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Novel gene therapy offers hope for some lymphomas
Not all patients with relapsed or refractory large B cell lymphoma (r/r LBCL) are candidates for high-dose chemotherapy or hematopoietic stem cell transplantation (HSCT), and options for second-line therapies for this population are limited, said Dr. Alison Sehgal of the University of Pittsburgh Medical Center in her presentation of the findings.
Lisocabtagene maraleucel (liso-cel) is a CD19-directed CAR T-cell product. In a previous phase 3 randomized trial (the TRANSFORM study), lisocabtagene showed superiority over salvage chemotherapy for LBCL patients who were fit candidates for stem cell transplant, but its use in older, frail patients who are not transplant candidates remains uncertain, wrote Dr. Sehgal and colleagues in their poster at the meeting.
In the study, the researchers identified 74 patients with r/r LBCL. Of these, 61 were treated with liso-cel. The patients ranged in age from 53 to 84 years, with a median age of 74 years, 61% were male, and 89% were white. Approximately half were refractory and half were relapsed.
For the therapy, patients underwent lymphodepletion with cyclophosphamide and fludarabine, followed 2-7 days later by an infusion of liso-cel at a target dose of 100 x 106 CAR+ T cells; all patients had at least 6 months of follow-up from their first response.
The primary endpoint of overall response rate occurred in 80% of the patients, and clinically meaningful complete response occurred in 54% over a median follow-up of 12.3 months.
“Clinically meaningful CRs were observed across all subgroups,” Dr. Sehgal said in her presentation.
The response lasted a median of 21.7 months, and the median follow-up for duration of response was 15.5 months. The median overall survival was not reached, but the median progression-free survival was 9.0 months, with a median follow-up period of 13.0 months.
Responses occurred across all prespecified subgroups, with no significant differences in either safety or efficacy based on hematopoietic cell transplantation–specific comorbidity index (HCT-CI) scores.
“Despite the advanced age and comorbidities of the population, the safety profile was consistent with previous reports,” and no new or increased safety signals appeared, Dr. Sehgal said.
The most common treatment-emergent adverse events of grade 3 or higher were neutropenia (48%), leukopenia (21%), thrombocytopenia (20%), and anemia (11%). Cytokine-release syndrome (CRS) occurred in 23 patients (38%); of these, 1 patient was grade 3 and none were grades 4 or 5.
Approximately one-third of the patients (31%) experienced neurological events during the study; three cases were grade 3, none were grades 4 or 5. Patients with CRS or NE were treated with tocilizumab (10%), corticosteroids (3%), or both (20%). Treatment-emergent adverse events of grade 3 or higher occurred in 79% of patients overall, including grade 5 events in two patients because of COVID-19.
The study findings were limited by the small sample size and lack of controls. However, the results support the potential use of liso-cel as a second-line therapy for r/r LBCL patients who are not candidates for HSCT, Dr. Sehgal concluded.
Addressing an ongoing unmet need
In an interview, study coauthor Dr. Leo I. Gordon of Northwestern University, Chicago, observed, “Patients with relapsed or refractory large B-cell lymphoma who are not considered candidates for stem cell transplant following first-line treatment, based on age, comorbidities, health status, or other prognostic factors, have more difficult-to-treat disease, poor prognosis, and more limited treatment options.”
Dr. Gordon noted that the PILOT study is the only trial to evaluate a CAR T-cell therapy as a second-line treatment for r/r LBCL patients who are not considered candidates for stem cell transplant.
“Data from the primary analysis of the PILOT study further demonstrate the potential value of using CAR T-cell therapies earlier in the treatment paradigm for relapsed or refractory LBCL to help improve clinical outcomes and address ongoing unmet need,” he said.
CAR T-cell therapies have shown benefits in later lines for r/r LBCL and as a second-line treatment for r/r LBCL patients who are deemed candidates for stem cell transplant, “so we were encouraged and not surprised by these data.”
However, Dr. Gordon noted, “There may be some patients with similar presentations that might have a transplant, so one limitation of the trial is how one defines patients where transplant is the intended therapy, and that assessment varies among institutions and clinicians.”
An application for liso-cel as a treatment for patients with r/r LBCL who have failed front-line therapy is currently under Priority Review with the FDA, with a Prescription Drug User Fee Act (PDUFA) goal date of June 24, 2022, he added.
Liso-cel may fill treatment gap as second-line therapy
The current study is important because “the long-term outcomes of patients with relapsed or refractory large B-cell lymphoma who are not candidates for stem cell transplantation is very poor,” said Dr. Brian Till of Fred Hutchinson Cancer Research Center, Seattle, in an interview.
“CAR T therapy leads to about a 40% cure rate, but is currently only available in this population after the failure of second-line therapy,” said Dr. Till, who was not involved in the study.
“Given that liso-cel was shown to improve outcomes in the second-line setting among transplant candidates, it is logical to consider it as second-line therapy in nontransplant candidates as well, who are otherwise fit enough to receive CAR T therapy,” Dr. Till explained.
“This study showed a rate of long-term progression-free survival similar to what has been observed in the third-line setting and was reasonably well tolerated in these older patients,” said Dr. Till. The results suggest “that second-line liso-cel may be an attractive treatment strategy for patients who are not candidates for stem cell transplantation due to advanced age or comorbidities,” he noted.
Dr. Till had no relevant financial conflicts to disclose.
The study was funded by Bristol Myers Squibb.
Not all patients with relapsed or refractory large B cell lymphoma (r/r LBCL) are candidates for high-dose chemotherapy or hematopoietic stem cell transplantation (HSCT), and options for second-line therapies for this population are limited, said Dr. Alison Sehgal of the University of Pittsburgh Medical Center in her presentation of the findings.
Lisocabtagene maraleucel (liso-cel) is a CD19-directed CAR T-cell product. In a previous phase 3 randomized trial (the TRANSFORM study), lisocabtagene showed superiority over salvage chemotherapy for LBCL patients who were fit candidates for stem cell transplant, but its use in older, frail patients who are not transplant candidates remains uncertain, wrote Dr. Sehgal and colleagues in their poster at the meeting.
In the study, the researchers identified 74 patients with r/r LBCL. Of these, 61 were treated with liso-cel. The patients ranged in age from 53 to 84 years, with a median age of 74 years, 61% were male, and 89% were white. Approximately half were refractory and half were relapsed.
For the therapy, patients underwent lymphodepletion with cyclophosphamide and fludarabine, followed 2-7 days later by an infusion of liso-cel at a target dose of 100 x 106 CAR+ T cells; all patients had at least 6 months of follow-up from their first response.
The primary endpoint of overall response rate occurred in 80% of the patients, and clinically meaningful complete response occurred in 54% over a median follow-up of 12.3 months.
“Clinically meaningful CRs were observed across all subgroups,” Dr. Sehgal said in her presentation.
The response lasted a median of 21.7 months, and the median follow-up for duration of response was 15.5 months. The median overall survival was not reached, but the median progression-free survival was 9.0 months, with a median follow-up period of 13.0 months.
Responses occurred across all prespecified subgroups, with no significant differences in either safety or efficacy based on hematopoietic cell transplantation–specific comorbidity index (HCT-CI) scores.
“Despite the advanced age and comorbidities of the population, the safety profile was consistent with previous reports,” and no new or increased safety signals appeared, Dr. Sehgal said.
The most common treatment-emergent adverse events of grade 3 or higher were neutropenia (48%), leukopenia (21%), thrombocytopenia (20%), and anemia (11%). Cytokine-release syndrome (CRS) occurred in 23 patients (38%); of these, 1 patient was grade 3 and none were grades 4 or 5.
Approximately one-third of the patients (31%) experienced neurological events during the study; three cases were grade 3, none were grades 4 or 5. Patients with CRS or NE were treated with tocilizumab (10%), corticosteroids (3%), or both (20%). Treatment-emergent adverse events of grade 3 or higher occurred in 79% of patients overall, including grade 5 events in two patients because of COVID-19.
The study findings were limited by the small sample size and lack of controls. However, the results support the potential use of liso-cel as a second-line therapy for r/r LBCL patients who are not candidates for HSCT, Dr. Sehgal concluded.
Addressing an ongoing unmet need
In an interview, study coauthor Dr. Leo I. Gordon of Northwestern University, Chicago, observed, “Patients with relapsed or refractory large B-cell lymphoma who are not considered candidates for stem cell transplant following first-line treatment, based on age, comorbidities, health status, or other prognostic factors, have more difficult-to-treat disease, poor prognosis, and more limited treatment options.”
Dr. Gordon noted that the PILOT study is the only trial to evaluate a CAR T-cell therapy as a second-line treatment for r/r LBCL patients who are not considered candidates for stem cell transplant.
“Data from the primary analysis of the PILOT study further demonstrate the potential value of using CAR T-cell therapies earlier in the treatment paradigm for relapsed or refractory LBCL to help improve clinical outcomes and address ongoing unmet need,” he said.
CAR T-cell therapies have shown benefits in later lines for r/r LBCL and as a second-line treatment for r/r LBCL patients who are deemed candidates for stem cell transplant, “so we were encouraged and not surprised by these data.”
However, Dr. Gordon noted, “There may be some patients with similar presentations that might have a transplant, so one limitation of the trial is how one defines patients where transplant is the intended therapy, and that assessment varies among institutions and clinicians.”
An application for liso-cel as a treatment for patients with r/r LBCL who have failed front-line therapy is currently under Priority Review with the FDA, with a Prescription Drug User Fee Act (PDUFA) goal date of June 24, 2022, he added.
Liso-cel may fill treatment gap as second-line therapy
The current study is important because “the long-term outcomes of patients with relapsed or refractory large B-cell lymphoma who are not candidates for stem cell transplantation is very poor,” said Dr. Brian Till of Fred Hutchinson Cancer Research Center, Seattle, in an interview.
“CAR T therapy leads to about a 40% cure rate, but is currently only available in this population after the failure of second-line therapy,” said Dr. Till, who was not involved in the study.
“Given that liso-cel was shown to improve outcomes in the second-line setting among transplant candidates, it is logical to consider it as second-line therapy in nontransplant candidates as well, who are otherwise fit enough to receive CAR T therapy,” Dr. Till explained.
“This study showed a rate of long-term progression-free survival similar to what has been observed in the third-line setting and was reasonably well tolerated in these older patients,” said Dr. Till. The results suggest “that second-line liso-cel may be an attractive treatment strategy for patients who are not candidates for stem cell transplantation due to advanced age or comorbidities,” he noted.
Dr. Till had no relevant financial conflicts to disclose.
The study was funded by Bristol Myers Squibb.
Not all patients with relapsed or refractory large B cell lymphoma (r/r LBCL) are candidates for high-dose chemotherapy or hematopoietic stem cell transplantation (HSCT), and options for second-line therapies for this population are limited, said Dr. Alison Sehgal of the University of Pittsburgh Medical Center in her presentation of the findings.
Lisocabtagene maraleucel (liso-cel) is a CD19-directed CAR T-cell product. In a previous phase 3 randomized trial (the TRANSFORM study), lisocabtagene showed superiority over salvage chemotherapy for LBCL patients who were fit candidates for stem cell transplant, but its use in older, frail patients who are not transplant candidates remains uncertain, wrote Dr. Sehgal and colleagues in their poster at the meeting.
In the study, the researchers identified 74 patients with r/r LBCL. Of these, 61 were treated with liso-cel. The patients ranged in age from 53 to 84 years, with a median age of 74 years, 61% were male, and 89% were white. Approximately half were refractory and half were relapsed.
For the therapy, patients underwent lymphodepletion with cyclophosphamide and fludarabine, followed 2-7 days later by an infusion of liso-cel at a target dose of 100 x 106 CAR+ T cells; all patients had at least 6 months of follow-up from their first response.
The primary endpoint of overall response rate occurred in 80% of the patients, and clinically meaningful complete response occurred in 54% over a median follow-up of 12.3 months.
“Clinically meaningful CRs were observed across all subgroups,” Dr. Sehgal said in her presentation.
The response lasted a median of 21.7 months, and the median follow-up for duration of response was 15.5 months. The median overall survival was not reached, but the median progression-free survival was 9.0 months, with a median follow-up period of 13.0 months.
Responses occurred across all prespecified subgroups, with no significant differences in either safety or efficacy based on hematopoietic cell transplantation–specific comorbidity index (HCT-CI) scores.
“Despite the advanced age and comorbidities of the population, the safety profile was consistent with previous reports,” and no new or increased safety signals appeared, Dr. Sehgal said.
The most common treatment-emergent adverse events of grade 3 or higher were neutropenia (48%), leukopenia (21%), thrombocytopenia (20%), and anemia (11%). Cytokine-release syndrome (CRS) occurred in 23 patients (38%); of these, 1 patient was grade 3 and none were grades 4 or 5.
Approximately one-third of the patients (31%) experienced neurological events during the study; three cases were grade 3, none were grades 4 or 5. Patients with CRS or NE were treated with tocilizumab (10%), corticosteroids (3%), or both (20%). Treatment-emergent adverse events of grade 3 or higher occurred in 79% of patients overall, including grade 5 events in two patients because of COVID-19.
The study findings were limited by the small sample size and lack of controls. However, the results support the potential use of liso-cel as a second-line therapy for r/r LBCL patients who are not candidates for HSCT, Dr. Sehgal concluded.
Addressing an ongoing unmet need
In an interview, study coauthor Dr. Leo I. Gordon of Northwestern University, Chicago, observed, “Patients with relapsed or refractory large B-cell lymphoma who are not considered candidates for stem cell transplant following first-line treatment, based on age, comorbidities, health status, or other prognostic factors, have more difficult-to-treat disease, poor prognosis, and more limited treatment options.”
Dr. Gordon noted that the PILOT study is the only trial to evaluate a CAR T-cell therapy as a second-line treatment for r/r LBCL patients who are not considered candidates for stem cell transplant.
“Data from the primary analysis of the PILOT study further demonstrate the potential value of using CAR T-cell therapies earlier in the treatment paradigm for relapsed or refractory LBCL to help improve clinical outcomes and address ongoing unmet need,” he said.
CAR T-cell therapies have shown benefits in later lines for r/r LBCL and as a second-line treatment for r/r LBCL patients who are deemed candidates for stem cell transplant, “so we were encouraged and not surprised by these data.”
However, Dr. Gordon noted, “There may be some patients with similar presentations that might have a transplant, so one limitation of the trial is how one defines patients where transplant is the intended therapy, and that assessment varies among institutions and clinicians.”
An application for liso-cel as a treatment for patients with r/r LBCL who have failed front-line therapy is currently under Priority Review with the FDA, with a Prescription Drug User Fee Act (PDUFA) goal date of June 24, 2022, he added.
Liso-cel may fill treatment gap as second-line therapy
The current study is important because “the long-term outcomes of patients with relapsed or refractory large B-cell lymphoma who are not candidates for stem cell transplantation is very poor,” said Dr. Brian Till of Fred Hutchinson Cancer Research Center, Seattle, in an interview.
“CAR T therapy leads to about a 40% cure rate, but is currently only available in this population after the failure of second-line therapy,” said Dr. Till, who was not involved in the study.
“Given that liso-cel was shown to improve outcomes in the second-line setting among transplant candidates, it is logical to consider it as second-line therapy in nontransplant candidates as well, who are otherwise fit enough to receive CAR T therapy,” Dr. Till explained.
“This study showed a rate of long-term progression-free survival similar to what has been observed in the third-line setting and was reasonably well tolerated in these older patients,” said Dr. Till. The results suggest “that second-line liso-cel may be an attractive treatment strategy for patients who are not candidates for stem cell transplantation due to advanced age or comorbidities,” he noted.
Dr. Till had no relevant financial conflicts to disclose.
The study was funded by Bristol Myers Squibb.
FROM ASCO 2022
Genetic testing for best antidepressant accurate, cost effective
new research suggests.
CYP2D6 and CYP2C19, from the cytochrome P450 family, are involved in the metabolism and elimination of various molecules, including medications. Variants in the genes encoding these enzymes affect the speed at which drugs are metabolized, altering their pharmacokinetic profiles.
The researchers studied 125 patients with MDD and used CYP2D6 and CYP2C19 genotyping to determine the presence of actionable phenotypes in line with Food and Drug Administration labeling.
They found that, in many cases, pharmacogenetic testing could have predicted poor response to the initial treatment selection and could have helped guide subsequent choices to improve outcomes.
In addition, a pharmacoeconomic evaluation that combined direct and indirect costs resulting from MDD with the prevalence of CYP2D6 and CYP2C19 phenotypes showed that testing for functional variants in both genes would be cost effective at a national level.
Had psychiatrists who treated patients in the study known about their metabolizing profiles, it “might have contributed to switches in medication” and could have reduced “delays in response,” said lead researcher Alessio Squassina, PhD, associate professor of pharmacology at the University of Cagliari (Italy).
