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CTO PCI success rates rising, with blip during COVID-19, registry shows
Technical and procedural success rates for chronic total occlusion percutaneous coronary intervention (CTO PCI) have increased steadily over the past 6 years, with rates of in-hospital major adverse cardiac events (MACE) declining to the 2%-or-lower range in that time.
“CTO PCI technical and procedural success rates are high and continue to increase over time,” Spyridon Kostantinis, MD said in presenting updated results from the international PROGRESS-CTO registry at the Society for Cardiovascular Angiography & Interventions annual scientific sessions.
“The overall success rate increased from 81.6% in 2018 to 88.1% in 2021,” he added. The overall incidence of in-hospital MACE in that time was “an acceptable” 2.1% without significant changes over that period.
The analysis examined clinical, angiographic and procedural outcomes of 10,249 CTO PCIs performed on 10,019 patients from 63 centers in nine countries during 2016-2021. PROGRESS-CTO stands for Prospective Global Registry for the Study of Chronic Total Occlusion Intervention.
The target CTOs were highly complex, he said, with an average J-CTO (multicenter CTO registry in Japan) score of 2.4 ± 1.3 and PROGRESS-CTO score of 1.3 ± 1. The most common CTO target vessel was the right coronary artery (53%), followed by the left anterior descending artery (26%) and the circumflex artery (19%).
The registry also tracked how characteristics of the CTO PCI procedures themselves changed over time. “The septal and the epicardial collaterals were the most common collaterals used for retrograde crossing, with a decreasing trend for epicardial collaterals over time,” said Dr. Kostantinis, a research fellow at the Minneapolis Heart Institute.
Septal collateral use varied between 64% and 69% of cases from 2016 to 2021, but the share of epicardial collaterals declined from 35% to 22% in that time.
“Over time, the range of antegrade wiring as the final successfully crossing strategy increased from 46% in 2016 to 61% in 2021, with a decrease in antegrade dissection and re-entry (ADR) and no change in the retrograde approach,” Dr. Kostantinis said. The percentage of procedures using ADR as the final crossing strategy declined from 18% in 2016 to 12% in 2021, with the rate of retrograde crossings peaking at 21% in 2016 but leveling off to 18% or 19% in the subsequent years.
“An increasing use in the efficiency of antegrade wiring may reflect an improvement in guidewire retrograde crossing as well as the increasing operator expertise,” Dr. Kostantinis said.
The study also found that contrast volume, air kerma radiation dose, fluoroscopy time, and procedure time declined steadily over time. “The potential explanations for these are using new x-ray systems as well as the use of intravascular imaging,” Dr. Kostantinis said.
In 2020, the rates of technical and procedural success, as well as the number of overall procedures, declined from 2019, while MACE rates ticked upward that year, probably because of the COVID-19 pandemic, Dr. Kostantinis said.
“It is true that we noticed a rise in MACE rate from 1.6% in 2019 to 2.7% in 2020, but in 2021 that decreased again to 1.7%,” he said in an interview. “Another potential explanation is the higher angiographic complexity of CTOs treated during that year (2020) that resulted in more adverse events.”
Previous results from the PROGRESS-CTO registry reported the difference in MACE between 2019 and 2020 was significant (P = .01). “So, yes, the difference between those 2 years is significant,” Dr. Kostantinis said. However, he noted, the overall trend was not significant, with a P value of .194.
The risk profile of CTO PCI has improved “slowly” over time, said Kirk N. Garratt, MD, but “it’s not yet were it needs to be.”
He added, “Undoubtedly we’ve learned that, without any question, one method for minimizing the risk is to concentrate these cases in the hands of those that do many of them.” As the number of procedures fell – an “embedded” pandemic impact –“I worry that it’s inevitable that complication rates will tick up a bit,” said Dr. Garratt, director of the Center for Heart and Vascular Health at Christiana Care in Newark, Del.
By the same token, he added, this situation with regard to CTOs “parallels what’s happening elsewhere in interventional medicine and medicine broadly; numbers are increasing and we’re busy again. In most domains we’re not as busy as we had been prepandemic, and time will allow us to catch up.”
PROGRESS-CTO has received funding from the Joseph F. and Mary M. Fleischhacker Foundation and the Abbott Northwestern Hospital Foundation Innovation Grant.
Dr. Kostantinis has no disclosures. Dr. Garratt is an advisory board member for Abbott.
Technical and procedural success rates for chronic total occlusion percutaneous coronary intervention (CTO PCI) have increased steadily over the past 6 years, with rates of in-hospital major adverse cardiac events (MACE) declining to the 2%-or-lower range in that time.
“CTO PCI technical and procedural success rates are high and continue to increase over time,” Spyridon Kostantinis, MD said in presenting updated results from the international PROGRESS-CTO registry at the Society for Cardiovascular Angiography & Interventions annual scientific sessions.
“The overall success rate increased from 81.6% in 2018 to 88.1% in 2021,” he added. The overall incidence of in-hospital MACE in that time was “an acceptable” 2.1% without significant changes over that period.
The analysis examined clinical, angiographic and procedural outcomes of 10,249 CTO PCIs performed on 10,019 patients from 63 centers in nine countries during 2016-2021. PROGRESS-CTO stands for Prospective Global Registry for the Study of Chronic Total Occlusion Intervention.
The target CTOs were highly complex, he said, with an average J-CTO (multicenter CTO registry in Japan) score of 2.4 ± 1.3 and PROGRESS-CTO score of 1.3 ± 1. The most common CTO target vessel was the right coronary artery (53%), followed by the left anterior descending artery (26%) and the circumflex artery (19%).
The registry also tracked how characteristics of the CTO PCI procedures themselves changed over time. “The septal and the epicardial collaterals were the most common collaterals used for retrograde crossing, with a decreasing trend for epicardial collaterals over time,” said Dr. Kostantinis, a research fellow at the Minneapolis Heart Institute.
Septal collateral use varied between 64% and 69% of cases from 2016 to 2021, but the share of epicardial collaterals declined from 35% to 22% in that time.
“Over time, the range of antegrade wiring as the final successfully crossing strategy increased from 46% in 2016 to 61% in 2021, with a decrease in antegrade dissection and re-entry (ADR) and no change in the retrograde approach,” Dr. Kostantinis said. The percentage of procedures using ADR as the final crossing strategy declined from 18% in 2016 to 12% in 2021, with the rate of retrograde crossings peaking at 21% in 2016 but leveling off to 18% or 19% in the subsequent years.
“An increasing use in the efficiency of antegrade wiring may reflect an improvement in guidewire retrograde crossing as well as the increasing operator expertise,” Dr. Kostantinis said.
The study also found that contrast volume, air kerma radiation dose, fluoroscopy time, and procedure time declined steadily over time. “The potential explanations for these are using new x-ray systems as well as the use of intravascular imaging,” Dr. Kostantinis said.
In 2020, the rates of technical and procedural success, as well as the number of overall procedures, declined from 2019, while MACE rates ticked upward that year, probably because of the COVID-19 pandemic, Dr. Kostantinis said.
“It is true that we noticed a rise in MACE rate from 1.6% in 2019 to 2.7% in 2020, but in 2021 that decreased again to 1.7%,” he said in an interview. “Another potential explanation is the higher angiographic complexity of CTOs treated during that year (2020) that resulted in more adverse events.”
Previous results from the PROGRESS-CTO registry reported the difference in MACE between 2019 and 2020 was significant (P = .01). “So, yes, the difference between those 2 years is significant,” Dr. Kostantinis said. However, he noted, the overall trend was not significant, with a P value of .194.
The risk profile of CTO PCI has improved “slowly” over time, said Kirk N. Garratt, MD, but “it’s not yet were it needs to be.”
He added, “Undoubtedly we’ve learned that, without any question, one method for minimizing the risk is to concentrate these cases in the hands of those that do many of them.” As the number of procedures fell – an “embedded” pandemic impact –“I worry that it’s inevitable that complication rates will tick up a bit,” said Dr. Garratt, director of the Center for Heart and Vascular Health at Christiana Care in Newark, Del.
By the same token, he added, this situation with regard to CTOs “parallels what’s happening elsewhere in interventional medicine and medicine broadly; numbers are increasing and we’re busy again. In most domains we’re not as busy as we had been prepandemic, and time will allow us to catch up.”
PROGRESS-CTO has received funding from the Joseph F. and Mary M. Fleischhacker Foundation and the Abbott Northwestern Hospital Foundation Innovation Grant.
Dr. Kostantinis has no disclosures. Dr. Garratt is an advisory board member for Abbott.
Technical and procedural success rates for chronic total occlusion percutaneous coronary intervention (CTO PCI) have increased steadily over the past 6 years, with rates of in-hospital major adverse cardiac events (MACE) declining to the 2%-or-lower range in that time.
“CTO PCI technical and procedural success rates are high and continue to increase over time,” Spyridon Kostantinis, MD said in presenting updated results from the international PROGRESS-CTO registry at the Society for Cardiovascular Angiography & Interventions annual scientific sessions.
“The overall success rate increased from 81.6% in 2018 to 88.1% in 2021,” he added. The overall incidence of in-hospital MACE in that time was “an acceptable” 2.1% without significant changes over that period.
The analysis examined clinical, angiographic and procedural outcomes of 10,249 CTO PCIs performed on 10,019 patients from 63 centers in nine countries during 2016-2021. PROGRESS-CTO stands for Prospective Global Registry for the Study of Chronic Total Occlusion Intervention.
The target CTOs were highly complex, he said, with an average J-CTO (multicenter CTO registry in Japan) score of 2.4 ± 1.3 and PROGRESS-CTO score of 1.3 ± 1. The most common CTO target vessel was the right coronary artery (53%), followed by the left anterior descending artery (26%) and the circumflex artery (19%).
The registry also tracked how characteristics of the CTO PCI procedures themselves changed over time. “The septal and the epicardial collaterals were the most common collaterals used for retrograde crossing, with a decreasing trend for epicardial collaterals over time,” said Dr. Kostantinis, a research fellow at the Minneapolis Heart Institute.
Septal collateral use varied between 64% and 69% of cases from 2016 to 2021, but the share of epicardial collaterals declined from 35% to 22% in that time.
“Over time, the range of antegrade wiring as the final successfully crossing strategy increased from 46% in 2016 to 61% in 2021, with a decrease in antegrade dissection and re-entry (ADR) and no change in the retrograde approach,” Dr. Kostantinis said. The percentage of procedures using ADR as the final crossing strategy declined from 18% in 2016 to 12% in 2021, with the rate of retrograde crossings peaking at 21% in 2016 but leveling off to 18% or 19% in the subsequent years.
“An increasing use in the efficiency of antegrade wiring may reflect an improvement in guidewire retrograde crossing as well as the increasing operator expertise,” Dr. Kostantinis said.
The study also found that contrast volume, air kerma radiation dose, fluoroscopy time, and procedure time declined steadily over time. “The potential explanations for these are using new x-ray systems as well as the use of intravascular imaging,” Dr. Kostantinis said.
In 2020, the rates of technical and procedural success, as well as the number of overall procedures, declined from 2019, while MACE rates ticked upward that year, probably because of the COVID-19 pandemic, Dr. Kostantinis said.
“It is true that we noticed a rise in MACE rate from 1.6% in 2019 to 2.7% in 2020, but in 2021 that decreased again to 1.7%,” he said in an interview. “Another potential explanation is the higher angiographic complexity of CTOs treated during that year (2020) that resulted in more adverse events.”
Previous results from the PROGRESS-CTO registry reported the difference in MACE between 2019 and 2020 was significant (P = .01). “So, yes, the difference between those 2 years is significant,” Dr. Kostantinis said. However, he noted, the overall trend was not significant, with a P value of .194.
The risk profile of CTO PCI has improved “slowly” over time, said Kirk N. Garratt, MD, but “it’s not yet were it needs to be.”
He added, “Undoubtedly we’ve learned that, without any question, one method for minimizing the risk is to concentrate these cases in the hands of those that do many of them.” As the number of procedures fell – an “embedded” pandemic impact –“I worry that it’s inevitable that complication rates will tick up a bit,” said Dr. Garratt, director of the Center for Heart and Vascular Health at Christiana Care in Newark, Del.
By the same token, he added, this situation with regard to CTOs “parallels what’s happening elsewhere in interventional medicine and medicine broadly; numbers are increasing and we’re busy again. In most domains we’re not as busy as we had been prepandemic, and time will allow us to catch up.”
PROGRESS-CTO has received funding from the Joseph F. and Mary M. Fleischhacker Foundation and the Abbott Northwestern Hospital Foundation Innovation Grant.
Dr. Kostantinis has no disclosures. Dr. Garratt is an advisory board member for Abbott.
FROM SCAI 2022
In utero COVID exposure tied to developmental differences in infants
suggests a small-scale analysis that points to the need for further study and monitoring during pregnancy.
The study included 24 pregnant women, half of whom had COVID-19 during pregnancy, and their offspring. It showed impairments at 6 weeks of age on the social interactive dimension of a neonatal assessment.
“Not all babies born to mothers infected with COVID show neurodevelopmental differences, but our data show that their risk is increased in comparison to those not exposed to COVID in the womb. We need a bigger study to confirm the exact extent of the difference,” said lead researcher Rosa Ayesa Arriola, PhD, Valdecilla Research Institute (IDIVAL), Hospital Universitario Marqués de Valdecilla, Santander, Spain, in a release.
The findings were presented at the virtual European Psychiatric Association 2022 Congress.
Differing responses to cuddling
Coauthor Águeda Castro Quintas, PhD student, Network Centre for Biomedical Research in Mental Health, University of Barcelona, explained that the tests showed the children born to mothers who had COVID-19 during pregnancy reacted “slightly differently to being held, or cuddled.”
“We need to note that these are preliminary results, but this is part of a project following a larger sample of 100 mothers and their babies,” she added. The authors plan to compare their results with those from a similar study.
The group will also monitor infant language and motor development aged between 18 and 42 months.
“This is an ongoing project, and we are at an early stage,” Ms. Castro Quintas said. “We don’t know if these effects will result in any longer-term issues,” but longer-term observation “may help us understand this.”
“Of course, in babies who are so young, there are several things we just can’t measure, such as language skills or cognition,” added coinvestigator Nerea San Martín González, department of evolutionary biology, ecology and environmental sciences, University of Barcelona.
While emphasizing the need for larger sample sizes, she said that “in the meantime, we need to stress the importance of medical monitoring to facilitate a healthy pregnancy.”
The researchers note that the consequences of the COVID-19 pandemic for the newborns of affected mothers remain “unknown.”
However, previous studies of other infections during pregnancy suggest that offspring could be “especially vulnerable,”as the pathophysiological mechanisms of the infection, such as cytokine storms and microcoagulation, “could clearly compromise fetal neurodevelopment.”
To investigate further, they examined the neurodevelopment of infants born both immediately before and during the COVID-19 pandemic, from 2017 to 2021.
Twenty-one women who had COVID-19 during pregnancy were matched with 21 healthy controls. They were studied both during pregnancy and in the postpartum period, completing hormonal and other biochemical tests, salivary tests, movement assessments, and psychological questionnaires, adjusted for various factors.
The team also administered the Brazelton Neonatal Behavioural Assessment Scale (NBAS) to the offspring at 6 weeks of age to evaluate neurologic, social, and behavioral aspects of function.
“We have been especially sensitive in how we have conducted these tests,” said Ms. Castro Quintas. “Each mother and baby were closely examined by clinicians with expert training in the field and in the tests.”
Among those offspring exposed to COVID-19 during pregnancy, there was a significant decrease in scores on the social interactive dimension of the NBAS, particularly if infection occurred before week 20 of gestation.
Other NBAS subscales were not associated with maternal COVID-19 during pregnancy.
More research needed
Commenting on the findings, Livio Provenzi, PhD, a psychologist and researcher in developmental psychobiology at the University of Pavia (Italy), noted there is a “great need” to study the direct and indirect effect of the COVID-19 pandemic on parents and their children. “Pregnancy is a period of life which shapes much of our subsequent development, and exposure to adversity in pregnancy can leave long-lasting biological footprints.”
Dr. Provenzi, who was not involved in the study, added in the release that the findings reinforce “evidence of epigenetic alterations in infants born from mothers exposed to pandemic-related stress during pregnancy.
“It shows we need more large-scale, international research to allow us to understand the developmental effects of this health emergency and to deliver better quality of care to parents and infants.”
The study was funded by the Spanish Ministry of Economy and Competitiveness, Instituto de Salud Carlos III through the University of Barcelona multicenter project and the Government of Cantabria. No relevant financial relationships were declared.
A version of this article first appeared on Medscape.com.
suggests a small-scale analysis that points to the need for further study and monitoring during pregnancy.
The study included 24 pregnant women, half of whom had COVID-19 during pregnancy, and their offspring. It showed impairments at 6 weeks of age on the social interactive dimension of a neonatal assessment.
“Not all babies born to mothers infected with COVID show neurodevelopmental differences, but our data show that their risk is increased in comparison to those not exposed to COVID in the womb. We need a bigger study to confirm the exact extent of the difference,” said lead researcher Rosa Ayesa Arriola, PhD, Valdecilla Research Institute (IDIVAL), Hospital Universitario Marqués de Valdecilla, Santander, Spain, in a release.
