User login
MDedge conference coverage features onsite reporting of the latest study results and expert perspectives from leading researchers.
COVID-19 risks in rheumatic disease remain unclear
ACR 2020 studies offer conflicting findings.
Among people with COVID-19, those with systemic autoimmune rheumatic diseases had an elevated 30-day risk of hospitalization, ICU admission, need for mechanical ventilation, and acute kidney injury, compared to a group without rheumatic diseases at 4 months in a match-controlled study.
When investigators expanded the study to 6 months, the difference in need for mechanical ventilation disappeared. However, relative risk for venous thromboembolism (VTE) emerged as 74% higher among people with COVID-19 and with rheumatic disease, said Kristin D’Silva, MD, who presented the findings during a plenary session at the virtual annual meeting of the American College of Rheumatology. She noted that rheumatic disease itself could contribute to VTE risk.
Comorbidities including hypertension, diabetes, and asthma were more common among people with systemic autoimmune rheumatic diseases (SARDs). After adjustment for comorbidities, “the risks of hospitalization and ICU admission were attenuated, suggesting comorbidities are likely key mediators of the increased risk of severe COVID-19 outcomes observed in SARDs patients versus comparators,” Dr. D’Silva, a rheumatology fellow at Massachusetts General Hospital in Boston, said in an interview.
“The risk of venous thromboembolism persisted even after adjusting for comorbidities,” Dr. D’Silva said. Patients with SARDs should be closely monitored for VTE during COVID-19 infection, she added. “Patients with significant cardiovascular, pulmonary, and metabolic comorbidities should be closely monitored for severe COVID-19.”
At the same time, a systematic review of 15 published studies revealed a low incidence of COVID-19 infection among people with rheumatic disease. Furthermore, most experienced a mild clinical course and low mortality, Akhil Sood, MD, said when presenting results of his poster at the meeting.
Underlying immunosuppression, chronic inflammation, comorbidities, and disparities based on racial, ethnic, and socioeconomic status could predispose people with rheumatic disease to poorer COVID-19 outcomes. However, the risks and outcomes of COVID-19 infection among this population “are not well understood,” said Dr. Sood, a second-year resident in internal medicine at the University of Texas Medical Branch in Galveston.
Elevated risks in match-controlled study
Dr. D’Silva and colleagues examined a COVID-19 population and compared 716 people with SARDs and another 716 people from the general public at 4 months, as well as 2,379 people each in similar groups at 6 months. They used real-time electronic medical record data from the TriNetX research network to identify ICD-10 codes for inflammatory arthritis, connective tissue diseases, and systemic vasculitis. They also used ICD-10 codes and positive PCR tests to identify people with COVID-19.
Mean age was 57 years and women accounted for 79% of both groups evaluated at 4 months. Those with SARDs were 23% more likely to be hospitalized (relative risk, 1.23; 95% confidence interval, 1.01-1.50). This group was 75% more likely to be admitted to the ICU (RR, 1.75; 95% CI, 1.11-2.75), 77% more likely to require mechanical ventilation (RR, 1.77; 95% CI, 1.06-2.96), and 83% more likely to experience acute kidney injury (RR, 1.83; 95% CI, 1.11-3.00).
Risk of death was not significantly higher in the SARDs group (RR, 1.16; 95% CI, 0.73-1.86).
When Dr. D’Silva expanded the study to more people at 6 months, they added additional 30-day outcomes of interest: renal replacement therapy, VTE, and ischemic stroke. Risk of need for renal replacement therapy, for example, was 81% higher in the SARDs group (RR, 1.81; 95% CI, 1.07-3.07). Risk of stroke was not significantly different between groups.The improvement in mechanical ventilation risk between 4 and 6 months was not completely unexpected, Dr. D’Silva said. The relative risk dropped from 1.77 to 1.05. “This is not particularly surprising given national trends in the general population reporting decreased severe outcomes of COVID-19 including mortality as the pandemic progresses. This is likely multifactorial including changes in COVID-19 management (such as increasing use of nonintubated prone positioning rather than early intubation and treatments such as dexamethasone and remdesivir), decreased strain on hospitals and staffing compared to the early crisis phase of the pandemic, and higher testing capacity leading to detection of milder cases.”
When the 6-month analysis was further adjusted for comorbidities and a history of prior hospitalization within 1 year, only risk for acute kidney injury and VTE remained significant with relative risks of 1.33 and 1.60, respectively, likely because comorbidities are causal intermediates of COVID-19 30-day outcomes rather than confounders.
When asked to comment on the results, session comoderator Victoria K. Shanmugam, MD, said in an interview that the study “is of great interest both to rheumatologists and to patients with rheumatic disease.”
The higher risk of hospitalization, ICU admission, mechanical ventilation, acute kidney injury, and heart failure “is an important finding with implications for how our patients navigate risk during this pandemic,” said Dr. Shanmugam, director of the division of rheumatology at George Washington University in Washington.
Lower risks emerge in systematic review
The 15 observational studies in the systematic review included 11,815 participants. A total of 179, or 1.5%, tested positive for COVID-19.
“The incidence of COVID-19 infection among patients with rheumatic disease was low,” Dr. Sood said.
Within the COVID-19-positive group, almost 50% required hospitalization, 10% required ICU admission, and 8% died. The pooled event rate for hospitalization was 0.440 (95% CI, 0.296-0.596), while for ICU admission it was 0.132 (95% CI, 0.087-0.194) and for death it was 0.125 (95% CI, 0.082-0.182).
Different calculations of risk
The two studies seem to offer contradictory findings, but the disparities could be explained by study design differences. For example, Dr. D’Silva’s study evaluated a population with COVID-19 and compared those with SARDs versus a matched group from the general public. Dr. Sood and colleagues assessed study populations with rheumatic disease and assessed incidence of SARS-CoV-2 infection and difference in outcomes.
“We are asking very different questions,” Dr. D’Silva said.
“The study by D’Silva et al. was able to account for different factors to reduce confounding,” Dr. Sood said, adding that Dr. D’Silva and colleagues included a high proportion of minorities, compared with a less diverse population in the systematic review, which featured a large number of studies from Italy.
The authors of the two studies had no relevant financial disclosures to report.
SOURCES: D’Silva K et al. Arthritis Rheumatol. 2020;72(suppl 10): Abstract 0430, and Sood A et al. Arthritis Rheumatol. 2020;72(suppl 10): Abstract 0008.
ACR 2020 studies offer conflicting findings.
ACR 2020 studies offer conflicting findings.
Among people with COVID-19, those with systemic autoimmune rheumatic diseases had an elevated 30-day risk of hospitalization, ICU admission, need for mechanical ventilation, and acute kidney injury, compared to a group without rheumatic diseases at 4 months in a match-controlled study.
When investigators expanded the study to 6 months, the difference in need for mechanical ventilation disappeared. However, relative risk for venous thromboembolism (VTE) emerged as 74% higher among people with COVID-19 and with rheumatic disease, said Kristin D’Silva, MD, who presented the findings during a plenary session at the virtual annual meeting of the American College of Rheumatology. She noted that rheumatic disease itself could contribute to VTE risk.
Comorbidities including hypertension, diabetes, and asthma were more common among people with systemic autoimmune rheumatic diseases (SARDs). After adjustment for comorbidities, “the risks of hospitalization and ICU admission were attenuated, suggesting comorbidities are likely key mediators of the increased risk of severe COVID-19 outcomes observed in SARDs patients versus comparators,” Dr. D’Silva, a rheumatology fellow at Massachusetts General Hospital in Boston, said in an interview.
“The risk of venous thromboembolism persisted even after adjusting for comorbidities,” Dr. D’Silva said. Patients with SARDs should be closely monitored for VTE during COVID-19 infection, she added. “Patients with significant cardiovascular, pulmonary, and metabolic comorbidities should be closely monitored for severe COVID-19.”
At the same time, a systematic review of 15 published studies revealed a low incidence of COVID-19 infection among people with rheumatic disease. Furthermore, most experienced a mild clinical course and low mortality, Akhil Sood, MD, said when presenting results of his poster at the meeting.
Underlying immunosuppression, chronic inflammation, comorbidities, and disparities based on racial, ethnic, and socioeconomic status could predispose people with rheumatic disease to poorer COVID-19 outcomes. However, the risks and outcomes of COVID-19 infection among this population “are not well understood,” said Dr. Sood, a second-year resident in internal medicine at the University of Texas Medical Branch in Galveston.
Elevated risks in match-controlled study
Dr. D’Silva and colleagues examined a COVID-19 population and compared 716 people with SARDs and another 716 people from the general public at 4 months, as well as 2,379 people each in similar groups at 6 months. They used real-time electronic medical record data from the TriNetX research network to identify ICD-10 codes for inflammatory arthritis, connective tissue diseases, and systemic vasculitis. They also used ICD-10 codes and positive PCR tests to identify people with COVID-19.
Mean age was 57 years and women accounted for 79% of both groups evaluated at 4 months. Those with SARDs were 23% more likely to be hospitalized (relative risk, 1.23; 95% confidence interval, 1.01-1.50). This group was 75% more likely to be admitted to the ICU (RR, 1.75; 95% CI, 1.11-2.75), 77% more likely to require mechanical ventilation (RR, 1.77; 95% CI, 1.06-2.96), and 83% more likely to experience acute kidney injury (RR, 1.83; 95% CI, 1.11-3.00).
Risk of death was not significantly higher in the SARDs group (RR, 1.16; 95% CI, 0.73-1.86).
When Dr. D’Silva expanded the study to more people at 6 months, they added additional 30-day outcomes of interest: renal replacement therapy, VTE, and ischemic stroke. Risk of need for renal replacement therapy, for example, was 81% higher in the SARDs group (RR, 1.81; 95% CI, 1.07-3.07). Risk of stroke was not significantly different between groups.The improvement in mechanical ventilation risk between 4 and 6 months was not completely unexpected, Dr. D’Silva said. The relative risk dropped from 1.77 to 1.05. “This is not particularly surprising given national trends in the general population reporting decreased severe outcomes of COVID-19 including mortality as the pandemic progresses. This is likely multifactorial including changes in COVID-19 management (such as increasing use of nonintubated prone positioning rather than early intubation and treatments such as dexamethasone and remdesivir), decreased strain on hospitals and staffing compared to the early crisis phase of the pandemic, and higher testing capacity leading to detection of milder cases.”
When the 6-month analysis was further adjusted for comorbidities and a history of prior hospitalization within 1 year, only risk for acute kidney injury and VTE remained significant with relative risks of 1.33 and 1.60, respectively, likely because comorbidities are causal intermediates of COVID-19 30-day outcomes rather than confounders.
When asked to comment on the results, session comoderator Victoria K. Shanmugam, MD, said in an interview that the study “is of great interest both to rheumatologists and to patients with rheumatic disease.”
The higher risk of hospitalization, ICU admission, mechanical ventilation, acute kidney injury, and heart failure “is an important finding with implications for how our patients navigate risk during this pandemic,” said Dr. Shanmugam, director of the division of rheumatology at George Washington University in Washington.
Lower risks emerge in systematic review
The 15 observational studies in the systematic review included 11,815 participants. A total of 179, or 1.5%, tested positive for COVID-19.
“The incidence of COVID-19 infection among patients with rheumatic disease was low,” Dr. Sood said.
Within the COVID-19-positive group, almost 50% required hospitalization, 10% required ICU admission, and 8% died. The pooled event rate for hospitalization was 0.440 (95% CI, 0.296-0.596), while for ICU admission it was 0.132 (95% CI, 0.087-0.194) and for death it was 0.125 (95% CI, 0.082-0.182).
Different calculations of risk
The two studies seem to offer contradictory findings, but the disparities could be explained by study design differences. For example, Dr. D’Silva’s study evaluated a population with COVID-19 and compared those with SARDs versus a matched group from the general public. Dr. Sood and colleagues assessed study populations with rheumatic disease and assessed incidence of SARS-CoV-2 infection and difference in outcomes.
“We are asking very different questions,” Dr. D’Silva said.
“The study by D’Silva et al. was able to account for different factors to reduce confounding,” Dr. Sood said, adding that Dr. D’Silva and colleagues included a high proportion of minorities, compared with a less diverse population in the systematic review, which featured a large number of studies from Italy.
The authors of the two studies had no relevant financial disclosures to report.
SOURCES: D’Silva K et al. Arthritis Rheumatol. 2020;72(suppl 10): Abstract 0430, and Sood A et al. Arthritis Rheumatol. 2020;72(suppl 10): Abstract 0008.
Among people with COVID-19, those with systemic autoimmune rheumatic diseases had an elevated 30-day risk of hospitalization, ICU admission, need for mechanical ventilation, and acute kidney injury, compared to a group without rheumatic diseases at 4 months in a match-controlled study.
When investigators expanded the study to 6 months, the difference in need for mechanical ventilation disappeared. However, relative risk for venous thromboembolism (VTE) emerged as 74% higher among people with COVID-19 and with rheumatic disease, said Kristin D’Silva, MD, who presented the findings during a plenary session at the virtual annual meeting of the American College of Rheumatology. She noted that rheumatic disease itself could contribute to VTE risk.
Comorbidities including hypertension, diabetes, and asthma were more common among people with systemic autoimmune rheumatic diseases (SARDs). After adjustment for comorbidities, “the risks of hospitalization and ICU admission were attenuated, suggesting comorbidities are likely key mediators of the increased risk of severe COVID-19 outcomes observed in SARDs patients versus comparators,” Dr. D’Silva, a rheumatology fellow at Massachusetts General Hospital in Boston, said in an interview.
“The risk of venous thromboembolism persisted even after adjusting for comorbidities,” Dr. D’Silva said. Patients with SARDs should be closely monitored for VTE during COVID-19 infection, she added. “Patients with significant cardiovascular, pulmonary, and metabolic comorbidities should be closely monitored for severe COVID-19.”
At the same time, a systematic review of 15 published studies revealed a low incidence of COVID-19 infection among people with rheumatic disease. Furthermore, most experienced a mild clinical course and low mortality, Akhil Sood, MD, said when presenting results of his poster at the meeting.
Underlying immunosuppression, chronic inflammation, comorbidities, and disparities based on racial, ethnic, and socioeconomic status could predispose people with rheumatic disease to poorer COVID-19 outcomes. However, the risks and outcomes of COVID-19 infection among this population “are not well understood,” said Dr. Sood, a second-year resident in internal medicine at the University of Texas Medical Branch in Galveston.
Elevated risks in match-controlled study
Dr. D’Silva and colleagues examined a COVID-19 population and compared 716 people with SARDs and another 716 people from the general public at 4 months, as well as 2,379 people each in similar groups at 6 months. They used real-time electronic medical record data from the TriNetX research network to identify ICD-10 codes for inflammatory arthritis, connective tissue diseases, and systemic vasculitis. They also used ICD-10 codes and positive PCR tests to identify people with COVID-19.
Mean age was 57 years and women accounted for 79% of both groups evaluated at 4 months. Those with SARDs were 23% more likely to be hospitalized (relative risk, 1.23; 95% confidence interval, 1.01-1.50). This group was 75% more likely to be admitted to the ICU (RR, 1.75; 95% CI, 1.11-2.75), 77% more likely to require mechanical ventilation (RR, 1.77; 95% CI, 1.06-2.96), and 83% more likely to experience acute kidney injury (RR, 1.83; 95% CI, 1.11-3.00).
Risk of death was not significantly higher in the SARDs group (RR, 1.16; 95% CI, 0.73-1.86).
When Dr. D’Silva expanded the study to more people at 6 months, they added additional 30-day outcomes of interest: renal replacement therapy, VTE, and ischemic stroke. Risk of need for renal replacement therapy, for example, was 81% higher in the SARDs group (RR, 1.81; 95% CI, 1.07-3.07). Risk of stroke was not significantly different between groups.The improvement in mechanical ventilation risk between 4 and 6 months was not completely unexpected, Dr. D’Silva said. The relative risk dropped from 1.77 to 1.05. “This is not particularly surprising given national trends in the general population reporting decreased severe outcomes of COVID-19 including mortality as the pandemic progresses. This is likely multifactorial including changes in COVID-19 management (such as increasing use of nonintubated prone positioning rather than early intubation and treatments such as dexamethasone and remdesivir), decreased strain on hospitals and staffing compared to the early crisis phase of the pandemic, and higher testing capacity leading to detection of milder cases.”
When the 6-month analysis was further adjusted for comorbidities and a history of prior hospitalization within 1 year, only risk for acute kidney injury and VTE remained significant with relative risks of 1.33 and 1.60, respectively, likely because comorbidities are causal intermediates of COVID-19 30-day outcomes rather than confounders.
When asked to comment on the results, session comoderator Victoria K. Shanmugam, MD, said in an interview that the study “is of great interest both to rheumatologists and to patients with rheumatic disease.”
The higher risk of hospitalization, ICU admission, mechanical ventilation, acute kidney injury, and heart failure “is an important finding with implications for how our patients navigate risk during this pandemic,” said Dr. Shanmugam, director of the division of rheumatology at George Washington University in Washington.
Lower risks emerge in systematic review
The 15 observational studies in the systematic review included 11,815 participants. A total of 179, or 1.5%, tested positive for COVID-19.
“The incidence of COVID-19 infection among patients with rheumatic disease was low,” Dr. Sood said.
Within the COVID-19-positive group, almost 50% required hospitalization, 10% required ICU admission, and 8% died. The pooled event rate for hospitalization was 0.440 (95% CI, 0.296-0.596), while for ICU admission it was 0.132 (95% CI, 0.087-0.194) and for death it was 0.125 (95% CI, 0.082-0.182).
Different calculations of risk
The two studies seem to offer contradictory findings, but the disparities could be explained by study design differences. For example, Dr. D’Silva’s study evaluated a population with COVID-19 and compared those with SARDs versus a matched group from the general public. Dr. Sood and colleagues assessed study populations with rheumatic disease and assessed incidence of SARS-CoV-2 infection and difference in outcomes.
“We are asking very different questions,” Dr. D’Silva said.
“The study by D’Silva et al. was able to account for different factors to reduce confounding,” Dr. Sood said, adding that Dr. D’Silva and colleagues included a high proportion of minorities, compared with a less diverse population in the systematic review, which featured a large number of studies from Italy.
The authors of the two studies had no relevant financial disclosures to report.