The findings were presented at the European Psychiatric Association 2022 Congress.
Highly variable response rates
Dr. Squassina noted that the response to antidepressants is a “highly variable trait,” and while it is known that genetics play a role, their contribution is “still not completely understood.”
He explained that the use of pharmacogenetics, which leverages genetic information to guide treatment decision-making, has increased significantly.
While regulatory bodies, including the FDA, have been “very active” in defining strict criteria for interpreting the information from pharmacogenetic tests, there remains some “discrepancy” in their clinical utility.
Dr. Squassina said the FDA provides guidance on use of genetic testing on the labels of 34 psychiatric medications. Of these, 79% relate to CYP2D6, 12% relate to CYP2C19, and 9% relate to other genes.
These labels provide guidance on when genetic testing is recommended or required, as well as potentially clinically actionable gene-drug associations in patients with certain functional alleles.
However, Dr. Squassina noted that the distribution of such alleles is not the same across Europe, so it’s possible that a psychiatrist in Italy may be less likely to treat a patient with a phenotype affecting response to treatment or risk of adverse events than one in Norway or Sweden.
For the study, the investigators examined the frequency of CYP2D6 and CYP2C19 phenotypes in psychiatric patients in Sardinia and their relationship with pharmacologic treatment and cost-effectiveness.
They set out to recruit 200 patients with MDD who had a documented 5-year medical and treatment history, including alterations in treatment, adverse events, hospitalizations, suicide, and symptom scores, as well as sociodemographic variables.
An interim analysis of the first 125 patients recruited to the study showed that the most common CYP2D6 phenotype was normal metabolizers (NM), at 60.5%, followed by intermediate metabolizers (IM), at 28.2%, ultrarapid metabolizers (UR), at 8.9%, and poor metabolizers (PM), at 2.4%.
For CYP2C19, the most common phenotype was NM (49%), followed by IM (29.0%), UR (25.0%), and PM (4.0%). While there were differences in the overall European averages, they were not significant.
To highlight the potential impact that pharmacogenetic testing could have had on patient care and outcome, Dr. Squassina highlighted two cases.
The first concerned a patient with a CYP2D6 IM and CYP2C19 UR phenotype, who did not respond to escitalopram. The FDA drug label indicates this phenotype is actionable and recommends an alternative drug.
The patient was subsequently switched to venlafaxine. The FDA drug label on venlafaxine notes that patients with this phenotype are likely to have a suboptimal response to this drug, and again, this patient did not respond to treatment.
Another patient with a CYP2D6 NM and CYP2C19 IM phenotype was also prescribed escitalopram. The FDA label on this drug notes that patients with this phenotype can try venlafaxine but may not respond. Indeed, this patient did not respond and was switched to venlafaxine and started responding.
“The psychiatrists [in these cases] may made have made different [drug] choices if they had known the genotypes in advance,” Dr. Squassina said.
Cost effective?
To determine the cost-effectiveness of screening for CYP2D6 and CYP2C19 phenotypes in patients with MDD, the researchers used real-world data to develop a Markov model with a hypothetical cohort of 2000 MDD patients, half of whom underwent pharmacogenetic testing, to determine the potential impact on outcomes over an 18-week period.
The model included the cost of medications and hospitalization, psychiatric counseling, loss of productivity, and the estimated probability of response and adverse events, adjusted for the patient’s likelihood of having a particular metabolizing phenotype.
Results showed that, for CYP2C19, compared to no testing, pharmacogenetic testing would be cost-effective at an incremental cost-effective ratio (ICER) of €60,000 ($64,000 USD) per quality-adjusted life-year (QALY).
This, Squassina said, is “below the willingness to pay threshold” for health authorities in developed countries.
For CYP2D6, pharmacogenetic testing would become cost-effective at an ICER of approximately €47,000 ($40,000 USD) per QALY.
The team plans to complete recruitment and perform a “detailed evaluation of all the variables, especially those relating to the medication history and changes in dosage, and adverse drug reactions.” The researchers would also like to study genetic phenotypes for other metabolizing enzymes and repeat the pharmacoeconomic analysis with the complete dataset.
A glimpse into the future
Approached for comment, Alessandro Serretti, MD, PhD, department of biomedical and neuromotor sciences, University of Bologna (Italy), who was not involved in the study, said the findings show there is a “small but evident benefit” from CYP profiling, “which makes sense.”
He added that in the Netherlands and other European countries, efforts are already underway to record the CYP status of patients at a national level. “Sooner or later, all Western countries will implement it as a routine,” he said in an interview.
He explained that, when such testing is widely available, electronic health record data will allow physicians to immediately select the optimal antidepressant for an individual patient. This will end the current trial-and-error process that leads to delayed treatment and will help avoid serious consequences, such as suicide.
While reducing a single patient’s treatment by a few weeks with the most appropriate antidepressant choice does not make a large difference in the cost per episode, at a population level, it has the potential to make a significant difference.
Dr. Serretti does not envisage genotyping all 333 million Europeans for the CYP phenotype at this point but imagines that in the future, individuals will undergo whole-genome sequencing to determine risks for cancer, dementia, and heart disease, at which point they will also undergo CYP functional allele profiling, and all these data will be recorded on individuals’ EHR.
“So, every doctor, a psychiatrist or cardiologist, can see everything, whenever they need it,” he said.
The study was funded by Fondazione di Sardegna and Regione Autonoma della Sardegna. The authors disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
new research suggests.
CYP2D6 and CYP2C19, from the cytochrome P450 family, are involved in the metabolism and elimination of various molecules, including medications. Variants in the genes encoding these enzymes affect the speed at which drugs are metabolized, altering their pharmacokinetic profiles.
The researchers studied 125 patients with MDD and used CYP2D6 and CYP2C19 genotyping to determine the presence of actionable phenotypes in line with Food and Drug Administration labeling.
They found that, in many cases, pharmacogenetic testing could have predicted poor response to the initial treatment selection and could have helped guide subsequent choices to improve outcomes.
In addition, a pharmacoeconomic evaluation that combined direct and indirect costs resulting from MDD with the prevalence of CYP2D6 and CYP2C19 phenotypes showed that testing for functional variants in both genes would be cost effective at a national level.
Had psychiatrists who treated patients in the study known about their metabolizing profiles, it “might have contributed to switches in medication” and could have reduced “delays in response,” said lead researcher Alessio Squassina, PhD, associate professor of pharmacology at the University of Cagliari (Italy).
The findings were presented at the European Psychiatric Association 2022 Congress.
Highly variable response rates
Dr. Squassina noted that the response to antidepressants is a “highly variable trait,” and while it is known that genetics play a role, their contribution is “still not completely understood.”
He explained that the use of pharmacogenetics, which leverages genetic information to guide treatment decision-making, has increased significantly.
While regulatory bodies, including the FDA, have been “very active” in defining strict criteria for interpreting the information from pharmacogenetic tests, there remains some “discrepancy” in their clinical utility.
Dr. Squassina said the FDA provides guidance on use of genetic testing on the labels of 34 psychiatric medications. Of these, 79% relate to CYP2D6, 12% relate to CYP2C19, and 9% relate to other genes.
These labels provide guidance on when genetic testing is recommended or required, as well as potentially clinically actionable gene-drug associations in patients with certain functional alleles.
However, Dr. Squassina noted that the distribution of such alleles is not the same across Europe, so it’s possible that a psychiatrist in Italy may be less likely to treat a patient with a phenotype affecting response to treatment or risk of adverse events than one in Norway or Sweden.
For the study, the investigators examined the frequency of CYP2D6 and CYP2C19 phenotypes in psychiatric patients in Sardinia and their relationship with pharmacologic treatment and cost-effectiveness.
They set out to recruit 200 patients with MDD who had a documented 5-year medical and treatment history, including alterations in treatment, adverse events, hospitalizations, suicide, and symptom scores, as well as sociodemographic variables.
An interim analysis of the first 125 patients recruited to the study showed that the most common CYP2D6 phenotype was normal metabolizers (NM), at 60.5%, followed by intermediate metabolizers (IM), at 28.2%, ultrarapid metabolizers (UR), at 8.9%, and poor metabolizers (PM), at 2.4%.
For CYP2C19, the most common phenotype was NM (49%), followed by IM (29.0%), UR (25.0%), and PM (4.0%). While there were differences in the overall European averages, they were not significant.
To highlight the potential impact that pharmacogenetic testing could have had on patient care and outcome, Dr. Squassina highlighted two cases.
The first concerned a patient with a CYP2D6 IM and CYP2C19 UR phenotype, who did not respond to escitalopram. The FDA drug label indicates this phenotype is actionable and recommends an alternative drug.
The patient was subsequently switched to venlafaxine. The FDA drug label on venlafaxine notes that patients with this phenotype are likely to have a suboptimal response to this drug, and again, this patient did not respond to treatment.
Another patient with a CYP2D6 NM and CYP2C19 IM phenotype was also prescribed escitalopram. The FDA label on this drug notes that patients with this phenotype can try venlafaxine but may not respond. Indeed, this patient did not respond and was switched to venlafaxine and started responding.
“The psychiatrists [in these cases] may made have made different [drug] choices if they had known the genotypes in advance,” Dr. Squassina said.
Cost effective?
To determine the cost-effectiveness of screening for CYP2D6 and CYP2C19 phenotypes in patients with MDD, the researchers used real-world data to develop a Markov model with a hypothetical cohort of 2000 MDD patients, half of whom underwent pharmacogenetic testing, to determine the potential impact on outcomes over an 18-week period.
The model included the cost of medications and hospitalization, psychiatric counseling, loss of productivity, and the estimated probability of response and adverse events, adjusted for the patient’s likelihood of having a particular metabolizing phenotype.
Results showed that, for CYP2C19, compared to no testing, pharmacogenetic testing would be cost-effective at an incremental cost-effective ratio (ICER) of €60,000 ($64,000 USD) per quality-adjusted life-year (QALY).
This, Squassina said, is “below the willingness to pay threshold” for health authorities in developed countries.
For CYP2D6, pharmacogenetic testing would become cost-effective at an ICER of approximately €47,000 ($40,000 USD) per QALY.
The team plans to complete recruitment and perform a “detailed evaluation of all the variables, especially those relating to the medication history and changes in dosage, and adverse drug reactions.” The researchers would also like to study genetic phenotypes for other metabolizing enzymes and repeat the pharmacoeconomic analysis with the complete dataset.
A glimpse into the future
Approached for comment, Alessandro Serretti, MD, PhD, department of biomedical and neuromotor sciences, University of Bologna (Italy), who was not involved in the study, said the findings show there is a “small but evident benefit” from CYP profiling, “which makes sense.”
He added that in the Netherlands and other European countries, efforts are already underway to record the CYP status of patients at a national level. “Sooner or later, all Western countries will implement it as a routine,” he said in an interview.
He explained that, when such testing is widely available, electronic health record data will allow physicians to immediately select the optimal antidepressant for an individual patient. This will end the current trial-and-error process that leads to delayed treatment and will help avoid serious consequences, such as suicide.
While reducing a single patient’s treatment by a few weeks with the most appropriate antidepressant choice does not make a large difference in the cost per episode, at a population level, it has the potential to make a significant difference.
Dr. Serretti does not envisage genotyping all 333 million Europeans for the CYP phenotype at this point but imagines that in the future, individuals will undergo whole-genome sequencing to determine risks for cancer, dementia, and heart disease, at which point they will also undergo CYP functional allele profiling, and all these data will be recorded on individuals’ EHR.
“So, every doctor, a psychiatrist or cardiologist, can see everything, whenever they need it,” he said.
The study was funded by Fondazione di Sardegna and Regione Autonoma della Sardegna. The authors disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
new research suggests.
CYP2D6 and CYP2C19, from the cytochrome P450 family, are involved in the metabolism and elimination of various molecules, including medications. Variants in the genes encoding these enzymes affect the speed at which drugs are metabolized, altering their pharmacokinetic profiles.
The researchers studied 125 patients with MDD and used CYP2D6 and CYP2C19 genotyping to determine the presence of actionable phenotypes in line with Food and Drug Administration labeling.
They found that, in many cases, pharmacogenetic testing could have predicted poor response to the initial treatment selection and could have helped guide subsequent choices to improve outcomes.
In addition, a pharmacoeconomic evaluation that combined direct and indirect costs resulting from MDD with the prevalence of CYP2D6 and CYP2C19 phenotypes showed that testing for functional variants in both genes would be cost effective at a national level.
Had psychiatrists who treated patients in the study known about their metabolizing profiles, it “might have contributed to switches in medication” and could have reduced “delays in response,” said lead researcher Alessio Squassina, PhD, associate professor of pharmacology at the University of Cagliari (Italy).
The findings were presented at the European Psychiatric Association 2022 Congress.
Highly variable response rates
Dr. Squassina noted that the response to antidepressants is a “highly variable trait,” and while it is known that genetics play a role, their contribution is “still not completely understood.”
He explained that the use of pharmacogenetics, which leverages genetic information to guide treatment decision-making, has increased significantly.
While regulatory bodies, including the FDA, have been “very active” in defining strict criteria for interpreting the information from pharmacogenetic tests, there remains some “discrepancy” in their clinical utility.
Dr. Squassina said the FDA provides guidance on use of genetic testing on the labels of 34 psychiatric medications. Of these, 79% relate to CYP2D6, 12% relate to CYP2C19, and 9% relate to other genes.
These labels provide guidance on when genetic testing is recommended or required, as well as potentially clinically actionable gene-drug associations in patients with certain functional alleles.
However, Dr. Squassina noted that the distribution of such alleles is not the same across Europe, so it’s possible that a psychiatrist in Italy may be less likely to treat a patient with a phenotype affecting response to treatment or risk of adverse events than one in Norway or Sweden.
For the study, the investigators examined the frequency of CYP2D6 and CYP2C19 phenotypes in psychiatric patients in Sardinia and their relationship with pharmacologic treatment and cost-effectiveness.
They set out to recruit 200 patients with MDD who had a documented 5-year medical and treatment history, including alterations in treatment, adverse events, hospitalizations, suicide, and symptom scores, as well as sociodemographic variables.
An interim analysis of the first 125 patients recruited to the study showed that the most common CYP2D6 phenotype was normal metabolizers (NM), at 60.5%, followed by intermediate metabolizers (IM), at 28.2%, ultrarapid metabolizers (UR), at 8.9%, and poor metabolizers (PM), at 2.4%.
For CYP2C19, the most common phenotype was NM (49%), followed by IM (29.0%), UR (25.0%), and PM (4.0%). While there were differences in the overall European averages, they were not significant.
To highlight the potential impact that pharmacogenetic testing could have had on patient care and outcome, Dr. Squassina highlighted two cases.
The first concerned a patient with a CYP2D6 IM and CYP2C19 UR phenotype, who did not respond to escitalopram. The FDA drug label indicates this phenotype is actionable and recommends an alternative drug.
The patient was subsequently switched to venlafaxine. The FDA drug label on venlafaxine notes that patients with this phenotype are likely to have a suboptimal response to this drug, and again, this patient did not respond to treatment.
Another patient with a CYP2D6 NM and CYP2C19 IM phenotype was also prescribed escitalopram. The FDA label on this drug notes that patients with this phenotype can try venlafaxine but may not respond. Indeed, this patient did not respond and was switched to venlafaxine and started responding.
“The psychiatrists [in these cases] may made have made different [drug] choices if they had known the genotypes in advance,” Dr. Squassina said.
Cost effective?
To determine the cost-effectiveness of screening for CYP2D6 and CYP2C19 phenotypes in patients with MDD, the researchers used real-world data to develop a Markov model with a hypothetical cohort of 2000 MDD patients, half of whom underwent pharmacogenetic testing, to determine the potential impact on outcomes over an 18-week period.
The model included the cost of medications and hospitalization, psychiatric counseling, loss of productivity, and the estimated probability of response and adverse events, adjusted for the patient’s likelihood of having a particular metabolizing phenotype.
Results showed that, for CYP2C19, compared to no testing, pharmacogenetic testing would be cost-effective at an incremental cost-effective ratio (ICER) of €60,000 ($64,000 USD) per quality-adjusted life-year (QALY).
This, Squassina said, is “below the willingness to pay threshold” for health authorities in developed countries.
For CYP2D6, pharmacogenetic testing would become cost-effective at an ICER of approximately €47,000 ($40,000 USD) per QALY.
The team plans to complete recruitment and perform a “detailed evaluation of all the variables, especially those relating to the medication history and changes in dosage, and adverse drug reactions.” The researchers would also like to study genetic phenotypes for other metabolizing enzymes and repeat the pharmacoeconomic analysis with the complete dataset.
