants had lower sleep regularity index (–19%; 95% CI, –20 to –16) and lower sleep efficiency (3.83 percentage points; 95% CI, 3.40-4.26).
Sleep disturbance after COVID hospitalization was also associated with lower lung function, from a 7% to a 14% reduction in predicted forced vital capacity, depending on which sleep measure used.
In an analysis of mediating factors active in the relationship between sleep disturbance and dyspnea/decreased lung function, the researchers found that reduced muscle function and anxiety, which are both recognized causes of dyspnea, could partially contribute to the association.
Regarding anxiety, and depending on the sleep metric, anxiety mediated 18%-39% of the effect of sleep disturbance on dyspnea, while muscle weakness mediated 27%-41% of this effect, reported Dr. Blaikley. Those with poor sleep quality were more likely to have mild, moderate, or severe anxiety, compared with participants who reported good-quality sleep.
A similar association was observed between anxiety and sleep quality deterioration.
“Two key questions are raised by our study: Do sleep interventions have a beneficial effect in post–COVID-19 syndrome, and are the associations causal?” asked Dr. Blaikley. “We hope to do a sleep intervention trial to answer these questions to explore if this is an effective treatment for post–COVID-19 syndrome.”
‘Underlying mechanisms remain unclear’
Amitava Banerjee, MD, professor of clinical data science and honorary consultant cardiologist, Institute of Health Informatics, UCL, London, welcomed the study but noted that it did not include nonhospitalized post-COVID patients.
“The majority of people with long COVID were not hospitalized for COVID, so the results may not be generalizable to this larger group,” she said in an interview. “Good-quality sleep is important for health and reduces risk of chronic diseases; quality of sleep is therefore likely to be important for those with long COVID in reducing their risk of chronic disease, but the role of sleep in the mechanism of long COVID needs further research.”
In a commentary also published in The Lancet Respiratory Medicine, W. Cameron McGuire, MD, pulmonary and critical care specialist from San Diego, California, and colleagues wrote: “These findings suggest that sleep disturbance, dyspnea, and anxiety are common after COVID-19 and are associated with one another, although the underlying mechanisms remain unclear.”
The commentators “applauded” the work overall but noted that the findings represent correlation rather than causation. “It is unclear whether sleep disturbance is causing anxiety or whether anxiety is contributing to poor sleep. ... For the sleep disturbances, increased BMI in the cohort reporting poor sleep, compared with those reporting good sleep might suggest underlying obstructive sleep apnea,” they wrote.
Dr. McGuire and colleagues added that many questions remain for researchers and clinicians, including “whether anxiety and dyspnoea are contributing to a low arousal threshold [disrupting sleep] ... whether the observed abnormalities (e.g., in dyspnea score) are clinically significant,” and “whether therapies such as glucocorticoids, anticoagulants, or previous vaccinations mitigate the observed abnormalities during COVID-19 recovery.”
Dr. Blaikley has received support to his institute from an MRC Transition Fellowship, Asthma + Lung UK, NIHR Manchester BRC, and UKRI; grants to his institution from the Small Business Research Initiative Home Spirometer and the National Institute of Academic Anaesthesia; and support from TEVA and Therakos for attending meetings. He is a committee member of the Royal Society of Medicine. A coauthor received funding from the National Institutes of Health and income for medical education from Zoll, Livanova, Jazz, and Eli Lilly. Dr. Banerjee is the chief investigator of STIMULATE-ICP (an NIHR-funded study) and has received research funding from AstraZeneca.
A version of this article first appeared on Medscape.com.
FROM ECCMID 2023
Metformin linked to reduced osteoarthritis risk
Patients taking metformin for type 2 diabetes had a lower risk of developing osteoarthritis than did patients taking a sulfonylurea, according to a cohort study published in JAMA Network Open. The findings jibe with those seen in a 2022 systematic review of preclinical and observational human studies finding potentially protective effects of metformin on osteoarthritis.
“Our study provides further, robust epidemiological evidence that metformin may be associated with protection in the development and progression of osteoarthritis in individuals with type 2 diabetes,” wrote Matthew C. Baker, MD, MS, an assistant professor of medicine in immunology and rheumatology at Stanford (Calif.) University, and his colleagues.
The findings also fit with the results of a poster presented at the Osteoarthritis Research Society International 2023 World Congress, although that abstract’s findings did not reach statistical significance.
In the published study, the researchers analyzed deidentified claims data from Optum’s Clinformatics Data Mart Database between December 2003 and December 2019. The database includes more than 15 million people with private insurance or Medicare Advantage Part D but does not include people with Medicaid, thereby excluding people from lower socioeconomic groups.
The researchers included all patients who were at least 40 years old, had type 2 diabetes, were taking metformin, and had been enrolled in the database for at least 1 uninterrupted year. They excluded anyone with type 1 diabetes or a prior diagnosis of osteoarthritis, inflammatory arthritis, or joint replacement. The authors then compared the incidence of osteoarthritis and joint replacement in these 20,937 participants to 20,937 control participants who were taking a sulfonylurea, matched to those taking metformin on the basis of age, sex, race, a comorbidity score, and duration of treatment. More than half the overall population (58%) was male with an average age of 62.
Patients needed to be on either drug for at least 3 months, but those who were initially treated with metformin before later taking a sulfonylurea could also be included and contribute to both groups. Those who first took a sulfonylurea and later switched to metformin were included only for the sulfonylurea group and censored after their switch to ensure the sulfonylurea group had enough participants. The comparison was further adjusted for age, sex, race, ethnicity, geographic region, education, comorbidities, and outpatient visit frequency.
The results revealed that those who were taking metformin were 24% less likely to develop osteoarthritis at least 3 months after starting the medication than were those taking a sulfonylurea (P < .001). The rate of joint replacements was not significantly different between those taking metformin and those taking a sulfonylurea. These two results did not change in a sensitivity analysis that compared patients who only ever took metformin or a sulfonylurea (as opposed to those who took one drug before switching to the other).
“When stratified by prior exposure to metformin within the sulfonylurea group, the observed benefit associated with metformin ... was attenuated in the people treated with a sulfonylurea with prior exposure to metformin, compared with those treated with a sulfonylurea with no prior exposure to metformin,” the authors further reported. A possible reason for this finding is that those taking a sulfonylurea after having previously taken metformin gained some protection from the earlier metformin exposure, the authors hypothesized.
This observational study could not show a causative effect from the metformin, but the researchers speculated on potential mechanisms if a causative effect were present, based on past research.
”Several preclinical studies have suggested a protective association of metformin in osteoarthritis through activating AMP-activated protein kinase signaling, decreasing the level of matrix metalloproteinase, increasing autophagy and reducing chondrocyte apoptosis, and augmenting chondroprotective and anti-inflammatory properties of mesenchymal stem cells,” the authors wrote.
Among this study’s limitations, however, was the lack of data on body mass index, which is associated with osteoarthritis in the literature and may differ between patients taking metformin versus a sulfonylurea. The researchers also did not have data on physical activity or a history of trauma to the joints, though there’s no reason to think these rates might differ between those taking one or the other medication.
Another substantial limitation is that all patients had type 2 diabetes, making it impossible to determine whether a similar protective effect from metformin might exist in people without diabetes.
Nonsignificant lower risk for posttraumatic knee osteoarthritis
Similar to the published study, the OARSI poster compared 5-year odds of incident osteoarthritis or total knee replacement surgery between patients taking metformin and those taking sulfonylureas, but it focused on younger patients, aged 18-40 years, who underwent anterior cruciate ligament or meniscus surgery.
Using data from MarketScan commercial insurance claims databases between 2006 and 2020, the authors identified 2,376 participants who were taking metformin or a sulfonylurea when they underwent their surgery or began taking it in the 6 months after their surgery. More than half the participants were female (57%) with an average age of 35.
Within 5 years, 10.8% of those taking metformin developed osteoarthritis, compared with 17.9% of those taking a sulfonylurea. In addition, 3% of those taking metformin underwent a total knee replacement, compared with 5.3% of those taking a sulfonylurea. After adjustment for age, sex, obesity, and a history of chronic kidney disease, liver disease, and depression, however, both risk difference and odds ratios were not statistically significant.
Risk of osteoarthritis was 17% lower in patients taking metformin (95% confidence interval, –0.18 to 0.09), whose odds of osteoarthritis were approximately half the odds of those taking a sulfonylurea (OR, 0.5; 95% CI, 0.21-1.67). Risk of a total knee replacement was 10% lower in metformin users (95% CI, –0.28 to 0.08) with a similar reduction in odds, compared with those taking a sulfonylurea (OR, 0.53; 95% CI, 0.2-1.44).
In this study, the researchers did not specifically determine whether the participants were diagnosed with diabetes, but they assumed all, or at least most, were, according to S. Reza Jafarzadeh, PhD, DVM, an assistant professor of medicine at Boston University.
“The goal was not to only focus on the diabetes population, but on people who received that exposure [of metformin or sulfonylureas],” Dr. Jafarzadeh said in an interview. Dr. Jafarzadeh noted that a larger randomized controlled trial is underway to look at whether metformin reduces the risk of osteoarthritis independent of whether a patient has diabetes.
The published study was funded by grants from the National Institutes of Health, the Department of Veterans Affairs, and Stanford University, and the authors reported no disclosures. The poster at OARSI was funded by NIH and the Arthritis Foundation, and the authors reported no disclosures.
Patients taking metformin for type 2 diabetes had a lower risk of developing osteoarthritis than did patients taking a sulfonylurea, according to a cohort study published in JAMA Network Open. The findings jibe with those seen in a 2022 systematic review of preclinical and observational human studies finding potentially protective effects of metformin on osteoarthritis.
“Our study provides further, robust epidemiological evidence that metformin may be associated with protection in the development and progression of osteoarthritis in individuals with type 2 diabetes,” wrote Matthew C. Baker, MD, MS, an assistant professor of medicine in immunology and rheumatology at Stanford (Calif.) University, and his colleagues.
The findings also fit with the results of a poster presented at the Osteoarthritis Research Society International 2023 World Congress, although that abstract’s findings did not reach statistical significance.
In the published study, the researchers analyzed deidentified claims data from Optum’s Clinformatics Data Mart Database between December 2003 and December 2019. The database includes more than 15 million people with private insurance or Medicare Advantage Part D but does not include people with Medicaid, thereby excluding people from lower socioeconomic groups.
The researchers included all patients who were at least 40 years old, had type 2 diabetes, were taking metformin, and had been enrolled in the database for at least 1 uninterrupted year. They excluded anyone with type 1 diabetes or a prior diagnosis of osteoarthritis, inflammatory arthritis, or joint replacement. The authors then compared the incidence of osteoarthritis and joint replacement in these 20,937 participants to 20,937 control participants who were taking a sulfonylurea, matched to those taking metformin on the basis of age, sex, race, a comorbidity score, and duration of treatment. More than half the overall population (58%) was male with an average age of 62.
Patients needed to be on either drug for at least 3 months, but those who were initially treated with metformin before later taking a sulfonylurea could also be included and contribute to both groups. Those who first took a sulfonylurea and later switched to metformin were included only for the sulfonylurea group and censored after their switch to ensure the sulfonylurea group had enough participants. The comparison was further adjusted for age, sex, race, ethnicity, geographic region, education, comorbidities, and outpatient visit frequency.
The results revealed that those who were taking metformin were 24% less likely to develop osteoarthritis at least 3 months after starting the medication than were those taking a sulfonylurea (P < .001). The rate of joint replacements was not significantly different between those taking metformin and those taking a sulfonylurea. These two results did not change in a sensitivity analysis that compared patients who only ever took metformin or a sulfonylurea (as opposed to those who took one drug before switching to the other).
“When stratified by prior exposure to metformin within the sulfonylurea group, the observed benefit associated with metformin ... was attenuated in the people treated with a sulfonylurea with prior exposure to metformin, compared with those treated with a sulfonylurea with no prior exposure to metformin,” the authors further reported. A possible reason for this finding is that those taking a sulfonylurea after having previously taken metformin gained some protection from the earlier metformin exposure, the authors hypothesized.
This observational study could not show a causative effect from the metformin, but the researchers speculated on potential mechanisms if a causative effect were present, based on past research.
”Several preclinical studies have suggested a protective association of metformin in osteoarthritis through activating AMP-activated protein kinase signaling, decreasing the level of matrix metalloproteinase, increasing autophagy and reducing chondrocyte apoptosis, and augmenting chondroprotective and anti-inflammatory properties of mesenchymal stem cells,” the authors wrote.
Among this study’s limitations, however, was the lack of data on body mass index, which is associated with osteoarthritis in the literature and may differ between patients taking metformin versus a sulfonylurea. The researchers also did not have data on physical activity or a history of trauma to the joints, though there’s no reason to think these rates might differ between those taking one or the other medication.
Another substantial limitation is that all patients had type 2 diabetes, making it impossible to determine whether a similar protective effect from metformin might exist in people without diabetes.
Nonsignificant lower risk for posttraumatic knee osteoarthritis
Similar to the published study, the OARSI poster compared 5-year odds of incident osteoarthritis or total knee replacement surgery between patients taking metformin and those taking sulfonylureas, but it focused on younger patients, aged 18-40 years, who underwent anterior cruciate ligament or meniscus surgery.
Using data from MarketScan commercial insurance claims databases between 2006 and 2020, the authors identified 2,376 participants who were taking metformin or a sulfonylurea when they underwent their surgery or began taking it in the 6 months after their surgery. More than half the participants were female (57%) with an average age of 35.
Within 5 years, 10.8% of those taking metformin developed osteoarthritis, compared with 17.9% of those taking a sulfonylurea. In addition, 3% of those taking metformin underwent a total knee replacement, compared with 5.3% of those taking a sulfonylurea. After adjustment for age, sex, obesity, and a history of chronic kidney disease, liver disease, and depression, however, both risk difference and odds ratios were not statistically significant.
Risk of osteoarthritis was 17% lower in patients taking metformin (95% confidence interval, –0.18 to 0.09), whose odds of osteoarthritis were approximately half the odds of those taking a sulfonylurea (OR, 0.5; 95% CI, 0.21-1.67). Risk of a total knee replacement was 10% lower in metformin users (95% CI, –0.28 to 0.08) with a similar reduction in odds, compared with those taking a sulfonylurea (OR, 0.53; 95% CI, 0.2-1.44).
In this study, the researchers did not specifically determine whether the participants were diagnosed with diabetes, but they assumed all, or at least most, were, according to S. Reza Jafarzadeh, PhD, DVM, an assistant professor of medicine at Boston University.
“The goal was not to only focus on the diabetes population, but on people who received that exposure [of metformin or sulfonylureas],” Dr. Jafarzadeh said in an interview. Dr. Jafarzadeh noted that a larger randomized controlled trial is underway to look at whether metformin reduces the risk of osteoarthritis independent of whether a patient has diabetes.
The published study was funded by grants from the National Institutes of Health, the Department of Veterans Affairs, and Stanford University, and the authors reported no disclosures. The poster at OARSI was funded by NIH and the Arthritis Foundation, and the authors reported no disclosures.
Patients taking metformin for type 2 diabetes had a lower risk of developing osteoarthritis than did patients taking a sulfonylurea, according to a cohort study published in JAMA Network Open. The findings jibe with those seen in a 2022 systematic review of preclinical and observational human studies finding potentially protective effects of metformin on osteoarthritis.
“Our study provides further, robust epidemiological evidence that metformin may be associated with protection in the development and progression of osteoarthritis in individuals with type 2 diabetes,” wrote Matthew C. Baker, MD, MS, an assistant professor of medicine in immunology and rheumatology at Stanford (Calif.) University, and his colleagues.
The findings also fit with the results of a poster presented at the Osteoarthritis Research Society International 2023 World Congress, although that abstract’s findings did not reach statistical significance.
In the published study, the researchers analyzed deidentified claims data from Optum’s Clinformatics Data Mart Database between December 2003 and December 2019. The database includes more than 15 million people with private insurance or Medicare Advantage Part D but does not include people with Medicaid, thereby excluding people from lower socioeconomic groups.
