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Once-daily nifedipine sufficient for hypertension in pregnancy
BALTIMORE – , according to research presented at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists.*
The findings suggest that starting patients on a once-daily 60-mg dose is therefore reasonable, Isabelle Band, BA, a medical student at the Icahn School of Medicine at Mount Sinai, New York, told attendees. Ms. Band said in an interview that there does not appear to be a consensus on the standard of care for nifedipine dosing regimen in this population but that previous in vitro studies have shown increased metabolism of nifedipine in a physiologic state that mimics pregnancy.
“I’ve spoken to some colleagues here who say that they frequently have this debate of which dosing regimen to go with,” Ms. Band said. “I was pleasantly surprised that there was no significant difference between the two dosing regimens because once-daily dosing is less burdensome for patients and will likely improve compliance and convenience for patients.” An additional benefit of once-daily dosing relates to payers because anecdotal reports suggest insurance companies do not tend to approve twice-daily dosing as readily as once-daily dosing, Ms. Band added.
Ms. Band and her colleagues conducted a retrospective chart review of all patients with hypertensive disorders of pregnancy who were admitted to the Mount Sinai Health System between Jan. 1, 2015, and April 30, 2021, and were prescribed nifedipine in a once-daily (60-mg) or twice-daily (two 30-mg) dose. They excluded patients with renal disease and those already taking hypertensives prior to admission.
Among 237 patients who met the criteria, 59% received 60 mg in a twice-daily 30-mg dose, and 41% received 60 mg in a once-daily dose. Among patients requiring an up titration, two-thirds (67%) needed an increase in the nifedipine dose – the most common adjustment – and 20.7% needed both an increase in nifedipine and an additional medication.
The researchers observed no statistically significant differences in the proportion of patients who required a dose increase or an additional antihypertensive in the group taking the twice-daily dose (33.8%) or those receiving the once-daily dose (35.7%). This finding remained statistically insignificant after controlling for gestational diabetes, delivery mode, administration of Lasix, and receipt of emergency antihypertensive treatment (P = .71). The time that passed before patients needed a dose increase was also statistically similar between the groups: 24.3 hours in the twice-daily group and 24 hours in the once-daily group (P = .49).
There were no statistically significant differences in the need for a dose increase or an additional hypertensive agent based on race, ethnicity, body mass index, or history of preeclampsia as well. However, 24.5% of those taking the once-daily dosage had a history of preeclampsia, compared with 7.2% of those taking the twice-daily dosage (P < .001). Further, the median number of prior pregnancies was two in the twice-daily group versus three in the once-daily group (P = .002).
The authors found no significant difference between the two dosing groups in the need for emergency hypertensive treatment after reaching the study dose or in readmission for blood pressure control. In the twice-daily group, 21.6% of patients needed emergency antihypertensive treatment, compared with 14.3% in the once-daily group (P = .19). Readmission was necessary for 7.2% of the twice-daily group and 6.1% of the once-daily group (P > .99).
A subgroup analysis compared those who started nifedipine antepartum and those who started it post partum, but again, no significant difference in the dosing regimens existed.
Michael Ruma, MD, a maternal-fetal medicine specialist at Perinatal Associates of New Mexico in Albuquerque, was not involved in the study and said he welcomed the results.
“We have too many choices in medicine, so we need to just simplify the plan of attack,” reducing the number of things that clinicians need to think about, Dr. Ruma said in an interview. “A singular dose is always easiest for the patient, always easier for nursing staff, and usually, if you can optimize the dosing, that’s the best approach.”
Annabeth Brewton, MD, a resident at University of Tennessee, Knoxville, agreed, adding that new parents already have a lot going on immediately post partum.
“They’re going to be breastfeeding, they’re not sleeping, they’re going to forget to take that [second] dose,” Dr. Brewton said.
Ms. Band and Dr. Brewton had no disclosures. Dr. Ruma reported consulting and speaking for Hologic and consulting for Philips Ultrasound.
Correction, 5/24/23: An earlier version of this article misstated the daily doses of nifedipine. The study compared a
BALTIMORE – , according to research presented at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists.*
The findings suggest that starting patients on a once-daily 60-mg dose is therefore reasonable, Isabelle Band, BA, a medical student at the Icahn School of Medicine at Mount Sinai, New York, told attendees. Ms. Band said in an interview that there does not appear to be a consensus on the standard of care for nifedipine dosing regimen in this population but that previous in vitro studies have shown increased metabolism of nifedipine in a physiologic state that mimics pregnancy.
“I’ve spoken to some colleagues here who say that they frequently have this debate of which dosing regimen to go with,” Ms. Band said. “I was pleasantly surprised that there was no significant difference between the two dosing regimens because once-daily dosing is less burdensome for patients and will likely improve compliance and convenience for patients.” An additional benefit of once-daily dosing relates to payers because anecdotal reports suggest insurance companies do not tend to approve twice-daily dosing as readily as once-daily dosing, Ms. Band added.
Ms. Band and her colleagues conducted a retrospective chart review of all patients with hypertensive disorders of pregnancy who were admitted to the Mount Sinai Health System between Jan. 1, 2015, and April 30, 2021, and were prescribed nifedipine in a once-daily (60-mg) or twice-daily (two 30-mg) dose. They excluded patients with renal disease and those already taking hypertensives prior to admission.
Among 237 patients who met the criteria, 59% received 60 mg in a twice-daily 30-mg dose, and 41% received 60 mg in a once-daily dose. Among patients requiring an up titration, two-thirds (67%) needed an increase in the nifedipine dose – the most common adjustment – and 20.7% needed both an increase in nifedipine and an additional medication.
The researchers observed no statistically significant differences in the proportion of patients who required a dose increase or an additional antihypertensive in the group taking the twice-daily dose (33.8%) or those receiving the once-daily dose (35.7%). This finding remained statistically insignificant after controlling for gestational diabetes, delivery mode, administration of Lasix, and receipt of emergency antihypertensive treatment (P = .71). The time that passed before patients needed a dose increase was also statistically similar between the groups: 24.3 hours in the twice-daily group and 24 hours in the once-daily group (P = .49).
There were no statistically significant differences in the need for a dose increase or an additional hypertensive agent based on race, ethnicity, body mass index, or history of preeclampsia as well. However, 24.5% of those taking the once-daily dosage had a history of preeclampsia, compared with 7.2% of those taking the twice-daily dosage (P < .001). Further, the median number of prior pregnancies was two in the twice-daily group versus three in the once-daily group (P = .002).
The authors found no significant difference between the two dosing groups in the need for emergency hypertensive treatment after reaching the study dose or in readmission for blood pressure control. In the twice-daily group, 21.6% of patients needed emergency antihypertensive treatment, compared with 14.3% in the once-daily group (P = .19). Readmission was necessary for 7.2% of the twice-daily group and 6.1% of the once-daily group (P > .99).
A subgroup analysis compared those who started nifedipine antepartum and those who started it post partum, but again, no significant difference in the dosing regimens existed.
Michael Ruma, MD, a maternal-fetal medicine specialist at Perinatal Associates of New Mexico in Albuquerque, was not involved in the study and said he welcomed the results.
“We have too many choices in medicine, so we need to just simplify the plan of attack,” reducing the number of things that clinicians need to think about, Dr. Ruma said in an interview. “A singular dose is always easiest for the patient, always easier for nursing staff, and usually, if you can optimize the dosing, that’s the best approach.”
Annabeth Brewton, MD, a resident at University of Tennessee, Knoxville, agreed, adding that new parents already have a lot going on immediately post partum.
“They’re going to be breastfeeding, they’re not sleeping, they’re going to forget to take that [second] dose,” Dr. Brewton said.
Ms. Band and Dr. Brewton had no disclosures. Dr. Ruma reported consulting and speaking for Hologic and consulting for Philips Ultrasound.
Correction, 5/24/23: An earlier version of this article misstated the daily doses of nifedipine. The study compared a
BALTIMORE – , according to research presented at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists.*
The findings suggest that starting patients on a once-daily 60-mg dose is therefore reasonable, Isabelle Band, BA, a medical student at the Icahn School of Medicine at Mount Sinai, New York, told attendees. Ms. Band said in an interview that there does not appear to be a consensus on the standard of care for nifedipine dosing regimen in this population but that previous in vitro studies have shown increased metabolism of nifedipine in a physiologic state that mimics pregnancy.
“I’ve spoken to some colleagues here who say that they frequently have this debate of which dosing regimen to go with,” Ms. Band said. “I was pleasantly surprised that there was no significant difference between the two dosing regimens because once-daily dosing is less burdensome for patients and will likely improve compliance and convenience for patients.” An additional benefit of once-daily dosing relates to payers because anecdotal reports suggest insurance companies do not tend to approve twice-daily dosing as readily as once-daily dosing, Ms. Band added.
Ms. Band and her colleagues conducted a retrospective chart review of all patients with hypertensive disorders of pregnancy who were admitted to the Mount Sinai Health System between Jan. 1, 2015, and April 30, 2021, and were prescribed nifedipine in a once-daily (60-mg) or twice-daily (two 30-mg) dose. They excluded patients with renal disease and those already taking hypertensives prior to admission.
Among 237 patients who met the criteria, 59% received 60 mg in a twice-daily 30-mg dose, and 41% received 60 mg in a once-daily dose. Among patients requiring an up titration, two-thirds (67%) needed an increase in the nifedipine dose – the most common adjustment – and 20.7% needed both an increase in nifedipine and an additional medication.
The researchers observed no statistically significant differences in the proportion of patients who required a dose increase or an additional antihypertensive in the group taking the twice-daily dose (33.8%) or those receiving the once-daily dose (35.7%). This finding remained statistically insignificant after controlling for gestational diabetes, delivery mode, administration of Lasix, and receipt of emergency antihypertensive treatment (P = .71). The time that passed before patients needed a dose increase was also statistically similar between the groups: 24.3 hours in the twice-daily group and 24 hours in the once-daily group (P = .49).
There were no statistically significant differences in the need for a dose increase or an additional hypertensive agent based on race, ethnicity, body mass index, or history of preeclampsia as well. However, 24.5% of those taking the once-daily dosage had a history of preeclampsia, compared with 7.2% of those taking the twice-daily dosage (P < .001). Further, the median number of prior pregnancies was two in the twice-daily group versus three in the once-daily group (P = .002).
The authors found no significant difference between the two dosing groups in the need for emergency hypertensive treatment after reaching the study dose or in readmission for blood pressure control. In the twice-daily group, 21.6% of patients needed emergency antihypertensive treatment, compared with 14.3% in the once-daily group (P = .19). Readmission was necessary for 7.2% of the twice-daily group and 6.1% of the once-daily group (P > .99).
A subgroup analysis compared those who started nifedipine antepartum and those who started it post partum, but again, no significant difference in the dosing regimens existed.
Michael Ruma, MD, a maternal-fetal medicine specialist at Perinatal Associates of New Mexico in Albuquerque, was not involved in the study and said he welcomed the results.
“We have too many choices in medicine, so we need to just simplify the plan of attack,” reducing the number of things that clinicians need to think about, Dr. Ruma said in an interview. “A singular dose is always easiest for the patient, always easier for nursing staff, and usually, if you can optimize the dosing, that’s the best approach.”
Annabeth Brewton, MD, a resident at University of Tennessee, Knoxville, agreed, adding that new parents already have a lot going on immediately post partum.
“They’re going to be breastfeeding, they’re not sleeping, they’re going to forget to take that [second] dose,” Dr. Brewton said.
Ms. Band and Dr. Brewton had no disclosures. Dr. Ruma reported consulting and speaking for Hologic and consulting for Philips Ultrasound.
Correction, 5/24/23: An earlier version of this article misstated the daily doses of nifedipine. The study compared a
AT ACOG 2023
Machine-learning model improves MI diagnosis
Use of a machine-learning model that incorporates information from a single troponin test as well as other clinical data was superior to current practice as an aid to the diagnosis of myocardial infarction in the emergency department in a new study.
“Our results suggest that and free up space in the emergency department,” senior author Nicholas L. Mills, MD, University of Edinburgh, Scotland, said in an interview.
“And, perhaps even more importantly, use of this model could also increase the proportion of patients who are correctly identified as at a high probability of having an MI,” he added.
The study was published online in Nature Medicine.
The authors explained that at present, the likelihood of an MI diagnosis for patients presenting to the emergency department with chest pain is based on a fixed troponin threshold in serial tests at specific time points, but there are several problems with this approach.
First, a fixed troponin threshold is generally used for all patients, which does not account for age, sex, or comorbidities that are known to influence cardiac troponin concentrations. Second, the need to perform tests at specific time points for serial testing can be challenging in busy emergency departments.
And third, patients are categorized as being at low, intermediate, or high risk of MI on the basis of troponin thresholds alone, and the test does not take into account other important factors, such as the time of symptom onset or findings on the electrocardiogram.
“Our current practice of using the same threshold to rule in and rule out an MI for everyone, regardless of whether they are an 18-year-old female without a history of heart disease or an 85-year-old male with known heart failure, doesn’t perform well, and there’s a significant risk of misdiagnosis. There is also a high likelihood for inequalities in care, particularly between men and women,” Dr. Mills said.
The current study evaluated whether use of a machine learning model known as CoDE-ACS to guide decision-making could overcome some of these challenges.
The machine learning model assesses the whole spectrum of troponin levels as a continuous variable (rather than use of a single threshold) and turns this measurement into a probability that an individual patient is having an MI after accounting for other factors, including age, sex, comorbidities, and time from symptom onset.
For the current study, the CoDE-ACS model was trained in 10,000 patients with suspected acute coronary syndrome (ACS) who presented to 10 hospitals in Scotland as part of the High-STEACS trial evaluating the implementation of a high-sensitivity cardiac troponin I assay. The results were then validated in another 10,000 patients from six countries around the world.
“Using this model, the patient can have a troponin test on arrival at the emergency department. The other information on age, sex, clinical history, and time since symptom onset is keyed in, and it gives a probability on a scale of 0–100 as to whether the patient is having an MI,” Dr. Mills noted.
“It also has the capacity to incorporate more information over time. So, if there is a second troponin measurement made, then the model automatically refines the probability score,” he added.
The current study showed that use of the CoDE-ACS model identified more patients at presentation as having a low probability of having an MI than fixed cardiac troponin thresholds (61% vs. 27%) with a similar negative predictive value.
It also identified fewer patients as having a high probability of having an MI (10% vs. 16%) with a greater positive predictive value.
Among patients who were identified as having a low probability of MI, the rate of cardiac death was lower than the rate among those with intermediate or high probability at 30 days (0.1% vs. 0.5% and 1.8%) and 1 year (0.3% vs. 2.8% and 4.2%).
“The results show that the machine learning model doubles the proportion of patients who can be discharged with a single test compared to the current practice of using the threshold approach. It really is a game changer in terms of its potential to improve health efficiency,” Dr. Mills said.
In terms of ruling patients in as possibly having an MI, he pointed out that troponin levels are increased in patients with a wide range of other conditions, including heart failure, kidney failure, and atrial fibrillation.
“When using the threshold approach, only one in four patients with an elevated troponin level will actually be having an MI, and that leads to confusion,” he said. “This model takes into consideration these other conditions and so it can correctly identify three out of four patients with a high probability of having an MI. We can therefore be more confident that it is appropriate to refer those patients to cardiology and save a lot of potentially unnecessary investigations and treatments in the others.”
Dr. Mills said the model also seems to work when assessing patients early on.
“Around one-third of patients present within 3 hours of symptom onset, and actually these are a high-risk group because people who have genuine cardiac pain are normally extremely uncomfortable and tend to present quickly. Current guidelines require that we do two tests in all these individuals, but this new model incorporates the time of symptom onset into its estimates of probability and therefore allows us to rule out patients even when they present very early.”
He reported that a second test is required in only one in five patients – those whose first test indicated intermediate probability.
“The second test allows us to refine the probability further, allowing us to rule another half of those patients out. We are then left with a small proportion of patients – about 1 in 10 – who remain of intermediate probability and will require additional clinical judgment.”
Should improve inequities in MI diagnosis
Dr. Mills said the CoDE-ACS model will improve current inequities in MI diagnosis, because of which MI is underrecognized in women and younger people.
“Women have troponin concentrations that are half those of men, and although sex-specific troponin thresholds are recommended in the guidelines, they are not widely used. This automatically leads to underrecognition of heart disease in women. But this new machine learning model performs identically in men and women because it has been trained to recognize the different normal levels in men and women,” he explained.
“It will also help us not to underdiagnose MI in younger people who often have a less classical presentation of MI, and they also generally have very low concentrations of troponin, so any increase in troponin way below the current diagnostic threshold may be very relevant to their risk,” he added.
The researchers are planning a randomized trial of the new model to demonstrate the impact it could have on equality of care and overcrowding in the emergency department. In the trial, patients will be randomly assigned to undergo decision-making on the basis of troponin thresholds (current practice) or to undergo decision-making through the CoDE-ACS model.
“The hope is that this trial will show reductions in unnecessary hospital admissions and length of stay in the emergency department,” Dr. Mills said. Results are expected sometime next year.
“This algorithm is very well trained. It has learned on 20,000 patients, so it has a lot more experience than I have, and I have been a professor of cardiology for 20 years,” Dr. Mills said.
He said he believes these models will get even smarter in the future as more data are added.
“I think the future for good decision-making in emergency care will be informed by clinical decision support from well-trained machine learning algorithms and they will help us guide not just the diagnosis of MI but also heart failure and other important cardiac conditions,” he said.
‘Elegant and exciting’ data
Commenting on the study, John W. McEvoy, MB, University of Galway, Ireland, said: “These are elegant and exciting data; however, the inputs into the machine learning algorithm include all the necessary information to actually diagnose MI. So why predict MI, when a human diagnosis can just be made directly? The answer to this question may depend on whether we trust machines more than humans.”
Dr. Mills noted that clinical judgment will always be an important part of MI diagnosis.
“Currently, using the troponin threshold approach, experienced clinicians will be able to nuance the results, but invariably, there is disagreement on this, and this can be a major source of tension within clinical care. By providing more individualized information, this will help enormously in the decision-making process,” he said.
“This model is not about replacing clinical decision-making. It’s more about augmenting decision-making and giving clinicians guidance to be able to improve efficiency and reduce inequality,” he added.
The study was funded with support from the National Institute for Health Research and NHSX, the British Heart Foundation, and Wellcome Leap. Dr. Mills has received honoraria or consultancy from Abbott Diagnostics, Roche Diagnostics, Siemens Healthineers, and LumiraDx. He is employed by the University of Edinburgh, which has filed a patent on the Collaboration for the Diagnosis and Evaluation of Acute Coronary Syndrome score.
A version of this article first appeared on Medscape.com.
Use of a machine-learning model that incorporates information from a single troponin test as well as other clinical data was superior to current practice as an aid to the diagnosis of myocardial infarction in the emergency department in a new study.
