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Plastic in Carotid Plaques Increased Risk of CV Event, Death
According to a new study, patients found to have microplastics and nanoplastics in their carotid artery plaque had a higher risk for death or major cardiovascular events compared with patients who had plaques where particles were not found.
, study coauthor Antonio Ceriello, MD, IRCCS MultiMedica, Milan, told this news organization.
“I believe we have demonstrated that plastics are a new risk factor for cardiovascular disease,” he added. And while plastics may have made our lives easier in many respects, it appears that the price we are paying for that is a shortening of our lives. That is not a good balance.”
The trial involved 304 patients undergoing carotid endarterectomy for asymptomatic carotid artery disease, whose excised plaque specimens were analyzed for the presence of microplastics and nanoplastics, ultimately found in almost 60% of patients.
After a mean follow-up of 34 months, patients in whom microplastics and nanoplastics were detected within the atheroma had a 4.5 times higher risk for the composite endpoint of all cause death, myocardial infarction, or stroke than those in whom these substances were not detected (hazard ratio, 4.53; 95% CI, 2.00-10.27; P < .001).
The study, led by Raffaele Marfella, MD, University of Campania Luigi Vanvitelli, Naples, Italy, was published in The New England Journal of Medicine on March 7, 2024.
The researchers say the study does not prove causality, and many other unmeasured confounding factors could have contributed to the findings.
However, Dr. Ceriello noted that many important risk factors such as diabetes, hypertension, and dyslipidemia, were controlled for.
“In this study, all the patients involved were at high risk of cardiovascular events and they were well treated with statins and antithrombotics, so the relationship between the presence of plastic particles in plaque and cardiovascular events is seen on top of good preventive therapy,” he said.
“While we cannot say for sure that we have shown a causal relationship, we found a large effect and there is a great deal of literature than supports this. We know that plastic particles can penetrate cells and act at the mitochondrial level to increase free radical production and produce chronic inflammation which is the basis for atherosclerosis,” Dr. Ceriello added.
He believes there is only one approach to addressing this issue, and that is to reduce the amount of plastic in the environment.
“Plastic is everywhere — in water pipes, in the ocean. We are hoping that this study will increase the push for government to act on this. This is even more important for the long-term health of our children, who will be exposed to high levels of plastics for the whole of their lives,” he said.
‘Strongly Suggestive of a Causal Relationship’
Commenting for this news organization, Philip J. Landrigan, MD, author of an editorial accompanying publication of the study in the NEJM, described the link as “strongly suggestive.”
“Because this was just a single observational study, it doesn’t prove cause and effect, but I think this is strongly suggestive of a causal relationship,” he said. “While there may be some other confounding factors at play, it is hard for me to imagine that these could account for a hazard ratio of 4.5 — that is a large and alarming increase in just 3 years.”
Dr. Landrigan, who is director of the Program for Global Public Health and the Common Good, Boston College, points out that although it is not known what other exposures may have contributed to the adverse outcomes in patients in this study, the finding of microplastics and nanoplastics in plaque tissue is itself a breakthrough discovery that raises a series of urgent questions. These include: “Should exposure to microplastics and nanoplastics be considered a cardiovascular risk factor? What organs in addition to the heart may be at risk? How can we reduce exposure?”
Dr. Landrigan said he was not surprised that plastic particles had been found in carotid plaques. “Previous studies have found microplastics in other tissues including the lungs, colon and placenta. Now they have turned up in the vessel wall,” he said. “But what is really striking about this study is that it suggests the presence of these plastic particles is causing serious harm.”
He says this should be a wake-up call. “It is telling us that we need to worry about the amount of plastic in our environment. And it is not something that’s going to be a problem down the line — it is affecting us now.”
Dr. Landrigan explained that plastic particles are taken into the body predominantly by ingestion, which could include drinking from plastic bottles or eating food wrapped in plastic. He said it is particularly damaging to use plastic containers to heat food in the microwave, as heating plastic up drives particles into the food. “That will really increase exposure.”
He noted that plastics are often already in the food itself, especially seafood.
“Plastics are dumped in the ocean, they break down and get picked up by the fish. Especially if you eat fish at the top of the food chain like tuna, or if you eat oysters or mussels that are filter feeders, you are more likely to ingest microplastics.”
Dr. Landrigan said he would not advise against eating fish in general, however. “Maybe tuna or other predatory fish may be an issue, but fish in general are good for us, and fish like salmon which have a mainly vegetarian diet are probably safer in this regard.”
The other route is inhalation, with these small plastic particles being widely present in the air, from sources such as vehicle tires becoming abraded from running along the highway.
While it is impossible to avoid taking in plastic completely, Dr. Landrigan says individuals can make efforts to reduce their exposure.
“People can make intelligent choices in their homes about what they purchase for themselves and their families, and they can act in their local environments and workplace to try and reduce plastics.”
He noted that 40% of all plastic currently being made is single use plastic, and that percentage is growing, with global production of plastic on track to double by 2040 and triple by 2060, and most of this rapid growth being single use plastic.
“We are all members of the broader society, and we need to become educated about the plastic situation and lobby our elected officials to come up with a good strong legally binding treaty that will place a cap on plastic production,” Dr. Landrigan said.
A version of this article appeared on Medscape.com.
According to a new study, patients found to have microplastics and nanoplastics in their carotid artery plaque had a higher risk for death or major cardiovascular events compared with patients who had plaques where particles were not found.
, study coauthor Antonio Ceriello, MD, IRCCS MultiMedica, Milan, told this news organization.
“I believe we have demonstrated that plastics are a new risk factor for cardiovascular disease,” he added. And while plastics may have made our lives easier in many respects, it appears that the price we are paying for that is a shortening of our lives. That is not a good balance.”
The trial involved 304 patients undergoing carotid endarterectomy for asymptomatic carotid artery disease, whose excised plaque specimens were analyzed for the presence of microplastics and nanoplastics, ultimately found in almost 60% of patients.
After a mean follow-up of 34 months, patients in whom microplastics and nanoplastics were detected within the atheroma had a 4.5 times higher risk for the composite endpoint of all cause death, myocardial infarction, or stroke than those in whom these substances were not detected (hazard ratio, 4.53; 95% CI, 2.00-10.27; P < .001).
The study, led by Raffaele Marfella, MD, University of Campania Luigi Vanvitelli, Naples, Italy, was published in The New England Journal of Medicine on March 7, 2024.
The researchers say the study does not prove causality, and many other unmeasured confounding factors could have contributed to the findings.
However, Dr. Ceriello noted that many important risk factors such as diabetes, hypertension, and dyslipidemia, were controlled for.
“In this study, all the patients involved were at high risk of cardiovascular events and they were well treated with statins and antithrombotics, so the relationship between the presence of plastic particles in plaque and cardiovascular events is seen on top of good preventive therapy,” he said.
“While we cannot say for sure that we have shown a causal relationship, we found a large effect and there is a great deal of literature than supports this. We know that plastic particles can penetrate cells and act at the mitochondrial level to increase free radical production and produce chronic inflammation which is the basis for atherosclerosis,” Dr. Ceriello added.
He believes there is only one approach to addressing this issue, and that is to reduce the amount of plastic in the environment.
“Plastic is everywhere — in water pipes, in the ocean. We are hoping that this study will increase the push for government to act on this. This is even more important for the long-term health of our children, who will be exposed to high levels of plastics for the whole of their lives,” he said.
‘Strongly Suggestive of a Causal Relationship’
Commenting for this news organization, Philip J. Landrigan, MD, author of an editorial accompanying publication of the study in the NEJM, described the link as “strongly suggestive.”
“Because this was just a single observational study, it doesn’t prove cause and effect, but I think this is strongly suggestive of a causal relationship,” he said. “While there may be some other confounding factors at play, it is hard for me to imagine that these could account for a hazard ratio of 4.5 — that is a large and alarming increase in just 3 years.”
Dr. Landrigan, who is director of the Program for Global Public Health and the Common Good, Boston College, points out that although it is not known what other exposures may have contributed to the adverse outcomes in patients in this study, the finding of microplastics and nanoplastics in plaque tissue is itself a breakthrough discovery that raises a series of urgent questions. These include: “Should exposure to microplastics and nanoplastics be considered a cardiovascular risk factor? What organs in addition to the heart may be at risk? How can we reduce exposure?”
Dr. Landrigan said he was not surprised that plastic particles had been found in carotid plaques. “Previous studies have found microplastics in other tissues including the lungs, colon and placenta. Now they have turned up in the vessel wall,” he said. “But what is really striking about this study is that it suggests the presence of these plastic particles is causing serious harm.”
He says this should be a wake-up call. “It is telling us that we need to worry about the amount of plastic in our environment. And it is not something that’s going to be a problem down the line — it is affecting us now.”
Dr. Landrigan explained that plastic particles are taken into the body predominantly by ingestion, which could include drinking from plastic bottles or eating food wrapped in plastic. He said it is particularly damaging to use plastic containers to heat food in the microwave, as heating plastic up drives particles into the food. “That will really increase exposure.”
He noted that plastics are often already in the food itself, especially seafood.
“Plastics are dumped in the ocean, they break down and get picked up by the fish. Especially if you eat fish at the top of the food chain like tuna, or if you eat oysters or mussels that are filter feeders, you are more likely to ingest microplastics.”
Dr. Landrigan said he would not advise against eating fish in general, however. “Maybe tuna or other predatory fish may be an issue, but fish in general are good for us, and fish like salmon which have a mainly vegetarian diet are probably safer in this regard.”
The other route is inhalation, with these small plastic particles being widely present in the air, from sources such as vehicle tires becoming abraded from running along the highway.
While it is impossible to avoid taking in plastic completely, Dr. Landrigan says individuals can make efforts to reduce their exposure.
“People can make intelligent choices in their homes about what they purchase for themselves and their families, and they can act in their local environments and workplace to try and reduce plastics.”
He noted that 40% of all plastic currently being made is single use plastic, and that percentage is growing, with global production of plastic on track to double by 2040 and triple by 2060, and most of this rapid growth being single use plastic.
“We are all members of the broader society, and we need to become educated about the plastic situation and lobby our elected officials to come up with a good strong legally binding treaty that will place a cap on plastic production,” Dr. Landrigan said.
A version of this article appeared on Medscape.com.
According to a new study, patients found to have microplastics and nanoplastics in their carotid artery plaque had a higher risk for death or major cardiovascular events compared with patients who had plaques where particles were not found.
, study coauthor Antonio Ceriello, MD, IRCCS MultiMedica, Milan, told this news organization.
“I believe we have demonstrated that plastics are a new risk factor for cardiovascular disease,” he added. And while plastics may have made our lives easier in many respects, it appears that the price we are paying for that is a shortening of our lives. That is not a good balance.”
The trial involved 304 patients undergoing carotid endarterectomy for asymptomatic carotid artery disease, whose excised plaque specimens were analyzed for the presence of microplastics and nanoplastics, ultimately found in almost 60% of patients.
After a mean follow-up of 34 months, patients in whom microplastics and nanoplastics were detected within the atheroma had a 4.5 times higher risk for the composite endpoint of all cause death, myocardial infarction, or stroke than those in whom these substances were not detected (hazard ratio, 4.53; 95% CI, 2.00-10.27; P < .001).
The study, led by Raffaele Marfella, MD, University of Campania Luigi Vanvitelli, Naples, Italy, was published in The New England Journal of Medicine on March 7, 2024.
The researchers say the study does not prove causality, and many other unmeasured confounding factors could have contributed to the findings.
However, Dr. Ceriello noted that many important risk factors such as diabetes, hypertension, and dyslipidemia, were controlled for.
“In this study, all the patients involved were at high risk of cardiovascular events and they were well treated with statins and antithrombotics, so the relationship between the presence of plastic particles in plaque and cardiovascular events is seen on top of good preventive therapy,” he said.
“While we cannot say for sure that we have shown a causal relationship, we found a large effect and there is a great deal of literature than supports this. We know that plastic particles can penetrate cells and act at the mitochondrial level to increase free radical production and produce chronic inflammation which is the basis for atherosclerosis,” Dr. Ceriello added.
He believes there is only one approach to addressing this issue, and that is to reduce the amount of plastic in the environment.
“Plastic is everywhere — in water pipes, in the ocean. We are hoping that this study will increase the push for government to act on this. This is even more important for the long-term health of our children, who will be exposed to high levels of plastics for the whole of their lives,” he said.
‘Strongly Suggestive of a Causal Relationship’
Commenting for this news organization, Philip J. Landrigan, MD, author of an editorial accompanying publication of the study in the NEJM, described the link as “strongly suggestive.”
“Because this was just a single observational study, it doesn’t prove cause and effect, but I think this is strongly suggestive of a causal relationship,” he said. “While there may be some other confounding factors at play, it is hard for me to imagine that these could account for a hazard ratio of 4.5 — that is a large and alarming increase in just 3 years.”
Dr. Landrigan, who is director of the Program for Global Public Health and the Common Good, Boston College, points out that although it is not known what other exposures may have contributed to the adverse outcomes in patients in this study, the finding of microplastics and nanoplastics in plaque tissue is itself a breakthrough discovery that raises a series of urgent questions. These include: “Should exposure to microplastics and nanoplastics be considered a cardiovascular risk factor? What organs in addition to the heart may be at risk? How can we reduce exposure?”
Dr. Landrigan said he was not surprised that plastic particles had been found in carotid plaques. “Previous studies have found microplastics in other tissues including the lungs, colon and placenta. Now they have turned up in the vessel wall,” he said. “But what is really striking about this study is that it suggests the presence of these plastic particles is causing serious harm.”
He says this should be a wake-up call. “It is telling us that we need to worry about the amount of plastic in our environment. And it is not something that’s going to be a problem down the line — it is affecting us now.”
Dr. Landrigan explained that plastic particles are taken into the body predominantly by ingestion, which could include drinking from plastic bottles or eating food wrapped in plastic. He said it is particularly damaging to use plastic containers to heat food in the microwave, as heating plastic up drives particles into the food. “That will really increase exposure.”
He noted that plastics are often already in the food itself, especially seafood.