The researchers included all patients who were at least 40 years old, had type 2 diabetes, were taking metformin, and had been enrolled in the database for at least 1 uninterrupted year. They excluded anyone with type 1 diabetes or a prior diagnosis of osteoarthritis, inflammatory arthritis, or joint replacement. The authors then compared the incidence of osteoarthritis and joint replacement in these 20,937 participants to 20,937 control participants who were taking a sulfonylurea, matched to those taking metformin on the basis of age, sex, race, a comorbidity score, and duration of treatment. More than half the overall population (58%) was male with an average age of 62.
Patients needed to be on either drug for at least 3 months, but those who were initially treated with metformin before later taking a sulfonylurea could also be included and contribute to both groups. Those who first took a sulfonylurea and later switched to metformin were included only for the sulfonylurea group and censored after their switch to ensure the sulfonylurea group had enough participants. The comparison was further adjusted for age, sex, race, ethnicity, geographic region, education, comorbidities, and outpatient visit frequency.
The results revealed that those who were taking metformin were 24% less likely to develop osteoarthritis at least 3 months after starting the medication than were those taking a sulfonylurea (P < .001). The rate of joint replacements was not significantly different between those taking metformin and those taking a sulfonylurea. These two results did not change in a sensitivity analysis that compared patients who only ever took metformin or a sulfonylurea (as opposed to those who took one drug before switching to the other).
“When stratified by prior exposure to metformin within the sulfonylurea group, the observed benefit associated with metformin ... was attenuated in the people treated with a sulfonylurea with prior exposure to metformin, compared with those treated with a sulfonylurea with no prior exposure to metformin,” the authors further reported. A possible reason for this finding is that those taking a sulfonylurea after having previously taken metformin gained some protection from the earlier metformin exposure, the authors hypothesized.
This observational study could not show a causative effect from the metformin, but the researchers speculated on potential mechanisms if a causative effect were present, based on past research.
”Several preclinical studies have suggested a protective association of metformin in osteoarthritis through activating AMP-activated protein kinase signaling, decreasing the level of matrix metalloproteinase, increasing autophagy and reducing chondrocyte apoptosis, and augmenting chondroprotective and anti-inflammatory properties of mesenchymal stem cells,” the authors wrote.
Among this study’s limitations, however, was the lack of data on body mass index, which is associated with osteoarthritis in the literature and may differ between patients taking metformin versus a sulfonylurea. The researchers also did not have data on physical activity or a history of trauma to the joints, though there’s no reason to think these rates might differ between those taking one or the other medication.
Another substantial limitation is that all patients had type 2 diabetes, making it impossible to determine whether a similar protective effect from metformin might exist in people without diabetes.
Nonsignificant lower risk for posttraumatic knee osteoarthritis
Similar to the published study, the OARSI poster compared 5-year odds of incident osteoarthritis or total knee replacement surgery between patients taking metformin and those taking sulfonylureas, but it focused on younger patients, aged 18-40 years, who underwent anterior cruciate ligament or meniscus surgery.
Using data from MarketScan commercial insurance claims databases between 2006 and 2020, the authors identified 2,376 participants who were taking metformin or a sulfonylurea when they underwent their surgery or began taking it in the 6 months after their surgery. More than half the participants were female (57%) with an average age of 35.
Within 5 years, 10.8% of those taking metformin developed osteoarthritis, compared with 17.9% of those taking a sulfonylurea. In addition, 3% of those taking metformin underwent a total knee replacement, compared with 5.3% of those taking a sulfonylurea. After adjustment for age, sex, obesity, and a history of chronic kidney disease, liver disease, and depression, however, both risk difference and odds ratios were not statistically significant.
Risk of osteoarthritis was 17% lower in patients taking metformin (95% confidence interval, –0.18 to 0.09), whose odds of osteoarthritis were approximately half the odds of those taking a sulfonylurea (OR, 0.5; 95% CI, 0.21-1.67). Risk of a total knee replacement was 10% lower in metformin users (95% CI, –0.28 to 0.08) with a similar reduction in odds, compared with those taking a sulfonylurea (OR, 0.53; 95% CI, 0.2-1.44).
In this study, the researchers did not specifically determine whether the participants were diagnosed with diabetes, but they assumed all, or at least most, were, according to S. Reza Jafarzadeh, PhD, DVM, an assistant professor of medicine at Boston University.
“The goal was not to only focus on the diabetes population, but on people who received that exposure [of metformin or sulfonylureas],” Dr. Jafarzadeh said in an interview. Dr. Jafarzadeh noted that a larger randomized controlled trial is underway to look at whether metformin reduces the risk of osteoarthritis independent of whether a patient has diabetes.
The published study was funded by grants from the National Institutes of Health, the Department of Veterans Affairs, and Stanford University, and the authors reported no disclosures. The poster at OARSI was funded by NIH and the Arthritis Foundation, and the authors reported no disclosures.
FROM JAMA NETWORK OPEN AND OARSI 2023
Relapsed CLL: New approaches prolong survival
NEW YORK –
“In people who are genomically unstable, almost half will have their CLL progress on single agent BTK inhibitor therapy. These patients, I’d like to treat with combination of a Bruton’s tyrosine kinase inhibitor plus venetoclax,” said Richard R. Furman, MD, Morton Coleman MD Distinguished Professor of medicine at Weill Cornell Medicine/New York Presbyterian Hospital. He presented on treating relapsed CLL at the Great Debates and Updates Hematologic Malignancies Conference in New York, April 13-15.
The efficacy of venetoclax (VX) in treating high risk CLL patients was demonstrated in the 2019 CLL14 trial (NCT02242942) in which the main entry criteria were being treatment-naive and being considered “unfit” for treatment, meaning that a patient’s Cumulative Illness Rating Scale score was >6, or they presented with decreased kidney function. Study participants were treated with six cycles of either venetoclax-obinutuzumab (VO) or chlorambucil-obinutuzumab (CO); the 4-year PFS was 74% vs. 35.4% (P < .0001) respectively. After 12 cycles of treatment, the 74% of patients in the VO group achieved undetectable minimal residual disease rate (MRD) vs. 32% in the CO group.
Achievement of MRD did predict for outcome, but Dr. Furman concluded that while MRD is a powerful prognostic tool, it is not clinically useful given the inability of its results to guide therapy. He went on to emphasize that “of those patients who achieved MRD levels of 10-4 after 12 cycles of venetoclax, 50% had worsening and 50% had improvement of the residual disease, suggesting that we do not know the optimal duration of venetoclax treatment, as half of the patients still continue to derive benefit.”
Dr. Furman noted that ibrutinib (IB) and the second-generation drugs zanubrutinib (ZB) and acalabrutinib (AL) are all effective, but that the second-generation Bruton’s tyrosine kinase inhibitors enable patients to derive the benefit of remaining on treatment longer, because the rate of concerning cardiac complications is lower than with IB.
The ALPINE trial (NCT03734016) confirmed ZB’s significantly improved overall response rate at 78.3% vs. IB’s 62.5%, as well as a lower rate of atrial fibrillation (2.5%) vs. IB (10.1%).
Noninferiority of AL vs. IB in high-risk relapsed CLL patients was demonstrated in the ELEVATE-RR trial (NCT02477696) with both drugs having a median PFS of 38.4 months. With a median follow up of 41 months, AL demonstrated less atrial fibrillation/atrial flutter, compared with IB (9.4% vs. 16.0%) with no difference in grade > 3 infections. Furthermore, AL’s half-life being shorter than that of IB means that side effects are shorter lived.
“That’s the advantage of the second generation of Bruton’s tyrosine kinase inhibitors,” said Stefan Glück, MD, PhD, a hematologic oncologist and independent consultant who was formerly affiliated with the Sylvester Comprehensive Cancer Center and taught at the Miller School of Medicine at the University of Miami.
Dr. Glück added that “acalabrutinib and zanubrutinib have demonstrated strong efficacy and safety. When patients no longer respond to these drugs, the addition of VX is crucial. It has a completely different mechanism of action and can reverse resistance to Bruton’s tyrosine kinase inhibitors, allowing them to start working again.”
Dr. Furman also discussed proteolysis-targeting chimeras (PROTACs), one area that he expects to make a significant impact as a future therapy for CLL and many other malignancies. Despite the fact these agents are in phase I studies, he commented that “they appear, thus far, to have tremendous potential.”
Dr. Furman disclosed relationships with Abbvie, Acerta/AstraZeneca, Beigene, Jansen, TG Therapeutics, Genentech-Roche, Incyte Corporation, Loxo Oncology, MEI Pharma, Morphosys, Pharmacyclics, Sanofi/Genzyme, and X4 Pharmaceuticals. Dr. Glück reported no conflicts of interest.
NEW YORK –
“In people who are genomically unstable, almost half will have their CLL progress on single agent BTK inhibitor therapy. These patients, I’d like to treat with combination of a Bruton’s tyrosine kinase inhibitor plus venetoclax,” said Richard R. Furman, MD, Morton Coleman MD Distinguished Professor of medicine at Weill Cornell Medicine/New York Presbyterian Hospital. He presented on treating relapsed CLL at the Great Debates and Updates Hematologic Malignancies Conference in New York, April 13-15.
The efficacy of venetoclax (VX) in treating high risk CLL patients was demonstrated in the 2019 CLL14 trial (NCT02242942) in which the main entry criteria were being treatment-naive and being considered “unfit” for treatment, meaning that a patient’s Cumulative Illness Rating Scale score was >6, or they presented with decreased kidney function. Study participants were treated with six cycles of either venetoclax-obinutuzumab (VO) or chlorambucil-obinutuzumab (CO); the 4-year PFS was 74% vs. 35.4% (P < .0001) respectively. After 12 cycles of treatment, the 74% of patients in the VO group achieved undetectable minimal residual disease rate (MRD) vs. 32% in the CO group.
Achievement of MRD did predict for outcome, but Dr. Furman concluded that while MRD is a powerful prognostic tool, it is not clinically useful given the inability of its results to guide therapy. He went on to emphasize that “of those patients who achieved MRD levels of 10-4 after 12 cycles of venetoclax, 50% had worsening and 50% had improvement of the residual disease, suggesting that we do not know the optimal duration of venetoclax treatment, as half of the patients still continue to derive benefit.”
Dr. Furman noted that ibrutinib (IB) and the second-generation drugs zanubrutinib (ZB) and acalabrutinib (AL) are all effective, but that the second-generation Bruton’s tyrosine kinase inhibitors enable patients to derive the benefit of remaining on treatment longer, because the rate of concerning cardiac complications is lower than with IB.
The ALPINE trial (NCT03734016) confirmed ZB’s significantly improved overall response rate at 78.3% vs. IB’s 62.5%, as well as a lower rate of atrial fibrillation (2.5%) vs. IB (10.1%).
Noninferiority of AL vs. IB in high-risk relapsed CLL patients was demonstrated in the ELEVATE-RR trial (NCT02477696) with both drugs having a median PFS of 38.4 months. With a median follow up of 41 months, AL demonstrated less atrial fibrillation/atrial flutter, compared with IB (9.4% vs. 16.0%) with no difference in grade > 3 infections. Furthermore, AL’s half-life being shorter than that of IB means that side effects are shorter lived.
“That’s the advantage of the second generation of Bruton’s tyrosine kinase inhibitors,” said Stefan Glück, MD, PhD, a hematologic oncologist and independent consultant who was formerly affiliated with the Sylvester Comprehensive Cancer Center and taught at the Miller School of Medicine at the University of Miami.
Dr. Glück added that “acalabrutinib and zanubrutinib have demonstrated strong efficacy and safety. When patients no longer respond to these drugs, the addition of VX is crucial. It has a completely different mechanism of action and can reverse resistance to Bruton’s tyrosine kinase inhibitors, allowing them to start working again.”
Dr. Furman also discussed proteolysis-targeting chimeras (PROTACs), one area that he expects to make a significant impact as a future therapy for CLL and many other malignancies. Despite the fact these agents are in phase I studies, he commented that “they appear, thus far, to have tremendous potential.”
Dr. Furman disclosed relationships with Abbvie, Acerta/AstraZeneca, Beigene, Jansen, TG Therapeutics, Genentech-Roche, Incyte Corporation, Loxo Oncology, MEI Pharma, Morphosys, Pharmacyclics, Sanofi/Genzyme, and X4 Pharmaceuticals. Dr. Glück reported no conflicts of interest.
NEW YORK –
“In people who are genomically unstable, almost half will have their CLL progress on single agent BTK inhibitor therapy. These patients, I’d like to treat with combination of a Bruton’s tyrosine kinase inhibitor plus venetoclax,” said Richard R. Furman, MD, Morton Coleman MD Distinguished Professor of medicine at Weill Cornell Medicine/New York Presbyterian Hospital. He presented on treating relapsed CLL at the Great Debates and Updates Hematologic Malignancies Conference in New York, April 13-15.
The efficacy of venetoclax (VX) in treating high risk CLL patients was demonstrated in the 2019 CLL14 trial (NCT02242942) in which the main entry criteria were being treatment-naive and being considered “unfit” for treatment, meaning that a patient’s Cumulative Illness Rating Scale score was >6, or they presented with decreased kidney function. Study participants were treated with six cycles of either venetoclax-obinutuzumab (VO) or chlorambucil-obinutuzumab (CO); the 4-year PFS was 74% vs. 35.4% (P < .0001) respectively. After 12 cycles of treatment, the 74% of patients in the VO group achieved undetectable minimal residual disease rate (MRD) vs. 32% in the CO group.
Achievement of MRD did predict for outcome, but Dr. Furman concluded that while MRD is a powerful prognostic tool, it is not clinically useful given the inability of its results to guide therapy. He went on to emphasize that “of those patients who achieved MRD levels of 10-4 after 12 cycles of venetoclax, 50% had worsening and 50% had improvement of the residual disease, suggesting that we do not know the optimal duration of venetoclax treatment, as half of the patients still continue to derive benefit.”
Dr. Furman noted that ibrutinib (IB) and the second-generation drugs zanubrutinib (ZB) and acalabrutinib (AL) are all effective, but that the second-generation Bruton’s tyrosine kinase inhibitors enable patients to derive the benefit of remaining on treatment longer, because the rate of concerning cardiac complications is lower than with IB.
The ALPINE trial (NCT03734016) confirmed ZB’s significantly improved overall response rate at 78.3% vs. IB’s 62.5%, as well as a lower rate of atrial fibrillation (2.5%) vs. IB (10.1%).
Noninferiority of AL vs. IB in high-risk relapsed CLL patients was demonstrated in the ELEVATE-RR trial (NCT02477696) with both drugs having a median PFS of 38.4 months. With a median follow up of 41 months, AL demonstrated less atrial fibrillation/atrial flutter, compared with IB (9.4% vs. 16.0%) with no difference in grade > 3 infections. Furthermore, AL’s half-life being shorter than that of IB means that side effects are shorter lived.
“That’s the advantage of the second generation of Bruton’s tyrosine kinase inhibitors,” said Stefan Glück, MD, PhD, a hematologic oncologist and independent consultant who was formerly affiliated with the Sylvester Comprehensive Cancer Center and taught at the Miller School of Medicine at the University of Miami.
Dr. Glück added that “acalabrutinib and zanubrutinib have demonstrated strong efficacy and safety. When patients no longer respond to these drugs, the addition of VX is crucial. It has a completely different mechanism of action and can reverse resistance to Bruton’s tyrosine kinase inhibitors, allowing them to start working again.”
Dr. Furman also discussed proteolysis-targeting chimeras (PROTACs), one area that he expects to make a significant impact as a future therapy for CLL and many other malignancies. Despite the fact these agents are in phase I studies, he commented that “they appear, thus far, to have tremendous potential.”
Dr. Furman disclosed relationships with Abbvie, Acerta/AstraZeneca, Beigene, Jansen, TG Therapeutics, Genentech-Roche, Incyte Corporation, Loxo Oncology, MEI Pharma, Morphosys, Pharmacyclics, Sanofi/Genzyme, and X4 Pharmaceuticals. Dr. Glück reported no conflicts of interest.