“Our results suggest that and free up space in the emergency department,” senior author Nicholas L. Mills, MD, University of Edinburgh, Scotland, said in an interview.
“And, perhaps even more importantly, use of this model could also increase the proportion of patients who are correctly identified as at a high probability of having an MI,” he added.
The study was published online in Nature Medicine.
The authors explained that at present, the likelihood of an MI diagnosis for patients presenting to the emergency department with chest pain is based on a fixed troponin threshold in serial tests at specific time points, but there are several problems with this approach.
First, a fixed troponin threshold is generally used for all patients, which does not account for age, sex, or comorbidities that are known to influence cardiac troponin concentrations. Second, the need to perform tests at specific time points for serial testing can be challenging in busy emergency departments.
And third, patients are categorized as being at low, intermediate, or high risk of MI on the basis of troponin thresholds alone, and the test does not take into account other important factors, such as the time of symptom onset or findings on the electrocardiogram.
“Our current practice of using the same threshold to rule in and rule out an MI for everyone, regardless of whether they are an 18-year-old female without a history of heart disease or an 85-year-old male with known heart failure, doesn’t perform well, and there’s a significant risk of misdiagnosis. There is also a high likelihood for inequalities in care, particularly between men and women,” Dr. Mills said.
The current study evaluated whether use of a machine learning model known as CoDE-ACS to guide decision-making could overcome some of these challenges.
The machine learning model assesses the whole spectrum of troponin levels as a continuous variable (rather than use of a single threshold) and turns this measurement into a probability that an individual patient is having an MI after accounting for other factors, including age, sex, comorbidities, and time from symptom onset.
For the current study, the CoDE-ACS model was trained in 10,000 patients with suspected acute coronary syndrome (ACS) who presented to 10 hospitals in Scotland as part of the High-STEACS trial evaluating the implementation of a high-sensitivity cardiac troponin I assay. The results were then validated in another 10,000 patients from six countries around the world.
“Using this model, the patient can have a troponin test on arrival at the emergency department. The other information on age, sex, clinical history, and time since symptom onset is keyed in, and it gives a probability on a scale of 0–100 as to whether the patient is having an MI,” Dr. Mills noted.
“It also has the capacity to incorporate more information over time. So, if there is a second troponin measurement made, then the model automatically refines the probability score,” he added.
The current study showed that use of the CoDE-ACS model identified more patients at presentation as having a low probability of having an MI than fixed cardiac troponin thresholds (61% vs. 27%) with a similar negative predictive value.
It also identified fewer patients as having a high probability of having an MI (10% vs. 16%) with a greater positive predictive value.
Among patients who were identified as having a low probability of MI, the rate of cardiac death was lower than the rate among those with intermediate or high probability at 30 days (0.1% vs. 0.5% and 1.8%) and 1 year (0.3% vs. 2.8% and 4.2%).
“The results show that the machine learning model doubles the proportion of patients who can be discharged with a single test compared to the current practice of using the threshold approach. It really is a game changer in terms of its potential to improve health efficiency,” Dr. Mills said.
In terms of ruling patients in as possibly having an MI, he pointed out that troponin levels are increased in patients with a wide range of other conditions, including heart failure, kidney failure, and atrial fibrillation.
“When using the threshold approach, only one in four patients with an elevated troponin level will actually be having an MI, and that leads to confusion,” he said. “This model takes into consideration these other conditions and so it can correctly identify three out of four patients with a high probability of having an MI. We can therefore be more confident that it is appropriate to refer those patients to cardiology and save a lot of potentially unnecessary investigations and treatments in the others.”
Dr. Mills said the model also seems to work when assessing patients early on.
“Around one-third of patients present within 3 hours of symptom onset, and actually these are a high-risk group because people who have genuine cardiac pain are normally extremely uncomfortable and tend to present quickly. Current guidelines require that we do two tests in all these individuals, but this new model incorporates the time of symptom onset into its estimates of probability and therefore allows us to rule out patients even when they present very early.”
He reported that a second test is required in only one in five patients – those whose first test indicated intermediate probability.
“The second test allows us to refine the probability further, allowing us to rule another half of those patients out. We are then left with a small proportion of patients – about 1 in 10 – who remain of intermediate probability and will require additional clinical judgment.”
Should improve inequities in MI diagnosis
Dr. Mills said the CoDE-ACS model will improve current inequities in MI diagnosis, because of which MI is underrecognized in women and younger people.
“Women have troponin concentrations that are half those of men, and although sex-specific troponin thresholds are recommended in the guidelines, they are not widely used. This automatically leads to underrecognition of heart disease in women. But this new machine learning model performs identically in men and women because it has been trained to recognize the different normal levels in men and women,” he explained.
“It will also help us not to underdiagnose MI in younger people who often have a less classical presentation of MI, and they also generally have very low concentrations of troponin, so any increase in troponin way below the current diagnostic threshold may be very relevant to their risk,” he added.
The researchers are planning a randomized trial of the new model to demonstrate the impact it could have on equality of care and overcrowding in the emergency department. In the trial, patients will be randomly assigned to undergo decision-making on the basis of troponin thresholds (current practice) or to undergo decision-making through the CoDE-ACS model.
“The hope is that this trial will show reductions in unnecessary hospital admissions and length of stay in the emergency department,” Dr. Mills said. Results are expected sometime next year.
“This algorithm is very well trained. It has learned on 20,000 patients, so it has a lot more experience than I have, and I have been a professor of cardiology for 20 years,” Dr. Mills said.
He said he believes these models will get even smarter in the future as more data are added.
“I think the future for good decision-making in emergency care will be informed by clinical decision support from well-trained machine learning algorithms and they will help us guide not just the diagnosis of MI but also heart failure and other important cardiac conditions,” he said.
‘Elegant and exciting’ data
Commenting on the study, John W. McEvoy, MB, University of Galway, Ireland, said: “These are elegant and exciting data; however, the inputs into the machine learning algorithm include all the necessary information to actually diagnose MI. So why predict MI, when a human diagnosis can just be made directly? The answer to this question may depend on whether we trust machines more than humans.”
Dr. Mills noted that clinical judgment will always be an important part of MI diagnosis.
“Currently, using the troponin threshold approach, experienced clinicians will be able to nuance the results, but invariably, there is disagreement on this, and this can be a major source of tension within clinical care. By providing more individualized information, this will help enormously in the decision-making process,” he said.
“This model is not about replacing clinical decision-making. It’s more about augmenting decision-making and giving clinicians guidance to be able to improve efficiency and reduce inequality,” he added.
The study was funded with support from the National Institute for Health Research and NHSX, the British Heart Foundation, and Wellcome Leap. Dr. Mills has received honoraria or consultancy from Abbott Diagnostics, Roche Diagnostics, Siemens Healthineers, and LumiraDx. He is employed by the University of Edinburgh, which has filed a patent on the Collaboration for the Diagnosis and Evaluation of Acute Coronary Syndrome score.
A version of this article first appeared on Medscape.com.
Use of a machine-learning model that incorporates information from a single troponin test as well as other clinical data was superior to current practice as an aid to the diagnosis of myocardial infarction in the emergency department in a new study.
“Our results suggest that and free up space in the emergency department,” senior author Nicholas L. Mills, MD, University of Edinburgh, Scotland, said in an interview.
“And, perhaps even more importantly, use of this model could also increase the proportion of patients who are correctly identified as at a high probability of having an MI,” he added.
The study was published online in Nature Medicine.
The authors explained that at present, the likelihood of an MI diagnosis for patients presenting to the emergency department with chest pain is based on a fixed troponin threshold in serial tests at specific time points, but there are several problems with this approach.
First, a fixed troponin threshold is generally used for all patients, which does not account for age, sex, or comorbidities that are known to influence cardiac troponin concentrations. Second, the need to perform tests at specific time points for serial testing can be challenging in busy emergency departments.
And third, patients are categorized as being at low, intermediate, or high risk of MI on the basis of troponin thresholds alone, and the test does not take into account other important factors, such as the time of symptom onset or findings on the electrocardiogram.
“Our current practice of using the same threshold to rule in and rule out an MI for everyone, regardless of whether they are an 18-year-old female without a history of heart disease or an 85-year-old male with known heart failure, doesn’t perform well, and there’s a significant risk of misdiagnosis. There is also a high likelihood for inequalities in care, particularly between men and women,” Dr. Mills said.
The current study evaluated whether use of a machine learning model known as CoDE-ACS to guide decision-making could overcome some of these challenges.
The machine learning model assesses the whole spectrum of troponin levels as a continuous variable (rather than use of a single threshold) and turns this measurement into a probability that an individual patient is having an MI after accounting for other factors, including age, sex, comorbidities, and time from symptom onset.
For the current study, the CoDE-ACS model was trained in 10,000 patients with suspected acute coronary syndrome (ACS) who presented to 10 hospitals in Scotland as part of the High-STEACS trial evaluating the implementation of a high-sensitivity cardiac troponin I assay. The results were then validated in another 10,000 patients from six countries around the world.
“Using this model, the patient can have a troponin test on arrival at the emergency department. The other information on age, sex, clinical history, and time since symptom onset is keyed in, and it gives a probability on a scale of 0–100 as to whether the patient is having an MI,” Dr. Mills noted.
“It also has the capacity to incorporate more information over time. So, if there is a second troponin measurement made, then the model automatically refines the probability score,” he added.
The current study showed that use of the CoDE-ACS model identified more patients at presentation as having a low probability of having an MI than fixed cardiac troponin thresholds (61% vs. 27%) with a similar negative predictive value.
It also identified fewer patients as having a high probability of having an MI (10% vs. 16%) with a greater positive predictive value.
Among patients who were identified as having a low probability of MI, the rate of cardiac death was lower than the rate among those with intermediate or high probability at 30 days (0.1% vs. 0.5% and 1.8%) and 1 year (0.3% vs. 2.8% and 4.2%).
“The results show that the machine learning model doubles the proportion of patients who can be discharged with a single test compared to the current practice of using the threshold approach. It really is a game changer in terms of its potential to improve health efficiency,” Dr. Mills said.
In terms of ruling patients in as possibly having an MI, he pointed out that troponin levels are increased in patients with a wide range of other conditions, including heart failure, kidney failure, and atrial fibrillation.
“When using the threshold approach, only one in four patients with an elevated troponin level will actually be having an MI, and that leads to confusion,” he said. “This model takes into consideration these other conditions and so it can correctly identify three out of four patients with a high probability of having an MI. We can therefore be more confident that it is appropriate to refer those patients to cardiology and save a lot of potentially unnecessary investigations and treatments in the others.”
Dr. Mills said the model also seems to work when assessing patients early on.
“Around one-third of patients present within 3 hours of symptom onset, and actually these are a high-risk group because people who have genuine cardiac pain are normally extremely uncomfortable and tend to present quickly. Current guidelines require that we do two tests in all these individuals, but this new model incorporates the time of symptom onset into its estimates of probability and therefore allows us to rule out patients even when they present very early.”
He reported that a second test is required in only one in five patients – those whose first test indicated intermediate probability.
“The second test allows us to refine the probability further, allowing us to rule another half of those patients out. We are then left with a small proportion of patients – about 1 in 10 – who remain of intermediate probability and will require additional clinical judgment.”
Should improve inequities in MI diagnosis
Dr. Mills said the CoDE-ACS model will improve current inequities in MI diagnosis, because of which MI is underrecognized in women and younger people.
“Women have troponin concentrations that are half those of men, and although sex-specific troponin thresholds are recommended in the guidelines, they are not widely used. This automatically leads to underrecognition of heart disease in women. But this new machine learning model performs identically in men and women because it has been trained to recognize the different normal levels in men and women,” he explained.
“It will also help us not to underdiagnose MI in younger people who often have a less classical presentation of MI, and they also generally have very low concentrations of troponin, so any increase in troponin way below the current diagnostic threshold may be very relevant to their risk,” he added.
The researchers are planning a randomized trial of the new model to demonstrate the impact it could have on equality of care and overcrowding in the emergency department. In the trial, patients will be randomly assigned to undergo decision-making on the basis of troponin thresholds (current practice) or to undergo decision-making through the CoDE-ACS model.
“The hope is that this trial will show reductions in unnecessary hospital admissions and length of stay in the emergency department,” Dr. Mills said. Results are expected sometime next year.
“This algorithm is very well trained. It has learned on 20,000 patients, so it has a lot more experience than I have, and I have been a professor of cardiology for 20 years,” Dr. Mills said.
He said he believes these models will get even smarter in the future as more data are added.
“I think the future for good decision-making in emergency care will be informed by clinical decision support from well-trained machine learning algorithms and they will help us guide not just the diagnosis of MI but also heart failure and other important cardiac conditions,” he said.
‘Elegant and exciting’ data
Commenting on the study, John W. McEvoy, MB, University of Galway, Ireland, said: “These are elegant and exciting data; however, the inputs into the machine learning algorithm include all the necessary information to actually diagnose MI. So why predict MI, when a human diagnosis can just be made directly? The answer to this question may depend on whether we trust machines more than humans.”
Dr. Mills noted that clinical judgment will always be an important part of MI diagnosis.
“Currently, using the troponin threshold approach, experienced clinicians will be able to nuance the results, but invariably, there is disagreement on this, and this can be a major source of tension within clinical care. By providing more individualized information, this will help enormously in the decision-making process,” he said.
“This model is not about replacing clinical decision-making. It’s more about augmenting decision-making and giving clinicians guidance to be able to improve efficiency and reduce inequality,” he added.
The study was funded with support from the National Institute for Health Research and NHSX, the British Heart Foundation, and Wellcome Leap. Dr. Mills has received honoraria or consultancy from Abbott Diagnostics, Roche Diagnostics, Siemens Healthineers, and LumiraDx. He is employed by the University of Edinburgh, which has filed a patent on the Collaboration for the Diagnosis and Evaluation of Acute Coronary Syndrome score.
A version of this article first appeared on Medscape.com.
FROM NATURE MEDICINE
Eating disorders in children is a global public health emergency
The high figures are concerning from a public health perspective and highlight the need to implement strategies for preventing eating disorders.
These disorders include anorexia nervosa, bulimia nervosa, binge eating disorder, and eating disorder–not otherwise specified. The prevalence of these disorders in young people has markedly increased globally over the past 50 years. Eating disorders are among the most life-threatening mental disorders; they were responsible for 318 deaths worldwide in 2019.
Because some individuals with eating disorders conceal core symptoms and avoid or delay seeking specialist care because of feelings of embarrassment, stigma, or ambivalence toward treatment, most cases of eating disorders remain undetected and untreated.
Brazilian researchers conducted studies to assess risky behaviors and predisposing factors among young people. The researchers observed that the probability of experiencing eating disorders was higher among young people who had an intense fear of gaining weight, who experienced thin-ideal internalization, who were excessively concerned about food, who experienced compulsive eating episodes, or who used laxatives. As previously reported, most participants in these studies had never sought professional help.
A study conducted in 2020 concluded that the media greatly influences the construction of one’s body image and the creation of aesthetic standards, particularly for adolescents. Adolescents then change their eating patterns and become more vulnerable to mental disorders related to eating.
A group of researchers from several countries, including Brazilians connected to the State University of Londrina, conducted the Global Proportion of Disordered Eating in Children and Adolescents – A Systematic Review and Meta-analysis. The study was coordinated by José Francisco López-Gil, PhD, of the University of Castilla–La Mancha (Spain). The investigators determined the rate of disordered eating among children and adolescents using the SCOFF (Sick, Control, One, Fat, Food) questionnaire, which is the most widely used screening measure for eating disorders.
Methods and results
Four databases were systematically searched (PubMed, Scopus, Web of Science, and the Cochrane Library); date limits were from January 1999 to November 2022. Studies were required to meet the following criteria: participants – studies of community samples of children and adolescents aged 6-18 years – and outcome – disordered eating assessed by the SCOFF questionnaire. The exclusion criteria were studies conducted with young people who had been diagnosed with physical or mental disorders; studies that were published before 1999, because the SCOFF questionnaire was designed in that year; studies in which data were collected during the COVID-19 pandemic, because of the possibility of selection bias; studies that employed data from the same surveys/studies, to avoid duplication; and systematic reviews and/or meta-analyses and qualitative and case studies.
In all, 32 studies, which involved a total of 63,181 participants from 16 countries, were included in the systematic review and meta-analysis, according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. The overall proportion of children and adolescents with disordered eating was 22.36% (95% confidence interval, 18.84%-26.09%; P < .001; n = 63,181). According to the researchers, girls were significantly more likely to report disordered eating (30.03%; 95% CI, 25.61%-34.65%; n = 27,548) than boys (16.98%; 95% CI, 13.46%-20.81%; n = 26,170; P < .001). It was also observed that disordered eating became more elevated with increasing age (B, 0.03; 95% CI, 0-0.06; P = .049) and BMI (B, 0.03; 95% CI, 0.01-0.05; P < .001).
Translation of outcomes
According to the authors, this was the first meta-analysis that comprehensively examined the overall proportion of children and adolescents with disordered eating in terms of gender, mean age, and BMI. They identified 14,856 (22.36%) children and adolescents with disordered eating in the population analyzed (n = 63,181). A relevant consideration made by the researchers is that, in general, disordered eating and eating disorders are not similar. “Not all children and adolescents who reported disordered eating behaviors (for example, selective eating) will necessarily be diagnosed with an eating disorder.” However, disordered eating in childhood or adolescence may predict outcomes associated with eating disorders in early adulthood. “For this reason, this high proportion found is worrisome and calls for urgent action to try to address this situation.”
The study also found that the proportion of children and adolescents with disordered eating was higher among girls than boys. The reasons for the difference in the prevalence with respect to the sex of the participants are not well understood. Boys are presumed to underreport the problem because of the societal perception that these disorders mostly affect girls and because disordered eating has usually been thought by the general population to be exclusive to girls and women. In addition, it has been noted that the current diagnostic criteria for eating disorders fail to detect disordered eating behaviors more commonly observed in boys than girls, such as intensely engaging in muscle mass gain and weight gain with the goal of improving body image satisfaction. On the other hand, the proportion of young people with disordered eating increased with increasing age and BMI. This finding is in line with the scientific literature worldwide.
The study has certain limitations. First, only studies that analyzed disordered eating using the SCOFF questionnaire were included. Second, because of the cross-sectional nature of most of the included studies, a causal relationship cannot be established. Third, owing to the inclusion of binge eating disorder and other eating disorders specified in the DSM-5, there is not enough evidence to support the use of SCOFF in primary care and community-based settings for screening for the range of eating disorders. Fourth, the meta-analysis included studies in which self-report questionnaires were used to assess disordered eating, and consequently, social desirability and recall bias could have influenced the findings.
