Clinician Reviews

Case: A 3-year-old girl presented to the emergency department after a brief seizure at home. She looked well on physical exam except for a fever of 103° F and thick rhinorrhea.

The intern on duty methodically worked through the standard list of questions. “Immunizations up to date?” she asked.

“Absolutely,” the child’s mom responded. “She’s had everything that’s recommended.”

“Including COVID-19 vaccine?” the intern prompted.

“No.” The mom responded with a shake of her head. “We don’t do that vaccine.”

That mom is not alone. 

COVID-19 vaccines for children as young as 6 months were given emergency-use authorization by the Food and Drug Administration in June 2022 and in February 2023, the Advisory Committee on Immunization Practices included COVID-19 vaccine on the routine childhood immunization schedule.

COVID-19 vaccines are safe in young children, and they prevent the most severe outcomes associated with infection, including hospitalization. Newly released data confirm that the COVID-19 vaccines produced by Moderna and Pfizer also provide protection against symptomatic infection for at least 4 months after completion of the monovalent primary series. 

In a Morbidity and Mortality Weekly Report released on Feb. 17, 2023, the Centers for Disease Control and Prevention reported the results of a test-negative design case-control study that enrolled symptomatic children tested for SARS-CoV-2 infection through Feb. 5, 2023, as part of the Increasing Community Access to Testing (ICATT) program.¹ ICATT provides SARS-CoV-2 testing to persons aged at least 3 years at pharmacy and community-based testing sites nationwide.

Two doses of monovalent Moderna vaccine (complete primary series) was 60% effective against symptomatic infection (95% confidence interval, 49%-68%) 2 weeks to 2 months after receipt of the second dose. Vaccine effectiveness dropped to 36% (95% CI, 15%-52%) 3-4 months after the second dose. Three doses of monovalent Pfizer-BioNTech vaccine (complete primary series) was 31% effective (95% CI, 7%-49%) at preventing symptomatic infection 2 weeks to 4 months after receipt of the third dose. A bivalent vaccine dose for eligible children is expected to provide more protection against currently circulating SARS-CoV-2 variants. 

Despite evidence of vaccine efficacy, very few parents are opting to protect their young children with the COVID-19 vaccine. The CDC reports that, as of March 1, 2023, only 8% of children under 2 years and 10.5% of children aged 2-4 years have initiated a COVID vaccine series. The American Academy of Pediatrics has emphasized that 15.0 million children between the ages of 6 months and 4 years have not yet received their first COVID-19 vaccine dose.

While the reasons underlying low COVID-19 vaccination rates in young children are complex, themes emerge. Socioeconomic disparities contributing to low vaccination rates in young children were highlighted in another recent MMWR article.² Through Dec. 1, 2022, vaccination coverage was lower in rural counties (3.4%) than in urban counties (10.5%). Rates were lower in Black and Hispanic children than in White and Asian children. 

According to the CDC, high rates of poverty in Black and Hispanic communities may affect vaccination coverage by affecting caregivers’ access to vaccination sites or ability to leave work to take their child to be vaccinated. Pediatric care providers have repeatedly been identified by parents as a source of trusted vaccine information and a strong provider recommendation is associated with vaccination, but not all families are receiving vaccine advice. In a 2022 Kaiser Family Foundation survey, parents of young children with annual household incomes above $90,000 were more likely to talk to their pediatrician about a COVID-19 vaccine than families with lower incomes.³Vaccine hesitancy, fueled by general confusion and skepticism, is another factor contributing to low vaccination rates. Admittedly, the recommendations are complex and on March 14, 2023, the FDA again revised the emergency-use authorization for young children. Some caregivers continue to express concerns about vaccine side effects as well as the belief that the vaccine won’t prevent their child from getting sick. 

Kendall Purcell, MD, a pediatrician with Norton Children’s Medical Group in Louisville, Ky., recommends COVID-19 vaccination for her patients because it reduces the risk of severe disease. That factored into her own decision to vaccinate her 4-year-old son and 1-year-old daughter, but she hasn’t been able to convince the parents of all her patients. “Some feel that COVID-19 is not as severe for children, so the risks don’t outweigh the benefits when it comes to vaccinating their children.” Back to our case: In the ED the intern reviewed the laboratory testing she had ordered. She then sat down with the mother of the 3-year-old girl to discuss the diagnosis: febrile seizure associated with COVID-19 infection. Febrile seizures are a well-recognized but uncommon complication of COVID-19 in children. In a retrospective cohort study using electronic health record data, febrile seizures occurred in 0.5% of 8,854 children aged 0-5 years with COVID-19 infection.⁴ About 9% of these children required critical care services. In another cohort of hospitalized children, neurologic complications occurred in 7% of children hospitalized with COVID-19.⁵ Febrile and nonfebrile seizures were most commonly observed.

“I really thought COVID-19 was no big deal in young kids,” the mom said. “Parents need the facts.”

The facts are these: Through Dec. 2, 2022, more than 3 million cases of COVID-19 have been reported in children aged younger than 5 years. While COVID is generally less severe in young children than older adults, it is difficult to predict which children will become seriously ill. When children are hospitalized, one in four requires intensive care. COVID-19 is now a vaccine-preventable disease, but too many children remain unprotected.

Dr. Bryant is a pediatrician specializing in infectious diseases at the University of Louisville (Ky.) and Norton Children’s Hospital, also in Louisville. She is a member of the AAP’s Committee on Infectious Diseases and one of the lead authors of the AAP’s Recommendations for Prevention and Control of Influenza in Children, 2022-2023. The opinions expressed in this article are her own. Dr. Bryant discloses that she has served as an investigator on clinical trials funded by Pfizer, Enanta, and Gilead. Email her at [email protected]. Ms. Ezell is a recent graduate from Indiana University Southeast with a Bachelor of Arts in English. They have no conflicts of interest.

References

1. Fleming-Dutra KE et al. Morb Mortal Wkly Rep. 2023;72:177-182.

2. Murthy BP et al. Morb Mortal Wkly Rep. 2023;72:183-9.

3. Lopes L et al. KFF COVID-19 vaccine monitor: July 2022. San Francisco: Kaiser Family Foundation, 2022.

4. Cadet K et al. J Child Neurol. 2022 Apr;37(5):410-5.

5. Antoon JW et al. Pediatrics. 2022 Nov 1;150(5):e2022058167.

Case: A 3-year-old girl presented to the emergency department after a brief seizure at home. She looked well on physical exam except for a fever of 103° F and thick rhinorrhea.

The intern on duty methodically worked through the standard list of questions. “Immunizations up to date?” she asked.

“Absolutely,” the child’s mom responded. “She’s had everything that’s recommended.”

“Including COVID-19 vaccine?” the intern prompted.

“No.” The mom responded with a shake of her head. “We don’t do that vaccine.”

That mom is not alone. 

COVID-19 vaccines for children as young as 6 months were given emergency-use authorization by the Food and Drug Administration in June 2022 and in February 2023, the Advisory Committee on Immunization Practices included COVID-19 vaccine on the routine childhood immunization schedule.

COVID-19 vaccines are safe in young children, and they prevent the most severe outcomes associated with infection, including hospitalization. Newly released data confirm that the COVID-19 vaccines produced by Moderna and Pfizer also provide protection against symptomatic infection for at least 4 months after completion of the monovalent primary series. 

In a Morbidity and Mortality Weekly Report released on Feb. 17, 2023, the Centers for Disease Control and Prevention reported the results of a test-negative design case-control study that enrolled symptomatic children tested for SARS-CoV-2 infection through Feb. 5, 2023, as part of the Increasing Community Access to Testing (ICATT) program.¹ ICATT provides SARS-CoV-2 testing to persons aged at least 3 years at pharmacy and community-based testing sites nationwide.

Two doses of monovalent Moderna vaccine (complete primary series) was 60% effective against symptomatic infection (95% confidence interval, 49%-68%) 2 weeks to 2 months after receipt of the second dose. Vaccine effectiveness dropped to 36% (95% CI, 15%-52%) 3-4 months after the second dose. Three doses of monovalent Pfizer-BioNTech vaccine (complete primary series) was 31% effective (95% CI, 7%-49%) at preventing symptomatic infection 2 weeks to 4 months after receipt of the third dose. A bivalent vaccine dose for eligible children is expected to provide more protection against currently circulating SARS-CoV-2 variants. 

Despite evidence of vaccine efficacy, very few parents are opting to protect their young children with the COVID-19 vaccine. The CDC reports that, as of March 1, 2023, only 8% of children under 2 years and 10.5% of children aged 2-4 years have initiated a COVID vaccine series. The American Academy of Pediatrics has emphasized that 15.0 million children between the ages of 6 months and 4 years have not yet received their first COVID-19 vaccine dose.

While the reasons underlying low COVID-19 vaccination rates in young children are complex, themes emerge. Socioeconomic disparities contributing to low vaccination rates in young children were highlighted in another recent MMWR article.² Through Dec. 1, 2022, vaccination coverage was lower in rural counties (3.4%) than in urban counties (10.5%). Rates were lower in Black and Hispanic children than in White and Asian children. 

According to the CDC, high rates of poverty in Black and Hispanic communities may affect vaccination coverage by affecting caregivers’ access to vaccination sites or ability to leave work to take their child to be vaccinated. Pediatric care providers have repeatedly been identified by parents as a source of trusted vaccine information and a strong provider recommendation is associated with vaccination, but not all families are receiving vaccine advice. In a 2022 Kaiser Family Foundation survey, parents of young children with annual household incomes above $90,000 were more likely to talk to their pediatrician about a COVID-19 vaccine than families with lower incomes.³Vaccine hesitancy, fueled by general confusion and skepticism, is another factor contributing to low vaccination rates. Admittedly, the recommendations are complex and on March 14, 2023, the FDA again revised the emergency-use authorization for young children. Some caregivers continue to express concerns about vaccine side effects as well as the belief that the vaccine won’t prevent their child from getting sick. 

Kendall Purcell, MD, a pediatrician with Norton Children’s Medical Group in Louisville, Ky., recommends COVID-19 vaccination for her patients because it reduces the risk of severe disease. That factored into her own decision to vaccinate her 4-year-old son and 1-year-old daughter, but she hasn’t been able to convince the parents of all her patients. “Some feel that COVID-19 is not as severe for children, so the risks don’t outweigh the benefits when it comes to vaccinating their children.” Back to our case: In the ED the intern reviewed the laboratory testing she had ordered. She then sat down with the mother of the 3-year-old girl to discuss the diagnosis: febrile seizure associated with COVID-19 infection. Febrile seizures are a well-recognized but uncommon complication of COVID-19 in children. In a retrospective cohort study using electronic health record data, febrile seizures occurred in 0.5% of 8,854 children aged 0-5 years with COVID-19 infection.⁴ About 9% of these children required critical care services. In another cohort of hospitalized children, neurologic complications occurred in 7% of children hospitalized with COVID-19.⁵ Febrile and nonfebrile seizures were most commonly observed.

“I really thought COVID-19 was no big deal in young kids,” the mom said. “Parents need the facts.”

The facts are these: Through Dec. 2, 2022, more than 3 million cases of COVID-19 have been reported in children aged younger than 5 years. While COVID is generally less severe in young children than older adults, it is difficult to predict which children will become seriously ill. When children are hospitalized, one in four requires intensive care. COVID-19 is now a vaccine-preventable disease, but too many children remain unprotected.

Dr. Bryant is a pediatrician specializing in infectious diseases at the University of Louisville (Ky.) and Norton Children’s Hospital, also in Louisville. She is a member of the AAP’s Committee on Infectious Diseases and one of the lead authors of the AAP’s Recommendations for Prevention and Control of Influenza in Children, 2022-2023. The opinions expressed in this article are her own. Dr. Bryant discloses that she has served as an investigator on clinical trials funded by Pfizer, Enanta, and Gilead. Email her at [email protected]. Ms. Ezell is a recent graduate from Indiana University Southeast with a Bachelor of Arts in English. They have no conflicts of interest.

References

1. Fleming-Dutra KE et al. Morb Mortal Wkly Rep. 2023;72:177-182.

2. Murthy BP et al. Morb Mortal Wkly Rep. 2023;72:183-9.

3. Lopes L et al. KFF COVID-19 vaccine monitor: July 2022. San Francisco: Kaiser Family Foundation, 2022.

4. Cadet K et al. J Child Neurol. 2022 Apr;37(5):410-5.

5. Antoon JW et al. Pediatrics. 2022 Nov 1;150(5):e2022058167.

Case: A 3-year-old girl presented to the emergency department after a brief seizure at home. She looked well on physical exam except for a fever of 103° F and thick rhinorrhea.

The intern on duty methodically worked through the standard list of questions. “Immunizations up to date?” she asked.

“Absolutely,” the child’s mom responded. “She’s had everything that’s recommended.”

“Including COVID-19 vaccine?” the intern prompted.

“No.” The mom responded with a shake of her head. “We don’t do that vaccine.”

That mom is not alone. 

COVID-19 vaccines for children as young as 6 months were given emergency-use authorization by the Food and Drug Administration in June 2022 and in February 2023, the Advisory Committee on Immunization Practices included COVID-19 vaccine on the routine childhood immunization schedule.

COVID-19 vaccines are safe in young children, and they prevent the most severe outcomes associated with infection, including hospitalization. Newly released data confirm that the COVID-19 vaccines produced by Moderna and Pfizer also provide protection against symptomatic infection for at least 4 months after completion of the monovalent primary series. 

In a Morbidity and Mortality Weekly Report released on Feb. 17, 2023, the Centers for Disease Control and Prevention reported the results of a test-negative design case-control study that enrolled symptomatic children tested for SARS-CoV-2 infection through Feb. 5, 2023, as part of the Increasing Community Access to Testing (ICATT) program.¹ ICATT provides SARS-CoV-2 testing to persons aged at least 3 years at pharmacy and community-based testing sites nationwide.

Two doses of monovalent Moderna vaccine (complete primary series) was 60% effective against symptomatic infection (95% confidence interval, 49%-68%) 2 weeks to 2 months after receipt of the second dose. Vaccine effectiveness dropped to 36% (95% CI, 15%-52%) 3-4 months after the second dose. Three doses of monovalent Pfizer-BioNTech vaccine (complete primary series) was 31% effective (95% CI, 7%-49%) at preventing symptomatic infection 2 weeks to 4 months after receipt of the third dose. A bivalent vaccine dose for eligible children is expected to provide more protection against currently circulating SARS-CoV-2 variants. 

Despite evidence of vaccine efficacy, very few parents are opting to protect their young children with the COVID-19 vaccine. The CDC reports that, as of March 1, 2023, only 8% of children under 2 years and 10.5% of children aged 2-4 years have initiated a COVID vaccine series. The American Academy of Pediatrics has emphasized that 15.0 million children between the ages of 6 months and 4 years have not yet received their first COVID-19 vaccine dose.

While the reasons underlying low COVID-19 vaccination rates in young children are complex, themes emerge. Socioeconomic disparities contributing to low vaccination rates in young children were highlighted in another recent MMWR article.² Through Dec. 1, 2022, vaccination coverage was lower in rural counties (3.4%) than in urban counties (10.5%). Rates were lower in Black and Hispanic children than in White and Asian children. 

According to the CDC, high rates of poverty in Black and Hispanic communities may affect vaccination coverage by affecting caregivers’ access to vaccination sites or ability to leave work to take their child to be vaccinated. Pediatric care providers have repeatedly been identified by parents as a source of trusted vaccine information and a strong provider recommendation is associated with vaccination, but not all families are receiving vaccine advice. In a 2022 Kaiser Family Foundation survey, parents of young children with annual household incomes above $90,000 were more likely to talk to their pediatrician about a COVID-19 vaccine than families with lower incomes.³Vaccine hesitancy, fueled by general confusion and skepticism, is another factor contributing to low vaccination rates. Admittedly, the recommendations are complex and on March 14, 2023, the FDA again revised the emergency-use authorization for young children. Some caregivers continue to express concerns about vaccine side effects as well as the belief that the vaccine won’t prevent their child from getting sick. 

Kendall Purcell, MD, a pediatrician with Norton Children’s Medical Group in Louisville, Ky., recommends COVID-19 vaccination for her patients because it reduces the risk of severe disease. That factored into her own decision to vaccinate her 4-year-old son and 1-year-old daughter, but she hasn’t been able to convince the parents of all her patients. “Some feel that COVID-19 is not as severe for children, so the risks don’t outweigh the benefits when it comes to vaccinating their children.” Back to our case: In the ED the intern reviewed the laboratory testing she had ordered. She then sat down with the mother of the 3-year-old girl to discuss the diagnosis: febrile seizure associated with COVID-19 infection. Febrile seizures are a well-recognized but uncommon complication of COVID-19 in children. In a retrospective cohort study using electronic health record data, febrile seizures occurred in 0.5% of 8,854 children aged 0-5 years with COVID-19 infection.⁴ About 9% of these children required critical care services. In another cohort of hospitalized children, neurologic complications occurred in 7% of children hospitalized with COVID-19.⁵ Febrile and nonfebrile seizures were most commonly observed.

“I really thought COVID-19 was no big deal in young kids,” the mom said. “Parents need the facts.”

The facts are these: Through Dec. 2, 2022, more than 3 million cases of COVID-19 have been reported in children aged younger than 5 years. While COVID is generally less severe in young children than older adults, it is difficult to predict which children will become seriously ill. When children are hospitalized, one in four requires intensive care. COVID-19 is now a vaccine-preventable disease, but too many children remain unprotected.

Dr. Bryant is a pediatrician specializing in infectious diseases at the University of Louisville (Ky.) and Norton Children’s Hospital, also in Louisville. She is a member of the AAP’s Committee on Infectious Diseases and one of the lead authors of the AAP’s Recommendations for Prevention and Control of Influenza in Children, 2022-2023. The opinions expressed in this article are her own. Dr. Bryant discloses that she has served as an investigator on clinical trials funded by Pfizer, Enanta, and Gilead. Email her at [email protected]. Ms. Ezell is a recent graduate from Indiana University Southeast with a Bachelor of Arts in English. They have no conflicts of interest.

References

1. Fleming-Dutra KE et al. Morb Mortal Wkly Rep. 2023;72:177-182.

2. Murthy BP et al. Morb Mortal Wkly Rep. 2023;72:183-9.

3. Lopes L et al. KFF COVID-19 vaccine monitor: July 2022. San Francisco: Kaiser Family Foundation, 2022.

4. Cadet K et al. J Child Neurol. 2022 Apr;37(5):410-5.

5. Antoon JW et al. Pediatrics. 2022 Nov 1;150(5):e2022058167.

Detecting melanoma early, when it is easier to treat, remains a “paramount goal,” but guidelines surrounding optimal melanoma screening practices and diagnostic evaluations need greater clarity, according to the authors of a new consensus statement.

That is why a group of expert panelists evaluated the existing evidence and a range of clinical scenarios to help clarify the optimal strategies for early detection and assessment of cutaneous melanoma.

Overall, the panelists agreed that a risk-stratified approach is likely the most appropriate strategy for melanoma screening and follow-up and supported the use of visual and dermoscopic examination. However, the panelists did not reach consensus on the role for gene expression profile (GEP) testing in clinical decision-making, citing the need for these assays to be validated in large randomized clinical trials.

In an accompanying editorial, two experts highlighted the importance of carefully evaluating the role of diagnostic tests.

“Diagnostic tests such as GEP must face critical scrutiny; if not, there are immediate concerns for patient care, such as the patient being erroneously informed that they do not have cancer or told that they do have cancer when they do not,” write Alan C. Geller, MPH, RN, from the Harvard T.H. Chan School of Public Health, Boston, and Marvin A. Weinstock, MD, PhD, from Brown University, Providence, R.I.

The consensus statement was published online in JAMA Dermatology.
 

The need for guidance

Although focusing melanoma screening on higher-risk populations may be cost effective, compared with population-based screening, the major guidelines lack consistent guidance to support a risk-stratified approach to skin cancer screening and best practices on diagnosing cutaneous melanoma.

In the prebiopsy setting, the appropriate use of diagnostic tools for evaluating the need for biopsy remain poorly defined, and, in the post-biopsy setting, questions remain concerning the diagnostic accuracy of molecular techniques, diagnostic GEP testing, next-generation sequencing, and immunohistochemical assessment for various markers of melanoma.