AT 2023 GREAT DEBATES AND UPDATES HEMATOLOGIC MALIGNANCIES CONFERENCE
Pembrolizumab monotherapy effective for rare melanoma
The findings could represent a new standard of treatment for this extremely rare tumor.
The study was inspired by a previous retrospective analysis which found an overall response rate of 77% and a complete response of 32% to anti–PD-1 monotherapy.
The ORR is about double what is seen in melanoma more generally, according to Kari Kendra, MD, PhD, who presented the study at the annual meeting of the American Association for Cancer Research.
“Our study was a positive study. Of note, in the retrospective study, they saw a complete response rate of 32%, which was amazingly similar to what we found. [The findings support] the use of single agent anti–PD-1 immunotherapy as first line treatment for most patients with unresectable desmoplastic melanoma. [There was 89% overall response and we saw] dramatic responses across the board,” said Dr. Kendra, who is a medical oncologist at Ohio State University Wexner Medical Center, Columbus.
The findings drew a strong reaction. “In a rare tumor session, to see response curves like that, it’s just outstanding,” said the session’s cochair Brian Van Tine, MD, PhD, who is a professor of medical oncology at Washington University in St. Louis.
“This really is one of the highest tumor response rates to immunotherapy that we are seeing in any cancer. And I think may also highlight the fact that we shouldn’t think of all cutaneous melanomas as one disease, given the heterogeneity in tumor responses based on some of the pathologic and molecular characteristics,” said Zeynep Aroglu, MD, who served as a discussant but was also one of the investigators who enrolled patients for the trial.
Desmoplastic melanoma represents about 4% of all cutaneous melanoma diagnoses, and its unique pathology can make it difficult to diagnose. That often leads to a late diagnosis, according to Dr. Aroglu. They typically occur in elderly patients, in the head and neck area, and are associated with sun exposure. DM also tends to have a high mutation burden, Dr. Aroglu said during the session.
It remains to be seen why there is such a high response rate in this tumor type, even among tumor types with mutation burdens that are nearly as high. DM tumors are often driven by neurofibromatosis type 1, but other tumors driven by NF-1 don’t have as high of a response rate to immunotherapy. The tumor environment could also play a role, she said.
“Is it a combination of all these factors? I think some of the ongoing analysis of tumor samples that Dr. Kendra mentioned may help to answer some of these questions,” Dr. Aroglu continued.
She also noted that the melanoma field is increasingly turning to combination of anti–PD-1 therapy with agents like that target LAG3 or CTLA4. Such combinations can achieve higher response rates, but at a cost of higher rates of grade 3-4 adverse events than anti–PD-1 inhibitors alone. “I wonder if for desmoplastic melanomas in light of this data, do we consider de-escalating therapy, given these very high response rates to PD-1 alone, given also the elderly age of many of these patients, because even the PD-1–LAG3 combo still has a higher rate of toxicity than PD-1 monotherapy. Perhaps the immunotherapy combinations can be reserved for those rare desmoplastic patients who are resistant to PD-1 alone,” said Dr. Aroglu.
Study details and adverse events
Twenty-seven patients were enrolled in the study; 93% were male, all were White, and 22% had elevated baseline lactate dehydrogenase. About 63% had disease located in the head and neck area, 33% experienced a complete response (P < .001), and 56% had a partial response for an ORR of 89%. The result surpassed the primary endpoint target of at least a 20% complete response rate.
The 2-year progression-free survival was 74%, and 2-year overall survival was 89%. The most common toxicities were fatigue (56%), diarrhea (33%), maculopapular rash (30%), pruritus (22%), anemia (19%), arthralgia (19%), and decreased lymphocyte count (19%). There were two grade 4 adverse events: a lipase increase and a lung infection accompanied by sepsis.
The researchers also carried out whole exome sequencing of biopsies and found that 67% had NF-1 loss of function mutations.
Dr. Aroglu has served on advisory boards for Pfizer, Array, Eisai, Genentech, Natera, Novartis, OncoSec, and Regeneron. She has received research support from Boehringer Ingelheim, Pfizer, and Novartis. Dr. Kendra has received institutional support from Bristol Myers-Squibb and trial support from CheckMate Pharmaceuticals, GlaxoSmithKline, Immunocore, Medspace, Merck, Novartis, and Varian Medical Systems. Dr. Van Tine has financial relationships with a wide range of pharmaceutical companies.
The findings could represent a new standard of treatment for this extremely rare tumor.
The study was inspired by a previous retrospective analysis which found an overall response rate of 77% and a complete response of 32% to anti–PD-1 monotherapy.
The ORR is about double what is seen in melanoma more generally, according to Kari Kendra, MD, PhD, who presented the study at the annual meeting of the American Association for Cancer Research.
“Our study was a positive study. Of note, in the retrospective study, they saw a complete response rate of 32%, which was amazingly similar to what we found. [The findings support] the use of single agent anti–PD-1 immunotherapy as first line treatment for most patients with unresectable desmoplastic melanoma. [There was 89% overall response and we saw] dramatic responses across the board,” said Dr. Kendra, who is a medical oncologist at Ohio State University Wexner Medical Center, Columbus.
The findings drew a strong reaction. “In a rare tumor session, to see response curves like that, it’s just outstanding,” said the session’s cochair Brian Van Tine, MD, PhD, who is a professor of medical oncology at Washington University in St. Louis.
“This really is one of the highest tumor response rates to immunotherapy that we are seeing in any cancer. And I think may also highlight the fact that we shouldn’t think of all cutaneous melanomas as one disease, given the heterogeneity in tumor responses based on some of the pathologic and molecular characteristics,” said Zeynep Aroglu, MD, who served as a discussant but was also one of the investigators who enrolled patients for the trial.
Desmoplastic melanoma represents about 4% of all cutaneous melanoma diagnoses, and its unique pathology can make it difficult to diagnose. That often leads to a late diagnosis, according to Dr. Aroglu. They typically occur in elderly patients, in the head and neck area, and are associated with sun exposure. DM also tends to have a high mutation burden, Dr. Aroglu said during the session.
It remains to be seen why there is such a high response rate in this tumor type, even among tumor types with mutation burdens that are nearly as high. DM tumors are often driven by neurofibromatosis type 1, but other tumors driven by NF-1 don’t have as high of a response rate to immunotherapy. The tumor environment could also play a role, she said.
“Is it a combination of all these factors? I think some of the ongoing analysis of tumor samples that Dr. Kendra mentioned may help to answer some of these questions,” Dr. Aroglu continued.
She also noted that the melanoma field is increasingly turning to combination of anti–PD-1 therapy with agents like that target LAG3 or CTLA4. Such combinations can achieve higher response rates, but at a cost of higher rates of grade 3-4 adverse events than anti–PD-1 inhibitors alone. “I wonder if for desmoplastic melanomas in light of this data, do we consider de-escalating therapy, given these very high response rates to PD-1 alone, given also the elderly age of many of these patients, because even the PD-1–LAG3 combo still has a higher rate of toxicity than PD-1 monotherapy. Perhaps the immunotherapy combinations can be reserved for those rare desmoplastic patients who are resistant to PD-1 alone,” said Dr. Aroglu.
Study details and adverse events
Twenty-seven patients were enrolled in the study; 93% were male, all were White, and 22% had elevated baseline lactate dehydrogenase. About 63% had disease located in the head and neck area, 33% experienced a complete response (P < .001), and 56% had a partial response for an ORR of 89%. The result surpassed the primary endpoint target of at least a 20% complete response rate.
The 2-year progression-free survival was 74%, and 2-year overall survival was 89%. The most common toxicities were fatigue (56%), diarrhea (33%), maculopapular rash (30%), pruritus (22%), anemia (19%), arthralgia (19%), and decreased lymphocyte count (19%). There were two grade 4 adverse events: a lipase increase and a lung infection accompanied by sepsis.
The researchers also carried out whole exome sequencing of biopsies and found that 67% had NF-1 loss of function mutations.
Dr. Aroglu has served on advisory boards for Pfizer, Array, Eisai, Genentech, Natera, Novartis, OncoSec, and Regeneron. She has received research support from Boehringer Ingelheim, Pfizer, and Novartis. Dr. Kendra has received institutional support from Bristol Myers-Squibb and trial support from CheckMate Pharmaceuticals, GlaxoSmithKline, Immunocore, Medspace, Merck, Novartis, and Varian Medical Systems. Dr. Van Tine has financial relationships with a wide range of pharmaceutical companies.
The findings could represent a new standard of treatment for this extremely rare tumor.
The study was inspired by a previous retrospective analysis which found an overall response rate of 77% and a complete response of 32% to anti–PD-1 monotherapy.
The ORR is about double what is seen in melanoma more generally, according to Kari Kendra, MD, PhD, who presented the study at the annual meeting of the American Association for Cancer Research.
“Our study was a positive study. Of note, in the retrospective study, they saw a complete response rate of 32%, which was amazingly similar to what we found. [The findings support] the use of single agent anti–PD-1 immunotherapy as first line treatment for most patients with unresectable desmoplastic melanoma. [There was 89% overall response and we saw] dramatic responses across the board,” said Dr. Kendra, who is a medical oncologist at Ohio State University Wexner Medical Center, Columbus.
The findings drew a strong reaction. “In a rare tumor session, to see response curves like that, it’s just outstanding,” said the session’s cochair Brian Van Tine, MD, PhD, who is a professor of medical oncology at Washington University in St. Louis.
“This really is one of the highest tumor response rates to immunotherapy that we are seeing in any cancer. And I think may also highlight the fact that we shouldn’t think of all cutaneous melanomas as one disease, given the heterogeneity in tumor responses based on some of the pathologic and molecular characteristics,” said Zeynep Aroglu, MD, who served as a discussant but was also one of the investigators who enrolled patients for the trial.
Desmoplastic melanoma represents about 4% of all cutaneous melanoma diagnoses, and its unique pathology can make it difficult to diagnose. That often leads to a late diagnosis, according to Dr. Aroglu. They typically occur in elderly patients, in the head and neck area, and are associated with sun exposure. DM also tends to have a high mutation burden, Dr. Aroglu said during the session.
It remains to be seen why there is such a high response rate in this tumor type, even among tumor types with mutation burdens that are nearly as high. DM tumors are often driven by neurofibromatosis type 1, but other tumors driven by NF-1 don’t have as high of a response rate to immunotherapy. The tumor environment could also play a role, she said.
“Is it a combination of all these factors? I think some of the ongoing analysis of tumor samples that Dr. Kendra mentioned may help to answer some of these questions,” Dr. Aroglu continued.
She also noted that the melanoma field is increasingly turning to combination of anti–PD-1 therapy with agents like that target LAG3 or CTLA4. Such combinations can achieve higher response rates, but at a cost of higher rates of grade 3-4 adverse events than anti–PD-1 inhibitors alone. “I wonder if for desmoplastic melanomas in light of this data, do we consider de-escalating therapy, given these very high response rates to PD-1 alone, given also the elderly age of many of these patients, because even the PD-1–LAG3 combo still has a higher rate of toxicity than PD-1 monotherapy. Perhaps the immunotherapy combinations can be reserved for those rare desmoplastic patients who are resistant to PD-1 alone,” said Dr. Aroglu.
Study details and adverse events
Twenty-seven patients were enrolled in the study; 93% were male, all were White, and 22% had elevated baseline lactate dehydrogenase. About 63% had disease located in the head and neck area, 33% experienced a complete response (P < .001), and 56% had a partial response for an ORR of 89%. The result surpassed the primary endpoint target of at least a 20% complete response rate.
The 2-year progression-free survival was 74%, and 2-year overall survival was 89%. The most common toxicities were fatigue (56%), diarrhea (33%), maculopapular rash (30%), pruritus (22%), anemia (19%), arthralgia (19%), and decreased lymphocyte count (19%). There were two grade 4 adverse events: a lipase increase and a lung infection accompanied by sepsis.
The researchers also carried out whole exome sequencing of biopsies and found that 67% had NF-1 loss of function mutations.
Dr. Aroglu has served on advisory boards for Pfizer, Array, Eisai, Genentech, Natera, Novartis, OncoSec, and Regeneron. She has received research support from Boehringer Ingelheim, Pfizer, and Novartis. Dr. Kendra has received institutional support from Bristol Myers-Squibb and trial support from CheckMate Pharmaceuticals, GlaxoSmithKline, Immunocore, Medspace, Merck, Novartis, and Varian Medical Systems. Dr. Van Tine has financial relationships with a wide range of pharmaceutical companies.
FROM AACR 2023
Cardiovascular disease deaths rise on and after high-pollution days
Cardiovascular disease deaths were significantly more common on days of high pollution and for the following 2 days, compared with other days, based on data from nearly 88,000 deaths over a 5-year period.
Previous research has shown the harmful effect of air pollution on human health in highly polluted areas, but Eastern Poland, a region with so-called “Polish smog” has exceptionally high levels of pollution. However, the specific impact of Polish smog, caused primarily by burning coal, on cardiovascular disease (CVD) mortality has not been well studied, said Michal Swieczkowski, MD, of the Medical University of Bialystok (Poland) in a presentation at the annual congress of the European Association of Preventive Cardiology.
Dr. Swieczkowski and colleagues reviewed all-cause deaths from five main cities in Eastern Poland during 2016-2020 for associations with pollution levels and days when deaths occurred. Mortality data were obtained from the Central Statistical Office. Air pollution concentrations for two types of particulate matter (PM2.5, PM10) and nitrogen oxide were collected from the Voivodeship Inspectorate for Environmental Protection. The main sources of the pollutants were road traffic and household heaters using coal or wood.
The final analysis included nearly 6 million person-years of follow-up. The researchers used a time-stratified case-crossover design. For each participant, the researchers compared levels of each pollutant on the day of the week a death occurred (such as a Wednesday) with pollutant levels on the same day of the week without any deaths in the same month (the remaining Wednesdays of that month). This design eliminated the potential confounding effects of participant characteristics, including other cardiovascular risk factors such as smoking and hyperlipidemia, and time trends. Essentially, participants “served as their own controls,” Dr. Swieczkowski said. The researchers conducted similar analyses for pollution levels 1 day and 2 days before a death occurred.
Overall, 87,990 deaths were identified during the study period; of these, 34,907 were from CVD, 9,688 from acute coronary syndromes, and 3,776 from ischemic stroke.
“Exposure to PM2.5 and PM10 was associated with increased mortality on the day of exposure, the next day, and up to 2 days after exposure,” said Dr. Swieczkowski.
Overall, an increase of 10 mcg/m3 in the three pollutants was significantly associated with increase in CVD mortality on the day of exposure to the increased pollution levels, with odds ratios of 1.034, 1.033, and 1.083 for PM2.5, PM10, and NO2, respectively (all P < .001).
The risks of dying from CVD were similar 1 and 2 days after the polluted day.
An increase in PM levels, but not NO2, was significantly associated with acute coronary syndrome (ACS) on the day of exposure to increased pollutants (ORs, 1.029 for PM2.5 [P = .002] and 1.015 [P = .049] for PM10). Both ischemic stroke and ACS mortality were significantly higher at 1 day after exposure, compared with other days. Ischemic stroke was associated with increases in PM2.5 and PM10, while ACS was associated with increases in PM2.5, PM10, and NO2.
When stratified by gender, the effects were more noticeable in women, Dr. Swieczkowski said. “Exposure to both types of particulate caused increased mortality due to acute coronary syndrome as well as ischemic stroke.” Among men, only death from acute coronary syndrome was significantly associated with exposure to increased particulate matter.
In a head-to-head comparison, women were more vulnerable to air pollution by up to 2.5%, he added.
When stratified by age, the effects of all three pollutants were associated with increased risk of death from ischemic stroke and ACS in participants older than 65 years. For those aged 65 years and younger, the only significant association was between ACS-associated mortality and ischemic stroke.
