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Medical societies advise on vitamin D in midst of COVID-19
Six medical societies from across the globe are emphasizing the importance of individuals obtaining the daily recommended dose of vitamin D, especially given the impact of the COVID-19 pandemic on outdoor time.
The statement, “Joint Guidance on Vitamin D in the Era of COVID-19,” is supported by the American Society for Bone and Mineral Research, the Endocrine Society, and the American Association of Clinical Endocrinologists, among others.
They felt the need to clarify the recommendations for clinicians. Central to the guidance is the recommendation to directly expose the skin to sunlight for 15-30 minutes per day, while taking care to avoid sunburn.
The statement noted that “vitamin D is very safe when taken at reasonable dosages and is important for musculoskeletal health. Levels are likely to decline as individuals reduce outside activity (sun exposure) during the pandemic.”
It added that “most older and younger adults can safely take 400-1000 IU daily to keep vitamin D levels within the optimal range as recommended by [the US] Institute of Medicine guidelines.”
The statement also noted that the scientific evidence clearly supports the benefits that vitamin D (in combination with calcium intake) plays in building a strong skeleton and preventing bone loss.
Other societies supporting the statement are the European Calcified Tissue Society, the National Osteoporosis Foundation, and the International Osteoporosis Foundation.
What role for vitamin D in COVID-19?
Over recent months, the role of vitamin D in relation to prevention of COVID-19 has been the subject of intense debate. Now, these societies have joined forces and endorsed evidence-based guidance to clarify the issue around obtaining the daily recommended dosage of vitamin D.
During the pandemic, orders to stay at home meant individuals were likely to spend less time outdoors and have less opportunity to draw their vitamin D directly from sunlight, which is its main source, other than a limited number of foods or as a dietary supplement, the societies explained.
However, they acknowledged that the role of vitamin D in COVID-19 remains unclear.
“The current data do not provide any evidence that vitamin D supplementation will help prevent or treat COVID-19 infection; however, our guidance does not preclude further study of the potential effects of vitamin D on COVID-19,” the joint statement said.
Research to date suggests that vitamin D may play a role in enhancing the immune response, and given prior work demonstrating a role for the activated form of vitamin D – 1,25(OH)2D – in immune responses, “further research into vitamin D supplementation in COVID-19 disease is warranted,” it added. “Trials to date have been observational and there have been no randomized, controlled trials from which firm conclusions about causal relationships can be drawn. Observational studies suggest associations between low vitamin D concentrations and higher rates of COVID-19 infection.”
Medscape Medical News previously reported on the existing observational data regarding vitamin D in COVID-19. A recent rapid evidence review by the National Institute for Health and Care Excellence failed to find any evidence that vitamin D supplementation reduces the risk or severity of COVID-19.
A version of this article originally appeared on Medscape.com.
Six medical societies from across the globe are emphasizing the importance of individuals obtaining the daily recommended dose of vitamin D, especially given the impact of the COVID-19 pandemic on outdoor time.
The statement, “Joint Guidance on Vitamin D in the Era of COVID-19,” is supported by the American Society for Bone and Mineral Research, the Endocrine Society, and the American Association of Clinical Endocrinologists, among others.
They felt the need to clarify the recommendations for clinicians. Central to the guidance is the recommendation to directly expose the skin to sunlight for 15-30 minutes per day, while taking care to avoid sunburn.
The statement noted that “vitamin D is very safe when taken at reasonable dosages and is important for musculoskeletal health. Levels are likely to decline as individuals reduce outside activity (sun exposure) during the pandemic.”
It added that “most older and younger adults can safely take 400-1000 IU daily to keep vitamin D levels within the optimal range as recommended by [the US] Institute of Medicine guidelines.”
The statement also noted that the scientific evidence clearly supports the benefits that vitamin D (in combination with calcium intake) plays in building a strong skeleton and preventing bone loss.
Other societies supporting the statement are the European Calcified Tissue Society, the National Osteoporosis Foundation, and the International Osteoporosis Foundation.
What role for vitamin D in COVID-19?
Over recent months, the role of vitamin D in relation to prevention of COVID-19 has been the subject of intense debate. Now, these societies have joined forces and endorsed evidence-based guidance to clarify the issue around obtaining the daily recommended dosage of vitamin D.
During the pandemic, orders to stay at home meant individuals were likely to spend less time outdoors and have less opportunity to draw their vitamin D directly from sunlight, which is its main source, other than a limited number of foods or as a dietary supplement, the societies explained.
However, they acknowledged that the role of vitamin D in COVID-19 remains unclear.
“The current data do not provide any evidence that vitamin D supplementation will help prevent or treat COVID-19 infection; however, our guidance does not preclude further study of the potential effects of vitamin D on COVID-19,” the joint statement said.
Research to date suggests that vitamin D may play a role in enhancing the immune response, and given prior work demonstrating a role for the activated form of vitamin D – 1,25(OH)2D – in immune responses, “further research into vitamin D supplementation in COVID-19 disease is warranted,” it added. “Trials to date have been observational and there have been no randomized, controlled trials from which firm conclusions about causal relationships can be drawn. Observational studies suggest associations between low vitamin D concentrations and higher rates of COVID-19 infection.”
Medscape Medical News previously reported on the existing observational data regarding vitamin D in COVID-19. A recent rapid evidence review by the National Institute for Health and Care Excellence failed to find any evidence that vitamin D supplementation reduces the risk or severity of COVID-19.
A version of this article originally appeared on Medscape.com.
Six medical societies from across the globe are emphasizing the importance of individuals obtaining the daily recommended dose of vitamin D, especially given the impact of the COVID-19 pandemic on outdoor time.
The statement, “Joint Guidance on Vitamin D in the Era of COVID-19,” is supported by the American Society for Bone and Mineral Research, the Endocrine Society, and the American Association of Clinical Endocrinologists, among others.
They felt the need to clarify the recommendations for clinicians. Central to the guidance is the recommendation to directly expose the skin to sunlight for 15-30 minutes per day, while taking care to avoid sunburn.
The statement noted that “vitamin D is very safe when taken at reasonable dosages and is important for musculoskeletal health. Levels are likely to decline as individuals reduce outside activity (sun exposure) during the pandemic.”
It added that “most older and younger adults can safely take 400-1000 IU daily to keep vitamin D levels within the optimal range as recommended by [the US] Institute of Medicine guidelines.”
The statement also noted that the scientific evidence clearly supports the benefits that vitamin D (in combination with calcium intake) plays in building a strong skeleton and preventing bone loss.
Other societies supporting the statement are the European Calcified Tissue Society, the National Osteoporosis Foundation, and the International Osteoporosis Foundation.
What role for vitamin D in COVID-19?
Over recent months, the role of vitamin D in relation to prevention of COVID-19 has been the subject of intense debate. Now, these societies have joined forces and endorsed evidence-based guidance to clarify the issue around obtaining the daily recommended dosage of vitamin D.
During the pandemic, orders to stay at home meant individuals were likely to spend less time outdoors and have less opportunity to draw their vitamin D directly from sunlight, which is its main source, other than a limited number of foods or as a dietary supplement, the societies explained.
However, they acknowledged that the role of vitamin D in COVID-19 remains unclear.
“The current data do not provide any evidence that vitamin D supplementation will help prevent or treat COVID-19 infection; however, our guidance does not preclude further study of the potential effects of vitamin D on COVID-19,” the joint statement said.
Research to date suggests that vitamin D may play a role in enhancing the immune response, and given prior work demonstrating a role for the activated form of vitamin D – 1,25(OH)2D – in immune responses, “further research into vitamin D supplementation in COVID-19 disease is warranted,” it added. “Trials to date have been observational and there have been no randomized, controlled trials from which firm conclusions about causal relationships can be drawn. Observational studies suggest associations between low vitamin D concentrations and higher rates of COVID-19 infection.”
Medscape Medical News previously reported on the existing observational data regarding vitamin D in COVID-19. A recent rapid evidence review by the National Institute for Health and Care Excellence failed to find any evidence that vitamin D supplementation reduces the risk or severity of COVID-19.
A version of this article originally appeared on Medscape.com.
Delayed diagnoses seen in children during COVID-19
There were also nine deaths where delayed presentation was considered a contributing factor, resulting mainly from sepsis and malignancy.
By comparison, over the same 2-week period of the survey there were three child deaths from COVID-19 directly, according to senior study author Shamez Ladhani, MRCPCH, PhD, chair of the British Paediatric Surveillance Unit (BPSU), Royal College of Paediatrics and Child Health, London.
“The unintended consequences of COVID are far greater, in children, than the disease itself. The way we are trying to prevent this is causing more harm than the disease,” he lamented.
One-third of senior U.K. pediatric specialists who responded to the survey reported dealing with so-called emergency delayed presentations in children who they would normally have expected to present much earlier.
After diabetes, the most commonly reported delayed diagnoses were sepsis and child protection issues. Cancer also featured prominently.
“We’ve found that there is great concern that children are not accessing healthcare as they should during lockdown and after,” Dr. Ladhani stressed. “Our emergency departments saw a 50% reduction during the peak, and now it is still 40% less than expected. The problem is improving but it remains.”
The survey findings were recently published online in Archives of Disease in Childhood, by first author Richard M. Lynn, MSc, of the Institute of Child Health, department of epidemiology and public health, University College London Research, and colleagues.
New diabetes cases presented very late during lockdown
Over the 2-week reporting period in mid-April 2020, type 1 diabetes was the most frequently reported delayed diagnosis, with 44 cases overall, 23 of which involved diabetic ketoacidosis.
“If you talk to the diabetes specialists, they tell us that generally, most cases of new diabetes arrive late because it has very nonspecific symptoms,” Dr. Ladhani explained.
However, he added, “pediatricians on the frontline know what to expect with diabetes. Those children who would have come in late prior to the pandemic are now arriving very late. Those consultants surveyed were not junior doctors but consultant pediatricians with many years of experience.”
In a recent article looking at pediatric delayed presentations, one patient with diabetes entered intensive care, and the BPSU report recorded one death possibly associated with diabetes, Dr. Ladhani pointed out.
“Pediatricians are worried that children are coming in late. We need to raise awareness that parents need to access healthcare and this message needs to go out now,” he said. “We can’t wait until a second wave. It has to be now because A&E [accident and emergency] attendance is still 40% [lower than] ... expected.”
BPSU survey covers over 90% of pediatricians in U.K. and Ireland
After numerous anecdotal reports of delayed presentations in the United Kingdom and abroad, the snapshot survey was conducted as part of routine monthly reports where pediatricians are asked to document any cases of rare conditions seen.
“We had heard stories of delayed presentations, but we wanted to know was this a real problem or just anecdotal?” Dr. Ladhani said.
The regular BPSU survey covers over 90% of U.K.- and Ireland-based pediatric consultants (numbering 4,075). On the back of this established communication, the BPSU decided to gauge the extent of delayed presentations during the peak weeks of the COVID-19 pandemic.
Over the next 7 days, 2,433 pediatricians, representing 60% of BPSU participants, responded.
“This response rate in 7 days highlights the importance given to the survey by pediatricians ... and the widespread professional concern about delayed presentations,” the authors wrote.
Participants were asked whether they had seen any children during the previous 14 days who, in their opinion, presented later than they would have expected prior to the COVID-19 pandemic.
“There’s no one definition for this but these senior clinicians know when something is unusual,” said Dr. Ladhani.
ED attendances were compared with figures for the same period last year. Overall, a total of 32% of 752 pediatricians working in EDs and pediatric assessment units reported witnessing delayed presentations, with 57 (8%) reporting at least three patients with delayed presentation.
“It was clear that those doctors on the frontline were seeing a lot of delayed presentations. Also, neonatologists reported women arriving late for labor, and community physicians said they just weren’t witnessing child protection cases anymore,” added Dr. Ladhani.
Other issues included early discharges following births because of COVID-19 concerns, before feeding had been established, prompting return visits because of feeding problems and dehydration.
The top five delayed diagnoses were diabetes (n = 44), sepsis (n = 21), child protection (n = 14), malignancy (n = 8), and appendicitis (n = 6). There were 10 delayed perinatal presentations.
Of the nine deaths, for which delayed presentation was considered to play a role, three were caused by sepsis, three were caused by new malignancy diagnoses, one was caused by new diagnosis of metabolic disease, and two did not have the cause reported.
The delays in presentation are likely to have been influenced by the U.K. government’s message to “stay at home” during the strict lockdown period, which perhaps was sometimes interpreted too literally, Dr. Ladhani suggested. “It was the right message socially, but not medically.”
Russell Viner, MB, PhD, president of the Royal College of Paediatrics and Child Health, said in a statement: “The impact for children is what we call ‘collateral damage’, including long absences from school and delays or interruptions to vital services. We know that parents adhered very strongly to the ‘stay at home’ [message] and we need to say clearly that this doesn’t apply if your child is very sick. Should we experience a second wave or regional outbreaks, it is vital that we get the message out to parents that we want to see unwell children at the earliest possible stage.”
Dr. Ladhani reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
There were also nine deaths where delayed presentation was considered a contributing factor, resulting mainly from sepsis and malignancy.
By comparison, over the same 2-week period of the survey there were three child deaths from COVID-19 directly, according to senior study author Shamez Ladhani, MRCPCH, PhD, chair of the British Paediatric Surveillance Unit (BPSU), Royal College of Paediatrics and Child Health, London.
“The unintended consequences of COVID are far greater, in children, than the disease itself. The way we are trying to prevent this is causing more harm than the disease,” he lamented.
One-third of senior U.K. pediatric specialists who responded to the survey reported dealing with so-called emergency delayed presentations in children who they would normally have expected to present much earlier.
After diabetes, the most commonly reported delayed diagnoses were sepsis and child protection issues. Cancer also featured prominently.
“We’ve found that there is great concern that children are not accessing healthcare as they should during lockdown and after,” Dr. Ladhani stressed. “Our emergency departments saw a 50% reduction during the peak, and now it is still 40% less than expected. The problem is improving but it remains.”
The survey findings were recently published online in Archives of Disease in Childhood, by first author Richard M. Lynn, MSc, of the Institute of Child Health, department of epidemiology and public health, University College London Research, and colleagues.
New diabetes cases presented very late during lockdown
Over the 2-week reporting period in mid-April 2020, type 1 diabetes was the most frequently reported delayed diagnosis, with 44 cases overall, 23 of which involved diabetic ketoacidosis.
“If you talk to the diabetes specialists, they tell us that generally, most cases of new diabetes arrive late because it has very nonspecific symptoms,” Dr. Ladhani explained.
However, he added, “pediatricians on the frontline know what to expect with diabetes. Those children who would have come in late prior to the pandemic are now arriving very late. Those consultants surveyed were not junior doctors but consultant pediatricians with many years of experience.”
In a recent article looking at pediatric delayed presentations, one patient with diabetes entered intensive care, and the BPSU report recorded one death possibly associated with diabetes, Dr. Ladhani pointed out.
“Pediatricians are worried that children are coming in late. We need to raise awareness that parents need to access healthcare and this message needs to go out now,” he said. “We can’t wait until a second wave. It has to be now because A&E [accident and emergency] attendance is still 40% [lower than] ... expected.”
BPSU survey covers over 90% of pediatricians in U.K. and Ireland
After numerous anecdotal reports of delayed presentations in the United Kingdom and abroad, the snapshot survey was conducted as part of routine monthly reports where pediatricians are asked to document any cases of rare conditions seen.
“We had heard stories of delayed presentations, but we wanted to know was this a real problem or just anecdotal?” Dr. Ladhani said.
The regular BPSU survey covers over 90% of U.K.- and Ireland-based pediatric consultants (numbering 4,075). On the back of this established communication, the BPSU decided to gauge the extent of delayed presentations during the peak weeks of the COVID-19 pandemic.
Over the next 7 days, 2,433 pediatricians, representing 60% of BPSU participants, responded.
“This response rate in 7 days highlights the importance given to the survey by pediatricians ... and the widespread professional concern about delayed presentations,” the authors wrote.
Participants were asked whether they had seen any children during the previous 14 days who, in their opinion, presented later than they would have expected prior to the COVID-19 pandemic.
“There’s no one definition for this but these senior clinicians know when something is unusual,” said Dr. Ladhani.
ED attendances were compared with figures for the same period last year. Overall, a total of 32% of 752 pediatricians working in EDs and pediatric assessment units reported witnessing delayed presentations, with 57 (8%) reporting at least three patients with delayed presentation.
“It was clear that those doctors on the frontline were seeing a lot of delayed presentations. Also, neonatologists reported women arriving late for labor, and community physicians said they just weren’t witnessing child protection cases anymore,” added Dr. Ladhani.
Other issues included early discharges following births because of COVID-19 concerns, before feeding had been established, prompting return visits because of feeding problems and dehydration.
The top five delayed diagnoses were diabetes (n = 44), sepsis (n = 21), child protection (n = 14), malignancy (n = 8), and appendicitis (n = 6). There were 10 delayed perinatal presentations.
Of the nine deaths, for which delayed presentation was considered to play a role, three were caused by sepsis, three were caused by new malignancy diagnoses, one was caused by new diagnosis of metabolic disease, and two did not have the cause reported.
The delays in presentation are likely to have been influenced by the U.K. government’s message to “stay at home” during the strict lockdown period, which perhaps was sometimes interpreted too literally, Dr. Ladhani suggested. “It was the right message socially, but not medically.”
Russell Viner, MB, PhD, president of the Royal College of Paediatrics and Child Health, said in a statement: “The impact for children is what we call ‘collateral damage’, including long absences from school and delays or interruptions to vital services. We know that parents adhered very strongly to the ‘stay at home’ [message] and we need to say clearly that this doesn’t apply if your child is very sick. Should we experience a second wave or regional outbreaks, it is vital that we get the message out to parents that we want to see unwell children at the earliest possible stage.”
Dr. Ladhani reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
There were also nine deaths where delayed presentation was considered a contributing factor, resulting mainly from sepsis and malignancy.
By comparison, over the same 2-week period of the survey there were three child deaths from COVID-19 directly, according to senior study author Shamez Ladhani, MRCPCH, PhD, chair of the British Paediatric Surveillance Unit (BPSU), Royal College of Paediatrics and Child Health, London.