A glimpse into the future
Approached for comment, Alessandro Serretti, MD, PhD, department of biomedical and neuromotor sciences, University of Bologna (Italy), who was not involved in the study, said the findings show there is a “small but evident benefit” from CYP profiling, “which makes sense.”
He added that in the Netherlands and other European countries, efforts are already underway to record the CYP status of patients at a national level. “Sooner or later, all Western countries will implement it as a routine,” he said in an interview.
He explained that, when such testing is widely available, electronic health record data will allow physicians to immediately select the optimal antidepressant for an individual patient. This will end the current trial-and-error process that leads to delayed treatment and will help avoid serious consequences, such as suicide.
While reducing a single patient’s treatment by a few weeks with the most appropriate antidepressant choice does not make a large difference in the cost per episode, at a population level, it has the potential to make a significant difference.
Dr. Serretti does not envisage genotyping all 333 million Europeans for the CYP phenotype at this point but imagines that in the future, individuals will undergo whole-genome sequencing to determine risks for cancer, dementia, and heart disease, at which point they will also undergo CYP functional allele profiling, and all these data will be recorded on individuals’ EHR.
“So, every doctor, a psychiatrist or cardiologist, can see everything, whenever they need it,” he said.
The study was funded by Fondazione di Sardegna and Regione Autonoma della Sardegna. The authors disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM EPA 2022
Alcohol, degraded sleep related in young adults
CHARLOTTE, N.C. – Sleep and alcohol consumption in young adults seems to follow a “vicious cycle,” as one observer called it. and those who went to bed earlier and slept longer tended to drink less the next day, a study of drinking and sleeping habits in 21- to 29-year-olds found.
“Sleep is a potential factor that we could intervene on to really identify how to improve drinking behaviors among young adults,” David Reichenberger, a graduate student at Penn State University, University Park, said in an interview after he presented his findings at the annual meeting of the Associated Professional Sleep Societies.
This is one of the few studies of alcohol consumption and sleep patterns that used an objective measure of alcohol consumption, Mr. Reichenberger said. The study evaluated sleep and alcohol consumption patterns in 222 regularly drinking young adults over 6 consecutive days. Study participants completed morning smartphone-based questionnaires, reporting their previous night’s bedtime, sleep duration, sleep quality, and number of drinks consumed. They also wore an alcohol monitor that continuously measured their transdermal alcohol consumption (TAC).
The study analyzed the data using two sets of multilevel models: A linear model that looked at how each drinking predictor was associated with each sleep variable and a Poisson model to determine how sleep predicted next-day alcohol use.
“We found that higher average peak TAC – that is, how intoxicated they got – was associated with a 19-minute later bedtime among young adults,” Mr. Reichenberger said. “Later bedtimes were then associated with a 26% greater TAC among those adults” (P < .02).
Patterns of alcohol consumption and sleep
On days when participants recorded a higher peak TAC, bedtime was delayed, sleep duration was shorter, and subjective sleep quality was worse, he said. However, none of the sleep variables predicted next-day peak TAC.
“We found an association between the duration of the drinking episode and later bedtimes among young adults,” he added. “And on days when the drinking episodes were longer, subsequent sleep was delayed and sleep quality was worse. But we also found that after nights when they had a later bedtime, next-day drinking episodes were about 7% longer.”
Conversely, young adults who had earlier bedtimes and longer sleep durations tended to consume fewer drinks and they achieved lower intoxication levels the next day, Mr. Reichenberger said.
Between-person results showed that young adults who tended to go to bed later drank on average 24% more the next day (P < .01). Also, each extra hour of sleep was associated with a 14% decrease in drinking the next day (P < .03).
Participants who drank more went to bed on average 12-19 minutes later (P < .01) and slept 5 fewer minutes (P < .01). Within-person results showed that on nights when participants drank more than usual they went to bed 8-13 minutes later (P < .01), slept 2-4 fewer minutes (P < .03), and had worse sleep quality (P < .01).
Mr. Reichenberger acknowledged one limitation of the study: Measuring sleep and alcohol consumption patterns over 6 days might not be long enough. Future studies should address that.
A ‘vicious cycle’
Hans P.A. Van Dongen, PhD, director of the Sleep and Performance Research Center at Washington State University, Spokane, said in an interview that the findings imply a “vicious cycle” between sleep and alcohol consumption. “You create a problem and then it perpetuates itself or reinforces itself.”
In older adults, alcohol tends to act as a “sleep aid,” Dr. Van Dongen noted. “Then it disrupts their sleep later on and then the next night they need to use the sleep aid again because they had a really poor night and they’re tired and they want to fall asleep.”
He added: “I think what is new here is that’s not very likely the mechanism that they’re using alcohol as a sleep aid in younger adults that we see in older adults, so I think there is a new element to it. Now does anybody know how that works exactly? No, that’s the next thing.”
The Penn State study identifies “a signal there that needs to be followed up on,” Dr. Van Dongen said. “There’s something nature’s trying to tell us but it’s not exactly clear what it’s trying to tell us.”
The National Institute on Drug Abuse provided funding for the study. Mr. Reichenberger has no relevant disclosures. Dr. Van Dongen has no disclosures to report.
CHARLOTTE, N.C. – Sleep and alcohol consumption in young adults seems to follow a “vicious cycle,” as one observer called it. and those who went to bed earlier and slept longer tended to drink less the next day, a study of drinking and sleeping habits in 21- to 29-year-olds found.
“Sleep is a potential factor that we could intervene on to really identify how to improve drinking behaviors among young adults,” David Reichenberger, a graduate student at Penn State University, University Park, said in an interview after he presented his findings at the annual meeting of the Associated Professional Sleep Societies.
This is one of the few studies of alcohol consumption and sleep patterns that used an objective measure of alcohol consumption, Mr. Reichenberger said. The study evaluated sleep and alcohol consumption patterns in 222 regularly drinking young adults over 6 consecutive days. Study participants completed morning smartphone-based questionnaires, reporting their previous night’s bedtime, sleep duration, sleep quality, and number of drinks consumed. They also wore an alcohol monitor that continuously measured their transdermal alcohol consumption (TAC).
The study analyzed the data using two sets of multilevel models: A linear model that looked at how each drinking predictor was associated with each sleep variable and a Poisson model to determine how sleep predicted next-day alcohol use.
“We found that higher average peak TAC – that is, how intoxicated they got – was associated with a 19-minute later bedtime among young adults,” Mr. Reichenberger said. “Later bedtimes were then associated with a 26% greater TAC among those adults” (P < .02).
Patterns of alcohol consumption and sleep
On days when participants recorded a higher peak TAC, bedtime was delayed, sleep duration was shorter, and subjective sleep quality was worse, he said. However, none of the sleep variables predicted next-day peak TAC.
“We found an association between the duration of the drinking episode and later bedtimes among young adults,” he added. “And on days when the drinking episodes were longer, subsequent sleep was delayed and sleep quality was worse. But we also found that after nights when they had a later bedtime, next-day drinking episodes were about 7% longer.”
Conversely, young adults who had earlier bedtimes and longer sleep durations tended to consume fewer drinks and they achieved lower intoxication levels the next day, Mr. Reichenberger said.
Between-person results showed that young adults who tended to go to bed later drank on average 24% more the next day (P < .01). Also, each extra hour of sleep was associated with a 14% decrease in drinking the next day (P < .03).
Participants who drank more went to bed on average 12-19 minutes later (P < .01) and slept 5 fewer minutes (P < .01). Within-person results showed that on nights when participants drank more than usual they went to bed 8-13 minutes later (P < .01), slept 2-4 fewer minutes (P < .03), and had worse sleep quality (P < .01).
Mr. Reichenberger acknowledged one limitation of the study: Measuring sleep and alcohol consumption patterns over 6 days might not be long enough. Future studies should address that.
A ‘vicious cycle’
Hans P.A. Van Dongen, PhD, director of the Sleep and Performance Research Center at Washington State University, Spokane, said in an interview that the findings imply a “vicious cycle” between sleep and alcohol consumption. “You create a problem and then it perpetuates itself or reinforces itself.”
In older adults, alcohol tends to act as a “sleep aid,” Dr. Van Dongen noted. “Then it disrupts their sleep later on and then the next night they need to use the sleep aid again because they had a really poor night and they’re tired and they want to fall asleep.”
He added: “I think what is new here is that’s not very likely the mechanism that they’re using alcohol as a sleep aid in younger adults that we see in older adults, so I think there is a new element to it. Now does anybody know how that works exactly? No, that’s the next thing.”
The Penn State study identifies “a signal there that needs to be followed up on,” Dr. Van Dongen said. “There’s something nature’s trying to tell us but it’s not exactly clear what it’s trying to tell us.”
The National Institute on Drug Abuse provided funding for the study. Mr. Reichenberger has no relevant disclosures. Dr. Van Dongen has no disclosures to report.
CHARLOTTE, N.C. – Sleep and alcohol consumption in young adults seems to follow a “vicious cycle,” as one observer called it. and those who went to bed earlier and slept longer tended to drink less the next day, a study of drinking and sleeping habits in 21- to 29-year-olds found.
“Sleep is a potential factor that we could intervene on to really identify how to improve drinking behaviors among young adults,” David Reichenberger, a graduate student at Penn State University, University Park, said in an interview after he presented his findings at the annual meeting of the Associated Professional Sleep Societies.
This is one of the few studies of alcohol consumption and sleep patterns that used an objective measure of alcohol consumption, Mr. Reichenberger said. The study evaluated sleep and alcohol consumption patterns in 222 regularly drinking young adults over 6 consecutive days. Study participants completed morning smartphone-based questionnaires, reporting their previous night’s bedtime, sleep duration, sleep quality, and number of drinks consumed. They also wore an alcohol monitor that continuously measured their transdermal alcohol consumption (TAC).
The study analyzed the data using two sets of multilevel models: A linear model that looked at how each drinking predictor was associated with each sleep variable and a Poisson model to determine how sleep predicted next-day alcohol use.
“We found that higher average peak TAC – that is, how intoxicated they got – was associated with a 19-minute later bedtime among young adults,” Mr. Reichenberger said. “Later bedtimes were then associated with a 26% greater TAC among those adults” (P < .02).
Patterns of alcohol consumption and sleep
On days when participants recorded a higher peak TAC, bedtime was delayed, sleep duration was shorter, and subjective sleep quality was worse, he said. However, none of the sleep variables predicted next-day peak TAC.
“We found an association between the duration of the drinking episode and later bedtimes among young adults,” he added. “And on days when the drinking episodes were longer, subsequent sleep was delayed and sleep quality was worse. But we also found that after nights when they had a later bedtime, next-day drinking episodes were about 7% longer.”
Conversely, young adults who had earlier bedtimes and longer sleep durations tended to consume fewer drinks and they achieved lower intoxication levels the next day, Mr. Reichenberger said.
Between-person results showed that young adults who tended to go to bed later drank on average 24% more the next day (P < .01). Also, each extra hour of sleep was associated with a 14% decrease in drinking the next day (P < .03).
Participants who drank more went to bed on average 12-19 minutes later (P < .01) and slept 5 fewer minutes (P < .01). Within-person results showed that on nights when participants drank more than usual they went to bed 8-13 minutes later (P < .01), slept 2-4 fewer minutes (P < .03), and had worse sleep quality (P < .01).
Mr. Reichenberger acknowledged one limitation of the study: Measuring sleep and alcohol consumption patterns over 6 days might not be long enough. Future studies should address that.
A ‘vicious cycle’
Hans P.A. Van Dongen, PhD, director of the Sleep and Performance Research Center at Washington State University, Spokane, said in an interview that the findings imply a “vicious cycle” between sleep and alcohol consumption. “You create a problem and then it perpetuates itself or reinforces itself.”
In older adults, alcohol tends to act as a “sleep aid,” Dr. Van Dongen noted. “Then it disrupts their sleep later on and then the next night they need to use the sleep aid again because they had a really poor night and they’re tired and they want to fall asleep.”
He added: “I think what is new here is that’s not very likely the mechanism that they’re using alcohol as a sleep aid in younger adults that we see in older adults, so I think there is a new element to it. Now does anybody know how that works exactly? No, that’s the next thing.”
The Penn State study identifies “a signal there that needs to be followed up on,” Dr. Van Dongen said. “There’s something nature’s trying to tell us but it’s not exactly clear what it’s trying to tell us.”
The National Institute on Drug Abuse provided funding for the study. Mr. Reichenberger has no relevant disclosures. Dr. Van Dongen has no disclosures to report.
At SLEEP 2022
Harmony pulmonary valve update: Regurgitation resolved 1 year out
The 1-year results of the Harmony transcatheter pulmonary valve to treat severe pulmonary regurgitation have shown a high rate of eliminating or reducing the degree of symptoms as well as freedom from endocarditis, sustained ventricular tachycardia, and the need for further interventions.
“Simply put, the good news is no endocarditis,” said Daniel S. Levi, MD, in presenting results from three different studies with 108 patients who received three different iterations of the device at the Society for Cardiovascular Angiography & Interventions annual scientific sessions.
“Endocarditis has been an issue for us in the pulmonary position; we have yet to have an endocarditis in these patients in 1 year,” he stressed.
The studies evaluated three different versions of the Harmony valve: TPV22 (42 patients), the first version with a 22-mm diameter; the Clinical TPV25 (17 patients), the first iteration of a 25 mm–wide device that has since been discontinued; and the modified TPV25 (45 patients), the second version of the 25-mm valve. The three studies are the early feasibility study of the TPV22, the continued-access study of the TPV22 and the mTPV25, and the pivotal study that included all three versions.
At baseline, 89% of patients had severe and 11% had moderate pulmonary regurgitation (PR). At 1 year, 92% had none or trace PR, 3% had mild PR, and 4% moderate disease.
Dr. Levi said the device “speaks for itself” in the results he presented. They include no deaths, no heart attacks, and no pulmonary thromboembolism. Other key outcomes include:
- One major stent fracture in one of the early feasibility study patients at 1-month follow-up.
- Four explants, with two in the discontinued cTPV25 and two with the TPV22 in the early-feasibility study.
- Four reinterventions, two with the discontinued cTPV25 and two valve-in-valve procedures with the mTPV25 in the continued-access study, one with stent placement in the right ventricular outflow tract.
Dr. Levi and coinvestigators also performed a breakdown of 1-year outcomes – freedom from PR, stenosis, and interventions – by device: 95.1% for TPV22; 89.7% for mTPV25; and 73.3% for the discontinued cTPV25.
Although the valve is indicated for adolescents and adults, most of the patients in the three studies were adults, with an average weight of 165 pounds (75 kg) who have had PR for decades, said Dr. Levi, an interventional pediatric cardiologist at the University of California, Los Angeles. “With a device like this we are hopefully shifting to treating that a little bit earlier, but fortunately we don’t usually need to treat it before puberty.” The 25-mm TPV gives “a really nice landing zone” for future valve placement. “The goal is to keep patients out of the operating room for at least a few decades if not their whole lives,” he said.
Dr. Levi said the Harmony investigators will follow outcomes with the 22- and modified 25-mm Harmony valves, both of which remain commercially available, out to 10 years.
The study represents the first collective cohort evaluating the Harmony device across the early feasibility, continued access and pivotal studies, said Brian Morray, MD. “It’s important that people understand that evolution and how that impacts the way we look at outcomes, because when you aggregate the data, particularly for the TPV25, some of the procedural outcomes and the adverse events are no longer really reflective in the current time frame.”
These Harmony results “represent another big step in the evolution of interventional cardiology and will be up there with development of the Melody valve and the utility and the use of the Sapien valve in the pulmonary position,” said Dr. Morray, an associate professor of pediatrics at the University of Washington, Seattle, and an interventional cardiologist at Seattle Children’s Hospital.
Dr. Levi disclosed he is a consultant to Medtronic and Edwards Lifesciences. Dr. Morray disclosed he is a clinical proctor for Abbott and a consultant to Medtronic, but not for the Harmony device.
The 1-year results of the Harmony transcatheter pulmonary valve to treat severe pulmonary regurgitation have shown a high rate of eliminating or reducing the degree of symptoms as well as freedom from endocarditis, sustained ventricular tachycardia, and the need for further interventions.
“Simply put, the good news is no endocarditis,” said Daniel S. Levi, MD, in presenting results from three different studies with 108 patients who received three different iterations of the device at the Society for Cardiovascular Angiography & Interventions annual scientific sessions.
“Endocarditis has been an issue for us in the pulmonary position; we have yet to have an endocarditis in these patients in 1 year,” he stressed.
The studies evaluated three different versions of the Harmony valve: TPV22 (42 patients), the first version with a 22-mm diameter; the Clinical TPV25 (17 patients), the first iteration of a 25 mm–wide device that has since been discontinued; and the modified TPV25 (45 patients), the second version of the 25-mm valve. The three studies are the early feasibility study of the TPV22, the continued-access study of the TPV22 and the mTPV25, and the pivotal study that included all three versions.