The results suggest “a special need for developing calculators to estimate the risk of CVD incidence depending on the place of residence that could be used for everyday practice,” said Dr. Swieczkowski. “Systemic changes should become a priority for policy makers, and, simultaneously, we as physicians should educate and protect our patients, especially those with high risk of cardiovascular disease,” he said.
Gender differences rooted in anatomy
When asked for an explanation of the difference in the impact of pollution on mortality between men and women, Dr. Swieczkowski explained that women are likely more vulnerable because of differences in anatomy of the pharynx and larynx, and breathing patterns. Previous studies have shown that air pollution causes more oxidative stress in women. Also, in the current study, the mean age of the women was 8 to 9 years older, he said.
The study design was an “elegant way to take away the impact of other cardiovascular risk factors,” noted session moderator Maryam Kavousi, MD, of Erasmus University Medical Center, Rotterdam, the Netherlands.
The study was supported by the National Science Centre, Poland. The researchers had no financial conflicts to disclose.
Cardiovascular disease deaths were significantly more common on days of high pollution and for the following 2 days, compared with other days, based on data from nearly 88,000 deaths over a 5-year period.
Previous research has shown the harmful effect of air pollution on human health in highly polluted areas, but Eastern Poland, a region with so-called “Polish smog” has exceptionally high levels of pollution. However, the specific impact of Polish smog, caused primarily by burning coal, on cardiovascular disease (CVD) mortality has not been well studied, said Michal Swieczkowski, MD, of the Medical University of Bialystok (Poland) in a presentation at the annual congress of the European Association of Preventive Cardiology.
Dr. Swieczkowski and colleagues reviewed all-cause deaths from five main cities in Eastern Poland during 2016-2020 for associations with pollution levels and days when deaths occurred. Mortality data were obtained from the Central Statistical Office. Air pollution concentrations for two types of particulate matter (PM2.5, PM10) and nitrogen oxide were collected from the Voivodeship Inspectorate for Environmental Protection. The main sources of the pollutants were road traffic and household heaters using coal or wood.
The final analysis included nearly 6 million person-years of follow-up. The researchers used a time-stratified case-crossover design. For each participant, the researchers compared levels of each pollutant on the day of the week a death occurred (such as a Wednesday) with pollutant levels on the same day of the week without any deaths in the same month (the remaining Wednesdays of that month). This design eliminated the potential confounding effects of participant characteristics, including other cardiovascular risk factors such as smoking and hyperlipidemia, and time trends. Essentially, participants “served as their own controls,” Dr. Swieczkowski said. The researchers conducted similar analyses for pollution levels 1 day and 2 days before a death occurred.
Overall, 87,990 deaths were identified during the study period; of these, 34,907 were from CVD, 9,688 from acute coronary syndromes, and 3,776 from ischemic stroke.
“Exposure to PM2.5 and PM10 was associated with increased mortality on the day of exposure, the next day, and up to 2 days after exposure,” said Dr. Swieczkowski.
Overall, an increase of 10 mcg/m3 in the three pollutants was significantly associated with increase in CVD mortality on the day of exposure to the increased pollution levels, with odds ratios of 1.034, 1.033, and 1.083 for PM2.5, PM10, and NO2, respectively (all P < .001).
The risks of dying from CVD were similar 1 and 2 days after the polluted day.
An increase in PM levels, but not NO2, was significantly associated with acute coronary syndrome (ACS) on the day of exposure to increased pollutants (ORs, 1.029 for PM2.5 [P = .002] and 1.015 [P = .049] for PM10). Both ischemic stroke and ACS mortality were significantly higher at 1 day after exposure, compared with other days. Ischemic stroke was associated with increases in PM2.5 and PM10, while ACS was associated with increases in PM2.5, PM10, and NO2.
When stratified by gender, the effects were more noticeable in women, Dr. Swieczkowski said. “Exposure to both types of particulate caused increased mortality due to acute coronary syndrome as well as ischemic stroke.” Among men, only death from acute coronary syndrome was significantly associated with exposure to increased particulate matter.
In a head-to-head comparison, women were more vulnerable to air pollution by up to 2.5%, he added.
When stratified by age, the effects of all three pollutants were associated with increased risk of death from ischemic stroke and ACS in participants older than 65 years. For those aged 65 years and younger, the only significant association was between ACS-associated mortality and ischemic stroke.
The results suggest “a special need for developing calculators to estimate the risk of CVD incidence depending on the place of residence that could be used for everyday practice,” said Dr. Swieczkowski. “Systemic changes should become a priority for policy makers, and, simultaneously, we as physicians should educate and protect our patients, especially those with high risk of cardiovascular disease,” he said.
Gender differences rooted in anatomy
When asked for an explanation of the difference in the impact of pollution on mortality between men and women, Dr. Swieczkowski explained that women are likely more vulnerable because of differences in anatomy of the pharynx and larynx, and breathing patterns. Previous studies have shown that air pollution causes more oxidative stress in women. Also, in the current study, the mean age of the women was 8 to 9 years older, he said.
The study design was an “elegant way to take away the impact of other cardiovascular risk factors,” noted session moderator Maryam Kavousi, MD, of Erasmus University Medical Center, Rotterdam, the Netherlands.
The study was supported by the National Science Centre, Poland. The researchers had no financial conflicts to disclose.
Cardiovascular disease deaths were significantly more common on days of high pollution and for the following 2 days, compared with other days, based on data from nearly 88,000 deaths over a 5-year period.
Previous research has shown the harmful effect of air pollution on human health in highly polluted areas, but Eastern Poland, a region with so-called “Polish smog” has exceptionally high levels of pollution. However, the specific impact of Polish smog, caused primarily by burning coal, on cardiovascular disease (CVD) mortality has not been well studied, said Michal Swieczkowski, MD, of the Medical University of Bialystok (Poland) in a presentation at the annual congress of the European Association of Preventive Cardiology.
Dr. Swieczkowski and colleagues reviewed all-cause deaths from five main cities in Eastern Poland during 2016-2020 for associations with pollution levels and days when deaths occurred. Mortality data were obtained from the Central Statistical Office. Air pollution concentrations for two types of particulate matter (PM2.5, PM10) and nitrogen oxide were collected from the Voivodeship Inspectorate for Environmental Protection. The main sources of the pollutants were road traffic and household heaters using coal or wood.
The final analysis included nearly 6 million person-years of follow-up. The researchers used a time-stratified case-crossover design. For each participant, the researchers compared levels of each pollutant on the day of the week a death occurred (such as a Wednesday) with pollutant levels on the same day of the week without any deaths in the same month (the remaining Wednesdays of that month). This design eliminated the potential confounding effects of participant characteristics, including other cardiovascular risk factors such as smoking and hyperlipidemia, and time trends. Essentially, participants “served as their own controls,” Dr. Swieczkowski said. The researchers conducted similar analyses for pollution levels 1 day and 2 days before a death occurred.
Overall, 87,990 deaths were identified during the study period; of these, 34,907 were from CVD, 9,688 from acute coronary syndromes, and 3,776 from ischemic stroke.
“Exposure to PM2.5 and PM10 was associated with increased mortality on the day of exposure, the next day, and up to 2 days after exposure,” said Dr. Swieczkowski.
Overall, an increase of 10 mcg/m3 in the three pollutants was significantly associated with increase in CVD mortality on the day of exposure to the increased pollution levels, with odds ratios of 1.034, 1.033, and 1.083 for PM2.5, PM10, and NO2, respectively (all P < .001).
The risks of dying from CVD were similar 1 and 2 days after the polluted day.
An increase in PM levels, but not NO2, was significantly associated with acute coronary syndrome (ACS) on the day of exposure to increased pollutants (ORs, 1.029 for PM2.5 [P = .002] and 1.015 [P = .049] for PM10). Both ischemic stroke and ACS mortality were significantly higher at 1 day after exposure, compared with other days. Ischemic stroke was associated with increases in PM2.5 and PM10, while ACS was associated with increases in PM2.5, PM10, and NO2.
When stratified by gender, the effects were more noticeable in women, Dr. Swieczkowski said. “Exposure to both types of particulate caused increased mortality due to acute coronary syndrome as well as ischemic stroke.” Among men, only death from acute coronary syndrome was significantly associated with exposure to increased particulate matter.
In a head-to-head comparison, women were more vulnerable to air pollution by up to 2.5%, he added.
When stratified by age, the effects of all three pollutants were associated with increased risk of death from ischemic stroke and ACS in participants older than 65 years. For those aged 65 years and younger, the only significant association was between ACS-associated mortality and ischemic stroke.
The results suggest “a special need for developing calculators to estimate the risk of CVD incidence depending on the place of residence that could be used for everyday practice,” said Dr. Swieczkowski. “Systemic changes should become a priority for policy makers, and, simultaneously, we as physicians should educate and protect our patients, especially those with high risk of cardiovascular disease,” he said.
Gender differences rooted in anatomy
When asked for an explanation of the difference in the impact of pollution on mortality between men and women, Dr. Swieczkowski explained that women are likely more vulnerable because of differences in anatomy of the pharynx and larynx, and breathing patterns. Previous studies have shown that air pollution causes more oxidative stress in women. Also, in the current study, the mean age of the women was 8 to 9 years older, he said.
The study design was an “elegant way to take away the impact of other cardiovascular risk factors,” noted session moderator Maryam Kavousi, MD, of Erasmus University Medical Center, Rotterdam, the Netherlands.
The study was supported by the National Science Centre, Poland. The researchers had no financial conflicts to disclose.
FROM ESC CONGRESS 2023
Exercise or neuromuscular stimulation in type 2 diabetes?
Studies indicate that physical activity improves glucose metabolism in patients with type 2 diabetes. In addition, other data suggest a decrease in cardiovascular morbidity and mortality through physical activity.
In the consensus report “Management of Hyperglycemia in Type 2 Diabetes, 2022,” the American Diabetes Association and the European Association for the Study of Diabetes, therefore, recommend at least 150 minutes per week of moderate- to vigorous-intensity aerobic activity, supplemented with two to three resistance, flexibility, or balance training sessions per week.
But even when such recommendations are integrated into a therapeutic education program, adherence is often transient or partial.
In this context, Michael Joubert, MD, PhD, and his team at Caen (France) University Hospital wondered about neuromuscular electrical stimulation (NMES), a physical treatment routinely used in functional rehabilitation to improve muscle strength and volume.
To answer this question, they conducted a crossover randomized controlled trial called ELECTRODIAB2. The results were presented at the 2023 Congress of the Francophone Diabetes Society.
A few small pilot studies found that NMES improved insulin sensitivity and glycemic control; therefore, it could indeed be an alternative. The metabolic effect of NMES, however, has not been widely studied.
A total of 40 patients were enrolled in ELECTRODIAB2. Of these participants, 35 were randomly assigned to one of three groups: 6 weeks without NMES (control, no intervention), electrostimulation on 3 days per week for 6 weeks (20-minute ambulatory biquadricipital electrostimulation sessions) (NMES3), and electrostimulation on 5 days per week for 6 weeks (20-minutes ambulatory biquadricipital electrostimulation sessions) (NMES5). The goal was to assess the glucose levels of sedentary patients with type 2 diabetes during these periods. At each session, NMES was applied at the maximum-tolerated intensity.
Data from 32 participants were analyzed. Mean age was 58 ± 10 years, and body mass index was 33.0 ± 4.3 kg/m2. Duration of diabetes was 8.6 ± 5.9 years. Regarding diabetes treatments, 47%, 31%, 9%, and 13% of the patients were taking 0, 1, 2, and 3 oral hypoglycemic agents or glucagonlike peptide–1 agonists, respectively.
No significant differences in glucose levels were observed between the three groups. The primary outcome was mean glucose level based on a 6-day continuous glucose monitoring (CGM) recording. Those levels were 181.4 ± 42.5 mg/dL (control, no intervention), 180.6 ± 45.8 mg/dL (NMES3), and 181.1 ± 48.9 mg/dL (NMES5).
Furthermore, secondary outcomes (rates of hyperglycemia and hypoglycemia) did not differ between the three groups.
The researchers concluded that, “with regard to the CGM criteria, this crossover randomized controlled trial did not show that the 6-week biquadricipital NMES sessions had any benefit. This finding conflicts with the results of preliminary pilot studies but it does not encourage further research on NMES in this population of patients with early-stage diabetes.”
Therefore, at this point, it does not look like NMES can be recommended as an alternative to physical activity for sedentary patients with type 2 diabetes.
This article was translated from the Medscape French edition. A version appeared on Medscape.com.
Studies indicate that physical activity improves glucose metabolism in patients with type 2 diabetes. In addition, other data suggest a decrease in cardiovascular morbidity and mortality through physical activity.
In the consensus report “Management of Hyperglycemia in Type 2 Diabetes, 2022,” the American Diabetes Association and the European Association for the Study of Diabetes, therefore, recommend at least 150 minutes per week of moderate- to vigorous-intensity aerobic activity, supplemented with two to three resistance, flexibility, or balance training sessions per week.
But even when such recommendations are integrated into a therapeutic education program, adherence is often transient or partial.
In this context, Michael Joubert, MD, PhD, and his team at Caen (France) University Hospital wondered about neuromuscular electrical stimulation (NMES), a physical treatment routinely used in functional rehabilitation to improve muscle strength and volume.
To answer this question, they conducted a crossover randomized controlled trial called ELECTRODIAB2. The results were presented at the 2023 Congress of the Francophone Diabetes Society.
A few small pilot studies found that NMES improved insulin sensitivity and glycemic control; therefore, it could indeed be an alternative. The metabolic effect of NMES, however, has not been widely studied.
A total of 40 patients were enrolled in ELECTRODIAB2. Of these participants, 35 were randomly assigned to one of three groups: 6 weeks without NMES (control, no intervention), electrostimulation on 3 days per week for 6 weeks (20-minute ambulatory biquadricipital electrostimulation sessions) (NMES3), and electrostimulation on 5 days per week for 6 weeks (20-minutes ambulatory biquadricipital electrostimulation sessions) (NMES5). The goal was to assess the glucose levels of sedentary patients with type 2 diabetes during these periods. At each session, NMES was applied at the maximum-tolerated intensity.
Data from 32 participants were analyzed. Mean age was 58 ± 10 years, and body mass index was 33.0 ± 4.3 kg/m2. Duration of diabetes was 8.6 ± 5.9 years. Regarding diabetes treatments, 47%, 31%, 9%, and 13% of the patients were taking 0, 1, 2, and 3 oral hypoglycemic agents or glucagonlike peptide–1 agonists, respectively.
No significant differences in glucose levels were observed between the three groups. The primary outcome was mean glucose level based on a 6-day continuous glucose monitoring (CGM) recording. Those levels were 181.4 ± 42.5 mg/dL (control, no intervention), 180.6 ± 45.8 mg/dL (NMES3), and 181.1 ± 48.9 mg/dL (NMES5).
Furthermore, secondary outcomes (rates of hyperglycemia and hypoglycemia) did not differ between the three groups.
The researchers concluded that, “with regard to the CGM criteria, this crossover randomized controlled trial did not show that the 6-week biquadricipital NMES sessions had any benefit. This finding conflicts with the results of preliminary pilot studies but it does not encourage further research on NMES in this population of patients with early-stage diabetes.”
Therefore, at this point, it does not look like NMES can be recommended as an alternative to physical activity for sedentary patients with type 2 diabetes.
This article was translated from the Medscape French edition. A version appeared on Medscape.com.
Studies indicate that physical activity improves glucose metabolism in patients with type 2 diabetes. In addition, other data suggest a decrease in cardiovascular morbidity and mortality through physical activity.
In the consensus report “Management of Hyperglycemia in Type 2 Diabetes, 2022,” the American Diabetes Association and the European Association for the Study of Diabetes, therefore, recommend at least 150 minutes per week of moderate- to vigorous-intensity aerobic activity, supplemented with two to three resistance, flexibility, or balance training sessions per week.
But even when such recommendations are integrated into a therapeutic education program, adherence is often transient or partial.