The findings were presented at the virtual European Psychiatric Association 2022 Congress.
Differing responses to cuddling
Coauthor Águeda Castro Quintas, PhD student, Network Centre for Biomedical Research in Mental Health, University of Barcelona, explained that the tests showed the children born to mothers who had COVID-19 during pregnancy reacted “slightly differently to being held, or cuddled.”
“We need to note that these are preliminary results, but this is part of a project following a larger sample of 100 mothers and their babies,” she added. The authors plan to compare their results with those from a similar study.
The group will also monitor infant language and motor development aged between 18 and 42 months.
“This is an ongoing project, and we are at an early stage,” Ms. Castro Quintas said. “We don’t know if these effects will result in any longer-term issues,” but longer-term observation “may help us understand this.”
“Of course, in babies who are so young, there are several things we just can’t measure, such as language skills or cognition,” added coinvestigator Nerea San Martín González, department of evolutionary biology, ecology and environmental sciences, University of Barcelona.
While emphasizing the need for larger sample sizes, she said that “in the meantime, we need to stress the importance of medical monitoring to facilitate a healthy pregnancy.”
The researchers note that the consequences of the COVID-19 pandemic for the newborns of affected mothers remain “unknown.”
However, previous studies of other infections during pregnancy suggest that offspring could be “especially vulnerable,”as the pathophysiological mechanisms of the infection, such as cytokine storms and microcoagulation, “could clearly compromise fetal neurodevelopment.”
To investigate further, they examined the neurodevelopment of infants born both immediately before and during the COVID-19 pandemic, from 2017 to 2021.
Twenty-one women who had COVID-19 during pregnancy were matched with 21 healthy controls. They were studied both during pregnancy and in the postpartum period, completing hormonal and other biochemical tests, salivary tests, movement assessments, and psychological questionnaires, adjusted for various factors.
The team also administered the Brazelton Neonatal Behavioural Assessment Scale (NBAS) to the offspring at 6 weeks of age to evaluate neurologic, social, and behavioral aspects of function.
“We have been especially sensitive in how we have conducted these tests,” said Ms. Castro Quintas. “Each mother and baby were closely examined by clinicians with expert training in the field and in the tests.”
Among those offspring exposed to COVID-19 during pregnancy, there was a significant decrease in scores on the social interactive dimension of the NBAS, particularly if infection occurred before week 20 of gestation.
Other NBAS subscales were not associated with maternal COVID-19 during pregnancy.
More research needed
Commenting on the findings, Livio Provenzi, PhD, a psychologist and researcher in developmental psychobiology at the University of Pavia (Italy), noted there is a “great need” to study the direct and indirect effect of the COVID-19 pandemic on parents and their children. “Pregnancy is a period of life which shapes much of our subsequent development, and exposure to adversity in pregnancy can leave long-lasting biological footprints.”
Dr. Provenzi, who was not involved in the study, added in the release that the findings reinforce “evidence of epigenetic alterations in infants born from mothers exposed to pandemic-related stress during pregnancy.
“It shows we need more large-scale, international research to allow us to understand the developmental effects of this health emergency and to deliver better quality of care to parents and infants.”
The study was funded by the Spanish Ministry of Economy and Competitiveness, Instituto de Salud Carlos III through the University of Barcelona multicenter project and the Government of Cantabria. No relevant financial relationships were declared.
A version of this article first appeared on Medscape.com.
suggests a small-scale analysis that points to the need for further study and monitoring during pregnancy.
The study included 24 pregnant women, half of whom had COVID-19 during pregnancy, and their offspring. It showed impairments at 6 weeks of age on the social interactive dimension of a neonatal assessment.
“Not all babies born to mothers infected with COVID show neurodevelopmental differences, but our data show that their risk is increased in comparison to those not exposed to COVID in the womb. We need a bigger study to confirm the exact extent of the difference,” said lead researcher Rosa Ayesa Arriola, PhD, Valdecilla Research Institute (IDIVAL), Hospital Universitario Marqués de Valdecilla, Santander, Spain, in a release.
The findings were presented at the virtual European Psychiatric Association 2022 Congress.
Differing responses to cuddling
Coauthor Águeda Castro Quintas, PhD student, Network Centre for Biomedical Research in Mental Health, University of Barcelona, explained that the tests showed the children born to mothers who had COVID-19 during pregnancy reacted “slightly differently to being held, or cuddled.”
“We need to note that these are preliminary results, but this is part of a project following a larger sample of 100 mothers and their babies,” she added. The authors plan to compare their results with those from a similar study.
The group will also monitor infant language and motor development aged between 18 and 42 months.
“This is an ongoing project, and we are at an early stage,” Ms. Castro Quintas said. “We don’t know if these effects will result in any longer-term issues,” but longer-term observation “may help us understand this.”
“Of course, in babies who are so young, there are several things we just can’t measure, such as language skills or cognition,” added coinvestigator Nerea San Martín González, department of evolutionary biology, ecology and environmental sciences, University of Barcelona.
While emphasizing the need for larger sample sizes, she said that “in the meantime, we need to stress the importance of medical monitoring to facilitate a healthy pregnancy.”
The researchers note that the consequences of the COVID-19 pandemic for the newborns of affected mothers remain “unknown.”
However, previous studies of other infections during pregnancy suggest that offspring could be “especially vulnerable,”as the pathophysiological mechanisms of the infection, such as cytokine storms and microcoagulation, “could clearly compromise fetal neurodevelopment.”
To investigate further, they examined the neurodevelopment of infants born both immediately before and during the COVID-19 pandemic, from 2017 to 2021.
Twenty-one women who had COVID-19 during pregnancy were matched with 21 healthy controls. They were studied both during pregnancy and in the postpartum period, completing hormonal and other biochemical tests, salivary tests, movement assessments, and psychological questionnaires, adjusted for various factors.
The team also administered the Brazelton Neonatal Behavioural Assessment Scale (NBAS) to the offspring at 6 weeks of age to evaluate neurologic, social, and behavioral aspects of function.
“We have been especially sensitive in how we have conducted these tests,” said Ms. Castro Quintas. “Each mother and baby were closely examined by clinicians with expert training in the field and in the tests.”
Among those offspring exposed to COVID-19 during pregnancy, there was a significant decrease in scores on the social interactive dimension of the NBAS, particularly if infection occurred before week 20 of gestation.
Other NBAS subscales were not associated with maternal COVID-19 during pregnancy.
More research needed
Commenting on the findings, Livio Provenzi, PhD, a psychologist and researcher in developmental psychobiology at the University of Pavia (Italy), noted there is a “great need” to study the direct and indirect effect of the COVID-19 pandemic on parents and their children. “Pregnancy is a period of life which shapes much of our subsequent development, and exposure to adversity in pregnancy can leave long-lasting biological footprints.”
Dr. Provenzi, who was not involved in the study, added in the release that the findings reinforce “evidence of epigenetic alterations in infants born from mothers exposed to pandemic-related stress during pregnancy.
“It shows we need more large-scale, international research to allow us to understand the developmental effects of this health emergency and to deliver better quality of care to parents and infants.”
The study was funded by the Spanish Ministry of Economy and Competitiveness, Instituto de Salud Carlos III through the University of Barcelona multicenter project and the Government of Cantabria. No relevant financial relationships were declared.
A version of this article first appeared on Medscape.com.
FROM EPA 2022
Stem cell transplants could be ‘transformational’ in type 1 diabetes
NEW ORLEANS – Two patients with type 1 diabetes have now experienced improved blood glucose control with Vertex Pharmaceutical’s investigational allogeneic stem cell–derived islets (VX-880), with the first person now completely insulin independent at 9 months post transplant.
Prior to the procedure, both patients had hypoglycemic unawareness and had experienced multiple episodes of severe hypoglycemia, conditions considered severe enough to justify the risk of immune suppression (which is required for such stem cell–derived islet transplants as they are “foreign” to the recipient).
The first patient, a 64-year-old man with type 1 diabetes for more than 40 years, now has a hemoglobin A1c in the normal range without taking any insulin more than 9 months after the procedure. The second, a 35-year-old woman with type 1 diabetes for 10.7 years, experienced a 30% reduction in insulin use and significant increased time spent in target glucose range, by 5 months post transplant. Both patients were given just half the targeted VX-880 dose.
Data for those two patients – the first in Vertex’s phase 1/2 multicenter, single-arm, open-label clinical trial of VX-880 – were reported at the annual scientific sessions of the American Diabetes Association, by James F. Markmann, MD, PhD.
He has been transplanting pancreatic islet cells from deceased donors into humans via infusion into the hepatic portal vein for over 20 years.
Transplantation of pancreatic islet cells obtained from cadavers have been shown to eliminate severe hypoglycemia and improve glycemic control in patients with type 1 diabetes, but they’re limited in quantity and are of variable quality. Islets that are manufactured via differentiation from human pluripotent stem cells represent an alternative, explained Dr. Markmann, chief of the division of transplant surgery at Massachusetts General Hospital, Boston.
“This is a new area. ... We hope this will be the same or potentially better. With stem cell–derived islets the quality, consistency, and reliability might produce a better result than with cadaveric islets,” he commented during a press briefing here.
A third patient has recently received the full targeted VX-880 dose but was not part of the current report. The planned enrollment is 17 patients. The trial is currently on clinical hold per the Food and Drug Administration concerning the criteria around dose escalation, but Vertex is working with the FDA to sort that out. Meanwhile, enrollment remains open in Canada, Dr. Markmann said.
In answer to a question about how patient 1 is doing now, Dr. Markmann replied, “He’s doing great. He’s probably the most appreciative patient I’ve ever met. His life was being destroyed by diabetes. He couldn’t work. He crashed his motorcycle from [low blood sugar]. He really was tremendously appreciative that he could participate.”
When Dr. Markmann explained the potential uncertainties and risks to the patient prior to the procedure, the patient replied: “I want to participate. If I die from this and I help somebody else I’d be happy, but I can’t go on living the way I’m living.”
“These people really suffer and this, I think, brings hope to them,” Dr. Markmann said.
‘Beautiful data’ seen in two patients, with ‘transformational’ potential
Asked to comment, Marlon Pragnell, PhD, vice president for Research & Science at the ADA, told this news organization: “It’s beautiful data. People who have type 1 diabetes lack [pancreatic] beta cells ... it was impossible to get sufficient beta cells from cadaveric transplants. It’s just nowhere near enough. If this is safe and effective, if they continue to show safety and efficacy like patient 1, this will be transformational.”
Dr. Markmann presented data for the most recent study visit for each of the two patients, 270 days for patient 1 and 150 days for patient 2. Prior to the transplants, patient 1 had experienced five severe hypoglycemic events and patient 2 had experienced three.
Both had undetectable C-peptide levels at baseline. In response to a mixed-meal tolerance test, patient 1 showed a “robust” C-peptide response by day 90, which increased by day 180. Those levels had dropped but were still detectable by day 270, “possibly due to improved insulin sensitivity,” Dr. Markmann said.
Similarly, Patient 2 also had increased C-peptide that increased to detectable range by day 90 with improved glucose disposal.
Hemoglobin A1c dropped in patient 1 from 8.6% at baseline to 6.9% at day 180, to a “remarkable” 5.2% at day 270. For patient 2, the drop was from 7.5% to a nadir of 6.4% by day 57, then reversing back to 7.1% at day 150.
Both patients also had significant reductions in insulin dose. For patient 1, the dose reduction was more than 90% – from 34 units at baseline to 2.6 units by day 90. By day 210 he was able to stop insulin and by day 270 he met formal criteria for insulin independence.
Patient 2 also had a significant reduction in insulin dose, from 25.9 units to 18.7 by day 57 and remained stable thereafter, at 18.2 units by day 150.
Asked why Patient 2’s results weren’t quite as impressive as patient 1’s, Dr. Markmann replied “I think what’s important is that both patients did great. And since this was a half-dose, we might have expected that the outcome was going to be more like patient 2 rather than patient 1. So, I think we’re just going to have to [study this in] more patients to understand where it falls.”
Although patient 1 experienced a cluster of six severe hypoglycemic events early in the posttransplant period, he had no further events after day 35. Patient 2 had no severe hypoglycemic events.
Other safety events were generally consistent with that seen with the immunosuppressive regimen in the perioperative period. Patient 1 had a “mild and self-limited” rise in liver function test and also experienced two severe adverse events: A rash from the immune suppression that resolved spontaneously, and dehydration requiring hospitalization on day 186. Patient 2’s adverse events were all mild to moderate, most commonly headache and hypomagnesemia and not related to VX-880.
Immunosuppression: Work is ongoing
The immunosuppression regimen used comprises a depletion of lymphocytes at induction, followed by a maintenance regimen of two standard agents used in kidney transplant patients and found to be well tolerated, Dr. Markmann said.
Still, the risk of immunosuppression generally outweighs the potential benefit for most people with type 1 diabetes who are managing reasonably well with insulin treatment.
“This is part one of a two-part problem. One is to have a reliable, consistent, effective cell therapy. The second is to develop an approach that doesn’t require immunosuppression. ... But if we had a way of transplanting the cells without the need for immunosuppression, then it could be really widely available. That’s an opportunity for the future since these cells can be made in unlimited quantities,” Dr. Markmann commented during the press briefing.
Asked for his thoughts about the immunosuppression aspect, Dr. Pragnell told this news organization: “Immune suppression is a concern, but I feel that this is just the start of so much research in this area. They’re going to take this step by step. This is just the start. My understanding is they have additional strategies around immune suppression, and in the future they might not even need immunosuppression. But even at this stage right now, it’s amazing.”
He added: “The ‘artificial pancreas’ is a huge step forward, but it’s just a bridge to a cure, whereas if they’re able to show safety and efficacy, this is potentially a cure. ... I’m very excited about it.”
Dr. Markmann serves on advisory boards for iTolerance, eGenesis, and QihanBio. He is a consultant to Vertex Pharmaceuticals. Dr. Pragnell is an ADA employee and has no further disclosures.
A version of this article first appeared on Medscape.com.
NEW ORLEANS – Two patients with type 1 diabetes have now experienced improved blood glucose control with Vertex Pharmaceutical’s investigational allogeneic stem cell–derived islets (VX-880), with the first person now completely insulin independent at 9 months post transplant.
Prior to the procedure, both patients had hypoglycemic unawareness and had experienced multiple episodes of severe hypoglycemia, conditions considered severe enough to justify the risk of immune suppression (which is required for such stem cell–derived islet transplants as they are “foreign” to the recipient).
The first patient, a 64-year-old man with type 1 diabetes for more than 40 years, now has a hemoglobin A1c in the normal range without taking any insulin more than 9 months after the procedure. The second, a 35-year-old woman with type 1 diabetes for 10.7 years, experienced a 30% reduction in insulin use and significant increased time spent in target glucose range, by 5 months post transplant. Both patients were given just half the targeted VX-880 dose.
Data for those two patients – the first in Vertex’s phase 1/2 multicenter, single-arm, open-label clinical trial of VX-880 – were reported at the annual scientific sessions of the American Diabetes Association, by James F. Markmann, MD, PhD.
He has been transplanting pancreatic islet cells from deceased donors into humans via infusion into the hepatic portal vein for over 20 years.
Transplantation of pancreatic islet cells obtained from cadavers have been shown to eliminate severe hypoglycemia and improve glycemic control in patients with type 1 diabetes, but they’re limited in quantity and are of variable quality. Islets that are manufactured via differentiation from human pluripotent stem cells represent an alternative, explained Dr. Markmann, chief of the division of transplant surgery at Massachusetts General Hospital, Boston.
“This is a new area. ... We hope this will be the same or potentially better. With stem cell–derived islets the quality, consistency, and reliability might produce a better result than with cadaveric islets,” he commented during a press briefing here.
A third patient has recently received the full targeted VX-880 dose but was not part of the current report. The planned enrollment is 17 patients. The trial is currently on clinical hold per the Food and Drug Administration concerning the criteria around dose escalation, but Vertex is working with the FDA to sort that out. Meanwhile, enrollment remains open in Canada, Dr. Markmann said.
In answer to a question about how patient 1 is doing now, Dr. Markmann replied, “He’s doing great. He’s probably the most appreciative patient I’ve ever met. His life was being destroyed by diabetes. He couldn’t work. He crashed his motorcycle from [low blood sugar]. He really was tremendously appreciative that he could participate.”
When Dr. Markmann explained the potential uncertainties and risks to the patient prior to the procedure, the patient replied: “I want to participate. If I die from this and I help somebody else I’d be happy, but I can’t go on living the way I’m living.”
“These people really suffer and this, I think, brings hope to them,” Dr. Markmann said.
‘Beautiful data’ seen in two patients, with ‘transformational’ potential
Asked to comment, Marlon Pragnell, PhD, vice president for Research & Science at the ADA, told this news organization: “It’s beautiful data. People who have type 1 diabetes lack [pancreatic] beta cells ... it was impossible to get sufficient beta cells from cadaveric transplants. It’s just nowhere near enough. If this is safe and effective, if they continue to show safety and efficacy like patient 1, this will be transformational.”
Dr. Markmann presented data for the most recent study visit for each of the two patients, 270 days for patient 1 and 150 days for patient 2. Prior to the transplants, patient 1 had experienced five severe hypoglycemic events and patient 2 had experienced three.