SOURCES: D’Silva K et al. Arthritis Rheumatol. 2020;72(suppl 10): Abstract 0430, and Sood A et al. Arthritis Rheumatol. 2020;72(suppl 10): Abstract 0008.
FROM ACR 2020
Distinguish ‘sleepiness’ from ‘fatigue’ to help diagnose hypersomnia
, according to Ruth M. Benca, MD, PhD.
Fatigue, feeling tired, and lack of energy are common complaints that accompany insomnia and psychiatric disorders, but these patients do not fall asleep quickly in a restful setting and will have normal multiple sleep latency test (MSLT) in a laboratory. In contrast, excessive sleepiness, or hypersomnia, occurs when patients sleep more than 11 hours in a 24-hour period.
Patients with hypersomnia fall asleep in low stimulus situations and devote more energy to staying awake during situations. This excessive sleepiness can be dangerous in the context of activities such as driving, Dr. Benca said. These patients will also have low sleep latencies (< 8 minutes) when tested through MSLT in a laboratory, she added. Patients with hypersomnia may be irritable, have reduced attention or concentration, and have poor memory.
The primary cause of hypersomnia is sleep deprivation, but “both hypersomnia and fatigue are common complaints in psychiatric patients, including depression, bipolar disorder, seasonal affective disorder, [and] psychosis,” Dr. Benca explained. Other causes of hypersomnia include sleep disorders such as sleep apnea, circadian rhythm disorders and periodic limb movements, neurologic or degenerative disorders, mental disorders, and effects of medication. Idiopathic hypersomnia and narcolepsy are uncommon causes of hypersomnia and usually diagnosed in a sleep laboratory setting, she said.
In patients with depression, hypersomnia looks like patients having “nonimperative sleepiness,” Dr. Benca said. “They may spend a lot of time in bed; they may report long and nonrefreshing naps or long sleep time.”
There also is an issue with sleep inertia in patients with depression and hypersomnia, and with patients taking a long time to wake up and begin their day. In these patients, “when we put them in the sleep laboratory, the objective studies generally do not show that they are excessively sleepy, despite their reports of subjectively being sleepy,” she said.
There is not much objective MSLT or subjective measure data for hypersomnia in patients with schizophrenia despite these patients reporting daytime sleepiness or hypersomnolence, Dr. Benca admitted. Hypersomnia in patients with schizophrenia may be related to drug effects, poor sleep hygiene, circadian rhythm abnormalities, or comorbid sleep disorders. “Excessive sleepiness may also be related to the schizophrenia itself,” she said.
Treatments for hypersomnia
The first priority for patients with hypersomnia is to avoid sleep deprivation and practice good sleep hygiene – factors that are important both in insomnia and hypersomnia. “Make sure that patients are having adequate time in bed and having regular hours of sleep,” Dr. Benca said.
For patients with comorbid psychiatric, medical and sleep disorders, focus on getting rid of medications that may cause sleepiness, including sedating medications and antidepressants, and consider using stimulants if appropriate. While there are Food and Drug Administration–approved medications for narcolepsy and some are approved for hypersomnia in patients with obstructive sleep apnea (OSA), none are officially approved to treat hypersomnia in psychiatric patients.
“Whenever we use these drugs for those reasons, we’re using them off label,” Dr. Benca said.
Modafinil/armodafinil, approved for narcolepsy, shift-work disorder, and OSA in Ehlers-Danlos syndrome, is one off-label option for patients with hypersomnia. “They are lower potency and less addictive than the amphetamines, [with] fewer side effects,” Dr. Benca explained, but should be prescribed with caution in some women because of potential reduced efficacy of oral contraceptives. Side effects of modafinil include headache, nausea, eosinophilia, diarrhea, dry mouth, and anorexia.
Methylphenidate is another option for hypersomnia, available in racemic mixture, pure D-isomer, and time-release formulations.
Patients taking methylphenidate may experience nervousness, insomnia, anorexia, nausea, dizziness, hypertension, hypotension, hypersensitivity reactions, tachycardia, and headache as side effects.
For patients with central nervous system hypersomnias, amphetamines can be used, with methamphetamines having a “very similar profile” and similar side effects, including insomnia, restlessness, tachycardia, dizziness, diarrhea, constipation, hypertension, impotence, and rare cases of psychotic episodes.
Practice parameters released by the American Academy of Sleep Medicine in 2007 suggest that modafinil may have efficacy in idiopathic hypersomnia, Parkinson’s disease, myotonic dystrophy, and multiple sclerosis. The practice parameters also suggest hypersomnias of central origin can be treated with modafinil, amphetamine, methamphetamine, dextroamphetamine, and methylphenidate based on evidence or “long history of use” (Sleep. 2007;30:1705-11).
“Interestingly, there is no mention of psychiatric disorders in these practice parameters, and they report that there are mixed results using stimulants off label for sleepiness and fatigue in traumatic brain injury and poststroke fatigue,” Dr. Benca said.
Dr. Benca reported that she is a consultant to Eisai, Idorsia, Jazz, Merck, and Sunovion. Global Academy and this news organization are owned by the same parent company.
, according to Ruth M. Benca, MD, PhD.
Fatigue, feeling tired, and lack of energy are common complaints that accompany insomnia and psychiatric disorders, but these patients do not fall asleep quickly in a restful setting and will have normal multiple sleep latency test (MSLT) in a laboratory. In contrast, excessive sleepiness, or hypersomnia, occurs when patients sleep more than 11 hours in a 24-hour period.
Patients with hypersomnia fall asleep in low stimulus situations and devote more energy to staying awake during situations. This excessive sleepiness can be dangerous in the context of activities such as driving, Dr. Benca said. These patients will also have low sleep latencies (< 8 minutes) when tested through MSLT in a laboratory, she added. Patients with hypersomnia may be irritable, have reduced attention or concentration, and have poor memory.
The primary cause of hypersomnia is sleep deprivation, but “both hypersomnia and fatigue are common complaints in psychiatric patients, including depression, bipolar disorder, seasonal affective disorder, [and] psychosis,” Dr. Benca explained. Other causes of hypersomnia include sleep disorders such as sleep apnea, circadian rhythm disorders and periodic limb movements, neurologic or degenerative disorders, mental disorders, and effects of medication. Idiopathic hypersomnia and narcolepsy are uncommon causes of hypersomnia and usually diagnosed in a sleep laboratory setting, she said.
In patients with depression, hypersomnia looks like patients having “nonimperative sleepiness,” Dr. Benca said. “They may spend a lot of time in bed; they may report long and nonrefreshing naps or long sleep time.”
There also is an issue with sleep inertia in patients with depression and hypersomnia, and with patients taking a long time to wake up and begin their day. In these patients, “when we put them in the sleep laboratory, the objective studies generally do not show that they are excessively sleepy, despite their reports of subjectively being sleepy,” she said.
There is not much objective MSLT or subjective measure data for hypersomnia in patients with schizophrenia despite these patients reporting daytime sleepiness or hypersomnolence, Dr. Benca admitted. Hypersomnia in patients with schizophrenia may be related to drug effects, poor sleep hygiene, circadian rhythm abnormalities, or comorbid sleep disorders. “Excessive sleepiness may also be related to the schizophrenia itself,” she said.
Treatments for hypersomnia
The first priority for patients with hypersomnia is to avoid sleep deprivation and practice good sleep hygiene – factors that are important both in insomnia and hypersomnia. “Make sure that patients are having adequate time in bed and having regular hours of sleep,” Dr. Benca said.
For patients with comorbid psychiatric, medical and sleep disorders, focus on getting rid of medications that may cause sleepiness, including sedating medications and antidepressants, and consider using stimulants if appropriate. While there are Food and Drug Administration–approved medications for narcolepsy and some are approved for hypersomnia in patients with obstructive sleep apnea (OSA), none are officially approved to treat hypersomnia in psychiatric patients.
“Whenever we use these drugs for those reasons, we’re using them off label,” Dr. Benca said.
Modafinil/armodafinil, approved for narcolepsy, shift-work disorder, and OSA in Ehlers-Danlos syndrome, is one off-label option for patients with hypersomnia. “They are lower potency and less addictive than the amphetamines, [with] fewer side effects,” Dr. Benca explained, but should be prescribed with caution in some women because of potential reduced efficacy of oral contraceptives. Side effects of modafinil include headache, nausea, eosinophilia, diarrhea, dry mouth, and anorexia.
Methylphenidate is another option for hypersomnia, available in racemic mixture, pure D-isomer, and time-release formulations.
Patients taking methylphenidate may experience nervousness, insomnia, anorexia, nausea, dizziness, hypertension, hypotension, hypersensitivity reactions, tachycardia, and headache as side effects.
For patients with central nervous system hypersomnias, amphetamines can be used, with methamphetamines having a “very similar profile” and similar side effects, including insomnia, restlessness, tachycardia, dizziness, diarrhea, constipation, hypertension, impotence, and rare cases of psychotic episodes.
Practice parameters released by the American Academy of Sleep Medicine in 2007 suggest that modafinil may have efficacy in idiopathic hypersomnia, Parkinson’s disease, myotonic dystrophy, and multiple sclerosis. The practice parameters also suggest hypersomnias of central origin can be treated with modafinil, amphetamine, methamphetamine, dextroamphetamine, and methylphenidate based on evidence or “long history of use” (Sleep. 2007;30:1705-11).
“Interestingly, there is no mention of psychiatric disorders in these practice parameters, and they report that there are mixed results using stimulants off label for sleepiness and fatigue in traumatic brain injury and poststroke fatigue,” Dr. Benca said.
Dr. Benca reported that she is a consultant to Eisai, Idorsia, Jazz, Merck, and Sunovion. Global Academy and this news organization are owned by the same parent company.
, according to Ruth M. Benca, MD, PhD.
Fatigue, feeling tired, and lack of energy are common complaints that accompany insomnia and psychiatric disorders, but these patients do not fall asleep quickly in a restful setting and will have normal multiple sleep latency test (MSLT) in a laboratory. In contrast, excessive sleepiness, or hypersomnia, occurs when patients sleep more than 11 hours in a 24-hour period.
Patients with hypersomnia fall asleep in low stimulus situations and devote more energy to staying awake during situations. This excessive sleepiness can be dangerous in the context of activities such as driving, Dr. Benca said. These patients will also have low sleep latencies (< 8 minutes) when tested through MSLT in a laboratory, she added. Patients with hypersomnia may be irritable, have reduced attention or concentration, and have poor memory.
The primary cause of hypersomnia is sleep deprivation, but “both hypersomnia and fatigue are common complaints in psychiatric patients, including depression, bipolar disorder, seasonal affective disorder, [and] psychosis,” Dr. Benca explained. Other causes of hypersomnia include sleep disorders such as sleep apnea, circadian rhythm disorders and periodic limb movements, neurologic or degenerative disorders, mental disorders, and effects of medication. Idiopathic hypersomnia and narcolepsy are uncommon causes of hypersomnia and usually diagnosed in a sleep laboratory setting, she said.
In patients with depression, hypersomnia looks like patients having “nonimperative sleepiness,” Dr. Benca said. “They may spend a lot of time in bed; they may report long and nonrefreshing naps or long sleep time.”
There also is an issue with sleep inertia in patients with depression and hypersomnia, and with patients taking a long time to wake up and begin their day. In these patients, “when we put them in the sleep laboratory, the objective studies generally do not show that they are excessively sleepy, despite their reports of subjectively being sleepy,” she said.
There is not much objective MSLT or subjective measure data for hypersomnia in patients with schizophrenia despite these patients reporting daytime sleepiness or hypersomnolence, Dr. Benca admitted. Hypersomnia in patients with schizophrenia may be related to drug effects, poor sleep hygiene, circadian rhythm abnormalities, or comorbid sleep disorders. “Excessive sleepiness may also be related to the schizophrenia itself,” she said.
Treatments for hypersomnia
The first priority for patients with hypersomnia is to avoid sleep deprivation and practice good sleep hygiene – factors that are important both in insomnia and hypersomnia. “Make sure that patients are having adequate time in bed and having regular hours of sleep,” Dr. Benca said.
For patients with comorbid psychiatric, medical and sleep disorders, focus on getting rid of medications that may cause sleepiness, including sedating medications and antidepressants, and consider using stimulants if appropriate. While there are Food and Drug Administration–approved medications for narcolepsy and some are approved for hypersomnia in patients with obstructive sleep apnea (OSA), none are officially approved to treat hypersomnia in psychiatric patients.
“Whenever we use these drugs for those reasons, we’re using them off label,” Dr. Benca said.
Modafinil/armodafinil, approved for narcolepsy, shift-work disorder, and OSA in Ehlers-Danlos syndrome, is one off-label option for patients with hypersomnia. “They are lower potency and less addictive than the amphetamines, [with] fewer side effects,” Dr. Benca explained, but should be prescribed with caution in some women because of potential reduced efficacy of oral contraceptives. Side effects of modafinil include headache, nausea, eosinophilia, diarrhea, dry mouth, and anorexia.
Methylphenidate is another option for hypersomnia, available in racemic mixture, pure D-isomer, and time-release formulations.
Patients taking methylphenidate may experience nervousness, insomnia, anorexia, nausea, dizziness, hypertension, hypotension, hypersensitivity reactions, tachycardia, and headache as side effects.
For patients with central nervous system hypersomnias, amphetamines can be used, with methamphetamines having a “very similar profile” and similar side effects, including insomnia, restlessness, tachycardia, dizziness, diarrhea, constipation, hypertension, impotence, and rare cases of psychotic episodes.
Practice parameters released by the American Academy of Sleep Medicine in 2007 suggest that modafinil may have efficacy in idiopathic hypersomnia, Parkinson’s disease, myotonic dystrophy, and multiple sclerosis. The practice parameters also suggest hypersomnias of central origin can be treated with modafinil, amphetamine, methamphetamine, dextroamphetamine, and methylphenidate based on evidence or “long history of use” (Sleep. 2007;30:1705-11).
“Interestingly, there is no mention of psychiatric disorders in these practice parameters, and they report that there are mixed results using stimulants off label for sleepiness and fatigue in traumatic brain injury and poststroke fatigue,” Dr. Benca said.
Dr. Benca reported that she is a consultant to Eisai, Idorsia, Jazz, Merck, and Sunovion. Global Academy and this news organization are owned by the same parent company.
FROM PSYCHOPHARMACOLOGY UPDATE
Lupus-specific predictors for CVD described in Black patients
Black patients with systemic lupus erythematosus (SLE) are known to have significantly elevated risk for stroke and ischemic heart disease (IHD), compared with non-Black patients with SLE.
Now a team of investigators has identified SLE-specific predictors for major cardiovascular complications in Black patients, pointing to potential prevention strategies in this high-risk population.
Among Black patients in a study of 336 patients with incident SLE, discoid rash at the time of SLE diagnosis predicted a fivefold higher risk for stroke, and renal disorder at the time of diagnosis was associated with a twofold higher risk, compared with non-Black patients, but neither of these symptoms predicted elevated risk of IHD.
In contrast, neurologic disorders, including prior psychosis or seizure, were associated with a fourfold higher risk for IHD, and immunologic disorders including anti-DNA, anti-Smith, or antiphospholipid antibodies were associated with a nearly fivefold greater risk for IHD in Black patients, but neither of these comorbidities predicted strokes, reported Shivani Garg, MD, assistant professor of medicine at the University of Wisconsin in Madison.
“Our study was one of the first to highlight racial disparities in CVD subtypes, with a threefold higher stroke risk and 24-fold higher ischemic heart disease risk in Black patients with lupus. Compared to previous studies in Black populations, our study highlights different peak timing of early stroke and ischemic heart disease in our cohort,“ she said at a plenary session during the virtual annual meeting of the American College of Rheumatology.
The study is one of the first to identify specific and unique SLE disease-related predictors of stroke and ischemic heart disease, she said.
Georgia Lupus Registry data
Dr. Garg and colleagues at the University of Wisconsin and Emory University in Atlanta drew on data from the Georgia Lupus Registry, a population-based registry of SLE patients from the Atlanta area. They identified patients diagnosed from 2002 through 2004 who had four or more ACR criteria for SLE, or three or more criteria plus a final diagnosis of SLE made by their board-certified rheumatologists.
The patients were matched to the Georgia Hospital Discharge Database and National Death Index from 2000 through 2013, with stroke- and IHD-related hospitalizations and deaths classified by the first three admission codes or cause-of-death codes.
Patients with transient ischemic attacks were included in the stroke category, and those with myocardial infarction and angina were included in the IHD category.
They identified 336 patients, 87% of whom were female, and 75% of whom were Black. The mean age at SLE diagnosis was 40 years. Among this cohort, there were 38 stroke-related events or deaths and 25 IHD-related events or deaths recorded from the period 2 years before through 14 years after an SLE diagnosis.
Early stroke, late IHD
The investigators first looked at the timing of stroke vs. IHD and found that a disproportionately high percentage of stroke events occurred in the second year after SLE diagnosis, whereas the peak of IHD-related events occurred in the 14th year after diagnosis.
They then performed a race-stratified Cox proportional hazard analysis, and found a threefold higher risk for stroke in Black patients versus non-Black patients (P = .007) and a 24-fold higher risk for IHD (P < .0001).
In multivariate analysis, significant predictors of stroke were Black race with a hazard ratio (HR) of 3.4 (P = .028), discoid rash (HR, 4.6; P = .0028), and renal disorder (HR, 2.4; P = .04). However, stroke was not predicted by age, sex, immunologic disorder, serositis, hematologic disorder, or ACR criteria total greater than four.
Significant predictors of IHD included age 65 and older (HR, 61; P = .0007), Black race (HR, 24; P = .004), neurologic disorder (HR, 4.0; P = .018), and immunologic disorder (HR, 4.7; P = .02). But IHD could not be predicted by oral ulcers, discoid rash, or ACR criteria more than four.
“In future studies, we will examine mechanisms that drive the different timing and predictors of CVD subtypes and disparities. We will also examine the impact of timely prevention in high-risk SLE subsets,” Dr. Garg said.