At baseline, 89% of patients had severe and 11% had moderate pulmonary regurgitation (PR). At 1 year, 92% had none or trace PR, 3% had mild PR, and 4% moderate disease.
Dr. Levi said the device “speaks for itself” in the results he presented. They include no deaths, no heart attacks, and no pulmonary thromboembolism. Other key outcomes include:
- One major stent fracture in one of the early feasibility study patients at 1-month follow-up.
- Four explants, with two in the discontinued cTPV25 and two with the TPV22 in the early-feasibility study.
- Four reinterventions, two with the discontinued cTPV25 and two valve-in-valve procedures with the mTPV25 in the continued-access study, one with stent placement in the right ventricular outflow tract.
Dr. Levi and coinvestigators also performed a breakdown of 1-year outcomes – freedom from PR, stenosis, and interventions – by device: 95.1% for TPV22; 89.7% for mTPV25; and 73.3% for the discontinued cTPV25.
Although the valve is indicated for adolescents and adults, most of the patients in the three studies were adults, with an average weight of 165 pounds (75 kg) who have had PR for decades, said Dr. Levi, an interventional pediatric cardiologist at the University of California, Los Angeles. “With a device like this we are hopefully shifting to treating that a little bit earlier, but fortunately we don’t usually need to treat it before puberty.” The 25-mm TPV gives “a really nice landing zone” for future valve placement. “The goal is to keep patients out of the operating room for at least a few decades if not their whole lives,” he said.
Dr. Levi said the Harmony investigators will follow outcomes with the 22- and modified 25-mm Harmony valves, both of which remain commercially available, out to 10 years.
The study represents the first collective cohort evaluating the Harmony device across the early feasibility, continued access and pivotal studies, said Brian Morray, MD. “It’s important that people understand that evolution and how that impacts the way we look at outcomes, because when you aggregate the data, particularly for the TPV25, some of the procedural outcomes and the adverse events are no longer really reflective in the current time frame.”
These Harmony results “represent another big step in the evolution of interventional cardiology and will be up there with development of the Melody valve and the utility and the use of the Sapien valve in the pulmonary position,” said Dr. Morray, an associate professor of pediatrics at the University of Washington, Seattle, and an interventional cardiologist at Seattle Children’s Hospital.
Dr. Levi disclosed he is a consultant to Medtronic and Edwards Lifesciences. Dr. Morray disclosed he is a clinical proctor for Abbott and a consultant to Medtronic, but not for the Harmony device.
The 1-year results of the Harmony transcatheter pulmonary valve to treat severe pulmonary regurgitation have shown a high rate of eliminating or reducing the degree of symptoms as well as freedom from endocarditis, sustained ventricular tachycardia, and the need for further interventions.
“Simply put, the good news is no endocarditis,” said Daniel S. Levi, MD, in presenting results from three different studies with 108 patients who received three different iterations of the device at the Society for Cardiovascular Angiography & Interventions annual scientific sessions.
“Endocarditis has been an issue for us in the pulmonary position; we have yet to have an endocarditis in these patients in 1 year,” he stressed.
The studies evaluated three different versions of the Harmony valve: TPV22 (42 patients), the first version with a 22-mm diameter; the Clinical TPV25 (17 patients), the first iteration of a 25 mm–wide device that has since been discontinued; and the modified TPV25 (45 patients), the second version of the 25-mm valve. The three studies are the early feasibility study of the TPV22, the continued-access study of the TPV22 and the mTPV25, and the pivotal study that included all three versions.
At baseline, 89% of patients had severe and 11% had moderate pulmonary regurgitation (PR). At 1 year, 92% had none or trace PR, 3% had mild PR, and 4% moderate disease.
Dr. Levi said the device “speaks for itself” in the results he presented. They include no deaths, no heart attacks, and no pulmonary thromboembolism. Other key outcomes include:
- One major stent fracture in one of the early feasibility study patients at 1-month follow-up.
- Four explants, with two in the discontinued cTPV25 and two with the TPV22 in the early-feasibility study.
- Four reinterventions, two with the discontinued cTPV25 and two valve-in-valve procedures with the mTPV25 in the continued-access study, one with stent placement in the right ventricular outflow tract.
Dr. Levi and coinvestigators also performed a breakdown of 1-year outcomes – freedom from PR, stenosis, and interventions – by device: 95.1% for TPV22; 89.7% for mTPV25; and 73.3% for the discontinued cTPV25.
Although the valve is indicated for adolescents and adults, most of the patients in the three studies were adults, with an average weight of 165 pounds (75 kg) who have had PR for decades, said Dr. Levi, an interventional pediatric cardiologist at the University of California, Los Angeles. “With a device like this we are hopefully shifting to treating that a little bit earlier, but fortunately we don’t usually need to treat it before puberty.” The 25-mm TPV gives “a really nice landing zone” for future valve placement. “The goal is to keep patients out of the operating room for at least a few decades if not their whole lives,” he said.
Dr. Levi said the Harmony investigators will follow outcomes with the 22- and modified 25-mm Harmony valves, both of which remain commercially available, out to 10 years.
The study represents the first collective cohort evaluating the Harmony device across the early feasibility, continued access and pivotal studies, said Brian Morray, MD. “It’s important that people understand that evolution and how that impacts the way we look at outcomes, because when you aggregate the data, particularly for the TPV25, some of the procedural outcomes and the adverse events are no longer really reflective in the current time frame.”
These Harmony results “represent another big step in the evolution of interventional cardiology and will be up there with development of the Melody valve and the utility and the use of the Sapien valve in the pulmonary position,” said Dr. Morray, an associate professor of pediatrics at the University of Washington, Seattle, and an interventional cardiologist at Seattle Children’s Hospital.
Dr. Levi disclosed he is a consultant to Medtronic and Edwards Lifesciences. Dr. Morray disclosed he is a clinical proctor for Abbott and a consultant to Medtronic, but not for the Harmony device.
FROM SCAI 2022
Therapeutic patient education can help with adherence to treatment
, Andreas Wollenberg, MD, said at the Revolutionizing Atopic Dermatitis symposium.
A major goal of patient education is increasing medication adherence, noted Dr. Wollenberg, professor in the department of dermatology and allergy at Ludwig Maximilian University of Munich. Quoting former U.S. Surgeon General C. Everett Koop, MD, he said, “drugs don’t work in patients who don’t take them.”
While this is a simple message, it is important, Dr. Wollenberg said, noting that there can be a gap between a physician’s well-intentioned message and how it is interpreted by the patient. “Our messages may not be heard, not understood, not accepted, and even if they are put into place, how long will they last?” he asked. “We need to find a way [to] place sticky messages in the brains of our patients who are sitting and interacting with us.”
One way to improve treatment adherence is through patient education, such as using a written action plan or graphics; simplifying treatment regimens; minimizing treatment costs; setting up reminder programs, early follow-up visits, and short-term treatment goals; and minimizing nocebo effects. “This is more than providing just leaflets to patients. It is a complete program. It is a holistic approach. It should be structured and should be interdisciplinary, and it should contain a psychological component,” Dr. Wollenberg said.
Therapeutic patient education is recommended at baseline for children and adults with moderate to severe AD in the 2020 European Task Force on Atopic Dermatitis (ETFAD) and European Academy of Dermatology and Venereology (EADV) position paper on the diagnosis and treatment of AD in adults and children, alongside other interventions, such as emollients, bath oils, and avoidance of clinically relevant allergens, noted Dr. Wollenberg, the first author . “Therapeutic patient education is an extremely helpful tool to address patient beliefs and questions regarding disease and treatment,” he and his coauthors wrote in the paper.
When considering a therapeutic patient education program for AD, content is key, but just as important is consideration of legal and cultural conditions in the local area, Dr. Wollenberg explained. Every country will need some degree of standardization of content, he noted. Clinicians interested in adopting a patient education program need to consider who will pay for it – patients, foundations, or insurance companies – as well as the time commitment needed.
Dr. Wollenberg said that his team uses an evidence-based education program for AD in Germany that works across patients with different personalities, with a multidisciplinary team that includes a dermatologist, a specialist nurse, a nutrition expert, and a psychologist. “Sometimes we replace the specialized nurse with the dermatology resident because, in Germany, it’s difficult to find any type of specialized nurse,” although this is not an issue in many other countries, he said.
The model for children involves six 90-minute sessions, which cover topics that include emollients and basic care, food allergies and diet, medical treatment, and psychology of itch. The program for adults involves six 2-hour sessions, which cover topics that include psychology, skin care/nutrition, and medical treatment.
While this education program improves adherence in patients with AD, he acknowledged it is time consuming, and may not work for people who live far away from a clinic or who have other time commitments, making an alternative format necessary.
In terms of improving patient adherence to a doctor’s recommendations regarding chronic skin disease, “we cannot change our patients, we cannot change the disease, but we can strongly influence the treatment that we choose and how we interact as physicians with our patients,” said Dr. Wollenberg.
“Therapeutic patient education is virtually free of side effects, but evidence based. Have a look [at] it and adapt it to your own practice,” he added.
Dr. Wollenberg is a consultant, speaker and receives fees from numerous pharmaceutical companies.
, Andreas Wollenberg, MD, said at the Revolutionizing Atopic Dermatitis symposium.
A major goal of patient education is increasing medication adherence, noted Dr. Wollenberg, professor in the department of dermatology and allergy at Ludwig Maximilian University of Munich. Quoting former U.S. Surgeon General C. Everett Koop, MD, he said, “drugs don’t work in patients who don’t take them.”
While this is a simple message, it is important, Dr. Wollenberg said, noting that there can be a gap between a physician’s well-intentioned message and how it is interpreted by the patient. “Our messages may not be heard, not understood, not accepted, and even if they are put into place, how long will they last?” he asked. “We need to find a way [to] place sticky messages in the brains of our patients who are sitting and interacting with us.”
One way to improve treatment adherence is through patient education, such as using a written action plan or graphics; simplifying treatment regimens; minimizing treatment costs; setting up reminder programs, early follow-up visits, and short-term treatment goals; and minimizing nocebo effects. “This is more than providing just leaflets to patients. It is a complete program. It is a holistic approach. It should be structured and should be interdisciplinary, and it should contain a psychological component,” Dr. Wollenberg said.
Therapeutic patient education is recommended at baseline for children and adults with moderate to severe AD in the 2020 European Task Force on Atopic Dermatitis (ETFAD) and European Academy of Dermatology and Venereology (EADV) position paper on the diagnosis and treatment of AD in adults and children, alongside other interventions, such as emollients, bath oils, and avoidance of clinically relevant allergens, noted Dr. Wollenberg, the first author . “Therapeutic patient education is an extremely helpful tool to address patient beliefs and questions regarding disease and treatment,” he and his coauthors wrote in the paper.
When considering a therapeutic patient education program for AD, content is key, but just as important is consideration of legal and cultural conditions in the local area, Dr. Wollenberg explained. Every country will need some degree of standardization of content, he noted. Clinicians interested in adopting a patient education program need to consider who will pay for it – patients, foundations, or insurance companies – as well as the time commitment needed.
Dr. Wollenberg said that his team uses an evidence-based education program for AD in Germany that works across patients with different personalities, with a multidisciplinary team that includes a dermatologist, a specialist nurse, a nutrition expert, and a psychologist. “Sometimes we replace the specialized nurse with the dermatology resident because, in Germany, it’s difficult to find any type of specialized nurse,” although this is not an issue in many other countries, he said.
The model for children involves six 90-minute sessions, which cover topics that include emollients and basic care, food allergies and diet, medical treatment, and psychology of itch. The program for adults involves six 2-hour sessions, which cover topics that include psychology, skin care/nutrition, and medical treatment.
While this education program improves adherence in patients with AD, he acknowledged it is time consuming, and may not work for people who live far away from a clinic or who have other time commitments, making an alternative format necessary.
In terms of improving patient adherence to a doctor’s recommendations regarding chronic skin disease, “we cannot change our patients, we cannot change the disease, but we can strongly influence the treatment that we choose and how we interact as physicians with our patients,” said Dr. Wollenberg.
“Therapeutic patient education is virtually free of side effects, but evidence based. Have a look [at] it and adapt it to your own practice,” he added.
Dr. Wollenberg is a consultant, speaker and receives fees from numerous pharmaceutical companies.
, Andreas Wollenberg, MD, said at the Revolutionizing Atopic Dermatitis symposium.
A major goal of patient education is increasing medication adherence, noted Dr. Wollenberg, professor in the department of dermatology and allergy at Ludwig Maximilian University of Munich. Quoting former U.S. Surgeon General C. Everett Koop, MD, he said, “drugs don’t work in patients who don’t take them.”
While this is a simple message, it is important, Dr. Wollenberg said, noting that there can be a gap between a physician’s well-intentioned message and how it is interpreted by the patient. “Our messages may not be heard, not understood, not accepted, and even if they are put into place, how long will they last?” he asked. “We need to find a way [to] place sticky messages in the brains of our patients who are sitting and interacting with us.”
One way to improve treatment adherence is through patient education, such as using a written action plan or graphics; simplifying treatment regimens; minimizing treatment costs; setting up reminder programs, early follow-up visits, and short-term treatment goals; and minimizing nocebo effects. “This is more than providing just leaflets to patients. It is a complete program. It is a holistic approach. It should be structured and should be interdisciplinary, and it should contain a psychological component,” Dr. Wollenberg said.
Therapeutic patient education is recommended at baseline for children and adults with moderate to severe AD in the 2020 European Task Force on Atopic Dermatitis (ETFAD) and European Academy of Dermatology and Venereology (EADV) position paper on the diagnosis and treatment of AD in adults and children, alongside other interventions, such as emollients, bath oils, and avoidance of clinically relevant allergens, noted Dr. Wollenberg, the first author . “Therapeutic patient education is an extremely helpful tool to address patient beliefs and questions regarding disease and treatment,” he and his coauthors wrote in the paper.
When considering a therapeutic patient education program for AD, content is key, but just as important is consideration of legal and cultural conditions in the local area, Dr. Wollenberg explained. Every country will need some degree of standardization of content, he noted. Clinicians interested in adopting a patient education program need to consider who will pay for it – patients, foundations, or insurance companies – as well as the time commitment needed.
Dr. Wollenberg said that his team uses an evidence-based education program for AD in Germany that works across patients with different personalities, with a multidisciplinary team that includes a dermatologist, a specialist nurse, a nutrition expert, and a psychologist. “Sometimes we replace the specialized nurse with the dermatology resident because, in Germany, it’s difficult to find any type of specialized nurse,” although this is not an issue in many other countries, he said.
The model for children involves six 90-minute sessions, which cover topics that include emollients and basic care, food allergies and diet, medical treatment, and psychology of itch. The program for adults involves six 2-hour sessions, which cover topics that include psychology, skin care/nutrition, and medical treatment.
While this education program improves adherence in patients with AD, he acknowledged it is time consuming, and may not work for people who live far away from a clinic or who have other time commitments, making an alternative format necessary.
In terms of improving patient adherence to a doctor’s recommendations regarding chronic skin disease, “we cannot change our patients, we cannot change the disease, but we can strongly influence the treatment that we choose and how we interact as physicians with our patients,” said Dr. Wollenberg.
“Therapeutic patient education is virtually free of side effects, but evidence based. Have a look [at] it and adapt it to your own practice,” he added.
Dr. Wollenberg is a consultant, speaker and receives fees from numerous pharmaceutical companies.
FROM RAD 2022
COVID tied to a profound impact on children’s sleep
During the first year of the pandemic, profound changes in screen use and sleep timing occurred among U.S. adolescents as a result of spending more time using electronic devices, going to bed later, and getting up later, compared with before the pandemic, new research indicates.
The excessive screen time negatively affected sleep, said lead investigator Orsolya Kiss, PhD, with the Center for Health Sciences at SRI International, Menlo Park, Calif.
And what’s “concerning,” she told this news organization, is that there is no indication of any spontaneous decline in screen use in 2021, when there were fewer restrictions.
Dr. Kiss said she is “very much interested to see what future studies will show.”
The findings were presented at the annual meeting of the Associated Professional Sleep Societies.
Sleep takes a pandemic hit
“Adolescents and families have turned to online activities and social platforms more than ever before to maintain wellbeing, [to] connect with friends and family, and for online schooling,” Dr. Kiss said in a conference statement.
She and her colleagues examined longitudinal data from 5,027 adolescents aged 11-14 years who are participating in the ongoing Adolescent Brain Cognitive Development (ABCD) study.
As part of the study, participants reported sleep and daily screen time use prior to and at six time points during the first year of the pandemic (May 2020 to March 2021).
