More than 40 value-based payment models – from direct contracting to bundled payments – have been introduced into the Medicare program in the past 10 years, with the goal of improving care while lowering costs. Hopes were high that they would be successful.

But despite the new alternative payment models, costs have not declined. If this continues, Medicare won’t have sufficient funds to cover benefit costs after 2024. Physicians could suffer a huge blow to their income.

Many of the value-based care models simply did not work as expected, said Seema Verma, head of the Centers for Medicare & Medicaid Services, at a recent HLTH Conference. “They are not producing the types of savings the taxpayers deserve,” Ms. Verma said.

The Medicare Payment Advisory Commission (MedPac) concluded that, while dozens of payment models were tested, most failed to generate net savings for Medicare. Even the most successful of the models produced only modest savings. MedPac elaborated: “The track record raises the question of whether changes to particular models or CMMI’s [Center for Medicare & Medicaid Innovation’s] broader strategies might be warranted.”

What will happen now, as government officials admit that their value-based programs haven’t worked? The value-based programs could become more stringent. Here’s what physicians will have to contend with.

More risk. Experts agree that risk – financial risk – will be a component of future programs. Two-sided risk is likely to be the norm. This means that both parties – the provider and the insurer – are at financial risk for the patients covered by the program.

For example, a plan with 50,000 beneficiary patients would estimate the cost of caring for those patients on the basis of multiple variables. If the actual cost is lower than anticipated, both parties share in the savings. However, both share in the loss if the cost of caring for their patient population exceeds expectations.

This may compel physicians to enhance efficiency and potentially limit the services provided to patients. Typically, however, the strategy is to make efforts to prevent services like ED visits and admissions by focusing on health maintenance.

In contrast to most current value-based models, which feature little to no downside risk for physicians, double-sided risk means physicians could lose money. The loss may incorporate a cap – 5%, for example – but programs may differ. Experts concur that double-sided risk will be a hallmark of future programs.

Better data. The majority of health care services are rendered via fee-for-service: Patients receive services and physicians are paid, yet little or no information about outcomes is exchanged between insurers and physicians.

Penny Noyes, president of Health Business Navigators and contract negotiator for physicians, is not a fan of the current crop of value-based programs and feels that data transparency is positive. Sound metrics can lead to improvement, she said, adding: “It’s not money that drives physicians to make decisions; it’s what’s in the best interest of their patients and their patients’ long-term care.”

Value-based programs can work but only if applicable data are developed and given to physicians so that they can better understand their current performance and how to improve.

Mandated participation. Participation in value-based programs has been voluntary, but that may have skewed the results, which were better than what typical practice would have shown. Acknowledging this may lead CMS to call for mandated participation as a component of future programs. Physicians may be brought into programs, if only to determine whether the models really work. To date, participation in the programs has been voluntary, but that may change in the future.

Innovation. The private insurance market may end up as a key player. Over the past 6 months, health insurers have either consolidated partnerships with telemedicine companies to provide no-cost care to beneficiaries or have launched their own initiatives.

Others are focused on bringing together patients and providers operating outside of the traditional health care system, such as Aetna’s merger with CVS which now offers retail-based acute care (MinuteClinic) and chronic care (HealthHUB). Still other payers are gambling with physician practice ownership, as in the case of United Healthcare’s OptumHealth, which now boasts around 50,000 physicians throughout the country.

New practice models are emerging in private practices as well. Physicians are embracing remote care, proactively managing care transitions, and seeking out more methods to keep patients healthy and at home.
 

Not much was expected from value-based plans 

Many are not surprised that the value-based models did not produce impressive results. Ms. Noyes doubted that positive outcomes will be achieved for physicians in comparison with what could have been attained under fee-for-service arrangements with lower administrative costs.

While the Affordable Care Act attempted to encourage alternative reimbursement, it limits the maximum medical loss ratio (MLR) a payer could achieve. For many plans, that maximum was 85%. Simply put, at least $0.85 of each premium collected had to be paid in claims; the remaining $0.15 went to margin, claims, and other administrative costs. A payer with an 82% MLR then would have to rebate the 3% difference to enrollees.

But that’s not what occurred, according to Ms. Noyes. Because value-based payments to providers are considered a claims expense, an MLR ratio of 82% allowed the payer to distribute the 3% difference to providers as value-based payments. Ms. Noyes said: “That may sound good for the provider, but the result was essentially a freeze on the provider’s fee-for-service reimbursement with the prospect of getting value-based payments like ‘shared savings.’ 

“When the providers tried to increase their base fee-for-service rates just to match inflation, payers often advised that any future raises had to be earned through value-based programs,” Ms. Noyes added. The value-based formulas confuse providers because payments are often made for periods as far back as 18 months, and providers do not have data systems to reconcile their payer report cards retrospectively. The result is that providers tended to accept whatever amount the payer distributed.

Executives at Lumeris, a company that helps health systems participate successfully in value-based care, see potential in a newer approach to alternative payments, such as CMS’ Direct Contracting initiative. This voluntary payment model offers options tailored to several types of organizations that aim to reduce costs while preserving or enhancing the quality of care for Medicare fee-for-service beneficiaries.

Jeff Smith, chief commercial officer for population health at Lumeris, explained that the Direct Contracting initiative can provide physicians with a more attractive option than prior value-based models because it adjusts for the complexity and fragility of patients with complex and chronic conditions. By allowing providers to participate in the savings generated, the initiative stands in stark contrast to what Mr. Smith described as the “shared savings to nothingness” experienced by providers in earlier-stage alternative payment models.

Physicians engaged with value-based programs like Direct Contracting are investing in nurses to aid with initiatives regarding health promotion and transitions of care. When a patient is discharged, for example, the nurse contacts the patient to discuss medications, schedule follow-up appointments, and so forth – tasks typically left to the patient (or caregiver) to navigate in the traditional system.

The initiative recognizes the importance of managing high-risk patients, those whom physicians identify as having an extraordinary number of ED visits and admissions. These patients, as well as so-called “rising-risk” patients, are targeted by nurses who proactively communicate with patients (and caregivers) to address patient’s needs, including social determinants of health.

Physicians who have a large load of patients in value-based programs are hiring social workers, pharmacists, and behavioral health experts to help. Of course, these personnel are costly, but that’s what the value-based programs aim to reimburse.

Still, the road ahead to value based is rocky and may not gain momentum for some time. Johns Hopkins University’s Doug Hough, PhD, an economist, recounts a government research study that sought to assess the university’s health system participation in a value-based payment program. While there were positive impacts on the program’s target population, Hough and his team discovered that the returns achieved by the optional model didn’t justify the health system’s financial support for it. The increasingly indebted health system ultimately decided to drop the optional program.

Dr. Hough indicated that the health system – Johns Hopkins Medicine – likely would have  continued its support for the program had the government at least allowed it to break even. Although the payment program under study was a 3-year project, the bigger challenge, declared Dr. Hough, is that “we can’t turn an aircraft carrier that quickly.”

“Three years won’t show whether value-based care is really working,” Dr. Hough said.

Robert Zipper, MD, a hospitalist and senior policy advisor for Sound Physicians, a company that works to improve outcomes in acute care, agreed with Dr. Hough that performance tends to improve with time. Yet, Dr. Zipper doesn’t see much change in the near term, because “after all, there is nothing to replace them [the programs].”

The problem gets even stickier for private payers because patients may be on an insurance panel for as little as a year or 2. Thanks to this rapid churn of beneficiaries, even the best-designed value-based program will have little time to prove its worth.

Dr. Zipper is among the many who don’t expect significant changes in the near term, asserting that “President Biden will want to get a few policy wins first, and health care is not the easiest place to start.”

But it’s likely that payers and others will want to see more emphasis on value-based programs despite these programs’ possible value to patients, physicians, and health systems alike.

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

More than 40 value-based payment models – from direct contracting to bundled payments – have been introduced into the Medicare program in the past 10 years, with the goal of improving care while lowering costs. Hopes were high that they would be successful.

But despite the new alternative payment models, costs have not declined. If this continues, Medicare won’t have sufficient funds to cover benefit costs after 2024. Physicians could suffer a huge blow to their income.

Many of the value-based care models simply did not work as expected, said Seema Verma, head of the Centers for Medicare & Medicaid Services, at a recent HLTH Conference. “They are not producing the types of savings the taxpayers deserve,” Ms. Verma said.

The Medicare Payment Advisory Commission (MedPac) concluded that, while dozens of payment models were tested, most failed to generate net savings for Medicare. Even the most successful of the models produced only modest savings. MedPac elaborated: “The track record raises the question of whether changes to particular models or CMMI’s [Center for Medicare & Medicaid Innovation’s] broader strategies might be warranted.”

What will happen now, as government officials admit that their value-based programs haven’t worked? The value-based programs could become more stringent. Here’s what physicians will have to contend with.

More risk. Experts agree that risk – financial risk – will be a component of future programs. Two-sided risk is likely to be the norm. This means that both parties – the provider and the insurer – are at financial risk for the patients covered by the program.

For example, a plan with 50,000 beneficiary patients would estimate the cost of caring for those patients on the basis of multiple variables. If the actual cost is lower than anticipated, both parties share in the savings. However, both share in the loss if the cost of caring for their patient population exceeds expectations.

This may compel physicians to enhance efficiency and potentially limit the services provided to patients. Typically, however, the strategy is to make efforts to prevent services like ED visits and admissions by focusing on health maintenance.

In contrast to most current value-based models, which feature little to no downside risk for physicians, double-sided risk means physicians could lose money. The loss may incorporate a cap – 5%, for example – but programs may differ. Experts concur that double-sided risk will be a hallmark of future programs.

Better data. The majority of health care services are rendered via fee-for-service: Patients receive services and physicians are paid, yet little or no information about outcomes is exchanged between insurers and physicians.

Penny Noyes, president of Health Business Navigators and contract negotiator for physicians, is not a fan of the current crop of value-based programs and feels that data transparency is positive. Sound metrics can lead to improvement, she said, adding: “It’s not money that drives physicians to make decisions; it’s what’s in the best interest of their patients and their patients’ long-term care.”

Value-based programs can work but only if applicable data are developed and given to physicians so that they can better understand their current performance and how to improve.

Mandated participation. Participation in value-based programs has been voluntary, but that may have skewed the results, which were better than what typical practice would have shown. Acknowledging this may lead CMS to call for mandated participation as a component of future programs. Physicians may be brought into programs, if only to determine whether the models really work. To date, participation in the programs has been voluntary, but that may change in the future.

Innovation. The private insurance market may end up as a key player. Over the past 6 months, health insurers have either consolidated partnerships with telemedicine companies to provide no-cost care to beneficiaries or have launched their own initiatives.

Others are focused on bringing together patients and providers operating outside of the traditional health care system, such as Aetna’s merger with CVS which now offers retail-based acute care (MinuteClinic) and chronic care (HealthHUB). Still other payers are gambling with physician practice ownership, as in the case of United Healthcare’s OptumHealth, which now boasts around 50,000 physicians throughout the country.

New practice models are emerging in private practices as well. Physicians are embracing remote care, proactively managing care transitions, and seeking out more methods to keep patients healthy and at home.
 

Not much was expected from value-based plans 

Many are not surprised that the value-based models did not produce impressive results. Ms. Noyes doubted that positive outcomes will be achieved for physicians in comparison with what could have been attained under fee-for-service arrangements with lower administrative costs.

While the Affordable Care Act attempted to encourage alternative reimbursement, it limits the maximum medical loss ratio (MLR) a payer could achieve. For many plans, that maximum was 85%. Simply put, at least $0.85 of each premium collected had to be paid in claims; the remaining $0.15 went to margin, claims, and other administrative costs. A payer with an 82% MLR then would have to rebate the 3% difference to enrollees.

But that’s not what occurred, according to Ms. Noyes. Because value-based payments to providers are considered a claims expense, an MLR ratio of 82% allowed the payer to distribute the 3% difference to providers as value-based payments. Ms. Noyes said: “That may sound good for the provider, but the result was essentially a freeze on the provider’s fee-for-service reimbursement with the prospect of getting value-based payments like ‘shared savings.’ 

“When the providers tried to increase their base fee-for-service rates just to match inflation, payers often advised that any future raises had to be earned through value-based programs,” Ms. Noyes added. The value-based formulas confuse providers because payments are often made for periods as far back as 18 months, and providers do not have data systems to reconcile their payer report cards retrospectively. The result is that providers tended to accept whatever amount the payer distributed.

Executives at Lumeris, a company that helps health systems participate successfully in value-based care, see potential in a newer approach to alternative payments, such as CMS’ Direct Contracting initiative. This voluntary payment model offers options tailored to several types of organizations that aim to reduce costs while preserving or enhancing the quality of care for Medicare fee-for-service beneficiaries.

Jeff Smith, chief commercial officer for population health at Lumeris, explained that the Direct Contracting initiative can provide physicians with a more attractive option than prior value-based models because it adjusts for the complexity and fragility of patients with complex and chronic conditions. By allowing providers to participate in the savings generated, the initiative stands in stark contrast to what Mr. Smith described as the “shared savings to nothingness” experienced by providers in earlier-stage alternative payment models.

Physicians engaged with value-based programs like Direct Contracting are investing in nurses to aid with initiatives regarding health promotion and transitions of care. When a patient is discharged, for example, the nurse contacts the patient to discuss medications, schedule follow-up appointments, and so forth – tasks typically left to the patient (or caregiver) to navigate in the traditional system.

The initiative recognizes the importance of managing high-risk patients, those whom physicians identify as having an extraordinary number of ED visits and admissions. These patients, as well as so-called “rising-risk” patients, are targeted by nurses who proactively communicate with patients (and caregivers) to address patient’s needs, including social determinants of health.

Physicians who have a large load of patients in value-based programs are hiring social workers, pharmacists, and behavioral health experts to help. Of course, these personnel are costly, but that’s what the value-based programs aim to reimburse.

Still, the road ahead to value based is rocky and may not gain momentum for some time. Johns Hopkins University’s Doug Hough, PhD, an economist, recounts a government research study that sought to assess the university’s health system participation in a value-based payment program. While there were positive impacts on the program’s target population, Hough and his team discovered that the returns achieved by the optional model didn’t justify the health system’s financial support for it. The increasingly indebted health system ultimately decided to drop the optional program.

Dr. Hough indicated that the health system – Johns Hopkins Medicine – likely would have  continued its support for the program had the government at least allowed it to break even. Although the payment program under study was a 3-year project, the bigger challenge, declared Dr. Hough, is that “we can’t turn an aircraft carrier that quickly.”

“Three years won’t show whether value-based care is really working,” Dr. Hough said.

Robert Zipper, MD, a hospitalist and senior policy advisor for Sound Physicians, a company that works to improve outcomes in acute care, agreed with Dr. Hough that performance tends to improve with time. Yet, Dr. Zipper doesn’t see much change in the near term, because “after all, there is nothing to replace them [the programs].”

The problem gets even stickier for private payers because patients may be on an insurance panel for as little as a year or 2. Thanks to this rapid churn of beneficiaries, even the best-designed value-based program will have little time to prove its worth.

Dr. Zipper is among the many who don’t expect significant changes in the near term, asserting that “President Biden will want to get a few policy wins first, and health care is not the easiest place to start.”

But it’s likely that payers and others will want to see more emphasis on value-based programs despite these programs’ possible value to patients, physicians, and health systems alike.

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

More than 40 value-based payment models – from direct contracting to bundled payments – have been introduced into the Medicare program in the past 10 years, with the goal of improving care while lowering costs. Hopes were high that they would be successful.

But despite the new alternative payment models, costs have not declined. If this continues, Medicare won’t have sufficient funds to cover benefit costs after 2024. Physicians could suffer a huge blow to their income.

Many of the value-based care models simply did not work as expected, said Seema Verma, head of the Centers for Medicare & Medicaid Services, at a recent HLTH Conference. “They are not producing the types of savings the taxpayers deserve,” Ms. Verma said.

The Medicare Payment Advisory Commission (MedPac) concluded that, while dozens of payment models were tested, most failed to generate net savings for Medicare. Even the most successful of the models produced only modest savings. MedPac elaborated: “The track record raises the question of whether changes to particular models or CMMI’s [Center for Medicare & Medicaid Innovation’s] broader strategies might be warranted.”

What will happen now, as government officials admit that their value-based programs haven’t worked? The value-based programs could become more stringent. Here’s what physicians will have to contend with.

More risk. Experts agree that risk – financial risk – will be a component of future programs. Two-sided risk is likely to be the norm. This means that both parties – the provider and the insurer – are at financial risk for the patients covered by the program.

For example, a plan with 50,000 beneficiary patients would estimate the cost of caring for those patients on the basis of multiple variables. If the actual cost is lower than anticipated, both parties share in the savings. However, both share in the loss if the cost of caring for their patient population exceeds expectations.

This may compel physicians to enhance efficiency and potentially limit the services provided to patients. Typically, however, the strategy is to make efforts to prevent services like ED visits and admissions by focusing on health maintenance.

In contrast to most current value-based models, which feature little to no downside risk for physicians, double-sided risk means physicians could lose money. The loss may incorporate a cap – 5%, for example – but programs may differ. Experts concur that double-sided risk will be a hallmark of future programs.

Better data. The majority of health care services are rendered via fee-for-service: Patients receive services and physicians are paid, yet little or no information about outcomes is exchanged between insurers and physicians.

Penny Noyes, president of Health Business Navigators and contract negotiator for physicians, is not a fan of the current crop of value-based programs and feels that data transparency is positive. Sound metrics can lead to improvement, she said, adding: “It’s not money that drives physicians to make decisions; it’s what’s in the best interest of their patients and their patients’ long-term care.”

Value-based programs can work but only if applicable data are developed and given to physicians so that they can better understand their current performance and how to improve.

Mandated participation. Participation in value-based programs has been voluntary, but that may have skewed the results, which were better than what typical practice would have shown. Acknowledging this may lead CMS to call for mandated participation as a component of future programs. Physicians may be brought into programs, if only to determine whether the models really work. To date, participation in the programs has been voluntary, but that may change in the future.

Innovation. The private insurance market may end up as a key player. Over the past 6 months, health insurers have either consolidated partnerships with telemedicine companies to provide no-cost care to beneficiaries or have launched their own initiatives.

Others are focused on bringing together patients and providers operating outside of the traditional health care system, such as Aetna’s merger with CVS which now offers retail-based acute care (MinuteClinic) and chronic care (HealthHUB). Still other payers are gambling with physician practice ownership, as in the case of United Healthcare’s OptumHealth, which now boasts around 50,000 physicians throughout the country.

New practice models are emerging in private practices as well. Physicians are embracing remote care, proactively managing care transitions, and seeking out more methods to keep patients healthy and at home.
 

