It might be possible to develop a simple test to identify newborn children who are at risk of later developing atopic dermatitis (AD), according to findings from a Danish prospective birth cohort study.

In the study, the Barrier Dysfunction in Atopic Newborns Study (BABY), several biomarkers were found in the skin cells of newborns that were predictive not only for having AD but also for having more severe disease.

“We are able to identify predictive immune biomarkers of atopic dermatitis using a noninvasive method that was not associated with any pain,” one of the study’s investigators, Anne-Sofie Halling, MD, said at a press briefing at the annual congress of the European Academy of Dermatology and Venereology.

“Importantly, we were able to predict atopic dermatitis occurring months after [sample] collection,” said Dr. Halling, who works at Bispebjerg Hospital and is a PhD student at the University of Copenhagen.

These findings could hopefully be used to help identify children “so that preventive strategies can target these children ... and decrease the incidence of this common disease,” she added.

AD is caused “by a complex interplay between skin barrier dysfunction and immune dysregulation,” Dr. Halling said, and it is “the first step in the so-called atopic march, where children also develop food allergy, asthma, and rhinitis.” Almost all cases of AD begin during the first years of life. Approximately 15%-20% of children can be affected, she noted, emphasizing the high burden of the disease and pointing out that strategies are shifting toward trying to prevent the disease in those at risk.

Copenhagen BABY cohort

This is where the BABY study comes in, Dr. Halling said. The study enrolled 450 children at birth and followed them until age 2 years. Gene mutation testing was performed at enrollment. All children underwent skin examination, and skin samples were taken using tape strips. Tape strips were applied to the back of the hand of children born at term and between the shoulder blades on the back of children who were premature.

Skin examinations were repeated, and skin samples were obtained again at age 2 months. They were taken again only if there were any signs of AD. For those diagnosed with AD, disease severity was assessed using the Eczema Area and Severity Index (EASI) by the treating physician. Children were excluded if they had AD at the time the tape strip testing was due to be performed.
 

Comparing term and preterm children

Dr. Halling noted that analyses were performed separately for the 300 children born at term and for the 150 who were preterm.

The prevalence of AD was higher among children born at term than among the preterm children (34.6% vs. 21.2%), and the median time to onset was shorter (6 months vs. 8 months). There were also differences in the EASI scores among those who developed AD; median scores were higher in the children born at term than in the preterm children (4.1 vs. 1.6).

More children born at term than preterm children had moderate to severe AD (23.3% vs. 8%), Dr. Halling reported.
 

TARC, IL-8, and IL-18 predictive of AD

Multiple immune biomarkers were tested, including various cytokines and filaggrin degradation products. On examination of skin samples collected at birth, no particular biomarkers were found at higher levels among children who developed AD in comparison with those who did not develop AD.

With regard to biomarkers examined in skin samples at 2 months of age, however, the results were different, Dr. Halling said. One particular cytokine, thymus and activation-regulated chemokine (TARC), was seen to double the risk of AD in the first 2 years of a child’s life.

This doubled risk was seen not only among the children born at term but also among those born preterm, although the data were only significant with regard to the children born at term.

The unadjusted hazard ratios and adjusted HRs (adjusted for parental atopy and filaggrin gene mutations) in term children were 2.11 (95% confidence interval, 1.36-3.26; P = .0008) and 1.85 (95% CI, 1.18-2.89; P = .007), respectively.

For preterm children, the HRs were 2.23 (95% CI, 0.85-5.86; P = .1) and 2.60 (95% CI, 0.98-6.85; P =.05), respectively.

These findings were in line with findings of other studies, Dr. Halling said. “It is well recognized that TARC is currently the best biomarker in patients with established atopic dermatitis.” Moreover, she reported that TARC was associated with a cumulative increase in the risk for AD and that levels were found to be higher in children in whom onset occurred at a later age than among those diagnosed before 6 months of age.

“This is important, as these findings shows that TARC levels predict atopic dermatitis that occurred many months later,” Dr. Halling said.

And, in term-born children at least, TARC upped the chances that the severity of AD would be greater than had it not been present (adjusted HR, 4.65; 95% CI, 1.91-11.31; P = .0007).

Increased levels of interleukin-8 (IL-8) and IL-18 at 2 months of age were also found to be predictive of having moderate to severe AD. The risk was more than double in comparison with those in whom levels were not increased, again only in term-born children.

‘Stimulating and interesting findings’

These data are “very stimulating and interesting,” Dedee Murrell, MD, professor and head of the department of dermatology at St. George Hospital, University of New South Wales, Sydney, observed at the press briefing.

“You found this significant association mainly in the newborn children born at term, and the association in the preterm babies wasn’t as high. Is that anything to do with how they were taken care of in the hospital?” Dr. Murrell asked.

“That’s a really good question,” Dr. Halling said. “Maybe they need to be exposed for a month or two before we are actually able to identify which children will develop atopic dermatitis.”

The study was funded by the Lundbeck Foundation. Dr. Halling has acted as a consultant for Coloplast and as a speaker for Leo Pharma. Dr. Murrell has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

It might be possible to develop a simple test to identify newborn children who are at risk of later developing atopic dermatitis (AD), according to findings from a Danish prospective birth cohort study.

In the study, the Barrier Dysfunction in Atopic Newborns Study (BABY), several biomarkers were found in the skin cells of newborns that were predictive not only for having AD but also for having more severe disease.

“We are able to identify predictive immune biomarkers of atopic dermatitis using a noninvasive method that was not associated with any pain,” one of the study’s investigators, Anne-Sofie Halling, MD, said at a press briefing at the annual congress of the European Academy of Dermatology and Venereology.

“Importantly, we were able to predict atopic dermatitis occurring months after [sample] collection,” said Dr. Halling, who works at Bispebjerg Hospital and is a PhD student at the University of Copenhagen.

These findings could hopefully be used to help identify children “so that preventive strategies can target these children ... and decrease the incidence of this common disease,” she added.

AD is caused “by a complex interplay between skin barrier dysfunction and immune dysregulation,” Dr. Halling said, and it is “the first step in the so-called atopic march, where children also develop food allergy, asthma, and rhinitis.” Almost all cases of AD begin during the first years of life. Approximately 15%-20% of children can be affected, she noted, emphasizing the high burden of the disease and pointing out that strategies are shifting toward trying to prevent the disease in those at risk.

Copenhagen BABY cohort

This is where the BABY study comes in, Dr. Halling said. The study enrolled 450 children at birth and followed them until age 2 years. Gene mutation testing was performed at enrollment. All children underwent skin examination, and skin samples were taken using tape strips. Tape strips were applied to the back of the hand of children born at term and between the shoulder blades on the back of children who were premature.

Skin examinations were repeated, and skin samples were obtained again at age 2 months. They were taken again only if there were any signs of AD. For those diagnosed with AD, disease severity was assessed using the Eczema Area and Severity Index (EASI) by the treating physician. Children were excluded if they had AD at the time the tape strip testing was due to be performed.
 

Comparing term and preterm children

Dr. Halling noted that analyses were performed separately for the 300 children born at term and for the 150 who were preterm.

The prevalence of AD was higher among children born at term than among the preterm children (34.6% vs. 21.2%), and the median time to onset was shorter (6 months vs. 8 months). There were also differences in the EASI scores among those who developed AD; median scores were higher in the children born at term than in the preterm children (4.1 vs. 1.6).

More children born at term than preterm children had moderate to severe AD (23.3% vs. 8%), Dr. Halling reported.
 

TARC, IL-8, and IL-18 predictive of AD

Multiple immune biomarkers were tested, including various cytokines and filaggrin degradation products. On examination of skin samples collected at birth, no particular biomarkers were found at higher levels among children who developed AD in comparison with those who did not develop AD.

With regard to biomarkers examined in skin samples at 2 months of age, however, the results were different, Dr. Halling said. One particular cytokine, thymus and activation-regulated chemokine (TARC), was seen to double the risk of AD in the first 2 years of a child’s life.

This doubled risk was seen not only among the children born at term but also among those born preterm, although the data were only significant with regard to the children born at term.

The unadjusted hazard ratios and adjusted HRs (adjusted for parental atopy and filaggrin gene mutations) in term children were 2.11 (95% confidence interval, 1.36-3.26; P = .0008) and 1.85 (95% CI, 1.18-2.89; P = .007), respectively.

For preterm children, the HRs were 2.23 (95% CI, 0.85-5.86; P = .1) and 2.60 (95% CI, 0.98-6.85; P =.05), respectively.

These findings were in line with findings of other studies, Dr. Halling said. “It is well recognized that TARC is currently the best biomarker in patients with established atopic dermatitis.” Moreover, she reported that TARC was associated with a cumulative increase in the risk for AD and that levels were found to be higher in children in whom onset occurred at a later age than among those diagnosed before 6 months of age.

“This is important, as these findings shows that TARC levels predict atopic dermatitis that occurred many months later,” Dr. Halling said.

And, in term-born children at least, TARC upped the chances that the severity of AD would be greater than had it not been present (adjusted HR, 4.65; 95% CI, 1.91-11.31; P = .0007).

Increased levels of interleukin-8 (IL-8) and IL-18 at 2 months of age were also found to be predictive of having moderate to severe AD. The risk was more than double in comparison with those in whom levels were not increased, again only in term-born children.

‘Stimulating and interesting findings’

These data are “very stimulating and interesting,” Dedee Murrell, MD, professor and head of the department of dermatology at St. George Hospital, University of New South Wales, Sydney, observed at the press briefing.

“You found this significant association mainly in the newborn children born at term, and the association in the preterm babies wasn’t as high. Is that anything to do with how they were taken care of in the hospital?” Dr. Murrell asked.

“That’s a really good question,” Dr. Halling said. “Maybe they need to be exposed for a month or two before we are actually able to identify which children will develop atopic dermatitis.”

The study was funded by the Lundbeck Foundation. Dr. Halling has acted as a consultant for Coloplast and as a speaker for Leo Pharma. Dr. Murrell has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

It might be possible to develop a simple test to identify newborn children who are at risk of later developing atopic dermatitis (AD), according to findings from a Danish prospective birth cohort study.

In the study, the Barrier Dysfunction in Atopic Newborns Study (BABY), several biomarkers were found in the skin cells of newborns that were predictive not only for having AD but also for having more severe disease.

“We are able to identify predictive immune biomarkers of atopic dermatitis using a noninvasive method that was not associated with any pain,” one of the study’s investigators, Anne-Sofie Halling, MD, said at a press briefing at the annual congress of the European Academy of Dermatology and Venereology.

“Importantly, we were able to predict atopic dermatitis occurring months after [sample] collection,” said Dr. Halling, who works at Bispebjerg Hospital and is a PhD student at the University of Copenhagen.

These findings could hopefully be used to help identify children “so that preventive strategies can target these children ... and decrease the incidence of this common disease,” she added.

AD is caused “by a complex interplay between skin barrier dysfunction and immune dysregulation,” Dr. Halling said, and it is “the first step in the so-called atopic march, where children also develop food allergy, asthma, and rhinitis.” Almost all cases of AD begin during the first years of life. Approximately 15%-20% of children can be affected, she noted, emphasizing the high burden of the disease and pointing out that strategies are shifting toward trying to prevent the disease in those at risk.

Copenhagen BABY cohort

This is where the BABY study comes in, Dr. Halling said. The study enrolled 450 children at birth and followed them until age 2 years. Gene mutation testing was performed at enrollment. All children underwent skin examination, and skin samples were taken using tape strips. Tape strips were applied to the back of the hand of children born at term and between the shoulder blades on the back of children who were premature.

Skin examinations were repeated, and skin samples were obtained again at age 2 months. They were taken again only if there were any signs of AD. For those diagnosed with AD, disease severity was assessed using the Eczema Area and Severity Index (EASI) by the treating physician. Children were excluded if they had AD at the time the tape strip testing was due to be performed.
 

Comparing term and preterm children

Dr. Halling noted that analyses were performed separately for the 300 children born at term and for the 150 who were preterm.

The prevalence of AD was higher among children born at term than among the preterm children (34.6% vs. 21.2%), and the median time to onset was shorter (6 months vs. 8 months). There were also differences in the EASI scores among those who developed AD; median scores were higher in the children born at term than in the preterm children (4.1 vs. 1.6).

More children born at term than preterm children had moderate to severe AD (23.3% vs. 8%), Dr. Halling reported.
 

TARC, IL-8, and IL-18 predictive of AD

Multiple immune biomarkers were tested, including various cytokines and filaggrin degradation products. On examination of skin samples collected at birth, no particular biomarkers were found at higher levels among children who developed AD in comparison with those who did not develop AD.

With regard to biomarkers examined in skin samples at 2 months of age, however, the results were different, Dr. Halling said. One particular cytokine, thymus and activation-regulated chemokine (TARC), was seen to double the risk of AD in the first 2 years of a child’s life.

This doubled risk was seen not only among the children born at term but also among those born preterm, although the data were only significant with regard to the children born at term.

The unadjusted hazard ratios and adjusted HRs (adjusted for parental atopy and filaggrin gene mutations) in term children were 2.11 (95% confidence interval, 1.36-3.26; P = .0008) and 1.85 (95% CI, 1.18-2.89; P = .007), respectively.

For preterm children, the HRs were 2.23 (95% CI, 0.85-5.86; P = .1) and 2.60 (95% CI, 0.98-6.85; P =.05), respectively.

These findings were in line with findings of other studies, Dr. Halling said. “It is well recognized that TARC is currently the best biomarker in patients with established atopic dermatitis.” Moreover, she reported that TARC was associated with a cumulative increase in the risk for AD and that levels were found to be higher in children in whom onset occurred at a later age than among those diagnosed before 6 months of age.

“This is important, as these findings shows that TARC levels predict atopic dermatitis that occurred many months later,” Dr. Halling said.

And, in term-born children at least, TARC upped the chances that the severity of AD would be greater than had it not been present (adjusted HR, 4.65; 95% CI, 1.91-11.31; P = .0007).

Increased levels of interleukin-8 (IL-8) and IL-18 at 2 months of age were also found to be predictive of having moderate to severe AD. The risk was more than double in comparison with those in whom levels were not increased, again only in term-born children.

‘Stimulating and interesting findings’

These data are “very stimulating and interesting,” Dedee Murrell, MD, professor and head of the department of dermatology at St. George Hospital, University of New South Wales, Sydney, observed at the press briefing.

“You found this significant association mainly in the newborn children born at term, and the association in the preterm babies wasn’t as high. Is that anything to do with how they were taken care of in the hospital?” Dr. Murrell asked.

“That’s a really good question,” Dr. Halling said. “Maybe they need to be exposed for a month or two before we are actually able to identify which children will develop atopic dermatitis.”

The study was funded by the Lundbeck Foundation. Dr. Halling has acted as a consultant for Coloplast and as a speaker for Leo Pharma. Dr. Murrell has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Ezetimibe given in combination with rosuvastatin has a beneficial effect on liver fat in people with nonalcoholic fatty liver disease (NAFLD), according results of a randomized, active-controlled trial.

The findings, which come from the investigator-initiated ESSENTIAL trial, are likely to add to the debate over whether or not the lipid-lowering combination could be of benefit beyond its effects in the blood.

Dr_Microbe/Getty Images

“We used magnetic resonance imaging-derived proton density fat fraction [MRI-PDFF], which is highly reliable method of assessing hepatic steatosis,” Youngjoon Kim, PhD, one of the study investigators, said at the annual meeting of the European Association for the Study of Diabetes in Barcelona.

“It enables accurate, repeatable and reproducible quantitative assessment of liver fat over the entire liver,” observed Dr. Kim, who works at Severance Hospital, part of Yonsei University in Seoul.

He reported that there was a significant 5.8% decrease in liver fat following 24 weeks’ treatment with ezetimibe and rosuvastatin comparing baseline with end of treatment MRI-PDFF values; a drop that was significant (18.2% vs. 12.3%, P < .001).

Rosuvastatin monotherapy also reduced liver fat from 15.0% at baseline to 12.4% after 24 weeks; this drop of 2.6% was also significant (P = .003).

This gave an absolute mean difference between the two study arms of 3.2% (P = .02).
 

Rationale for the ESSENTIAL study

Dr. Kim observed during his presentation that NAFLD is burgeoning problem around the world. Ezetimibe plus rosuvastatin was a combination treatment already used widely in clinical practice, and there had been some suggestion that ezetimibe might have an effect on liver fat.

“Although the effect of ezetimibe on hepatic steatosis is still controversial, ezetimibe has been reported to reduce visceral fat and improve insulin resistance in several studies” Dr. Kim said.

“Recently, our group reported that the use of ezetimibe affects autophagy of hepatocytes and the NLRP3 [NOD-like receptors containing pyrin domain 3] inflammasome,” he said.

Moreover, he added, “ezetimibe improved NASH [nonalcoholic steatohepatitis] in an animal model. However, the effects of ezetimibe have not been clearly shown in a human study.”

Dr. Kim also acknowledged a prior randomized control trial that had looked at the role of ezetimibe in 50 patients with NASH, but had not shown a benefit for the drug over placebo in terms of liver fat reduction.
 

Addressing the Hawthorne effect

“The size of the effect by that might actually be more modest due to the Hawthorne effect,” said session chair Onno Holleboom, MD, PhD, of Amsterdam UMC in the Netherlands.

“What we observe in the large clinical trials is an enormous Hawthorne effect – participating in a NAFLD trial makes people live healthier because they have health checks,” he said.

“That’s a major problem for showing efficacy for the intervention arm,” he added, but of course the open design meant that the trial only had intervention arms; “there was no placebo arm.”
 

A randomized, active-controlled, clinician-initiated trial

The main objective of the ESSENTIAL trial was therefore to take another look at the potential effect of ezetimibe on hepatic steatosis and doing so in the setting of statin therapy.

In all, 70 patients with NAFLD that had been confirmed via ultrasound were recruited into the prospective, single center, phase 4 trial. Participants were randomized 1:1 to received either ezetimibe 10 mg plus rosuvastatin 5 mg daily or rosuvastatin 5 mg for up to 24 weeks.

Change in liver fat was measured via MRI-PDFF, taking the average values in each of nine liver segments. Magnetic resonance elastography (MRE) was also used to measure liver fibrosis, although results did not show any differences either from baseline to end of treatment values in either group or when the two treatment groups were compared.

Dr. Kim reported that both treatment with the ezetimibe-rosuvastatin combination and rosuvastatin monotherapy reduced parameters that might be associated with a negative outcome in NAFLD, such as body mass index and waist circumference, triglycerides, and LDL cholesterol. There was also a reduction in C-reactive protein levels in the blood, and interleulin-18. There was no change in liver enzymes.

Several subgroup analyses were performed indicating that “individuals with higher BMI, type 2 diabetes, insulin resistance, and severe liver fibrosis were likely to be good responders to ezetimibe treatment,” Dr. Kim said.

“These data indicate that ezetimibe plus rosuvastatin is a safe and effective therapeutic option to treat patients with NAFLD and dyslipidemia,” he concluded.

The results of the ESSENTIAL study have been published in BMC Medicine.

The study was funded by the Yuhan Corporation. Dr. Kim had no conflicts of interest to report. Dr. Holleboom was not involved in the study and had no conflicts of interest.

Ezetimibe given in combination with rosuvastatin has a beneficial effect on liver fat in people with nonalcoholic fatty liver disease (NAFLD), according results of a randomized, active-controlled trial.

The findings, which come from the investigator-initiated ESSENTIAL trial, are likely to add to the debate over whether or not the lipid-lowering combination could be of benefit beyond its effects in the blood.

Dr_Microbe/Getty Images

“We used magnetic resonance imaging-derived proton density fat fraction [MRI-PDFF], which is highly reliable method of assessing hepatic steatosis,” Youngjoon Kim, PhD, one of the study investigators, said at the annual meeting of the European Association for the Study of Diabetes in Barcelona.

“It enables accurate, repeatable and reproducible quantitative assessment of liver fat over the entire liver,” observed Dr. Kim, who works at Severance Hospital, part of Yonsei University in Seoul.

He reported that there was a significant 5.8% decrease in liver fat following 24 weeks’ treatment with ezetimibe and rosuvastatin comparing baseline with end of treatment MRI-PDFF values; a drop that was significant (18.2% vs. 12.3%, P < .001).

Rosuvastatin monotherapy also reduced liver fat from 15.0% at baseline to 12.4% after 24 weeks; this drop of 2.6% was also significant (P = .003).

This gave an absolute mean difference between the two study arms of 3.2% (P = .02).
 

Rationale for the ESSENTIAL study

Dr. Kim observed during his presentation that NAFLD is burgeoning problem around the world. Ezetimibe plus rosuvastatin was a combination treatment already used widely in clinical practice, and there had been some suggestion that ezetimibe might have an effect on liver fat.