To provide consensus recommendations on optimal screening practices, prebiopsy and postbiopsy diagnostics, and prognostic assessment of cutaneous melanoma, a group of 42 panelists voted on hypothetical scenarios via an emailed survey. The panel then came together for a consensus conference, which included 51 experts who discussed their approach to the various clinical case scenarios. Most attendees (45 of the 51) answered a follow-up survey for their final recommendations.

The panelists reached a consensus, with 70% agreement, to support a risk-stratified approach to melanoma screening in clinical settings and public screening events. The experts agreed that higher-risk individuals (those with a relative risk of 5 or greater) could be appropriately screened by a general dermatologist or pigmented lesion evaluation. Higher-risk individuals included those with severe skin damage from the sun, systemic immunosuppression, or a personal history of nonmelanoma or melanoma skin cancer.

Panelists agreed that those at general or lower risk (RR < 2) could be screened by a primary care provider or through regular self- or partner examinations, whereas those at moderate risk could be screened by their primary care clinician or general dermatologist. The experts observed “a shift in acceptance” of primary care physicians screening the general population, and an acknowledgement of the importance of self- and partner examinations as screening adjuncts for all populations.

In the prebiopsy setting, panelists reached consensus that visual and dermoscopic examination was appropriate for evaluating patients with “no new, changing, or unusual skin lesions or with a new lesion that is not visually concerning.”

The panelists also reached consensus that lesions deemed clinically suspicious for cancer or showing features of cancer on reflectance confocal microscopy should be biopsied. Although most respondents (86%) did not currently use epidermal tape stripping routinely, they agreed that, in a hypothetical situation where epidermal tape stripping was used, that lesions positive for PRAME or LINC should be biopsied.

In the postbiopsy setting, views on the use of GEP scores varied. Although panelists agreed that a low-risk prognostic GEP score should not outweigh concerning histologic features when patients are selected to undergo sentinel lymph node biopsy (SLNB), they did not reach consensus for imaging recommendations in the setting of a high-risk prognostic GEP score and low-risk histology and/or negative nodal status.

“The panelists await future, well-designed prospective studies to determine if use of these and newer technologies improves the care of patients with melanoma,” the panelists write.

In the editorial, Mr. Geller and Dr. Weinstock highlighted concerns about the cost and potential access issues associated with these newer technologies, given that the current cost of GEP testing exceeds $7,000.

The editorialists also emphasize that “going forward, the field should be advanced by tackling one of the more pressing, common, potentially morbid, and costly procedures – the prognostic use of sentinel lymph node biopsy.”

Of critical importance is “whether GEP can reduce morbidity and cost by safely reducing the number of SLNBs performed,” Mr. Geller and Dr. Weinstock write.

The funding for the administration and facilitation of the consensus development conference and the development of the manuscript was provided by Dermtech, in an unrestricted award overseen by the Melanoma Research Foundation and managed and executed at UPMC by the principal investigator. Several of the coauthors disclosed relationships with industry. Mr. Geller is a contributor to UptoDate for which he receives royalties. Dr. Weinstock receives consulting fees from AbbVie.

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

Detecting melanoma early, when it is easier to treat, remains a “paramount goal,” but guidelines surrounding optimal melanoma screening practices and diagnostic evaluations need greater clarity, according to the authors of a new consensus statement.

That is why a group of expert panelists evaluated the existing evidence and a range of clinical scenarios to help clarify the optimal strategies for early detection and assessment of cutaneous melanoma.

Overall, the panelists agreed that a risk-stratified approach is likely the most appropriate strategy for melanoma screening and follow-up and supported the use of visual and dermoscopic examination. However, the panelists did not reach consensus on the role for gene expression profile (GEP) testing in clinical decision-making, citing the need for these assays to be validated in large randomized clinical trials.

In an accompanying editorial, two experts highlighted the importance of carefully evaluating the role of diagnostic tests.

“Diagnostic tests such as GEP must face critical scrutiny; if not, there are immediate concerns for patient care, such as the patient being erroneously informed that they do not have cancer or told that they do have cancer when they do not,” write Alan C. Geller, MPH, RN, from the Harvard T.H. Chan School of Public Health, Boston, and Marvin A. Weinstock, MD, PhD, from Brown University, Providence, R.I.

The consensus statement was published online in JAMA Dermatology.
 

The need for guidance

Although focusing melanoma screening on higher-risk populations may be cost effective, compared with population-based screening, the major guidelines lack consistent guidance to support a risk-stratified approach to skin cancer screening and best practices on diagnosing cutaneous melanoma.

In the prebiopsy setting, the appropriate use of diagnostic tools for evaluating the need for biopsy remain poorly defined, and, in the post-biopsy setting, questions remain concerning the diagnostic accuracy of molecular techniques, diagnostic GEP testing, next-generation sequencing, and immunohistochemical assessment for various markers of melanoma.

To provide consensus recommendations on optimal screening practices, prebiopsy and postbiopsy diagnostics, and prognostic assessment of cutaneous melanoma, a group of 42 panelists voted on hypothetical scenarios via an emailed survey. The panel then came together for a consensus conference, which included 51 experts who discussed their approach to the various clinical case scenarios. Most attendees (45 of the 51) answered a follow-up survey for their final recommendations.

The panelists reached a consensus, with 70% agreement, to support a risk-stratified approach to melanoma screening in clinical settings and public screening events. The experts agreed that higher-risk individuals (those with a relative risk of 5 or greater) could be appropriately screened by a general dermatologist or pigmented lesion evaluation. Higher-risk individuals included those with severe skin damage from the sun, systemic immunosuppression, or a personal history of nonmelanoma or melanoma skin cancer.

Panelists agreed that those at general or lower risk (RR < 2) could be screened by a primary care provider or through regular self- or partner examinations, whereas those at moderate risk could be screened by their primary care clinician or general dermatologist. The experts observed “a shift in acceptance” of primary care physicians screening the general population, and an acknowledgement of the importance of self- and partner examinations as screening adjuncts for all populations.

In the prebiopsy setting, panelists reached consensus that visual and dermoscopic examination was appropriate for evaluating patients with “no new, changing, or unusual skin lesions or with a new lesion that is not visually concerning.”

The panelists also reached consensus that lesions deemed clinically suspicious for cancer or showing features of cancer on reflectance confocal microscopy should be biopsied. Although most respondents (86%) did not currently use epidermal tape stripping routinely, they agreed that, in a hypothetical situation where epidermal tape stripping was used, that lesions positive for PRAME or LINC should be biopsied.

In the postbiopsy setting, views on the use of GEP scores varied. Although panelists agreed that a low-risk prognostic GEP score should not outweigh concerning histologic features when patients are selected to undergo sentinel lymph node biopsy (SLNB), they did not reach consensus for imaging recommendations in the setting of a high-risk prognostic GEP score and low-risk histology and/or negative nodal status.

“The panelists await future, well-designed prospective studies to determine if use of these and newer technologies improves the care of patients with melanoma,” the panelists write.

In the editorial, Mr. Geller and Dr. Weinstock highlighted concerns about the cost and potential access issues associated with these newer technologies, given that the current cost of GEP testing exceeds $7,000.

The editorialists also emphasize that “going forward, the field should be advanced by tackling one of the more pressing, common, potentially morbid, and costly procedures – the prognostic use of sentinel lymph node biopsy.”

Of critical importance is “whether GEP can reduce morbidity and cost by safely reducing the number of SLNBs performed,” Mr. Geller and Dr. Weinstock write.

The funding for the administration and facilitation of the consensus development conference and the development of the manuscript was provided by Dermtech, in an unrestricted award overseen by the Melanoma Research Foundation and managed and executed at UPMC by the principal investigator. Several of the coauthors disclosed relationships with industry. Mr. Geller is a contributor to UptoDate for which he receives royalties. Dr. Weinstock receives consulting fees from AbbVie.

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

Detecting melanoma early, when it is easier to treat, remains a “paramount goal,” but guidelines surrounding optimal melanoma screening practices and diagnostic evaluations need greater clarity, according to the authors of a new consensus statement.

That is why a group of expert panelists evaluated the existing evidence and a range of clinical scenarios to help clarify the optimal strategies for early detection and assessment of cutaneous melanoma.

Overall, the panelists agreed that a risk-stratified approach is likely the most appropriate strategy for melanoma screening and follow-up and supported the use of visual and dermoscopic examination. However, the panelists did not reach consensus on the role for gene expression profile (GEP) testing in clinical decision-making, citing the need for these assays to be validated in large randomized clinical trials.

In an accompanying editorial, two experts highlighted the importance of carefully evaluating the role of diagnostic tests.

“Diagnostic tests such as GEP must face critical scrutiny; if not, there are immediate concerns for patient care, such as the patient being erroneously informed that they do not have cancer or told that they do have cancer when they do not,” write Alan C. Geller, MPH, RN, from the Harvard T.H. Chan School of Public Health, Boston, and Marvin A. Weinstock, MD, PhD, from Brown University, Providence, R.I.

The consensus statement was published online in JAMA Dermatology.
 

The need for guidance

Although focusing melanoma screening on higher-risk populations may be cost effective, compared with population-based screening, the major guidelines lack consistent guidance to support a risk-stratified approach to skin cancer screening and best practices on diagnosing cutaneous melanoma.

In the prebiopsy setting, the appropriate use of diagnostic tools for evaluating the need for biopsy remain poorly defined, and, in the post-biopsy setting, questions remain concerning the diagnostic accuracy of molecular techniques, diagnostic GEP testing, next-generation sequencing, and immunohistochemical assessment for various markers of melanoma.

To provide consensus recommendations on optimal screening practices, prebiopsy and postbiopsy diagnostics, and prognostic assessment of cutaneous melanoma, a group of 42 panelists voted on hypothetical scenarios via an emailed survey. The panel then came together for a consensus conference, which included 51 experts who discussed their approach to the various clinical case scenarios. Most attendees (45 of the 51) answered a follow-up survey for their final recommendations.

The panelists reached a consensus, with 70% agreement, to support a risk-stratified approach to melanoma screening in clinical settings and public screening events. The experts agreed that higher-risk individuals (those with a relative risk of 5 or greater) could be appropriately screened by a general dermatologist or pigmented lesion evaluation. Higher-risk individuals included those with severe skin damage from the sun, systemic immunosuppression, or a personal history of nonmelanoma or melanoma skin cancer.

Panelists agreed that those at general or lower risk (RR < 2) could be screened by a primary care provider or through regular self- or partner examinations, whereas those at moderate risk could be screened by their primary care clinician or general dermatologist. The experts observed “a shift in acceptance” of primary care physicians screening the general population, and an acknowledgement of the importance of self- and partner examinations as screening adjuncts for all populations.

In the prebiopsy setting, panelists reached consensus that visual and dermoscopic examination was appropriate for evaluating patients with “no new, changing, or unusual skin lesions or with a new lesion that is not visually concerning.”

The panelists also reached consensus that lesions deemed clinically suspicious for cancer or showing features of cancer on reflectance confocal microscopy should be biopsied. Although most respondents (86%) did not currently use epidermal tape stripping routinely, they agreed that, in a hypothetical situation where epidermal tape stripping was used, that lesions positive for PRAME or LINC should be biopsied.

In the postbiopsy setting, views on the use of GEP scores varied. Although panelists agreed that a low-risk prognostic GEP score should not outweigh concerning histologic features when patients are selected to undergo sentinel lymph node biopsy (SLNB), they did not reach consensus for imaging recommendations in the setting of a high-risk prognostic GEP score and low-risk histology and/or negative nodal status.

“The panelists await future, well-designed prospective studies to determine if use of these and newer technologies improves the care of patients with melanoma,” the panelists write.

In the editorial, Mr. Geller and Dr. Weinstock highlighted concerns about the cost and potential access issues associated with these newer technologies, given that the current cost of GEP testing exceeds $7,000.

The editorialists also emphasize that “going forward, the field should be advanced by tackling one of the more pressing, common, potentially morbid, and costly procedures – the prognostic use of sentinel lymph node biopsy.”

Of critical importance is “whether GEP can reduce morbidity and cost by safely reducing the number of SLNBs performed,” Mr. Geller and Dr. Weinstock write.

The funding for the administration and facilitation of the consensus development conference and the development of the manuscript was provided by Dermtech, in an unrestricted award overseen by the Melanoma Research Foundation and managed and executed at UPMC by the principal investigator. Several of the coauthors disclosed relationships with industry. Mr. Geller is a contributor to UptoDate for which he receives royalties. Dr. Weinstock receives consulting fees from AbbVie.

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

NEW ORLEANS – All but one Janus kinase (JAK) inhibitor with dermatologic indications carries a boxed warning that lists multiple risks for drugs in this class, including the risk of major adverse cardiac events (MACE), even though the basis for all the risks is a rheumatoid arthritis study, according to a critical review at the annual meeting of the American Academy of Dermatology.  

Given the fact that the postmarketing RA study was specifically enriched with high-risk patients by requiring an age at enrollment of at least 50 years and the presence of at least one cardiovascular risk factor, the extrapolation of these risks to dermatologic indications is “not necessarily data-driven,” said Brett A. King, MD, PhD, associate professor of dermatology, Yale University, New Haven, Conn.

The recently approved deucravacitinib is the only JAK inhibitor that has so far been exempt from these warnings. Instead, based on the ORAL Surveillance study, published in the New England Journal of Medicine, the Food and Drug Administration requires a boxed warning in nearly identical language for all the other JAK inhibitors. Relative to tofacitinib, the JAK inhibitor tested in ORAL Surveillance, many of these drugs differ by JAK selectivity and other characteristics that are likely relevant to risk of adverse events, Dr. King said. The same language has even been applied to topical ruxolitinib cream. 
 

Basis of boxed warnings

In ORAL Surveillance, about 4,300 high-risk patients with RA were randomized to one of two doses of tofacitinib (5 mg or 10 mg) twice daily or a tumor necrosis factor (TNF) inhibitor. All patients in the trial were taking methotrexate, and almost 60% were taking concomitant corticosteroids. The average body mass index of the study population was about 30 kg/m².

After a median 4 years of follow-up (about 5,000 patient-years), the incidence of many of the adverse events tracked in the study were higher in the tofacitinib groups, including serious infections, MACE, thromboembolic events, and cancer. Dr. King did not challenge the importance of these data, but he questioned whether they are reasonably extrapolated to dermatologic indications, particularly as many of those treated are younger than those common to an RA population.

In fact, despite a study enriched for a higher risk of many events tracked, most adverse events were only slightly elevated, Dr. King pointed out. For example, the incidence of MACE over the 4 years of follow-up was 3.4% among those taking any dose of tofacitinib versus 2.5% of those randomized to TNF inhibitor. Rates of cancer were 4.2% versus 2.9%, respectively. There were also absolute increases in the number of serious infections and thromboembolic events for tofacitinib relative to TNF inhibitor.

Dr. King acknowledged that the numbers in ORAL Surveillance associated tofacitinib with a higher risk of serious events than TNF inhibitor in patients with RA, but he believes that “JAK inhibitor safety is almost certainly not the same in dermatology as it is in rheumatology patients.”
 

Evidence of difference in dermatology

There is some evidence to back this up. Dr. King cited a recently published study in RMD Open that evaluated the safety profile of the JAK inhibitor upadacitinib in nearly 7,000 patients over 15,000 patient-years of follow-up. Drug safety data were evaluated with up to 5.5 years of follow-up from 12 clinical trials of the four diseases for which upadacitinib is now indicated. Three were rheumatologic (RA, psoriatic arthritis, and ankylosing spondylitis), and the fourth was atopic dermatitis (AD). Fourteen outcomes, including numerous types of infection, MACE, hepatic complications, and malignancy, were compared with methotrexate and the TNF inhibitor adalimumab.

For the RA diseases, upadacitinib was associated with a greater risk than comparators for several outcomes, including serious infections. But in AD, there was a smaller increased risk of adverse outcomes for the JAK inhibitor relative to comparators.

When evaluated by risk of adverse events across indications, for MACE, the exposure-adjusted event rates for upadacitinib were less than 0.1 in patients treated for AD over the observation period versus 0.3 and 0.4 for RA and psoriatic arthritis, respectively. Similarly, for venous thromboembolism, the rates for upadacitinib were again less than 0.1 in patients with AD versus 0.4 and 0.2 in RA and psoriatic arthritis, respectively.

Referring back to the postmarketing study, Dr. King emphasized that it is essential to consider how the boxed warning for JAK inhibitors was generated before applying them to dermatologic indications.

“Is a 30-year-old patient with a dermatologic disorder possibly at the same risk as the patients in the study from which we got the boxed warning? The answer is simply no,” he said.

Like the tofacitinib data in the ORAL Surveillance study, the upadacitinib clinical trial data are not necessarily relevant to other JAK inhibitors. In fact, Dr. King pointed out that the safety profiles of the available JAK inhibitors are not identical, an observation that is consistent with differences in JAK inhibitor selectivity that has implications for off-target events.  

Dr. King does not dismiss the potential risks outlined in the current regulatory cautions about the use of JAK inhibitors, but he believes that dermatologists should be cognizant of “where the black box warning comes from.”

“We need to think carefully about the risk-to-benefit ratio in older patients or patients with risk factors, such as obesity and diabetes,” he said. But the safety profile of JAK inhibitors “is almost certainly better” than the profile suggested in boxed warnings applied to JAK inhibitors for dermatologic indications, he advised.
 

Risk-benefit considerations in dermatology

This position was supported by numerous other experts when asked for their perspectives. “I fully agree,” said Emma Guttman-Yassky, MD, PhD, system chair of dermatology and immunology, Icahn School of Medicine, Mount Sinai, New York.

Like Dr. King, Dr. Guttman-Yassky did not dismiss the potential risks of JAK inhibitors when treating dermatologic diseases.

“While JAK inhibitors need monitoring as advised, adopting a boxed warning from an RA study for patients who are older [is problematic],” she commented. A study with the nonselective tofacitinib in this population “cannot be compared to more selective inhibitors in a much younger population, such as those treated [for] alopecia areata or atopic dermatitis.”

George Z. Han, MD, PhD, an associate professor of dermatology, Zucker School of Medicine, Hofstra, Northwell Medical Center, New Hyde Park, New York, also agreed but added some caveats.

“The comments about the ORAL Surveillance study are salient,” he said in an interview. “This kind of data should not directly be extrapolated to other patient types or to other medications.” However, one of Dr. Han’s most important caveats involves long-term use.

“JAK inhibitors are still relatively narrow-therapeutic-window drugs that in a dose-dependent fashion could lead to negative effects, including thromboembolic events, abnormalities in red blood cells, white blood cells, platelets, and lipids,” he said. While doses used in dermatology “are generally below the level of any major concern,” Dr. Han cautioned that “we lack definitive data” on long-term use, and this is important for understanding “any potential small risk of rare events, such as malignancy or thromboembolism.”

Saakshi Khattri, MD, a colleague of Dr. Guttman-Yassky at Mount Sinai, said the risks of JAK inhibitors should not be underestimated, but she also agreed that risk “needs to be delivered in the right context.” Dr. Khattri, who is board certified in both dermatology and rheumatology, noted the safety profiles of available JAK inhibitors differ and that extrapolating safety from an RA study to dermatologic indications does not make sense. “Different diseases, different age groups,” she said.

Dr. King has reported financial relationships with more than 15 pharmaceutical companies, including companies that make JAK inhibitors. Dr. Guttman-Yassky has reported financial relationships with more than 20 pharmaceutical companies, including companies that make JAK inhibitors. Dr. Han reports financial relationships with Amgen, Athenex, Boehringer Ingelheim, Bond Avillion, Bristol-Myers Squibb, Celgene, Janssen, Lilly, Novartis, PellePharm, Pfizer, and UCB. Dr. Khattri has reported financial relationships with AbbVie, Arcutis, Bristol-Myers Squibb, Janssen, Leo, Lilly, Novartis, Pfizer, and UCB.

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

NEW ORLEANS – All but one Janus kinase (JAK) inhibitor with dermatologic indications carries a boxed warning that lists multiple risks for drugs in this class, including the risk of major adverse cardiac events (MACE), even though the basis for all the risks is a rheumatoid arthritis study, according to a critical review at the annual meeting of the American Academy of Dermatology.  

Given the fact that the postmarketing RA study was specifically enriched with high-risk patients by requiring an age at enrollment of at least 50 years and the presence of at least one cardiovascular risk factor, the extrapolation of these risks to dermatologic indications is “not necessarily data-driven,” said Brett A. King, MD, PhD, associate professor of dermatology, Yale University, New Haven, Conn.