“The unintended consequences of COVID are far greater, in children, than the disease itself. The way we are trying to prevent this is causing more harm than the disease,” he lamented.
One-third of senior U.K. pediatric specialists who responded to the survey reported dealing with so-called emergency delayed presentations in children who they would normally have expected to present much earlier.
After diabetes, the most commonly reported delayed diagnoses were sepsis and child protection issues. Cancer also featured prominently.
“We’ve found that there is great concern that children are not accessing healthcare as they should during lockdown and after,” Dr. Ladhani stressed. “Our emergency departments saw a 50% reduction during the peak, and now it is still 40% less than expected. The problem is improving but it remains.”
The survey findings were recently published online in Archives of Disease in Childhood, by first author Richard M. Lynn, MSc, of the Institute of Child Health, department of epidemiology and public health, University College London Research, and colleagues.
New diabetes cases presented very late during lockdown
Over the 2-week reporting period in mid-April 2020, type 1 diabetes was the most frequently reported delayed diagnosis, with 44 cases overall, 23 of which involved diabetic ketoacidosis.
“If you talk to the diabetes specialists, they tell us that generally, most cases of new diabetes arrive late because it has very nonspecific symptoms,” Dr. Ladhani explained.
However, he added, “pediatricians on the frontline know what to expect with diabetes. Those children who would have come in late prior to the pandemic are now arriving very late. Those consultants surveyed were not junior doctors but consultant pediatricians with many years of experience.”
In a recent article looking at pediatric delayed presentations, one patient with diabetes entered intensive care, and the BPSU report recorded one death possibly associated with diabetes, Dr. Ladhani pointed out.
“Pediatricians are worried that children are coming in late. We need to raise awareness that parents need to access healthcare and this message needs to go out now,” he said. “We can’t wait until a second wave. It has to be now because A&E [accident and emergency] attendance is still 40% [lower than] ... expected.”
BPSU survey covers over 90% of pediatricians in U.K. and Ireland
After numerous anecdotal reports of delayed presentations in the United Kingdom and abroad, the snapshot survey was conducted as part of routine monthly reports where pediatricians are asked to document any cases of rare conditions seen.
“We had heard stories of delayed presentations, but we wanted to know was this a real problem or just anecdotal?” Dr. Ladhani said.
The regular BPSU survey covers over 90% of U.K.- and Ireland-based pediatric consultants (numbering 4,075). On the back of this established communication, the BPSU decided to gauge the extent of delayed presentations during the peak weeks of the COVID-19 pandemic.
Over the next 7 days, 2,433 pediatricians, representing 60% of BPSU participants, responded.
“This response rate in 7 days highlights the importance given to the survey by pediatricians ... and the widespread professional concern about delayed presentations,” the authors wrote.
Participants were asked whether they had seen any children during the previous 14 days who, in their opinion, presented later than they would have expected prior to the COVID-19 pandemic.
“There’s no one definition for this but these senior clinicians know when something is unusual,” said Dr. Ladhani.
ED attendances were compared with figures for the same period last year. Overall, a total of 32% of 752 pediatricians working in EDs and pediatric assessment units reported witnessing delayed presentations, with 57 (8%) reporting at least three patients with delayed presentation.
“It was clear that those doctors on the frontline were seeing a lot of delayed presentations. Also, neonatologists reported women arriving late for labor, and community physicians said they just weren’t witnessing child protection cases anymore,” added Dr. Ladhani.
Other issues included early discharges following births because of COVID-19 concerns, before feeding had been established, prompting return visits because of feeding problems and dehydration.
The top five delayed diagnoses were diabetes (n = 44), sepsis (n = 21), child protection (n = 14), malignancy (n = 8), and appendicitis (n = 6). There were 10 delayed perinatal presentations.
Of the nine deaths, for which delayed presentation was considered to play a role, three were caused by sepsis, three were caused by new malignancy diagnoses, one was caused by new diagnosis of metabolic disease, and two did not have the cause reported.
The delays in presentation are likely to have been influenced by the U.K. government’s message to “stay at home” during the strict lockdown period, which perhaps was sometimes interpreted too literally, Dr. Ladhani suggested. “It was the right message socially, but not medically.”
Russell Viner, MB, PhD, president of the Royal College of Paediatrics and Child Health, said in a statement: “The impact for children is what we call ‘collateral damage’, including long absences from school and delays or interruptions to vital services. We know that parents adhered very strongly to the ‘stay at home’ [message] and we need to say clearly that this doesn’t apply if your child is very sick. Should we experience a second wave or regional outbreaks, it is vital that we get the message out to parents that we want to see unwell children at the earliest possible stage.”
Dr. Ladhani reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
FDA recalls extended-release metformin due to NDMA impurities
The US Food and Drug Administration (FDA) has recommended voluntary recall of certain extended-release (ER) versions of metformin because testing has revealed excessive levels of N-nitrosodimethylamine (NDMA) in these products.
Metformin is the most commonly prescribed drug used to treat type 2 diabetes worldwide.
NDMA is a contaminant with the potential to be carcinogenic if there is exposure to above-acceptable levels over the long-term.
Five pharmaceutical firms in particular are being contacted by the FDA with notices (posted on the FDA website) recommending they voluntarily recall their products. At the time of writing, only one was listed, Apotex Corp and its metformin hydrochloride ER tablets, USP 500 mg.
The recall does not apply to immediate-release metformin products, the most commonly prescribed ones for diabetes, the agency stresses.
It also recommends that clinicians continue to prescribe metformin when clinically appropriate.
In late 2019, the FDA announced it had become aware of NDMA in some metformin products in other countries. The agency immediately began testing to determine whether the metformin in the US supply was at risk, as part of the ongoing investigation into nitrosamine impurities across medication types, which included recalls of hypertension and heartburn medications within the past 2 years.
By February 2020, the agency had identified very low levels of NDMA in some samples, but at that time, no FDA-tested sample of metformin exceeded the acceptable intake limit for NDMA, as reported by Medscape Medical News.
“Now that we have identified some metformin products that do not meet our standards, we’re taking action. As we have been doing since this impurity was first identified, we will communicate as new scientific information becomes available and will take further action, if appropriate,” Patrizia Cavazzoni, MD, acting director of the FDA Center for Drug Evaluation and Research, said in a press release.
Requests for recall apply only to affected products
The recall was instigated after the FDA became aware of reports of higher levels of NDMA in certain ER formulations of metformin through a citizen petition filed by a private laboratory. The agency confirmed unacceptable NDMA levels in some, but not all, of those lots.
“In other instances, our laboratory detected NDMA in lots that the private laboratory did not,” it notes.
The FDA says it is working closely with manufacturers of the recalled tablets to identify the source of the NDMA impurity and ensure appropriate testing is carried out.
Elevated levels of NDMA have been found in some finished-dose tablets of the ER formulations but NDMA has not been detected in samples of the metformin active pharmaceutical ingredient.
The FDA also stresses there are many other additional manufacturers that supply metformin ER products to much of the US market, and they are not being asked to recall their products.
Work is also ongoing to determine whether the drug recalls will result in shortages, and if so, the agency says it will collaborate with manufacturers to prevent or reduce any impact of shortages.
“We understand that patients may have concerns about possible impurities in their medicines and want to assure the public that we have been looking closely at this problem over many months in order to provide patients and healthcare professionals with clear and accurate answers,” Cavazzoni said.
For more information about NDMA, visit the FDA nitrosamines web page.
This article first appeared on Medscape.com.
The US Food and Drug Administration (FDA) has recommended voluntary recall of certain extended-release (ER) versions of metformin because testing has revealed excessive levels of N-nitrosodimethylamine (NDMA) in these products.
Metformin is the most commonly prescribed drug used to treat type 2 diabetes worldwide.
NDMA is a contaminant with the potential to be carcinogenic if there is exposure to above-acceptable levels over the long-term.
Five pharmaceutical firms in particular are being contacted by the FDA with notices (posted on the FDA website) recommending they voluntarily recall their products. At the time of writing, only one was listed, Apotex Corp and its metformin hydrochloride ER tablets, USP 500 mg.
The recall does not apply to immediate-release metformin products, the most commonly prescribed ones for diabetes, the agency stresses.
It also recommends that clinicians continue to prescribe metformin when clinically appropriate.
In late 2019, the FDA announced it had become aware of NDMA in some metformin products in other countries. The agency immediately began testing to determine whether the metformin in the US supply was at risk, as part of the ongoing investigation into nitrosamine impurities across medication types, which included recalls of hypertension and heartburn medications within the past 2 years.
By February 2020, the agency had identified very low levels of NDMA in some samples, but at that time, no FDA-tested sample of metformin exceeded the acceptable intake limit for NDMA, as reported by Medscape Medical News.
“Now that we have identified some metformin products that do not meet our standards, we’re taking action. As we have been doing since this impurity was first identified, we will communicate as new scientific information becomes available and will take further action, if appropriate,” Patrizia Cavazzoni, MD, acting director of the FDA Center for Drug Evaluation and Research, said in a press release.
Requests for recall apply only to affected products
The recall was instigated after the FDA became aware of reports of higher levels of NDMA in certain ER formulations of metformin through a citizen petition filed by a private laboratory. The agency confirmed unacceptable NDMA levels in some, but not all, of those lots.
“In other instances, our laboratory detected NDMA in lots that the private laboratory did not,” it notes.
The FDA says it is working closely with manufacturers of the recalled tablets to identify the source of the NDMA impurity and ensure appropriate testing is carried out.
Elevated levels of NDMA have been found in some finished-dose tablets of the ER formulations but NDMA has not been detected in samples of the metformin active pharmaceutical ingredient.
The FDA also stresses there are many other additional manufacturers that supply metformin ER products to much of the US market, and they are not being asked to recall their products.
Work is also ongoing to determine whether the drug recalls will result in shortages, and if so, the agency says it will collaborate with manufacturers to prevent or reduce any impact of shortages.
“We understand that patients may have concerns about possible impurities in their medicines and want to assure the public that we have been looking closely at this problem over many months in order to provide patients and healthcare professionals with clear and accurate answers,” Cavazzoni said.
For more information about NDMA, visit the FDA nitrosamines web page.
This article first appeared on Medscape.com.
The US Food and Drug Administration (FDA) has recommended voluntary recall of certain extended-release (ER) versions of metformin because testing has revealed excessive levels of N-nitrosodimethylamine (NDMA) in these products.
Metformin is the most commonly prescribed drug used to treat type 2 diabetes worldwide.
NDMA is a contaminant with the potential to be carcinogenic if there is exposure to above-acceptable levels over the long-term.
Five pharmaceutical firms in particular are being contacted by the FDA with notices (posted on the FDA website) recommending they voluntarily recall their products. At the time of writing, only one was listed, Apotex Corp and its metformin hydrochloride ER tablets, USP 500 mg.
The recall does not apply to immediate-release metformin products, the most commonly prescribed ones for diabetes, the agency stresses.
It also recommends that clinicians continue to prescribe metformin when clinically appropriate.
In late 2019, the FDA announced it had become aware of NDMA in some metformin products in other countries. The agency immediately began testing to determine whether the metformin in the US supply was at risk, as part of the ongoing investigation into nitrosamine impurities across medication types, which included recalls of hypertension and heartburn medications within the past 2 years.
By February 2020, the agency had identified very low levels of NDMA in some samples, but at that time, no FDA-tested sample of metformin exceeded the acceptable intake limit for NDMA, as reported by Medscape Medical News.
“Now that we have identified some metformin products that do not meet our standards, we’re taking action. As we have been doing since this impurity was first identified, we will communicate as new scientific information becomes available and will take further action, if appropriate,” Patrizia Cavazzoni, MD, acting director of the FDA Center for Drug Evaluation and Research, said in a press release.
Requests for recall apply only to affected products
The recall was instigated after the FDA became aware of reports of higher levels of NDMA in certain ER formulations of metformin through a citizen petition filed by a private laboratory. The agency confirmed unacceptable NDMA levels in some, but not all, of those lots.
“In other instances, our laboratory detected NDMA in lots that the private laboratory did not,” it notes.
The FDA says it is working closely with manufacturers of the recalled tablets to identify the source of the NDMA impurity and ensure appropriate testing is carried out.
Elevated levels of NDMA have been found in some finished-dose tablets of the ER formulations but NDMA has not been detected in samples of the metformin active pharmaceutical ingredient.
The FDA also stresses there are many other additional manufacturers that supply metformin ER products to much of the US market, and they are not being asked to recall their products.
Work is also ongoing to determine whether the drug recalls will result in shortages, and if so, the agency says it will collaborate with manufacturers to prevent or reduce any impact of shortages.
“We understand that patients may have concerns about possible impurities in their medicines and want to assure the public that we have been looking closely at this problem over many months in order to provide patients and healthcare professionals with clear and accurate answers,” Cavazzoni said.
For more information about NDMA, visit the FDA nitrosamines web page.
This article first appeared on Medscape.com.
Vitamin D: A low-hanging fruit in COVID-19?
Mainstream media outlets have been flooded recently with reports speculating on what role, if any, vitamin D may play in reducing the severity of COVID-19 infection.
as well as mortality, with the further suggestion of an effect of vitamin D on the immune response to infection.
But other studies question such a link, including any association between vitamin D concentration and differences in COVID-19 severity by ethnic group.
And while some researchers and clinicians believe people should get tested to see if they have adequate vitamin D levels during this pandemic – in particular frontline health care workers – most doctors say the best way to ensure that people have adequate levels of vitamin D during COVID-19 is to simply take supplements at currently recommended levels.
This is especially important given the fact that, during “lockdown” scenarios, many people are spending more time than usual indoors.
Clifford Rosen, MD, senior scientist at Maine Medical Center’s Research Institute in Scarborough, has been researching vitamin D for 25 years.
“There’s no randomized, controlled trial for sure, and that’s the gold standard,” he said in an interview, and “the observational data are so confounded, it’s difficult to know.”
Whether from diet or supplementation, having adequate vitamin D is important, especially for those at the highest risk of COVID-19, he said. Still, robust data supporting a role of vitamin D in prevention of COVID-19, or as any kind of “therapy” for the infection, are currently lacking.
Rose Anne Kenny, MD, professor of medical gerontology at Trinity College Dublin, recently coauthored an article detailing an inverse association between vitamin D levels and mortality from COVID-19 across countries in Europe.
“At no stage are any of us saying this is a given, but there’s a probability that [vitamin D] – a low-hanging fruit – is a contributory factor and we can do something about it now,” she said in an interview.
Dr. Kenny is calling for the Irish government to formally change their recommendations. “We call on the Irish government to update guidelines as a matter of urgency and encourage all adults to take [vitamin D] supplements during the COVID-19 crisis.” Northern Ireland, part of the United Kingdom, also has not yet made this recommendation, she said.
Meanwhile, Harpreet S. Bajaj, MD, MPH, a practicing endocrinologist from Mount Sinai Hospital, Toronto, said: “Vitamin D could have any of three potential roles in risk for COVID-19 and/or its severity: no role, simply a marker, or a causal factor.”
Dr. Bajaj said – as did Dr. Rosen and Dr. Kenny – that randomized, controlled trials (RCTs) are sorely needed to help ascertain whether there is a specific role of vitamin D.
“Until then, we should continue to follow established public health recommendations for vitamin D supplementation, in addition to following COVID-19 prevention guidance and evolving guidelines for COVID-19 treatment.”
What is the role of vitamin D fortification?
In their study in the Irish Medical Journal, Dr. Kenny and colleagues noted that, in Europe, despite being sunny, Spain and Northern Italy had high rates of vitamin D deficiency and have experienced some of the highest COVID-19 infection and mortality rates in the world.
But these countries do not formally fortify foods or recommend supplementation with vitamin D.
Conversely, the northern countries of Norway, Finland, and Sweden had higher vitamin D levels despite less UVB sunlight exposure, as a result of common supplementation and formal fortification of foods. These Nordic countries also had lower levels of COVID-19 infection and mortality.
Overall, the correlation between low vitamin D levels and mortality from COVID-19 was statistically significant (P = .046), the investigators reported.
“Optimizing vitamin D status to recommendations by national and international public health agencies will certainly have ... potential benefits for COVID-19,” they concluded.
“We’re not saying there aren’t any confounders. This can absolutely be the case, but this [finding] needs to be in the mix of evidence,” Dr. Kenny said.
Dr. Kenny also noted that countries in the Southern Hemisphere have been seeing a relatively low mortality from COVID-19, although she acknowledged the explanation could be that the virus spread later to those countries.
Dr. Rosen has doubts on this issue, too.
“Sure, vitamin D supplementation may have worked for [Nordic countries], their COVID-19 has been better controlled, but there’s no causality here; there’s another step to actually prove this. Other factors might be at play,” he said.
“Look at Brazil, it’s at the equator but the disease is devastating the country. Right now, I just don’t believe it.”
Does vitamin D have a role to play in immune modulation?
One theory currently circulating is that, if vitamin D does have any role to play in modulating response to COVID-19, this may be via a blunting of the immune system reaction to the virus.
In a recent preprint study, Ali Daneshkhah, PhD, and colleagues from Northwestern University, Chicago, interrogated hospital data from China, France, Germany, Italy, Iran, South Korea, Spain, Switzerland, the United Kingdom, and the United States.
Specifically, the risk of severe COVID-19 cases among patients with severe vitamin D deficiency was 17.3%, whereas the equivalent figure for patients with normal vitamin D levels was 14.6% (a reduction of 15.6%).
“This potential effect may be attributed to vitamin D’s ability to suppress the adaptive immune system, regulating cytokine levels and thereby reducing the risk of developing severe COVID-19,” said the researchers.
Likewise, JoAnn E. Manson, MD, chief of the division of preventive medicine at Brigham and Women’s Hospital in Boston, in a recent commentary, noted evidence from an observational study from three South Asian hospitals, in which the prevalence of vitamin D deficiency was much higher among those with severe COVID-19 illness compared with those with mild illness.
“We also know that vitamin D has an immune-modulating effect and can lower inflammation, and this may be relevant to the respiratory response during COVID-19 and the cytokine storm that’s been demonstrated,” she noted.