Both had undetectable C-peptide levels at baseline. In response to a mixed-meal tolerance test, patient 1 showed a “robust” C-peptide response by day 90, which increased by day 180. Those levels had dropped but were still detectable by day 270, “possibly due to improved insulin sensitivity,” Dr. Markmann said.
Similarly, Patient 2 also had increased C-peptide that increased to detectable range by day 90 with improved glucose disposal.
Hemoglobin A1c dropped in patient 1 from 8.6% at baseline to 6.9% at day 180, to a “remarkable” 5.2% at day 270. For patient 2, the drop was from 7.5% to a nadir of 6.4% by day 57, then reversing back to 7.1% at day 150.
Both patients also had significant reductions in insulin dose. For patient 1, the dose reduction was more than 90% – from 34 units at baseline to 2.6 units by day 90. By day 210 he was able to stop insulin and by day 270 he met formal criteria for insulin independence.
Patient 2 also had a significant reduction in insulin dose, from 25.9 units to 18.7 by day 57 and remained stable thereafter, at 18.2 units by day 150.
Asked why Patient 2’s results weren’t quite as impressive as patient 1’s, Dr. Markmann replied “I think what’s important is that both patients did great. And since this was a half-dose, we might have expected that the outcome was going to be more like patient 2 rather than patient 1. So, I think we’re just going to have to [study this in] more patients to understand where it falls.”
Although patient 1 experienced a cluster of six severe hypoglycemic events early in the posttransplant period, he had no further events after day 35. Patient 2 had no severe hypoglycemic events.
Other safety events were generally consistent with that seen with the immunosuppressive regimen in the perioperative period. Patient 1 had a “mild and self-limited” rise in liver function test and also experienced two severe adverse events: A rash from the immune suppression that resolved spontaneously, and dehydration requiring hospitalization on day 186. Patient 2’s adverse events were all mild to moderate, most commonly headache and hypomagnesemia and not related to VX-880.
Immunosuppression: Work is ongoing
The immunosuppression regimen used comprises a depletion of lymphocytes at induction, followed by a maintenance regimen of two standard agents used in kidney transplant patients and found to be well tolerated, Dr. Markmann said.
Still, the risk of immunosuppression generally outweighs the potential benefit for most people with type 1 diabetes who are managing reasonably well with insulin treatment.
“This is part one of a two-part problem. One is to have a reliable, consistent, effective cell therapy. The second is to develop an approach that doesn’t require immunosuppression. ... But if we had a way of transplanting the cells without the need for immunosuppression, then it could be really widely available. That’s an opportunity for the future since these cells can be made in unlimited quantities,” Dr. Markmann commented during the press briefing.
Asked for his thoughts about the immunosuppression aspect, Dr. Pragnell told this news organization: “Immune suppression is a concern, but I feel that this is just the start of so much research in this area. They’re going to take this step by step. This is just the start. My understanding is they have additional strategies around immune suppression, and in the future they might not even need immunosuppression. But even at this stage right now, it’s amazing.”
He added: “The ‘artificial pancreas’ is a huge step forward, but it’s just a bridge to a cure, whereas if they’re able to show safety and efficacy, this is potentially a cure. ... I’m very excited about it.”
Dr. Markmann serves on advisory boards for iTolerance, eGenesis, and QihanBio. He is a consultant to Vertex Pharmaceuticals. Dr. Pragnell is an ADA employee and has no further disclosures.
A version of this article first appeared on Medscape.com.
NEW ORLEANS – Two patients with type 1 diabetes have now experienced improved blood glucose control with Vertex Pharmaceutical’s investigational allogeneic stem cell–derived islets (VX-880), with the first person now completely insulin independent at 9 months post transplant.
Prior to the procedure, both patients had hypoglycemic unawareness and had experienced multiple episodes of severe hypoglycemia, conditions considered severe enough to justify the risk of immune suppression (which is required for such stem cell–derived islet transplants as they are “foreign” to the recipient).
The first patient, a 64-year-old man with type 1 diabetes for more than 40 years, now has a hemoglobin A1c in the normal range without taking any insulin more than 9 months after the procedure. The second, a 35-year-old woman with type 1 diabetes for 10.7 years, experienced a 30% reduction in insulin use and significant increased time spent in target glucose range, by 5 months post transplant. Both patients were given just half the targeted VX-880 dose.
Data for those two patients – the first in Vertex’s phase 1/2 multicenter, single-arm, open-label clinical trial of VX-880 – were reported at the annual scientific sessions of the American Diabetes Association, by James F. Markmann, MD, PhD.
He has been transplanting pancreatic islet cells from deceased donors into humans via infusion into the hepatic portal vein for over 20 years.
Transplantation of pancreatic islet cells obtained from cadavers have been shown to eliminate severe hypoglycemia and improve glycemic control in patients with type 1 diabetes, but they’re limited in quantity and are of variable quality. Islets that are manufactured via differentiation from human pluripotent stem cells represent an alternative, explained Dr. Markmann, chief of the division of transplant surgery at Massachusetts General Hospital, Boston.
“This is a new area. ... We hope this will be the same or potentially better. With stem cell–derived islets the quality, consistency, and reliability might produce a better result than with cadaveric islets,” he commented during a press briefing here.
A third patient has recently received the full targeted VX-880 dose but was not part of the current report. The planned enrollment is 17 patients. The trial is currently on clinical hold per the Food and Drug Administration concerning the criteria around dose escalation, but Vertex is working with the FDA to sort that out. Meanwhile, enrollment remains open in Canada, Dr. Markmann said.
In answer to a question about how patient 1 is doing now, Dr. Markmann replied, “He’s doing great. He’s probably the most appreciative patient I’ve ever met. His life was being destroyed by diabetes. He couldn’t work. He crashed his motorcycle from [low blood sugar]. He really was tremendously appreciative that he could participate.”
When Dr. Markmann explained the potential uncertainties and risks to the patient prior to the procedure, the patient replied: “I want to participate. If I die from this and I help somebody else I’d be happy, but I can’t go on living the way I’m living.”
“These people really suffer and this, I think, brings hope to them,” Dr. Markmann said.
‘Beautiful data’ seen in two patients, with ‘transformational’ potential
Asked to comment, Marlon Pragnell, PhD, vice president for Research & Science at the ADA, told this news organization: “It’s beautiful data. People who have type 1 diabetes lack [pancreatic] beta cells ... it was impossible to get sufficient beta cells from cadaveric transplants. It’s just nowhere near enough. If this is safe and effective, if they continue to show safety and efficacy like patient 1, this will be transformational.”
Dr. Markmann presented data for the most recent study visit for each of the two patients, 270 days for patient 1 and 150 days for patient 2. Prior to the transplants, patient 1 had experienced five severe hypoglycemic events and patient 2 had experienced three.
Both had undetectable C-peptide levels at baseline. In response to a mixed-meal tolerance test, patient 1 showed a “robust” C-peptide response by day 90, which increased by day 180. Those levels had dropped but were still detectable by day 270, “possibly due to improved insulin sensitivity,” Dr. Markmann said.
Similarly, Patient 2 also had increased C-peptide that increased to detectable range by day 90 with improved glucose disposal.
Hemoglobin A1c dropped in patient 1 from 8.6% at baseline to 6.9% at day 180, to a “remarkable” 5.2% at day 270. For patient 2, the drop was from 7.5% to a nadir of 6.4% by day 57, then reversing back to 7.1% at day 150.
Both patients also had significant reductions in insulin dose. For patient 1, the dose reduction was more than 90% – from 34 units at baseline to 2.6 units by day 90. By day 210 he was able to stop insulin and by day 270 he met formal criteria for insulin independence.
Patient 2 also had a significant reduction in insulin dose, from 25.9 units to 18.7 by day 57 and remained stable thereafter, at 18.2 units by day 150.
Asked why Patient 2’s results weren’t quite as impressive as patient 1’s, Dr. Markmann replied “I think what’s important is that both patients did great. And since this was a half-dose, we might have expected that the outcome was going to be more like patient 2 rather than patient 1. So, I think we’re just going to have to [study this in] more patients to understand where it falls.”
Although patient 1 experienced a cluster of six severe hypoglycemic events early in the posttransplant period, he had no further events after day 35. Patient 2 had no severe hypoglycemic events.
Other safety events were generally consistent with that seen with the immunosuppressive regimen in the perioperative period. Patient 1 had a “mild and self-limited” rise in liver function test and also experienced two severe adverse events: A rash from the immune suppression that resolved spontaneously, and dehydration requiring hospitalization on day 186. Patient 2’s adverse events were all mild to moderate, most commonly headache and hypomagnesemia and not related to VX-880.
Immunosuppression: Work is ongoing
The immunosuppression regimen used comprises a depletion of lymphocytes at induction, followed by a maintenance regimen of two standard agents used in kidney transplant patients and found to be well tolerated, Dr. Markmann said.
Still, the risk of immunosuppression generally outweighs the potential benefit for most people with type 1 diabetes who are managing reasonably well with insulin treatment.
“This is part one of a two-part problem. One is to have a reliable, consistent, effective cell therapy. The second is to develop an approach that doesn’t require immunosuppression. ... But if we had a way of transplanting the cells without the need for immunosuppression, then it could be really widely available. That’s an opportunity for the future since these cells can be made in unlimited quantities,” Dr. Markmann commented during the press briefing.
Asked for his thoughts about the immunosuppression aspect, Dr. Pragnell told this news organization: “Immune suppression is a concern, but I feel that this is just the start of so much research in this area. They’re going to take this step by step. This is just the start. My understanding is they have additional strategies around immune suppression, and in the future they might not even need immunosuppression. But even at this stage right now, it’s amazing.”
He added: “The ‘artificial pancreas’ is a huge step forward, but it’s just a bridge to a cure, whereas if they’re able to show safety and efficacy, this is potentially a cure. ... I’m very excited about it.”
Dr. Markmann serves on advisory boards for iTolerance, eGenesis, and QihanBio. He is a consultant to Vertex Pharmaceuticals. Dr. Pragnell is an ADA employee and has no further disclosures.
A version of this article first appeared on Medscape.com.
AT ADA 2022
Novel drug ‘promising’ for concomitant depression, insomnia
In a randomized, placebo-controlled, adaptive dose–finding study conducted in more than 200 patients with MDD, those with more severe insomnia at baseline had a greater improvement in depressive symptoms versus those with less severe insomnia.
“As seltorexant is an orexin receptor antagonist, it is related to other medications that are marketed as sleeping pills, so it was important to show that its antidepressant efficacy was actually caused by improved sleep,” coinvestigator Michael E. Thase, MD, professor of psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, told this news organization.
“This novel antidepressant may well turn out to be a treatment of choice for depressed patients with insomnia,” said Dr. Thase, who is also a member of the medical and research staff of the Corporal Michael J. Crescenz Department of Veterans Affairs Medical Center.
The findings were presented at the American Society of Clinical Psychopharmacology annual meeting.
Clinically meaningful?
In an earlier exploratory study, seltorexant showed antidepressant and sleep-promoting effects in patients with MDD. In a phase 2b study, a 20-mg dose of the drug showed clinically meaningful improvement in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score after 6 weeks of treatment.
In the current analysis, the investigators evaluated the effect of seltorexant in improving depressive symptoms beyond sleep-related improvement in patients with MDD, using the MADRS-WOSI (MADRS without the sleep item).
They also used the six-item core MADRS subscale, which excludes sleep, anxiety, and appetite items.
The 283 participants were randomly assigned 3:3:1 to receive seltorexant 10 mg or 20 mg or placebo once daily. They were also stratified into two groups according to the severity of their insomnia: those with a baseline Insomnia Severity Index [ISI] score of 15 or higher (58%) and those with a baseline ISI score of less than 15 (42%).
Results showed that the group receiving the 20-mg/day dose of seltorexant (n = 61 patients) obtained a statistically and clinically meaningful response, compared with the placebo group (n = 137 patients) after removing the insomnia and other “not core items” of the MADRS. The effect was clearest among those with high insomnia ratings.
Improvement in the MADRS-WOSI score was also observed in the seltorexant 20-mg group at week 3 and week 6, compared with the placebo group.
The LSM average distance
The least squares mean (LSM) average difference between the treatment and placebo groups in the MADRS-WOSI score at week 3 was −3.8 (90% confidence interval, −5.98 to −1.57; P = .005).
At week 6, the LSM between the groups in the MADRS-WOSI score was −2.5 (90% CI, −5.24 to 0.15; P = .12).
The results were consistent with improvement in the MADRS total score. At week 3, the LSM in the MADRS total score was -4.5 (90% CI, -6.96 to -2.07; P = .003) and, at week 6, it was -3.1 (90% CI, -6.13 to -0.16; P = .083).
Seltorexant 20 mg was especially effective in patients who had more severe insomnia.
Commenting on the study, Nagy Youssef, MD, PhD, professor of psychiatry, The Ohio State University Wexner Medical Center, Columbus, said this was “a well-designed study examining a promising compound.”
“Especially if replicated, this study shows the promise of this molecule for this patient population,” said Dr. Youssef, who was not involved with the research.
The study was funded by Janssen Pharmaceutical of Johnson & Johnson. Dr. Thase reports financial relationships with numerous companies. Dr. Youssef reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In a randomized, placebo-controlled, adaptive dose–finding study conducted in more than 200 patients with MDD, those with more severe insomnia at baseline had a greater improvement in depressive symptoms versus those with less severe insomnia.
“As seltorexant is an orexin receptor antagonist, it is related to other medications that are marketed as sleeping pills, so it was important to show that its antidepressant efficacy was actually caused by improved sleep,” coinvestigator Michael E. Thase, MD, professor of psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, told this news organization.
“This novel antidepressant may well turn out to be a treatment of choice for depressed patients with insomnia,” said Dr. Thase, who is also a member of the medical and research staff of the Corporal Michael J. Crescenz Department of Veterans Affairs Medical Center.
The findings were presented at the American Society of Clinical Psychopharmacology annual meeting.
Clinically meaningful?
In an earlier exploratory study, seltorexant showed antidepressant and sleep-promoting effects in patients with MDD. In a phase 2b study, a 20-mg dose of the drug showed clinically meaningful improvement in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score after 6 weeks of treatment.
In the current analysis, the investigators evaluated the effect of seltorexant in improving depressive symptoms beyond sleep-related improvement in patients with MDD, using the MADRS-WOSI (MADRS without the sleep item).
They also used the six-item core MADRS subscale, which excludes sleep, anxiety, and appetite items.
The 283 participants were randomly assigned 3:3:1 to receive seltorexant 10 mg or 20 mg or placebo once daily. They were also stratified into two groups according to the severity of their insomnia: those with a baseline Insomnia Severity Index [ISI] score of 15 or higher (58%) and those with a baseline ISI score of less than 15 (42%).
Results showed that the group receiving the 20-mg/day dose of seltorexant (n = 61 patients) obtained a statistically and clinically meaningful response, compared with the placebo group (n = 137 patients) after removing the insomnia and other “not core items” of the MADRS. The effect was clearest among those with high insomnia ratings.
Improvement in the MADRS-WOSI score was also observed in the seltorexant 20-mg group at week 3 and week 6, compared with the placebo group.
The LSM average distance
The least squares mean (LSM) average difference between the treatment and placebo groups in the MADRS-WOSI score at week 3 was −3.8 (90% confidence interval, −5.98 to −1.57; P = .005).
At week 6, the LSM between the groups in the MADRS-WOSI score was −2.5 (90% CI, −5.24 to 0.15; P = .12).
The results were consistent with improvement in the MADRS total score. At week 3, the LSM in the MADRS total score was -4.5 (90% CI, -6.96 to -2.07; P = .003) and, at week 6, it was -3.1 (90% CI, -6.13 to -0.16; P = .083).
Seltorexant 20 mg was especially effective in patients who had more severe insomnia.
Commenting on the study, Nagy Youssef, MD, PhD, professor of psychiatry, The Ohio State University Wexner Medical Center, Columbus, said this was “a well-designed study examining a promising compound.”
“Especially if replicated, this study shows the promise of this molecule for this patient population,” said Dr. Youssef, who was not involved with the research.
The study was funded by Janssen Pharmaceutical of Johnson & Johnson. Dr. Thase reports financial relationships with numerous companies. Dr. Youssef reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In a randomized, placebo-controlled, adaptive dose–finding study conducted in more than 200 patients with MDD, those with more severe insomnia at baseline had a greater improvement in depressive symptoms versus those with less severe insomnia.
“As seltorexant is an orexin receptor antagonist, it is related to other medications that are marketed as sleeping pills, so it was important to show that its antidepressant efficacy was actually caused by improved sleep,” coinvestigator Michael E. Thase, MD, professor of psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, told this news organization.
“This novel antidepressant may well turn out to be a treatment of choice for depressed patients with insomnia,” said Dr. Thase, who is also a member of the medical and research staff of the Corporal Michael J. Crescenz Department of Veterans Affairs Medical Center.
The findings were presented at the American Society of Clinical Psychopharmacology annual meeting.
Clinically meaningful?
In an earlier exploratory study, seltorexant showed antidepressant and sleep-promoting effects in patients with MDD. In a phase 2b study, a 20-mg dose of the drug showed clinically meaningful improvement in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score after 6 weeks of treatment.