Managing CVD risk
Angus Worthing, MD, from Arthritis & Rheumatism Associates in Chevy Chase, Md., and Washington, D.C., who moderated a press briefing where Dr. Garg discussed her data, routinely treats patients of different racial backgrounds with lupus. When asked how he manages patients with SLE and suspected cardiovascular complications, Dr. Worthing said, “I tend to, in my practice – and these kinds of studies may change what I do – watch for symptoms that might reflect coronary artery disease or cerebrovascular disease, potentially looking at the smaller arteries in the hands and feet as clues, and I will refer promptly to a vascular surgery expert or cardiologist for screening,” he said.
Dr. Garg added that in her practice, she and colleagues treat high-risk subsets of patients, such as those with lupus nephritis or multiple comorbidities, with aggressive blood pressure control and monitoring, as well as smoking cessation recommendations and lipid monitoring. They also try to limit or, if possible, decrease steroid doses to reduce risk for cardiovascular side effects.
Support for the study came in part from the U.S. Centers for Disease Control and Prevention. Dr. Garg and Dr. Worthing reported having no relevant disclosures.
SOURCE: Garg S et al. Arthritis Rheumatol. 2020;72(suppl 10): Abstract 433 .
Black patients with systemic lupus erythematosus (SLE) are known to have significantly elevated risk for stroke and ischemic heart disease (IHD), compared with non-Black patients with SLE.
Now a team of investigators has identified SLE-specific predictors for major cardiovascular complications in Black patients, pointing to potential prevention strategies in this high-risk population.
Among Black patients in a study of 336 patients with incident SLE, discoid rash at the time of SLE diagnosis predicted a fivefold higher risk for stroke, and renal disorder at the time of diagnosis was associated with a twofold higher risk, compared with non-Black patients, but neither of these symptoms predicted elevated risk of IHD.
In contrast, neurologic disorders, including prior psychosis or seizure, were associated with a fourfold higher risk for IHD, and immunologic disorders including anti-DNA, anti-Smith, or antiphospholipid antibodies were associated with a nearly fivefold greater risk for IHD in Black patients, but neither of these comorbidities predicted strokes, reported Shivani Garg, MD, assistant professor of medicine at the University of Wisconsin in Madison.
“Our study was one of the first to highlight racial disparities in CVD subtypes, with a threefold higher stroke risk and 24-fold higher ischemic heart disease risk in Black patients with lupus. Compared to previous studies in Black populations, our study highlights different peak timing of early stroke and ischemic heart disease in our cohort,“ she said at a plenary session during the virtual annual meeting of the American College of Rheumatology.
The study is one of the first to identify specific and unique SLE disease-related predictors of stroke and ischemic heart disease, she said.
Georgia Lupus Registry data
Dr. Garg and colleagues at the University of Wisconsin and Emory University in Atlanta drew on data from the Georgia Lupus Registry, a population-based registry of SLE patients from the Atlanta area. They identified patients diagnosed from 2002 through 2004 who had four or more ACR criteria for SLE, or three or more criteria plus a final diagnosis of SLE made by their board-certified rheumatologists.
The patients were matched to the Georgia Hospital Discharge Database and National Death Index from 2000 through 2013, with stroke- and IHD-related hospitalizations and deaths classified by the first three admission codes or cause-of-death codes.
Patients with transient ischemic attacks were included in the stroke category, and those with myocardial infarction and angina were included in the IHD category.
They identified 336 patients, 87% of whom were female, and 75% of whom were Black. The mean age at SLE diagnosis was 40 years. Among this cohort, there were 38 stroke-related events or deaths and 25 IHD-related events or deaths recorded from the period 2 years before through 14 years after an SLE diagnosis.
Early stroke, late IHD
The investigators first looked at the timing of stroke vs. IHD and found that a disproportionately high percentage of stroke events occurred in the second year after SLE diagnosis, whereas the peak of IHD-related events occurred in the 14th year after diagnosis.
They then performed a race-stratified Cox proportional hazard analysis, and found a threefold higher risk for stroke in Black patients versus non-Black patients (P = .007) and a 24-fold higher risk for IHD (P < .0001).
In multivariate analysis, significant predictors of stroke were Black race with a hazard ratio (HR) of 3.4 (P = .028), discoid rash (HR, 4.6; P = .0028), and renal disorder (HR, 2.4; P = .04). However, stroke was not predicted by age, sex, immunologic disorder, serositis, hematologic disorder, or ACR criteria total greater than four.
Significant predictors of IHD included age 65 and older (HR, 61; P = .0007), Black race (HR, 24; P = .004), neurologic disorder (HR, 4.0; P = .018), and immunologic disorder (HR, 4.7; P = .02). But IHD could not be predicted by oral ulcers, discoid rash, or ACR criteria more than four.
“In future studies, we will examine mechanisms that drive the different timing and predictors of CVD subtypes and disparities. We will also examine the impact of timely prevention in high-risk SLE subsets,” Dr. Garg said.
Managing CVD risk
Angus Worthing, MD, from Arthritis & Rheumatism Associates in Chevy Chase, Md., and Washington, D.C., who moderated a press briefing where Dr. Garg discussed her data, routinely treats patients of different racial backgrounds with lupus. When asked how he manages patients with SLE and suspected cardiovascular complications, Dr. Worthing said, “I tend to, in my practice – and these kinds of studies may change what I do – watch for symptoms that might reflect coronary artery disease or cerebrovascular disease, potentially looking at the smaller arteries in the hands and feet as clues, and I will refer promptly to a vascular surgery expert or cardiologist for screening,” he said.
Dr. Garg added that in her practice, she and colleagues treat high-risk subsets of patients, such as those with lupus nephritis or multiple comorbidities, with aggressive blood pressure control and monitoring, as well as smoking cessation recommendations and lipid monitoring. They also try to limit or, if possible, decrease steroid doses to reduce risk for cardiovascular side effects.
Support for the study came in part from the U.S. Centers for Disease Control and Prevention. Dr. Garg and Dr. Worthing reported having no relevant disclosures.
SOURCE: Garg S et al. Arthritis Rheumatol. 2020;72(suppl 10): Abstract 433 .
Black patients with systemic lupus erythematosus (SLE) are known to have significantly elevated risk for stroke and ischemic heart disease (IHD), compared with non-Black patients with SLE.
Now a team of investigators has identified SLE-specific predictors for major cardiovascular complications in Black patients, pointing to potential prevention strategies in this high-risk population.
Among Black patients in a study of 336 patients with incident SLE, discoid rash at the time of SLE diagnosis predicted a fivefold higher risk for stroke, and renal disorder at the time of diagnosis was associated with a twofold higher risk, compared with non-Black patients, but neither of these symptoms predicted elevated risk of IHD.
In contrast, neurologic disorders, including prior psychosis or seizure, were associated with a fourfold higher risk for IHD, and immunologic disorders including anti-DNA, anti-Smith, or antiphospholipid antibodies were associated with a nearly fivefold greater risk for IHD in Black patients, but neither of these comorbidities predicted strokes, reported Shivani Garg, MD, assistant professor of medicine at the University of Wisconsin in Madison.
“Our study was one of the first to highlight racial disparities in CVD subtypes, with a threefold higher stroke risk and 24-fold higher ischemic heart disease risk in Black patients with lupus. Compared to previous studies in Black populations, our study highlights different peak timing of early stroke and ischemic heart disease in our cohort,“ she said at a plenary session during the virtual annual meeting of the American College of Rheumatology.
The study is one of the first to identify specific and unique SLE disease-related predictors of stroke and ischemic heart disease, she said.
Georgia Lupus Registry data
Dr. Garg and colleagues at the University of Wisconsin and Emory University in Atlanta drew on data from the Georgia Lupus Registry, a population-based registry of SLE patients from the Atlanta area. They identified patients diagnosed from 2002 through 2004 who had four or more ACR criteria for SLE, or three or more criteria plus a final diagnosis of SLE made by their board-certified rheumatologists.
The patients were matched to the Georgia Hospital Discharge Database and National Death Index from 2000 through 2013, with stroke- and IHD-related hospitalizations and deaths classified by the first three admission codes or cause-of-death codes.
Patients with transient ischemic attacks were included in the stroke category, and those with myocardial infarction and angina were included in the IHD category.
They identified 336 patients, 87% of whom were female, and 75% of whom were Black. The mean age at SLE diagnosis was 40 years. Among this cohort, there were 38 stroke-related events or deaths and 25 IHD-related events or deaths recorded from the period 2 years before through 14 years after an SLE diagnosis.
Early stroke, late IHD
The investigators first looked at the timing of stroke vs. IHD and found that a disproportionately high percentage of stroke events occurred in the second year after SLE diagnosis, whereas the peak of IHD-related events occurred in the 14th year after diagnosis.
They then performed a race-stratified Cox proportional hazard analysis, and found a threefold higher risk for stroke in Black patients versus non-Black patients (P = .007) and a 24-fold higher risk for IHD (P < .0001).
In multivariate analysis, significant predictors of stroke were Black race with a hazard ratio (HR) of 3.4 (P = .028), discoid rash (HR, 4.6; P = .0028), and renal disorder (HR, 2.4; P = .04). However, stroke was not predicted by age, sex, immunologic disorder, serositis, hematologic disorder, or ACR criteria total greater than four.
Significant predictors of IHD included age 65 and older (HR, 61; P = .0007), Black race (HR, 24; P = .004), neurologic disorder (HR, 4.0; P = .018), and immunologic disorder (HR, 4.7; P = .02). But IHD could not be predicted by oral ulcers, discoid rash, or ACR criteria more than four.
“In future studies, we will examine mechanisms that drive the different timing and predictors of CVD subtypes and disparities. We will also examine the impact of timely prevention in high-risk SLE subsets,” Dr. Garg said.
Managing CVD risk
Angus Worthing, MD, from Arthritis & Rheumatism Associates in Chevy Chase, Md., and Washington, D.C., who moderated a press briefing where Dr. Garg discussed her data, routinely treats patients of different racial backgrounds with lupus. When asked how he manages patients with SLE and suspected cardiovascular complications, Dr. Worthing said, “I tend to, in my practice – and these kinds of studies may change what I do – watch for symptoms that might reflect coronary artery disease or cerebrovascular disease, potentially looking at the smaller arteries in the hands and feet as clues, and I will refer promptly to a vascular surgery expert or cardiologist for screening,” he said.
Dr. Garg added that in her practice, she and colleagues treat high-risk subsets of patients, such as those with lupus nephritis or multiple comorbidities, with aggressive blood pressure control and monitoring, as well as smoking cessation recommendations and lipid monitoring. They also try to limit or, if possible, decrease steroid doses to reduce risk for cardiovascular side effects.
Support for the study came in part from the U.S. Centers for Disease Control and Prevention. Dr. Garg and Dr. Worthing reported having no relevant disclosures.
SOURCE: Garg S et al. Arthritis Rheumatol. 2020;72(suppl 10): Abstract 433 .
FROM ACR 2020
COVID-19–related HCQ shortages affected rheumatology patients worldwide
New data document the global fallout for rheumatology patients when hydroxychloroquine (HCQ) supplies were being diverted to hospitals for COVID-19 patients.
Demand for HCQ soared on evidence-lacking claims that the drug was effective in treating and preventing SARS-CoV-2 infection. Further research has since shown HCQ to be ineffective for COVID-19 and potentially harmful to patients.
But during the height of the COVID-19-related hype, patients worldwide with autoimmune diseases, particularly lupus and rheumatoid arthritis, had trouble getting the pills at all or couldn’t get as many as they needed for their chronic conditions.
Emily Sirotich, MSc, a PhD student at McMaster University in Hamilton, Ont., presented data at the virtual annual meeting of the American College of Rheumatology demonstrating that the severity of shortages differed widely.
Whereas 26.7% of rheumatology patients in Africa and 21.4% in southeast Asia said their pharmacy ran short of HCQ – which was originally developed as an antimalarial drug but has been found effective in treating some rheumatic diseases – only 6.8% of patients in the Americas and 2.1% in European regions reported the shortages.
“There are large regional disparities in access to antimalarials whether they were caused by the COVID-19 pandemic or already existed,” she said in an interview.
Global survey polled patient experience
Ms. Sirotich’s team analyzed data from the Global Rheumatology Alliance Patient Experience Survey.
They found that from 9,393 respondents (average age 46.1 years and 90% female), 3,872 (41.2%) were taking antimalarials. Of these, 230 (6.2% globally) were unable to keep taking the drugs because their pharmacy ran out.
Researchers evaluated the effect of drug shortages on disease activity, mental health, and physical health by comparing mean values with two-sided independent t-tests to identify significant differences.
They found that patients who were unable to obtain antimalarials had significantly higher levels of rheumatic disease activity as well as poorer mental and physical health (all P < .001).
The survey was distributed online through patient support groups and on social media. Patients with rheumatic diseases or their parents anonymously entered data including their rheumatic disease diagnosis, medications, COVID-19 status, and disease outcomes.
Ms. Sirotich said they are currently gathering new data to see if the gaps in access to HCQ persist and whether the physical and mental consequences of not having the medications continue.
Hospitals stockpiled HCQ in the U.S.
Michael Ganio, PharmD, senior director of pharmacy practice and quality at the American Society of Health-System Pharmacists (ASHP), said in an interview that hospitals in the United States received large amounts of HCQ in late spring and early summer, donated by pharmaceutical companies for COVID-19 before the lack of evidence for efficacy became clear.
Hospitals found themselves sitting on large quantities of HCQ they couldn’t use while prescriptions for rheumatology outpatients were going unfilled.
It is only in recent months that the U.S. Department of Health and Human Services has given clear direction to hospitals on how to redistribute those supplies, Dr. Ganio said.
“There’s no good real good way to move a product from a hospital to a [drug store] down the street,” he said.
The Food and Drug Administration now lists the HCQ shortages as resolved.
Declined prescriptions have frustrated physicians
Brett Smith, DO, a pediatric and adult rheumatologist in Alcoa, Tenn., said he was frustrated by pharmacies declining his prescriptions for HCQ for patients with rheumatoid arthritis.
“I got notes from pharmacies that I should consider alternative agents,” he said in an interview. But the safety profiles of the alternatives were not as good, he said.
“Hydroxychloroquine has no risk of infection and no risk of malignancy, and they were proposing alternative agents that carry those risks,” he said.
“I had some people with RA who couldn’t get [HCQ] who had a substantial increase in swollen joints and pain without it,” he said.
Dr. Smith said some patients who use HCQ for off-label uses such as certain skin disorders still aren’t getting the drug, as off-label use has been discouraged to make sure those with lupus and RA have enough, he said.
Saira Sheikh, MD, director of the University of North Carolina Rheumatology Lupus Clinic in Chapel Hill, said in an interview that during the summer months pharmacists required additional documentation of the diagnosis of autoimmune disease, resulting in unnecessary delays even when patients had been on the medication for many years.
She said emerging research has found patient-reported barriers to filling prescriptions, interruptions in HCQ treatment, and reported emotional stress and anxiety related to medication access during the COVID-19 pandemic.
“This experience with HCQ during the COVID-19 pandemic teaches us that while swift action and progress to address the immediate threats of the pandemic should be commended, it is important that we move forward in a conscious manner, guided by an evidence base that comes from high-quality research, not from rushed judgments based on preliminary studies, or pressure from political leaders,” Dr. Sheikh said.
Ms. Sirotich, Dr. Smith, Dr. Sheikh, and Dr. Ganio have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
New data document the global fallout for rheumatology patients when hydroxychloroquine (HCQ) supplies were being diverted to hospitals for COVID-19 patients.
Demand for HCQ soared on evidence-lacking claims that the drug was effective in treating and preventing SARS-CoV-2 infection. Further research has since shown HCQ to be ineffective for COVID-19 and potentially harmful to patients.
But during the height of the COVID-19-related hype, patients worldwide with autoimmune diseases, particularly lupus and rheumatoid arthritis, had trouble getting the pills at all or couldn’t get as many as they needed for their chronic conditions.
Emily Sirotich, MSc, a PhD student at McMaster University in Hamilton, Ont., presented data at the virtual annual meeting of the American College of Rheumatology demonstrating that the severity of shortages differed widely.
Whereas 26.7% of rheumatology patients in Africa and 21.4% in southeast Asia said their pharmacy ran short of HCQ – which was originally developed as an antimalarial drug but has been found effective in treating some rheumatic diseases – only 6.8% of patients in the Americas and 2.1% in European regions reported the shortages.
“There are large regional disparities in access to antimalarials whether they were caused by the COVID-19 pandemic or already existed,” she said in an interview.
Global survey polled patient experience
Ms. Sirotich’s team analyzed data from the Global Rheumatology Alliance Patient Experience Survey.
They found that from 9,393 respondents (average age 46.1 years and 90% female), 3,872 (41.2%) were taking antimalarials. Of these, 230 (6.2% globally) were unable to keep taking the drugs because their pharmacy ran out.
Researchers evaluated the effect of drug shortages on disease activity, mental health, and physical health by comparing mean values with two-sided independent t-tests to identify significant differences.
They found that patients who were unable to obtain antimalarials had significantly higher levels of rheumatic disease activity as well as poorer mental and physical health (all P < .001).
The survey was distributed online through patient support groups and on social media. Patients with rheumatic diseases or their parents anonymously entered data including their rheumatic disease diagnosis, medications, COVID-19 status, and disease outcomes.
Ms. Sirotich said they are currently gathering new data to see if the gaps in access to HCQ persist and whether the physical and mental consequences of not having the medications continue.
Hospitals stockpiled HCQ in the U.S.
Michael Ganio, PharmD, senior director of pharmacy practice and quality at the American Society of Health-System Pharmacists (ASHP), said in an interview that hospitals in the United States received large amounts of HCQ in late spring and early summer, donated by pharmaceutical companies for COVID-19 before the lack of evidence for efficacy became clear.
Hospitals found themselves sitting on large quantities of HCQ they couldn’t use while prescriptions for rheumatology outpatients were going unfilled.
It is only in recent months that the U.S. Department of Health and Human Services has given clear direction to hospitals on how to redistribute those supplies, Dr. Ganio said.
“There’s no good real good way to move a product from a hospital to a [drug store] down the street,” he said.
The Food and Drug Administration now lists the HCQ shortages as resolved.
Declined prescriptions have frustrated physicians
Brett Smith, DO, a pediatric and adult rheumatologist in Alcoa, Tenn., said he was frustrated by pharmacies declining his prescriptions for HCQ for patients with rheumatoid arthritis.