Dr. Rosen said he is willing to listen on the issue of a potential role of vitamin D in immune modulation.
“I’ve been a huge skeptic from the get-go, and loudly criticized the data for doing nothing. I am surprised at myself for saying there might be some effect,” he said.
“Clearly most people don’t get this [cytokine storm] but of those that do, it’s unclear why they do. Maybe if you are vitamin D sufficient, it might have some impact down the road on your response to an infection,” Dr. Rosen said. “Vitamin D may induce proteins important in modulating the function of macrophages of the immune system.”
Ethnic minorities disproportionately affected
It is also well recognized that COVID-19 disproportionately affects black and Asian minority ethnic individuals.
But on the issue of vitamin D in this context, one recent peer-reviewed study using UK Biobank data found no evidence to support a potential role for vitamin D concentration to explain susceptibility to COVID-19 infection either overall or in explaining differences between ethnic groups.
“Vitamin D is unlikely to be the underlying mechanism for the higher risk observed in black and minority ethnic individuals, and vitamin D supplements are unlikely to provide an effective intervention,” Claire Hastie, PhD, of the University of Glasgow and colleagues concluded.
But this hasn’t stopped two endocrinologists from appealing to members of the British Association of Physicians of Indian Origin (BAPIO) to get their vitamin D levels tested.
The black and Asian minority ethnic population, “especially frontline staff, should get their Vitamin D3 levels checked and get appropriate replacement as required,” said Parag Singhal, MD, of Weston General Hospital, Weston-Super-Mare, England, and David C. Anderson, a retired endocrinologist, said in a letter to BAPIO members.
Indeed, they suggested a booster dose of 100,000 IU as a one-off for black and Asian minority ethnic health care staff that should raise vitamin D levels for 2-3 months. They referred to a systematic review that concludes that “single vitamin D3 doses ≥300,000 IU are most effective at improving vitamin D status ... for up to 3 months”.
Commenting on the idea, Dr. Rosen remarked that, in general, the high-dose 50,000-500,000 IU given as a one-off does not confer any greater benefit than a single dose of 1,000 IU per day, except that the blood levels go up quicker and higher.
“Really there is no evidence that getting to super-high levels of vitamin D confer a greater benefit than normal levels,” he said. “So if health care workers suspect vitamin D deficiency, daily doses of 1,000 IU seem reasonable; even if they miss doses, the blood levels are relatively stable.”
On the specific question of vitamin D needs in ethnic minorities, Dr. Rosen said while such individuals do have lower serum levels of vitamin D, the issue is whether there are meaningful clinical implications related to this.
“The real question is whether [ethnic minority individuals] have physiologically adapted for this in other ways because these low levels have been so for thousands of years. In fact, African Americans have lower vitamin D levels but they absolutely have better bones than [whites],” he pointed out.
Testing and governmental recommendations during COVID-19
The U.S. National Institutes of Health in general advises 400 IU to 800 IU per day intake of vitamin D, depending on age, with those over 70 years requiring the highest daily dose. This will result in blood levels that are sufficient to maintain bone health and normal calcium metabolism in healthy people. There are no additional recommendations specific to vitamin D intake during the COVID-19 pandemic, however.
And Dr. Rosen pointed out that there is no evidence for mass screening of vitamin D levels among the U.S. population.
“U.S. public health guidance was pre-COVID, and I think high-risk individuals might want to think about their levels; for example, someone with inflammatory bowel disease or liver or pancreatic disease. These people are at higher risk anyway, and it could be because their vitamin D is low,” he said.
“Skip the test and ensure you are getting adequate levels of vitamin D whether via diet or supplement [400-800 IU per day],” he suggested. “It won’t harm.”
The U.K.’s Public Health England (PHE) clarified its advice on vitamin D supplementation during COVID-19. Alison Tedstone, PhD, chief nutritionist at PHE, said: “Many people are spending more time indoors and may not get all the vitamin D they need from sunlight. To protect their bone and muscle health, they should consider taking a daily supplement containing 10 micrograms [400 IU] of vitamin D.”
However, “there is no sufficient evidence to support recommending Vitamin D for reducing the risk of COVID-19,” she stressed.
Dr. Bajaj is on the advisory board of Medscape Diabetes & Endocrinology. He has ties with Amgen, AstraZeneca Boehringer Ingelheim, Janssen, Merck, Novo Nordisk, Sanofi, Eli Lilly,Valeant, Canadian Collaborative Research Network, CMS Knowledge Translation, Diabetes Canada Scientific Group, LMC Healthcare,mdBriefCase,Medscape, andMeducom. Dr. Kenny, Dr. Rosen, and Dr. Singhal have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Mainstream media outlets have been flooded recently with reports speculating on what role, if any, vitamin D may play in reducing the severity of COVID-19 infection.
as well as mortality, with the further suggestion of an effect of vitamin D on the immune response to infection.
But other studies question such a link, including any association between vitamin D concentration and differences in COVID-19 severity by ethnic group.
And while some researchers and clinicians believe people should get tested to see if they have adequate vitamin D levels during this pandemic – in particular frontline health care workers – most doctors say the best way to ensure that people have adequate levels of vitamin D during COVID-19 is to simply take supplements at currently recommended levels.
This is especially important given the fact that, during “lockdown” scenarios, many people are spending more time than usual indoors.
Clifford Rosen, MD, senior scientist at Maine Medical Center’s Research Institute in Scarborough, has been researching vitamin D for 25 years.
“There’s no randomized, controlled trial for sure, and that’s the gold standard,” he said in an interview, and “the observational data are so confounded, it’s difficult to know.”
Whether from diet or supplementation, having adequate vitamin D is important, especially for those at the highest risk of COVID-19, he said. Still, robust data supporting a role of vitamin D in prevention of COVID-19, or as any kind of “therapy” for the infection, are currently lacking.
Rose Anne Kenny, MD, professor of medical gerontology at Trinity College Dublin, recently coauthored an article detailing an inverse association between vitamin D levels and mortality from COVID-19 across countries in Europe.
“At no stage are any of us saying this is a given, but there’s a probability that [vitamin D] – a low-hanging fruit – is a contributory factor and we can do something about it now,” she said in an interview.
Dr. Kenny is calling for the Irish government to formally change their recommendations. “We call on the Irish government to update guidelines as a matter of urgency and encourage all adults to take [vitamin D] supplements during the COVID-19 crisis.” Northern Ireland, part of the United Kingdom, also has not yet made this recommendation, she said.
Meanwhile, Harpreet S. Bajaj, MD, MPH, a practicing endocrinologist from Mount Sinai Hospital, Toronto, said: “Vitamin D could have any of three potential roles in risk for COVID-19 and/or its severity: no role, simply a marker, or a causal factor.”
Dr. Bajaj said – as did Dr. Rosen and Dr. Kenny – that randomized, controlled trials (RCTs) are sorely needed to help ascertain whether there is a specific role of vitamin D.
“Until then, we should continue to follow established public health recommendations for vitamin D supplementation, in addition to following COVID-19 prevention guidance and evolving guidelines for COVID-19 treatment.”
What is the role of vitamin D fortification?
In their study in the Irish Medical Journal, Dr. Kenny and colleagues noted that, in Europe, despite being sunny, Spain and Northern Italy had high rates of vitamin D deficiency and have experienced some of the highest COVID-19 infection and mortality rates in the world.
But these countries do not formally fortify foods or recommend supplementation with vitamin D.
Conversely, the northern countries of Norway, Finland, and Sweden had higher vitamin D levels despite less UVB sunlight exposure, as a result of common supplementation and formal fortification of foods. These Nordic countries also had lower levels of COVID-19 infection and mortality.
Overall, the correlation between low vitamin D levels and mortality from COVID-19 was statistically significant (P = .046), the investigators reported.
“Optimizing vitamin D status to recommendations by national and international public health agencies will certainly have ... potential benefits for COVID-19,” they concluded.
“We’re not saying there aren’t any confounders. This can absolutely be the case, but this [finding] needs to be in the mix of evidence,” Dr. Kenny said.
Dr. Kenny also noted that countries in the Southern Hemisphere have been seeing a relatively low mortality from COVID-19, although she acknowledged the explanation could be that the virus spread later to those countries.
Dr. Rosen has doubts on this issue, too.
“Sure, vitamin D supplementation may have worked for [Nordic countries], their COVID-19 has been better controlled, but there’s no causality here; there’s another step to actually prove this. Other factors might be at play,” he said.
“Look at Brazil, it’s at the equator but the disease is devastating the country. Right now, I just don’t believe it.”
Does vitamin D have a role to play in immune modulation?
One theory currently circulating is that, if vitamin D does have any role to play in modulating response to COVID-19, this may be via a blunting of the immune system reaction to the virus.
In a recent preprint study, Ali Daneshkhah, PhD, and colleagues from Northwestern University, Chicago, interrogated hospital data from China, France, Germany, Italy, Iran, South Korea, Spain, Switzerland, the United Kingdom, and the United States.
Specifically, the risk of severe COVID-19 cases among patients with severe vitamin D deficiency was 17.3%, whereas the equivalent figure for patients with normal vitamin D levels was 14.6% (a reduction of 15.6%).
“This potential effect may be attributed to vitamin D’s ability to suppress the adaptive immune system, regulating cytokine levels and thereby reducing the risk of developing severe COVID-19,” said the researchers.
Likewise, JoAnn E. Manson, MD, chief of the division of preventive medicine at Brigham and Women’s Hospital in Boston, in a recent commentary, noted evidence from an observational study from three South Asian hospitals, in which the prevalence of vitamin D deficiency was much higher among those with severe COVID-19 illness compared with those with mild illness.
“We also know that vitamin D has an immune-modulating effect and can lower inflammation, and this may be relevant to the respiratory response during COVID-19 and the cytokine storm that’s been demonstrated,” she noted.
Dr. Rosen said he is willing to listen on the issue of a potential role of vitamin D in immune modulation.
“I’ve been a huge skeptic from the get-go, and loudly criticized the data for doing nothing. I am surprised at myself for saying there might be some effect,” he said.
“Clearly most people don’t get this [cytokine storm] but of those that do, it’s unclear why they do. Maybe if you are vitamin D sufficient, it might have some impact down the road on your response to an infection,” Dr. Rosen said. “Vitamin D may induce proteins important in modulating the function of macrophages of the immune system.”
Ethnic minorities disproportionately affected
It is also well recognized that COVID-19 disproportionately affects black and Asian minority ethnic individuals.
But on the issue of vitamin D in this context, one recent peer-reviewed study using UK Biobank data found no evidence to support a potential role for vitamin D concentration to explain susceptibility to COVID-19 infection either overall or in explaining differences between ethnic groups.
“Vitamin D is unlikely to be the underlying mechanism for the higher risk observed in black and minority ethnic individuals, and vitamin D supplements are unlikely to provide an effective intervention,” Claire Hastie, PhD, of the University of Glasgow and colleagues concluded.
But this hasn’t stopped two endocrinologists from appealing to members of the British Association of Physicians of Indian Origin (BAPIO) to get their vitamin D levels tested.
The black and Asian minority ethnic population, “especially frontline staff, should get their Vitamin D3 levels checked and get appropriate replacement as required,” said Parag Singhal, MD, of Weston General Hospital, Weston-Super-Mare, England, and David C. Anderson, a retired endocrinologist, said in a letter to BAPIO members.
Indeed, they suggested a booster dose of 100,000 IU as a one-off for black and Asian minority ethnic health care staff that should raise vitamin D levels for 2-3 months. They referred to a systematic review that concludes that “single vitamin D3 doses ≥300,000 IU are most effective at improving vitamin D status ... for up to 3 months”.
Commenting on the idea, Dr. Rosen remarked that, in general, the high-dose 50,000-500,000 IU given as a one-off does not confer any greater benefit than a single dose of 1,000 IU per day, except that the blood levels go up quicker and higher.
“Really there is no evidence that getting to super-high levels of vitamin D confer a greater benefit than normal levels,” he said. “So if health care workers suspect vitamin D deficiency, daily doses of 1,000 IU seem reasonable; even if they miss doses, the blood levels are relatively stable.”
On the specific question of vitamin D needs in ethnic minorities, Dr. Rosen said while such individuals do have lower serum levels of vitamin D, the issue is whether there are meaningful clinical implications related to this.
“The real question is whether [ethnic minority individuals] have physiologically adapted for this in other ways because these low levels have been so for thousands of years. In fact, African Americans have lower vitamin D levels but they absolutely have better bones than [whites],” he pointed out.
Testing and governmental recommendations during COVID-19
The U.S. National Institutes of Health in general advises 400 IU to 800 IU per day intake of vitamin D, depending on age, with those over 70 years requiring the highest daily dose. This will result in blood levels that are sufficient to maintain bone health and normal calcium metabolism in healthy people. There are no additional recommendations specific to vitamin D intake during the COVID-19 pandemic, however.
And Dr. Rosen pointed out that there is no evidence for mass screening of vitamin D levels among the U.S. population.
“U.S. public health guidance was pre-COVID, and I think high-risk individuals might want to think about their levels; for example, someone with inflammatory bowel disease or liver or pancreatic disease. These people are at higher risk anyway, and it could be because their vitamin D is low,” he said.
“Skip the test and ensure you are getting adequate levels of vitamin D whether via diet or supplement [400-800 IU per day],” he suggested. “It won’t harm.”
The U.K.’s Public Health England (PHE) clarified its advice on vitamin D supplementation during COVID-19. Alison Tedstone, PhD, chief nutritionist at PHE, said: “Many people are spending more time indoors and may not get all the vitamin D they need from sunlight. To protect their bone and muscle health, they should consider taking a daily supplement containing 10 micrograms [400 IU] of vitamin D.”
However, “there is no sufficient evidence to support recommending Vitamin D for reducing the risk of COVID-19,” she stressed.
Dr. Bajaj is on the advisory board of Medscape Diabetes & Endocrinology. He has ties with Amgen, AstraZeneca Boehringer Ingelheim, Janssen, Merck, Novo Nordisk, Sanofi, Eli Lilly,Valeant, Canadian Collaborative Research Network, CMS Knowledge Translation, Diabetes Canada Scientific Group, LMC Healthcare,mdBriefCase,Medscape, andMeducom. Dr. Kenny, Dr. Rosen, and Dr. Singhal have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Mainstream media outlets have been flooded recently with reports speculating on what role, if any, vitamin D may play in reducing the severity of COVID-19 infection.
as well as mortality, with the further suggestion of an effect of vitamin D on the immune response to infection.
But other studies question such a link, including any association between vitamin D concentration and differences in COVID-19 severity by ethnic group.
And while some researchers and clinicians believe people should get tested to see if they have adequate vitamin D levels during this pandemic – in particular frontline health care workers – most doctors say the best way to ensure that people have adequate levels of vitamin D during COVID-19 is to simply take supplements at currently recommended levels.
This is especially important given the fact that, during “lockdown” scenarios, many people are spending more time than usual indoors.
Clifford Rosen, MD, senior scientist at Maine Medical Center’s Research Institute in Scarborough, has been researching vitamin D for 25 years.
“There’s no randomized, controlled trial for sure, and that’s the gold standard,” he said in an interview, and “the observational data are so confounded, it’s difficult to know.”
Whether from diet or supplementation, having adequate vitamin D is important, especially for those at the highest risk of COVID-19, he said. Still, robust data supporting a role of vitamin D in prevention of COVID-19, or as any kind of “therapy” for the infection, are currently lacking.
Rose Anne Kenny, MD, professor of medical gerontology at Trinity College Dublin, recently coauthored an article detailing an inverse association between vitamin D levels and mortality from COVID-19 across countries in Europe.
“At no stage are any of us saying this is a given, but there’s a probability that [vitamin D] – a low-hanging fruit – is a contributory factor and we can do something about it now,” she said in an interview.
Dr. Kenny is calling for the Irish government to formally change their recommendations. “We call on the Irish government to update guidelines as a matter of urgency and encourage all adults to take [vitamin D] supplements during the COVID-19 crisis.” Northern Ireland, part of the United Kingdom, also has not yet made this recommendation, she said.
Meanwhile, Harpreet S. Bajaj, MD, MPH, a practicing endocrinologist from Mount Sinai Hospital, Toronto, said: “Vitamin D could have any of three potential roles in risk for COVID-19 and/or its severity: no role, simply a marker, or a causal factor.”
Dr. Bajaj said – as did Dr. Rosen and Dr. Kenny – that randomized, controlled trials (RCTs) are sorely needed to help ascertain whether there is a specific role of vitamin D.
“Until then, we should continue to follow established public health recommendations for vitamin D supplementation, in addition to following COVID-19 prevention guidance and evolving guidelines for COVID-19 treatment.”
What is the role of vitamin D fortification?
In their study in the Irish Medical Journal, Dr. Kenny and colleagues noted that, in Europe, despite being sunny, Spain and Northern Italy had high rates of vitamin D deficiency and have experienced some of the highest COVID-19 infection and mortality rates in the world.
But these countries do not formally fortify foods or recommend supplementation with vitamin D.
Conversely, the northern countries of Norway, Finland, and Sweden had higher vitamin D levels despite less UVB sunlight exposure, as a result of common supplementation and formal fortification of foods. These Nordic countries also had lower levels of COVID-19 infection and mortality.
Overall, the correlation between low vitamin D levels and mortality from COVID-19 was statistically significant (P = .046), the investigators reported.
“Optimizing vitamin D status to recommendations by national and international public health agencies will certainly have ... potential benefits for COVID-19,” they concluded.
“We’re not saying there aren’t any confounders. This can absolutely be the case, but this [finding] needs to be in the mix of evidence,” Dr. Kenny said.
Dr. Kenny also noted that countries in the Southern Hemisphere have been seeing a relatively low mortality from COVID-19, although she acknowledged the explanation could be that the virus spread later to those countries.
Dr. Rosen has doubts on this issue, too.
“Sure, vitamin D supplementation may have worked for [Nordic countries], their COVID-19 has been better controlled, but there’s no causality here; there’s another step to actually prove this. Other factors might be at play,” he said.
“Look at Brazil, it’s at the equator but the disease is devastating the country. Right now, I just don’t believe it.”