The recently approved deucravacitinib is the only JAK inhibitor that has so far been exempt from these warnings. Instead, based on the ORAL Surveillance study, published in the New England Journal of Medicine, the Food and Drug Administration requires a boxed warning in nearly identical language for all the other JAK inhibitors. Relative to tofacitinib, the JAK inhibitor tested in ORAL Surveillance, many of these drugs differ by JAK selectivity and other characteristics that are likely relevant to risk of adverse events, Dr. King said. The same language has even been applied to topical ruxolitinib cream. 
 

Basis of boxed warnings

In ORAL Surveillance, about 4,300 high-risk patients with RA were randomized to one of two doses of tofacitinib (5 mg or 10 mg) twice daily or a tumor necrosis factor (TNF) inhibitor. All patients in the trial were taking methotrexate, and almost 60% were taking concomitant corticosteroids. The average body mass index of the study population was about 30 kg/m².

After a median 4 years of follow-up (about 5,000 patient-years), the incidence of many of the adverse events tracked in the study were higher in the tofacitinib groups, including serious infections, MACE, thromboembolic events, and cancer. Dr. King did not challenge the importance of these data, but he questioned whether they are reasonably extrapolated to dermatologic indications, particularly as many of those treated are younger than those common to an RA population.

In fact, despite a study enriched for a higher risk of many events tracked, most adverse events were only slightly elevated, Dr. King pointed out. For example, the incidence of MACE over the 4 years of follow-up was 3.4% among those taking any dose of tofacitinib versus 2.5% of those randomized to TNF inhibitor. Rates of cancer were 4.2% versus 2.9%, respectively. There were also absolute increases in the number of serious infections and thromboembolic events for tofacitinib relative to TNF inhibitor.

Dr. King acknowledged that the numbers in ORAL Surveillance associated tofacitinib with a higher risk of serious events than TNF inhibitor in patients with RA, but he believes that “JAK inhibitor safety is almost certainly not the same in dermatology as it is in rheumatology patients.”
 

Evidence of difference in dermatology

There is some evidence to back this up. Dr. King cited a recently published study in RMD Open that evaluated the safety profile of the JAK inhibitor upadacitinib in nearly 7,000 patients over 15,000 patient-years of follow-up. Drug safety data were evaluated with up to 5.5 years of follow-up from 12 clinical trials of the four diseases for which upadacitinib is now indicated. Three were rheumatologic (RA, psoriatic arthritis, and ankylosing spondylitis), and the fourth was atopic dermatitis (AD). Fourteen outcomes, including numerous types of infection, MACE, hepatic complications, and malignancy, were compared with methotrexate and the TNF inhibitor adalimumab.

For the RA diseases, upadacitinib was associated with a greater risk than comparators for several outcomes, including serious infections. But in AD, there was a smaller increased risk of adverse outcomes for the JAK inhibitor relative to comparators.

When evaluated by risk of adverse events across indications, for MACE, the exposure-adjusted event rates for upadacitinib were less than 0.1 in patients treated for AD over the observation period versus 0.3 and 0.4 for RA and psoriatic arthritis, respectively. Similarly, for venous thromboembolism, the rates for upadacitinib were again less than 0.1 in patients with AD versus 0.4 and 0.2 in RA and psoriatic arthritis, respectively.

Referring back to the postmarketing study, Dr. King emphasized that it is essential to consider how the boxed warning for JAK inhibitors was generated before applying them to dermatologic indications.

“Is a 30-year-old patient with a dermatologic disorder possibly at the same risk as the patients in the study from which we got the boxed warning? The answer is simply no,” he said.

Like the tofacitinib data in the ORAL Surveillance study, the upadacitinib clinical trial data are not necessarily relevant to other JAK inhibitors. In fact, Dr. King pointed out that the safety profiles of the available JAK inhibitors are not identical, an observation that is consistent with differences in JAK inhibitor selectivity that has implications for off-target events.  

Dr. King does not dismiss the potential risks outlined in the current regulatory cautions about the use of JAK inhibitors, but he believes that dermatologists should be cognizant of “where the black box warning comes from.”

“We need to think carefully about the risk-to-benefit ratio in older patients or patients with risk factors, such as obesity and diabetes,” he said. But the safety profile of JAK inhibitors “is almost certainly better” than the profile suggested in boxed warnings applied to JAK inhibitors for dermatologic indications, he advised.
 

Risk-benefit considerations in dermatology

This position was supported by numerous other experts when asked for their perspectives. “I fully agree,” said Emma Guttman-Yassky, MD, PhD, system chair of dermatology and immunology, Icahn School of Medicine, Mount Sinai, New York.

Like Dr. King, Dr. Guttman-Yassky did not dismiss the potential risks of JAK inhibitors when treating dermatologic diseases.

“While JAK inhibitors need monitoring as advised, adopting a boxed warning from an RA study for patients who are older [is problematic],” she commented. A study with the nonselective tofacitinib in this population “cannot be compared to more selective inhibitors in a much younger population, such as those treated [for] alopecia areata or atopic dermatitis.”

George Z. Han, MD, PhD, an associate professor of dermatology, Zucker School of Medicine, Hofstra, Northwell Medical Center, New Hyde Park, New York, also agreed but added some caveats.

“The comments about the ORAL Surveillance study are salient,” he said in an interview. “This kind of data should not directly be extrapolated to other patient types or to other medications.” However, one of Dr. Han’s most important caveats involves long-term use.

“JAK inhibitors are still relatively narrow-therapeutic-window drugs that in a dose-dependent fashion could lead to negative effects, including thromboembolic events, abnormalities in red blood cells, white blood cells, platelets, and lipids,” he said. While doses used in dermatology “are generally below the level of any major concern,” Dr. Han cautioned that “we lack definitive data” on long-term use, and this is important for understanding “any potential small risk of rare events, such as malignancy or thromboembolism.”

Saakshi Khattri, MD, a colleague of Dr. Guttman-Yassky at Mount Sinai, said the risks of JAK inhibitors should not be underestimated, but she also agreed that risk “needs to be delivered in the right context.” Dr. Khattri, who is board certified in both dermatology and rheumatology, noted the safety profiles of available JAK inhibitors differ and that extrapolating safety from an RA study to dermatologic indications does not make sense. “Different diseases, different age groups,” she said.

Dr. King has reported financial relationships with more than 15 pharmaceutical companies, including companies that make JAK inhibitors. Dr. Guttman-Yassky has reported financial relationships with more than 20 pharmaceutical companies, including companies that make JAK inhibitors. Dr. Han reports financial relationships with Amgen, Athenex, Boehringer Ingelheim, Bond Avillion, Bristol-Myers Squibb, Celgene, Janssen, Lilly, Novartis, PellePharm, Pfizer, and UCB. Dr. Khattri has reported financial relationships with AbbVie, Arcutis, Bristol-Myers Squibb, Janssen, Leo, Lilly, Novartis, Pfizer, and UCB.

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

NEW ORLEANS – All but one Janus kinase (JAK) inhibitor with dermatologic indications carries a boxed warning that lists multiple risks for drugs in this class, including the risk of major adverse cardiac events (MACE), even though the basis for all the risks is a rheumatoid arthritis study, according to a critical review at the annual meeting of the American Academy of Dermatology.  

Given the fact that the postmarketing RA study was specifically enriched with high-risk patients by requiring an age at enrollment of at least 50 years and the presence of at least one cardiovascular risk factor, the extrapolation of these risks to dermatologic indications is “not necessarily data-driven,” said Brett A. King, MD, PhD, associate professor of dermatology, Yale University, New Haven, Conn.

The recently approved deucravacitinib is the only JAK inhibitor that has so far been exempt from these warnings. Instead, based on the ORAL Surveillance study, published in the New England Journal of Medicine, the Food and Drug Administration requires a boxed warning in nearly identical language for all the other JAK inhibitors. Relative to tofacitinib, the JAK inhibitor tested in ORAL Surveillance, many of these drugs differ by JAK selectivity and other characteristics that are likely relevant to risk of adverse events, Dr. King said. The same language has even been applied to topical ruxolitinib cream. 
 

Basis of boxed warnings

In ORAL Surveillance, about 4,300 high-risk patients with RA were randomized to one of two doses of tofacitinib (5 mg or 10 mg) twice daily or a tumor necrosis factor (TNF) inhibitor. All patients in the trial were taking methotrexate, and almost 60% were taking concomitant corticosteroids. The average body mass index of the study population was about 30 kg/m².

After a median 4 years of follow-up (about 5,000 patient-years), the incidence of many of the adverse events tracked in the study were higher in the tofacitinib groups, including serious infections, MACE, thromboembolic events, and cancer. Dr. King did not challenge the importance of these data, but he questioned whether they are reasonably extrapolated to dermatologic indications, particularly as many of those treated are younger than those common to an RA population.

In fact, despite a study enriched for a higher risk of many events tracked, most adverse events were only slightly elevated, Dr. King pointed out. For example, the incidence of MACE over the 4 years of follow-up was 3.4% among those taking any dose of tofacitinib versus 2.5% of those randomized to TNF inhibitor. Rates of cancer were 4.2% versus 2.9%, respectively. There were also absolute increases in the number of serious infections and thromboembolic events for tofacitinib relative to TNF inhibitor.

Dr. King acknowledged that the numbers in ORAL Surveillance associated tofacitinib with a higher risk of serious events than TNF inhibitor in patients with RA, but he believes that “JAK inhibitor safety is almost certainly not the same in dermatology as it is in rheumatology patients.”
 

Evidence of difference in dermatology

There is some evidence to back this up. Dr. King cited a recently published study in RMD Open that evaluated the safety profile of the JAK inhibitor upadacitinib in nearly 7,000 patients over 15,000 patient-years of follow-up. Drug safety data were evaluated with up to 5.5 years of follow-up from 12 clinical trials of the four diseases for which upadacitinib is now indicated. Three were rheumatologic (RA, psoriatic arthritis, and ankylosing spondylitis), and the fourth was atopic dermatitis (AD). Fourteen outcomes, including numerous types of infection, MACE, hepatic complications, and malignancy, were compared with methotrexate and the TNF inhibitor adalimumab.

For the RA diseases, upadacitinib was associated with a greater risk than comparators for several outcomes, including serious infections. But in AD, there was a smaller increased risk of adverse outcomes for the JAK inhibitor relative to comparators.

When evaluated by risk of adverse events across indications, for MACE, the exposure-adjusted event rates for upadacitinib were less than 0.1 in patients treated for AD over the observation period versus 0.3 and 0.4 for RA and psoriatic arthritis, respectively. Similarly, for venous thromboembolism, the rates for upadacitinib were again less than 0.1 in patients with AD versus 0.4 and 0.2 in RA and psoriatic arthritis, respectively.

Referring back to the postmarketing study, Dr. King emphasized that it is essential to consider how the boxed warning for JAK inhibitors was generated before applying them to dermatologic indications.

“Is a 30-year-old patient with a dermatologic disorder possibly at the same risk as the patients in the study from which we got the boxed warning? The answer is simply no,” he said.

Like the tofacitinib data in the ORAL Surveillance study, the upadacitinib clinical trial data are not necessarily relevant to other JAK inhibitors. In fact, Dr. King pointed out that the safety profiles of the available JAK inhibitors are not identical, an observation that is consistent with differences in JAK inhibitor selectivity that has implications for off-target events.  

Dr. King does not dismiss the potential risks outlined in the current regulatory cautions about the use of JAK inhibitors, but he believes that dermatologists should be cognizant of “where the black box warning comes from.”

“We need to think carefully about the risk-to-benefit ratio in older patients or patients with risk factors, such as obesity and diabetes,” he said. But the safety profile of JAK inhibitors “is almost certainly better” than the profile suggested in boxed warnings applied to JAK inhibitors for dermatologic indications, he advised.
 

Risk-benefit considerations in dermatology

This position was supported by numerous other experts when asked for their perspectives. “I fully agree,” said Emma Guttman-Yassky, MD, PhD, system chair of dermatology and immunology, Icahn School of Medicine, Mount Sinai, New York.

Like Dr. King, Dr. Guttman-Yassky did not dismiss the potential risks of JAK inhibitors when treating dermatologic diseases.

“While JAK inhibitors need monitoring as advised, adopting a boxed warning from an RA study for patients who are older [is problematic],” she commented. A study with the nonselective tofacitinib in this population “cannot be compared to more selective inhibitors in a much younger population, such as those treated [for] alopecia areata or atopic dermatitis.”

George Z. Han, MD, PhD, an associate professor of dermatology, Zucker School of Medicine, Hofstra, Northwell Medical Center, New Hyde Park, New York, also agreed but added some caveats.

“The comments about the ORAL Surveillance study are salient,” he said in an interview. “This kind of data should not directly be extrapolated to other patient types or to other medications.” However, one of Dr. Han’s most important caveats involves long-term use.

“JAK inhibitors are still relatively narrow-therapeutic-window drugs that in a dose-dependent fashion could lead to negative effects, including thromboembolic events, abnormalities in red blood cells, white blood cells, platelets, and lipids,” he said. While doses used in dermatology “are generally below the level of any major concern,” Dr. Han cautioned that “we lack definitive data” on long-term use, and this is important for understanding “any potential small risk of rare events, such as malignancy or thromboembolism.”

Saakshi Khattri, MD, a colleague of Dr. Guttman-Yassky at Mount Sinai, said the risks of JAK inhibitors should not be underestimated, but she also agreed that risk “needs to be delivered in the right context.” Dr. Khattri, who is board certified in both dermatology and rheumatology, noted the safety profiles of available JAK inhibitors differ and that extrapolating safety from an RA study to dermatologic indications does not make sense. “Different diseases, different age groups,” she said.

Dr. King has reported financial relationships with more than 15 pharmaceutical companies, including companies that make JAK inhibitors. Dr. Guttman-Yassky has reported financial relationships with more than 20 pharmaceutical companies, including companies that make JAK inhibitors. Dr. Han reports financial relationships with Amgen, Athenex, Boehringer Ingelheim, Bond Avillion, Bristol-Myers Squibb, Celgene, Janssen, Lilly, Novartis, PellePharm, Pfizer, and UCB. Dr. Khattri has reported financial relationships with AbbVie, Arcutis, Bristol-Myers Squibb, Janssen, Leo, Lilly, Novartis, Pfizer, and UCB.

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

Lanolin, known mainly for its emollient properties, has been named by the American Contact Dermatitis Society as the Contact Allergen of the Year for 2023.

Lanolin is a complex and varying mixture of high molecular weight esters, aliphatic alcohols, sterols, fatty acids, and hydrocarbons, but the allergic components are mainly the free lanolin alcohols, especially alkanediols, said Donald V. Belsito, MD, professor of dermatology, Columbia University, New York, who announced the Allergen of the Year at the society’s annual meeting.

Criteria for selection can include a known allergen with a new twist or increasing frequency or a newly reported allergen with mini-epidemics that may have been missed for years, Dr. Belsito said.

“The prevalence and severity of allergy to ‘lanolin’ have been hotly debated” since a potential case was first reported in the 1920s, wrote Dr. Belsito and Blair A. Jenkins, MD, PhD, a dermatology resident at New York–Presbyterian Hospital, Columbia Campus, in a review published in Dermatitis.

“ ‘Lanolin’ is indeed a paradox allergen,” wrote Dr. Jenkins and Dr. Belsito. “The most appropriate patch test preparation(s) for detecting allergy remain disputed. Detection of lanolin-induced contact dermatitis in diseased skin by patch testing on normal skin may lead to false negative results.”

And those who test positive for a lanolin allergy on diseased skin may be able to use lanolin products on normal skin, they wrote.

“From my perspective, this was a timely year to think about lanolin, as there is significant ongoing controversy about whether it is allergenic,” Dr. Jenkins said in an interview. “Numerous companies market lanolin-containing topicals as safe and effective emollients,” she said.
 

Medical grade and highly purified anhydrous lanolin, which contain less than 2.5% and less than 1.5% of free alcohols, respectively, can still elicit or induce a contact allergy, Dr. Belsito said in his presentation. Hydrogenated lanolin has shown more allergenicity than lanolin alcohol, while lanolin wax, lanolin acid, and lanolin esters possess lower allergenicity than lanolin alcohol, he said.

Notably, modern wool textiles do not contain lanolin, and lanolin-allergic patients need not avoid wool, Dr. Belsito added.

Amerchol L-101, a common trade name on products containing lanolin, contains 10% wool wax alcohols obtained from the hydrolysis of wool fat dissolved in mineral oil at a 1:1 ratio, said Dr. Belsito. He recommended testing lanolin alcohols (in 30% petrolatum) and Amerchol L-101 (in 50% petrolatum) simultaneously with or without other lanolin derivatives and/or the patient’s products in cases of possible allergy, he said.
 

Consider high-risk groups

Current evidence suggests that the prevalence of contact allergy in the western European population is 0.4%, wrote Dr. Jenkins and Dr. Belsito.

Although the frequency of lanolin allergy is relatively low, certain conditions convey greater risk, such as stasis dermatitis, leg ulcers, perianal/genital dermatitis, and atopic dermatitis, they wrote. Older adults and children are at increased risk because they are more likely to have these conditions. Demographic data also suggest that lanolin allergy is more common in non-Hispanic Whites than in non-Hispanic Blacks, they wrote.

Looking ahead, “I think further exploration of allergy across different skin types and ethnicities is warranted,” Dr. Jenkins said. “Further investigation of ideal [lanolin] allergens for patch testing is also needed.”

Dr. Jenkins and Dr. Belsito said they had no relevant financial conflicts to disclose.

Lanolin, known mainly for its emollient properties, has been named by the American Contact Dermatitis Society as the Contact Allergen of the Year for 2023.

Lanolin is a complex and varying mixture of high molecular weight esters, aliphatic alcohols, sterols, fatty acids, and hydrocarbons, but the allergic components are mainly the free lanolin alcohols, especially alkanediols, said Donald V. Belsito, MD, professor of dermatology, Columbia University, New York, who announced the Allergen of the Year at the society’s annual meeting.

Criteria for selection can include a known allergen with a new twist or increasing frequency or a newly reported allergen with mini-epidemics that may have been missed for years, Dr. Belsito said.

“The prevalence and severity of allergy to ‘lanolin’ have been hotly debated” since a potential case was first reported in the 1920s, wrote Dr. Belsito and Blair A. Jenkins, MD, PhD, a dermatology resident at New York–Presbyterian Hospital, Columbia Campus, in a review published in Dermatitis.

“ ‘Lanolin’ is indeed a paradox allergen,” wrote Dr. Jenkins and Dr. Belsito. “The most appropriate patch test preparation(s) for detecting allergy remain disputed. Detection of lanolin-induced contact dermatitis in diseased skin by patch testing on normal skin may lead to false negative results.”

And those who test positive for a lanolin allergy on diseased skin may be able to use lanolin products on normal skin, they wrote.

“From my perspective, this was a timely year to think about lanolin, as there is significant ongoing controversy about whether it is allergenic,” Dr. Jenkins said in an interview. “Numerous companies market lanolin-containing topicals as safe and effective emollients,” she said.
 

Medical grade and highly purified anhydrous lanolin, which contain less than 2.5% and less than 1.5% of free alcohols, respectively, can still elicit or induce a contact allergy, Dr. Belsito said in his presentation. Hydrogenated lanolin has shown more allergenicity than lanolin alcohol, while lanolin wax, lanolin acid, and lanolin esters possess lower allergenicity than lanolin alcohol, he said.

Notably, modern wool textiles do not contain lanolin, and lanolin-allergic patients need not avoid wool, Dr. Belsito added.

Amerchol L-101, a common trade name on products containing lanolin, contains 10% wool wax alcohols obtained from the hydrolysis of wool fat dissolved in mineral oil at a 1:1 ratio, said Dr. Belsito. He recommended testing lanolin alcohols (in 30% petrolatum) and Amerchol L-101 (in 50% petrolatum) simultaneously with or without other lanolin derivatives and/or the patient’s products in cases of possible allergy, he said.
 

Consider high-risk groups

Current evidence suggests that the prevalence of contact allergy in the western European population is 0.4%, wrote Dr. Jenkins and Dr. Belsito.