In this context, Michael Joubert, MD, PhD, and his team at Caen (France) University Hospital wondered about neuromuscular electrical stimulation (NMES), a physical treatment routinely used in functional rehabilitation to improve muscle strength and volume.
To answer this question, they conducted a crossover randomized controlled trial called ELECTRODIAB2. The results were presented at the 2023 Congress of the Francophone Diabetes Society.
A few small pilot studies found that NMES improved insulin sensitivity and glycemic control; therefore, it could indeed be an alternative. The metabolic effect of NMES, however, has not been widely studied.
A total of 40 patients were enrolled in ELECTRODIAB2. Of these participants, 35 were randomly assigned to one of three groups: 6 weeks without NMES (control, no intervention), electrostimulation on 3 days per week for 6 weeks (20-minute ambulatory biquadricipital electrostimulation sessions) (NMES3), and electrostimulation on 5 days per week for 6 weeks (20-minutes ambulatory biquadricipital electrostimulation sessions) (NMES5). The goal was to assess the glucose levels of sedentary patients with type 2 diabetes during these periods. At each session, NMES was applied at the maximum-tolerated intensity.
Data from 32 participants were analyzed. Mean age was 58 ± 10 years, and body mass index was 33.0 ± 4.3 kg/m2. Duration of diabetes was 8.6 ± 5.9 years. Regarding diabetes treatments, 47%, 31%, 9%, and 13% of the patients were taking 0, 1, 2, and 3 oral hypoglycemic agents or glucagonlike peptide–1 agonists, respectively.
No significant differences in glucose levels were observed between the three groups. The primary outcome was mean glucose level based on a 6-day continuous glucose monitoring (CGM) recording. Those levels were 181.4 ± 42.5 mg/dL (control, no intervention), 180.6 ± 45.8 mg/dL (NMES3), and 181.1 ± 48.9 mg/dL (NMES5).
Furthermore, secondary outcomes (rates of hyperglycemia and hypoglycemia) did not differ between the three groups.
The researchers concluded that, “with regard to the CGM criteria, this crossover randomized controlled trial did not show that the 6-week biquadricipital NMES sessions had any benefit. This finding conflicts with the results of preliminary pilot studies but it does not encourage further research on NMES in this population of patients with early-stage diabetes.”
Therefore, at this point, it does not look like NMES can be recommended as an alternative to physical activity for sedentary patients with type 2 diabetes.
This article was translated from the Medscape French edition. A version appeared on Medscape.com.
Study compares noninvasive treatments of cutaneous neurofibromas
PHOENIX – after only one treatment, according to preliminary results of an ongoing prospective trial that compared several treatment modalities.
“Neurofibromatosis type 1 is the most common single-gene disease of mankind, but there is so much we have yet to learn about it,” study author Patricia Richey, MD, who practices Mohs surgery and cosmetic dermatology in Washington, D.C., said in an interview in advance of the annual conference of the American Society for Laser Medicine and Surgery, where she presented the results during an abstract session. Dr. Richey also conducts research for the Wellman Center for Photomedicine and the Dermatology Laser and Cosmetic Center at Massachusetts General Hospital, Boston, and is working with R. Rox Anderson, MD, director of the Wellman Center, on this project. In his words, she said, “the lack of better treatments for cNF is a ‘problem worth solving.’ ”
“The accepted and widely available treatments for cNF result in scars and hypopigmentation. Our treatments do not,” she added. Since the epidermis overlying cNF is normal, “there is no reason to use nonselective or surgical methods and destroy a perfectly good epidermis when you don’t need to.”
Four treatments vs. controls
For the study, Dr. Richey and colleagues enrolled 19 adults with a total of 307 cNFs measuring 2-4 mm in size to receive one of four treatments: electrocautery with an insulated radiofrequency needle; 755-nm alexandrite laser with negative pressure (8-mm spot size, 100 J/cm2 fluence, 3-ms pulse duration); 980-nm diode laser (delivered via 8-mm sapphire skin-contact window), and intratumoral injection of 10 mg/mL deoxycholic acid at a volume approximately equal to that of the tumor. The average age of the participants was 49 years and 15 were female.
The investigators applied 5% lidocaine/prilocaine for 40 minutes to treatment sites before randomizing the tumors to treatment or to the control arm (no treatment). They compared safety, tolerability (including pain scores), and efficacy of each modality as measured by the change in cNF volume/height via three-dimensional imaging and clinical improvement via physician assessment at 6 months. All 19 participants have completed the 6-month assessment.
All modalities reduced or eliminated some of the cNFs by 6 months after treatment, with statistically significant reductions in height and volume across all four treatments. A wide variation of responses was observed. Specifically, the mean tumor volume changes for each modality, compared with controls, were –33.4% versus –5.1% among those treated with the 755-nm alexandrite laser; –24.9% versus –9.2% among those treated with the 980-nm diode laser, –23.3% versus –0.8% among those treated with insulated-needle radiofrequency coagulation, and –29.4% versus –3.7% among those treated with deoxycholic acid.
The variation in responses “may be due to histologic diversity of cNF or may indicate a need for more fine-tuned dosimetry, or a combination,” Dr. Richey said. “Our future trials will address this. We will also be treating all skin types in our upcoming trials.”
No adverse events categorized as higher than grade 2 occurred in any of the treatment groups, and no signs of regrowth or growth stimulation have been observed to date.
Tolerability of treatments
As for general tolerability, the 980-nm laser treatment caused moderate to severe pain; the alexandrite laser caused mild pain; insulated-needle radiofrequency coagulation caused mild pain, though more than deoxycholic acid injections or alexandrite laser, and pain associated with the deoxycholic acid injections was minimal.
When residual neurofibroma tumor was present histologically, its appearance was similar to that of untreated tumors in controls. There was no evidence of atypia, mitosis, or tumor inflammation, and mild fibrosis was present at the sites of prior tumor.
“It was surprising that all four modalities did work to some extent,” Dr. Richey said, noting that the lack of ulceration with deoxycholic acid injection “was pleasantly surprising.” Treatment with the 980-nm diode laser “was a bit more painful than we anticipated.”
The positive results of this trial has raised “more questions for us to answer. We have three additional trials in the works to fine tune these treatments and optimize dose/delivery, with the end goal of treating younger people.”
Dr. Richey said that she was “amazed” by how motivated the enrollees were to participate in the trial, noting that many patients with cNF undergo general anesthesia to have dozens of tumors surgically removed at once. “They pay $10,000-$20,000 on average out of pocket, as this surgery is considered cosmetic,” she said.
“This very important study could lead to effective, relatively noninvasive, therapy for small neurofibromas,” said Jeffrey S. Dover, MD, codirector of SkinCare Physicians in Chestnut Hill, Mass., who was not involved with the study and was asked to comment on the results.
“Remarkably, all four treatments worked to varying degrees, but of all the treatments, the selective alexandrite laser appeared to achieve the best results. Further study will be needed to see just how effective these treatments are, and to determine the best and safest treatment parameters. Given how common this autosomal dominant disease is, and how disfiguring neurofibromas become as they enlarge, a well-tolerated noninvasive nonsurgical treatment with limited side effects is highly sought after.”
The study, which was named the best clinical abstract at the meeting, was supported by the Neurofibromatosis Therapeutic Acceleration Program. Dr. Anderson is supported in part as the Lancer Endowed Chair in Dermatology at MGH. Dr. Dover reported having no relevant disclosures.
PHOENIX – after only one treatment, according to preliminary results of an ongoing prospective trial that compared several treatment modalities.
“Neurofibromatosis type 1 is the most common single-gene disease of mankind, but there is so much we have yet to learn about it,” study author Patricia Richey, MD, who practices Mohs surgery and cosmetic dermatology in Washington, D.C., said in an interview in advance of the annual conference of the American Society for Laser Medicine and Surgery, where she presented the results during an abstract session. Dr. Richey also conducts research for the Wellman Center for Photomedicine and the Dermatology Laser and Cosmetic Center at Massachusetts General Hospital, Boston, and is working with R. Rox Anderson, MD, director of the Wellman Center, on this project. In his words, she said, “the lack of better treatments for cNF is a ‘problem worth solving.’ ”
“The accepted and widely available treatments for cNF result in scars and hypopigmentation. Our treatments do not,” she added. Since the epidermis overlying cNF is normal, “there is no reason to use nonselective or surgical methods and destroy a perfectly good epidermis when you don’t need to.”
Four treatments vs. controls
For the study, Dr. Richey and colleagues enrolled 19 adults with a total of 307 cNFs measuring 2-4 mm in size to receive one of four treatments: electrocautery with an insulated radiofrequency needle; 755-nm alexandrite laser with negative pressure (8-mm spot size, 100 J/cm2 fluence, 3-ms pulse duration); 980-nm diode laser (delivered via 8-mm sapphire skin-contact window), and intratumoral injection of 10 mg/mL deoxycholic acid at a volume approximately equal to that of the tumor. The average age of the participants was 49 years and 15 were female.
The investigators applied 5% lidocaine/prilocaine for 40 minutes to treatment sites before randomizing the tumors to treatment or to the control arm (no treatment). They compared safety, tolerability (including pain scores), and efficacy of each modality as measured by the change in cNF volume/height via three-dimensional imaging and clinical improvement via physician assessment at 6 months. All 19 participants have completed the 6-month assessment.
All modalities reduced or eliminated some of the cNFs by 6 months after treatment, with statistically significant reductions in height and volume across all four treatments. A wide variation of responses was observed. Specifically, the mean tumor volume changes for each modality, compared with controls, were –33.4% versus –5.1% among those treated with the 755-nm alexandrite laser; –24.9% versus –9.2% among those treated with the 980-nm diode laser, –23.3% versus –0.8% among those treated with insulated-needle radiofrequency coagulation, and –29.4% versus –3.7% among those treated with deoxycholic acid.
The variation in responses “may be due to histologic diversity of cNF or may indicate a need for more fine-tuned dosimetry, or a combination,” Dr. Richey said. “Our future trials will address this. We will also be treating all skin types in our upcoming trials.”
No adverse events categorized as higher than grade 2 occurred in any of the treatment groups, and no signs of regrowth or growth stimulation have been observed to date.
Tolerability of treatments
As for general tolerability, the 980-nm laser treatment caused moderate to severe pain; the alexandrite laser caused mild pain; insulated-needle radiofrequency coagulation caused mild pain, though more than deoxycholic acid injections or alexandrite laser, and pain associated with the deoxycholic acid injections was minimal.
When residual neurofibroma tumor was present histologically, its appearance was similar to that of untreated tumors in controls. There was no evidence of atypia, mitosis, or tumor inflammation, and mild fibrosis was present at the sites of prior tumor.
“It was surprising that all four modalities did work to some extent,” Dr. Richey said, noting that the lack of ulceration with deoxycholic acid injection “was pleasantly surprising.” Treatment with the 980-nm diode laser “was a bit more painful than we anticipated.”
The positive results of this trial has raised “more questions for us to answer. We have three additional trials in the works to fine tune these treatments and optimize dose/delivery, with the end goal of treating younger people.”
Dr. Richey said that she was “amazed” by how motivated the enrollees were to participate in the trial, noting that many patients with cNF undergo general anesthesia to have dozens of tumors surgically removed at once. “They pay $10,000-$20,000 on average out of pocket, as this surgery is considered cosmetic,” she said.
“This very important study could lead to effective, relatively noninvasive, therapy for small neurofibromas,” said Jeffrey S. Dover, MD, codirector of SkinCare Physicians in Chestnut Hill, Mass., who was not involved with the study and was asked to comment on the results.
“Remarkably, all four treatments worked to varying degrees, but of all the treatments, the selective alexandrite laser appeared to achieve the best results. Further study will be needed to see just how effective these treatments are, and to determine the best and safest treatment parameters. Given how common this autosomal dominant disease is, and how disfiguring neurofibromas become as they enlarge, a well-tolerated noninvasive nonsurgical treatment with limited side effects is highly sought after.”
The study, which was named the best clinical abstract at the meeting, was supported by the Neurofibromatosis Therapeutic Acceleration Program. Dr. Anderson is supported in part as the Lancer Endowed Chair in Dermatology at MGH. Dr. Dover reported having no relevant disclosures.
PHOENIX – after only one treatment, according to preliminary results of an ongoing prospective trial that compared several treatment modalities.
“Neurofibromatosis type 1 is the most common single-gene disease of mankind, but there is so much we have yet to learn about it,” study author Patricia Richey, MD, who practices Mohs surgery and cosmetic dermatology in Washington, D.C., said in an interview in advance of the annual conference of the American Society for Laser Medicine and Surgery, where she presented the results during an abstract session. Dr. Richey also conducts research for the Wellman Center for Photomedicine and the Dermatology Laser and Cosmetic Center at Massachusetts General Hospital, Boston, and is working with R. Rox Anderson, MD, director of the Wellman Center, on this project. In his words, she said, “the lack of better treatments for cNF is a ‘problem worth solving.’ ”
“The accepted and widely available treatments for cNF result in scars and hypopigmentation. Our treatments do not,” she added. Since the epidermis overlying cNF is normal, “there is no reason to use nonselective or surgical methods and destroy a perfectly good epidermis when you don’t need to.”
Four treatments vs. controls
For the study, Dr. Richey and colleagues enrolled 19 adults with a total of 307 cNFs measuring 2-4 mm in size to receive one of four treatments: electrocautery with an insulated radiofrequency needle; 755-nm alexandrite laser with negative pressure (8-mm spot size, 100 J/cm2 fluence, 3-ms pulse duration); 980-nm diode laser (delivered via 8-mm sapphire skin-contact window), and intratumoral injection of 10 mg/mL deoxycholic acid at a volume approximately equal to that of the tumor. The average age of the participants was 49 years and 15 were female.
The investigators applied 5% lidocaine/prilocaine for 40 minutes to treatment sites before randomizing the tumors to treatment or to the control arm (no treatment). They compared safety, tolerability (including pain scores), and efficacy of each modality as measured by the change in cNF volume/height via three-dimensional imaging and clinical improvement via physician assessment at 6 months. All 19 participants have completed the 6-month assessment.
All modalities reduced or eliminated some of the cNFs by 6 months after treatment, with statistically significant reductions in height and volume across all four treatments. A wide variation of responses was observed. Specifically, the mean tumor volume changes for each modality, compared with controls, were –33.4% versus –5.1% among those treated with the 755-nm alexandrite laser; –24.9% versus –9.2% among those treated with the 980-nm diode laser, –23.3% versus –0.8% among those treated with insulated-needle radiofrequency coagulation, and –29.4% versus –3.7% among those treated with deoxycholic acid.
The variation in responses “may be due to histologic diversity of cNF or may indicate a need for more fine-tuned dosimetry, or a combination,” Dr. Richey said. “Our future trials will address this. We will also be treating all skin types in our upcoming trials.”
No adverse events categorized as higher than grade 2 occurred in any of the treatment groups, and no signs of regrowth or growth stimulation have been observed to date.
Tolerability of treatments
As for general tolerability, the 980-nm laser treatment caused moderate to severe pain; the alexandrite laser caused mild pain; insulated-needle radiofrequency coagulation caused mild pain, though more than deoxycholic acid injections or alexandrite laser, and pain associated with the deoxycholic acid injections was minimal.
When residual neurofibroma tumor was present histologically, its appearance was similar to that of untreated tumors in controls. There was no evidence of atypia, mitosis, or tumor inflammation, and mild fibrosis was present at the sites of prior tumor.
“It was surprising that all four modalities did work to some extent,” Dr. Richey said, noting that the lack of ulceration with deoxycholic acid injection “was pleasantly surprising.” Treatment with the 980-nm diode laser “was a bit more painful than we anticipated.”
The positive results of this trial has raised “more questions for us to answer. We have three additional trials in the works to fine tune these treatments and optimize dose/delivery, with the end goal of treating younger people.”
Dr. Richey said that she was “amazed” by how motivated the enrollees were to participate in the trial, noting that many patients with cNF undergo general anesthesia to have dozens of tumors surgically removed at once. “They pay $10,000-$20,000 on average out of pocket, as this surgery is considered cosmetic,” she said.