Does vitamin D have a role to play in immune modulation?
One theory currently circulating is that, if vitamin D does have any role to play in modulating response to COVID-19, this may be via a blunting of the immune system reaction to the virus.
In a recent preprint study, Ali Daneshkhah, PhD, and colleagues from Northwestern University, Chicago, interrogated hospital data from China, France, Germany, Italy, Iran, South Korea, Spain, Switzerland, the United Kingdom, and the United States.
Specifically, the risk of severe COVID-19 cases among patients with severe vitamin D deficiency was 17.3%, whereas the equivalent figure for patients with normal vitamin D levels was 14.6% (a reduction of 15.6%).
“This potential effect may be attributed to vitamin D’s ability to suppress the adaptive immune system, regulating cytokine levels and thereby reducing the risk of developing severe COVID-19,” said the researchers.
Likewise, JoAnn E. Manson, MD, chief of the division of preventive medicine at Brigham and Women’s Hospital in Boston, in a recent commentary, noted evidence from an observational study from three South Asian hospitals, in which the prevalence of vitamin D deficiency was much higher among those with severe COVID-19 illness compared with those with mild illness.
“We also know that vitamin D has an immune-modulating effect and can lower inflammation, and this may be relevant to the respiratory response during COVID-19 and the cytokine storm that’s been demonstrated,” she noted.
Dr. Rosen said he is willing to listen on the issue of a potential role of vitamin D in immune modulation.
“I’ve been a huge skeptic from the get-go, and loudly criticized the data for doing nothing. I am surprised at myself for saying there might be some effect,” he said.
“Clearly most people don’t get this [cytokine storm] but of those that do, it’s unclear why they do. Maybe if you are vitamin D sufficient, it might have some impact down the road on your response to an infection,” Dr. Rosen said. “Vitamin D may induce proteins important in modulating the function of macrophages of the immune system.”
Ethnic minorities disproportionately affected
It is also well recognized that COVID-19 disproportionately affects black and Asian minority ethnic individuals.
But on the issue of vitamin D in this context, one recent peer-reviewed study using UK Biobank data found no evidence to support a potential role for vitamin D concentration to explain susceptibility to COVID-19 infection either overall or in explaining differences between ethnic groups.
“Vitamin D is unlikely to be the underlying mechanism for the higher risk observed in black and minority ethnic individuals, and vitamin D supplements are unlikely to provide an effective intervention,” Claire Hastie, PhD, of the University of Glasgow and colleagues concluded.
But this hasn’t stopped two endocrinologists from appealing to members of the British Association of Physicians of Indian Origin (BAPIO) to get their vitamin D levels tested.
The black and Asian minority ethnic population, “especially frontline staff, should get their Vitamin D3 levels checked and get appropriate replacement as required,” said Parag Singhal, MD, of Weston General Hospital, Weston-Super-Mare, England, and David C. Anderson, a retired endocrinologist, said in a letter to BAPIO members.
Indeed, they suggested a booster dose of 100,000 IU as a one-off for black and Asian minority ethnic health care staff that should raise vitamin D levels for 2-3 months. They referred to a systematic review that concludes that “single vitamin D3 doses ≥300,000 IU are most effective at improving vitamin D status ... for up to 3 months”.
Commenting on the idea, Dr. Rosen remarked that, in general, the high-dose 50,000-500,000 IU given as a one-off does not confer any greater benefit than a single dose of 1,000 IU per day, except that the blood levels go up quicker and higher.
“Really there is no evidence that getting to super-high levels of vitamin D confer a greater benefit than normal levels,” he said. “So if health care workers suspect vitamin D deficiency, daily doses of 1,000 IU seem reasonable; even if they miss doses, the blood levels are relatively stable.”
On the specific question of vitamin D needs in ethnic minorities, Dr. Rosen said while such individuals do have lower serum levels of vitamin D, the issue is whether there are meaningful clinical implications related to this.
“The real question is whether [ethnic minority individuals] have physiologically adapted for this in other ways because these low levels have been so for thousands of years. In fact, African Americans have lower vitamin D levels but they absolutely have better bones than [whites],” he pointed out.
Testing and governmental recommendations during COVID-19
The U.S. National Institutes of Health in general advises 400 IU to 800 IU per day intake of vitamin D, depending on age, with those over 70 years requiring the highest daily dose. This will result in blood levels that are sufficient to maintain bone health and normal calcium metabolism in healthy people. There are no additional recommendations specific to vitamin D intake during the COVID-19 pandemic, however.
And Dr. Rosen pointed out that there is no evidence for mass screening of vitamin D levels among the U.S. population.
“U.S. public health guidance was pre-COVID, and I think high-risk individuals might want to think about their levels; for example, someone with inflammatory bowel disease or liver or pancreatic disease. These people are at higher risk anyway, and it could be because their vitamin D is low,” he said.
“Skip the test and ensure you are getting adequate levels of vitamin D whether via diet or supplement [400-800 IU per day],” he suggested. “It won’t harm.”
The U.K.’s Public Health England (PHE) clarified its advice on vitamin D supplementation during COVID-19. Alison Tedstone, PhD, chief nutritionist at PHE, said: “Many people are spending more time indoors and may not get all the vitamin D they need from sunlight. To protect their bone and muscle health, they should consider taking a daily supplement containing 10 micrograms [400 IU] of vitamin D.”
However, “there is no sufficient evidence to support recommending Vitamin D for reducing the risk of COVID-19,” she stressed.
Dr. Bajaj is on the advisory board of Medscape Diabetes & Endocrinology. He has ties with Amgen, AstraZeneca Boehringer Ingelheim, Janssen, Merck, Novo Nordisk, Sanofi, Eli Lilly,Valeant, Canadian Collaborative Research Network, CMS Knowledge Translation, Diabetes Canada Scientific Group, LMC Healthcare,mdBriefCase,Medscape, andMeducom. Dr. Kenny, Dr. Rosen, and Dr. Singhal have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Keep calm: Under 25s with diabetes aren't being hospitalized for COVID-19
Reports from pediatric endocrinologists in COVID-19 hot spots globally indicate that children, adolescents, and young adults with diabetes have so far not shown a different disease pattern with the virus compared to children and younger people who do not have diabetes.
Indeed, to date [as of March 24]” according to a new statement from the International Society for Pediatric and Adolescent Diabetes (ISPAD), which currently has about 1,300 members around the globe and has instituted a discussion forum about the topic of treating children with both diabetes and COVID-19.
“We find these reports [from colleagues around the world], though anecdotal, to be reassuring,” it notes. However, there are real worries regarding other potentially dangerous effects. ISPAD has expressed concern, for example, that the COVID-19 pandemic will prevent youngsters with existing diabetes who are having diabetic emergencies from seeking hospital care.
Chinese physicians have reported to ISPAD a number of cases of delayed hospital admissions for diabetic ketoacidosis (DKA) in children with known type 1 diabetes because hospital services were closed for non–COVID-19 care.
Andrea Scaramuzza, MD, a pediatric endocrinologist at Ospedale Maggiore di Cremona, Italy, has similarly reported multiple cases of patients presenting to emergency services there with severe DKA.
“These experiences reinforce the importance of continued attentiveness to standard diabetes care to avoid the need for hospitalization and emergency or urgent care visits,” says ISPAD, under the strapline: “Keep calm and mind your diabetes care.”
But it nevertheless stresses that these resources should be used “if needed.”
Worries that new-onset diabetes will be missed during COVID-19
Dr. Scaramuzza said in an interview that there also are concerns regarding delays in diagnoses of new cases of type 1 diabetes “due to the fear families have to go to the emergency department because of COVID-19.”
Indeed, in Italy, a few patients have arrived with very serious DKA, he said. Dr. Scaramuzza noted a colleague from Naples, Dario Iafusco, MD, and colleagues have made a video to keep awareness high regarding new-onset diabetes.
“This coronavirus pandemic can be defeated if you stay at home, but if you know of a child who has excessive thirst, frequent urination, or who starts vomiting,” seek health care advice immediately. “This child could have [type 1] diabetes. Prevent severe DKA, or worse, death,” Dr. Iafusco of the Regional Centre of Paediatric Diabetology G.Stoppoloni Via S. Andrea delle Dame, Naples, said in the video.
Physicians from China have similar observations, reporting to ISPAD several cases of delayed admissions of newly diagnosed type 1 diabetes because hospital services were closed for non–COVID-19 care.
Keep calm and mind your diabetes care; physicians use telemedicine
Meanwhile, last week ISPAD issued guidance for young people with diabetes and their carers about what to do if COVID-19 infection is suspected.
Most advice is the same as for the general public because reports of COVID-19 infection suggest it is much less severe in children and adolescents, and the summary currently serves “as reassurance that youth with diabetes are not more affected by COVID-19 than peers,” it adds.
“Our approach to treating a child with diabetes would be to follow the ISPAD sick-day guidelines, which provide generalized diabetes management in any flu-like illness. We wouldn’t do anything very different right now,” one of the authors, Jamie Wood, MD, associate professor of clinical pediatrics at Case Western Reserve University, Cleveland, said in an interview.
“Any illness makes diabetes more difficult to manage and can increase the risk of DKA,” she emphasized.
“We would reinforce frequent monitoring of blood glucose and ketone levels, to never stop insulin – in fact, when most people are ill, the body is stressed and requires more insulin – and to stay hydrated and treat the underlying symptoms.”
And make sure to “treat the fever,” she stressed. “When patients with type 1 diabetes get fever, they have a tendency to make more ketones, so we recommend aggressive control of fever.”
ISPAD recommends young people aim to keep blood glucose levels between 4 and 10 mmol/L (72-180 mg/dL) and blood ketones below 0.6 mmol/L (10.8 mg/dL) during illness and to never stop insulin.
Guidance is provided on when to seek urgent specialist advice with possible referral to emergency care, for example, in cases in which the patient has DKA symptoms, such as persistent and/or worsened fruity breath odor or vomiting.
Dr. Scaramuzza said in an interview that, in Italy, he and his colleagues have increased their use of telemedicine to keep monitoring their patients with diabetes even from a distance and that it was working very well.
“Technology – such as downloading [records from] insulin pumps, continuous glucose monitoring systems, and the possibility to use Skype or other platforms – really helps,” he noted.
“There has been a rapid increase in telehealth as a way to continue to care for youth with diabetes and decrease risk for infection,” said ISPAD.
“Communication between patients, families, and health care teams is vitally important. Methods to do so that avoid visits to clinics or hospitals can provide needed diabetes advice and reduce risk for COVID-19 transmission.”
A version of this article originally appeared on Medscape.com.
Reports from pediatric endocrinologists in COVID-19 hot spots globally indicate that children, adolescents, and young adults with diabetes have so far not shown a different disease pattern with the virus compared to children and younger people who do not have diabetes.
Indeed, to date [as of March 24]” according to a new statement from the International Society for Pediatric and Adolescent Diabetes (ISPAD), which currently has about 1,300 members around the globe and has instituted a discussion forum about the topic of treating children with both diabetes and COVID-19.
“We find these reports [from colleagues around the world], though anecdotal, to be reassuring,” it notes. However, there are real worries regarding other potentially dangerous effects. ISPAD has expressed concern, for example, that the COVID-19 pandemic will prevent youngsters with existing diabetes who are having diabetic emergencies from seeking hospital care.
Chinese physicians have reported to ISPAD a number of cases of delayed hospital admissions for diabetic ketoacidosis (DKA) in children with known type 1 diabetes because hospital services were closed for non–COVID-19 care.
Andrea Scaramuzza, MD, a pediatric endocrinologist at Ospedale Maggiore di Cremona, Italy, has similarly reported multiple cases of patients presenting to emergency services there with severe DKA.
“These experiences reinforce the importance of continued attentiveness to standard diabetes care to avoid the need for hospitalization and emergency or urgent care visits,” says ISPAD, under the strapline: “Keep calm and mind your diabetes care.”
But it nevertheless stresses that these resources should be used “if needed.”
Worries that new-onset diabetes will be missed during COVID-19
Dr. Scaramuzza said in an interview that there also are concerns regarding delays in diagnoses of new cases of type 1 diabetes “due to the fear families have to go to the emergency department because of COVID-19.”
Indeed, in Italy, a few patients have arrived with very serious DKA, he said. Dr. Scaramuzza noted a colleague from Naples, Dario Iafusco, MD, and colleagues have made a video to keep awareness high regarding new-onset diabetes.
“This coronavirus pandemic can be defeated if you stay at home, but if you know of a child who has excessive thirst, frequent urination, or who starts vomiting,” seek health care advice immediately. “This child could have [type 1] diabetes. Prevent severe DKA, or worse, death,” Dr. Iafusco of the Regional Centre of Paediatric Diabetology G.Stoppoloni Via S. Andrea delle Dame, Naples, said in the video.
Physicians from China have similar observations, reporting to ISPAD several cases of delayed admissions of newly diagnosed type 1 diabetes because hospital services were closed for non–COVID-19 care.
Keep calm and mind your diabetes care; physicians use telemedicine
Meanwhile, last week ISPAD issued guidance for young people with diabetes and their carers about what to do if COVID-19 infection is suspected.
Most advice is the same as for the general public because reports of COVID-19 infection suggest it is much less severe in children and adolescents, and the summary currently serves “as reassurance that youth with diabetes are not more affected by COVID-19 than peers,” it adds.
“Our approach to treating a child with diabetes would be to follow the ISPAD sick-day guidelines, which provide generalized diabetes management in any flu-like illness. We wouldn’t do anything very different right now,” one of the authors, Jamie Wood, MD, associate professor of clinical pediatrics at Case Western Reserve University, Cleveland, said in an interview.
“Any illness makes diabetes more difficult to manage and can increase the risk of DKA,” she emphasized.
“We would reinforce frequent monitoring of blood glucose and ketone levels, to never stop insulin – in fact, when most people are ill, the body is stressed and requires more insulin – and to stay hydrated and treat the underlying symptoms.”
And make sure to “treat the fever,” she stressed. “When patients with type 1 diabetes get fever, they have a tendency to make more ketones, so we recommend aggressive control of fever.”
ISPAD recommends young people aim to keep blood glucose levels between 4 and 10 mmol/L (72-180 mg/dL) and blood ketones below 0.6 mmol/L (10.8 mg/dL) during illness and to never stop insulin.
Guidance is provided on when to seek urgent specialist advice with possible referral to emergency care, for example, in cases in which the patient has DKA symptoms, such as persistent and/or worsened fruity breath odor or vomiting.
Dr. Scaramuzza said in an interview that, in Italy, he and his colleagues have increased their use of telemedicine to keep monitoring their patients with diabetes even from a distance and that it was working very well.
“Technology – such as downloading [records from] insulin pumps, continuous glucose monitoring systems, and the possibility to use Skype or other platforms – really helps,” he noted.
“There has been a rapid increase in telehealth as a way to continue to care for youth with diabetes and decrease risk for infection,” said ISPAD.
“Communication between patients, families, and health care teams is vitally important. Methods to do so that avoid visits to clinics or hospitals can provide needed diabetes advice and reduce risk for COVID-19 transmission.”
A version of this article originally appeared on Medscape.com.
Reports from pediatric endocrinologists in COVID-19 hot spots globally indicate that children, adolescents, and young adults with diabetes have so far not shown a different disease pattern with the virus compared to children and younger people who do not have diabetes.
Indeed, to date [as of March 24]” according to a new statement from the International Society for Pediatric and Adolescent Diabetes (ISPAD), which currently has about 1,300 members around the globe and has instituted a discussion forum about the topic of treating children with both diabetes and COVID-19.
“We find these reports [from colleagues around the world], though anecdotal, to be reassuring,” it notes. However, there are real worries regarding other potentially dangerous effects. ISPAD has expressed concern, for example, that the COVID-19 pandemic will prevent youngsters with existing diabetes who are having diabetic emergencies from seeking hospital care.
Chinese physicians have reported to ISPAD a number of cases of delayed hospital admissions for diabetic ketoacidosis (DKA) in children with known type 1 diabetes because hospital services were closed for non–COVID-19 care.
Andrea Scaramuzza, MD, a pediatric endocrinologist at Ospedale Maggiore di Cremona, Italy, has similarly reported multiple cases of patients presenting to emergency services there with severe DKA.
“These experiences reinforce the importance of continued attentiveness to standard diabetes care to avoid the need for hospitalization and emergency or urgent care visits,” says ISPAD, under the strapline: “Keep calm and mind your diabetes care.”
But it nevertheless stresses that these resources should be used “if needed.”
Worries that new-onset diabetes will be missed during COVID-19
Dr. Scaramuzza said in an interview that there also are concerns regarding delays in diagnoses of new cases of type 1 diabetes “due to the fear families have to go to the emergency department because of COVID-19.”
Indeed, in Italy, a few patients have arrived with very serious DKA, he said. Dr. Scaramuzza noted a colleague from Naples, Dario Iafusco, MD, and colleagues have made a video to keep awareness high regarding new-onset diabetes.
“This coronavirus pandemic can be defeated if you stay at home, but if you know of a child who has excessive thirst, frequent urination, or who starts vomiting,” seek health care advice immediately. “This child could have [type 1] diabetes. Prevent severe DKA, or worse, death,” Dr. Iafusco of the Regional Centre of Paediatric Diabetology G.Stoppoloni Via S. Andrea delle Dame, Naples, said in the video.
Physicians from China have similar observations, reporting to ISPAD several cases of delayed admissions of newly diagnosed type 1 diabetes because hospital services were closed for non–COVID-19 care.
Keep calm and mind your diabetes care; physicians use telemedicine
Meanwhile, last week ISPAD issued guidance for young people with diabetes and their carers about what to do if COVID-19 infection is suspected.
Most advice is the same as for the general public because reports of COVID-19 infection suggest it is much less severe in children and adolescents, and the summary currently serves “as reassurance that youth with diabetes are not more affected by COVID-19 than peers,” it adds.
“Our approach to treating a child with diabetes would be to follow the ISPAD sick-day guidelines, which provide generalized diabetes management in any flu-like illness. We wouldn’t do anything very different right now,” one of the authors, Jamie Wood, MD, associate professor of clinical pediatrics at Case Western Reserve University, Cleveland, said in an interview.