Although the frequency of lanolin allergy is relatively low, certain conditions convey greater risk, such as stasis dermatitis, leg ulcers, perianal/genital dermatitis, and atopic dermatitis, they wrote. Older adults and children are at increased risk because they are more likely to have these conditions. Demographic data also suggest that lanolin allergy is more common in non-Hispanic Whites than in non-Hispanic Blacks, they wrote.

Looking ahead, “I think further exploration of allergy across different skin types and ethnicities is warranted,” Dr. Jenkins said. “Further investigation of ideal [lanolin] allergens for patch testing is also needed.”

Dr. Jenkins and Dr. Belsito said they had no relevant financial conflicts to disclose.

Lanolin, known mainly for its emollient properties, has been named by the American Contact Dermatitis Society as the Contact Allergen of the Year for 2023.

Lanolin is a complex and varying mixture of high molecular weight esters, aliphatic alcohols, sterols, fatty acids, and hydrocarbons, but the allergic components are mainly the free lanolin alcohols, especially alkanediols, said Donald V. Belsito, MD, professor of dermatology, Columbia University, New York, who announced the Allergen of the Year at the society’s annual meeting.

Criteria for selection can include a known allergen with a new twist or increasing frequency or a newly reported allergen with mini-epidemics that may have been missed for years, Dr. Belsito said.

“The prevalence and severity of allergy to ‘lanolin’ have been hotly debated” since a potential case was first reported in the 1920s, wrote Dr. Belsito and Blair A. Jenkins, MD, PhD, a dermatology resident at New York–Presbyterian Hospital, Columbia Campus, in a review published in Dermatitis.

“ ‘Lanolin’ is indeed a paradox allergen,” wrote Dr. Jenkins and Dr. Belsito. “The most appropriate patch test preparation(s) for detecting allergy remain disputed. Detection of lanolin-induced contact dermatitis in diseased skin by patch testing on normal skin may lead to false negative results.”

And those who test positive for a lanolin allergy on diseased skin may be able to use lanolin products on normal skin, they wrote.

“From my perspective, this was a timely year to think about lanolin, as there is significant ongoing controversy about whether it is allergenic,” Dr. Jenkins said in an interview. “Numerous companies market lanolin-containing topicals as safe and effective emollients,” she said.
 

Medical grade and highly purified anhydrous lanolin, which contain less than 2.5% and less than 1.5% of free alcohols, respectively, can still elicit or induce a contact allergy, Dr. Belsito said in his presentation. Hydrogenated lanolin has shown more allergenicity than lanolin alcohol, while lanolin wax, lanolin acid, and lanolin esters possess lower allergenicity than lanolin alcohol, he said.

Notably, modern wool textiles do not contain lanolin, and lanolin-allergic patients need not avoid wool, Dr. Belsito added.

Amerchol L-101, a common trade name on products containing lanolin, contains 10% wool wax alcohols obtained from the hydrolysis of wool fat dissolved in mineral oil at a 1:1 ratio, said Dr. Belsito. He recommended testing lanolin alcohols (in 30% petrolatum) and Amerchol L-101 (in 50% petrolatum) simultaneously with or without other lanolin derivatives and/or the patient’s products in cases of possible allergy, he said.
 

Consider high-risk groups

Current evidence suggests that the prevalence of contact allergy in the western European population is 0.4%, wrote Dr. Jenkins and Dr. Belsito.

Although the frequency of lanolin allergy is relatively low, certain conditions convey greater risk, such as stasis dermatitis, leg ulcers, perianal/genital dermatitis, and atopic dermatitis, they wrote. Older adults and children are at increased risk because they are more likely to have these conditions. Demographic data also suggest that lanolin allergy is more common in non-Hispanic Whites than in non-Hispanic Blacks, they wrote.

Looking ahead, “I think further exploration of allergy across different skin types and ethnicities is warranted,” Dr. Jenkins said. “Further investigation of ideal [lanolin] allergens for patch testing is also needed.”

Dr. Jenkins and Dr. Belsito said they had no relevant financial conflicts to disclose.

A common chemical that is used in correction fluid, paint removers, gun cleaners, aerosol cleaning products, and dry cleaning may be the key culprit behind the dramatic increase in Parkinson’s disease (PD), researchers say.

An international team of researchers reviewed previous research and cited data that suggest the chemical trichloroethylene (TCE) is associated with as much as a 500% increased risk for Parkinson’s disease (PD).

Lead investigator Ray Dorsey, MD, professor of neurology, University of Rochester, N.Y., called PD “the world’s fastest-growing brain disease,” and told this news organization that it “may be largely preventable.”

“Countless people have died over generations from cancer and other disease linked to TCE [and] Parkinson’s may be the latest,” he said. “Banning these chemicals, containing contaminated sites, and protecting homes, schools, and buildings at risk may all create a world where Parkinson’s is increasingly rare, not common.”

The paper was published online in the Journal of Parkinson’s Disease.
 

Invisible, ubiquitous

TCE was first synthesized in a lab in 1864, with commercial production beginning in 1920, the researchers noted.

“Because of its unique properties, TCE has had countless industrial, commercial, military, and medical applications,” including producing refrigerants, cleaning electronics, and degreasing engine parts.

In addition, it’s been used in dry cleaning, although a similar chemical (perchloroethylene [PCE]) is currently more widely used for that purpose. Nevertheless, the authors noted, in anaerobic conditions, perchloroethylene often transforms into TCE “and their toxicity may be similar.”

Consumer products in which TCE is found include typewriter correction fluid, paint removers, gun cleaners, and aerosol cleaning products. Up until the 1970s, it was used to decaffeinate coffee.

TCE exposure isn’t confined to those who work with it. It also pollutes outdoor air, taints groundwater, and contaminates indoor air. It’s present in a substantial amount of groundwater in the United States and it “evaporates from underlying soil and groundwater and enters homes, workplaces, or schools, often undetected,” the researchers noted.

“Exposure can come via occupation or the environment and is often largely unknown at the time it occurs,” Dr. Dorsey said.

He noted that the rapid increase in PD incidence cannot be explained by genetic factors alone, which affect only about 15% of patients with PD, nor can it be explained by aging alone. “Certain pesticides ... are likely causes but would not explain the high prevalence of PD in urban areas, as is the case in the U.S.” Rather, “other factors” are involved, and “TCE is likely one such factor.”

Yet, “despite widespread contamination and increasing industrial, commercial, and military use, clinical investigations of TCE and PD have been limited.”

To fill this knowledge gap, Dr. Dorsey and his coauthors of the book, “Ending Parkinson’s Disease: A Prescription for Action,” took a deep dive into studies focusing on the potential association of TCE and PD and presented seven cases to illustrate the association.

“Like many genetic mutations (e.g., Parkin) and other environmental toxicants ... TCE damages the energy-producing parts of cells, i.e., the mitochondria,” said Dr. Dorsey.

TCE and PCE “likely mediate their toxicity through a common metabolite.” Because both are lipophilic, they “readily distribute in the brain and body tissues and appear to cause mitochondrial dysfunction at high doses,” the researchers hypothesized.

Dopaminergic neurons are particularly sensitive to mitochondrial neurotoxicants, so this might “partially explain the link to PD.”

Animal studies have shown that TCE “caused selective loss of dopaminergic neurons.” Moreover, PD-related neuropathology was found in the substantia nigra of rodents exposed to TCE over time. In addition, studies as early as 1960 were showing an association between TCE and parkinsonism.

The authors describe TCE as “ubiquitous” in the 1970s, with 10 million Americans working with the chemical or other organic solvents daily. The review details an extensive list of industries and occupations in which TCE exposure continues to occur.

People working with TCE might inhale it or touch it; but “millions more encounter the chemical unknowingly through outdoor air, contaminated groundwater, and indoor air pollution.”

They noted that TCE contaminates up to one-third of U.S. drinking water, has polluted the groundwater in more than 20 different countries on five continents, and is found in half of the 1,300 most toxic “Superfund” sites that are “part of a federal clean-up program, including 15 in California’s Silicon Valley, where TCE was used to clean electronics.”

Although the U.S. military stopped using TCE, numerous sites have been contaminated, including Marine Corps Base Camp Lejeune in North Carolina, where TCE and PCE were found in drinking water at 280 times the recommended safety standards.

The researchers highlighted seven cases of individuals who developed PD after likely exposure to TCE, including NBA basketball player Brian Grant, who developed symptoms of PD in 2006 at the age of 34.

Mr. Grant and his family had lived in Camp Lejeune when he was a child, during which time he drank, bathed, and swam in contaminated water, “unaware of its toxicity.” His father also died of esophageal cancer, “which is linked to TCE,” the authors of the study wrote. Mr. Grant has created a foundation to inspire and support patients with PD.

All of the individuals either grew up in or spent time in an area where they were extensively exposed to TCE, PCE, or other chemicals, or experienced occupational exposure.

The authors acknowledged that the role of TCE in PD, as illustrated by the cases, is “far from definitive.” For example, exposure to TCE is often combined with exposure to other toxins, or with unmeasured genetic risk factors.

They highlighted the need for more research and called for cleaning and containing contaminated sites, monitoring TCE levels, and publicly communicating risk and a ban on TCE.
 

Recall bias?

Commenting for this news organization, Rebecca Gilbert, MD, PhD, chief scientific officer, American Parkinson Disease Association (APDA), noted that the authors “are very frank about the limitations of this approach [illustrative cases] as proof of causation between PD and TCE exposure.”

Another limitation is that TCE exposure is very common, “as argued in the paper.” But “most people with exposure do not develop PD,” Dr. Gilbert pointed out. “By probing the TCE exposure of those who already have PD, there is a danger of recall bias.”

Dr. Gilbert, associate professor of neurology at NYU Langone Health, who was not involved with the study, acknowledged that the authors “present their work as hypothesis and clearly state that more work is needed to understand the connection between TCE and PD.”

In the meantime, however, there are “well-established health risks of TCE exposure, including development of various cancers,” she said. Therefore, the authors’ goals appear to be educating the public about known health risks, working to clean up known sites of contamination, and advocating to ban future use of TCE.

These goals “do not need to wait for [proof of] firm causation between TCE and PD,” she stated.

Dr. Dorsey reported he has received honoraria for speaking at the American Academy of Neurology and at multiple other societies and foundations and has received compensation for consulting services from pharmaceutical companies, foundations, medical education companies, and medical publications; he owns stock in several companies. The other authors’ disclosures can be found in the original paper. Dr. Gilbert is employed by the American Parkinson Disease Association and Bellevue Hospital Center in New York City.
 

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

A common chemical that is used in correction fluid, paint removers, gun cleaners, aerosol cleaning products, and dry cleaning may be the key culprit behind the dramatic increase in Parkinson’s disease (PD), researchers say.

An international team of researchers reviewed previous research and cited data that suggest the chemical trichloroethylene (TCE) is associated with as much as a 500% increased risk for Parkinson’s disease (PD).

Lead investigator Ray Dorsey, MD, professor of neurology, University of Rochester, N.Y., called PD “the world’s fastest-growing brain disease,” and told this news organization that it “may be largely preventable.”

“Countless people have died over generations from cancer and other disease linked to TCE [and] Parkinson’s may be the latest,” he said. “Banning these chemicals, containing contaminated sites, and protecting homes, schools, and buildings at risk may all create a world where Parkinson’s is increasingly rare, not common.”

The paper was published online in the Journal of Parkinson’s Disease.
 

Invisible, ubiquitous

TCE was first synthesized in a lab in 1864, with commercial production beginning in 1920, the researchers noted.

“Because of its unique properties, TCE has had countless industrial, commercial, military, and medical applications,” including producing refrigerants, cleaning electronics, and degreasing engine parts.

In addition, it’s been used in dry cleaning, although a similar chemical (perchloroethylene [PCE]) is currently more widely used for that purpose. Nevertheless, the authors noted, in anaerobic conditions, perchloroethylene often transforms into TCE “and their toxicity may be similar.”

Consumer products in which TCE is found include typewriter correction fluid, paint removers, gun cleaners, and aerosol cleaning products. Up until the 1970s, it was used to decaffeinate coffee.

TCE exposure isn’t confined to those who work with it. It also pollutes outdoor air, taints groundwater, and contaminates indoor air. It’s present in a substantial amount of groundwater in the United States and it “evaporates from underlying soil and groundwater and enters homes, workplaces, or schools, often undetected,” the researchers noted.

“Exposure can come via occupation or the environment and is often largely unknown at the time it occurs,” Dr. Dorsey said.

He noted that the rapid increase in PD incidence cannot be explained by genetic factors alone, which affect only about 15% of patients with PD, nor can it be explained by aging alone. “Certain pesticides ... are likely causes but would not explain the high prevalence of PD in urban areas, as is the case in the U.S.” Rather, “other factors” are involved, and “TCE is likely one such factor.”

Yet, “despite widespread contamination and increasing industrial, commercial, and military use, clinical investigations of TCE and PD have been limited.”

To fill this knowledge gap, Dr. Dorsey and his coauthors of the book, “Ending Parkinson’s Disease: A Prescription for Action,” took a deep dive into studies focusing on the potential association of TCE and PD and presented seven cases to illustrate the association.

“Like many genetic mutations (e.g., Parkin) and other environmental toxicants ... TCE damages the energy-producing parts of cells, i.e., the mitochondria,” said Dr. Dorsey.

TCE and PCE “likely mediate their toxicity through a common metabolite.” Because both are lipophilic, they “readily distribute in the brain and body tissues and appear to cause mitochondrial dysfunction at high doses,” the researchers hypothesized.

Dopaminergic neurons are particularly sensitive to mitochondrial neurotoxicants, so this might “partially explain the link to PD.”

Animal studies have shown that TCE “caused selective loss of dopaminergic neurons.” Moreover, PD-related neuropathology was found in the substantia nigra of rodents exposed to TCE over time. In addition, studies as early as 1960 were showing an association between TCE and parkinsonism.

The authors describe TCE as “ubiquitous” in the 1970s, with 10 million Americans working with the chemical or other organic solvents daily. The review details an extensive list of industries and occupations in which TCE exposure continues to occur.

People working with TCE might inhale it or touch it; but “millions more encounter the chemical unknowingly through outdoor air, contaminated groundwater, and indoor air pollution.”

They noted that TCE contaminates up to one-third of U.S. drinking water, has polluted the groundwater in more than 20 different countries on five continents, and is found in half of the 1,300 most toxic “Superfund” sites that are “part of a federal clean-up program, including 15 in California’s Silicon Valley, where TCE was used to clean electronics.”

Although the U.S. military stopped using TCE, numerous sites have been contaminated, including Marine Corps Base Camp Lejeune in North Carolina, where TCE and PCE were found in drinking water at 280 times the recommended safety standards.

The researchers highlighted seven cases of individuals who developed PD after likely exposure to TCE, including NBA basketball player Brian Grant, who developed symptoms of PD in 2006 at the age of 34.

Mr. Grant and his family had lived in Camp Lejeune when he was a child, during which time he drank, bathed, and swam in contaminated water, “unaware of its toxicity.” His father also died of esophageal cancer, “which is linked to TCE,” the authors of the study wrote. Mr. Grant has created a foundation to inspire and support patients with PD.

All of the individuals either grew up in or spent time in an area where they were extensively exposed to TCE, PCE, or other chemicals, or experienced occupational exposure.

The authors acknowledged that the role of TCE in PD, as illustrated by the cases, is “far from definitive.” For example, exposure to TCE is often combined with exposure to other toxins, or with unmeasured genetic risk factors.

They highlighted the need for more research and called for cleaning and containing contaminated sites, monitoring TCE levels, and publicly communicating risk and a ban on TCE.
 

Recall bias?

Commenting for this news organization, Rebecca Gilbert, MD, PhD, chief scientific officer, American Parkinson Disease Association (APDA), noted that the authors “are very frank about the limitations of this approach [illustrative cases] as proof of causation between PD and TCE exposure.”

Another limitation is that TCE exposure is very common, “as argued in the paper.” But “most people with exposure do not develop PD,” Dr. Gilbert pointed out. “By probing the TCE exposure of those who already have PD, there is a danger of recall bias.”

Dr. Gilbert, associate professor of neurology at NYU Langone Health, who was not involved with the study, acknowledged that the authors “present their work as hypothesis and clearly state that more work is needed to understand the connection between TCE and PD.”

In the meantime, however, there are “well-established health risks of TCE exposure, including development of various cancers,” she said. Therefore, the authors’ goals appear to be educating the public about known health risks, working to clean up known sites of contamination, and advocating to ban future use of TCE.

These goals “do not need to wait for [proof of] firm causation between TCE and PD,” she stated.

Dr. Dorsey reported he has received honoraria for speaking at the American Academy of Neurology and at multiple other societies and foundations and has received compensation for consulting services from pharmaceutical companies, foundations, medical education companies, and medical publications; he owns stock in several companies. The other authors’ disclosures can be found in the original paper. Dr. Gilbert is employed by the American Parkinson Disease Association and Bellevue Hospital Center in New York City.
 

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

A common chemical that is used in correction fluid, paint removers, gun cleaners, aerosol cleaning products, and dry cleaning may be the key culprit behind the dramatic increase in Parkinson’s disease (PD), researchers say.

An international team of researchers reviewed previous research and cited data that suggest the chemical trichloroethylene (TCE) is associated with as much as a 500% increased risk for Parkinson’s disease (PD).

Lead investigator Ray Dorsey, MD, professor of neurology, University of Rochester, N.Y., called PD “the world’s fastest-growing brain disease,” and told this news organization that it “may be largely preventable.”

“Countless people have died over generations from cancer and other disease linked to TCE [and] Parkinson’s may be the latest,” he said. “Banning these chemicals, containing contaminated sites, and protecting homes, schools, and buildings at risk may all create a world where Parkinson’s is increasingly rare, not common.”

The paper was published online in the Journal of Parkinson’s Disease.
 

Invisible, ubiquitous

TCE was first synthesized in a lab in 1864, with commercial production beginning in 1920, the researchers noted.

“Because of its unique properties, TCE has had countless industrial, commercial, military, and medical applications,” including producing refrigerants, cleaning electronics, and degreasing engine parts.

In addition, it’s been used in dry cleaning, although a similar chemical (perchloroethylene [PCE]) is currently more widely used for that purpose. Nevertheless, the authors noted, in anaerobic conditions, perchloroethylene often transforms into TCE “and their toxicity may be similar.”

Consumer products in which TCE is found include typewriter correction fluid, paint removers, gun cleaners, and aerosol cleaning products. Up until the 1970s, it was used to decaffeinate coffee.

TCE exposure isn’t confined to those who work with it. It also pollutes outdoor air, taints groundwater, and contaminates indoor air. It’s present in a substantial amount of groundwater in the United States and it “evaporates from underlying soil and groundwater and enters homes, workplaces, or schools, often undetected,” the researchers noted.

“Exposure can come via occupation or the environment and is often largely unknown at the time it occurs,” Dr. Dorsey said.

He noted that the rapid increase in PD incidence cannot be explained by genetic factors alone, which affect only about 15% of patients with PD, nor can it be explained by aging alone. “Certain pesticides ... are likely causes but would not explain the high prevalence of PD in urban areas, as is the case in the U.S.” Rather, “other factors” are involved, and “TCE is likely one such factor.”

Yet, “despite widespread contamination and increasing industrial, commercial, and military use, clinical investigations of TCE and PD have been limited.”

To fill this knowledge gap, Dr. Dorsey and his coauthors of the book, “Ending Parkinson’s Disease: A Prescription for Action,” took a deep dive into studies focusing on the potential association of TCE and PD and presented seven cases to illustrate the association.

“Like many genetic mutations (e.g., Parkin) and other environmental toxicants ... TCE damages the energy-producing parts of cells, i.e., the mitochondria,” said Dr. Dorsey.

TCE and PCE “likely mediate their toxicity through a common metabolite.” Because both are lipophilic, they “readily distribute in the brain and body tissues and appear to cause mitochondrial dysfunction at high doses,” the researchers hypothesized.

Dopaminergic neurons are particularly sensitive to mitochondrial neurotoxicants, so this might “partially explain the link to PD.”

Animal studies have shown that TCE “caused selective loss of dopaminergic neurons.” Moreover, PD-related neuropathology was found in the substantia nigra of rodents exposed to TCE over time. In addition, studies as early as 1960 were showing an association between TCE and parkinsonism.

The authors describe TCE as “ubiquitous” in the 1970s, with 10 million Americans working with the chemical or other organic solvents daily. The review details an extensive list of industries and occupations in which TCE exposure continues to occur.