“I got notes from pharmacies that I should consider alternative agents,” he said in an interview. But the safety profiles of the alternatives were not as good, he said.
“Hydroxychloroquine has no risk of infection and no risk of malignancy, and they were proposing alternative agents that carry those risks,” he said.
“I had some people with RA who couldn’t get [HCQ] who had a substantial increase in swollen joints and pain without it,” he said.
Dr. Smith said some patients who use HCQ for off-label uses such as certain skin disorders still aren’t getting the drug, as off-label use has been discouraged to make sure those with lupus and RA have enough, he said.
Saira Sheikh, MD, director of the University of North Carolina Rheumatology Lupus Clinic in Chapel Hill, said in an interview that during the summer months pharmacists required additional documentation of the diagnosis of autoimmune disease, resulting in unnecessary delays even when patients had been on the medication for many years.
She said emerging research has found patient-reported barriers to filling prescriptions, interruptions in HCQ treatment, and reported emotional stress and anxiety related to medication access during the COVID-19 pandemic.
“This experience with HCQ during the COVID-19 pandemic teaches us that while swift action and progress to address the immediate threats of the pandemic should be commended, it is important that we move forward in a conscious manner, guided by an evidence base that comes from high-quality research, not from rushed judgments based on preliminary studies, or pressure from political leaders,” Dr. Sheikh said.
Ms. Sirotich, Dr. Smith, Dr. Sheikh, and Dr. Ganio have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
New data document the global fallout for rheumatology patients when hydroxychloroquine (HCQ) supplies were being diverted to hospitals for COVID-19 patients.
Demand for HCQ soared on evidence-lacking claims that the drug was effective in treating and preventing SARS-CoV-2 infection. Further research has since shown HCQ to be ineffective for COVID-19 and potentially harmful to patients.
But during the height of the COVID-19-related hype, patients worldwide with autoimmune diseases, particularly lupus and rheumatoid arthritis, had trouble getting the pills at all or couldn’t get as many as they needed for their chronic conditions.
Emily Sirotich, MSc, a PhD student at McMaster University in Hamilton, Ont., presented data at the virtual annual meeting of the American College of Rheumatology demonstrating that the severity of shortages differed widely.
Whereas 26.7% of rheumatology patients in Africa and 21.4% in southeast Asia said their pharmacy ran short of HCQ – which was originally developed as an antimalarial drug but has been found effective in treating some rheumatic diseases – only 6.8% of patients in the Americas and 2.1% in European regions reported the shortages.
“There are large regional disparities in access to antimalarials whether they were caused by the COVID-19 pandemic or already existed,” she said in an interview.
Global survey polled patient experience
Ms. Sirotich’s team analyzed data from the Global Rheumatology Alliance Patient Experience Survey.
They found that from 9,393 respondents (average age 46.1 years and 90% female), 3,872 (41.2%) were taking antimalarials. Of these, 230 (6.2% globally) were unable to keep taking the drugs because their pharmacy ran out.
Researchers evaluated the effect of drug shortages on disease activity, mental health, and physical health by comparing mean values with two-sided independent t-tests to identify significant differences.
They found that patients who were unable to obtain antimalarials had significantly higher levels of rheumatic disease activity as well as poorer mental and physical health (all P < .001).
The survey was distributed online through patient support groups and on social media. Patients with rheumatic diseases or their parents anonymously entered data including their rheumatic disease diagnosis, medications, COVID-19 status, and disease outcomes.
Ms. Sirotich said they are currently gathering new data to see if the gaps in access to HCQ persist and whether the physical and mental consequences of not having the medications continue.
Hospitals stockpiled HCQ in the U.S.
Michael Ganio, PharmD, senior director of pharmacy practice and quality at the American Society of Health-System Pharmacists (ASHP), said in an interview that hospitals in the United States received large amounts of HCQ in late spring and early summer, donated by pharmaceutical companies for COVID-19 before the lack of evidence for efficacy became clear.
Hospitals found themselves sitting on large quantities of HCQ they couldn’t use while prescriptions for rheumatology outpatients were going unfilled.
It is only in recent months that the U.S. Department of Health and Human Services has given clear direction to hospitals on how to redistribute those supplies, Dr. Ganio said.
“There’s no good real good way to move a product from a hospital to a [drug store] down the street,” he said.
The Food and Drug Administration now lists the HCQ shortages as resolved.
Declined prescriptions have frustrated physicians
Brett Smith, DO, a pediatric and adult rheumatologist in Alcoa, Tenn., said he was frustrated by pharmacies declining his prescriptions for HCQ for patients with rheumatoid arthritis.
“I got notes from pharmacies that I should consider alternative agents,” he said in an interview. But the safety profiles of the alternatives were not as good, he said.
“Hydroxychloroquine has no risk of infection and no risk of malignancy, and they were proposing alternative agents that carry those risks,” he said.
“I had some people with RA who couldn’t get [HCQ] who had a substantial increase in swollen joints and pain without it,” he said.
Dr. Smith said some patients who use HCQ for off-label uses such as certain skin disorders still aren’t getting the drug, as off-label use has been discouraged to make sure those with lupus and RA have enough, he said.
Saira Sheikh, MD, director of the University of North Carolina Rheumatology Lupus Clinic in Chapel Hill, said in an interview that during the summer months pharmacists required additional documentation of the diagnosis of autoimmune disease, resulting in unnecessary delays even when patients had been on the medication for many years.
She said emerging research has found patient-reported barriers to filling prescriptions, interruptions in HCQ treatment, and reported emotional stress and anxiety related to medication access during the COVID-19 pandemic.
“This experience with HCQ during the COVID-19 pandemic teaches us that while swift action and progress to address the immediate threats of the pandemic should be commended, it is important that we move forward in a conscious manner, guided by an evidence base that comes from high-quality research, not from rushed judgments based on preliminary studies, or pressure from political leaders,” Dr. Sheikh said.
Ms. Sirotich, Dr. Smith, Dr. Sheikh, and Dr. Ganio have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Smartphones can differentiate bipolar from borderline personality disorder
There’s a reason they’re called smartphones.
Indeed, how patients use their smartphones and where they take them provides insight into what has been termed their “digital phenotype.” It’s information that, analyzed correctly, becomes useful in differentiating bipolar disorder from borderline personality disorder, a distinction that’s often challenging in clinical practice, Kate E.A. Saunders, MD, DPhil, said at the virtual congress of the European College of Neuropsychopharmacology.
Dr. Saunders, a psychiatrist at the University of Oxford (England), and colleagues have developed a smartphone app enabling patients to briefly characterize their current mood on a daily basis, as well as a machine learning model to analyze this data stream as patients’ moods evolve over time. In their prospective longitudinal Automated Monitoring of Symptom Severity (AMoSS) study of 48 patients with a confirmed diagnosis of bipolar disorder, 31 with borderline personality disorder, and 51 healthy volunteers, the tool correctly classified 75% of participants into the correct diagnostic category on the basis of 20 daily mood ratings (Transl Psychiatry. 2018 Dec 13;81:274. doi: 10.1038/s41398-018-0334-0).
The app also monitors activity via accelerometry and geolocation to assess an individual’s circadian rest-activity patterns, as well as telephone use and texting behavior. In another report from AMoSS, Dr. Saunders and coinvestigators showed that these patterns also distinguish persons with bipolar disorder from those with borderline personality disorder, who in turn differ from healthy controls (Transl Psychiatry. 2019 Aug 20;91:195. doi: 10.1038/s41398-019-0526-2).
It doesn’t replace doctors, but clearly it can add to diagnostic accuracy,” she said.
Borderline personality disorder and bipolar disorder are common diagnoses with quite different treatment approaches and prognoses. Studies have shown that rates of misdiagnosis of the two disorders are significant. The challenge is that they share overlapping diagnostic criteria, including prominent mood instability, which is difficult to assess reliably in clinical practice. That’s because the assessment relies on retrospective self-report of how patients felt in the past, which is often colored by their present mood state. The smartphone app sidesteps that limitation by having patients rate their mood daily digitally across six categories – anxiety, elation, sadness, anger, irritability, and energy – on a 1-7 scale.
The machine learning model that analyzes this information organizes the voluminous data into what Dr. Saunders called “signatures of mood” and breaks them down using rough path theory, a mathematical concept based upon differential equations. Dr. Saunders and colleagues have demonstrated that the shifting daily mood self-rating patterns can be used not only to sharpen the differential diagnosis between bipolar disorder and borderline personality disorder, but also to predict future mood. Automated analysis of the past 20 previous mood self-ratings predicted the next day’s mood in healthy controls with 89%-98% accuracy, depending upon which of the six mood categories was under scrutiny.
The predictive power in patients with bipolar disorder was also good, ranging from 82% accuracy for the energetic and anxious domains to 90% for the angry mood category. This ability to predict future mood states could have clinical value by assisting bipolar patients in enhancing proactive self-management and managing their mood stability to avoid depressive or manic relapse, although this has yet to be studied.
“For borderline personality disorder the predictive accuracy was not so good – 70%-78% – but perhaps that doesn’t matter,” Dr. Saunders said. “Perhaps that difficulty in predicting mood may actually be quite a useful diagnostic marker.”
‘Mr. Jones, the doctor is ready to see your phone now.’
The app’s accelerometry and geolocation capabilities can also enhance diagnostic accuracy, as has been shown in the AMoSS study.
The geolocation analysis generates data on the places a patient has gone and how much time was spent there. Feeding that information into the machine learning model predicted the presence or absence of depression with 85% accuracy for bipolar disorder, but couldn’t predict depression at all in borderline personality disorder.
“So we get a sense that people with bipolar disorder have behavioral manifestations of their mood symptoms which are much more consistent with one another and appear to change very consistently with their mood state, whereas borderline personality disorder seems to be characterized by something that’s much more unstable and unpredictable – and we can pick up these predictive variables using our smartphones,” Dr. Saunders said.
As depressive symptoms arise in patients with bipolar disorder, affected individuals display much less day-to-day variability in movement as measured by accelerometry. These changes predicted bipolar disorder with 76% specificity and 48% sensitivity.
“That’s OK. But we can’t do that at all in people with borderline personality disorder, again highlighting the fact that behavioral manifestations and symptoms in these groups are very, very different,” Dr. Saunders observed.
In AMoSS, analysis of activity, geolocation, and distal temperature rhythms showed that the individuals with borderline personality disorder displayed evidence of delayed circadian function, with a distinctive rest-activity pattern that differed from persons with bipolar disorder. This delayed circadian function might provide a novel therapeutic target in borderline personality disorder, a condition for which there is a notable lack of effective pharmacologic and psychotherapeutic interventions.
Phone use patterns were revealing. Patients with bipolar disorder had an increased total telephone call frequency relative to the healthy controls, whereas those with borderline personality disorder used text messaging much more frequently, consistent with the notion that borderline patients have difficulty in interpersonal communication.
Smartphone-based diagnostic differentiation between bipolar disorder and borderline personality disorder isn’t ready for prime time use in clinical practice, Dr. Saunders said. This is groundbreaking work that needs to be refined and replicated in larger studies. There are important ethical and data protection issues that require attention. But patients are gung-ho. Dr. Saunders noted that participant compliance in AMoSS was “extraordinarily good,” at 82%. Moreover, even though the study lasted for 3 months, more than 60% of subjects continued filing mood reports for 12 months.
“Smartphones may also give us an improved understanding of the lived experience of people with mental health problems. That’s certainly the feedback we got a lot from patients. They enjoy using this technology. They feel it’s helpful to be able to show their clinician this is what it’s like for them,” Dr. Saunders said.
Clinical usefulness is limited
The study was interesting as a pilot, and it is technologically very innovative. However, at this stage, it is unclear how the results can be used clinically, said Igor Galynker, MD, PhD, when asked about the findings.
There is a place for using this type of technology for patients living in remote areas, for example. However, Dr. Galynker, director of the Richard and Cynthia Zirinsky Center for Bipolar Disorder in New York, said such technology should be viewed as augmentation rather than as a substitute for face-to-face treatment.
“Typically, if clinicians have enough time to speak to the patient and to take history, they can differentiate between bipolar disorder and borderline personality disorder: The former is cyclical, the latter is less so. However, this is hard to do without face-to-face contact, or when you only have 10 minutes,” said Dr. Galynker, professor of psychiatry at the Icahn School of Medicine and director of the Galynker Research and Prevention Laboratory, both at Mount Sinai in New York.
Dr. Saunders’ work is funded by the Wellcome Trust and the National Institute for Health Research. Dr. Galynker reported receiving funding from the National Institute of Mental Health and the American Foundation for Suicide Prevention. He has no other disclosures.
SOURCE: ECNP 2020. Session S21.
There’s a reason they’re called smartphones.
Indeed, how patients use their smartphones and where they take them provides insight into what has been termed their “digital phenotype.” It’s information that, analyzed correctly, becomes useful in differentiating bipolar disorder from borderline personality disorder, a distinction that’s often challenging in clinical practice, Kate E.A. Saunders, MD, DPhil, said at the virtual congress of the European College of Neuropsychopharmacology.
Dr. Saunders, a psychiatrist at the University of Oxford (England), and colleagues have developed a smartphone app enabling patients to briefly characterize their current mood on a daily basis, as well as a machine learning model to analyze this data stream as patients’ moods evolve over time. In their prospective longitudinal Automated Monitoring of Symptom Severity (AMoSS) study of 48 patients with a confirmed diagnosis of bipolar disorder, 31 with borderline personality disorder, and 51 healthy volunteers, the tool correctly classified 75% of participants into the correct diagnostic category on the basis of 20 daily mood ratings (Transl Psychiatry. 2018 Dec 13;81:274. doi: 10.1038/s41398-018-0334-0).
The app also monitors activity via accelerometry and geolocation to assess an individual’s circadian rest-activity patterns, as well as telephone use and texting behavior. In another report from AMoSS, Dr. Saunders and coinvestigators showed that these patterns also distinguish persons with bipolar disorder from those with borderline personality disorder, who in turn differ from healthy controls (Transl Psychiatry. 2019 Aug 20;91:195. doi: 10.1038/s41398-019-0526-2).
It doesn’t replace doctors, but clearly it can add to diagnostic accuracy,” she said.
Borderline personality disorder and bipolar disorder are common diagnoses with quite different treatment approaches and prognoses. Studies have shown that rates of misdiagnosis of the two disorders are significant. The challenge is that they share overlapping diagnostic criteria, including prominent mood instability, which is difficult to assess reliably in clinical practice. That’s because the assessment relies on retrospective self-report of how patients felt in the past, which is often colored by their present mood state. The smartphone app sidesteps that limitation by having patients rate their mood daily digitally across six categories – anxiety, elation, sadness, anger, irritability, and energy – on a 1-7 scale.
The machine learning model that analyzes this information organizes the voluminous data into what Dr. Saunders called “signatures of mood” and breaks them down using rough path theory, a mathematical concept based upon differential equations. Dr. Saunders and colleagues have demonstrated that the shifting daily mood self-rating patterns can be used not only to sharpen the differential diagnosis between bipolar disorder and borderline personality disorder, but also to predict future mood. Automated analysis of the past 20 previous mood self-ratings predicted the next day’s mood in healthy controls with 89%-98% accuracy, depending upon which of the six mood categories was under scrutiny.
The predictive power in patients with bipolar disorder was also good, ranging from 82% accuracy for the energetic and anxious domains to 90% for the angry mood category. This ability to predict future mood states could have clinical value by assisting bipolar patients in enhancing proactive self-management and managing their mood stability to avoid depressive or manic relapse, although this has yet to be studied.
“For borderline personality disorder the predictive accuracy was not so good – 70%-78% – but perhaps that doesn’t matter,” Dr. Saunders said. “Perhaps that difficulty in predicting mood may actually be quite a useful diagnostic marker.”
‘Mr. Jones, the doctor is ready to see your phone now.’
The app’s accelerometry and geolocation capabilities can also enhance diagnostic accuracy, as has been shown in the AMoSS study.
The geolocation analysis generates data on the places a patient has gone and how much time was spent there. Feeding that information into the machine learning model predicted the presence or absence of depression with 85% accuracy for bipolar disorder, but couldn’t predict depression at all in borderline personality disorder.
“So we get a sense that people with bipolar disorder have behavioral manifestations of their mood symptoms which are much more consistent with one another and appear to change very consistently with their mood state, whereas borderline personality disorder seems to be characterized by something that’s much more unstable and unpredictable – and we can pick up these predictive variables using our smartphones,” Dr. Saunders said.
As depressive symptoms arise in patients with bipolar disorder, affected individuals display much less day-to-day variability in movement as measured by accelerometry. These changes predicted bipolar disorder with 76% specificity and 48% sensitivity.
“That’s OK. But we can’t do that at all in people with borderline personality disorder, again highlighting the fact that behavioral manifestations and symptoms in these groups are very, very different,” Dr. Saunders observed.
In AMoSS, analysis of activity, geolocation, and distal temperature rhythms showed that the individuals with borderline personality disorder displayed evidence of delayed circadian function, with a distinctive rest-activity pattern that differed from persons with bipolar disorder. This delayed circadian function might provide a novel therapeutic target in borderline personality disorder, a condition for which there is a notable lack of effective pharmacologic and psychotherapeutic interventions.
Phone use patterns were revealing. Patients with bipolar disorder had an increased total telephone call frequency relative to the healthy controls, whereas those with borderline personality disorder used text messaging much more frequently, consistent with the notion that borderline patients have difficulty in interpersonal communication.
Smartphone-based diagnostic differentiation between bipolar disorder and borderline personality disorder isn’t ready for prime time use in clinical practice, Dr. Saunders said. This is groundbreaking work that needs to be refined and replicated in larger studies. There are important ethical and data protection issues that require attention. But patients are gung-ho. Dr. Saunders noted that participant compliance in AMoSS was “extraordinarily good,” at 82%. Moreover, even though the study lasted for 3 months, more than 60% of subjects continued filing mood reports for 12 months.
“Smartphones may also give us an improved understanding of the lived experience of people with mental health problems. That’s certainly the feedback we got a lot from patients. They enjoy using this technology. They feel it’s helpful to be able to show their clinician this is what it’s like for them,” Dr. Saunders said.
Clinical usefulness is limited
The study was interesting as a pilot, and it is technologically very innovative. However, at this stage, it is unclear how the results can be used clinically, said Igor Galynker, MD, PhD, when asked about the findings.