In the current analysis, the investigators evaluated the effect of seltorexant in improving depressive symptoms beyond sleep-related improvement in patients with MDD, using the MADRS-WOSI (MADRS without the sleep item).
They also used the six-item core MADRS subscale, which excludes sleep, anxiety, and appetite items.
The 283 participants were randomly assigned 3:3:1 to receive seltorexant 10 mg or 20 mg or placebo once daily. They were also stratified into two groups according to the severity of their insomnia: those with a baseline Insomnia Severity Index [ISI] score of 15 or higher (58%) and those with a baseline ISI score of less than 15 (42%).
Results showed that the group receiving the 20-mg/day dose of seltorexant (n = 61 patients) obtained a statistically and clinically meaningful response, compared with the placebo group (n = 137 patients) after removing the insomnia and other “not core items” of the MADRS. The effect was clearest among those with high insomnia ratings.
Improvement in the MADRS-WOSI score was also observed in the seltorexant 20-mg group at week 3 and week 6, compared with the placebo group.
The LSM average distance
The least squares mean (LSM) average difference between the treatment and placebo groups in the MADRS-WOSI score at week 3 was −3.8 (90% confidence interval, −5.98 to −1.57; P = .005).
At week 6, the LSM between the groups in the MADRS-WOSI score was −2.5 (90% CI, −5.24 to 0.15; P = .12).
The results were consistent with improvement in the MADRS total score. At week 3, the LSM in the MADRS total score was -4.5 (90% CI, -6.96 to -2.07; P = .003) and, at week 6, it was -3.1 (90% CI, -6.13 to -0.16; P = .083).
Seltorexant 20 mg was especially effective in patients who had more severe insomnia.
Commenting on the study, Nagy Youssef, MD, PhD, professor of psychiatry, The Ohio State University Wexner Medical Center, Columbus, said this was “a well-designed study examining a promising compound.”
“Especially if replicated, this study shows the promise of this molecule for this patient population,” said Dr. Youssef, who was not involved with the research.
The study was funded by Janssen Pharmaceutical of Johnson & Johnson. Dr. Thase reports financial relationships with numerous companies. Dr. Youssef reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ASCP 2022
Biologics, Women, and Pregnancy: What’s Known?
As the and the child’s development.
“I get asked a lot about fertility,” Vivian Shi, MD, associate professor of dermatology at the University of Arkansas, Little Rock, said at MedscapeLive’s Women’s and Pediatric Dermatology Seminar. Patients want to know, she said, if they go on a specific drug, whether it will affect their chances of conceiving and what else they need to know about safety.
She told the audience what she tells her patients: The answers are not complete but are evolving at a steady pace.
“Putting this talk together was kind of like a scavenger hunt,” said Dr. Shi, who gathered data from pregnancy exposure registries, published research, the Food and Drug Administration, and other sources on biologics. As more studies emerge each year, she said, recommendations will become stronger for considering treatment by certain biological drugs, taking into account effects on fertility, pregnancy, lactation, and the infant.
Among the biologics commonly used in dermatology are:
- Tumor necrosis factor (TNF) inhibitors (etanercept, adalimumab, infliximab, certolizumab).
- Interleukin (IL)–12 and -23 antagonist (ustekinumab).
- IL-17 antagonists (ixekizumab, secukinumab, brodalumab).
- IL-23 antagonists (risankizumab, tildrakizumab, guselkumab).
- IL-4, -13 antagonist (dupilumab) and IL-13 antagonist (tralokinumab).
- CD20-directed cytolytic antibody (rituximab).
To help with decision-making, Dr. Shi discussed the relatively new FDA labeling regulations as well as pregnancy exposure registries, research studies, and recommendations.
FDA pregnancy risk summaries
Under the previous system of classification of drugs in pregnancy, the FDA rated drugs as A, B, C, D, X. These categories ranged from showing no risks to the fetus to clear risk, but were oversimplistic and confusing, Dr. Shi said. Category C was especially confusing, as a drug with no animal or human data was put in the same category as a drug with adverse fetal effects on animals, she noted.
However, effective June 30, 2015, the FDA replaced pregnancy categories with risk summaries by medication. As of June, 2020, all prescription drugs were to remove pregnancy letter labeling. The risk summaries note human data when they are available and also note when no data are available. This information, Dr. Shi said, originates from many sources, including studies published in the medical literature, postmarketing studies conducted by companies, and pregnancy exposure registries, conducted by some companies and others. The FDA does not endorse any specific registries, but does post a list of such registries. Another helpful resource, she said, is Mother to Baby, a service of the nonprofit Organization of Teratology Information Specialists (OTIS).
Known, not known
Citing published literature, Dr. Shi said that TNF inhibitors have the most robust safety data from preconception to after birth. Less is known, she said, about the reproductive safety effects of other biologics used for dermatologic conditions, as they are newer than the anti-TNF medicines.
She reviewed a variety of research studies evaluating the safety of biologics during pregnancy and beyond. Highlights include results from a large registry, the Psoriasis Longitudinal Assessment and Registry (PSOLAR), of 298 pregnancies in about 220 women from 2007 to 2019, looking at 13 different biologics. The overall and live-birth outcomes in the women on biologics for psoriasis were similar to those for the general population and the rate of congenital anomalies was 0.8%, researchers reported in 2021, lower than the generally cited annual figure of U.S. births.
Studies evaluating biologics for nondermatologic conditions suggest safety. A prospective cohort study of women who took adalimumab in pregnancy (for rheumatoid arthritis or Crohn’s disease) found no increased risk for birth defects. In another study looking at women who were breastfeeding, researchers found no increased risk of infections or delay in developmental milestones in the children of women taking biologics for inflammatory bowel disease, compared with those not on the medications.
A report using data from the World Health Organization concludes that dupilumab appears to be safe during pregnancy, based on an evaluation of 36 pregnancy-related reports among more than 37,000 unique adverse event reports related to dupilumab in a global database.
Recommendations about biologic use from different organizations don’t always mesh, Dr. Shi said, noting that European guidelines tend to be stricter, as some reviews show.
If a mother is exposed to any biologic therapy other than certolizumab during the third trimester, after 27 weeks, Dr. Shi said, “you want to consider avoiding a live vaccine for the first 6 months of the baby’s life.” It turns out, she said, the only recommended live vaccine during that period is the rotavirus vaccine, and she suggests doctors recommend postponing that one until the babies are older if women have been on biologics other than certolizumab.
Her other take-home messages: TNF inhibitors have the most robust safety data from before conception through lactation. Under current guidelines, certolizumab is viewed as the safest to use throughout pregnancy. Dr. Shi’s message to her colleagues fielding the same questions she gets from patients: “There is more data coming out every year. Ultimately, we will have better information to inform our patients.”
At the conference, Lawrence F. Eichenfield, MD, a course director and professor of dermatology and pediatrics at the University of California, San Diego and Rady Children’s Hospital San Diego, encouraged Dr. Shi to write up her presentation as a resource for other dermatologists – which she said is in progress.
Medscape Live and this news organization are owned by the same parent company. Dr. Shi disclosed consulting and investigative and research funding from several pharmaceutical firms, but not directly related to the content of her presentation.
As the and the child’s development.
“I get asked a lot about fertility,” Vivian Shi, MD, associate professor of dermatology at the University of Arkansas, Little Rock, said at MedscapeLive’s Women’s and Pediatric Dermatology Seminar. Patients want to know, she said, if they go on a specific drug, whether it will affect their chances of conceiving and what else they need to know about safety.
She told the audience what she tells her patients: The answers are not complete but are evolving at a steady pace.
“Putting this talk together was kind of like a scavenger hunt,” said Dr. Shi, who gathered data from pregnancy exposure registries, published research, the Food and Drug Administration, and other sources on biologics. As more studies emerge each year, she said, recommendations will become stronger for considering treatment by certain biological drugs, taking into account effects on fertility, pregnancy, lactation, and the infant.
Among the biologics commonly used in dermatology are:
- Tumor necrosis factor (TNF) inhibitors (etanercept, adalimumab, infliximab, certolizumab).
- Interleukin (IL)–12 and -23 antagonist (ustekinumab).
- IL-17 antagonists (ixekizumab, secukinumab, brodalumab).
- IL-23 antagonists (risankizumab, tildrakizumab, guselkumab).
- IL-4, -13 antagonist (dupilumab) and IL-13 antagonist (tralokinumab).
- CD20-directed cytolytic antibody (rituximab).
To help with decision-making, Dr. Shi discussed the relatively new FDA labeling regulations as well as pregnancy exposure registries, research studies, and recommendations.
FDA pregnancy risk summaries
Under the previous system of classification of drugs in pregnancy, the FDA rated drugs as A, B, C, D, X. These categories ranged from showing no risks to the fetus to clear risk, but were oversimplistic and confusing, Dr. Shi said. Category C was especially confusing, as a drug with no animal or human data was put in the same category as a drug with adverse fetal effects on animals, she noted.
However, effective June 30, 2015, the FDA replaced pregnancy categories with risk summaries by medication. As of June, 2020, all prescription drugs were to remove pregnancy letter labeling. The risk summaries note human data when they are available and also note when no data are available. This information, Dr. Shi said, originates from many sources, including studies published in the medical literature, postmarketing studies conducted by companies, and pregnancy exposure registries, conducted by some companies and others. The FDA does not endorse any specific registries, but does post a list of such registries. Another helpful resource, she said, is Mother to Baby, a service of the nonprofit Organization of Teratology Information Specialists (OTIS).
Known, not known
Citing published literature, Dr. Shi said that TNF inhibitors have the most robust safety data from preconception to after birth. Less is known, she said, about the reproductive safety effects of other biologics used for dermatologic conditions, as they are newer than the anti-TNF medicines.
She reviewed a variety of research studies evaluating the safety of biologics during pregnancy and beyond. Highlights include results from a large registry, the Psoriasis Longitudinal Assessment and Registry (PSOLAR), of 298 pregnancies in about 220 women from 2007 to 2019, looking at 13 different biologics. The overall and live-birth outcomes in the women on biologics for psoriasis were similar to those for the general population and the rate of congenital anomalies was 0.8%, researchers reported in 2021, lower than the generally cited annual figure of U.S. births.
Studies evaluating biologics for nondermatologic conditions suggest safety. A prospective cohort study of women who took adalimumab in pregnancy (for rheumatoid arthritis or Crohn’s disease) found no increased risk for birth defects. In another study looking at women who were breastfeeding, researchers found no increased risk of infections or delay in developmental milestones in the children of women taking biologics for inflammatory bowel disease, compared with those not on the medications.
A report using data from the World Health Organization concludes that dupilumab appears to be safe during pregnancy, based on an evaluation of 36 pregnancy-related reports among more than 37,000 unique adverse event reports related to dupilumab in a global database.
Recommendations about biologic use from different organizations don’t always mesh, Dr. Shi said, noting that European guidelines tend to be stricter, as some reviews show.
If a mother is exposed to any biologic therapy other than certolizumab during the third trimester, after 27 weeks, Dr. Shi said, “you want to consider avoiding a live vaccine for the first 6 months of the baby’s life.” It turns out, she said, the only recommended live vaccine during that period is the rotavirus vaccine, and she suggests doctors recommend postponing that one until the babies are older if women have been on biologics other than certolizumab.
Her other take-home messages: TNF inhibitors have the most robust safety data from before conception through lactation. Under current guidelines, certolizumab is viewed as the safest to use throughout pregnancy. Dr. Shi’s message to her colleagues fielding the same questions she gets from patients: “There is more data coming out every year. Ultimately, we will have better information to inform our patients.”
At the conference, Lawrence F. Eichenfield, MD, a course director and professor of dermatology and pediatrics at the University of California, San Diego and Rady Children’s Hospital San Diego, encouraged Dr. Shi to write up her presentation as a resource for other dermatologists – which she said is in progress.
Medscape Live and this news organization are owned by the same parent company. Dr. Shi disclosed consulting and investigative and research funding from several pharmaceutical firms, but not directly related to the content of her presentation.
As the and the child’s development.
“I get asked a lot about fertility,” Vivian Shi, MD, associate professor of dermatology at the University of Arkansas, Little Rock, said at MedscapeLive’s Women’s and Pediatric Dermatology Seminar. Patients want to know, she said, if they go on a specific drug, whether it will affect their chances of conceiving and what else they need to know about safety.
She told the audience what she tells her patients: The answers are not complete but are evolving at a steady pace.
“Putting this talk together was kind of like a scavenger hunt,” said Dr. Shi, who gathered data from pregnancy exposure registries, published research, the Food and Drug Administration, and other sources on biologics. As more studies emerge each year, she said, recommendations will become stronger for considering treatment by certain biological drugs, taking into account effects on fertility, pregnancy, lactation, and the infant.
Among the biologics commonly used in dermatology are:
- Tumor necrosis factor (TNF) inhibitors (etanercept, adalimumab, infliximab, certolizumab).
- Interleukin (IL)–12 and -23 antagonist (ustekinumab).
- IL-17 antagonists (ixekizumab, secukinumab, brodalumab).
- IL-23 antagonists (risankizumab, tildrakizumab, guselkumab).
- IL-4, -13 antagonist (dupilumab) and IL-13 antagonist (tralokinumab).
- CD20-directed cytolytic antibody (rituximab).
To help with decision-making, Dr. Shi discussed the relatively new FDA labeling regulations as well as pregnancy exposure registries, research studies, and recommendations.
FDA pregnancy risk summaries
Under the previous system of classification of drugs in pregnancy, the FDA rated drugs as A, B, C, D, X. These categories ranged from showing no risks to the fetus to clear risk, but were oversimplistic and confusing, Dr. Shi said. Category C was especially confusing, as a drug with no animal or human data was put in the same category as a drug with adverse fetal effects on animals, she noted.
However, effective June 30, 2015, the FDA replaced pregnancy categories with risk summaries by medication. As of June, 2020, all prescription drugs were to remove pregnancy letter labeling. The risk summaries note human data when they are available and also note when no data are available. This information, Dr. Shi said, originates from many sources, including studies published in the medical literature, postmarketing studies conducted by companies, and pregnancy exposure registries, conducted by some companies and others. The FDA does not endorse any specific registries, but does post a list of such registries. Another helpful resource, she said, is Mother to Baby, a service of the nonprofit Organization of Teratology Information Specialists (OTIS).
Known, not known
Citing published literature, Dr. Shi said that TNF inhibitors have the most robust safety data from preconception to after birth. Less is known, she said, about the reproductive safety effects of other biologics used for dermatologic conditions, as they are newer than the anti-TNF medicines.
She reviewed a variety of research studies evaluating the safety of biologics during pregnancy and beyond. Highlights include results from a large registry, the Psoriasis Longitudinal Assessment and Registry (PSOLAR), of 298 pregnancies in about 220 women from 2007 to 2019, looking at 13 different biologics. The overall and live-birth outcomes in the women on biologics for psoriasis were similar to those for the general population and the rate of congenital anomalies was 0.8%, researchers reported in 2021, lower than the generally cited annual figure of U.S. births.
Studies evaluating biologics for nondermatologic conditions suggest safety. A prospective cohort study of women who took adalimumab in pregnancy (for rheumatoid arthritis or Crohn’s disease) found no increased risk for birth defects. In another study looking at women who were breastfeeding, researchers found no increased risk of infections or delay in developmental milestones in the children of women taking biologics for inflammatory bowel disease, compared with those not on the medications.
A report using data from the World Health Organization concludes that dupilumab appears to be safe during pregnancy, based on an evaluation of 36 pregnancy-related reports among more than 37,000 unique adverse event reports related to dupilumab in a global database.
Recommendations about biologic use from different organizations don’t always mesh, Dr. Shi said, noting that European guidelines tend to be stricter, as some reviews show.
If a mother is exposed to any biologic therapy other than certolizumab during the third trimester, after 27 weeks, Dr. Shi said, “you want to consider avoiding a live vaccine for the first 6 months of the baby’s life.” It turns out, she said, the only recommended live vaccine during that period is the rotavirus vaccine, and she suggests doctors recommend postponing that one until the babies are older if women have been on biologics other than certolizumab.
Her other take-home messages: TNF inhibitors have the most robust safety data from before conception through lactation. Under current guidelines, certolizumab is viewed as the safest to use throughout pregnancy. Dr. Shi’s message to her colleagues fielding the same questions she gets from patients: “There is more data coming out every year. Ultimately, we will have better information to inform our patients.”
At the conference, Lawrence F. Eichenfield, MD, a course director and professor of dermatology and pediatrics at the University of California, San Diego and Rady Children’s Hospital San Diego, encouraged Dr. Shi to write up her presentation as a resource for other dermatologists – which she said is in progress.
Medscape Live and this news organization are owned by the same parent company. Dr. Shi disclosed consulting and investigative and research funding from several pharmaceutical firms, but not directly related to the content of her presentation.
FROM MEDSCAPELIVE WOMEN’S & PEDIATRIC DERMATOLOGY SEMINAR
Acetaminophen linked to diminished response to immunotherapy in cancer
The team found a strong association between the use of acetaminophen and a decreased response to immune checkpoint inhibitors in a study of three clinical cohorts involving more than 600 patients with advanced cancer.