“Plastics are dumped in the ocean, they break down and get picked up by the fish. Especially if you eat fish at the top of the food chain like tuna, or if you eat oysters or mussels that are filter feeders, you are more likely to ingest microplastics.”
Dr. Landrigan said he would not advise against eating fish in general, however. “Maybe tuna or other predatory fish may be an issue, but fish in general are good for us, and fish like salmon which have a mainly vegetarian diet are probably safer in this regard.”
The other route is inhalation, with these small plastic particles being widely present in the air, from sources such as vehicle tires becoming abraded from running along the highway.
While it is impossible to avoid taking in plastic completely, Dr. Landrigan says individuals can make efforts to reduce their exposure.
“People can make intelligent choices in their homes about what they purchase for themselves and their families, and they can act in their local environments and workplace to try and reduce plastics.”
He noted that 40% of all plastic currently being made is single use plastic, and that percentage is growing, with global production of plastic on track to double by 2040 and triple by 2060, and most of this rapid growth being single use plastic.
“We are all members of the broader society, and we need to become educated about the plastic situation and lobby our elected officials to come up with a good strong legally binding treaty that will place a cap on plastic production,” Dr. Landrigan said.
A version of this article appeared on Medscape.com.
Drug Derived from LSD Granted FDA Breakthrough Status for Anxiety
The US Food and Drug Administration (FDA) has granted breakthrough designation to an LSD-based treatment for generalized anxiety disorder (GAD) based on promising topline data from a phase 2b clinical trial. Mind Medicine (MindMed) Inc is developing the treatment — MM120 (lysergide d-tartrate).
In a news release,
The company previously announced statistically significant improvements on the HAM-A compared with placebo at 4 weeks, which was the trial’s primary endpoint.
“I’ve conducted clinical research studies in psychiatry for over two decades and have seen studies of many drugs under development for the treatment of anxiety. That MM120 exhibited rapid and robust efficacy, solidly sustained for 12 weeks after a single dose, is truly remarkable,” study investigator David Feifel, MD, PhD, professor emeritus of psychiatry at the University of California, San Diego, and director of the Kadima Neuropsychiatry Institute in La Jolla, California, said in the news release.
“These results suggest the potential MM120 has in the treatment of anxiety, and those of us who struggle every day to alleviate anxiety in our patients look forward to seeing results from future phase 3 trials,” Dr. Feifel added.
MM120 was administered as a single dose in a monitored clinical setting with no additional therapeutic intervention. Prior to treatment with MM120, study participants were clinically tapered and then washed out from any anxiolytic or antidepressant treatments and did not receive any form of study-related psychotherapy for the duration of their participation in the study.
MM120 100 µg — the dose that demonstrated optimal clinical activity — produced a 7.7-point improvement over placebo at week 12 (P < .003; Cohen’s d = 0.81), with a 65% clinical response rate and a 48% clinical remission rate sustained to week 12.
Also at week 12, Clinical Global Impressions–Severity (CGI-S) scores on average improved from 4.8 to 2.2 in the 100-µg dose group, representing a two-category shift from ‘markedly ill’ to ‘borderline ill’ at week 12 (P < .004), the company reported.
Improvement was noted as early as study day 2, and durable with further improvements observed in mean HAM-A or CGI-S scores between 4 and 12 weeks.
MM120 was generally well-tolerated with most adverse events rated as mild to moderate and transient and occurred on the day of administration day, in line with the expected acute effects of the study drug.
The most common adverse events on dosing day included illusion, hallucinations, euphoric mood, anxiety, abnormal thinking, headache, paresthesia, dizziness, tremor, nausea, vomiting, feeling abnormal, mydriasis, and hyperhidrosis.
The company plans to hold an end-of-phase 2 meeting with the FDA in the first half of 2024 and start phase 3 testing in the second half of 2024.
“The FDA’s decision to designate MM120 as a breakthrough therapy for GAD and the durability data from our phase 2b study provide further validation of the important potential role this treatment can play in addressing the huge unmet need among individuals living with GAD,” Robert Barrow, director and CEO of MindMed said in the release.
The primary data analyses from the trial will be presented at the American Psychiatric Association (APA) annual meeting in May.
A version of this article appeared on Medscape.com.
The US Food and Drug Administration (FDA) has granted breakthrough designation to an LSD-based treatment for generalized anxiety disorder (GAD) based on promising topline data from a phase 2b clinical trial. Mind Medicine (MindMed) Inc is developing the treatment — MM120 (lysergide d-tartrate).
In a news release,
The company previously announced statistically significant improvements on the HAM-A compared with placebo at 4 weeks, which was the trial’s primary endpoint.
“I’ve conducted clinical research studies in psychiatry for over two decades and have seen studies of many drugs under development for the treatment of anxiety. That MM120 exhibited rapid and robust efficacy, solidly sustained for 12 weeks after a single dose, is truly remarkable,” study investigator David Feifel, MD, PhD, professor emeritus of psychiatry at the University of California, San Diego, and director of the Kadima Neuropsychiatry Institute in La Jolla, California, said in the news release.
“These results suggest the potential MM120 has in the treatment of anxiety, and those of us who struggle every day to alleviate anxiety in our patients look forward to seeing results from future phase 3 trials,” Dr. Feifel added.
MM120 was administered as a single dose in a monitored clinical setting with no additional therapeutic intervention. Prior to treatment with MM120, study participants were clinically tapered and then washed out from any anxiolytic or antidepressant treatments and did not receive any form of study-related psychotherapy for the duration of their participation in the study.
MM120 100 µg — the dose that demonstrated optimal clinical activity — produced a 7.7-point improvement over placebo at week 12 (P < .003; Cohen’s d = 0.81), with a 65% clinical response rate and a 48% clinical remission rate sustained to week 12.
Also at week 12, Clinical Global Impressions–Severity (CGI-S) scores on average improved from 4.8 to 2.2 in the 100-µg dose group, representing a two-category shift from ‘markedly ill’ to ‘borderline ill’ at week 12 (P < .004), the company reported.
Improvement was noted as early as study day 2, and durable with further improvements observed in mean HAM-A or CGI-S scores between 4 and 12 weeks.
MM120 was generally well-tolerated with most adverse events rated as mild to moderate and transient and occurred on the day of administration day, in line with the expected acute effects of the study drug.
The most common adverse events on dosing day included illusion, hallucinations, euphoric mood, anxiety, abnormal thinking, headache, paresthesia, dizziness, tremor, nausea, vomiting, feeling abnormal, mydriasis, and hyperhidrosis.
The company plans to hold an end-of-phase 2 meeting with the FDA in the first half of 2024 and start phase 3 testing in the second half of 2024.
“The FDA’s decision to designate MM120 as a breakthrough therapy for GAD and the durability data from our phase 2b study provide further validation of the important potential role this treatment can play in addressing the huge unmet need among individuals living with GAD,” Robert Barrow, director and CEO of MindMed said in the release.
The primary data analyses from the trial will be presented at the American Psychiatric Association (APA) annual meeting in May.
A version of this article appeared on Medscape.com.
The US Food and Drug Administration (FDA) has granted breakthrough designation to an LSD-based treatment for generalized anxiety disorder (GAD) based on promising topline data from a phase 2b clinical trial. Mind Medicine (MindMed) Inc is developing the treatment — MM120 (lysergide d-tartrate).
In a news release,
The company previously announced statistically significant improvements on the HAM-A compared with placebo at 4 weeks, which was the trial’s primary endpoint.
“I’ve conducted clinical research studies in psychiatry for over two decades and have seen studies of many drugs under development for the treatment of anxiety. That MM120 exhibited rapid and robust efficacy, solidly sustained for 12 weeks after a single dose, is truly remarkable,” study investigator David Feifel, MD, PhD, professor emeritus of psychiatry at the University of California, San Diego, and director of the Kadima Neuropsychiatry Institute in La Jolla, California, said in the news release.
“These results suggest the potential MM120 has in the treatment of anxiety, and those of us who struggle every day to alleviate anxiety in our patients look forward to seeing results from future phase 3 trials,” Dr. Feifel added.
MM120 was administered as a single dose in a monitored clinical setting with no additional therapeutic intervention. Prior to treatment with MM120, study participants were clinically tapered and then washed out from any anxiolytic or antidepressant treatments and did not receive any form of study-related psychotherapy for the duration of their participation in the study.
MM120 100 µg — the dose that demonstrated optimal clinical activity — produced a 7.7-point improvement over placebo at week 12 (P < .003; Cohen’s d = 0.81), with a 65% clinical response rate and a 48% clinical remission rate sustained to week 12.
Also at week 12, Clinical Global Impressions–Severity (CGI-S) scores on average improved from 4.8 to 2.2 in the 100-µg dose group, representing a two-category shift from ‘markedly ill’ to ‘borderline ill’ at week 12 (P < .004), the company reported.
Improvement was noted as early as study day 2, and durable with further improvements observed in mean HAM-A or CGI-S scores between 4 and 12 weeks.
MM120 was generally well-tolerated with most adverse events rated as mild to moderate and transient and occurred on the day of administration day, in line with the expected acute effects of the study drug.
The most common adverse events on dosing day included illusion, hallucinations, euphoric mood, anxiety, abnormal thinking, headache, paresthesia, dizziness, tremor, nausea, vomiting, feeling abnormal, mydriasis, and hyperhidrosis.
The company plans to hold an end-of-phase 2 meeting with the FDA in the first half of 2024 and start phase 3 testing in the second half of 2024.
“The FDA’s decision to designate MM120 as a breakthrough therapy for GAD and the durability data from our phase 2b study provide further validation of the important potential role this treatment can play in addressing the huge unmet need among individuals living with GAD,” Robert Barrow, director and CEO of MindMed said in the release.
The primary data analyses from the trial will be presented at the American Psychiatric Association (APA) annual meeting in May.
A version of this article appeared on Medscape.com.
Zanubrutinib Label Expands to Include RR Follicular Lymphoma
Approval was based on the ROSEWOOD trial, which included 217 adults with relapsed or refractory follicular lymphoma randomized 2:1 to obinutuzumab plus zanubrutinib 160 mg orally twice daily until disease progression or unacceptable toxicity or to obinutuzumab alone. Participants had a median of three prior lines of treatment and as many as 11.
The overall response rate was 69% with zanubrutinib add-on vs 46% with stand-alone obinutuzumab (P = .0012). After a median follow-up of 19 months, the median duration of response was 14 months with obinutuzumab alone but not reached in the combination arm and estimated to be 69% at 18 months.
Across clinical trials, the most common adverse events with zanubrutinib were decreased neutrophil counts (51%), decreased platelet counts (41%), upper respiratory tract infection (38%), hemorrhage (32%), and musculoskeletal pain (31%). Serious adverse reactions occurred in 35% of patients.
The recommended zanubrutinib dose is 160 mg taken orally twice daily or 320 mg taken orally once daily until disease progression or unacceptable toxicity.
Previously approved indications for the kinase inhibitor include mantle cell lymphoma, Waldenström’s macroglobulinemia, chronic lymphocytic leukemia, and small lymphocytic lymphoma.
According to drugs.com, 120 80-mg capsules cost $15,874.
A version of this article appeared on Medscape.com .
Approval was based on the ROSEWOOD trial, which included 217 adults with relapsed or refractory follicular lymphoma randomized 2:1 to obinutuzumab plus zanubrutinib 160 mg orally twice daily until disease progression or unacceptable toxicity or to obinutuzumab alone. Participants had a median of three prior lines of treatment and as many as 11.
The overall response rate was 69% with zanubrutinib add-on vs 46% with stand-alone obinutuzumab (P = .0012). After a median follow-up of 19 months, the median duration of response was 14 months with obinutuzumab alone but not reached in the combination arm and estimated to be 69% at 18 months.
Across clinical trials, the most common adverse events with zanubrutinib were decreased neutrophil counts (51%), decreased platelet counts (41%), upper respiratory tract infection (38%), hemorrhage (32%), and musculoskeletal pain (31%). Serious adverse reactions occurred in 35% of patients.
The recommended zanubrutinib dose is 160 mg taken orally twice daily or 320 mg taken orally once daily until disease progression or unacceptable toxicity.
Previously approved indications for the kinase inhibitor include mantle cell lymphoma, Waldenström’s macroglobulinemia, chronic lymphocytic leukemia, and small lymphocytic lymphoma.
According to drugs.com, 120 80-mg capsules cost $15,874.
A version of this article appeared on Medscape.com .
Approval was based on the ROSEWOOD trial, which included 217 adults with relapsed or refractory follicular lymphoma randomized 2:1 to obinutuzumab plus zanubrutinib 160 mg orally twice daily until disease progression or unacceptable toxicity or to obinutuzumab alone. Participants had a median of three prior lines of treatment and as many as 11.
The overall response rate was 69% with zanubrutinib add-on vs 46% with stand-alone obinutuzumab (P = .0012). After a median follow-up of 19 months, the median duration of response was 14 months with obinutuzumab alone but not reached in the combination arm and estimated to be 69% at 18 months.
Across clinical trials, the most common adverse events with zanubrutinib were decreased neutrophil counts (51%), decreased platelet counts (41%), upper respiratory tract infection (38%), hemorrhage (32%), and musculoskeletal pain (31%). Serious adverse reactions occurred in 35% of patients.
The recommended zanubrutinib dose is 160 mg taken orally twice daily or 320 mg taken orally once daily until disease progression or unacceptable toxicity.
Previously approved indications for the kinase inhibitor include mantle cell lymphoma, Waldenström’s macroglobulinemia, chronic lymphocytic leukemia, and small lymphocytic lymphoma.
According to drugs.com, 120 80-mg capsules cost $15,874.
A version of this article appeared on Medscape.com .
Sulfites Selected as ACDS Allergen of the Year
by the American Contact Dermatitis Society (ACDS).
Sulfites are currently not found in most screening patch test series, so may be missed as a relevant contact allergen, Donald V. Belsito, MD, emeritus professor in the Department of Dermatology at Columbia University, New York City, said in his presentation on the Allergen of the Year on March 7 at the annual meeting of the American Contact Dermatitis Society in San Diego. Sulfites, he noted, are distinct from sulfates, and the groups do not cross-react with each other.