“Although the effect of ezetimibe on hepatic steatosis is still controversial, ezetimibe has been reported to reduce visceral fat and improve insulin resistance in several studies” Dr. Kim said.

“Recently, our group reported that the use of ezetimibe affects autophagy of hepatocytes and the NLRP3 [NOD-like receptors containing pyrin domain 3] inflammasome,” he said.

Moreover, he added, “ezetimibe improved NASH [nonalcoholic steatohepatitis] in an animal model. However, the effects of ezetimibe have not been clearly shown in a human study.”

Dr. Kim also acknowledged a prior randomized control trial that had looked at the role of ezetimibe in 50 patients with NASH, but had not shown a benefit for the drug over placebo in terms of liver fat reduction.
 

Addressing the Hawthorne effect

“The size of the effect by that might actually be more modest due to the Hawthorne effect,” said session chair Onno Holleboom, MD, PhD, of Amsterdam UMC in the Netherlands.

“What we observe in the large clinical trials is an enormous Hawthorne effect – participating in a NAFLD trial makes people live healthier because they have health checks,” he said.

“That’s a major problem for showing efficacy for the intervention arm,” he added, but of course the open design meant that the trial only had intervention arms; “there was no placebo arm.”
 

A randomized, active-controlled, clinician-initiated trial

The main objective of the ESSENTIAL trial was therefore to take another look at the potential effect of ezetimibe on hepatic steatosis and doing so in the setting of statin therapy.

In all, 70 patients with NAFLD that had been confirmed via ultrasound were recruited into the prospective, single center, phase 4 trial. Participants were randomized 1:1 to received either ezetimibe 10 mg plus rosuvastatin 5 mg daily or rosuvastatin 5 mg for up to 24 weeks.

Change in liver fat was measured via MRI-PDFF, taking the average values in each of nine liver segments. Magnetic resonance elastography (MRE) was also used to measure liver fibrosis, although results did not show any differences either from baseline to end of treatment values in either group or when the two treatment groups were compared.

Dr. Kim reported that both treatment with the ezetimibe-rosuvastatin combination and rosuvastatin monotherapy reduced parameters that might be associated with a negative outcome in NAFLD, such as body mass index and waist circumference, triglycerides, and LDL cholesterol. There was also a reduction in C-reactive protein levels in the blood, and interleulin-18. There was no change in liver enzymes.

Several subgroup analyses were performed indicating that “individuals with higher BMI, type 2 diabetes, insulin resistance, and severe liver fibrosis were likely to be good responders to ezetimibe treatment,” Dr. Kim said.

“These data indicate that ezetimibe plus rosuvastatin is a safe and effective therapeutic option to treat patients with NAFLD and dyslipidemia,” he concluded.

The results of the ESSENTIAL study have been published in BMC Medicine.

The study was funded by the Yuhan Corporation. Dr. Kim had no conflicts of interest to report. Dr. Holleboom was not involved in the study and had no conflicts of interest.

Ezetimibe given in combination with rosuvastatin has a beneficial effect on liver fat in people with nonalcoholic fatty liver disease (NAFLD), according results of a randomized, active-controlled trial.

The findings, which come from the investigator-initiated ESSENTIAL trial, are likely to add to the debate over whether or not the lipid-lowering combination could be of benefit beyond its effects in the blood.

Dr_Microbe/Getty Images

“We used magnetic resonance imaging-derived proton density fat fraction [MRI-PDFF], which is highly reliable method of assessing hepatic steatosis,” Youngjoon Kim, PhD, one of the study investigators, said at the annual meeting of the European Association for the Study of Diabetes in Barcelona.

“It enables accurate, repeatable and reproducible quantitative assessment of liver fat over the entire liver,” observed Dr. Kim, who works at Severance Hospital, part of Yonsei University in Seoul.

He reported that there was a significant 5.8% decrease in liver fat following 24 weeks’ treatment with ezetimibe and rosuvastatin comparing baseline with end of treatment MRI-PDFF values; a drop that was significant (18.2% vs. 12.3%, P < .001).

Rosuvastatin monotherapy also reduced liver fat from 15.0% at baseline to 12.4% after 24 weeks; this drop of 2.6% was also significant (P = .003).

This gave an absolute mean difference between the two study arms of 3.2% (P = .02).
 

Rationale for the ESSENTIAL study

Dr. Kim observed during his presentation that NAFLD is burgeoning problem around the world. Ezetimibe plus rosuvastatin was a combination treatment already used widely in clinical practice, and there had been some suggestion that ezetimibe might have an effect on liver fat.

“Although the effect of ezetimibe on hepatic steatosis is still controversial, ezetimibe has been reported to reduce visceral fat and improve insulin resistance in several studies” Dr. Kim said.

“Recently, our group reported that the use of ezetimibe affects autophagy of hepatocytes and the NLRP3 [NOD-like receptors containing pyrin domain 3] inflammasome,” he said.

Moreover, he added, “ezetimibe improved NASH [nonalcoholic steatohepatitis] in an animal model. However, the effects of ezetimibe have not been clearly shown in a human study.”

Dr. Kim also acknowledged a prior randomized control trial that had looked at the role of ezetimibe in 50 patients with NASH, but had not shown a benefit for the drug over placebo in terms of liver fat reduction.
 

Addressing the Hawthorne effect

“The size of the effect by that might actually be more modest due to the Hawthorne effect,” said session chair Onno Holleboom, MD, PhD, of Amsterdam UMC in the Netherlands.

“What we observe in the large clinical trials is an enormous Hawthorne effect – participating in a NAFLD trial makes people live healthier because they have health checks,” he said.

“That’s a major problem for showing efficacy for the intervention arm,” he added, but of course the open design meant that the trial only had intervention arms; “there was no placebo arm.”
 

A randomized, active-controlled, clinician-initiated trial

The main objective of the ESSENTIAL trial was therefore to take another look at the potential effect of ezetimibe on hepatic steatosis and doing so in the setting of statin therapy.

In all, 70 patients with NAFLD that had been confirmed via ultrasound were recruited into the prospective, single center, phase 4 trial. Participants were randomized 1:1 to received either ezetimibe 10 mg plus rosuvastatin 5 mg daily or rosuvastatin 5 mg for up to 24 weeks.

Change in liver fat was measured via MRI-PDFF, taking the average values in each of nine liver segments. Magnetic resonance elastography (MRE) was also used to measure liver fibrosis, although results did not show any differences either from baseline to end of treatment values in either group or when the two treatment groups were compared.

Dr. Kim reported that both treatment with the ezetimibe-rosuvastatin combination and rosuvastatin monotherapy reduced parameters that might be associated with a negative outcome in NAFLD, such as body mass index and waist circumference, triglycerides, and LDL cholesterol. There was also a reduction in C-reactive protein levels in the blood, and interleulin-18. There was no change in liver enzymes.

Several subgroup analyses were performed indicating that “individuals with higher BMI, type 2 diabetes, insulin resistance, and severe liver fibrosis were likely to be good responders to ezetimibe treatment,” Dr. Kim said.

“These data indicate that ezetimibe plus rosuvastatin is a safe and effective therapeutic option to treat patients with NAFLD and dyslipidemia,” he concluded.

The results of the ESSENTIAL study have been published in BMC Medicine.

The study was funded by the Yuhan Corporation. Dr. Kim had no conflicts of interest to report. Dr. Holleboom was not involved in the study and had no conflicts of interest.

Employed physicians are often torn. Many relish the steady salary and ability to focus on being a physician rather than handle administrative duties, but they bemoan their employers’ rules and their lack of input into key decisions. And thus, many doctors are leaving employment to start a private practice. For this article, seven physicians talked about why they chose private practice.

Leaving employment is ‘an invigorating time’

On Sept. 9, Aaron Przybysz, MD, gave notice to his employer, a large academic medical center in Southern California, that he would be leaving to start a private practice.

“It’s an invigorating time,” said Dr. Przybysz, 41, an anesthesiologist and pain management physician who plans to open his new pain management practice on Dec. 1 in Orange County. He has picked out the space he will rent but has not yet hired his staff.

“I’ve been serious about doing this for at least a year,” Dr. Przybysz said. “What held me back is the concern that my business could fail. But even if that happens, what’s the worst that could occur? I’d have to find a new job as an employed physician.

“I feel comfortable with the business side of medicine,” he said. His father was an executive in the automotive industry and his father-in-law is an entrepreneur in construction and housing.

“One of the biggest reasons for moving to private practice is making sure I don’t miss my kids’ activities,” he said, referring to his children, ages 9 and 7. Recently, he said, “I had to spend the whole weekend on call in the hospital. I came home and had to sleep most of the next day.

“I love the people that I have been working with and I’ve learned and matured as a physician during that time,” he said. “But it was time to move on.”
 

The desire to be in charge

In Medscape’s recent Employed Physicians Report, doctors said they enjoy the steady salary and ability to focus on patients, which comes with being employed.

Other physicians feel differently. John Machata, MD, a solo family physician in the village of Wickford, R.I., 20 miles south of Providence, chose private practice because “I have total control,” he said. “I make decisions that I couldn’t have made as an employed physician, such as closing my practice to new patients.”

He can also decide on his work hours. “I see patients for 35 hours, 4 days a week and then I have a 3-day weekend.” In a large organization, “the focus is on revenue,” said Dr. Machata. “They’re always measuring your productivity. If you are slower, you won’t make enough money for them.”

When he worked for a large group practice about a decade ago, “I felt burnt out every day,” he said. “I had to see patients every 10 minutes, with no breaks for anything in between. Within a month I was devising my exit strategy.”

Dr. Machata maintains long appointments – 25 minutes for a typical follow-up visit and 55 minutes for an annual check-in – but he still earns above the state average for primary care doctors. “I have no nurse or front-office staff, which means I can save $125,000 to $150,000 a year,” he said.  

In 2018, for the first time, employed physicians outnumbered self-employed physicians, according to a survey by the American Medical Association (AMA). By the end of 2021, more than half (52.1%) of U.S. physicians were employed by hospitals or health systems.

Yet the negatives of employment have begun to turn some physicians back toward private practice. Many physicians who were employed by a hospital or a large practice have become disillusioned and want to return to private practice.
 

His practice is the ‘best of both worlds’

Adam Bruggeman, MD, a 42-year-old spine surgeon who is CEO of Texas Spine Care Center, a solo practice in San Antonio, said he has “the best of both worlds.”

“As a solo physician, I have total control over how I practice,” he said. “But I also have access to value-based contracts and the data and staff needed to implement them.

“You need a lot of administrative overhead to take on these contracts, which a private practice normally doesn’t have,” he said. But Dr. Bruggeman gets this work done through a clinically integrated network (CIN) of private practices, Spinalytics of Texas, where he is chief medical director.

The CIN represents 150 musculoskeletal care providers and provides access to bundled networks, such as a total joint bundle with Blue Cross Blue Shield of Texas, as well as fee-for-service contracts.

He is also building a new ambulatory surgery center (ASC) that is scheduled to open in January. There, he plans to perform total joint and spine surgeries at a lower cost than at the hospital, which will be useful for value-based contracts through the CIN.

Dr. Bruggeman said it would be hard to run his private practice without the CIN and the ASC. “Private practice has changed,” he said. “The days of hanging up a shingle and immediately being successful are gone. You’ve got to be smart about business to run a successful practice.”
 

He started his practice while the pandemic raged

Joe Greene, MD, 42, an orthopedic surgeon in Louisville, Ky., had to open his hip and knee surgery practice when the COVID-19 pandemic was raging a year and a half ago, but that did not stop him.

“Federal financing of small bank loans completely stopped, but that only amounted to a small delay because our bank took care of it,” said Dr. Greene, who codirects his new practice with another orthopedic surgeon.

Even during the pandemic, “we could be very nimble,” he said. “For instance, when we want to institute new technology or a new patient-centric educational platform, we can do it immediately rather than going through an approval process at a health system.”

The partners, both ex-employees of a health system, also have an ASC, which allows them better control over their surgery schedules. “At a hospital, you can be bumped from the schedule by other surgeries, and you can’t be as productive as an ASC in the number of surgeries per day,” he said.

Dr. Greene attributes the practice’s success to long and careful planning. “We had to learn about business,” he said. “We did 3 to 4 years of research to find the right business model and implement it.”

As they were considering the new practice, a survey of patients showed that more than 75% chose them by word-of-mouth – because they specialize in complex and revision surgeries – rather than through referrals within their health system. This meant they could survive without their employer.

Planning for the new practice took up all his free time, but now he can relax and spend time with his three daughters, ages 12, 10, and 8. Dr. Greene currently coaches two of their teams. “We’re loving it,” he said.
 

Colleagues want to know how he did it

Clinton Sheets, MD, an ophthalmologist in Hudson and Clearwater, Fla., went solo in 2019 after being in a group practice for 11 years. Since he opened up, “I get phone calls from colleagues all the time, asking me about how I did it,” he said. “At least two of them followed in my footsteps.

“I tell them it’s very doable,” he said. “If you have the motivation, you can do it. Depending on your competence, you can outsource as much or as little as you want. Some management companies can do almost all of the nonclinical work for you.

“Smaller practices can streamline processes because they have a flatter organizational structure and have fewer issues with administrative bloat than larger organizations,” he said.

“Technology hinders and helps a private practice,” he said. On the one hand, he had to buy a lot of expensive equipment that otherwise would be shared by a group of doctors. On the other hand, using the cloud makes it possible to easily store practice management software and the electronic health record. 
 

He’s opening a private practice while staying employed

In December, Dev Basu, MD, a hospitalist in Baltimore, plans to start his own private practice, seeing patients in skilled nursing homes, while still working as a nocturnist in a large health care system.  

He said his employer has been supportive of his plans. “My work will not directly compete with them and it will benefit them by serving patients discharged from their hospitals,” said Dr. Basu, 38. He added, however, that he will be allowed to work only at certain facilities, and these will be subject to annual review.

“The financial risk of the new practice is low, because I haven’t had to invest much,” he said. “I won’t have a staff or an office.” He plans to maintain his full schedule as an employee, working 12 nights a month, because it will give him a great deal of time to do the new work.

“I also have no particular interest in running a business,” he said. “I come from a family of doctors, professors, and teachers who never ran a business. But I’m willing to learn so that I can practice medicine the way I want to.

“The ability to set my own schedule and deal with patients in the way I think is best is very important to me,” he said.
 

Private practitioners don’t have to face ‘moral distress’

One thing private practitioners typically don’t have to contend with is “moral distress,” which occurs when you have to follow institutional concerns on how much time you can spend with a patient or on the need to keep referrals in-house, according to Marie T. Brown, MD.

Dr. Brown is an internist who ran a small private practice in Oak Park, Ill., and is now the physician lead for the American Medical Association’s STEPS Forward program, which provides strategies on how to improve a medical practice.

“In my private practice, I could control the time I spent with each patient,” she said. “I also had control over my schedule. If I didn’t have the time, I just took a lower income, but that was okay.”

Dr. Brown said it is a myth that employment offers a better work-life balance. “Young physicians who take employment for this reason may find that they’re not allowed to drop off and pick up their children from school at a certain time. But you can do that in a private practice.”

She said it’s not that hard to run a practice. “Young physicians don’t think they could run a practice because they don’t have any business skills,” she said. “Yes, you do need some management skills, and you have to devote time to management. But you don’t need to have special expertise. You can outsource much of the work.”
 

A growing trend?

David J. Zetter, a consultant in Mechanicsburg, Pa., who helps doctors set up private practices, sees more interest in this in the past 5 years. “The overwhelming trend used to be private practices being bought up by hospitals and other entities,” he said. “Now we’re seeing the pendulum swing in the opposite direction.

“Generally, these doctors are fed up with being employed at a large organization,” he added. “Recently I got a call from a doctor who had never thought about running his own business, but he’s had it with being an employed physician.”

Switching to private practice is scary for a lot of them, but the alternative is worse. “A podiatrist I’m working with tells me she is scared to death about setting up a private practice, but she’s doing it because she doesn’t want to be employed anymore,” Mr. Zetter said.

A version of this article first appeared on Medscape.com.

Employed physicians are often torn. Many relish the steady salary and ability to focus on being a physician rather than handle administrative duties, but they bemoan their employers’ rules and their lack of input into key decisions. And thus, many doctors are leaving employment to start a private practice. For this article, seven physicians talked about why they chose private practice.

Leaving employment is ‘an invigorating time’

On Sept. 9, Aaron Przybysz, MD, gave notice to his employer, a large academic medical center in Southern California, that he would be leaving to start a private practice.

“It’s an invigorating time,” said Dr. Przybysz, 41, an anesthesiologist and pain management physician who plans to open his new pain management practice on Dec. 1 in Orange County. He has picked out the space he will rent but has not yet hired his staff.

“I’ve been serious about doing this for at least a year,” Dr. Przybysz said. “What held me back is the concern that my business could fail. But even if that happens, what’s the worst that could occur? I’d have to find a new job as an employed physician.

“I feel comfortable with the business side of medicine,” he said. His father was an executive in the automotive industry and his father-in-law is an entrepreneur in construction and housing.

“One of the biggest reasons for moving to private practice is making sure I don’t miss my kids’ activities,” he said, referring to his children, ages 9 and 7. Recently, he said, “I had to spend the whole weekend on call in the hospital. I came home and had to sleep most of the next day.

“I love the people that I have been working with and I’ve learned and matured as a physician during that time,” he said. “But it was time to move on.”
 

The desire to be in charge

In Medscape’s recent Employed Physicians Report, doctors said they enjoy the steady salary and ability to focus on patients, which comes with being employed.

Other physicians feel differently. John Machata, MD, a solo family physician in the village of Wickford, R.I., 20 miles south of Providence, chose private practice because “I have total control,” he said. “I make decisions that I couldn’t have made as an employed physician, such as closing my practice to new patients.”

He can also decide on his work hours. “I see patients for 35 hours, 4 days a week and then I have a 3-day weekend.” In a large organization, “the focus is on revenue,” said Dr. Machata. “They’re always measuring your productivity. If you are slower, you won’t make enough money for them.”

When he worked for a large group practice about a decade ago, “I felt burnt out every day,” he said. “I had to see patients every 10 minutes, with no breaks for anything in between. Within a month I was devising my exit strategy.”

Dr. Machata maintains long appointments – 25 minutes for a typical follow-up visit and 55 minutes for an annual check-in – but he still earns above the state average for primary care doctors. “I have no nurse or front-office staff, which means I can save $125,000 to $150,000 a year,” he said.  

In 2018, for the first time, employed physicians outnumbered self-employed physicians, according to a survey by the American Medical Association (AMA). By the end of 2021, more than half (52.1%) of U.S. physicians were employed by hospitals or health systems.

Yet the negatives of employment have begun to turn some physicians back toward private practice. Many physicians who were employed by a hospital or a large practice have become disillusioned and want to return to private practice.
 

His practice is the ‘best of both worlds’

Adam Bruggeman, MD, a 42-year-old spine surgeon who is CEO of Texas Spine Care Center, a solo practice in San Antonio, said he has “the best of both worlds.”

“As a solo physician, I have total control over how I practice,” he said. “But I also have access to value-based contracts and the data and staff needed to implement them.

“You need a lot of administrative overhead to take on these contracts, which a private practice normally doesn’t have,” he said. But Dr. Bruggeman gets this work done through a clinically integrated network (CIN) of private practices, Spinalytics of Texas, where he is chief medical director.

The CIN represents 150 musculoskeletal care providers and provides access to bundled networks, such as a total joint bundle with Blue Cross Blue Shield of Texas, as well as fee-for-service contracts.

He is also building a new ambulatory surgery center (ASC) that is scheduled to open in January. There, he plans to perform total joint and spine surgeries at a lower cost than at the hospital, which will be useful for value-based contracts through the CIN.

Dr. Bruggeman said it would be hard to run his private practice without the CIN and the ASC. “Private practice has changed,” he said. “The days of hanging up a shingle and immediately being successful are gone. You’ve got to be smart about business to run a successful practice.”
 

He started his practice while the pandemic raged

Joe Greene, MD, 42, an orthopedic surgeon in Louisville, Ky., had to open his hip and knee surgery practice when the COVID-19 pandemic was raging a year and a half ago, but that did not stop him.

“Federal financing of small bank loans completely stopped, but that only amounted to a small delay because our bank took care of it,” said Dr. Greene, who codirects his new practice with another orthopedic surgeon.

Even during the pandemic, “we could be very nimble,” he said. “For instance, when we want to institute new technology or a new patient-centric educational platform, we can do it immediately rather than going through an approval process at a health system.”