During the first year of the pandemic, relative to before the pandemic, recreational screen time was dramatically higher, with adolescents spending about 45 minutes more on social media and 20 minutes more playing video games, Dr. Kiss reported.
The jump in screen time was coupled with changes in sleep patterns.
Adolescents’ wake up times were delayed about 1.5 hours during May and August 2020, relative to prepandemic levels. The delay was partly due to summer break; wake-up times returned to earlier times in the fall of 2020.
During all pandemic assessments, bedtimes were delayed by about 1 hour, even when the new school year started. This was particularly the case in older adolescents and girls.
The findings highlight the need to promote “balanced and informed use of social media platforms, video games, and other digital technology to ensure adequate opportunity to sleep and maintain other healthy behaviors during this critical period of developmental change,” the authors wrote in their conference abstract.
Mental illness risk
In an interview, Ruth Benca, MD, PhD, co-chair of the Alliance for Sleep, noted that “during adolescence, the tendency to become more of a night owl naturally worsens, and when kids have no sleep schedule imposed on them, these patterns become exacerbated.”
Dr. Benca, who was not involved in the study, also noted that altered sleep patterns are risk factors for psychiatric illness.
“Adolescence, in particular, is so critical for brain development, and it really raises the question of whether sleep disturbances in adolescence or poor sleep patterns are contributing to the increase psychiatric epidemic we’re seeing in adolescents and children these days,” said Dr. Benca, with Wake Forest University School of Medicine and Atrium Health Wake Forest Baptist, Winston-Salem, N.C.
Also weighing in on the study, journalist and author Lisa Lewis, MS, based in Southern California, said, “It’s not surprising that tech use and social media – which is such an important part of their social worlds – went up during the pandemic.”
Ms. Lewis, a parent of two teenagers, played a key role in California’s new healthy school start times law, the first of its kind in the nation, and is the author of the newly released book, The Sleep-Deprived Teen (Mango Publishing).
“Far too many adolescents aren’t getting anywhere close to the 8-10 hours of nightly sleep they need,” Ms. Lewis said in an interview.
She noted that the the American Academy of Pediatrics recommends no tech use an hour before bed.
“And there are other house rules parents can implement, such as charging all devices in a central location, like the kitchen. Making sleep a priority helps teens, but it helps parents too: No one functions well when they’re sleep-deprived,” Ms. Lewis added.
Support for the study was provided by the National Institutes of Health. The authors have disclosed no relevant financial relationships. Dr. Benca is a consultant for Idorsia Pharmaceuticals. Ms. Lewis has no relevant disclosures.
A version of this article first appeared on Medscape.com.
During the first year of the pandemic, profound changes in screen use and sleep timing occurred among U.S. adolescents as a result of spending more time using electronic devices, going to bed later, and getting up later, compared with before the pandemic, new research indicates.
The excessive screen time negatively affected sleep, said lead investigator Orsolya Kiss, PhD, with the Center for Health Sciences at SRI International, Menlo Park, Calif.
And what’s “concerning,” she told this news organization, is that there is no indication of any spontaneous decline in screen use in 2021, when there were fewer restrictions.
Dr. Kiss said she is “very much interested to see what future studies will show.”
The findings were presented at the annual meeting of the Associated Professional Sleep Societies.
Sleep takes a pandemic hit
“Adolescents and families have turned to online activities and social platforms more than ever before to maintain wellbeing, [to] connect with friends and family, and for online schooling,” Dr. Kiss said in a conference statement.
She and her colleagues examined longitudinal data from 5,027 adolescents aged 11-14 years who are participating in the ongoing Adolescent Brain Cognitive Development (ABCD) study.
As part of the study, participants reported sleep and daily screen time use prior to and at six time points during the first year of the pandemic (May 2020 to March 2021).
During the first year of the pandemic, relative to before the pandemic, recreational screen time was dramatically higher, with adolescents spending about 45 minutes more on social media and 20 minutes more playing video games, Dr. Kiss reported.
The jump in screen time was coupled with changes in sleep patterns.
Adolescents’ wake up times were delayed about 1.5 hours during May and August 2020, relative to prepandemic levels. The delay was partly due to summer break; wake-up times returned to earlier times in the fall of 2020.
During all pandemic assessments, bedtimes were delayed by about 1 hour, even when the new school year started. This was particularly the case in older adolescents and girls.
The findings highlight the need to promote “balanced and informed use of social media platforms, video games, and other digital technology to ensure adequate opportunity to sleep and maintain other healthy behaviors during this critical period of developmental change,” the authors wrote in their conference abstract.
Mental illness risk
In an interview, Ruth Benca, MD, PhD, co-chair of the Alliance for Sleep, noted that “during adolescence, the tendency to become more of a night owl naturally worsens, and when kids have no sleep schedule imposed on them, these patterns become exacerbated.”
Dr. Benca, who was not involved in the study, also noted that altered sleep patterns are risk factors for psychiatric illness.
“Adolescence, in particular, is so critical for brain development, and it really raises the question of whether sleep disturbances in adolescence or poor sleep patterns are contributing to the increase psychiatric epidemic we’re seeing in adolescents and children these days,” said Dr. Benca, with Wake Forest University School of Medicine and Atrium Health Wake Forest Baptist, Winston-Salem, N.C.
Also weighing in on the study, journalist and author Lisa Lewis, MS, based in Southern California, said, “It’s not surprising that tech use and social media – which is such an important part of their social worlds – went up during the pandemic.”
Ms. Lewis, a parent of two teenagers, played a key role in California’s new healthy school start times law, the first of its kind in the nation, and is the author of the newly released book, The Sleep-Deprived Teen (Mango Publishing).
“Far too many adolescents aren’t getting anywhere close to the 8-10 hours of nightly sleep they need,” Ms. Lewis said in an interview.
She noted that the the American Academy of Pediatrics recommends no tech use an hour before bed.
“And there are other house rules parents can implement, such as charging all devices in a central location, like the kitchen. Making sleep a priority helps teens, but it helps parents too: No one functions well when they’re sleep-deprived,” Ms. Lewis added.
Support for the study was provided by the National Institutes of Health. The authors have disclosed no relevant financial relationships. Dr. Benca is a consultant for Idorsia Pharmaceuticals. Ms. Lewis has no relevant disclosures.
A version of this article first appeared on Medscape.com.
During the first year of the pandemic, profound changes in screen use and sleep timing occurred among U.S. adolescents as a result of spending more time using electronic devices, going to bed later, and getting up later, compared with before the pandemic, new research indicates.
The excessive screen time negatively affected sleep, said lead investigator Orsolya Kiss, PhD, with the Center for Health Sciences at SRI International, Menlo Park, Calif.
And what’s “concerning,” she told this news organization, is that there is no indication of any spontaneous decline in screen use in 2021, when there were fewer restrictions.
Dr. Kiss said she is “very much interested to see what future studies will show.”
The findings were presented at the annual meeting of the Associated Professional Sleep Societies.
Sleep takes a pandemic hit
“Adolescents and families have turned to online activities and social platforms more than ever before to maintain wellbeing, [to] connect with friends and family, and for online schooling,” Dr. Kiss said in a conference statement.
She and her colleagues examined longitudinal data from 5,027 adolescents aged 11-14 years who are participating in the ongoing Adolescent Brain Cognitive Development (ABCD) study.
As part of the study, participants reported sleep and daily screen time use prior to and at six time points during the first year of the pandemic (May 2020 to March 2021).
During the first year of the pandemic, relative to before the pandemic, recreational screen time was dramatically higher, with adolescents spending about 45 minutes more on social media and 20 minutes more playing video games, Dr. Kiss reported.
The jump in screen time was coupled with changes in sleep patterns.
Adolescents’ wake up times were delayed about 1.5 hours during May and August 2020, relative to prepandemic levels. The delay was partly due to summer break; wake-up times returned to earlier times in the fall of 2020.
During all pandemic assessments, bedtimes were delayed by about 1 hour, even when the new school year started. This was particularly the case in older adolescents and girls.
The findings highlight the need to promote “balanced and informed use of social media platforms, video games, and other digital technology to ensure adequate opportunity to sleep and maintain other healthy behaviors during this critical period of developmental change,” the authors wrote in their conference abstract.
Mental illness risk
In an interview, Ruth Benca, MD, PhD, co-chair of the Alliance for Sleep, noted that “during adolescence, the tendency to become more of a night owl naturally worsens, and when kids have no sleep schedule imposed on them, these patterns become exacerbated.”
Dr. Benca, who was not involved in the study, also noted that altered sleep patterns are risk factors for psychiatric illness.
“Adolescence, in particular, is so critical for brain development, and it really raises the question of whether sleep disturbances in adolescence or poor sleep patterns are contributing to the increase psychiatric epidemic we’re seeing in adolescents and children these days,” said Dr. Benca, with Wake Forest University School of Medicine and Atrium Health Wake Forest Baptist, Winston-Salem, N.C.
Also weighing in on the study, journalist and author Lisa Lewis, MS, based in Southern California, said, “It’s not surprising that tech use and social media – which is such an important part of their social worlds – went up during the pandemic.”
Ms. Lewis, a parent of two teenagers, played a key role in California’s new healthy school start times law, the first of its kind in the nation, and is the author of the newly released book, The Sleep-Deprived Teen (Mango Publishing).
“Far too many adolescents aren’t getting anywhere close to the 8-10 hours of nightly sleep they need,” Ms. Lewis said in an interview.
She noted that the the American Academy of Pediatrics recommends no tech use an hour before bed.
“And there are other house rules parents can implement, such as charging all devices in a central location, like the kitchen. Making sleep a priority helps teens, but it helps parents too: No one functions well when they’re sleep-deprived,” Ms. Lewis added.
Support for the study was provided by the National Institutes of Health. The authors have disclosed no relevant financial relationships. Dr. Benca is a consultant for Idorsia Pharmaceuticals. Ms. Lewis has no relevant disclosures.
A version of this article first appeared on Medscape.com.
FROM SLEEP 2022
Glofitamab prevails against r/r DLBCL
“We know that relapsed diffuse large B-cell lymphoma has a particularly poor prognosis,” especially for patients who have undergone at least two therapies, Dr. Michael Dickinson, MBBS, of the University of Melbourne said in a presentation at the annual meeting of the American Society of Clinical Oncology.
Bispecific T cell–recruiting antibodies are emerging as a novel treatment option for B-cell cancers, said Dr. Dickinson.
Glofitamab is distinct among these therapies for its configuration that is bivalent for CD20 and monovalent for CD3, providing more potency than a 1:1 format, Dr. Dickinson explained in his presentation.
The study population included 154 adults aged 21-90 years with DLBCL who had received at least two prior treatments; all had received prior anti-CD20 Ab, and 149 had received anthracycline. The median age of the patients was 66 years, 65% were male, 75% had Ann Arbor stage III or IV disease, and 90% were refractory to any prior therapy.
The patients received intravenous glutamate-pyruvate transaminase, followed by an initial intravenous dose of glofitamab 7 days later. Glofitamab was given as step-up doses starting with 2.5 mg to a target of 30 mg.
The primary endpoint was complete response (CR) during initial treatment using Independent Review Committee (IRC) criteria, with overall response rate, duration of response, duration of complete response, progression-free survival, and overall survival as key secondary outcomes.
At a median of 12.6 months’ follow-up, the CR and overall response rates were 39.4% and 51.6%, respectively.
“Responses were achieved early; the median time to first complete response was 42 days,” Dr. Dickinson reported. Of the 38 patients with CR at the data cutoff point, 33 remained in complete remission (87%) based on IRC criteria. Complete response rates were consistent across prespecified subgroups, notably 42% of patients with no prior chimeric antigen receptor T-cell therapy and 70% and 34%, of those who were relapsed or refractory, respectively, to their last prior treatments.
The median duration of overall response was 18.4 months, and the median duration of complete response had not yet been estimated, Dr. Dickinson said. The median progression-free survival and overall survival rates were 4.9 months and 11.5 months, respectively, and the estimated 12-month overall survival was 49.8%.
“These are highly clinically significant results for this difficult to treat population,” Dr. Dickinson said in his presentation.
The most common adverse event was cytokine release syndrome (CRS), which occurred in 63% of patients. Of these, 3.9% were grade 3 or 4. Patients received corticosteroids (27.8%) or tocilizumab for management of CRS.
“As we have shown before, this is a first-course phenomenon, becoming far less frequent once step up dosing is complete,” Dr. Dickinson said in the presentation. “The median time to CRS is predictable, occurring around 10 hours after the IV infusion,” he said. Overall, 3.2% of the patients discontinued because of an adverse event.
A total of eight deaths occurred during the study; five of these were related to COVID-19 and the remaining three were in patients with manifest progression of disease.
Infections are to be expected in such a heavily treated population, and 14.9% of patients developed infections of grade 3 or higher, said Dr. Dickinson. Neutropenia of any grade occurred in 37.7%, febrile neutropenia in 2.6%. Neurological events occurred in 38.3% of patients; 3.2% were grade 3 or higher.
The study did not prospectively record immune effector cell–associated neurotoxicity syndrome, Dr. Dickinson said, but an estimate suggests a rate of 2.6%, and none of the events were considered to be related to glofitamab, he noted.
The researchers also looked at a supporting cohort of 35 patients with a median follow up of more than 2 years. In this group, the complete remission rate was 35% and the median duration of remission was 34.2 months. “Our six longest patients have been in remission for longer than 3 years,” Dr. Dickinson said.
The latest glofitamab data “reflect routine practice and an area of need for this disease,” said Dr. Dickinson.
“I think these results will prove to be very meaningful for our patients with large cell lymphoma, and this drug will prove to be an important treatment option,” he said.
More follow-up needed, but findings show promise
A number of CD20/CD3-bispecific antibodies are in development for patients with relapsed/refractory B-cell lymphomas, said study discussant Kerry J. Savage, MD, of the University of British Columbia, Vancouver, who served as the discussant for the session.
Glofitamab differs from other treatments in that it is bivalent for CD20 and monovalent for CD3, “which imparts greater potency,” she noted. Glofitamab also has a silent Fc region that is designed to extend half-life and reduce toxicity.
Patients in the current study had at least two prior regimens, and importantly, “CR rates were similar, regardless of prior therapy,” said Dr. Savage. The longer follow-up cohort provides “a hint that the response may be durable.”
Looking ahead, “the important thing will be response durability” with longer follow-up, she added. “We don’t know the curative potential yet, but the results are encouraging so far.”
In the meantime, “the best use of bispecific antibodies is through clinical trials,” Dr. Savage said. “Keep an eye out for bispecific antibody combination trials as well.”
The study was funded by F. Hoffmann–La Roche. Dr. Dickinson disclosed honoraria from or serving as a consultant to companies including Amgen, Bristol Myers-Squibb, Gilead Sciences, Janssen, MSD, Novartis, and Roche. Dr. Savage disclosed relationships, funding, and support from multiple companies including Bristol Myers-Squibb, Janssen Oncology, Kyowa, Merck, Novartis Canada Pharmaceuticals, Seattle Genetics and Roche.
“We know that relapsed diffuse large B-cell lymphoma has a particularly poor prognosis,” especially for patients who have undergone at least two therapies, Dr. Michael Dickinson, MBBS, of the University of Melbourne said in a presentation at the annual meeting of the American Society of Clinical Oncology.
Bispecific T cell–recruiting antibodies are emerging as a novel treatment option for B-cell cancers, said Dr. Dickinson.
Glofitamab is distinct among these therapies for its configuration that is bivalent for CD20 and monovalent for CD3, providing more potency than a 1:1 format, Dr. Dickinson explained in his presentation.
The study population included 154 adults aged 21-90 years with DLBCL who had received at least two prior treatments; all had received prior anti-CD20 Ab, and 149 had received anthracycline. The median age of the patients was 66 years, 65% were male, 75% had Ann Arbor stage III or IV disease, and 90% were refractory to any prior therapy.
The patients received intravenous glutamate-pyruvate transaminase, followed by an initial intravenous dose of glofitamab 7 days later. Glofitamab was given as step-up doses starting with 2.5 mg to a target of 30 mg.
The primary endpoint was complete response (CR) during initial treatment using Independent Review Committee (IRC) criteria, with overall response rate, duration of response, duration of complete response, progression-free survival, and overall survival as key secondary outcomes.
At a median of 12.6 months’ follow-up, the CR and overall response rates were 39.4% and 51.6%, respectively.
“Responses were achieved early; the median time to first complete response was 42 days,” Dr. Dickinson reported. Of the 38 patients with CR at the data cutoff point, 33 remained in complete remission (87%) based on IRC criteria. Complete response rates were consistent across prespecified subgroups, notably 42% of patients with no prior chimeric antigen receptor T-cell therapy and 70% and 34%, of those who were relapsed or refractory, respectively, to their last prior treatments.