“Any illness makes diabetes more difficult to manage and can increase the risk of DKA,” she emphasized.
“We would reinforce frequent monitoring of blood glucose and ketone levels, to never stop insulin – in fact, when most people are ill, the body is stressed and requires more insulin – and to stay hydrated and treat the underlying symptoms.”
And make sure to “treat the fever,” she stressed. “When patients with type 1 diabetes get fever, they have a tendency to make more ketones, so we recommend aggressive control of fever.”
ISPAD recommends young people aim to keep blood glucose levels between 4 and 10 mmol/L (72-180 mg/dL) and blood ketones below 0.6 mmol/L (10.8 mg/dL) during illness and to never stop insulin.
Guidance is provided on when to seek urgent specialist advice with possible referral to emergency care, for example, in cases in which the patient has DKA symptoms, such as persistent and/or worsened fruity breath odor or vomiting.
Dr. Scaramuzza said in an interview that, in Italy, he and his colleagues have increased their use of telemedicine to keep monitoring their patients with diabetes even from a distance and that it was working very well.
“Technology – such as downloading [records from] insulin pumps, continuous glucose monitoring systems, and the possibility to use Skype or other platforms – really helps,” he noted.
“There has been a rapid increase in telehealth as a way to continue to care for youth with diabetes and decrease risk for infection,” said ISPAD.
“Communication between patients, families, and health care teams is vitally important. Methods to do so that avoid visits to clinics or hospitals can provide needed diabetes advice and reduce risk for COVID-19 transmission.”
A version of this article originally appeared on Medscape.com.
New frontier: Transgender men yield eggs, babies, even after testosterone
Transgender men who were assigned female sex at birth show a similar response to ovarian stimulation as cisgender women, even after using testosterone, shows the first formal study of its kind in this patient group.
The transgender patients each had an average of 20 eggs retrieved, and all who transferred embryos eventually achieved a successful pregnancy and delivery, “representing the largest cohort of transgender male patients to be described in the literature thus far,” wrote Nina Resetkova, MD, and colleagues in their article, published in Fertility and Sterility.
The research has been hailed as groundbreaking.
Dr. Resetkova, a reproductive endocrinologist at Boston IVF, Beth Israel Deaconess Medical Center, said in an interview that “these new data show it is reasonable for transmen [female-to-male transition], even those who have used testosterone for some time, to undergo assisted reproductive technology [ART].
“We’ve found that there isn’t a decrease in oocyte retrieval and may actually be a slight increase. We found this to be remarkable,” she said, emphasizing that these findings should be very reassuring for transgender male patients concerned about fertility.
“Transmales worry that they’ve thrown in the towel, and by committing to testosterone have started on a pathway with no return, but these data suggest they still have options,” Dr. Resetkova explained.
“Our study shows that these patients can have ovarian stimulation outcomes that are similar to those of cisgender counterparts, and this seems to be true even in cases of patients who have already initiated hormonal transition with the use of testosterone,” she said.
The researcher hopes the results will encourage more referrals for transgender men wishing to explore their fertility options. “Previously, many doctors were reluctant to refer to a fertility practice if their transmale patient had already started testosterone therapy or they had been on it for several years,” she said.
In a comment, Joshua Safer, MD, a spokesperson on transgender issues for the Endocrine Society, said that “fertility compromise may represent the single largest risk of medical treatment for some transgender persons. At meetings and in personal communications, several clinical groups have reported successful egg harvest from transgender men.
“However, this is the first careful study of a defined cohort published formally. As such, it serves as an important reference in advancing transgender medical care,” noted Dr. Safer, executive director of the Mount Sinai Center for Transgender Medicine and Surgery, New York.
Need for guidance
Previously, there has been an assumption that transgender individuals were not interested in maintaining their reproductive potential, but this has proven untrue. “Several recent studies have demonstrated that transgender people do desire parenthood, or at the least wish to preserve that possibility,” noted Dr. Resetkova and colleagues.
Both the American Society for Reproductive Medicine and the European Society of Human Reproduction and Embryology have issued opinions that transgender patients should have the same access to fertility options as cisgender patients and that fertility preservation options should be discussed before gender transition, they noted.
The first and key intervention needed is the ability to preserve fertility through the cryopreservation of gametes before medical or surgical transition. In transgender men, this can be done via oocyte, embryo, or ovarian tissue cryopreservation.
Dr. Resetkova and the team at Boston IVF realized there was no published evidence, bar a couple of case reports, to guide clinicians caring for transgender men who wanted to preserve their fertility.
To help fill the research gap, they drew data from a retrospective cohort using electronic medical records from a single large in vitro fertilization (IVF) clinic. The search was conducted from January 2010 to July 2018, because the first transgender man was treated at the clinic in 2010.
To be included in the study, the patient had to identify as a transgender man and have completed an ovarian stimulation cycle for oocyte cryopreservation, embryo cryopreservation, or intended uterine transfer.
“This is the first study to describe transgender cycle parameters and outcomes in such detail and scope,” the authors noted in their article.
The study aimed to investigate ART outcomes in a female-to-male transgender cohort (n = 26) who wished to preserve fertility through egg freezing and/or undergo IVF with the intention of pregnancy.
Each transgender man was matched with five cisgender women for age, body mass index, and anti-Müllerian hormone level, and egg yield was compared. The 130 cisgender women were in straight relationships where there was difficulty conceiving, mostly because of male-factor, or tubal-factor, infertility; cisgender women with ovulatory dysfunction were excluded.
Egg harvest and T
The transgender patients were aged 14-39 years, with an average age at cycle start of 28 years. Some patients had not yet undergone any form of medical transition but planned to do so after ART.
The majority (61%) had received testosterone hormonal therapy, and a small number had undergone surgery, for example mastectomy and reconstruction, but none had undergone a hysterectomy or ovary removal (so-called “bottom” or gender-reassignment surgery).
Prior to ART, all patients taking testosterone came off the hormone on average 4 months prior to starting treatment. The mean time on testosterone before seeking ART treatment was 3.7 years and ranged from 3 months to 17 years.
“All patients had intact uterus and ovaries, and all patients had gone through puberty and had not received puberty blocking. This was required for ovarian stimulation and egg freezing,” Dr. Resetkova explained in an interview.
Researchers tracked patient records for outcomes, including oocyte yield, number of mature oocytes, total gonadotropin dose, and peak estradiol levels.
A mean of 19.9 +/– 8.7 oocytes were retrieved per cycle in the transgender cohort, compared with 15.9 +/– 9.6 in the cisgender female group; peak estradiol levels were similar between the two groups. However, the total dose of gonadotropins used was higher in the transgender group compared with the cisgender group (3,892 IU vs. 2,599 IU).
Of the 26 transgender men, 16 had egg preservation (oocyte banking) only. Seven couples had fresh or frozen embryo transfers, with all achieving live births.
Among the patients who planned for IVF with embryo transfer, two intended to carry the pregnancy themselves and the remaining five transferred embryos to their cisgender female partner.
The authors noted that many of the transgender patients who ultimately did not choose to proceed with treatment did so because of the need to stop testosterone therapy before initiating a cycle or the burden of cost.
“For many transgender patients, stopping androgen therapy can be both physically and psychologically distressing, especially because many experience the resumption of menses,” they observed.
“A logical follow-up question is whether ovarian stimulation can be done with any measure of success without the cessation of testosterone,” they noted.
“Although our findings are certainly reassuring for patients who have already initiated androgens, they were still all required to stop therapy to proceed with stimulation. This is a barrier to access that should be investigated, and if overcome may increase utilization of ART by transgender male patients,” they wrote.
Dr. Safer said that, to his knowledge, “a couple of fertility groups ... have been clear that the egg harvest could take place while the transgender men were using testosterone.”
Higher yield
The results with regard to the use of testosterone prior to ART were particularly enlightening, said Dr. Resetkova, who noted that testosterone therapy did not seem to affect ovarian stimulation.
“Before this study, we did not know if long-term testosterone use had a negative impact on egg reserve but, remarkably, testosterone does not appear to have an effect on the ovarian reserve as measured by egg count,” she noted, although she acknowledged that the “study is small.”
“In fact, in some ways, it looks like testosterone might even have a beneficial effect on egg count with a trend towards a higher number of eggs in the transmales who used it,” she added.
But this is “speculative,” she acknowledged, given the low numbers.
Reflecting on why long-term testosterone use may have shown a trend towards greater egg retrieval, Dr. Resetkova explained that the environment might be more similar to an individual with underlying elevated testosterone as seen in polycystic ovarian syndrome, and she noted these patients typically have a higher egg yield during IVF therapy.
Commenting on the higher doses of gonadotropins used in transgender patients, Dr. Resetkova suggested there could be various reasons for this, given that dosing was at the physician’s discretion, including the possibility that they knew the patient only had one chance and therefore higher doses of gonadotropins may have been administered.
Furthermore, each round of treatment is expensive. The researcher stressed, however, there was no conclusion in this respect based on their data.
Puberty blocking and fertility
When asked whether a transgender man who had undergone puberty blocking before transitioning (i.e., someone who had not gone through natural puberty) would be able to follow a similar course to pregnancy as the study participants, Dr. Resetkova acknowledged that is a more challenging area.
“We have little data so it’s hard to be conclusive, but it’s unlikely these patients would have mature hormonal responses and the ovaries might be in a naive state,” she hypothesized. “I don’t know that they would retain so many options as someone who had gone through natural puberty.”
“However, there are research protocols in place at some academic institutions for transgender patients planning to undergo puberty blocking,” she observed.
Finally, referring to individuals who transition from male to female using estrogen therapy, Dr. Resetkova said that the quality of sperm production might be impaired with long-term estrogen exposure. She added that other centers are looking at this.
“As transgender individuals increasingly seek access to reproductive services, we seek to shed light on the optimal way to provide effective care to these patients,” Dr. Dr. Resetkova and colleagues conclude.
Dr. Resetkova has reported no relevant financial relationships.
This article first appeared on Medscape.com.
SOURCE: Resetkova N et al. Fertil Steril. 2019;112:858-65.
Transgender men who were assigned female sex at birth show a similar response to ovarian stimulation as cisgender women, even after using testosterone, shows the first formal study of its kind in this patient group.
The transgender patients each had an average of 20 eggs retrieved, and all who transferred embryos eventually achieved a successful pregnancy and delivery, “representing the largest cohort of transgender male patients to be described in the literature thus far,” wrote Nina Resetkova, MD, and colleagues in their article, published in Fertility and Sterility.
The research has been hailed as groundbreaking.
Dr. Resetkova, a reproductive endocrinologist at Boston IVF, Beth Israel Deaconess Medical Center, said in an interview that “these new data show it is reasonable for transmen [female-to-male transition], even those who have used testosterone for some time, to undergo assisted reproductive technology [ART].
“We’ve found that there isn’t a decrease in oocyte retrieval and may actually be a slight increase. We found this to be remarkable,” she said, emphasizing that these findings should be very reassuring for transgender male patients concerned about fertility.
“Transmales worry that they’ve thrown in the towel, and by committing to testosterone have started on a pathway with no return, but these data suggest they still have options,” Dr. Resetkova explained.
“Our study shows that these patients can have ovarian stimulation outcomes that are similar to those of cisgender counterparts, and this seems to be true even in cases of patients who have already initiated hormonal transition with the use of testosterone,” she said.
The researcher hopes the results will encourage more referrals for transgender men wishing to explore their fertility options. “Previously, many doctors were reluctant to refer to a fertility practice if their transmale patient had already started testosterone therapy or they had been on it for several years,” she said.
In a comment, Joshua Safer, MD, a spokesperson on transgender issues for the Endocrine Society, said that “fertility compromise may represent the single largest risk of medical treatment for some transgender persons. At meetings and in personal communications, several clinical groups have reported successful egg harvest from transgender men.
“However, this is the first careful study of a defined cohort published formally. As such, it serves as an important reference in advancing transgender medical care,” noted Dr. Safer, executive director of the Mount Sinai Center for Transgender Medicine and Surgery, New York.
Need for guidance
Previously, there has been an assumption that transgender individuals were not interested in maintaining their reproductive potential, but this has proven untrue. “Several recent studies have demonstrated that transgender people do desire parenthood, or at the least wish to preserve that possibility,” noted Dr. Resetkova and colleagues.
Both the American Society for Reproductive Medicine and the European Society of Human Reproduction and Embryology have issued opinions that transgender patients should have the same access to fertility options as cisgender patients and that fertility preservation options should be discussed before gender transition, they noted.
The first and key intervention needed is the ability to preserve fertility through the cryopreservation of gametes before medical or surgical transition. In transgender men, this can be done via oocyte, embryo, or ovarian tissue cryopreservation.
Dr. Resetkova and the team at Boston IVF realized there was no published evidence, bar a couple of case reports, to guide clinicians caring for transgender men who wanted to preserve their fertility.
To help fill the research gap, they drew data from a retrospective cohort using electronic medical records from a single large in vitro fertilization (IVF) clinic. The search was conducted from January 2010 to July 2018, because the first transgender man was treated at the clinic in 2010.
To be included in the study, the patient had to identify as a transgender man and have completed an ovarian stimulation cycle for oocyte cryopreservation, embryo cryopreservation, or intended uterine transfer.
“This is the first study to describe transgender cycle parameters and outcomes in such detail and scope,” the authors noted in their article.
The study aimed to investigate ART outcomes in a female-to-male transgender cohort (n = 26) who wished to preserve fertility through egg freezing and/or undergo IVF with the intention of pregnancy.
Each transgender man was matched with five cisgender women for age, body mass index, and anti-Müllerian hormone level, and egg yield was compared. The 130 cisgender women were in straight relationships where there was difficulty conceiving, mostly because of male-factor, or tubal-factor, infertility; cisgender women with ovulatory dysfunction were excluded.
Egg harvest and T
The transgender patients were aged 14-39 years, with an average age at cycle start of 28 years. Some patients had not yet undergone any form of medical transition but planned to do so after ART.
The majority (61%) had received testosterone hormonal therapy, and a small number had undergone surgery, for example mastectomy and reconstruction, but none had undergone a hysterectomy or ovary removal (so-called “bottom” or gender-reassignment surgery).
Prior to ART, all patients taking testosterone came off the hormone on average 4 months prior to starting treatment. The mean time on testosterone before seeking ART treatment was 3.7 years and ranged from 3 months to 17 years.
“All patients had intact uterus and ovaries, and all patients had gone through puberty and had not received puberty blocking. This was required for ovarian stimulation and egg freezing,” Dr. Resetkova explained in an interview.
Researchers tracked patient records for outcomes, including oocyte yield, number of mature oocytes, total gonadotropin dose, and peak estradiol levels.
A mean of 19.9 +/– 8.7 oocytes were retrieved per cycle in the transgender cohort, compared with 15.9 +/– 9.6 in the cisgender female group; peak estradiol levels were similar between the two groups. However, the total dose of gonadotropins used was higher in the transgender group compared with the cisgender group (3,892 IU vs. 2,599 IU).
Of the 26 transgender men, 16 had egg preservation (oocyte banking) only. Seven couples had fresh or frozen embryo transfers, with all achieving live births.
Among the patients who planned for IVF with embryo transfer, two intended to carry the pregnancy themselves and the remaining five transferred embryos to their cisgender female partner.
The authors noted that many of the transgender patients who ultimately did not choose to proceed with treatment did so because of the need to stop testosterone therapy before initiating a cycle or the burden of cost.
“For many transgender patients, stopping androgen therapy can be both physically and psychologically distressing, especially because many experience the resumption of menses,” they observed.
“A logical follow-up question is whether ovarian stimulation can be done with any measure of success without the cessation of testosterone,” they noted.
“Although our findings are certainly reassuring for patients who have already initiated androgens, they were still all required to stop therapy to proceed with stimulation. This is a barrier to access that should be investigated, and if overcome may increase utilization of ART by transgender male patients,” they wrote.
Dr. Safer said that, to his knowledge, “a couple of fertility groups ... have been clear that the egg harvest could take place while the transgender men were using testosterone.”
Higher yield
The results with regard to the use of testosterone prior to ART were particularly enlightening, said Dr. Resetkova, who noted that testosterone therapy did not seem to affect ovarian stimulation.
“Before this study, we did not know if long-term testosterone use had a negative impact on egg reserve but, remarkably, testosterone does not appear to have an effect on the ovarian reserve as measured by egg count,” she noted, although she acknowledged that the “study is small.”
“In fact, in some ways, it looks like testosterone might even have a beneficial effect on egg count with a trend towards a higher number of eggs in the transmales who used it,” she added.
But this is “speculative,” she acknowledged, given the low numbers.
Reflecting on why long-term testosterone use may have shown a trend towards greater egg retrieval, Dr. Resetkova explained that the environment might be more similar to an individual with underlying elevated testosterone as seen in polycystic ovarian syndrome, and she noted these patients typically have a higher egg yield during IVF therapy.
Commenting on the higher doses of gonadotropins used in transgender patients, Dr. Resetkova suggested there could be various reasons for this, given that dosing was at the physician’s discretion, including the possibility that they knew the patient only had one chance and therefore higher doses of gonadotropins may have been administered.
Furthermore, each round of treatment is expensive. The researcher stressed, however, there was no conclusion in this respect based on their data.
Puberty blocking and fertility
When asked whether a transgender man who had undergone puberty blocking before transitioning (i.e., someone who had not gone through natural puberty) would be able to follow a similar course to pregnancy as the study participants, Dr. Resetkova acknowledged that is a more challenging area.
“We have little data so it’s hard to be conclusive, but it’s unlikely these patients would have mature hormonal responses and the ovaries might be in a naive state,” she hypothesized. “I don’t know that they would retain so many options as someone who had gone through natural puberty.”
“However, there are research protocols in place at some academic institutions for transgender patients planning to undergo puberty blocking,” she observed.
Finally, referring to individuals who transition from male to female using estrogen therapy, Dr. Resetkova said that the quality of sperm production might be impaired with long-term estrogen exposure. She added that other centers are looking at this.