The partners, both ex-employees of a health system, also have an ASC, which allows them better control over their surgery schedules. “At a hospital, you can be bumped from the schedule by other surgeries, and you can’t be as productive as an ASC in the number of surgeries per day,” he said.

Dr. Greene attributes the practice’s success to long and careful planning. “We had to learn about business,” he said. “We did 3 to 4 years of research to find the right business model and implement it.”

As they were considering the new practice, a survey of patients showed that more than 75% chose them by word-of-mouth – because they specialize in complex and revision surgeries – rather than through referrals within their health system. This meant they could survive without their employer.

Planning for the new practice took up all his free time, but now he can relax and spend time with his three daughters, ages 12, 10, and 8. Dr. Greene currently coaches two of their teams. “We’re loving it,” he said.
 

Colleagues want to know how he did it

Clinton Sheets, MD, an ophthalmologist in Hudson and Clearwater, Fla., went solo in 2019 after being in a group practice for 11 years. Since he opened up, “I get phone calls from colleagues all the time, asking me about how I did it,” he said. “At least two of them followed in my footsteps.

“I tell them it’s very doable,” he said. “If you have the motivation, you can do it. Depending on your competence, you can outsource as much or as little as you want. Some management companies can do almost all of the nonclinical work for you.

“Smaller practices can streamline processes because they have a flatter organizational structure and have fewer issues with administrative bloat than larger organizations,” he said.

“Technology hinders and helps a private practice,” he said. On the one hand, he had to buy a lot of expensive equipment that otherwise would be shared by a group of doctors. On the other hand, using the cloud makes it possible to easily store practice management software and the electronic health record. 
 

He’s opening a private practice while staying employed

In December, Dev Basu, MD, a hospitalist in Baltimore, plans to start his own private practice, seeing patients in skilled nursing homes, while still working as a nocturnist in a large health care system.  

He said his employer has been supportive of his plans. “My work will not directly compete with them and it will benefit them by serving patients discharged from their hospitals,” said Dr. Basu, 38. He added, however, that he will be allowed to work only at certain facilities, and these will be subject to annual review.

“The financial risk of the new practice is low, because I haven’t had to invest much,” he said. “I won’t have a staff or an office.” He plans to maintain his full schedule as an employee, working 12 nights a month, because it will give him a great deal of time to do the new work.

“I also have no particular interest in running a business,” he said. “I come from a family of doctors, professors, and teachers who never ran a business. But I’m willing to learn so that I can practice medicine the way I want to.

“The ability to set my own schedule and deal with patients in the way I think is best is very important to me,” he said.
 

Private practitioners don’t have to face ‘moral distress’

One thing private practitioners typically don’t have to contend with is “moral distress,” which occurs when you have to follow institutional concerns on how much time you can spend with a patient or on the need to keep referrals in-house, according to Marie T. Brown, MD.

Dr. Brown is an internist who ran a small private practice in Oak Park, Ill., and is now the physician lead for the American Medical Association’s STEPS Forward program, which provides strategies on how to improve a medical practice.

“In my private practice, I could control the time I spent with each patient,” she said. “I also had control over my schedule. If I didn’t have the time, I just took a lower income, but that was okay.”

Dr. Brown said it is a myth that employment offers a better work-life balance. “Young physicians who take employment for this reason may find that they’re not allowed to drop off and pick up their children from school at a certain time. But you can do that in a private practice.”

She said it’s not that hard to run a practice. “Young physicians don’t think they could run a practice because they don’t have any business skills,” she said. “Yes, you do need some management skills, and you have to devote time to management. But you don’t need to have special expertise. You can outsource much of the work.”
 

A growing trend?

David J. Zetter, a consultant in Mechanicsburg, Pa., who helps doctors set up private practices, sees more interest in this in the past 5 years. “The overwhelming trend used to be private practices being bought up by hospitals and other entities,” he said. “Now we’re seeing the pendulum swing in the opposite direction.

“Generally, these doctors are fed up with being employed at a large organization,” he added. “Recently I got a call from a doctor who had never thought about running his own business, but he’s had it with being an employed physician.”

Switching to private practice is scary for a lot of them, but the alternative is worse. “A podiatrist I’m working with tells me she is scared to death about setting up a private practice, but she’s doing it because she doesn’t want to be employed anymore,” Mr. Zetter said.

A version of this article first appeared on Medscape.com.

Employed physicians are often torn. Many relish the steady salary and ability to focus on being a physician rather than handle administrative duties, but they bemoan their employers’ rules and their lack of input into key decisions. And thus, many doctors are leaving employment to start a private practice. For this article, seven physicians talked about why they chose private practice.

Leaving employment is ‘an invigorating time’

On Sept. 9, Aaron Przybysz, MD, gave notice to his employer, a large academic medical center in Southern California, that he would be leaving to start a private practice.

“It’s an invigorating time,” said Dr. Przybysz, 41, an anesthesiologist and pain management physician who plans to open his new pain management practice on Dec. 1 in Orange County. He has picked out the space he will rent but has not yet hired his staff.

“I’ve been serious about doing this for at least a year,” Dr. Przybysz said. “What held me back is the concern that my business could fail. But even if that happens, what’s the worst that could occur? I’d have to find a new job as an employed physician.

“I feel comfortable with the business side of medicine,” he said. His father was an executive in the automotive industry and his father-in-law is an entrepreneur in construction and housing.

“One of the biggest reasons for moving to private practice is making sure I don’t miss my kids’ activities,” he said, referring to his children, ages 9 and 7. Recently, he said, “I had to spend the whole weekend on call in the hospital. I came home and had to sleep most of the next day.

“I love the people that I have been working with and I’ve learned and matured as a physician during that time,” he said. “But it was time to move on.”
 

The desire to be in charge

In Medscape’s recent Employed Physicians Report, doctors said they enjoy the steady salary and ability to focus on patients, which comes with being employed.

Other physicians feel differently. John Machata, MD, a solo family physician in the village of Wickford, R.I., 20 miles south of Providence, chose private practice because “I have total control,” he said. “I make decisions that I couldn’t have made as an employed physician, such as closing my practice to new patients.”

He can also decide on his work hours. “I see patients for 35 hours, 4 days a week and then I have a 3-day weekend.” In a large organization, “the focus is on revenue,” said Dr. Machata. “They’re always measuring your productivity. If you are slower, you won’t make enough money for them.”

When he worked for a large group practice about a decade ago, “I felt burnt out every day,” he said. “I had to see patients every 10 minutes, with no breaks for anything in between. Within a month I was devising my exit strategy.”

Dr. Machata maintains long appointments – 25 minutes for a typical follow-up visit and 55 minutes for an annual check-in – but he still earns above the state average for primary care doctors. “I have no nurse or front-office staff, which means I can save $125,000 to $150,000 a year,” he said.  

In 2018, for the first time, employed physicians outnumbered self-employed physicians, according to a survey by the American Medical Association (AMA). By the end of 2021, more than half (52.1%) of U.S. physicians were employed by hospitals or health systems.

Yet the negatives of employment have begun to turn some physicians back toward private practice. Many physicians who were employed by a hospital or a large practice have become disillusioned and want to return to private practice.
 

His practice is the ‘best of both worlds’

Adam Bruggeman, MD, a 42-year-old spine surgeon who is CEO of Texas Spine Care Center, a solo practice in San Antonio, said he has “the best of both worlds.”

“As a solo physician, I have total control over how I practice,” he said. “But I also have access to value-based contracts and the data and staff needed to implement them.

“You need a lot of administrative overhead to take on these contracts, which a private practice normally doesn’t have,” he said. But Dr. Bruggeman gets this work done through a clinically integrated network (CIN) of private practices, Spinalytics of Texas, where he is chief medical director.

The CIN represents 150 musculoskeletal care providers and provides access to bundled networks, such as a total joint bundle with Blue Cross Blue Shield of Texas, as well as fee-for-service contracts.

He is also building a new ambulatory surgery center (ASC) that is scheduled to open in January. There, he plans to perform total joint and spine surgeries at a lower cost than at the hospital, which will be useful for value-based contracts through the CIN.

Dr. Bruggeman said it would be hard to run his private practice without the CIN and the ASC. “Private practice has changed,” he said. “The days of hanging up a shingle and immediately being successful are gone. You’ve got to be smart about business to run a successful practice.”
 

He started his practice while the pandemic raged

Joe Greene, MD, 42, an orthopedic surgeon in Louisville, Ky., had to open his hip and knee surgery practice when the COVID-19 pandemic was raging a year and a half ago, but that did not stop him.

“Federal financing of small bank loans completely stopped, but that only amounted to a small delay because our bank took care of it,” said Dr. Greene, who codirects his new practice with another orthopedic surgeon.

Even during the pandemic, “we could be very nimble,” he said. “For instance, when we want to institute new technology or a new patient-centric educational platform, we can do it immediately rather than going through an approval process at a health system.”

The partners, both ex-employees of a health system, also have an ASC, which allows them better control over their surgery schedules. “At a hospital, you can be bumped from the schedule by other surgeries, and you can’t be as productive as an ASC in the number of surgeries per day,” he said.

Dr. Greene attributes the practice’s success to long and careful planning. “We had to learn about business,” he said. “We did 3 to 4 years of research to find the right business model and implement it.”

As they were considering the new practice, a survey of patients showed that more than 75% chose them by word-of-mouth – because they specialize in complex and revision surgeries – rather than through referrals within their health system. This meant they could survive without their employer.

Planning for the new practice took up all his free time, but now he can relax and spend time with his three daughters, ages 12, 10, and 8. Dr. Greene currently coaches two of their teams. “We’re loving it,” he said.
 

Colleagues want to know how he did it

Clinton Sheets, MD, an ophthalmologist in Hudson and Clearwater, Fla., went solo in 2019 after being in a group practice for 11 years. Since he opened up, “I get phone calls from colleagues all the time, asking me about how I did it,” he said. “At least two of them followed in my footsteps.

“I tell them it’s very doable,” he said. “If you have the motivation, you can do it. Depending on your competence, you can outsource as much or as little as you want. Some management companies can do almost all of the nonclinical work for you.

“Smaller practices can streamline processes because they have a flatter organizational structure and have fewer issues with administrative bloat than larger organizations,” he said.

“Technology hinders and helps a private practice,” he said. On the one hand, he had to buy a lot of expensive equipment that otherwise would be shared by a group of doctors. On the other hand, using the cloud makes it possible to easily store practice management software and the electronic health record. 
 

He’s opening a private practice while staying employed

In December, Dev Basu, MD, a hospitalist in Baltimore, plans to start his own private practice, seeing patients in skilled nursing homes, while still working as a nocturnist in a large health care system.  

He said his employer has been supportive of his plans. “My work will not directly compete with them and it will benefit them by serving patients discharged from their hospitals,” said Dr. Basu, 38. He added, however, that he will be allowed to work only at certain facilities, and these will be subject to annual review.

“The financial risk of the new practice is low, because I haven’t had to invest much,” he said. “I won’t have a staff or an office.” He plans to maintain his full schedule as an employee, working 12 nights a month, because it will give him a great deal of time to do the new work.

“I also have no particular interest in running a business,” he said. “I come from a family of doctors, professors, and teachers who never ran a business. But I’m willing to learn so that I can practice medicine the way I want to.

“The ability to set my own schedule and deal with patients in the way I think is best is very important to me,” he said.
 

Private practitioners don’t have to face ‘moral distress’

One thing private practitioners typically don’t have to contend with is “moral distress,” which occurs when you have to follow institutional concerns on how much time you can spend with a patient or on the need to keep referrals in-house, according to Marie T. Brown, MD.

Dr. Brown is an internist who ran a small private practice in Oak Park, Ill., and is now the physician lead for the American Medical Association’s STEPS Forward program, which provides strategies on how to improve a medical practice.

“In my private practice, I could control the time I spent with each patient,” she said. “I also had control over my schedule. If I didn’t have the time, I just took a lower income, but that was okay.”

Dr. Brown said it is a myth that employment offers a better work-life balance. “Young physicians who take employment for this reason may find that they’re not allowed to drop off and pick up their children from school at a certain time. But you can do that in a private practice.”

She said it’s not that hard to run a practice. “Young physicians don’t think they could run a practice because they don’t have any business skills,” she said. “Yes, you do need some management skills, and you have to devote time to management. But you don’t need to have special expertise. You can outsource much of the work.”
 

A growing trend?

David J. Zetter, a consultant in Mechanicsburg, Pa., who helps doctors set up private practices, sees more interest in this in the past 5 years. “The overwhelming trend used to be private practices being bought up by hospitals and other entities,” he said. “Now we’re seeing the pendulum swing in the opposite direction.

“Generally, these doctors are fed up with being employed at a large organization,” he added. “Recently I got a call from a doctor who had never thought about running his own business, but he’s had it with being an employed physician.”

Switching to private practice is scary for a lot of them, but the alternative is worse. “A podiatrist I’m working with tells me she is scared to death about setting up a private practice, but she’s doing it because she doesn’t want to be employed anymore,” Mr. Zetter said.

A version of this article first appeared on Medscape.com.

STOCKHOLM – It remains inconclusive whether SARS-CoV-2 infection predisposes children and adolescents to a higher risk of type 1 diabetes. Data from two new studies and a recently published research letter add to the growing body of knowledge on the subject, but still can’t draw any definitive conclusions.

The latest results from a Norwegian and a Scottish study both examine incidence of type 1 diabetes in young people with a history of SARS-CoV-2 infection and were reported at the annual meeting of the European Association for the Study of Diabetes.

A 60% increased risk for type 1 diabetes at least 31 days after SARS-CoV-2 infection (adjusted hazard ratio, 1.63) was found in the Norwegian study, while in contrast, the Scottish study only found an increased risk in the first few months of the pandemic, in 2020, but importantly, no association over a much longer time period (March 2020–November 2021).

In a comment on Twitter on the two studies presented at EASD, session moderator Kamlesh Khunti, MD, professor of primary care diabetes and vascular medicine at the University of Leicester, (England), said: “In summary, two studies showing no or weak association of type 1 diabetes with COVID.”

But new data in the research letter published in JAMA Network Open, based on U.S. figures, also found an almost doubling of type 1 diabetes in children in the first few months after COVID-19 infection relative to infection with other respiratory viruses.

Lead author of the Scottish study, Helen Colhoun, PhD, honorary public health consultant at Public Health Scotland, commented: “Data in children are variable year on year, which emphasizes the need to be cautious over taking a tiny snapshot.”

Nevertheless, this is “a hugely important question and we must not drop the ball. [We must] keep looking at it and maintain scientific equipoise. ... [This] reinforces the need to carry on this analysis into the future to obtain an unequivocal picture,” she emphasized.
 

Norwegian study: If there is an association, the risk is small

German Tapia, PhD, from the Norwegian Institute of Public Health, Oslo, presented the results of a study of SARS-CoV-2 infection and subsequent risk of type 1 diabetes in 1.2 million children in Norway.

Of these, 424,354 children had been infected with SARS-CoV-2, and there were 990 incident cases of type 1 diabetes.

“What we do know about COVID-19 in children is that the symptoms are mild and only a small proportion are hospitalized with more serious symptoms. But we do not know the long-term effects of COVID-19 infection because this requires a longer follow-up period,” remarked Dr. Tapia, adding that other viral infections are thought to be linked to the development of type 1 diabetes, in particular, respiratory infections.

The data were sourced from the Norwegian Emergency Preparedness Register for COVID-19, which gathers daily data updates including infections (positive and negative results for free-of-charge testing), diagnoses (primary and secondary care), vaccinations (also free of charge), prescribed medications, and basic demographics.

“We link these data using the personal identification number that every Norwegian citizen has,” explained Dr. Tapia.

He presented results from two cohorts: firstly, results in children only, including those tested for SARS-CoV-2 infection, and secondly, a full national Norwegian population cohort.

Regarding the first cohort, those under 18 years who tested positive for SARS-CoV-2 infection, from March 2020 to March 2022, had a significantly increased risk of type 1 diabetes at least 31 days after infection, with an adjusted hazard ratio of 1.63 (95% confidence interval, 1.08-2.47; P = .02). Adjustments were made for age, sex, non-Nordic country of origin, geographic area, and socioeconomic factors.

For children who developed type 1 diabetes within 30 days of a SARS-CoV-2 infection, the HR was 1.26 (95% CI, 0.72-2.19; P = .42), which did not reach statistical significance.

“The fact that fewer people developed type 1 diabetes within 30 days is not surprising because we know that type 1 diabetes develops over a long period of time,” Dr. Tapia said.

“For this reason, we would not expect to find new cases of those people who develop type 1 diabetes within 30 days of COVID-19 infection,” he explained. In these cases, “it is most likely that they already had [type 1 diabetes], and the infection probably triggered clinical symptoms, so their type 1 diabetes was discovered.”

Turning to the full population cohort and diagnoses of type 1 diabetes over 30 days after SARS-CoV-2 infection, the Norwegian researchers found an association, with an HR of 1.57 (95% CI, 1.06-2.33; P = .03), while diagnosis of type 1 diabetes at 30 days or less generated a hazard ratio of 1.22 (95% CI, 0.72-2.19; P = .42).

“So very similar results were found, and after adjustment for confounders, results were still similar,” reported Dr. Tapia.

He also conducted a similar analysis with vaccination as an exposure but found no association between vaccination against SARS-CoV-2 and diagnosis of type 1 diabetes.

“From these results, we conclude that this suggests an increase in diagnosis of type 1 diabetes after SARS-CoV-2 infection, but it must be noted that the absolute risk of developing type 1 diabetes after infection in children is low, with most children not developing the disease,” he emphasized. “There are nearly half a million children who have been infected with SARS-CoV-2 in Norway, but only a very small proportion develop type 1 diabetes.”
 

Scottish study: No association found over longer term

Dr. Colhoun and colleagues looked at the relationship between incident type 1 diabetes and SARS-CoV-2 infection in children in Scotland using e-health record linkage.

The study involved 1.8 million people under 35 years of age and found very weak, if any, evidence of an association between incident type 1 diabetes and SARS-CoV-2.

Examining data between March 2020 and November 2021, Dr. Colhoun and colleagues identified 365,080 individuals up to age 35 with at least one detected SARS-CoV-2 infection during follow-up and 1,074 who developed type 1 diabetes.

“In children under 16 years, suspected cases of type 1 diabetes are admitted to hospital, and 97% of diagnosis dates are recorded in the Scottish Care Information – Diabetes Collaboration register [SCI-Diabetes] prior to or within 2 days of the first hospital admission for type 1 diabetes,” Dr. Colhoun said, stressing the timeliness of the data.

“We found the incidence of type 1 diabetes diagnosis increased 1.2-fold in those aged 0-14 years, but we did not find any association at an individual level of COVID-19 infection over 30 days prior to a type 1 diabetes diagnosis, in this particular dataset,” she reported. In young people aged 15-34, there was a linear increase in incident type 1 diabetes from 2015 to 2021 with no pandemic increase.

Referring to the 1.2-fold increase soon after the pandemic started, she explained that, in 0- to 14-year-olds, the increase followed a drop in the preceding months prepandemic in 2019. They also found that the seasonal pattern of type 1 diabetes diagnoses remained roughly the same across the pandemic months, with typical peaks in February and September.

In the cohort of under 35s, researchers also found a rate ratio of 2.62 (95% CI, 1.81-3.78) within a 30-day window of SARS-CoV-2 infection, but beyond 30 days, no evidence was seen of an association, with a RR of 0.86 (95% CI, 0.62-1.21; P = .40), she reported.

She explained her reasons for not considering diagnoses within 30 days of COVID-19 as causative. Echoing Dr. Tapia, Dr. Colhoun said the median time from symptom onset to diagnosis of type 1 diabetes is 25 days. “This suggests that 50% have had symptoms for over 25 days at diagnosis.”

She also stressed that when they compared the timing of SARS-CoV-2 testing with diagnosis, they found a much higher rate of COVID-19 testing around diagnosis. “This was not least because everyone admitted to hospital had to have a COVID-19 test.”
 

Latest U.S. data point to a link

Meanwhile, for the new data reported in JAMA Network Open, medical student Ellen K. Kendall of Case Western Reserve University, Cleveland, matched 571,256 pediatric patients: 285,628 with COVID-19 and 285,628 with non–COVID-19 respiratory infections.

By 6 months after COVID-19, 123 patients (0.043%) had received a new diagnosis of type 1 diabetes, but only 72 (0.025%) were diagnosed with type 1 diabetes within 6 months after non–COVID-19 respiratory infection.

At 1, 3, and 6 months after infection, risk of diagnosis of type 1 diabetes was greater among those infected with SARS-CoV-2, compared with those with non–COVID-19 respiratory infection (1 month: HR, 1.96; 3 months: HR, 2.10; and 6 months: HR, 1.83), and in subgroups of patients aged 0-9 years, a group unlikely to develop type 2 diabetes.