Patients who took acetaminophen at the start of immunotherapy – with acetaminophen exposure confirmed by plasma testing – were found to have worse overall survival and progression-free survival than patients who did not take the analgesic. Multivariate analysis confirmed the association independent of other prognostic factors. “It is unlikely that our data are the result of bias or unmeasured confounding,” the authors comment.
The findings “present a compelling case for caution” in using acetaminophen in patients with cancer who are receiving immune checkpoint blockers, senior investigator Antoine Italiano, MD, PhD, a medical oncologist at the University of Bordeaux (France), and colleagues concluded.
The study was presented at the annual meeting of the American Society of Clinical Oncology and published simultaneously in Annals of Oncology.
“Patients with advanced cancer taking [acetaminophen] during immunotherapy experience worse clinical outcomes, which suggests that [acetaminophen] decreases T cell–mediated antitumor immunity,” the authors comment.
They also report bench research and blood studies in four healthy volunteers, which showed an up-regulation of immunosuppressive regulatory T cells (Tregs) with acetaminophen, and other findings that together suggest that acetaminophen undermines the antitumor immune processes by which checkpoint inhibitors work.
Reconsider acetaminophen pretreatment
After hearing Dr. Italiano present the results at the meeting, a Polish oncologist in the audience said he was concerned that his clinic premedicates with acetaminophen before immune checkpoint blockade and wanted to know if they should stop doing it.
“I don’t think inducing Tregs ... in cancer patients is a good approach. I do a lot of clinical trials,” and “I do not understand why in several cases sponsors required mandatory premedication with acetaminophen. I think ... we should reconsider this approach,” Dr. Italiano said.
There’s precedence for the findings. Acetaminophen – also known as paracetamol – has been shown in some studies to limit immune cell proliferation, T-cell–dependent antibody response, and viral clearance, among other things. After a randomized trial showing blunted responses to vaccines in individuals who were taking acetaminophen, the World Health Organization recommended in 2015 against concurrent use of acetaminophen with vaccines.
Steroids, antibiotics, and proton pump inhibitors have also recently been shown to worsen outcomes with pembrolizumab, noted invited discussant, Margaret Gatti-Mays, MD, a medical oncologist at Ohio State University, Columbus.
“We are starting to understand that ... commonly used medications may have a larger impact on the efficacy and toxicity of immune checkpoint blockade than historically seen with chemotherapy,” she said.
However, she expressed some uncertainty over the French findings, as she was concerned that even the multivariate analysis didn’t completely rule out that acetaminophen users had worse disease to begin with and so would be expected to have worse outcomes.
She was also unsure of how much acetaminophen is too much.
Acetaminophen has a half-life of around 3 hours or less, where the immune checkpoint inhibitors have a half-life of around 20 days or more.
Given that, Dr. Gatti-Mays wondered whether “a single dose of acetaminophen [is] enough to derail the benefit of checkpoint inhibition? Does exposure need to be continuous?”
She allowed that acetaminophen use may turn out to be one more of the many patient-level factors emerging lately – such as chronic stress, diet, body flora, and physiological age, among others – that might help explain why checkpoint inhibition works in only about 20% of eligible patients with cancer.
Study details
Dr. Italiano and his team analyzed plasma samples from 297 participants in the CheckMate 025 trial of nivolumab for renal cancer; 34 participants in the BIP study into actionable molecular alterations in cancer; and 297 participants in the PREMIS immune-related adverse events study. The patients in these last two studies had a variety of cancers and were taking various agents.
All 628 patients were on checkpoint inhibitors. The investigators divided them according to who had acetaminophen or its metabolite acetaminophen glucuronide in their plasma when they started checkpoint inhibition and those who did not.
In CheckMate 025, overall survival was significantly worse among participants who had detectable acetaminophen or its metabolite in plasma (hazard ratio, 0.67; P = .004).
None of the acetaminophen-positive participants in the BIP study responded to checkpoint blockade, compared with almost 30% of those who were negative. Acetaminophen-positive participants also trended toward worse progression-free survival (median, 1.87 vs. 4.72 months) and overall survival (median, 7.87 vs. 16.56 months).
In PREMIS, progression-free survival was a median of 2.63 months in the acetaminophen group versus 5.03 months in negative participants (P = .009); median overall survival was 8.43 months versus 14.93 months, respectively (P < .0001).
A multivariate analysis was performed in PREMIS. Acetaminophen exposure was associated with both progression-free survival (hazard ratio, 1.43; P =.015) and overall survival (HR, 1.78; P =.006) independently of performance status, liver metastases, bone metastases, number of metastases sites, tumor type, number of previous lines of treatment, steroid/antibiotic use, lactate dehydrogenase levels, and other factors.
There was no funding for the work. Dr. Italiano is a consultant for AstraZeneca, Bayer, Chugai, Deciphera, Merck, Parthenon, Roche, and Springworks, He also has grants from AstraZeneca, Bayer, Bristol-Myers Squibb, Merck, MSD, Novartis, Pharmamar, and Roche. Two authors work for Explicyte and one works for Amgen. Dr. Gatti-Mays is a consultant for Seattle Genetics.
A version of this article first appeared on Medscape.com.
The team found a strong association between the use of acetaminophen and a decreased response to immune checkpoint inhibitors in a study of three clinical cohorts involving more than 600 patients with advanced cancer.
Patients who took acetaminophen at the start of immunotherapy – with acetaminophen exposure confirmed by plasma testing – were found to have worse overall survival and progression-free survival than patients who did not take the analgesic. Multivariate analysis confirmed the association independent of other prognostic factors. “It is unlikely that our data are the result of bias or unmeasured confounding,” the authors comment.
The findings “present a compelling case for caution” in using acetaminophen in patients with cancer who are receiving immune checkpoint blockers, senior investigator Antoine Italiano, MD, PhD, a medical oncologist at the University of Bordeaux (France), and colleagues concluded.
The study was presented at the annual meeting of the American Society of Clinical Oncology and published simultaneously in Annals of Oncology.
“Patients with advanced cancer taking [acetaminophen] during immunotherapy experience worse clinical outcomes, which suggests that [acetaminophen] decreases T cell–mediated antitumor immunity,” the authors comment.
They also report bench research and blood studies in four healthy volunteers, which showed an up-regulation of immunosuppressive regulatory T cells (Tregs) with acetaminophen, and other findings that together suggest that acetaminophen undermines the antitumor immune processes by which checkpoint inhibitors work.
Reconsider acetaminophen pretreatment
After hearing Dr. Italiano present the results at the meeting, a Polish oncologist in the audience said he was concerned that his clinic premedicates with acetaminophen before immune checkpoint blockade and wanted to know if they should stop doing it.
“I don’t think inducing Tregs ... in cancer patients is a good approach. I do a lot of clinical trials,” and “I do not understand why in several cases sponsors required mandatory premedication with acetaminophen. I think ... we should reconsider this approach,” Dr. Italiano said.
There’s precedence for the findings. Acetaminophen – also known as paracetamol – has been shown in some studies to limit immune cell proliferation, T-cell–dependent antibody response, and viral clearance, among other things. After a randomized trial showing blunted responses to vaccines in individuals who were taking acetaminophen, the World Health Organization recommended in 2015 against concurrent use of acetaminophen with vaccines.
Steroids, antibiotics, and proton pump inhibitors have also recently been shown to worsen outcomes with pembrolizumab, noted invited discussant, Margaret Gatti-Mays, MD, a medical oncologist at Ohio State University, Columbus.
“We are starting to understand that ... commonly used medications may have a larger impact on the efficacy and toxicity of immune checkpoint blockade than historically seen with chemotherapy,” she said.
However, she expressed some uncertainty over the French findings, as she was concerned that even the multivariate analysis didn’t completely rule out that acetaminophen users had worse disease to begin with and so would be expected to have worse outcomes.
She was also unsure of how much acetaminophen is too much.
Acetaminophen has a half-life of around 3 hours or less, where the immune checkpoint inhibitors have a half-life of around 20 days or more.
Given that, Dr. Gatti-Mays wondered whether “a single dose of acetaminophen [is] enough to derail the benefit of checkpoint inhibition? Does exposure need to be continuous?”
She allowed that acetaminophen use may turn out to be one more of the many patient-level factors emerging lately – such as chronic stress, diet, body flora, and physiological age, among others – that might help explain why checkpoint inhibition works in only about 20% of eligible patients with cancer.
Study details
Dr. Italiano and his team analyzed plasma samples from 297 participants in the CheckMate 025 trial of nivolumab for renal cancer; 34 participants in the BIP study into actionable molecular alterations in cancer; and 297 participants in the PREMIS immune-related adverse events study. The patients in these last two studies had a variety of cancers and were taking various agents.
All 628 patients were on checkpoint inhibitors. The investigators divided them according to who had acetaminophen or its metabolite acetaminophen glucuronide in their plasma when they started checkpoint inhibition and those who did not.
In CheckMate 025, overall survival was significantly worse among participants who had detectable acetaminophen or its metabolite in plasma (hazard ratio, 0.67; P = .004).
None of the acetaminophen-positive participants in the BIP study responded to checkpoint blockade, compared with almost 30% of those who were negative. Acetaminophen-positive participants also trended toward worse progression-free survival (median, 1.87 vs. 4.72 months) and overall survival (median, 7.87 vs. 16.56 months).
In PREMIS, progression-free survival was a median of 2.63 months in the acetaminophen group versus 5.03 months in negative participants (P = .009); median overall survival was 8.43 months versus 14.93 months, respectively (P < .0001).
A multivariate analysis was performed in PREMIS. Acetaminophen exposure was associated with both progression-free survival (hazard ratio, 1.43; P =.015) and overall survival (HR, 1.78; P =.006) independently of performance status, liver metastases, bone metastases, number of metastases sites, tumor type, number of previous lines of treatment, steroid/antibiotic use, lactate dehydrogenase levels, and other factors.
There was no funding for the work. Dr. Italiano is a consultant for AstraZeneca, Bayer, Chugai, Deciphera, Merck, Parthenon, Roche, and Springworks, He also has grants from AstraZeneca, Bayer, Bristol-Myers Squibb, Merck, MSD, Novartis, Pharmamar, and Roche. Two authors work for Explicyte and one works for Amgen. Dr. Gatti-Mays is a consultant for Seattle Genetics.
A version of this article first appeared on Medscape.com.
The team found a strong association between the use of acetaminophen and a decreased response to immune checkpoint inhibitors in a study of three clinical cohorts involving more than 600 patients with advanced cancer.
Patients who took acetaminophen at the start of immunotherapy – with acetaminophen exposure confirmed by plasma testing – were found to have worse overall survival and progression-free survival than patients who did not take the analgesic. Multivariate analysis confirmed the association independent of other prognostic factors. “It is unlikely that our data are the result of bias or unmeasured confounding,” the authors comment.
The findings “present a compelling case for caution” in using acetaminophen in patients with cancer who are receiving immune checkpoint blockers, senior investigator Antoine Italiano, MD, PhD, a medical oncologist at the University of Bordeaux (France), and colleagues concluded.
The study was presented at the annual meeting of the American Society of Clinical Oncology and published simultaneously in Annals of Oncology.
“Patients with advanced cancer taking [acetaminophen] during immunotherapy experience worse clinical outcomes, which suggests that [acetaminophen] decreases T cell–mediated antitumor immunity,” the authors comment.
They also report bench research and blood studies in four healthy volunteers, which showed an up-regulation of immunosuppressive regulatory T cells (Tregs) with acetaminophen, and other findings that together suggest that acetaminophen undermines the antitumor immune processes by which checkpoint inhibitors work.
Reconsider acetaminophen pretreatment
After hearing Dr. Italiano present the results at the meeting, a Polish oncologist in the audience said he was concerned that his clinic premedicates with acetaminophen before immune checkpoint blockade and wanted to know if they should stop doing it.
“I don’t think inducing Tregs ... in cancer patients is a good approach. I do a lot of clinical trials,” and “I do not understand why in several cases sponsors required mandatory premedication with acetaminophen. I think ... we should reconsider this approach,” Dr. Italiano said.
There’s precedence for the findings. Acetaminophen – also known as paracetamol – has been shown in some studies to limit immune cell proliferation, T-cell–dependent antibody response, and viral clearance, among other things. After a randomized trial showing blunted responses to vaccines in individuals who were taking acetaminophen, the World Health Organization recommended in 2015 against concurrent use of acetaminophen with vaccines.
Steroids, antibiotics, and proton pump inhibitors have also recently been shown to worsen outcomes with pembrolizumab, noted invited discussant, Margaret Gatti-Mays, MD, a medical oncologist at Ohio State University, Columbus.
“We are starting to understand that ... commonly used medications may have a larger impact on the efficacy and toxicity of immune checkpoint blockade than historically seen with chemotherapy,” she said.
However, she expressed some uncertainty over the French findings, as she was concerned that even the multivariate analysis didn’t completely rule out that acetaminophen users had worse disease to begin with and so would be expected to have worse outcomes.
She was also unsure of how much acetaminophen is too much.
Acetaminophen has a half-life of around 3 hours or less, where the immune checkpoint inhibitors have a half-life of around 20 days or more.
Given that, Dr. Gatti-Mays wondered whether “a single dose of acetaminophen [is] enough to derail the benefit of checkpoint inhibition? Does exposure need to be continuous?”
She allowed that acetaminophen use may turn out to be one more of the many patient-level factors emerging lately – such as chronic stress, diet, body flora, and physiological age, among others – that might help explain why checkpoint inhibition works in only about 20% of eligible patients with cancer.
Study details
Dr. Italiano and his team analyzed plasma samples from 297 participants in the CheckMate 025 trial of nivolumab for renal cancer; 34 participants in the BIP study into actionable molecular alterations in cancer; and 297 participants in the PREMIS immune-related adverse events study. The patients in these last two studies had a variety of cancers and were taking various agents.
All 628 patients were on checkpoint inhibitors. The investigators divided them according to who had acetaminophen or its metabolite acetaminophen glucuronide in their plasma when they started checkpoint inhibition and those who did not.
In CheckMate 025, overall survival was significantly worse among participants who had detectable acetaminophen or its metabolite in plasma (hazard ratio, 0.67; P = .004).
None of the acetaminophen-positive participants in the BIP study responded to checkpoint blockade, compared with almost 30% of those who were negative. Acetaminophen-positive participants also trended toward worse progression-free survival (median, 1.87 vs. 4.72 months) and overall survival (median, 7.87 vs. 16.56 months).
In PREMIS, progression-free survival was a median of 2.63 months in the acetaminophen group versus 5.03 months in negative participants (P = .009); median overall survival was 8.43 months versus 14.93 months, respectively (P < .0001).
A multivariate analysis was performed in PREMIS. Acetaminophen exposure was associated with both progression-free survival (hazard ratio, 1.43; P =.015) and overall survival (HR, 1.78; P =.006) independently of performance status, liver metastases, bone metastases, number of metastases sites, tumor type, number of previous lines of treatment, steroid/antibiotic use, lactate dehydrogenase levels, and other factors.
There was no funding for the work. Dr. Italiano is a consultant for AstraZeneca, Bayer, Chugai, Deciphera, Merck, Parthenon, Roche, and Springworks, He also has grants from AstraZeneca, Bayer, Bristol-Myers Squibb, Merck, MSD, Novartis, Pharmamar, and Roche. Two authors work for Explicyte and one works for Amgen. Dr. Gatti-Mays is a consultant for Seattle Genetics.
A version of this article first appeared on Medscape.com.
FROM ASCO 2022
‘Alarming’ new data on disordered sleep after COVID-19
Such disturbances are especially common among Black people, new research shows.
The “high” prevalence of moderate to severe sleep disturbances is “alarming,” study investigator Cinthya Pena Orbea, MD, sleep specialist at the Cleveland Clinic, said in an interview.
The findings were presented at the annual meeting of the Associated Professional Sleep Societies.
Dr. Pena and colleagues analyzed data on 962 patients with PASC seen at the Cleveland Clinic ReCOVer Clinic between February 2021 and April 2022.
More than two-thirds of patients (67.2%) reported at least moderate fatigue, while 21.8% reported severe fatigue, Dr. Pena reported.
In addition, 41.3% reported at least moderate sleep disturbances, while 8% of patients reported severe sleep disturbances, including insomnia, “which may impair quality of life,” Dr. Pena said.
Obesity, mood disorders, and Black race emerged as contributors to problems with sleep and fatigue after COVID.
Notably, after adjusting for demographics, Black race conferred threefold higher odds of moderate to severe sleep disturbances.
“We don’t know why this is, and one of our next steps is to better understand race-specific determinants of sleep disturbances after COVID and create targeted interventions,” Dr. Pena said.
How long after COVID the fatigue and sleep problems last “remains uncertain,” Dr. Pena acknowledged. However, in her clinical experience with therapy, patients’ sleep and fatigue may improve after 6 or 8 months.
Ruth Benca, MD, PhD, cochair of the Alliance for Sleep, is not surprised by the Cleveland Clinic findings.
“Sleep disturbances and fatigue are part of the sequelae of COVID,” Dr. Benca, who was not involved in the study, said in an interview.