Sodium disulfite, an inorganic compound, belongs to a group of sulfiting agents, which contain the sulfite ion SO32− and include ammonium sulfite, potassium sulfite, and sodium sulfite, Dr. Belsito said. Sulfites function as antioxidants and preservatives in a range of products including food and beverages, personal care products, and pharmaceuticals.
The type of sulfite allergy diagnosed by patch testing is type IV hypersensitivity or delayed-type hypersensitivity, where patients present with pruritic, red, scaling macules, papulovesicles, and patches, Dr. Belsito told this news organization. “It is not the type I, immediate hypersensitivity that causes hives and, in some cases, anaphylaxis,” he said. Sulfites also can cause these side effects, so correct labeling of food and beverages is important, he noted.
Some common nonoccupational sulfite sources include hair coloring and bleach products, hairspray, tanning lotions, makeup, sunscreens, and deodorants, Dr. Belsito said in his presentation. Medications including topical antifungals, topical corticosteroids, and nasal solutions can be culprits, as can water in swimming pools, he noted.
In occupational settings, sulfites may be present not only in food and drink products but also can be used in production of products, such as those used for sterilization during beer and wine fermentation, Dr. Belsito said. Other potential occupational sources of sulfite exposure include healthcare settings and textile, chemical, rubber, and pharmaceutical manufacturing.
High-sulfite food products (> 100 ppm) to be aware of include dried fruit (raisins and prunes are exceptions), bottled lemon or lime juice (but not frozen products), wine, molasses, grape juice (white, or white, pink, and red sparkling), and pickled cocktail onions, Dr. Belsito said.
“Like other contact allergens, the clinical presentation correlates with exposure,” he added. A study by the North American Contact Dermatitis Group (NACDG) found that 28.8% of patients positive for sulfite allergy on patch testing presented with facial dermatitis, which was not only related to cosmetics and medications used on the face but also from products, such as shampoo, used on the scalp that dripped onto the face. “The scalp is relatively resistant to the expression of contact allergy and may not be involved at all,” he said.
According to the NACDG study, the hands were the second most common site of dermatitis associated with sulfites (20.5%) followed by generalized distribution (13.6%). These sites are to be expected, given the sources of food and beverage, personal care products, and occupational materials, Dr. Belsito said.
“Eczematous dermatitis of the lips is also common in patients with ingested food sources of sulfites,” he said.
Systemic contact dermatitis to sulfites has been documented following oral, rectal, and parental exposure, Dr. Belsito told this news organization. “Systemic dermatitis may present as a scattered/generalized dermatitis, symmetrical drug-related intertriginous and flexural exanthema (also referred to as baboon syndrome), or erythroderma,” he said.
How to Spot Sulfite Allergies
The exclusion of sulfites from most patch test series means that sulfite allergy diagnoses are often missed, despite the wide range of potential exposures, Dr. Belsito said.
“Most cases of allergic contact dermatitis occur at the site of application of the allergen,” he noted. Depending on the location of the dermatitis, a detailed history of exposures that includes cosmetics and topical medications, work-related materials, and foods and beverages might suggest a sulfite allergy, he said.
Given the range of potential clinical presentations and the many and varied exposures to sulfites, Dr. Belsito’s best tip for clinicians is to routinely screen for them and evaluate the many avenues of exposure if a patch test is positive, he said.
For now, he said he does not think additional research is needed on sulfites as allergens; instead, sulfites, such as sodium metabisulfite/sodium disulfite, should be included in all clinicians’ baseline screening series, he said.
The Allergen of the Year was also recently announced in the journal Dermatitis. Authors Samuel F. Ekstein, MS, and Erin M. Warshaw, MD, from the Department of Dermatology, Park Nicollet Health Services, Minneapolis, Minnesota, noted that the ACDS hoped to raise awareness of sulfites as a “significant allergen” and called for their increased inclusion in screening patch test series.
Patients identified with sulfite allergies can find alternative products on the ACDS CAMP (Contact Allergen Management Program) website, Dr. Warshaw said in an interview.
She also highlighted some examples of sulfites as allergens in healthcare settings in particular. She described one patient who presented with dermatitis at the site of three previous hand orthopedic procedures.
“Although surgical cleansers were suspected, the patient reacted to sodium metabisulfite. Review of the operating room contactants confirmed sulfites as preservatives in an injectable anesthetic and antibiotic used for wound irrigation,” she said. Another patient who had been treated for recurrent otitis externa and seborrheic dermatitis was found to be allergic to sulfites in an otic antibiotic suspension as well as in a ketoconazole cream product, she added.
In the paper, Dr. Warshaw and Mr. Ekstein called for the addition of sulfites to the test series. Although the NACDG added sodium metabisulfite to the series in 2017, sulfites are not part of the American Contact Dermatitis Core Series, they wrote. Sodium metabisulfite, they said, was added to the European baseline standard series after review of the 2019-2020 patch test reactivity and clinical relevance data.
The ACDS meeting is held every year the day before the annual meeting of the American Academy of Dermatology.
Dr. Belsito and Dr. Warshaw had no financial conflicts to disclose.
A version of this article appeared on Medscape.com.
by the American Contact Dermatitis Society (ACDS).
Sulfites are currently not found in most screening patch test series, so may be missed as a relevant contact allergen, Donald V. Belsito, MD, emeritus professor in the Department of Dermatology at Columbia University, New York City, said in his presentation on the Allergen of the Year on March 7 at the annual meeting of the American Contact Dermatitis Society in San Diego. Sulfites, he noted, are distinct from sulfates, and the groups do not cross-react with each other.
Sodium disulfite, an inorganic compound, belongs to a group of sulfiting agents, which contain the sulfite ion SO32− and include ammonium sulfite, potassium sulfite, and sodium sulfite, Dr. Belsito said. Sulfites function as antioxidants and preservatives in a range of products including food and beverages, personal care products, and pharmaceuticals.
The type of sulfite allergy diagnosed by patch testing is type IV hypersensitivity or delayed-type hypersensitivity, where patients present with pruritic, red, scaling macules, papulovesicles, and patches, Dr. Belsito told this news organization. “It is not the type I, immediate hypersensitivity that causes hives and, in some cases, anaphylaxis,” he said. Sulfites also can cause these side effects, so correct labeling of food and beverages is important, he noted.
Some common nonoccupational sulfite sources include hair coloring and bleach products, hairspray, tanning lotions, makeup, sunscreens, and deodorants, Dr. Belsito said in his presentation. Medications including topical antifungals, topical corticosteroids, and nasal solutions can be culprits, as can water in swimming pools, he noted.
In occupational settings, sulfites may be present not only in food and drink products but also can be used in production of products, such as those used for sterilization during beer and wine fermentation, Dr. Belsito said. Other potential occupational sources of sulfite exposure include healthcare settings and textile, chemical, rubber, and pharmaceutical manufacturing.
High-sulfite food products (> 100 ppm) to be aware of include dried fruit (raisins and prunes are exceptions), bottled lemon or lime juice (but not frozen products), wine, molasses, grape juice (white, or white, pink, and red sparkling), and pickled cocktail onions, Dr. Belsito said.
“Like other contact allergens, the clinical presentation correlates with exposure,” he added. A study by the North American Contact Dermatitis Group (NACDG) found that 28.8% of patients positive for sulfite allergy on patch testing presented with facial dermatitis, which was not only related to cosmetics and medications used on the face but also from products, such as shampoo, used on the scalp that dripped onto the face. “The scalp is relatively resistant to the expression of contact allergy and may not be involved at all,” he said.
According to the NACDG study, the hands were the second most common site of dermatitis associated with sulfites (20.5%) followed by generalized distribution (13.6%). These sites are to be expected, given the sources of food and beverage, personal care products, and occupational materials, Dr. Belsito said.
“Eczematous dermatitis of the lips is also common in patients with ingested food sources of sulfites,” he said.
Systemic contact dermatitis to sulfites has been documented following oral, rectal, and parental exposure, Dr. Belsito told this news organization. “Systemic dermatitis may present as a scattered/generalized dermatitis, symmetrical drug-related intertriginous and flexural exanthema (also referred to as baboon syndrome), or erythroderma,” he said.
How to Spot Sulfite Allergies
The exclusion of sulfites from most patch test series means that sulfite allergy diagnoses are often missed, despite the wide range of potential exposures, Dr. Belsito said.
“Most cases of allergic contact dermatitis occur at the site of application of the allergen,” he noted. Depending on the location of the dermatitis, a detailed history of exposures that includes cosmetics and topical medications, work-related materials, and foods and beverages might suggest a sulfite allergy, he said.
Given the range of potential clinical presentations and the many and varied exposures to sulfites, Dr. Belsito’s best tip for clinicians is to routinely screen for them and evaluate the many avenues of exposure if a patch test is positive, he said.
For now, he said he does not think additional research is needed on sulfites as allergens; instead, sulfites, such as sodium metabisulfite/sodium disulfite, should be included in all clinicians’ baseline screening series, he said.
The Allergen of the Year was also recently announced in the journal Dermatitis. Authors Samuel F. Ekstein, MS, and Erin M. Warshaw, MD, from the Department of Dermatology, Park Nicollet Health Services, Minneapolis, Minnesota, noted that the ACDS hoped to raise awareness of sulfites as a “significant allergen” and called for their increased inclusion in screening patch test series.
Patients identified with sulfite allergies can find alternative products on the ACDS CAMP (Contact Allergen Management Program) website, Dr. Warshaw said in an interview.
She also highlighted some examples of sulfites as allergens in healthcare settings in particular. She described one patient who presented with dermatitis at the site of three previous hand orthopedic procedures.
“Although surgical cleansers were suspected, the patient reacted to sodium metabisulfite. Review of the operating room contactants confirmed sulfites as preservatives in an injectable anesthetic and antibiotic used for wound irrigation,” she said. Another patient who had been treated for recurrent otitis externa and seborrheic dermatitis was found to be allergic to sulfites in an otic antibiotic suspension as well as in a ketoconazole cream product, she added.
In the paper, Dr. Warshaw and Mr. Ekstein called for the addition of sulfites to the test series. Although the NACDG added sodium metabisulfite to the series in 2017, sulfites are not part of the American Contact Dermatitis Core Series, they wrote. Sodium metabisulfite, they said, was added to the European baseline standard series after review of the 2019-2020 patch test reactivity and clinical relevance data.
The ACDS meeting is held every year the day before the annual meeting of the American Academy of Dermatology.
Dr. Belsito and Dr. Warshaw had no financial conflicts to disclose.
A version of this article appeared on Medscape.com.
by the American Contact Dermatitis Society (ACDS).
Sulfites are currently not found in most screening patch test series, so may be missed as a relevant contact allergen, Donald V. Belsito, MD, emeritus professor in the Department of Dermatology at Columbia University, New York City, said in his presentation on the Allergen of the Year on March 7 at the annual meeting of the American Contact Dermatitis Society in San Diego. Sulfites, he noted, are distinct from sulfates, and the groups do not cross-react with each other.
Sodium disulfite, an inorganic compound, belongs to a group of sulfiting agents, which contain the sulfite ion SO32− and include ammonium sulfite, potassium sulfite, and sodium sulfite, Dr. Belsito said. Sulfites function as antioxidants and preservatives in a range of products including food and beverages, personal care products, and pharmaceuticals.
The type of sulfite allergy diagnosed by patch testing is type IV hypersensitivity or delayed-type hypersensitivity, where patients present with pruritic, red, scaling macules, papulovesicles, and patches, Dr. Belsito told this news organization. “It is not the type I, immediate hypersensitivity that causes hives and, in some cases, anaphylaxis,” he said. Sulfites also can cause these side effects, so correct labeling of food and beverages is important, he noted.
Some common nonoccupational sulfite sources include hair coloring and bleach products, hairspray, tanning lotions, makeup, sunscreens, and deodorants, Dr. Belsito said in his presentation. Medications including topical antifungals, topical corticosteroids, and nasal solutions can be culprits, as can water in swimming pools, he noted.
In occupational settings, sulfites may be present not only in food and drink products but also can be used in production of products, such as those used for sterilization during beer and wine fermentation, Dr. Belsito said. Other potential occupational sources of sulfite exposure include healthcare settings and textile, chemical, rubber, and pharmaceutical manufacturing.
High-sulfite food products (> 100 ppm) to be aware of include dried fruit (raisins and prunes are exceptions), bottled lemon or lime juice (but not frozen products), wine, molasses, grape juice (white, or white, pink, and red sparkling), and pickled cocktail onions, Dr. Belsito said.
“Like other contact allergens, the clinical presentation correlates with exposure,” he added. A study by the North American Contact Dermatitis Group (NACDG) found that 28.8% of patients positive for sulfite allergy on patch testing presented with facial dermatitis, which was not only related to cosmetics and medications used on the face but also from products, such as shampoo, used on the scalp that dripped onto the face. “The scalp is relatively resistant to the expression of contact allergy and may not be involved at all,” he said.
According to the NACDG study, the hands were the second most common site of dermatitis associated with sulfites (20.5%) followed by generalized distribution (13.6%). These sites are to be expected, given the sources of food and beverage, personal care products, and occupational materials, Dr. Belsito said.
“Eczematous dermatitis of the lips is also common in patients with ingested food sources of sulfites,” he said.
Systemic contact dermatitis to sulfites has been documented following oral, rectal, and parental exposure, Dr. Belsito told this news organization. “Systemic dermatitis may present as a scattered/generalized dermatitis, symmetrical drug-related intertriginous and flexural exanthema (also referred to as baboon syndrome), or erythroderma,” he said.
How to Spot Sulfite Allergies
The exclusion of sulfites from most patch test series means that sulfite allergy diagnoses are often missed, despite the wide range of potential exposures, Dr. Belsito said.
“Most cases of allergic contact dermatitis occur at the site of application of the allergen,” he noted. Depending on the location of the dermatitis, a detailed history of exposures that includes cosmetics and topical medications, work-related materials, and foods and beverages might suggest a sulfite allergy, he said.