“In this study, new type 1 diabetes diagnoses were more likely to occur among pediatric patients with prior COVID-19 than among those with other respiratory infections (or with other encounters with health systems),” noted Ms. Kendall and coauthors. “Respiratory infections have previously been associated with onset of type 1 diabetes, but this risk was even higher among those with COVID-19 in our study, raising concern for long-term, post–COVID-19 autoimmune complications among youths.”

“The increased risk of new-onset type 1 diabetes after COVID-19 adds an important consideration for risk–benefit discussions for prevention and treatment of SARS-CoV-2 infection in pediatric populations,” they concluded.

A study from the Centers for Disease Control and Prevention published in January 2022, also concluded there was a link between COVID-19 and diabetes in children, but not with other acute respiratory infections. Children were 2.5 times more likely to be diagnosed with diabetes following a SARS-CoV-2 infection, it found.

However, the study has been criticized because it pooled all types of diabetes together and did not account for other health conditions, medications that can increase blood glucose levels, race, obesity, and other social determinants of health that might influence a child’s risk of acquiring COVID-19 or diabetes.

“I’ve no doubt that the CDC data were incorrect because the incidence rate for ... diabetes, even in those never exposed to COVID-19 infection, was 10 times the rate ever reported in the U.S.,” Dr. Colhoun said. “There’s no way these data are correct. I believe there was a confusion between incidence and prevalence of diabetes.”

“This paper caused a great deal of panic, especially among those who have a child with type 1diabetes, so we need to be very careful not to cause undue alarm until we have more definitive evidence in this arena,” she stressed.

However, she also acknowledged that the new Norwegian study was well conducted, and she has no methodological concerns about it, so “I think we just have to wait and see.”

Given the inconclusiveness on the issue, there is an ongoing CoviDiab registry collecting data on this very subject.

Dr. Tapia presented on behalf of lead author Dr. Gulseth, who has reported no relevant financial relationships. Dr. Colhoun also reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

STOCKHOLM – It remains inconclusive whether SARS-CoV-2 infection predisposes children and adolescents to a higher risk of type 1 diabetes. Data from two new studies and a recently published research letter add to the growing body of knowledge on the subject, but still can’t draw any definitive conclusions.

The latest results from a Norwegian and a Scottish study both examine incidence of type 1 diabetes in young people with a history of SARS-CoV-2 infection and were reported at the annual meeting of the European Association for the Study of Diabetes.

A 60% increased risk for type 1 diabetes at least 31 days after SARS-CoV-2 infection (adjusted hazard ratio, 1.63) was found in the Norwegian study, while in contrast, the Scottish study only found an increased risk in the first few months of the pandemic, in 2020, but importantly, no association over a much longer time period (March 2020–November 2021).

In a comment on Twitter on the two studies presented at EASD, session moderator Kamlesh Khunti, MD, professor of primary care diabetes and vascular medicine at the University of Leicester, (England), said: “In summary, two studies showing no or weak association of type 1 diabetes with COVID.”

But new data in the research letter published in JAMA Network Open, based on U.S. figures, also found an almost doubling of type 1 diabetes in children in the first few months after COVID-19 infection relative to infection with other respiratory viruses.

Lead author of the Scottish study, Helen Colhoun, PhD, honorary public health consultant at Public Health Scotland, commented: “Data in children are variable year on year, which emphasizes the need to be cautious over taking a tiny snapshot.”

Nevertheless, this is “a hugely important question and we must not drop the ball. [We must] keep looking at it and maintain scientific equipoise. ... [This] reinforces the need to carry on this analysis into the future to obtain an unequivocal picture,” she emphasized.
 

Norwegian study: If there is an association, the risk is small

German Tapia, PhD, from the Norwegian Institute of Public Health, Oslo, presented the results of a study of SARS-CoV-2 infection and subsequent risk of type 1 diabetes in 1.2 million children in Norway.

Of these, 424,354 children had been infected with SARS-CoV-2, and there were 990 incident cases of type 1 diabetes.

“What we do know about COVID-19 in children is that the symptoms are mild and only a small proportion are hospitalized with more serious symptoms. But we do not know the long-term effects of COVID-19 infection because this requires a longer follow-up period,” remarked Dr. Tapia, adding that other viral infections are thought to be linked to the development of type 1 diabetes, in particular, respiratory infections.

The data were sourced from the Norwegian Emergency Preparedness Register for COVID-19, which gathers daily data updates including infections (positive and negative results for free-of-charge testing), diagnoses (primary and secondary care), vaccinations (also free of charge), prescribed medications, and basic demographics.

“We link these data using the personal identification number that every Norwegian citizen has,” explained Dr. Tapia.

He presented results from two cohorts: firstly, results in children only, including those tested for SARS-CoV-2 infection, and secondly, a full national Norwegian population cohort.

Regarding the first cohort, those under 18 years who tested positive for SARS-CoV-2 infection, from March 2020 to March 2022, had a significantly increased risk of type 1 diabetes at least 31 days after infection, with an adjusted hazard ratio of 1.63 (95% confidence interval, 1.08-2.47; P = .02). Adjustments were made for age, sex, non-Nordic country of origin, geographic area, and socioeconomic factors.

For children who developed type 1 diabetes within 30 days of a SARS-CoV-2 infection, the HR was 1.26 (95% CI, 0.72-2.19; P = .42), which did not reach statistical significance.

“The fact that fewer people developed type 1 diabetes within 30 days is not surprising because we know that type 1 diabetes develops over a long period of time,” Dr. Tapia said.

“For this reason, we would not expect to find new cases of those people who develop type 1 diabetes within 30 days of COVID-19 infection,” he explained. In these cases, “it is most likely that they already had [type 1 diabetes], and the infection probably triggered clinical symptoms, so their type 1 diabetes was discovered.”

Turning to the full population cohort and diagnoses of type 1 diabetes over 30 days after SARS-CoV-2 infection, the Norwegian researchers found an association, with an HR of 1.57 (95% CI, 1.06-2.33; P = .03), while diagnosis of type 1 diabetes at 30 days or less generated a hazard ratio of 1.22 (95% CI, 0.72-2.19; P = .42).

“So very similar results were found, and after adjustment for confounders, results were still similar,” reported Dr. Tapia.

He also conducted a similar analysis with vaccination as an exposure but found no association between vaccination against SARS-CoV-2 and diagnosis of type 1 diabetes.

“From these results, we conclude that this suggests an increase in diagnosis of type 1 diabetes after SARS-CoV-2 infection, but it must be noted that the absolute risk of developing type 1 diabetes after infection in children is low, with most children not developing the disease,” he emphasized. “There are nearly half a million children who have been infected with SARS-CoV-2 in Norway, but only a very small proportion develop type 1 diabetes.”
 

Scottish study: No association found over longer term

Dr. Colhoun and colleagues looked at the relationship between incident type 1 diabetes and SARS-CoV-2 infection in children in Scotland using e-health record linkage.

The study involved 1.8 million people under 35 years of age and found very weak, if any, evidence of an association between incident type 1 diabetes and SARS-CoV-2.

Examining data between March 2020 and November 2021, Dr. Colhoun and colleagues identified 365,080 individuals up to age 35 with at least one detected SARS-CoV-2 infection during follow-up and 1,074 who developed type 1 diabetes.

“In children under 16 years, suspected cases of type 1 diabetes are admitted to hospital, and 97% of diagnosis dates are recorded in the Scottish Care Information – Diabetes Collaboration register [SCI-Diabetes] prior to or within 2 days of the first hospital admission for type 1 diabetes,” Dr. Colhoun said, stressing the timeliness of the data.

“We found the incidence of type 1 diabetes diagnosis increased 1.2-fold in those aged 0-14 years, but we did not find any association at an individual level of COVID-19 infection over 30 days prior to a type 1 diabetes diagnosis, in this particular dataset,” she reported. In young people aged 15-34, there was a linear increase in incident type 1 diabetes from 2015 to 2021 with no pandemic increase.

Referring to the 1.2-fold increase soon after the pandemic started, she explained that, in 0- to 14-year-olds, the increase followed a drop in the preceding months prepandemic in 2019. They also found that the seasonal pattern of type 1 diabetes diagnoses remained roughly the same across the pandemic months, with typical peaks in February and September.

In the cohort of under 35s, researchers also found a rate ratio of 2.62 (95% CI, 1.81-3.78) within a 30-day window of SARS-CoV-2 infection, but beyond 30 days, no evidence was seen of an association, with a RR of 0.86 (95% CI, 0.62-1.21; P = .40), she reported.

She explained her reasons for not considering diagnoses within 30 days of COVID-19 as causative. Echoing Dr. Tapia, Dr. Colhoun said the median time from symptom onset to diagnosis of type 1 diabetes is 25 days. “This suggests that 50% have had symptoms for over 25 days at diagnosis.”

She also stressed that when they compared the timing of SARS-CoV-2 testing with diagnosis, they found a much higher rate of COVID-19 testing around diagnosis. “This was not least because everyone admitted to hospital had to have a COVID-19 test.”
 

Latest U.S. data point to a link

Meanwhile, for the new data reported in JAMA Network Open, medical student Ellen K. Kendall of Case Western Reserve University, Cleveland, matched 571,256 pediatric patients: 285,628 with COVID-19 and 285,628 with non–COVID-19 respiratory infections.

By 6 months after COVID-19, 123 patients (0.043%) had received a new diagnosis of type 1 diabetes, but only 72 (0.025%) were diagnosed with type 1 diabetes within 6 months after non–COVID-19 respiratory infection.

At 1, 3, and 6 months after infection, risk of diagnosis of type 1 diabetes was greater among those infected with SARS-CoV-2, compared with those with non–COVID-19 respiratory infection (1 month: HR, 1.96; 3 months: HR, 2.10; and 6 months: HR, 1.83), and in subgroups of patients aged 0-9 years, a group unlikely to develop type 2 diabetes.

“In this study, new type 1 diabetes diagnoses were more likely to occur among pediatric patients with prior COVID-19 than among those with other respiratory infections (or with other encounters with health systems),” noted Ms. Kendall and coauthors. “Respiratory infections have previously been associated with onset of type 1 diabetes, but this risk was even higher among those with COVID-19 in our study, raising concern for long-term, post–COVID-19 autoimmune complications among youths.”

“The increased risk of new-onset type 1 diabetes after COVID-19 adds an important consideration for risk–benefit discussions for prevention and treatment of SARS-CoV-2 infection in pediatric populations,” they concluded.

A study from the Centers for Disease Control and Prevention published in January 2022, also concluded there was a link between COVID-19 and diabetes in children, but not with other acute respiratory infections. Children were 2.5 times more likely to be diagnosed with diabetes following a SARS-CoV-2 infection, it found.

However, the study has been criticized because it pooled all types of diabetes together and did not account for other health conditions, medications that can increase blood glucose levels, race, obesity, and other social determinants of health that might influence a child’s risk of acquiring COVID-19 or diabetes.

“I’ve no doubt that the CDC data were incorrect because the incidence rate for ... diabetes, even in those never exposed to COVID-19 infection, was 10 times the rate ever reported in the U.S.,” Dr. Colhoun said. “There’s no way these data are correct. I believe there was a confusion between incidence and prevalence of diabetes.”

“This paper caused a great deal of panic, especially among those who have a child with type 1diabetes, so we need to be very careful not to cause undue alarm until we have more definitive evidence in this arena,” she stressed.

However, she also acknowledged that the new Norwegian study was well conducted, and she has no methodological concerns about it, so “I think we just have to wait and see.”

Given the inconclusiveness on the issue, there is an ongoing CoviDiab registry collecting data on this very subject.

Dr. Tapia presented on behalf of lead author Dr. Gulseth, who has reported no relevant financial relationships. Dr. Colhoun also reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

STOCKHOLM – It remains inconclusive whether SARS-CoV-2 infection predisposes children and adolescents to a higher risk of type 1 diabetes. Data from two new studies and a recently published research letter add to the growing body of knowledge on the subject, but still can’t draw any definitive conclusions.

The latest results from a Norwegian and a Scottish study both examine incidence of type 1 diabetes in young people with a history of SARS-CoV-2 infection and were reported at the annual meeting of the European Association for the Study of Diabetes.

A 60% increased risk for type 1 diabetes at least 31 days after SARS-CoV-2 infection (adjusted hazard ratio, 1.63) was found in the Norwegian study, while in contrast, the Scottish study only found an increased risk in the first few months of the pandemic, in 2020, but importantly, no association over a much longer time period (March 2020–November 2021).

In a comment on Twitter on the two studies presented at EASD, session moderator Kamlesh Khunti, MD, professor of primary care diabetes and vascular medicine at the University of Leicester, (England), said: “In summary, two studies showing no or weak association of type 1 diabetes with COVID.”

But new data in the research letter published in JAMA Network Open, based on U.S. figures, also found an almost doubling of type 1 diabetes in children in the first few months after COVID-19 infection relative to infection with other respiratory viruses.

Lead author of the Scottish study, Helen Colhoun, PhD, honorary public health consultant at Public Health Scotland, commented: “Data in children are variable year on year, which emphasizes the need to be cautious over taking a tiny snapshot.”

Nevertheless, this is “a hugely important question and we must not drop the ball. [We must] keep looking at it and maintain scientific equipoise. ... [This] reinforces the need to carry on this analysis into the future to obtain an unequivocal picture,” she emphasized.
 

Norwegian study: If there is an association, the risk is small

German Tapia, PhD, from the Norwegian Institute of Public Health, Oslo, presented the results of a study of SARS-CoV-2 infection and subsequent risk of type 1 diabetes in 1.2 million children in Norway.

Of these, 424,354 children had been infected with SARS-CoV-2, and there were 990 incident cases of type 1 diabetes.

“What we do know about COVID-19 in children is that the symptoms are mild and only a small proportion are hospitalized with more serious symptoms. But we do not know the long-term effects of COVID-19 infection because this requires a longer follow-up period,” remarked Dr. Tapia, adding that other viral infections are thought to be linked to the development of type 1 diabetes, in particular, respiratory infections.

The data were sourced from the Norwegian Emergency Preparedness Register for COVID-19, which gathers daily data updates including infections (positive and negative results for free-of-charge testing), diagnoses (primary and secondary care), vaccinations (also free of charge), prescribed medications, and basic demographics.

“We link these data using the personal identification number that every Norwegian citizen has,” explained Dr. Tapia.

He presented results from two cohorts: firstly, results in children only, including those tested for SARS-CoV-2 infection, and secondly, a full national Norwegian population cohort.

Regarding the first cohort, those under 18 years who tested positive for SARS-CoV-2 infection, from March 2020 to March 2022, had a significantly increased risk of type 1 diabetes at least 31 days after infection, with an adjusted hazard ratio of 1.63 (95% confidence interval, 1.08-2.47; P = .02). Adjustments were made for age, sex, non-Nordic country of origin, geographic area, and socioeconomic factors.

For children who developed type 1 diabetes within 30 days of a SARS-CoV-2 infection, the HR was 1.26 (95% CI, 0.72-2.19; P = .42), which did not reach statistical significance.

“The fact that fewer people developed type 1 diabetes within 30 days is not surprising because we know that type 1 diabetes develops over a long period of time,” Dr. Tapia said.

“For this reason, we would not expect to find new cases of those people who develop type 1 diabetes within 30 days of COVID-19 infection,” he explained. In these cases, “it is most likely that they already had [type 1 diabetes], and the infection probably triggered clinical symptoms, so their type 1 diabetes was discovered.”

Turning to the full population cohort and diagnoses of type 1 diabetes over 30 days after SARS-CoV-2 infection, the Norwegian researchers found an association, with an HR of 1.57 (95% CI, 1.06-2.33; P = .03), while diagnosis of type 1 diabetes at 30 days or less generated a hazard ratio of 1.22 (95% CI, 0.72-2.19; P = .42).

“So very similar results were found, and after adjustment for confounders, results were still similar,” reported Dr. Tapia.

He also conducted a similar analysis with vaccination as an exposure but found no association between vaccination against SARS-CoV-2 and diagnosis of type 1 diabetes.

“From these results, we conclude that this suggests an increase in diagnosis of type 1 diabetes after SARS-CoV-2 infection, but it must be noted that the absolute risk of developing type 1 diabetes after infection in children is low, with most children not developing the disease,” he emphasized. “There are nearly half a million children who have been infected with SARS-CoV-2 in Norway, but only a very small proportion develop type 1 diabetes.”
 

Scottish study: No association found over longer term

Dr. Colhoun and colleagues looked at the relationship between incident type 1 diabetes and SARS-CoV-2 infection in children in Scotland using e-health record linkage.

The study involved 1.8 million people under 35 years of age and found very weak, if any, evidence of an association between incident type 1 diabetes and SARS-CoV-2.

Examining data between March 2020 and November 2021, Dr. Colhoun and colleagues identified 365,080 individuals up to age 35 with at least one detected SARS-CoV-2 infection during follow-up and 1,074 who developed type 1 diabetes.

“In children under 16 years, suspected cases of type 1 diabetes are admitted to hospital, and 97% of diagnosis dates are recorded in the Scottish Care Information – Diabetes Collaboration register [SCI-Diabetes] prior to or within 2 days of the first hospital admission for type 1 diabetes,” Dr. Colhoun said, stressing the timeliness of the data.

“We found the incidence of type 1 diabetes diagnosis increased 1.2-fold in those aged 0-14 years, but we did not find any association at an individual level of COVID-19 infection over 30 days prior to a type 1 diabetes diagnosis, in this particular dataset,” she reported. In young people aged 15-34, there was a linear increase in incident type 1 diabetes from 2015 to 2021 with no pandemic increase.

Referring to the 1.2-fold increase soon after the pandemic started, she explained that, in 0- to 14-year-olds, the increase followed a drop in the preceding months prepandemic in 2019. They also found that the seasonal pattern of type 1 diabetes diagnoses remained roughly the same across the pandemic months, with typical peaks in February and September.

In the cohort of under 35s, researchers also found a rate ratio of 2.62 (95% CI, 1.81-3.78) within a 30-day window of SARS-CoV-2 infection, but beyond 30 days, no evidence was seen of an association, with a RR of 0.86 (95% CI, 0.62-1.21; P = .40), she reported.

She explained her reasons for not considering diagnoses within 30 days of COVID-19 as causative. Echoing Dr. Tapia, Dr. Colhoun said the median time from symptom onset to diagnosis of type 1 diabetes is 25 days. “This suggests that 50% have had symptoms for over 25 days at diagnosis.”

She also stressed that when they compared the timing of SARS-CoV-2 testing with diagnosis, they found a much higher rate of COVID-19 testing around diagnosis. “This was not least because everyone admitted to hospital had to have a COVID-19 test.”
 

Latest U.S. data point to a link

Meanwhile, for the new data reported in JAMA Network Open, medical student Ellen K. Kendall of Case Western Reserve University, Cleveland, matched 571,256 pediatric patients: 285,628 with COVID-19 and 285,628 with non–COVID-19 respiratory infections.

By 6 months after COVID-19, 123 patients (0.043%) had received a new diagnosis of type 1 diabetes, but only 72 (0.025%) were diagnosed with type 1 diabetes within 6 months after non–COVID-19 respiratory infection.

At 1, 3, and 6 months after infection, risk of diagnosis of type 1 diabetes was greater among those infected with SARS-CoV-2, compared with those with non–COVID-19 respiratory infection (1 month: HR, 1.96; 3 months: HR, 2.10; and 6 months: HR, 1.83), and in subgroups of patients aged 0-9 years, a group unlikely to develop type 2 diabetes.

“In this study, new type 1 diabetes diagnoses were more likely to occur among pediatric patients with prior COVID-19 than among those with other respiratory infections (or with other encounters with health systems),” noted Ms. Kendall and coauthors. “Respiratory infections have previously been associated with onset of type 1 diabetes, but this risk was even higher among those with COVID-19 in our study, raising concern for long-term, post–COVID-19 autoimmune complications among youths.”

“The increased risk of new-onset type 1 diabetes after COVID-19 adds an important consideration for risk–benefit discussions for prevention and treatment of SARS-CoV-2 infection in pediatric populations,” they concluded.

A study from the Centers for Disease Control and Prevention published in January 2022, also concluded there was a link between COVID-19 and diabetes in children, but not with other acute respiratory infections. Children were 2.5 times more likely to be diagnosed with diabetes following a SARS-CoV-2 infection, it found.

However, the study has been criticized because it pooled all types of diabetes together and did not account for other health conditions, medications that can increase blood glucose levels, race, obesity, and other social determinants of health that might influence a child’s risk of acquiring COVID-19 or diabetes.