“This very important study could lead to effective, relatively noninvasive, therapy for small neurofibromas,” said Jeffrey S. Dover, MD, codirector of SkinCare Physicians in Chestnut Hill, Mass., who was not involved with the study and was asked to comment on the results.
“Remarkably, all four treatments worked to varying degrees, but of all the treatments, the selective alexandrite laser appeared to achieve the best results. Further study will be needed to see just how effective these treatments are, and to determine the best and safest treatment parameters. Given how common this autosomal dominant disease is, and how disfiguring neurofibromas become as they enlarge, a well-tolerated noninvasive nonsurgical treatment with limited side effects is highly sought after.”
The study, which was named the best clinical abstract at the meeting, was supported by the Neurofibromatosis Therapeutic Acceleration Program. Dr. Anderson is supported in part as the Lancer Endowed Chair in Dermatology at MGH. Dr. Dover reported having no relevant disclosures.
AT ASLMS 2023
Insurers refusing MRI for women at high risk for breast cancer
Women harboring BRCA1/2 gene mutations are at high risk for breast cancer, and thus it’s recommended they undergo annual breast MRI screening in addition to mammogram screening.
However, some women are finding that their insurer is refusing to cover the cost of the MRI.
A new study exploring this issue was presented at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer.
“Despite guidelines supporting annual breast MRI for screening in patients with gBRCA1/2, insurance denials were present in 11% of patients,” said lead author Sushmita Gordhandas, MD, a gynecologic oncology fellow at Memorial Sloan Kettering Cancer Center, New York. “In a high-resource setting, up to 14% of patients who were denied coverage did not undergo recommended MRI screening.”
She also pointed out that the rate of denials was rising. “Compared to 2020, there were significantly more denials, and denials on appeal, in 2021,” Dr. Gordhandas said. “This suggested worsening barriers and added burden on health care systems.”
The addition of MRI to mammography is a standard recommendation for women with BRCA mutations, she pointed out, as it has been shown improve detection of early disease and decrease interval cancer development.
An expert not involved in the study noted that the recommendation for annual MRI screening in women at high risk for breast cancer is “substantiated by many publications, including multiple prospective clinical trials.”
Linda Moy, MD, a radiologist at NYU Langone’s Perlmutter Cancer Center and professor of radiology at NYU Grossman School of Medicine, both in New York, noted that the American Cancer Society’s Guidelines for screening breast MRI recommends annual breast MRI in women with a lifetime risk of greater than 20% – which includes women who are BRCA carriers – and recommends the screening begins at age 30.
“The lifetime breast cancer risk is 72% among BRCA1 and 69% among BRCA2 carriers,” she said, adding that the “American College of Radiology also recommends for BRCA carriers to undergo annual screening MRI at age 30.”
The National Comprehensive Cancer Network recommends that women at high risk for breast cancer undergo a mammogram and breast MRI every year starting at age 25 to 40, depending on the type of gene mutation, noted Dr. Gordhandas. “These guidelines are consistent with those from American College of Obstetricians and Gynecologists, the American Cancer Society, and the American College of Radiology.”
Denials increased over time
For the study, Dr. Gordhandas and colleagues looked at the frequency of insurance denials for indicated breast MRI screening in women with germline BRCA1/2 pathogenic variants, and also looked at recent trends in denials over time.
The cohort comprised 682 women with BRCA1/2 gene mutations who were followed in a specialized high-risk breast cancer clinic, and who had breast MRIs ordered from 2020 to 2021. They were then cross-referenced with a database of insurance denials. Radiology records were also accessed to determine if screening breast MRIs had been performed in 2020 and 2021, and rates of MRI denials and results after appeals were determined. The rates between the 2 years were then compared.
The team found that overall, 73 women (11%) had an MRI denied. The median age of women who received a denial was 38 years, whereas those who had it approved was 44 years. “Patients with denials were significantly younger and more likely to be in the Medicaid population,” said Dr. Gordhandas.
In 2020, 29 breast MRIs (5%) were denied, and on appeal, 8 (28%) were denied and 21 (72%) approved. The number of denials rose in 2021 but approvals remained the same; 45 breast MRIs were denied (8%); on appeal, 23 (51%) were denied, and 22 (49%) approved.
Thus, noted the authors, there were significantly more denials in 2021 as compared with 2020 (P = .044), and the denials in 2021 denials were statistically more likely to be denied on appeal (P = .045).
Among the women whose coverage was denied, four (14%) in 2020 and five (11%) in 2021 did not have an MRI screening performed. And within this group, 17 women (2.5%) received a diagnosis of cancer; 12 (1.8%) had invasive carcinoma, and 5 (0.7%) had ductal carcinoma in situ (DCIS). One patient with DCIS had an MRI denial prior to receiving her diagnosis.
“The top reasons given for denials were that they were outside the approved time frame, authorization on file for a similar study, and that the clinician failed to show medical necessity,” she explained.
Additional data are needed to establish a trend. “We are working to increase the approval time frame, which is currently 45 days, and provide resources for the patient to deal with denials,” Dr. Gordhandas added. “We also have to advocate for updates to [U.S. Preventive Services Task Force] screening recommendations in high-risk patients.”
Dr. Gordhandas reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Women harboring BRCA1/2 gene mutations are at high risk for breast cancer, and thus it’s recommended they undergo annual breast MRI screening in addition to mammogram screening.
However, some women are finding that their insurer is refusing to cover the cost of the MRI.
A new study exploring this issue was presented at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer.
“Despite guidelines supporting annual breast MRI for screening in patients with gBRCA1/2, insurance denials were present in 11% of patients,” said lead author Sushmita Gordhandas, MD, a gynecologic oncology fellow at Memorial Sloan Kettering Cancer Center, New York. “In a high-resource setting, up to 14% of patients who were denied coverage did not undergo recommended MRI screening.”
She also pointed out that the rate of denials was rising. “Compared to 2020, there were significantly more denials, and denials on appeal, in 2021,” Dr. Gordhandas said. “This suggested worsening barriers and added burden on health care systems.”
The addition of MRI to mammography is a standard recommendation for women with BRCA mutations, she pointed out, as it has been shown improve detection of early disease and decrease interval cancer development.
An expert not involved in the study noted that the recommendation for annual MRI screening in women at high risk for breast cancer is “substantiated by many publications, including multiple prospective clinical trials.”
Linda Moy, MD, a radiologist at NYU Langone’s Perlmutter Cancer Center and professor of radiology at NYU Grossman School of Medicine, both in New York, noted that the American Cancer Society’s Guidelines for screening breast MRI recommends annual breast MRI in women with a lifetime risk of greater than 20% – which includes women who are BRCA carriers – and recommends the screening begins at age 30.
“The lifetime breast cancer risk is 72% among BRCA1 and 69% among BRCA2 carriers,” she said, adding that the “American College of Radiology also recommends for BRCA carriers to undergo annual screening MRI at age 30.”
The National Comprehensive Cancer Network recommends that women at high risk for breast cancer undergo a mammogram and breast MRI every year starting at age 25 to 40, depending on the type of gene mutation, noted Dr. Gordhandas. “These guidelines are consistent with those from American College of Obstetricians and Gynecologists, the American Cancer Society, and the American College of Radiology.”
Denials increased over time
For the study, Dr. Gordhandas and colleagues looked at the frequency of insurance denials for indicated breast MRI screening in women with germline BRCA1/2 pathogenic variants, and also looked at recent trends in denials over time.
The cohort comprised 682 women with BRCA1/2 gene mutations who were followed in a specialized high-risk breast cancer clinic, and who had breast MRIs ordered from 2020 to 2021. They were then cross-referenced with a database of insurance denials. Radiology records were also accessed to determine if screening breast MRIs had been performed in 2020 and 2021, and rates of MRI denials and results after appeals were determined. The rates between the 2 years were then compared.
The team found that overall, 73 women (11%) had an MRI denied. The median age of women who received a denial was 38 years, whereas those who had it approved was 44 years. “Patients with denials were significantly younger and more likely to be in the Medicaid population,” said Dr. Gordhandas.
In 2020, 29 breast MRIs (5%) were denied, and on appeal, 8 (28%) were denied and 21 (72%) approved. The number of denials rose in 2021 but approvals remained the same; 45 breast MRIs were denied (8%); on appeal, 23 (51%) were denied, and 22 (49%) approved.
Thus, noted the authors, there were significantly more denials in 2021 as compared with 2020 (P = .044), and the denials in 2021 denials were statistically more likely to be denied on appeal (P = .045).
Among the women whose coverage was denied, four (14%) in 2020 and five (11%) in 2021 did not have an MRI screening performed. And within this group, 17 women (2.5%) received a diagnosis of cancer; 12 (1.8%) had invasive carcinoma, and 5 (0.7%) had ductal carcinoma in situ (DCIS). One patient with DCIS had an MRI denial prior to receiving her diagnosis.
“The top reasons given for denials were that they were outside the approved time frame, authorization on file for a similar study, and that the clinician failed to show medical necessity,” she explained.
Additional data are needed to establish a trend. “We are working to increase the approval time frame, which is currently 45 days, and provide resources for the patient to deal with denials,” Dr. Gordhandas added. “We also have to advocate for updates to [U.S. Preventive Services Task Force] screening recommendations in high-risk patients.”
Dr. Gordhandas reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Women harboring BRCA1/2 gene mutations are at high risk for breast cancer, and thus it’s recommended they undergo annual breast MRI screening in addition to mammogram screening.
However, some women are finding that their insurer is refusing to cover the cost of the MRI.
A new study exploring this issue was presented at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer.
“Despite guidelines supporting annual breast MRI for screening in patients with gBRCA1/2, insurance denials were present in 11% of patients,” said lead author Sushmita Gordhandas, MD, a gynecologic oncology fellow at Memorial Sloan Kettering Cancer Center, New York. “In a high-resource setting, up to 14% of patients who were denied coverage did not undergo recommended MRI screening.”
She also pointed out that the rate of denials was rising. “Compared to 2020, there were significantly more denials, and denials on appeal, in 2021,” Dr. Gordhandas said. “This suggested worsening barriers and added burden on health care systems.”
The addition of MRI to mammography is a standard recommendation for women with BRCA mutations, she pointed out, as it has been shown improve detection of early disease and decrease interval cancer development.
An expert not involved in the study noted that the recommendation for annual MRI screening in women at high risk for breast cancer is “substantiated by many publications, including multiple prospective clinical trials.”
Linda Moy, MD, a radiologist at NYU Langone’s Perlmutter Cancer Center and professor of radiology at NYU Grossman School of Medicine, both in New York, noted that the American Cancer Society’s Guidelines for screening breast MRI recommends annual breast MRI in women with a lifetime risk of greater than 20% – which includes women who are BRCA carriers – and recommends the screening begins at age 30.
“The lifetime breast cancer risk is 72% among BRCA1 and 69% among BRCA2 carriers,” she said, adding that the “American College of Radiology also recommends for BRCA carriers to undergo annual screening MRI at age 30.”
The National Comprehensive Cancer Network recommends that women at high risk for breast cancer undergo a mammogram and breast MRI every year starting at age 25 to 40, depending on the type of gene mutation, noted Dr. Gordhandas. “These guidelines are consistent with those from American College of Obstetricians and Gynecologists, the American Cancer Society, and the American College of Radiology.”
Denials increased over time
For the study, Dr. Gordhandas and colleagues looked at the frequency of insurance denials for indicated breast MRI screening in women with germline BRCA1/2 pathogenic variants, and also looked at recent trends in denials over time.
The cohort comprised 682 women with BRCA1/2 gene mutations who were followed in a specialized high-risk breast cancer clinic, and who had breast MRIs ordered from 2020 to 2021. They were then cross-referenced with a database of insurance denials. Radiology records were also accessed to determine if screening breast MRIs had been performed in 2020 and 2021, and rates of MRI denials and results after appeals were determined. The rates between the 2 years were then compared.
The team found that overall, 73 women (11%) had an MRI denied. The median age of women who received a denial was 38 years, whereas those who had it approved was 44 years. “Patients with denials were significantly younger and more likely to be in the Medicaid population,” said Dr. Gordhandas.
In 2020, 29 breast MRIs (5%) were denied, and on appeal, 8 (28%) were denied and 21 (72%) approved. The number of denials rose in 2021 but approvals remained the same; 45 breast MRIs were denied (8%); on appeal, 23 (51%) were denied, and 22 (49%) approved.
Thus, noted the authors, there were significantly more denials in 2021 as compared with 2020 (P = .044), and the denials in 2021 denials were statistically more likely to be denied on appeal (P = .045).
Among the women whose coverage was denied, four (14%) in 2020 and five (11%) in 2021 did not have an MRI screening performed. And within this group, 17 women (2.5%) received a diagnosis of cancer; 12 (1.8%) had invasive carcinoma, and 5 (0.7%) had ductal carcinoma in situ (DCIS). One patient with DCIS had an MRI denial prior to receiving her diagnosis.
“The top reasons given for denials were that they were outside the approved time frame, authorization on file for a similar study, and that the clinician failed to show medical necessity,” she explained.
Additional data are needed to establish a trend. “We are working to increase the approval time frame, which is currently 45 days, and provide resources for the patient to deal with denials,” Dr. Gordhandas added. “We also have to advocate for updates to [U.S. Preventive Services Task Force] screening recommendations in high-risk patients.”
Dr. Gordhandas reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM SGO 2023
Answers sought for mental health challenges in pediatric rheumatology patients
NEW ORLEANS – Pediatric patients with rheumatologic diseases experience a particularly high prevalence of psychological distress and depression and anxiety symptoms, according to research presented at the Pediatric Rheumatology Symposium. Although this finding is not necessarily surprising, the extent to which depression and psychological distress impacts these young patients’ quality of life has led to greater research and innovation in seeking ways to identify, address, and treat depression and anxiety in children and adolescents with diseases such as juvenile idiopathic arthritis (JIA) or systemic lupus erythematosus (SLE).
Accordingly, other studies presented at the conference examined more efficient ways to screen adolescent patients for depression and assessed programs designed to improve symptoms. In fact, the American College of Rheumatology award for the top Quality, Health Services, and Education Research abstract at this year’s symposium went to Lauren Harper, MD, a pediatric rheumatology fellow at Nationwide Children’s Hospital, Columbus, whose research examined the effects of automating depression screening during check-in for adolescent patients with SLE. Her findings revealed that automation of screening increased detection of depression and suicidality, thereby increasing interventions and ultimately resulting in a reduction in depression prevalence.
“The key clinical takeaway is that mental health screening is really important – it affects our patients in so many different ways – and it’s very doable in your rheumatology clinic,” Dr. Harper said in an interview. “It’s also important because they’re coming to us very frequently, but they don’t see their PCP [primary care provider] very often, so we can’t leave screening to the PCPs.”
Two other studies assessed the effectiveness of a 6-week cognitive-behavioral intervention for youth called Treatment and Education Approach for Childhood-Onset Lupus (TEACH). One study found that remote delivery of TEACH resulted in improved mood symptoms and reduced fatigue, and another found the program particularly effective in improving mood for patients deemed “high risk” because of greater depression and fatigue symptoms.
The impact of growing mental health problems has been enormous both in the pediatric rheumatology population and society at large, Daria Sosna, MSc, a research coordinator at the University of Calgary (Alta.), said in an interview as she visited the research posters related to psychological stress and depression.
“We need to do something,” said Ms. Sosna, whose department is currently applying for funding to develop a research project to improve mental health outcomes in adolescents with lupus. “This population, specifically, has higher numbers than anyone else does because they have chronic illness” – and those issues need to be addressed.