Not much was expected from value-based plans 

Many are not surprised that the value-based models did not produce impressive results. Ms. Noyes doubted that positive outcomes will be achieved for physicians in comparison with what could have been attained under fee-for-service arrangements with lower administrative costs.

While the Affordable Care Act attempted to encourage alternative reimbursement, it limits the maximum medical loss ratio (MLR) a payer could achieve. For many plans, that maximum was 85%. Simply put, at least $0.85 of each premium collected had to be paid in claims; the remaining $0.15 went to margin, claims, and other administrative costs. A payer with an 82% MLR then would have to rebate the 3% difference to enrollees.

But that’s not what occurred, according to Ms. Noyes. Because value-based payments to providers are considered a claims expense, an MLR ratio of 82% allowed the payer to distribute the 3% difference to providers as value-based payments. Ms. Noyes said: “That may sound good for the provider, but the result was essentially a freeze on the provider’s fee-for-service reimbursement with the prospect of getting value-based payments like ‘shared savings.’ 

“When the providers tried to increase their base fee-for-service rates just to match inflation, payers often advised that any future raises had to be earned through value-based programs,” Ms. Noyes added. The value-based formulas confuse providers because payments are often made for periods as far back as 18 months, and providers do not have data systems to reconcile their payer report cards retrospectively. The result is that providers tended to accept whatever amount the payer distributed.

Executives at Lumeris, a company that helps health systems participate successfully in value-based care, see potential in a newer approach to alternative payments, such as CMS’ Direct Contracting initiative. This voluntary payment model offers options tailored to several types of organizations that aim to reduce costs while preserving or enhancing the quality of care for Medicare fee-for-service beneficiaries.

Jeff Smith, chief commercial officer for population health at Lumeris, explained that the Direct Contracting initiative can provide physicians with a more attractive option than prior value-based models because it adjusts for the complexity and fragility of patients with complex and chronic conditions. By allowing providers to participate in the savings generated, the initiative stands in stark contrast to what Mr. Smith described as the “shared savings to nothingness” experienced by providers in earlier-stage alternative payment models.

Physicians engaged with value-based programs like Direct Contracting are investing in nurses to aid with initiatives regarding health promotion and transitions of care. When a patient is discharged, for example, the nurse contacts the patient to discuss medications, schedule follow-up appointments, and so forth – tasks typically left to the patient (or caregiver) to navigate in the traditional system.

The initiative recognizes the importance of managing high-risk patients, those whom physicians identify as having an extraordinary number of ED visits and admissions. These patients, as well as so-called “rising-risk” patients, are targeted by nurses who proactively communicate with patients (and caregivers) to address patient’s needs, including social determinants of health.

Physicians who have a large load of patients in value-based programs are hiring social workers, pharmacists, and behavioral health experts to help. Of course, these personnel are costly, but that’s what the value-based programs aim to reimburse.

Still, the road ahead to value based is rocky and may not gain momentum for some time. Johns Hopkins University’s Doug Hough, PhD, an economist, recounts a government research study that sought to assess the university’s health system participation in a value-based payment program. While there were positive impacts on the program’s target population, Hough and his team discovered that the returns achieved by the optional model didn’t justify the health system’s financial support for it. The increasingly indebted health system ultimately decided to drop the optional program.

Dr. Hough indicated that the health system – Johns Hopkins Medicine – likely would have  continued its support for the program had the government at least allowed it to break even. Although the payment program under study was a 3-year project, the bigger challenge, declared Dr. Hough, is that “we can’t turn an aircraft carrier that quickly.”

“Three years won’t show whether value-based care is really working,” Dr. Hough said.

Robert Zipper, MD, a hospitalist and senior policy advisor for Sound Physicians, a company that works to improve outcomes in acute care, agreed with Dr. Hough that performance tends to improve with time. Yet, Dr. Zipper doesn’t see much change in the near term, because “after all, there is nothing to replace them [the programs].”

The problem gets even stickier for private payers because patients may be on an insurance panel for as little as a year or 2. Thanks to this rapid churn of beneficiaries, even the best-designed value-based program will have little time to prove its worth.

Dr. Zipper is among the many who don’t expect significant changes in the near term, asserting that “President Biden will want to get a few policy wins first, and health care is not the easiest place to start.”

But it’s likely that payers and others will want to see more emphasis on value-based programs despite these programs’ possible value to patients, physicians, and health systems alike.

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

In 2014, I began taking care of a patient (see photo) who had developed over 25 basal cell carcinomas on her lower legs, which were surgically removed. Given the results of a 2015 study by Chen et al. on the protective effects of nicotinamide in the prevention of nonmelanoma skin cancers, I began her on oral nicotinamide, 500 mg twice daily. She has been clear of any skin cancers in the last 2 years since starting supplementation.

Lily Talakoub, MD

Nicotinamide, also known as niacinamide, is a water soluble form of vitamin B3 that has been shown to enhance the repair of UV-induced DNA damage. Nicotinamide is found naturally in meat, fish, nuts, grains, and legumes, and is a key component of the glycolysis pathway, by generating nicotinamide adenine dinucleotide for adenosine triphosphate production. Nicotinamide deficiency causes photosensitive dermatitis, diarrhea, and dementia. It has been studied for its anti-inflammatory benefits as an adjunct treatment for rosacea, bullous diseases, acne, and melasma.

Nonmelanoma skin cancers are known to be caused primarily by UV radiation. The supplementation of nicotinamide orally twice daily has been shown to reduce the rate of actinic keratoses and new nonmelanoma skin cancers compared with placebo after 1 year in patients who previously had skin cancer. In the phase 3 study published in 2015, a randomized, controlled trial of 386 patients who had at least two nonmelanoma skin cancers within the previous 5-year period, oral nicotinamide 500 mg given twice daily for a 12-month period significantly reduced the number of new nonmelanoma skin cancers by 23% versus those on placebo.

The recommended dose for nicotinamide, which is available over the counter as Vitamin B3, is 500 mg twice a day. Nicotinamide should not be confused with niacin (nicotinic acid), which has been used to treat high cholesterol and cardiovascular disease. There are no significant side effects from long-term use; however nicotinamide should not be used in patients with end-stage kidney disease or chronic kidney disease. (Niacin, however, can cause elevation of liver enzymes, headache, flushing, and increased blood pressure.) Nicotinamide crosses the placenta and should not be used in pregnancy as it has not been studied in pregnant populations.

We should counsel patients that this is not an oral sunscreen, and that sun avoidance, sunscreen, and yearly skin cancer checks are still the mainstay of skin cancer prevention. However, given the safety profile of nicotinamide and the protective effects, should all of our skin cancer patients be taking nicotinamide daily? In my practice they are, all of whom swear by it and have had significant reductions of both actinic keratoses and nonmelanoma skin cancers.

Dr. Talakoub and Dr. Wesley are cocontributors to this column. Dr. Talakoub is in private practice in McLean, Va. Dr. Wesley practices dermatology in Beverly Hills, Calif. This month’s column is by Dr. Talakoub. Write to them at dermnews@mdedge.com. They had no relevant disclosures.

In 2014, I began taking care of a patient (see photo) who had developed over 25 basal cell carcinomas on her lower legs, which were surgically removed. Given the results of a 2015 study by Chen et al. on the protective effects of nicotinamide in the prevention of nonmelanoma skin cancers, I began her on oral nicotinamide, 500 mg twice daily. She has been clear of any skin cancers in the last 2 years since starting supplementation.

Lily Talakoub, MD

Nicotinamide, also known as niacinamide, is a water soluble form of vitamin B3 that has been shown to enhance the repair of UV-induced DNA damage. Nicotinamide is found naturally in meat, fish, nuts, grains, and legumes, and is a key component of the glycolysis pathway, by generating nicotinamide adenine dinucleotide for adenosine triphosphate production. Nicotinamide deficiency causes photosensitive dermatitis, diarrhea, and dementia. It has been studied for its anti-inflammatory benefits as an adjunct treatment for rosacea, bullous diseases, acne, and melasma.

Nonmelanoma skin cancers are known to be caused primarily by UV radiation. The supplementation of nicotinamide orally twice daily has been shown to reduce the rate of actinic keratoses and new nonmelanoma skin cancers compared with placebo after 1 year in patients who previously had skin cancer. In the phase 3 study published in 2015, a randomized, controlled trial of 386 patients who had at least two nonmelanoma skin cancers within the previous 5-year period, oral nicotinamide 500 mg given twice daily for a 12-month period significantly reduced the number of new nonmelanoma skin cancers by 23% versus those on placebo.

The recommended dose for nicotinamide, which is available over the counter as Vitamin B3, is 500 mg twice a day. Nicotinamide should not be confused with niacin (nicotinic acid), which has been used to treat high cholesterol and cardiovascular disease. There are no significant side effects from long-term use; however nicotinamide should not be used in patients with end-stage kidney disease or chronic kidney disease. (Niacin, however, can cause elevation of liver enzymes, headache, flushing, and increased blood pressure.) Nicotinamide crosses the placenta and should not be used in pregnancy as it has not been studied in pregnant populations.

We should counsel patients that this is not an oral sunscreen, and that sun avoidance, sunscreen, and yearly skin cancer checks are still the mainstay of skin cancer prevention. However, given the safety profile of nicotinamide and the protective effects, should all of our skin cancer patients be taking nicotinamide daily? In my practice they are, all of whom swear by it and have had significant reductions of both actinic keratoses and nonmelanoma skin cancers.

Dr. Talakoub and Dr. Wesley are cocontributors to this column. Dr. Talakoub is in private practice in McLean, Va. Dr. Wesley practices dermatology in Beverly Hills, Calif. This month’s column is by Dr. Talakoub. Write to them at dermnews@mdedge.com. They had no relevant disclosures.

In 2014, I began taking care of a patient (see photo) who had developed over 25 basal cell carcinomas on her lower legs, which were surgically removed. Given the results of a 2015 study by Chen et al. on the protective effects of nicotinamide in the prevention of nonmelanoma skin cancers, I began her on oral nicotinamide, 500 mg twice daily. She has been clear of any skin cancers in the last 2 years since starting supplementation.

Lily Talakoub, MD

Nicotinamide, also known as niacinamide, is a water soluble form of vitamin B3 that has been shown to enhance the repair of UV-induced DNA damage. Nicotinamide is found naturally in meat, fish, nuts, grains, and legumes, and is a key component of the glycolysis pathway, by generating nicotinamide adenine dinucleotide for adenosine triphosphate production. Nicotinamide deficiency causes photosensitive dermatitis, diarrhea, and dementia. It has been studied for its anti-inflammatory benefits as an adjunct treatment for rosacea, bullous diseases, acne, and melasma.

Nonmelanoma skin cancers are known to be caused primarily by UV radiation. The supplementation of nicotinamide orally twice daily has been shown to reduce the rate of actinic keratoses and new nonmelanoma skin cancers compared with placebo after 1 year in patients who previously had skin cancer. In the phase 3 study published in 2015, a randomized, controlled trial of 386 patients who had at least two nonmelanoma skin cancers within the previous 5-year period, oral nicotinamide 500 mg given twice daily for a 12-month period significantly reduced the number of new nonmelanoma skin cancers by 23% versus those on placebo.

The recommended dose for nicotinamide, which is available over the counter as Vitamin B3, is 500 mg twice a day. Nicotinamide should not be confused with niacin (nicotinic acid), which has been used to treat high cholesterol and cardiovascular disease. There are no significant side effects from long-term use; however nicotinamide should not be used in patients with end-stage kidney disease or chronic kidney disease. (Niacin, however, can cause elevation of liver enzymes, headache, flushing, and increased blood pressure.) Nicotinamide crosses the placenta and should not be used in pregnancy as it has not been studied in pregnant populations.

We should counsel patients that this is not an oral sunscreen, and that sun avoidance, sunscreen, and yearly skin cancer checks are still the mainstay of skin cancer prevention. However, given the safety profile of nicotinamide and the protective effects, should all of our skin cancer patients be taking nicotinamide daily? In my practice they are, all of whom swear by it and have had significant reductions of both actinic keratoses and nonmelanoma skin cancers.

Dr. Talakoub and Dr. Wesley are cocontributors to this column. Dr. Talakoub is in private practice in McLean, Va. Dr. Wesley practices dermatology in Beverly Hills, Calif. This month’s column is by Dr. Talakoub. Write to them at dermnews@mdedge.com. They had no relevant disclosures.

As the COVID-19 vaccine candidates have begun to roll off the production lines into the distribution networks by the millions, media coverage almost universally includes a still photo or video of someone receiving an injection. Ever observant, a retired lawyer friend of mine who learned to give shots when he was in the Army and again more recently while taking a wilderness survival course emailed me his concerns about what he felt were examples of poor injection technique. Included in his commentary was an Internet link in which a physician, who I suspect may have been a pediatrician, demonstrated what the physician considered proper intramuscular injection technique, which included a single-handed aspiration prior to giving the injection allowing the free hand to stabilize the patient’s – in this case a child’s – arm during the entire process.

Sean Locke/iStockphoto

I replied to my friend that I too was often troubled by what I considered to be poor injection technique. But, I said the physician in the link touting his improved technique was misguided. My understanding has been that unless the injection site is in the gluteus, there is no need aspirate prior to an intramuscular vaccine injection because the risk of intravascular injection is so small. I then confirmed this by reviewing the Centers for Disease Control and Prevention’s Vaccine Recommendations and Guidelines of the Advisory Committee on Immunization Practices, which was updated in June 2019. Included in those recommendations was the observation that the vaccine administrator does not need to wear gloves unless he or she has open lesions or is at risk from contacting the recipient’s body fluids.

My little research project into proper injection technique got me thinking about how and when I learned to give shots. Like many of the technical skills one learns in training, giving intramuscular injections is probably an example of the “see one, do one, teach one” mantra. But in the case of giving shots, I don’t recall any teaching. Do you? It was more “see a dozen and get on with it.” Or maybe you trained in an environment in which nurses gave all the injections. I hope not.

When it comes to giving immunizations to children, the art is in entering into that encounter with a calm, matter-of-fact attitude and body language, hiding the needle, firmly restraining the child, and moving quickly and smoothly. Aspirating and glove donning merely add to the drama and waste time. But how did I learn that art? No one taught me. Like many clinical skills, I watched scores of nurses and physicians, mentally logging in their tricks and mistakes that would help me craft my style.

I always felt and still feel that providing immunizations was per hour spent, the most valuable investment of my time. Doing the injecting myself was both the most efficient way to provide the service, and also emphasized the importance that I placed on the immunization. In the process of my 40-plus–year career, that included several hundred thousand patient encounters in which I gave innumerable injections. And, I egotistically assumed that I was good at it because many infants never cried, and a few children said, “That didn’t hurt.” I suspect you can make the same claim.

Injecting millions of adults with a COVID-19 vaccine, on the other hand, is a piece of cake because restraining the recipient shouldn’t factor into the scenario. However, I wonder who is going to administer all those millions of injections and who is going to train them? How many of the trainers are aware of the CDC-ACIP guidelines? Or, are they going to fall back on old techniques that lack evidence support?

From the efficiency standpoint, it probably doesn’t make much difference. The injection takes but a few seconds. Filling out the paperwork and waiting for the recipient to figure out how to expose his or her deltoid can take fifty times that long.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.

As the COVID-19 vaccine candidates have begun to roll off the production lines into the distribution networks by the millions, media coverage almost universally includes a still photo or video of someone receiving an injection. Ever observant, a retired lawyer friend of mine who learned to give shots when he was in the Army and again more recently while taking a wilderness survival course emailed me his concerns about what he felt were examples of poor injection technique. Included in his commentary was an Internet link in which a physician, who I suspect may have been a pediatrician, demonstrated what the physician considered proper intramuscular injection technique, which included a single-handed aspiration prior to giving the injection allowing the free hand to stabilize the patient’s – in this case a child’s – arm during the entire process.

Sean Locke/iStockphoto

I replied to my friend that I too was often troubled by what I considered to be poor injection technique. But, I said the physician in the link touting his improved technique was misguided. My understanding has been that unless the injection site is in the gluteus, there is no need aspirate prior to an intramuscular vaccine injection because the risk of intravascular injection is so small. I then confirmed this by reviewing the Centers for Disease Control and Prevention’s Vaccine Recommendations and Guidelines of the Advisory Committee on Immunization Practices, which was updated in June 2019. Included in those recommendations was the observation that the vaccine administrator does not need to wear gloves unless he or she has open lesions or is at risk from contacting the recipient’s body fluids.

My little research project into proper injection technique got me thinking about how and when I learned to give shots. Like many of the technical skills one learns in training, giving intramuscular injections is probably an example of the “see one, do one, teach one” mantra. But in the case of giving shots, I don’t recall any teaching. Do you? It was more “see a dozen and get on with it.” Or maybe you trained in an environment in which nurses gave all the injections. I hope not.

When it comes to giving immunizations to children, the art is in entering into that encounter with a calm, matter-of-fact attitude and body language, hiding the needle, firmly restraining the child, and moving quickly and smoothly. Aspirating and glove donning merely add to the drama and waste time. But how did I learn that art? No one taught me. Like many clinical skills, I watched scores of nurses and physicians, mentally logging in their tricks and mistakes that would help me craft my style.

I always felt and still feel that providing immunizations was per hour spent, the most valuable investment of my time. Doing the injecting myself was both the most efficient way to provide the service, and also emphasized the importance that I placed on the immunization. In the process of my 40-plus–year career, that included several hundred thousand patient encounters in which I gave innumerable injections. And, I egotistically assumed that I was good at it because many infants never cried, and a few children said, “That didn’t hurt.” I suspect you can make the same claim.

Injecting millions of adults with a COVID-19 vaccine, on the other hand, is a piece of cake because restraining the recipient shouldn’t factor into the scenario. However, I wonder who is going to administer all those millions of injections and who is going to train them? How many of the trainers are aware of the CDC-ACIP guidelines? Or, are they going to fall back on old techniques that lack evidence support?

From the efficiency standpoint, it probably doesn’t make much difference. The injection takes but a few seconds. Filling out the paperwork and waiting for the recipient to figure out how to expose his or her deltoid can take fifty times that long.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.

As the COVID-19 vaccine candidates have begun to roll off the production lines into the distribution networks by the millions, media coverage almost universally includes a still photo or video of someone receiving an injection. Ever observant, a retired lawyer friend of mine who learned to give shots when he was in the Army and again more recently while taking a wilderness survival course emailed me his concerns about what he felt were examples of poor injection technique. Included in his commentary was an Internet link in which a physician, who I suspect may have been a pediatrician, demonstrated what the physician considered proper intramuscular injection technique, which included a single-handed aspiration prior to giving the injection allowing the free hand to stabilize the patient’s – in this case a child’s – arm during the entire process.