Given the range of potential clinical presentations and the many and varied exposures to sulfites, Dr. Belsito’s best tip for clinicians is to routinely screen for them and evaluate the many avenues of exposure if a patch test is positive, he said.
For now, he said he does not think additional research is needed on sulfites as allergens; instead, sulfites, such as sodium metabisulfite/sodium disulfite, should be included in all clinicians’ baseline screening series, he said.
The Allergen of the Year was also recently announced in the journal Dermatitis. Authors Samuel F. Ekstein, MS, and Erin M. Warshaw, MD, from the Department of Dermatology, Park Nicollet Health Services, Minneapolis, Minnesota, noted that the ACDS hoped to raise awareness of sulfites as a “significant allergen” and called for their increased inclusion in screening patch test series.
Patients identified with sulfite allergies can find alternative products on the ACDS CAMP (Contact Allergen Management Program) website, Dr. Warshaw said in an interview.
She also highlighted some examples of sulfites as allergens in healthcare settings in particular. She described one patient who presented with dermatitis at the site of three previous hand orthopedic procedures.
“Although surgical cleansers were suspected, the patient reacted to sodium metabisulfite. Review of the operating room contactants confirmed sulfites as preservatives in an injectable anesthetic and antibiotic used for wound irrigation,” she said. Another patient who had been treated for recurrent otitis externa and seborrheic dermatitis was found to be allergic to sulfites in an otic antibiotic suspension as well as in a ketoconazole cream product, she added.
In the paper, Dr. Warshaw and Mr. Ekstein called for the addition of sulfites to the test series. Although the NACDG added sodium metabisulfite to the series in 2017, sulfites are not part of the American Contact Dermatitis Core Series, they wrote. Sodium metabisulfite, they said, was added to the European baseline standard series after review of the 2019-2020 patch test reactivity and clinical relevance data.
The ACDS meeting is held every year the day before the annual meeting of the American Academy of Dermatology.
Dr. Belsito and Dr. Warshaw had no financial conflicts to disclose.
A version of this article appeared on Medscape.com.
FROM ACDS 2024
Second FDA-Approved Tocilizumab Biosimilar Has Intravenous, Subcutaneous Formulations
The US Food and Drug Administration (FDA) has approved the biosimilar tocilizumab-aazg (Tyenne), Fresenius Kabi, the drug’s manufacturer, announced on March 7.
This is the second tocilizumab biosimilar approved by the regulatory agency and the first to be approved in both intravenous (IV) and subcutaneous formulations that are available with the reference product, Actemra, the company said in a press release. 
Tocilizumab-aazg is an interleukin-6 (IL-6) receptor antagonist indicated for:
- Adults with moderate to severe rheumatoid arthritis who have had an inadequate response to one or more disease-modifying antirheumatic drugs
- Adults with giant cell arteritis
- Patients aged 2 years or older with active polyarticular juvenile idiopathic arthritis
- Patients aged 2 years or older with active systemic juvenile idiopathic arthritis
“Fresenius Kabi is leading the way as the first company to receive FDA approval for both IV and subcutaneous formulations of its tocilizumab biosimilar and is available in prefilled syringe, pen injector, and vial presentations,” Fabrice Romanet, senior vice president of innovation and development at Fresenius Kabi Biopharma, said in a statement.
The FDA approved the first tocilizumab biosimilar, manufactured by Biogen, in late September 2023. It is administered by IV infusion.
Tocilizumab-aazg’s approval was based on outcome and safety data from a dozen clinical studies. The drug can be administered via intravenous formulation (20 mg/mL) or subcutaneously via a single-dose 162-mg/0.9-mL prefilled syringe or single-dose prefilled autoinjector.
The most common side effects for tocilizumab-aazg include upper respiratory tract infections, headache, hypertension, and injection site reactions. The most serious side effects include serious infections, perforation of the stomach or intestines, hepatotoxicity, and changes in certain lab results.
Tocilizumab-aazg has already launched in 10 countries, Fresenius Kabi shared in the press release, and plans to launch in additional countries in 2024 and 2025. It is not clear when tocilizumab-aazg will be made available in the United States.
“In accordance with its patent settlement agreement with Genentech, Fresenius Kabi has a license to market its tocilizumab products in the United States commencing on the license dates, which are confidential,” the company noted.
A version of this article appeared on Medscape.com.
The US Food and Drug Administration (FDA) has approved the biosimilar tocilizumab-aazg (Tyenne), Fresenius Kabi, the drug’s manufacturer, announced on March 7.
This is the second tocilizumab biosimilar approved by the regulatory agency and the first to be approved in both intravenous (IV) and subcutaneous formulations that are available with the reference product, Actemra, the company said in a press release.
Tocilizumab-aazg is an interleukin-6 (IL-6) receptor antagonist indicated for:
- Adults with moderate to severe rheumatoid arthritis who have had an inadequate response to one or more disease-modifying antirheumatic drugs
- Adults with giant cell arteritis
- Patients aged 2 years or older with active polyarticular juvenile idiopathic arthritis
- Patients aged 2 years or older with active systemic juvenile idiopathic arthritis
“Fresenius Kabi is leading the way as the first company to receive FDA approval for both IV and subcutaneous formulations of its tocilizumab biosimilar and is available in prefilled syringe, pen injector, and vial presentations,” Fabrice Romanet, senior vice president of innovation and development at Fresenius Kabi Biopharma, said in a statement.
The FDA approved the first tocilizumab biosimilar, manufactured by Biogen, in late September 2023. It is administered by IV infusion.
Tocilizumab-aazg’s approval was based on outcome and safety data from a dozen clinical studies. The drug can be administered via intravenous formulation (20 mg/mL) or subcutaneously via a single-dose 162-mg/0.9-mL prefilled syringe or single-dose prefilled autoinjector.
The most common side effects for tocilizumab-aazg include upper respiratory tract infections, headache, hypertension, and injection site reactions. The most serious side effects include serious infections, perforation of the stomach or intestines, hepatotoxicity, and changes in certain lab results.
Tocilizumab-aazg has already launched in 10 countries, Fresenius Kabi shared in the press release, and plans to launch in additional countries in 2024 and 2025. It is not clear when tocilizumab-aazg will be made available in the United States.
“In accordance with its patent settlement agreement with Genentech, Fresenius Kabi has a license to market its tocilizumab products in the United States commencing on the license dates, which are confidential,” the company noted.
A version of this article appeared on Medscape.com.
The US Food and Drug Administration (FDA) has approved the biosimilar tocilizumab-aazg (Tyenne), Fresenius Kabi, the drug’s manufacturer, announced on March 7.
This is the second tocilizumab biosimilar approved by the regulatory agency and the first to be approved in both intravenous (IV) and subcutaneous formulations that are available with the reference product, Actemra, the company said in a press release.
Tocilizumab-aazg is an interleukin-6 (IL-6) receptor antagonist indicated for:
- Adults with moderate to severe rheumatoid arthritis who have had an inadequate response to one or more disease-modifying antirheumatic drugs
- Adults with giant cell arteritis
- Patients aged 2 years or older with active polyarticular juvenile idiopathic arthritis
- Patients aged 2 years or older with active systemic juvenile idiopathic arthritis
“Fresenius Kabi is leading the way as the first company to receive FDA approval for both IV and subcutaneous formulations of its tocilizumab biosimilar and is available in prefilled syringe, pen injector, and vial presentations,” Fabrice Romanet, senior vice president of innovation and development at Fresenius Kabi Biopharma, said in a statement.
The FDA approved the first tocilizumab biosimilar, manufactured by Biogen, in late September 2023. It is administered by IV infusion.
Tocilizumab-aazg’s approval was based on outcome and safety data from a dozen clinical studies. The drug can be administered via intravenous formulation (20 mg/mL) or subcutaneously via a single-dose 162-mg/0.9-mL prefilled syringe or single-dose prefilled autoinjector.
The most common side effects for tocilizumab-aazg include upper respiratory tract infections, headache, hypertension, and injection site reactions. The most serious side effects include serious infections, perforation of the stomach or intestines, hepatotoxicity, and changes in certain lab results.
Tocilizumab-aazg has already launched in 10 countries, Fresenius Kabi shared in the press release, and plans to launch in additional countries in 2024 and 2025. It is not clear when tocilizumab-aazg will be made available in the United States.
“In accordance with its patent settlement agreement with Genentech, Fresenius Kabi has a license to market its tocilizumab products in the United States commencing on the license dates, which are confidential,” the company noted.
A version of this article appeared on Medscape.com.
Nivolumab Wins First-Line Indication in Metastatic Urothelial Carcinoma
Approval was based on the CHECKMATE-901 trial in 608 patients randomized equally to either cisplatin and gemcitabine for ≤ six cycles or nivolumab plus cisplatin and gemcitabine for ≤ six cycles, followed by nivolumab alone for ≤ 2 years.
Median overall survival was 21.7 months with nivolumab add-on vs 18.9 months with cisplatin/gemcitabine alone (hazard ratio [HR], 0.78; P = .0171). The nivolumab group had a slightly higher median progression-free survival of 7.9 months vs 7.6 months in the cisplatin and gemcitabine group (HR, 0.72; P = .0012).
The most common adverse events, occurring in ≥ 15% of nivolumab patients, were nausea, fatigue, musculoskeletal pain, constipation, decreased appetite, rash, vomiting, peripheral neuropathy, urinary tract infection, diarrhea, edema, hypothyroidism, and pruritus.
Among numerous other oncology indications, nivolumab was previously approved for adjuvant treatment following urothelial carcinoma resection and for locally advanced or metastatic urothelial carcinoma that progresses during or following platinum-containing chemotherapy.
A version of this article appeared on Medscape.com .
Approval was based on the CHECKMATE-901 trial in 608 patients randomized equally to either cisplatin and gemcitabine for ≤ six cycles or nivolumab plus cisplatin and gemcitabine for ≤ six cycles, followed by nivolumab alone for ≤ 2 years.
Median overall survival was 21.7 months with nivolumab add-on vs 18.9 months with cisplatin/gemcitabine alone (hazard ratio [HR], 0.78; P = .0171). The nivolumab group had a slightly higher median progression-free survival of 7.9 months vs 7.6 months in the cisplatin and gemcitabine group (HR, 0.72; P = .0012).
The most common adverse events, occurring in ≥ 15% of nivolumab patients, were nausea, fatigue, musculoskeletal pain, constipation, decreased appetite, rash, vomiting, peripheral neuropathy, urinary tract infection, diarrhea, edema, hypothyroidism, and pruritus.
Among numerous other oncology indications, nivolumab was previously approved for adjuvant treatment following urothelial carcinoma resection and for locally advanced or metastatic urothelial carcinoma that progresses during or following platinum-containing chemotherapy.
A version of this article appeared on Medscape.com .
Approval was based on the CHECKMATE-901 trial in 608 patients randomized equally to either cisplatin and gemcitabine for ≤ six cycles or nivolumab plus cisplatin and gemcitabine for ≤ six cycles, followed by nivolumab alone for ≤ 2 years.
Median overall survival was 21.7 months with nivolumab add-on vs 18.9 months with cisplatin/gemcitabine alone (hazard ratio [HR], 0.78; P = .0171). The nivolumab group had a slightly higher median progression-free survival of 7.9 months vs 7.6 months in the cisplatin and gemcitabine group (HR, 0.72; P = .0012).
The most common adverse events, occurring in ≥ 15% of nivolumab patients, were nausea, fatigue, musculoskeletal pain, constipation, decreased appetite, rash, vomiting, peripheral neuropathy, urinary tract infection, diarrhea, edema, hypothyroidism, and pruritus.
Among numerous other oncology indications, nivolumab was previously approved for adjuvant treatment following urothelial carcinoma resection and for locally advanced or metastatic urothelial carcinoma that progresses during or following platinum-containing chemotherapy.
A version of this article appeared on Medscape.com .
Leflunomide: A Fresh Look at an Old Drug
The Food and Drug Administration’s approval of leflunomide in September 1998 as a treatment for rheumatoid arthritis was sandwiched between the debuts of infliximab (Remicade and biosimilars) and etanercept (Enbrel) in August and November of that year, the latter of which was so exciting that “within 2 months you couldn’t get [it],” recalled Eric M. Ruderman, MD. And “like every middle child, [leflunomide] was underloved, underappreciated, and largely dismissed.”
Yet should it have been? Is it worth another look today?
At the 2024 Rheumatology Winter Clinical Symposium, Dr. Ruderman reflected on some of the clinical trial data published after leflunomide’s approval that “got lost in the shuffle” of the rightful embrace of biologics in United States practice, and urged reconsideration of the loading strategy still advised in the drug’s labeling.
“I’m not telling you that you should be using [leflunomide] in place of biologics, instead of biologics, or before biologics … but it should be in your toolkit,” said Dr. Ruderman, professor of medicine and associate chief of clinical affairs in the division of rheumatology at Northwestern University Feinberg School of Medicine, Chicago. The drug “still has a role in RA, including in combination with methotrexate, and a potential role in other rheumatic diseases.”
“In our PsA clinic,” he noted, “we’ve actually not infrequently added leflunomide to some of the other agents we’ve been using.”
Key Findings Over the Years in RA
Leflunomide showed efficacy similar to that of sulfasalazine in a randomized trial published in 1999 that used primary endpoints of tender/swollen joints and physician and patient global scores. Then, against methotrexate, it proved just as efficacious in achieving at least 20% improvement in American College of Rheumatology composite response criteria (ACR20) over 52 weeks, and in meeting endpoints similar to those of the sulfasalazine trial, in two trials, one published in 1999 and another in 2000.
“So here were two big trials [comparing it with methotrexate] that suggested the drug was just as good as what had become our standard of care by that point,” Dr. Ruderman said.
Each of these three trials used a loading dose of 100 mg leflunomide for 3 days, followed by 20 mg daily. Sulfasalazine was initiated at 2 g and escalated over 4 weeks. Methotrexate was initiated in one of the trials at a dose of 7.5 mg, then increased to 15 mg in almost two-thirds of patients; in the other methotrexate trial the initial dose was 15 mg escalated over 3 months.
Side effects of leflunomide — GI issues, rash, alopecia (reversible), and elevated liver function tests — were similar across the trials, and represented “about the same toxicities as methotrexate,” he said.