High psychological stress levels
The study looking at psychological stress in pediatric rheumatology patients, led by Natalie Rosenwasser, MD, of Seattle Children’s Hospital, relied on cross-sectional data from patients enrolled in two Childhood Arthritis and Rheumatology Research Alliance sites, one in Utah and one in Seattle. The average age of the 71 patients who completed the surveys was 13, and the researchers reported the findings in two separate age groups: those aged 13-17, who completed the surveys themselves, and those aged 8-12, whose parents completed the surveys. Nearly all the patients (94.4%) had JIA, but one had lupus and three had juvenile dermatomyositis.
The participants completed the Patient-Reported Outcomes Measurement Information System (PROMIS) for psychological stress, physical stress, and depressive symptoms. They also filled out the National Institutes of Health–Toolbox Perceived Stress survey, the 9-item Patient Health Questionnaire (PHQ-9), the Screen for Child Anxiety Related Disorders (SCARED), a visual analog scale for COVID-related distress, and a questionnaire asking about how receptive they were to mental health screening. The researchers determined that a score 1 standard deviation above the mean on the PROMIS and NIH-Toolbox assessments qualified as a high level of psychological stress.
“There are data that suggest that psychological stress can be a precursor to depression and anxiety, which raises the concern that not every patient who’s experiencing mental health symptoms is going to be picked up on traditional measures that meet that clinical threshold, but they may really need interventions to protect their mental health,” presenter Erin Treemarcki, DO, an assistant professor of pediatric rheumatology at the University of Utah, Salt Lake City, said in an interview. “Not every patient may necessarily need referral to a mental health specialist, but there are still potential interventions that we can do in the clinical setting to address mental health, which in turn can improve outcomes, including medication compliance and knowing how patients are feeling.”
More than one-third of the patients (39%) reported a high level of psychological stress, and 43% had elevated physical stress. Broken down by age, 26% of the teens and 15% of the younger patients reported high levels of perceived stress. The PROMIS only identified increased depressive symptoms in 26% of the participants, whereas more than half (54%) had a positive PHQ-9 depression screen. Furthermore, half the patients had SCARED scores (50%) that likely indicated anxiety disorder. Only 6% of patients reported severe stress specifically related to the pandemic, but most reported mild distress from the pandemic.
“Psychological stress was highly correlated with physical stress, perceived stress, depressive symptoms [PROMIS and PHQ-9], and anxiety,” the authors reported (P < .05). The authors next plan to expand their assessment to a third CARRA site and then explore the interaction between psychological distress and sociodemographic factors.
“There’s such an increase in mental health disorders right now, and we’re overwhelmed in general,” Ms. Sosna said in an interview. “There have to be interventions that approach this. We can use pharmacological approaches, we can use CBT, we can use a lot of these things that are very well established, and they’re absolutely fantastic, but we don’t necessarily have the resources or capabilities to do that all the time.”
Benefits of automated depression screening
To reduce the likelihood of depression screenings falling through the cracks during visits, Dr. Harper’s study assessed the impact of automating screens in an adolescent population. In her presentation, she noted previous research finding that nearly half of youth with lupus (47%) had depression, compared with 24% of adults with lupus. Pediatric patients have nearly three times the odds of depression and more than five times the odds of suicidal ideation, she told attendees. These mood disorders are correlated with greater physical disability, higher cardiovascular risk, more disease activity, higher risk of premature death, and decreased educational attainment, medication compliance, and quality of life.
Despite recommendations for depression screening from the U.S. Preventive Services Task Force and the American Academy of Pediatrics, only 2% of pediatric rheumatology patients are routinely screened for depression with a validated instrument, and only 7% of those with depressive symptoms are screened, according to a 2016 study that Dr. Harper cited. Yet the same study found that nearly all pediatric rheumatologists (95%) supported routine depression screening every 6-12 months. Hence her team’s decision to test whether automating screening improved their screening rates.
Their population included lupus patients aged 12 and older seen at Nationwide Children’s Hospital between 2014 and 2022. Initially, patients completed the PHQ-9 on paper, which was then transcribed into the electronic health record. The process became automated and administered on an iPad at every visit in 2022. Positive screens – those endorsing suicidality or with a score of at least 10 – caused an alert to pop up for clinicians during their workflow so that they would talk to the mental health team about the patient’s needs.
A total of 149 patients completed 529 screenings during the study’s 8 years. Only 1 patient completed a PHQ-9 in 2014, which increased to just 17 patients in 2017. Automation resulted in 225 screens (P < .01). Subsequently, positive screens increased from 0% in 2014 to 25%-30% in 2018-2021, but then fell to 12% in 2022 (P < .01). The median PHQ-9 score was 3; overall scores decreased as screening increased.
The overall incidence of positive screens during the study period was 20% and prevalence was 38%, the authors reported. Of the 10 automated alerts triggered by positive screens, 90% resulted in a meeting with a psychologist or social worker, and 90% completed a suicide risk assessment. The intrusive alert for clinicians requires them to acknowledge the alert, agreeing to initiate a risk assessment, before they can enter data into the patient’s chart.
The study findings reveal “that you can successfully screen a high-risk population using an automated, seamless process, and you can alert providers without too much disruption to their typical clinic flow,” Dr. Harper told attendees. “And all of these processes have led to sustainability for routine depression screening in our lupus clinic.”
Dr. Harper’s team next plans to expand the automated screenings to populations with other diseases, to add an automated screening for anxiety, and to explore how PHQ-9 scores correlate with disease activity.
Treating patients’ mental health
Another two other abstracts at the symposium looked at another option, the 6-week cognitive-behavioral TEACH program. Deborah Levy, MD, MS, an associate professor of pediatrics at the University of Toronto and the clinical director of rheumatology at The Hospital for Sick Children, and colleagues assessed the program’s success when delivered remotely to adolescent patients with lupus. Pilot testing with TEACH had already shown improvements in fatigue and mood, Dr. Levy told attendees, but barriers to in-person delivery limited its utility even before the pandemic, so this study aimed to determine a remote version’s feasibility and effects, compared with treatment as usual.
The randomized, controlled trial, led by Natoshia Cunningham, PhD, from Michigan State University, Grand Rapids, included 57 participants, aged 12-22, from seven U.S. and Canadian rheumatology sites. All had been diagnosed with childhood-onset SLE by age 18 and had elevated symptoms in fatigue, pain, or depression. A PROMIS Fatigue T score of 60 or greater indicated elevated fatigue scores, whereas a high pain score was at least a 3/10 on a visual analog scale, and a high depression T score was at least a 60 but not higher than 80 on the Children’s Depression Inventory–2 or the Beck Depression Inventory–II (depending on the patient’s age).
Patients with other chronic medical conditions, developmental delays, or untreated major psychiatric illness were excluded from the study, as were patients who were receiving overlapping treatment, such as cognitive-behavioral therapy for pain or mood. Thirty patients were randomly assigned to receive treatment as usual while 27 patients were assigned to participate in the remote TEACH program.
Nearly all the patients (94%) were female, but they were racially diverse, with 42% White, 28% Asian, 19% Black, 19% Hispanic, and 4% multiracial. The patients were an average 16 years old and had been diagnosed for a median 5 years. Three of the intervention’s six modules involved the caregivers or, for older patients, their partners if desired. The communication strategies taught in the program were also tailored to patients’ ages.
“All of these strategies are educational, cognitive, behavioral, mindfulness strategies that target fatigue [and] pain, and they also developed web content for participants to use on their own,” Dr. Levy told attendees.
The researchers had complete postassessment data from 88% of participants, but they also reported some of the statements made during qualitative interviews about the program’s feasibility.
“I think it makes people more aware of themselves to become a better version of themselves, whether that’s in their normal life or in handling a lupus kind of life,” one participant said about the program’s benefits. Another appreciated the “alternative ways of thinking,” including “being more mindful of my thoughts and how those kind of aggravate my stress.”
The quantitative findings revealed a statistically significant reduction in depressive symptoms and fatigue for TEACH participants, compared with treatment as usual. Mood scores fell by an average 13.7 points in the TEACH group, compared with a drop of 2.4 points in the treatment as usual group (P < .001). Scores for fatigue fell 9.16 points in the TEACH group and 2.93 in the control group (P = .003). No statistically significant difference showed up in pain scores between the groups, although pain, medication adherence, and disease activity did improve slightly more in the TEACH group.
In addition to the significant improvements in mood and fatigue, therefore, “completion of TEACH may be associated with improved medication adherence and disease activity versus treatment as usual,” Dr. Levy said.
A much smaller study authored by some of the same researchers also assessed TEACH’s impact not in remote form but in terms of its value specifically for adolescent patients with SLE and elevated depression and fatigue scores. Comparison of 6 high-risk patients with 10 low-risk patients who underwent TEACH suggested that the program was especially effective for improving depression in high-risk patients since these patients had a statistically significantly greater improvement in mood. Fatigue, pain, anxiety, quality of life, and disease activity scores did not statistically differ between the groups.
Authors of the automated depression screening study reported no disclosures or outside funding. The study assessing psychological distress was funded by a CARRA–Arthritis Foundation grant, and the authors reported no disclosures. The remote TEACH study was funded by a CARRA–Arthritis Foundation grant, and all but one author reported no disclosures. One author had disclosures with Janssen, Roche, and Sobi. The high-risk TEACH study was also funded by a CARRA grant, and the authors had no disclosures.
NEW ORLEANS – Pediatric patients with rheumatologic diseases experience a particularly high prevalence of psychological distress and depression and anxiety symptoms, according to research presented at the Pediatric Rheumatology Symposium. Although this finding is not necessarily surprising, the extent to which depression and psychological distress impacts these young patients’ quality of life has led to greater research and innovation in seeking ways to identify, address, and treat depression and anxiety in children and adolescents with diseases such as juvenile idiopathic arthritis (JIA) or systemic lupus erythematosus (SLE).
Accordingly, other studies presented at the conference examined more efficient ways to screen adolescent patients for depression and assessed programs designed to improve symptoms. In fact, the American College of Rheumatology award for the top Quality, Health Services, and Education Research abstract at this year’s symposium went to Lauren Harper, MD, a pediatric rheumatology fellow at Nationwide Children’s Hospital, Columbus, whose research examined the effects of automating depression screening during check-in for adolescent patients with SLE. Her findings revealed that automation of screening increased detection of depression and suicidality, thereby increasing interventions and ultimately resulting in a reduction in depression prevalence.
“The key clinical takeaway is that mental health screening is really important – it affects our patients in so many different ways – and it’s very doable in your rheumatology clinic,” Dr. Harper said in an interview. “It’s also important because they’re coming to us very frequently, but they don’t see their PCP [primary care provider] very often, so we can’t leave screening to the PCPs.”
Two other studies assessed the effectiveness of a 6-week cognitive-behavioral intervention for youth called Treatment and Education Approach for Childhood-Onset Lupus (TEACH). One study found that remote delivery of TEACH resulted in improved mood symptoms and reduced fatigue, and another found the program particularly effective in improving mood for patients deemed “high risk” because of greater depression and fatigue symptoms.
The impact of growing mental health problems has been enormous both in the pediatric rheumatology population and society at large, Daria Sosna, MSc, a research coordinator at the University of Calgary (Alta.), said in an interview as she visited the research posters related to psychological stress and depression.
“We need to do something,” said Ms. Sosna, whose department is currently applying for funding to develop a research project to improve mental health outcomes in adolescents with lupus. “This population, specifically, has higher numbers than anyone else does because they have chronic illness” – and those issues need to be addressed.
High psychological stress levels
The study looking at psychological stress in pediatric rheumatology patients, led by Natalie Rosenwasser, MD, of Seattle Children’s Hospital, relied on cross-sectional data from patients enrolled in two Childhood Arthritis and Rheumatology Research Alliance sites, one in Utah and one in Seattle. The average age of the 71 patients who completed the surveys was 13, and the researchers reported the findings in two separate age groups: those aged 13-17, who completed the surveys themselves, and those aged 8-12, whose parents completed the surveys. Nearly all the patients (94.4%) had JIA, but one had lupus and three had juvenile dermatomyositis.
The participants completed the Patient-Reported Outcomes Measurement Information System (PROMIS) for psychological stress, physical stress, and depressive symptoms. They also filled out the National Institutes of Health–Toolbox Perceived Stress survey, the 9-item Patient Health Questionnaire (PHQ-9), the Screen for Child Anxiety Related Disorders (SCARED), a visual analog scale for COVID-related distress, and a questionnaire asking about how receptive they were to mental health screening. The researchers determined that a score 1 standard deviation above the mean on the PROMIS and NIH-Toolbox assessments qualified as a high level of psychological stress.
“There are data that suggest that psychological stress can be a precursor to depression and anxiety, which raises the concern that not every patient who’s experiencing mental health symptoms is going to be picked up on traditional measures that meet that clinical threshold, but they may really need interventions to protect their mental health,” presenter Erin Treemarcki, DO, an assistant professor of pediatric rheumatology at the University of Utah, Salt Lake City, said in an interview. “Not every patient may necessarily need referral to a mental health specialist, but there are still potential interventions that we can do in the clinical setting to address mental health, which in turn can improve outcomes, including medication compliance and knowing how patients are feeling.”
More than one-third of the patients (39%) reported a high level of psychological stress, and 43% had elevated physical stress. Broken down by age, 26% of the teens and 15% of the younger patients reported high levels of perceived stress. The PROMIS only identified increased depressive symptoms in 26% of the participants, whereas more than half (54%) had a positive PHQ-9 depression screen. Furthermore, half the patients had SCARED scores (50%) that likely indicated anxiety disorder. Only 6% of patients reported severe stress specifically related to the pandemic, but most reported mild distress from the pandemic.
“Psychological stress was highly correlated with physical stress, perceived stress, depressive symptoms [PROMIS and PHQ-9], and anxiety,” the authors reported (P < .05). The authors next plan to expand their assessment to a third CARRA site and then explore the interaction between psychological distress and sociodemographic factors.
“There’s such an increase in mental health disorders right now, and we’re overwhelmed in general,” Ms. Sosna said in an interview. “There have to be interventions that approach this. We can use pharmacological approaches, we can use CBT, we can use a lot of these things that are very well established, and they’re absolutely fantastic, but we don’t necessarily have the resources or capabilities to do that all the time.”
Benefits of automated depression screening
To reduce the likelihood of depression screenings falling through the cracks during visits, Dr. Harper’s study assessed the impact of automating screens in an adolescent population. In her presentation, she noted previous research finding that nearly half of youth with lupus (47%) had depression, compared with 24% of adults with lupus. Pediatric patients have nearly three times the odds of depression and more than five times the odds of suicidal ideation, she told attendees. These mood disorders are correlated with greater physical disability, higher cardiovascular risk, more disease activity, higher risk of premature death, and decreased educational attainment, medication compliance, and quality of life.
Despite recommendations for depression screening from the U.S. Preventive Services Task Force and the American Academy of Pediatrics, only 2% of pediatric rheumatology patients are routinely screened for depression with a validated instrument, and only 7% of those with depressive symptoms are screened, according to a 2016 study that Dr. Harper cited. Yet the same study found that nearly all pediatric rheumatologists (95%) supported routine depression screening every 6-12 months. Hence her team’s decision to test whether automating screening improved their screening rates.
Their population included lupus patients aged 12 and older seen at Nationwide Children’s Hospital between 2014 and 2022. Initially, patients completed the PHQ-9 on paper, which was then transcribed into the electronic health record. The process became automated and administered on an iPad at every visit in 2022. Positive screens – those endorsing suicidality or with a score of at least 10 – caused an alert to pop up for clinicians during their workflow so that they would talk to the mental health team about the patient’s needs.
A total of 149 patients completed 529 screenings during the study’s 8 years. Only 1 patient completed a PHQ-9 in 2014, which increased to just 17 patients in 2017. Automation resulted in 225 screens (P < .01). Subsequently, positive screens increased from 0% in 2014 to 25%-30% in 2018-2021, but then fell to 12% in 2022 (P < .01). The median PHQ-9 score was 3; overall scores decreased as screening increased.
The overall incidence of positive screens during the study period was 20% and prevalence was 38%, the authors reported. Of the 10 automated alerts triggered by positive screens, 90% resulted in a meeting with a psychologist or social worker, and 90% completed a suicide risk assessment. The intrusive alert for clinicians requires them to acknowledge the alert, agreeing to initiate a risk assessment, before they can enter data into the patient’s chart.