The median duration of overall response was 18.4 months, and the median duration of complete response had not yet been estimated, Dr. Dickinson said. The median progression-free survival and overall survival rates were 4.9 months and 11.5 months, respectively, and the estimated 12-month overall survival was 49.8%.
“These are highly clinically significant results for this difficult to treat population,” Dr. Dickinson said in his presentation.
The most common adverse event was cytokine release syndrome (CRS), which occurred in 63% of patients. Of these, 3.9% were grade 3 or 4. Patients received corticosteroids (27.8%) or tocilizumab for management of CRS.
“As we have shown before, this is a first-course phenomenon, becoming far less frequent once step up dosing is complete,” Dr. Dickinson said in the presentation. “The median time to CRS is predictable, occurring around 10 hours after the IV infusion,” he said. Overall, 3.2% of the patients discontinued because of an adverse event.
A total of eight deaths occurred during the study; five of these were related to COVID-19 and the remaining three were in patients with manifest progression of disease.
Infections are to be expected in such a heavily treated population, and 14.9% of patients developed infections of grade 3 or higher, said Dr. Dickinson. Neutropenia of any grade occurred in 37.7%, febrile neutropenia in 2.6%. Neurological events occurred in 38.3% of patients; 3.2% were grade 3 or higher.
The study did not prospectively record immune effector cell–associated neurotoxicity syndrome, Dr. Dickinson said, but an estimate suggests a rate of 2.6%, and none of the events were considered to be related to glofitamab, he noted.
The researchers also looked at a supporting cohort of 35 patients with a median follow up of more than 2 years. In this group, the complete remission rate was 35% and the median duration of remission was 34.2 months. “Our six longest patients have been in remission for longer than 3 years,” Dr. Dickinson said.
The latest glofitamab data “reflect routine practice and an area of need for this disease,” said Dr. Dickinson.
“I think these results will prove to be very meaningful for our patients with large cell lymphoma, and this drug will prove to be an important treatment option,” he said.
More follow-up needed, but findings show promise
A number of CD20/CD3-bispecific antibodies are in development for patients with relapsed/refractory B-cell lymphomas, said study discussant Kerry J. Savage, MD, of the University of British Columbia, Vancouver, who served as the discussant for the session.
Glofitamab differs from other treatments in that it is bivalent for CD20 and monovalent for CD3, “which imparts greater potency,” she noted. Glofitamab also has a silent Fc region that is designed to extend half-life and reduce toxicity.
Patients in the current study had at least two prior regimens, and importantly, “CR rates were similar, regardless of prior therapy,” said Dr. Savage. The longer follow-up cohort provides “a hint that the response may be durable.”
Looking ahead, “the important thing will be response durability” with longer follow-up, she added. “We don’t know the curative potential yet, but the results are encouraging so far.”
In the meantime, “the best use of bispecific antibodies is through clinical trials,” Dr. Savage said. “Keep an eye out for bispecific antibody combination trials as well.”
The study was funded by F. Hoffmann–La Roche. Dr. Dickinson disclosed honoraria from or serving as a consultant to companies including Amgen, Bristol Myers-Squibb, Gilead Sciences, Janssen, MSD, Novartis, and Roche. Dr. Savage disclosed relationships, funding, and support from multiple companies including Bristol Myers-Squibb, Janssen Oncology, Kyowa, Merck, Novartis Canada Pharmaceuticals, Seattle Genetics and Roche.
“We know that relapsed diffuse large B-cell lymphoma has a particularly poor prognosis,” especially for patients who have undergone at least two therapies, Dr. Michael Dickinson, MBBS, of the University of Melbourne said in a presentation at the annual meeting of the American Society of Clinical Oncology.
Bispecific T cell–recruiting antibodies are emerging as a novel treatment option for B-cell cancers, said Dr. Dickinson.
Glofitamab is distinct among these therapies for its configuration that is bivalent for CD20 and monovalent for CD3, providing more potency than a 1:1 format, Dr. Dickinson explained in his presentation.
The study population included 154 adults aged 21-90 years with DLBCL who had received at least two prior treatments; all had received prior anti-CD20 Ab, and 149 had received anthracycline. The median age of the patients was 66 years, 65% were male, 75% had Ann Arbor stage III or IV disease, and 90% were refractory to any prior therapy.
The patients received intravenous glutamate-pyruvate transaminase, followed by an initial intravenous dose of glofitamab 7 days later. Glofitamab was given as step-up doses starting with 2.5 mg to a target of 30 mg.
The primary endpoint was complete response (CR) during initial treatment using Independent Review Committee (IRC) criteria, with overall response rate, duration of response, duration of complete response, progression-free survival, and overall survival as key secondary outcomes.
At a median of 12.6 months’ follow-up, the CR and overall response rates were 39.4% and 51.6%, respectively.
“Responses were achieved early; the median time to first complete response was 42 days,” Dr. Dickinson reported. Of the 38 patients with CR at the data cutoff point, 33 remained in complete remission (87%) based on IRC criteria. Complete response rates were consistent across prespecified subgroups, notably 42% of patients with no prior chimeric antigen receptor T-cell therapy and 70% and 34%, of those who were relapsed or refractory, respectively, to their last prior treatments.
The median duration of overall response was 18.4 months, and the median duration of complete response had not yet been estimated, Dr. Dickinson said. The median progression-free survival and overall survival rates were 4.9 months and 11.5 months, respectively, and the estimated 12-month overall survival was 49.8%.
“These are highly clinically significant results for this difficult to treat population,” Dr. Dickinson said in his presentation.
The most common adverse event was cytokine release syndrome (CRS), which occurred in 63% of patients. Of these, 3.9% were grade 3 or 4. Patients received corticosteroids (27.8%) or tocilizumab for management of CRS.
“As we have shown before, this is a first-course phenomenon, becoming far less frequent once step up dosing is complete,” Dr. Dickinson said in the presentation. “The median time to CRS is predictable, occurring around 10 hours after the IV infusion,” he said. Overall, 3.2% of the patients discontinued because of an adverse event.
A total of eight deaths occurred during the study; five of these were related to COVID-19 and the remaining three were in patients with manifest progression of disease.
Infections are to be expected in such a heavily treated population, and 14.9% of patients developed infections of grade 3 or higher, said Dr. Dickinson. Neutropenia of any grade occurred in 37.7%, febrile neutropenia in 2.6%. Neurological events occurred in 38.3% of patients; 3.2% were grade 3 or higher.
The study did not prospectively record immune effector cell–associated neurotoxicity syndrome, Dr. Dickinson said, but an estimate suggests a rate of 2.6%, and none of the events were considered to be related to glofitamab, he noted.
The researchers also looked at a supporting cohort of 35 patients with a median follow up of more than 2 years. In this group, the complete remission rate was 35% and the median duration of remission was 34.2 months. “Our six longest patients have been in remission for longer than 3 years,” Dr. Dickinson said.
The latest glofitamab data “reflect routine practice and an area of need for this disease,” said Dr. Dickinson.
“I think these results will prove to be very meaningful for our patients with large cell lymphoma, and this drug will prove to be an important treatment option,” he said.
More follow-up needed, but findings show promise
A number of CD20/CD3-bispecific antibodies are in development for patients with relapsed/refractory B-cell lymphomas, said study discussant Kerry J. Savage, MD, of the University of British Columbia, Vancouver, who served as the discussant for the session.
Glofitamab differs from other treatments in that it is bivalent for CD20 and monovalent for CD3, “which imparts greater potency,” she noted. Glofitamab also has a silent Fc region that is designed to extend half-life and reduce toxicity.
Patients in the current study had at least two prior regimens, and importantly, “CR rates were similar, regardless of prior therapy,” said Dr. Savage. The longer follow-up cohort provides “a hint that the response may be durable.”
Looking ahead, “the important thing will be response durability” with longer follow-up, she added. “We don’t know the curative potential yet, but the results are encouraging so far.”
In the meantime, “the best use of bispecific antibodies is through clinical trials,” Dr. Savage said. “Keep an eye out for bispecific antibody combination trials as well.”
The study was funded by F. Hoffmann–La Roche. Dr. Dickinson disclosed honoraria from or serving as a consultant to companies including Amgen, Bristol Myers-Squibb, Gilead Sciences, Janssen, MSD, Novartis, and Roche. Dr. Savage disclosed relationships, funding, and support from multiple companies including Bristol Myers-Squibb, Janssen Oncology, Kyowa, Merck, Novartis Canada Pharmaceuticals, Seattle Genetics and Roche.
FROM ASCO 2022
Stopping immunosuppressives in lupus nephritis isn’t noninferior to continuing
COPENHAGEN – Discontinuing maintenance immunosuppressive therapy (IST) in patients with proliferative lupus nephritis in remission proved less effective than continuing it in terms of the rates of renal relapse and severe systemic lupus erythematosus (SLE) flare, results from the WIN-Lupus trial show.
Lead researcher Noemie Jourde-Chiche, MD, assistant professor at Aix-Marseille (France) University, presented the results at the annual European Congress of Rheumatology.
The randomized, controlled trial aimed to determine the optimal duration of maintenance IST for proliferative lupus nephritis, by asking whether discontinuation of such therapy after 2-3 years was noninferior to IST continuation for 2 more years.
“This is the first randomized IST trial in proliferative lupus nephritis,” Dr. Jourde-Chiche reported. “We found that noninferiority of IST discontinuation was not demonstrated, and those who discontinued had a higher risk of SLE flares, but the majority of patients who discontinued did not experience flare.”
Regarding the incidence of renal relapse, no statistically significant difference was found between patients who continued versus those who discontinued IST.
Rheumatologist Christophe Richez, MD, of the Groupe Hospitalier Pellegrin-CHU de Bordeaux (France) welcomed the trial. “The work does not find a significant difference but suggests that with more power, the difference would have been significant,” he said in an interview.
He added that a significant number of patients refused to enter the study for several reasons, including scheduling a pregnancy and fear of relapse after stopping the treatment. “This in itself shows that we need this type of study to know if we can stop the treatment to plan a pregnancy or if a relay treatment is necessary. These data also mean we can now better inform our patients about the benefit-risk [profile] of continuing treatment or not.”
Dr. Richez, who was not involved in the trial, noted that the data provide information that strongly suggest more research is needed to better determine which patients are at risk of relapse, and consequently, for which patients is discontinuation possible. “There’s also a need for further analysis of tolerance to the immunosuppressive drugs according to the strategy.”
Finally, he referred to the issue around therapeutic adherence that is often faced with management of lupus. “The data from this study will allow us to better explain to patients the need to continue or discontinue their treatments, including hydroxychloroquine, and also the possibility of decreasing the immunosuppressive drugs to half-dose.”
Maintenance therapy in lupus nephritis: To continue or not?
Conducted in 28 French centers, participants had class III or IV lupus nephritis with active lesions and had previously received induction IST of cyclophosphamide or mycophenolate mofetil with hydroxychloroquine and glucocorticoids. Maintenance IST was azathioprine or mycophenolate mofetil, hydroxychloroquine, and possibly low-dose glucocorticoids (below 10 mg/day).
A total of 96 patients were randomized into two groups: continuation of maintenance therapy (azathioprine or mycophenolate mofetil for 2-3 more years, hydroxychloroquine, and possibly low-dose glucocorticoids (below 10 mg/day), or discontinuation of maintenance therapy (azathioprine or mycophenolate mofetil) over 3 months.
Both study arms were similar with a mean age of 36-37 years, and 82%-86% of patients were female, 59%-67% were White. They had a mean disease duration of 7-9 years, and 72%-80% had experienced their first flare of proliferative nephritis. A total of 54%-65% had received cyclophosphamide induction therapy, and 75%-81% were on mycophenolate mofetil maintenance therapy that had been ongoing for a mean of 2.8 years. Tests of patients’ kidney function revealed a mean serum creatinine of 67-72 micromol/L and estimated glomerular filtration rate (eGFR) of 94-101 mL/min per 1.73 m2. The mean SLE Disease Activity Index score was around 2.
Follow-up visits were conducted every 3 months for 2 years, and the trial had a primary end point of renal relapse rate at 24 months (confirmed by kidney biopsy), while secondary endpoints included rate of severe SLE flares, survival without renal relapse, or severe flare and adverse events, among others.
Patients were excluded if they were not taking hydroxychloroquine, had extrarenal SLE, an eGFR less than 30 mL/min per 1.73 m2 or stage VI disease. After some participants did not finish the trial because of pregnancy, wish for pregnancy, or adverse events, data from a total of 40 in the IST continuation group and 44 in the discontinuation group were analyzed.
Noninferiority of discontinuation versus continuation not shown
A total of 12.5% in the continuation arm experienced renal relapse over 24 months, compared with 27.3% in the discontinuation arm (P = .079).
“The endpoint of noninferiority of discontinuation of immunosuppressive therapy was not shown, but no statistically significant difference was found between groups for renal relapse,” Dr. Jourde-Chiche said.
Severe SLE flares (renal or extrarenal) occurred significantly less often over 24 months in the continuation arm at 12.5% versus 31.8% in the discontinuation arm (P = .034).
However, Dr. Jourde-Chiche pointed out that “the majority of patients who discontinued treatment did not experience a flare.”
No differences were seen between groups with respect to any secondary endpoints. “Fortunately, no patients died or reached end-stage renal disease, and overall, the adverse events did not differ between groups,” she reported.
The study identified several risk factors for renal relapse, among which were low complement component 3 and higher baseline urinary protein to creatinine ratio.
Longer immunosuppressive therapy prediscontinuation leads to better results
Gabriella Moroni, MD, of the nephrology unit at Ospedale Maggiore Policlinico, Milan, authored a review of studies that attempted to interrupt glucocorticoids and other immunosuppressive agents in lupus nephritis and in SLE. Her review concluded that “the available data suggest that therapy withdrawal is feasible at least in patients enjoying a complete clinical remission after a prolonged therapy.”
Asked to comment on the French study, Dr. Moroni said the trial was very welcome. “In our long-term experience, we have stopped IST in 73 patients with lupus nephritis, followed for a mean of 23 years. Of these, 32 never reassumed therapy and 20 had at least one flare.”
Dr. Moroni noted that those participants who did not experience flares had significantly longer IST and longer remission before discontinuation and took hydroxychloroquine more frequently.
“We feel that, to prevent severe flares, firstly, lupus nephritis should be in complete remission for at least 3 years, and secondly, patients should have received IST for at least 5 years before discontinuation; immunosuppressive drugs should be tapered off very slowly and after strict clinical surveillance, and finally, hydroxychloroquine can prevent extrarenal flares.
Dr. Jourde-Chiche reported serving on a speakers bureau for Vifor Pharma and receiving grant/research support from Fresenius Medical Care. Some coauthors reported financial ties to many pharmaceutical companies. Dr. Richez said he has received fees for lectures or boards from GlaxoSmithKline, AstraZeneca, and Novartis. Dr. Moroni had no relevant disclosures.
COPENHAGEN – Discontinuing maintenance immunosuppressive therapy (IST) in patients with proliferative lupus nephritis in remission proved less effective than continuing it in terms of the rates of renal relapse and severe systemic lupus erythematosus (SLE) flare, results from the WIN-Lupus trial show.
Lead researcher Noemie Jourde-Chiche, MD, assistant professor at Aix-Marseille (France) University, presented the results at the annual European Congress of Rheumatology.
The randomized, controlled trial aimed to determine the optimal duration of maintenance IST for proliferative lupus nephritis, by asking whether discontinuation of such therapy after 2-3 years was noninferior to IST continuation for 2 more years.
“This is the first randomized IST trial in proliferative lupus nephritis,” Dr. Jourde-Chiche reported. “We found that noninferiority of IST discontinuation was not demonstrated, and those who discontinued had a higher risk of SLE flares, but the majority of patients who discontinued did not experience flare.”
Regarding the incidence of renal relapse, no statistically significant difference was found between patients who continued versus those who discontinued IST.
Rheumatologist Christophe Richez, MD, of the Groupe Hospitalier Pellegrin-CHU de Bordeaux (France) welcomed the trial. “The work does not find a significant difference but suggests that with more power, the difference would have been significant,” he said in an interview.
He added that a significant number of patients refused to enter the study for several reasons, including scheduling a pregnancy and fear of relapse after stopping the treatment. “This in itself shows that we need this type of study to know if we can stop the treatment to plan a pregnancy or if a relay treatment is necessary. These data also mean we can now better inform our patients about the benefit-risk [profile] of continuing treatment or not.”
Dr. Richez, who was not involved in the trial, noted that the data provide information that strongly suggest more research is needed to better determine which patients are at risk of relapse, and consequently, for which patients is discontinuation possible. “There’s also a need for further analysis of tolerance to the immunosuppressive drugs according to the strategy.”