“We know that people who have had COVID have more trouble sleeping afterwards. There is the COVID insomnia created in all of us just out of our worries, fears, isolation, and stress. And then there’s an actual impact of having the infection itself on worsening sleep,” said Dr. Benca, with Wake Forest University and Atrium Health Wake Forest Baptist, both in Winston-Salem, N.C.
The study had no specific funding. The authors have disclosed no relevant financial relationships. Dr. Benca is a consultant for Idorsia Pharmaceuticals.
A version of this article first appeared on Medscape.com.
Such disturbances are especially common among Black people, new research shows.
The “high” prevalence of moderate to severe sleep disturbances is “alarming,” study investigator Cinthya Pena Orbea, MD, sleep specialist at the Cleveland Clinic, said in an interview.
The findings were presented at the annual meeting of the Associated Professional Sleep Societies.
Dr. Pena and colleagues analyzed data on 962 patients with PASC seen at the Cleveland Clinic ReCOVer Clinic between February 2021 and April 2022.
More than two-thirds of patients (67.2%) reported at least moderate fatigue, while 21.8% reported severe fatigue, Dr. Pena reported.
In addition, 41.3% reported at least moderate sleep disturbances, while 8% of patients reported severe sleep disturbances, including insomnia, “which may impair quality of life,” Dr. Pena said.
Obesity, mood disorders, and Black race emerged as contributors to problems with sleep and fatigue after COVID.
Notably, after adjusting for demographics, Black race conferred threefold higher odds of moderate to severe sleep disturbances.
“We don’t know why this is, and one of our next steps is to better understand race-specific determinants of sleep disturbances after COVID and create targeted interventions,” Dr. Pena said.
How long after COVID the fatigue and sleep problems last “remains uncertain,” Dr. Pena acknowledged. However, in her clinical experience with therapy, patients’ sleep and fatigue may improve after 6 or 8 months.
Ruth Benca, MD, PhD, cochair of the Alliance for Sleep, is not surprised by the Cleveland Clinic findings.
“Sleep disturbances and fatigue are part of the sequelae of COVID,” Dr. Benca, who was not involved in the study, said in an interview.
“We know that people who have had COVID have more trouble sleeping afterwards. There is the COVID insomnia created in all of us just out of our worries, fears, isolation, and stress. And then there’s an actual impact of having the infection itself on worsening sleep,” said Dr. Benca, with Wake Forest University and Atrium Health Wake Forest Baptist, both in Winston-Salem, N.C.
The study had no specific funding. The authors have disclosed no relevant financial relationships. Dr. Benca is a consultant for Idorsia Pharmaceuticals.
A version of this article first appeared on Medscape.com.
Such disturbances are especially common among Black people, new research shows.
The “high” prevalence of moderate to severe sleep disturbances is “alarming,” study investigator Cinthya Pena Orbea, MD, sleep specialist at the Cleveland Clinic, said in an interview.
The findings were presented at the annual meeting of the Associated Professional Sleep Societies.
Dr. Pena and colleagues analyzed data on 962 patients with PASC seen at the Cleveland Clinic ReCOVer Clinic between February 2021 and April 2022.
More than two-thirds of patients (67.2%) reported at least moderate fatigue, while 21.8% reported severe fatigue, Dr. Pena reported.
In addition, 41.3% reported at least moderate sleep disturbances, while 8% of patients reported severe sleep disturbances, including insomnia, “which may impair quality of life,” Dr. Pena said.
Obesity, mood disorders, and Black race emerged as contributors to problems with sleep and fatigue after COVID.
Notably, after adjusting for demographics, Black race conferred threefold higher odds of moderate to severe sleep disturbances.
“We don’t know why this is, and one of our next steps is to better understand race-specific determinants of sleep disturbances after COVID and create targeted interventions,” Dr. Pena said.
How long after COVID the fatigue and sleep problems last “remains uncertain,” Dr. Pena acknowledged. However, in her clinical experience with therapy, patients’ sleep and fatigue may improve after 6 or 8 months.
Ruth Benca, MD, PhD, cochair of the Alliance for Sleep, is not surprised by the Cleveland Clinic findings.
“Sleep disturbances and fatigue are part of the sequelae of COVID,” Dr. Benca, who was not involved in the study, said in an interview.
“We know that people who have had COVID have more trouble sleeping afterwards. There is the COVID insomnia created in all of us just out of our worries, fears, isolation, and stress. And then there’s an actual impact of having the infection itself on worsening sleep,” said Dr. Benca, with Wake Forest University and Atrium Health Wake Forest Baptist, both in Winston-Salem, N.C.
The study had no specific funding. The authors have disclosed no relevant financial relationships. Dr. Benca is a consultant for Idorsia Pharmaceuticals.
A version of this article first appeared on Medscape.com.
FROM SLEEP 2022
Social activities may offset psychosis risk in poor communities
, new research suggests.
A study of more than 170 young participants showed reduced hippocampal volume in those living in poor neighborhoods who had low social engagement versus their peers with greater community engagement.
“These findings demonstrate the importance of considering broader environmental influences and indices of social engagement when conceptualizing adversity and potential interventions for individuals at clinical high risk for psychosis,” co-investigator Benson Ku, MD, a postdoctoral fellow and psychiatry resident at Emory University School of Medicine, Atlanta, told this news organization.
The results were presented at the virtual American Society of Clinical Psychopharmacology annual meeting.
A personal connection
It’s well known that growing up in low-income housing is associated with lower hippocampal volume and an increased risk for schizophrenia, said Dr. Ku.
“The inverse relationship between poverty and hippocampal gray matter volume has [also] been shown to be mediated by social stress, which can include things like lack of parental caregiving and stressful life events,” he added.
Dr. Ku himself grew up in a socioeconomically disadvantaged family in Queens, New York, and he said he had initially performed poorly in school. His early experiences have helped inform his clinical and research interests in the social determinants of mental health.
“I found community support in the Boys’ Club of New York and a local Magic Shop near where I lived, which helped me thrive and become the successful man I am today. I have also heard from my patients how their living conditions and neighborhood have significantly impacted their mental health,” Dr. Ku said.
“A more in-depth understanding of the social determinants of mental health has helped build rapport and empathy with my patients,” he added.
To explore the association between neighborhood poverty, social engagement, and hippocampal volume in youth at high risk for psychosis, the researchers analyzed data from the North American Prodrome Longitudinal Study Phase 2, a multisite consortium.
The researchers recruited and followed up with help-seeking adolescents and young adults from diverse neighborhoods. The analysis included 174 youth, ages 12-33 years, at high clinical risk for psychosis.
Hippocampal volume was assessed using structural MRI. Neighborhood poverty was defined as the percentage of residents with an annual income below the poverty level in the past year.
Social engagement was derived from the desirable events subscale items of the Life Events Scale. These activities included involvement in a church or synagogue; participation in a club, neighborhood, or other organization; taking a vacation; engaging in a hobby, sport, craft, or recreational activity; acquiring a pet; or making new friends.
Lower hippocampal volume
Results showed neighborhood poverty was associated with reduced hippocampal volume, even after controlling for several confounders, including race/ethnicity, family history of mental illnesses, household poverty, educational level, and stressful life events.
Among the 77 participants with lower social engagement, which was defined as three or fewer social activities, neighborhood poverty was associated with reduced hippocampal volume.
However, in the 97 participants who reported greater social engagement, which was defined as four or more social activities, neighborhood poverty was not significantly associated with hippocampal volume.
“It is possible that social engagement may mitigate the deleterious effects of neighborhood poverty on brain morphology, which may inform interventions offered to individuals from disadvantaged neighborhoods,” Dr. Ku said.
“If replication of the relationships between neighborhood poverty, hippocampal volume, and social engagement is established in other populations in longitudinal studies, then targeted interventions at the community level and increased social engagement may potentially play a major role in disease prevention among at-risk youth,” he said.
Dr. Ku noted social engagement might look different in urban versus rural settings.
“In urban areas, it might mean friends, clubs, neighborhood organizations, etc. In rural areas, it might mean family, pets, crafts, etc. The level of social engagement may also depend on neighborhood characteristics, and more research would be needed to better understand how geographic area characteristics – remote, rural, urban – affects social engagement,” he said.
Interesting, innovative
Nagy Youssef, MD, PhD, director of clinical research and professor of psychiatry, Ohio State University College of Medicine, Columbus, said the study suggests “social engagement may reduce the negative effect of poverty in this population, and if replicated in a larger study, could assist and be a part of the early intervention and prevention in psychosis.”
Overall, “this is an interesting and innovative study that has important medical and social implications and is a good step toward helping us understand these relationships and mitigate and prevent negative consequences, as best as possible, in this population,” said Dr. Youssef, who was not part of the research.
The analysis was supported by a grant from the National Institute of Mental Health to the North American Prodrome Longitudinal Study. Dr. Ku and Dr. Youssef report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, new research suggests.
A study of more than 170 young participants showed reduced hippocampal volume in those living in poor neighborhoods who had low social engagement versus their peers with greater community engagement.
“These findings demonstrate the importance of considering broader environmental influences and indices of social engagement when conceptualizing adversity and potential interventions for individuals at clinical high risk for psychosis,” co-investigator Benson Ku, MD, a postdoctoral fellow and psychiatry resident at Emory University School of Medicine, Atlanta, told this news organization.
The results were presented at the virtual American Society of Clinical Psychopharmacology annual meeting.
A personal connection
It’s well known that growing up in low-income housing is associated with lower hippocampal volume and an increased risk for schizophrenia, said Dr. Ku.
“The inverse relationship between poverty and hippocampal gray matter volume has [also] been shown to be mediated by social stress, which can include things like lack of parental caregiving and stressful life events,” he added.
Dr. Ku himself grew up in a socioeconomically disadvantaged family in Queens, New York, and he said he had initially performed poorly in school. His early experiences have helped inform his clinical and research interests in the social determinants of mental health.
“I found community support in the Boys’ Club of New York and a local Magic Shop near where I lived, which helped me thrive and become the successful man I am today. I have also heard from my patients how their living conditions and neighborhood have significantly impacted their mental health,” Dr. Ku said.
“A more in-depth understanding of the social determinants of mental health has helped build rapport and empathy with my patients,” he added.
To explore the association between neighborhood poverty, social engagement, and hippocampal volume in youth at high risk for psychosis, the researchers analyzed data from the North American Prodrome Longitudinal Study Phase 2, a multisite consortium.
The researchers recruited and followed up with help-seeking adolescents and young adults from diverse neighborhoods. The analysis included 174 youth, ages 12-33 years, at high clinical risk for psychosis.
Hippocampal volume was assessed using structural MRI. Neighborhood poverty was defined as the percentage of residents with an annual income below the poverty level in the past year.
Social engagement was derived from the desirable events subscale items of the Life Events Scale. These activities included involvement in a church or synagogue; participation in a club, neighborhood, or other organization; taking a vacation; engaging in a hobby, sport, craft, or recreational activity; acquiring a pet; or making new friends.
Lower hippocampal volume
Results showed neighborhood poverty was associated with reduced hippocampal volume, even after controlling for several confounders, including race/ethnicity, family history of mental illnesses, household poverty, educational level, and stressful life events.
Among the 77 participants with lower social engagement, which was defined as three or fewer social activities, neighborhood poverty was associated with reduced hippocampal volume.
However, in the 97 participants who reported greater social engagement, which was defined as four or more social activities, neighborhood poverty was not significantly associated with hippocampal volume.
“It is possible that social engagement may mitigate the deleterious effects of neighborhood poverty on brain morphology, which may inform interventions offered to individuals from disadvantaged neighborhoods,” Dr. Ku said.
“If replication of the relationships between neighborhood poverty, hippocampal volume, and social engagement is established in other populations in longitudinal studies, then targeted interventions at the community level and increased social engagement may potentially play a major role in disease prevention among at-risk youth,” he said.
Dr. Ku noted social engagement might look different in urban versus rural settings.
“In urban areas, it might mean friends, clubs, neighborhood organizations, etc. In rural areas, it might mean family, pets, crafts, etc. The level of social engagement may also depend on neighborhood characteristics, and more research would be needed to better understand how geographic area characteristics – remote, rural, urban – affects social engagement,” he said.
Interesting, innovative
Nagy Youssef, MD, PhD, director of clinical research and professor of psychiatry, Ohio State University College of Medicine, Columbus, said the study suggests “social engagement may reduce the negative effect of poverty in this population, and if replicated in a larger study, could assist and be a part of the early intervention and prevention in psychosis.”
Overall, “this is an interesting and innovative study that has important medical and social implications and is a good step toward helping us understand these relationships and mitigate and prevent negative consequences, as best as possible, in this population,” said Dr. Youssef, who was not part of the research.
The analysis was supported by a grant from the National Institute of Mental Health to the North American Prodrome Longitudinal Study. Dr. Ku and Dr. Youssef report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, new research suggests.
A study of more than 170 young participants showed reduced hippocampal volume in those living in poor neighborhoods who had low social engagement versus their peers with greater community engagement.
“These findings demonstrate the importance of considering broader environmental influences and indices of social engagement when conceptualizing adversity and potential interventions for individuals at clinical high risk for psychosis,” co-investigator Benson Ku, MD, a postdoctoral fellow and psychiatry resident at Emory University School of Medicine, Atlanta, told this news organization.
The results were presented at the virtual American Society of Clinical Psychopharmacology annual meeting.
A personal connection
It’s well known that growing up in low-income housing is associated with lower hippocampal volume and an increased risk for schizophrenia, said Dr. Ku.
“The inverse relationship between poverty and hippocampal gray matter volume has [also] been shown to be mediated by social stress, which can include things like lack of parental caregiving and stressful life events,” he added.
Dr. Ku himself grew up in a socioeconomically disadvantaged family in Queens, New York, and he said he had initially performed poorly in school. His early experiences have helped inform his clinical and research interests in the social determinants of mental health.
“I found community support in the Boys’ Club of New York and a local Magic Shop near where I lived, which helped me thrive and become the successful man I am today. I have also heard from my patients how their living conditions and neighborhood have significantly impacted their mental health,” Dr. Ku said.
“A more in-depth understanding of the social determinants of mental health has helped build rapport and empathy with my patients,” he added.
To explore the association between neighborhood poverty, social engagement, and hippocampal volume in youth at high risk for psychosis, the researchers analyzed data from the North American Prodrome Longitudinal Study Phase 2, a multisite consortium.
The researchers recruited and followed up with help-seeking adolescents and young adults from diverse neighborhoods. The analysis included 174 youth, ages 12-33 years, at high clinical risk for psychosis.
Hippocampal volume was assessed using structural MRI. Neighborhood poverty was defined as the percentage of residents with an annual income below the poverty level in the past year.
Social engagement was derived from the desirable events subscale items of the Life Events Scale. These activities included involvement in a church or synagogue; participation in a club, neighborhood, or other organization; taking a vacation; engaging in a hobby, sport, craft, or recreational activity; acquiring a pet; or making new friends.
Lower hippocampal volume
Results showed neighborhood poverty was associated with reduced hippocampal volume, even after controlling for several confounders, including race/ethnicity, family history of mental illnesses, household poverty, educational level, and stressful life events.
Among the 77 participants with lower social engagement, which was defined as three or fewer social activities, neighborhood poverty was associated with reduced hippocampal volume.
However, in the 97 participants who reported greater social engagement, which was defined as four or more social activities, neighborhood poverty was not significantly associated with hippocampal volume.
“It is possible that social engagement may mitigate the deleterious effects of neighborhood poverty on brain morphology, which may inform interventions offered to individuals from disadvantaged neighborhoods,” Dr. Ku said.
“If replication of the relationships between neighborhood poverty, hippocampal volume, and social engagement is established in other populations in longitudinal studies, then targeted interventions at the community level and increased social engagement may potentially play a major role in disease prevention among at-risk youth,” he said.
Dr. Ku noted social engagement might look different in urban versus rural settings.
“In urban areas, it might mean friends, clubs, neighborhood organizations, etc. In rural areas, it might mean family, pets, crafts, etc. The level of social engagement may also depend on neighborhood characteristics, and more research would be needed to better understand how geographic area characteristics – remote, rural, urban – affects social engagement,” he said.
Interesting, innovative
Nagy Youssef, MD, PhD, director of clinical research and professor of psychiatry, Ohio State University College of Medicine, Columbus, said the study suggests “social engagement may reduce the negative effect of poverty in this population, and if replicated in a larger study, could assist and be a part of the early intervention and prevention in psychosis.”
Overall, “this is an interesting and innovative study that has important medical and social implications and is a good step toward helping us understand these relationships and mitigate and prevent negative consequences, as best as possible, in this population,” said Dr. Youssef, who was not part of the research.
The analysis was supported by a grant from the National Institute of Mental Health to the North American Prodrome Longitudinal Study. Dr. Ku and Dr. Youssef report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ASCP 2022
Women are not being warned that anesthetic may reduce birth pill efficacy
The effectiveness of hormonal contraceptives, including the pill and mini-pill, may be compromised by sugammadex, a drug widely used in anesthesia for reversing neuromuscular blockade induced by rocuronium or vecuronium.
Yet women are not routinely informed that the drug may make their contraception less effective, delegates at Euroanaesthesia, the annual meeting of the European Society of Anaesthesiology and Intensive Care in Milan were told.