“As transgender individuals increasingly seek access to reproductive services, we seek to shed light on the optimal way to provide effective care to these patients,” Dr. Dr. Resetkova and colleagues conclude.
Dr. Resetkova has reported no relevant financial relationships.
This article first appeared on Medscape.com.
SOURCE: Resetkova N et al. Fertil Steril. 2019;112:858-65.
Transgender men who were assigned female sex at birth show a similar response to ovarian stimulation as cisgender women, even after using testosterone, shows the first formal study of its kind in this patient group.
The transgender patients each had an average of 20 eggs retrieved, and all who transferred embryos eventually achieved a successful pregnancy and delivery, “representing the largest cohort of transgender male patients to be described in the literature thus far,” wrote Nina Resetkova, MD, and colleagues in their article, published in Fertility and Sterility.
The research has been hailed as groundbreaking.
Dr. Resetkova, a reproductive endocrinologist at Boston IVF, Beth Israel Deaconess Medical Center, said in an interview that “these new data show it is reasonable for transmen [female-to-male transition], even those who have used testosterone for some time, to undergo assisted reproductive technology [ART].
“We’ve found that there isn’t a decrease in oocyte retrieval and may actually be a slight increase. We found this to be remarkable,” she said, emphasizing that these findings should be very reassuring for transgender male patients concerned about fertility.
“Transmales worry that they’ve thrown in the towel, and by committing to testosterone have started on a pathway with no return, but these data suggest they still have options,” Dr. Resetkova explained.
“Our study shows that these patients can have ovarian stimulation outcomes that are similar to those of cisgender counterparts, and this seems to be true even in cases of patients who have already initiated hormonal transition with the use of testosterone,” she said.
The researcher hopes the results will encourage more referrals for transgender men wishing to explore their fertility options. “Previously, many doctors were reluctant to refer to a fertility practice if their transmale patient had already started testosterone therapy or they had been on it for several years,” she said.
In a comment, Joshua Safer, MD, a spokesperson on transgender issues for the Endocrine Society, said that “fertility compromise may represent the single largest risk of medical treatment for some transgender persons. At meetings and in personal communications, several clinical groups have reported successful egg harvest from transgender men.
“However, this is the first careful study of a defined cohort published formally. As such, it serves as an important reference in advancing transgender medical care,” noted Dr. Safer, executive director of the Mount Sinai Center for Transgender Medicine and Surgery, New York.
Need for guidance
Previously, there has been an assumption that transgender individuals were not interested in maintaining their reproductive potential, but this has proven untrue. “Several recent studies have demonstrated that transgender people do desire parenthood, or at the least wish to preserve that possibility,” noted Dr. Resetkova and colleagues.
Both the American Society for Reproductive Medicine and the European Society of Human Reproduction and Embryology have issued opinions that transgender patients should have the same access to fertility options as cisgender patients and that fertility preservation options should be discussed before gender transition, they noted.
The first and key intervention needed is the ability to preserve fertility through the cryopreservation of gametes before medical or surgical transition. In transgender men, this can be done via oocyte, embryo, or ovarian tissue cryopreservation.
Dr. Resetkova and the team at Boston IVF realized there was no published evidence, bar a couple of case reports, to guide clinicians caring for transgender men who wanted to preserve their fertility.
To help fill the research gap, they drew data from a retrospective cohort using electronic medical records from a single large in vitro fertilization (IVF) clinic. The search was conducted from January 2010 to July 2018, because the first transgender man was treated at the clinic in 2010.
To be included in the study, the patient had to identify as a transgender man and have completed an ovarian stimulation cycle for oocyte cryopreservation, embryo cryopreservation, or intended uterine transfer.
“This is the first study to describe transgender cycle parameters and outcomes in such detail and scope,” the authors noted in their article.
The study aimed to investigate ART outcomes in a female-to-male transgender cohort (n = 26) who wished to preserve fertility through egg freezing and/or undergo IVF with the intention of pregnancy.
Each transgender man was matched with five cisgender women for age, body mass index, and anti-Müllerian hormone level, and egg yield was compared. The 130 cisgender women were in straight relationships where there was difficulty conceiving, mostly because of male-factor, or tubal-factor, infertility; cisgender women with ovulatory dysfunction were excluded.
Egg harvest and T
The transgender patients were aged 14-39 years, with an average age at cycle start of 28 years. Some patients had not yet undergone any form of medical transition but planned to do so after ART.
The majority (61%) had received testosterone hormonal therapy, and a small number had undergone surgery, for example mastectomy and reconstruction, but none had undergone a hysterectomy or ovary removal (so-called “bottom” or gender-reassignment surgery).
Prior to ART, all patients taking testosterone came off the hormone on average 4 months prior to starting treatment. The mean time on testosterone before seeking ART treatment was 3.7 years and ranged from 3 months to 17 years.
“All patients had intact uterus and ovaries, and all patients had gone through puberty and had not received puberty blocking. This was required for ovarian stimulation and egg freezing,” Dr. Resetkova explained in an interview.
Researchers tracked patient records for outcomes, including oocyte yield, number of mature oocytes, total gonadotropin dose, and peak estradiol levels.
A mean of 19.9 +/– 8.7 oocytes were retrieved per cycle in the transgender cohort, compared with 15.9 +/– 9.6 in the cisgender female group; peak estradiol levels were similar between the two groups. However, the total dose of gonadotropins used was higher in the transgender group compared with the cisgender group (3,892 IU vs. 2,599 IU).
Of the 26 transgender men, 16 had egg preservation (oocyte banking) only. Seven couples had fresh or frozen embryo transfers, with all achieving live births.
Among the patients who planned for IVF with embryo transfer, two intended to carry the pregnancy themselves and the remaining five transferred embryos to their cisgender female partner.
The authors noted that many of the transgender patients who ultimately did not choose to proceed with treatment did so because of the need to stop testosterone therapy before initiating a cycle or the burden of cost.
“For many transgender patients, stopping androgen therapy can be both physically and psychologically distressing, especially because many experience the resumption of menses,” they observed.
“A logical follow-up question is whether ovarian stimulation can be done with any measure of success without the cessation of testosterone,” they noted.
“Although our findings are certainly reassuring for patients who have already initiated androgens, they were still all required to stop therapy to proceed with stimulation. This is a barrier to access that should be investigated, and if overcome may increase utilization of ART by transgender male patients,” they wrote.
Dr. Safer said that, to his knowledge, “a couple of fertility groups ... have been clear that the egg harvest could take place while the transgender men were using testosterone.”
Higher yield
The results with regard to the use of testosterone prior to ART were particularly enlightening, said Dr. Resetkova, who noted that testosterone therapy did not seem to affect ovarian stimulation.
“Before this study, we did not know if long-term testosterone use had a negative impact on egg reserve but, remarkably, testosterone does not appear to have an effect on the ovarian reserve as measured by egg count,” she noted, although she acknowledged that the “study is small.”
“In fact, in some ways, it looks like testosterone might even have a beneficial effect on egg count with a trend towards a higher number of eggs in the transmales who used it,” she added.
But this is “speculative,” she acknowledged, given the low numbers.
Reflecting on why long-term testosterone use may have shown a trend towards greater egg retrieval, Dr. Resetkova explained that the environment might be more similar to an individual with underlying elevated testosterone as seen in polycystic ovarian syndrome, and she noted these patients typically have a higher egg yield during IVF therapy.
Commenting on the higher doses of gonadotropins used in transgender patients, Dr. Resetkova suggested there could be various reasons for this, given that dosing was at the physician’s discretion, including the possibility that they knew the patient only had one chance and therefore higher doses of gonadotropins may have been administered.
Furthermore, each round of treatment is expensive. The researcher stressed, however, there was no conclusion in this respect based on their data.
Puberty blocking and fertility
When asked whether a transgender man who had undergone puberty blocking before transitioning (i.e., someone who had not gone through natural puberty) would be able to follow a similar course to pregnancy as the study participants, Dr. Resetkova acknowledged that is a more challenging area.
“We have little data so it’s hard to be conclusive, but it’s unlikely these patients would have mature hormonal responses and the ovaries might be in a naive state,” she hypothesized. “I don’t know that they would retain so many options as someone who had gone through natural puberty.”
“However, there are research protocols in place at some academic institutions for transgender patients planning to undergo puberty blocking,” she observed.
Finally, referring to individuals who transition from male to female using estrogen therapy, Dr. Resetkova said that the quality of sperm production might be impaired with long-term estrogen exposure. She added that other centers are looking at this.
“As transgender individuals increasingly seek access to reproductive services, we seek to shed light on the optimal way to provide effective care to these patients,” Dr. Dr. Resetkova and colleagues conclude.
Dr. Resetkova has reported no relevant financial relationships.
This article first appeared on Medscape.com.
SOURCE: Resetkova N et al. Fertil Steril. 2019;112:858-65.
Serious CNS Events in Lupus Seen in Only 4% of Cases
BERLIN – The prevalence of major central nervous system manifestations in patients with systemic lupus erythematosus is considerably lower than commonly reported, according to a 3-year study presented at the annual European Congress of Rheumatology.
The prevalence of major CNS involvement was found to be "very low" at 4.3% (7.8 cases/100 person-years), "whilst in most studies when the prevalence of all CNS events is recorded, this figure can be between 15-40%," said Dr. Eleni Kampylafka of the pathophysiology department at the National University of Athens.
Previous studies of CNS involvement probably yielded high estimates because they did not tease out minor from major CNS events, clouding the true picture. "There are lots of nonspecific manifestations such as headache and mild depression, and we wanted to know the true prevalence of major events, which have an impact on the patient’s status and outcome," she said.
In the study, Dr. Kampylafka and her colleagues also investigated associations between CNS involvement, disease activity, and neuromyelitis optica (NMO)-IgG antibodies, which can be predictors of disease and are highly specific for both neuromyelitis optica and myelitis in lupus, though not lupus itself.
According to Dr. Kampylafka, minor CNS manifestations included headache, mild cognitive dysfunction, depression, and anxiety. Major CNS involvements were seizures, demyelinating syndrome, acute confusional state, psychosis, aseptic meningitis, chorea, myelopathy, and cerebral vascular events (mainly stroke).
From an initial cohort of 1,093 patients with systemic lupus erythematosus (SLE), the investigators focused on 458 patients who underwent regular follow-up for the 3 years. Only patients without a prior history of SLE-related CNS involvement were included, leaving 370 in the analysis.
Of these patients, 16 (4.3%) were found to have major CNS involvement. All CNS manifestations were recorded and codified according to American College of Rheumatology criteria, but minor CNS events were excluded. Furthermore, patients’ disease activity was evaluated using the ECLAM (European Consensus Lupus Activity Measurement) score and the SLEDAI (Systemic Lupus Erythematosus Disease Activity Index) SELENA Modification. Accumulated damage associated with the disease was assessed using the SLICC/ACR (Systemic Lupus International Collaborating Clinics/ACR) Damage Index.
Patients were routinely assessed for 3 years using clinical, laboratory, neurological, serological, and immunological tests. "Whenever a new CNS event occurred, an expert neurologist conducted neurological tests with magnetic resonance imaging, electroencephalograms, and cerebrospinal fluid studies, if necessary," reported Dr. Kampylafka.
Out of a total of 23 CNS events, the most common were epileptic seizures (35%), strokes (26%), and myelopathy (22%).
"We also found that nearly half of our patients presented their CNS event at diagnosis," she noted. "This shows that CNS involvement is an early event in lupus, which is something expected."
There was a stark contrast in disease activity measures between patients with CNS involvement and those without it. Lupus patients with CNS involvement had a mean ECLAM score of 4.8, versus 1.4 in patients who lacked CNS involvement (P less than .001). The mean SLEDAI score was 18 in lupus patients with CNS involvement, in contrast to 3 in patients without CNS involvement (P less than .001).
"An important finding here is the presence of NMO-IgG antibodies, which have been shown to exist in patients with lupus and myelopathy specifically, which is a subgroup of manifestations in the disease," said Dr. Kampylafka.
Epileptic seizures correlated with a high ECLAM/SLEDAI score; myelopathy correlated with low ECLAM/SLEDAI scores and NMO-IgG antibody levels; and strokes correlated with antiphospholipid syndrome.
Dr. Kampylafka concluded that overall, the study results demonstrate that CNS involvement correlates with high disease activity at the time of its appearance. But she added a note of caution: Patients presenting with a neurological complication should always receive a complete assessment, because the event might not be related to the patient’s lupus.
Dr. Kampylafka reported having no conflicts of interest.
CNS involvement, Dr. Eleni Kampylafka, neuromyelitis optica (NMO)-IgG antibodies, myelitis in lupus, headache, mild cognitive dysfunction, depression, anxiety, seizures, demyelinating syndrome, acute confusional state, psychosis, aseptic meningitis, chorea, myelopathy, and cerebral vascular events, stroke, ECLAM, European Consensus Lupus Activity Measurement score, SLEDAI, Systemic Lupus Erythematosus Disease Activity Index SELENA Modification, SLICC/ACR, Systemic Lupus International Collaborating Clinics/ACR Damage Index,
BERLIN – The prevalence of major central nervous system manifestations in patients with systemic lupus erythematosus is considerably lower than commonly reported, according to a 3-year study presented at the annual European Congress of Rheumatology.
The prevalence of major CNS involvement was found to be "very low" at 4.3% (7.8 cases/100 person-years), "whilst in most studies when the prevalence of all CNS events is recorded, this figure can be between 15-40%," said Dr. Eleni Kampylafka of the pathophysiology department at the National University of Athens.
Previous studies of CNS involvement probably yielded high estimates because they did not tease out minor from major CNS events, clouding the true picture. "There are lots of nonspecific manifestations such as headache and mild depression, and we wanted to know the true prevalence of major events, which have an impact on the patient’s status and outcome," she said.
In the study, Dr. Kampylafka and her colleagues also investigated associations between CNS involvement, disease activity, and neuromyelitis optica (NMO)-IgG antibodies, which can be predictors of disease and are highly specific for both neuromyelitis optica and myelitis in lupus, though not lupus itself.
According to Dr. Kampylafka, minor CNS manifestations included headache, mild cognitive dysfunction, depression, and anxiety. Major CNS involvements were seizures, demyelinating syndrome, acute confusional state, psychosis, aseptic meningitis, chorea, myelopathy, and cerebral vascular events (mainly stroke).
From an initial cohort of 1,093 patients with systemic lupus erythematosus (SLE), the investigators focused on 458 patients who underwent regular follow-up for the 3 years. Only patients without a prior history of SLE-related CNS involvement were included, leaving 370 in the analysis.
Of these patients, 16 (4.3%) were found to have major CNS involvement. All CNS manifestations were recorded and codified according to American College of Rheumatology criteria, but minor CNS events were excluded. Furthermore, patients’ disease activity was evaluated using the ECLAM (European Consensus Lupus Activity Measurement) score and the SLEDAI (Systemic Lupus Erythematosus Disease Activity Index) SELENA Modification. Accumulated damage associated with the disease was assessed using the SLICC/ACR (Systemic Lupus International Collaborating Clinics/ACR) Damage Index.
Patients were routinely assessed for 3 years using clinical, laboratory, neurological, serological, and immunological tests. "Whenever a new CNS event occurred, an expert neurologist conducted neurological tests with magnetic resonance imaging, electroencephalograms, and cerebrospinal fluid studies, if necessary," reported Dr. Kampylafka.
Out of a total of 23 CNS events, the most common were epileptic seizures (35%), strokes (26%), and myelopathy (22%).
"We also found that nearly half of our patients presented their CNS event at diagnosis," she noted. "This shows that CNS involvement is an early event in lupus, which is something expected."
There was a stark contrast in disease activity measures between patients with CNS involvement and those without it. Lupus patients with CNS involvement had a mean ECLAM score of 4.8, versus 1.4 in patients who lacked CNS involvement (P less than .001). The mean SLEDAI score was 18 in lupus patients with CNS involvement, in contrast to 3 in patients without CNS involvement (P less than .001).
"An important finding here is the presence of NMO-IgG antibodies, which have been shown to exist in patients with lupus and myelopathy specifically, which is a subgroup of manifestations in the disease," said Dr. Kampylafka.
Epileptic seizures correlated with a high ECLAM/SLEDAI score; myelopathy correlated with low ECLAM/SLEDAI scores and NMO-IgG antibody levels; and strokes correlated with antiphospholipid syndrome.
Dr. Kampylafka concluded that overall, the study results demonstrate that CNS involvement correlates with high disease activity at the time of its appearance. But she added a note of caution: Patients presenting with a neurological complication should always receive a complete assessment, because the event might not be related to the patient’s lupus.
Dr. Kampylafka reported having no conflicts of interest.
BERLIN – The prevalence of major central nervous system manifestations in patients with systemic lupus erythematosus is considerably lower than commonly reported, according to a 3-year study presented at the annual European Congress of Rheumatology.
The prevalence of major CNS involvement was found to be "very low" at 4.3% (7.8 cases/100 person-years), "whilst in most studies when the prevalence of all CNS events is recorded, this figure can be between 15-40%," said Dr. Eleni Kampylafka of the pathophysiology department at the National University of Athens.
Previous studies of CNS involvement probably yielded high estimates because they did not tease out minor from major CNS events, clouding the true picture. "There are lots of nonspecific manifestations such as headache and mild depression, and we wanted to know the true prevalence of major events, which have an impact on the patient’s status and outcome," she said.
In the study, Dr. Kampylafka and her colleagues also investigated associations between CNS involvement, disease activity, and neuromyelitis optica (NMO)-IgG antibodies, which can be predictors of disease and are highly specific for both neuromyelitis optica and myelitis in lupus, though not lupus itself.
According to Dr. Kampylafka, minor CNS manifestations included headache, mild cognitive dysfunction, depression, and anxiety. Major CNS involvements were seizures, demyelinating syndrome, acute confusional state, psychosis, aseptic meningitis, chorea, myelopathy, and cerebral vascular events (mainly stroke).
From an initial cohort of 1,093 patients with systemic lupus erythematosus (SLE), the investigators focused on 458 patients who underwent regular follow-up for the 3 years. Only patients without a prior history of SLE-related CNS involvement were included, leaving 370 in the analysis.