There is a place for using this type of technology for patients living in remote areas, for example. However, Dr. Galynker, director of the Richard and Cynthia Zirinsky Center for Bipolar Disorder in New York, said such technology should be viewed as augmentation rather than as a substitute for face-to-face treatment.
“Typically, if clinicians have enough time to speak to the patient and to take history, they can differentiate between bipolar disorder and borderline personality disorder: The former is cyclical, the latter is less so. However, this is hard to do without face-to-face contact, or when you only have 10 minutes,” said Dr. Galynker, professor of psychiatry at the Icahn School of Medicine and director of the Galynker Research and Prevention Laboratory, both at Mount Sinai in New York.
Dr. Saunders’ work is funded by the Wellcome Trust and the National Institute for Health Research. Dr. Galynker reported receiving funding from the National Institute of Mental Health and the American Foundation for Suicide Prevention. He has no other disclosures.
SOURCE: ECNP 2020. Session S21.
There’s a reason they’re called smartphones.
Indeed, how patients use their smartphones and where they take them provides insight into what has been termed their “digital phenotype.” It’s information that, analyzed correctly, becomes useful in differentiating bipolar disorder from borderline personality disorder, a distinction that’s often challenging in clinical practice, Kate E.A. Saunders, MD, DPhil, said at the virtual congress of the European College of Neuropsychopharmacology.
Dr. Saunders, a psychiatrist at the University of Oxford (England), and colleagues have developed a smartphone app enabling patients to briefly characterize their current mood on a daily basis, as well as a machine learning model to analyze this data stream as patients’ moods evolve over time. In their prospective longitudinal Automated Monitoring of Symptom Severity (AMoSS) study of 48 patients with a confirmed diagnosis of bipolar disorder, 31 with borderline personality disorder, and 51 healthy volunteers, the tool correctly classified 75% of participants into the correct diagnostic category on the basis of 20 daily mood ratings (Transl Psychiatry. 2018 Dec 13;81:274. doi: 10.1038/s41398-018-0334-0).
The app also monitors activity via accelerometry and geolocation to assess an individual’s circadian rest-activity patterns, as well as telephone use and texting behavior. In another report from AMoSS, Dr. Saunders and coinvestigators showed that these patterns also distinguish persons with bipolar disorder from those with borderline personality disorder, who in turn differ from healthy controls (Transl Psychiatry. 2019 Aug 20;91:195. doi: 10.1038/s41398-019-0526-2).
It doesn’t replace doctors, but clearly it can add to diagnostic accuracy,” she said.
Borderline personality disorder and bipolar disorder are common diagnoses with quite different treatment approaches and prognoses. Studies have shown that rates of misdiagnosis of the two disorders are significant. The challenge is that they share overlapping diagnostic criteria, including prominent mood instability, which is difficult to assess reliably in clinical practice. That’s because the assessment relies on retrospective self-report of how patients felt in the past, which is often colored by their present mood state. The smartphone app sidesteps that limitation by having patients rate their mood daily digitally across six categories – anxiety, elation, sadness, anger, irritability, and energy – on a 1-7 scale.
The machine learning model that analyzes this information organizes the voluminous data into what Dr. Saunders called “signatures of mood” and breaks them down using rough path theory, a mathematical concept based upon differential equations. Dr. Saunders and colleagues have demonstrated that the shifting daily mood self-rating patterns can be used not only to sharpen the differential diagnosis between bipolar disorder and borderline personality disorder, but also to predict future mood. Automated analysis of the past 20 previous mood self-ratings predicted the next day’s mood in healthy controls with 89%-98% accuracy, depending upon which of the six mood categories was under scrutiny.
The predictive power in patients with bipolar disorder was also good, ranging from 82% accuracy for the energetic and anxious domains to 90% for the angry mood category. This ability to predict future mood states could have clinical value by assisting bipolar patients in enhancing proactive self-management and managing their mood stability to avoid depressive or manic relapse, although this has yet to be studied.
“For borderline personality disorder the predictive accuracy was not so good – 70%-78% – but perhaps that doesn’t matter,” Dr. Saunders said. “Perhaps that difficulty in predicting mood may actually be quite a useful diagnostic marker.”
‘Mr. Jones, the doctor is ready to see your phone now.’
The app’s accelerometry and geolocation capabilities can also enhance diagnostic accuracy, as has been shown in the AMoSS study.
The geolocation analysis generates data on the places a patient has gone and how much time was spent there. Feeding that information into the machine learning model predicted the presence or absence of depression with 85% accuracy for bipolar disorder, but couldn’t predict depression at all in borderline personality disorder.
“So we get a sense that people with bipolar disorder have behavioral manifestations of their mood symptoms which are much more consistent with one another and appear to change very consistently with their mood state, whereas borderline personality disorder seems to be characterized by something that’s much more unstable and unpredictable – and we can pick up these predictive variables using our smartphones,” Dr. Saunders said.
As depressive symptoms arise in patients with bipolar disorder, affected individuals display much less day-to-day variability in movement as measured by accelerometry. These changes predicted bipolar disorder with 76% specificity and 48% sensitivity.
“That’s OK. But we can’t do that at all in people with borderline personality disorder, again highlighting the fact that behavioral manifestations and symptoms in these groups are very, very different,” Dr. Saunders observed.
In AMoSS, analysis of activity, geolocation, and distal temperature rhythms showed that the individuals with borderline personality disorder displayed evidence of delayed circadian function, with a distinctive rest-activity pattern that differed from persons with bipolar disorder. This delayed circadian function might provide a novel therapeutic target in borderline personality disorder, a condition for which there is a notable lack of effective pharmacologic and psychotherapeutic interventions.
Phone use patterns were revealing. Patients with bipolar disorder had an increased total telephone call frequency relative to the healthy controls, whereas those with borderline personality disorder used text messaging much more frequently, consistent with the notion that borderline patients have difficulty in interpersonal communication.
Smartphone-based diagnostic differentiation between bipolar disorder and borderline personality disorder isn’t ready for prime time use in clinical practice, Dr. Saunders said. This is groundbreaking work that needs to be refined and replicated in larger studies. There are important ethical and data protection issues that require attention. But patients are gung-ho. Dr. Saunders noted that participant compliance in AMoSS was “extraordinarily good,” at 82%. Moreover, even though the study lasted for 3 months, more than 60% of subjects continued filing mood reports for 12 months.
“Smartphones may also give us an improved understanding of the lived experience of people with mental health problems. That’s certainly the feedback we got a lot from patients. They enjoy using this technology. They feel it’s helpful to be able to show their clinician this is what it’s like for them,” Dr. Saunders said.
Clinical usefulness is limited
The study was interesting as a pilot, and it is technologically very innovative. However, at this stage, it is unclear how the results can be used clinically, said Igor Galynker, MD, PhD, when asked about the findings.
There is a place for using this type of technology for patients living in remote areas, for example. However, Dr. Galynker, director of the Richard and Cynthia Zirinsky Center for Bipolar Disorder in New York, said such technology should be viewed as augmentation rather than as a substitute for face-to-face treatment.
“Typically, if clinicians have enough time to speak to the patient and to take history, they can differentiate between bipolar disorder and borderline personality disorder: The former is cyclical, the latter is less so. However, this is hard to do without face-to-face contact, or when you only have 10 minutes,” said Dr. Galynker, professor of psychiatry at the Icahn School of Medicine and director of the Galynker Research and Prevention Laboratory, both at Mount Sinai in New York.
Dr. Saunders’ work is funded by the Wellcome Trust and the National Institute for Health Research. Dr. Galynker reported receiving funding from the National Institute of Mental Health and the American Foundation for Suicide Prevention. He has no other disclosures.
SOURCE: ECNP 2020. Session S21.
FROM ECNP 2020
Topical tapinarof effective in pivotal psoriasis trials
in two identical pivotal phase 3, randomized trials, Mark G. Lebwohl, MD, reported at the virtual annual congress of the European Academy of Dermatology and Venereology.
“Tapinarof cream has the potential to be a first-in-class topical therapeutic aryl hydrocarbon receptor modulating agent and will provide physicians and patients with a novel nonsteroidal topical treatment option that’s effective and well tolerated,” predicted Dr. Lebwohl, professor and chair of the department of dermatology at the Icahn School of Medicine at Mount Sinai, New York.
Dermavant Sciences, the company developing topical tapinarof for treatment of atopic dermatitis as well as psoriasis, announced that upon completion of an ongoing long-term extension study the company plans to file for approval of the drug for psoriasis in 2021.
The two pivotal phase 3 trials, PSOARING 1 and PSOARING 2, randomized a total of 1,025 patients with plaque psoriasis to once-daily tapinarof cream 1% or its vehicle. “This was a fairly difficult group of patients,” Dr. Lebwohl said. Roughly 80% had moderate psoriasis as defined by a baseline Physician Global Assessment (PGA) score of 3, with the remainder split evenly between mild and severe disease. Participants averaged 8% body surface area involvement. Body mass index was on average greater than 31 kg/m2.
The primary efficacy endpoint was a PGA score of 0 or 1 – that is, clear or almost clear – plus at least a 2-grade improvement in PGA from baseline at week 12. This was achieved in 35.4% of patients on tapinarof cream once daily in PSOARING 1 and 40.2% in PSOARING 2, compared with 6.0% and 6.3% of vehicle-treated controls, a highly significant difference (both P < .0001).
The prespecified secondary endpoint was a 75% improvement in Psoriasis Area and Severity Index (PASI) score from baseline to week 12. The PASI 75 rates were 36.1% and 47.6% with tapinarof, significantly better than the 10.2% and 6.9% rates in controls.
The most common adverse event associated with tapinarof was folliculitis, which occurred in 20.6% of treated patients in PSOARING 1 and in 15.7% in PSOARING 2. More than 98% of cases were mild or moderate. The folliculitis led to study discontinuation in only 1.8% and 0.9% of subjects in the two trials.
The other noteworthy adverse event was contact dermatitis. It occurred in 3.8% and 4.7% of tapinarof-treated patients, again with low study discontinuation rates of 1.5% and 2.2%.
During the audience discussion, Linda Stein Gold, MD, lead investigator for PSOARING 2, was asked about this folliculitis. She said the mechanism is unclear, as is the best management. She encountered it in patients, didn’t treat it, and it went away on its own. It’s not a bacterial folliculitis; when cultured it invariably proved culture negative, she noted.
The comparative efficacy of tapinarof cream versus the potent and superpotent topical corticosteroids commonly used in the treatment of psoriasis hasn’t been evaluated in head-to-head studies. Her experience and that of the other investigators has been that tapinarof’s efficacy is comparably strong, “but we don’t have the steroid side effects,” said Dr. Stein Gold, director of dermatology clinical research at Henry Ford Health System in Detroit.
In an interview, Dr. Lebwohl said tapinarof, if approved, could help meet a major unmet need for new and better topical therapies for psoriasis.
“You keep hearing about all these biologic agents and small-molecule pills coming out, but the majority of patients still only need topical therapy,” he observed.
Moreover, even when patients with more severe disease achieve a PASI 75 or PASI 90 response with systemic therapy, they usually still need supplemental topical therapy to get them closer to the goal of clear skin.
The superpotent steroids that are the current mainstay of topical therapy come with predictable side effects that dictate a 2- to 4-week limit on their approved use. Also, they’re not supposed to be applied to the face or to intertriginous sites, including the groin, axillae, and under the breasts. In contrast, tapinarof has proved safe and effective in these sensitive areas.
Asked to predict how tapinarof is likely to be used in clinical practice, Dr. Lebwohl replied: “The efficacy was equivalent to strong topical steroids, so I think it could be used first line in place of topical steroids. And in particular, in patients with psoriasis at facial and intertriginous sites, I think an argument can be made for insisting that it be first line.”
He also expects that physicians will end up utilizing tapinarof for a varied group of steroid-responsive dermatoses beyond psoriasis and atopic dermatitis.
“It clearly reduces inflammation, which is why I would expect it would work well for those,” the dermatologist said.
The mechanism of action of tapinarof has been worked out. The drug enters the cell and binds to the aryl hydrocarbon receptor, forming a complex that enters the nucleus. There it joins with the aryl hydrocarbon receptor nuclear translocator, which regulates gene expression so as to reduce production of inflammatory cytokines while promoting an increase in skin barrier proteins, which is why tapinarof is also being developed as an atopic dermatitis therapy.
Dr. Lebwohl and Dr. Stein Gold reported receiving research funds from and serving as consultants to Dermavant Sciences as well as numerous other pharmaceutical companies.
in two identical pivotal phase 3, randomized trials, Mark G. Lebwohl, MD, reported at the virtual annual congress of the European Academy of Dermatology and Venereology.
“Tapinarof cream has the potential to be a first-in-class topical therapeutic aryl hydrocarbon receptor modulating agent and will provide physicians and patients with a novel nonsteroidal topical treatment option that’s effective and well tolerated,” predicted Dr. Lebwohl, professor and chair of the department of dermatology at the Icahn School of Medicine at Mount Sinai, New York.
Dermavant Sciences, the company developing topical tapinarof for treatment of atopic dermatitis as well as psoriasis, announced that upon completion of an ongoing long-term extension study the company plans to file for approval of the drug for psoriasis in 2021.
The two pivotal phase 3 trials, PSOARING 1 and PSOARING 2, randomized a total of 1,025 patients with plaque psoriasis to once-daily tapinarof cream 1% or its vehicle. “This was a fairly difficult group of patients,” Dr. Lebwohl said. Roughly 80% had moderate psoriasis as defined by a baseline Physician Global Assessment (PGA) score of 3, with the remainder split evenly between mild and severe disease. Participants averaged 8% body surface area involvement. Body mass index was on average greater than 31 kg/m2.
The primary efficacy endpoint was a PGA score of 0 or 1 – that is, clear or almost clear – plus at least a 2-grade improvement in PGA from baseline at week 12. This was achieved in 35.4% of patients on tapinarof cream once daily in PSOARING 1 and 40.2% in PSOARING 2, compared with 6.0% and 6.3% of vehicle-treated controls, a highly significant difference (both P < .0001).
The prespecified secondary endpoint was a 75% improvement in Psoriasis Area and Severity Index (PASI) score from baseline to week 12. The PASI 75 rates were 36.1% and 47.6% with tapinarof, significantly better than the 10.2% and 6.9% rates in controls.
The most common adverse event associated with tapinarof was folliculitis, which occurred in 20.6% of treated patients in PSOARING 1 and in 15.7% in PSOARING 2. More than 98% of cases were mild or moderate. The folliculitis led to study discontinuation in only 1.8% and 0.9% of subjects in the two trials.
The other noteworthy adverse event was contact dermatitis. It occurred in 3.8% and 4.7% of tapinarof-treated patients, again with low study discontinuation rates of 1.5% and 2.2%.
During the audience discussion, Linda Stein Gold, MD, lead investigator for PSOARING 2, was asked about this folliculitis. She said the mechanism is unclear, as is the best management. She encountered it in patients, didn’t treat it, and it went away on its own. It’s not a bacterial folliculitis; when cultured it invariably proved culture negative, she noted.
The comparative efficacy of tapinarof cream versus the potent and superpotent topical corticosteroids commonly used in the treatment of psoriasis hasn’t been evaluated in head-to-head studies. Her experience and that of the other investigators has been that tapinarof’s efficacy is comparably strong, “but we don’t have the steroid side effects,” said Dr. Stein Gold, director of dermatology clinical research at Henry Ford Health System in Detroit.
In an interview, Dr. Lebwohl said tapinarof, if approved, could help meet a major unmet need for new and better topical therapies for psoriasis.
“You keep hearing about all these biologic agents and small-molecule pills coming out, but the majority of patients still only need topical therapy,” he observed.
Moreover, even when patients with more severe disease achieve a PASI 75 or PASI 90 response with systemic therapy, they usually still need supplemental topical therapy to get them closer to the goal of clear skin.
The superpotent steroids that are the current mainstay of topical therapy come with predictable side effects that dictate a 2- to 4-week limit on their approved use. Also, they’re not supposed to be applied to the face or to intertriginous sites, including the groin, axillae, and under the breasts. In contrast, tapinarof has proved safe and effective in these sensitive areas.
Asked to predict how tapinarof is likely to be used in clinical practice, Dr. Lebwohl replied: “The efficacy was equivalent to strong topical steroids, so I think it could be used first line in place of topical steroids. And in particular, in patients with psoriasis at facial and intertriginous sites, I think an argument can be made for insisting that it be first line.”
He also expects that physicians will end up utilizing tapinarof for a varied group of steroid-responsive dermatoses beyond psoriasis and atopic dermatitis.
“It clearly reduces inflammation, which is why I would expect it would work well for those,” the dermatologist said.
The mechanism of action of tapinarof has been worked out. The drug enters the cell and binds to the aryl hydrocarbon receptor, forming a complex that enters the nucleus. There it joins with the aryl hydrocarbon receptor nuclear translocator, which regulates gene expression so as to reduce production of inflammatory cytokines while promoting an increase in skin barrier proteins, which is why tapinarof is also being developed as an atopic dermatitis therapy.
Dr. Lebwohl and Dr. Stein Gold reported receiving research funds from and serving as consultants to Dermavant Sciences as well as numerous other pharmaceutical companies.
in two identical pivotal phase 3, randomized trials, Mark G. Lebwohl, MD, reported at the virtual annual congress of the European Academy of Dermatology and Venereology.
“Tapinarof cream has the potential to be a first-in-class topical therapeutic aryl hydrocarbon receptor modulating agent and will provide physicians and patients with a novel nonsteroidal topical treatment option that’s effective and well tolerated,” predicted Dr. Lebwohl, professor and chair of the department of dermatology at the Icahn School of Medicine at Mount Sinai, New York.
Dermavant Sciences, the company developing topical tapinarof for treatment of atopic dermatitis as well as psoriasis, announced that upon completion of an ongoing long-term extension study the company plans to file for approval of the drug for psoriasis in 2021.
The two pivotal phase 3 trials, PSOARING 1 and PSOARING 2, randomized a total of 1,025 patients with plaque psoriasis to once-daily tapinarof cream 1% or its vehicle. “This was a fairly difficult group of patients,” Dr. Lebwohl said. Roughly 80% had moderate psoriasis as defined by a baseline Physician Global Assessment (PGA) score of 3, with the remainder split evenly between mild and severe disease. Participants averaged 8% body surface area involvement. Body mass index was on average greater than 31 kg/m2.