Researchers then tested leflunomide as an add-on to methotrexate in patients who had inadequate response, which “was a little bit daunting since we were still concerned about the toxicity of methotrexate at this point,” Dr. Ruderman said. “The idea that we’d take another drug with similar toxicities and add it on to the methotrexate was a little scary.”
But it worked. Patients on a mean background dose of 16.5 mg methotrexate were randomized to placebo or to a 2-day leflunomide loading dose followed by 10 mg/day that could be escalated at 8 weeks to 20 mg if needed. At 6 months, 19.5% and 46.2%, respectively, met ACR20 (P < .001), and “interestingly,” he said, “adverse events were pretty similar” between combination therapy and methotrexate monotherapy.
“This was very much like all the studies we’ve seen over the years with new biologics — they were all added to background methotrexate,” he said. “And the truth is, the [46%] response seen when adding leflunomide to background methotrexate wasn’t very different from the 50% [ACR20] response you tend to see when you add a biologic.”
However, despite the study’s conclusion that combination therapy provided significant benefit to patients with inadequate response to methotrexate alone, “the drug got lost, because everyone was prescribing the biologics,” Dr. Ruderman said.
He said he found only one study comparing leflunomide with a biologic. In a notably small but well-designed study from Sri Lanka published in 2017, 40 patients with an inadequate response to methotrexate were randomized to low-dose rituximab (500 mg x 2) or 20 mg/day leflunomide (no loading dose). At week 24, ACR20 was nearly identical (85% vs 84%), with a similar rate of adverse events.
The researchers pointed out “that there’s a potential cost benefit in developing countries where biologics aren’t as accessible,” he said, agreeing that “the big opportunity for a drug like leflunomide is outside the US, where you don’t have access to the drugs we take advantage of all the time.”
A meeting participant from Canada pointed out that rheumatologists there are “mandated to use it for PsA in combination with methotrexate before we can get a biologic, and for RA we can use it with Plaquenil [hydroxychloroquine] and methotrexate before we get a biologic, so we’re using it all the time.”
Asked about efficacy, the physician said the combination with methotrexate is “absolutely” efficacious. “It works really well” he said. “The problem is, you really have to watch the white cell count and liver function … and the half-life is long.”
Indeed, Dr. Ruderman said during his talk, the plasma half-life of teriflunomide, its active metabolite, is 15.5 days, which is challenging when adverse events occur. “And it’s a terrible drug in young women thinking about pregnancy because it’s teratogenic and stays around,” he said.
Leflunomide, which, notably, was “developed specifically for RA from the get-go” and not borrowed from another specialty, works by blocking de novo pyrimidine synthesis, Dr. Ruderman said. T-cell activation requires the upregulation of pyrimidine production (salvage pathways are insufficient); the “drug prevents that” by inhibiting an enzyme that catalyzes conversion of dihydroorotate to orotate, which, in turn, is converted to pyrimidine ribonucleotides, he explained.
Other potential mechanisms of action have been proposed — mainly, inhibition of tumor necrosis factor signaling and inhibition of kinase activity, including the JAK/STAT pathway — but “there’s not great data for any of them,” he said.
Loading vs Not Loading, and Its Role in PsA and Other Diseases
“We stopped loading years ago because at 100 mg for 3 days in a row, everyone has GI issues,” Dr. Ruderman said. “It may have made sense from a pharmacokinetic standpoint because [based on the long half-life] you could get to a higher drug level quicker, but not a practical standpoint, because patients would stop the drug — they couldn’t take it.” The first study to examine the necessity of loading leflunomide in a “prospective, careful way” was published in 2013. It randomized 120 patients to 100 mg or 20 mg for 3 days, followed by a 3-month open-label period of 20 mg, and found no clinical benefit with loading but more diarrhea and elevated liver enzymes.
“It tells us something about how we need to think about half-lives,” he said. “Maybe [loading is] not necessary because the biological effects are different than the drug levels.”
In the PsA space, in 2004, researchers reported a double-blind randomized trial in which 190 patients with active PsA and cutaneous psoriasis with at least 3% body surface area involvement were randomized to receive leflunomide (a loading dose followed by 20 mg/day) or placebo for 24 weeks. Almost 60% of leflunomide-treated patients, compared with 30% of placebo-treated patients, were classified as responders by the Psoriatic Arthritis Response criteria (P < .0001), “which is a soft endpoint” but was utilized at the time, Dr. Ruderman said. The researchers noted improvements in ACR20 and skin responses as well, and toxicity was similar to that reported in the RA studies.
However, approval was never sought, and the drug was infrequently prescribed, “because etanercept came out for this disease, and then adalimumab … and then the world changed,” he said.
More recently, a single-center, double-blind, randomized trial that included 78 Dutch patients with PsA tested leflunomide plus methotrexate vs methotrexate monotherapy and was published in The Lancet Rheumatology. After 16 weeks, mean Psoriatic Arthritis Disease Activity Score (PASDAS) had improved for patients in the combination therapy group in comparison with the monotherapy group (3.1 [standard deviation (SD), 1.4] vs 3.7 [SD, 1.3]; treatment difference, -0.6; 90% CI, -1.0 to -0.1; P = .025). The combination therapy group also achieved PASDAS low disease activity at a higher rate (59%) than that of the monotherapy group (34%; P = .019). Three patients in the combination therapy group experienced serious adverse events, two of which were deemed unrelated to leflunomide. The most frequently occurring adverse events were nausea or vomiting, tiredness, and elevated alanine aminotransferase. Mild adverse events were more common in the methotrexate plus leflunomide group.
In an interview after the meeting, Dr. Ruderman explained that in his practice, about 15 years ago, leflunomide was sometimes prescribed as an alternative to a biologic change for patients whose skin disease improved significantly with ustekinumab (Stelara) but who “suddenly had more joint symptoms that they didn’t have before.”
And “we’ve found ourselves a bit recently with the same sort of story, where patients are prescribed IL-23 inhibitors like Skyrizi [risankizumab] and Tremfya [guselkumab] and their skin does really well but now they’re having more joint symptoms than previously,” he said. “Our choices are to switch to a whole different biologic, or to think about adding something as an adjunct — and maybe leflunomide is a reasonable option.”
In the last 5 years, Dr. Ruderman noted, randomized trial data has been published on leflunomide in lupus nephritis induction, and in lupus nephritis maintenance, as well as in IgG4-related disease.
Dr. Ruderman disclosed consulting and/or drug safety monitoring board work for AbbVie, Amgen, Bristol-Myers Squibb, Janssen, Lilly, Merck, Novartis, NS Pharma, and UCB.
The Food and Drug Administration’s approval of leflunomide in September 1998 as a treatment for rheumatoid arthritis was sandwiched between the debuts of infliximab (Remicade and biosimilars) and etanercept (Enbrel) in August and November of that year, the latter of which was so exciting that “within 2 months you couldn’t get [it],” recalled Eric M. Ruderman, MD. And “like every middle child, [leflunomide] was underloved, underappreciated, and largely dismissed.”
Yet should it have been? Is it worth another look today?
At the 2024 Rheumatology Winter Clinical Symposium, Dr. Ruderman reflected on some of the clinical trial data published after leflunomide’s approval that “got lost in the shuffle” of the rightful embrace of biologics in United States practice, and urged reconsideration of the loading strategy still advised in the drug’s labeling.
“I’m not telling you that you should be using [leflunomide] in place of biologics, instead of biologics, or before biologics … but it should be in your toolkit,” said Dr. Ruderman, professor of medicine and associate chief of clinical affairs in the division of rheumatology at Northwestern University Feinberg School of Medicine, Chicago. The drug “still has a role in RA, including in combination with methotrexate, and a potential role in other rheumatic diseases.”
“In our PsA clinic,” he noted, “we’ve actually not infrequently added leflunomide to some of the other agents we’ve been using.”
Key Findings Over the Years in RA
Leflunomide showed efficacy similar to that of sulfasalazine in a randomized trial published in 1999 that used primary endpoints of tender/swollen joints and physician and patient global scores. Then, against methotrexate, it proved just as efficacious in achieving at least 20% improvement in American College of Rheumatology composite response criteria (ACR20) over 52 weeks, and in meeting endpoints similar to those of the sulfasalazine trial, in two trials, one published in 1999 and another in 2000.
“So here were two big trials [comparing it with methotrexate] that suggested the drug was just as good as what had become our standard of care by that point,” Dr. Ruderman said.
Each of these three trials used a loading dose of 100 mg leflunomide for 3 days, followed by 20 mg daily. Sulfasalazine was initiated at 2 g and escalated over 4 weeks. Methotrexate was initiated in one of the trials at a dose of 7.5 mg, then increased to 15 mg in almost two-thirds of patients; in the other methotrexate trial the initial dose was 15 mg escalated over 3 months.
Side effects of leflunomide — GI issues, rash, alopecia (reversible), and elevated liver function tests — were similar across the trials, and represented “about the same toxicities as methotrexate,” he said.
Researchers then tested leflunomide as an add-on to methotrexate in patients who had inadequate response, which “was a little bit daunting since we were still concerned about the toxicity of methotrexate at this point,” Dr. Ruderman said. “The idea that we’d take another drug with similar toxicities and add it on to the methotrexate was a little scary.”
But it worked. Patients on a mean background dose of 16.5 mg methotrexate were randomized to placebo or to a 2-day leflunomide loading dose followed by 10 mg/day that could be escalated at 8 weeks to 20 mg if needed. At 6 months, 19.5% and 46.2%, respectively, met ACR20 (P < .001), and “interestingly,” he said, “adverse events were pretty similar” between combination therapy and methotrexate monotherapy.
“This was very much like all the studies we’ve seen over the years with new biologics — they were all added to background methotrexate,” he said. “And the truth is, the [46%] response seen when adding leflunomide to background methotrexate wasn’t very different from the 50% [ACR20] response you tend to see when you add a biologic.”
However, despite the study’s conclusion that combination therapy provided significant benefit to patients with inadequate response to methotrexate alone, “the drug got lost, because everyone was prescribing the biologics,” Dr. Ruderman said.
He said he found only one study comparing leflunomide with a biologic. In a notably small but well-designed study from Sri Lanka published in 2017, 40 patients with an inadequate response to methotrexate were randomized to low-dose rituximab (500 mg x 2) or 20 mg/day leflunomide (no loading dose). At week 24, ACR20 was nearly identical (85% vs 84%), with a similar rate of adverse events.
The researchers pointed out “that there’s a potential cost benefit in developing countries where biologics aren’t as accessible,” he said, agreeing that “the big opportunity for a drug like leflunomide is outside the US, where you don’t have access to the drugs we take advantage of all the time.”
A meeting participant from Canada pointed out that rheumatologists there are “mandated to use it for PsA in combination with methotrexate before we can get a biologic, and for RA we can use it with Plaquenil [hydroxychloroquine] and methotrexate before we get a biologic, so we’re using it all the time.”
Asked about efficacy, the physician said the combination with methotrexate is “absolutely” efficacious. “It works really well” he said. “The problem is, you really have to watch the white cell count and liver function … and the half-life is long.”
Indeed, Dr. Ruderman said during his talk, the plasma half-life of teriflunomide, its active metabolite, is 15.5 days, which is challenging when adverse events occur. “And it’s a terrible drug in young women thinking about pregnancy because it’s teratogenic and stays around,” he said.
Leflunomide, which, notably, was “developed specifically for RA from the get-go” and not borrowed from another specialty, works by blocking de novo pyrimidine synthesis, Dr. Ruderman said. T-cell activation requires the upregulation of pyrimidine production (salvage pathways are insufficient); the “drug prevents that” by inhibiting an enzyme that catalyzes conversion of dihydroorotate to orotate, which, in turn, is converted to pyrimidine ribonucleotides, he explained.
Other potential mechanisms of action have been proposed — mainly, inhibition of tumor necrosis factor signaling and inhibition of kinase activity, including the JAK/STAT pathway — but “there’s not great data for any of them,” he said.
Loading vs Not Loading, and Its Role in PsA and Other Diseases
“We stopped loading years ago because at 100 mg for 3 days in a row, everyone has GI issues,” Dr. Ruderman said. “It may have made sense from a pharmacokinetic standpoint because [based on the long half-life] you could get to a higher drug level quicker, but not a practical standpoint, because patients would stop the drug — they couldn’t take it.” The first study to examine the necessity of loading leflunomide in a “prospective, careful way” was published in 2013. It randomized 120 patients to 100 mg or 20 mg for 3 days, followed by a 3-month open-label period of 20 mg, and found no clinical benefit with loading but more diarrhea and elevated liver enzymes.
“It tells us something about how we need to think about half-lives,” he said. “Maybe [loading is] not necessary because the biological effects are different than the drug levels.”
In the PsA space, in 2004, researchers reported a double-blind randomized trial in which 190 patients with active PsA and cutaneous psoriasis with at least 3% body surface area involvement were randomized to receive leflunomide (a loading dose followed by 20 mg/day) or placebo for 24 weeks. Almost 60% of leflunomide-treated patients, compared with 30% of placebo-treated patients, were classified as responders by the Psoriatic Arthritis Response criteria (P < .0001), “which is a soft endpoint” but was utilized at the time, Dr. Ruderman said. The researchers noted improvements in ACR20 and skin responses as well, and toxicity was similar to that reported in the RA studies.
However, approval was never sought, and the drug was infrequently prescribed, “because etanercept came out for this disease, and then adalimumab … and then the world changed,” he said.
More recently, a single-center, double-blind, randomized trial that included 78 Dutch patients with PsA tested leflunomide plus methotrexate vs methotrexate monotherapy and was published in The Lancet Rheumatology. After 16 weeks, mean Psoriatic Arthritis Disease Activity Score (PASDAS) had improved for patients in the combination therapy group in comparison with the monotherapy group (3.1 [standard deviation (SD), 1.4] vs 3.7 [SD, 1.3]; treatment difference, -0.6; 90% CI, -1.0 to -0.1; P = .025). The combination therapy group also achieved PASDAS low disease activity at a higher rate (59%) than that of the monotherapy group (34%; P = .019). Three patients in the combination therapy group experienced serious adverse events, two of which were deemed unrelated to leflunomide. The most frequently occurring adverse events were nausea or vomiting, tiredness, and elevated alanine aminotransferase. Mild adverse events were more common in the methotrexate plus leflunomide group.