Sean Locke/iStockphoto

I replied to my friend that I too was often troubled by what I considered to be poor injection technique. But, I said the physician in the link touting his improved technique was misguided. My understanding has been that unless the injection site is in the gluteus, there is no need aspirate prior to an intramuscular vaccine injection because the risk of intravascular injection is so small. I then confirmed this by reviewing the Centers for Disease Control and Prevention’s Vaccine Recommendations and Guidelines of the Advisory Committee on Immunization Practices, which was updated in June 2019. Included in those recommendations was the observation that the vaccine administrator does not need to wear gloves unless he or she has open lesions or is at risk from contacting the recipient’s body fluids.

My little research project into proper injection technique got me thinking about how and when I learned to give shots. Like many of the technical skills one learns in training, giving intramuscular injections is probably an example of the “see one, do one, teach one” mantra. But in the case of giving shots, I don’t recall any teaching. Do you? It was more “see a dozen and get on with it.” Or maybe you trained in an environment in which nurses gave all the injections. I hope not.

When it comes to giving immunizations to children, the art is in entering into that encounter with a calm, matter-of-fact attitude and body language, hiding the needle, firmly restraining the child, and moving quickly and smoothly. Aspirating and glove donning merely add to the drama and waste time. But how did I learn that art? No one taught me. Like many clinical skills, I watched scores of nurses and physicians, mentally logging in their tricks and mistakes that would help me craft my style.

I always felt and still feel that providing immunizations was per hour spent, the most valuable investment of my time. Doing the injecting myself was both the most efficient way to provide the service, and also emphasized the importance that I placed on the immunization. In the process of my 40-plus–year career, that included several hundred thousand patient encounters in which I gave innumerable injections. And, I egotistically assumed that I was good at it because many infants never cried, and a few children said, “That didn’t hurt.” I suspect you can make the same claim.

Injecting millions of adults with a COVID-19 vaccine, on the other hand, is a piece of cake because restraining the recipient shouldn’t factor into the scenario. However, I wonder who is going to administer all those millions of injections and who is going to train them? How many of the trainers are aware of the CDC-ACIP guidelines? Or, are they going to fall back on old techniques that lack evidence support?

From the efficiency standpoint, it probably doesn’t make much difference. The injection takes but a few seconds. Filling out the paperwork and waiting for the recipient to figure out how to expose his or her deltoid can take fifty times that long.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.

The antibody–drug conjugate sacituzumab govitecan (SG) appears to be effective across biomarker subgroups for women with metastatic triple-negative breast cancer (mTNBC) that has progressed after multiple lines of therapy, a biomarker evaluation from the phase 3 ASCENT trial shows.

But both an observer and the lead study author cautioned that the results were hypothesis generating.

Nonetheless, the data suggest the drug yields good survival outcomes in comparison with placebo in both BRCA1/2-positive and -negative patients and is effective even for those with low expression of the target protein, trophoblast cell surface antigen 2 (Trop-2).

The research was presented at the San Antonio Breast Cancer Symposium (SABCS) 2020.

Study presenter Sara Hurvitz, MD, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, urged caution in interpreting the data, given the small sample sizes in the Trop-2–low subgroup and germline BRCA1/2-positive subgroup.

Jennifer K. Litton, MD, University of Texas MD Anderson Cancer Center, Houston, Texas, who was not involved in the research, echoed those comments.

She told Medscape Medical News that the numbers, particularly for the BRCA1/2 analysis, were “very small.”

She added: “This was not a prespecified group, so it represents an interesting analysis to be hypothesis generating for future studies but not anything applicable to current clinical practice.”

Nevertheless, Litton said the data from the primary analysis of ASCENT remain “practice changing” for women with mTNBC who have received at least two previous lines of therapy.

As to whether SG will eventually move beyond this advanced setting, she emphasized that “more trials would need to be done and reported evaluating its role in other settings, and hopefully expanding its usefulness for patients.”

SG is a first-in-class drug comprising an antibody directed at Trop-2, which is highly expressed in breast cancer, and linked to SN-38, the active metabolite of irinotecan.

On the basis of positive phase 1/2 trial data, SG was granted accelerated approval by the US Food and Drug Administration for patients with mTNBC who experience disease progression after at least two prior therapies.

As reported by Medscape Medical News, primary results from ASCENT that were presented at ESMO 2020 showed that SG improved progression-free survival (PFS) by nearly 4 months and overall survival by more than 5 months for women with pretreated mTNBC compared to chemotherapy.
 

Study details

At SABCS, Hurvitz presented an exploratory biomarker evaluation of data from the trial regarding the association between SG efficacy and Trop-2 expression, as well as germline BRCA1/2 mutation status.

She reminded the audience that, in ASCENT, 529 patients with mTNBC who had experienced disease progression after undergoing at least two chemotherapy regimens for advanced disease were randomly assigned in a 1:1 ratio to receive intravenous SG on days 1 and 8 of a 21-day cycle or physician’s choice of treatment.

Treatment was continued until disease progression or unacceptable toxicity occurred.

For the current analysis, which focused on patients who did not have brain metastases, the team studied primary or metastatic archival biopsy or surgical specimens collected at study entry.

These were analyzed using a validated immunohistochemistry assay. Tumors were categorized as Trop-2–low, –medium, or –-high expressers on the basis of H-score, which is a weighted summation of percent staining. In addition, germline BRCA1/2 mutation status was determined at baseline.

Mutation status was known for 149 SG patients and 143 control patients. Of those, the majority (57% and 54%, respectively) were BRCA1/2 negative.

Among 151 SG patients for whom Trop-2 expression status was available, 56% had tumors of high expression; 26%, medium expression; and 18%, low expression. In the control group, Trop-2 expression was known in 139 patients, of whom 52% had tumors of high expression; 25%, medium expression; and 23%, low expression.

Hurvitz reported that, although median PFS among patients given SG decreased with decreasing Trop-2 expression, it remained longer than that seen with control treatment. In patients with tumors of Trop-2–high status, median PFS was 6.9 months with SG, vs. 2.5 for patients who underwent control treatment. This fell to 5.6 months vs. 2.2 months in the Trop-2–medium group and 2.7 months vs 1.6 months in Trop-2–low group.

A similar pattern was seen for overall survival. In the Trop-2–high group, median overall survival was 14.2 months with SG, vs. 6.9 months with control therapy; 14.9 months vs. 6.9 months in the Trop-2–medium group; and 9.3 months vs. 7.6 months in the Trop-2–low group.

Again, the objective response rate fell from 44% to 38% and then to 22% with SG in the Trop-2–high, –medium, and –low groups, compared with 1%, 11%, and 6%, respectively, with control treatment.

There did not seem to be any interaction between Trop-2 expression and treatment-related adverse events of special interest. Rates of neutropenia, diarrhea, and anemia were consistently higher in SG-treated patients than in those given placebo.

Hurvitz said the objective response rate was markedly higher with SG vs. control treatment in both BRCA1/2-positive and -negative patients, at 19% vs. 6% in the positive group and 33% vs. 6% in the negative group.

This was reflected in improved median PFS with SG in both subgroups, at 4.6 months vs. 2.5 months with control therapy in BRCA1/2-positive patients and 4.9 months vs. 1.6 months in BRCA1/2-negative patients.

Overall survival was 15.6 months with SG, vs. 4.4 months with control treatment in BRCA1/2-positive patients. In BRCA1/2-negative patients, the respective figures were 10.9 months and 7.0 months.

The study was sponsored by Immunomedics. Hurvitz has financial ties to Immunomedics and multiple other pharmaceutical companies. Litton has financial ties to multiple companies, including Medscape and companies developing and marketing breast cancer therapies.

This article first appeared on Medscape.com.

The antibody–drug conjugate sacituzumab govitecan (SG) appears to be effective across biomarker subgroups for women with metastatic triple-negative breast cancer (mTNBC) that has progressed after multiple lines of therapy, a biomarker evaluation from the phase 3 ASCENT trial shows.

But both an observer and the lead study author cautioned that the results were hypothesis generating.

Nonetheless, the data suggest the drug yields good survival outcomes in comparison with placebo in both BRCA1/2-positive and -negative patients and is effective even for those with low expression of the target protein, trophoblast cell surface antigen 2 (Trop-2).

The research was presented at the San Antonio Breast Cancer Symposium (SABCS) 2020.

Study presenter Sara Hurvitz, MD, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, urged caution in interpreting the data, given the small sample sizes in the Trop-2–low subgroup and germline BRCA1/2-positive subgroup.

Jennifer K. Litton, MD, University of Texas MD Anderson Cancer Center, Houston, Texas, who was not involved in the research, echoed those comments.

She told Medscape Medical News that the numbers, particularly for the BRCA1/2 analysis, were “very small.”

She added: “This was not a prespecified group, so it represents an interesting analysis to be hypothesis generating for future studies but not anything applicable to current clinical practice.”

Nevertheless, Litton said the data from the primary analysis of ASCENT remain “practice changing” for women with mTNBC who have received at least two previous lines of therapy.

As to whether SG will eventually move beyond this advanced setting, she emphasized that “more trials would need to be done and reported evaluating its role in other settings, and hopefully expanding its usefulness for patients.”

SG is a first-in-class drug comprising an antibody directed at Trop-2, which is highly expressed in breast cancer, and linked to SN-38, the active metabolite of irinotecan.

On the basis of positive phase 1/2 trial data, SG was granted accelerated approval by the US Food and Drug Administration for patients with mTNBC who experience disease progression after at least two prior therapies.

As reported by Medscape Medical News, primary results from ASCENT that were presented at ESMO 2020 showed that SG improved progression-free survival (PFS) by nearly 4 months and overall survival by more than 5 months for women with pretreated mTNBC compared to chemotherapy.
 

Study details

At SABCS, Hurvitz presented an exploratory biomarker evaluation of data from the trial regarding the association between SG efficacy and Trop-2 expression, as well as germline BRCA1/2 mutation status.

She reminded the audience that, in ASCENT, 529 patients with mTNBC who had experienced disease progression after undergoing at least two chemotherapy regimens for advanced disease were randomly assigned in a 1:1 ratio to receive intravenous SG on days 1 and 8 of a 21-day cycle or physician’s choice of treatment.

Treatment was continued until disease progression or unacceptable toxicity occurred.

For the current analysis, which focused on patients who did not have brain metastases, the team studied primary or metastatic archival biopsy or surgical specimens collected at study entry.

These were analyzed using a validated immunohistochemistry assay. Tumors were categorized as Trop-2–low, –medium, or –-high expressers on the basis of H-score, which is a weighted summation of percent staining. In addition, germline BRCA1/2 mutation status was determined at baseline.

Mutation status was known for 149 SG patients and 143 control patients. Of those, the majority (57% and 54%, respectively) were BRCA1/2 negative.

Among 151 SG patients for whom Trop-2 expression status was available, 56% had tumors of high expression; 26%, medium expression; and 18%, low expression. In the control group, Trop-2 expression was known in 139 patients, of whom 52% had tumors of high expression; 25%, medium expression; and 23%, low expression.

Hurvitz reported that, although median PFS among patients given SG decreased with decreasing Trop-2 expression, it remained longer than that seen with control treatment. In patients with tumors of Trop-2–high status, median PFS was 6.9 months with SG, vs. 2.5 for patients who underwent control treatment. This fell to 5.6 months vs. 2.2 months in the Trop-2–medium group and 2.7 months vs 1.6 months in Trop-2–low group.

A similar pattern was seen for overall survival. In the Trop-2–high group, median overall survival was 14.2 months with SG, vs. 6.9 months with control therapy; 14.9 months vs. 6.9 months in the Trop-2–medium group; and 9.3 months vs. 7.6 months in the Trop-2–low group.

Again, the objective response rate fell from 44% to 38% and then to 22% with SG in the Trop-2–high, –medium, and –low groups, compared with 1%, 11%, and 6%, respectively, with control treatment.

There did not seem to be any interaction between Trop-2 expression and treatment-related adverse events of special interest. Rates of neutropenia, diarrhea, and anemia were consistently higher in SG-treated patients than in those given placebo.

Hurvitz said the objective response rate was markedly higher with SG vs. control treatment in both BRCA1/2-positive and -negative patients, at 19% vs. 6% in the positive group and 33% vs. 6% in the negative group.

This was reflected in improved median PFS with SG in both subgroups, at 4.6 months vs. 2.5 months with control therapy in BRCA1/2-positive patients and 4.9 months vs. 1.6 months in BRCA1/2-negative patients.

Overall survival was 15.6 months with SG, vs. 4.4 months with control treatment in BRCA1/2-positive patients. In BRCA1/2-negative patients, the respective figures were 10.9 months and 7.0 months.

The study was sponsored by Immunomedics. Hurvitz has financial ties to Immunomedics and multiple other pharmaceutical companies. Litton has financial ties to multiple companies, including Medscape and companies developing and marketing breast cancer therapies.

This article first appeared on Medscape.com.

The antibody–drug conjugate sacituzumab govitecan (SG) appears to be effective across biomarker subgroups for women with metastatic triple-negative breast cancer (mTNBC) that has progressed after multiple lines of therapy, a biomarker evaluation from the phase 3 ASCENT trial shows.

But both an observer and the lead study author cautioned that the results were hypothesis generating.

Nonetheless, the data suggest the drug yields good survival outcomes in comparison with placebo in both BRCA1/2-positive and -negative patients and is effective even for those with low expression of the target protein, trophoblast cell surface antigen 2 (Trop-2).

The research was presented at the San Antonio Breast Cancer Symposium (SABCS) 2020.

Study presenter Sara Hurvitz, MD, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, urged caution in interpreting the data, given the small sample sizes in the Trop-2–low subgroup and germline BRCA1/2-positive subgroup.

Jennifer K. Litton, MD, University of Texas MD Anderson Cancer Center, Houston, Texas, who was not involved in the research, echoed those comments.

She told Medscape Medical News that the numbers, particularly for the BRCA1/2 analysis, were “very small.”

She added: “This was not a prespecified group, so it represents an interesting analysis to be hypothesis generating for future studies but not anything applicable to current clinical practice.”

Nevertheless, Litton said the data from the primary analysis of ASCENT remain “practice changing” for women with mTNBC who have received at least two previous lines of therapy.

As to whether SG will eventually move beyond this advanced setting, she emphasized that “more trials would need to be done and reported evaluating its role in other settings, and hopefully expanding its usefulness for patients.”

SG is a first-in-class drug comprising an antibody directed at Trop-2, which is highly expressed in breast cancer, and linked to SN-38, the active metabolite of irinotecan.

On the basis of positive phase 1/2 trial data, SG was granted accelerated approval by the US Food and Drug Administration for patients with mTNBC who experience disease progression after at least two prior therapies.

As reported by Medscape Medical News, primary results from ASCENT that were presented at ESMO 2020 showed that SG improved progression-free survival (PFS) by nearly 4 months and overall survival by more than 5 months for women with pretreated mTNBC compared to chemotherapy.
 

Study details

At SABCS, Hurvitz presented an exploratory biomarker evaluation of data from the trial regarding the association between SG efficacy and Trop-2 expression, as well as germline BRCA1/2 mutation status.

She reminded the audience that, in ASCENT, 529 patients with mTNBC who had experienced disease progression after undergoing at least two chemotherapy regimens for advanced disease were randomly assigned in a 1:1 ratio to receive intravenous SG on days 1 and 8 of a 21-day cycle or physician’s choice of treatment.

Treatment was continued until disease progression or unacceptable toxicity occurred.

For the current analysis, which focused on patients who did not have brain metastases, the team studied primary or metastatic archival biopsy or surgical specimens collected at study entry.

These were analyzed using a validated immunohistochemistry assay. Tumors were categorized as Trop-2–low, –medium, or –-high expressers on the basis of H-score, which is a weighted summation of percent staining. In addition, germline BRCA1/2 mutation status was determined at baseline.

Mutation status was known for 149 SG patients and 143 control patients. Of those, the majority (57% and 54%, respectively) were BRCA1/2 negative.

Among 151 SG patients for whom Trop-2 expression status was available, 56% had tumors of high expression; 26%, medium expression; and 18%, low expression. In the control group, Trop-2 expression was known in 139 patients, of whom 52% had tumors of high expression; 25%, medium expression; and 23%, low expression.

Hurvitz reported that, although median PFS among patients given SG decreased with decreasing Trop-2 expression, it remained longer than that seen with control treatment. In patients with tumors of Trop-2–high status, median PFS was 6.9 months with SG, vs. 2.5 for patients who underwent control treatment. This fell to 5.6 months vs. 2.2 months in the Trop-2–medium group and 2.7 months vs 1.6 months in Trop-2–low group.

A similar pattern was seen for overall survival. In the Trop-2–high group, median overall survival was 14.2 months with SG, vs. 6.9 months with control therapy; 14.9 months vs. 6.9 months in the Trop-2–medium group; and 9.3 months vs. 7.6 months in the Trop-2–low group.

Again, the objective response rate fell from 44% to 38% and then to 22% with SG in the Trop-2–high, –medium, and –low groups, compared with 1%, 11%, and 6%, respectively, with control treatment.

There did not seem to be any interaction between Trop-2 expression and treatment-related adverse events of special interest. Rates of neutropenia, diarrhea, and anemia were consistently higher in SG-treated patients than in those given placebo.

Hurvitz said the objective response rate was markedly higher with SG vs. control treatment in both BRCA1/2-positive and -negative patients, at 19% vs. 6% in the positive group and 33% vs. 6% in the negative group.

This was reflected in improved median PFS with SG in both subgroups, at 4.6 months vs. 2.5 months with control therapy in BRCA1/2-positive patients and 4.9 months vs. 1.6 months in BRCA1/2-negative patients.

Overall survival was 15.6 months with SG, vs. 4.4 months with control treatment in BRCA1/2-positive patients. In BRCA1/2-negative patients, the respective figures were 10.9 months and 7.0 months.

The study was sponsored by Immunomedics. Hurvitz has financial ties to Immunomedics and multiple other pharmaceutical companies. Litton has financial ties to multiple companies, including Medscape and companies developing and marketing breast cancer therapies.

This article first appeared on Medscape.com.

A phase 1 first-in-human study demonstrated synthetic T-cell receptor and antigen receptor (STAR) technical feasibility, clinical safety and efficacy in treating CD19+ relapsed/refractory B-cell acute lymphoblastic leukemia (ALL), according to senior study author Peihua Lu, MD, Beijing Lu Daopei Institute of Hematology, Beijing, China. STAR T cells were found to be superior to conventional chimeric antigen receptor (CAR) T cells with respect to signaling capacity, cytokine production and antitumor potency in an animal model study, according to Dr. Lu’s presentation at the annual meeting of the American Society of Hematology.
 