“I’ve no doubt that the CDC data were incorrect because the incidence rate for ... diabetes, even in those never exposed to COVID-19 infection, was 10 times the rate ever reported in the U.S.,” Dr. Colhoun said. “There’s no way these data are correct. I believe there was a confusion between incidence and prevalence of diabetes.”

“This paper caused a great deal of panic, especially among those who have a child with type 1diabetes, so we need to be very careful not to cause undue alarm until we have more definitive evidence in this arena,” she stressed.

However, she also acknowledged that the new Norwegian study was well conducted, and she has no methodological concerns about it, so “I think we just have to wait and see.”

Given the inconclusiveness on the issue, there is an ongoing CoviDiab registry collecting data on this very subject.

Dr. Tapia presented on behalf of lead author Dr. Gulseth, who has reported no relevant financial relationships. Dr. Colhoun also reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Aspirin may be of specific benefit for the primary prevention of cardiovascular disease in individuals with raised Lp(a) levels, a new study has suggested.

The study analyzed data from the ASPREE (ASPirin in Reducing Events in the Elderly) trial, which randomized 19,000 individuals aged 70 years or older without a history of cardiovascular disease to aspirin (100 mg/day) or placebo. While the main results, reported previously, showed no net benefit of aspirin in the overall population, the current analysis suggests there may be a benefit in individuals with raised Lp(a) levels.

jimdeli/Fotolia

Similar findings in the Women’s Health Study

Dr. Lacaze and colleagues point out that similar results have also been seen in another large aspirin primary prevention study – the Women’s Health Study (WHS).

The WHS compared aspirin 100 mg every other day with placebo in initially healthy younger women. Previously reported results showed that women carrying the rs3798220-C variant, associated with highly elevated Lp(a) levels, had a twofold higher risk of cardiovascular events than noncarrier women in the placebo group, but this risk was reduced in the aspirin group. And there was no increased risk of bleeding in women with elevated Lp(a).

“These results, in the absence of any other randomized controlled trial evidence or approved therapy for treating Lp(a)-associated risk, have been used by some physicians as justification for prescribing aspirin in patients with elevated Lp(a),” Dr. Lacaze and colleagues note.

“In the present study of the ASPREE trial population, our results were consistent with the WHS analysis, despite randomizing older individuals (both men and women),” they add.

They say this validation of the WHS result provides evidence that a very high-risk subgroup of individuals with highly elevated Lp(a) – those carrying the rs3798220-C allele – may benefit from low-dose aspirin for the primary prevention of cardiovascular events. Further, the benefits in this subgroup specifically may outweigh any bleeding risk.

But they point out that rs3798220-C carriers comprise only a small portion of all individuals with elevated Lp(a) in the general population, while the polygenic LPA-GRS explains about 60% of the variation in directly measured plasma Lp(a) levels and has the potential advantage of being able to identify a larger group of individuals at increased risk.

The researchers note, however, that it is not clear to what extent the LPA-GRS results add further evidence to suggest that individuals with elevated Lp(a), beyond rs3798220-C carriers, may be more likely to benefit from aspirin.

“If the benefit of aspirin extends beyond very high-risk rs3798220-C carriers alone, to the broader 20%-30% of individuals with elevated Lp(a), the potential utility of aspirin for the primary prevention of cardiovascular events would increase substantially,” they say.
 

‘Very high clinical relevance’

In an accompanying editorial, Ana Devesa, MD, Borja Ibanez, MD, PhD, and Valentin Fuster, MD, PhD, The National Center for Cardiovascular Research, Madrid, say that: “[Dr.] Lacaze et al. are to be congratulated for a study of very high clinical relevance that represents a first indication for primary prevention for patients at high cardiovascular risk.”

They explain that the pathogenic mechanism of Lp(a) is believed to be a combination of prothrombotic and proatherogenic effects, and the current findings support the hypothesis that the prothrombotic mechanism of Lp(a) is mediated by platelet aggregation. 

This would explain the occurrence of thrombotic events in the presence of atherosclerosis in that elevated Lp(a) levels may induce platelet adhesion and aggregation to the activated atherosclerotic plaque, thus enhancing the atherothrombotic process. Moreover, activated platelets release several mediators that result in cell adhesion and attraction of chemokines and proinflammatory cytokines, driving an inflammatory response and mediating atherosclerosis progression, they add.

The editorialists highlight the limitations of the study already acknowledged by the authors: The analysis used genotypes rather than elevated Lp(a) levels and included only those of European ancestry, meaning the results are difficult to extrapolate to other populations.

“The next steps in clinical practice should be defined, and there are still questions to be answered,” they conclude. “Will every patient benefit from antithrombotic therapies? Should all patients who have elevated Lp(a) levels be treated with aspirin?”

The ASPREE Biobank is supported by grants from the Commonwealth Scientific and Industrial Research Organisation, Monash University, Menzies Research Institute, Australian National University, University of Melbourne, National Institutes of Health, National Health and Medical Research Council of Australia, and the Victorian Cancer Agency. Dr. Lacaze is supported by a National Heart Foundation Future Leader Fellowship.

A version of this article first appeared on Medscape.com.

Aspirin may be of specific benefit for the primary prevention of cardiovascular disease in individuals with raised Lp(a) levels, a new study has suggested.

The study analyzed data from the ASPREE (ASPirin in Reducing Events in the Elderly) trial, which randomized 19,000 individuals aged 70 years or older without a history of cardiovascular disease to aspirin (100 mg/day) or placebo. While the main results, reported previously, showed no net benefit of aspirin in the overall population, the current analysis suggests there may be a benefit in individuals with raised Lp(a) levels.

jimdeli/Fotolia

Similar findings in the Women’s Health Study

Dr. Lacaze and colleagues point out that similar results have also been seen in another large aspirin primary prevention study – the Women’s Health Study (WHS).

The WHS compared aspirin 100 mg every other day with placebo in initially healthy younger women. Previously reported results showed that women carrying the rs3798220-C variant, associated with highly elevated Lp(a) levels, had a twofold higher risk of cardiovascular events than noncarrier women in the placebo group, but this risk was reduced in the aspirin group. And there was no increased risk of bleeding in women with elevated Lp(a).

“These results, in the absence of any other randomized controlled trial evidence or approved therapy for treating Lp(a)-associated risk, have been used by some physicians as justification for prescribing aspirin in patients with elevated Lp(a),” Dr. Lacaze and colleagues note.

“In the present study of the ASPREE trial population, our results were consistent with the WHS analysis, despite randomizing older individuals (both men and women),” they add.

They say this validation of the WHS result provides evidence that a very high-risk subgroup of individuals with highly elevated Lp(a) – those carrying the rs3798220-C allele – may benefit from low-dose aspirin for the primary prevention of cardiovascular events. Further, the benefits in this subgroup specifically may outweigh any bleeding risk.

But they point out that rs3798220-C carriers comprise only a small portion of all individuals with elevated Lp(a) in the general population, while the polygenic LPA-GRS explains about 60% of the variation in directly measured plasma Lp(a) levels and has the potential advantage of being able to identify a larger group of individuals at increased risk.

The researchers note, however, that it is not clear to what extent the LPA-GRS results add further evidence to suggest that individuals with elevated Lp(a), beyond rs3798220-C carriers, may be more likely to benefit from aspirin.

“If the benefit of aspirin extends beyond very high-risk rs3798220-C carriers alone, to the broader 20%-30% of individuals with elevated Lp(a), the potential utility of aspirin for the primary prevention of cardiovascular events would increase substantially,” they say.
 

‘Very high clinical relevance’

In an accompanying editorial, Ana Devesa, MD, Borja Ibanez, MD, PhD, and Valentin Fuster, MD, PhD, The National Center for Cardiovascular Research, Madrid, say that: “[Dr.] Lacaze et al. are to be congratulated for a study of very high clinical relevance that represents a first indication for primary prevention for patients at high cardiovascular risk.”

They explain that the pathogenic mechanism of Lp(a) is believed to be a combination of prothrombotic and proatherogenic effects, and the current findings support the hypothesis that the prothrombotic mechanism of Lp(a) is mediated by platelet aggregation. 

This would explain the occurrence of thrombotic events in the presence of atherosclerosis in that elevated Lp(a) levels may induce platelet adhesion and aggregation to the activated atherosclerotic plaque, thus enhancing the atherothrombotic process. Moreover, activated platelets release several mediators that result in cell adhesion and attraction of chemokines and proinflammatory cytokines, driving an inflammatory response and mediating atherosclerosis progression, they add.

The editorialists highlight the limitations of the study already acknowledged by the authors: The analysis used genotypes rather than elevated Lp(a) levels and included only those of European ancestry, meaning the results are difficult to extrapolate to other populations.

“The next steps in clinical practice should be defined, and there are still questions to be answered,” they conclude. “Will every patient benefit from antithrombotic therapies? Should all patients who have elevated Lp(a) levels be treated with aspirin?”

The ASPREE Biobank is supported by grants from the Commonwealth Scientific and Industrial Research Organisation, Monash University, Menzies Research Institute, Australian National University, University of Melbourne, National Institutes of Health, National Health and Medical Research Council of Australia, and the Victorian Cancer Agency. Dr. Lacaze is supported by a National Heart Foundation Future Leader Fellowship.

A version of this article first appeared on Medscape.com.

Aspirin may be of specific benefit for the primary prevention of cardiovascular disease in individuals with raised Lp(a) levels, a new study has suggested.

The study analyzed data from the ASPREE (ASPirin in Reducing Events in the Elderly) trial, which randomized 19,000 individuals aged 70 years or older without a history of cardiovascular disease to aspirin (100 mg/day) or placebo. While the main results, reported previously, showed no net benefit of aspirin in the overall population, the current analysis suggests there may be a benefit in individuals with raised Lp(a) levels.

jimdeli/Fotolia

Similar findings in the Women’s Health Study

Dr. Lacaze and colleagues point out that similar results have also been seen in another large aspirin primary prevention study – the Women’s Health Study (WHS).

The WHS compared aspirin 100 mg every other day with placebo in initially healthy younger women. Previously reported results showed that women carrying the rs3798220-C variant, associated with highly elevated Lp(a) levels, had a twofold higher risk of cardiovascular events than noncarrier women in the placebo group, but this risk was reduced in the aspirin group. And there was no increased risk of bleeding in women with elevated Lp(a).

“These results, in the absence of any other randomized controlled trial evidence or approved therapy for treating Lp(a)-associated risk, have been used by some physicians as justification for prescribing aspirin in patients with elevated Lp(a),” Dr. Lacaze and colleagues note.

“In the present study of the ASPREE trial population, our results were consistent with the WHS analysis, despite randomizing older individuals (both men and women),” they add.

They say this validation of the WHS result provides evidence that a very high-risk subgroup of individuals with highly elevated Lp(a) – those carrying the rs3798220-C allele – may benefit from low-dose aspirin for the primary prevention of cardiovascular events. Further, the benefits in this subgroup specifically may outweigh any bleeding risk.

But they point out that rs3798220-C carriers comprise only a small portion of all individuals with elevated Lp(a) in the general population, while the polygenic LPA-GRS explains about 60% of the variation in directly measured plasma Lp(a) levels and has the potential advantage of being able to identify a larger group of individuals at increased risk.

The researchers note, however, that it is not clear to what extent the LPA-GRS results add further evidence to suggest that individuals with elevated Lp(a), beyond rs3798220-C carriers, may be more likely to benefit from aspirin.

“If the benefit of aspirin extends beyond very high-risk rs3798220-C carriers alone, to the broader 20%-30% of individuals with elevated Lp(a), the potential utility of aspirin for the primary prevention of cardiovascular events would increase substantially,” they say.
 

‘Very high clinical relevance’

In an accompanying editorial, Ana Devesa, MD, Borja Ibanez, MD, PhD, and Valentin Fuster, MD, PhD, The National Center for Cardiovascular Research, Madrid, say that: “[Dr.] Lacaze et al. are to be congratulated for a study of very high clinical relevance that represents a first indication for primary prevention for patients at high cardiovascular risk.”

They explain that the pathogenic mechanism of Lp(a) is believed to be a combination of prothrombotic and proatherogenic effects, and the current findings support the hypothesis that the prothrombotic mechanism of Lp(a) is mediated by platelet aggregation. 

This would explain the occurrence of thrombotic events in the presence of atherosclerosis in that elevated Lp(a) levels may induce platelet adhesion and aggregation to the activated atherosclerotic plaque, thus enhancing the atherothrombotic process. Moreover, activated platelets release several mediators that result in cell adhesion and attraction of chemokines and proinflammatory cytokines, driving an inflammatory response and mediating atherosclerosis progression, they add.

The editorialists highlight the limitations of the study already acknowledged by the authors: The analysis used genotypes rather than elevated Lp(a) levels and included only those of European ancestry, meaning the results are difficult to extrapolate to other populations.

“The next steps in clinical practice should be defined, and there are still questions to be answered,” they conclude. “Will every patient benefit from antithrombotic therapies? Should all patients who have elevated Lp(a) levels be treated with aspirin?”

The ASPREE Biobank is supported by grants from the Commonwealth Scientific and Industrial Research Organisation, Monash University, Menzies Research Institute, Australian National University, University of Melbourne, National Institutes of Health, National Health and Medical Research Council of Australia, and the Victorian Cancer Agency. Dr. Lacaze is supported by a National Heart Foundation Future Leader Fellowship.

A version of this article first appeared on Medscape.com.

The diagnosis and management of refractory celiac disease remains challenging, but ongoing studies can provide the proper diagnostic criteria and identify the optimal management strategies, according to a new American Gastroenterological Association expert review published in Gastroenterology.

Celiac disease is present in about 1% of the U.S. population and can cause various symptoms, wrote Peter H. R. Green, MD, director of the Celiac Disease Center at Columbia University, New York, and colleagues. Adhering to a strict gluten-free diet can improve symptoms, normalize serum antibody levels, and reverse small bowel villous atrophy. However, persistent or recurrent symptoms and elevated celiac antibodies can persist in some patients after a year of trying a gluten-free diet, a condition called nonresponsive celiac disease. In some patients, this raises concern for refractory celiac disease, or RCD.

“RCD is believed to occur in only approximately 1% of patients with celiac disease, although this may be an overestimate, as data are obtained from referral centers,” the authors wrote.

RCD can be classified into two subtypes with different diagnostic criteria, prognoses, and therapy responses. The first, called RCD1, is characterized by villous atrophy but has intraepithelial lymphocytes similar to conventional celiac disease. The other, called RCD2, is characterized by aberrant clonal T-cell expansion in the intestinal tract and other organs, has a poorer prognosis than RCD1, and has a risk of developing ulcerative jejunoileitis or enteropathy-associated T-cell lymphoma.

The experts developed 10 clinical practice advice statements based on a review of the published literature and expert opinion.

First, in patients who have persistent or recurring symptoms, an initial celiac disease diagnosis should be confirmed through review of prior diagnostic testing, including serologies, endoscopies, and histologic findings. Celiac disease can overlap with other gastrointestinal conditions, and some pathologic findings aren’t specific to celiac disease. Results of serologic testing with tissue transglutaminase immunoglobulin A, deamidated gliadin peptide IgA and IgG, and endomysial antibodies should be reviewed or obtained if not previously performed.

Next, in those with confirmed but nonresponsive celiac disease, ongoing gluten ingestion should be excluded as a cause of symptoms with serologic testing, dietitian review, and potentially detection of immunogenic peptides in stool or urine samples. The authors noted that persistent gluten ingestion, whether intentional or inadvertent, accounts for 40%-50% of patients with nonresponsive celiac disease. In these cases, esophagogastroduodenoscopy and small bowel biopsies should be performed to look for persistent villous atrophy, which can also be caused by common variable immunodeficiency, autoimmune enteropathy, tropical sprue, and medication-induced enteropathy. Patients with villous atrophy due to other causes won’t respond to a gluten-free diet.

After excluding gluten, clinicians should perform a systematic evaluation for other potential causes of symptoms, including functional bowel disorders, lactose or fructose intolerance, microscopic colitis, pancreatic insufficiency, inflammatory bowel disease, and small intestinal bacterial growth. Irritable bowel syndrome, for instance, may contribute to persistent symptoms and respond to fermentable oligo-, di-, and monosaccharides and polyols (FODMAP) restriction. RCD should be strongly considered in patients with persistent symptoms or signs of malabsorption after the exclusion of the other causes.

To distinguish between the two subtypes of RCD and exclude enteropathy-associated T-cell lymphoma, clinicians should use flow cytometry, immunohistochemistry, and T-cell receptor rearrangement studies. RCD1 has a normal intraepithelial lymphocyte population, and RCD2 has an aberrant, clonal intraepithelial lymphocyte population. Consulting with a hematopathologist may be necessary to interpret these studies.

After RCD2 is diagnosed, complications such as enteropathy-associated T-cell lymphoma and ulcerative jejunoileitis should be excluded through small bowel imaging with capsule endoscopy and either computed tomography (CT) or magnetic resonance enterography. In general, the extent and severity of villous atrophy is greater in patients with RCD2, compared with RCD1.

In patients diagnosed with RCD, clinicians should complete a detailed nutritional assessment with investigation of micronutrient and macronutrient deficiencies. Check albumin as an independent prognostic factor. Then, try to correct deficiencies with oral supplements. Malnourished patients may need enteral support, and those with severe malnutrition due to malabsorption may need parenteral support.

So far, RCD management suggestions are based on small retrospective studies and expert opinion, with minimal prospective data and no Food and Drug Administration–approved therapies. The goals should be to improve symptoms and duodenal mucosal abnormalities, manage malnutrition, and prevent lymphoma. Glucocorticoids are considered first-line therapy, typically open-capsule budesonide given as 3 mg three times daily. Prednisone serves as an alternative with proven efficacy but a higher risk for adverse effects.

The optimal choice for second-line therapy is unknown, but the addition of an immunosuppressant agent to steroids appears to be effective in RCD1, including azathioprine, mercaptopurine, and tioguanine. The best treatment for RCD2 is unknown, though clinical response has been reported with steroids, and cladribine has been well tolerated in some patients.

Patients with RCD who don’t respond to steroids may benefit from referral to a center with expertise for management or evaluation for inclusion in clinical trials. Frequent medical visits are advised until the disease is well controlled, with regular follow-up after that. 

Ultimately, “patients with RCD benefit from evaluation and regular follow-up by a multidisciplinary team, including gastroenterologists and dietitians, to assess clinical and histologic response to therapy,” the authors wrote. “Identify local experts with expertise in celiac disease to assist with management.”

The authors reported no grant support or funding sources for this study. One author has received research report from Freenome, and another is on the celiac disease advisory board for Takeda. The remaining authors disclosed no conflicts.

The diagnosis and management of refractory celiac disease remains challenging, but ongoing studies can provide the proper diagnostic criteria and identify the optimal management strategies, according to a new American Gastroenterological Association expert review published in Gastroenterology.

Celiac disease is present in about 1% of the U.S. population and can cause various symptoms, wrote Peter H. R. Green, MD, director of the Celiac Disease Center at Columbia University, New York, and colleagues. Adhering to a strict gluten-free diet can improve symptoms, normalize serum antibody levels, and reverse small bowel villous atrophy. However, persistent or recurrent symptoms and elevated celiac antibodies can persist in some patients after a year of trying a gluten-free diet, a condition called nonresponsive celiac disease. In some patients, this raises concern for refractory celiac disease, or RCD.

“RCD is believed to occur in only approximately 1% of patients with celiac disease, although this may be an overestimate, as data are obtained from referral centers,” the authors wrote.

RCD can be classified into two subtypes with different diagnostic criteria, prognoses, and therapy responses. The first, called RCD1, is characterized by villous atrophy but has intraepithelial lymphocytes similar to conventional celiac disease. The other, called RCD2, is characterized by aberrant clonal T-cell expansion in the intestinal tract and other organs, has a poorer prognosis than RCD1, and has a risk of developing ulcerative jejunoileitis or enteropathy-associated T-cell lymphoma.

The experts developed 10 clinical practice advice statements based on a review of the published literature and expert opinion.

First, in patients who have persistent or recurring symptoms, an initial celiac disease diagnosis should be confirmed through review of prior diagnostic testing, including serologies, endoscopies, and histologic findings. Celiac disease can overlap with other gastrointestinal conditions, and some pathologic findings aren’t specific to celiac disease. Results of serologic testing with tissue transglutaminase immunoglobulin A, deamidated gliadin peptide IgA and IgG, and endomysial antibodies should be reviewed or obtained if not previously performed.