The primary efficacy endpoint was a PGA score of 0 or 1 – that is, clear or almost clear – plus at least a 2-grade improvement in PGA from baseline at week 12. This was achieved in 35.4% of patients on tapinarof cream once daily in PSOARING 1 and 40.2% in PSOARING 2, compared with 6.0% and 6.3% of vehicle-treated controls, a highly significant difference (both P < .0001).
The prespecified secondary endpoint was a 75% improvement in Psoriasis Area and Severity Index (PASI) score from baseline to week 12. The PASI 75 rates were 36.1% and 47.6% with tapinarof, significantly better than the 10.2% and 6.9% rates in controls.
The most common adverse event associated with tapinarof was folliculitis, which occurred in 20.6% of treated patients in PSOARING 1 and in 15.7% in PSOARING 2. More than 98% of cases were mild or moderate. The folliculitis led to study discontinuation in only 1.8% and 0.9% of subjects in the two trials.
The other noteworthy adverse event was contact dermatitis. It occurred in 3.8% and 4.7% of tapinarof-treated patients, again with low study discontinuation rates of 1.5% and 2.2%.
During the audience discussion, Linda Stein Gold, MD, lead investigator for PSOARING 2, was asked about this folliculitis. She said the mechanism is unclear, as is the best management. She encountered it in patients, didn’t treat it, and it went away on its own. It’s not a bacterial folliculitis; when cultured it invariably proved culture negative, she noted.
The comparative efficacy of tapinarof cream versus the potent and superpotent topical corticosteroids commonly used in the treatment of psoriasis hasn’t been evaluated in head-to-head studies. Her experience and that of the other investigators has been that tapinarof’s efficacy is comparably strong, “but we don’t have the steroid side effects,” said Dr. Stein Gold, director of dermatology clinical research at Henry Ford Health System in Detroit.
In an interview, Dr. Lebwohl said tapinarof, if approved, could help meet a major unmet need for new and better topical therapies for psoriasis.
“You keep hearing about all these biologic agents and small-molecule pills coming out, but the majority of patients still only need topical therapy,” he observed.
Moreover, even when patients with more severe disease achieve a PASI 75 or PASI 90 response with systemic therapy, they usually still need supplemental topical therapy to get them closer to the goal of clear skin.
The superpotent steroids that are the current mainstay of topical therapy come with predictable side effects that dictate a 2- to 4-week limit on their approved use. Also, they’re not supposed to be applied to the face or to intertriginous sites, including the groin, axillae, and under the breasts. In contrast, tapinarof has proved safe and effective in these sensitive areas.
Asked to predict how tapinarof is likely to be used in clinical practice, Dr. Lebwohl replied: “The efficacy was equivalent to strong topical steroids, so I think it could be used first line in place of topical steroids. And in particular, in patients with psoriasis at facial and intertriginous sites, I think an argument can be made for insisting that it be first line.”
He also expects that physicians will end up utilizing tapinarof for a varied group of steroid-responsive dermatoses beyond psoriasis and atopic dermatitis.
“It clearly reduces inflammation, which is why I would expect it would work well for those,” the dermatologist said.
The mechanism of action of tapinarof has been worked out. The drug enters the cell and binds to the aryl hydrocarbon receptor, forming a complex that enters the nucleus. There it joins with the aryl hydrocarbon receptor nuclear translocator, which regulates gene expression so as to reduce production of inflammatory cytokines while promoting an increase in skin barrier proteins, which is why tapinarof is also being developed as an atopic dermatitis therapy.
Dr. Lebwohl and Dr. Stein Gold reported receiving research funds from and serving as consultants to Dermavant Sciences as well as numerous other pharmaceutical companies.
FROM THE EADV CONGRESS
Who’s at risk for depression on isotretinoin?
A Sanaa Butt, MD, reported at the virtual annual congress of the European Academy of Dermatology and Venereology.
This was, however, the sole identifiable risk factor for treatment-limiting depressive symptoms in acne patients on isotretinoin in the study of 3,151 consecutive acne patients taking isotretinoin. There was no significant difference between those who did or did not develop depression on the oral retinoid in terms of age, gender, or daily dose of the drug at the time it was discontinued.
“Depressive symptoms occurred at any time from the date of initiation of isotretinoin up to 6 months into therapy, with no identifiable peak time period,” said Dr. Butt, a dermatologist with the U.K. National Health Service Tayside district at Ninewells Hospital, Dundee, Scotland. “Lower doses appear not to be protective,” she added.
The Tayside district has a catchment of roughly 450,000 people. The local population tends to stay put because Tayside is an economically disadvantaged and remote part of Scotland. There are very few private practice dermatologists in the area, so Dr. Butt and coinvestigators are confident their observational study of NHS patients captured the great majority of isotretinoin users in northern Scotland.
The investigators utilized software to analyze the contents of more than 8,000 digitized letters exchanged between NHS Tayside dermatologists and general practitioners during 2005-2018, zeroing in on 3,151 consecutive patients on isotretinoin for acne and 158 on the drug for other conditions, most often rosacea or folliculitis. They then drilled down further through the letters, electronically searching for key words such as suicide, depression, and anxiety. In this way, they ultimately identified 30 patients who discontinued the drug because they developed depressive symptoms. All 30 were on the drug for acne.
The annual incidence of treatment-limiting depressive mood changes was 0.96%, a figure that remained steady over the 13-year study period, even though prescribing of isotretinoin increased over time. This flat incidence rate effectively rules out the potential for confounding because of assessor bias, especially since many different NHS dermatologists were prescribing the drug, Dr. Butt said.
Half of acne patients prescribed isotretinoin were female and 50% were male. And 15 cases of treatment discontinuation caused by development of depressive symptoms occurred in females, 15 in males. A history of past depressive illness was present in 9.3% of females who started on isotretinoin and in 4.5% of the males. The relative risk of treatment-limiting depressive mood changes was increased 790% among females with a prior history of depressive illness and 440% in males with such a history.
Dr. Butt reported having no financial conflicts regarding her NHS-funded study.
A Sanaa Butt, MD, reported at the virtual annual congress of the European Academy of Dermatology and Venereology.
This was, however, the sole identifiable risk factor for treatment-limiting depressive symptoms in acne patients on isotretinoin in the study of 3,151 consecutive acne patients taking isotretinoin. There was no significant difference between those who did or did not develop depression on the oral retinoid in terms of age, gender, or daily dose of the drug at the time it was discontinued.
“Depressive symptoms occurred at any time from the date of initiation of isotretinoin up to 6 months into therapy, with no identifiable peak time period,” said Dr. Butt, a dermatologist with the U.K. National Health Service Tayside district at Ninewells Hospital, Dundee, Scotland. “Lower doses appear not to be protective,” she added.
The Tayside district has a catchment of roughly 450,000 people. The local population tends to stay put because Tayside is an economically disadvantaged and remote part of Scotland. There are very few private practice dermatologists in the area, so Dr. Butt and coinvestigators are confident their observational study of NHS patients captured the great majority of isotretinoin users in northern Scotland.
The investigators utilized software to analyze the contents of more than 8,000 digitized letters exchanged between NHS Tayside dermatologists and general practitioners during 2005-2018, zeroing in on 3,151 consecutive patients on isotretinoin for acne and 158 on the drug for other conditions, most often rosacea or folliculitis. They then drilled down further through the letters, electronically searching for key words such as suicide, depression, and anxiety. In this way, they ultimately identified 30 patients who discontinued the drug because they developed depressive symptoms. All 30 were on the drug for acne.
The annual incidence of treatment-limiting depressive mood changes was 0.96%, a figure that remained steady over the 13-year study period, even though prescribing of isotretinoin increased over time. This flat incidence rate effectively rules out the potential for confounding because of assessor bias, especially since many different NHS dermatologists were prescribing the drug, Dr. Butt said.
Half of acne patients prescribed isotretinoin were female and 50% were male. And 15 cases of treatment discontinuation caused by development of depressive symptoms occurred in females, 15 in males. A history of past depressive illness was present in 9.3% of females who started on isotretinoin and in 4.5% of the males. The relative risk of treatment-limiting depressive mood changes was increased 790% among females with a prior history of depressive illness and 440% in males with such a history.
Dr. Butt reported having no financial conflicts regarding her NHS-funded study.
A Sanaa Butt, MD, reported at the virtual annual congress of the European Academy of Dermatology and Venereology.
This was, however, the sole identifiable risk factor for treatment-limiting depressive symptoms in acne patients on isotretinoin in the study of 3,151 consecutive acne patients taking isotretinoin. There was no significant difference between those who did or did not develop depression on the oral retinoid in terms of age, gender, or daily dose of the drug at the time it was discontinued.
“Depressive symptoms occurred at any time from the date of initiation of isotretinoin up to 6 months into therapy, with no identifiable peak time period,” said Dr. Butt, a dermatologist with the U.K. National Health Service Tayside district at Ninewells Hospital, Dundee, Scotland. “Lower doses appear not to be protective,” she added.
The Tayside district has a catchment of roughly 450,000 people. The local population tends to stay put because Tayside is an economically disadvantaged and remote part of Scotland. There are very few private practice dermatologists in the area, so Dr. Butt and coinvestigators are confident their observational study of NHS patients captured the great majority of isotretinoin users in northern Scotland.
The investigators utilized software to analyze the contents of more than 8,000 digitized letters exchanged between NHS Tayside dermatologists and general practitioners during 2005-2018, zeroing in on 3,151 consecutive patients on isotretinoin for acne and 158 on the drug for other conditions, most often rosacea or folliculitis. They then drilled down further through the letters, electronically searching for key words such as suicide, depression, and anxiety. In this way, they ultimately identified 30 patients who discontinued the drug because they developed depressive symptoms. All 30 were on the drug for acne.
The annual incidence of treatment-limiting depressive mood changes was 0.96%, a figure that remained steady over the 13-year study period, even though prescribing of isotretinoin increased over time. This flat incidence rate effectively rules out the potential for confounding because of assessor bias, especially since many different NHS dermatologists were prescribing the drug, Dr. Butt said.
Half of acne patients prescribed isotretinoin were female and 50% were male. And 15 cases of treatment discontinuation caused by development of depressive symptoms occurred in females, 15 in males. A history of past depressive illness was present in 9.3% of females who started on isotretinoin and in 4.5% of the males. The relative risk of treatment-limiting depressive mood changes was increased 790% among females with a prior history of depressive illness and 440% in males with such a history.
Dr. Butt reported having no financial conflicts regarding her NHS-funded study.
FROM THE EADV CONGRESS
Gene-replacement therapy shows promise in X-linked myotubular myopathy
, according to research presented at the 2020 CNS-ICNA Conjoint Meeting, which was held virtually this year. The treatment also appears to improve patients’ motor function significantly and help them to achieve motor milestones.
The results come from a phase 1/2 study of two doses of AT132. Three of 17 patients who received the higher dose had fatal liver dysfunction. The researchers are investigating these cases and will communicate their findings.
X-linked myotubular myopathy is a rare and often fatal neuromuscular disease. Mutations in MTM1, which encodes the myotubularin enzyme that is required for the development and function of skeletal muscle, cause the disease, which affects about one in 50,000 to one in 40,000 newborn boys. The disease is associated with profound muscle weakness and impairment of neuromuscular and respiratory function. Patients with X-linked myotubular myopathy achieve motor milestones much later or not at all, and most require a ventilator or a feeding tube. The mortality by age 18 months is approximately 50%.
The ASPIRO trial
Investigators theorized that muscle tissue would be an appropriate therapeutic target because it does not display dystrophic or inflammatory changes in most patients. They identified adeno-associated virus AAV8 as a potential carrier for gene therapy, since it targets skeletal muscle effectively.
Nancy L. Kuntz, MD, an attending physician at Ann and Robert H. Lurie Children’s Hospital of Chicago, and colleagues conducted the ASPIRO trial to examine AT132 as a potential treatment for X-linked myotubular myopathy. Eligible patients were younger than 5 years or had previously enrolled in a natural history study of the disease, required ventilator support at baseline, and had no clinically significant underlying liver disease. Patients were randomly assigned to 1 × 1014 vg/kg of AAT132, 3 × 1014 vg/kg of AT132, or delayed treatment. Participants assigned to delayed treatment served as the study’s control group.
The study’s primary end points were safety and change in hours of daily ventilator support from baseline to week 24 after dosing. The investigators also examined a respiratory endpoint (i.e., maximal inspiratory pressure [MIP]) and neuromuscular endpoints (i.e., motor milestones, CHOP INTEND score, and muscle biopsy).
Treatment improved respiratory function
As of July 28, Dr. Kuntz and colleagues had enrolled 23 patients in the trial. Six participants received the lower dose of therapy, and 17 received the higher dose. Median age was 1.7 years for the low-dose group and 2.6 years for the high-dose group.
Patients assigned to receive the higher dose of therapy received treatment more recently than the low-dose group, and not all of the former have reached 48 weeks since treatment, said Dr. Kuntz. Fewer efficacy data are thus available for the high-dose group.
Each dose of AT132 was associated with a significantly greater decrease from baseline in least squares mean daily hours of ventilator dependence, compared with the control condition. At week 48, the mean reduction was approximately 19 hours/day for patients receiving 1 × 1014 vg/kg of AAT132 and approximately 13 hours per day for patients receiving 3 × 1014 vg/kg of AT132. The investigators did not perform a statistical comparison of the two doses because of differing protocols for ventilator weaning between groups. All six patients who received the lower dose achieved ventilator independence, as did one patient who received the higher dose.
In addition, all treated patients had significantly greater increases from baseline in least squares mean MIP, compared with controls. The mean increase was 45.7 cmH2O for the low-dose group, 46.1 cmH2O for the high-dose group, and −8.0 cmH2O for controls.
Before treatment, most patients had not achieved any of the motor milestones that investigators assessed. After treatment, five of six patients receiving the low dose achieved independent walking, as did one in 10 patients receiving the high dose. No controls achieved this milestone. Treated patients also had significantly greater increases from baseline in least squares mean CHOP INTEND scores, compared with controls. At least at one time point, five of six patients receiving the low dose, six of 10 patients receiving the high dose, and one control patient achieved the mean score observed in healthy infants.
Patients in both treatment arms had improvements in muscle pathology at weeks 24 and 48, including improvements in organelle localization and fiber size. In addition, patients in both treatment arms had continued detectable vector copies and myotubularin protein expression at both time points.
Deaths under investigation
In the low-dose group, one patient had four serious treatment-emergent adverse events, and in the high-dose group, eight patients had 27 serious treatment-emergent adverse events. The three patients in the high-dose group who developed fatal liver dysfunction were among the older, heavier patients in the study and, consequently, received among the highest total doses of treatment. These patients had evidence of likely preexisting intrahepatic cholestasis.
“This clinical trial is on hold pending discussions between regulatory agencies and the study sponsor regarding additional recruitment and the duration of follow-up,” said Dr. Kuntz.
Audentes Therapeutics, which is developing AT132, funded the trial. Dr. Kuntz had no conflicts of interest.
SOURCE: Bönnemann CG et al. CNS-ICNA 2020, Abstract P.62.
, according to research presented at the 2020 CNS-ICNA Conjoint Meeting, which was held virtually this year. The treatment also appears to improve patients’ motor function significantly and help them to achieve motor milestones.
The results come from a phase 1/2 study of two doses of AT132. Three of 17 patients who received the higher dose had fatal liver dysfunction. The researchers are investigating these cases and will communicate their findings.
X-linked myotubular myopathy is a rare and often fatal neuromuscular disease. Mutations in MTM1, which encodes the myotubularin enzyme that is required for the development and function of skeletal muscle, cause the disease, which affects about one in 50,000 to one in 40,000 newborn boys. The disease is associated with profound muscle weakness and impairment of neuromuscular and respiratory function. Patients with X-linked myotubular myopathy achieve motor milestones much later or not at all, and most require a ventilator or a feeding tube. The mortality by age 18 months is approximately 50%.
The ASPIRO trial
Investigators theorized that muscle tissue would be an appropriate therapeutic target because it does not display dystrophic or inflammatory changes in most patients. They identified adeno-associated virus AAV8 as a potential carrier for gene therapy, since it targets skeletal muscle effectively.
Nancy L. Kuntz, MD, an attending physician at Ann and Robert H. Lurie Children’s Hospital of Chicago, and colleagues conducted the ASPIRO trial to examine AT132 as a potential treatment for X-linked myotubular myopathy. Eligible patients were younger than 5 years or had previously enrolled in a natural history study of the disease, required ventilator support at baseline, and had no clinically significant underlying liver disease. Patients were randomly assigned to 1 × 1014 vg/kg of AAT132, 3 × 1014 vg/kg of AT132, or delayed treatment. Participants assigned to delayed treatment served as the study’s control group.
The study’s primary end points were safety and change in hours of daily ventilator support from baseline to week 24 after dosing. The investigators also examined a respiratory endpoint (i.e., maximal inspiratory pressure [MIP]) and neuromuscular endpoints (i.e., motor milestones, CHOP INTEND score, and muscle biopsy).
Treatment improved respiratory function
As of July 28, Dr. Kuntz and colleagues had enrolled 23 patients in the trial. Six participants received the lower dose of therapy, and 17 received the higher dose. Median age was 1.7 years for the low-dose group and 2.6 years for the high-dose group.
Patients assigned to receive the higher dose of therapy received treatment more recently than the low-dose group, and not all of the former have reached 48 weeks since treatment, said Dr. Kuntz. Fewer efficacy data are thus available for the high-dose group.
Each dose of AT132 was associated with a significantly greater decrease from baseline in least squares mean daily hours of ventilator dependence, compared with the control condition. At week 48, the mean reduction was approximately 19 hours/day for patients receiving 1 × 1014 vg/kg of AAT132 and approximately 13 hours per day for patients receiving 3 × 1014 vg/kg of AT132. The investigators did not perform a statistical comparison of the two doses because of differing protocols for ventilator weaning between groups. All six patients who received the lower dose achieved ventilator independence, as did one patient who received the higher dose.