Quick measures required
Identifying the magnitude of disordered eating and its distribution in at-risk populations is crucial for planning and executing actions aimed at preventing, detecting, and treating them. Eating disorders are a global public health problem that health care professionals, families, and other community members involved in caring for children and adolescents must not ignore, the researchers said. In addition to diagnosed eating disorders, parents, guardians, and health care professionals should be aware of symptoms of disordered eating, which include behaviors such as weight-loss dieting, binge eating, self-induced vomiting, excessive exercise, and the use of laxatives or diuretics without medical prescription.
This article was translated from the Medscape Portuguese Edition. A version of this article appeared on Medscape.com.
The high figures are concerning from a public health perspective and highlight the need to implement strategies for preventing eating disorders.
These disorders include anorexia nervosa, bulimia nervosa, binge eating disorder, and eating disorder–not otherwise specified. The prevalence of these disorders in young people has markedly increased globally over the past 50 years. Eating disorders are among the most life-threatening mental disorders; they were responsible for 318 deaths worldwide in 2019.
Because some individuals with eating disorders conceal core symptoms and avoid or delay seeking specialist care because of feelings of embarrassment, stigma, or ambivalence toward treatment, most cases of eating disorders remain undetected and untreated.
Brazilian researchers conducted studies to assess risky behaviors and predisposing factors among young people. The researchers observed that the probability of experiencing eating disorders was higher among young people who had an intense fear of gaining weight, who experienced thin-ideal internalization, who were excessively concerned about food, who experienced compulsive eating episodes, or who used laxatives. As previously reported, most participants in these studies had never sought professional help.
A study conducted in 2020 concluded that the media greatly influences the construction of one’s body image and the creation of aesthetic standards, particularly for adolescents. Adolescents then change their eating patterns and become more vulnerable to mental disorders related to eating.
A group of researchers from several countries, including Brazilians connected to the State University of Londrina, conducted the Global Proportion of Disordered Eating in Children and Adolescents – A Systematic Review and Meta-analysis. The study was coordinated by José Francisco López-Gil, PhD, of the University of Castilla–La Mancha (Spain). The investigators determined the rate of disordered eating among children and adolescents using the SCOFF (Sick, Control, One, Fat, Food) questionnaire, which is the most widely used screening measure for eating disorders.
Methods and results
Four databases were systematically searched (PubMed, Scopus, Web of Science, and the Cochrane Library); date limits were from January 1999 to November 2022. Studies were required to meet the following criteria: participants – studies of community samples of children and adolescents aged 6-18 years – and outcome – disordered eating assessed by the SCOFF questionnaire. The exclusion criteria were studies conducted with young people who had been diagnosed with physical or mental disorders; studies that were published before 1999, because the SCOFF questionnaire was designed in that year; studies in which data were collected during the COVID-19 pandemic, because of the possibility of selection bias; studies that employed data from the same surveys/studies, to avoid duplication; and systematic reviews and/or meta-analyses and qualitative and case studies.
In all, 32 studies, which involved a total of 63,181 participants from 16 countries, were included in the systematic review and meta-analysis, according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. The overall proportion of children and adolescents with disordered eating was 22.36% (95% confidence interval, 18.84%-26.09%; P < .001; n = 63,181). According to the researchers, girls were significantly more likely to report disordered eating (30.03%; 95% CI, 25.61%-34.65%; n = 27,548) than boys (16.98%; 95% CI, 13.46%-20.81%; n = 26,170; P < .001). It was also observed that disordered eating became more elevated with increasing age (B, 0.03; 95% CI, 0-0.06; P = .049) and BMI (B, 0.03; 95% CI, 0.01-0.05; P < .001).
Translation of outcomes
According to the authors, this was the first meta-analysis that comprehensively examined the overall proportion of children and adolescents with disordered eating in terms of gender, mean age, and BMI. They identified 14,856 (22.36%) children and adolescents with disordered eating in the population analyzed (n = 63,181). A relevant consideration made by the researchers is that, in general, disordered eating and eating disorders are not similar. “Not all children and adolescents who reported disordered eating behaviors (for example, selective eating) will necessarily be diagnosed with an eating disorder.” However, disordered eating in childhood or adolescence may predict outcomes associated with eating disorders in early adulthood. “For this reason, this high proportion found is worrisome and calls for urgent action to try to address this situation.”
The study also found that the proportion of children and adolescents with disordered eating was higher among girls than boys. The reasons for the difference in the prevalence with respect to the sex of the participants are not well understood. Boys are presumed to underreport the problem because of the societal perception that these disorders mostly affect girls and because disordered eating has usually been thought by the general population to be exclusive to girls and women. In addition, it has been noted that the current diagnostic criteria for eating disorders fail to detect disordered eating behaviors more commonly observed in boys than girls, such as intensely engaging in muscle mass gain and weight gain with the goal of improving body image satisfaction. On the other hand, the proportion of young people with disordered eating increased with increasing age and BMI. This finding is in line with the scientific literature worldwide.
The study has certain limitations. First, only studies that analyzed disordered eating using the SCOFF questionnaire were included. Second, because of the cross-sectional nature of most of the included studies, a causal relationship cannot be established. Third, owing to the inclusion of binge eating disorder and other eating disorders specified in the DSM-5, there is not enough evidence to support the use of SCOFF in primary care and community-based settings for screening for the range of eating disorders. Fourth, the meta-analysis included studies in which self-report questionnaires were used to assess disordered eating, and consequently, social desirability and recall bias could have influenced the findings.
Quick measures required
Identifying the magnitude of disordered eating and its distribution in at-risk populations is crucial for planning and executing actions aimed at preventing, detecting, and treating them. Eating disorders are a global public health problem that health care professionals, families, and other community members involved in caring for children and adolescents must not ignore, the researchers said. In addition to diagnosed eating disorders, parents, guardians, and health care professionals should be aware of symptoms of disordered eating, which include behaviors such as weight-loss dieting, binge eating, self-induced vomiting, excessive exercise, and the use of laxatives or diuretics without medical prescription.
This article was translated from the Medscape Portuguese Edition. A version of this article appeared on Medscape.com.
The high figures are concerning from a public health perspective and highlight the need to implement strategies for preventing eating disorders.
These disorders include anorexia nervosa, bulimia nervosa, binge eating disorder, and eating disorder–not otherwise specified. The prevalence of these disorders in young people has markedly increased globally over the past 50 years. Eating disorders are among the most life-threatening mental disorders; they were responsible for 318 deaths worldwide in 2019.
Because some individuals with eating disorders conceal core symptoms and avoid or delay seeking specialist care because of feelings of embarrassment, stigma, or ambivalence toward treatment, most cases of eating disorders remain undetected and untreated.
Brazilian researchers conducted studies to assess risky behaviors and predisposing factors among young people. The researchers observed that the probability of experiencing eating disorders was higher among young people who had an intense fear of gaining weight, who experienced thin-ideal internalization, who were excessively concerned about food, who experienced compulsive eating episodes, or who used laxatives. As previously reported, most participants in these studies had never sought professional help.
A study conducted in 2020 concluded that the media greatly influences the construction of one’s body image and the creation of aesthetic standards, particularly for adolescents. Adolescents then change their eating patterns and become more vulnerable to mental disorders related to eating.
A group of researchers from several countries, including Brazilians connected to the State University of Londrina, conducted the Global Proportion of Disordered Eating in Children and Adolescents – A Systematic Review and Meta-analysis. The study was coordinated by José Francisco López-Gil, PhD, of the University of Castilla–La Mancha (Spain). The investigators determined the rate of disordered eating among children and adolescents using the SCOFF (Sick, Control, One, Fat, Food) questionnaire, which is the most widely used screening measure for eating disorders.
Methods and results
Four databases were systematically searched (PubMed, Scopus, Web of Science, and the Cochrane Library); date limits were from January 1999 to November 2022. Studies were required to meet the following criteria: participants – studies of community samples of children and adolescents aged 6-18 years – and outcome – disordered eating assessed by the SCOFF questionnaire. The exclusion criteria were studies conducted with young people who had been diagnosed with physical or mental disorders; studies that were published before 1999, because the SCOFF questionnaire was designed in that year; studies in which data were collected during the COVID-19 pandemic, because of the possibility of selection bias; studies that employed data from the same surveys/studies, to avoid duplication; and systematic reviews and/or meta-analyses and qualitative and case studies.
In all, 32 studies, which involved a total of 63,181 participants from 16 countries, were included in the systematic review and meta-analysis, according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. The overall proportion of children and adolescents with disordered eating was 22.36% (95% confidence interval, 18.84%-26.09%; P < .001; n = 63,181). According to the researchers, girls were significantly more likely to report disordered eating (30.03%; 95% CI, 25.61%-34.65%; n = 27,548) than boys (16.98%; 95% CI, 13.46%-20.81%; n = 26,170; P < .001). It was also observed that disordered eating became more elevated with increasing age (B, 0.03; 95% CI, 0-0.06; P = .049) and BMI (B, 0.03; 95% CI, 0.01-0.05; P < .001).
Translation of outcomes
According to the authors, this was the first meta-analysis that comprehensively examined the overall proportion of children and adolescents with disordered eating in terms of gender, mean age, and BMI. They identified 14,856 (22.36%) children and adolescents with disordered eating in the population analyzed (n = 63,181). A relevant consideration made by the researchers is that, in general, disordered eating and eating disorders are not similar. “Not all children and adolescents who reported disordered eating behaviors (for example, selective eating) will necessarily be diagnosed with an eating disorder.” However, disordered eating in childhood or adolescence may predict outcomes associated with eating disorders in early adulthood. “For this reason, this high proportion found is worrisome and calls for urgent action to try to address this situation.”
The study also found that the proportion of children and adolescents with disordered eating was higher among girls than boys. The reasons for the difference in the prevalence with respect to the sex of the participants are not well understood. Boys are presumed to underreport the problem because of the societal perception that these disorders mostly affect girls and because disordered eating has usually been thought by the general population to be exclusive to girls and women. In addition, it has been noted that the current diagnostic criteria for eating disorders fail to detect disordered eating behaviors more commonly observed in boys than girls, such as intensely engaging in muscle mass gain and weight gain with the goal of improving body image satisfaction. On the other hand, the proportion of young people with disordered eating increased with increasing age and BMI. This finding is in line with the scientific literature worldwide.
The study has certain limitations. First, only studies that analyzed disordered eating using the SCOFF questionnaire were included. Second, because of the cross-sectional nature of most of the included studies, a causal relationship cannot be established. Third, owing to the inclusion of binge eating disorder and other eating disorders specified in the DSM-5, there is not enough evidence to support the use of SCOFF in primary care and community-based settings for screening for the range of eating disorders. Fourth, the meta-analysis included studies in which self-report questionnaires were used to assess disordered eating, and consequently, social desirability and recall bias could have influenced the findings.
Quick measures required
Identifying the magnitude of disordered eating and its distribution in at-risk populations is crucial for planning and executing actions aimed at preventing, detecting, and treating them. Eating disorders are a global public health problem that health care professionals, families, and other community members involved in caring for children and adolescents must not ignore, the researchers said. In addition to diagnosed eating disorders, parents, guardians, and health care professionals should be aware of symptoms of disordered eating, which include behaviors such as weight-loss dieting, binge eating, self-induced vomiting, excessive exercise, and the use of laxatives or diuretics without medical prescription.
This article was translated from the Medscape Portuguese Edition. A version of this article appeared on Medscape.com.
FROM JAMA PEDIATRICS
AD in infancy: Diagnostic advice and treatment tips
WASHINGTON – mean it is often “woefully undertreated,” Robert Sidbury, MD, MPH, said at the annual Revolutionizing Atopic Dermatitis conference.
Identifying and mitigating triggers – such as irritation, contact allergy, and infection – is a cornerstone of treatment in infants, but tailored therapy with topical corticosteroids, topical calcineurin inhibitors (TCIs), and topical phosphodiesterase 4 (PDE4) inhibitors also have roles to play, said Dr. Sidbury, chief of dermatology at Seattle Children’s Hospital and professor in the department of pediatrics at the University of Washington, Seattle.
Views on the use of dupilumab as a systemic agent for severe infantile AD, meanwhile, have shifted significantly in the past year with the Food and Drug Administration approval of the biologic for children aged 6 months to 5 years and with extended experience with the biologic in all ages, including children, Lawrence F. Eichenfield, MD, professor of dermatology and pediatrics at the University of California, San Diego, said at the meeting.
The pediatric dermatologists spoke during a session devoted to AD in infants, during which the diagnosis of AD and the role – and risks – of food allergy testing were also discussed. Diagnosis, said Elaine C. Siegfried, MD, who also spoke during the session, requires careful consideration of mimicking conditions and a broader list of differential diagnoses in those infants with poor growth or frequent infections.
Here are some of the experts’ pearls for practice.
Diagnosing AD in infants
Among infants who are growing well and otherwise healthy, the infantile eczema phenotype encompasses AD, seborrheic dermatitis, contact dermatitis, psoriasis – and overlap of more than one of these conditions. “Overlap is common,” said Dr. Siegfried, professor of pediatrics and dermatology at Saint Louis University, and director of the division of pediatric dermatology at Cardinal Glennon Children’s Hospital.
(Initial topical treatment for all these conditions is similar, but optimal treatment may differ for young children with moderate to severe disease that requires systemic treatment, she said in an interview after the meeting.)
Sparing of the diaper area that reflects skin barrier integrity is a classic feature of AD in infants and can be a useful diagnostic sign. In addition, “hypopigmentation is more characteristic of psoriasis” than AD, whereas AD tends to be hyperpigmented, which is most obvious in skin-of-color patients, Dr. Siegfried said.
Disease-specific pigment changes may be related to microbial colonization – such as Malassezia-associated hypopigmentation – or cell turnover, which is faster in psoriasis and slower in AD – with corresponding differences in pigment retention, and may be more obvious in children than adults, she said.
A less common scenario is dermatitis in infants who are not growing well. For these patients, she noted, the differential diagnosis includes metabolic or immune deficiency dermatitis as well as a variety of genodermatoses.
Generalized redness and scaling present on the first day of life is suggestive of non-atopic dermatitis. “If you’re born with red scaly skin, that’s very different than if you develop red skin in the first month or two of life,” Dr. Siegfried said.
When there is diaper area involvement with AD, contact dermatitis, impetigo, and Candida may be complicating factors. And in infants with other morbidities – especially those who are not growing well – diaper area involvement suggests a broader differential diagnosis. “I implore you, if you see children, make sure you weigh and measure them at every appointment,” she said.
Dr. Siegfried has seen infants with Netherton syndrome, and those with cystic fibrosis with zinc deficiency, for instance, presenting with “an eczematous-like picture,” diaper-area involvement, and other morbidities.
For infants with AD, she maintains a high index of suspicion for secondary infections such as molluscum, herpes simplex virus (HSV) with or without streptococci, scabies, tinea, and group A streptococci. “Secondary infections ... may be incognito,” she said. “Look for subtle signs. Even molluscum can be very subtle.”
Secondary allergic contact dermatitis is also common although it’s “technically difficult to confirm the diagnosis,” she said. Patch testing in infants is technically challenging, sensitivity is low, and monosensitization is uncommon. “So I do initial empiric topical allergen avoidance,” she said, keeping in mind ubiquitous and avoidable topical allergens such as Kathon, cocamidopropyl betaine, propylene glycol, disperse blue, and adhesives.
Treating AD in infancy
Irritation “is probably one of the biggest triggers” of AD in infants, and the often “pristine” diaper area compared with inflamed eczema elsewhere can demonstrate the importance of moisturization for healthy skin in atopic infants, Dr. Sidbury said.
Among treatments that “punch above their weight” for AD in infants is an ointment-based barrier applied around the mouth, chin, and chest – where the wet/dry impact of drooling is maximal – before and after meals, he said.
Another is hydrocortisone 2.5% mixed 1:1 with mupirocin for those infants who have secondary infections and “that exudative, weepy-looking appearance on the face,” he said. The topical antibiotic in the combination cream “lessens the potency of the steroid and oftentimes by synergy, makes it more effective” by simultaneously treating inflammation, he said. He cautions against products containing neomycin, which can be an allergen.
A combination antibiotic-steroid-emollient cream (the Aron Regimen) can also “sometimes punch above its weight,” Dr. Sidbury said.
Infections typically involve Staphylococcus aureus, but in up to 16% of cases Streptococcus is involved. And notably, lurking underneath the honey-colored crusting of S. aureus infections may be the grouped vesicles that characterize eczema herpeticum, Dr. Sidbury said.
“Counsel [parents] preemptively to treat cold sores immediately [in order to] decrease HSV shedding and minimize risk to their baby,” Dr. Sidbury said.
For treating AD-associated inflammation in skin not affected by secondary infections, over-the-counter 1% hydrocortisone cream is often sufficient, and “for very young babies and preemies in particular, I generally don’t use anything stronger because their skin barrier isn’t fully complete yet, so they absorb more than an older child does,” he said, referring to ages 2 months corrected as a marker for considering a stronger formulation if needed.
Many parents are “very concerned” about topical corticosteroid (TCS) use and pediatricians are also “often concerned,” Dr. Sidbury said. Addressing this concern, he tries to provide context and promote adherence by pointing out that infants have an easily visible vein at the temple area where the skin is naturally thin. If parents were to see this appearance for the first time in other areas while using topical steroids, he tells them, it may be the first sign of skin thinning, but “it’s entirely reversible at that stage.”
He also stressed the cost of not treating. It’s unknown whether “treating aggressively early on prevents any future development or manifestation of eczema, or future comorbidities, but we don’t know that it doesn’t,” Dr. Sidbury said. “And we certainly know how miserable that baby with eczema can be in the short term. So we need to use these medicines.”
Dr. Sidbury utilizes tacrolimus 0.03% ointment, a topical calcineurin inhibitor (TCI), only if he is worried about overuse of steroids, and uses a regimen that alternates the TCI (used in infants off-label because it is approved for ages 2 years and older) with TCS in periods of similar duration (for example, treatment with TCS for 1 week and TCI for 1 week, or rotations of 2 weeks each or 3 days each). “And these rotations may be dynamic depending on severity of the flare at any given time,” he said after the meeting.
Preapproval data from the pivotal trials of tacrolimus are reassuring and can be shared with parents. “Two-year-olds had 90% of BSA [body surface area] treated for 12 weeks” with no signs of systemic risks, Dr. Sidbury said at the meeting.
Crisaborole, a topical phosphodiesterase 4 (PDE4) inhibitor approved for AD down to age 3 months, does not, like tacrolimus, have a boxed warning about a possible risk for cancer, and may also be alternated with TCSs. It will cause stinging in some children, but TCSs and TCIs can also sting in some children, he said, noting that samples can be helpful to predict what will or won’t sting each infant.
Systemic treatment in infants
The Liberty AD PRESCHOOL phase 3 trial that supported the FDA’s approval of dupilumab down to 6 months of age, published in 2022 in The Lancet, covered ages 6 months to 5 years but included only six children under the age of 2, “leaving us with a very limited dataset in this age group,” Dr. Eichenfield said at the meeting.