Of these patients, 16 (4.3%) were found to have major CNS involvement. All CNS manifestations were recorded and codified according to American College of Rheumatology criteria, but minor CNS events were excluded. Furthermore, patients’ disease activity was evaluated using the ECLAM (European Consensus Lupus Activity Measurement) score and the SLEDAI (Systemic Lupus Erythematosus Disease Activity Index) SELENA Modification. Accumulated damage associated with the disease was assessed using the SLICC/ACR (Systemic Lupus International Collaborating Clinics/ACR) Damage Index.
Patients were routinely assessed for 3 years using clinical, laboratory, neurological, serological, and immunological tests. "Whenever a new CNS event occurred, an expert neurologist conducted neurological tests with magnetic resonance imaging, electroencephalograms, and cerebrospinal fluid studies, if necessary," reported Dr. Kampylafka.
Out of a total of 23 CNS events, the most common were epileptic seizures (35%), strokes (26%), and myelopathy (22%).
"We also found that nearly half of our patients presented their CNS event at diagnosis," she noted. "This shows that CNS involvement is an early event in lupus, which is something expected."
There was a stark contrast in disease activity measures between patients with CNS involvement and those without it. Lupus patients with CNS involvement had a mean ECLAM score of 4.8, versus 1.4 in patients who lacked CNS involvement (P less than .001). The mean SLEDAI score was 18 in lupus patients with CNS involvement, in contrast to 3 in patients without CNS involvement (P less than .001).
"An important finding here is the presence of NMO-IgG antibodies, which have been shown to exist in patients with lupus and myelopathy specifically, which is a subgroup of manifestations in the disease," said Dr. Kampylafka.
Epileptic seizures correlated with a high ECLAM/SLEDAI score; myelopathy correlated with low ECLAM/SLEDAI scores and NMO-IgG antibody levels; and strokes correlated with antiphospholipid syndrome.
Dr. Kampylafka concluded that overall, the study results demonstrate that CNS involvement correlates with high disease activity at the time of its appearance. But she added a note of caution: Patients presenting with a neurological complication should always receive a complete assessment, because the event might not be related to the patient’s lupus.
Dr. Kampylafka reported having no conflicts of interest.
CNS involvement, Dr. Eleni Kampylafka, neuromyelitis optica (NMO)-IgG antibodies, myelitis in lupus, headache, mild cognitive dysfunction, depression, anxiety, seizures, demyelinating syndrome, acute confusional state, psychosis, aseptic meningitis, chorea, myelopathy, and cerebral vascular events, stroke, ECLAM, European Consensus Lupus Activity Measurement score, SLEDAI, Systemic Lupus Erythematosus Disease Activity Index SELENA Modification, SLICC/ACR, Systemic Lupus International Collaborating Clinics/ACR Damage Index,
CNS involvement, Dr. Eleni Kampylafka, neuromyelitis optica (NMO)-IgG antibodies, myelitis in lupus, headache, mild cognitive dysfunction, depression, anxiety, seizures, demyelinating syndrome, acute confusional state, psychosis, aseptic meningitis, chorea, myelopathy, and cerebral vascular events, stroke, ECLAM, European Consensus Lupus Activity Measurement score, SLEDAI, Systemic Lupus Erythematosus Disease Activity Index SELENA Modification, SLICC/ACR, Systemic Lupus International Collaborating Clinics/ACR Damage Index,
AT THE ANNUAL EUROPEAN CONGRESS OF RHEUMATOLOGY
Early Detection, Treatment of Spondyloarthritis Urged
BERLIN – Patients with nonradiographic axial spondyloarthritis should be treated as aggressively as patients with ankylosing spondylitis, as the burden of disease is comparable based on clinical disease activity measures, pain levels, and global assessment scores.
Using data from registries and randomized controlled trials, Dr. Joachim Sieper, head of the medical clinic of rheumatology at the Benjamin Franklin University Clinic, Charité Medical University Berlin, compared disease burden in the two patient groups. "The question arises as to whether patients in the earlier phase of disease have a similar level of disease activity, pain, and stiffness as later-stage patients with ankylosing spondylitis," he said at the annual European Congress of Rheumatology.
Dr. Sieper explained that it is known that a delay exists between the onset of symptoms and the final diagnosis of ankylosing spondylitis (AS). Data from the ABILITY 1 trial showed that time to diagnosis was delayed by a mean of 7.2 years in patients with nonradiographic axial spondyloarthritis.
Even when patients have symptoms, diagnosis can take several years, suggesting that referral needs to be considered earlier in patients presenting with symptoms.
Before the onset of structural damage, a diagnosis can be made on the basis of an MRI scan that shows bone inflammation, he explained. "However, we also know that MRI can have limited sensitivity, so we might miss some patients." It is possible, however, to classify these patients on the basis of clinical findings.
According to the new ASAS (Assessment of Spondyloarthritis International Society) classification criteria for axial spondyloarthritis, patients can be divided into those who have already developed radiographic damage as seen in the sacroiliac joints on x-ray, termed AS patients, and those who do not yet have structural damage, termed nonradiographic axial spondyloarthritis (nr axSpA) patients, who require MRI or clinical parameters for diagnosis (Best Pract. Res. Clin. Rheumatol. 2012;26:135-45).
Dr. Sieper analyzed baseline disease activity data derived from spondyloarthritis registries and randomized controlled trials to determine the extent of disease burden between the two classifications of axial SpA patients.
Analysis showed that the ages of patients between the two groups were similar across the databases, at around 35-40 years, as were the levels of human leukocyte antigen-B27 (HLA-B27) positivity. The ratio of females was higher in patients with nr axSpA (around 60%) than in patients with established AS (around 25%). "This is probably because females develop structural damage later, but they still have a similar level of inflammation all the time," he pointed out.
Scores on the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) hovered at 6.3-6.5 in both groups. Pain level and patient global assessment were similar in the two groups, according to the registry data and a randomized controlled trial.
The proportion of abnormal C-reactive protein levels was higher in the AS patients than in the nr axSpA patients (68% vs. 36%-38%, depending on the trial).
"The level of total pain is comparable no matter which of the groups a patient falls into," he said.
Nor were there differences between the groups in terms of patient and physician global assessment scores. The Patient’s Global Assessment of Disease Activity on a 0-10 visual analog scale was 5.0 for AS patients and 4.9 for nr axSpA patients, according to one trial.
Dr. Sieper disclosed ties with Abbott, Merck, Pfizer, and UCB.
BERLIN – Patients with nonradiographic axial spondyloarthritis should be treated as aggressively as patients with ankylosing spondylitis, as the burden of disease is comparable based on clinical disease activity measures, pain levels, and global assessment scores.
Using data from registries and randomized controlled trials, Dr. Joachim Sieper, head of the medical clinic of rheumatology at the Benjamin Franklin University Clinic, Charité Medical University Berlin, compared disease burden in the two patient groups. "The question arises as to whether patients in the earlier phase of disease have a similar level of disease activity, pain, and stiffness as later-stage patients with ankylosing spondylitis," he said at the annual European Congress of Rheumatology.
Dr. Sieper explained that it is known that a delay exists between the onset of symptoms and the final diagnosis of ankylosing spondylitis (AS). Data from the ABILITY 1 trial showed that time to diagnosis was delayed by a mean of 7.2 years in patients with nonradiographic axial spondyloarthritis.
Even when patients have symptoms, diagnosis can take several years, suggesting that referral needs to be considered earlier in patients presenting with symptoms.
Before the onset of structural damage, a diagnosis can be made on the basis of an MRI scan that shows bone inflammation, he explained. "However, we also know that MRI can have limited sensitivity, so we might miss some patients." It is possible, however, to classify these patients on the basis of clinical findings.
According to the new ASAS (Assessment of Spondyloarthritis International Society) classification criteria for axial spondyloarthritis, patients can be divided into those who have already developed radiographic damage as seen in the sacroiliac joints on x-ray, termed AS patients, and those who do not yet have structural damage, termed nonradiographic axial spondyloarthritis (nr axSpA) patients, who require MRI or clinical parameters for diagnosis (Best Pract. Res. Clin. Rheumatol. 2012;26:135-45).
Dr. Sieper analyzed baseline disease activity data derived from spondyloarthritis registries and randomized controlled trials to determine the extent of disease burden between the two classifications of axial SpA patients.
Analysis showed that the ages of patients between the two groups were similar across the databases, at around 35-40 years, as were the levels of human leukocyte antigen-B27 (HLA-B27) positivity. The ratio of females was higher in patients with nr axSpA (around 60%) than in patients with established AS (around 25%). "This is probably because females develop structural damage later, but they still have a similar level of inflammation all the time," he pointed out.
Scores on the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) hovered at 6.3-6.5 in both groups. Pain level and patient global assessment were similar in the two groups, according to the registry data and a randomized controlled trial.
The proportion of abnormal C-reactive protein levels was higher in the AS patients than in the nr axSpA patients (68% vs. 36%-38%, depending on the trial).
"The level of total pain is comparable no matter which of the groups a patient falls into," he said.
Nor were there differences between the groups in terms of patient and physician global assessment scores. The Patient’s Global Assessment of Disease Activity on a 0-10 visual analog scale was 5.0 for AS patients and 4.9 for nr axSpA patients, according to one trial.
Dr. Sieper disclosed ties with Abbott, Merck, Pfizer, and UCB.
BERLIN – Patients with nonradiographic axial spondyloarthritis should be treated as aggressively as patients with ankylosing spondylitis, as the burden of disease is comparable based on clinical disease activity measures, pain levels, and global assessment scores.
Using data from registries and randomized controlled trials, Dr. Joachim Sieper, head of the medical clinic of rheumatology at the Benjamin Franklin University Clinic, Charité Medical University Berlin, compared disease burden in the two patient groups. "The question arises as to whether patients in the earlier phase of disease have a similar level of disease activity, pain, and stiffness as later-stage patients with ankylosing spondylitis," he said at the annual European Congress of Rheumatology.
Dr. Sieper explained that it is known that a delay exists between the onset of symptoms and the final diagnosis of ankylosing spondylitis (AS). Data from the ABILITY 1 trial showed that time to diagnosis was delayed by a mean of 7.2 years in patients with nonradiographic axial spondyloarthritis.
Even when patients have symptoms, diagnosis can take several years, suggesting that referral needs to be considered earlier in patients presenting with symptoms.
Before the onset of structural damage, a diagnosis can be made on the basis of an MRI scan that shows bone inflammation, he explained. "However, we also know that MRI can have limited sensitivity, so we might miss some patients." It is possible, however, to classify these patients on the basis of clinical findings.
According to the new ASAS (Assessment of Spondyloarthritis International Society) classification criteria for axial spondyloarthritis, patients can be divided into those who have already developed radiographic damage as seen in the sacroiliac joints on x-ray, termed AS patients, and those who do not yet have structural damage, termed nonradiographic axial spondyloarthritis (nr axSpA) patients, who require MRI or clinical parameters for diagnosis (Best Pract. Res. Clin. Rheumatol. 2012;26:135-45).
Dr. Sieper analyzed baseline disease activity data derived from spondyloarthritis registries and randomized controlled trials to determine the extent of disease burden between the two classifications of axial SpA patients.
Analysis showed that the ages of patients between the two groups were similar across the databases, at around 35-40 years, as were the levels of human leukocyte antigen-B27 (HLA-B27) positivity. The ratio of females was higher in patients with nr axSpA (around 60%) than in patients with established AS (around 25%). "This is probably because females develop structural damage later, but they still have a similar level of inflammation all the time," he pointed out.
Scores on the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) hovered at 6.3-6.5 in both groups. Pain level and patient global assessment were similar in the two groups, according to the registry data and a randomized controlled trial.
The proportion of abnormal C-reactive protein levels was higher in the AS patients than in the nr axSpA patients (68% vs. 36%-38%, depending on the trial).
"The level of total pain is comparable no matter which of the groups a patient falls into," he said.
Nor were there differences between the groups in terms of patient and physician global assessment scores. The Patient’s Global Assessment of Disease Activity on a 0-10 visual analog scale was 5.0 for AS patients and 4.9 for nr axSpA patients, according to one trial.
Dr. Sieper disclosed ties with Abbott, Merck, Pfizer, and UCB.
AT THE ANNUAL EUROPEAN CONGRESS OF RHEUMATOLOGY
Lupus Severity May Contribute Significantly to Heart Damage
BERLIN – The risk of cardiovascular events in patients with systemic lupus erythematosus is sevenfold higher than the risk predicted by the Framingham equation, a study shows.
The role of risk factors varies widely, with the presence of high triglyceride levels upping the risk nearly fourfold while use of cyclophosphamide, which may be a proxy for disease severity, raises the risk almost 17-fold, Dr. Sarah Skeoch, a clinical research fellow at the Arthritis Research UK Epidemiology Unit at the University of Manchester, England, said at the annual European Congress of Rheumatology.
The research also showed that triglyceride level was the only independent traditional risk factor, with a 3.6-fold increased risk association. Damage related to lupus, according to the Systemic Lupus International Collaborating Clinics (SLICC) damage index, increased risk 10-fold. Cyclophosphamide therapy was associated with a 16.7-fold increase in risk.
Although the patients have more of the classical risk factors, this does not seem to account for all the increased risk. Disease characteristics such as chronic inflammation or treatments may contribute, she suggested.
"We wanted to look at the association between risk and disease, for example, how active their lupus is, damage accrued over time, whether they have renal disease, and also whether their treatments are associated with CV events like heart disease and stroke," Dr. Skeoch added.
The study looked at these factors in 200 patients who were diagnosed between 2000 and 2003.
At baseline, 12 patients of the eventual 124 who were followed up had experienced a prior CV event. Also at baseline, the SLE disease activity index (SLEDAI) score was 1, indicating low disease activity, and the SLICC damage index was low.
All patients included in the study were over 18 years of age, female, and white. Their lupus was stable with therapy for at least 2 months prior to inclusion in the study. "They were a relatively well population of patients," said Dr. Skeoch.
Blood tests and clinical assessments were carried out to determine levels of traditional risk factors, lupus disease activity, and lupus-related damage, as well as measurements related to disease therapies.
After a 5-year interval, patients were invited back for assessments and the incidence of CV events, including coronary events, cerebral events, and peripheral vascular disease over the elapsed time period, was recorded.
Next, a comparison was made between the predicted CV risk at baseline according to the Framingham equation and the observed results in 112 patients with no prior CV disease.
CV Risk Higher Than Expected
Upon follow-up, patients were, on average, 56 years old and had had disease for approximately 16 years. Out of the 124 patients followed up over approximately 5 years, 12 (9.7%) had a CV event. Coronary events accounted for seven of these, cerebrovascular events were recorded in five patients, and peripheral vascular disease occurred in one patient. "One patient had both a coronary event and a cerebral event within the follow up," Dr. Skeoch said.
In those who had no prior CV event at baseline, predicted risk of a CV event according to the Framingham equation suggested that 1% of patients should have an event in the next 5 years. "In fact, we found 7% had an event – so seven times higher than predicted. This excess risk is most likely attributed to uncaptured traditional risk factors or alternatively, the disease itself, which is more likely," she commented.
The investigators looked at independent risk factors for a CV event regardless of which other risk factors a patient had and found that triglyceride levels were the only traditional risk factor, with an odds ratio (OR) of 3.61 (95% confidence interval, 1.23-10.56). Triglyceride levels often were not the primary target of lipid-lowering therapy, which was usually aimed at reducing total cholesterol or cholesterol ratio, she noted.
Other multivariable analyses of baseline characteristics associated with CV events suggested that the risk was elevated by two factors: the SLICC damage score (OR, 9.62; CI, 1.46-63.5) and cyclophosphamide therapy (OR, 16.7; CI, 1.46-123). "Factors associated with the patients’ lupus disease included having had a venous thromboembolism, damage related to SLE in the past, cyclophosphamide exposure, and a higher steroid dose at baseline which predisposed the patient to having an event," Dr. Skeoch said.
Marker for Disease Severity
"This is the first time cyclophosphamide [therapy] has been marked as an example of an independent predictor of CV risk. We don’t think it is the cyclophosphamide itself because it has been used in a number of diseases and there’s no known evidence to suggest it causes heart disease, but we think it is a measure of people with severe disease. Also, patients exposed to cyclophosphamide tend to have had more steroids," she explained.
If patients with lupus had severe disease, then they might be more likely to be at risk of CV events in the future, she concluded. "We have found that patients with SLE are at higher risk than expected of CV disease and that those with severe disease may be most at risk. We should endeavor to monitor and treat traditional risk factors and aim for good control of SLE disease activity in order to minimize this risk."
Dr. Skeoch has no relevant conflicts of interest. She is funded by the UK Medical Research Council.
BERLIN – The risk of cardiovascular events in patients with systemic lupus erythematosus is sevenfold higher than the risk predicted by the Framingham equation, a study shows.
The role of risk factors varies widely, with the presence of high triglyceride levels upping the risk nearly fourfold while use of cyclophosphamide, which may be a proxy for disease severity, raises the risk almost 17-fold, Dr. Sarah Skeoch, a clinical research fellow at the Arthritis Research UK Epidemiology Unit at the University of Manchester, England, said at the annual European Congress of Rheumatology.
The research also showed that triglyceride level was the only independent traditional risk factor, with a 3.6-fold increased risk association. Damage related to lupus, according to the Systemic Lupus International Collaborating Clinics (SLICC) damage index, increased risk 10-fold. Cyclophosphamide therapy was associated with a 16.7-fold increase in risk.
Although the patients have more of the classical risk factors, this does not seem to account for all the increased risk. Disease characteristics such as chronic inflammation or treatments may contribute, she suggested.
"We wanted to look at the association between risk and disease, for example, how active their lupus is, damage accrued over time, whether they have renal disease, and also whether their treatments are associated with CV events like heart disease and stroke," Dr. Skeoch added.
The study looked at these factors in 200 patients who were diagnosed between 2000 and 2003.
At baseline, 12 patients of the eventual 124 who were followed up had experienced a prior CV event. Also at baseline, the SLE disease activity index (SLEDAI) score was 1, indicating low disease activity, and the SLICC damage index was low.