Remission can be improved

While CAR T-cell therapy has demonstrated high response rates in patients with B-cell malignancies, remission durability and safety can be improved, Dr Lu said. Her team developed STAR, a novel double-chain chimeric receptor consisting of two protein modules, each containing an antibody light or heavy chain variable region, the T cell receptor (TCR) alpha or beta chain constant region fused to the OX-40 costimulatory domain. The 2 modules are linked by a self-cleaving Furin-p2A sequence that allows the modules to be proteolytically separated and reconstituted. In preclinical in vitro research, STAR-T-cells showed a much faster and stronger cell activation, compared with CAR T cells and superior target cell–killing ability, and higher levels of interferon-y after coculture with the CD19+ Raji cell. In a murine in vivo study, STAR-T cells had higher antileukemia activity, compared with CAR-T cells, and significantly inhibited tumor cell growth, Dr. Lu stated. All animals were sustainably tumor free 5 days after STAR-T cell injection.

The first-in-human study included 18 CD19+ relapsed/refractory B-cell ALL (median age 22.5 years) patients, with a median bone marrow blast level pre–CAR T of 15.3%.

The manufacture success rate was 100% and took about 9 days (7-13). Transduction efficacy was 57.4% (41.0%-78.2%). Subjects received a conditioning regimen of intravenous fludarabine (25mg/m² per day) and cyclophosphamide (250mg/m² per day) for 3 days followed by a single STAR T-cell infusion. Patients were given the option, after they achieved complete remission (CR), of proceeding to consolidation allogeneic hematopoietic stem cell transplantation (allo-HSCT).
 

100% MRD negative

On day 14 following transplant, 18/18 had achieved minimal residual disease–negative complete response/CRi (with incomplete hematologic recovery). One patient relapsed after allogeneic transplant, becoming minimal residual disease positive on day 28. After a median follow-up of 105 days, 11/18 bridged into allo-HSCT without relapse. Among the seven patients who did not undergo allo-HSCT, one relapsed on day 58 and died on day 63. The patient had CNS leukemia and 87% bone marrow blasts before receiving STAR T. The others, Dr. Lu said, remain in CR.

Mild cytokine release syndrome (CRS) occurred in only 10 patients (55.6%), with grade 1 CRS in 8 patients and grade 2 in 2 patients. Grade 3 neurotoxicity occurred in two patients.

Reporting cellular kinetics of STAR T cells in peripheral blood by fluorescence-activated cell sorting (FACS)/quantitative PCR showed the highest STAR-T proliferation ratio (STAR/CD3) of 88.1%. Median peak level was 4.9 x 10⁴ copies number/mcg genomic DNA. The peak time was day 8.5 and the longest detection time was 6 months after STAR T infusion (STAR T ratio, 0.46%-1.85%). High in vivo proliferation and persistence was observed regardless of infusion dose.
 

STAR holds promise

Dr. Lu concluded: “The phase 1 first-in-human study demonstrated technical feasibility, clinical safety and efficacy of STAR T in treating CD19+ relapsed/refractory B-cell acute lymphoblastic leukemia.” She noted also that long-term observation of these patients and studies of larger patient cohorts are warranted to evaluate a beneficial advantage of the STAR T over the conventional CAR T product.

Asked about future directions in the discussion period, Dr. Lu responded that “this product holds great promise, No. 1 because it is actually between a T-cell receptor and a CAR T, and so clearly has fewer side effects. It potentially can recognize and target the tumor intracellular antigen better than a conventional CAR T. It is easier to construct – and holds great promise for treating solid tumors.”

Dr. Lu reported that she had no relevant disclosures.

SOURCE: Lu P et al. ASH 2020, Abstract 270.

A phase 1 first-in-human study demonstrated synthetic T-cell receptor and antigen receptor (STAR) technical feasibility, clinical safety and efficacy in treating CD19+ relapsed/refractory B-cell acute lymphoblastic leukemia (ALL), according to senior study author Peihua Lu, MD, Beijing Lu Daopei Institute of Hematology, Beijing, China. STAR T cells were found to be superior to conventional chimeric antigen receptor (CAR) T cells with respect to signaling capacity, cytokine production and antitumor potency in an animal model study, according to Dr. Lu’s presentation at the annual meeting of the American Society of Hematology.
 

Remission can be improved

While CAR T-cell therapy has demonstrated high response rates in patients with B-cell malignancies, remission durability and safety can be improved, Dr Lu said. Her team developed STAR, a novel double-chain chimeric receptor consisting of two protein modules, each containing an antibody light or heavy chain variable region, the T cell receptor (TCR) alpha or beta chain constant region fused to the OX-40 costimulatory domain. The 2 modules are linked by a self-cleaving Furin-p2A sequence that allows the modules to be proteolytically separated and reconstituted. In preclinical in vitro research, STAR-T-cells showed a much faster and stronger cell activation, compared with CAR T cells and superior target cell–killing ability, and higher levels of interferon-y after coculture with the CD19+ Raji cell. In a murine in vivo study, STAR-T cells had higher antileukemia activity, compared with CAR-T cells, and significantly inhibited tumor cell growth, Dr. Lu stated. All animals were sustainably tumor free 5 days after STAR-T cell injection.

The first-in-human study included 18 CD19+ relapsed/refractory B-cell ALL (median age 22.5 years) patients, with a median bone marrow blast level pre–CAR T of 15.3%.

The manufacture success rate was 100% and took about 9 days (7-13). Transduction efficacy was 57.4% (41.0%-78.2%). Subjects received a conditioning regimen of intravenous fludarabine (25mg/m² per day) and cyclophosphamide (250mg/m² per day) for 3 days followed by a single STAR T-cell infusion. Patients were given the option, after they achieved complete remission (CR), of proceeding to consolidation allogeneic hematopoietic stem cell transplantation (allo-HSCT).
 

100% MRD negative

On day 14 following transplant, 18/18 had achieved minimal residual disease–negative complete response/CRi (with incomplete hematologic recovery). One patient relapsed after allogeneic transplant, becoming minimal residual disease positive on day 28. After a median follow-up of 105 days, 11/18 bridged into allo-HSCT without relapse. Among the seven patients who did not undergo allo-HSCT, one relapsed on day 58 and died on day 63. The patient had CNS leukemia and 87% bone marrow blasts before receiving STAR T. The others, Dr. Lu said, remain in CR.

Mild cytokine release syndrome (CRS) occurred in only 10 patients (55.6%), with grade 1 CRS in 8 patients and grade 2 in 2 patients. Grade 3 neurotoxicity occurred in two patients.

Reporting cellular kinetics of STAR T cells in peripheral blood by fluorescence-activated cell sorting (FACS)/quantitative PCR showed the highest STAR-T proliferation ratio (STAR/CD3) of 88.1%. Median peak level was 4.9 x 10⁴ copies number/mcg genomic DNA. The peak time was day 8.5 and the longest detection time was 6 months after STAR T infusion (STAR T ratio, 0.46%-1.85%). High in vivo proliferation and persistence was observed regardless of infusion dose.
 

STAR holds promise

Dr. Lu concluded: “The phase 1 first-in-human study demonstrated technical feasibility, clinical safety and efficacy of STAR T in treating CD19+ relapsed/refractory B-cell acute lymphoblastic leukemia.” She noted also that long-term observation of these patients and studies of larger patient cohorts are warranted to evaluate a beneficial advantage of the STAR T over the conventional CAR T product.

Asked about future directions in the discussion period, Dr. Lu responded that “this product holds great promise, No. 1 because it is actually between a T-cell receptor and a CAR T, and so clearly has fewer side effects. It potentially can recognize and target the tumor intracellular antigen better than a conventional CAR T. It is easier to construct – and holds great promise for treating solid tumors.”

Dr. Lu reported that she had no relevant disclosures.

SOURCE: Lu P et al. ASH 2020, Abstract 270.

A phase 1 first-in-human study demonstrated synthetic T-cell receptor and antigen receptor (STAR) technical feasibility, clinical safety and efficacy in treating CD19+ relapsed/refractory B-cell acute lymphoblastic leukemia (ALL), according to senior study author Peihua Lu, MD, Beijing Lu Daopei Institute of Hematology, Beijing, China. STAR T cells were found to be superior to conventional chimeric antigen receptor (CAR) T cells with respect to signaling capacity, cytokine production and antitumor potency in an animal model study, according to Dr. Lu’s presentation at the annual meeting of the American Society of Hematology.
 

Remission can be improved

While CAR T-cell therapy has demonstrated high response rates in patients with B-cell malignancies, remission durability and safety can be improved, Dr Lu said. Her team developed STAR, a novel double-chain chimeric receptor consisting of two protein modules, each containing an antibody light or heavy chain variable region, the T cell receptor (TCR) alpha or beta chain constant region fused to the OX-40 costimulatory domain. The 2 modules are linked by a self-cleaving Furin-p2A sequence that allows the modules to be proteolytically separated and reconstituted. In preclinical in vitro research, STAR-T-cells showed a much faster and stronger cell activation, compared with CAR T cells and superior target cell–killing ability, and higher levels of interferon-y after coculture with the CD19+ Raji cell. In a murine in vivo study, STAR-T cells had higher antileukemia activity, compared with CAR-T cells, and significantly inhibited tumor cell growth, Dr. Lu stated. All animals were sustainably tumor free 5 days after STAR-T cell injection.

The first-in-human study included 18 CD19+ relapsed/refractory B-cell ALL (median age 22.5 years) patients, with a median bone marrow blast level pre–CAR T of 15.3%.

The manufacture success rate was 100% and took about 9 days (7-13). Transduction efficacy was 57.4% (41.0%-78.2%). Subjects received a conditioning regimen of intravenous fludarabine (25mg/m² per day) and cyclophosphamide (250mg/m² per day) for 3 days followed by a single STAR T-cell infusion. Patients were given the option, after they achieved complete remission (CR), of proceeding to consolidation allogeneic hematopoietic stem cell transplantation (allo-HSCT).
 

100% MRD negative

On day 14 following transplant, 18/18 had achieved minimal residual disease–negative complete response/CRi (with incomplete hematologic recovery). One patient relapsed after allogeneic transplant, becoming minimal residual disease positive on day 28. After a median follow-up of 105 days, 11/18 bridged into allo-HSCT without relapse. Among the seven patients who did not undergo allo-HSCT, one relapsed on day 58 and died on day 63. The patient had CNS leukemia and 87% bone marrow blasts before receiving STAR T. The others, Dr. Lu said, remain in CR.

Mild cytokine release syndrome (CRS) occurred in only 10 patients (55.6%), with grade 1 CRS in 8 patients and grade 2 in 2 patients. Grade 3 neurotoxicity occurred in two patients.

Reporting cellular kinetics of STAR T cells in peripheral blood by fluorescence-activated cell sorting (FACS)/quantitative PCR showed the highest STAR-T proliferation ratio (STAR/CD3) of 88.1%. Median peak level was 4.9 x 10⁴ copies number/mcg genomic DNA. The peak time was day 8.5 and the longest detection time was 6 months after STAR T infusion (STAR T ratio, 0.46%-1.85%). High in vivo proliferation and persistence was observed regardless of infusion dose.
 

STAR holds promise

Dr. Lu concluded: “The phase 1 first-in-human study demonstrated technical feasibility, clinical safety and efficacy of STAR T in treating CD19+ relapsed/refractory B-cell acute lymphoblastic leukemia.” She noted also that long-term observation of these patients and studies of larger patient cohorts are warranted to evaluate a beneficial advantage of the STAR T over the conventional CAR T product.

Asked about future directions in the discussion period, Dr. Lu responded that “this product holds great promise, No. 1 because it is actually between a T-cell receptor and a CAR T, and so clearly has fewer side effects. It potentially can recognize and target the tumor intracellular antigen better than a conventional CAR T. It is easier to construct – and holds great promise for treating solid tumors.”

Dr. Lu reported that she had no relevant disclosures.

SOURCE: Lu P et al. ASH 2020, Abstract 270.

The beneficial effects of sacubitril/valsartan on reverse cardiac remodeling in patients with heart failure and reduced ejection fraction have been well established, but those benefits haven’t been as clearly demonstrated to carry over to HFrEF patients who also have type 2 diabetes mellitus (T2DM).

Now, a post-hoc analysis of a pivotal clinical trial reports that those benefits do extend to patients with HFrEF and T2DM.

“It’s really not about a Sophie’s choice of whether you give this or that drug in these patients,” said corresponding author Javed Butler, MD, MPH, MBA. “We really ought to be giving all of these drugs – the angiotensin receptor neprilysin inhibitors (ARNIs) and sodium-glucose transporter 2 (SGLT-2) inhibitors – to our patients for the best outcomes.”

The post-hoc analysis, published in JACC: Heart Failure, evaluated 361 patients with T2DM who were enrolled in the PROVE-HF trial of sac/val therapy for HF, published in JAMA.

PROVE-HF evaluated biomarkers, myocardial remodeling, and outcomes through a year of treatment with sac/val. The primary endpoint was the level of changes in natriuretic peptide (NT-proBNP) concentrations, left-ventricle ejection fraction (LVEF) and overall Kansas City Cardiomyopathy Questionnaire (KCCQ)-23 scores through 12 months of treatment.

The post hoc study reported that baseline NT-proBNP concentrations were higher in the DM patients (854 pg/mL vs. 706 pg/mL), but at 12 months those levels were 513 and 441 pg/mL, respectively.

LVEF changed similarly from baseline to 12 months in both groups: from 28.3% to 37% in the DM patients and from 28.1% to 38.34% in non-DM patients. Overall KCCQ-23 scores improved similarly in both groups, but longitudinal analyses found modestly higher gains in the T2DM group, 9.3 vs. 8.6 points (P = .07).

“The real reason I wanted to do this study is that I’m a huge fan of all the SGLT-2 inhibitors, and I’m very involved in those trials, and there is right now so much momentum behind SGLT-2 inhibitors that I don’t want people to forget that ARNI is still the base therapy for HF,” said Dr. Butler, chair of cardiovascular research and the department of medicine at the University of Mississippi in Jackson.

He noted that the size of the diabetes cohort in PROVE-HF “is a nonissue” for evaluating power of the post hoc analysis because it tracked key measures in the study population continuously at eight intervals over the 12 months.

The analysis further demonstrates the synergistic effects of ARNI and SGLT-2 inhibitors in patients with T2DM and HF that were also reported in the PARADIGM-HF study, Dr. Butler said.

“We have sort of moved on, saying that SGLT-2 inhibitors have a benefit on the heart, but the reverse is also true: ARNIs are still heart failure drugs, and we don’t think of them as diabetes drugs, but the PARADIGM-HF data showed that there was a substantial reduction in hemoglobin A1c in those who had diabetes,” he said.

The researchers noted that an absence of a control group may contribute to an overestimation of reverse cardiac remodeling in the T2DM patients, and that the PROVE-HF study wasn’t prospectively powered to delineate differences in how sac/val therapy affected patients with or without diabetes. “Future investigations seeking to evaluate differences by T2DM status after sacubitril/valsartan initiation may use our findings to plan prospective sample sizes,” the researchers wrote.

Dr. Butler disclosed financial relationships with Abbott, Amgen, Array, AstraZeneca, Bayer, Boehringer Ingelheim, CVRx, Eli Lilly, G3 Pharmaceutical, Impulse Dynamics, Innolife, Janssen, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Sequana, StealthPeptide and Vifor. Lead author Muhammad Shahzeb Khan, MD, MSc, a professor at the University of Mississippi, has no relevant financial relationships to disclose.

SOURCE: Kahn MS et al. JACC: HF. 2020 Dec 9. doi: 10.1016/j.jchf.2020.09.014.
 

The beneficial effects of sacubitril/valsartan on reverse cardiac remodeling in patients with heart failure and reduced ejection fraction have been well established, but those benefits haven’t been as clearly demonstrated to carry over to HFrEF patients who also have type 2 diabetes mellitus (T2DM).

Now, a post-hoc analysis of a pivotal clinical trial reports that those benefits do extend to patients with HFrEF and T2DM.

“It’s really not about a Sophie’s choice of whether you give this or that drug in these patients,” said corresponding author Javed Butler, MD, MPH, MBA. “We really ought to be giving all of these drugs – the angiotensin receptor neprilysin inhibitors (ARNIs) and sodium-glucose transporter 2 (SGLT-2) inhibitors – to our patients for the best outcomes.”

The post-hoc analysis, published in JACC: Heart Failure, evaluated 361 patients with T2DM who were enrolled in the PROVE-HF trial of sac/val therapy for HF, published in JAMA.

PROVE-HF evaluated biomarkers, myocardial remodeling, and outcomes through a year of treatment with sac/val. The primary endpoint was the level of changes in natriuretic peptide (NT-proBNP) concentrations, left-ventricle ejection fraction (LVEF) and overall Kansas City Cardiomyopathy Questionnaire (KCCQ)-23 scores through 12 months of treatment.

The post hoc study reported that baseline NT-proBNP concentrations were higher in the DM patients (854 pg/mL vs. 706 pg/mL), but at 12 months those levels were 513 and 441 pg/mL, respectively.

LVEF changed similarly from baseline to 12 months in both groups: from 28.3% to 37% in the DM patients and from 28.1% to 38.34% in non-DM patients. Overall KCCQ-23 scores improved similarly in both groups, but longitudinal analyses found modestly higher gains in the T2DM group, 9.3 vs. 8.6 points (P = .07).

“The real reason I wanted to do this study is that I’m a huge fan of all the SGLT-2 inhibitors, and I’m very involved in those trials, and there is right now so much momentum behind SGLT-2 inhibitors that I don’t want people to forget that ARNI is still the base therapy for HF,” said Dr. Butler, chair of cardiovascular research and the department of medicine at the University of Mississippi in Jackson.

He noted that the size of the diabetes cohort in PROVE-HF “is a nonissue” for evaluating power of the post hoc analysis because it tracked key measures in the study population continuously at eight intervals over the 12 months.

The analysis further demonstrates the synergistic effects of ARNI and SGLT-2 inhibitors in patients with T2DM and HF that were also reported in the PARADIGM-HF study, Dr. Butler said.

“We have sort of moved on, saying that SGLT-2 inhibitors have a benefit on the heart, but the reverse is also true: ARNIs are still heart failure drugs, and we don’t think of them as diabetes drugs, but the PARADIGM-HF data showed that there was a substantial reduction in hemoglobin A1c in those who had diabetes,” he said.

The researchers noted that an absence of a control group may contribute to an overestimation of reverse cardiac remodeling in the T2DM patients, and that the PROVE-HF study wasn’t prospectively powered to delineate differences in how sac/val therapy affected patients with or without diabetes. “Future investigations seeking to evaluate differences by T2DM status after sacubitril/valsartan initiation may use our findings to plan prospective sample sizes,” the researchers wrote.