In addition, all treated patients had significantly greater increases from baseline in least squares mean MIP, compared with controls. The mean increase was 45.7 cmH2O for the low-dose group, 46.1 cmH2O for the high-dose group, and −8.0 cmH2O for controls.
Before treatment, most patients had not achieved any of the motor milestones that investigators assessed. After treatment, five of six patients receiving the low dose achieved independent walking, as did one in 10 patients receiving the high dose. No controls achieved this milestone. Treated patients also had significantly greater increases from baseline in least squares mean CHOP INTEND scores, compared with controls. At least at one time point, five of six patients receiving the low dose, six of 10 patients receiving the high dose, and one control patient achieved the mean score observed in healthy infants.
Patients in both treatment arms had improvements in muscle pathology at weeks 24 and 48, including improvements in organelle localization and fiber size. In addition, patients in both treatment arms had continued detectable vector copies and myotubularin protein expression at both time points.
Deaths under investigation
In the low-dose group, one patient had four serious treatment-emergent adverse events, and in the high-dose group, eight patients had 27 serious treatment-emergent adverse events. The three patients in the high-dose group who developed fatal liver dysfunction were among the older, heavier patients in the study and, consequently, received among the highest total doses of treatment. These patients had evidence of likely preexisting intrahepatic cholestasis.
“This clinical trial is on hold pending discussions between regulatory agencies and the study sponsor regarding additional recruitment and the duration of follow-up,” said Dr. Kuntz.
Audentes Therapeutics, which is developing AT132, funded the trial. Dr. Kuntz had no conflicts of interest.
SOURCE: Bönnemann CG et al. CNS-ICNA 2020, Abstract P.62.
, according to research presented at the 2020 CNS-ICNA Conjoint Meeting, which was held virtually this year. The treatment also appears to improve patients’ motor function significantly and help them to achieve motor milestones.
The results come from a phase 1/2 study of two doses of AT132. Three of 17 patients who received the higher dose had fatal liver dysfunction. The researchers are investigating these cases and will communicate their findings.
X-linked myotubular myopathy is a rare and often fatal neuromuscular disease. Mutations in MTM1, which encodes the myotubularin enzyme that is required for the development and function of skeletal muscle, cause the disease, which affects about one in 50,000 to one in 40,000 newborn boys. The disease is associated with profound muscle weakness and impairment of neuromuscular and respiratory function. Patients with X-linked myotubular myopathy achieve motor milestones much later or not at all, and most require a ventilator or a feeding tube. The mortality by age 18 months is approximately 50%.
The ASPIRO trial
Investigators theorized that muscle tissue would be an appropriate therapeutic target because it does not display dystrophic or inflammatory changes in most patients. They identified adeno-associated virus AAV8 as a potential carrier for gene therapy, since it targets skeletal muscle effectively.
Nancy L. Kuntz, MD, an attending physician at Ann and Robert H. Lurie Children’s Hospital of Chicago, and colleagues conducted the ASPIRO trial to examine AT132 as a potential treatment for X-linked myotubular myopathy. Eligible patients were younger than 5 years or had previously enrolled in a natural history study of the disease, required ventilator support at baseline, and had no clinically significant underlying liver disease. Patients were randomly assigned to 1 × 1014 vg/kg of AAT132, 3 × 1014 vg/kg of AT132, or delayed treatment. Participants assigned to delayed treatment served as the study’s control group.
The study’s primary end points were safety and change in hours of daily ventilator support from baseline to week 24 after dosing. The investigators also examined a respiratory endpoint (i.e., maximal inspiratory pressure [MIP]) and neuromuscular endpoints (i.e., motor milestones, CHOP INTEND score, and muscle biopsy).
Treatment improved respiratory function
As of July 28, Dr. Kuntz and colleagues had enrolled 23 patients in the trial. Six participants received the lower dose of therapy, and 17 received the higher dose. Median age was 1.7 years for the low-dose group and 2.6 years for the high-dose group.
Patients assigned to receive the higher dose of therapy received treatment more recently than the low-dose group, and not all of the former have reached 48 weeks since treatment, said Dr. Kuntz. Fewer efficacy data are thus available for the high-dose group.
Each dose of AT132 was associated with a significantly greater decrease from baseline in least squares mean daily hours of ventilator dependence, compared with the control condition. At week 48, the mean reduction was approximately 19 hours/day for patients receiving 1 × 1014 vg/kg of AAT132 and approximately 13 hours per day for patients receiving 3 × 1014 vg/kg of AT132. The investigators did not perform a statistical comparison of the two doses because of differing protocols for ventilator weaning between groups. All six patients who received the lower dose achieved ventilator independence, as did one patient who received the higher dose.
In addition, all treated patients had significantly greater increases from baseline in least squares mean MIP, compared with controls. The mean increase was 45.7 cmH2O for the low-dose group, 46.1 cmH2O for the high-dose group, and −8.0 cmH2O for controls.
Before treatment, most patients had not achieved any of the motor milestones that investigators assessed. After treatment, five of six patients receiving the low dose achieved independent walking, as did one in 10 patients receiving the high dose. No controls achieved this milestone. Treated patients also had significantly greater increases from baseline in least squares mean CHOP INTEND scores, compared with controls. At least at one time point, five of six patients receiving the low dose, six of 10 patients receiving the high dose, and one control patient achieved the mean score observed in healthy infants.
Patients in both treatment arms had improvements in muscle pathology at weeks 24 and 48, including improvements in organelle localization and fiber size. In addition, patients in both treatment arms had continued detectable vector copies and myotubularin protein expression at both time points.
Deaths under investigation
In the low-dose group, one patient had four serious treatment-emergent adverse events, and in the high-dose group, eight patients had 27 serious treatment-emergent adverse events. The three patients in the high-dose group who developed fatal liver dysfunction were among the older, heavier patients in the study and, consequently, received among the highest total doses of treatment. These patients had evidence of likely preexisting intrahepatic cholestasis.
“This clinical trial is on hold pending discussions between regulatory agencies and the study sponsor regarding additional recruitment and the duration of follow-up,” said Dr. Kuntz.
Audentes Therapeutics, which is developing AT132, funded the trial. Dr. Kuntz had no conflicts of interest.
SOURCE: Bönnemann CG et al. CNS-ICNA 2020, Abstract P.62.
FROM CNS-ICNA 2020
Home spirometry improved monitoring of cystic fibrosis patients during COVID-19 pandemic
Home spirometry has become increasingly used among cystic fibrosis patients during the COVID-19 pandemic, and new research suggests that home devices perform reasonably well. Forced expiratory volume in 1 second (FEV1) values were a bit lower than values seen in clinical spirometry performed in the same patient at a nearby time point, but the procedure reliably picked up decreases in FEV1, potentially helping patients and clinicians spot exacerbations early.
“Home spirometry was sort of a curiosity that was slowly working its way into cystic fibrosis research in 2019, and then all of a sudden in 2020 it became front and center as the only way to continue with clinical monitoring and research in many cases,” Alexander Paynter, MS, a biostatistician at the Cystic Fibrosis Foundation’s Therapeutic Development Network Coordinating Center, said during a talk at the virtual North American Cystic Fibrosis Conference.
To better determine how closely home spirometry matches clinical spirometry, Mr. Paynter and his colleagues analyzed data from the eICE study, which included 267 cystic fibrosis patients aged 14 and over at 14 cystic fibrosis centers. They were randomized to use home spirometry as an early intervention to detect exacerbations, or to continue usual clinic care with visits to the clinic every 3 months. The dataset includes twice-weekly home spirometry values, with a full-year of follow-up data. The researchers compared the home spirometry data to the clinical data closest in time to it. Clinic spirometry data with no corresponding home data within 7 days were discarded.
There was an estimated difference of –2.01 mL between home and clinic tests, with home spirometry producing lower values (95% confidence interval, –3.56 to –0.45). “There is actually a bias in home spirometry as compared to clinic spirometry,” concluded Mr. Paynter.
One explanation for lower values in home spirometry is that users are inexperienced with the device. If that’s true, then agreement should improve over time, but the researchers didn’t see strong evidence of that. Among 44 patients who completed five clinical visits, there was a difference of –2.97 (standard deviation [SD], 10.51) at baseline, –1.66 at 3 months (SD, 13.49), –3.7 at 6 months (SD, 12.44), –0.86 at 9 months (SD, 13.73), and –0.53 at 12 months (SD, 13.35). Though there was improvement over time, “we don’t find a lot of evidence that this bias completely resolves,” said Mr. Paynter.
In fact, a more likely explanation is the presence of coaching by a technician during clinical spirometry, according to Robert J. Giusti, MD, clinical professor of pediatrics and director of the Pediatric Cystic Fibrosis Center at New York University. “When they’re doing it at home, they don’t do it with the same effort, so I think that coaching through telemedicine during the home spirometry would make that difference disappear,” he said when asked to comment on the study.
The researchers found that change-based endpoints were similar between clinic and at-home spirometry. Compared to baseline, the two showed similar declines over time. “The clinic and home observations tend to track each other pretty well. At 6 months, for instance, it’s about a change of three points decrease (in both). But the bad news is that the variability is much greater in home devices,” said Mr. Paynter, noting larger confidence intervals and standard deviation values associated with home spirometry. That could influence future clinical designs that may rely on home spirometry, since a larger confidence interval means reduced power, which could double or even quadruple the number of participants needed to achieve the required power, he said.
But from a clinical standpoint, the ability of home spirometry to consistently detect a change from baseline could be quite valuable to future patient management, according to Dr. Giusti. “It looks like home spirometry will show that kind of a decrease, so that it’s still sensitive to pick up the concern that a patient is getting worse at home,” he said.
That could be useful even after the COVID-19 pandemic passes, as patients continue to embrace home monitoring. Physicians could keep track of patients and keep them focused on their care and treatment through frequent telemedicine visits combined with home spirometry. “I really think home spirometry will keep us more focused on how the patients are doing and make for better outcomes,” said Dr. Giusti.
Mr. Paynter and Dr. Giusti have no relevant financial disclosures.
SOURCE: Alex Paynter et al. NACFC 2020. Poster 643.
Home spirometry has become increasingly used among cystic fibrosis patients during the COVID-19 pandemic, and new research suggests that home devices perform reasonably well. Forced expiratory volume in 1 second (FEV1) values were a bit lower than values seen in clinical spirometry performed in the same patient at a nearby time point, but the procedure reliably picked up decreases in FEV1, potentially helping patients and clinicians spot exacerbations early.
“Home spirometry was sort of a curiosity that was slowly working its way into cystic fibrosis research in 2019, and then all of a sudden in 2020 it became front and center as the only way to continue with clinical monitoring and research in many cases,” Alexander Paynter, MS, a biostatistician at the Cystic Fibrosis Foundation’s Therapeutic Development Network Coordinating Center, said during a talk at the virtual North American Cystic Fibrosis Conference.
To better determine how closely home spirometry matches clinical spirometry, Mr. Paynter and his colleagues analyzed data from the eICE study, which included 267 cystic fibrosis patients aged 14 and over at 14 cystic fibrosis centers. They were randomized to use home spirometry as an early intervention to detect exacerbations, or to continue usual clinic care with visits to the clinic every 3 months. The dataset includes twice-weekly home spirometry values, with a full-year of follow-up data. The researchers compared the home spirometry data to the clinical data closest in time to it. Clinic spirometry data with no corresponding home data within 7 days were discarded.
There was an estimated difference of –2.01 mL between home and clinic tests, with home spirometry producing lower values (95% confidence interval, –3.56 to –0.45). “There is actually a bias in home spirometry as compared to clinic spirometry,” concluded Mr. Paynter.
One explanation for lower values in home spirometry is that users are inexperienced with the device. If that’s true, then agreement should improve over time, but the researchers didn’t see strong evidence of that. Among 44 patients who completed five clinical visits, there was a difference of –2.97 (standard deviation [SD], 10.51) at baseline, –1.66 at 3 months (SD, 13.49), –3.7 at 6 months (SD, 12.44), –0.86 at 9 months (SD, 13.73), and –0.53 at 12 months (SD, 13.35). Though there was improvement over time, “we don’t find a lot of evidence that this bias completely resolves,” said Mr. Paynter.
In fact, a more likely explanation is the presence of coaching by a technician during clinical spirometry, according to Robert J. Giusti, MD, clinical professor of pediatrics and director of the Pediatric Cystic Fibrosis Center at New York University. “When they’re doing it at home, they don’t do it with the same effort, so I think that coaching through telemedicine during the home spirometry would make that difference disappear,” he said when asked to comment on the study.
The researchers found that change-based endpoints were similar between clinic and at-home spirometry. Compared to baseline, the two showed similar declines over time. “The clinic and home observations tend to track each other pretty well. At 6 months, for instance, it’s about a change of three points decrease (in both). But the bad news is that the variability is much greater in home devices,” said Mr. Paynter, noting larger confidence intervals and standard deviation values associated with home spirometry. That could influence future clinical designs that may rely on home spirometry, since a larger confidence interval means reduced power, which could double or even quadruple the number of participants needed to achieve the required power, he said.
But from a clinical standpoint, the ability of home spirometry to consistently detect a change from baseline could be quite valuable to future patient management, according to Dr. Giusti. “It looks like home spirometry will show that kind of a decrease, so that it’s still sensitive to pick up the concern that a patient is getting worse at home,” he said.
That could be useful even after the COVID-19 pandemic passes, as patients continue to embrace home monitoring. Physicians could keep track of patients and keep them focused on their care and treatment through frequent telemedicine visits combined with home spirometry. “I really think home spirometry will keep us more focused on how the patients are doing and make for better outcomes,” said Dr. Giusti.
Mr. Paynter and Dr. Giusti have no relevant financial disclosures.
SOURCE: Alex Paynter et al. NACFC 2020. Poster 643.
Home spirometry has become increasingly used among cystic fibrosis patients during the COVID-19 pandemic, and new research suggests that home devices perform reasonably well. Forced expiratory volume in 1 second (FEV1) values were a bit lower than values seen in clinical spirometry performed in the same patient at a nearby time point, but the procedure reliably picked up decreases in FEV1, potentially helping patients and clinicians spot exacerbations early.
“Home spirometry was sort of a curiosity that was slowly working its way into cystic fibrosis research in 2019, and then all of a sudden in 2020 it became front and center as the only way to continue with clinical monitoring and research in many cases,” Alexander Paynter, MS, a biostatistician at the Cystic Fibrosis Foundation’s Therapeutic Development Network Coordinating Center, said during a talk at the virtual North American Cystic Fibrosis Conference.
To better determine how closely home spirometry matches clinical spirometry, Mr. Paynter and his colleagues analyzed data from the eICE study, which included 267 cystic fibrosis patients aged 14 and over at 14 cystic fibrosis centers. They were randomized to use home spirometry as an early intervention to detect exacerbations, or to continue usual clinic care with visits to the clinic every 3 months. The dataset includes twice-weekly home spirometry values, with a full-year of follow-up data. The researchers compared the home spirometry data to the clinical data closest in time to it. Clinic spirometry data with no corresponding home data within 7 days were discarded.
There was an estimated difference of –2.01 mL between home and clinic tests, with home spirometry producing lower values (95% confidence interval, –3.56 to –0.45). “There is actually a bias in home spirometry as compared to clinic spirometry,” concluded Mr. Paynter.
One explanation for lower values in home spirometry is that users are inexperienced with the device. If that’s true, then agreement should improve over time, but the researchers didn’t see strong evidence of that. Among 44 patients who completed five clinical visits, there was a difference of –2.97 (standard deviation [SD], 10.51) at baseline, –1.66 at 3 months (SD, 13.49), –3.7 at 6 months (SD, 12.44), –0.86 at 9 months (SD, 13.73), and –0.53 at 12 months (SD, 13.35). Though there was improvement over time, “we don’t find a lot of evidence that this bias completely resolves,” said Mr. Paynter.
In fact, a more likely explanation is the presence of coaching by a technician during clinical spirometry, according to Robert J. Giusti, MD, clinical professor of pediatrics and director of the Pediatric Cystic Fibrosis Center at New York University. “When they’re doing it at home, they don’t do it with the same effort, so I think that coaching through telemedicine during the home spirometry would make that difference disappear,” he said when asked to comment on the study.
The researchers found that change-based endpoints were similar between clinic and at-home spirometry. Compared to baseline, the two showed similar declines over time. “The clinic and home observations tend to track each other pretty well. At 6 months, for instance, it’s about a change of three points decrease (in both). But the bad news is that the variability is much greater in home devices,” said Mr. Paynter, noting larger confidence intervals and standard deviation values associated with home spirometry. That could influence future clinical designs that may rely on home spirometry, since a larger confidence interval means reduced power, which could double or even quadruple the number of participants needed to achieve the required power, he said.
But from a clinical standpoint, the ability of home spirometry to consistently detect a change from baseline could be quite valuable to future patient management, according to Dr. Giusti. “It looks like home spirometry will show that kind of a decrease, so that it’s still sensitive to pick up the concern that a patient is getting worse at home,” he said.
That could be useful even after the COVID-19 pandemic passes, as patients continue to embrace home monitoring. Physicians could keep track of patients and keep them focused on their care and treatment through frequent telemedicine visits combined with home spirometry. “I really think home spirometry will keep us more focused on how the patients are doing and make for better outcomes,” said Dr. Giusti.
Mr. Paynter and Dr. Giusti have no relevant financial disclosures.
SOURCE: Alex Paynter et al. NACFC 2020. Poster 643.
FROM NACFC 2020
Low-dose radiotherapy for lung inflammation in severe COVID-19
The first study to suggest benefit from low-dose radiotherapy for severe COVID-19–induced pneumonia involved only 20 patients, but the results were so promising that two larger randomized trials are now underway.
“RESCUE-119 was a trial based on the hypothesis that low-dose radiation therapy may help eliminate the stormy cytokine release and unchecked edema in hospitalized COVID-19 patients,” said Mohammed Khan, MD, PhD, Winship Cancer Institute of Emory University, Atlanta.
“We found patients had a quicker improvement in their time to clinical recovery with low-dose radiation therapy, compared to controls, and this was significant even in this small cohort of patients,” he said.
Dr. Khan was speaking at a special press briefing held during the virtual American Society for Radiation Oncology Annual Meeting 2020.