In an interview after the meeting, Dr. Ruderman explained that in his practice, about 15 years ago, leflunomide was sometimes prescribed as an alternative to a biologic change for patients whose skin disease improved significantly with ustekinumab (Stelara) but who “suddenly had more joint symptoms that they didn’t have before.”
And “we’ve found ourselves a bit recently with the same sort of story, where patients are prescribed IL-23 inhibitors like Skyrizi [risankizumab] and Tremfya [guselkumab] and their skin does really well but now they’re having more joint symptoms than previously,” he said. “Our choices are to switch to a whole different biologic, or to think about adding something as an adjunct — and maybe leflunomide is a reasonable option.”
In the last 5 years, Dr. Ruderman noted, randomized trial data has been published on leflunomide in lupus nephritis induction, and in lupus nephritis maintenance, as well as in IgG4-related disease.
Dr. Ruderman disclosed consulting and/or drug safety monitoring board work for AbbVie, Amgen, Bristol-Myers Squibb, Janssen, Lilly, Merck, Novartis, NS Pharma, and UCB.
The Food and Drug Administration’s approval of leflunomide in September 1998 as a treatment for rheumatoid arthritis was sandwiched between the debuts of infliximab (Remicade and biosimilars) and etanercept (Enbrel) in August and November of that year, the latter of which was so exciting that “within 2 months you couldn’t get [it],” recalled Eric M. Ruderman, MD. And “like every middle child, [leflunomide] was underloved, underappreciated, and largely dismissed.”
Yet should it have been? Is it worth another look today?
At the 2024 Rheumatology Winter Clinical Symposium, Dr. Ruderman reflected on some of the clinical trial data published after leflunomide’s approval that “got lost in the shuffle” of the rightful embrace of biologics in United States practice, and urged reconsideration of the loading strategy still advised in the drug’s labeling.
“I’m not telling you that you should be using [leflunomide] in place of biologics, instead of biologics, or before biologics … but it should be in your toolkit,” said Dr. Ruderman, professor of medicine and associate chief of clinical affairs in the division of rheumatology at Northwestern University Feinberg School of Medicine, Chicago. The drug “still has a role in RA, including in combination with methotrexate, and a potential role in other rheumatic diseases.”
“In our PsA clinic,” he noted, “we’ve actually not infrequently added leflunomide to some of the other agents we’ve been using.”
Key Findings Over the Years in RA
Leflunomide showed efficacy similar to that of sulfasalazine in a randomized trial published in 1999 that used primary endpoints of tender/swollen joints and physician and patient global scores. Then, against methotrexate, it proved just as efficacious in achieving at least 20% improvement in American College of Rheumatology composite response criteria (ACR20) over 52 weeks, and in meeting endpoints similar to those of the sulfasalazine trial, in two trials, one published in 1999 and another in 2000.
“So here were two big trials [comparing it with methotrexate] that suggested the drug was just as good as what had become our standard of care by that point,” Dr. Ruderman said.
Each of these three trials used a loading dose of 100 mg leflunomide for 3 days, followed by 20 mg daily. Sulfasalazine was initiated at 2 g and escalated over 4 weeks. Methotrexate was initiated in one of the trials at a dose of 7.5 mg, then increased to 15 mg in almost two-thirds of patients; in the other methotrexate trial the initial dose was 15 mg escalated over 3 months.
Side effects of leflunomide — GI issues, rash, alopecia (reversible), and elevated liver function tests — were similar across the trials, and represented “about the same toxicities as methotrexate,” he said.
Researchers then tested leflunomide as an add-on to methotrexate in patients who had inadequate response, which “was a little bit daunting since we were still concerned about the toxicity of methotrexate at this point,” Dr. Ruderman said. “The idea that we’d take another drug with similar toxicities and add it on to the methotrexate was a little scary.”
But it worked. Patients on a mean background dose of 16.5 mg methotrexate were randomized to placebo or to a 2-day leflunomide loading dose followed by 10 mg/day that could be escalated at 8 weeks to 20 mg if needed. At 6 months, 19.5% and 46.2%, respectively, met ACR20 (P < .001), and “interestingly,” he said, “adverse events were pretty similar” between combination therapy and methotrexate monotherapy.
“This was very much like all the studies we’ve seen over the years with new biologics — they were all added to background methotrexate,” he said. “And the truth is, the [46%] response seen when adding leflunomide to background methotrexate wasn’t very different from the 50% [ACR20] response you tend to see when you add a biologic.”
However, despite the study’s conclusion that combination therapy provided significant benefit to patients with inadequate response to methotrexate alone, “the drug got lost, because everyone was prescribing the biologics,” Dr. Ruderman said.
He said he found only one study comparing leflunomide with a biologic. In a notably small but well-designed study from Sri Lanka published in 2017, 40 patients with an inadequate response to methotrexate were randomized to low-dose rituximab (500 mg x 2) or 20 mg/day leflunomide (no loading dose). At week 24, ACR20 was nearly identical (85% vs 84%), with a similar rate of adverse events.
The researchers pointed out “that there’s a potential cost benefit in developing countries where biologics aren’t as accessible,” he said, agreeing that “the big opportunity for a drug like leflunomide is outside the US, where you don’t have access to the drugs we take advantage of all the time.”
A meeting participant from Canada pointed out that rheumatologists there are “mandated to use it for PsA in combination with methotrexate before we can get a biologic, and for RA we can use it with Plaquenil [hydroxychloroquine] and methotrexate before we get a biologic, so we’re using it all the time.”
Asked about efficacy, the physician said the combination with methotrexate is “absolutely” efficacious. “It works really well” he said. “The problem is, you really have to watch the white cell count and liver function … and the half-life is long.”
Indeed, Dr. Ruderman said during his talk, the plasma half-life of teriflunomide, its active metabolite, is 15.5 days, which is challenging when adverse events occur. “And it’s a terrible drug in young women thinking about pregnancy because it’s teratogenic and stays around,” he said.
Leflunomide, which, notably, was “developed specifically for RA from the get-go” and not borrowed from another specialty, works by blocking de novo pyrimidine synthesis, Dr. Ruderman said. T-cell activation requires the upregulation of pyrimidine production (salvage pathways are insufficient); the “drug prevents that” by inhibiting an enzyme that catalyzes conversion of dihydroorotate to orotate, which, in turn, is converted to pyrimidine ribonucleotides, he explained.
Other potential mechanisms of action have been proposed — mainly, inhibition of tumor necrosis factor signaling and inhibition of kinase activity, including the JAK/STAT pathway — but “there’s not great data for any of them,” he said.
Loading vs Not Loading, and Its Role in PsA and Other Diseases
“We stopped loading years ago because at 100 mg for 3 days in a row, everyone has GI issues,” Dr. Ruderman said. “It may have made sense from a pharmacokinetic standpoint because [based on the long half-life] you could get to a higher drug level quicker, but not a practical standpoint, because patients would stop the drug — they couldn’t take it.” The first study to examine the necessity of loading leflunomide in a “prospective, careful way” was published in 2013. It randomized 120 patients to 100 mg or 20 mg for 3 days, followed by a 3-month open-label period of 20 mg, and found no clinical benefit with loading but more diarrhea and elevated liver enzymes.
“It tells us something about how we need to think about half-lives,” he said. “Maybe [loading is] not necessary because the biological effects are different than the drug levels.”
In the PsA space, in 2004, researchers reported a double-blind randomized trial in which 190 patients with active PsA and cutaneous psoriasis with at least 3% body surface area involvement were randomized to receive leflunomide (a loading dose followed by 20 mg/day) or placebo for 24 weeks. Almost 60% of leflunomide-treated patients, compared with 30% of placebo-treated patients, were classified as responders by the Psoriatic Arthritis Response criteria (P < .0001), “which is a soft endpoint” but was utilized at the time, Dr. Ruderman said. The researchers noted improvements in ACR20 and skin responses as well, and toxicity was similar to that reported in the RA studies.
However, approval was never sought, and the drug was infrequently prescribed, “because etanercept came out for this disease, and then adalimumab … and then the world changed,” he said.
More recently, a single-center, double-blind, randomized trial that included 78 Dutch patients with PsA tested leflunomide plus methotrexate vs methotrexate monotherapy and was published in The Lancet Rheumatology. After 16 weeks, mean Psoriatic Arthritis Disease Activity Score (PASDAS) had improved for patients in the combination therapy group in comparison with the monotherapy group (3.1 [standard deviation (SD), 1.4] vs 3.7 [SD, 1.3]; treatment difference, -0.6; 90% CI, -1.0 to -0.1; P = .025). The combination therapy group also achieved PASDAS low disease activity at a higher rate (59%) than that of the monotherapy group (34%; P = .019). Three patients in the combination therapy group experienced serious adverse events, two of which were deemed unrelated to leflunomide. The most frequently occurring adverse events were nausea or vomiting, tiredness, and elevated alanine aminotransferase. Mild adverse events were more common in the methotrexate plus leflunomide group.
In an interview after the meeting, Dr. Ruderman explained that in his practice, about 15 years ago, leflunomide was sometimes prescribed as an alternative to a biologic change for patients whose skin disease improved significantly with ustekinumab (Stelara) but who “suddenly had more joint symptoms that they didn’t have before.”
And “we’ve found ourselves a bit recently with the same sort of story, where patients are prescribed IL-23 inhibitors like Skyrizi [risankizumab] and Tremfya [guselkumab] and their skin does really well but now they’re having more joint symptoms than previously,” he said. “Our choices are to switch to a whole different biologic, or to think about adding something as an adjunct — and maybe leflunomide is a reasonable option.”
In the last 5 years, Dr. Ruderman noted, randomized trial data has been published on leflunomide in lupus nephritis induction, and in lupus nephritis maintenance, as well as in IgG4-related disease.
Dr. Ruderman disclosed consulting and/or drug safety monitoring board work for AbbVie, Amgen, Bristol-Myers Squibb, Janssen, Lilly, Merck, Novartis, NS Pharma, and UCB.
FROM RWCS 2024
TIL for Melanoma: What Are the Costs and Other Challenges to Getting It to Patients?
The US Food and Drug Administration (FDA) recently approved the tumor-infiltrating lymphocyte cell therapy (TIL) for use in certain adults with unresectable or metastatic melanoma. This marks the first time the FDA has allowed a cellular therapy to be marketed for a solid tumor cancer.
Lifileucel is made from a patient’s surgically removed tumor. Tissue from that tumor is then sent to a manufacturing center. Turnaround time to when the drug is ready to be sent back to the cancer center for use is approximately 34 days, according to the drug’s manufacturer, Iovance.
Insurance Adjustments
The cost of the one-time lifileucel treatment is $515,000, according to the manufacturer.
Two investigators in the clinical trials of lifileucel, Allison Betof Warner, MD, of Stanford University, Stanford, California, and Igor Puzanov, MD, of Roswell Park Comprehensive Cancer Center, Buffalo, New York, shared their expectations regarding factors that would contribute to how much a patient paid for the drug.
Given the drug’s recent approval, the logistical details are still being worked out between cancer centers and insurers regarding how much patients will pay out of pocket for lifileucel, said Dr. Betof Warner, who is assistant professor in the Department of Medicine, Division of Medical Oncology at Stanford University.
The associated costs, including the surgery that is needed to procure the TIL cells for expansion into the final drug product, will be different for each patient, she told this publication.
Patients’ costs for lifileucel will vary based on their insurance, explained Dr. Puzanov, chief of melanoma and professor of oncology at Roswell Park Comprehensive Cancer Center.
At Roswell Park, “we will work with our regionally-based payers on a case-by-case basis to seek approval for those patients we believe can most benefit from lifileucel,” he said in an interview. Preauthorization will be required, as is standard for many cancer treatments, he added.
Once payer approval is in place, Dr. Puzanov said, he did not anticipate significant delays in access for patients.
Certified centers such as the multidisciplinary team at Roswell Park are ready to treat patients now. Other centers are similarly prepared, especially those involved in the clinical trials of lifileucel, he said.
Logistics and Infrastructure
A position article and guidelines on the management of and best practices for TIL was published in the Journal for ImmunoTherapy of Cancer on February 29. The paper, of which both Dr. Betof Warner and Dr. Puzanov served as authors, noted that one of the barriers to the use of TIL cell therapy in clinical practice is the need for state-of-the art infrastructure at centers that want to offer the treatment. Scheduling, patient referrals, and surgery, as well as the production and infusion of TIL, must be organized and streamlined for successful treatment, the authors wrote.
The two supply chains involved in TIL — the transportation of the tumor tissue from the treatment center to the manufacturer and transport of the TIL infusion product back to the treatment center — must be timely and precise, they emphasized.
Docs Hope TIL Improves in Several Ways
Although the TIL technology is a breakthrough, “we hope to see even better efficacy and lower toxicity as further research looks at ways to improve on the current TIL standard,” Dr. Puzanov said.
More research and dose adjustments may impact patient costs and side effects, he noted. “I am looking to see TILs used in the front line, with or without checkpoint inhibitors.”
Research is needed to explore how to lower the chemotherapy doses and possibly the associated toxicity, he added. Finally, researchers must consider whether high-dose IL-2 therapy — given as part of the TIL cell therapy — could be replaced with other cytokines, or whether the number of doses could be lowered. Another avenue of exploration is engineering genes for cytokines into TILs, he said.
“The key is to think about TIL therapy before you need it — ideally, when the patient is still doing well on their frontline checkpoint inhibition immunotherapy,” Dr. Puzanov said in an interview. That is the time for evaluation, and specialty centers can provide an expert assessment, he said.
“We are constantly working to improve TIL therapy,” Dr. Betof Warner told this publication. More research is needed optimize the regimen to reduce side effects, which would not only make treatment easier for currently eligible patients, but might allow treatment for patients not currently eligible.