People working with TCE might inhale it or touch it; but “millions more encounter the chemical unknowingly through outdoor air, contaminated groundwater, and indoor air pollution.”

They noted that TCE contaminates up to one-third of U.S. drinking water, has polluted the groundwater in more than 20 different countries on five continents, and is found in half of the 1,300 most toxic “Superfund” sites that are “part of a federal clean-up program, including 15 in California’s Silicon Valley, where TCE was used to clean electronics.”

Although the U.S. military stopped using TCE, numerous sites have been contaminated, including Marine Corps Base Camp Lejeune in North Carolina, where TCE and PCE were found in drinking water at 280 times the recommended safety standards.

The researchers highlighted seven cases of individuals who developed PD after likely exposure to TCE, including NBA basketball player Brian Grant, who developed symptoms of PD in 2006 at the age of 34.

Mr. Grant and his family had lived in Camp Lejeune when he was a child, during which time he drank, bathed, and swam in contaminated water, “unaware of its toxicity.” His father also died of esophageal cancer, “which is linked to TCE,” the authors of the study wrote. Mr. Grant has created a foundation to inspire and support patients with PD.

All of the individuals either grew up in or spent time in an area where they were extensively exposed to TCE, PCE, or other chemicals, or experienced occupational exposure.

The authors acknowledged that the role of TCE in PD, as illustrated by the cases, is “far from definitive.” For example, exposure to TCE is often combined with exposure to other toxins, or with unmeasured genetic risk factors.

They highlighted the need for more research and called for cleaning and containing contaminated sites, monitoring TCE levels, and publicly communicating risk and a ban on TCE.
 

Recall bias?

Commenting for this news organization, Rebecca Gilbert, MD, PhD, chief scientific officer, American Parkinson Disease Association (APDA), noted that the authors “are very frank about the limitations of this approach [illustrative cases] as proof of causation between PD and TCE exposure.”

Another limitation is that TCE exposure is very common, “as argued in the paper.” But “most people with exposure do not develop PD,” Dr. Gilbert pointed out. “By probing the TCE exposure of those who already have PD, there is a danger of recall bias.”

Dr. Gilbert, associate professor of neurology at NYU Langone Health, who was not involved with the study, acknowledged that the authors “present their work as hypothesis and clearly state that more work is needed to understand the connection between TCE and PD.”

In the meantime, however, there are “well-established health risks of TCE exposure, including development of various cancers,” she said. Therefore, the authors’ goals appear to be educating the public about known health risks, working to clean up known sites of contamination, and advocating to ban future use of TCE.

These goals “do not need to wait for [proof of] firm causation between TCE and PD,” she stated.

Dr. Dorsey reported he has received honoraria for speaking at the American Academy of Neurology and at multiple other societies and foundations and has received compensation for consulting services from pharmaceutical companies, foundations, medical education companies, and medical publications; he owns stock in several companies. The other authors’ disclosures can be found in the original paper. Dr. Gilbert is employed by the American Parkinson Disease Association and Bellevue Hospital Center in New York City.
 

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

As a field service representative for a slot machine company, Ryan Alexander, 37, of Louisville, Ky., spends his working hours in casinos, covering a large territory including Norfolk, Va., Indianapolis, and Charlotte. Social distancing in the casinos is not the norm. Despite all this up-close contact with people, he said he is still COVID-free, 3 years into the pandemic.

There was one nervous night when his temperature rose to 101° F, and he figured the virus had caught up with him. “I took a test and was fine,” he said, relieved that the result was negative. The fever disappeared, and he was back to normal soon. “Maybe it was just an exhausting day.”

Mr. Alexander is one of those people who have managed – or at least think they have managed – to avoid getting COVID-19.

He is, some say, a NOVID. While some scientists cringe at the term, it’s caught on to describe these virus super-dodgers. Online entrepreneurs offer NOVID-19 T-shirts, masks, and stickers, in case these super-healthy or super-lucky folks want to publicize their good luck. On Twitter, NOVIDs share stories of how they’ve done it.
 

How many NOVIDs?

As of March 16, according to the CDC, almost 104 million cases of COVID – about one-third of the U.S. population – have been reported, but many cases are known to go unreported. About half of American adults surveyed said they have had COVID, according to a December report by the COVID States Project, a multiuniversity effort to supply pandemic data.

As the numbers settle over time, though, it becomes clearer that some in the U.S. have apparently managed to avoid the virus.

While the exact number of people who have remained uninfected isn’t known with certainty, a review of comprehensive serologic data shows about 15% of Americans may not have gotten infected with COVID, Eric Topol, MD, editor-in-chief of Medscape (WebMD’s sister site for medical professionals) wrote in his substack Ground Truths.

But some scientists bristle at the term NOVIDs. They prefer the term “resisters,” according to Elena Hsieh, MD, associate professor of pediatrics and immunology at the University of Colorado at Denver, Aurora. Currently, she said, there is much more information on who is more susceptible to contracting severe COVID than who is resistant.

Dr. Hsieh is one of the regional coordinators for the COVID Human Genetic Effort, an international consortium of more than 250 researchers and doctors dedicated to discovering the genetic and immunological bases of the forms of SARS-CoV-2 infection. These researchers and others are looking for explanations for why some people get severe COVID while others seem resistant despite repeated exposure.
 

Resistance research

In determining explanations for resistance to infection, “the needle in the haystack that we are looking for is a change in the genetic code that would allow for you to avoid entry of the virus into the cell,” Dr. Hsieh said. “That is what being resistant to infection is.”

Part of the reason it’s so difficult to study resistance is defining a resister, she said. While many people consider themselves among that group because they’re been exposed multiple times – even with close family members infected and sick, yet they still felt fine – that doesn’t necessarily make them a resister, she said.

Those people could have been infected but remained without symptoms. “Resistance means the virus was inside you, it was near your cell and it did not infect your cell,” Dr. Hsieh said.

“I don’t think we know a lot so far,” Dr. Hsieh said about resisters. “I do believe that, just like there are genetic defects that make someone more susceptible, there are likely to be genetic defects that make somebody less susceptible.’’

“To identify genetic variants that are protective is a really challenging thing to do,” agreed Peter K. Gregersen, MD, professor of genetics at the Feinstein Institutes for Medical Research at Northwell Health in Manhasset, N.Y. Dr. Gregersen is also a regional coordinator for the COVID Human Genetic Effort.

He suspects the number found to be truly resistant to COVID – versus dodging it so far – is going to be very small or not found at all.

“It may exist for COVID or it may not,” he said. Some people may simply have what he calls a robust immune response in the upper part of the throat, perhaps killing off the virus quickly as soon as it enters, so they don’t get a positive test.

Genetic resistance has been found for other diseases, such as HIV.

“For HIV, scientists have been able to identify a specific gene that codes for a protein that can prevent individuals from getting infected,” said Sabrina Assoumou, MD, MPH, professor of medicine at Boston University, who researches HIV.

However, she said, “we haven’t yet found a similar gene or protein that can prevent people from getting infected with SARS-CoV-2.”

What has been found “is that some people might have a mutation in a gene that encodes for what’s called human leukocyte antigen (HLA),” Dr. Assoumou said. HLA, a molecule found on the surface of most cells, has a crucial role in the immune response to foreign substances. “A mutation in HLA can make people less likely to have symptoms if they get infected. Individuals still get infected, but they are less likely to have symptoms.”

Other research has found that those with food allergies are also less likely to be infected. The researchers have speculated that the inflammation characteristic of allergic conditions may reduce levels of a protein called the ACE2 receptor on the surface of airway cells. The SARS-CoV-2 virus uses the receptor to enter the cells, so if levels are low, that could reduce the ability of the virus to infect people.

The COVID Human Genetic Effort continues to search for participants, both those who were admitted to a hospital or repeatedly seen at a hospital because of COVID, as well as those who did not get infected, even after “intense and repeated” exposure.

The number of people likely to be resistant is much smaller, Dr. Hsieh said, than the number of people susceptible to severe disease.
 

The testing ... or lack thereof factor

The timing of testing and a person’s “infection profile” may be factors in people incorrectly declaring themselves NOVIDs, said Anne Wyllie, PhD, a research scientist in epidemiology at the Yale School of Public Health in New Haven, Conn., and a codeveloper of a saliva PCR test for COVID.

“Infection profiles can vary between individuals,” she said. For some, the infection may start in the lower respiratory tract, others in the higher respiratory tract. “Depending on where the virus takes up residence, that can affect test results.”

Then there’s the following-instructions factor. “It’s very likely that due to tests not being done at the right time, with the right sample, or not repeated if there is ongoing evidence of symptoms, that there are individuals out there who believe they are NOVIDs but just missed catching their infection at the window of opportunity.” Dr. Wyllie said.
 

Susceptibility research

“The part we have proven is the genetic defect that would make you more susceptible to having severe disease,” Dr. Hsieh said.

Many published papers report that inherited and/or autoimmune deficiencies of type I interferon immunity, important for combating viral infections and modulating the immune response, can be a significant cause of life-threatening COVID pneumonia.

More recently, researchers, including Jean-Laurent Casanova, MD, PhD, professor at Rockefeller University, New York, and cofounder of the COVID Human Genome Effort, reported that deficiencies in a gene that plays a role in built-in immunity (the early response), and a gene involved in signaling within the immune cells, impair interferon production and may be the basis of severe COVID pneumonia.
 

NOVIDs’ habits run the gamut

As scientists continue their research, the NOVIDs have their own ideas about why they’ve dodged the pandemic bullet, and they have a variety of approaches to handling the pandemic now.

Ryan Alexander, the field rep who travels to casinos, is up to date on his vaccinations and has gotten all the recommended COVID shots. “I was wearing a mask when told to wear masks,” he said.

He still observes the social distance habit but lives life. “I’ve been to three or four concerts in the past couple of years.”

And does he worry his number will eventually be up? “Not at this point, no,” he said.

Joe Asher, 46, said he has not gotten COVID despite being in contact with about 100 people a day, on average. He works as a bartender at an Evansville, Ind., brewery.

“On a Friday night, we can get 500 people,” he said. “I feel like almost everyone at the brewery got it. There’s no way I wasn’t exposed to it all the time.”

However, he said, his coworkers who did get sick were very cautious about not infecting others, partly to help protect a coworker’s family with newborn twins, so that may have helped him stay uninfected, too.

Mr. Asher said he’s in good physical shape, and he’s worked around the public for a long time, so figures maybe that has strengthened his immune system. He’s always been careful about handwashing and said he’s perhaps a bit more conscious of germs than others might be.

Roselyn Mena, 68, a retired teacher in Richmond, Calif., about 16 miles northeast of San Francisco, said she’s managed to avoid the virus even though her husband, Jesus Mena, got infected, as did her two adult children. Now, she remains vigilant about wearing a mask. She tries not to eat inside at restaurants. “I’m super careful,” she said.

Besides her teacher training, Ms. Mena had training as a medical assistant and learned a lot about sanitizing methods. She gets an annual flu shot, washes her hands often, and uses hand sanitizer.

When she shops, she will ask salespeople not wearing masks to please mask. “Only one refused, and she got someone else [to wait on her].”

One reason she is always careful about hygiene, Ms. Mena said, is that “when I get a cold, I get really sick. It last and lasts.” Now, she does worry she might still get it, she said, with the prospect of getting long COVID driving that worry.

In the beginning of the pandemic, Rhonda Fleming, 68, of Los Angeles, lived in a “COVID bubble,” interacting with just a few close family members. As cases went down, she enlarged the bubble. Her two grown daughters got infected, but her granddaughter did not.

She has been vigilant about masking, she said, “and I do still mask in public places.” She has a mask wardrobe, including basic black as well as glittery masks for dressier occasions. “I always carry a mask because inevitably, a cougher surrounds me.”

Now, she will bypass restaurants if she doesn’t feel comfortable with the environment, choosing ones with good air flow. When she flew to Mexico recently, she masked on the plane.

At this point, she said she doesn’t worry about getting infected but remains careful.

Recently, two friends, who have been as diligent as she has about precautions, got infected, “and they don’t know how they got it.”
 

Bragging rights?

Until researchers separate out the true resisters from those who claim to be, some NOVIDs are simply quietly grateful for their luck, while others mention their COVID-free status to anyone who asks or who will listen, and are proud of it. 

And what about those who wear a “NOVID” T-shirt?

“I would think they have a need to convey to the world they are different, perhaps special, because they beat COVID,” said Richard B. Joelson, a New York–based doctor of social work, a psychotherapist, and the author of Help Me! A Psychotherapist’s Tried-and-True Techniques for a Happier Relationship with Yourself and the People You Love. “They didn’t beat COVID, they just didn’t get it.”

Or they may be relieved they didn’t get sick, he said, because they feel defeated when they do. So “it’s a source of pride.” It might be the same people who tell anyone who will listen they never need a doctor or take no medicines, he said.

Even though science may prove many NOVIDs are inaccurate when they call themselves resisters, Dr. Hsieh understands the temptation to talk about it. “It’s kind of cool to think you are supernatural,” she said. “It’s much more attractive than being susceptible. It’s a lot sexier.” ■

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

As a field service representative for a slot machine company, Ryan Alexander, 37, of Louisville, Ky., spends his working hours in casinos, covering a large territory including Norfolk, Va., Indianapolis, and Charlotte. Social distancing in the casinos is not the norm. Despite all this up-close contact with people, he said he is still COVID-free, 3 years into the pandemic.

There was one nervous night when his temperature rose to 101° F, and he figured the virus had caught up with him. “I took a test and was fine,” he said, relieved that the result was negative. The fever disappeared, and he was back to normal soon. “Maybe it was just an exhausting day.”

Mr. Alexander is one of those people who have managed – or at least think they have managed – to avoid getting COVID-19.

He is, some say, a NOVID. While some scientists cringe at the term, it’s caught on to describe these virus super-dodgers. Online entrepreneurs offer NOVID-19 T-shirts, masks, and stickers, in case these super-healthy or super-lucky folks want to publicize their good luck. On Twitter, NOVIDs share stories of how they’ve done it.
 

How many NOVIDs?

As of March 16, according to the CDC, almost 104 million cases of COVID – about one-third of the U.S. population – have been reported, but many cases are known to go unreported. About half of American adults surveyed said they have had COVID, according to a December report by the COVID States Project, a multiuniversity effort to supply pandemic data.

As the numbers settle over time, though, it becomes clearer that some in the U.S. have apparently managed to avoid the virus.

While the exact number of people who have remained uninfected isn’t known with certainty, a review of comprehensive serologic data shows about 15% of Americans may not have gotten infected with COVID, Eric Topol, MD, editor-in-chief of Medscape (WebMD’s sister site for medical professionals) wrote in his substack Ground Truths.

But some scientists bristle at the term NOVIDs. They prefer the term “resisters,” according to Elena Hsieh, MD, associate professor of pediatrics and immunology at the University of Colorado at Denver, Aurora. Currently, she said, there is much more information on who is more susceptible to contracting severe COVID than who is resistant.

Dr. Hsieh is one of the regional coordinators for the COVID Human Genetic Effort, an international consortium of more than 250 researchers and doctors dedicated to discovering the genetic and immunological bases of the forms of SARS-CoV-2 infection. These researchers and others are looking for explanations for why some people get severe COVID while others seem resistant despite repeated exposure.
 

Resistance research

In determining explanations for resistance to infection, “the needle in the haystack that we are looking for is a change in the genetic code that would allow for you to avoid entry of the virus into the cell,” Dr. Hsieh said. “That is what being resistant to infection is.”

Part of the reason it’s so difficult to study resistance is defining a resister, she said. While many people consider themselves among that group because they’re been exposed multiple times – even with close family members infected and sick, yet they still felt fine – that doesn’t necessarily make them a resister, she said.

Those people could have been infected but remained without symptoms. “Resistance means the virus was inside you, it was near your cell and it did not infect your cell,” Dr. Hsieh said.

“I don’t think we know a lot so far,” Dr. Hsieh said about resisters. “I do believe that, just like there are genetic defects that make someone more susceptible, there are likely to be genetic defects that make somebody less susceptible.’’

“To identify genetic variants that are protective is a really challenging thing to do,” agreed Peter K. Gregersen, MD, professor of genetics at the Feinstein Institutes for Medical Research at Northwell Health in Manhasset, N.Y. Dr. Gregersen is also a regional coordinator for the COVID Human Genetic Effort.

He suspects the number found to be truly resistant to COVID – versus dodging it so far – is going to be very small or not found at all.

“It may exist for COVID or it may not,” he said. Some people may simply have what he calls a robust immune response in the upper part of the throat, perhaps killing off the virus quickly as soon as it enters, so they don’t get a positive test.

Genetic resistance has been found for other diseases, such as HIV.

“For HIV, scientists have been able to identify a specific gene that codes for a protein that can prevent individuals from getting infected,” said Sabrina Assoumou, MD, MPH, professor of medicine at Boston University, who researches HIV.

However, she said, “we haven’t yet found a similar gene or protein that can prevent people from getting infected with SARS-CoV-2.”

What has been found “is that some people might have a mutation in a gene that encodes for what’s called human leukocyte antigen (HLA),” Dr. Assoumou said. HLA, a molecule found on the surface of most cells, has a crucial role in the immune response to foreign substances. “A mutation in HLA can make people less likely to have symptoms if they get infected. Individuals still get infected, but they are less likely to have symptoms.”

Other research has found that those with food allergies are also less likely to be infected. The researchers have speculated that the inflammation characteristic of allergic conditions may reduce levels of a protein called the ACE2 receptor on the surface of airway cells. The SARS-CoV-2 virus uses the receptor to enter the cells, so if levels are low, that could reduce the ability of the virus to infect people.

The COVID Human Genetic Effort continues to search for participants, both those who were admitted to a hospital or repeatedly seen at a hospital because of COVID, as well as those who did not get infected, even after “intense and repeated” exposure.

The number of people likely to be resistant is much smaller, Dr. Hsieh said, than the number of people susceptible to severe disease.
 

The testing ... or lack thereof factor

The timing of testing and a person’s “infection profile” may be factors in people incorrectly declaring themselves NOVIDs, said Anne Wyllie, PhD, a research scientist in epidemiology at the Yale School of Public Health in New Haven, Conn., and a codeveloper of a saliva PCR test for COVID.

“Infection profiles can vary between individuals,” she said. For some, the infection may start in the lower respiratory tract, others in the higher respiratory tract. “Depending on where the virus takes up residence, that can affect test results.”

Then there’s the following-instructions factor. “It’s very likely that due to tests not being done at the right time, with the right sample, or not repeated if there is ongoing evidence of symptoms, that there are individuals out there who believe they are NOVIDs but just missed catching their infection at the window of opportunity.” Dr. Wyllie said.
 

Susceptibility research

“The part we have proven is the genetic defect that would make you more susceptible to having severe disease,” Dr. Hsieh said.

Many published papers report that inherited and/or autoimmune deficiencies of type I interferon immunity, important for combating viral infections and modulating the immune response, can be a significant cause of life-threatening COVID pneumonia.

More recently, researchers, including Jean-Laurent Casanova, MD, PhD, professor at Rockefeller University, New York, and cofounder of the COVID Human Genome Effort, reported that deficiencies in a gene that plays a role in built-in immunity (the early response), and a gene involved in signaling within the immune cells, impair interferon production and may be the basis of severe COVID pneumonia.
 

NOVIDs’ habits run the gamut

As scientists continue their research, the NOVIDs have their own ideas about why they’ve dodged the pandemic bullet, and they have a variety of approaches to handling the pandemic now.

Ryan Alexander, the field rep who travels to casinos, is up to date on his vaccinations and has gotten all the recommended COVID shots. “I was wearing a mask when told to wear masks,” he said.

He still observes the social distance habit but lives life. “I’ve been to three or four concerts in the past couple of years.”

And does he worry his number will eventually be up? “Not at this point, no,” he said.

Joe Asher, 46, said he has not gotten COVID despite being in contact with about 100 people a day, on average. He works as a bartender at an Evansville, Ind., brewery.

“On a Friday night, we can get 500 people,” he said. “I feel like almost everyone at the brewery got it. There’s no way I wasn’t exposed to it all the time.”

However, he said, his coworkers who did get sick were very cautious about not infecting others, partly to help protect a coworker’s family with newborn twins, so that may have helped him stay uninfected, too.

Mr. Asher said he’s in good physical shape, and he’s worked around the public for a long time, so figures maybe that has strengthened his immune system. He’s always been careful about handwashing and said he’s perhaps a bit more conscious of germs than others might be.