Finally, he referred to the issue around therapeutic adherence that is often faced with management of lupus. “The data from this study will allow us to better explain to patients the need to continue or discontinue their treatments, including hydroxychloroquine, and also the possibility of decreasing the immunosuppressive drugs to half-dose.”
Maintenance therapy in lupus nephritis: To continue or not?
Conducted in 28 French centers, participants had class III or IV lupus nephritis with active lesions and had previously received induction IST of cyclophosphamide or mycophenolate mofetil with hydroxychloroquine and glucocorticoids. Maintenance IST was azathioprine or mycophenolate mofetil, hydroxychloroquine, and possibly low-dose glucocorticoids (below 10 mg/day).
A total of 96 patients were randomized into two groups: continuation of maintenance therapy (azathioprine or mycophenolate mofetil for 2-3 more years, hydroxychloroquine, and possibly low-dose glucocorticoids (below 10 mg/day), or discontinuation of maintenance therapy (azathioprine or mycophenolate mofetil) over 3 months.
Both study arms were similar with a mean age of 36-37 years, and 82%-86% of patients were female, 59%-67% were White. They had a mean disease duration of 7-9 years, and 72%-80% had experienced their first flare of proliferative nephritis. A total of 54%-65% had received cyclophosphamide induction therapy, and 75%-81% were on mycophenolate mofetil maintenance therapy that had been ongoing for a mean of 2.8 years. Tests of patients’ kidney function revealed a mean serum creatinine of 67-72 micromol/L and estimated glomerular filtration rate (eGFR) of 94-101 mL/min per 1.73 m2. The mean SLE Disease Activity Index score was around 2.
Follow-up visits were conducted every 3 months for 2 years, and the trial had a primary end point of renal relapse rate at 24 months (confirmed by kidney biopsy), while secondary endpoints included rate of severe SLE flares, survival without renal relapse, or severe flare and adverse events, among others.
Patients were excluded if they were not taking hydroxychloroquine, had extrarenal SLE, an eGFR less than 30 mL/min per 1.73 m2 or stage VI disease. After some participants did not finish the trial because of pregnancy, wish for pregnancy, or adverse events, data from a total of 40 in the IST continuation group and 44 in the discontinuation group were analyzed.
Noninferiority of discontinuation versus continuation not shown
A total of 12.5% in the continuation arm experienced renal relapse over 24 months, compared with 27.3% in the discontinuation arm (P = .079).
“The endpoint of noninferiority of discontinuation of immunosuppressive therapy was not shown, but no statistically significant difference was found between groups for renal relapse,” Dr. Jourde-Chiche said.
Severe SLE flares (renal or extrarenal) occurred significantly less often over 24 months in the continuation arm at 12.5% versus 31.8% in the discontinuation arm (P = .034).
However, Dr. Jourde-Chiche pointed out that “the majority of patients who discontinued treatment did not experience a flare.”
No differences were seen between groups with respect to any secondary endpoints. “Fortunately, no patients died or reached end-stage renal disease, and overall, the adverse events did not differ between groups,” she reported.
The study identified several risk factors for renal relapse, among which were low complement component 3 and higher baseline urinary protein to creatinine ratio.
Longer immunosuppressive therapy prediscontinuation leads to better results
Gabriella Moroni, MD, of the nephrology unit at Ospedale Maggiore Policlinico, Milan, authored a review of studies that attempted to interrupt glucocorticoids and other immunosuppressive agents in lupus nephritis and in SLE. Her review concluded that “the available data suggest that therapy withdrawal is feasible at least in patients enjoying a complete clinical remission after a prolonged therapy.”
Asked to comment on the French study, Dr. Moroni said the trial was very welcome. “In our long-term experience, we have stopped IST in 73 patients with lupus nephritis, followed for a mean of 23 years. Of these, 32 never reassumed therapy and 20 had at least one flare.”
Dr. Moroni noted that those participants who did not experience flares had significantly longer IST and longer remission before discontinuation and took hydroxychloroquine more frequently.
“We feel that, to prevent severe flares, firstly, lupus nephritis should be in complete remission for at least 3 years, and secondly, patients should have received IST for at least 5 years before discontinuation; immunosuppressive drugs should be tapered off very slowly and after strict clinical surveillance, and finally, hydroxychloroquine can prevent extrarenal flares.
Dr. Jourde-Chiche reported serving on a speakers bureau for Vifor Pharma and receiving grant/research support from Fresenius Medical Care. Some coauthors reported financial ties to many pharmaceutical companies. Dr. Richez said he has received fees for lectures or boards from GlaxoSmithKline, AstraZeneca, and Novartis. Dr. Moroni had no relevant disclosures.
COPENHAGEN – Discontinuing maintenance immunosuppressive therapy (IST) in patients with proliferative lupus nephritis in remission proved less effective than continuing it in terms of the rates of renal relapse and severe systemic lupus erythematosus (SLE) flare, results from the WIN-Lupus trial show.
Lead researcher Noemie Jourde-Chiche, MD, assistant professor at Aix-Marseille (France) University, presented the results at the annual European Congress of Rheumatology.
The randomized, controlled trial aimed to determine the optimal duration of maintenance IST for proliferative lupus nephritis, by asking whether discontinuation of such therapy after 2-3 years was noninferior to IST continuation for 2 more years.
“This is the first randomized IST trial in proliferative lupus nephritis,” Dr. Jourde-Chiche reported. “We found that noninferiority of IST discontinuation was not demonstrated, and those who discontinued had a higher risk of SLE flares, but the majority of patients who discontinued did not experience flare.”
Regarding the incidence of renal relapse, no statistically significant difference was found between patients who continued versus those who discontinued IST.
Rheumatologist Christophe Richez, MD, of the Groupe Hospitalier Pellegrin-CHU de Bordeaux (France) welcomed the trial. “The work does not find a significant difference but suggests that with more power, the difference would have been significant,” he said in an interview.
He added that a significant number of patients refused to enter the study for several reasons, including scheduling a pregnancy and fear of relapse after stopping the treatment. “This in itself shows that we need this type of study to know if we can stop the treatment to plan a pregnancy or if a relay treatment is necessary. These data also mean we can now better inform our patients about the benefit-risk [profile] of continuing treatment or not.”
Dr. Richez, who was not involved in the trial, noted that the data provide information that strongly suggest more research is needed to better determine which patients are at risk of relapse, and consequently, for which patients is discontinuation possible. “There’s also a need for further analysis of tolerance to the immunosuppressive drugs according to the strategy.”
Finally, he referred to the issue around therapeutic adherence that is often faced with management of lupus. “The data from this study will allow us to better explain to patients the need to continue or discontinue their treatments, including hydroxychloroquine, and also the possibility of decreasing the immunosuppressive drugs to half-dose.”
Maintenance therapy in lupus nephritis: To continue or not?
Conducted in 28 French centers, participants had class III or IV lupus nephritis with active lesions and had previously received induction IST of cyclophosphamide or mycophenolate mofetil with hydroxychloroquine and glucocorticoids. Maintenance IST was azathioprine or mycophenolate mofetil, hydroxychloroquine, and possibly low-dose glucocorticoids (below 10 mg/day).
A total of 96 patients were randomized into two groups: continuation of maintenance therapy (azathioprine or mycophenolate mofetil for 2-3 more years, hydroxychloroquine, and possibly low-dose glucocorticoids (below 10 mg/day), or discontinuation of maintenance therapy (azathioprine or mycophenolate mofetil) over 3 months.
Both study arms were similar with a mean age of 36-37 years, and 82%-86% of patients were female, 59%-67% were White. They had a mean disease duration of 7-9 years, and 72%-80% had experienced their first flare of proliferative nephritis. A total of 54%-65% had received cyclophosphamide induction therapy, and 75%-81% were on mycophenolate mofetil maintenance therapy that had been ongoing for a mean of 2.8 years. Tests of patients’ kidney function revealed a mean serum creatinine of 67-72 micromol/L and estimated glomerular filtration rate (eGFR) of 94-101 mL/min per 1.73 m2. The mean SLE Disease Activity Index score was around 2.
Follow-up visits were conducted every 3 months for 2 years, and the trial had a primary end point of renal relapse rate at 24 months (confirmed by kidney biopsy), while secondary endpoints included rate of severe SLE flares, survival without renal relapse, or severe flare and adverse events, among others.
Patients were excluded if they were not taking hydroxychloroquine, had extrarenal SLE, an eGFR less than 30 mL/min per 1.73 m2 or stage VI disease. After some participants did not finish the trial because of pregnancy, wish for pregnancy, or adverse events, data from a total of 40 in the IST continuation group and 44 in the discontinuation group were analyzed.
Noninferiority of discontinuation versus continuation not shown
A total of 12.5% in the continuation arm experienced renal relapse over 24 months, compared with 27.3% in the discontinuation arm (P = .079).
“The endpoint of noninferiority of discontinuation of immunosuppressive therapy was not shown, but no statistically significant difference was found between groups for renal relapse,” Dr. Jourde-Chiche said.
Severe SLE flares (renal or extrarenal) occurred significantly less often over 24 months in the continuation arm at 12.5% versus 31.8% in the discontinuation arm (P = .034).
However, Dr. Jourde-Chiche pointed out that “the majority of patients who discontinued treatment did not experience a flare.”
No differences were seen between groups with respect to any secondary endpoints. “Fortunately, no patients died or reached end-stage renal disease, and overall, the adverse events did not differ between groups,” she reported.
The study identified several risk factors for renal relapse, among which were low complement component 3 and higher baseline urinary protein to creatinine ratio.
Longer immunosuppressive therapy prediscontinuation leads to better results
Gabriella Moroni, MD, of the nephrology unit at Ospedale Maggiore Policlinico, Milan, authored a review of studies that attempted to interrupt glucocorticoids and other immunosuppressive agents in lupus nephritis and in SLE. Her review concluded that “the available data suggest that therapy withdrawal is feasible at least in patients enjoying a complete clinical remission after a prolonged therapy.”
Asked to comment on the French study, Dr. Moroni said the trial was very welcome. “In our long-term experience, we have stopped IST in 73 patients with lupus nephritis, followed for a mean of 23 years. Of these, 32 never reassumed therapy and 20 had at least one flare.”
Dr. Moroni noted that those participants who did not experience flares had significantly longer IST and longer remission before discontinuation and took hydroxychloroquine more frequently.
“We feel that, to prevent severe flares, firstly, lupus nephritis should be in complete remission for at least 3 years, and secondly, patients should have received IST for at least 5 years before discontinuation; immunosuppressive drugs should be tapered off very slowly and after strict clinical surveillance, and finally, hydroxychloroquine can prevent extrarenal flares.
Dr. Jourde-Chiche reported serving on a speakers bureau for Vifor Pharma and receiving grant/research support from Fresenius Medical Care. Some coauthors reported financial ties to many pharmaceutical companies. Dr. Richez said he has received fees for lectures or boards from GlaxoSmithKline, AstraZeneca, and Novartis. Dr. Moroni had no relevant disclosures.
AT THE EULAR 2022 CONGRESS
Schizophrenia patients in long-term facilities benefit from lower-dose antipsychotics
NEW ORLEANS –
“There is an argument by some experts in the field that state hospital populations represent a different set of patients who require higher antipsychotic dosages, with no alternative, but I don’t agree with that,” study lead author Mujeeb U. Shad, MD, GME-psychiatry program director and adjunct professor at the University of Nevada, Las Vegas, said in an interview.
In reducing doses, “patients appeared to blossom, becoming more active and less ‘zombie-like’; they started taking more interest in activities and their social [involvement] increased,” he said.
The study was among several presenting pros and cons of high antipsychotic doses at the 2022 annual meeting of the American Psychiatric Association.
Higher doses of antipsychotics are often relied upon when patients with acute psychosis fail to respond to standard treatment, however evidence supporting the approach is lacking.
And while some studies in fact show no benefit from the higher-dose maintenance therapy over conventional or even lower doses of antipsychotics, evidence regarding forensic patients hospitalized in long-term psychiatric facilities is also scant.
Meanwhile, the need to restore competency among those patients can be more pressing than normal.
“In a forensic population where executive cognitive function is one of the key elements to restore competency to stand trial, the continuation of high-dose therapy with excessive dopamine blockade may further compromise preexisting executive dysfunction to delay competency restoration,” Dr. Shad notes in the study.
The study describes a case series in which antipsychotic doses were lowered among 22 of Dr. Shad’s patients who had been determined to be incompetent to stand trial and referred to a state hospital to restore their competency.
With the objective of regaining the mental fitness to stand trial and being discharged from the facility, those on high doses of therapy, defined as a dose greater than 50% of the average package-insert dose, had their doses reduced to conventional dosages.
The approach led to as many as 68% of the patients being stabilized and discharged after having their competency restored, without symptom relapse, following an average antipsychotic dose reduction of 44%.
The average time to discharge following the dose reduction was just 2.3 months, after an average total hospitalization time of 11 months.
The shortest hospitalization durations (less than 7 months) were observed among those who did not receive changes in doses as they were already achieving efficacy with standard dosages.
Among two patients who were treated subtherapeutically, dose increases were required and they had the longest overall hospitalization (14.5 months)
Additional benefits of reduced dosages
Dr. Shad noted that, in addition to the earlier discharges, patients also had reductions in their polypharmacy, and in prolactin.
“We know that high prolactin level is such a huge problem, especially for female patients because it can cause osteoporosis, infertility, and abnormal menstruation, and the reductions in hyperprolactinemia can help reduce weight gain,” he said.
Dr. Shad added that he let some of those effects be his guide in making dose reductions.
“I was trying to gradually minimize the dose while monitoring the patients for relapse, and I used extrapyramidal symptoms and prolactin levels as my guide, looking for a sweet spot with the dosing,” he said.
“For example, if patients were taking an average of about 40-60 mg of a drug, I brought it down close to 20 mg, or close to the average package insert,” Dr. Shad said.
Key concerns among clinicians about reducing antipsychotic doses include the emergence of discontinuation or rebound symptoms, including psychosis, akathisia, or Parkinsonian symptoms, and studies, including a recent meta-analysis have supported those concerns, urging caution in reducing doses below standard levels.
However, Dr. Shad said his series suggests that reducing doses gradually while carefully monitoring extrapyramidal symptoms and prolactin levels may indeed pay off.
“They’re not the perfect guides, but they’re good guides, and with the right approach, [some] may be able to do this,” Dr. Shad said.
“However, the key to a successful dose reduction or discontinuation of an [antipsychotic medication] is to avoid abrupt discontinuation and follow a gradual dose reduction while monitoring symptoms and tolerability,” he said.
Commenting on the research, T. Scott Stroup, MD, a professor of psychiatry at Columbia University, New York, chimed in on the side of urging caution with higher doses and supporting possible benefits with the lower-dose approach.
“I agree that people who need antipsychotic medications should receive the lowest effective dose and that often this is identified by careful dose reduction,” he said in an interview.
Dr. Shad and Stroup had no disclosures to report.
NEW ORLEANS –
“There is an argument by some experts in the field that state hospital populations represent a different set of patients who require higher antipsychotic dosages, with no alternative, but I don’t agree with that,” study lead author Mujeeb U. Shad, MD, GME-psychiatry program director and adjunct professor at the University of Nevada, Las Vegas, said in an interview.
In reducing doses, “patients appeared to blossom, becoming more active and less ‘zombie-like’; they started taking more interest in activities and their social [involvement] increased,” he said.
The study was among several presenting pros and cons of high antipsychotic doses at the 2022 annual meeting of the American Psychiatric Association.
Higher doses of antipsychotics are often relied upon when patients with acute psychosis fail to respond to standard treatment, however evidence supporting the approach is lacking.
And while some studies in fact show no benefit from the higher-dose maintenance therapy over conventional or even lower doses of antipsychotics, evidence regarding forensic patients hospitalized in long-term psychiatric facilities is also scant.
Meanwhile, the need to restore competency among those patients can be more pressing than normal.
“In a forensic population where executive cognitive function is one of the key elements to restore competency to stand trial, the continuation of high-dose therapy with excessive dopamine blockade may further compromise preexisting executive dysfunction to delay competency restoration,” Dr. Shad notes in the study.
The study describes a case series in which antipsychotic doses were lowered among 22 of Dr. Shad’s patients who had been determined to be incompetent to stand trial and referred to a state hospital to restore their competency.
With the objective of regaining the mental fitness to stand trial and being discharged from the facility, those on high doses of therapy, defined as a dose greater than 50% of the average package-insert dose, had their doses reduced to conventional dosages.
The approach led to as many as 68% of the patients being stabilized and discharged after having their competency restored, without symptom relapse, following an average antipsychotic dose reduction of 44%.
The average time to discharge following the dose reduction was just 2.3 months, after an average total hospitalization time of 11 months.
The shortest hospitalization durations (less than 7 months) were observed among those who did not receive changes in doses as they were already achieving efficacy with standard dosages.