Next, in those with confirmed but nonresponsive celiac disease, ongoing gluten ingestion should be excluded as a cause of symptoms with serologic testing, dietitian review, and potentially detection of immunogenic peptides in stool or urine samples. The authors noted that persistent gluten ingestion, whether intentional or inadvertent, accounts for 40%-50% of patients with nonresponsive celiac disease. In these cases, esophagogastroduodenoscopy and small bowel biopsies should be performed to look for persistent villous atrophy, which can also be caused by common variable immunodeficiency, autoimmune enteropathy, tropical sprue, and medication-induced enteropathy. Patients with villous atrophy due to other causes won’t respond to a gluten-free diet.

After excluding gluten, clinicians should perform a systematic evaluation for other potential causes of symptoms, including functional bowel disorders, lactose or fructose intolerance, microscopic colitis, pancreatic insufficiency, inflammatory bowel disease, and small intestinal bacterial growth. Irritable bowel syndrome, for instance, may contribute to persistent symptoms and respond to fermentable oligo-, di-, and monosaccharides and polyols (FODMAP) restriction. RCD should be strongly considered in patients with persistent symptoms or signs of malabsorption after the exclusion of the other causes.

To distinguish between the two subtypes of RCD and exclude enteropathy-associated T-cell lymphoma, clinicians should use flow cytometry, immunohistochemistry, and T-cell receptor rearrangement studies. RCD1 has a normal intraepithelial lymphocyte population, and RCD2 has an aberrant, clonal intraepithelial lymphocyte population. Consulting with a hematopathologist may be necessary to interpret these studies.

After RCD2 is diagnosed, complications such as enteropathy-associated T-cell lymphoma and ulcerative jejunoileitis should be excluded through small bowel imaging with capsule endoscopy and either computed tomography (CT) or magnetic resonance enterography. In general, the extent and severity of villous atrophy is greater in patients with RCD2, compared with RCD1.

In patients diagnosed with RCD, clinicians should complete a detailed nutritional assessment with investigation of micronutrient and macronutrient deficiencies. Check albumin as an independent prognostic factor. Then, try to correct deficiencies with oral supplements. Malnourished patients may need enteral support, and those with severe malnutrition due to malabsorption may need parenteral support.

So far, RCD management suggestions are based on small retrospective studies and expert opinion, with minimal prospective data and no Food and Drug Administration–approved therapies. The goals should be to improve symptoms and duodenal mucosal abnormalities, manage malnutrition, and prevent lymphoma. Glucocorticoids are considered first-line therapy, typically open-capsule budesonide given as 3 mg three times daily. Prednisone serves as an alternative with proven efficacy but a higher risk for adverse effects.

The optimal choice for second-line therapy is unknown, but the addition of an immunosuppressant agent to steroids appears to be effective in RCD1, including azathioprine, mercaptopurine, and tioguanine. The best treatment for RCD2 is unknown, though clinical response has been reported with steroids, and cladribine has been well tolerated in some patients.

Patients with RCD who don’t respond to steroids may benefit from referral to a center with expertise for management or evaluation for inclusion in clinical trials. Frequent medical visits are advised until the disease is well controlled, with regular follow-up after that. 

Ultimately, “patients with RCD benefit from evaluation and regular follow-up by a multidisciplinary team, including gastroenterologists and dietitians, to assess clinical and histologic response to therapy,” the authors wrote. “Identify local experts with expertise in celiac disease to assist with management.”

The authors reported no grant support or funding sources for this study. One author has received research report from Freenome, and another is on the celiac disease advisory board for Takeda. The remaining authors disclosed no conflicts.

The diagnosis and management of refractory celiac disease remains challenging, but ongoing studies can provide the proper diagnostic criteria and identify the optimal management strategies, according to a new American Gastroenterological Association expert review published in Gastroenterology.

Celiac disease is present in about 1% of the U.S. population and can cause various symptoms, wrote Peter H. R. Green, MD, director of the Celiac Disease Center at Columbia University, New York, and colleagues. Adhering to a strict gluten-free diet can improve symptoms, normalize serum antibody levels, and reverse small bowel villous atrophy. However, persistent or recurrent symptoms and elevated celiac antibodies can persist in some patients after a year of trying a gluten-free diet, a condition called nonresponsive celiac disease. In some patients, this raises concern for refractory celiac disease, or RCD.

“RCD is believed to occur in only approximately 1% of patients with celiac disease, although this may be an overestimate, as data are obtained from referral centers,” the authors wrote.

RCD can be classified into two subtypes with different diagnostic criteria, prognoses, and therapy responses. The first, called RCD1, is characterized by villous atrophy but has intraepithelial lymphocytes similar to conventional celiac disease. The other, called RCD2, is characterized by aberrant clonal T-cell expansion in the intestinal tract and other organs, has a poorer prognosis than RCD1, and has a risk of developing ulcerative jejunoileitis or enteropathy-associated T-cell lymphoma.

The experts developed 10 clinical practice advice statements based on a review of the published literature and expert opinion.

First, in patients who have persistent or recurring symptoms, an initial celiac disease diagnosis should be confirmed through review of prior diagnostic testing, including serologies, endoscopies, and histologic findings. Celiac disease can overlap with other gastrointestinal conditions, and some pathologic findings aren’t specific to celiac disease. Results of serologic testing with tissue transglutaminase immunoglobulin A, deamidated gliadin peptide IgA and IgG, and endomysial antibodies should be reviewed or obtained if not previously performed.

Next, in those with confirmed but nonresponsive celiac disease, ongoing gluten ingestion should be excluded as a cause of symptoms with serologic testing, dietitian review, and potentially detection of immunogenic peptides in stool or urine samples. The authors noted that persistent gluten ingestion, whether intentional or inadvertent, accounts for 40%-50% of patients with nonresponsive celiac disease. In these cases, esophagogastroduodenoscopy and small bowel biopsies should be performed to look for persistent villous atrophy, which can also be caused by common variable immunodeficiency, autoimmune enteropathy, tropical sprue, and medication-induced enteropathy. Patients with villous atrophy due to other causes won’t respond to a gluten-free diet.

After excluding gluten, clinicians should perform a systematic evaluation for other potential causes of symptoms, including functional bowel disorders, lactose or fructose intolerance, microscopic colitis, pancreatic insufficiency, inflammatory bowel disease, and small intestinal bacterial growth. Irritable bowel syndrome, for instance, may contribute to persistent symptoms and respond to fermentable oligo-, di-, and monosaccharides and polyols (FODMAP) restriction. RCD should be strongly considered in patients with persistent symptoms or signs of malabsorption after the exclusion of the other causes.

To distinguish between the two subtypes of RCD and exclude enteropathy-associated T-cell lymphoma, clinicians should use flow cytometry, immunohistochemistry, and T-cell receptor rearrangement studies. RCD1 has a normal intraepithelial lymphocyte population, and RCD2 has an aberrant, clonal intraepithelial lymphocyte population. Consulting with a hematopathologist may be necessary to interpret these studies.

After RCD2 is diagnosed, complications such as enteropathy-associated T-cell lymphoma and ulcerative jejunoileitis should be excluded through small bowel imaging with capsule endoscopy and either computed tomography (CT) or magnetic resonance enterography. In general, the extent and severity of villous atrophy is greater in patients with RCD2, compared with RCD1.

In patients diagnosed with RCD, clinicians should complete a detailed nutritional assessment with investigation of micronutrient and macronutrient deficiencies. Check albumin as an independent prognostic factor. Then, try to correct deficiencies with oral supplements. Malnourished patients may need enteral support, and those with severe malnutrition due to malabsorption may need parenteral support.

So far, RCD management suggestions are based on small retrospective studies and expert opinion, with minimal prospective data and no Food and Drug Administration–approved therapies. The goals should be to improve symptoms and duodenal mucosal abnormalities, manage malnutrition, and prevent lymphoma. Glucocorticoids are considered first-line therapy, typically open-capsule budesonide given as 3 mg three times daily. Prednisone serves as an alternative with proven efficacy but a higher risk for adverse effects.

The optimal choice for second-line therapy is unknown, but the addition of an immunosuppressant agent to steroids appears to be effective in RCD1, including azathioprine, mercaptopurine, and tioguanine. The best treatment for RCD2 is unknown, though clinical response has been reported with steroids, and cladribine has been well tolerated in some patients.

Patients with RCD who don’t respond to steroids may benefit from referral to a center with expertise for management or evaluation for inclusion in clinical trials. Frequent medical visits are advised until the disease is well controlled, with regular follow-up after that. 

Ultimately, “patients with RCD benefit from evaluation and regular follow-up by a multidisciplinary team, including gastroenterologists and dietitians, to assess clinical and histologic response to therapy,” the authors wrote. “Identify local experts with expertise in celiac disease to assist with management.”

The authors reported no grant support or funding sources for this study. One author has received research report from Freenome, and another is on the celiac disease advisory board for Takeda. The remaining authors disclosed no conflicts.

In a rare second review of a new drug application, a Food and Drug Association advisory panel has voted to recommend approval of a novel drug to treat amyotrophic lateral sclerosis (ALS).

By a vote of 7-2, the FDA Peripheral and Central Nervous System Drugs Advisory Committee reversed course on AMX0035 (Amylyx Pharmaceuticals), a combination of sodium phenylbutyrate and taurursodiol.

The panel previously voted 6-4 to reject the drug, ruling that data provided by Amylyx had failed to demonstrate that the survival benefit reported in the only clinical trial of AMX0035 so far was a direct result of the drug.

This time, two panelists who previously voted no were swayed by the drug maker’s new analysis of previously presented research, more than 1,300 public comments in support of the drug, supportive testimony from ALS patients and clinicians, and assurances from company executives that Amylyx would pull the drug from the market if results of an ongoing phase 3 clinical trial show the drug doesn’t work.

“As in March, today we have to have an internal dialogue between our scientific scrutiny and clinical compassion,” said Liana G. Apostolova, MD, from Indiana University, Indianapolis, who originally voted against the application.

“Today I also saw additional confirmatory evidence that was not unequivocally persuasive but was nonetheless reassuring,” Dr. Apostolova said. “Because of that I am voting in support of AMX0035.”
 

A rare second chance

ALS (Lou Gehrig’s disease) is a progressive, fatal neurodegenerative disease affecting nerve cells in the brain and spinal cord that causes loss of motor control. It is rare, affecting about 30,000 people in the United States with another 5,000 new cases diagnosed each year. Most people with the disease die within 2 years of diagnosis.

The FDA has approved two therapies for ALS, but both have limited efficacy.

Typically, FDA approval requires two large studies or one study with a “very persuasive” effect on survival.

Amylyx’s application is based on a single study, the multicenter, two-phase CENTAUR trial. In that trial, 137 people with ALS received AMX0035 or placebo for 24 weeks.

Researchers found that patients receiving AMX0035 had a 25% slower decline in function, compared with the those taking placebo. A change of 20% or more is considered clinically meaningful.

The investigators also found a statistically significant median difference of 4.8 months in time to death, first hospitalization, or tracheostomy/permanent assisted ventilation in the group originally assigned to receive AMX0035 compared with the group originally assigned to receive placebo (hazard ratio, 0.62; P = .023).

In the panel’s previous vote against the drug application, members cited several issues with the study, concluding that it did not offer persuasive or robust evidence of efficacy. They also cited missing data assumptions in the primary analysis, issues of randomization and imbalances in concomitant use of riluzole and edaravone, the two FDA-approved drugs for ALS.

The FDA later requested additional information from Amylyx, delayed its final ruling on the new drug application to Sept. 29, and called for a second review meeting – a virtually unheard-of move.

An FDA review posted in advance of the meeting Sept. 29 had hinted at a different outcome. In that report, regulators said new data from Amylyx were not “sufficiently independent or persuasive” to establish effectiveness.

However, FDA officials in the meeting stressed the importance of considering unmet medical need in ALS in the panel’s decision-making process.

“Recognizing the substantial unmet medical need in ALS, we feel that it is important that the committee is afforded the opportunity to consider this new information, along with the information presented at the prior meeting, in that context,” Billy Dunn, MD, director of the FDA Office of Neuroscience, said during the meeting.

Panelists heard additional data that Amylyx claims confirms the results of the CENTAUR study, including new analyses of the previously submitted survival data and new data from that study and an open-label extension.

They also provided new information on a biomarker data from a phase 2 study of AMX0035 to treat Alzheimer’s disease.

“I think we note the limitations of the analyses, but we still haven’t taken it off the table that they could be considered as confirmatory evidence and that’s why we’re here today,” said Teresa Buracchio, MD, director of the division of neurology for the FDA.

Two members of the panel who voted no in March stuck with that position at the Sept. 29 meeting.

“Unfortunately, I don’t believe the new evidence we’ve reviewed, while promising, combined with that prior evidence, constitutes substantial evidence of effectiveness,” said panelist Caleb Alexander, MD, a professor of epidemiology and medicine at the Johns Hopkins University Center for Drug Safety and Effectiveness, Baltimore.

Dr. Alexander, who also voted no in March, said that post hoc data presented at the meeting were not enough to assuage concerns that led him and others to reject the drug in March.
 

A challenging situation

Amylyx is currently leading the 48-week international, phase 3, placebo-controlled PHOENIX clinical trial of AMX0035. The study has enrolled about half of its 600-patient target.

“Undoubtedly, the results of the phase 3 study would be highly informative for a regulatory decision on the current ... review for AMX0035,” said Emily Freilich, MD, of the FDA.

However, results aren’t expected until late 2023 or early 2024, which “places the agency in a challenging situation of potentially making a regulatory decision that may not be subsequently confirmed by the results of the ongoing study.”

In June, Amylyx received conditional approval in Canada for the drug, but final approval depends on the outcome of the PHOENIX trial. The FDA does not offer a conditional approval track.

“If AMX0035 is not approved now, the FDA anticipated decision will likely happen in 2025, underscoring the critical importance of today’s outcome,” said Tammy Sarnelli, MPAHC, global head of Regulatory Affairs for Amylyx Pharmaceuticals.

If the FDA were to approve AMX0035 and results from the PHOENIX trial ultimately fail to prove efficacy, Justin Klee, co-CEO and cofounder of Amylyx Pharmaceuticals, said the company would withdraw the drug.

“To be clear, if PHOENIX is not successful, we will do what is right for patients, which includes voluntarily removing the product from the market,” Mr. Klee said.

Regardless of the company’s decision, FDA officials noted that the agency does have the ability to recall a drug from the market if studies show that it no longer meets requirements for approval.

“The FDA, with all due respect, significantly understates the complexity and likelihood of their pulling a product from the market,” Dr. Alexander said. “Whether or not they can ultimately pull a product from the market is no substitute for the evidentiary thresholds that are required for market access.”

A version of this article first appeared on Medscape.com.

In a rare second review of a new drug application, a Food and Drug Association advisory panel has voted to recommend approval of a novel drug to treat amyotrophic lateral sclerosis (ALS).

By a vote of 7-2, the FDA Peripheral and Central Nervous System Drugs Advisory Committee reversed course on AMX0035 (Amylyx Pharmaceuticals), a combination of sodium phenylbutyrate and taurursodiol.

The panel previously voted 6-4 to reject the drug, ruling that data provided by Amylyx had failed to demonstrate that the survival benefit reported in the only clinical trial of AMX0035 so far was a direct result of the drug.

This time, two panelists who previously voted no were swayed by the drug maker’s new analysis of previously presented research, more than 1,300 public comments in support of the drug, supportive testimony from ALS patients and clinicians, and assurances from company executives that Amylyx would pull the drug from the market if results of an ongoing phase 3 clinical trial show the drug doesn’t work.

“As in March, today we have to have an internal dialogue between our scientific scrutiny and clinical compassion,” said Liana G. Apostolova, MD, from Indiana University, Indianapolis, who originally voted against the application.

“Today I also saw additional confirmatory evidence that was not unequivocally persuasive but was nonetheless reassuring,” Dr. Apostolova said. “Because of that I am voting in support of AMX0035.”
 

A rare second chance

ALS (Lou Gehrig’s disease) is a progressive, fatal neurodegenerative disease affecting nerve cells in the brain and spinal cord that causes loss of motor control. It is rare, affecting about 30,000 people in the United States with another 5,000 new cases diagnosed each year. Most people with the disease die within 2 years of diagnosis.

The FDA has approved two therapies for ALS, but both have limited efficacy.

Typically, FDA approval requires two large studies or one study with a “very persuasive” effect on survival.

Amylyx’s application is based on a single study, the multicenter, two-phase CENTAUR trial. In that trial, 137 people with ALS received AMX0035 or placebo for 24 weeks.

Researchers found that patients receiving AMX0035 had a 25% slower decline in function, compared with the those taking placebo. A change of 20% or more is considered clinically meaningful.

The investigators also found a statistically significant median difference of 4.8 months in time to death, first hospitalization, or tracheostomy/permanent assisted ventilation in the group originally assigned to receive AMX0035 compared with the group originally assigned to receive placebo (hazard ratio, 0.62; P = .023).

In the panel’s previous vote against the drug application, members cited several issues with the study, concluding that it did not offer persuasive or robust evidence of efficacy. They also cited missing data assumptions in the primary analysis, issues of randomization and imbalances in concomitant use of riluzole and edaravone, the two FDA-approved drugs for ALS.

The FDA later requested additional information from Amylyx, delayed its final ruling on the new drug application to Sept. 29, and called for a second review meeting – a virtually unheard-of move.

An FDA review posted in advance of the meeting Sept. 29 had hinted at a different outcome. In that report, regulators said new data from Amylyx were not “sufficiently independent or persuasive” to establish effectiveness.

However, FDA officials in the meeting stressed the importance of considering unmet medical need in ALS in the panel’s decision-making process.

“Recognizing the substantial unmet medical need in ALS, we feel that it is important that the committee is afforded the opportunity to consider this new information, along with the information presented at the prior meeting, in that context,” Billy Dunn, MD, director of the FDA Office of Neuroscience, said during the meeting.

Panelists heard additional data that Amylyx claims confirms the results of the CENTAUR study, including new analyses of the previously submitted survival data and new data from that study and an open-label extension.

They also provided new information on a biomarker data from a phase 2 study of AMX0035 to treat Alzheimer’s disease.

“I think we note the limitations of the analyses, but we still haven’t taken it off the table that they could be considered as confirmatory evidence and that’s why we’re here today,” said Teresa Buracchio, MD, director of the division of neurology for the FDA.

Two members of the panel who voted no in March stuck with that position at the Sept. 29 meeting.

“Unfortunately, I don’t believe the new evidence we’ve reviewed, while promising, combined with that prior evidence, constitutes substantial evidence of effectiveness,” said panelist Caleb Alexander, MD, a professor of epidemiology and medicine at the Johns Hopkins University Center for Drug Safety and Effectiveness, Baltimore.

Dr. Alexander, who also voted no in March, said that post hoc data presented at the meeting were not enough to assuage concerns that led him and others to reject the drug in March.
 

A challenging situation

Amylyx is currently leading the 48-week international, phase 3, placebo-controlled PHOENIX clinical trial of AMX0035. The study has enrolled about half of its 600-patient target.

“Undoubtedly, the results of the phase 3 study would be highly informative for a regulatory decision on the current ... review for AMX0035,” said Emily Freilich, MD, of the FDA.

However, results aren’t expected until late 2023 or early 2024, which “places the agency in a challenging situation of potentially making a regulatory decision that may not be subsequently confirmed by the results of the ongoing study.”

In June, Amylyx received conditional approval in Canada for the drug, but final approval depends on the outcome of the PHOENIX trial. The FDA does not offer a conditional approval track.

“If AMX0035 is not approved now, the FDA anticipated decision will likely happen in 2025, underscoring the critical importance of today’s outcome,” said Tammy Sarnelli, MPAHC, global head of Regulatory Affairs for Amylyx Pharmaceuticals.

If the FDA were to approve AMX0035 and results from the PHOENIX trial ultimately fail to prove efficacy, Justin Klee, co-CEO and cofounder of Amylyx Pharmaceuticals, said the company would withdraw the drug.

“To be clear, if PHOENIX is not successful, we will do what is right for patients, which includes voluntarily removing the product from the market,” Mr. Klee said.

Regardless of the company’s decision, FDA officials noted that the agency does have the ability to recall a drug from the market if studies show that it no longer meets requirements for approval.

“The FDA, with all due respect, significantly understates the complexity and likelihood of their pulling a product from the market,” Dr. Alexander said. “Whether or not they can ultimately pull a product from the market is no substitute for the evidentiary thresholds that are required for market access.”

A version of this article first appeared on Medscape.com.

In a rare second review of a new drug application, a Food and Drug Association advisory panel has voted to recommend approval of a novel drug to treat amyotrophic lateral sclerosis (ALS).