New research presented at the meeting supports the authors’ experience that “robust methods for identifying at-risk patients and informing them of the associated risk of contraceptive failures is not common practice across anesthetic departments within the United Kingdom, and likely further afield.”
This is according to a survey of almost 150 anesthetic professionals, including consultants, junior doctors, and physician assistants, working at University College London Hospitals NHS Foundation Trust.
Dr. Neha Passi, Dr. Matt Oliver, and colleagues at the trust’s department of anesthesiology sent out a seven-question survey to their 150 colleagues and received 82 responses, 94% of which claimed awareness of the risk of contraceptive failure with sugammadex. However, 70% of the respondents admitted that they do not routinely discuss this with patients who have received the drug.
Risk with all forms of hormonal contraceptive
Yet current guidance is to inform women of child-bearing age that they have received the drug and, because of increased risk of contraceptive failure, advise those taking oral hormonal contraceptives to follow the missed pill advice in the leaflet that comes with their contraceptives. It also counsels that clinicians should advise women using other types of hormonal contraceptive to use an additional nonhormonal means of contraception for 7 days.
The study authors also carried out a retrospective audit of sugammadex use in the trust and reported that during the 6 weeks covered by the audit, 234 patients were administered sugammadex of whom 65 (28%) were women of childbearing age. Of these, 17 had a medical history that meant they weren’t at risk of pregnancy, but the other 48 should have received advice on the risks of contraceptive failure – however there was no record in the medical notes of such advice having been given for any of the at-risk 48 women.
While sugammadex is the only anesthetic drug known to have this effect, it is recognized to interact with progesterone and so may reduce the effectiveness of hormonal contraceptives, including the progesterone-only pill, combined pill, vaginal rings, implants, and intrauterine devices.
Dr. Passi said: “It is concerning that we are so seldom informing patients of the risk of contraceptive failure following sugammadex use.
“Use of sugammadex is expected to rise as it becomes cheaper in the future, and ensuring that women receiving this medicine are aware it may increase their risk of unwanted pregnancy must be a priority.”
She added: “It is important to note, however, that most patients receiving an anesthetic do not need a muscle relaxant and that sugammadex is one of several drugs available to reverse muscle relaxation.”
Dr. Oliver said: “We only studied one hospital trust but we expect the results to be similar in elsewhere in the U.K.”
In response to their findings, the study’s authors have created patient information leaflets and letters and programmed the trust’s electronic patient record system to identify “at-risk” patients and deliver electronic prompts to the anesthetists caring for them in the perioperative period.
A version of this article first appeared on Medscape UK.
The effectiveness of hormonal contraceptives, including the pill and mini-pill, may be compromised by sugammadex, a drug widely used in anesthesia for reversing neuromuscular blockade induced by rocuronium or vecuronium.
Yet women are not routinely informed that the drug may make their contraception less effective, delegates at Euroanaesthesia, the annual meeting of the European Society of Anaesthesiology and Intensive Care in Milan were told.
New research presented at the meeting supports the authors’ experience that “robust methods for identifying at-risk patients and informing them of the associated risk of contraceptive failures is not common practice across anesthetic departments within the United Kingdom, and likely further afield.”
This is according to a survey of almost 150 anesthetic professionals, including consultants, junior doctors, and physician assistants, working at University College London Hospitals NHS Foundation Trust.
Dr. Neha Passi, Dr. Matt Oliver, and colleagues at the trust’s department of anesthesiology sent out a seven-question survey to their 150 colleagues and received 82 responses, 94% of which claimed awareness of the risk of contraceptive failure with sugammadex. However, 70% of the respondents admitted that they do not routinely discuss this with patients who have received the drug.
Risk with all forms of hormonal contraceptive
Yet current guidance is to inform women of child-bearing age that they have received the drug and, because of increased risk of contraceptive failure, advise those taking oral hormonal contraceptives to follow the missed pill advice in the leaflet that comes with their contraceptives. It also counsels that clinicians should advise women using other types of hormonal contraceptive to use an additional nonhormonal means of contraception for 7 days.
The study authors also carried out a retrospective audit of sugammadex use in the trust and reported that during the 6 weeks covered by the audit, 234 patients were administered sugammadex of whom 65 (28%) were women of childbearing age. Of these, 17 had a medical history that meant they weren’t at risk of pregnancy, but the other 48 should have received advice on the risks of contraceptive failure – however there was no record in the medical notes of such advice having been given for any of the at-risk 48 women.
While sugammadex is the only anesthetic drug known to have this effect, it is recognized to interact with progesterone and so may reduce the effectiveness of hormonal contraceptives, including the progesterone-only pill, combined pill, vaginal rings, implants, and intrauterine devices.
Dr. Passi said: “It is concerning that we are so seldom informing patients of the risk of contraceptive failure following sugammadex use.
“Use of sugammadex is expected to rise as it becomes cheaper in the future, and ensuring that women receiving this medicine are aware it may increase their risk of unwanted pregnancy must be a priority.”
She added: “It is important to note, however, that most patients receiving an anesthetic do not need a muscle relaxant and that sugammadex is one of several drugs available to reverse muscle relaxation.”
Dr. Oliver said: “We only studied one hospital trust but we expect the results to be similar in elsewhere in the U.K.”
In response to their findings, the study’s authors have created patient information leaflets and letters and programmed the trust’s electronic patient record system to identify “at-risk” patients and deliver electronic prompts to the anesthetists caring for them in the perioperative period.
A version of this article first appeared on Medscape UK.
The effectiveness of hormonal contraceptives, including the pill and mini-pill, may be compromised by sugammadex, a drug widely used in anesthesia for reversing neuromuscular blockade induced by rocuronium or vecuronium.
Yet women are not routinely informed that the drug may make their contraception less effective, delegates at Euroanaesthesia, the annual meeting of the European Society of Anaesthesiology and Intensive Care in Milan were told.
New research presented at the meeting supports the authors’ experience that “robust methods for identifying at-risk patients and informing them of the associated risk of contraceptive failures is not common practice across anesthetic departments within the United Kingdom, and likely further afield.”
This is according to a survey of almost 150 anesthetic professionals, including consultants, junior doctors, and physician assistants, working at University College London Hospitals NHS Foundation Trust.
Dr. Neha Passi, Dr. Matt Oliver, and colleagues at the trust’s department of anesthesiology sent out a seven-question survey to their 150 colleagues and received 82 responses, 94% of which claimed awareness of the risk of contraceptive failure with sugammadex. However, 70% of the respondents admitted that they do not routinely discuss this with patients who have received the drug.
Risk with all forms of hormonal contraceptive
Yet current guidance is to inform women of child-bearing age that they have received the drug and, because of increased risk of contraceptive failure, advise those taking oral hormonal contraceptives to follow the missed pill advice in the leaflet that comes with their contraceptives. It also counsels that clinicians should advise women using other types of hormonal contraceptive to use an additional nonhormonal means of contraception for 7 days.
The study authors also carried out a retrospective audit of sugammadex use in the trust and reported that during the 6 weeks covered by the audit, 234 patients were administered sugammadex of whom 65 (28%) were women of childbearing age. Of these, 17 had a medical history that meant they weren’t at risk of pregnancy, but the other 48 should have received advice on the risks of contraceptive failure – however there was no record in the medical notes of such advice having been given for any of the at-risk 48 women.
While sugammadex is the only anesthetic drug known to have this effect, it is recognized to interact with progesterone and so may reduce the effectiveness of hormonal contraceptives, including the progesterone-only pill, combined pill, vaginal rings, implants, and intrauterine devices.
Dr. Passi said: “It is concerning that we are so seldom informing patients of the risk of contraceptive failure following sugammadex use.
“Use of sugammadex is expected to rise as it becomes cheaper in the future, and ensuring that women receiving this medicine are aware it may increase their risk of unwanted pregnancy must be a priority.”
She added: “It is important to note, however, that most patients receiving an anesthetic do not need a muscle relaxant and that sugammadex is one of several drugs available to reverse muscle relaxation.”
Dr. Oliver said: “We only studied one hospital trust but we expect the results to be similar in elsewhere in the U.K.”
In response to their findings, the study’s authors have created patient information leaflets and letters and programmed the trust’s electronic patient record system to identify “at-risk” patients and deliver electronic prompts to the anesthetists caring for them in the perioperative period.
A version of this article first appeared on Medscape UK.
FROM EUROANAESTHESIA
Immunosuppressed rheumatic patients not at high risk of breakthrough COVID-19
COPENHAGEN – Most patients with immune-mediated inflammatory diseases (IMID) should not be considered at high risk for severe COVID-19 breakthrough infections, but those on anti-CD20 therapy are the exception, data from a large prospective, cohort study show.
“Overall, the data are reassuring, with conventional risk factors, such as age, and comorbidities seeming to be more important regarding risk of severe COVID-19 breakthrough infections than rheumatic disease or immunosuppressant medication,” said Laura Boekel, MD, from Amsterdam UMC, who presented the study at the annual European Congress of Rheumatology.
But, she added, there was an exception for anti-CD20 therapy. “This is especially relevant for patients with conventional risk factors that might accumulate, and rheumatologists might want to consider alternative treatment options if possible. It is important to inform patients about the risks of anti-CD20.”
Another study, presented during the same session at the congress by Rebecca Hasseli, MD, from the University of Giessen (Germany) saw no deaths and no COVID-19 related complications in a cohort of triple-vaccinated patients with inflammatory rheumatic diseases, despite a higher median age and a higher rate of comorbidities compared to double-vaccinated and unvaccinated cohorts.
Ingrid Jyssum, MD, from Diakonhjemmet Hospital, Oslo, who presented results of the Nor-vaC study investigating the impact of different DMARDs on the immunogenicity of a third COVID-19 vaccine dose, welcomed the research by Dr. Boekel and Dr. Hasseli.
“The findings of Hasseli are interesting in the light of our data on serological response after the third dose, with a lack of breakthrough infections after three doses corresponding well to the robust antibody response that we found in our cohort,” she remarked. “This is very reassuring for our patients. Our own work together with the findings of Hasseli and Boekel demonstrate that additional vaccine doses are important to keep this population well protected against severe COVID-19 infections.”
The Nor-vaC study was conducted with a cohort of 1,100 patients with inflammatory joint and bowel diseases. “These patients had attenuated antibody responses after two vaccine doses; however, we found that a third vaccine dose brought the humoral response in patients up to the antibody levels that healthy controls had after two doses,” said Dr. Jyssum. “In addition, we found that the decline in antibodies after the third dose was less than the decline seen after the second dose. Importantly, the third dose was safe in our patients, with no new safety issues.”
Breakthrough infections and immunosuppressants
“Like the rest of the world, we were wondering if our patients were at increased risk of COVID-19, and if the immunosuppressants used by these patients influenced their risk,” said Dr. Boekel.
The researchers compared both the incidence and severity of COVID-19 breakthrough infections with the SARS-CoV-2 Delta variant in a population of fully vaccinated IMID patients taking immunosuppressants and controls (IMID patients not taking immunosuppressants and healthy controls).
Two large ongoing, prospective, multicenter cohort studies provided pooled data collected between February and December 2021 using digital questionnaires, standardized electronic case record forms, and medical files.
Finger-prick tests were used to collect blood samples that were analyzed after vaccination against SARS-CoV-2 for anti–receptor-binding domain (RBD) antibodies, and antinucleocapsid antibodies to identify asymptomatic breakthrough infections. Any associations between antibodies and the incidence of breakthrough infections were generated, and results were adjusted for sex, cardiovascular disease, chronic pulmonary disease, obesity, and vaccine type.
The analysis included 3,207 IMID patients taking immunosuppressants, and 1,810 controls (985 IMID patients not on immunosuppressants and 825 healthy controls).
Initially, Dr. Boekel and her colleagues looked at incidence of infections and hospitalizations prior to vaccination, and then after vaccination, which was the main aim of the study.
Prior to vaccination, hospitalization risk for COVID-19 was somewhat higher for IMID patients overall compared with controls, reported Dr. Boekel. “But those treated with anti-CD20 therapy, demonstrated much greater risk for severe disease.”
After the SARS-CoV-2 vaccination campaign began, the researchers then looked at how immunosuppressants influenced humoral response to SARS-CoV-2 vaccination.
“Anti-CD20 therapy showed the greatest impact on humoral immune response after SARS-CoV-2 vaccination,” said Dr. Boekel. Other immunosuppressant drugs had variable effects on humoral and cellular immunity.
Once they had established that immunosuppressant drugs impaired immune responses to SARS-CoV-2 vaccination, the researchers wanted to determine if this affected clinical outcomes. Blood samples taken 28 days after the second vaccination enabled Dr. Boekel and her colleagues to see if antibody production was associated with breakthrough infections.
Breakthrough infections were seen in 5% of patients on immunosuppressants, 5% of patients not on immunosuppressants, and 4% of healthy controls. Also, asymptomatic COVID-19 breakthrough cases were comparable between IMID patients taking immunosuppressants and controls, at 10% in each group.
“We saw that the incidence [of getting COVID-19] was comparable between groups, independent of whether they were receiving immunosuppressants or not, or healthy controls. However, if they developed antibodies against the two vaccinations the chance of getting infected was lower,” reported Dr. Boekel.
Hospitalization (severe disease) rates were also comparable between groups. “Patients with rheumatic diseases, even when treated with immunosuppressants were not at increased risk of severe disease from Delta breakthrough infections,” added the researcher. “Cases that were hospitalized were mainly elderly and those with comorbidities, for example cardiovascular disease and cardiopulmonary disease.”
Hospital admissions were 5.4% in patients on immunosuppressants, 5.7% in those not on immunosuppressants, and 6% in health controls.
However, once again, there was one exception, Dr. Boekel stressed. “Patients treated with anti-CD20 therapy were at increased risk of severe disease and hospitalization.”
Omicron variant has a different transmissibility than Delta, so the researchers continued the study looking at the Omicron variant. The data “were mostly reassuring,” said Dr. Boekel. “As expected, hospitalization rates decreased overall, with the exception of patients on anti-CD20 therapy where, despite overall reduced pathogenicity, patients remain at increased risk.”
She said that they were awaiting long-term data so the data reflect only short-term immunity against Omicron. “However, we included many elderly and patients with comorbidities, so this made the analysis very sensitive to detect severe cases,” she added.
Breakthrough infection among double- and triple-vaccinated patients
A lower rate of COVID-19 related complications and deaths were seen in patients who were triple-vaccinated against SARS-CoV-2, than in double-vaccinated or unvaccinated patients, despite the former having more comorbidities and use of rituximab (Rituxan), said Dr. Hasseli.
“These data support the recommendation of booster vaccination to reduce COVID-19-related mortality in patients with inflammatory rheumatic diseases [IRDs],” she said.
“A small number of COVID-19 cases were seen in patients with IRD after vaccinations, and in a few cases, hospitalizations were required. Breakthrough infections were mostly seen in patients on B-cell depletion therapy,” she added.
Dr. Hasseli and her colleagues looked at the characteristics and outcomes of SARS-CoV-2 breakthrough infections among double- and triple-vaccinated patients with IRD.
“We wanted to understand if patients with IRD are protected in the same way as the general population following vaccination, given that these patients receive drugs that might impair the immune response,” she explained.
Data for analysis were drawn from the German COVID-19-IRD registry covering February 2021 and January 2022, and patients who were double- or triple- vaccinated against COVID-19 either 14 days or more prior to a SARS-CoV-2 infection were included. Type of IRD, vaccine, immunomodulation, comorbidities, and outcome of the infection were compared with 737 unvaccinated IRD patients with COVID-19. Those with prior COVID-19 were excluded.
Cases were stratified by vaccinations status: unvaccinated (1,388 patients, median age 57 years); double vaccinated (462, 56 years) and triple vaccinated (301, 53 years). Body mass index was similar across groups (25-26 kg/m2), and time between SARS-CoV-2 infection and last vaccination was 156 days in double-vaccinated patients, and 62 days in triple-vaccinated patients.
Patients had rheumatoid arthritis in 44.7% and 44.4% of unvaccinated and double-vaccinated patients respectively, but fewer triple-vaccinated patients had RA (37.2%). Triple vaccination was seen in 32.2% of patients with spondyloarthritis, 16.6% connective tissue diseases, 5.3% other vasculitis, and 3.3% ANCA-associated vasculitis. Of triple-vaccinated patients, 26.2% were treated with tumor necrosis factor-alpha (TNF-alpha) inhibitors, and 6.3% with rituximab, while 5.3% were not on immunomodulation. At least 25% were treated with glucocorticoids, reported Dr. Hasseli.
“Arterial hypertension and diabetes, that might be risk factors for COVID-19, were less frequently reported in triple-vaccinated patients. More patients in the double-vaccinated group [42.9%] than the triple-vaccinated [23.8%] reported absence of relevant comorbidities,” she said.
COVID-19 related complications were less often reported in double- and triple-vaccinated groups with hospitalizations at 9.5% and 4.3% in double and triple-vaccinated people respectively.
Dr. Boekel and Dr. Hasseli report no relevant conflicts of interest.
COPENHAGEN – Most patients with immune-mediated inflammatory diseases (IMID) should not be considered at high risk for severe COVID-19 breakthrough infections, but those on anti-CD20 therapy are the exception, data from a large prospective, cohort study show.