Other data and analyses that have provided reassurance, such as a laboratory safety analysis published online in 2022 showing no meaningful changes in laboratory safety parameters in children as young as 6 months, and pediatric data (not including infants) presented at a RAD meeting in 2022 showing that dupilumab, an interleukin-4 receptor alpha antagonist, may have positive effects on bone mineral density.
Data from the Liberty AD PRESCHOOL open-label extension study presented at the American Academy of Dermatology meeting in 2023, meanwhile, show that “the adverse event profile is not looking much different than what we see in older children,” Dr. Eichenfield said. “There are low rates of severe adverse events and a very low rate of discontinuations.”
At Rady Children’s Hospital, where Dr. Eichenfield is chief of pediatric and adolescent dermatology, dupilumab has become a first-line systemic agent for severe infantile AD, supplanting prior traditional but little used systemic agents such as oral corticosteroids, cyclosporine, methotrexate, azathioprine, or mycophenolate, he said after the meeting.
The decision to use systemics in the first 2 years of life is “a comprehensive one,” requiring knowledge of the child’s history, disease course, and assessment of response to prior therapies, comorbidities and severity, he said.
Food allergy in infants with AD
Food allergy is common in children with moderate to severe AD, but true food-triggered AD, with AD being the only symptom of food allergy, is rare, said Anne Marie Singh, MD, associate professor in the division of allergy and immunology and rheumatology at the University of Wisconsin, Madison, who focuses on pediatrics.
Over the years, studies of double-blind placebo-controlled food challenge tests in children with AD have tended to conflate immediate IgE hypersensitivity (and skin symptoms like urticaria) with AD, said Dr. Singh, who directs the university’s Food Allergy Research and Education Center of Excellence. In a recently published study she led involving 374 children with AD referred to allergy and/or dermatology subspecialty clinics at the University of Wisconsin, Madison, 55% had a food allergy but only 2% had food-triggered AD “where eczema is the only symptom and removal of the food cleared up the eczema and its return brought it back,” Dr. Singh said at the meeting. Another 4% had combined IgE-mediated food allergy and food-triggered AD. Almost half of the children with food-triggered AD were under 1 year of age, and egg was the most common trigger, she noted.
Food should be implicated largely by history, Dr. Singh emphasized.
Food allergy testing in the context of AD can be done but is challenging, with the clinical relevance of skin prick testing and food-specific immunoglobulin E (sIgE) difficult to predict. Predictive values of sIgE levels are established for immediate IgE mediated food allergy, but “cut-offs” for food-triggered AD are not established, she explained, noting that “cut-offs are likely higher for our children with AD.”
Elimination diets, moreover, pose significant risks of future oral tolerance and risks of nutritional deficiencies and poor growth, Dr. Singh said. New and immediate reactions to foods that are reintroduced after an elimination diet are common, and research has shown that 20% or more of such reactions involve anaphylaxis. “If an elimination diet is undertaken, you need emergency action plans, injectable epinephrine, and nutrition counseling,” she said.
A recent systematic review and meta-analysis conditionally recommended against elimination diets for the treatment of AD, Dr. Singh noted.
Asked by Dr. Sidbury whether there “is a sweet spot where you can eliminate [foods] without going all the way,” Dr. Singh said she will sometimes do a “diagnostic elimination trial” with food elimination for 2-4 weeks only – a time period after which “I’ll feel really comfortable reintroducing the food.”
Dr. Singh urged dermatologists to “know your allergist” because “patients respond best with a consistent message.”
Dr. Sidbury reported ties with Regeneron, UCB, Pfizer, Leo Pharma, Lilly, and Beiersdorf. Dr. Siegfried reported ties with Pfizer, Regeneron, Sanofi Genzyme, Pfizer, UCB, Novan and Leo Pharma. Dr. Singh reported ties with Incyte and Siolta Therapeutics. Dr. Eichenfield reported ties with Pfizer, Regeneron, Sanofi Genzyme, Incyte, and Pfizer.
WASHINGTON – mean it is often “woefully undertreated,” Robert Sidbury, MD, MPH, said at the annual Revolutionizing Atopic Dermatitis conference.
Identifying and mitigating triggers – such as irritation, contact allergy, and infection – is a cornerstone of treatment in infants, but tailored therapy with topical corticosteroids, topical calcineurin inhibitors (TCIs), and topical phosphodiesterase 4 (PDE4) inhibitors also have roles to play, said Dr. Sidbury, chief of dermatology at Seattle Children’s Hospital and professor in the department of pediatrics at the University of Washington, Seattle.
Views on the use of dupilumab as a systemic agent for severe infantile AD, meanwhile, have shifted significantly in the past year with the Food and Drug Administration approval of the biologic for children aged 6 months to 5 years and with extended experience with the biologic in all ages, including children, Lawrence F. Eichenfield, MD, professor of dermatology and pediatrics at the University of California, San Diego, said at the meeting.
The pediatric dermatologists spoke during a session devoted to AD in infants, during which the diagnosis of AD and the role – and risks – of food allergy testing were also discussed. Diagnosis, said Elaine C. Siegfried, MD, who also spoke during the session, requires careful consideration of mimicking conditions and a broader list of differential diagnoses in those infants with poor growth or frequent infections.
Here are some of the experts’ pearls for practice.
Diagnosing AD in infants
Among infants who are growing well and otherwise healthy, the infantile eczema phenotype encompasses AD, seborrheic dermatitis, contact dermatitis, psoriasis – and overlap of more than one of these conditions. “Overlap is common,” said Dr. Siegfried, professor of pediatrics and dermatology at Saint Louis University, and director of the division of pediatric dermatology at Cardinal Glennon Children’s Hospital.
(Initial topical treatment for all these conditions is similar, but optimal treatment may differ for young children with moderate to severe disease that requires systemic treatment, she said in an interview after the meeting.)
Sparing of the diaper area that reflects skin barrier integrity is a classic feature of AD in infants and can be a useful diagnostic sign. In addition, “hypopigmentation is more characteristic of psoriasis” than AD, whereas AD tends to be hyperpigmented, which is most obvious in skin-of-color patients, Dr. Siegfried said.
Disease-specific pigment changes may be related to microbial colonization – such as Malassezia-associated hypopigmentation – or cell turnover, which is faster in psoriasis and slower in AD – with corresponding differences in pigment retention, and may be more obvious in children than adults, she said.
A less common scenario is dermatitis in infants who are not growing well. For these patients, she noted, the differential diagnosis includes metabolic or immune deficiency dermatitis as well as a variety of genodermatoses.
Generalized redness and scaling present on the first day of life is suggestive of non-atopic dermatitis. “If you’re born with red scaly skin, that’s very different than if you develop red skin in the first month or two of life,” Dr. Siegfried said.
When there is diaper area involvement with AD, contact dermatitis, impetigo, and Candida may be complicating factors. And in infants with other morbidities – especially those who are not growing well – diaper area involvement suggests a broader differential diagnosis. “I implore you, if you see children, make sure you weigh and measure them at every appointment,” she said.
Dr. Siegfried has seen infants with Netherton syndrome, and those with cystic fibrosis with zinc deficiency, for instance, presenting with “an eczematous-like picture,” diaper-area involvement, and other morbidities.
For infants with AD, she maintains a high index of suspicion for secondary infections such as molluscum, herpes simplex virus (HSV) with or without streptococci, scabies, tinea, and group A streptococci. “Secondary infections ... may be incognito,” she said. “Look for subtle signs. Even molluscum can be very subtle.”
Secondary allergic contact dermatitis is also common although it’s “technically difficult to confirm the diagnosis,” she said. Patch testing in infants is technically challenging, sensitivity is low, and monosensitization is uncommon. “So I do initial empiric topical allergen avoidance,” she said, keeping in mind ubiquitous and avoidable topical allergens such as Kathon, cocamidopropyl betaine, propylene glycol, disperse blue, and adhesives.
Treating AD in infancy
Irritation “is probably one of the biggest triggers” of AD in infants, and the often “pristine” diaper area compared with inflamed eczema elsewhere can demonstrate the importance of moisturization for healthy skin in atopic infants, Dr. Sidbury said.
Among treatments that “punch above their weight” for AD in infants is an ointment-based barrier applied around the mouth, chin, and chest – where the wet/dry impact of drooling is maximal – before and after meals, he said.
Another is hydrocortisone 2.5% mixed 1:1 with mupirocin for those infants who have secondary infections and “that exudative, weepy-looking appearance on the face,” he said. The topical antibiotic in the combination cream “lessens the potency of the steroid and oftentimes by synergy, makes it more effective” by simultaneously treating inflammation, he said. He cautions against products containing neomycin, which can be an allergen.
A combination antibiotic-steroid-emollient cream (the Aron Regimen) can also “sometimes punch above its weight,” Dr. Sidbury said.
Infections typically involve Staphylococcus aureus, but in up to 16% of cases Streptococcus is involved. And notably, lurking underneath the honey-colored crusting of S. aureus infections may be the grouped vesicles that characterize eczema herpeticum, Dr. Sidbury said.
“Counsel [parents] preemptively to treat cold sores immediately [in order to] decrease HSV shedding and minimize risk to their baby,” Dr. Sidbury said.
For treating AD-associated inflammation in skin not affected by secondary infections, over-the-counter 1% hydrocortisone cream is often sufficient, and “for very young babies and preemies in particular, I generally don’t use anything stronger because their skin barrier isn’t fully complete yet, so they absorb more than an older child does,” he said, referring to ages 2 months corrected as a marker for considering a stronger formulation if needed.
Many parents are “very concerned” about topical corticosteroid (TCS) use and pediatricians are also “often concerned,” Dr. Sidbury said. Addressing this concern, he tries to provide context and promote adherence by pointing out that infants have an easily visible vein at the temple area where the skin is naturally thin. If parents were to see this appearance for the first time in other areas while using topical steroids, he tells them, it may be the first sign of skin thinning, but “it’s entirely reversible at that stage.”
He also stressed the cost of not treating. It’s unknown whether “treating aggressively early on prevents any future development or manifestation of eczema, or future comorbidities, but we don’t know that it doesn’t,” Dr. Sidbury said. “And we certainly know how miserable that baby with eczema can be in the short term. So we need to use these medicines.”
Dr. Sidbury utilizes tacrolimus 0.03% ointment, a topical calcineurin inhibitor (TCI), only if he is worried about overuse of steroids, and uses a regimen that alternates the TCI (used in infants off-label because it is approved for ages 2 years and older) with TCS in periods of similar duration (for example, treatment with TCS for 1 week and TCI for 1 week, or rotations of 2 weeks each or 3 days each). “And these rotations may be dynamic depending on severity of the flare at any given time,” he said after the meeting.
Preapproval data from the pivotal trials of tacrolimus are reassuring and can be shared with parents. “Two-year-olds had 90% of BSA [body surface area] treated for 12 weeks” with no signs of systemic risks, Dr. Sidbury said at the meeting.
Crisaborole, a topical phosphodiesterase 4 (PDE4) inhibitor approved for AD down to age 3 months, does not, like tacrolimus, have a boxed warning about a possible risk for cancer, and may also be alternated with TCSs. It will cause stinging in some children, but TCSs and TCIs can also sting in some children, he said, noting that samples can be helpful to predict what will or won’t sting each infant.
Systemic treatment in infants
The Liberty AD PRESCHOOL phase 3 trial that supported the FDA’s approval of dupilumab down to 6 months of age, published in 2022 in The Lancet, covered ages 6 months to 5 years but included only six children under the age of 2, “leaving us with a very limited dataset in this age group,” Dr. Eichenfield said at the meeting.
Other data and analyses that have provided reassurance, such as a laboratory safety analysis published online in 2022 showing no meaningful changes in laboratory safety parameters in children as young as 6 months, and pediatric data (not including infants) presented at a RAD meeting in 2022 showing that dupilumab, an interleukin-4 receptor alpha antagonist, may have positive effects on bone mineral density.
Data from the Liberty AD PRESCHOOL open-label extension study presented at the American Academy of Dermatology meeting in 2023, meanwhile, show that “the adverse event profile is not looking much different than what we see in older children,” Dr. Eichenfield said. “There are low rates of severe adverse events and a very low rate of discontinuations.”
At Rady Children’s Hospital, where Dr. Eichenfield is chief of pediatric and adolescent dermatology, dupilumab has become a first-line systemic agent for severe infantile AD, supplanting prior traditional but little used systemic agents such as oral corticosteroids, cyclosporine, methotrexate, azathioprine, or mycophenolate, he said after the meeting.
The decision to use systemics in the first 2 years of life is “a comprehensive one,” requiring knowledge of the child’s history, disease course, and assessment of response to prior therapies, comorbidities and severity, he said.
Food allergy in infants with AD
Food allergy is common in children with moderate to severe AD, but true food-triggered AD, with AD being the only symptom of food allergy, is rare, said Anne Marie Singh, MD, associate professor in the division of allergy and immunology and rheumatology at the University of Wisconsin, Madison, who focuses on pediatrics.
Over the years, studies of double-blind placebo-controlled food challenge tests in children with AD have tended to conflate immediate IgE hypersensitivity (and skin symptoms like urticaria) with AD, said Dr. Singh, who directs the university’s Food Allergy Research and Education Center of Excellence. In a recently published study she led involving 374 children with AD referred to allergy and/or dermatology subspecialty clinics at the University of Wisconsin, Madison, 55% had a food allergy but only 2% had food-triggered AD “where eczema is the only symptom and removal of the food cleared up the eczema and its return brought it back,” Dr. Singh said at the meeting. Another 4% had combined IgE-mediated food allergy and food-triggered AD. Almost half of the children with food-triggered AD were under 1 year of age, and egg was the most common trigger, she noted.
Food should be implicated largely by history, Dr. Singh emphasized.
Food allergy testing in the context of AD can be done but is challenging, with the clinical relevance of skin prick testing and food-specific immunoglobulin E (sIgE) difficult to predict. Predictive values of sIgE levels are established for immediate IgE mediated food allergy, but “cut-offs” for food-triggered AD are not established, she explained, noting that “cut-offs are likely higher for our children with AD.”
Elimination diets, moreover, pose significant risks of future oral tolerance and risks of nutritional deficiencies and poor growth, Dr. Singh said. New and immediate reactions to foods that are reintroduced after an elimination diet are common, and research has shown that 20% or more of such reactions involve anaphylaxis. “If an elimination diet is undertaken, you need emergency action plans, injectable epinephrine, and nutrition counseling,” she said.
A recent systematic review and meta-analysis conditionally recommended against elimination diets for the treatment of AD, Dr. Singh noted.
Asked by Dr. Sidbury whether there “is a sweet spot where you can eliminate [foods] without going all the way,” Dr. Singh said she will sometimes do a “diagnostic elimination trial” with food elimination for 2-4 weeks only – a time period after which “I’ll feel really comfortable reintroducing the food.”
Dr. Singh urged dermatologists to “know your allergist” because “patients respond best with a consistent message.”
Dr. Sidbury reported ties with Regeneron, UCB, Pfizer, Leo Pharma, Lilly, and Beiersdorf. Dr. Siegfried reported ties with Pfizer, Regeneron, Sanofi Genzyme, Pfizer, UCB, Novan and Leo Pharma. Dr. Singh reported ties with Incyte and Siolta Therapeutics. Dr. Eichenfield reported ties with Pfizer, Regeneron, Sanofi Genzyme, Incyte, and Pfizer.
WASHINGTON – mean it is often “woefully undertreated,” Robert Sidbury, MD, MPH, said at the annual Revolutionizing Atopic Dermatitis conference.
Identifying and mitigating triggers – such as irritation, contact allergy, and infection – is a cornerstone of treatment in infants, but tailored therapy with topical corticosteroids, topical calcineurin inhibitors (TCIs), and topical phosphodiesterase 4 (PDE4) inhibitors also have roles to play, said Dr. Sidbury, chief of dermatology at Seattle Children’s Hospital and professor in the department of pediatrics at the University of Washington, Seattle.
Views on the use of dupilumab as a systemic agent for severe infantile AD, meanwhile, have shifted significantly in the past year with the Food and Drug Administration approval of the biologic for children aged 6 months to 5 years and with extended experience with the biologic in all ages, including children, Lawrence F. Eichenfield, MD, professor of dermatology and pediatrics at the University of California, San Diego, said at the meeting.
The pediatric dermatologists spoke during a session devoted to AD in infants, during which the diagnosis of AD and the role – and risks – of food allergy testing were also discussed. Diagnosis, said Elaine C. Siegfried, MD, who also spoke during the session, requires careful consideration of mimicking conditions and a broader list of differential diagnoses in those infants with poor growth or frequent infections.
Here are some of the experts’ pearls for practice.
Diagnosing AD in infants
Among infants who are growing well and otherwise healthy, the infantile eczema phenotype encompasses AD, seborrheic dermatitis, contact dermatitis, psoriasis – and overlap of more than one of these conditions. “Overlap is common,” said Dr. Siegfried, professor of pediatrics and dermatology at Saint Louis University, and director of the division of pediatric dermatology at Cardinal Glennon Children’s Hospital.
(Initial topical treatment for all these conditions is similar, but optimal treatment may differ for young children with moderate to severe disease that requires systemic treatment, she said in an interview after the meeting.)
Sparing of the diaper area that reflects skin barrier integrity is a classic feature of AD in infants and can be a useful diagnostic sign. In addition, “hypopigmentation is more characteristic of psoriasis” than AD, whereas AD tends to be hyperpigmented, which is most obvious in skin-of-color patients, Dr. Siegfried said.
Disease-specific pigment changes may be related to microbial colonization – such as Malassezia-associated hypopigmentation – or cell turnover, which is faster in psoriasis and slower in AD – with corresponding differences in pigment retention, and may be more obvious in children than adults, she said.
A less common scenario is dermatitis in infants who are not growing well. For these patients, she noted, the differential diagnosis includes metabolic or immune deficiency dermatitis as well as a variety of genodermatoses.
Generalized redness and scaling present on the first day of life is suggestive of non-atopic dermatitis. “If you’re born with red scaly skin, that’s very different than if you develop red skin in the first month or two of life,” Dr. Siegfried said.
When there is diaper area involvement with AD, contact dermatitis, impetigo, and Candida may be complicating factors. And in infants with other morbidities – especially those who are not growing well – diaper area involvement suggests a broader differential diagnosis. “I implore you, if you see children, make sure you weigh and measure them at every appointment,” she said.
Dr. Siegfried has seen infants with Netherton syndrome, and those with cystic fibrosis with zinc deficiency, for instance, presenting with “an eczematous-like picture,” diaper-area involvement, and other morbidities.