Roselyn Mena, 68, a retired teacher in Richmond, Calif., about 16 miles northeast of San Francisco, said she’s managed to avoid the virus even though her husband, Jesus Mena, got infected, as did her two adult children. Now, she remains vigilant about wearing a mask. She tries not to eat inside at restaurants. “I’m super careful,” she said.

Besides her teacher training, Ms. Mena had training as a medical assistant and learned a lot about sanitizing methods. She gets an annual flu shot, washes her hands often, and uses hand sanitizer.

When she shops, she will ask salespeople not wearing masks to please mask. “Only one refused, and she got someone else [to wait on her].”

One reason she is always careful about hygiene, Ms. Mena said, is that “when I get a cold, I get really sick. It last and lasts.” Now, she does worry she might still get it, she said, with the prospect of getting long COVID driving that worry.

In the beginning of the pandemic, Rhonda Fleming, 68, of Los Angeles, lived in a “COVID bubble,” interacting with just a few close family members. As cases went down, she enlarged the bubble. Her two grown daughters got infected, but her granddaughter did not.

She has been vigilant about masking, she said, “and I do still mask in public places.” She has a mask wardrobe, including basic black as well as glittery masks for dressier occasions. “I always carry a mask because inevitably, a cougher surrounds me.”

Now, she will bypass restaurants if she doesn’t feel comfortable with the environment, choosing ones with good air flow. When she flew to Mexico recently, she masked on the plane.

At this point, she said she doesn’t worry about getting infected but remains careful.

Recently, two friends, who have been as diligent as she has about precautions, got infected, “and they don’t know how they got it.”
 

Bragging rights?

Until researchers separate out the true resisters from those who claim to be, some NOVIDs are simply quietly grateful for their luck, while others mention their COVID-free status to anyone who asks or who will listen, and are proud of it. 

And what about those who wear a “NOVID” T-shirt?

“I would think they have a need to convey to the world they are different, perhaps special, because they beat COVID,” said Richard B. Joelson, a New York–based doctor of social work, a psychotherapist, and the author of Help Me! A Psychotherapist’s Tried-and-True Techniques for a Happier Relationship with Yourself and the People You Love. “They didn’t beat COVID, they just didn’t get it.”

Or they may be relieved they didn’t get sick, he said, because they feel defeated when they do. So “it’s a source of pride.” It might be the same people who tell anyone who will listen they never need a doctor or take no medicines, he said.

Even though science may prove many NOVIDs are inaccurate when they call themselves resisters, Dr. Hsieh understands the temptation to talk about it. “It’s kind of cool to think you are supernatural,” she said. “It’s much more attractive than being susceptible. It’s a lot sexier.” ■

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

As a field service representative for a slot machine company, Ryan Alexander, 37, of Louisville, Ky., spends his working hours in casinos, covering a large territory including Norfolk, Va., Indianapolis, and Charlotte. Social distancing in the casinos is not the norm. Despite all this up-close contact with people, he said he is still COVID-free, 3 years into the pandemic.

There was one nervous night when his temperature rose to 101° F, and he figured the virus had caught up with him. “I took a test and was fine,” he said, relieved that the result was negative. The fever disappeared, and he was back to normal soon. “Maybe it was just an exhausting day.”

Mr. Alexander is one of those people who have managed – or at least think they have managed – to avoid getting COVID-19.

He is, some say, a NOVID. While some scientists cringe at the term, it’s caught on to describe these virus super-dodgers. Online entrepreneurs offer NOVID-19 T-shirts, masks, and stickers, in case these super-healthy or super-lucky folks want to publicize their good luck. On Twitter, NOVIDs share stories of how they’ve done it.
 

How many NOVIDs?

As of March 16, according to the CDC, almost 104 million cases of COVID – about one-third of the U.S. population – have been reported, but many cases are known to go unreported. About half of American adults surveyed said they have had COVID, according to a December report by the COVID States Project, a multiuniversity effort to supply pandemic data.

As the numbers settle over time, though, it becomes clearer that some in the U.S. have apparently managed to avoid the virus.

While the exact number of people who have remained uninfected isn’t known with certainty, a review of comprehensive serologic data shows about 15% of Americans may not have gotten infected with COVID, Eric Topol, MD, editor-in-chief of Medscape (WebMD’s sister site for medical professionals) wrote in his substack Ground Truths.

But some scientists bristle at the term NOVIDs. They prefer the term “resisters,” according to Elena Hsieh, MD, associate professor of pediatrics and immunology at the University of Colorado at Denver, Aurora. Currently, she said, there is much more information on who is more susceptible to contracting severe COVID than who is resistant.

Dr. Hsieh is one of the regional coordinators for the COVID Human Genetic Effort, an international consortium of more than 250 researchers and doctors dedicated to discovering the genetic and immunological bases of the forms of SARS-CoV-2 infection. These researchers and others are looking for explanations for why some people get severe COVID while others seem resistant despite repeated exposure.
 

Resistance research

In determining explanations for resistance to infection, “the needle in the haystack that we are looking for is a change in the genetic code that would allow for you to avoid entry of the virus into the cell,” Dr. Hsieh said. “That is what being resistant to infection is.”

Part of the reason it’s so difficult to study resistance is defining a resister, she said. While many people consider themselves among that group because they’re been exposed multiple times – even with close family members infected and sick, yet they still felt fine – that doesn’t necessarily make them a resister, she said.

Those people could have been infected but remained without symptoms. “Resistance means the virus was inside you, it was near your cell and it did not infect your cell,” Dr. Hsieh said.

“I don’t think we know a lot so far,” Dr. Hsieh said about resisters. “I do believe that, just like there are genetic defects that make someone more susceptible, there are likely to be genetic defects that make somebody less susceptible.’’

“To identify genetic variants that are protective is a really challenging thing to do,” agreed Peter K. Gregersen, MD, professor of genetics at the Feinstein Institutes for Medical Research at Northwell Health in Manhasset, N.Y. Dr. Gregersen is also a regional coordinator for the COVID Human Genetic Effort.

He suspects the number found to be truly resistant to COVID – versus dodging it so far – is going to be very small or not found at all.

“It may exist for COVID or it may not,” he said. Some people may simply have what he calls a robust immune response in the upper part of the throat, perhaps killing off the virus quickly as soon as it enters, so they don’t get a positive test.

Genetic resistance has been found for other diseases, such as HIV.

“For HIV, scientists have been able to identify a specific gene that codes for a protein that can prevent individuals from getting infected,” said Sabrina Assoumou, MD, MPH, professor of medicine at Boston University, who researches HIV.

However, she said, “we haven’t yet found a similar gene or protein that can prevent people from getting infected with SARS-CoV-2.”

What has been found “is that some people might have a mutation in a gene that encodes for what’s called human leukocyte antigen (HLA),” Dr. Assoumou said. HLA, a molecule found on the surface of most cells, has a crucial role in the immune response to foreign substances. “A mutation in HLA can make people less likely to have symptoms if they get infected. Individuals still get infected, but they are less likely to have symptoms.”

Other research has found that those with food allergies are also less likely to be infected. The researchers have speculated that the inflammation characteristic of allergic conditions may reduce levels of a protein called the ACE2 receptor on the surface of airway cells. The SARS-CoV-2 virus uses the receptor to enter the cells, so if levels are low, that could reduce the ability of the virus to infect people.

The COVID Human Genetic Effort continues to search for participants, both those who were admitted to a hospital or repeatedly seen at a hospital because of COVID, as well as those who did not get infected, even after “intense and repeated” exposure.

The number of people likely to be resistant is much smaller, Dr. Hsieh said, than the number of people susceptible to severe disease.
 

The testing ... or lack thereof factor

The timing of testing and a person’s “infection profile” may be factors in people incorrectly declaring themselves NOVIDs, said Anne Wyllie, PhD, a research scientist in epidemiology at the Yale School of Public Health in New Haven, Conn., and a codeveloper of a saliva PCR test for COVID.

“Infection profiles can vary between individuals,” she said. For some, the infection may start in the lower respiratory tract, others in the higher respiratory tract. “Depending on where the virus takes up residence, that can affect test results.”

Then there’s the following-instructions factor. “It’s very likely that due to tests not being done at the right time, with the right sample, or not repeated if there is ongoing evidence of symptoms, that there are individuals out there who believe they are NOVIDs but just missed catching their infection at the window of opportunity.” Dr. Wyllie said.
 

Susceptibility research

“The part we have proven is the genetic defect that would make you more susceptible to having severe disease,” Dr. Hsieh said.

Many published papers report that inherited and/or autoimmune deficiencies of type I interferon immunity, important for combating viral infections and modulating the immune response, can be a significant cause of life-threatening COVID pneumonia.

More recently, researchers, including Jean-Laurent Casanova, MD, PhD, professor at Rockefeller University, New York, and cofounder of the COVID Human Genome Effort, reported that deficiencies in a gene that plays a role in built-in immunity (the early response), and a gene involved in signaling within the immune cells, impair interferon production and may be the basis of severe COVID pneumonia.
 

NOVIDs’ habits run the gamut

As scientists continue their research, the NOVIDs have their own ideas about why they’ve dodged the pandemic bullet, and they have a variety of approaches to handling the pandemic now.

Ryan Alexander, the field rep who travels to casinos, is up to date on his vaccinations and has gotten all the recommended COVID shots. “I was wearing a mask when told to wear masks,” he said.

He still observes the social distance habit but lives life. “I’ve been to three or four concerts in the past couple of years.”

And does he worry his number will eventually be up? “Not at this point, no,” he said.

Joe Asher, 46, said he has not gotten COVID despite being in contact with about 100 people a day, on average. He works as a bartender at an Evansville, Ind., brewery.

“On a Friday night, we can get 500 people,” he said. “I feel like almost everyone at the brewery got it. There’s no way I wasn’t exposed to it all the time.”

However, he said, his coworkers who did get sick were very cautious about not infecting others, partly to help protect a coworker’s family with newborn twins, so that may have helped him stay uninfected, too.

Mr. Asher said he’s in good physical shape, and he’s worked around the public for a long time, so figures maybe that has strengthened his immune system. He’s always been careful about handwashing and said he’s perhaps a bit more conscious of germs than others might be.

Roselyn Mena, 68, a retired teacher in Richmond, Calif., about 16 miles northeast of San Francisco, said she’s managed to avoid the virus even though her husband, Jesus Mena, got infected, as did her two adult children. Now, she remains vigilant about wearing a mask. She tries not to eat inside at restaurants. “I’m super careful,” she said.

Besides her teacher training, Ms. Mena had training as a medical assistant and learned a lot about sanitizing methods. She gets an annual flu shot, washes her hands often, and uses hand sanitizer.

When she shops, she will ask salespeople not wearing masks to please mask. “Only one refused, and she got someone else [to wait on her].”

One reason she is always careful about hygiene, Ms. Mena said, is that “when I get a cold, I get really sick. It last and lasts.” Now, she does worry she might still get it, she said, with the prospect of getting long COVID driving that worry.

In the beginning of the pandemic, Rhonda Fleming, 68, of Los Angeles, lived in a “COVID bubble,” interacting with just a few close family members. As cases went down, she enlarged the bubble. Her two grown daughters got infected, but her granddaughter did not.

She has been vigilant about masking, she said, “and I do still mask in public places.” She has a mask wardrobe, including basic black as well as glittery masks for dressier occasions. “I always carry a mask because inevitably, a cougher surrounds me.”

Now, she will bypass restaurants if she doesn’t feel comfortable with the environment, choosing ones with good air flow. When she flew to Mexico recently, she masked on the plane.

At this point, she said she doesn’t worry about getting infected but remains careful.

Recently, two friends, who have been as diligent as she has about precautions, got infected, “and they don’t know how they got it.”
 

Bragging rights?

Until researchers separate out the true resisters from those who claim to be, some NOVIDs are simply quietly grateful for their luck, while others mention their COVID-free status to anyone who asks or who will listen, and are proud of it. 

And what about those who wear a “NOVID” T-shirt?

“I would think they have a need to convey to the world they are different, perhaps special, because they beat COVID,” said Richard B. Joelson, a New York–based doctor of social work, a psychotherapist, and the author of Help Me! A Psychotherapist’s Tried-and-True Techniques for a Happier Relationship with Yourself and the People You Love. “They didn’t beat COVID, they just didn’t get it.”

Or they may be relieved they didn’t get sick, he said, because they feel defeated when they do. So “it’s a source of pride.” It might be the same people who tell anyone who will listen they never need a doctor or take no medicines, he said.

Even though science may prove many NOVIDs are inaccurate when they call themselves resisters, Dr. Hsieh understands the temptation to talk about it. “It’s kind of cool to think you are supernatural,” she said. “It’s much more attractive than being susceptible. It’s a lot sexier.” ■

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

The Environmental Protection Agency is proposing a new rule that would greatly limit the concentration of endocrine-disrupting “forever” chemicals in drinking water. 

The EPA on Tuesday announced the proposed National Primary Drinking Water Regulation (NPDWR) for six polyfluoroalkyl substances, more commonly known as PFAS, which are human-made chemicals used as oil and water repellents and coatings for common products including cookware, carpets, and textiles. Such substances are also widely used in cosmetics and food packaging.

curtoicurto/Getty Images

The Endocrine Society, which represents more than 18,000 doctors who treat hormone disorders, says it fully supports the new EPA proposal. It explains that these substances, also known as endocrine-disrupting chemicals, “do not break down when they are released into the environment, and they continue to accumulate over time. They pose health dangers at incredibly low levels and have been linked to endocrine disorders such as cancer, thyroid disruption, and reproductive difficulties.”

“This is the first time the government has regulated a new chemical in drinking water in more than 30 years,” the society notes, adding, this “will require major water treatment upgrades at utilities across the country.”

Robert F. Powelson, president and CEO of the National Association of Water Companies, says addressing the PFAS in the nation’s water supply will cost “billions of dollars.”

“It’s a burden that under the current structure will disproportionately fall on water and wastewater customers in small communities and low-income families,” Mr. Powelson says in a statement. He says the onus should instead fall on “the polluters” – those who manufacture and use PFAS chemicals, who “should be held directly responsible for the clean-up costs.” 

Although the EPA is proposing a health-based maximum contaminant level goal of zero for these chemicals in drinking water, it acknowledges that this is unenforceable and so has set what it considers an enforceable level, or maximum contaminant level (MCL), of 4 parts per trillion for two of the PFAS, perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS). 

A different standard has been proposed for the remaining four chemicals: perfluorononanoic acid (PFNA) and hexafluoropropylene oxide dimer acid (HFPO-DA) – known together as GenX chemicals – perfluorohexane sulfonic acid (PFHxS), and perfluorobutane sulfonic acid (PFBS).

Officials from the EPA told The Washington Post that these proposed limits would be as strong or stronger than limits from about a dozen states that have set their own drinking water standards in recent years. 

“The experts here felt this was the level of stringency required to protect public health, and that the law would allow for us,” EPA Administrator Michael Regan told the newspaper. “This is a transformative action that we’re taking.”

The EPA is requesting public comment on the proposed regulation and will hold a public hearing on May 4, which members of the public can register to attend and comment on the rule proposal. The last day to register is April 28. 

The EPA wants to finalize regulation by the end of 2023, although delays are common on new rules. 

If it is fully implemented, “the rule will prevent thousands of deaths and reduce tens of thousands of serious PFAS-attributable illnesses,” the EPA statement says.

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

The Environmental Protection Agency is proposing a new rule that would greatly limit the concentration of endocrine-disrupting “forever” chemicals in drinking water. 

The EPA on Tuesday announced the proposed National Primary Drinking Water Regulation (NPDWR) for six polyfluoroalkyl substances, more commonly known as PFAS, which are human-made chemicals used as oil and water repellents and coatings for common products including cookware, carpets, and textiles. Such substances are also widely used in cosmetics and food packaging.

curtoicurto/Getty Images

The Endocrine Society, which represents more than 18,000 doctors who treat hormone disorders, says it fully supports the new EPA proposal. It explains that these substances, also known as endocrine-disrupting chemicals, “do not break down when they are released into the environment, and they continue to accumulate over time. They pose health dangers at incredibly low levels and have been linked to endocrine disorders such as cancer, thyroid disruption, and reproductive difficulties.”

“This is the first time the government has regulated a new chemical in drinking water in more than 30 years,” the society notes, adding, this “will require major water treatment upgrades at utilities across the country.”

Robert F. Powelson, president and CEO of the National Association of Water Companies, says addressing the PFAS in the nation’s water supply will cost “billions of dollars.”

“It’s a burden that under the current structure will disproportionately fall on water and wastewater customers in small communities and low-income families,” Mr. Powelson says in a statement. He says the onus should instead fall on “the polluters” – those who manufacture and use PFAS chemicals, who “should be held directly responsible for the clean-up costs.” 

Although the EPA is proposing a health-based maximum contaminant level goal of zero for these chemicals in drinking water, it acknowledges that this is unenforceable and so has set what it considers an enforceable level, or maximum contaminant level (MCL), of 4 parts per trillion for two of the PFAS, perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS). 

A different standard has been proposed for the remaining four chemicals: perfluorononanoic acid (PFNA) and hexafluoropropylene oxide dimer acid (HFPO-DA) – known together as GenX chemicals – perfluorohexane sulfonic acid (PFHxS), and perfluorobutane sulfonic acid (PFBS).

Officials from the EPA told The Washington Post that these proposed limits would be as strong or stronger than limits from about a dozen states that have set their own drinking water standards in recent years. 

“The experts here felt this was the level of stringency required to protect public health, and that the law would allow for us,” EPA Administrator Michael Regan told the newspaper. “This is a transformative action that we’re taking.”

The EPA is requesting public comment on the proposed regulation and will hold a public hearing on May 4, which members of the public can register to attend and comment on the rule proposal. The last day to register is April 28. 

The EPA wants to finalize regulation by the end of 2023, although delays are common on new rules. 

If it is fully implemented, “the rule will prevent thousands of deaths and reduce tens of thousands of serious PFAS-attributable illnesses,” the EPA statement says.

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

The Environmental Protection Agency is proposing a new rule that would greatly limit the concentration of endocrine-disrupting “forever” chemicals in drinking water. 

The EPA on Tuesday announced the proposed National Primary Drinking Water Regulation (NPDWR) for six polyfluoroalkyl substances, more commonly known as PFAS, which are human-made chemicals used as oil and water repellents and coatings for common products including cookware, carpets, and textiles. Such substances are also widely used in cosmetics and food packaging.

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The Endocrine Society, which represents more than 18,000 doctors who treat hormone disorders, says it fully supports the new EPA proposal. It explains that these substances, also known as endocrine-disrupting chemicals, “do not break down when they are released into the environment, and they continue to accumulate over time. They pose health dangers at incredibly low levels and have been linked to endocrine disorders such as cancer, thyroid disruption, and reproductive difficulties.”

“This is the first time the government has regulated a new chemical in drinking water in more than 30 years,” the society notes, adding, this “will require major water treatment upgrades at utilities across the country.”

Robert F. Powelson, president and CEO of the National Association of Water Companies, says addressing the PFAS in the nation’s water supply will cost “billions of dollars.”

“It’s a burden that under the current structure will disproportionately fall on water and wastewater customers in small communities and low-income families,” Mr. Powelson says in a statement. He says the onus should instead fall on “the polluters” – those who manufacture and use PFAS chemicals, who “should be held directly responsible for the clean-up costs.” 

Although the EPA is proposing a health-based maximum contaminant level goal of zero for these chemicals in drinking water, it acknowledges that this is unenforceable and so has set what it considers an enforceable level, or maximum contaminant level (MCL), of 4 parts per trillion for two of the PFAS, perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS). 

A different standard has been proposed for the remaining four chemicals: perfluorononanoic acid (PFNA) and hexafluoropropylene oxide dimer acid (HFPO-DA) – known together as GenX chemicals – perfluorohexane sulfonic acid (PFHxS), and perfluorobutane sulfonic acid (PFBS).

Officials from the EPA told The Washington Post that these proposed limits would be as strong or stronger than limits from about a dozen states that have set their own drinking water standards in recent years. 

“The experts here felt this was the level of stringency required to protect public health, and that the law would allow for us,” EPA Administrator Michael Regan told the newspaper. “This is a transformative action that we’re taking.”