Among two patients who were treated subtherapeutically, dose increases were required and they had the longest overall hospitalization (14.5 months)
Additional benefits of reduced dosages
Dr. Shad noted that, in addition to the earlier discharges, patients also had reductions in their polypharmacy, and in prolactin.
“We know that high prolactin level is such a huge problem, especially for female patients because it can cause osteoporosis, infertility, and abnormal menstruation, and the reductions in hyperprolactinemia can help reduce weight gain,” he said.
Dr. Shad added that he let some of those effects be his guide in making dose reductions.
“I was trying to gradually minimize the dose while monitoring the patients for relapse, and I used extrapyramidal symptoms and prolactin levels as my guide, looking for a sweet spot with the dosing,” he said.
“For example, if patients were taking an average of about 40-60 mg of a drug, I brought it down close to 20 mg, or close to the average package insert,” Dr. Shad said.
Key concerns among clinicians about reducing antipsychotic doses include the emergence of discontinuation or rebound symptoms, including psychosis, akathisia, or Parkinsonian symptoms, and studies, including a recent meta-analysis have supported those concerns, urging caution in reducing doses below standard levels.
However, Dr. Shad said his series suggests that reducing doses gradually while carefully monitoring extrapyramidal symptoms and prolactin levels may indeed pay off.
“They’re not the perfect guides, but they’re good guides, and with the right approach, [some] may be able to do this,” Dr. Shad said.
“However, the key to a successful dose reduction or discontinuation of an [antipsychotic medication] is to avoid abrupt discontinuation and follow a gradual dose reduction while monitoring symptoms and tolerability,” he said.
Commenting on the research, T. Scott Stroup, MD, a professor of psychiatry at Columbia University, New York, chimed in on the side of urging caution with higher doses and supporting possible benefits with the lower-dose approach.
“I agree that people who need antipsychotic medications should receive the lowest effective dose and that often this is identified by careful dose reduction,” he said in an interview.
Dr. Shad and Stroup had no disclosures to report.
NEW ORLEANS –
“There is an argument by some experts in the field that state hospital populations represent a different set of patients who require higher antipsychotic dosages, with no alternative, but I don’t agree with that,” study lead author Mujeeb U. Shad, MD, GME-psychiatry program director and adjunct professor at the University of Nevada, Las Vegas, said in an interview.
In reducing doses, “patients appeared to blossom, becoming more active and less ‘zombie-like’; they started taking more interest in activities and their social [involvement] increased,” he said.
The study was among several presenting pros and cons of high antipsychotic doses at the 2022 annual meeting of the American Psychiatric Association.
Higher doses of antipsychotics are often relied upon when patients with acute psychosis fail to respond to standard treatment, however evidence supporting the approach is lacking.
And while some studies in fact show no benefit from the higher-dose maintenance therapy over conventional or even lower doses of antipsychotics, evidence regarding forensic patients hospitalized in long-term psychiatric facilities is also scant.
Meanwhile, the need to restore competency among those patients can be more pressing than normal.
“In a forensic population where executive cognitive function is one of the key elements to restore competency to stand trial, the continuation of high-dose therapy with excessive dopamine blockade may further compromise preexisting executive dysfunction to delay competency restoration,” Dr. Shad notes in the study.
The study describes a case series in which antipsychotic doses were lowered among 22 of Dr. Shad’s patients who had been determined to be incompetent to stand trial and referred to a state hospital to restore their competency.
With the objective of regaining the mental fitness to stand trial and being discharged from the facility, those on high doses of therapy, defined as a dose greater than 50% of the average package-insert dose, had their doses reduced to conventional dosages.
The approach led to as many as 68% of the patients being stabilized and discharged after having their competency restored, without symptom relapse, following an average antipsychotic dose reduction of 44%.
The average time to discharge following the dose reduction was just 2.3 months, after an average total hospitalization time of 11 months.
The shortest hospitalization durations (less than 7 months) were observed among those who did not receive changes in doses as they were already achieving efficacy with standard dosages.
Among two patients who were treated subtherapeutically, dose increases were required and they had the longest overall hospitalization (14.5 months)
Additional benefits of reduced dosages
Dr. Shad noted that, in addition to the earlier discharges, patients also had reductions in their polypharmacy, and in prolactin.
“We know that high prolactin level is such a huge problem, especially for female patients because it can cause osteoporosis, infertility, and abnormal menstruation, and the reductions in hyperprolactinemia can help reduce weight gain,” he said.
Dr. Shad added that he let some of those effects be his guide in making dose reductions.
“I was trying to gradually minimize the dose while monitoring the patients for relapse, and I used extrapyramidal symptoms and prolactin levels as my guide, looking for a sweet spot with the dosing,” he said.
“For example, if patients were taking an average of about 40-60 mg of a drug, I brought it down close to 20 mg, or close to the average package insert,” Dr. Shad said.
Key concerns among clinicians about reducing antipsychotic doses include the emergence of discontinuation or rebound symptoms, including psychosis, akathisia, or Parkinsonian symptoms, and studies, including a recent meta-analysis have supported those concerns, urging caution in reducing doses below standard levels.
However, Dr. Shad said his series suggests that reducing doses gradually while carefully monitoring extrapyramidal symptoms and prolactin levels may indeed pay off.
“They’re not the perfect guides, but they’re good guides, and with the right approach, [some] may be able to do this,” Dr. Shad said.
“However, the key to a successful dose reduction or discontinuation of an [antipsychotic medication] is to avoid abrupt discontinuation and follow a gradual dose reduction while monitoring symptoms and tolerability,” he said.
Commenting on the research, T. Scott Stroup, MD, a professor of psychiatry at Columbia University, New York, chimed in on the side of urging caution with higher doses and supporting possible benefits with the lower-dose approach.
“I agree that people who need antipsychotic medications should receive the lowest effective dose and that often this is identified by careful dose reduction,” he said in an interview.
Dr. Shad and Stroup had no disclosures to report.
FROM APA 2022
Using the skin to probe within: the promise of intradermal microdialysis
SAN DIEGO – When Lacy M. Alexander, PhD, began her career as a kinesiology researcher, she focused on the skin as a model of circulation for examining mechanisms of vascular function and dysfunction in diseases, as well as the influence of drug interventions.
“The skin is an accessible circulation; we see many of the same neural and endothelial pathways mediating vasodilation that we see throughout the entire vascular system,” Dr. Alexander, professor of kinesiology at Penn State University’s College of Health and Human Development, University Park, Pa., said during a lecture at the annual meeting of the American College for Sports Medicine.
The main . “This catheter has the ability to perfuse or infuse various substances into a bidirectional membrane,” Dr. Alexander explained. “This enables us to recover various substances into that catheter. We pair this with a measurement of skin blood flow with Doppler probes as well as the ability to control local temperature to either isolate reflex control of the human cutaneous circulation or elicit local changes in temperature to elicit vasodilation and vasoconstriction.”
In a 2005 article on evaluating the microcirculation in vascular disease, microvascular dysfunction is described as “a systemic disease process that occurs in a similar fashion in multiple tissue beds throughout the body”. Therefore, early identification of the mechanism leading to microvascular dysfunction is important, Dr. Alexander said. “We can also monitor the progression of disease and the progression of a given treatment if we have a noninvasive way to do that.”
A question that clinicians often ask Dr. Alexander is, do changes in forearm skin blood flow represent changes in, say, leg skin blood flow, or blood flow in other parts of the body? “The answer to that question is yes; we see similar changes in forearm skin that we see in other regions of the body,” she said. “We tend to use the forearm skin because there’s less UV damage, especially when we’re looking at questions related to human aging.”
Over the years, she and other investigators have used intradermal microdialysis to develop and refine many skin-specific approaches for examining endothelial function, including reactive hyperemia, direct drug delivery, local heating, whole body heating, local cooling, whole body cooling, and spectral analysis. For example, using this approach in the direct drug delivery realm, researchers have discovered that oral atorvastatin therapy restores cutaneous microvascular function by decreasing arginase activity in hypercholesterolemic middle-aged adults.
In more recent work using intradermal microdialysis, researchers have observed that peripheral microvascular function is impaired in adults with hypertension.
Another study using intradermal microdialysis found that 16 weeks of a sulfhydryl intervention improved endothelial function through nitric oxide and hydrogen sulfide-dependent mechanisms in adults with hypertension.
The technology has also helped to further understanding of nontraditional risk factors of microvascular dysfunction. In one study, researchers found that endothelium-dependent vasodilation is blunted in adults with major depressive disorder due to a reduced functional contribution of nitric oxide.
According to Dr. Alexander, a study being reviewed for publication found that microvascular endothelial function is impaired in women with endometriosis.
Also in 2019, a European Academy of Allergy and Clinical Immunology (EAACI) position paper on the use of intradermal microdialysis in investigations of the pathogenesis of chronic inflammatory skin diseases was published.
The broad focus of Dr. Alexander’s current projects includes examining the roles of arginase in nitric oxide synthase uncoupling in human vasculature with hypercholesterolemia and hypertension; inflammation-induced alteration in vasodilatory signaling with essential hypertension; the role of reactive oxygen species in altering vasoconstriction and vascular remodeling with hypertension, and the effects of common platelet inhibitors on microvascular function in human skin as they relate to basic mechanisms of skin blood flow and functional thermoregulatory outcomes. “The hope is that we can intervene with things like dietary and exercise interventions early on to mitigate this progression to avert cardiovascular disease,” she said.
Dr. Alexander disclosed that she has received research support from the National Heart, Lung, and Blood Institute, the National Dairy Council, the American College of Sports Medicine, and the American Heart Association.
SAN DIEGO – When Lacy M. Alexander, PhD, began her career as a kinesiology researcher, she focused on the skin as a model of circulation for examining mechanisms of vascular function and dysfunction in diseases, as well as the influence of drug interventions.
“The skin is an accessible circulation; we see many of the same neural and endothelial pathways mediating vasodilation that we see throughout the entire vascular system,” Dr. Alexander, professor of kinesiology at Penn State University’s College of Health and Human Development, University Park, Pa., said during a lecture at the annual meeting of the American College for Sports Medicine.
The main . “This catheter has the ability to perfuse or infuse various substances into a bidirectional membrane,” Dr. Alexander explained. “This enables us to recover various substances into that catheter. We pair this with a measurement of skin blood flow with Doppler probes as well as the ability to control local temperature to either isolate reflex control of the human cutaneous circulation or elicit local changes in temperature to elicit vasodilation and vasoconstriction.”
In a 2005 article on evaluating the microcirculation in vascular disease, microvascular dysfunction is described as “a systemic disease process that occurs in a similar fashion in multiple tissue beds throughout the body”. Therefore, early identification of the mechanism leading to microvascular dysfunction is important, Dr. Alexander said. “We can also monitor the progression of disease and the progression of a given treatment if we have a noninvasive way to do that.”
A question that clinicians often ask Dr. Alexander is, do changes in forearm skin blood flow represent changes in, say, leg skin blood flow, or blood flow in other parts of the body? “The answer to that question is yes; we see similar changes in forearm skin that we see in other regions of the body,” she said. “We tend to use the forearm skin because there’s less UV damage, especially when we’re looking at questions related to human aging.”
Over the years, she and other investigators have used intradermal microdialysis to develop and refine many skin-specific approaches for examining endothelial function, including reactive hyperemia, direct drug delivery, local heating, whole body heating, local cooling, whole body cooling, and spectral analysis. For example, using this approach in the direct drug delivery realm, researchers have discovered that oral atorvastatin therapy restores cutaneous microvascular function by decreasing arginase activity in hypercholesterolemic middle-aged adults.
In more recent work using intradermal microdialysis, researchers have observed that peripheral microvascular function is impaired in adults with hypertension.
Another study using intradermal microdialysis found that 16 weeks of a sulfhydryl intervention improved endothelial function through nitric oxide and hydrogen sulfide-dependent mechanisms in adults with hypertension.
The technology has also helped to further understanding of nontraditional risk factors of microvascular dysfunction. In one study, researchers found that endothelium-dependent vasodilation is blunted in adults with major depressive disorder due to a reduced functional contribution of nitric oxide.
According to Dr. Alexander, a study being reviewed for publication found that microvascular endothelial function is impaired in women with endometriosis.
Also in 2019, a European Academy of Allergy and Clinical Immunology (EAACI) position paper on the use of intradermal microdialysis in investigations of the pathogenesis of chronic inflammatory skin diseases was published.
The broad focus of Dr. Alexander’s current projects includes examining the roles of arginase in nitric oxide synthase uncoupling in human vasculature with hypercholesterolemia and hypertension; inflammation-induced alteration in vasodilatory signaling with essential hypertension; the role of reactive oxygen species in altering vasoconstriction and vascular remodeling with hypertension, and the effects of common platelet inhibitors on microvascular function in human skin as they relate to basic mechanisms of skin blood flow and functional thermoregulatory outcomes. “The hope is that we can intervene with things like dietary and exercise interventions early on to mitigate this progression to avert cardiovascular disease,” she said.
Dr. Alexander disclosed that she has received research support from the National Heart, Lung, and Blood Institute, the National Dairy Council, the American College of Sports Medicine, and the American Heart Association.
SAN DIEGO – When Lacy M. Alexander, PhD, began her career as a kinesiology researcher, she focused on the skin as a model of circulation for examining mechanisms of vascular function and dysfunction in diseases, as well as the influence of drug interventions.
“The skin is an accessible circulation; we see many of the same neural and endothelial pathways mediating vasodilation that we see throughout the entire vascular system,” Dr. Alexander, professor of kinesiology at Penn State University’s College of Health and Human Development, University Park, Pa., said during a lecture at the annual meeting of the American College for Sports Medicine.
The main . “This catheter has the ability to perfuse or infuse various substances into a bidirectional membrane,” Dr. Alexander explained. “This enables us to recover various substances into that catheter. We pair this with a measurement of skin blood flow with Doppler probes as well as the ability to control local temperature to either isolate reflex control of the human cutaneous circulation or elicit local changes in temperature to elicit vasodilation and vasoconstriction.”
In a 2005 article on evaluating the microcirculation in vascular disease, microvascular dysfunction is described as “a systemic disease process that occurs in a similar fashion in multiple tissue beds throughout the body”. Therefore, early identification of the mechanism leading to microvascular dysfunction is important, Dr. Alexander said. “We can also monitor the progression of disease and the progression of a given treatment if we have a noninvasive way to do that.”
A question that clinicians often ask Dr. Alexander is, do changes in forearm skin blood flow represent changes in, say, leg skin blood flow, or blood flow in other parts of the body? “The answer to that question is yes; we see similar changes in forearm skin that we see in other regions of the body,” she said. “We tend to use the forearm skin because there’s less UV damage, especially when we’re looking at questions related to human aging.”
Over the years, she and other investigators have used intradermal microdialysis to develop and refine many skin-specific approaches for examining endothelial function, including reactive hyperemia, direct drug delivery, local heating, whole body heating, local cooling, whole body cooling, and spectral analysis. For example, using this approach in the direct drug delivery realm, researchers have discovered that oral atorvastatin therapy restores cutaneous microvascular function by decreasing arginase activity in hypercholesterolemic middle-aged adults.
In more recent work using intradermal microdialysis, researchers have observed that peripheral microvascular function is impaired in adults with hypertension.
Another study using intradermal microdialysis found that 16 weeks of a sulfhydryl intervention improved endothelial function through nitric oxide and hydrogen sulfide-dependent mechanisms in adults with hypertension.
The technology has also helped to further understanding of nontraditional risk factors of microvascular dysfunction. In one study, researchers found that endothelium-dependent vasodilation is blunted in adults with major depressive disorder due to a reduced functional contribution of nitric oxide.
According to Dr. Alexander, a study being reviewed for publication found that microvascular endothelial function is impaired in women with endometriosis.
Also in 2019, a European Academy of Allergy and Clinical Immunology (EAACI) position paper on the use of intradermal microdialysis in investigations of the pathogenesis of chronic inflammatory skin diseases was published.
The broad focus of Dr. Alexander’s current projects includes examining the roles of arginase in nitric oxide synthase uncoupling in human vasculature with hypercholesterolemia and hypertension; inflammation-induced alteration in vasodilatory signaling with essential hypertension; the role of reactive oxygen species in altering vasoconstriction and vascular remodeling with hypertension, and the effects of common platelet inhibitors on microvascular function in human skin as they relate to basic mechanisms of skin blood flow and functional thermoregulatory outcomes. “The hope is that we can intervene with things like dietary and exercise interventions early on to mitigate this progression to avert cardiovascular disease,” she said.
Dr. Alexander disclosed that she has received research support from the National Heart, Lung, and Blood Institute, the National Dairy Council, the American College of Sports Medicine, and the American Heart Association.
AT ACSM 2022