For infants with AD, she maintains a high index of suspicion for secondary infections such as molluscum, herpes simplex virus (HSV) with or without streptococci, scabies, tinea, and group A streptococci. “Secondary infections ... may be incognito,” she said. “Look for subtle signs. Even molluscum can be very subtle.”
Secondary allergic contact dermatitis is also common although it’s “technically difficult to confirm the diagnosis,” she said. Patch testing in infants is technically challenging, sensitivity is low, and monosensitization is uncommon. “So I do initial empiric topical allergen avoidance,” she said, keeping in mind ubiquitous and avoidable topical allergens such as Kathon, cocamidopropyl betaine, propylene glycol, disperse blue, and adhesives.
Treating AD in infancy
Irritation “is probably one of the biggest triggers” of AD in infants, and the often “pristine” diaper area compared with inflamed eczema elsewhere can demonstrate the importance of moisturization for healthy skin in atopic infants, Dr. Sidbury said.
Among treatments that “punch above their weight” for AD in infants is an ointment-based barrier applied around the mouth, chin, and chest – where the wet/dry impact of drooling is maximal – before and after meals, he said.
Another is hydrocortisone 2.5% mixed 1:1 with mupirocin for those infants who have secondary infections and “that exudative, weepy-looking appearance on the face,” he said. The topical antibiotic in the combination cream “lessens the potency of the steroid and oftentimes by synergy, makes it more effective” by simultaneously treating inflammation, he said. He cautions against products containing neomycin, which can be an allergen.
A combination antibiotic-steroid-emollient cream (the Aron Regimen) can also “sometimes punch above its weight,” Dr. Sidbury said.
Infections typically involve Staphylococcus aureus, but in up to 16% of cases Streptococcus is involved. And notably, lurking underneath the honey-colored crusting of S. aureus infections may be the grouped vesicles that characterize eczema herpeticum, Dr. Sidbury said.
“Counsel [parents] preemptively to treat cold sores immediately [in order to] decrease HSV shedding and minimize risk to their baby,” Dr. Sidbury said.
For treating AD-associated inflammation in skin not affected by secondary infections, over-the-counter 1% hydrocortisone cream is often sufficient, and “for very young babies and preemies in particular, I generally don’t use anything stronger because their skin barrier isn’t fully complete yet, so they absorb more than an older child does,” he said, referring to ages 2 months corrected as a marker for considering a stronger formulation if needed.
Many parents are “very concerned” about topical corticosteroid (TCS) use and pediatricians are also “often concerned,” Dr. Sidbury said. Addressing this concern, he tries to provide context and promote adherence by pointing out that infants have an easily visible vein at the temple area where the skin is naturally thin. If parents were to see this appearance for the first time in other areas while using topical steroids, he tells them, it may be the first sign of skin thinning, but “it’s entirely reversible at that stage.”
He also stressed the cost of not treating. It’s unknown whether “treating aggressively early on prevents any future development or manifestation of eczema, or future comorbidities, but we don’t know that it doesn’t,” Dr. Sidbury said. “And we certainly know how miserable that baby with eczema can be in the short term. So we need to use these medicines.”
Dr. Sidbury utilizes tacrolimus 0.03% ointment, a topical calcineurin inhibitor (TCI), only if he is worried about overuse of steroids, and uses a regimen that alternates the TCI (used in infants off-label because it is approved for ages 2 years and older) with TCS in periods of similar duration (for example, treatment with TCS for 1 week and TCI for 1 week, or rotations of 2 weeks each or 3 days each). “And these rotations may be dynamic depending on severity of the flare at any given time,” he said after the meeting.
Preapproval data from the pivotal trials of tacrolimus are reassuring and can be shared with parents. “Two-year-olds had 90% of BSA [body surface area] treated for 12 weeks” with no signs of systemic risks, Dr. Sidbury said at the meeting.
Crisaborole, a topical phosphodiesterase 4 (PDE4) inhibitor approved for AD down to age 3 months, does not, like tacrolimus, have a boxed warning about a possible risk for cancer, and may also be alternated with TCSs. It will cause stinging in some children, but TCSs and TCIs can also sting in some children, he said, noting that samples can be helpful to predict what will or won’t sting each infant.
Systemic treatment in infants
The Liberty AD PRESCHOOL phase 3 trial that supported the FDA’s approval of dupilumab down to 6 months of age, published in 2022 in The Lancet, covered ages 6 months to 5 years but included only six children under the age of 2, “leaving us with a very limited dataset in this age group,” Dr. Eichenfield said at the meeting.
Other data and analyses that have provided reassurance, such as a laboratory safety analysis published online in 2022 showing no meaningful changes in laboratory safety parameters in children as young as 6 months, and pediatric data (not including infants) presented at a RAD meeting in 2022 showing that dupilumab, an interleukin-4 receptor alpha antagonist, may have positive effects on bone mineral density.
Data from the Liberty AD PRESCHOOL open-label extension study presented at the American Academy of Dermatology meeting in 2023, meanwhile, show that “the adverse event profile is not looking much different than what we see in older children,” Dr. Eichenfield said. “There are low rates of severe adverse events and a very low rate of discontinuations.”
At Rady Children’s Hospital, where Dr. Eichenfield is chief of pediatric and adolescent dermatology, dupilumab has become a first-line systemic agent for severe infantile AD, supplanting prior traditional but little used systemic agents such as oral corticosteroids, cyclosporine, methotrexate, azathioprine, or mycophenolate, he said after the meeting.
The decision to use systemics in the first 2 years of life is “a comprehensive one,” requiring knowledge of the child’s history, disease course, and assessment of response to prior therapies, comorbidities and severity, he said.
Food allergy in infants with AD
Food allergy is common in children with moderate to severe AD, but true food-triggered AD, with AD being the only symptom of food allergy, is rare, said Anne Marie Singh, MD, associate professor in the division of allergy and immunology and rheumatology at the University of Wisconsin, Madison, who focuses on pediatrics.
Over the years, studies of double-blind placebo-controlled food challenge tests in children with AD have tended to conflate immediate IgE hypersensitivity (and skin symptoms like urticaria) with AD, said Dr. Singh, who directs the university’s Food Allergy Research and Education Center of Excellence. In a recently published study she led involving 374 children with AD referred to allergy and/or dermatology subspecialty clinics at the University of Wisconsin, Madison, 55% had a food allergy but only 2% had food-triggered AD “where eczema is the only symptom and removal of the food cleared up the eczema and its return brought it back,” Dr. Singh said at the meeting. Another 4% had combined IgE-mediated food allergy and food-triggered AD. Almost half of the children with food-triggered AD were under 1 year of age, and egg was the most common trigger, she noted.
Food should be implicated largely by history, Dr. Singh emphasized.
Food allergy testing in the context of AD can be done but is challenging, with the clinical relevance of skin prick testing and food-specific immunoglobulin E (sIgE) difficult to predict. Predictive values of sIgE levels are established for immediate IgE mediated food allergy, but “cut-offs” for food-triggered AD are not established, she explained, noting that “cut-offs are likely higher for our children with AD.”
Elimination diets, moreover, pose significant risks of future oral tolerance and risks of nutritional deficiencies and poor growth, Dr. Singh said. New and immediate reactions to foods that are reintroduced after an elimination diet are common, and research has shown that 20% or more of such reactions involve anaphylaxis. “If an elimination diet is undertaken, you need emergency action plans, injectable epinephrine, and nutrition counseling,” she said.
A recent systematic review and meta-analysis conditionally recommended against elimination diets for the treatment of AD, Dr. Singh noted.
Asked by Dr. Sidbury whether there “is a sweet spot where you can eliminate [foods] without going all the way,” Dr. Singh said she will sometimes do a “diagnostic elimination trial” with food elimination for 2-4 weeks only – a time period after which “I’ll feel really comfortable reintroducing the food.”
Dr. Singh urged dermatologists to “know your allergist” because “patients respond best with a consistent message.”
Dr. Sidbury reported ties with Regeneron, UCB, Pfizer, Leo Pharma, Lilly, and Beiersdorf. Dr. Siegfried reported ties with Pfizer, Regeneron, Sanofi Genzyme, Pfizer, UCB, Novan and Leo Pharma. Dr. Singh reported ties with Incyte and Siolta Therapeutics. Dr. Eichenfield reported ties with Pfizer, Regeneron, Sanofi Genzyme, Incyte, and Pfizer.
AT RAD 2023
Over half of pregnant patients not properly screened for thyroid disease
BALTIMORE – Less than half of the pregnant patients who met the criteria for thyroid screening were actually screened by their clinician, according to a retrospective cohort study presented at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists in Baltimore. Those who met criteria and did receive screening had higher live birth rates and lower miscarriage rates than those who met the criteria but did not undergo screening, the study found.
“These results suggest that improving thyroid screening adherence may lead to improved pregnancy outcomes,” lead author Allan Dong, MD, of Advocate Lutheran General Hospital in Des Plaines, Ill., told attendees. “However, following targeted screening guidelines can be difficult for clinicians. In practice, universal screening for diabetes and pregnancy may provide more comprehensive screening coverage and potentially lead to improved outcomes.”
Instead of universal screening for thyroid disease, ACOG and the American Thyroid Association recommend targeted screening of high-risk patients, though ATA’s criteria are substantially broader than ACOG’s. But, Dr. Dong told attendees, “guidelines are only beneficial if they are followed appropriately,” and Ob.Gyns. have limited time to screen for risk factors in the midst of other clinical priorities. So he aimed to learn whether Ob.Gyns. were following the guidelines of either organization in screening people at higher risk for thyroid disease.
Dr. Dong and his coauthor, Melisa Lott, DO, reviewed the charts of all 1,025 patients who presented at their institution for new obstetrical visits in 2020 to determine which ones had risk factors that would qualify them for screening under ATA or ACOG guidelines. ACOG’s screening criteria included having a personal or family history of thyroid disease or type 1 diabetes, or there being clinical suspicion for thyroid disease. ATA’s screening criteria included the following:
- Personal or family history of thyroid disease.
- History of head or neck radiation.
- History of a prior thyroid surgery.
- Over age 30.
- Any autoimmune disease.
- A body mass index greater than 40 kg/m2.
- History of pregnancy loss, preterm delivery, or infertility.
- Recently used amiodarone lithium or iodine-based contrast.
- Lived in an area of known iodine deficiency.
- Clinical suspicion of thyroid disease.
ATA screening criteria identified four times as many patients requiring screening than did ACOG criteria, Dr. Dong noted. Of the 198 patients who met ACOG’s criteria, 43.9% were screened with thyroid function testing. Meanwhile, 826 patients – including all those who met ACOG’s criteria – met ATA’s criteria for screening, but only 13.1% of them underwent thyroid function testing.
Live birth rates were significantly higher among patients who met ATA criteria and were screened (92.6%) than among patients who met ATA criteria but were not screened (83.3%, P = .006). Similarly, the miscarriage rate was 4.6% in patients who met ATA criteria and were screened, compared to 12.4% in patients who met the criteria but did not undergo thyroid function testing (P = .009).
“A similar difference, although not statistically significant, was noted when comparing patients who were screened appropriately per ACOG criteria with those who met criteria for screening but were not screened,” Dr. Dong told attendees. “However, our study was underpowered to detect this difference due to the lower number of patients who meet criteria for screening under ACOG guidelines.”
The researchers did not find any significant difference in preterm delivery rates.
Anna Whelan, MD, of Women & Infants Hospital of Brown University, Providence, R.I., was not involved in the study but viewed the poster and pointed out that many of the patients, if seen by a primary care provider prior to pregnancy, would likely have been screened by their PCP. The rate of underscreening therefore suggests that patients “are not getting good, consistent primary care because there’s a lack of primary care physicians,” Dr. Whelan said in an interview.
In addition, she added, “maybe not all obstetricians and those providing care, such as midwives and other providers, are aware of the [ATA] guidelines on who should be screened.” She added that additional education about thyroid screening guidelines might be helpful for providers.
Dr. Dong reported being a stock shareholder in 3M, AbbVie, General Electric, Johnson & Johnson, Medtronic, Pfizer, and Viking Therapeutics. Dr. Whelan had no disclosures.
BALTIMORE – Less than half of the pregnant patients who met the criteria for thyroid screening were actually screened by their clinician, according to a retrospective cohort study presented at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists in Baltimore. Those who met criteria and did receive screening had higher live birth rates and lower miscarriage rates than those who met the criteria but did not undergo screening, the study found.
“These results suggest that improving thyroid screening adherence may lead to improved pregnancy outcomes,” lead author Allan Dong, MD, of Advocate Lutheran General Hospital in Des Plaines, Ill., told attendees. “However, following targeted screening guidelines can be difficult for clinicians. In practice, universal screening for diabetes and pregnancy may provide more comprehensive screening coverage and potentially lead to improved outcomes.”
Instead of universal screening for thyroid disease, ACOG and the American Thyroid Association recommend targeted screening of high-risk patients, though ATA’s criteria are substantially broader than ACOG’s. But, Dr. Dong told attendees, “guidelines are only beneficial if they are followed appropriately,” and Ob.Gyns. have limited time to screen for risk factors in the midst of other clinical priorities. So he aimed to learn whether Ob.Gyns. were following the guidelines of either organization in screening people at higher risk for thyroid disease.
Dr. Dong and his coauthor, Melisa Lott, DO, reviewed the charts of all 1,025 patients who presented at their institution for new obstetrical visits in 2020 to determine which ones had risk factors that would qualify them for screening under ATA or ACOG guidelines. ACOG’s screening criteria included having a personal or family history of thyroid disease or type 1 diabetes, or there being clinical suspicion for thyroid disease. ATA’s screening criteria included the following:
- Personal or family history of thyroid disease.
- History of head or neck radiation.
- History of a prior thyroid surgery.
- Over age 30.
- Any autoimmune disease.
- A body mass index greater than 40 kg/m2.
- History of pregnancy loss, preterm delivery, or infertility.
- Recently used amiodarone lithium or iodine-based contrast.
- Lived in an area of known iodine deficiency.
- Clinical suspicion of thyroid disease.
ATA screening criteria identified four times as many patients requiring screening than did ACOG criteria, Dr. Dong noted. Of the 198 patients who met ACOG’s criteria, 43.9% were screened with thyroid function testing. Meanwhile, 826 patients – including all those who met ACOG’s criteria – met ATA’s criteria for screening, but only 13.1% of them underwent thyroid function testing.
Live birth rates were significantly higher among patients who met ATA criteria and were screened (92.6%) than among patients who met ATA criteria but were not screened (83.3%, P = .006). Similarly, the miscarriage rate was 4.6% in patients who met ATA criteria and were screened, compared to 12.4% in patients who met the criteria but did not undergo thyroid function testing (P = .009).
“A similar difference, although not statistically significant, was noted when comparing patients who were screened appropriately per ACOG criteria with those who met criteria for screening but were not screened,” Dr. Dong told attendees. “However, our study was underpowered to detect this difference due to the lower number of patients who meet criteria for screening under ACOG guidelines.”
The researchers did not find any significant difference in preterm delivery rates.
Anna Whelan, MD, of Women & Infants Hospital of Brown University, Providence, R.I., was not involved in the study but viewed the poster and pointed out that many of the patients, if seen by a primary care provider prior to pregnancy, would likely have been screened by their PCP. The rate of underscreening therefore suggests that patients “are not getting good, consistent primary care because there’s a lack of primary care physicians,” Dr. Whelan said in an interview.
In addition, she added, “maybe not all obstetricians and those providing care, such as midwives and other providers, are aware of the [ATA] guidelines on who should be screened.” She added that additional education about thyroid screening guidelines might be helpful for providers.
Dr. Dong reported being a stock shareholder in 3M, AbbVie, General Electric, Johnson & Johnson, Medtronic, Pfizer, and Viking Therapeutics. Dr. Whelan had no disclosures.
BALTIMORE – Less than half of the pregnant patients who met the criteria for thyroid screening were actually screened by their clinician, according to a retrospective cohort study presented at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists in Baltimore. Those who met criteria and did receive screening had higher live birth rates and lower miscarriage rates than those who met the criteria but did not undergo screening, the study found.
“These results suggest that improving thyroid screening adherence may lead to improved pregnancy outcomes,” lead author Allan Dong, MD, of Advocate Lutheran General Hospital in Des Plaines, Ill., told attendees. “However, following targeted screening guidelines can be difficult for clinicians. In practice, universal screening for diabetes and pregnancy may provide more comprehensive screening coverage and potentially lead to improved outcomes.”
Instead of universal screening for thyroid disease, ACOG and the American Thyroid Association recommend targeted screening of high-risk patients, though ATA’s criteria are substantially broader than ACOG’s. But, Dr. Dong told attendees, “guidelines are only beneficial if they are followed appropriately,” and Ob.Gyns. have limited time to screen for risk factors in the midst of other clinical priorities. So he aimed to learn whether Ob.Gyns. were following the guidelines of either organization in screening people at higher risk for thyroid disease.
Dr. Dong and his coauthor, Melisa Lott, DO, reviewed the charts of all 1,025 patients who presented at their institution for new obstetrical visits in 2020 to determine which ones had risk factors that would qualify them for screening under ATA or ACOG guidelines. ACOG’s screening criteria included having a personal or family history of thyroid disease or type 1 diabetes, or there being clinical suspicion for thyroid disease. ATA’s screening criteria included the following:
- Personal or family history of thyroid disease.
- History of head or neck radiation.
- History of a prior thyroid surgery.
- Over age 30.
- Any autoimmune disease.
- A body mass index greater than 40 kg/m2.
- History of pregnancy loss, preterm delivery, or infertility.
- Recently used amiodarone lithium or iodine-based contrast.
- Lived in an area of known iodine deficiency.
- Clinical suspicion of thyroid disease.
ATA screening criteria identified four times as many patients requiring screening than did ACOG criteria, Dr. Dong noted. Of the 198 patients who met ACOG’s criteria, 43.9% were screened with thyroid function testing. Meanwhile, 826 patients – including all those who met ACOG’s criteria – met ATA’s criteria for screening, but only 13.1% of them underwent thyroid function testing.
Live birth rates were significantly higher among patients who met ATA criteria and were screened (92.6%) than among patients who met ATA criteria but were not screened (83.3%, P = .006). Similarly, the miscarriage rate was 4.6% in patients who met ATA criteria and were screened, compared to 12.4% in patients who met the criteria but did not undergo thyroid function testing (P = .009).
“A similar difference, although not statistically significant, was noted when comparing patients who were screened appropriately per ACOG criteria with those who met criteria for screening but were not screened,” Dr. Dong told attendees. “However, our study was underpowered to detect this difference due to the lower number of patients who meet criteria for screening under ACOG guidelines.”
The researchers did not find any significant difference in preterm delivery rates.
Anna Whelan, MD, of Women & Infants Hospital of Brown University, Providence, R.I., was not involved in the study but viewed the poster and pointed out that many of the patients, if seen by a primary care provider prior to pregnancy, would likely have been screened by their PCP. The rate of underscreening therefore suggests that patients “are not getting good, consistent primary care because there’s a lack of primary care physicians,” Dr. Whelan said in an interview.