Dr. Butler disclosed financial relationships with Abbott, Amgen, Array, AstraZeneca, Bayer, Boehringer Ingelheim, CVRx, Eli Lilly, G3 Pharmaceutical, Impulse Dynamics, Innolife, Janssen, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Sequana, StealthPeptide and Vifor. Lead author Muhammad Shahzeb Khan, MD, MSc, a professor at the University of Mississippi, has no relevant financial relationships to disclose.

SOURCE: Kahn MS et al. JACC: HF. 2020 Dec 9. doi: 10.1016/j.jchf.2020.09.014.
 

The beneficial effects of sacubitril/valsartan on reverse cardiac remodeling in patients with heart failure and reduced ejection fraction have been well established, but those benefits haven’t been as clearly demonstrated to carry over to HFrEF patients who also have type 2 diabetes mellitus (T2DM).

Now, a post-hoc analysis of a pivotal clinical trial reports that those benefits do extend to patients with HFrEF and T2DM.

“It’s really not about a Sophie’s choice of whether you give this or that drug in these patients,” said corresponding author Javed Butler, MD, MPH, MBA. “We really ought to be giving all of these drugs – the angiotensin receptor neprilysin inhibitors (ARNIs) and sodium-glucose transporter 2 (SGLT-2) inhibitors – to our patients for the best outcomes.”

The post-hoc analysis, published in JACC: Heart Failure, evaluated 361 patients with T2DM who were enrolled in the PROVE-HF trial of sac/val therapy for HF, published in JAMA.

PROVE-HF evaluated biomarkers, myocardial remodeling, and outcomes through a year of treatment with sac/val. The primary endpoint was the level of changes in natriuretic peptide (NT-proBNP) concentrations, left-ventricle ejection fraction (LVEF) and overall Kansas City Cardiomyopathy Questionnaire (KCCQ)-23 scores through 12 months of treatment.

The post hoc study reported that baseline NT-proBNP concentrations were higher in the DM patients (854 pg/mL vs. 706 pg/mL), but at 12 months those levels were 513 and 441 pg/mL, respectively.

LVEF changed similarly from baseline to 12 months in both groups: from 28.3% to 37% in the DM patients and from 28.1% to 38.34% in non-DM patients. Overall KCCQ-23 scores improved similarly in both groups, but longitudinal analyses found modestly higher gains in the T2DM group, 9.3 vs. 8.6 points (P = .07).

“The real reason I wanted to do this study is that I’m a huge fan of all the SGLT-2 inhibitors, and I’m very involved in those trials, and there is right now so much momentum behind SGLT-2 inhibitors that I don’t want people to forget that ARNI is still the base therapy for HF,” said Dr. Butler, chair of cardiovascular research and the department of medicine at the University of Mississippi in Jackson.

He noted that the size of the diabetes cohort in PROVE-HF “is a nonissue” for evaluating power of the post hoc analysis because it tracked key measures in the study population continuously at eight intervals over the 12 months.

The analysis further demonstrates the synergistic effects of ARNI and SGLT-2 inhibitors in patients with T2DM and HF that were also reported in the PARADIGM-HF study, Dr. Butler said.

“We have sort of moved on, saying that SGLT-2 inhibitors have a benefit on the heart, but the reverse is also true: ARNIs are still heart failure drugs, and we don’t think of them as diabetes drugs, but the PARADIGM-HF data showed that there was a substantial reduction in hemoglobin A1c in those who had diabetes,” he said.

The researchers noted that an absence of a control group may contribute to an overestimation of reverse cardiac remodeling in the T2DM patients, and that the PROVE-HF study wasn’t prospectively powered to delineate differences in how sac/val therapy affected patients with or without diabetes. “Future investigations seeking to evaluate differences by T2DM status after sacubitril/valsartan initiation may use our findings to plan prospective sample sizes,” the researchers wrote.

Dr. Butler disclosed financial relationships with Abbott, Amgen, Array, AstraZeneca, Bayer, Boehringer Ingelheim, CVRx, Eli Lilly, G3 Pharmaceutical, Impulse Dynamics, Innolife, Janssen, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Sequana, StealthPeptide and Vifor. Lead author Muhammad Shahzeb Khan, MD, MSc, a professor at the University of Mississippi, has no relevant financial relationships to disclose.

SOURCE: Kahn MS et al. JACC: HF. 2020 Dec 9. doi: 10.1016/j.jchf.2020.09.014.
 

The Diagnosis: Cutaneous B-cell Lymphoma  

Histopathology was suggestive of cutaneous B-cell lymphoma (Figure). Further immunohistochemical studies including Bcl-6 positivity and Bcl-2 negativity in the large atypical cells supported a diagnosis of primary cutaneous follicle center lymphoma (PCFCL). The designation of primary cutaneous B-cell lymphoma includes several different types of lymphoma, including marginal zone lymphoma, diffuse large B-cell lymphoma, and intravascular lymphoma. To be considered a primary cutaneous lymphoma, there must be evidence of the lymphoma in the skin without concomitant evidence of systemic involvement, as determined through a full staging workup. Primary cutaneous follicle center lymphoma is an indolent lymphoma that most commonly presents as solitary or grouped, pink to plum-colored papules, plaques, nodules, and tumors on the scalp, forehead, or back.¹ The lesions often are biopsied as suspected basal cell carcinomas or Merkel cell carcinomas (MCCs). Lesions on the face or scalp may easily evade diagnosis, as they initially may mimic rosacea or insect bites. Less common presentations include infiltrative lesions that cause rhinophymatous changes or scarring alopecia. Multifocal or disseminated lesions rarely can be observed. This case presentation is unique in its patchy appearance that clinically resembled angiosarcoma.² When identified and treated, the disease-specific 5-year survival rate for PCFCL is greater than 95%.³  

Merkel cell carcinoma was first described in 1972 and has been diagnosed with increasing frequency each year.⁴ It generally presents as an erythematous or violaceous, tender, indurated nodule on sun-exposed skin of the head or neck in elderly White men. However, other presentations have been reported, including papules, plaques, cystlike structures, pruritic tumors, pedunculated lesions, subcutaneous masses, and telangiectatic papules.⁵ Histopathologically, MCC is characterized by dermal nests and sheets of basaloid cells with finely granular salt and pepper-like chromatin. The histologic features can resemble other small blue cell tumors; therefore, the differential diagnosis can be broad.⁵ Immunohistochemistry that can confirm the diagnosis of MCC generally will be positive for cytokeratin 20 and neuroendocrine markers but negative for cytokeratin ⁷ and thyroid transcription factor ¹. Merkel cell carcinoma is an aggressive tumor with a high risk for local recurrence and distant metastasis that carries a generally poor prognosis, especially when there is evidence of metastatic disease at presentation.^5,6  

Rosacea can appear as telangiectatic patches, though generally not as one discrete patch limited to the forehead, as in our patient. Histologic features vary based on the age of the lesion and clinical variant. In early lesions there is a mild perivascular lymphoplasmacytic infiltrate within the dermis, while older lesions can have a mixed infiltrate crowded around vessels and adnexal structures. Granulomas often are seen near hair follicles and interspersed throughout the dermis with ectatic vessels and dermal edema.⁷  

Angiosarcoma is divided into 3 clinicopathological subtypes: idiopathic angiosarcoma of the head and neck, angiosarcoma in the setting of lymphedema, and postirradiation angiosarcoma.⁷ Idiopathic angiosarcoma most closely mimics PCFCL, as it can present as single or multifocal nodules, plaques, or patches. Histologically, the 3 groups appear similar with poorly circumscribed, infiltrative, dermal tumors. The neoplastic endothelial cells have large hyperchromatic nuclei that protrude into vascular lumens. The prognosis for idiopathic angiosarcoma of the head and neck is poor, with a 5-year survival rate of 15% to 34%, which often is due to delayed diagnosis.⁷ 

Pigmented purpuric dermatoses (PPDs) are chronic skin disorders characterized by purpura due to extravasation of blood from capillaries; the resulting hemosiderin deposition leads to pigmentation.⁷ There are various forms of PPD, which are classified into groups based on clinical appearance including Schamberg disease, purpura annularis telangiectodes of Majocchi, pigmented purpuric lichenoid dermatosis of Gougerot and Blum, lichen aureus, and others including eczematid and itching variants, which some consider to be distinct entities. Purpura annularis telangiectodes of Majocchi is the specific PPD that should be included in the clinical differential for PCFCL because it presents as annular patches with telangiectasias. Histologically, PPDs are characterized by a CD4⁺ lymphocytic infiltrate in the upper dermis with extravasated red blood cells and the presence of hemosiderin mostly within macrophages and a lack of true vasculitis. Clonality of the T cells has been shown, and there is some evidence that PPD may overlap with mycosis fungoides. However, this overlap mainly has been seen in patients with widespread lesions and would not apply to this case. In general, patients with PPD can be reassured of the benign process. In cases of widespread PPD, patients should be followed clinically to assess for progression to mycosis fungoides, though the likelihood is low.⁷  

Our patient underwent a full staging workup, which confirmed the diagnosis of PCFCL. He was treated with radiation to the forehead that resulted in clearance of the lesion. Approximately 2 years after the initial diagnosis, the patient was alive and well with no evidence of recurrence of PCFCL. 

In conclusion, it is imperative to identify unusual, macular, vascular-appearing patches, especially on the head and neck in older individuals. Because the clinical presentations of PCFCL, angiosarcoma, rosacea, MCC, and PPD can overlap with one another as well as with other entities, it is necessary to have a high level of suspicion and low threshold to biopsy these types of lesions, as outcomes can be drastically different. 

The Diagnosis: Cutaneous B-cell Lymphoma  

Histopathology was suggestive of cutaneous B-cell lymphoma (Figure). Further immunohistochemical studies including Bcl-6 positivity and Bcl-2 negativity in the large atypical cells supported a diagnosis of primary cutaneous follicle center lymphoma (PCFCL). The designation of primary cutaneous B-cell lymphoma includes several different types of lymphoma, including marginal zone lymphoma, diffuse large B-cell lymphoma, and intravascular lymphoma. To be considered a primary cutaneous lymphoma, there must be evidence of the lymphoma in the skin without concomitant evidence of systemic involvement, as determined through a full staging workup. Primary cutaneous follicle center lymphoma is an indolent lymphoma that most commonly presents as solitary or grouped, pink to plum-colored papules, plaques, nodules, and tumors on the scalp, forehead, or back.¹ The lesions often are biopsied as suspected basal cell carcinomas or Merkel cell carcinomas (MCCs). Lesions on the face or scalp may easily evade diagnosis, as they initially may mimic rosacea or insect bites. Less common presentations include infiltrative lesions that cause rhinophymatous changes or scarring alopecia. Multifocal or disseminated lesions rarely can be observed. This case presentation is unique in its patchy appearance that clinically resembled angiosarcoma.² When identified and treated, the disease-specific 5-year survival rate for PCFCL is greater than 95%.³  

Merkel cell carcinoma was first described in 1972 and has been diagnosed with increasing frequency each year.⁴ It generally presents as an erythematous or violaceous, tender, indurated nodule on sun-exposed skin of the head or neck in elderly White men. However, other presentations have been reported, including papules, plaques, cystlike structures, pruritic tumors, pedunculated lesions, subcutaneous masses, and telangiectatic papules.⁵ Histopathologically, MCC is characterized by dermal nests and sheets of basaloid cells with finely granular salt and pepper-like chromatin. The histologic features can resemble other small blue cell tumors; therefore, the differential diagnosis can be broad.⁵ Immunohistochemistry that can confirm the diagnosis of MCC generally will be positive for cytokeratin 20 and neuroendocrine markers but negative for cytokeratin ⁷ and thyroid transcription factor ¹. Merkel cell carcinoma is an aggressive tumor with a high risk for local recurrence and distant metastasis that carries a generally poor prognosis, especially when there is evidence of metastatic disease at presentation.^5,6  

Rosacea can appear as telangiectatic patches, though generally not as one discrete patch limited to the forehead, as in our patient. Histologic features vary based on the age of the lesion and clinical variant. In early lesions there is a mild perivascular lymphoplasmacytic infiltrate within the dermis, while older lesions can have a mixed infiltrate crowded around vessels and adnexal structures. Granulomas often are seen near hair follicles and interspersed throughout the dermis with ectatic vessels and dermal edema.⁷  

Angiosarcoma is divided into 3 clinicopathological subtypes: idiopathic angiosarcoma of the head and neck, angiosarcoma in the setting of lymphedema, and postirradiation angiosarcoma.⁷ Idiopathic angiosarcoma most closely mimics PCFCL, as it can present as single or multifocal nodules, plaques, or patches. Histologically, the 3 groups appear similar with poorly circumscribed, infiltrative, dermal tumors. The neoplastic endothelial cells have large hyperchromatic nuclei that protrude into vascular lumens. The prognosis for idiopathic angiosarcoma of the head and neck is poor, with a 5-year survival rate of 15% to 34%, which often is due to delayed diagnosis.⁷ 

Pigmented purpuric dermatoses (PPDs) are chronic skin disorders characterized by purpura due to extravasation of blood from capillaries; the resulting hemosiderin deposition leads to pigmentation.⁷ There are various forms of PPD, which are classified into groups based on clinical appearance including Schamberg disease, purpura annularis telangiectodes of Majocchi, pigmented purpuric lichenoid dermatosis of Gougerot and Blum, lichen aureus, and others including eczematid and itching variants, which some consider to be distinct entities. Purpura annularis telangiectodes of Majocchi is the specific PPD that should be included in the clinical differential for PCFCL because it presents as annular patches with telangiectasias. Histologically, PPDs are characterized by a CD4⁺ lymphocytic infiltrate in the upper dermis with extravasated red blood cells and the presence of hemosiderin mostly within macrophages and a lack of true vasculitis. Clonality of the T cells has been shown, and there is some evidence that PPD may overlap with mycosis fungoides. However, this overlap mainly has been seen in patients with widespread lesions and would not apply to this case. In general, patients with PPD can be reassured of the benign process. In cases of widespread PPD, patients should be followed clinically to assess for progression to mycosis fungoides, though the likelihood is low.⁷  

Our patient underwent a full staging workup, which confirmed the diagnosis of PCFCL. He was treated with radiation to the forehead that resulted in clearance of the lesion. Approximately 2 years after the initial diagnosis, the patient was alive and well with no evidence of recurrence of PCFCL. 

In conclusion, it is imperative to identify unusual, macular, vascular-appearing patches, especially on the head and neck in older individuals. Because the clinical presentations of PCFCL, angiosarcoma, rosacea, MCC, and PPD can overlap with one another as well as with other entities, it is necessary to have a high level of suspicion and low threshold to biopsy these types of lesions, as outcomes can be drastically different. 

The Diagnosis: Cutaneous B-cell Lymphoma  

Histopathology was suggestive of cutaneous B-cell lymphoma (Figure). Further immunohistochemical studies including Bcl-6 positivity and Bcl-2 negativity in the large atypical cells supported a diagnosis of primary cutaneous follicle center lymphoma (PCFCL). The designation of primary cutaneous B-cell lymphoma includes several different types of lymphoma, including marginal zone lymphoma, diffuse large B-cell lymphoma, and intravascular lymphoma. To be considered a primary cutaneous lymphoma, there must be evidence of the lymphoma in the skin without concomitant evidence of systemic involvement, as determined through a full staging workup. Primary cutaneous follicle center lymphoma is an indolent lymphoma that most commonly presents as solitary or grouped, pink to plum-colored papules, plaques, nodules, and tumors on the scalp, forehead, or back.¹ The lesions often are biopsied as suspected basal cell carcinomas or Merkel cell carcinomas (MCCs). Lesions on the face or scalp may easily evade diagnosis, as they initially may mimic rosacea or insect bites. Less common presentations include infiltrative lesions that cause rhinophymatous changes or scarring alopecia. Multifocal or disseminated lesions rarely can be observed. This case presentation is unique in its patchy appearance that clinically resembled angiosarcoma.² When identified and treated, the disease-specific 5-year survival rate for PCFCL is greater than 95%.³  

Merkel cell carcinoma was first described in 1972 and has been diagnosed with increasing frequency each year.⁴ It generally presents as an erythematous or violaceous, tender, indurated nodule on sun-exposed skin of the head or neck in elderly White men. However, other presentations have been reported, including papules, plaques, cystlike structures, pruritic tumors, pedunculated lesions, subcutaneous masses, and telangiectatic papules.⁵ Histopathologically, MCC is characterized by dermal nests and sheets of basaloid cells with finely granular salt and pepper-like chromatin. The histologic features can resemble other small blue cell tumors; therefore, the differential diagnosis can be broad.⁵ Immunohistochemistry that can confirm the diagnosis of MCC generally will be positive for cytokeratin 20 and neuroendocrine markers but negative for cytokeratin ⁷ and thyroid transcription factor ¹. Merkel cell carcinoma is an aggressive tumor with a high risk for local recurrence and distant metastasis that carries a generally poor prognosis, especially when there is evidence of metastatic disease at presentation.^5,6  

Rosacea can appear as telangiectatic patches, though generally not as one discrete patch limited to the forehead, as in our patient. Histologic features vary based on the age of the lesion and clinical variant. In early lesions there is a mild perivascular lymphoplasmacytic infiltrate within the dermis, while older lesions can have a mixed infiltrate crowded around vessels and adnexal structures. Granulomas often are seen near hair follicles and interspersed throughout the dermis with ectatic vessels and dermal edema.⁷  

Angiosarcoma is divided into 3 clinicopathological subtypes: idiopathic angiosarcoma of the head and neck, angiosarcoma in the setting of lymphedema, and postirradiation angiosarcoma.⁷ Idiopathic angiosarcoma most closely mimics PCFCL, as it can present as single or multifocal nodules, plaques, or patches. Histologically, the 3 groups appear similar with poorly circumscribed, infiltrative, dermal tumors. The neoplastic endothelial cells have large hyperchromatic nuclei that protrude into vascular lumens. The prognosis for idiopathic angiosarcoma of the head and neck is poor, with a 5-year survival rate of 15% to 34%, which often is due to delayed diagnosis.⁷ 

Pigmented purpuric dermatoses (PPDs) are chronic skin disorders characterized by purpura due to extravasation of blood from capillaries; the resulting hemosiderin deposition leads to pigmentation.⁷ There are various forms of PPD, which are classified into groups based on clinical appearance including Schamberg disease, purpura annularis telangiectodes of Majocchi, pigmented purpuric lichenoid dermatosis of Gougerot and Blum, lichen aureus, and others including eczematid and itching variants, which some consider to be distinct entities. Purpura annularis telangiectodes of Majocchi is the specific PPD that should be included in the clinical differential for PCFCL because it presents as annular patches with telangiectasias. Histologically, PPDs are characterized by a CD4⁺ lymphocytic infiltrate in the upper dermis with extravasated red blood cells and the presence of hemosiderin mostly within macrophages and a lack of true vasculitis. Clonality of the T cells has been shown, and there is some evidence that PPD may overlap with mycosis fungoides. However, this overlap mainly has been seen in patients with widespread lesions and would not apply to this case. In general, patients with PPD can be reassured of the benign process. In cases of widespread PPD, patients should be followed clinically to assess for progression to mycosis fungoides, though the likelihood is low.⁷  

Our patient underwent a full staging workup, which confirmed the diagnosis of PCFCL. He was treated with radiation to the forehead that resulted in clearance of the lesion. Approximately 2 years after the initial diagnosis, the patient was alive and well with no evidence of recurrence of PCFCL. 