“Overall, the data are reassuring, with conventional risk factors, such as age, and comorbidities seeming to be more important regarding risk of severe COVID-19 breakthrough infections than rheumatic disease or immunosuppressant medication,” said Laura Boekel, MD, from Amsterdam UMC, who presented the study at the annual European Congress of Rheumatology.
But, she added, there was an exception for anti-CD20 therapy. “This is especially relevant for patients with conventional risk factors that might accumulate, and rheumatologists might want to consider alternative treatment options if possible. It is important to inform patients about the risks of anti-CD20.”
Another study, presented during the same session at the congress by Rebecca Hasseli, MD, from the University of Giessen (Germany) saw no deaths and no COVID-19 related complications in a cohort of triple-vaccinated patients with inflammatory rheumatic diseases, despite a higher median age and a higher rate of comorbidities compared to double-vaccinated and unvaccinated cohorts.
Ingrid Jyssum, MD, from Diakonhjemmet Hospital, Oslo, who presented results of the Nor-vaC study investigating the impact of different DMARDs on the immunogenicity of a third COVID-19 vaccine dose, welcomed the research by Dr. Boekel and Dr. Hasseli.
“The findings of Hasseli are interesting in the light of our data on serological response after the third dose, with a lack of breakthrough infections after three doses corresponding well to the robust antibody response that we found in our cohort,” she remarked. “This is very reassuring for our patients. Our own work together with the findings of Hasseli and Boekel demonstrate that additional vaccine doses are important to keep this population well protected against severe COVID-19 infections.”
The Nor-vaC study was conducted with a cohort of 1,100 patients with inflammatory joint and bowel diseases. “These patients had attenuated antibody responses after two vaccine doses; however, we found that a third vaccine dose brought the humoral response in patients up to the antibody levels that healthy controls had after two doses,” said Dr. Jyssum. “In addition, we found that the decline in antibodies after the third dose was less than the decline seen after the second dose. Importantly, the third dose was safe in our patients, with no new safety issues.”
Breakthrough infections and immunosuppressants
“Like the rest of the world, we were wondering if our patients were at increased risk of COVID-19, and if the immunosuppressants used by these patients influenced their risk,” said Dr. Boekel.
The researchers compared both the incidence and severity of COVID-19 breakthrough infections with the SARS-CoV-2 Delta variant in a population of fully vaccinated IMID patients taking immunosuppressants and controls (IMID patients not taking immunosuppressants and healthy controls).
Two large ongoing, prospective, multicenter cohort studies provided pooled data collected between February and December 2021 using digital questionnaires, standardized electronic case record forms, and medical files.
Finger-prick tests were used to collect blood samples that were analyzed after vaccination against SARS-CoV-2 for anti–receptor-binding domain (RBD) antibodies, and antinucleocapsid antibodies to identify asymptomatic breakthrough infections. Any associations between antibodies and the incidence of breakthrough infections were generated, and results were adjusted for sex, cardiovascular disease, chronic pulmonary disease, obesity, and vaccine type.
The analysis included 3,207 IMID patients taking immunosuppressants, and 1,810 controls (985 IMID patients not on immunosuppressants and 825 healthy controls).
Initially, Dr. Boekel and her colleagues looked at incidence of infections and hospitalizations prior to vaccination, and then after vaccination, which was the main aim of the study.
Prior to vaccination, hospitalization risk for COVID-19 was somewhat higher for IMID patients overall compared with controls, reported Dr. Boekel. “But those treated with anti-CD20 therapy, demonstrated much greater risk for severe disease.”
After the SARS-CoV-2 vaccination campaign began, the researchers then looked at how immunosuppressants influenced humoral response to SARS-CoV-2 vaccination.
“Anti-CD20 therapy showed the greatest impact on humoral immune response after SARS-CoV-2 vaccination,” said Dr. Boekel. Other immunosuppressant drugs had variable effects on humoral and cellular immunity.
Once they had established that immunosuppressant drugs impaired immune responses to SARS-CoV-2 vaccination, the researchers wanted to determine if this affected clinical outcomes. Blood samples taken 28 days after the second vaccination enabled Dr. Boekel and her colleagues to see if antibody production was associated with breakthrough infections.
Breakthrough infections were seen in 5% of patients on immunosuppressants, 5% of patients not on immunosuppressants, and 4% of healthy controls. Also, asymptomatic COVID-19 breakthrough cases were comparable between IMID patients taking immunosuppressants and controls, at 10% in each group.
“We saw that the incidence [of getting COVID-19] was comparable between groups, independent of whether they were receiving immunosuppressants or not, or healthy controls. However, if they developed antibodies against the two vaccinations the chance of getting infected was lower,” reported Dr. Boekel.
Hospitalization (severe disease) rates were also comparable between groups. “Patients with rheumatic diseases, even when treated with immunosuppressants were not at increased risk of severe disease from Delta breakthrough infections,” added the researcher. “Cases that were hospitalized were mainly elderly and those with comorbidities, for example cardiovascular disease and cardiopulmonary disease.”
Hospital admissions were 5.4% in patients on immunosuppressants, 5.7% in those not on immunosuppressants, and 6% in health controls.
However, once again, there was one exception, Dr. Boekel stressed. “Patients treated with anti-CD20 therapy were at increased risk of severe disease and hospitalization.”
Omicron variant has a different transmissibility than Delta, so the researchers continued the study looking at the Omicron variant. The data “were mostly reassuring,” said Dr. Boekel. “As expected, hospitalization rates decreased overall, with the exception of patients on anti-CD20 therapy where, despite overall reduced pathogenicity, patients remain at increased risk.”
She said that they were awaiting long-term data so the data reflect only short-term immunity against Omicron. “However, we included many elderly and patients with comorbidities, so this made the analysis very sensitive to detect severe cases,” she added.
Breakthrough infection among double- and triple-vaccinated patients
A lower rate of COVID-19 related complications and deaths were seen in patients who were triple-vaccinated against SARS-CoV-2, than in double-vaccinated or unvaccinated patients, despite the former having more comorbidities and use of rituximab (Rituxan), said Dr. Hasseli.
“These data support the recommendation of booster vaccination to reduce COVID-19-related mortality in patients with inflammatory rheumatic diseases [IRDs],” she said.
“A small number of COVID-19 cases were seen in patients with IRD after vaccinations, and in a few cases, hospitalizations were required. Breakthrough infections were mostly seen in patients on B-cell depletion therapy,” she added.
Dr. Hasseli and her colleagues looked at the characteristics and outcomes of SARS-CoV-2 breakthrough infections among double- and triple-vaccinated patients with IRD.
“We wanted to understand if patients with IRD are protected in the same way as the general population following vaccination, given that these patients receive drugs that might impair the immune response,” she explained.
Data for analysis were drawn from the German COVID-19-IRD registry covering February 2021 and January 2022, and patients who were double- or triple- vaccinated against COVID-19 either 14 days or more prior to a SARS-CoV-2 infection were included. Type of IRD, vaccine, immunomodulation, comorbidities, and outcome of the infection were compared with 737 unvaccinated IRD patients with COVID-19. Those with prior COVID-19 were excluded.
Cases were stratified by vaccinations status: unvaccinated (1,388 patients, median age 57 years); double vaccinated (462, 56 years) and triple vaccinated (301, 53 years). Body mass index was similar across groups (25-26 kg/m2), and time between SARS-CoV-2 infection and last vaccination was 156 days in double-vaccinated patients, and 62 days in triple-vaccinated patients.
Patients had rheumatoid arthritis in 44.7% and 44.4% of unvaccinated and double-vaccinated patients respectively, but fewer triple-vaccinated patients had RA (37.2%). Triple vaccination was seen in 32.2% of patients with spondyloarthritis, 16.6% connective tissue diseases, 5.3% other vasculitis, and 3.3% ANCA-associated vasculitis. Of triple-vaccinated patients, 26.2% were treated with tumor necrosis factor-alpha (TNF-alpha) inhibitors, and 6.3% with rituximab, while 5.3% were not on immunomodulation. At least 25% were treated with glucocorticoids, reported Dr. Hasseli.
“Arterial hypertension and diabetes, that might be risk factors for COVID-19, were less frequently reported in triple-vaccinated patients. More patients in the double-vaccinated group [42.9%] than the triple-vaccinated [23.8%] reported absence of relevant comorbidities,” she said.
COVID-19 related complications were less often reported in double- and triple-vaccinated groups with hospitalizations at 9.5% and 4.3% in double and triple-vaccinated people respectively.
Dr. Boekel and Dr. Hasseli report no relevant conflicts of interest.
COPENHAGEN – Most patients with immune-mediated inflammatory diseases (IMID) should not be considered at high risk for severe COVID-19 breakthrough infections, but those on anti-CD20 therapy are the exception, data from a large prospective, cohort study show.
“Overall, the data are reassuring, with conventional risk factors, such as age, and comorbidities seeming to be more important regarding risk of severe COVID-19 breakthrough infections than rheumatic disease or immunosuppressant medication,” said Laura Boekel, MD, from Amsterdam UMC, who presented the study at the annual European Congress of Rheumatology.
But, she added, there was an exception for anti-CD20 therapy. “This is especially relevant for patients with conventional risk factors that might accumulate, and rheumatologists might want to consider alternative treatment options if possible. It is important to inform patients about the risks of anti-CD20.”
Another study, presented during the same session at the congress by Rebecca Hasseli, MD, from the University of Giessen (Germany) saw no deaths and no COVID-19 related complications in a cohort of triple-vaccinated patients with inflammatory rheumatic diseases, despite a higher median age and a higher rate of comorbidities compared to double-vaccinated and unvaccinated cohorts.
Ingrid Jyssum, MD, from Diakonhjemmet Hospital, Oslo, who presented results of the Nor-vaC study investigating the impact of different DMARDs on the immunogenicity of a third COVID-19 vaccine dose, welcomed the research by Dr. Boekel and Dr. Hasseli.
“The findings of Hasseli are interesting in the light of our data on serological response after the third dose, with a lack of breakthrough infections after three doses corresponding well to the robust antibody response that we found in our cohort,” she remarked. “This is very reassuring for our patients. Our own work together with the findings of Hasseli and Boekel demonstrate that additional vaccine doses are important to keep this population well protected against severe COVID-19 infections.”
The Nor-vaC study was conducted with a cohort of 1,100 patients with inflammatory joint and bowel diseases. “These patients had attenuated antibody responses after two vaccine doses; however, we found that a third vaccine dose brought the humoral response in patients up to the antibody levels that healthy controls had after two doses,” said Dr. Jyssum. “In addition, we found that the decline in antibodies after the third dose was less than the decline seen after the second dose. Importantly, the third dose was safe in our patients, with no new safety issues.”
Breakthrough infections and immunosuppressants
“Like the rest of the world, we were wondering if our patients were at increased risk of COVID-19, and if the immunosuppressants used by these patients influenced their risk,” said Dr. Boekel.
The researchers compared both the incidence and severity of COVID-19 breakthrough infections with the SARS-CoV-2 Delta variant in a population of fully vaccinated IMID patients taking immunosuppressants and controls (IMID patients not taking immunosuppressants and healthy controls).
Two large ongoing, prospective, multicenter cohort studies provided pooled data collected between February and December 2021 using digital questionnaires, standardized electronic case record forms, and medical files.
Finger-prick tests were used to collect blood samples that were analyzed after vaccination against SARS-CoV-2 for anti–receptor-binding domain (RBD) antibodies, and antinucleocapsid antibodies to identify asymptomatic breakthrough infections. Any associations between antibodies and the incidence of breakthrough infections were generated, and results were adjusted for sex, cardiovascular disease, chronic pulmonary disease, obesity, and vaccine type.
The analysis included 3,207 IMID patients taking immunosuppressants, and 1,810 controls (985 IMID patients not on immunosuppressants and 825 healthy controls).
Initially, Dr. Boekel and her colleagues looked at incidence of infections and hospitalizations prior to vaccination, and then after vaccination, which was the main aim of the study.
Prior to vaccination, hospitalization risk for COVID-19 was somewhat higher for IMID patients overall compared with controls, reported Dr. Boekel. “But those treated with anti-CD20 therapy, demonstrated much greater risk for severe disease.”
After the SARS-CoV-2 vaccination campaign began, the researchers then looked at how immunosuppressants influenced humoral response to SARS-CoV-2 vaccination.
“Anti-CD20 therapy showed the greatest impact on humoral immune response after SARS-CoV-2 vaccination,” said Dr. Boekel. Other immunosuppressant drugs had variable effects on humoral and cellular immunity.
Once they had established that immunosuppressant drugs impaired immune responses to SARS-CoV-2 vaccination, the researchers wanted to determine if this affected clinical outcomes. Blood samples taken 28 days after the second vaccination enabled Dr. Boekel and her colleagues to see if antibody production was associated with breakthrough infections.
Breakthrough infections were seen in 5% of patients on immunosuppressants, 5% of patients not on immunosuppressants, and 4% of healthy controls. Also, asymptomatic COVID-19 breakthrough cases were comparable between IMID patients taking immunosuppressants and controls, at 10% in each group.
“We saw that the incidence [of getting COVID-19] was comparable between groups, independent of whether they were receiving immunosuppressants or not, or healthy controls. However, if they developed antibodies against the two vaccinations the chance of getting infected was lower,” reported Dr. Boekel.
Hospitalization (severe disease) rates were also comparable between groups. “Patients with rheumatic diseases, even when treated with immunosuppressants were not at increased risk of severe disease from Delta breakthrough infections,” added the researcher. “Cases that were hospitalized were mainly elderly and those with comorbidities, for example cardiovascular disease and cardiopulmonary disease.”
Hospital admissions were 5.4% in patients on immunosuppressants, 5.7% in those not on immunosuppressants, and 6% in health controls.
However, once again, there was one exception, Dr. Boekel stressed. “Patients treated with anti-CD20 therapy were at increased risk of severe disease and hospitalization.”
Omicron variant has a different transmissibility than Delta, so the researchers continued the study looking at the Omicron variant. The data “were mostly reassuring,” said Dr. Boekel. “As expected, hospitalization rates decreased overall, with the exception of patients on anti-CD20 therapy where, despite overall reduced pathogenicity, patients remain at increased risk.”
She said that they were awaiting long-term data so the data reflect only short-term immunity against Omicron. “However, we included many elderly and patients with comorbidities, so this made the analysis very sensitive to detect severe cases,” she added.
Breakthrough infection among double- and triple-vaccinated patients
A lower rate of COVID-19 related complications and deaths were seen in patients who were triple-vaccinated against SARS-CoV-2, than in double-vaccinated or unvaccinated patients, despite the former having more comorbidities and use of rituximab (Rituxan), said Dr. Hasseli.
“These data support the recommendation of booster vaccination to reduce COVID-19-related mortality in patients with inflammatory rheumatic diseases [IRDs],” she said.
“A small number of COVID-19 cases were seen in patients with IRD after vaccinations, and in a few cases, hospitalizations were required. Breakthrough infections were mostly seen in patients on B-cell depletion therapy,” she added.
Dr. Hasseli and her colleagues looked at the characteristics and outcomes of SARS-CoV-2 breakthrough infections among double- and triple-vaccinated patients with IRD.
“We wanted to understand if patients with IRD are protected in the same way as the general population following vaccination, given that these patients receive drugs that might impair the immune response,” she explained.
Data for analysis were drawn from the German COVID-19-IRD registry covering February 2021 and January 2022, and patients who were double- or triple- vaccinated against COVID-19 either 14 days or more prior to a SARS-CoV-2 infection were included. Type of IRD, vaccine, immunomodulation, comorbidities, and outcome of the infection were compared with 737 unvaccinated IRD patients with COVID-19. Those with prior COVID-19 were excluded.
Cases were stratified by vaccinations status: unvaccinated (1,388 patients, median age 57 years); double vaccinated (462, 56 years) and triple vaccinated (301, 53 years). Body mass index was similar across groups (25-26 kg/m2), and time between SARS-CoV-2 infection and last vaccination was 156 days in double-vaccinated patients, and 62 days in triple-vaccinated patients.
Patients had rheumatoid arthritis in 44.7% and 44.4% of unvaccinated and double-vaccinated patients respectively, but fewer triple-vaccinated patients had RA (37.2%). Triple vaccination was seen in 32.2% of patients with spondyloarthritis, 16.6% connective tissue diseases, 5.3% other vasculitis, and 3.3% ANCA-associated vasculitis. Of triple-vaccinated patients, 26.2% were treated with tumor necrosis factor-alpha (TNF-alpha) inhibitors, and 6.3% with rituximab, while 5.3% were not on immunomodulation. At least 25% were treated with glucocorticoids, reported Dr. Hasseli.
“Arterial hypertension and diabetes, that might be risk factors for COVID-19, were less frequently reported in triple-vaccinated patients. More patients in the double-vaccinated group [42.9%] than the triple-vaccinated [23.8%] reported absence of relevant comorbidities,” she said.
COVID-19 related complications were less often reported in double- and triple-vaccinated groups with hospitalizations at 9.5% and 4.3% in double and triple-vaccinated people respectively.
Dr. Boekel and Dr. Hasseli report no relevant conflicts of interest.
AT THE EULAR 2022 CONGRESS