By a vote of 7-2, the FDA Peripheral and Central Nervous System Drugs Advisory Committee reversed course on AMX0035 (Amylyx Pharmaceuticals), a combination of sodium phenylbutyrate and taurursodiol.

The panel previously voted 6-4 to reject the drug, ruling that data provided by Amylyx had failed to demonstrate that the survival benefit reported in the only clinical trial of AMX0035 so far was a direct result of the drug.

This time, two panelists who previously voted no were swayed by the drug maker’s new analysis of previously presented research, more than 1,300 public comments in support of the drug, supportive testimony from ALS patients and clinicians, and assurances from company executives that Amylyx would pull the drug from the market if results of an ongoing phase 3 clinical trial show the drug doesn’t work.

“As in March, today we have to have an internal dialogue between our scientific scrutiny and clinical compassion,” said Liana G. Apostolova, MD, from Indiana University, Indianapolis, who originally voted against the application.

“Today I also saw additional confirmatory evidence that was not unequivocally persuasive but was nonetheless reassuring,” Dr. Apostolova said. “Because of that I am voting in support of AMX0035.”
 

A rare second chance

ALS (Lou Gehrig’s disease) is a progressive, fatal neurodegenerative disease affecting nerve cells in the brain and spinal cord that causes loss of motor control. It is rare, affecting about 30,000 people in the United States with another 5,000 new cases diagnosed each year. Most people with the disease die within 2 years of diagnosis.

The FDA has approved two therapies for ALS, but both have limited efficacy.

Typically, FDA approval requires two large studies or one study with a “very persuasive” effect on survival.

Amylyx’s application is based on a single study, the multicenter, two-phase CENTAUR trial. In that trial, 137 people with ALS received AMX0035 or placebo for 24 weeks.

Researchers found that patients receiving AMX0035 had a 25% slower decline in function, compared with the those taking placebo. A change of 20% or more is considered clinically meaningful.

The investigators also found a statistically significant median difference of 4.8 months in time to death, first hospitalization, or tracheostomy/permanent assisted ventilation in the group originally assigned to receive AMX0035 compared with the group originally assigned to receive placebo (hazard ratio, 0.62; P = .023).

In the panel’s previous vote against the drug application, members cited several issues with the study, concluding that it did not offer persuasive or robust evidence of efficacy. They also cited missing data assumptions in the primary analysis, issues of randomization and imbalances in concomitant use of riluzole and edaravone, the two FDA-approved drugs for ALS.

The FDA later requested additional information from Amylyx, delayed its final ruling on the new drug application to Sept. 29, and called for a second review meeting – a virtually unheard-of move.

An FDA review posted in advance of the meeting Sept. 29 had hinted at a different outcome. In that report, regulators said new data from Amylyx were not “sufficiently independent or persuasive” to establish effectiveness.

However, FDA officials in the meeting stressed the importance of considering unmet medical need in ALS in the panel’s decision-making process.

“Recognizing the substantial unmet medical need in ALS, we feel that it is important that the committee is afforded the opportunity to consider this new information, along with the information presented at the prior meeting, in that context,” Billy Dunn, MD, director of the FDA Office of Neuroscience, said during the meeting.

Panelists heard additional data that Amylyx claims confirms the results of the CENTAUR study, including new analyses of the previously submitted survival data and new data from that study and an open-label extension.

They also provided new information on a biomarker data from a phase 2 study of AMX0035 to treat Alzheimer’s disease.

“I think we note the limitations of the analyses, but we still haven’t taken it off the table that they could be considered as confirmatory evidence and that’s why we’re here today,” said Teresa Buracchio, MD, director of the division of neurology for the FDA.

Two members of the panel who voted no in March stuck with that position at the Sept. 29 meeting.

“Unfortunately, I don’t believe the new evidence we’ve reviewed, while promising, combined with that prior evidence, constitutes substantial evidence of effectiveness,” said panelist Caleb Alexander, MD, a professor of epidemiology and medicine at the Johns Hopkins University Center for Drug Safety and Effectiveness, Baltimore.

Dr. Alexander, who also voted no in March, said that post hoc data presented at the meeting were not enough to assuage concerns that led him and others to reject the drug in March.
 

A challenging situation

Amylyx is currently leading the 48-week international, phase 3, placebo-controlled PHOENIX clinical trial of AMX0035. The study has enrolled about half of its 600-patient target.

“Undoubtedly, the results of the phase 3 study would be highly informative for a regulatory decision on the current ... review for AMX0035,” said Emily Freilich, MD, of the FDA.

However, results aren’t expected until late 2023 or early 2024, which “places the agency in a challenging situation of potentially making a regulatory decision that may not be subsequently confirmed by the results of the ongoing study.”

In June, Amylyx received conditional approval in Canada for the drug, but final approval depends on the outcome of the PHOENIX trial. The FDA does not offer a conditional approval track.

“If AMX0035 is not approved now, the FDA anticipated decision will likely happen in 2025, underscoring the critical importance of today’s outcome,” said Tammy Sarnelli, MPAHC, global head of Regulatory Affairs for Amylyx Pharmaceuticals.

If the FDA were to approve AMX0035 and results from the PHOENIX trial ultimately fail to prove efficacy, Justin Klee, co-CEO and cofounder of Amylyx Pharmaceuticals, said the company would withdraw the drug.

“To be clear, if PHOENIX is not successful, we will do what is right for patients, which includes voluntarily removing the product from the market,” Mr. Klee said.

Regardless of the company’s decision, FDA officials noted that the agency does have the ability to recall a drug from the market if studies show that it no longer meets requirements for approval.

“The FDA, with all due respect, significantly understates the complexity and likelihood of their pulling a product from the market,” Dr. Alexander said. “Whether or not they can ultimately pull a product from the market is no substitute for the evidentiary thresholds that are required for market access.”

A version of this article first appeared on Medscape.com.

In a new scientific statement, the American Heart Association highlights the unique drivers of burnout in academic cardiovascular medicine physicians and proposes system-level and personal interventions to support individual wellness in this setting.

“The future cardiovascular health of Americans relies on a well-trained and experienced physician workforce created by rigorous academic medical training,” the writing group says in Circulation.

“Cardiovascular physicians pursuing careers in academic medicine are critical to continuing this mission, which includes providing clinical care for common and increasingly complex disease, educating and training the next generation of physicians/health care workers, and pursuing scientific discovery and innovation to treat and cure disease,” write Elisa Bradley, Penn State Health Heart and Vascular Institute, Hershey, Pa., and coauthors.

Given the multitasking nature of academic medicine, exhaustion and burnout uniquely threaten future and early career academic physicians, they say.

Drivers of burnout in this setting include productivity-driven compensation models that force competition for time between clinical care and academics; the requirement for promotion in systems that have not evolved to consider combined clinical and academic expectations; and distinct expectations based on faculty pathway, such as grant funding and publications.

In addition, at the early career and fellow-in-training level, drivers of burnout also include significant changes in personal and family life, coupled with long hours and high clinical and research demands, as well as financial strain and educational debt.

Many of the drivers of burnout in academic medicine are external and beyond the control of a single individual. Therefore, proposed solutions must be largely at the level of organizations, institutions, and government, the writing group says.

These solutions include appropriate mentorship, goal planning, efficiency in the workplace, time management and time “protection,” and manageable schedules.

Professional satisfaction “should be a shared responsibility between the clinician and the institution. Each must adapt their values to find a middle ground that meets the needs of both, recognizing that health care is both personal and a business,” the writing group says.

“Interventions to support efficiency of practice and a culture of wellness span normalizing and supporting flexible work environments to enhancing clinical support,” they add.

To enhance flexible clinical environments, organizations should consider “float teams” to provide care to bridge gaps when a physician is not available, job sharing and flexible hours, and telemedicine, the writing group says.

At the individual level, academic cardiovascular professionals should build individualized strategies to combat fatigue and to promote wellness, focusing on self-care and healthy habits (adequate sleep, healthy nutrition, exercise, outside interests, meaningful social relationships), they advise.

With help, “young academicians can look forward to a fulfilling and long career in academic cardiovascular medicine,” they conclude.

This research had no commercial funding. Members of the writing group reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

In a new scientific statement, the American Heart Association highlights the unique drivers of burnout in academic cardiovascular medicine physicians and proposes system-level and personal interventions to support individual wellness in this setting.

“The future cardiovascular health of Americans relies on a well-trained and experienced physician workforce created by rigorous academic medical training,” the writing group says in Circulation.

“Cardiovascular physicians pursuing careers in academic medicine are critical to continuing this mission, which includes providing clinical care for common and increasingly complex disease, educating and training the next generation of physicians/health care workers, and pursuing scientific discovery and innovation to treat and cure disease,” write Elisa Bradley, Penn State Health Heart and Vascular Institute, Hershey, Pa., and coauthors.

Given the multitasking nature of academic medicine, exhaustion and burnout uniquely threaten future and early career academic physicians, they say.

Drivers of burnout in this setting include productivity-driven compensation models that force competition for time between clinical care and academics; the requirement for promotion in systems that have not evolved to consider combined clinical and academic expectations; and distinct expectations based on faculty pathway, such as grant funding and publications.

In addition, at the early career and fellow-in-training level, drivers of burnout also include significant changes in personal and family life, coupled with long hours and high clinical and research demands, as well as financial strain and educational debt.

Many of the drivers of burnout in academic medicine are external and beyond the control of a single individual. Therefore, proposed solutions must be largely at the level of organizations, institutions, and government, the writing group says.

These solutions include appropriate mentorship, goal planning, efficiency in the workplace, time management and time “protection,” and manageable schedules.

Professional satisfaction “should be a shared responsibility between the clinician and the institution. Each must adapt their values to find a middle ground that meets the needs of both, recognizing that health care is both personal and a business,” the writing group says.

“Interventions to support efficiency of practice and a culture of wellness span normalizing and supporting flexible work environments to enhancing clinical support,” they add.

To enhance flexible clinical environments, organizations should consider “float teams” to provide care to bridge gaps when a physician is not available, job sharing and flexible hours, and telemedicine, the writing group says.

At the individual level, academic cardiovascular professionals should build individualized strategies to combat fatigue and to promote wellness, focusing on self-care and healthy habits (adequate sleep, healthy nutrition, exercise, outside interests, meaningful social relationships), they advise.

With help, “young academicians can look forward to a fulfilling and long career in academic cardiovascular medicine,” they conclude.

This research had no commercial funding. Members of the writing group reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

In a new scientific statement, the American Heart Association highlights the unique drivers of burnout in academic cardiovascular medicine physicians and proposes system-level and personal interventions to support individual wellness in this setting.

“The future cardiovascular health of Americans relies on a well-trained and experienced physician workforce created by rigorous academic medical training,” the writing group says in Circulation.

“Cardiovascular physicians pursuing careers in academic medicine are critical to continuing this mission, which includes providing clinical care for common and increasingly complex disease, educating and training the next generation of physicians/health care workers, and pursuing scientific discovery and innovation to treat and cure disease,” write Elisa Bradley, Penn State Health Heart and Vascular Institute, Hershey, Pa., and coauthors.

Given the multitasking nature of academic medicine, exhaustion and burnout uniquely threaten future and early career academic physicians, they say.

Drivers of burnout in this setting include productivity-driven compensation models that force competition for time between clinical care and academics; the requirement for promotion in systems that have not evolved to consider combined clinical and academic expectations; and distinct expectations based on faculty pathway, such as grant funding and publications.

In addition, at the early career and fellow-in-training level, drivers of burnout also include significant changes in personal and family life, coupled with long hours and high clinical and research demands, as well as financial strain and educational debt.

Many of the drivers of burnout in academic medicine are external and beyond the control of a single individual. Therefore, proposed solutions must be largely at the level of organizations, institutions, and government, the writing group says.

These solutions include appropriate mentorship, goal planning, efficiency in the workplace, time management and time “protection,” and manageable schedules.

Professional satisfaction “should be a shared responsibility between the clinician and the institution. Each must adapt their values to find a middle ground that meets the needs of both, recognizing that health care is both personal and a business,” the writing group says.

“Interventions to support efficiency of practice and a culture of wellness span normalizing and supporting flexible work environments to enhancing clinical support,” they add.

To enhance flexible clinical environments, organizations should consider “float teams” to provide care to bridge gaps when a physician is not available, job sharing and flexible hours, and telemedicine, the writing group says.

At the individual level, academic cardiovascular professionals should build individualized strategies to combat fatigue and to promote wellness, focusing on self-care and healthy habits (adequate sleep, healthy nutrition, exercise, outside interests, meaningful social relationships), they advise.

With help, “young academicians can look forward to a fulfilling and long career in academic cardiovascular medicine,” they conclude.

This research had no commercial funding. Members of the writing group reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A retrospective study that analyzed sex disparities in patients with COVID-19 and rheumatoid arthritis found that men had more baseline comorbidities and increased risk of COVID-19–related outcomes, compared with women.

“Differences in genetics between sex and sex steroid hormones may play a role in predisposition to COVID-19 infection as well as modulating the disease progression,” according to Xiaofeng Zhou, PhD, senior director at Pfizer, New York, and the study’s lead author.

Dr. Zhou presented her findings at The Lancet Summit on Sex and Gender in Rheumatology.

Patients with chronic rheumatic diseases treated with immunomodulatory therapies may be at higher risk for more severe COVID-19 outcomes, including hospitalization, complications, and death. Research on sex-based disparities in RA patients with COVID-19 in the United States is limited, said Dr. Zhou, who embarked on a retrospective cohort study to examine the demographic and clinical characteristics of RA patients with COVID-19 and estimate the risk of possible COVID-19 outcomes by sex.

Dr. Zhou and colleagues used U.S. COVID-19 data collected through electronic health records by Optum during 2020 to June 2021. The study included adult patients with RA and a COVID-19 diagnosis (≥ 1 diagnosis code or positive SARS-CoV-2 laboratory test) and greater than or equal to 183 days of database enrollment who received treatment with immunomodulatory therapies prior to the diagnosis date. They were stratified by sex.

Investigators used logistic regression to estimate the risk of 11 possible COVID-19–related outcomes within 30 days of the COVID-19 diagnosis (hospitalization, ICU admission, pneumonia, kidney failure, thrombotic event, heart failure, acute respiratory distress syndrome [ARDS], sepsis/septic shock, mechanical ventilation/extracorporeal membrane oxygenation [ECMO], in-hospital death, and all-cause mortality), adjusting for demographics and baseline clinical covariates.

A total of 4,476 COVID-19 patients with RA (78% female) took part in the study. Male patients trended older (64 vs. 60 years) and had lower African American representation and Medicaid enrollment than female patients, but they had more baseline comorbidities such as hypertension (55% vs. 45%), hyperlipidemia (45% vs. 33%), diabetes (25% vs. 20%), coronary artery disease (28% vs. 12%), and chronic kidney disease (20% vs. 15%).

Eight of the eleven COVID-19 outcomes were significantly more likely to occur in men than women (hospitalization: odds ratio, 1.32 [95% confidence interval (CI), 1.11-1.56]; ICU admission: OR, 1.80 [95% CI, 1.36-2.40]; mechanical ventilation/ECMO: OR, 1.48 [95% CI, 1.04-2.11]; in-hospital death: OR, 1.53 [95% CI, 1.13-2.07]; all-cause mortality: OR, 1.42 [95% CI, 1.09-1.86]; sepsis: OR, 1.55 [95% CI, 1.20-2.02]; kidney failure: OR, 1.46 [95% CI, 1.15-1.85]; ARDS: OR, 1.39 [95% CI, 1.15-1.69]).

Sex hormones factor into risk

The data illustrated that men with RA had more baseline comorbidities and increased risk of COVID-19 outcomes than women.

Sex hormones regulate virus entry into host cells, respiratory function, immune response, the cardiovascular system, and coagulation, explained Dr. Zhou.

Estrogen and progesterone in women could help develop stronger and efficient immune responses to viruses and reduce virus entry into the host cells. Also, “[the] larger number of copies of ACE2 genes in women, [which] is linked with protection in the lungs against edema, permeability, and pulmonary damage, could be associated with lower incidence of severe COVID-19 outcomes, such as respiratory-related mortality and mortality,” Dr. Zhou said.

By comparison, androgens in men may increase virus entry into the host cells and promote unfavorable immune response through the induction of cytokine production and reducing the antibody response to the virus. This could lead to severe infection, Dr. Zhou said.

Sex-based differences in steroid hormones may also explain the higher incidence of morbidity and fatality that’s been observed in other studies of male patients with other infectious diseases, such as severe acute respiratory syndrome and Middle East respiratory syndrome.
 

Study bolsters evidence on sex disparities

The results add real-world evidence to the limited literature on sex disparities in COVID-19 outcomes among patients with RA in the United States, Dr. Zhou said. “The differential role in sex steroid hormones among women and men may shed light on clinical management of COVID-19 patients and the need to consider sex-specific approaches in clinical trials in preventing and treating COVID-19 patients,” she said.

Considering that all patients are recommended to get COVID-19 vaccinations, “it is difficult to say how this impacts clinical practice,” said Janet Pope, MD, MPH, professor of medicine in the division of rheumatology at the University of Western Ontario, London, who was not involved with the study.

Sharing results with some patients may help to encourage vaccination, thus reducing risk of poor COVID-19 outcomes, Dr. Pope said.

In future studies, Dr. Zhou suggests using multiple databases and considering other geographies beyond the United States to further understand the etiology of sexual dimorphism in COVID-19 and expand generalizability. “In addition, future research will seek to provide insights into health equity gaps in the management of COVID-19. This may inform development of precision medicines and vaccines, especially among patients on immunosuppressive treatments,” she said.

The study was sponsored by Pfizer. Dr. Zhou and other study authors are Pfizer employees and hold Pfizer stock.

A version of this article first appeared on Medscape.com.

A retrospective study that analyzed sex disparities in patients with COVID-19 and rheumatoid arthritis found that men had more baseline comorbidities and increased risk of COVID-19–related outcomes, compared with women.

“Differences in genetics between sex and sex steroid hormones may play a role in predisposition to COVID-19 infection as well as modulating the disease progression,” according to Xiaofeng Zhou, PhD, senior director at Pfizer, New York, and the study’s lead author.

Dr. Zhou presented her findings at The Lancet Summit on Sex and Gender in Rheumatology.

Patients with chronic rheumatic diseases treated with immunomodulatory therapies may be at higher risk for more severe COVID-19 outcomes, including hospitalization, complications, and death. Research on sex-based disparities in RA patients with COVID-19 in the United States is limited, said Dr. Zhou, who embarked on a retrospective cohort study to examine the demographic and clinical characteristics of RA patients with COVID-19 and estimate the risk of possible COVID-19 outcomes by sex.

Dr. Zhou and colleagues used U.S. COVID-19 data collected through electronic health records by Optum during 2020 to June 2021. The study included adult patients with RA and a COVID-19 diagnosis (≥ 1 diagnosis code or positive SARS-CoV-2 laboratory test) and greater than or equal to 183 days of database enrollment who received treatment with immunomodulatory therapies prior to the diagnosis date. They were stratified by sex.

Investigators used logistic regression to estimate the risk of 11 possible COVID-19–related outcomes within 30 days of the COVID-19 diagnosis (hospitalization, ICU admission, pneumonia, kidney failure, thrombotic event, heart failure, acute respiratory distress syndrome [ARDS], sepsis/septic shock, mechanical ventilation/extracorporeal membrane oxygenation [ECMO], in-hospital death, and all-cause mortality), adjusting for demographics and baseline clinical covariates.

A total of 4,476 COVID-19 patients with RA (78% female) took part in the study. Male patients trended older (64 vs. 60 years) and had lower African American representation and Medicaid enrollment than female patients, but they had more baseline comorbidities such as hypertension (55% vs. 45%), hyperlipidemia (45% vs. 33%), diabetes (25% vs. 20%), coronary artery disease (28% vs. 12%), and chronic kidney disease (20% vs. 15%).

Eight of the eleven COVID-19 outcomes were significantly more likely to occur in men than women (hospitalization: odds ratio, 1.32 [95% confidence interval (CI), 1.11-1.56]; ICU admission: OR, 1.80 [95% CI, 1.36-2.40]; mechanical ventilation/ECMO: OR, 1.48 [95% CI, 1.04-2.11]; in-hospital death: OR, 1.53 [95% CI, 1.13-2.07]; all-cause mortality: OR, 1.42 [95% CI, 1.09-1.86]; sepsis: OR, 1.55 [95% CI, 1.20-2.02]; kidney failure: OR, 1.46 [95% CI, 1.15-1.85]; ARDS: OR, 1.39 [95% CI, 1.15-1.69]).

Sex hormones factor into risk

The data illustrated that men with RA had more baseline comorbidities and increased risk of COVID-19 outcomes than women.