In conclusion, it is imperative to identify unusual, macular, vascular-appearing patches, especially on the head and neck in older individuals. Because the clinical presentations of PCFCL, angiosarcoma, rosacea, MCC, and PPD can overlap with one another as well as with other entities, it is necessary to have a high level of suspicion and low threshold to biopsy these types of lesions, as outcomes can be drastically different. 

The Food and Drug Administration has clarified its guidance on administration of the Pfizer/BioNTech COVID-19 vaccine, stating that it is safe for people with any history of allergies, but not for those who might have a known history of severe allergic reaction to any component of the vaccine.

The warning is included in the FDA’s information sheet for health care providers, but questions are arising as to whether the vaccine – which was authorized for emergency use by the FDA on Friday – should not be given to anyone with a history of allergies.

Sara Oliver, MD, an epidemic intelligence service officer with the Centers for Disease Control and Prevention reported at a Dec. 11 meeting of the agency’s Advisory Committee on Immunization Practices that two U.K. health care workers with a history of significant allergic reactions had a reaction to the Pfizer vaccine. A third health care worker with no history of allergies developed tachycardia, Dr. Oliver said.

“I want to reassure the public that although there were these few reactions in Great Britain, these were not seen in the larger clinical trial datasets,” said Peter Marks, MD, PhD, director of the Center for Biologics Evaluation and Research at the FDA, during a press briefing on Dec. 12.

The Pfizer vaccine “is one that we’re comfortable giving to patients who have had other allergic reactions besides those other than severe allergic reactions to a vaccine or one of its components,” he said.

Dr. Marks suggested that individuals let their physicians know about any history of allergic reactions. He also noted that the federal government will be supplying vaccine administration sites, at least initially, with epinephrine, diphenhydramine, hydrocortisone, and other medications needed to manage allergic reactions.

The FDA is going to monitor side effects such as allergic reactions very closely, “but I think we still need to learn more and that’s why we’re going to be taking precautions. We may have to modify things as we move forward,” said Dr. Marks.

Dr. Oliver said that on Dec. 12 the CDC convened an external panel with experience in vaccine safety, immunology, and allergies “to collate expert knowledge regarding possible cases,” and that the FDA is getting more data from U.K. regulatory authorities.
 

Pregnancy concerns

Agency officials had little to say, however, about the safety or efficacy of the vaccine for pregnant or breastfeeding women.

The FDA’s information to health care professionals noted that “available data on Pfizer-BioNTech COVID-19 vaccine administered to pregnant women are insufficient to inform vaccine-associated risks in pregnancy.”

Additionally, the agency stated, “data are not available to assess the effects of Pfizer-BioNTech COVID-19 vaccine on the breastfed infant or on milk production/excretion.”

Dr. Marks said that, for pregnant women and people who are immunocompromised, “it will be something that providers will need to consider on an individual basis.” He suggested that individuals consult with physicians to weigh the potential benefits and potential risks.

“Certainly, COVID-19 in a pregnant woman is not a good thing,” Dr. Marks said.

An individual might decide to go ahead with vaccination. “But that’s not something we’re recommending, that’s something we’re leaving up to the individual,” he said.

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

The Food and Drug Administration has clarified its guidance on administration of the Pfizer/BioNTech COVID-19 vaccine, stating that it is safe for people with any history of allergies, but not for those who might have a known history of severe allergic reaction to any component of the vaccine.

The warning is included in the FDA’s information sheet for health care providers, but questions are arising as to whether the vaccine – which was authorized for emergency use by the FDA on Friday – should not be given to anyone with a history of allergies.

Sara Oliver, MD, an epidemic intelligence service officer with the Centers for Disease Control and Prevention reported at a Dec. 11 meeting of the agency’s Advisory Committee on Immunization Practices that two U.K. health care workers with a history of significant allergic reactions had a reaction to the Pfizer vaccine. A third health care worker with no history of allergies developed tachycardia, Dr. Oliver said.

“I want to reassure the public that although there were these few reactions in Great Britain, these were not seen in the larger clinical trial datasets,” said Peter Marks, MD, PhD, director of the Center for Biologics Evaluation and Research at the FDA, during a press briefing on Dec. 12.

The Pfizer vaccine “is one that we’re comfortable giving to patients who have had other allergic reactions besides those other than severe allergic reactions to a vaccine or one of its components,” he said.

Dr. Marks suggested that individuals let their physicians know about any history of allergic reactions. He also noted that the federal government will be supplying vaccine administration sites, at least initially, with epinephrine, diphenhydramine, hydrocortisone, and other medications needed to manage allergic reactions.

The FDA is going to monitor side effects such as allergic reactions very closely, “but I think we still need to learn more and that’s why we’re going to be taking precautions. We may have to modify things as we move forward,” said Dr. Marks.

Dr. Oliver said that on Dec. 12 the CDC convened an external panel with experience in vaccine safety, immunology, and allergies “to collate expert knowledge regarding possible cases,” and that the FDA is getting more data from U.K. regulatory authorities.
 

Pregnancy concerns

Agency officials had little to say, however, about the safety or efficacy of the vaccine for pregnant or breastfeeding women.

The FDA’s information to health care professionals noted that “available data on Pfizer-BioNTech COVID-19 vaccine administered to pregnant women are insufficient to inform vaccine-associated risks in pregnancy.”

Additionally, the agency stated, “data are not available to assess the effects of Pfizer-BioNTech COVID-19 vaccine on the breastfed infant or on milk production/excretion.”

Dr. Marks said that, for pregnant women and people who are immunocompromised, “it will be something that providers will need to consider on an individual basis.” He suggested that individuals consult with physicians to weigh the potential benefits and potential risks.

“Certainly, COVID-19 in a pregnant woman is not a good thing,” Dr. Marks said.

An individual might decide to go ahead with vaccination. “But that’s not something we’re recommending, that’s something we’re leaving up to the individual,” he said.

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

The Food and Drug Administration has clarified its guidance on administration of the Pfizer/BioNTech COVID-19 vaccine, stating that it is safe for people with any history of allergies, but not for those who might have a known history of severe allergic reaction to any component of the vaccine.

The warning is included in the FDA’s information sheet for health care providers, but questions are arising as to whether the vaccine – which was authorized for emergency use by the FDA on Friday – should not be given to anyone with a history of allergies.

Sara Oliver, MD, an epidemic intelligence service officer with the Centers for Disease Control and Prevention reported at a Dec. 11 meeting of the agency’s Advisory Committee on Immunization Practices that two U.K. health care workers with a history of significant allergic reactions had a reaction to the Pfizer vaccine. A third health care worker with no history of allergies developed tachycardia, Dr. Oliver said.

“I want to reassure the public that although there were these few reactions in Great Britain, these were not seen in the larger clinical trial datasets,” said Peter Marks, MD, PhD, director of the Center for Biologics Evaluation and Research at the FDA, during a press briefing on Dec. 12.

The Pfizer vaccine “is one that we’re comfortable giving to patients who have had other allergic reactions besides those other than severe allergic reactions to a vaccine or one of its components,” he said.

Dr. Marks suggested that individuals let their physicians know about any history of allergic reactions. He also noted that the federal government will be supplying vaccine administration sites, at least initially, with epinephrine, diphenhydramine, hydrocortisone, and other medications needed to manage allergic reactions.

The FDA is going to monitor side effects such as allergic reactions very closely, “but I think we still need to learn more and that’s why we’re going to be taking precautions. We may have to modify things as we move forward,” said Dr. Marks.

Dr. Oliver said that on Dec. 12 the CDC convened an external panel with experience in vaccine safety, immunology, and allergies “to collate expert knowledge regarding possible cases,” and that the FDA is getting more data from U.K. regulatory authorities.
 

Pregnancy concerns

Agency officials had little to say, however, about the safety or efficacy of the vaccine for pregnant or breastfeeding women.

The FDA’s information to health care professionals noted that “available data on Pfizer-BioNTech COVID-19 vaccine administered to pregnant women are insufficient to inform vaccine-associated risks in pregnancy.”

Additionally, the agency stated, “data are not available to assess the effects of Pfizer-BioNTech COVID-19 vaccine on the breastfed infant or on milk production/excretion.”

Dr. Marks said that, for pregnant women and people who are immunocompromised, “it will be something that providers will need to consider on an individual basis.” He suggested that individuals consult with physicians to weigh the potential benefits and potential risks.

“Certainly, COVID-19 in a pregnant woman is not a good thing,” Dr. Marks said.

An individual might decide to go ahead with vaccination. “But that’s not something we’re recommending, that’s something we’re leaving up to the individual,” he said.

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

In mid-November, Pfizer/BioNTech were the first with surprising positive protection interim data for their coronavirus vaccine, BNT162b2. A week later, Moderna released interim efficacy results showing its coronavirus vaccine, mRNA-1273, also protected patients from developing SARS-CoV-2 infections. Both studies included mostly healthy adults. A diverse ethnic and racial vaccinated population was included. A reasonable number of persons aged over 65 years, and persons with stable compromising medical conditions were included. Adolescents aged 16 years and over were included. Younger adolescents have been vaccinated or such studies are in the planning or early implementation stage as 2020 came to a close.

These are new and revolutionary vaccines, although the ability to inject mRNA into animals dates back to 1990, technological advances today make it a reality.¹ Traditional vaccines typically involve injection with antigens such as purified proteins or polysaccharides or inactivated/attenuated viruses. mRNA vaccines work differently. They do not contain antigens. Instead, they contain a blueprint for the antigen in the form of genetic material, mRNA. In the case of Pfizer’s and Moderna’s vaccines, the mRNA provides the genetic information to synthesize the spike protein that the SARS-CoV-2 virus uses to attach to and infect human cells. Each type of vaccine is packaged in proprietary lipid nanoparticles to protect the mRNA from rapid degradation, and the nanoparticles serve as an adjuvant to attract immune cells to the site of injection. (The properties of the respective lipid nanoparticle packaging may be the factor that impacts storage requirements discussed below.) When injected into muscle (myocyte), the lipid nanoparticles containing the mRNA inside are taken into muscle cells, where the cytoplasmic ribosomes detect and decode the mRNA resulting in the production of the spike protein antigen. It should be noted that the mRNA does not enter the nucleus, where the genetic information (DNA) of a cell is located, and can’t be reproduced or integrated into the DNA. The antigen is exported to the myocyte cell surface where the immune system’s antigen presenting cells detect the protein, ingest it, and take it to regional lymph nodes where interactions with T cells and B cells results in antibodies, T cell–mediated immunity, and generation of immune memory T cells and B cells. A particular subset of T cells – cytotoxic or killer T cells – destroy cells that have been infected by a pathogen. The SARS-CoV-2 mRNA vaccine from Pfizer was reported to induce powerful cytotoxic T-cell responses. Results for Moderna’s vaccine had not been reported at the time this column was prepared, but I anticipate the same positive results.

The revolutionary aspect of mRNA vaccines is the speed at which they can be designed and produced. This is why they lead the pack among the SARS-CoV-2 vaccine candidates and why the National Institute of Allergy and Infectious Diseases provided financial, technical, and/or clinical support. Indeed, once the amino acid sequence of a protein can be determined (a relatively easy task these days) it’s straightforward to synthesize mRNA in the lab – and it can be done incredibly fast. It is reported that the mRNA code for the vaccine by Moderna was made in 2 days and production development was completed in about 2 months.²

A 2007 World Health Organization report noted that infectious diseases are emerging at “the historically unprecedented rate of one per year.”³ Severe acute respiratory syndrome (SARS), Zika, Ebola, and avian and swine flu are recent examples. For most vaccines against emerging diseases, the challenge is about speed: developing and manufacturing a vaccine and getting it to persons who need it as quickly as possible. The current seasonal flu vaccine takes about 6 months to develop; it takes years for most of the traditional vaccines. That’s why once the infrastructure is in place, mRNA vaccines may prove to offer a big advantage as vaccines against emerging pathogens.
 

Early efficacy results have been surprising

Both vaccines were reported to produce about 95% efficacy in the final analysis. That was unexpectedly high because most vaccines for respiratory illness achieve efficacy of 60%-80%, e.g., flu vaccines. However, the efficacy rate may drop as time goes by because stimulation of short-term immunity would be in the earliest reported results.

Preventing SARS-CoV-2 cases is an important aspect of a coronavirus vaccine, but preventing severe illness is especially important considering that severe cases can result in prolonged intubation/artificial ventilation, prolonged disability and death. Pfizer/BioNTech had not released any data on the breakdown of severe cases as this column was finalized. In Moderna’s clinical trial, a secondary endpoint analyzed severe cases of COVID-19 and included 30 severe cases (as defined in the study protocol) in this analysis. All 30 cases occurred in the placebo group and none in the mRNA-1273–vaccinated group. In the Pfizer/BioNTech trial there were too few cases of severe illness to calculate efficacy.

Duration of immunity and need to revaccinate after initial primary vaccination are unknowns. Study of induction of B- and T-cell memory and levels of long-term protection have not been reported thus far.
 

Could mRNA COVID-19 vaccines be dangerous in the long term?

These will be the first-ever mRNA vaccines brought to market for humans. In order to receive Food and Drug Administration approval, the companies had to prove there were no immediate or short-term negative adverse effects from the vaccines. The companies reported that their independent data-monitoring committees hadn’t “reported any serious safety concerns.” However, fairly significant local reactions at the site of injection, fever, malaise, and fatigue occur with modest frequency following vaccinations with these products, reportedly in 10%-15% of vaccinees. Overall, the immediate reaction profile appears to be more severe than what occurs following seasonal influenza vaccination. When mass inoculations with these completely new and revolutionary vaccines begins, we will know virtually nothing about their long-term side effects. The possibility of systemic inflammatory responses that could lead to autoimmune conditions, persistence of the induced immunogen expression, development of autoreactive antibodies, and toxic effects of delivery components have been raised as theoretical concerns.^4-6 None of these theoretical risks have been observed to date and postmarketing phase 4 safety monitoring studies are in place from the Centers for Disease Control and Prevention and the companies that produce the vaccines. This is a risk public health authorities are willing to take because the risk to benefit calculation strongly favors taking theoretical risks, compared with clear benefits in preventing severe illnesses and death.

What about availability?

Pfizer/BioNTech expects to be able to produce up to 50 million vaccine doses in 2020 and up to 1.3 billion doses in 2021. Moderna expects to produce 20 million doses by the end of 2020, and 500 million to 1 billion doses in 2021. Storage requirements are inherent to the composition of the vaccines with their differing lipid nanoparticle delivery systems. Pfizer/BioNTech’s BNT162b2 has to be stored and transported at –80° C, which requires specialized freezers, which most doctors’ offices and pharmacies are unlikely to have on site, or dry ice containers. Once the vaccine is thawed, it can only remain in the refrigerator for 24 hours. Moderna’s mRNA-1273 will be much easier to distribute. The vaccine is stable in a standard freezer at –20° C for up to 6 months, in a refrigerator for up to 30 days within that 6-month shelf life, and at room temperature for up to 12 hours.

Timelines and testing other vaccines

Strong efficacy data from the two leading SARS-CoV-2 vaccines and emergency-use authorization Food and Drug Administration approval suggest the window for testing additional vaccine candidates in the United States could soon start to close. Of the more than 200 vaccines in development for SARS-CoV-2, at least 7 have a chance of gathering pivotal data before the front-runners become broadly available.

Testing diverse vaccine candidates, based on different technologies, is important for ensuring sufficient supply and could lead to products with tolerability and safety profiles that make them better suited, or more attractive, to subsets of the population. Different vaccine antigens and technologies also may yield different durations of protection, a question that will not be answered until long after the first products are on the market.

AstraZeneca enrolled about 23,000 subjects into its two phase 3 trials of AZD1222 (ChAdOx1 nCoV-19): a 40,000-subject U.S. trial and a 10,000-subject study in Brazil. AstraZeneca’s AZD1222, developed with the University of Oxford (England), uses a replication defective simian adenovirus vector called ChAdOx1.AZD1222 which encodes the SARS-CoV-2 spike protein. After injection, the viral vector delivers recombinant DNA that is decoded to mRNA, followed by mRNA decoding to become a protein. A serendipitous manufacturing error for the first 3,000 doses resulted in a half dose for those subjects before the error was discovered. Full doses were given to those subjects on second injections and those subjects showed 90% efficacy. Subjects who received 2 full doses showed 62% efficacy. A vaccine cannot be licensed based on 3,000 subjects so AstraZeneca has started a new phase 3 trial involving many more subjects to receive the combination lower dose followed by the full dose.

Johnson and Johnson (J&J) started its phase 3 trial evaluating a single dose of JNJ-78436735 in September. Phase 3 data may be reported by the end of2020. In November, J&J announced it was starting a second phase 3 trial to test two doses of the candidate. J&J’s JNJ-78436735 encodes the SARS-CoV-2 spike protein in an adenovirus serotype 26 (Ad26) vector, which is one of the two adenovirus vectors used in Sputnik V, the Russian vaccine reported to have 90% efficacy at an early interim analysis.

Sanofi and Novavax are both developing protein-based vaccines, a proven modality. Sanofi, in partnership with GlaxoSmithKline started a phase 1/2 clinical trial in the Fall 2020 with plans to commence a phase 3 trial in late December. Sanofi developed the protein ingredients and GlaxoSmithKline added one of their novel adjuvants. Novavax expects data from a U.K. phase 3 trial of NVX-CoV2373 in early 2021 and began a U.S. phase 3 study in late November. NVX-CoV2373 was created using Novavax’ recombinant nanoparticle technology to generate antigen derived from the coronavirus spike protein and contains Novavax’s patented saponin-based Matrix-M adjuvant.

Inovio Pharmaceuticals was gearing up to start a U.S. phase 2/3 trial of DNA vaccine INO-4800 by the end of 2020.

After Moderna and Pfizer-BioNTech, CureVac has the next most advanced mRNA vaccine. It was planned that a phase 2b/3 trial of CVnCoV would be conducted in Europe, Latin America, Africa, and Asia. Sanofi is also developing a mRNA vaccine as a second product in addition to its protein vaccine.