The EPA is requesting public comment on the proposed regulation and will hold a public hearing on May 4, which members of the public can register to attend and comment on the rule proposal. The last day to register is April 28. 

The EPA wants to finalize regulation by the end of 2023, although delays are common on new rules. 

If it is fully implemented, “the rule will prevent thousands of deaths and reduce tens of thousands of serious PFAS-attributable illnesses,” the EPA statement says.

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

The reversible oral Janus kinase (JAK) inhibitor upadacitinib (Rinvoq, AbbVie) was associated with superior endoscopic outcomes at 12 weeks and 1 year compared with placebo among people with moderately to severely active Crohn’s disease.

The findings of this subanalysis come from two phase 3 induction trials (U-EXCEL and U-EXCEED) and one maintenance study (U-ENDURE) of upadacitinib in this patient population.

“Upadacitinib shows large differences relative to placebo in endoscopic response and remission ... in a difficult-to-treat population of patients, the majority of whom had failed an advanced therapy,” lead investigator Brian Feagan, MD, senior scientific director of the GI contract research firm Alimentiv in London, Ontario, said in an interview.

“The absolute magnitude of the finding was unanticipated – a greater treatment effect than might be anticipated for these outcomes compared with other advanced treatments for Crohn’s disease in these higher-risk patients,” he said.

Dr. Feagan presented the research at the annual congress of the European Crohn’s and Colitis Organisation.
 

Research methodology

At baseline, participants had an average daily stool frequency of 4 or more and/or an abdominal pain score of 2 or greater. They also had a Simple Endoscopic Score for Crohn’s disease of 6 or more, excluding a narrowing component, or a score of 4 or more for isolated ileal Crohn’s disease.

In the treatment induction phase, patients were randomly assigned 2:1, with 674 people receiving 45 mg upadacitinib and 347 taking a placebo once daily for 12 weeks.

Participants who experienced at least a 30% decrease in stool frequency and/or daily abdominal pain scores were enrolled in the maintenance phase of the study. For this phase, patients were randomly assigned again, with 168 receiving 30 mg upadacitinib, 169 receiving 15 mg upadacitinib, and 165 taking a placebo once daily for 52 weeks.

In each induction and maintenance cohort, more than 70% of patients had failed one prior biologic therapy, with failure defined as inadequate response or intolerance. Among those who failed a previous biologic in induction, 96% had also failed prior treatment with an anti–tumor necrosis factor (anti-TNF) inhibitor.

Participants’ mean age was 38-40 years, and 52%-55% were men. Patients who had not failed previous therapy had Crohn’s disease for a median of 6-7 years. In contrast, the prior-failure group had Crohn’s disease for a median of 9-10 years.
 

Key outcomes

At 12 weeks, endoscopic response among patients who had not failed a prior biologic was 52% in the treatment group versus 16% of the placebo group. In the prior-failure group, endoscopic response was observed in 36% and 5%, respectively.

Endoscopic remission at 12 weeks among patients who had not failed a prior biologic was 36% in the treatment group versus 10% in the placebo group. In the prior-failure group, endoscopic remission was 20% in the treatment group versus 3% in those who took placebo.

Participants in the treatment groups of the 52-week maintenance phase of the study experienced higher endoscopic response and endoscopic remission rates compared with those who received placebo.

Endoscopic response in the group without prior biologic failure was 44% in the 30-mg upadacitinib group, 40% in the 15-mg group, and 18% in the placebo group. Among those with prior biologic failure, endoscopic response was seen in 39% of the 30-mg upadacitinib group, 23% of the 15-mg group, and 4% of the placebo group.

There is a “very striking difference in endoscopic response rates between the high dose and placebo,” Dr. Feagan said. “That difference here is in the response rate. You see dose separation.”

Endoscopic remission among those without prior biologic failure was observed in 34% of the 30-mg upadacitinib group, 27% of the 15-mg group, and 16% of the placebo group. Among those with prior biologic failure, endoscopic remission was seen in 27% of the 30-mg upadacitinib group, 16% of the 15-mg group, and 2% of the placebo group.

The results show “a clear advantage for the 30-mg dose versus the 15-mg in the maintenance component, especially in patients who had failed an advanced therapy,” Dr. Feagan said.
 

Safety signals

Upadacitinib was well tolerated in the induction and maintenance phases, and no new safety risks were observed compared with the known safety profile of the drug, the researchers noted.

For example, during the induction studies, the rate of any adverse event among patients without prior biologic failure was 60% in the 45-mg upadacitinib group and 53% in the placebo group. Among those who failed a prior biologic, the rates were 67% in the 45-mg upadacitinib group and 66% in the placebo group.

The adverse events were “issues that have already been identified with JAK inhibitors, the biochemical abnormalities with CPK [creatine phosphokinase] elevations and transaminase elevations,” Dr. Feagan said.

There were no cases of herpes zoster among patients who received placebo compared with five cases in the 45-mg upadacitinib group without prior biologic failure and 10 cases in the prior biologic failure group.

“The zoster signal is there even at induction with the 45-mg dose versus placebo,” Dr. Feagan said.
 

‘Encouraging’ results

The study indicates that upadacitinib is effective in improving endoscopic outcomes for patients with Crohn’s disease, regardless of their prior biologic treatments, Robin L. Dalal, MD, assistant professor of medicine at Vanderbilt University in Nashville, Tenn., said when asked to comment on the study.

“This is important because, as the treatment landscape for Crohn’s disease has expanded, sequencing of therapies has become more complex,” added Dr. Dalal, who was not involved in the research. “For upadacitinib in Crohn’s disease, prior biologic use may not be a factor in endoscopic response rates.”

The findings are “very encouraging for physicians and practitioners who treat IBD [inflammatory bowel disease] patients,” Maithili Chitnavis, MD, of the inflammatory bowel disease section at Atrium Health Gastroenterology in Charlotte, N.C., said when asked for comment.

“We clearly care about how patients feel overall, but endoscopic and histologic outcomes are important to investigate because we want to ensure there is internal healing to prevent a lot of the longstanding complications of Crohn’s disease, such as malignancy, strictures, fistulizing/penetrating disease, and need for surgery,” said Dr. Chitnavis, who was not involved with the study.

Upadacitinib is an oral agent, which distinguishes it from the injectable or infusion-based biologic therapies for Crohn’s disease, Dr. Chitnavis noted.

The finding that the medication works in patients with or without prior biologic failure is important, she said.

“With its anticipated ... approval for Crohn’s disease [by the Food and Drug Administration], it is expected that patients will have had to have demonstrated a lack of or loss of response to another biologic, specifically in the anti-TNF category (for example, infliximab, adalimumab, certolizumab) prior to starting upadacitinib due to concerns of potential side effects associated with the class of medications to which it belongs,” Dr. Chitnavis said. “Therefore, it makes it even more relevant to know how patients who have failed a prior biologic respond to this therapy.”

Dr. Feagan has reported serving as a consultant and speaker for AbbVie. Dr. Dalal has reported being a consultant for AbbVie in 2021. Dr. Chitnavis has reported no relevant financial relationships.

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

The reversible oral Janus kinase (JAK) inhibitor upadacitinib (Rinvoq, AbbVie) was associated with superior endoscopic outcomes at 12 weeks and 1 year compared with placebo among people with moderately to severely active Crohn’s disease.

The findings of this subanalysis come from two phase 3 induction trials (U-EXCEL and U-EXCEED) and one maintenance study (U-ENDURE) of upadacitinib in this patient population.

“Upadacitinib shows large differences relative to placebo in endoscopic response and remission ... in a difficult-to-treat population of patients, the majority of whom had failed an advanced therapy,” lead investigator Brian Feagan, MD, senior scientific director of the GI contract research firm Alimentiv in London, Ontario, said in an interview.

“The absolute magnitude of the finding was unanticipated – a greater treatment effect than might be anticipated for these outcomes compared with other advanced treatments for Crohn’s disease in these higher-risk patients,” he said.

Dr. Feagan presented the research at the annual congress of the European Crohn’s and Colitis Organisation.
 

Research methodology

At baseline, participants had an average daily stool frequency of 4 or more and/or an abdominal pain score of 2 or greater. They also had a Simple Endoscopic Score for Crohn’s disease of 6 or more, excluding a narrowing component, or a score of 4 or more for isolated ileal Crohn’s disease.

In the treatment induction phase, patients were randomly assigned 2:1, with 674 people receiving 45 mg upadacitinib and 347 taking a placebo once daily for 12 weeks.

Participants who experienced at least a 30% decrease in stool frequency and/or daily abdominal pain scores were enrolled in the maintenance phase of the study. For this phase, patients were randomly assigned again, with 168 receiving 30 mg upadacitinib, 169 receiving 15 mg upadacitinib, and 165 taking a placebo once daily for 52 weeks.

In each induction and maintenance cohort, more than 70% of patients had failed one prior biologic therapy, with failure defined as inadequate response or intolerance. Among those who failed a previous biologic in induction, 96% had also failed prior treatment with an anti–tumor necrosis factor (anti-TNF) inhibitor.

Participants’ mean age was 38-40 years, and 52%-55% were men. Patients who had not failed previous therapy had Crohn’s disease for a median of 6-7 years. In contrast, the prior-failure group had Crohn’s disease for a median of 9-10 years.
 

Key outcomes

At 12 weeks, endoscopic response among patients who had not failed a prior biologic was 52% in the treatment group versus 16% of the placebo group. In the prior-failure group, endoscopic response was observed in 36% and 5%, respectively.

Endoscopic remission at 12 weeks among patients who had not failed a prior biologic was 36% in the treatment group versus 10% in the placebo group. In the prior-failure group, endoscopic remission was 20% in the treatment group versus 3% in those who took placebo.

Participants in the treatment groups of the 52-week maintenance phase of the study experienced higher endoscopic response and endoscopic remission rates compared with those who received placebo.

Endoscopic response in the group without prior biologic failure was 44% in the 30-mg upadacitinib group, 40% in the 15-mg group, and 18% in the placebo group. Among those with prior biologic failure, endoscopic response was seen in 39% of the 30-mg upadacitinib group, 23% of the 15-mg group, and 4% of the placebo group.

There is a “very striking difference in endoscopic response rates between the high dose and placebo,” Dr. Feagan said. “That difference here is in the response rate. You see dose separation.”

Endoscopic remission among those without prior biologic failure was observed in 34% of the 30-mg upadacitinib group, 27% of the 15-mg group, and 16% of the placebo group. Among those with prior biologic failure, endoscopic remission was seen in 27% of the 30-mg upadacitinib group, 16% of the 15-mg group, and 2% of the placebo group.

The results show “a clear advantage for the 30-mg dose versus the 15-mg in the maintenance component, especially in patients who had failed an advanced therapy,” Dr. Feagan said.
 

Safety signals

Upadacitinib was well tolerated in the induction and maintenance phases, and no new safety risks were observed compared with the known safety profile of the drug, the researchers noted.

For example, during the induction studies, the rate of any adverse event among patients without prior biologic failure was 60% in the 45-mg upadacitinib group and 53% in the placebo group. Among those who failed a prior biologic, the rates were 67% in the 45-mg upadacitinib group and 66% in the placebo group.

The adverse events were “issues that have already been identified with JAK inhibitors, the biochemical abnormalities with CPK [creatine phosphokinase] elevations and transaminase elevations,” Dr. Feagan said.

There were no cases of herpes zoster among patients who received placebo compared with five cases in the 45-mg upadacitinib group without prior biologic failure and 10 cases in the prior biologic failure group.

“The zoster signal is there even at induction with the 45-mg dose versus placebo,” Dr. Feagan said.
 

‘Encouraging’ results

The study indicates that upadacitinib is effective in improving endoscopic outcomes for patients with Crohn’s disease, regardless of their prior biologic treatments, Robin L. Dalal, MD, assistant professor of medicine at Vanderbilt University in Nashville, Tenn., said when asked to comment on the study.

“This is important because, as the treatment landscape for Crohn’s disease has expanded, sequencing of therapies has become more complex,” added Dr. Dalal, who was not involved in the research. “For upadacitinib in Crohn’s disease, prior biologic use may not be a factor in endoscopic response rates.”

The findings are “very encouraging for physicians and practitioners who treat IBD [inflammatory bowel disease] patients,” Maithili Chitnavis, MD, of the inflammatory bowel disease section at Atrium Health Gastroenterology in Charlotte, N.C., said when asked for comment.

“We clearly care about how patients feel overall, but endoscopic and histologic outcomes are important to investigate because we want to ensure there is internal healing to prevent a lot of the longstanding complications of Crohn’s disease, such as malignancy, strictures, fistulizing/penetrating disease, and need for surgery,” said Dr. Chitnavis, who was not involved with the study.

Upadacitinib is an oral agent, which distinguishes it from the injectable or infusion-based biologic therapies for Crohn’s disease, Dr. Chitnavis noted.

The finding that the medication works in patients with or without prior biologic failure is important, she said.

“With its anticipated ... approval for Crohn’s disease [by the Food and Drug Administration], it is expected that patients will have had to have demonstrated a lack of or loss of response to another biologic, specifically in the anti-TNF category (for example, infliximab, adalimumab, certolizumab) prior to starting upadacitinib due to concerns of potential side effects associated with the class of medications to which it belongs,” Dr. Chitnavis said. “Therefore, it makes it even more relevant to know how patients who have failed a prior biologic respond to this therapy.”

Dr. Feagan has reported serving as a consultant and speaker for AbbVie. Dr. Dalal has reported being a consultant for AbbVie in 2021. Dr. Chitnavis has reported no relevant financial relationships.

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

The reversible oral Janus kinase (JAK) inhibitor upadacitinib (Rinvoq, AbbVie) was associated with superior endoscopic outcomes at 12 weeks and 1 year compared with placebo among people with moderately to severely active Crohn’s disease.

The findings of this subanalysis come from two phase 3 induction trials (U-EXCEL and U-EXCEED) and one maintenance study (U-ENDURE) of upadacitinib in this patient population.

“Upadacitinib shows large differences relative to placebo in endoscopic response and remission ... in a difficult-to-treat population of patients, the majority of whom had failed an advanced therapy,” lead investigator Brian Feagan, MD, senior scientific director of the GI contract research firm Alimentiv in London, Ontario, said in an interview.

“The absolute magnitude of the finding was unanticipated – a greater treatment effect than might be anticipated for these outcomes compared with other advanced treatments for Crohn’s disease in these higher-risk patients,” he said.

Dr. Feagan presented the research at the annual congress of the European Crohn’s and Colitis Organisation.
 

Research methodology

At baseline, participants had an average daily stool frequency of 4 or more and/or an abdominal pain score of 2 or greater. They also had a Simple Endoscopic Score for Crohn’s disease of 6 or more, excluding a narrowing component, or a score of 4 or more for isolated ileal Crohn’s disease.

In the treatment induction phase, patients were randomly assigned 2:1, with 674 people receiving 45 mg upadacitinib and 347 taking a placebo once daily for 12 weeks.

Participants who experienced at least a 30% decrease in stool frequency and/or daily abdominal pain scores were enrolled in the maintenance phase of the study. For this phase, patients were randomly assigned again, with 168 receiving 30 mg upadacitinib, 169 receiving 15 mg upadacitinib, and 165 taking a placebo once daily for 52 weeks.

In each induction and maintenance cohort, more than 70% of patients had failed one prior biologic therapy, with failure defined as inadequate response or intolerance. Among those who failed a previous biologic in induction, 96% had also failed prior treatment with an anti–tumor necrosis factor (anti-TNF) inhibitor.

Participants’ mean age was 38-40 years, and 52%-55% were men. Patients who had not failed previous therapy had Crohn’s disease for a median of 6-7 years. In contrast, the prior-failure group had Crohn’s disease for a median of 9-10 years.
 

Key outcomes

At 12 weeks, endoscopic response among patients who had not failed a prior biologic was 52% in the treatment group versus 16% of the placebo group. In the prior-failure group, endoscopic response was observed in 36% and 5%, respectively.

Endoscopic remission at 12 weeks among patients who had not failed a prior biologic was 36% in the treatment group versus 10% in the placebo group. In the prior-failure group, endoscopic remission was 20% in the treatment group versus 3% in those who took placebo.

Participants in the treatment groups of the 52-week maintenance phase of the study experienced higher endoscopic response and endoscopic remission rates compared with those who received placebo.

Endoscopic response in the group without prior biologic failure was 44% in the 30-mg upadacitinib group, 40% in the 15-mg group, and 18% in the placebo group. Among those with prior biologic failure, endoscopic response was seen in 39% of the 30-mg upadacitinib group, 23% of the 15-mg group, and 4% of the placebo group.

There is a “very striking difference in endoscopic response rates between the high dose and placebo,” Dr. Feagan said. “That difference here is in the response rate. You see dose separation.”

Endoscopic remission among those without prior biologic failure was observed in 34% of the 30-mg upadacitinib group, 27% of the 15-mg group, and 16% of the placebo group. Among those with prior biologic failure, endoscopic remission was seen in 27% of the 30-mg upadacitinib group, 16% of the 15-mg group, and 2% of the placebo group.

The results show “a clear advantage for the 30-mg dose versus the 15-mg in the maintenance component, especially in patients who had failed an advanced therapy,” Dr. Feagan said.
 

Safety signals

Upadacitinib was well tolerated in the induction and maintenance phases, and no new safety risks were observed compared with the known safety profile of the drug, the researchers noted.

For example, during the induction studies, the rate of any adverse event among patients without prior biologic failure was 60% in the 45-mg upadacitinib group and 53% in the placebo group. Among those who failed a prior biologic, the rates were 67% in the 45-mg upadacitinib group and 66% in the placebo group.

The adverse events were “issues that have already been identified with JAK inhibitors, the biochemical abnormalities with CPK [creatine phosphokinase] elevations and transaminase elevations,” Dr. Feagan said.

There were no cases of herpes zoster among patients who received placebo compared with five cases in the 45-mg upadacitinib group without prior biologic failure and 10 cases in the prior biologic failure group.

“The zoster signal is there even at induction with the 45-mg dose versus placebo,” Dr. Feagan said.
 

‘Encouraging’ results

The study indicates that upadacitinib is effective in improving endoscopic outcomes for patients with Crohn’s disease, regardless of their prior biologic treatments, Robin L. Dalal, MD, assistant professor of medicine at Vanderbilt University in Nashville, Tenn., said when asked to comment on the study.

“This is important because, as the treatment landscape for Crohn’s disease has expanded, sequencing of therapies has become more complex,” added Dr. Dalal, who was not involved in the research. “For upadacitinib in Crohn’s disease, prior biologic use may not be a factor in endoscopic response rates.”

The findings are “very encouraging for physicians and practitioners who treat IBD [inflammatory bowel disease] patients,” Maithili Chitnavis, MD, of the inflammatory bowel disease section at Atrium Health Gastroenterology in Charlotte, N.C., said when asked for comment.

“We clearly care about how patients feel overall, but endoscopic and histologic outcomes are important to investigate because we want to ensure there is internal healing to prevent a lot of the longstanding complications of Crohn’s disease, such as malignancy, strictures, fistulizing/penetrating disease, and need for surgery,” said Dr. Chitnavis, who was not involved with the study.

Upadacitinib is an oral agent, which distinguishes it from the injectable or infusion-based biologic therapies for Crohn’s disease, Dr. Chitnavis noted.

The finding that the medication works in patients with or without prior biologic failure is important, she said.

“With its anticipated ... approval for Crohn’s disease [by the Food and Drug Administration], it is expected that patients will have had to have demonstrated a lack of or loss of response to another biologic, specifically in the anti-TNF category (for example, infliximab, adalimumab, certolizumab) prior to starting upadacitinib due to concerns of potential side effects associated with the class of medications to which it belongs,” Dr. Chitnavis said. “Therefore, it makes it even more relevant to know how patients who have failed a prior biologic respond to this therapy.”

Dr. Feagan has reported serving as a consultant and speaker for AbbVie. Dr. Dalal has reported being a consultant for AbbVie in 2021. Dr. Chitnavis has reported no relevant financial relationships.

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

A hybrid closed-loop automated insulin delivery system improved time-in-range for blood glucose, compared with standard care, for children with type 1 diabetes in a 13-week trial.

The hybrid closed-loop system, also called automated insulin delivery or artificial pancreas, was composed of a t:slim X2 insulin pump, a Dexcom G6 continuous glucose monitor (CGM), and Control-IQ technology system algorithm software (Tandem Diabetes Care). The system was approved in the United States in 2018 for adults and children as young as 6 years.