In addition, she added, “maybe not all obstetricians and those providing care, such as midwives and other providers, are aware of the [ATA] guidelines on who should be screened.” She added that additional education about thyroid screening guidelines might be helpful for providers.
Dr. Dong reported being a stock shareholder in 3M, AbbVie, General Electric, Johnson & Johnson, Medtronic, Pfizer, and Viking Therapeutics. Dr. Whelan had no disclosures.
FROM ACOG 2023
Venetoclax boosts ibrutinib in high-risk CLL
Of 45 patients, 57% reached U-MRD at 12 months, and 55% reached complete remission, according to the study, published in Leukemia.
By adding venetoclax, “you can get very deep remissions in high-risk patients with ibrutinib,” lead author Philip A. Thompson, MBBS, a hematologist-oncologist with the University of Melbourne and Peter MacCallum Cancer Center, also in Melbourne, said in an interview. “This is a significant advance for really high-risk patients.”
According to Dr. Thompson, Bruton’s tyrosine kinase inhibitors like ibrutinib have revolutionized the treatment of high-risk CLL by forcing the disease into remission for several years and allowing patients to avoid stem cell transplants. “But the drug doesn’t eradicate the disease,” he said, “so eventually these patients develop progression.”
The current hope, he said, is to use a combination therapy like ibrutinib and venetoclax to send CLL into remission with lower chance of drug resistance and then allow patients to stop taking the medications.
Previous research has supported the combination of ibrutinib and venetoclax in CLL in the frontline setting, and the European Commission approved it in 2022 for that use. But “ours is the first [study] that looked at patients who’ve been on ibrutinib for a long time and added venetoclax,” Dr. Thompson said. In some cases, he said, patients in the study had been on ibrutinib for several years.
For the new study, researchers at the University of Texas MD Anderson Cancer Center in Houston – where Dr. Thompson used to work – tracked 45 patients (average age, 68.5 years; 51-80 years) with CLL or small lymphocytic lymphoma who had MRD but no clinical disease progression. They all had at least 1 high-risk feature such as a mutated TP53. They’d been on ibrutinib for a median of 32 months (12-73 months), and two were in complete remission but with MRD.
An intention-to-treat analysis found that 71% reached U-MRD when they finished taking venetoclax. “We were actually pleasantly surprised by the high rate of undetectable MRD,” Dr. Thompson said.
At a median 41-month follow-up, 11% of patients had progressed, but none had died of CLL or Richter transformation, a deadly complication of CLL. “The main side effects were neutropenia and diarrhea, which we were manageable,” Dr. Thompson said.
It’s not clear why the drug combination is especially effective, he said, but it may be because the medications are synergistic. According to the National Cancer Institute, synergy in medicine refers to “the interaction of two or more drugs when their combined effect is greater than the sum of the effects seen when each drug is given alone.”
The findings suggest that “you can get deep remissions in high-risk patients with ibrutinib and venetoclax with very with good tolerability and very low risk of on-treatment progression,” Dr. Thompson said. “We don’t yet have enough progression events to talk about retreatment data, but we do feel that retreatment with Bruton’s tyrosine kinase inhibitors – plus or minus venetoclax – will be successful in the vast majority of patients.”
The combination can be given off label in the United States, Dr. Thompson added. As for expense, adding venetoclax will double the cost of ibrutinib. The two drugs are some of the most expensive medications in the world. But patients will save money if they can stop therapy when they reach remission.
In an interview, hematologist-oncologist Kerry A. Rogers, MD, of Ohio State University, Columbus, who is not involved with the study, praised the research: “While small, this study does say quite a bit about this as a strategy to help people discontinue ibrutinib prior to resistance developing.”
She noted that Bruton’s tyrosine kinase inhibitors “are generally given as a continuous monotherapy, and venetoclax is usually given for a fixed duration in combination with an anti-CD20 antibody.”
Going forward, she said, “the fact that the study was in high-risk patients who have the most to gain from such a combination suggests that similar or better rates of undetectable minimal residual disease might be seen in non–high-risk groups. Additional follow-up should be reported as well as use of this strategy in a larger group of patients before this should be considered a standard approach.”
AbbVie funding the study and provided study drugs. MD Anderson Cancer Center conducted the study and discloses funding from the National Cancer Institute. Dr. Thompson reported ties with AbbVie, Pharmacyclics, Lilly, Adaptive Biotechnologies, Janssen, BeiGene, and Genentech. The other study authors reported multiple disclosures. Dr. Rogers disclosed relationships with Genentech, AbbVie, Novartis, Janssen, Pharmacyclics, BeiGene, Lilly, and AstraZeneca.
Of 45 patients, 57% reached U-MRD at 12 months, and 55% reached complete remission, according to the study, published in Leukemia.
By adding venetoclax, “you can get very deep remissions in high-risk patients with ibrutinib,” lead author Philip A. Thompson, MBBS, a hematologist-oncologist with the University of Melbourne and Peter MacCallum Cancer Center, also in Melbourne, said in an interview. “This is a significant advance for really high-risk patients.”
According to Dr. Thompson, Bruton’s tyrosine kinase inhibitors like ibrutinib have revolutionized the treatment of high-risk CLL by forcing the disease into remission for several years and allowing patients to avoid stem cell transplants. “But the drug doesn’t eradicate the disease,” he said, “so eventually these patients develop progression.”
The current hope, he said, is to use a combination therapy like ibrutinib and venetoclax to send CLL into remission with lower chance of drug resistance and then allow patients to stop taking the medications.
Previous research has supported the combination of ibrutinib and venetoclax in CLL in the frontline setting, and the European Commission approved it in 2022 for that use. But “ours is the first [study] that looked at patients who’ve been on ibrutinib for a long time and added venetoclax,” Dr. Thompson said. In some cases, he said, patients in the study had been on ibrutinib for several years.
For the new study, researchers at the University of Texas MD Anderson Cancer Center in Houston – where Dr. Thompson used to work – tracked 45 patients (average age, 68.5 years; 51-80 years) with CLL or small lymphocytic lymphoma who had MRD but no clinical disease progression. They all had at least 1 high-risk feature such as a mutated TP53. They’d been on ibrutinib for a median of 32 months (12-73 months), and two were in complete remission but with MRD.
An intention-to-treat analysis found that 71% reached U-MRD when they finished taking venetoclax. “We were actually pleasantly surprised by the high rate of undetectable MRD,” Dr. Thompson said.
At a median 41-month follow-up, 11% of patients had progressed, but none had died of CLL or Richter transformation, a deadly complication of CLL. “The main side effects were neutropenia and diarrhea, which we were manageable,” Dr. Thompson said.
It’s not clear why the drug combination is especially effective, he said, but it may be because the medications are synergistic. According to the National Cancer Institute, synergy in medicine refers to “the interaction of two or more drugs when their combined effect is greater than the sum of the effects seen when each drug is given alone.”
The findings suggest that “you can get deep remissions in high-risk patients with ibrutinib and venetoclax with very with good tolerability and very low risk of on-treatment progression,” Dr. Thompson said. “We don’t yet have enough progression events to talk about retreatment data, but we do feel that retreatment with Bruton’s tyrosine kinase inhibitors – plus or minus venetoclax – will be successful in the vast majority of patients.”
The combination can be given off label in the United States, Dr. Thompson added. As for expense, adding venetoclax will double the cost of ibrutinib. The two drugs are some of the most expensive medications in the world. But patients will save money if they can stop therapy when they reach remission.
In an interview, hematologist-oncologist Kerry A. Rogers, MD, of Ohio State University, Columbus, who is not involved with the study, praised the research: “While small, this study does say quite a bit about this as a strategy to help people discontinue ibrutinib prior to resistance developing.”
She noted that Bruton’s tyrosine kinase inhibitors “are generally given as a continuous monotherapy, and venetoclax is usually given for a fixed duration in combination with an anti-CD20 antibody.”
Going forward, she said, “the fact that the study was in high-risk patients who have the most to gain from such a combination suggests that similar or better rates of undetectable minimal residual disease might be seen in non–high-risk groups. Additional follow-up should be reported as well as use of this strategy in a larger group of patients before this should be considered a standard approach.”
AbbVie funding the study and provided study drugs. MD Anderson Cancer Center conducted the study and discloses funding from the National Cancer Institute. Dr. Thompson reported ties with AbbVie, Pharmacyclics, Lilly, Adaptive Biotechnologies, Janssen, BeiGene, and Genentech. The other study authors reported multiple disclosures. Dr. Rogers disclosed relationships with Genentech, AbbVie, Novartis, Janssen, Pharmacyclics, BeiGene, Lilly, and AstraZeneca.
Of 45 patients, 57% reached U-MRD at 12 months, and 55% reached complete remission, according to the study, published in Leukemia.
By adding venetoclax, “you can get very deep remissions in high-risk patients with ibrutinib,” lead author Philip A. Thompson, MBBS, a hematologist-oncologist with the University of Melbourne and Peter MacCallum Cancer Center, also in Melbourne, said in an interview. “This is a significant advance for really high-risk patients.”
According to Dr. Thompson, Bruton’s tyrosine kinase inhibitors like ibrutinib have revolutionized the treatment of high-risk CLL by forcing the disease into remission for several years and allowing patients to avoid stem cell transplants. “But the drug doesn’t eradicate the disease,” he said, “so eventually these patients develop progression.”
The current hope, he said, is to use a combination therapy like ibrutinib and venetoclax to send CLL into remission with lower chance of drug resistance and then allow patients to stop taking the medications.
Previous research has supported the combination of ibrutinib and venetoclax in CLL in the frontline setting, and the European Commission approved it in 2022 for that use. But “ours is the first [study] that looked at patients who’ve been on ibrutinib for a long time and added venetoclax,” Dr. Thompson said. In some cases, he said, patients in the study had been on ibrutinib for several years.
For the new study, researchers at the University of Texas MD Anderson Cancer Center in Houston – where Dr. Thompson used to work – tracked 45 patients (average age, 68.5 years; 51-80 years) with CLL or small lymphocytic lymphoma who had MRD but no clinical disease progression. They all had at least 1 high-risk feature such as a mutated TP53. They’d been on ibrutinib for a median of 32 months (12-73 months), and two were in complete remission but with MRD.
An intention-to-treat analysis found that 71% reached U-MRD when they finished taking venetoclax. “We were actually pleasantly surprised by the high rate of undetectable MRD,” Dr. Thompson said.
At a median 41-month follow-up, 11% of patients had progressed, but none had died of CLL or Richter transformation, a deadly complication of CLL. “The main side effects were neutropenia and diarrhea, which we were manageable,” Dr. Thompson said.
It’s not clear why the drug combination is especially effective, he said, but it may be because the medications are synergistic. According to the National Cancer Institute, synergy in medicine refers to “the interaction of two or more drugs when their combined effect is greater than the sum of the effects seen when each drug is given alone.”
The findings suggest that “you can get deep remissions in high-risk patients with ibrutinib and venetoclax with very with good tolerability and very low risk of on-treatment progression,” Dr. Thompson said. “We don’t yet have enough progression events to talk about retreatment data, but we do feel that retreatment with Bruton’s tyrosine kinase inhibitors – plus or minus venetoclax – will be successful in the vast majority of patients.”
The combination can be given off label in the United States, Dr. Thompson added. As for expense, adding venetoclax will double the cost of ibrutinib. The two drugs are some of the most expensive medications in the world. But patients will save money if they can stop therapy when they reach remission.
In an interview, hematologist-oncologist Kerry A. Rogers, MD, of Ohio State University, Columbus, who is not involved with the study, praised the research: “While small, this study does say quite a bit about this as a strategy to help people discontinue ibrutinib prior to resistance developing.”
She noted that Bruton’s tyrosine kinase inhibitors “are generally given as a continuous monotherapy, and venetoclax is usually given for a fixed duration in combination with an anti-CD20 antibody.”
Going forward, she said, “the fact that the study was in high-risk patients who have the most to gain from such a combination suggests that similar or better rates of undetectable minimal residual disease might be seen in non–high-risk groups. Additional follow-up should be reported as well as use of this strategy in a larger group of patients before this should be considered a standard approach.”
AbbVie funding the study and provided study drugs. MD Anderson Cancer Center conducted the study and discloses funding from the National Cancer Institute. Dr. Thompson reported ties with AbbVie, Pharmacyclics, Lilly, Adaptive Biotechnologies, Janssen, BeiGene, and Genentech. The other study authors reported multiple disclosures. Dr. Rogers disclosed relationships with Genentech, AbbVie, Novartis, Janssen, Pharmacyclics, BeiGene, Lilly, and AstraZeneca.
FROM LEUKEMIA
Which drug best reduces sleepiness in patients with OSA?
Solriamfetol who have residual daytime sleepiness after conventional treatment, according to a systematic review and meta-analysis.
In a systematic review of 14 trials that included more than 3,000 patients, solriamfetol was associated with improvements of 3.85 points on the Epworth Sleepiness Scale (ESS) score, compared with placebo.
“We found that solriamfetol is almost twice as effective as modafinil-armodafinil – the cheaper, older option – in improving the ESS score and much more effective at improving the Maintenance of Wakefulness Test (MWT),” study author Tyler Pitre, MD, an internal medicine physician at McMaster University, Hamilton, Ont., said in an interview.
The findings were published online in Annals of Internal Medicine.
High-certainty evidence
The analysis included 3,085 adults with excessive daytime sleepiness (EDS) who were receiving or were eligible for conventional OSA treatment such as positive airway pressure. Participants were randomly assigned to either placebo or any EDS pharmacotherapy (armodafinil, modafinil, solriamfetol, or pitolisant). The primary outcomes of the analysis were change in ESS and MWT. Secondary outcomes were drug-related adverse events.
The trials had a median follow-up time of 4 weeks. The meta-analysis showed that solriamfetol improves ESS to a greater extent than placebo (high certainty), armodafinil-modafinil and pitolisant (moderate certainty). Compared with placebo, the mean difference in ESS scores for solriamfetol, armodafinil-modafinil, and pitolisant was –3.85, –2.25, and –2.78, respectively.
The analysis yielded high-certainty evidence that solriamfetol and armodafinil-modafinil improved MWT, compared with placebo. The former was “probably superior,” while pitolisant “may have little to no effect on MWT, compared with placebo,” write the authors. The standardized mean difference in MWT scores, compared with placebo, was 0.90 for solriamfetol and 0.41 for armodafinil-modafinil. “Solriamfetol is probably superior to armodafinil-modafinil in improving MWT (SMD, 0.49),” say the authors.
Compared with placebo, armodafinil-modafinil probably increases the risk for discontinuation due to adverse events (relative risk, 2.01), and solriamfetol may increase the risk for discontinuation (RR, 2.04), according to the authors. Pitolisant “may have little to no effect on drug discontinuations due to adverse events,” write the authors.
Although solriamfetol may have led to more discontinuations than armodafinil-modafinil, “we did not find convincing evidence of serious adverse events, albeit with very short-term follow-up,” they add.
The most common side effects for all interventions were headaches, insomnia, and anxiety. Headaches were most likely with armodafinil-modafinil (RR, 1.87), and insomnia was most likely with pitolisant (RR, 7.25).
“Although solriamfetol appears most effective, comorbid hypertension and costs may be barriers to its use,” say the researchers. “Furthermore, there are potentially effective candidate therapies such as methylphenidate, atomoxetine, or caffeine, which have not been examined in randomized clinical trials.”
Although EDS is reported in 40%-58% of patients with OSA and can persist in 6%-18% despite PAP therapy, most non-sleep specialists may not be aware of pharmacologic options, said Dr. Pitre. “I have not seen a study that looks at the prescribing habits of physicians for this condition, but I suspect that primary care physicians are not prescribing modafinil-armodafinil frequently for this and less so for solriamfetol,” he said. “I hope this paper builds awareness of this condition and also informs clinicians on the options available to patients, as well as common side effects to counsel them on before starting treatment.”
Dr. Pitre was surprised at the magnitude of solriamfetol’s superiority to modafinil-armodafinil but cautioned that solriamfetol has been shown to increase blood pressure in higher doses. It therefore must be prescribed carefully, “especially to a population of patients who often have comorbid hypertension,” he said.
Some limitations of the analysis were that all trials were conducted in high-income countries (most commonly the United States). Moreover, 77% of participants were White, and 71% were male.
Beneficial adjunctive therapy
Commenting on the findings, Sogol Javaheri, MD, MPH, who was not involved in the research, said that they confirm those of prior studies and are “consistent with what my colleagues and I experience in our clinical practices.”
Dr. Javaheri is associate program director of the sleep medicine fellowship at Brigham and Women’s Hospital and assistant professor of medicine at Harvard Medical School, both in Boston.
While sleep medicine specialists are more likely than others to prescribe these medications, “any clinician may use these medications, ideally if they have ruled out other potential reversible causes of EDS,” said Dr. Javaheri. “The medications do not treat the underlying cause, which is why it’s important to use them as an adjunct to conventional therapy that actually treats the underlying sleep disorder and to rule out additional potential causes of sleepiness that are treatable.”
These potential causes might include insufficient sleep (less than 7 hours per night), untreated anemia, and incompletely treated sleep disorders, she explained. In sleep medicine, modafinil is usually the treatment of choice because of its lower cost, but it may reduce the efficacy of hormonal contraception. Solriamfetol, however, does not. “Additionally, I look forward to validation of pitolisant for treatment of EDS in OSA patients, as it is not a controlled substance and may benefit patients with a history of substance abuse or who may be at higher risk of addiction,” said Dr. Javaheri.
The study was conducted without outside funding. Dr. Pitre and Dr. Javaheri report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Solriamfetol who have residual daytime sleepiness after conventional treatment, according to a systematic review and meta-analysis.
In a systematic review of 14 trials that included more than 3,000 patients, solriamfetol was associated with improvements of 3.85 points on the Epworth Sleepiness Scale (ESS) score, compared with placebo.
“We found that solriamfetol is almost twice as effective as modafinil-armodafinil – the cheaper, older option – in improving the ESS score and much more effective at improving the Maintenance of Wakefulness Test (MWT),” study author Tyler Pitre, MD, an internal medicine physician at McMaster University, Hamilton, Ont., said in an interview.
The findings were published online in Annals of Internal Medicine.
High-certainty evidence
The analysis included 3,085 adults with excessive daytime sleepiness (EDS) who were receiving or were eligible for conventional OSA treatment such as positive airway pressure. Participants were randomly assigned to either placebo or any EDS pharmacotherapy (armodafinil, modafinil, solriamfetol, or pitolisant). The primary outcomes of the analysis were change in ESS and MWT. Secondary outcomes were drug-related adverse events.