Vaxxinity planned to begin phase 3 testing of UB-612, a multitope peptide–based vaccine, in Brazil by the end of 2020.

However, emergency-use authorizations for the Pfizer and Moderna vaccines could hinder trial recruitment in at least two ways. Given the gravity of the pandemic, some stakeholders believe it would be ethical to unblind ongoing trials to give subjects the opportunity to switch to a vaccine proven to be effective. Even if unblinding doesn’t occur, as the two authorized vaccines start to become widely available, volunteering for clinical trials may become less attractive.
 

Dr. Pichichero is a specialist in pediatric infectious diseases, and director of the Research Institute at Rochester (N.Y.) General Hospital. He said he has no relevant financial disclosures. Email Dr. Pichichero at pdnews@mdedge.com.

References

1. Wolff JA et al. Science. 1990 Mar 23. doi: 10.1126/science.1690918.

2. Jackson LA et al. N Engl J Med. 2020 Nov 12. doi: 10.1056/NEJMoa2022483.

3. Prentice T and Reinders LT. The world health report 2007. (Geneva Switzerland: World Health Organization, 2007).

4. Peck KM and Lauring AS. J Virol. 2018. doi: 10.1128/JVI.01031-17.

5. Pepini T et al. J Immunol. 2017 May 15. doi: 10.4049/jimmunol.1601877.

6. Theofilopoulos AN et al. Annu Rev Immunol. 2005. doi: 10.1146/annurev.immunol.23.021704.115843.

In mid-November, Pfizer/BioNTech were the first with surprising positive protection interim data for their coronavirus vaccine, BNT162b2. A week later, Moderna released interim efficacy results showing its coronavirus vaccine, mRNA-1273, also protected patients from developing SARS-CoV-2 infections. Both studies included mostly healthy adults. A diverse ethnic and racial vaccinated population was included. A reasonable number of persons aged over 65 years, and persons with stable compromising medical conditions were included. Adolescents aged 16 years and over were included. Younger adolescents have been vaccinated or such studies are in the planning or early implementation stage as 2020 came to a close.

These are new and revolutionary vaccines, although the ability to inject mRNA into animals dates back to 1990, technological advances today make it a reality.¹ Traditional vaccines typically involve injection with antigens such as purified proteins or polysaccharides or inactivated/attenuated viruses. mRNA vaccines work differently. They do not contain antigens. Instead, they contain a blueprint for the antigen in the form of genetic material, mRNA. In the case of Pfizer’s and Moderna’s vaccines, the mRNA provides the genetic information to synthesize the spike protein that the SARS-CoV-2 virus uses to attach to and infect human cells. Each type of vaccine is packaged in proprietary lipid nanoparticles to protect the mRNA from rapid degradation, and the nanoparticles serve as an adjuvant to attract immune cells to the site of injection. (The properties of the respective lipid nanoparticle packaging may be the factor that impacts storage requirements discussed below.) When injected into muscle (myocyte), the lipid nanoparticles containing the mRNA inside are taken into muscle cells, where the cytoplasmic ribosomes detect and decode the mRNA resulting in the production of the spike protein antigen. It should be noted that the mRNA does not enter the nucleus, where the genetic information (DNA) of a cell is located, and can’t be reproduced or integrated into the DNA. The antigen is exported to the myocyte cell surface where the immune system’s antigen presenting cells detect the protein, ingest it, and take it to regional lymph nodes where interactions with T cells and B cells results in antibodies, T cell–mediated immunity, and generation of immune memory T cells and B cells. A particular subset of T cells – cytotoxic or killer T cells – destroy cells that have been infected by a pathogen. The SARS-CoV-2 mRNA vaccine from Pfizer was reported to induce powerful cytotoxic T-cell responses. Results for Moderna’s vaccine had not been reported at the time this column was prepared, but I anticipate the same positive results.

The revolutionary aspect of mRNA vaccines is the speed at which they can be designed and produced. This is why they lead the pack among the SARS-CoV-2 vaccine candidates and why the National Institute of Allergy and Infectious Diseases provided financial, technical, and/or clinical support. Indeed, once the amino acid sequence of a protein can be determined (a relatively easy task these days) it’s straightforward to synthesize mRNA in the lab – and it can be done incredibly fast. It is reported that the mRNA code for the vaccine by Moderna was made in 2 days and production development was completed in about 2 months.²

A 2007 World Health Organization report noted that infectious diseases are emerging at “the historically unprecedented rate of one per year.”³ Severe acute respiratory syndrome (SARS), Zika, Ebola, and avian and swine flu are recent examples. For most vaccines against emerging diseases, the challenge is about speed: developing and manufacturing a vaccine and getting it to persons who need it as quickly as possible. The current seasonal flu vaccine takes about 6 months to develop; it takes years for most of the traditional vaccines. That’s why once the infrastructure is in place, mRNA vaccines may prove to offer a big advantage as vaccines against emerging pathogens.
 

Early efficacy results have been surprising

Both vaccines were reported to produce about 95% efficacy in the final analysis. That was unexpectedly high because most vaccines for respiratory illness achieve efficacy of 60%-80%, e.g., flu vaccines. However, the efficacy rate may drop as time goes by because stimulation of short-term immunity would be in the earliest reported results.

Preventing SARS-CoV-2 cases is an important aspect of a coronavirus vaccine, but preventing severe illness is especially important considering that severe cases can result in prolonged intubation/artificial ventilation, prolonged disability and death. Pfizer/BioNTech had not released any data on the breakdown of severe cases as this column was finalized. In Moderna’s clinical trial, a secondary endpoint analyzed severe cases of COVID-19 and included 30 severe cases (as defined in the study protocol) in this analysis. All 30 cases occurred in the placebo group and none in the mRNA-1273–vaccinated group. In the Pfizer/BioNTech trial there were too few cases of severe illness to calculate efficacy.

Duration of immunity and need to revaccinate after initial primary vaccination are unknowns. Study of induction of B- and T-cell memory and levels of long-term protection have not been reported thus far.
 

Could mRNA COVID-19 vaccines be dangerous in the long term?

These will be the first-ever mRNA vaccines brought to market for humans. In order to receive Food and Drug Administration approval, the companies had to prove there were no immediate or short-term negative adverse effects from the vaccines. The companies reported that their independent data-monitoring committees hadn’t “reported any serious safety concerns.” However, fairly significant local reactions at the site of injection, fever, malaise, and fatigue occur with modest frequency following vaccinations with these products, reportedly in 10%-15% of vaccinees. Overall, the immediate reaction profile appears to be more severe than what occurs following seasonal influenza vaccination. When mass inoculations with these completely new and revolutionary vaccines begins, we will know virtually nothing about their long-term side effects. The possibility of systemic inflammatory responses that could lead to autoimmune conditions, persistence of the induced immunogen expression, development of autoreactive antibodies, and toxic effects of delivery components have been raised as theoretical concerns.^4-6 None of these theoretical risks have been observed to date and postmarketing phase 4 safety monitoring studies are in place from the Centers for Disease Control and Prevention and the companies that produce the vaccines. This is a risk public health authorities are willing to take because the risk to benefit calculation strongly favors taking theoretical risks, compared with clear benefits in preventing severe illnesses and death.

What about availability?

Pfizer/BioNTech expects to be able to produce up to 50 million vaccine doses in 2020 and up to 1.3 billion doses in 2021. Moderna expects to produce 20 million doses by the end of 2020, and 500 million to 1 billion doses in 2021. Storage requirements are inherent to the composition of the vaccines with their differing lipid nanoparticle delivery systems. Pfizer/BioNTech’s BNT162b2 has to be stored and transported at –80° C, which requires specialized freezers, which most doctors’ offices and pharmacies are unlikely to have on site, or dry ice containers. Once the vaccine is thawed, it can only remain in the refrigerator for 24 hours. Moderna’s mRNA-1273 will be much easier to distribute. The vaccine is stable in a standard freezer at –20° C for up to 6 months, in a refrigerator for up to 30 days within that 6-month shelf life, and at room temperature for up to 12 hours.

Timelines and testing other vaccines

Strong efficacy data from the two leading SARS-CoV-2 vaccines and emergency-use authorization Food and Drug Administration approval suggest the window for testing additional vaccine candidates in the United States could soon start to close. Of the more than 200 vaccines in development for SARS-CoV-2, at least 7 have a chance of gathering pivotal data before the front-runners become broadly available.

Testing diverse vaccine candidates, based on different technologies, is important for ensuring sufficient supply and could lead to products with tolerability and safety profiles that make them better suited, or more attractive, to subsets of the population. Different vaccine antigens and technologies also may yield different durations of protection, a question that will not be answered until long after the first products are on the market.

AstraZeneca enrolled about 23,000 subjects into its two phase 3 trials of AZD1222 (ChAdOx1 nCoV-19): a 40,000-subject U.S. trial and a 10,000-subject study in Brazil. AstraZeneca’s AZD1222, developed with the University of Oxford (England), uses a replication defective simian adenovirus vector called ChAdOx1.AZD1222 which encodes the SARS-CoV-2 spike protein. After injection, the viral vector delivers recombinant DNA that is decoded to mRNA, followed by mRNA decoding to become a protein. A serendipitous manufacturing error for the first 3,000 doses resulted in a half dose for those subjects before the error was discovered. Full doses were given to those subjects on second injections and those subjects showed 90% efficacy. Subjects who received 2 full doses showed 62% efficacy. A vaccine cannot be licensed based on 3,000 subjects so AstraZeneca has started a new phase 3 trial involving many more subjects to receive the combination lower dose followed by the full dose.

Johnson and Johnson (J&J) started its phase 3 trial evaluating a single dose of JNJ-78436735 in September. Phase 3 data may be reported by the end of2020. In November, J&J announced it was starting a second phase 3 trial to test two doses of the candidate. J&J’s JNJ-78436735 encodes the SARS-CoV-2 spike protein in an adenovirus serotype 26 (Ad26) vector, which is one of the two adenovirus vectors used in Sputnik V, the Russian vaccine reported to have 90% efficacy at an early interim analysis.

Sanofi and Novavax are both developing protein-based vaccines, a proven modality. Sanofi, in partnership with GlaxoSmithKline started a phase 1/2 clinical trial in the Fall 2020 with plans to commence a phase 3 trial in late December. Sanofi developed the protein ingredients and GlaxoSmithKline added one of their novel adjuvants. Novavax expects data from a U.K. phase 3 trial of NVX-CoV2373 in early 2021 and began a U.S. phase 3 study in late November. NVX-CoV2373 was created using Novavax’ recombinant nanoparticle technology to generate antigen derived from the coronavirus spike protein and contains Novavax’s patented saponin-based Matrix-M adjuvant.

Inovio Pharmaceuticals was gearing up to start a U.S. phase 2/3 trial of DNA vaccine INO-4800 by the end of 2020.

After Moderna and Pfizer-BioNTech, CureVac has the next most advanced mRNA vaccine. It was planned that a phase 2b/3 trial of CVnCoV would be conducted in Europe, Latin America, Africa, and Asia. Sanofi is also developing a mRNA vaccine as a second product in addition to its protein vaccine.

Vaxxinity planned to begin phase 3 testing of UB-612, a multitope peptide–based vaccine, in Brazil by the end of 2020.

However, emergency-use authorizations for the Pfizer and Moderna vaccines could hinder trial recruitment in at least two ways. Given the gravity of the pandemic, some stakeholders believe it would be ethical to unblind ongoing trials to give subjects the opportunity to switch to a vaccine proven to be effective. Even if unblinding doesn’t occur, as the two authorized vaccines start to become widely available, volunteering for clinical trials may become less attractive.
 

Dr. Pichichero is a specialist in pediatric infectious diseases, and director of the Research Institute at Rochester (N.Y.) General Hospital. He said he has no relevant financial disclosures. Email Dr. Pichichero at pdnews@mdedge.com.

References

1. Wolff JA et al. Science. 1990 Mar 23. doi: 10.1126/science.1690918.

2. Jackson LA et al. N Engl J Med. 2020 Nov 12. doi: 10.1056/NEJMoa2022483.

3. Prentice T and Reinders LT. The world health report 2007. (Geneva Switzerland: World Health Organization, 2007).

4. Peck KM and Lauring AS. J Virol. 2018. doi: 10.1128/JVI.01031-17.

5. Pepini T et al. J Immunol. 2017 May 15. doi: 10.4049/jimmunol.1601877.

6. Theofilopoulos AN et al. Annu Rev Immunol. 2005. doi: 10.1146/annurev.immunol.23.021704.115843.

In mid-November, Pfizer/BioNTech were the first with surprising positive protection interim data for their coronavirus vaccine, BNT162b2. A week later, Moderna released interim efficacy results showing its coronavirus vaccine, mRNA-1273, also protected patients from developing SARS-CoV-2 infections. Both studies included mostly healthy adults. A diverse ethnic and racial vaccinated population was included. A reasonable number of persons aged over 65 years, and persons with stable compromising medical conditions were included. Adolescents aged 16 years and over were included. Younger adolescents have been vaccinated or such studies are in the planning or early implementation stage as 2020 came to a close.

These are new and revolutionary vaccines, although the ability to inject mRNA into animals dates back to 1990, technological advances today make it a reality.¹ Traditional vaccines typically involve injection with antigens such as purified proteins or polysaccharides or inactivated/attenuated viruses. mRNA vaccines work differently. They do not contain antigens. Instead, they contain a blueprint for the antigen in the form of genetic material, mRNA. In the case of Pfizer’s and Moderna’s vaccines, the mRNA provides the genetic information to synthesize the spike protein that the SARS-CoV-2 virus uses to attach to and infect human cells. Each type of vaccine is packaged in proprietary lipid nanoparticles to protect the mRNA from rapid degradation, and the nanoparticles serve as an adjuvant to attract immune cells to the site of injection. (The properties of the respective lipid nanoparticle packaging may be the factor that impacts storage requirements discussed below.) When injected into muscle (myocyte), the lipid nanoparticles containing the mRNA inside are taken into muscle cells, where the cytoplasmic ribosomes detect and decode the mRNA resulting in the production of the spike protein antigen. It should be noted that the mRNA does not enter the nucleus, where the genetic information (DNA) of a cell is located, and can’t be reproduced or integrated into the DNA. The antigen is exported to the myocyte cell surface where the immune system’s antigen presenting cells detect the protein, ingest it, and take it to regional lymph nodes where interactions with T cells and B cells results in antibodies, T cell–mediated immunity, and generation of immune memory T cells and B cells. A particular subset of T cells – cytotoxic or killer T cells – destroy cells that have been infected by a pathogen. The SARS-CoV-2 mRNA vaccine from Pfizer was reported to induce powerful cytotoxic T-cell responses. Results for Moderna’s vaccine had not been reported at the time this column was prepared, but I anticipate the same positive results.

The revolutionary aspect of mRNA vaccines is the speed at which they can be designed and produced. This is why they lead the pack among the SARS-CoV-2 vaccine candidates and why the National Institute of Allergy and Infectious Diseases provided financial, technical, and/or clinical support. Indeed, once the amino acid sequence of a protein can be determined (a relatively easy task these days) it’s straightforward to synthesize mRNA in the lab – and it can be done incredibly fast. It is reported that the mRNA code for the vaccine by Moderna was made in 2 days and production development was completed in about 2 months.²

A 2007 World Health Organization report noted that infectious diseases are emerging at “the historically unprecedented rate of one per year.”³ Severe acute respiratory syndrome (SARS), Zika, Ebola, and avian and swine flu are recent examples. For most vaccines against emerging diseases, the challenge is about speed: developing and manufacturing a vaccine and getting it to persons who need it as quickly as possible. The current seasonal flu vaccine takes about 6 months to develop; it takes years for most of the traditional vaccines. That’s why once the infrastructure is in place, mRNA vaccines may prove to offer a big advantage as vaccines against emerging pathogens.
 

Early efficacy results have been surprising

Both vaccines were reported to produce about 95% efficacy in the final analysis. That was unexpectedly high because most vaccines for respiratory illness achieve efficacy of 60%-80%, e.g., flu vaccines. However, the efficacy rate may drop as time goes by because stimulation of short-term immunity would be in the earliest reported results.

Preventing SARS-CoV-2 cases is an important aspect of a coronavirus vaccine, but preventing severe illness is especially important considering that severe cases can result in prolonged intubation/artificial ventilation, prolonged disability and death. Pfizer/BioNTech had not released any data on the breakdown of severe cases as this column was finalized. In Moderna’s clinical trial, a secondary endpoint analyzed severe cases of COVID-19 and included 30 severe cases (as defined in the study protocol) in this analysis. All 30 cases occurred in the placebo group and none in the mRNA-1273–vaccinated group. In the Pfizer/BioNTech trial there were too few cases of severe illness to calculate efficacy.

Duration of immunity and need to revaccinate after initial primary vaccination are unknowns. Study of induction of B- and T-cell memory and levels of long-term protection have not been reported thus far.
 

Could mRNA COVID-19 vaccines be dangerous in the long term?

These will be the first-ever mRNA vaccines brought to market for humans. In order to receive Food and Drug Administration approval, the companies had to prove there were no immediate or short-term negative adverse effects from the vaccines. The companies reported that their independent data-monitoring committees hadn’t “reported any serious safety concerns.” However, fairly significant local reactions at the site of injection, fever, malaise, and fatigue occur with modest frequency following vaccinations with these products, reportedly in 10%-15% of vaccinees. Overall, the immediate reaction profile appears to be more severe than what occurs following seasonal influenza vaccination. When mass inoculations with these completely new and revolutionary vaccines begins, we will know virtually nothing about their long-term side effects. The possibility of systemic inflammatory responses that could lead to autoimmune conditions, persistence of the induced immunogen expression, development of autoreactive antibodies, and toxic effects of delivery components have been raised as theoretical concerns.^4-6 None of these theoretical risks have been observed to date and postmarketing phase 4 safety monitoring studies are in place from the Centers for Disease Control and Prevention and the companies that produce the vaccines. This is a risk public health authorities are willing to take because the risk to benefit calculation strongly favors taking theoretical risks, compared with clear benefits in preventing severe illnesses and death.

What about availability?

Pfizer/BioNTech expects to be able to produce up to 50 million vaccine doses in 2020 and up to 1.3 billion doses in 2021. Moderna expects to produce 20 million doses by the end of 2020, and 500 million to 1 billion doses in 2021. Storage requirements are inherent to the composition of the vaccines with their differing lipid nanoparticle delivery systems. Pfizer/BioNTech’s BNT162b2 has to be stored and transported at –80° C, which requires specialized freezers, which most doctors’ offices and pharmacies are unlikely to have on site, or dry ice containers. Once the vaccine is thawed, it can only remain in the refrigerator for 24 hours. Moderna’s mRNA-1273 will be much easier to distribute. The vaccine is stable in a standard freezer at –20° C for up to 6 months, in a refrigerator for up to 30 days within that 6-month shelf life, and at room temperature for up to 12 hours.