Sex hormones regulate virus entry into host cells, respiratory function, immune response, the cardiovascular system, and coagulation, explained Dr. Zhou.

Estrogen and progesterone in women could help develop stronger and efficient immune responses to viruses and reduce virus entry into the host cells. Also, “[the] larger number of copies of ACE2 genes in women, [which] is linked with protection in the lungs against edema, permeability, and pulmonary damage, could be associated with lower incidence of severe COVID-19 outcomes, such as respiratory-related mortality and mortality,” Dr. Zhou said.

By comparison, androgens in men may increase virus entry into the host cells and promote unfavorable immune response through the induction of cytokine production and reducing the antibody response to the virus. This could lead to severe infection, Dr. Zhou said.

Sex-based differences in steroid hormones may also explain the higher incidence of morbidity and fatality that’s been observed in other studies of male patients with other infectious diseases, such as severe acute respiratory syndrome and Middle East respiratory syndrome.
 

Study bolsters evidence on sex disparities

The results add real-world evidence to the limited literature on sex disparities in COVID-19 outcomes among patients with RA in the United States, Dr. Zhou said. “The differential role in sex steroid hormones among women and men may shed light on clinical management of COVID-19 patients and the need to consider sex-specific approaches in clinical trials in preventing and treating COVID-19 patients,” she said.

Considering that all patients are recommended to get COVID-19 vaccinations, “it is difficult to say how this impacts clinical practice,” said Janet Pope, MD, MPH, professor of medicine in the division of rheumatology at the University of Western Ontario, London, who was not involved with the study.

Sharing results with some patients may help to encourage vaccination, thus reducing risk of poor COVID-19 outcomes, Dr. Pope said.

In future studies, Dr. Zhou suggests using multiple databases and considering other geographies beyond the United States to further understand the etiology of sexual dimorphism in COVID-19 and expand generalizability. “In addition, future research will seek to provide insights into health equity gaps in the management of COVID-19. This may inform development of precision medicines and vaccines, especially among patients on immunosuppressive treatments,” she said.

The study was sponsored by Pfizer. Dr. Zhou and other study authors are Pfizer employees and hold Pfizer stock.

A version of this article first appeared on Medscape.com.

A retrospective study that analyzed sex disparities in patients with COVID-19 and rheumatoid arthritis found that men had more baseline comorbidities and increased risk of COVID-19–related outcomes, compared with women.

“Differences in genetics between sex and sex steroid hormones may play a role in predisposition to COVID-19 infection as well as modulating the disease progression,” according to Xiaofeng Zhou, PhD, senior director at Pfizer, New York, and the study’s lead author.

Dr. Zhou presented her findings at The Lancet Summit on Sex and Gender in Rheumatology.

Patients with chronic rheumatic diseases treated with immunomodulatory therapies may be at higher risk for more severe COVID-19 outcomes, including hospitalization, complications, and death. Research on sex-based disparities in RA patients with COVID-19 in the United States is limited, said Dr. Zhou, who embarked on a retrospective cohort study to examine the demographic and clinical characteristics of RA patients with COVID-19 and estimate the risk of possible COVID-19 outcomes by sex.

Dr. Zhou and colleagues used U.S. COVID-19 data collected through electronic health records by Optum during 2020 to June 2021. The study included adult patients with RA and a COVID-19 diagnosis (≥ 1 diagnosis code or positive SARS-CoV-2 laboratory test) and greater than or equal to 183 days of database enrollment who received treatment with immunomodulatory therapies prior to the diagnosis date. They were stratified by sex.

Investigators used logistic regression to estimate the risk of 11 possible COVID-19–related outcomes within 30 days of the COVID-19 diagnosis (hospitalization, ICU admission, pneumonia, kidney failure, thrombotic event, heart failure, acute respiratory distress syndrome [ARDS], sepsis/septic shock, mechanical ventilation/extracorporeal membrane oxygenation [ECMO], in-hospital death, and all-cause mortality), adjusting for demographics and baseline clinical covariates.

A total of 4,476 COVID-19 patients with RA (78% female) took part in the study. Male patients trended older (64 vs. 60 years) and had lower African American representation and Medicaid enrollment than female patients, but they had more baseline comorbidities such as hypertension (55% vs. 45%), hyperlipidemia (45% vs. 33%), diabetes (25% vs. 20%), coronary artery disease (28% vs. 12%), and chronic kidney disease (20% vs. 15%).

Eight of the eleven COVID-19 outcomes were significantly more likely to occur in men than women (hospitalization: odds ratio, 1.32 [95% confidence interval (CI), 1.11-1.56]; ICU admission: OR, 1.80 [95% CI, 1.36-2.40]; mechanical ventilation/ECMO: OR, 1.48 [95% CI, 1.04-2.11]; in-hospital death: OR, 1.53 [95% CI, 1.13-2.07]; all-cause mortality: OR, 1.42 [95% CI, 1.09-1.86]; sepsis: OR, 1.55 [95% CI, 1.20-2.02]; kidney failure: OR, 1.46 [95% CI, 1.15-1.85]; ARDS: OR, 1.39 [95% CI, 1.15-1.69]).

Sex hormones factor into risk

The data illustrated that men with RA had more baseline comorbidities and increased risk of COVID-19 outcomes than women.

Sex hormones regulate virus entry into host cells, respiratory function, immune response, the cardiovascular system, and coagulation, explained Dr. Zhou.

Estrogen and progesterone in women could help develop stronger and efficient immune responses to viruses and reduce virus entry into the host cells. Also, “[the] larger number of copies of ACE2 genes in women, [which] is linked with protection in the lungs against edema, permeability, and pulmonary damage, could be associated with lower incidence of severe COVID-19 outcomes, such as respiratory-related mortality and mortality,” Dr. Zhou said.

By comparison, androgens in men may increase virus entry into the host cells and promote unfavorable immune response through the induction of cytokine production and reducing the antibody response to the virus. This could lead to severe infection, Dr. Zhou said.

Sex-based differences in steroid hormones may also explain the higher incidence of morbidity and fatality that’s been observed in other studies of male patients with other infectious diseases, such as severe acute respiratory syndrome and Middle East respiratory syndrome.
 

Study bolsters evidence on sex disparities

The results add real-world evidence to the limited literature on sex disparities in COVID-19 outcomes among patients with RA in the United States, Dr. Zhou said. “The differential role in sex steroid hormones among women and men may shed light on clinical management of COVID-19 patients and the need to consider sex-specific approaches in clinical trials in preventing and treating COVID-19 patients,” she said.

Considering that all patients are recommended to get COVID-19 vaccinations, “it is difficult to say how this impacts clinical practice,” said Janet Pope, MD, MPH, professor of medicine in the division of rheumatology at the University of Western Ontario, London, who was not involved with the study.

Sharing results with some patients may help to encourage vaccination, thus reducing risk of poor COVID-19 outcomes, Dr. Pope said.

In future studies, Dr. Zhou suggests using multiple databases and considering other geographies beyond the United States to further understand the etiology of sexual dimorphism in COVID-19 and expand generalizability. “In addition, future research will seek to provide insights into health equity gaps in the management of COVID-19. This may inform development of precision medicines and vaccines, especially among patients on immunosuppressive treatments,” she said.

The study was sponsored by Pfizer. Dr. Zhou and other study authors are Pfizer employees and hold Pfizer stock.

A version of this article first appeared on Medscape.com.

The COVID-19 pandemic has been associated with the development of anorexia nervosa in Canadian children and adolescents, data suggest.

Preliminary results of the Canadian Paediatric Surveillance Program (CPSP) indicate that the pandemic has been a precipitating factor in the development of anorexia nervosa in almost half of children and adolescents studied. The pandemic also has precipitated hospitalizations for anorexia in more than one-third of cases.

“Data globally, and certainly our data here in Canada, have shown a real increase in health care utilization with the onset of the COVID-19 pandemic,” study author Debra Katzman, MD, professor of pediatrics at the Hospital for Sick Children in Toronto and the University of Toronto, said in an interview. “And when I talk about health care utilization, I’m talking about hospitalizations for eating disorders.”

The data were included in the 2021 results of the CPSP.
 

Focus on appearance

CPSP is a collaboration between the Public Health Agency of Canada and the Canadian Pediatric Society that consists of a network of 2,800 pediatricians and pediatric subspecialists across Canada. The latest results include surveillance studies on 14 diseases and conditions, with data collected during various periods.

From April 2020 to May 2021, researchers identified 1,800 COVID-19 cases in children and collected detailed information on 1,456 of them, including 405 cases hospitalized with pediatric inflammatory multisystem syndrome (PIMS). The median age of hospitalized cases was 3.2 years for SARS-CoV-2 infection and 5.4 years for PIMS.

Dr. Katzman and colleagues observed 118 first-time hospitalizations for anorexia nervosa between Sept. 1 and Dec. 31, 2021. More than 90% of reported cases were female, with 66% of verified cases in teens aged 14-17 years and the remainder in adolescents aged 11-13 years.

In 49% of cases, the reporting physician identified the COVID-19 pandemic as a precipitating factor in the development of anorexia nervosa. In 37% of cases, the reporting physician identified the pandemic as having precipitated the anorexia-related hospitalization.

Last year, a cross-sectional analysis of children in Canada reported that monthly hospitalizations for anorexia nervosa increased from 7.5 to 20 from March through November 2020. The monthly rate in the CPSP study was closer to 30 for first-time hospitalizations.

Dr. Katzman said that the findings about anorexia nervosa didn’t surprise her. “There was so much disruption and [so many] restrictions to young peoples’ daily routines – closures of schools and recreational activities – they lost regular connection with their peers, and they lost extracurricular and social activities,” she said. “That led to heightened anxiety and depression and really a lack of control.”

Adolescents and teens were also spending more time on social media than they were before the pandemic, she noted. “They were looking at themselves all the time, so they were getting preoccupied with their body image. There was a heightened focus on appearance, and I think that things like public-health mitigation strategies – things like hand washing, social distancing, mask wearing – may have impacted the psychological well-being of young people.”

The closure of outpatient facilities, long waiting lists to get into facilities that were opened, and “coronaphobia” about going to physicians’ offices and emergency departments compounded the problem, Dr. Katzman added.

The long-term effects of COVID and eating disorders in children are unknown, Dr. Katzman said. “This is sort of a wake-up call for the health care system that during times of stress or pandemics or crises, these kinds of things can happen, and we need to be prepared to provide the resources for vulnerable populations moving forward,” she said.
 

Heightened anxiety

Commenting on the data, Margaret Thew, APNP, director of the eating disorders program at Children’s Wisconsin in Milwaukee, said that isolation due to school closures and negative social media messages created the “perfect storm” for eating disorders in adolescents and teenagers because of higher rates of anxiety and depression. Ms. Thew was not involved in the research.

The storm is not over yet, she said. “What everyone needs to keep in mind is that we still have this very heightened state of anxiety and depression ... for adolescents, teenagers, and preteens alike,” Ms. Thew said in an interview, “and we know that many of them are not coping with their anxiety very well.”

In her experience, since the start of the pandemic, the average age of pediatric patients with eating disorders declined from 16 to 15 years, and the youngest age declined from 12 to 11 years.

Overall, the CPSP results show that children are affected by mental health issues at an earlier age than before the pandemic, said Ms. Thew. “Years ago, we wouldn’t have thought that an 8-year-old needed to be screened for some of these risk factors, but now we’re definitely getting more younger children who are struggling, and I think it’s taking too long for them to get the care they need because it’s being overlooked,” she said.

The report was funded by the Public Health Agency of Canada, Health Canada, Alberta Children’s Hospital Research Institute, Bethanys Hope Foundation, CHEO Research Institute, and Children’s Hospital Research Institute of Manitoba. Dr. Katzman and Ms. Thew have no relevant disclosures.

A version of this article first appeared on Medscape.com.

The COVID-19 pandemic has been associated with the development of anorexia nervosa in Canadian children and adolescents, data suggest.

Preliminary results of the Canadian Paediatric Surveillance Program (CPSP) indicate that the pandemic has been a precipitating factor in the development of anorexia nervosa in almost half of children and adolescents studied. The pandemic also has precipitated hospitalizations for anorexia in more than one-third of cases.

“Data globally, and certainly our data here in Canada, have shown a real increase in health care utilization with the onset of the COVID-19 pandemic,” study author Debra Katzman, MD, professor of pediatrics at the Hospital for Sick Children in Toronto and the University of Toronto, said in an interview. “And when I talk about health care utilization, I’m talking about hospitalizations for eating disorders.”

The data were included in the 2021 results of the CPSP.
 

Focus on appearance

CPSP is a collaboration between the Public Health Agency of Canada and the Canadian Pediatric Society that consists of a network of 2,800 pediatricians and pediatric subspecialists across Canada. The latest results include surveillance studies on 14 diseases and conditions, with data collected during various periods.

From April 2020 to May 2021, researchers identified 1,800 COVID-19 cases in children and collected detailed information on 1,456 of them, including 405 cases hospitalized with pediatric inflammatory multisystem syndrome (PIMS). The median age of hospitalized cases was 3.2 years for SARS-CoV-2 infection and 5.4 years for PIMS.

Dr. Katzman and colleagues observed 118 first-time hospitalizations for anorexia nervosa between Sept. 1 and Dec. 31, 2021. More than 90% of reported cases were female, with 66% of verified cases in teens aged 14-17 years and the remainder in adolescents aged 11-13 years.

In 49% of cases, the reporting physician identified the COVID-19 pandemic as a precipitating factor in the development of anorexia nervosa. In 37% of cases, the reporting physician identified the pandemic as having precipitated the anorexia-related hospitalization.

Last year, a cross-sectional analysis of children in Canada reported that monthly hospitalizations for anorexia nervosa increased from 7.5 to 20 from March through November 2020. The monthly rate in the CPSP study was closer to 30 for first-time hospitalizations.

Dr. Katzman said that the findings about anorexia nervosa didn’t surprise her. “There was so much disruption and [so many] restrictions to young peoples’ daily routines – closures of schools and recreational activities – they lost regular connection with their peers, and they lost extracurricular and social activities,” she said. “That led to heightened anxiety and depression and really a lack of control.”

Adolescents and teens were also spending more time on social media than they were before the pandemic, she noted. “They were looking at themselves all the time, so they were getting preoccupied with their body image. There was a heightened focus on appearance, and I think that things like public-health mitigation strategies – things like hand washing, social distancing, mask wearing – may have impacted the psychological well-being of young people.”

The closure of outpatient facilities, long waiting lists to get into facilities that were opened, and “coronaphobia” about going to physicians’ offices and emergency departments compounded the problem, Dr. Katzman added.

The long-term effects of COVID and eating disorders in children are unknown, Dr. Katzman said. “This is sort of a wake-up call for the health care system that during times of stress or pandemics or crises, these kinds of things can happen, and we need to be prepared to provide the resources for vulnerable populations moving forward,” she said.
 

Heightened anxiety

Commenting on the data, Margaret Thew, APNP, director of the eating disorders program at Children’s Wisconsin in Milwaukee, said that isolation due to school closures and negative social media messages created the “perfect storm” for eating disorders in adolescents and teenagers because of higher rates of anxiety and depression. Ms. Thew was not involved in the research.

The storm is not over yet, she said. “What everyone needs to keep in mind is that we still have this very heightened state of anxiety and depression ... for adolescents, teenagers, and preteens alike,” Ms. Thew said in an interview, “and we know that many of them are not coping with their anxiety very well.”

In her experience, since the start of the pandemic, the average age of pediatric patients with eating disorders declined from 16 to 15 years, and the youngest age declined from 12 to 11 years.

Overall, the CPSP results show that children are affected by mental health issues at an earlier age than before the pandemic, said Ms. Thew. “Years ago, we wouldn’t have thought that an 8-year-old needed to be screened for some of these risk factors, but now we’re definitely getting more younger children who are struggling, and I think it’s taking too long for them to get the care they need because it’s being overlooked,” she said.

The report was funded by the Public Health Agency of Canada, Health Canada, Alberta Children’s Hospital Research Institute, Bethanys Hope Foundation, CHEO Research Institute, and Children’s Hospital Research Institute of Manitoba. Dr. Katzman and Ms. Thew have no relevant disclosures.

A version of this article first appeared on Medscape.com.

The COVID-19 pandemic has been associated with the development of anorexia nervosa in Canadian children and adolescents, data suggest.

Preliminary results of the Canadian Paediatric Surveillance Program (CPSP) indicate that the pandemic has been a precipitating factor in the development of anorexia nervosa in almost half of children and adolescents studied. The pandemic also has precipitated hospitalizations for anorexia in more than one-third of cases.

“Data globally, and certainly our data here in Canada, have shown a real increase in health care utilization with the onset of the COVID-19 pandemic,” study author Debra Katzman, MD, professor of pediatrics at the Hospital for Sick Children in Toronto and the University of Toronto, said in an interview. “And when I talk about health care utilization, I’m talking about hospitalizations for eating disorders.”

The data were included in the 2021 results of the CPSP.
 

Focus on appearance

CPSP is a collaboration between the Public Health Agency of Canada and the Canadian Pediatric Society that consists of a network of 2,800 pediatricians and pediatric subspecialists across Canada. The latest results include surveillance studies on 14 diseases and conditions, with data collected during various periods.

From April 2020 to May 2021, researchers identified 1,800 COVID-19 cases in children and collected detailed information on 1,456 of them, including 405 cases hospitalized with pediatric inflammatory multisystem syndrome (PIMS). The median age of hospitalized cases was 3.2 years for SARS-CoV-2 infection and 5.4 years for PIMS.

Dr. Katzman and colleagues observed 118 first-time hospitalizations for anorexia nervosa between Sept. 1 and Dec. 31, 2021. More than 90% of reported cases were female, with 66% of verified cases in teens aged 14-17 years and the remainder in adolescents aged 11-13 years.

In 49% of cases, the reporting physician identified the COVID-19 pandemic as a precipitating factor in the development of anorexia nervosa. In 37% of cases, the reporting physician identified the pandemic as having precipitated the anorexia-related hospitalization.

Last year, a cross-sectional analysis of children in Canada reported that monthly hospitalizations for anorexia nervosa increased from 7.5 to 20 from March through November 2020. The monthly rate in the CPSP study was closer to 30 for first-time hospitalizations.

Dr. Katzman said that the findings about anorexia nervosa didn’t surprise her. “There was so much disruption and [so many] restrictions to young peoples’ daily routines – closures of schools and recreational activities – they lost regular connection with their peers, and they lost extracurricular and social activities,” she said. “That led to heightened anxiety and depression and really a lack of control.”

Adolescents and teens were also spending more time on social media than they were before the pandemic, she noted. “They were looking at themselves all the time, so they were getting preoccupied with their body image. There was a heightened focus on appearance, and I think that things like public-health mitigation strategies – things like hand washing, social distancing, mask wearing – may have impacted the psychological well-being of young people.”

The closure of outpatient facilities, long waiting lists to get into facilities that were opened, and “coronaphobia” about going to physicians’ offices and emergency departments compounded the problem, Dr. Katzman added.

The long-term effects of COVID and eating disorders in children are unknown, Dr. Katzman said. “This is sort of a wake-up call for the health care system that during times of stress or pandemics or crises, these kinds of things can happen, and we need to be prepared to provide the resources for vulnerable populations moving forward,” she said.
 

Heightened anxiety

Commenting on the data, Margaret Thew, APNP, director of the eating disorders program at Children’s Wisconsin in Milwaukee, said that isolation due to school closures and negative social media messages created the “perfect storm” for eating disorders in adolescents and teenagers because of higher rates of anxiety and depression. Ms. Thew was not involved in the research.

The storm is not over yet, she said. “What everyone needs to keep in mind is that we still have this very heightened state of anxiety and depression ... for adolescents, teenagers, and preteens alike,” Ms. Thew said in an interview, “and we know that many of them are not coping with their anxiety very well.”

In her experience, since the start of the pandemic, the average age of pediatric patients with eating disorders declined from 16 to 15 years, and the youngest age declined from 12 to 11 years.

Overall, the CPSP results show that children are affected by mental health issues at an earlier age than before the pandemic, said Ms. Thew. “Years ago, we wouldn’t have thought that an 8-year-old needed to be screened for some of these risk factors, but now we’re definitely getting more younger children who are struggling, and I think it’s taking too long for them to get the care they need because it’s being overlooked,” she said.

The report was funded by the Public Health Agency of Canada, Health Canada, Alberta Children’s Hospital Research Institute, Bethanys Hope Foundation, CHEO Research Institute, and Children’s Hospital Research Institute of Manitoba. Dr. Katzman and Ms. Thew have no relevant disclosures.

A version of this article first appeared on Medscape.com.