All patients included in the study were over 18 years of age, female, and white. Their lupus was stable with therapy for at least 2 months prior to inclusion in the study. "They were a relatively well population of patients," said Dr. Skeoch.
Blood tests and clinical assessments were carried out to determine levels of traditional risk factors, lupus disease activity, and lupus-related damage, as well as measurements related to disease therapies.
After a 5-year interval, patients were invited back for assessments and the incidence of CV events, including coronary events, cerebral events, and peripheral vascular disease over the elapsed time period, was recorded.
Next, a comparison was made between the predicted CV risk at baseline according to the Framingham equation and the observed results in 112 patients with no prior CV disease.
CV Risk Higher Than Expected
Upon follow-up, patients were, on average, 56 years old and had had disease for approximately 16 years. Out of the 124 patients followed up over approximately 5 years, 12 (9.7%) had a CV event. Coronary events accounted for seven of these, cerebrovascular events were recorded in five patients, and peripheral vascular disease occurred in one patient. "One patient had both a coronary event and a cerebral event within the follow up," Dr. Skeoch said.
In those who had no prior CV event at baseline, predicted risk of a CV event according to the Framingham equation suggested that 1% of patients should have an event in the next 5 years. "In fact, we found 7% had an event – so seven times higher than predicted. This excess risk is most likely attributed to uncaptured traditional risk factors or alternatively, the disease itself, which is more likely," she commented.
The investigators looked at independent risk factors for a CV event regardless of which other risk factors a patient had and found that triglyceride levels were the only traditional risk factor, with an odds ratio (OR) of 3.61 (95% confidence interval, 1.23-10.56). Triglyceride levels often were not the primary target of lipid-lowering therapy, which was usually aimed at reducing total cholesterol or cholesterol ratio, she noted.
Other multivariable analyses of baseline characteristics associated with CV events suggested that the risk was elevated by two factors: the SLICC damage score (OR, 9.62; CI, 1.46-63.5) and cyclophosphamide therapy (OR, 16.7; CI, 1.46-123). "Factors associated with the patients’ lupus disease included having had a venous thromboembolism, damage related to SLE in the past, cyclophosphamide exposure, and a higher steroid dose at baseline which predisposed the patient to having an event," Dr. Skeoch said.
Marker for Disease Severity
"This is the first time cyclophosphamide [therapy] has been marked as an example of an independent predictor of CV risk. We don’t think it is the cyclophosphamide itself because it has been used in a number of diseases and there’s no known evidence to suggest it causes heart disease, but we think it is a measure of people with severe disease. Also, patients exposed to cyclophosphamide tend to have had more steroids," she explained.
If patients with lupus had severe disease, then they might be more likely to be at risk of CV events in the future, she concluded. "We have found that patients with SLE are at higher risk than expected of CV disease and that those with severe disease may be most at risk. We should endeavor to monitor and treat traditional risk factors and aim for good control of SLE disease activity in order to minimize this risk."
Dr. Skeoch has no relevant conflicts of interest. She is funded by the UK Medical Research Council.
BERLIN – The risk of cardiovascular events in patients with systemic lupus erythematosus is sevenfold higher than the risk predicted by the Framingham equation, a study shows.
The role of risk factors varies widely, with the presence of high triglyceride levels upping the risk nearly fourfold while use of cyclophosphamide, which may be a proxy for disease severity, raises the risk almost 17-fold, Dr. Sarah Skeoch, a clinical research fellow at the Arthritis Research UK Epidemiology Unit at the University of Manchester, England, said at the annual European Congress of Rheumatology.
The research also showed that triglyceride level was the only independent traditional risk factor, with a 3.6-fold increased risk association. Damage related to lupus, according to the Systemic Lupus International Collaborating Clinics (SLICC) damage index, increased risk 10-fold. Cyclophosphamide therapy was associated with a 16.7-fold increase in risk.
Although the patients have more of the classical risk factors, this does not seem to account for all the increased risk. Disease characteristics such as chronic inflammation or treatments may contribute, she suggested.
"We wanted to look at the association between risk and disease, for example, how active their lupus is, damage accrued over time, whether they have renal disease, and also whether their treatments are associated with CV events like heart disease and stroke," Dr. Skeoch added.
The study looked at these factors in 200 patients who were diagnosed between 2000 and 2003.
At baseline, 12 patients of the eventual 124 who were followed up had experienced a prior CV event. Also at baseline, the SLE disease activity index (SLEDAI) score was 1, indicating low disease activity, and the SLICC damage index was low.
All patients included in the study were over 18 years of age, female, and white. Their lupus was stable with therapy for at least 2 months prior to inclusion in the study. "They were a relatively well population of patients," said Dr. Skeoch.
Blood tests and clinical assessments were carried out to determine levels of traditional risk factors, lupus disease activity, and lupus-related damage, as well as measurements related to disease therapies.
After a 5-year interval, patients were invited back for assessments and the incidence of CV events, including coronary events, cerebral events, and peripheral vascular disease over the elapsed time period, was recorded.
Next, a comparison was made between the predicted CV risk at baseline according to the Framingham equation and the observed results in 112 patients with no prior CV disease.
CV Risk Higher Than Expected
Upon follow-up, patients were, on average, 56 years old and had had disease for approximately 16 years. Out of the 124 patients followed up over approximately 5 years, 12 (9.7%) had a CV event. Coronary events accounted for seven of these, cerebrovascular events were recorded in five patients, and peripheral vascular disease occurred in one patient. "One patient had both a coronary event and a cerebral event within the follow up," Dr. Skeoch said.
In those who had no prior CV event at baseline, predicted risk of a CV event according to the Framingham equation suggested that 1% of patients should have an event in the next 5 years. "In fact, we found 7% had an event – so seven times higher than predicted. This excess risk is most likely attributed to uncaptured traditional risk factors or alternatively, the disease itself, which is more likely," she commented.
The investigators looked at independent risk factors for a CV event regardless of which other risk factors a patient had and found that triglyceride levels were the only traditional risk factor, with an odds ratio (OR) of 3.61 (95% confidence interval, 1.23-10.56). Triglyceride levels often were not the primary target of lipid-lowering therapy, which was usually aimed at reducing total cholesterol or cholesterol ratio, she noted.
Other multivariable analyses of baseline characteristics associated with CV events suggested that the risk was elevated by two factors: the SLICC damage score (OR, 9.62; CI, 1.46-63.5) and cyclophosphamide therapy (OR, 16.7; CI, 1.46-123). "Factors associated with the patients’ lupus disease included having had a venous thromboembolism, damage related to SLE in the past, cyclophosphamide exposure, and a higher steroid dose at baseline which predisposed the patient to having an event," Dr. Skeoch said.
Marker for Disease Severity
"This is the first time cyclophosphamide [therapy] has been marked as an example of an independent predictor of CV risk. We don’t think it is the cyclophosphamide itself because it has been used in a number of diseases and there’s no known evidence to suggest it causes heart disease, but we think it is a measure of people with severe disease. Also, patients exposed to cyclophosphamide tend to have had more steroids," she explained.
If patients with lupus had severe disease, then they might be more likely to be at risk of CV events in the future, she concluded. "We have found that patients with SLE are at higher risk than expected of CV disease and that those with severe disease may be most at risk. We should endeavor to monitor and treat traditional risk factors and aim for good control of SLE disease activity in order to minimize this risk."
Dr. Skeoch has no relevant conflicts of interest. She is funded by the UK Medical Research Council.
AT THE ANNUAL EUROPEAN CONGRESS OF RHEUMATOLOGY
Major finding: Cyclophosphamide use is a marker of disease severity that correlates with risk of cardiovascular events in lupus patients (odds ratio, 16.7).
Data source: The longitudinal cohort study involved 200 lupus patients over 5 years.
Disclosures: Dr. Skeoch has no relevant conflicts of interest. She is funded by the UK Medical Research Council.
Meta-Analysis Shows 75% Increased Risk Herpes Zoster With Anti-TNF
BERLIN – Patients who have inflammatory rheumatic diseases and are on anti–tumor necrosis factor therapy have nearly double the risk of herpes zoster when they are compared with patients on disease-modifying antirheumatic drugs, according to the first meta-analysis in these patient populations.
Although the risk of bacterial infection is known to be increased among patients on anti-TNF therapy, less well known is whether the use of anti-TNF agents increases the risk for viral infections, especially herpes zoster, said Dr. Cedric Lukas of the department of rheumatology at Lapeyronie Hospital in Montpellier, France.
The meta-analysis of literature that was published between 2002 and 2010 involved a review of 655 articles and 134 congress abstracts, of which 22 articles and 28 abstracts eventually were included in the study. The anti-TNF therapies that were investigated included etanercept (Enbrel), adalimumab (Humira), and infliximab (Remicade), which were the agents available at the time.
National registries from the United States, United Kingdom, and other European countries were included in the meta-analysis, including BSRBR (British Society for Rheumatology Biologics Register), BIOBADASER (Spanish Registry of Adverse Events of Biological Therapies in Rheumatic Diseases), CORRONA (Consortium of Rheumatology Researchers of North America), the McDonald cohort of U.S. veterans (Clin. Infect. Dis. 2009;48:1364-71), and RABBIT (the German Rheumatoid Arthritis Observation of Biologic Therapy) were selected for inclusion. After selection for appropriate treatment regimens and diseases, 124, 966 patient years were included.
Upon meta-analysis, Dr. Lukas showed that there was a similar trend across the different registries, and no significant heterogeneity among data sources.
The meta-analysis showed an overall increased risk of herpes zoster infection up to 75% in patients whose inflammatory rheumatic diseases were treated with anti-TNF inhibitors. Overall, the pooled odds ratio for herpes zoster infection with anti-TNF therapy was 1.75 (95% confidence interval, 1.50-2.04). This was almost a twofold risk of developing disease with these drugs compared with DMARDs, Dr. Lukas said at the annual European Congress of Rheumatology.
Odds ratios by national registries were BIOBADASER, 2.45; BSRBR, 1.45; CORRONA, 2.34; McDonald, 1.33; and RABBIT, 1.82.
In addition to the meta-analysis, investigators used data from three registries specifically to determine whether the use of any particular anti-TNF drug was associated with a higher risk. "We found that one registry showed [that] infliximab had a somewhat higher risk, but this was only one out of three studies. The other two studies showed a similar risk across all anti-TNF agents."
In the McDonald registry, the risk was found to e higher with infliximab (OR, 1.32; 95% CI, 0.85-2.03) compared with etanercept (OR, 0.62; 95% CI, 0.40-0.95) and adalimumab (OR 0.53; 95% CI, 0.31-0.91).
"We already knew that these patients were prone to herpes zoster; we see the lesions in clinics." But there are preventive measures available that one can take, he said.
In the United States, there are vaccines to prevent herpes zoster, which are available to people who are older than age 60 years, or are at high specific risk of developing herpes zoster infection. "In these patients, we could think about vaccines before treatment is started," pointed out Dr. Lukas. "It is a live vaccine so it should be given a month before start of anti-TNF therapy. In Europe, where the vaccine is unavailable, we need to give patients prophylaxis."
Dr. Lukas reported no relevant conflicts of interest. The study was supported by an unrestricted educational grant from Abbott France.
BERLIN – Patients who have inflammatory rheumatic diseases and are on anti–tumor necrosis factor therapy have nearly double the risk of herpes zoster when they are compared with patients on disease-modifying antirheumatic drugs, according to the first meta-analysis in these patient populations.
Although the risk of bacterial infection is known to be increased among patients on anti-TNF therapy, less well known is whether the use of anti-TNF agents increases the risk for viral infections, especially herpes zoster, said Dr. Cedric Lukas of the department of rheumatology at Lapeyronie Hospital in Montpellier, France.
The meta-analysis of literature that was published between 2002 and 2010 involved a review of 655 articles and 134 congress abstracts, of which 22 articles and 28 abstracts eventually were included in the study. The anti-TNF therapies that were investigated included etanercept (Enbrel), adalimumab (Humira), and infliximab (Remicade), which were the agents available at the time.
National registries from the United States, United Kingdom, and other European countries were included in the meta-analysis, including BSRBR (British Society for Rheumatology Biologics Register), BIOBADASER (Spanish Registry of Adverse Events of Biological Therapies in Rheumatic Diseases), CORRONA (Consortium of Rheumatology Researchers of North America), the McDonald cohort of U.S. veterans (Clin. Infect. Dis. 2009;48:1364-71), and RABBIT (the German Rheumatoid Arthritis Observation of Biologic Therapy) were selected for inclusion. After selection for appropriate treatment regimens and diseases, 124, 966 patient years were included.
Upon meta-analysis, Dr. Lukas showed that there was a similar trend across the different registries, and no significant heterogeneity among data sources.
The meta-analysis showed an overall increased risk of herpes zoster infection up to 75% in patients whose inflammatory rheumatic diseases were treated with anti-TNF inhibitors. Overall, the pooled odds ratio for herpes zoster infection with anti-TNF therapy was 1.75 (95% confidence interval, 1.50-2.04). This was almost a twofold risk of developing disease with these drugs compared with DMARDs, Dr. Lukas said at the annual European Congress of Rheumatology.
Odds ratios by national registries were BIOBADASER, 2.45; BSRBR, 1.45; CORRONA, 2.34; McDonald, 1.33; and RABBIT, 1.82.
In addition to the meta-analysis, investigators used data from three registries specifically to determine whether the use of any particular anti-TNF drug was associated with a higher risk. "We found that one registry showed [that] infliximab had a somewhat higher risk, but this was only one out of three studies. The other two studies showed a similar risk across all anti-TNF agents."
In the McDonald registry, the risk was found to e higher with infliximab (OR, 1.32; 95% CI, 0.85-2.03) compared with etanercept (OR, 0.62; 95% CI, 0.40-0.95) and adalimumab (OR 0.53; 95% CI, 0.31-0.91).
"We already knew that these patients were prone to herpes zoster; we see the lesions in clinics." But there are preventive measures available that one can take, he said.
In the United States, there are vaccines to prevent herpes zoster, which are available to people who are older than age 60 years, or are at high specific risk of developing herpes zoster infection. "In these patients, we could think about vaccines before treatment is started," pointed out Dr. Lukas. "It is a live vaccine so it should be given a month before start of anti-TNF therapy. In Europe, where the vaccine is unavailable, we need to give patients prophylaxis."
Dr. Lukas reported no relevant conflicts of interest. The study was supported by an unrestricted educational grant from Abbott France.
BERLIN – Patients who have inflammatory rheumatic diseases and are on anti–tumor necrosis factor therapy have nearly double the risk of herpes zoster when they are compared with patients on disease-modifying antirheumatic drugs, according to the first meta-analysis in these patient populations.
Although the risk of bacterial infection is known to be increased among patients on anti-TNF therapy, less well known is whether the use of anti-TNF agents increases the risk for viral infections, especially herpes zoster, said Dr. Cedric Lukas of the department of rheumatology at Lapeyronie Hospital in Montpellier, France.
The meta-analysis of literature that was published between 2002 and 2010 involved a review of 655 articles and 134 congress abstracts, of which 22 articles and 28 abstracts eventually were included in the study. The anti-TNF therapies that were investigated included etanercept (Enbrel), adalimumab (Humira), and infliximab (Remicade), which were the agents available at the time.
National registries from the United States, United Kingdom, and other European countries were included in the meta-analysis, including BSRBR (British Society for Rheumatology Biologics Register), BIOBADASER (Spanish Registry of Adverse Events of Biological Therapies in Rheumatic Diseases), CORRONA (Consortium of Rheumatology Researchers of North America), the McDonald cohort of U.S. veterans (Clin. Infect. Dis. 2009;48:1364-71), and RABBIT (the German Rheumatoid Arthritis Observation of Biologic Therapy) were selected for inclusion. After selection for appropriate treatment regimens and diseases, 124, 966 patient years were included.
Upon meta-analysis, Dr. Lukas showed that there was a similar trend across the different registries, and no significant heterogeneity among data sources.
The meta-analysis showed an overall increased risk of herpes zoster infection up to 75% in patients whose inflammatory rheumatic diseases were treated with anti-TNF inhibitors. Overall, the pooled odds ratio for herpes zoster infection with anti-TNF therapy was 1.75 (95% confidence interval, 1.50-2.04). This was almost a twofold risk of developing disease with these drugs compared with DMARDs, Dr. Lukas said at the annual European Congress of Rheumatology.
Odds ratios by national registries were BIOBADASER, 2.45; BSRBR, 1.45; CORRONA, 2.34; McDonald, 1.33; and RABBIT, 1.82.
In addition to the meta-analysis, investigators used data from three registries specifically to determine whether the use of any particular anti-TNF drug was associated with a higher risk. "We found that one registry showed [that] infliximab had a somewhat higher risk, but this was only one out of three studies. The other two studies showed a similar risk across all anti-TNF agents."
In the McDonald registry, the risk was found to e higher with infliximab (OR, 1.32; 95% CI, 0.85-2.03) compared with etanercept (OR, 0.62; 95% CI, 0.40-0.95) and adalimumab (OR 0.53; 95% CI, 0.31-0.91).
"We already knew that these patients were prone to herpes zoster; we see the lesions in clinics." But there are preventive measures available that one can take, he said.
In the United States, there are vaccines to prevent herpes zoster, which are available to people who are older than age 60 years, or are at high specific risk of developing herpes zoster infection. "In these patients, we could think about vaccines before treatment is started," pointed out Dr. Lukas. "It is a live vaccine so it should be given a month before start of anti-TNF therapy. In Europe, where the vaccine is unavailable, we need to give patients prophylaxis."
Dr. Lukas reported no relevant conflicts of interest. The study was supported by an unrestricted educational grant from Abbott France.
AT THE ANNUAL EUROPEAN CONGRESS OF RHEUMATOLOGY
Major finding: Compared with patients on DMARDs, the risk of herpes zoster in patients on anti-TNF inhibitors has an odds ratio of 1.75.
Data source: The data came from a meta-analysis of five national registries and 124,966 patient years of anti-TNF or DMARD use.
Disclosures: Dr. Lukas reported no relevant conflicts of interest. The study was supported by an unrestricted educational grant from Abbott France.