The study findings reveal “that you can successfully screen a high-risk population using an automated, seamless process, and you can alert providers without too much disruption to their typical clinic flow,” Dr. Harper told attendees. “And all of these processes have led to sustainability for routine depression screening in our lupus clinic.”
Dr. Harper’s team next plans to expand the automated screenings to populations with other diseases, to add an automated screening for anxiety, and to explore how PHQ-9 scores correlate with disease activity.
Treating patients’ mental health
Another two other abstracts at the symposium looked at another option, the 6-week cognitive-behavioral TEACH program. Deborah Levy, MD, MS, an associate professor of pediatrics at the University of Toronto and the clinical director of rheumatology at The Hospital for Sick Children, and colleagues assessed the program’s success when delivered remotely to adolescent patients with lupus. Pilot testing with TEACH had already shown improvements in fatigue and mood, Dr. Levy told attendees, but barriers to in-person delivery limited its utility even before the pandemic, so this study aimed to determine a remote version’s feasibility and effects, compared with treatment as usual.
The randomized, controlled trial, led by Natoshia Cunningham, PhD, from Michigan State University, Grand Rapids, included 57 participants, aged 12-22, from seven U.S. and Canadian rheumatology sites. All had been diagnosed with childhood-onset SLE by age 18 and had elevated symptoms in fatigue, pain, or depression. A PROMIS Fatigue T score of 60 or greater indicated elevated fatigue scores, whereas a high pain score was at least a 3/10 on a visual analog scale, and a high depression T score was at least a 60 but not higher than 80 on the Children’s Depression Inventory–2 or the Beck Depression Inventory–II (depending on the patient’s age).
Patients with other chronic medical conditions, developmental delays, or untreated major psychiatric illness were excluded from the study, as were patients who were receiving overlapping treatment, such as cognitive-behavioral therapy for pain or mood. Thirty patients were randomly assigned to receive treatment as usual while 27 patients were assigned to participate in the remote TEACH program.
Nearly all the patients (94%) were female, but they were racially diverse, with 42% White, 28% Asian, 19% Black, 19% Hispanic, and 4% multiracial. The patients were an average 16 years old and had been diagnosed for a median 5 years. Three of the intervention’s six modules involved the caregivers or, for older patients, their partners if desired. The communication strategies taught in the program were also tailored to patients’ ages.
“All of these strategies are educational, cognitive, behavioral, mindfulness strategies that target fatigue [and] pain, and they also developed web content for participants to use on their own,” Dr. Levy told attendees.
The researchers had complete postassessment data from 88% of participants, but they also reported some of the statements made during qualitative interviews about the program’s feasibility.
“I think it makes people more aware of themselves to become a better version of themselves, whether that’s in their normal life or in handling a lupus kind of life,” one participant said about the program’s benefits. Another appreciated the “alternative ways of thinking,” including “being more mindful of my thoughts and how those kind of aggravate my stress.”
The quantitative findings revealed a statistically significant reduction in depressive symptoms and fatigue for TEACH participants, compared with treatment as usual. Mood scores fell by an average 13.7 points in the TEACH group, compared with a drop of 2.4 points in the treatment as usual group (P < .001). Scores for fatigue fell 9.16 points in the TEACH group and 2.93 in the control group (P = .003). No statistically significant difference showed up in pain scores between the groups, although pain, medication adherence, and disease activity did improve slightly more in the TEACH group.
In addition to the significant improvements in mood and fatigue, therefore, “completion of TEACH may be associated with improved medication adherence and disease activity versus treatment as usual,” Dr. Levy said.
A much smaller study authored by some of the same researchers also assessed TEACH’s impact not in remote form but in terms of its value specifically for adolescent patients with SLE and elevated depression and fatigue scores. Comparison of 6 high-risk patients with 10 low-risk patients who underwent TEACH suggested that the program was especially effective for improving depression in high-risk patients since these patients had a statistically significantly greater improvement in mood. Fatigue, pain, anxiety, quality of life, and disease activity scores did not statistically differ between the groups.
Authors of the automated depression screening study reported no disclosures or outside funding. The study assessing psychological distress was funded by a CARRA–Arthritis Foundation grant, and the authors reported no disclosures. The remote TEACH study was funded by a CARRA–Arthritis Foundation grant, and all but one author reported no disclosures. One author had disclosures with Janssen, Roche, and Sobi. The high-risk TEACH study was also funded by a CARRA grant, and the authors had no disclosures.
NEW ORLEANS – Pediatric patients with rheumatologic diseases experience a particularly high prevalence of psychological distress and depression and anxiety symptoms, according to research presented at the Pediatric Rheumatology Symposium. Although this finding is not necessarily surprising, the extent to which depression and psychological distress impacts these young patients’ quality of life has led to greater research and innovation in seeking ways to identify, address, and treat depression and anxiety in children and adolescents with diseases such as juvenile idiopathic arthritis (JIA) or systemic lupus erythematosus (SLE).
Accordingly, other studies presented at the conference examined more efficient ways to screen adolescent patients for depression and assessed programs designed to improve symptoms. In fact, the American College of Rheumatology award for the top Quality, Health Services, and Education Research abstract at this year’s symposium went to Lauren Harper, MD, a pediatric rheumatology fellow at Nationwide Children’s Hospital, Columbus, whose research examined the effects of automating depression screening during check-in for adolescent patients with SLE. Her findings revealed that automation of screening increased detection of depression and suicidality, thereby increasing interventions and ultimately resulting in a reduction in depression prevalence.
“The key clinical takeaway is that mental health screening is really important – it affects our patients in so many different ways – and it’s very doable in your rheumatology clinic,” Dr. Harper said in an interview. “It’s also important because they’re coming to us very frequently, but they don’t see their PCP [primary care provider] very often, so we can’t leave screening to the PCPs.”
Two other studies assessed the effectiveness of a 6-week cognitive-behavioral intervention for youth called Treatment and Education Approach for Childhood-Onset Lupus (TEACH). One study found that remote delivery of TEACH resulted in improved mood symptoms and reduced fatigue, and another found the program particularly effective in improving mood for patients deemed “high risk” because of greater depression and fatigue symptoms.
The impact of growing mental health problems has been enormous both in the pediatric rheumatology population and society at large, Daria Sosna, MSc, a research coordinator at the University of Calgary (Alta.), said in an interview as she visited the research posters related to psychological stress and depression.
“We need to do something,” said Ms. Sosna, whose department is currently applying for funding to develop a research project to improve mental health outcomes in adolescents with lupus. “This population, specifically, has higher numbers than anyone else does because they have chronic illness” – and those issues need to be addressed.
High psychological stress levels
The study looking at psychological stress in pediatric rheumatology patients, led by Natalie Rosenwasser, MD, of Seattle Children’s Hospital, relied on cross-sectional data from patients enrolled in two Childhood Arthritis and Rheumatology Research Alliance sites, one in Utah and one in Seattle. The average age of the 71 patients who completed the surveys was 13, and the researchers reported the findings in two separate age groups: those aged 13-17, who completed the surveys themselves, and those aged 8-12, whose parents completed the surveys. Nearly all the patients (94.4%) had JIA, but one had lupus and three had juvenile dermatomyositis.
The participants completed the Patient-Reported Outcomes Measurement Information System (PROMIS) for psychological stress, physical stress, and depressive symptoms. They also filled out the National Institutes of Health–Toolbox Perceived Stress survey, the 9-item Patient Health Questionnaire (PHQ-9), the Screen for Child Anxiety Related Disorders (SCARED), a visual analog scale for COVID-related distress, and a questionnaire asking about how receptive they were to mental health screening. The researchers determined that a score 1 standard deviation above the mean on the PROMIS and NIH-Toolbox assessments qualified as a high level of psychological stress.
“There are data that suggest that psychological stress can be a precursor to depression and anxiety, which raises the concern that not every patient who’s experiencing mental health symptoms is going to be picked up on traditional measures that meet that clinical threshold, but they may really need interventions to protect their mental health,” presenter Erin Treemarcki, DO, an assistant professor of pediatric rheumatology at the University of Utah, Salt Lake City, said in an interview. “Not every patient may necessarily need referral to a mental health specialist, but there are still potential interventions that we can do in the clinical setting to address mental health, which in turn can improve outcomes, including medication compliance and knowing how patients are feeling.”
More than one-third of the patients (39%) reported a high level of psychological stress, and 43% had elevated physical stress. Broken down by age, 26% of the teens and 15% of the younger patients reported high levels of perceived stress. The PROMIS only identified increased depressive symptoms in 26% of the participants, whereas more than half (54%) had a positive PHQ-9 depression screen. Furthermore, half the patients had SCARED scores (50%) that likely indicated anxiety disorder. Only 6% of patients reported severe stress specifically related to the pandemic, but most reported mild distress from the pandemic.
“Psychological stress was highly correlated with physical stress, perceived stress, depressive symptoms [PROMIS and PHQ-9], and anxiety,” the authors reported (P < .05). The authors next plan to expand their assessment to a third CARRA site and then explore the interaction between psychological distress and sociodemographic factors.
“There’s such an increase in mental health disorders right now, and we’re overwhelmed in general,” Ms. Sosna said in an interview. “There have to be interventions that approach this. We can use pharmacological approaches, we can use CBT, we can use a lot of these things that are very well established, and they’re absolutely fantastic, but we don’t necessarily have the resources or capabilities to do that all the time.”
Benefits of automated depression screening
To reduce the likelihood of depression screenings falling through the cracks during visits, Dr. Harper’s study assessed the impact of automating screens in an adolescent population. In her presentation, she noted previous research finding that nearly half of youth with lupus (47%) had depression, compared with 24% of adults with lupus. Pediatric patients have nearly three times the odds of depression and more than five times the odds of suicidal ideation, she told attendees. These mood disorders are correlated with greater physical disability, higher cardiovascular risk, more disease activity, higher risk of premature death, and decreased educational attainment, medication compliance, and quality of life.
Despite recommendations for depression screening from the U.S. Preventive Services Task Force and the American Academy of Pediatrics, only 2% of pediatric rheumatology patients are routinely screened for depression with a validated instrument, and only 7% of those with depressive symptoms are screened, according to a 2016 study that Dr. Harper cited. Yet the same study found that nearly all pediatric rheumatologists (95%) supported routine depression screening every 6-12 months. Hence her team’s decision to test whether automating screening improved their screening rates.
Their population included lupus patients aged 12 and older seen at Nationwide Children’s Hospital between 2014 and 2022. Initially, patients completed the PHQ-9 on paper, which was then transcribed into the electronic health record. The process became automated and administered on an iPad at every visit in 2022. Positive screens – those endorsing suicidality or with a score of at least 10 – caused an alert to pop up for clinicians during their workflow so that they would talk to the mental health team about the patient’s needs.
A total of 149 patients completed 529 screenings during the study’s 8 years. Only 1 patient completed a PHQ-9 in 2014, which increased to just 17 patients in 2017. Automation resulted in 225 screens (P < .01). Subsequently, positive screens increased from 0% in 2014 to 25%-30% in 2018-2021, but then fell to 12% in 2022 (P < .01). The median PHQ-9 score was 3; overall scores decreased as screening increased.
The overall incidence of positive screens during the study period was 20% and prevalence was 38%, the authors reported. Of the 10 automated alerts triggered by positive screens, 90% resulted in a meeting with a psychologist or social worker, and 90% completed a suicide risk assessment. The intrusive alert for clinicians requires them to acknowledge the alert, agreeing to initiate a risk assessment, before they can enter data into the patient’s chart.
The study findings reveal “that you can successfully screen a high-risk population using an automated, seamless process, and you can alert providers without too much disruption to their typical clinic flow,” Dr. Harper told attendees. “And all of these processes have led to sustainability for routine depression screening in our lupus clinic.”
Dr. Harper’s team next plans to expand the automated screenings to populations with other diseases, to add an automated screening for anxiety, and to explore how PHQ-9 scores correlate with disease activity.
Treating patients’ mental health
Another two other abstracts at the symposium looked at another option, the 6-week cognitive-behavioral TEACH program. Deborah Levy, MD, MS, an associate professor of pediatrics at the University of Toronto and the clinical director of rheumatology at The Hospital for Sick Children, and colleagues assessed the program’s success when delivered remotely to adolescent patients with lupus. Pilot testing with TEACH had already shown improvements in fatigue and mood, Dr. Levy told attendees, but barriers to in-person delivery limited its utility even before the pandemic, so this study aimed to determine a remote version’s feasibility and effects, compared with treatment as usual.
The randomized, controlled trial, led by Natoshia Cunningham, PhD, from Michigan State University, Grand Rapids, included 57 participants, aged 12-22, from seven U.S. and Canadian rheumatology sites. All had been diagnosed with childhood-onset SLE by age 18 and had elevated symptoms in fatigue, pain, or depression. A PROMIS Fatigue T score of 60 or greater indicated elevated fatigue scores, whereas a high pain score was at least a 3/10 on a visual analog scale, and a high depression T score was at least a 60 but not higher than 80 on the Children’s Depression Inventory–2 or the Beck Depression Inventory–II (depending on the patient’s age).
Patients with other chronic medical conditions, developmental delays, or untreated major psychiatric illness were excluded from the study, as were patients who were receiving overlapping treatment, such as cognitive-behavioral therapy for pain or mood. Thirty patients were randomly assigned to receive treatment as usual while 27 patients were assigned to participate in the remote TEACH program.
Nearly all the patients (94%) were female, but they were racially diverse, with 42% White, 28% Asian, 19% Black, 19% Hispanic, and 4% multiracial. The patients were an average 16 years old and had been diagnosed for a median 5 years. Three of the intervention’s six modules involved the caregivers or, for older patients, their partners if desired. The communication strategies taught in the program were also tailored to patients’ ages.
“All of these strategies are educational, cognitive, behavioral, mindfulness strategies that target fatigue [and] pain, and they also developed web content for participants to use on their own,” Dr. Levy told attendees.
The researchers had complete postassessment data from 88% of participants, but they also reported some of the statements made during qualitative interviews about the program’s feasibility.
“I think it makes people more aware of themselves to become a better version of themselves, whether that’s in their normal life or in handling a lupus kind of life,” one participant said about the program’s benefits. Another appreciated the “alternative ways of thinking,” including “being more mindful of my thoughts and how those kind of aggravate my stress.”
The quantitative findings revealed a statistically significant reduction in depressive symptoms and fatigue for TEACH participants, compared with treatment as usual. Mood scores fell by an average 13.7 points in the TEACH group, compared with a drop of 2.4 points in the treatment as usual group (P < .001). Scores for fatigue fell 9.16 points in the TEACH group and 2.93 in the control group (P = .003). No statistically significant difference showed up in pain scores between the groups, although pain, medication adherence, and disease activity did improve slightly more in the TEACH group.
In addition to the significant improvements in mood and fatigue, therefore, “completion of TEACH may be associated with improved medication adherence and disease activity versus treatment as usual,” Dr. Levy said.
A much smaller study authored by some of the same researchers also assessed TEACH’s impact not in remote form but in terms of its value specifically for adolescent patients with SLE and elevated depression and fatigue scores. Comparison of 6 high-risk patients with 10 low-risk patients who underwent TEACH suggested that the program was especially effective for improving depression in high-risk patients since these patients had a statistically significantly greater improvement in mood. Fatigue, pain, anxiety, quality of life, and disease activity scores did not statistically differ between the groups.
Authors of the automated depression screening study reported no disclosures or outside funding. The study assessing psychological distress was funded by a CARRA–Arthritis Foundation grant, and the authors reported no disclosures. The remote TEACH study was funded by a CARRA–Arthritis Foundation grant, and all but one author reported no disclosures. One author had disclosures with Janssen, Roche, and Sobi. The high-risk TEACH study was also funded by a CARRA grant, and the authors had no disclosures.
AT PRSYM 2023