A total of 20 patients were involved in the trial. Ten patients were treated with low-dose radiotherapy; 10 others, who served as control patients, were treated with the best supportive care and COVID-directed therapies. The control patients were matched for age and comorbidities. All these patients were hospitalized and were oxygen dependent, Dr. Khan noted. In addition, for all patients, serial x-rays demonstrated consolidation and damage in the lung.
The intervention consisted of whole-lung low-dose radiotherapy delivered at a dose of 1.5 Gy.
The first five patients were assessed at an interim endpoint of 7 days to confirm the safety of the procedure. Subsequently, a total of 10 patients were treated with radiotherapy and were followed to day 28.
The main study endpoints were time to clinical recovery, determined on the basis of the patient’s being taken off oxygen, and improvement, evidenced on either serial x-rays or by inflammatory biomarkers.
The median time to clinical recovery was almost three times faster for the patients who received low-dose radiotherapy, at a median of 3 days; for control patients, the median was 12 days (P = .048).
“We also saw a trend toward getting patients out of hospital sooner,” Dr. Khan added. The mean time to hospital discharge was 12 days for the patients who received low-dose radiotherapy, compared with 20 days for control patients (P = .19).
Only one patient required intubation after receiving low-dose radiotherapy, whereas 4 of 10 control patients required some sort of intubation (P = .12), he noted.
Investigators also saw improvements on serial x-rays in 9 of 10 patients treated with low-dose radiotherapy, compared with only 4 patients in the control group. There was also a significant improvement in delirium among the low-dose radiotherapy group compared with control patients (P < .01). Before receiving low-dose radiotherapy, C-reactive protein levels increased by 22% per day. After receiving the 1.5-Gy radiation treatment, there was a sharp reduction in C-reactive protein levels (P < .01) as well as in lactate dehydrogenase levels (P = .03).
Overall survival, however, did not differ between the two treatment groups; 90% of both groups were alive at day 28.
“By focally dampening cytokine hyperactivation, [low-dose radiotherapy] may improve COVID-19 outcomes through immunomodulation,” Dr. Khan explained.
VENTED and PRE-VENT trials
These results from the small RESCUE-119 trial led to the launch of two larger phase 2 trials, the VENTED and the PRE-VENT trials, noted Arnab Chakravarti, MD, professor and chair of radiation oncology, the Ohio State University Comprehensive Cancer Center, Columbus.
To be enrolled in the VENTED trial, patients must have received mechanical ventilation. They will receive at least one dose of ultra-low-dose bilateral whole-lung radiotherapy, with the option of receiving a second dose. The primary objective is 30-day mortality rate.
“The hypothesis is that low-dose thoracic radiation will decrease inflammation and improve outcomes for these intubated COVID-19 patients,” Dr. Chakravarti explained.
The PRE-VENT trial will explore low-dose thoracic radiotherapy for hospitalized patients with severe respiratory compromise who have not yet been intubated. Two doses of low-dose radiotherapy will be tested and compared. The primary study objective is to determine which of the two doses appears to be the most efficacious, Dr. Chakravarti noted.
“The ultimate question to which we remain agnostic is whether the potential benefits of low-dose radiation therapy outweigh the risks,” he said.
Low-dose radiotherapy is readily available in most countries, unlike the newly developed COVID-19 drugs, which are only available in the developed world, he noted. “This creates a bit more economic equity in terms of COVID-19 treatment.”
In addition, it may offer a therapeutic option that could be useful in the future, “as low-dose radiation therapy does not discriminate against various viruses that may cause another pandemic,” he commented. It could offer “a stopgap measure where we don’t have to shut down society completely, which, as we have all witnessed, can cause tremendous financial and social unrest.”
Reasonable question
Whether or not radiotherapy has value for the short-term management of severe pulmonary inflammation caused by COVID-19 is a reasonable question to evaluate in clinical trials, commented discussant Ramesh Rengan, MD, PhD, professor and chair, department of radiation oncology, University of Washington, Seattle.
He noted that inflammatory cells are highly sensitive to radiation, and low-dose radiotherapy has been used effectively in other inflammatory conditions, such as arthritis. Indeed, before the discovery of antibiotics, low-dose radiation was used with reasonable efficacy to treat pneumonia.
“The pneumonia associated with this viral infection is a bit unique in that what happens is the infection triggers an inflammatory cascade – the so-called cytokine storm – that essentially overwhelms the lungs, thereby leading, unfortunately, to mortality,” Dr. Rengan noted. “So a big focus of our energy is how to stop this inflammatory cascade from occurring.”
Corticosteroids are currently the only therapeutic intervention that has shown any mortality benefit in COVID-19, he pointed out.
The question now being asked is: “Can we suppress inflammation specifically within the lung?” Dr. Rengan continued. The main problem with radiotherapy is that it has different effects on various tissues, both immediately and over the long term.
“The immediate benefit that we will likely see from these studies is the immediate sterilization of inflammatory cells,” he said. However, injury to normal lung tissue from low-dose radiotherapy could lead to inflammation weeks or months later, and this could contribute to the disease burden and increase the risk of dying.
Dr. Rengan also noted that there are some very real practical concerns about offering radiotherapy to COVID-19 patients, including potential COVID-19 transmission to vulnerable cancer patients.
Nevertheless, Dr. Rengan said the results to date are very important and that ongoing trials will provide important new information about the long-term impact of this particular treatment in high-risk patients.
“This is a race to the bottom – we are trying to find the lowest possible dose of radiation therapy that we can deliver to sterilize these inflammatory cells without creating any harm to the surrounding tissue,” he said.
“It also brings radiation oncologists into the fight against this deadly disease,” he added.
Dr. Rengan has received honoraria from Novocur and has served as a consultant to AstraZeneca.
A version of this article originally appeared on Medscape.com.
The first study to suggest benefit from low-dose radiotherapy for severe COVID-19–induced pneumonia involved only 20 patients, but the results were so promising that two larger randomized trials are now underway.
“RESCUE-119 was a trial based on the hypothesis that low-dose radiation therapy may help eliminate the stormy cytokine release and unchecked edema in hospitalized COVID-19 patients,” said Mohammed Khan, MD, PhD, Winship Cancer Institute of Emory University, Atlanta.
“We found patients had a quicker improvement in their time to clinical recovery with low-dose radiation therapy, compared to controls, and this was significant even in this small cohort of patients,” he said.
Dr. Khan was speaking at a special press briefing held during the virtual American Society for Radiation Oncology Annual Meeting 2020.
A total of 20 patients were involved in the trial. Ten patients were treated with low-dose radiotherapy; 10 others, who served as control patients, were treated with the best supportive care and COVID-directed therapies. The control patients were matched for age and comorbidities. All these patients were hospitalized and were oxygen dependent, Dr. Khan noted. In addition, for all patients, serial x-rays demonstrated consolidation and damage in the lung.
The intervention consisted of whole-lung low-dose radiotherapy delivered at a dose of 1.5 Gy.
The first five patients were assessed at an interim endpoint of 7 days to confirm the safety of the procedure. Subsequently, a total of 10 patients were treated with radiotherapy and were followed to day 28.
The main study endpoints were time to clinical recovery, determined on the basis of the patient’s being taken off oxygen, and improvement, evidenced on either serial x-rays or by inflammatory biomarkers.
The median time to clinical recovery was almost three times faster for the patients who received low-dose radiotherapy, at a median of 3 days; for control patients, the median was 12 days (P = .048).
“We also saw a trend toward getting patients out of hospital sooner,” Dr. Khan added. The mean time to hospital discharge was 12 days for the patients who received low-dose radiotherapy, compared with 20 days for control patients (P = .19).
Only one patient required intubation after receiving low-dose radiotherapy, whereas 4 of 10 control patients required some sort of intubation (P = .12), he noted.
Investigators also saw improvements on serial x-rays in 9 of 10 patients treated with low-dose radiotherapy, compared with only 4 patients in the control group. There was also a significant improvement in delirium among the low-dose radiotherapy group compared with control patients (P < .01). Before receiving low-dose radiotherapy, C-reactive protein levels increased by 22% per day. After receiving the 1.5-Gy radiation treatment, there was a sharp reduction in C-reactive protein levels (P < .01) as well as in lactate dehydrogenase levels (P = .03).
Overall survival, however, did not differ between the two treatment groups; 90% of both groups were alive at day 28.
“By focally dampening cytokine hyperactivation, [low-dose radiotherapy] may improve COVID-19 outcomes through immunomodulation,” Dr. Khan explained.
VENTED and PRE-VENT trials
These results from the small RESCUE-119 trial led to the launch of two larger phase 2 trials, the VENTED and the PRE-VENT trials, noted Arnab Chakravarti, MD, professor and chair of radiation oncology, the Ohio State University Comprehensive Cancer Center, Columbus.
To be enrolled in the VENTED trial, patients must have received mechanical ventilation. They will receive at least one dose of ultra-low-dose bilateral whole-lung radiotherapy, with the option of receiving a second dose. The primary objective is 30-day mortality rate.
“The hypothesis is that low-dose thoracic radiation will decrease inflammation and improve outcomes for these intubated COVID-19 patients,” Dr. Chakravarti explained.
The PRE-VENT trial will explore low-dose thoracic radiotherapy for hospitalized patients with severe respiratory compromise who have not yet been intubated. Two doses of low-dose radiotherapy will be tested and compared. The primary study objective is to determine which of the two doses appears to be the most efficacious, Dr. Chakravarti noted.
“The ultimate question to which we remain agnostic is whether the potential benefits of low-dose radiation therapy outweigh the risks,” he said.
Low-dose radiotherapy is readily available in most countries, unlike the newly developed COVID-19 drugs, which are only available in the developed world, he noted. “This creates a bit more economic equity in terms of COVID-19 treatment.”
In addition, it may offer a therapeutic option that could be useful in the future, “as low-dose radiation therapy does not discriminate against various viruses that may cause another pandemic,” he commented. It could offer “a stopgap measure where we don’t have to shut down society completely, which, as we have all witnessed, can cause tremendous financial and social unrest.”
Reasonable question
Whether or not radiotherapy has value for the short-term management of severe pulmonary inflammation caused by COVID-19 is a reasonable question to evaluate in clinical trials, commented discussant Ramesh Rengan, MD, PhD, professor and chair, department of radiation oncology, University of Washington, Seattle.
He noted that inflammatory cells are highly sensitive to radiation, and low-dose radiotherapy has been used effectively in other inflammatory conditions, such as arthritis. Indeed, before the discovery of antibiotics, low-dose radiation was used with reasonable efficacy to treat pneumonia.
“The pneumonia associated with this viral infection is a bit unique in that what happens is the infection triggers an inflammatory cascade – the so-called cytokine storm – that essentially overwhelms the lungs, thereby leading, unfortunately, to mortality,” Dr. Rengan noted. “So a big focus of our energy is how to stop this inflammatory cascade from occurring.”
Corticosteroids are currently the only therapeutic intervention that has shown any mortality benefit in COVID-19, he pointed out.
The question now being asked is: “Can we suppress inflammation specifically within the lung?” Dr. Rengan continued. The main problem with radiotherapy is that it has different effects on various tissues, both immediately and over the long term.
“The immediate benefit that we will likely see from these studies is the immediate sterilization of inflammatory cells,” he said. However, injury to normal lung tissue from low-dose radiotherapy could lead to inflammation weeks or months later, and this could contribute to the disease burden and increase the risk of dying.
Dr. Rengan also noted that there are some very real practical concerns about offering radiotherapy to COVID-19 patients, including potential COVID-19 transmission to vulnerable cancer patients.
Nevertheless, Dr. Rengan said the results to date are very important and that ongoing trials will provide important new information about the long-term impact of this particular treatment in high-risk patients.
“This is a race to the bottom – we are trying to find the lowest possible dose of radiation therapy that we can deliver to sterilize these inflammatory cells without creating any harm to the surrounding tissue,” he said.
“It also brings radiation oncologists into the fight against this deadly disease,” he added.
Dr. Rengan has received honoraria from Novocur and has served as a consultant to AstraZeneca.
A version of this article originally appeared on Medscape.com.
The first study to suggest benefit from low-dose radiotherapy for severe COVID-19–induced pneumonia involved only 20 patients, but the results were so promising that two larger randomized trials are now underway.
“RESCUE-119 was a trial based on the hypothesis that low-dose radiation therapy may help eliminate the stormy cytokine release and unchecked edema in hospitalized COVID-19 patients,” said Mohammed Khan, MD, PhD, Winship Cancer Institute of Emory University, Atlanta.
“We found patients had a quicker improvement in their time to clinical recovery with low-dose radiation therapy, compared to controls, and this was significant even in this small cohort of patients,” he said.
Dr. Khan was speaking at a special press briefing held during the virtual American Society for Radiation Oncology Annual Meeting 2020.
A total of 20 patients were involved in the trial. Ten patients were treated with low-dose radiotherapy; 10 others, who served as control patients, were treated with the best supportive care and COVID-directed therapies. The control patients were matched for age and comorbidities. All these patients were hospitalized and were oxygen dependent, Dr. Khan noted. In addition, for all patients, serial x-rays demonstrated consolidation and damage in the lung.
The intervention consisted of whole-lung low-dose radiotherapy delivered at a dose of 1.5 Gy.
The first five patients were assessed at an interim endpoint of 7 days to confirm the safety of the procedure. Subsequently, a total of 10 patients were treated with radiotherapy and were followed to day 28.
The main study endpoints were time to clinical recovery, determined on the basis of the patient’s being taken off oxygen, and improvement, evidenced on either serial x-rays or by inflammatory biomarkers.
The median time to clinical recovery was almost three times faster for the patients who received low-dose radiotherapy, at a median of 3 days; for control patients, the median was 12 days (P = .048).
“We also saw a trend toward getting patients out of hospital sooner,” Dr. Khan added. The mean time to hospital discharge was 12 days for the patients who received low-dose radiotherapy, compared with 20 days for control patients (P = .19).
Only one patient required intubation after receiving low-dose radiotherapy, whereas 4 of 10 control patients required some sort of intubation (P = .12), he noted.
Investigators also saw improvements on serial x-rays in 9 of 10 patients treated with low-dose radiotherapy, compared with only 4 patients in the control group. There was also a significant improvement in delirium among the low-dose radiotherapy group compared with control patients (P < .01). Before receiving low-dose radiotherapy, C-reactive protein levels increased by 22% per day. After receiving the 1.5-Gy radiation treatment, there was a sharp reduction in C-reactive protein levels (P < .01) as well as in lactate dehydrogenase levels (P = .03).
Overall survival, however, did not differ between the two treatment groups; 90% of both groups were alive at day 28.
“By focally dampening cytokine hyperactivation, [low-dose radiotherapy] may improve COVID-19 outcomes through immunomodulation,” Dr. Khan explained.
VENTED and PRE-VENT trials
These results from the small RESCUE-119 trial led to the launch of two larger phase 2 trials, the VENTED and the PRE-VENT trials, noted Arnab Chakravarti, MD, professor and chair of radiation oncology, the Ohio State University Comprehensive Cancer Center, Columbus.
To be enrolled in the VENTED trial, patients must have received mechanical ventilation. They will receive at least one dose of ultra-low-dose bilateral whole-lung radiotherapy, with the option of receiving a second dose. The primary objective is 30-day mortality rate.
“The hypothesis is that low-dose thoracic radiation will decrease inflammation and improve outcomes for these intubated COVID-19 patients,” Dr. Chakravarti explained.
The PRE-VENT trial will explore low-dose thoracic radiotherapy for hospitalized patients with severe respiratory compromise who have not yet been intubated. Two doses of low-dose radiotherapy will be tested and compared. The primary study objective is to determine which of the two doses appears to be the most efficacious, Dr. Chakravarti noted.
“The ultimate question to which we remain agnostic is whether the potential benefits of low-dose radiation therapy outweigh the risks,” he said.
Low-dose radiotherapy is readily available in most countries, unlike the newly developed COVID-19 drugs, which are only available in the developed world, he noted. “This creates a bit more economic equity in terms of COVID-19 treatment.”
In addition, it may offer a therapeutic option that could be useful in the future, “as low-dose radiation therapy does not discriminate against various viruses that may cause another pandemic,” he commented. It could offer “a stopgap measure where we don’t have to shut down society completely, which, as we have all witnessed, can cause tremendous financial and social unrest.”
Reasonable question
Whether or not radiotherapy has value for the short-term management of severe pulmonary inflammation caused by COVID-19 is a reasonable question to evaluate in clinical trials, commented discussant Ramesh Rengan, MD, PhD, professor and chair, department of radiation oncology, University of Washington, Seattle.
He noted that inflammatory cells are highly sensitive to radiation, and low-dose radiotherapy has been used effectively in other inflammatory conditions, such as arthritis. Indeed, before the discovery of antibiotics, low-dose radiation was used with reasonable efficacy to treat pneumonia.
“The pneumonia associated with this viral infection is a bit unique in that what happens is the infection triggers an inflammatory cascade – the so-called cytokine storm – that essentially overwhelms the lungs, thereby leading, unfortunately, to mortality,” Dr. Rengan noted. “So a big focus of our energy is how to stop this inflammatory cascade from occurring.”
Corticosteroids are currently the only therapeutic intervention that has shown any mortality benefit in COVID-19, he pointed out.
The question now being asked is: “Can we suppress inflammation specifically within the lung?” Dr. Rengan continued. The main problem with radiotherapy is that it has different effects on various tissues, both immediately and over the long term.
“The immediate benefit that we will likely see from these studies is the immediate sterilization of inflammatory cells,” he said. However, injury to normal lung tissue from low-dose radiotherapy could lead to inflammation weeks or months later, and this could contribute to the disease burden and increase the risk of dying.
Dr. Rengan also noted that there are some very real practical concerns about offering radiotherapy to COVID-19 patients, including potential COVID-19 transmission to vulnerable cancer patients.
Nevertheless, Dr. Rengan said the results to date are very important and that ongoing trials will provide important new information about the long-term impact of this particular treatment in high-risk patients.
“This is a race to the bottom – we are trying to find the lowest possible dose of radiation therapy that we can deliver to sterilize these inflammatory cells without creating any harm to the surrounding tissue,” he said.
“It also brings radiation oncologists into the fight against this deadly disease,” he added.
Dr. Rengan has received honoraria from Novocur and has served as a consultant to AstraZeneca.
A version of this article originally appeared on Medscape.com.