“For example, we are looking for ways to reduce the dose of preparative chemotherapy, which prepares the body for the cells to maximize their longevity and efficacy, and to reduce or eliminate the need to give IL-2 after the cell administration,” continued Dr. Betof Warner, who is also Director of Melanoma Medical Oncology, Director of Solid Tumor Cellular Therapy, and Codirector of the Pigmented Lesion and Melanoma Program at Stanford University. “We are also actively studying next-generation TIL therapies to try to increase the efficacy.”
“Lifileucel has about a 30% success rate for melanoma that has progressed after standard therapy; we are working hard to do better than that,” she noted.
In a press release, Iovance summarized the results of the trial that supported the FDA’s accelerated approval of lifileucel. In an open-label single-arm study, including multiple sites worldwide, 73 adults with unresectable or metastatic melanoma who had received at least one previous systemic therapy underwent a lymphodepleting regimen followed by treatments with fludarabine and aldesleukin. Patients then received lifileucel at a median dose of 21.1 x 109 viable cells; the recommended dose ranges from 7.5 x 109 to 72 x 109 cells.
The primary efficacy outcome was objective response rate (ORR). The ORR in the study was 31.5%, and the median time to initial lifileucel response was 1.5 months.
The clinical trials of lifileucel for which Dr. Betof Warner and Dr. Puzanov served as investigators were sponsored by Iovance.
The US Food and Drug Administration (FDA) recently approved the tumor-infiltrating lymphocyte cell therapy (TIL) for use in certain adults with unresectable or metastatic melanoma. This marks the first time the FDA has allowed a cellular therapy to be marketed for a solid tumor cancer.
Lifileucel is made from a patient’s surgically removed tumor. Tissue from that tumor is then sent to a manufacturing center. Turnaround time to when the drug is ready to be sent back to the cancer center for use is approximately 34 days, according to the drug’s manufacturer, Iovance.
Insurance Adjustments
The cost of the one-time lifileucel treatment is $515,000, according to the manufacturer.
Two investigators in the clinical trials of lifileucel, Allison Betof Warner, MD, of Stanford University, Stanford, California, and Igor Puzanov, MD, of Roswell Park Comprehensive Cancer Center, Buffalo, New York, shared their expectations regarding factors that would contribute to how much a patient paid for the drug.
Given the drug’s recent approval, the logistical details are still being worked out between cancer centers and insurers regarding how much patients will pay out of pocket for lifileucel, said Dr. Betof Warner, who is assistant professor in the Department of Medicine, Division of Medical Oncology at Stanford University.
The associated costs, including the surgery that is needed to procure the TIL cells for expansion into the final drug product, will be different for each patient, she told this publication.
Patients’ costs for lifileucel will vary based on their insurance, explained Dr. Puzanov, chief of melanoma and professor of oncology at Roswell Park Comprehensive Cancer Center.
At Roswell Park, “we will work with our regionally-based payers on a case-by-case basis to seek approval for those patients we believe can most benefit from lifileucel,” he said in an interview. Preauthorization will be required, as is standard for many cancer treatments, he added.
Once payer approval is in place, Dr. Puzanov said, he did not anticipate significant delays in access for patients.
Certified centers such as the multidisciplinary team at Roswell Park are ready to treat patients now. Other centers are similarly prepared, especially those involved in the clinical trials of lifileucel, he said.
Logistics and Infrastructure
A position article and guidelines on the management of and best practices for TIL was published in the Journal for ImmunoTherapy of Cancer on February 29. The paper, of which both Dr. Betof Warner and Dr. Puzanov served as authors, noted that one of the barriers to the use of TIL cell therapy in clinical practice is the need for state-of-the art infrastructure at centers that want to offer the treatment. Scheduling, patient referrals, and surgery, as well as the production and infusion of TIL, must be organized and streamlined for successful treatment, the authors wrote.
The two supply chains involved in TIL — the transportation of the tumor tissue from the treatment center to the manufacturer and transport of the TIL infusion product back to the treatment center — must be timely and precise, they emphasized.
Docs Hope TIL Improves in Several Ways
Although the TIL technology is a breakthrough, “we hope to see even better efficacy and lower toxicity as further research looks at ways to improve on the current TIL standard,” Dr. Puzanov said.
More research and dose adjustments may impact patient costs and side effects, he noted. “I am looking to see TILs used in the front line, with or without checkpoint inhibitors.”
Research is needed to explore how to lower the chemotherapy doses and possibly the associated toxicity, he added. Finally, researchers must consider whether high-dose IL-2 therapy — given as part of the TIL cell therapy — could be replaced with other cytokines, or whether the number of doses could be lowered. Another avenue of exploration is engineering genes for cytokines into TILs, he said.
“The key is to think about TIL therapy before you need it — ideally, when the patient is still doing well on their frontline checkpoint inhibition immunotherapy,” Dr. Puzanov said in an interview. That is the time for evaluation, and specialty centers can provide an expert assessment, he said.
“We are constantly working to improve TIL therapy,” Dr. Betof Warner told this publication. More research is needed optimize the regimen to reduce side effects, which would not only make treatment easier for currently eligible patients, but might allow treatment for patients not currently eligible.
“For example, we are looking for ways to reduce the dose of preparative chemotherapy, which prepares the body for the cells to maximize their longevity and efficacy, and to reduce or eliminate the need to give IL-2 after the cell administration,” continued Dr. Betof Warner, who is also Director of Melanoma Medical Oncology, Director of Solid Tumor Cellular Therapy, and Codirector of the Pigmented Lesion and Melanoma Program at Stanford University. “We are also actively studying next-generation TIL therapies to try to increase the efficacy.”
“Lifileucel has about a 30% success rate for melanoma that has progressed after standard therapy; we are working hard to do better than that,” she noted.
In a press release, Iovance summarized the results of the trial that supported the FDA’s accelerated approval of lifileucel. In an open-label single-arm study, including multiple sites worldwide, 73 adults with unresectable or metastatic melanoma who had received at least one previous systemic therapy underwent a lymphodepleting regimen followed by treatments with fludarabine and aldesleukin. Patients then received lifileucel at a median dose of 21.1 x 109 viable cells; the recommended dose ranges from 7.5 x 109 to 72 x 109 cells.
The primary efficacy outcome was objective response rate (ORR). The ORR in the study was 31.5%, and the median time to initial lifileucel response was 1.5 months.
The clinical trials of lifileucel for which Dr. Betof Warner and Dr. Puzanov served as investigators were sponsored by Iovance.
The US Food and Drug Administration (FDA) recently approved the tumor-infiltrating lymphocyte cell therapy (TIL) for use in certain adults with unresectable or metastatic melanoma. This marks the first time the FDA has allowed a cellular therapy to be marketed for a solid tumor cancer.
Lifileucel is made from a patient’s surgically removed tumor. Tissue from that tumor is then sent to a manufacturing center. Turnaround time to when the drug is ready to be sent back to the cancer center for use is approximately 34 days, according to the drug’s manufacturer, Iovance.
Insurance Adjustments
The cost of the one-time lifileucel treatment is $515,000, according to the manufacturer.
Two investigators in the clinical trials of lifileucel, Allison Betof Warner, MD, of Stanford University, Stanford, California, and Igor Puzanov, MD, of Roswell Park Comprehensive Cancer Center, Buffalo, New York, shared their expectations regarding factors that would contribute to how much a patient paid for the drug.
Given the drug’s recent approval, the logistical details are still being worked out between cancer centers and insurers regarding how much patients will pay out of pocket for lifileucel, said Dr. Betof Warner, who is assistant professor in the Department of Medicine, Division of Medical Oncology at Stanford University.
The associated costs, including the surgery that is needed to procure the TIL cells for expansion into the final drug product, will be different for each patient, she told this publication.
Patients’ costs for lifileucel will vary based on their insurance, explained Dr. Puzanov, chief of melanoma and professor of oncology at Roswell Park Comprehensive Cancer Center.
At Roswell Park, “we will work with our regionally-based payers on a case-by-case basis to seek approval for those patients we believe can most benefit from lifileucel,” he said in an interview. Preauthorization will be required, as is standard for many cancer treatments, he added.
Once payer approval is in place, Dr. Puzanov said, he did not anticipate significant delays in access for patients.
Certified centers such as the multidisciplinary team at Roswell Park are ready to treat patients now. Other centers are similarly prepared, especially those involved in the clinical trials of lifileucel, he said.
Logistics and Infrastructure
A position article and guidelines on the management of and best practices for TIL was published in the Journal for ImmunoTherapy of Cancer on February 29. The paper, of which both Dr. Betof Warner and Dr. Puzanov served as authors, noted that one of the barriers to the use of TIL cell therapy in clinical practice is the need for state-of-the art infrastructure at centers that want to offer the treatment. Scheduling, patient referrals, and surgery, as well as the production and infusion of TIL, must be organized and streamlined for successful treatment, the authors wrote.
The two supply chains involved in TIL — the transportation of the tumor tissue from the treatment center to the manufacturer and transport of the TIL infusion product back to the treatment center — must be timely and precise, they emphasized.
Docs Hope TIL Improves in Several Ways
Although the TIL technology is a breakthrough, “we hope to see even better efficacy and lower toxicity as further research looks at ways to improve on the current TIL standard,” Dr. Puzanov said.
More research and dose adjustments may impact patient costs and side effects, he noted. “I am looking to see TILs used in the front line, with or without checkpoint inhibitors.”
Research is needed to explore how to lower the chemotherapy doses and possibly the associated toxicity, he added. Finally, researchers must consider whether high-dose IL-2 therapy — given as part of the TIL cell therapy — could be replaced with other cytokines, or whether the number of doses could be lowered. Another avenue of exploration is engineering genes for cytokines into TILs, he said.
“The key is to think about TIL therapy before you need it — ideally, when the patient is still doing well on their frontline checkpoint inhibition immunotherapy,” Dr. Puzanov said in an interview. That is the time for evaluation, and specialty centers can provide an expert assessment, he said.
“We are constantly working to improve TIL therapy,” Dr. Betof Warner told this publication. More research is needed optimize the regimen to reduce side effects, which would not only make treatment easier for currently eligible patients, but might allow treatment for patients not currently eligible.
“For example, we are looking for ways to reduce the dose of preparative chemotherapy, which prepares the body for the cells to maximize their longevity and efficacy, and to reduce or eliminate the need to give IL-2 after the cell administration,” continued Dr. Betof Warner, who is also Director of Melanoma Medical Oncology, Director of Solid Tumor Cellular Therapy, and Codirector of the Pigmented Lesion and Melanoma Program at Stanford University. “We are also actively studying next-generation TIL therapies to try to increase the efficacy.”
“Lifileucel has about a 30% success rate for melanoma that has progressed after standard therapy; we are working hard to do better than that,” she noted.
In a press release, Iovance summarized the results of the trial that supported the FDA’s accelerated approval of lifileucel. In an open-label single-arm study, including multiple sites worldwide, 73 adults with unresectable or metastatic melanoma who had received at least one previous systemic therapy underwent a lymphodepleting regimen followed by treatments with fludarabine and aldesleukin. Patients then received lifileucel at a median dose of 21.1 x 109 viable cells; the recommended dose ranges from 7.5 x 109 to 72 x 109 cells.
The primary efficacy outcome was objective response rate (ORR). The ORR in the study was 31.5%, and the median time to initial lifileucel response was 1.5 months.
The clinical trials of lifileucel for which Dr. Betof Warner and Dr. Puzanov served as investigators were sponsored by Iovance.
Air Pollution Tied to Greater Amyloid Burden in the Brain
TOPLINE:
, a new postmortem study showed.
METHODOLOGY:
- Investigators examined the brain tissue of 224 people living in the Atlanta area who agreed to donate their brains after death (average age of death, 76 years) for the presence of amyloid plaques and tau tangles.
- They also studied the amount of fine particulate matter < 2.5 microns (PM2.5) from traffic-related air pollution at participants’ home addresses at 1, 3, and 5 years before death.
- The presence of the APOE e4 gene was examined for evidence of any effect on the relationship between air pollution and evidence of Alzheimer’s disease (AD).
TAKEAWAY:
The average level of exposure in the year before death was 1.32 µg/m3 and 1.35 µg/m3 in the 3 years before death.
People with 1 µg/m3 higher PM2.5 exposure in the year before death were nearly twice as likely to have higher levels of plaques (odds ratio [OR], 1.92; 95% CI, 1.12-3.30), while those with higher exposure in the 3 years before death were 87% more likely to have higher levels of plaques (OR, 1.87; 95% CI, 1.01-3.17).
A little more than half (56%) of the sample were positive for the APOE e4 genotype, but the strongest association between pollution and neuropathology markers was for noncarriers of the genotype, although this relationship did not reach statistical significance.
IN PRACTICE:
“More research is needed to establish causality for the association between PM2.5 and AD, including epidemiologic and mechanistic studies. Future studies should also investigate the association between PM2.5 and other dementia-related pathologies, including cerebrovascular pathology,” the study authors wrote.
SOURCE:
Anke Hüls, PhD, of Emory University in Atlanta, led the study, which was published online on February 21, 2024, in Neurology.
LIMITATIONS:
The sample was not population-based but a convenience sample composed mostly of highly educated White participants.
DISCLOSURES:
The study was funded by the National Institute of Environmental Health Sciences, the Goizueta Alzheimer’s Disease Research Center, the National Institute on Aging, and the National Institutes of Health. There were no relevant disclosures.
A version of this article appeared on Medscape.com.
TOPLINE:
, a new postmortem study showed.
METHODOLOGY:
- Investigators examined the brain tissue of 224 people living in the Atlanta area who agreed to donate their brains after death (average age of death, 76 years) for the presence of amyloid plaques and tau tangles.
- They also studied the amount of fine particulate matter < 2.5 microns (PM2.5) from traffic-related air pollution at participants’ home addresses at 1, 3, and 5 years before death.
- The presence of the APOE e4 gene was examined for evidence of any effect on the relationship between air pollution and evidence of Alzheimer’s disease (AD).
TAKEAWAY:
The average level of exposure in the year before death was 1.32 µg/m3 and 1.35 µg/m3 in the 3 years before death.