The trials had a median follow-up time of 4 weeks. The meta-analysis showed that solriamfetol improves ESS to a greater extent than placebo (high certainty), armodafinil-modafinil and pitolisant (moderate certainty). Compared with placebo, the mean difference in ESS scores for solriamfetol, armodafinil-modafinil, and pitolisant was –3.85, –2.25, and –2.78, respectively.
The analysis yielded high-certainty evidence that solriamfetol and armodafinil-modafinil improved MWT, compared with placebo. The former was “probably superior,” while pitolisant “may have little to no effect on MWT, compared with placebo,” write the authors. The standardized mean difference in MWT scores, compared with placebo, was 0.90 for solriamfetol and 0.41 for armodafinil-modafinil. “Solriamfetol is probably superior to armodafinil-modafinil in improving MWT (SMD, 0.49),” say the authors.
Compared with placebo, armodafinil-modafinil probably increases the risk for discontinuation due to adverse events (relative risk, 2.01), and solriamfetol may increase the risk for discontinuation (RR, 2.04), according to the authors. Pitolisant “may have little to no effect on drug discontinuations due to adverse events,” write the authors.
Although solriamfetol may have led to more discontinuations than armodafinil-modafinil, “we did not find convincing evidence of serious adverse events, albeit with very short-term follow-up,” they add.
The most common side effects for all interventions were headaches, insomnia, and anxiety. Headaches were most likely with armodafinil-modafinil (RR, 1.87), and insomnia was most likely with pitolisant (RR, 7.25).
“Although solriamfetol appears most effective, comorbid hypertension and costs may be barriers to its use,” say the researchers. “Furthermore, there are potentially effective candidate therapies such as methylphenidate, atomoxetine, or caffeine, which have not been examined in randomized clinical trials.”
Although EDS is reported in 40%-58% of patients with OSA and can persist in 6%-18% despite PAP therapy, most non-sleep specialists may not be aware of pharmacologic options, said Dr. Pitre. “I have not seen a study that looks at the prescribing habits of physicians for this condition, but I suspect that primary care physicians are not prescribing modafinil-armodafinil frequently for this and less so for solriamfetol,” he said. “I hope this paper builds awareness of this condition and also informs clinicians on the options available to patients, as well as common side effects to counsel them on before starting treatment.”
Dr. Pitre was surprised at the magnitude of solriamfetol’s superiority to modafinil-armodafinil but cautioned that solriamfetol has been shown to increase blood pressure in higher doses. It therefore must be prescribed carefully, “especially to a population of patients who often have comorbid hypertension,” he said.
Some limitations of the analysis were that all trials were conducted in high-income countries (most commonly the United States). Moreover, 77% of participants were White, and 71% were male.
Beneficial adjunctive therapy
Commenting on the findings, Sogol Javaheri, MD, MPH, who was not involved in the research, said that they confirm those of prior studies and are “consistent with what my colleagues and I experience in our clinical practices.”
Dr. Javaheri is associate program director of the sleep medicine fellowship at Brigham and Women’s Hospital and assistant professor of medicine at Harvard Medical School, both in Boston.
While sleep medicine specialists are more likely than others to prescribe these medications, “any clinician may use these medications, ideally if they have ruled out other potential reversible causes of EDS,” said Dr. Javaheri. “The medications do not treat the underlying cause, which is why it’s important to use them as an adjunct to conventional therapy that actually treats the underlying sleep disorder and to rule out additional potential causes of sleepiness that are treatable.”
These potential causes might include insufficient sleep (less than 7 hours per night), untreated anemia, and incompletely treated sleep disorders, she explained. In sleep medicine, modafinil is usually the treatment of choice because of its lower cost, but it may reduce the efficacy of hormonal contraception. Solriamfetol, however, does not. “Additionally, I look forward to validation of pitolisant for treatment of EDS in OSA patients, as it is not a controlled substance and may benefit patients with a history of substance abuse or who may be at higher risk of addiction,” said Dr. Javaheri.
The study was conducted without outside funding. Dr. Pitre and Dr. Javaheri report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Solriamfetol who have residual daytime sleepiness after conventional treatment, according to a systematic review and meta-analysis.
In a systematic review of 14 trials that included more than 3,000 patients, solriamfetol was associated with improvements of 3.85 points on the Epworth Sleepiness Scale (ESS) score, compared with placebo.
“We found that solriamfetol is almost twice as effective as modafinil-armodafinil – the cheaper, older option – in improving the ESS score and much more effective at improving the Maintenance of Wakefulness Test (MWT),” study author Tyler Pitre, MD, an internal medicine physician at McMaster University, Hamilton, Ont., said in an interview.
The findings were published online in Annals of Internal Medicine.
High-certainty evidence
The analysis included 3,085 adults with excessive daytime sleepiness (EDS) who were receiving or were eligible for conventional OSA treatment such as positive airway pressure. Participants were randomly assigned to either placebo or any EDS pharmacotherapy (armodafinil, modafinil, solriamfetol, or pitolisant). The primary outcomes of the analysis were change in ESS and MWT. Secondary outcomes were drug-related adverse events.
The trials had a median follow-up time of 4 weeks. The meta-analysis showed that solriamfetol improves ESS to a greater extent than placebo (high certainty), armodafinil-modafinil and pitolisant (moderate certainty). Compared with placebo, the mean difference in ESS scores for solriamfetol, armodafinil-modafinil, and pitolisant was –3.85, –2.25, and –2.78, respectively.
The analysis yielded high-certainty evidence that solriamfetol and armodafinil-modafinil improved MWT, compared with placebo. The former was “probably superior,” while pitolisant “may have little to no effect on MWT, compared with placebo,” write the authors. The standardized mean difference in MWT scores, compared with placebo, was 0.90 for solriamfetol and 0.41 for armodafinil-modafinil. “Solriamfetol is probably superior to armodafinil-modafinil in improving MWT (SMD, 0.49),” say the authors.
Compared with placebo, armodafinil-modafinil probably increases the risk for discontinuation due to adverse events (relative risk, 2.01), and solriamfetol may increase the risk for discontinuation (RR, 2.04), according to the authors. Pitolisant “may have little to no effect on drug discontinuations due to adverse events,” write the authors.
Although solriamfetol may have led to more discontinuations than armodafinil-modafinil, “we did not find convincing evidence of serious adverse events, albeit with very short-term follow-up,” they add.
The most common side effects for all interventions were headaches, insomnia, and anxiety. Headaches were most likely with armodafinil-modafinil (RR, 1.87), and insomnia was most likely with pitolisant (RR, 7.25).
“Although solriamfetol appears most effective, comorbid hypertension and costs may be barriers to its use,” say the researchers. “Furthermore, there are potentially effective candidate therapies such as methylphenidate, atomoxetine, or caffeine, which have not been examined in randomized clinical trials.”
Although EDS is reported in 40%-58% of patients with OSA and can persist in 6%-18% despite PAP therapy, most non-sleep specialists may not be aware of pharmacologic options, said Dr. Pitre. “I have not seen a study that looks at the prescribing habits of physicians for this condition, but I suspect that primary care physicians are not prescribing modafinil-armodafinil frequently for this and less so for solriamfetol,” he said. “I hope this paper builds awareness of this condition and also informs clinicians on the options available to patients, as well as common side effects to counsel them on before starting treatment.”
Dr. Pitre was surprised at the magnitude of solriamfetol’s superiority to modafinil-armodafinil but cautioned that solriamfetol has been shown to increase blood pressure in higher doses. It therefore must be prescribed carefully, “especially to a population of patients who often have comorbid hypertension,” he said.
Some limitations of the analysis were that all trials were conducted in high-income countries (most commonly the United States). Moreover, 77% of participants were White, and 71% were male.
Beneficial adjunctive therapy
Commenting on the findings, Sogol Javaheri, MD, MPH, who was not involved in the research, said that they confirm those of prior studies and are “consistent with what my colleagues and I experience in our clinical practices.”
Dr. Javaheri is associate program director of the sleep medicine fellowship at Brigham and Women’s Hospital and assistant professor of medicine at Harvard Medical School, both in Boston.
While sleep medicine specialists are more likely than others to prescribe these medications, “any clinician may use these medications, ideally if they have ruled out other potential reversible causes of EDS,” said Dr. Javaheri. “The medications do not treat the underlying cause, which is why it’s important to use them as an adjunct to conventional therapy that actually treats the underlying sleep disorder and to rule out additional potential causes of sleepiness that are treatable.”
These potential causes might include insufficient sleep (less than 7 hours per night), untreated anemia, and incompletely treated sleep disorders, she explained. In sleep medicine, modafinil is usually the treatment of choice because of its lower cost, but it may reduce the efficacy of hormonal contraception. Solriamfetol, however, does not. “Additionally, I look forward to validation of pitolisant for treatment of EDS in OSA patients, as it is not a controlled substance and may benefit patients with a history of substance abuse or who may be at higher risk of addiction,” said Dr. Javaheri.
The study was conducted without outside funding. Dr. Pitre and Dr. Javaheri report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ANNALS OF INTERNAL MEDICINE
FDA advisory committee votes against approval for NASH drug
The Food and Drug Administration’s Gastrointestinal Drugs Advisory Committee has voted against the accelerated approval of Intercept Pharmaceuticals’ obeticholic acid (OCA) for treatment of nonalcoholic steatohepatitis (NASH) with stage 2 or 3 fibrosis.
This is the second time that Intercept has sought FDA approval for OCA in treating NASH.
The committee voted 12 to 2 (with 2 abstentions) that the benefits of OCA did not outweigh the risks to this patient population. While OCA showed a modest benefit of improving fibrosis in NASH patients, safety concerns included increased risk for drug-induced liver injury (DILI), cholelithiasis, pruritus, dyslipidemia, and dysglycemia.
Committee members were most concerned with the increased risk for DILI in patients taking OCA. Intercept said that frequent monitoring for DILI in such a large eligible population – an estimated 6-8 million individuals taking the drug to treat the condition – would be difficult.
“Typically, in clinical practice, NASH patients are followed every 6-12 months, so more frequent monitoring would be a substantial change and may not be achievable outside of the clinical trial setting,” according to a briefing document released before the committee meeting.
The FDA estimates that 16.8 million U.S. adults have NASH, with 5.7 million having NASH with advanced fibrosis, according to briefing documents. NASH is the second leading cause of liver transplants in the United States and is the leading cause in women. There are currently no FDA-approved therapies to treat NASH.
OCA, sold under the commercial name Ocaliva, was first approved in 2016 to treat primary biliary cholangitis, and is prescribed at up to 10 mg per day. Intercept proposed that OCA be given in daily 25-mg doses in the treatment of precirrhotic fibrosis attributable to NASH.
In 2019, Intercept initially filed for a new drug application (NDA) for OCA for the treatment of precirrhotic fibrosis attributable to NASH but were issued a Complete Response Letter after the FDA determined that the medication had an “unfavorable risk benefit-risk assessment.” Intercept resubmitted an NDA for OCA in December 2022, including two 18-month analyses from a phase 3 study, REGENERATE (Randomized Global Phase 3 Study to Evaluate the Impact on NASH with Fibrosis of Obeticholic Acid Treatment). In the study, which included data from 931 patients, OCA 25 mg outperformed placebo in improving fibrosis with no worsening of NASH over 18 months, one of two primary endpoints of the clinical trial. The estimated risk difference ranged from 8.6 to 12.8 across different analyses, which the FDA categorized as a “modest treatment effect.”
There was no significant difference between OCA 25 mg and placebo in NASH resolution with no worsening fibrosis. Both endpoints were surrogate endpoints, meaning that they were “reasonably likely to predict clinical benefit.” The FDA noted that it is not known if a decrease in fibrosis stage would lead to clinically meaningful outcomes, such as reduction in liver-related events.
The committee members voted 15-1 to defer approval until clinical outcome data is submitted and reviewed. The FDA has set a target decision date regarding the accelerated approval of OCA for NASH for June 22, 2023.
A version of this article first appeared on Medscape.com.
The Food and Drug Administration’s Gastrointestinal Drugs Advisory Committee has voted against the accelerated approval of Intercept Pharmaceuticals’ obeticholic acid (OCA) for treatment of nonalcoholic steatohepatitis (NASH) with stage 2 or 3 fibrosis.
This is the second time that Intercept has sought FDA approval for OCA in treating NASH.
The committee voted 12 to 2 (with 2 abstentions) that the benefits of OCA did not outweigh the risks to this patient population. While OCA showed a modest benefit of improving fibrosis in NASH patients, safety concerns included increased risk for drug-induced liver injury (DILI), cholelithiasis, pruritus, dyslipidemia, and dysglycemia.
Committee members were most concerned with the increased risk for DILI in patients taking OCA. Intercept said that frequent monitoring for DILI in such a large eligible population – an estimated 6-8 million individuals taking the drug to treat the condition – would be difficult.
“Typically, in clinical practice, NASH patients are followed every 6-12 months, so more frequent monitoring would be a substantial change and may not be achievable outside of the clinical trial setting,” according to a briefing document released before the committee meeting.
The FDA estimates that 16.8 million U.S. adults have NASH, with 5.7 million having NASH with advanced fibrosis, according to briefing documents. NASH is the second leading cause of liver transplants in the United States and is the leading cause in women. There are currently no FDA-approved therapies to treat NASH.
OCA, sold under the commercial name Ocaliva, was first approved in 2016 to treat primary biliary cholangitis, and is prescribed at up to 10 mg per day. Intercept proposed that OCA be given in daily 25-mg doses in the treatment of precirrhotic fibrosis attributable to NASH.
In 2019, Intercept initially filed for a new drug application (NDA) for OCA for the treatment of precirrhotic fibrosis attributable to NASH but were issued a Complete Response Letter after the FDA determined that the medication had an “unfavorable risk benefit-risk assessment.” Intercept resubmitted an NDA for OCA in December 2022, including two 18-month analyses from a phase 3 study, REGENERATE (Randomized Global Phase 3 Study to Evaluate the Impact on NASH with Fibrosis of Obeticholic Acid Treatment). In the study, which included data from 931 patients, OCA 25 mg outperformed placebo in improving fibrosis with no worsening of NASH over 18 months, one of two primary endpoints of the clinical trial. The estimated risk difference ranged from 8.6 to 12.8 across different analyses, which the FDA categorized as a “modest treatment effect.”
There was no significant difference between OCA 25 mg and placebo in NASH resolution with no worsening fibrosis. Both endpoints were surrogate endpoints, meaning that they were “reasonably likely to predict clinical benefit.” The FDA noted that it is not known if a decrease in fibrosis stage would lead to clinically meaningful outcomes, such as reduction in liver-related events.
The committee members voted 15-1 to defer approval until clinical outcome data is submitted and reviewed. The FDA has set a target decision date regarding the accelerated approval of OCA for NASH for June 22, 2023.
A version of this article first appeared on Medscape.com.
The Food and Drug Administration’s Gastrointestinal Drugs Advisory Committee has voted against the accelerated approval of Intercept Pharmaceuticals’ obeticholic acid (OCA) for treatment of nonalcoholic steatohepatitis (NASH) with stage 2 or 3 fibrosis.
This is the second time that Intercept has sought FDA approval for OCA in treating NASH.
The committee voted 12 to 2 (with 2 abstentions) that the benefits of OCA did not outweigh the risks to this patient population. While OCA showed a modest benefit of improving fibrosis in NASH patients, safety concerns included increased risk for drug-induced liver injury (DILI), cholelithiasis, pruritus, dyslipidemia, and dysglycemia.
Committee members were most concerned with the increased risk for DILI in patients taking OCA. Intercept said that frequent monitoring for DILI in such a large eligible population – an estimated 6-8 million individuals taking the drug to treat the condition – would be difficult.
“Typically, in clinical practice, NASH patients are followed every 6-12 months, so more frequent monitoring would be a substantial change and may not be achievable outside of the clinical trial setting,” according to a briefing document released before the committee meeting.
The FDA estimates that 16.8 million U.S. adults have NASH, with 5.7 million having NASH with advanced fibrosis, according to briefing documents. NASH is the second leading cause of liver transplants in the United States and is the leading cause in women. There are currently no FDA-approved therapies to treat NASH.
OCA, sold under the commercial name Ocaliva, was first approved in 2016 to treat primary biliary cholangitis, and is prescribed at up to 10 mg per day. Intercept proposed that OCA be given in daily 25-mg doses in the treatment of precirrhotic fibrosis attributable to NASH.
In 2019, Intercept initially filed for a new drug application (NDA) for OCA for the treatment of precirrhotic fibrosis attributable to NASH but were issued a Complete Response Letter after the FDA determined that the medication had an “unfavorable risk benefit-risk assessment.” Intercept resubmitted an NDA for OCA in December 2022, including two 18-month analyses from a phase 3 study, REGENERATE (Randomized Global Phase 3 Study to Evaluate the Impact on NASH with Fibrosis of Obeticholic Acid Treatment). In the study, which included data from 931 patients, OCA 25 mg outperformed placebo in improving fibrosis with no worsening of NASH over 18 months, one of two primary endpoints of the clinical trial. The estimated risk difference ranged from 8.6 to 12.8 across different analyses, which the FDA categorized as a “modest treatment effect.”
There was no significant difference between OCA 25 mg and placebo in NASH resolution with no worsening fibrosis. Both endpoints were surrogate endpoints, meaning that they were “reasonably likely to predict clinical benefit.” The FDA noted that it is not known if a decrease in fibrosis stage would lead to clinically meaningful outcomes, such as reduction in liver-related events.
The committee members voted 15-1 to defer approval until clinical outcome data is submitted and reviewed. The FDA has set a target decision date regarding the accelerated approval of OCA for NASH for June 22, 2023.
A version of this article first appeared on Medscape.com.
Study says casual pot use harmful to teens
Teenagers who use cannabis recreationally are two to three times more likely to have depression and suicidal thoughts than those who don’t use it. And teens who have cannabis use disorder – which means they can’t stop using it despite health and social problems – are four times more likely to have those same thoughts and feelings.
The study was published in JAMA. It looked at information from 68,000 teens in the National Survey on Drug Use and Health.
Marijuana use was also linked to other issues including not doing well in school, skipping school, and getting in trouble with the police. 
“Kids, year by year, have been moving towards a view that marijuana is safe and benign – that’s factually incorrect,” lead author of the study, Ryan Sultan, MD, an assistant professor of clinical psychiatry at Columbia University, New York, told Yahoo Life.
Dr. Sultan said he was surprised that recreational users had a much higher risk of mental health issues. “We typically think of recreational use as not being a concerning behavior.”
The study did not seek to explain the link between mental health problems and cannabis use.
“The more you use it, the more it negatively affects your thinking. That’s increasing the likelihood of depression and more suicidal thoughts,” Dr. Sultan said. “It’s feedback that spirals downward and gets to a place that really concerns us as child psychiatrists.”
Dr. Sultan said parents should talk to their children about marijuana use, depression, and anxiety.