Timelines and testing other vaccines

Strong efficacy data from the two leading SARS-CoV-2 vaccines and emergency-use authorization Food and Drug Administration approval suggest the window for testing additional vaccine candidates in the United States could soon start to close. Of the more than 200 vaccines in development for SARS-CoV-2, at least 7 have a chance of gathering pivotal data before the front-runners become broadly available.

Testing diverse vaccine candidates, based on different technologies, is important for ensuring sufficient supply and could lead to products with tolerability and safety profiles that make them better suited, or more attractive, to subsets of the population. Different vaccine antigens and technologies also may yield different durations of protection, a question that will not be answered until long after the first products are on the market.

AstraZeneca enrolled about 23,000 subjects into its two phase 3 trials of AZD1222 (ChAdOx1 nCoV-19): a 40,000-subject U.S. trial and a 10,000-subject study in Brazil. AstraZeneca’s AZD1222, developed with the University of Oxford (England), uses a replication defective simian adenovirus vector called ChAdOx1.AZD1222 which encodes the SARS-CoV-2 spike protein. After injection, the viral vector delivers recombinant DNA that is decoded to mRNA, followed by mRNA decoding to become a protein. A serendipitous manufacturing error for the first 3,000 doses resulted in a half dose for those subjects before the error was discovered. Full doses were given to those subjects on second injections and those subjects showed 90% efficacy. Subjects who received 2 full doses showed 62% efficacy. A vaccine cannot be licensed based on 3,000 subjects so AstraZeneca has started a new phase 3 trial involving many more subjects to receive the combination lower dose followed by the full dose.

Johnson and Johnson (J&J) started its phase 3 trial evaluating a single dose of JNJ-78436735 in September. Phase 3 data may be reported by the end of2020. In November, J&J announced it was starting a second phase 3 trial to test two doses of the candidate. J&J’s JNJ-78436735 encodes the SARS-CoV-2 spike protein in an adenovirus serotype 26 (Ad26) vector, which is one of the two adenovirus vectors used in Sputnik V, the Russian vaccine reported to have 90% efficacy at an early interim analysis.

Sanofi and Novavax are both developing protein-based vaccines, a proven modality. Sanofi, in partnership with GlaxoSmithKline started a phase 1/2 clinical trial in the Fall 2020 with plans to commence a phase 3 trial in late December. Sanofi developed the protein ingredients and GlaxoSmithKline added one of their novel adjuvants. Novavax expects data from a U.K. phase 3 trial of NVX-CoV2373 in early 2021 and began a U.S. phase 3 study in late November. NVX-CoV2373 was created using Novavax’ recombinant nanoparticle technology to generate antigen derived from the coronavirus spike protein and contains Novavax’s patented saponin-based Matrix-M adjuvant.

Inovio Pharmaceuticals was gearing up to start a U.S. phase 2/3 trial of DNA vaccine INO-4800 by the end of 2020.

After Moderna and Pfizer-BioNTech, CureVac has the next most advanced mRNA vaccine. It was planned that a phase 2b/3 trial of CVnCoV would be conducted in Europe, Latin America, Africa, and Asia. Sanofi is also developing a mRNA vaccine as a second product in addition to its protein vaccine.

Vaxxinity planned to begin phase 3 testing of UB-612, a multitope peptide–based vaccine, in Brazil by the end of 2020.

However, emergency-use authorizations for the Pfizer and Moderna vaccines could hinder trial recruitment in at least two ways. Given the gravity of the pandemic, some stakeholders believe it would be ethical to unblind ongoing trials to give subjects the opportunity to switch to a vaccine proven to be effective. Even if unblinding doesn’t occur, as the two authorized vaccines start to become widely available, volunteering for clinical trials may become less attractive.
 

Dr. Pichichero is a specialist in pediatric infectious diseases, and director of the Research Institute at Rochester (N.Y.) General Hospital. He said he has no relevant financial disclosures. Email Dr. Pichichero at pdnews@mdedge.com.

References

1. Wolff JA et al. Science. 1990 Mar 23. doi: 10.1126/science.1690918.

2. Jackson LA et al. N Engl J Med. 2020 Nov 12. doi: 10.1056/NEJMoa2022483.

3. Prentice T and Reinders LT. The world health report 2007. (Geneva Switzerland: World Health Organization, 2007).

4. Peck KM and Lauring AS. J Virol. 2018. doi: 10.1128/JVI.01031-17.

5. Pepini T et al. J Immunol. 2017 May 15. doi: 10.4049/jimmunol.1601877.

6. Theofilopoulos AN et al. Annu Rev Immunol. 2005. doi: 10.1146/annurev.immunol.23.021704.115843.

Dermatologists frequently learn about skin conditions that are directly linked to diet. For example, we know that nutritional deficiencies can impact the hair, skin, and nails, and that celiac disease manifests with dermatitis herpetiformis of the skin. Patients commonly ask their dermatologists about the impact of diet on their skin. There are many outdated myths, but research on the subject is increasingly demonstrating important associations. Dermatologists must become familiar with the data on this topic so that we can provide informed counseling for our patients. This article reviews the current literature on associations between diet and 3 common cutaneous conditions—acne, psoriasis, and atopic dermatitis [AD]—and provides tips on how to best address our patients’ questions on this topic.

Acne

Studies increasingly support an association between a high glycemic diet (foods that lead to a spike in serum glucose) and acne; Bowe et al1 provided an excellent summary of the topic in 2010. This year, a large prospective cohort study of more than 24,000 participants demonstrated an association between adult acne and a diet high in milk, sugary beverages and foods, and fatty foods.2 In prospective cohort studies of more than 6000 adolescent girls and 4000 adolescent boys, Adebamowo et al3^,4 demonstrated a correlation between skim milk consumption and acne. Whey protein supplementation also has been implicated in acne flares.^5,6 The biological mechanism of the impact of high glycemic index foods and acne is believed to be mainly via activation of the insulinlike growth factor 1 (IGF-1) pathway, which promotes androgen synthesis and increases androgen bioavailability via decreased synthesis of sex hormone binding globulin.^1,2 Insulinlike growth factor 1 also stimulates its downstream target, mammalian target of rapamycin (mTOR), leading to activation of antiapoptotic and proliferation signaling, ultimately resulting in oxidative stress and inflammation causing acne.² Penso et al² noted that patients with IGF-1 deficiency (Laron syndrome) never develop acne unless treated with exogenous IGF-1, further supporting its role in acne formation.⁷ There currently is a paucity of randomized controlled trials assessing the impact of diet on acne.

Psoriasis 

The literature consistently shows that obesity is a predisposing factor for psoriasis. Additionally, weight gain may cause flares of existing psoriasis.⁸ Promotion of a healthy diet is an important factor in the management of obesity, alongside physical activity and, in some cases, medication and bariatric surgery.⁹ Patients with psoriasis who are overweight have been shown to experience improvement in their psoriasis after weight loss secondary to diet and exercise.^8,10 The joint American Academy of Dermatology and National Psoriasis Foundation guidelines recommend that dermatologists advise patients to practice a healthy lifestyle including a healthy diet and communicate with a patient’s primary care provider so they can be appropriately evaluated and treated for comorbidities including metabolic syndrome, diabetes, and hyperlipidemia.¹¹ In the NutriNet-Santé cohort study, investigators found an inverse correlation between psoriasis severity and adherence to a Mediterranean diet, which the authors conclude supports the hypothesis that this may slow the progression of psoriasis.¹² In a single meta-analysis, it was reported that patients with psoriasis have a 3-fold increased risk for celiac disease compared to the general population.1³ It remains unknown if these data are generalizable to the US population. Dermatologists should consider screening patients with psoriasis for celiac disease based on reported symptoms. When suspected, it is necessary to order appropriate serologies and consider referral to gastroenterology prior to recommending a gluten-free diet, as elimination of gluten prior to testing may lead to false-negative results.

Atopic Dermatitis

Patients and parents/guardians of children with AD often ask about the impact of diet on the condition. A small minority of patients may experience flares of AD due to ongoing, non–IgE-mediated allergen exposure.¹⁴ Diet as a trigger for flares should be suspected in children with persistent, moderate to severe AD. In these patients, allergen avoidance may lead to improvement but not resolution of AD. Allergens ordered from most common to least common are the following: eggs, milk, peanuts/tree nuts, shellfish, soy, and wheat.¹⁵ Additionally, it is important to note that children with AD are at higher risk for developing life-threatening, IgE-mediated food allergies compared to the general population (37% vs 6.8%).^16,17 The LEAP (Learning Early about Peanut Allergy) study led to a paradigm shift in prevention of peanut allergies in high-risk children (ie, those with severe AD and/or egg allergy), providing data to support the idea that early introduction of allergenic foods such as peanuts may prevent severe allergies.¹⁸ Further studies are necessary to clarify the population in which allergen testing and recommendations on food avoidance are warranted vs early introduction.¹⁹

Conclusion

Early data support the relationship between diet and many common dermatologic conditions, including acne, psoriasis, and AD. Dermatologists should be familiar with the evidence supporting the relationship between diet and various skin conditions to best answer patients’ questions and counsel as appropriate. It is important for dermatologists to continue to stay up-to-date on the literature on this subject as new data emerge. Knowledge about the relationship between diet and skin allows dermatologists to not only support our patients’ skin health but their overall health as well.

Dermatologists frequently learn about skin conditions that are directly linked to diet. For example, we know that nutritional deficiencies can impact the hair, skin, and nails, and that celiac disease manifests with dermatitis herpetiformis of the skin. Patients commonly ask their dermatologists about the impact of diet on their skin. There are many outdated myths, but research on the subject is increasingly demonstrating important associations. Dermatologists must become familiar with the data on this topic so that we can provide informed counseling for our patients. This article reviews the current literature on associations between diet and 3 common cutaneous conditions—acne, psoriasis, and atopic dermatitis [AD]—and provides tips on how to best address our patients’ questions on this topic.

Acne

Studies increasingly support an association between a high glycemic diet (foods that lead to a spike in serum glucose) and acne; Bowe et al1 provided an excellent summary of the topic in 2010. This year, a large prospective cohort study of more than 24,000 participants demonstrated an association between adult acne and a diet high in milk, sugary beverages and foods, and fatty foods.2 In prospective cohort studies of more than 6000 adolescent girls and 4000 adolescent boys, Adebamowo et al3^,4 demonstrated a correlation between skim milk consumption and acne. Whey protein supplementation also has been implicated in acne flares.^5,6 The biological mechanism of the impact of high glycemic index foods and acne is believed to be mainly via activation of the insulinlike growth factor 1 (IGF-1) pathway, which promotes androgen synthesis and increases androgen bioavailability via decreased synthesis of sex hormone binding globulin.^1,2 Insulinlike growth factor 1 also stimulates its downstream target, mammalian target of rapamycin (mTOR), leading to activation of antiapoptotic and proliferation signaling, ultimately resulting in oxidative stress and inflammation causing acne.² Penso et al² noted that patients with IGF-1 deficiency (Laron syndrome) never develop acne unless treated with exogenous IGF-1, further supporting its role in acne formation.⁷ There currently is a paucity of randomized controlled trials assessing the impact of diet on acne.

Psoriasis 

The literature consistently shows that obesity is a predisposing factor for psoriasis. Additionally, weight gain may cause flares of existing psoriasis.⁸ Promotion of a healthy diet is an important factor in the management of obesity, alongside physical activity and, in some cases, medication and bariatric surgery.⁹ Patients with psoriasis who are overweight have been shown to experience improvement in their psoriasis after weight loss secondary to diet and exercise.^8,10 The joint American Academy of Dermatology and National Psoriasis Foundation guidelines recommend that dermatologists advise patients to practice a healthy lifestyle including a healthy diet and communicate with a patient’s primary care provider so they can be appropriately evaluated and treated for comorbidities including metabolic syndrome, diabetes, and hyperlipidemia.¹¹ In the NutriNet-Santé cohort study, investigators found an inverse correlation between psoriasis severity and adherence to a Mediterranean diet, which the authors conclude supports the hypothesis that this may slow the progression of psoriasis.¹² In a single meta-analysis, it was reported that patients with psoriasis have a 3-fold increased risk for celiac disease compared to the general population.1³ It remains unknown if these data are generalizable to the US population. Dermatologists should consider screening patients with psoriasis for celiac disease based on reported symptoms. When suspected, it is necessary to order appropriate serologies and consider referral to gastroenterology prior to recommending a gluten-free diet, as elimination of gluten prior to testing may lead to false-negative results.

Atopic Dermatitis

Patients and parents/guardians of children with AD often ask about the impact of diet on the condition. A small minority of patients may experience flares of AD due to ongoing, non–IgE-mediated allergen exposure.¹⁴ Diet as a trigger for flares should be suspected in children with persistent, moderate to severe AD. In these patients, allergen avoidance may lead to improvement but not resolution of AD. Allergens ordered from most common to least common are the following: eggs, milk, peanuts/tree nuts, shellfish, soy, and wheat.¹⁵ Additionally, it is important to note that children with AD are at higher risk for developing life-threatening, IgE-mediated food allergies compared to the general population (37% vs 6.8%).^16,17 The LEAP (Learning Early about Peanut Allergy) study led to a paradigm shift in prevention of peanut allergies in high-risk children (ie, those with severe AD and/or egg allergy), providing data to support the idea that early introduction of allergenic foods such as peanuts may prevent severe allergies.¹⁸ Further studies are necessary to clarify the population in which allergen testing and recommendations on food avoidance are warranted vs early introduction.¹⁹

Conclusion

Early data support the relationship between diet and many common dermatologic conditions, including acne, psoriasis, and AD. Dermatologists should be familiar with the evidence supporting the relationship between diet and various skin conditions to best answer patients’ questions and counsel as appropriate. It is important for dermatologists to continue to stay up-to-date on the literature on this subject as new data emerge. Knowledge about the relationship between diet and skin allows dermatologists to not only support our patients’ skin health but their overall health as well.

Dermatologists frequently learn about skin conditions that are directly linked to diet. For example, we know that nutritional deficiencies can impact the hair, skin, and nails, and that celiac disease manifests with dermatitis herpetiformis of the skin. Patients commonly ask their dermatologists about the impact of diet on their skin. There are many outdated myths, but research on the subject is increasingly demonstrating important associations. Dermatologists must become familiar with the data on this topic so that we can provide informed counseling for our patients. This article reviews the current literature on associations between diet and 3 common cutaneous conditions—acne, psoriasis, and atopic dermatitis [AD]—and provides tips on how to best address our patients’ questions on this topic.

Acne

Studies increasingly support an association between a high glycemic diet (foods that lead to a spike in serum glucose) and acne; Bowe et al1 provided an excellent summary of the topic in 2010. This year, a large prospective cohort study of more than 24,000 participants demonstrated an association between adult acne and a diet high in milk, sugary beverages and foods, and fatty foods.2 In prospective cohort studies of more than 6000 adolescent girls and 4000 adolescent boys, Adebamowo et al3^,4 demonstrated a correlation between skim milk consumption and acne. Whey protein supplementation also has been implicated in acne flares.^5,6 The biological mechanism of the impact of high glycemic index foods and acne is believed to be mainly via activation of the insulinlike growth factor 1 (IGF-1) pathway, which promotes androgen synthesis and increases androgen bioavailability via decreased synthesis of sex hormone binding globulin.^1,2 Insulinlike growth factor 1 also stimulates its downstream target, mammalian target of rapamycin (mTOR), leading to activation of antiapoptotic and proliferation signaling, ultimately resulting in oxidative stress and inflammation causing acne.² Penso et al² noted that patients with IGF-1 deficiency (Laron syndrome) never develop acne unless treated with exogenous IGF-1, further supporting its role in acne formation.⁷ There currently is a paucity of randomized controlled trials assessing the impact of diet on acne.

Psoriasis 

The literature consistently shows that obesity is a predisposing factor for psoriasis. Additionally, weight gain may cause flares of existing psoriasis.⁸ Promotion of a healthy diet is an important factor in the management of obesity, alongside physical activity and, in some cases, medication and bariatric surgery.⁹ Patients with psoriasis who are overweight have been shown to experience improvement in their psoriasis after weight loss secondary to diet and exercise.^8,10 The joint American Academy of Dermatology and National Psoriasis Foundation guidelines recommend that dermatologists advise patients to practice a healthy lifestyle including a healthy diet and communicate with a patient’s primary care provider so they can be appropriately evaluated and treated for comorbidities including metabolic syndrome, diabetes, and hyperlipidemia.¹¹ In the NutriNet-Santé cohort study, investigators found an inverse correlation between psoriasis severity and adherence to a Mediterranean diet, which the authors conclude supports the hypothesis that this may slow the progression of psoriasis.¹² In a single meta-analysis, it was reported that patients with psoriasis have a 3-fold increased risk for celiac disease compared to the general population.1³ It remains unknown if these data are generalizable to the US population. Dermatologists should consider screening patients with psoriasis for celiac disease based on reported symptoms. When suspected, it is necessary to order appropriate serologies and consider referral to gastroenterology prior to recommending a gluten-free diet, as elimination of gluten prior to testing may lead to false-negative results.

Atopic Dermatitis

Patients and parents/guardians of children with AD often ask about the impact of diet on the condition. A small minority of patients may experience flares of AD due to ongoing, non–IgE-mediated allergen exposure.¹⁴ Diet as a trigger for flares should be suspected in children with persistent, moderate to severe AD. In these patients, allergen avoidance may lead to improvement but not resolution of AD. Allergens ordered from most common to least common are the following: eggs, milk, peanuts/tree nuts, shellfish, soy, and wheat.¹⁵ Additionally, it is important to note that children with AD are at higher risk for developing life-threatening, IgE-mediated food allergies compared to the general population (37% vs 6.8%).^16,17 The LEAP (Learning Early about Peanut Allergy) study led to a paradigm shift in prevention of peanut allergies in high-risk children (ie, those with severe AD and/or egg allergy), providing data to support the idea that early introduction of allergenic foods such as peanuts may prevent severe allergies.¹⁸ Further studies are necessary to clarify the population in which allergen testing and recommendations on food avoidance are warranted vs early introduction.¹⁹

Conclusion

Early data support the relationship between diet and many common dermatologic conditions, including acne, psoriasis, and AD. Dermatologists should be familiar with the evidence supporting the relationship between diet and various skin conditions to best answer patients’ questions and counsel as appropriate. It is important for dermatologists to continue to stay up-to-date on the literature on this subject as new data emerge. Knowledge about the relationship between diet and skin allows dermatologists to not only support our patients’ skin health but their overall health as well.