Type 1 diabetes treatment is particularly challenging in children younger than 6 because of their small insulin dosing requirements and unpredictable eating and activity habits, lead author R. Paul Wadwa, MD, of the Barbara Davis Center for Diabetes, University of Colorado at Denver, Aurora, and colleagues wrote.

Thus far in the United States, only the Medtronic MiniMed 770G and the Omnipod 5 automated insulin delivery systems are approved for children as young as 2 years, they noted.

In the current study of 102 children with type 1 diabetes aged at least 2 years but younger than 6 years, time-in-range over 13 weeks was higher for those randomized to the hybrid closed-loop system, compared with standard of care; the latter included either an insulin pump or multiple daily injections plus a separate Dexcom G6 CGM.

The hybrid closed-loop system added an average of about 3 hours in ideal blood glucose range over the 13 weeks, compared with no change with standard care.

Moreover, the trial was conducted during the COVID-19 pandemic, necessitating virtual care for most of the study participants. As a result, more than 80% of the training on use of the system and over 90% of all the visits were conducted virtually.

“Successful use of the closed-loop system under these conditions is an important finding that could affect the approach to initiating and monitoring the use of the closed-loop system and expand the use of such systems, particularly in patients living in areas without an endocrinologist but with reliable internet access,” the investigators wrote.

Their findings were published online in the New England Journal of Medicine.

“These results suggest that, in very young children, closed-loop systems are superior to standard care with respect to glucose control,” Daniela Bruttomesso, MD, PhD, of the University of Padua (Italy) wrote in an accompanying editorial.

“Moreover, they show that the closed-loop system can be started remotely in children in this age range, with results that are similar to those obtained when parents or guardians receive face-to-face education about the use of these systems. The closed-loop system used in this trial appeared to be safe and effective.”

Dr. Bruttomesso added: “Although the results were solid, the trial period was only 13 weeks, and there were more unscheduled contacts in the closed-loop group than in the standard care group. In addition, the authors compared a closed-loop system with standard care, rather than in-person initiation of a closed-loop system with remote initiation.”
 

More time-in-range, no hypoglycemia with automated system

The 102 children were enrolled in the trial between April 28, 2021, and Jan. 13, 2022, at three different U.S. study sites; 68 children were randomized to the closed-loop system and 34 children to standard care. All but one participant completed the 13-week study.

Both groups had virtual or in-person trial visits at 2, 6, and 13 weeks after randomization, and telephone contact at 1 and 10 weeks. Training was virtual for 55 of the 68 children in the closed-loop group (81%). A total of 91% of 407 study visits in the closed-loop and 96% of 204 study visits in the standard-care group were also virtual.

The mean percentage of time spent in target glucose range (70-180 mg/dL) increased from 56.9% at baseline to 69.3% at 13 weeks for the closed-loop group, compared with virtually no change, from 54.9% to 55.9%, in the standard-care group. The mean adjusted difference between the two groups was significant (P < .001).

The closed-loop group also spent significantly less time than the standard-care group with glucose levels above 250 mg/dL during the study period (8.4% vs. 15.0%; P < .001), had lower mean glucose levels (155 vs. 174 mg/dL; P < .001), and lower hemoglobin A1c (7.0% vs. 7.5%; P < .001).

However, time spent with glucose levels below 70 mg/dL (3.0% vs. 3.0%; P = .57) and below 54 mg/dL (0.6% vs. 0.5%) didn’t differ between the groups. 

There were two cases of severe hypoglycemia in the closed-loop group and one in the standard-care group. One case of diabetic ketoacidosis related to infusion set failure occurred in the closed-loop group versus none in the standard-care group.

Dr. Bruttomesso commented that a virtual approach has several advantages over in-person visits, including “a more relaxed environment, lower travel costs, and greater ease of contact with clinicians.”

At the same time, though, “patient preferences, possible legal issues, and accessibility to technology ... are all important considerations in choosing the most appropriate way to communicate with patients at the initiation of a closed-loop system or during routine follow-up.” The families of the patients in this trial had above-average incomes, she pointed out.

Ultimately, she said, “A mix of face-to-face visits and virtual clinic meetings may become routine in the management of diabetes in young children.”

The study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Wadwa reported receiving grants/contracts from Beta Bionics, Dexcom, Eli Lilly, and MannKind, travel fees from Eli Lilly, and lecture fees from Tandem Diabetes Care, and serves as a consultant for Dexcom. Dr. Bruttomesso reported no relevant financial relationships.

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

A hybrid closed-loop automated insulin delivery system improved time-in-range for blood glucose, compared with standard care, for children with type 1 diabetes in a 13-week trial.

The hybrid closed-loop system, also called automated insulin delivery or artificial pancreas, was composed of a t:slim X2 insulin pump, a Dexcom G6 continuous glucose monitor (CGM), and Control-IQ technology system algorithm software (Tandem Diabetes Care). The system was approved in the United States in 2018 for adults and children as young as 6 years.

Type 1 diabetes treatment is particularly challenging in children younger than 6 because of their small insulin dosing requirements and unpredictable eating and activity habits, lead author R. Paul Wadwa, MD, of the Barbara Davis Center for Diabetes, University of Colorado at Denver, Aurora, and colleagues wrote.

Thus far in the United States, only the Medtronic MiniMed 770G and the Omnipod 5 automated insulin delivery systems are approved for children as young as 2 years, they noted.

In the current study of 102 children with type 1 diabetes aged at least 2 years but younger than 6 years, time-in-range over 13 weeks was higher for those randomized to the hybrid closed-loop system, compared with standard of care; the latter included either an insulin pump or multiple daily injections plus a separate Dexcom G6 CGM.

The hybrid closed-loop system added an average of about 3 hours in ideal blood glucose range over the 13 weeks, compared with no change with standard care.

Moreover, the trial was conducted during the COVID-19 pandemic, necessitating virtual care for most of the study participants. As a result, more than 80% of the training on use of the system and over 90% of all the visits were conducted virtually.

“Successful use of the closed-loop system under these conditions is an important finding that could affect the approach to initiating and monitoring the use of the closed-loop system and expand the use of such systems, particularly in patients living in areas without an endocrinologist but with reliable internet access,” the investigators wrote.

Their findings were published online in the New England Journal of Medicine.

“These results suggest that, in very young children, closed-loop systems are superior to standard care with respect to glucose control,” Daniela Bruttomesso, MD, PhD, of the University of Padua (Italy) wrote in an accompanying editorial.

“Moreover, they show that the closed-loop system can be started remotely in children in this age range, with results that are similar to those obtained when parents or guardians receive face-to-face education about the use of these systems. The closed-loop system used in this trial appeared to be safe and effective.”

Dr. Bruttomesso added: “Although the results were solid, the trial period was only 13 weeks, and there were more unscheduled contacts in the closed-loop group than in the standard care group. In addition, the authors compared a closed-loop system with standard care, rather than in-person initiation of a closed-loop system with remote initiation.”
 

More time-in-range, no hypoglycemia with automated system

The 102 children were enrolled in the trial between April 28, 2021, and Jan. 13, 2022, at three different U.S. study sites; 68 children were randomized to the closed-loop system and 34 children to standard care. All but one participant completed the 13-week study.

Both groups had virtual or in-person trial visits at 2, 6, and 13 weeks after randomization, and telephone contact at 1 and 10 weeks. Training was virtual for 55 of the 68 children in the closed-loop group (81%). A total of 91% of 407 study visits in the closed-loop and 96% of 204 study visits in the standard-care group were also virtual.

The mean percentage of time spent in target glucose range (70-180 mg/dL) increased from 56.9% at baseline to 69.3% at 13 weeks for the closed-loop group, compared with virtually no change, from 54.9% to 55.9%, in the standard-care group. The mean adjusted difference between the two groups was significant (P < .001).

The closed-loop group also spent significantly less time than the standard-care group with glucose levels above 250 mg/dL during the study period (8.4% vs. 15.0%; P < .001), had lower mean glucose levels (155 vs. 174 mg/dL; P < .001), and lower hemoglobin A1c (7.0% vs. 7.5%; P < .001).

However, time spent with glucose levels below 70 mg/dL (3.0% vs. 3.0%; P = .57) and below 54 mg/dL (0.6% vs. 0.5%) didn’t differ between the groups. 

There were two cases of severe hypoglycemia in the closed-loop group and one in the standard-care group. One case of diabetic ketoacidosis related to infusion set failure occurred in the closed-loop group versus none in the standard-care group.

Dr. Bruttomesso commented that a virtual approach has several advantages over in-person visits, including “a more relaxed environment, lower travel costs, and greater ease of contact with clinicians.”

At the same time, though, “patient preferences, possible legal issues, and accessibility to technology ... are all important considerations in choosing the most appropriate way to communicate with patients at the initiation of a closed-loop system or during routine follow-up.” The families of the patients in this trial had above-average incomes, she pointed out.

Ultimately, she said, “A mix of face-to-face visits and virtual clinic meetings may become routine in the management of diabetes in young children.”

The study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Wadwa reported receiving grants/contracts from Beta Bionics, Dexcom, Eli Lilly, and MannKind, travel fees from Eli Lilly, and lecture fees from Tandem Diabetes Care, and serves as a consultant for Dexcom. Dr. Bruttomesso reported no relevant financial relationships.

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

A hybrid closed-loop automated insulin delivery system improved time-in-range for blood glucose, compared with standard care, for children with type 1 diabetes in a 13-week trial.

The hybrid closed-loop system, also called automated insulin delivery or artificial pancreas, was composed of a t:slim X2 insulin pump, a Dexcom G6 continuous glucose monitor (CGM), and Control-IQ technology system algorithm software (Tandem Diabetes Care). The system was approved in the United States in 2018 for adults and children as young as 6 years.

Type 1 diabetes treatment is particularly challenging in children younger than 6 because of their small insulin dosing requirements and unpredictable eating and activity habits, lead author R. Paul Wadwa, MD, of the Barbara Davis Center for Diabetes, University of Colorado at Denver, Aurora, and colleagues wrote.

Thus far in the United States, only the Medtronic MiniMed 770G and the Omnipod 5 automated insulin delivery systems are approved for children as young as 2 years, they noted.

In the current study of 102 children with type 1 diabetes aged at least 2 years but younger than 6 years, time-in-range over 13 weeks was higher for those randomized to the hybrid closed-loop system, compared with standard of care; the latter included either an insulin pump or multiple daily injections plus a separate Dexcom G6 CGM.

The hybrid closed-loop system added an average of about 3 hours in ideal blood glucose range over the 13 weeks, compared with no change with standard care.

Moreover, the trial was conducted during the COVID-19 pandemic, necessitating virtual care for most of the study participants. As a result, more than 80% of the training on use of the system and over 90% of all the visits were conducted virtually.

“Successful use of the closed-loop system under these conditions is an important finding that could affect the approach to initiating and monitoring the use of the closed-loop system and expand the use of such systems, particularly in patients living in areas without an endocrinologist but with reliable internet access,” the investigators wrote.

Their findings were published online in the New England Journal of Medicine.

“These results suggest that, in very young children, closed-loop systems are superior to standard care with respect to glucose control,” Daniela Bruttomesso, MD, PhD, of the University of Padua (Italy) wrote in an accompanying editorial.

“Moreover, they show that the closed-loop system can be started remotely in children in this age range, with results that are similar to those obtained when parents or guardians receive face-to-face education about the use of these systems. The closed-loop system used in this trial appeared to be safe and effective.”

Dr. Bruttomesso added: “Although the results were solid, the trial period was only 13 weeks, and there were more unscheduled contacts in the closed-loop group than in the standard care group. In addition, the authors compared a closed-loop system with standard care, rather than in-person initiation of a closed-loop system with remote initiation.”
 

More time-in-range, no hypoglycemia with automated system

The 102 children were enrolled in the trial between April 28, 2021, and Jan. 13, 2022, at three different U.S. study sites; 68 children were randomized to the closed-loop system and 34 children to standard care. All but one participant completed the 13-week study.

Both groups had virtual or in-person trial visits at 2, 6, and 13 weeks after randomization, and telephone contact at 1 and 10 weeks. Training was virtual for 55 of the 68 children in the closed-loop group (81%). A total of 91% of 407 study visits in the closed-loop and 96% of 204 study visits in the standard-care group were also virtual.

The mean percentage of time spent in target glucose range (70-180 mg/dL) increased from 56.9% at baseline to 69.3% at 13 weeks for the closed-loop group, compared with virtually no change, from 54.9% to 55.9%, in the standard-care group. The mean adjusted difference between the two groups was significant (P < .001).

The closed-loop group also spent significantly less time than the standard-care group with glucose levels above 250 mg/dL during the study period (8.4% vs. 15.0%; P < .001), had lower mean glucose levels (155 vs. 174 mg/dL; P < .001), and lower hemoglobin A1c (7.0% vs. 7.5%; P < .001).

However, time spent with glucose levels below 70 mg/dL (3.0% vs. 3.0%; P = .57) and below 54 mg/dL (0.6% vs. 0.5%) didn’t differ between the groups. 

There were two cases of severe hypoglycemia in the closed-loop group and one in the standard-care group. One case of diabetic ketoacidosis related to infusion set failure occurred in the closed-loop group versus none in the standard-care group.

Dr. Bruttomesso commented that a virtual approach has several advantages over in-person visits, including “a more relaxed environment, lower travel costs, and greater ease of contact with clinicians.”

At the same time, though, “patient preferences, possible legal issues, and accessibility to technology ... are all important considerations in choosing the most appropriate way to communicate with patients at the initiation of a closed-loop system or during routine follow-up.” The families of the patients in this trial had above-average incomes, she pointed out.

Ultimately, she said, “A mix of face-to-face visits and virtual clinic meetings may become routine in the management of diabetes in young children.”

The study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Wadwa reported receiving grants/contracts from Beta Bionics, Dexcom, Eli Lilly, and MannKind, travel fees from Eli Lilly, and lecture fees from Tandem Diabetes Care, and serves as a consultant for Dexcom. Dr. Bruttomesso reported no relevant financial relationships.

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

Diagnosed prevalent cases of ulcerative colitis (UC) in the United States and seven other countries are projected to increase from 1.9 million in 2021 to 2.1 million in 2031, at an annual growth rate of 0.63%, according to a new report by GlobalData.

The data and analytics company’s report offers projections for diagnosed incident and prevalent cases of UC in the United States, United Kingdom, Germany, Spain, Japan, Italy, France, and Canada.

In 2031, the United States will have the highest number of diagnosed prevalent cases of UC, with 655,317 cases, whereas Canada will have the fewest, with 91,186 cases, the company projects.

“UC can occur at any age, although most people are diagnosed in their mid-thirties. Men and women are equally likely to be affected, but older men are more likely to be diagnosed than older women,” Bharti Prabhakar, MPH, associate project manager at GlobalData, said in a statement.

In all eight countries, adults aged 30-69 years accounted for more than 65% of the diagnosed prevalent cases of UC, whereas those younger than 20 years made up less than 3% of the cases, GlobalData noted.
 

Incidence also rising

Diagnosed incident cases of UC in the eight countries are expected to increase from 160,122 cases in 2021 to 168,467 cases in 2031, at an annual growth rate of 0.52%, the company said.

In 2031, the United States will have the highest number of diagnosed incident cases of UC, with 104,795 cases, and France will have the fewest, with 2972 cases, the company predicted.

GlobalData epidemiologists attribute the predicted increases in UC prevalence and incidence to changes in population dynamics in each country.

The forecast is supported by historical data obtained from peer-reviewed articles and population-based studies, the firm noted.

The methodology was kept consistent across the eight countries to allow for a meaningful comparison of the forecast incident and prevalent cases of UC across these markets, GlobalData added.

“UC can affect people of any racial or ethnic group,” Ms. Prabhakar stated. “Genes, abnormal immune reactions, the microbiome, diet, stress, and the environment have all been suggested as triggers, but there is no definite evidence that any one of these factors is the cause of UC.”

Western countries have reported high incidence and prevalence of UC, Ms. Prabhaker noted. “Therefore, environmental factors may either suppress or reinforce inherent predispositions for UC and might also be crucial in triggering disease onset.”

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

Diagnosed prevalent cases of ulcerative colitis (UC) in the United States and seven other countries are projected to increase from 1.9 million in 2021 to 2.1 million in 2031, at an annual growth rate of 0.63%, according to a new report by GlobalData.

The data and analytics company’s report offers projections for diagnosed incident and prevalent cases of UC in the United States, United Kingdom, Germany, Spain, Japan, Italy, France, and Canada.

In 2031, the United States will have the highest number of diagnosed prevalent cases of UC, with 655,317 cases, whereas Canada will have the fewest, with 91,186 cases, the company projects.

“UC can occur at any age, although most people are diagnosed in their mid-thirties. Men and women are equally likely to be affected, but older men are more likely to be diagnosed than older women,” Bharti Prabhakar, MPH, associate project manager at GlobalData, said in a statement.

In all eight countries, adults aged 30-69 years accounted for more than 65% of the diagnosed prevalent cases of UC, whereas those younger than 20 years made up less than 3% of the cases, GlobalData noted.
 

Incidence also rising

Diagnosed incident cases of UC in the eight countries are expected to increase from 160,122 cases in 2021 to 168,467 cases in 2031, at an annual growth rate of 0.52%, the company said.

In 2031, the United States will have the highest number of diagnosed incident cases of UC, with 104,795 cases, and France will have the fewest, with 2972 cases, the company predicted.

GlobalData epidemiologists attribute the predicted increases in UC prevalence and incidence to changes in population dynamics in each country.

The forecast is supported by historical data obtained from peer-reviewed articles and population-based studies, the firm noted.

The methodology was kept consistent across the eight countries to allow for a meaningful comparison of the forecast incident and prevalent cases of UC across these markets, GlobalData added.

“UC can affect people of any racial or ethnic group,” Ms. Prabhakar stated. “Genes, abnormal immune reactions, the microbiome, diet, stress, and the environment have all been suggested as triggers, but there is no definite evidence that any one of these factors is the cause of UC.”

Western countries have reported high incidence and prevalence of UC, Ms. Prabhaker noted. “Therefore, environmental factors may either suppress or reinforce inherent predispositions for UC and might also be crucial in triggering disease onset.”

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

Diagnosed prevalent cases of ulcerative colitis (UC) in the United States and seven other countries are projected to increase from 1.9 million in 2021 to 2.1 million in 2031, at an annual growth rate of 0.63%, according to a new report by GlobalData.

The data and analytics company’s report offers projections for diagnosed incident and prevalent cases of UC in the United States, United Kingdom, Germany, Spain, Japan, Italy, France, and Canada.

In 2031, the United States will have the highest number of diagnosed prevalent cases of UC, with 655,317 cases, whereas Canada will have the fewest, with 91,186 cases, the company projects.

“UC can occur at any age, although most people are diagnosed in their mid-thirties. Men and women are equally likely to be affected, but older men are more likely to be diagnosed than older women,” Bharti Prabhakar, MPH, associate project manager at GlobalData, said in a statement.

In all eight countries, adults aged 30-69 years accounted for more than 65% of the diagnosed prevalent cases of UC, whereas those younger than 20 years made up less than 3% of the cases, GlobalData noted.
 

Incidence also rising

Diagnosed incident cases of UC in the eight countries are expected to increase from 160,122 cases in 2021 to 168,467 cases in 2031, at an annual growth rate of 0.52%, the company said.

In 2031, the United States will have the highest number of diagnosed incident cases of UC, with 104,795 cases, and France will have the fewest, with 2972 cases, the company predicted.

GlobalData epidemiologists attribute the predicted increases in UC prevalence and incidence to changes in population dynamics in each country.

The forecast is supported by historical data obtained from peer-reviewed articles and population-based studies, the firm noted.

The methodology was kept consistent across the eight countries to allow for a meaningful comparison of the forecast incident and prevalent cases of UC across these markets, GlobalData added.

“UC can affect people of any racial or ethnic group,” Ms. Prabhakar stated. “Genes, abnormal immune reactions, the microbiome, diet, stress, and the environment have all been suggested as triggers, but there is no definite evidence that any one of these factors is the cause of UC.”

Western countries have reported high incidence and prevalence of UC, Ms. Prabhaker noted. “Therefore, environmental factors may either suppress or reinforce inherent predispositions for UC and might also be crucial in triggering disease onset.”

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