NIDA and American Academy of Child and Adolescent Psychiatry provided funding for the study. One coauthor reported receiving grants and personal fees from several medical and sports organizations. The other authors reported no conflicts of interest.
A version of this article first appeared on WebMD.com.
Teenagers who use cannabis recreationally are two to three times more likely to have depression and suicidal thoughts than those who don’t use it. And teens who have cannabis use disorder – which means they can’t stop using it despite health and social problems – are four times more likely to have those same thoughts and feelings.
The study was published in JAMA. It looked at information from 68,000 teens in the National Survey on Drug Use and Health.
Marijuana use was also linked to other issues including not doing well in school, skipping school, and getting in trouble with the police.
“Kids, year by year, have been moving towards a view that marijuana is safe and benign – that’s factually incorrect,” lead author of the study, Ryan Sultan, MD, an assistant professor of clinical psychiatry at Columbia University, New York, told Yahoo Life.
Dr. Sultan said he was surprised that recreational users had a much higher risk of mental health issues. “We typically think of recreational use as not being a concerning behavior.”
The study did not seek to explain the link between mental health problems and cannabis use.
“The more you use it, the more it negatively affects your thinking. That’s increasing the likelihood of depression and more suicidal thoughts,” Dr. Sultan said. “It’s feedback that spirals downward and gets to a place that really concerns us as child psychiatrists.”
Dr. Sultan said parents should talk to their children about marijuana use, depression, and anxiety.
NIDA and American Academy of Child and Adolescent Psychiatry provided funding for the study. One coauthor reported receiving grants and personal fees from several medical and sports organizations. The other authors reported no conflicts of interest.
A version of this article first appeared on WebMD.com.
Teenagers who use cannabis recreationally are two to three times more likely to have depression and suicidal thoughts than those who don’t use it. And teens who have cannabis use disorder – which means they can’t stop using it despite health and social problems – are four times more likely to have those same thoughts and feelings.
The study was published in JAMA. It looked at information from 68,000 teens in the National Survey on Drug Use and Health.
Marijuana use was also linked to other issues including not doing well in school, skipping school, and getting in trouble with the police.
“Kids, year by year, have been moving towards a view that marijuana is safe and benign – that’s factually incorrect,” lead author of the study, Ryan Sultan, MD, an assistant professor of clinical psychiatry at Columbia University, New York, told Yahoo Life.
Dr. Sultan said he was surprised that recreational users had a much higher risk of mental health issues. “We typically think of recreational use as not being a concerning behavior.”
The study did not seek to explain the link between mental health problems and cannabis use.
“The more you use it, the more it negatively affects your thinking. That’s increasing the likelihood of depression and more suicidal thoughts,” Dr. Sultan said. “It’s feedback that spirals downward and gets to a place that really concerns us as child psychiatrists.”
Dr. Sultan said parents should talk to their children about marijuana use, depression, and anxiety.
NIDA and American Academy of Child and Adolescent Psychiatry provided funding for the study. One coauthor reported receiving grants and personal fees from several medical and sports organizations. The other authors reported no conflicts of interest.
A version of this article first appeared on WebMD.com.
FROM JAMA
FDA OKs first-ever topical gene therapy, for rare skin disease
(DEB), a rare skin disease.
The therapy, Vyjuvek (beremagene geperpavec, formerly known as B-VEC), uses a nonreplicating herpes simplex virus type 1 (HSV-1) vector to deliver the COL7A1 gene directly to skin cells, restoring the COL7 protein fibrils that stabilize skin structure.
Vyjuvek, developed by Krystal Biotech, is designed to be used repetitively to heal a single wound or on more than one wound. In the pivotal study, the gene therapy, delivered in a topical gel, was administered once a week for 6 months.
The FDA gave Vyjuvek priority review, approving the therapy just 9 months after Krystal filed its application for approval. Vyjuvek is also an orphan drug, giving it potentially 7 years of marketing exclusivity.
“Vyjuvek is the first FDA-approved gene therapy treatment for DEB, a rare and serious genetic skin disorder,” said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, in the FDA’s statement announcing the approval.
“With the FDA approval of Vyjuvek, the DEB population has reached a monumental milestone in the treatment of this horrible disorder,” said Brett Kopelan, executive director of debra of America, a national advocacy group for people with DEB, in a statement issued by Krystal Biotech. “Our hopes have now been realized for a safe and effective treatment for one of the most devastating symptoms of the disorder,” said Mr. Kopelan.
“This is a devastating disease,” said M. Peter Marinkovich, MD, primary investigator of Krystal’s pivotal GEM-3 trial and director of the Blistering Disease Clinic at Stanford Health Care, in the statement issued by Krystal. “Until now, doctors and nurses had no way to stop blisters and wounds from developing on dystrophic EB patient skin, and all we could do was to give them bandages and helplessly watch as new blisters formed,” said Dr. Marinkovich, who is also associate professor of dermatology at Stanford (Calif.) University School of Medicine.
“Because it’s safe and easy to apply directly to wounds, it doesn’t require a lot of supporting technology or specialized expertise, making Vyjuvek highly accessible even to patients who live far away from specialized centers,” he said.
Paras P. Vakharia, MD, PharmD, assistant professor of dermatology at Northwestern University, Chicago, said that Vyjuvek is an important advance for DEB. “This to me would be a treatment that I would consider for almost all patients,” Dr. Vakharia said in an interview.
Dr. Vakharia, who was not involved with trials of Vyjuvek, said he had concerns about whether patients might develop antibodies to either HSV or C7 but that the greater initial worry is if Vyjuvek will be affordable and accessible. “I envision that it will be a costly medication,” he said.
Mr. Kopelan, the patient advocate, said that his organization “will continue to work closely with Krystal to assure patients have ready access to Vyjuvek.”
Krystal did not respond before press time to a request for comment on pricing.
Dystrophic epidermolysis bullosa affects 1 to 3 people per million in the United States. It is caused by mutations in the COL7A1 gene, which encodes the alpha-1 chain of collagen type VII (C7) protein. C7 forms the anchoring fibrils that attach the epidermis to the underlying dermal connective tissue. COL71A mutations that lead to defective, decreased, or absent C7 can make the skin so fragile that it tears with the slightest touch.
DEB usually presents at birth and is divided into two major types depending on the inheritance pattern: recessive dystrophic epidermolysis bullosa and dominant dystrophic epidermolysis bullosa.
People with the dominant form typically have mild cases with blistering primarily on the hands, feet, knees, and elbows. The recessive form can be painful and debilitating, causing widespread blistering. Depending on the severity, it can lead to nonhealing wounds, fusing of fingers and toes, anemia, weak bones, and esophageal and genitourinary strictures. Squamous cell cancers are a frequent cause of death.
Vyjuvek is mixed into an inactive gel and is evenly applied to a wound once a week by a health care professional, according to the FDA.
The agency recommends the following precautions for patients and caregivers:
- Avoid direct contact with treated wounds and dressings of treated wounds for 24 hours following application. Clean any area that is accidentally exposed.
- Wash hands and wear protective gloves when changing wound dressings.
- Disinfect the bandages used for the first dressing with a viricidal agent, such as 70% isopropyl alcohol, 6% hydrogen peroxide, or less than 0.4% ammonium chloride, and dispose of them in a separate, sealed plastic bag in household waste. Subsequent used dressings and cleaning materials should be disposed of in sealed plastic bags in household waste.
FDA approval of Vyjuvek was based on a randomized, double-blinded, placebo-controlled, 31-patient, phase 3 trial published in the New England Journal of Medicine, which showed that 71% of wounds treated with the gene therapy had complete healing at 3 months, compared with 20% of those treated with placebo (95% confidence interval, 29-73; P < .001). At 6 months, 67% of wounds treated with the gene therapy had complete healing, compared with 22% of wounds treated with placebo (95% CI, 24-68; P = .002).
Almost two-thirds of the patients had at least one adverse event. Most were mild or moderate. The most common events were pruritus, chills, and squamous cell carcinoma, reported in three patients each. SCC cases occurred at wound sites that had not been exposed to Vyjuvek or placebo. Serious adverse events, which were unrelated to the treatment, occurred in three patients and included diarrhea, anemia, and cellulitis.
Krystal will also be seeking marketing approval for Vyjuvek in the European Union, likely in 2024, said the company. In September, the European Medicines Agency’s Pediatric Committee issued a positive opinion on the gene therapy and Krystal’s plan to test B-VEC in children.
Dr. Marinkovich and Dr. Vakharia have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
(DEB), a rare skin disease.
The therapy, Vyjuvek (beremagene geperpavec, formerly known as B-VEC), uses a nonreplicating herpes simplex virus type 1 (HSV-1) vector to deliver the COL7A1 gene directly to skin cells, restoring the COL7 protein fibrils that stabilize skin structure.
Vyjuvek, developed by Krystal Biotech, is designed to be used repetitively to heal a single wound or on more than one wound. In the pivotal study, the gene therapy, delivered in a topical gel, was administered once a week for 6 months.
The FDA gave Vyjuvek priority review, approving the therapy just 9 months after Krystal filed its application for approval. Vyjuvek is also an orphan drug, giving it potentially 7 years of marketing exclusivity.
“Vyjuvek is the first FDA-approved gene therapy treatment for DEB, a rare and serious genetic skin disorder,” said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, in the FDA’s statement announcing the approval.
“With the FDA approval of Vyjuvek, the DEB population has reached a monumental milestone in the treatment of this horrible disorder,” said Brett Kopelan, executive director of debra of America, a national advocacy group for people with DEB, in a statement issued by Krystal Biotech. “Our hopes have now been realized for a safe and effective treatment for one of the most devastating symptoms of the disorder,” said Mr. Kopelan.
“This is a devastating disease,” said M. Peter Marinkovich, MD, primary investigator of Krystal’s pivotal GEM-3 trial and director of the Blistering Disease Clinic at Stanford Health Care, in the statement issued by Krystal. “Until now, doctors and nurses had no way to stop blisters and wounds from developing on dystrophic EB patient skin, and all we could do was to give them bandages and helplessly watch as new blisters formed,” said Dr. Marinkovich, who is also associate professor of dermatology at Stanford (Calif.) University School of Medicine.
“Because it’s safe and easy to apply directly to wounds, it doesn’t require a lot of supporting technology or specialized expertise, making Vyjuvek highly accessible even to patients who live far away from specialized centers,” he said.
Paras P. Vakharia, MD, PharmD, assistant professor of dermatology at Northwestern University, Chicago, said that Vyjuvek is an important advance for DEB. “This to me would be a treatment that I would consider for almost all patients,” Dr. Vakharia said in an interview.
Dr. Vakharia, who was not involved with trials of Vyjuvek, said he had concerns about whether patients might develop antibodies to either HSV or C7 but that the greater initial worry is if Vyjuvek will be affordable and accessible. “I envision that it will be a costly medication,” he said.
Mr. Kopelan, the patient advocate, said that his organization “will continue to work closely with Krystal to assure patients have ready access to Vyjuvek.”
Krystal did not respond before press time to a request for comment on pricing.
Dystrophic epidermolysis bullosa affects 1 to 3 people per million in the United States. It is caused by mutations in the COL7A1 gene, which encodes the alpha-1 chain of collagen type VII (C7) protein. C7 forms the anchoring fibrils that attach the epidermis to the underlying dermal connective tissue. COL71A mutations that lead to defective, decreased, or absent C7 can make the skin so fragile that it tears with the slightest touch.
DEB usually presents at birth and is divided into two major types depending on the inheritance pattern: recessive dystrophic epidermolysis bullosa and dominant dystrophic epidermolysis bullosa.
People with the dominant form typically have mild cases with blistering primarily on the hands, feet, knees, and elbows. The recessive form can be painful and debilitating, causing widespread blistering. Depending on the severity, it can lead to nonhealing wounds, fusing of fingers and toes, anemia, weak bones, and esophageal and genitourinary strictures. Squamous cell cancers are a frequent cause of death.
Vyjuvek is mixed into an inactive gel and is evenly applied to a wound once a week by a health care professional, according to the FDA.
The agency recommends the following precautions for patients and caregivers:
- Avoid direct contact with treated wounds and dressings of treated wounds for 24 hours following application. Clean any area that is accidentally exposed.
- Wash hands and wear protective gloves when changing wound dressings.
- Disinfect the bandages used for the first dressing with a viricidal agent, such as 70% isopropyl alcohol, 6% hydrogen peroxide, or less than 0.4% ammonium chloride, and dispose of them in a separate, sealed plastic bag in household waste. Subsequent used dressings and cleaning materials should be disposed of in sealed plastic bags in household waste.
FDA approval of Vyjuvek was based on a randomized, double-blinded, placebo-controlled, 31-patient, phase 3 trial published in the New England Journal of Medicine, which showed that 71% of wounds treated with the gene therapy had complete healing at 3 months, compared with 20% of those treated with placebo (95% confidence interval, 29-73; P < .001). At 6 months, 67% of wounds treated with the gene therapy had complete healing, compared with 22% of wounds treated with placebo (95% CI, 24-68; P = .002).
Almost two-thirds of the patients had at least one adverse event. Most were mild or moderate. The most common events were pruritus, chills, and squamous cell carcinoma, reported in three patients each. SCC cases occurred at wound sites that had not been exposed to Vyjuvek or placebo. Serious adverse events, which were unrelated to the treatment, occurred in three patients and included diarrhea, anemia, and cellulitis.
Krystal will also be seeking marketing approval for Vyjuvek in the European Union, likely in 2024, said the company. In September, the European Medicines Agency’s Pediatric Committee issued a positive opinion on the gene therapy and Krystal’s plan to test B-VEC in children.
Dr. Marinkovich and Dr. Vakharia have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
(DEB), a rare skin disease.
The therapy, Vyjuvek (beremagene geperpavec, formerly known as B-VEC), uses a nonreplicating herpes simplex virus type 1 (HSV-1) vector to deliver the COL7A1 gene directly to skin cells, restoring the COL7 protein fibrils that stabilize skin structure.
Vyjuvek, developed by Krystal Biotech, is designed to be used repetitively to heal a single wound or on more than one wound. In the pivotal study, the gene therapy, delivered in a topical gel, was administered once a week for 6 months.
The FDA gave Vyjuvek priority review, approving the therapy just 9 months after Krystal filed its application for approval. Vyjuvek is also an orphan drug, giving it potentially 7 years of marketing exclusivity.
“Vyjuvek is the first FDA-approved gene therapy treatment for DEB, a rare and serious genetic skin disorder,” said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, in the FDA’s statement announcing the approval.
“With the FDA approval of Vyjuvek, the DEB population has reached a monumental milestone in the treatment of this horrible disorder,” said Brett Kopelan, executive director of debra of America, a national advocacy group for people with DEB, in a statement issued by Krystal Biotech. “Our hopes have now been realized for a safe and effective treatment for one of the most devastating symptoms of the disorder,” said Mr. Kopelan.
“This is a devastating disease,” said M. Peter Marinkovich, MD, primary investigator of Krystal’s pivotal GEM-3 trial and director of the Blistering Disease Clinic at Stanford Health Care, in the statement issued by Krystal. “Until now, doctors and nurses had no way to stop blisters and wounds from developing on dystrophic EB patient skin, and all we could do was to give them bandages and helplessly watch as new blisters formed,” said Dr. Marinkovich, who is also associate professor of dermatology at Stanford (Calif.) University School of Medicine.
“Because it’s safe and easy to apply directly to wounds, it doesn’t require a lot of supporting technology or specialized expertise, making Vyjuvek highly accessible even to patients who live far away from specialized centers,” he said.
Paras P. Vakharia, MD, PharmD, assistant professor of dermatology at Northwestern University, Chicago, said that Vyjuvek is an important advance for DEB. “This to me would be a treatment that I would consider for almost all patients,” Dr. Vakharia said in an interview.
Dr. Vakharia, who was not involved with trials of Vyjuvek, said he had concerns about whether patients might develop antibodies to either HSV or C7 but that the greater initial worry is if Vyjuvek will be affordable and accessible. “I envision that it will be a costly medication,” he said.
Mr. Kopelan, the patient advocate, said that his organization “will continue to work closely with Krystal to assure patients have ready access to Vyjuvek.”
Krystal did not respond before press time to a request for comment on pricing.
Dystrophic epidermolysis bullosa affects 1 to 3 people per million in the United States. It is caused by mutations in the COL7A1 gene, which encodes the alpha-1 chain of collagen type VII (C7) protein. C7 forms the anchoring fibrils that attach the epidermis to the underlying dermal connective tissue. COL71A mutations that lead to defective, decreased, or absent C7 can make the skin so fragile that it tears with the slightest touch.
DEB usually presents at birth and is divided into two major types depending on the inheritance pattern: recessive dystrophic epidermolysis bullosa and dominant dystrophic epidermolysis bullosa.
People with the dominant form typically have mild cases with blistering primarily on the hands, feet, knees, and elbows. The recessive form can be painful and debilitating, causing widespread blistering. Depending on the severity, it can lead to nonhealing wounds, fusing of fingers and toes, anemia, weak bones, and esophageal and genitourinary strictures. Squamous cell cancers are a frequent cause of death.
Vyjuvek is mixed into an inactive gel and is evenly applied to a wound once a week by a health care professional, according to the FDA.
The agency recommends the following precautions for patients and caregivers:
- Avoid direct contact with treated wounds and dressings of treated wounds for 24 hours following application. Clean any area that is accidentally exposed.
- Wash hands and wear protective gloves when changing wound dressings.
- Disinfect the bandages used for the first dressing with a viricidal agent, such as 70% isopropyl alcohol, 6% hydrogen peroxide, or less than 0.4% ammonium chloride, and dispose of them in a separate, sealed plastic bag in household waste. Subsequent used dressings and cleaning materials should be disposed of in sealed plastic bags in household waste.
FDA approval of Vyjuvek was based on a randomized, double-blinded, placebo-controlled, 31-patient, phase 3 trial published in the New England Journal of Medicine, which showed that 71% of wounds treated with the gene therapy had complete healing at 3 months, compared with 20% of those treated with placebo (95% confidence interval, 29-73; P < .001). At 6 months, 67% of wounds treated with the gene therapy had complete healing, compared with 22% of wounds treated with placebo (95% CI, 24-68; P = .002).
Almost two-thirds of the patients had at least one adverse event. Most were mild or moderate. The most common events were pruritus, chills, and squamous cell carcinoma, reported in three patients each. SCC cases occurred at wound sites that had not been exposed to Vyjuvek or placebo. Serious adverse events, which were unrelated to the treatment, occurred in three patients and included diarrhea, anemia, and cellulitis.
Krystal will also be seeking marketing approval for Vyjuvek in the European Union, likely in 2024, said the company. In September, the European Medicines Agency’s Pediatric Committee issued a positive opinion on the gene therapy and Krystal’s plan to test B-VEC in children.
Dr. Marinkovich and Dr. Vakharia have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.