People with 1 µg/m3 higher PM2.5 exposure in the year before death were nearly twice as likely to have higher levels of plaques (odds ratio [OR], 1.92; 95% CI, 1.12-3.30), while those with higher exposure in the 3 years before death were 87% more likely to have higher levels of plaques (OR, 1.87; 95% CI, 1.01-3.17).
A little more than half (56%) of the sample were positive for the APOE e4 genotype, but the strongest association between pollution and neuropathology markers was for noncarriers of the genotype, although this relationship did not reach statistical significance.
IN PRACTICE:
“More research is needed to establish causality for the association between PM2.5 and AD, including epidemiologic and mechanistic studies. Future studies should also investigate the association between PM2.5 and other dementia-related pathologies, including cerebrovascular pathology,” the study authors wrote.
SOURCE:
Anke Hüls, PhD, of Emory University in Atlanta, led the study, which was published online on February 21, 2024, in Neurology.
LIMITATIONS:
The sample was not population-based but a convenience sample composed mostly of highly educated White participants.
DISCLOSURES:
The study was funded by the National Institute of Environmental Health Sciences, the Goizueta Alzheimer’s Disease Research Center, the National Institute on Aging, and the National Institutes of Health. There were no relevant disclosures.
A version of this article appeared on Medscape.com.
TOPLINE:
, a new postmortem study showed.
METHODOLOGY:
- Investigators examined the brain tissue of 224 people living in the Atlanta area who agreed to donate their brains after death (average age of death, 76 years) for the presence of amyloid plaques and tau tangles.
- They also studied the amount of fine particulate matter < 2.5 microns (PM2.5) from traffic-related air pollution at participants’ home addresses at 1, 3, and 5 years before death.
- The presence of the APOE e4 gene was examined for evidence of any effect on the relationship between air pollution and evidence of Alzheimer’s disease (AD).
TAKEAWAY:
The average level of exposure in the year before death was 1.32 µg/m3 and 1.35 µg/m3 in the 3 years before death.
People with 1 µg/m3 higher PM2.5 exposure in the year before death were nearly twice as likely to have higher levels of plaques (odds ratio [OR], 1.92; 95% CI, 1.12-3.30), while those with higher exposure in the 3 years before death were 87% more likely to have higher levels of plaques (OR, 1.87; 95% CI, 1.01-3.17).
A little more than half (56%) of the sample were positive for the APOE e4 genotype, but the strongest association between pollution and neuropathology markers was for noncarriers of the genotype, although this relationship did not reach statistical significance.
IN PRACTICE:
“More research is needed to establish causality for the association between PM2.5 and AD, including epidemiologic and mechanistic studies. Future studies should also investigate the association between PM2.5 and other dementia-related pathologies, including cerebrovascular pathology,” the study authors wrote.
SOURCE:
Anke Hüls, PhD, of Emory University in Atlanta, led the study, which was published online on February 21, 2024, in Neurology.
LIMITATIONS:
The sample was not population-based but a convenience sample composed mostly of highly educated White participants.
DISCLOSURES:
The study was funded by the National Institute of Environmental Health Sciences, the Goizueta Alzheimer’s Disease Research Center, the National Institute on Aging, and the National Institutes of Health. There were no relevant disclosures.
A version of this article appeared on Medscape.com.
AGA Guides Usage of GLP-1 Receptor Agonists Before Endoscopy
The American Gastroenterological Association (AGA) has issued a rapid clinical practice update on the use of glucagon-like peptide 1 (GLP-1) receptor agonists prior to endoscopy.
The update was partly prompted by consensus-based perioperative guidance issued by the American Society of Anesthesiologists in June 2023, which advises withholding GLP-1 receptor agonists before endoscopy. This recommendation has caused some anesthesia providers to cancel or postpone endoscopic procedures, or even elect general endotracheal intubation over standard sedation.
“Many facilities and medical centers are now struggling to revise preprocedural protocols for patients taking this class of medications despite the lack of high-level evidence regarding how to proceed,” the panelists wrote in Clinical Gastroenterology and Hepatology. “Important questions include whether these preprocedural changes are necessary, if they truly mitigate periprocedural aspiration, or if the delays instituted by following this guidance might further compound the major problem currently faced nationwide: that of large numbers of patients awaiting endoscopic procedures because of delays from the COVID-19 pandemic, reduction in the recommended age threshold to start colorectal cancer screening in 2018, and workforce challenges.”
The rapid clinical practice update, commissioned and approved by the AGA, includes background on the relationship between GLP-1 receptor agonists and endoscopic procedures, followed by clinical strategies for patients taking these medications.
Lead panelist Jana G. Al Hashash, MD, MSc, AGAF, of Mayo Clinic, Jacksonville, Florida, and colleagues began by noting that GLP-1 receptor agonists have been associated with increased gastric residue in patients with diabetes, and among nondiabetic patients, increased gastric retention of solids but not liquids. Delayed gastric emptying and increased residual gastric contents may be more common among patients on GLP-1 agonists who have vomiting, nausea, dyspepsia, or abdominal bloating, they added.
The above findings “imply an increased risk of aspiration in patients receiving GLP-1 receptor agonist medications who present for procedures that require sedation,” the panelists wrote, but more data is needed to support this hypothesis.
Yet the implications for endoscopic risk are still unclear.
Residual liquid in the stomach, at least, is “less of an issue,” according to the update, since “it is easily removed during an esophagogastroduodenoscopy, and this is the first maneuver performed by endoscopists on entering the stomach.”
While residual solids in the stomach could theoretically increase risk of aspiration, other patients with gastroparesis, such as those taking opioids, are not routinely given “special dietary precautions or medication adjustments” prior to endoscopy, Dr. Al Hashash and colleagues wrote. Even patients with severe gastroparesis who are undergoing gastric peroral endoscopic myotomy (which depends upon an empty stomach), are only required to stop ingesting solid foods the day before the procedure, they noted.
“It is appropriate that the ASA’s perioperative suggestions for patients on GLP-1 [receptor agonists] are labeled ‘consensus-based guidance on perioperative management,’ because there is clearly insufficient published evidence for a robust systematic review and guideline,” they wrote. “As such, the ASA’s suggestions are expert opinions, which may inform but should not replace clinical judgment.”
, for whom withholding these medications “might provide more risk than benefit.”
Withholding GLP-1 receptor agonists may be safe and reasonable for patients taking them solely for weight loss, but “this should not be considered mandatory or evidence-based,” as it remains unclear whether withholding one dose is enough to restore normal gastric motility.
“Generally, in patients on GLP-1 receptor agonists who have followed standard perioperative procedures (typically an 8-hour solid-food fast and a 2-hour liquid fast) and who do not have symptoms of nausea, vomiting, dyspepsia, or abdominal distention, we advise proceeding with upper and/or lower endoscopy,” the panelists concluded.
The rapid clinical practice update was commissioned and approved by the AGA. The update panelists disclosed relationships with Apollo Endosurgery, Medtronic, Boston Scientific, and others.
The American Gastroenterological Association (AGA) has issued a rapid clinical practice update on the use of glucagon-like peptide 1 (GLP-1) receptor agonists prior to endoscopy.
The update was partly prompted by consensus-based perioperative guidance issued by the American Society of Anesthesiologists in June 2023, which advises withholding GLP-1 receptor agonists before endoscopy. This recommendation has caused some anesthesia providers to cancel or postpone endoscopic procedures, or even elect general endotracheal intubation over standard sedation.
“Many facilities and medical centers are now struggling to revise preprocedural protocols for patients taking this class of medications despite the lack of high-level evidence regarding how to proceed,” the panelists wrote in Clinical Gastroenterology and Hepatology. “Important questions include whether these preprocedural changes are necessary, if they truly mitigate periprocedural aspiration, or if the delays instituted by following this guidance might further compound the major problem currently faced nationwide: that of large numbers of patients awaiting endoscopic procedures because of delays from the COVID-19 pandemic, reduction in the recommended age threshold to start colorectal cancer screening in 2018, and workforce challenges.”
The rapid clinical practice update, commissioned and approved by the AGA, includes background on the relationship between GLP-1 receptor agonists and endoscopic procedures, followed by clinical strategies for patients taking these medications.
Lead panelist Jana G. Al Hashash, MD, MSc, AGAF, of Mayo Clinic, Jacksonville, Florida, and colleagues began by noting that GLP-1 receptor agonists have been associated with increased gastric residue in patients with diabetes, and among nondiabetic patients, increased gastric retention of solids but not liquids. Delayed gastric emptying and increased residual gastric contents may be more common among patients on GLP-1 agonists who have vomiting, nausea, dyspepsia, or abdominal bloating, they added.
The above findings “imply an increased risk of aspiration in patients receiving GLP-1 receptor agonist medications who present for procedures that require sedation,” the panelists wrote, but more data is needed to support this hypothesis.
Yet the implications for endoscopic risk are still unclear.
Residual liquid in the stomach, at least, is “less of an issue,” according to the update, since “it is easily removed during an esophagogastroduodenoscopy, and this is the first maneuver performed by endoscopists on entering the stomach.”
While residual solids in the stomach could theoretically increase risk of aspiration, other patients with gastroparesis, such as those taking opioids, are not routinely given “special dietary precautions or medication adjustments” prior to endoscopy, Dr. Al Hashash and colleagues wrote. Even patients with severe gastroparesis who are undergoing gastric peroral endoscopic myotomy (which depends upon an empty stomach), are only required to stop ingesting solid foods the day before the procedure, they noted.
“It is appropriate that the ASA’s perioperative suggestions for patients on GLP-1 [receptor agonists] are labeled ‘consensus-based guidance on perioperative management,’ because there is clearly insufficient published evidence for a robust systematic review and guideline,” they wrote. “As such, the ASA’s suggestions are expert opinions, which may inform but should not replace clinical judgment.”
, for whom withholding these medications “might provide more risk than benefit.”
Withholding GLP-1 receptor agonists may be safe and reasonable for patients taking them solely for weight loss, but “this should not be considered mandatory or evidence-based,” as it remains unclear whether withholding one dose is enough to restore normal gastric motility.
“Generally, in patients on GLP-1 receptor agonists who have followed standard perioperative procedures (typically an 8-hour solid-food fast and a 2-hour liquid fast) and who do not have symptoms of nausea, vomiting, dyspepsia, or abdominal distention, we advise proceeding with upper and/or lower endoscopy,” the panelists concluded.
The rapid clinical practice update was commissioned and approved by the AGA. The update panelists disclosed relationships with Apollo Endosurgery, Medtronic, Boston Scientific, and others.
The American Gastroenterological Association (AGA) has issued a rapid clinical practice update on the use of glucagon-like peptide 1 (GLP-1) receptor agonists prior to endoscopy.
The update was partly prompted by consensus-based perioperative guidance issued by the American Society of Anesthesiologists in June 2023, which advises withholding GLP-1 receptor agonists before endoscopy. This recommendation has caused some anesthesia providers to cancel or postpone endoscopic procedures, or even elect general endotracheal intubation over standard sedation.
“Many facilities and medical centers are now struggling to revise preprocedural protocols for patients taking this class of medications despite the lack of high-level evidence regarding how to proceed,” the panelists wrote in Clinical Gastroenterology and Hepatology. “Important questions include whether these preprocedural changes are necessary, if they truly mitigate periprocedural aspiration, or if the delays instituted by following this guidance might further compound the major problem currently faced nationwide: that of large numbers of patients awaiting endoscopic procedures because of delays from the COVID-19 pandemic, reduction in the recommended age threshold to start colorectal cancer screening in 2018, and workforce challenges.”
The rapid clinical practice update, commissioned and approved by the AGA, includes background on the relationship between GLP-1 receptor agonists and endoscopic procedures, followed by clinical strategies for patients taking these medications.
Lead panelist Jana G. Al Hashash, MD, MSc, AGAF, of Mayo Clinic, Jacksonville, Florida, and colleagues began by noting that GLP-1 receptor agonists have been associated with increased gastric residue in patients with diabetes, and among nondiabetic patients, increased gastric retention of solids but not liquids. Delayed gastric emptying and increased residual gastric contents may be more common among patients on GLP-1 agonists who have vomiting, nausea, dyspepsia, or abdominal bloating, they added.
The above findings “imply an increased risk of aspiration in patients receiving GLP-1 receptor agonist medications who present for procedures that require sedation,” the panelists wrote, but more data is needed to support this hypothesis.
Yet the implications for endoscopic risk are still unclear.
Residual liquid in the stomach, at least, is “less of an issue,” according to the update, since “it is easily removed during an esophagogastroduodenoscopy, and this is the first maneuver performed by endoscopists on entering the stomach.”
While residual solids in the stomach could theoretically increase risk of aspiration, other patients with gastroparesis, such as those taking opioids, are not routinely given “special dietary precautions or medication adjustments” prior to endoscopy, Dr. Al Hashash and colleagues wrote. Even patients with severe gastroparesis who are undergoing gastric peroral endoscopic myotomy (which depends upon an empty stomach), are only required to stop ingesting solid foods the day before the procedure, they noted.
“It is appropriate that the ASA’s perioperative suggestions for patients on GLP-1 [receptor agonists] are labeled ‘consensus-based guidance on perioperative management,’ because there is clearly insufficient published evidence for a robust systematic review and guideline,” they wrote. “As such, the ASA’s suggestions are expert opinions, which may inform but should not replace clinical judgment.”
, for whom withholding these medications “might provide more risk than benefit.”
Withholding GLP-1 receptor agonists may be safe and reasonable for patients taking them solely for weight loss, but “this should not be considered mandatory or evidence-based,” as it remains unclear whether withholding one dose is enough to restore normal gastric motility.
“Generally, in patients on GLP-1 receptor agonists who have followed standard perioperative procedures (typically an 8-hour solid-food fast and a 2-hour liquid fast) and who do not have symptoms of nausea, vomiting, dyspepsia, or abdominal distention, we advise proceeding with upper and/or lower endoscopy,” the panelists concluded.
The rapid clinical practice update was commissioned and approved by the AGA. The update panelists disclosed relationships with Apollo Endosurgery, Medtronic, Boston Scientific, and others.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY