Dermatology News

The Department of Health & Human Services is proposing an overhaul of HIPAA that will make it easier to access patients’ personal health information, including the health records of patients with mental illness. The proposal would also do away with the requirement that all patients sign a notice of privacy practices.

The changes are contained in a 357-page proposed rule, which was unveiled by federal officials Dec. 10. Roger Severino, director of HHS’ Office for Civil Rights, said in a briefing that the sweeping proposal would empower patients, reduce the administrative burden for health care providers, and pave the way to better-coordinated care.

HHS estimated that the rule could save $3.2 billion over 5 years, but it’s not clear how much of that would accrue to clinical practices.

The most obvious cost-saving aspect for medical and dental practices is the proposal that practitioners would no longer have to provide and collect signed notifications of privacy practices.

“This has been a tremendous waste of time and effort and has caused massive confusion,” said Mr. Severino. He said some patients thought they were waiving privacy rights and that, in some cases, physicians refused to administer care unless patients signed the notices. “That was never the intent.”

Requiring that patients sign the form and that practices keep copies for 6 years is an “unnecessary burden,” said Mr. Severino. “We’ve lost whole forests from this regulation.”

Under the new proposal, health care providers would merely have to let patients know where to find their privacy policies.
 

Sharing mental health info

The rule would also ease the standard for sharing information about a patient who is in a mental health crisis, such as an exacerbation of a serious mental illness or a crisis related to a substance use disorder, including an overdose.

Currently, clinicians can choose to disclose protected health information – to a family member, a caregiver, a law enforcement official, a doctor, or an insurer – if they believe that doing so is advisable in their “professional judgment.” The rule proposes to ease that to a “good faith” belief that a disclosure would be in the best interest of the patient. In both instances, the patient can still object and block the disclosure.

As an example, HHS said that, in the case of a young adult who had experienced an overdose of opioids, a licensed health care professional could make the determination to “disclose relevant information to a parent who is involved in the patient’s treatment and who the young adult would expect, based on their relationship, to participate in or be involved with the patient’s recovery from the overdose.”

HHS is also proposing to let clinicians disclose information in cases in which an individual might be a threat to himself or others, provided the harm is “serious and reasonably foreseeable.”

Currently, information can only be disclosed if it appears there is a “serious and imminent” threat to health or safety. If an individual experienced suicidal ideation, for instance, a health care professional could notify family that the individual is at risk.
 

Fast, no-cost access

The rule also aims to make it easier for patients to get access to their own health care information quickly – within 15 days of a request – instead of the 30 days currently allowed, and sometimes at no cost.

The 30-day time frame is “a relic of a pre-Internet age that should be dispensed with,” said Mr. Severino.

Patients can also request that a treating physician get his or her records from a clinician who had previously treated the individual. The request would be fulfilled within 15 days, although extensions might be possible.

“That takes away the burden of coordination from the patient and puts it on those parties that are responsible for the actual provision of care and that are better positioned to do that coordination,” Mr. Severino said.

Health care professionals will also have to share with patients a fee schedule for records requests. However, if records are shared through a patient portal with view, download, and transmit capabilities, the provider can’t charge the patient for the time it took to upload the information into the system.

“We do not believe a patient’s personal medical record should be profit centers for providers,” Mr. Severino said.

Patients will be allowed to take photos with a smartphone of personal health information – such as an x-ray or sonogram – while receiving care.

The rule is open for public comment until mid-February. After that, it will become final in 180 days. The agency said it would not begin enforcement until 240 days after the final rule was published.

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

The Department of Health & Human Services is proposing an overhaul of HIPAA that will make it easier to access patients’ personal health information, including the health records of patients with mental illness. The proposal would also do away with the requirement that all patients sign a notice of privacy practices.

The changes are contained in a 357-page proposed rule, which was unveiled by federal officials Dec. 10. Roger Severino, director of HHS’ Office for Civil Rights, said in a briefing that the sweeping proposal would empower patients, reduce the administrative burden for health care providers, and pave the way to better-coordinated care.

HHS estimated that the rule could save $3.2 billion over 5 years, but it’s not clear how much of that would accrue to clinical practices.

The most obvious cost-saving aspect for medical and dental practices is the proposal that practitioners would no longer have to provide and collect signed notifications of privacy practices.

“This has been a tremendous waste of time and effort and has caused massive confusion,” said Mr. Severino. He said some patients thought they were waiving privacy rights and that, in some cases, physicians refused to administer care unless patients signed the notices. “That was never the intent.”

Requiring that patients sign the form and that practices keep copies for 6 years is an “unnecessary burden,” said Mr. Severino. “We’ve lost whole forests from this regulation.”

Under the new proposal, health care providers would merely have to let patients know where to find their privacy policies.
 

Sharing mental health info

The rule would also ease the standard for sharing information about a patient who is in a mental health crisis, such as an exacerbation of a serious mental illness or a crisis related to a substance use disorder, including an overdose.

Currently, clinicians can choose to disclose protected health information – to a family member, a caregiver, a law enforcement official, a doctor, or an insurer – if they believe that doing so is advisable in their “professional judgment.” The rule proposes to ease that to a “good faith” belief that a disclosure would be in the best interest of the patient. In both instances, the patient can still object and block the disclosure.

As an example, HHS said that, in the case of a young adult who had experienced an overdose of opioids, a licensed health care professional could make the determination to “disclose relevant information to a parent who is involved in the patient’s treatment and who the young adult would expect, based on their relationship, to participate in or be involved with the patient’s recovery from the overdose.”

HHS is also proposing to let clinicians disclose information in cases in which an individual might be a threat to himself or others, provided the harm is “serious and reasonably foreseeable.”

Currently, information can only be disclosed if it appears there is a “serious and imminent” threat to health or safety. If an individual experienced suicidal ideation, for instance, a health care professional could notify family that the individual is at risk.
 

Fast, no-cost access

The rule also aims to make it easier for patients to get access to their own health care information quickly – within 15 days of a request – instead of the 30 days currently allowed, and sometimes at no cost.

The 30-day time frame is “a relic of a pre-Internet age that should be dispensed with,” said Mr. Severino.

Patients can also request that a treating physician get his or her records from a clinician who had previously treated the individual. The request would be fulfilled within 15 days, although extensions might be possible.

“That takes away the burden of coordination from the patient and puts it on those parties that are responsible for the actual provision of care and that are better positioned to do that coordination,” Mr. Severino said.

Health care professionals will also have to share with patients a fee schedule for records requests. However, if records are shared through a patient portal with view, download, and transmit capabilities, the provider can’t charge the patient for the time it took to upload the information into the system.

“We do not believe a patient’s personal medical record should be profit centers for providers,” Mr. Severino said.

Patients will be allowed to take photos with a smartphone of personal health information – such as an x-ray or sonogram – while receiving care.

The rule is open for public comment until mid-February. After that, it will become final in 180 days. The agency said it would not begin enforcement until 240 days after the final rule was published.

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

The Department of Health & Human Services is proposing an overhaul of HIPAA that will make it easier to access patients’ personal health information, including the health records of patients with mental illness. The proposal would also do away with the requirement that all patients sign a notice of privacy practices.

The changes are contained in a 357-page proposed rule, which was unveiled by federal officials Dec. 10. Roger Severino, director of HHS’ Office for Civil Rights, said in a briefing that the sweeping proposal would empower patients, reduce the administrative burden for health care providers, and pave the way to better-coordinated care.

HHS estimated that the rule could save $3.2 billion over 5 years, but it’s not clear how much of that would accrue to clinical practices.

The most obvious cost-saving aspect for medical and dental practices is the proposal that practitioners would no longer have to provide and collect signed notifications of privacy practices.

“This has been a tremendous waste of time and effort and has caused massive confusion,” said Mr. Severino. He said some patients thought they were waiving privacy rights and that, in some cases, physicians refused to administer care unless patients signed the notices. “That was never the intent.”

Requiring that patients sign the form and that practices keep copies for 6 years is an “unnecessary burden,” said Mr. Severino. “We’ve lost whole forests from this regulation.”

Under the new proposal, health care providers would merely have to let patients know where to find their privacy policies.
 

Sharing mental health info

The rule would also ease the standard for sharing information about a patient who is in a mental health crisis, such as an exacerbation of a serious mental illness or a crisis related to a substance use disorder, including an overdose.

Currently, clinicians can choose to disclose protected health information – to a family member, a caregiver, a law enforcement official, a doctor, or an insurer – if they believe that doing so is advisable in their “professional judgment.” The rule proposes to ease that to a “good faith” belief that a disclosure would be in the best interest of the patient. In both instances, the patient can still object and block the disclosure.

As an example, HHS said that, in the case of a young adult who had experienced an overdose of opioids, a licensed health care professional could make the determination to “disclose relevant information to a parent who is involved in the patient’s treatment and who the young adult would expect, based on their relationship, to participate in or be involved with the patient’s recovery from the overdose.”

HHS is also proposing to let clinicians disclose information in cases in which an individual might be a threat to himself or others, provided the harm is “serious and reasonably foreseeable.”

Currently, information can only be disclosed if it appears there is a “serious and imminent” threat to health or safety. If an individual experienced suicidal ideation, for instance, a health care professional could notify family that the individual is at risk.
 

Fast, no-cost access

The rule also aims to make it easier for patients to get access to their own health care information quickly – within 15 days of a request – instead of the 30 days currently allowed, and sometimes at no cost.

The 30-day time frame is “a relic of a pre-Internet age that should be dispensed with,” said Mr. Severino.

Patients can also request that a treating physician get his or her records from a clinician who had previously treated the individual. The request would be fulfilled within 15 days, although extensions might be possible.

“That takes away the burden of coordination from the patient and puts it on those parties that are responsible for the actual provision of care and that are better positioned to do that coordination,” Mr. Severino said.

Health care professionals will also have to share with patients a fee schedule for records requests. However, if records are shared through a patient portal with view, download, and transmit capabilities, the provider can’t charge the patient for the time it took to upload the information into the system.

“We do not believe a patient’s personal medical record should be profit centers for providers,” Mr. Severino said.

Patients will be allowed to take photos with a smartphone of personal health information – such as an x-ray or sonogram – while receiving care.

The rule is open for public comment until mid-February. After that, it will become final in 180 days. The agency said it would not begin enforcement until 240 days after the final rule was published.

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

On close evaluation of the picture on her chest, she has pale macules and patches surrounded by erythematous ill-defined patches consistent with nevus anemicus. She also has several brown macules and light brown patches on the neck suggestive of café au lait macules. The findings of the picture raise the suspicion for neurofibromatosis, and it was recommended for her to be evaluated in person.

She comes several days later to the clinic. The caretaker, who is her aunt, reports she does not know much of the girl’s medical history as she recently moved from South America to live with her. The girl is a very nice and pleasant 8-year-old. She reports noticing the spots on her chest for about a year and that they seem to get a little itchier and more noticeable when she is hot or when she is running. She also reports increasing headaches for several months. She is being home schooled, and according to her aunt she is at par with her cousins who are about the same age. There is no history of seizures. She has had back surgery in the past. There is no history of hypertension. There is no family history of any genetic disorder or similar lesions.

On physical exam, her vital signs are normal, but her head circumference is over the 90th percentile. She is pleasant and interactive. On skin examination, she has slightly noticeable pale macules and patches on the chest and back that become more apparent after rubbing her skin. She has multiple light brown macules and oval patches on the chest, back, and neck. She has no axillary or inguinal freckling. She has scars on the back from her prior surgery.

As she was having worsening headaches, an MRI of the brain was ordered, which showed a left optic glioma. She was then referred to ophthalmology, neurology, and genetics.

Neurofibromatosis type 1 (NF1) is a common genetic autosomal dominant disorder cause by mutations on the NF1 gene on chromosome 17, which encodes for the protein neurofibromin. This protein works in the Ras-mitogen–activated protein kinase pathway as a negative regulator. Based on the National Institute of Health criteria, children need two or more of the following to be diagnosed with NF1: more than six café au lait macules larger than 5 mm in prepubescent children and 2.5 cm after puberty; axillary or inguinal freckling; two or more Lisch nodules; optic gliomas; two or more neurofibromas or one plexiform neurofibroma; or a first degree relative with a diagnosis of NF1. With these criteria, about 70% of the children can be diagnosed before the age of 1 year.¹

Nevus anemicus is an uncommon birthmark, sometimes overlooked, that is characterized by pale, hypopigmented, well-defined macules and patches that do not turn red after trauma or changes in temperature. Nevus anemicus is usually localized on the torso but can be seen on the face, neck, and extremities. These lesions are present in 1%-2% of the general population. They are thought to occur because of increased sensitivity of the affected blood vessels to catecholamines, which causes permanent vasoconstriction, which leads to hypopigmentation on the area.² These lesions are usually present at birth and have been described in patients with tuberous sclerosis, neurofibromatosis, and phakomatosis pigmentovascularis.

Recent studies of patients with neurofibromatosis and other RASopathies have noticed that nevus anemicus is present in about 8.8%-51% of the patients studied with a diagnosis NF1, compared with only 2% of the controls.^3,4 The studies failed to report any cases of nevus anemicus in patients with other RASopathies associated with café au lait macules. Bulteel and colleagues recently reported two cases of non-NF1 RASopathies also associated with nevus anemicus in a patient with Legius syndrome and a patient with Noonan syndrome with multiple lentigines.⁵ The nevus anemicus was reported to occur most commonly on the anterior chest and be multiple, as seen in our patient.

The authors of the published studies advocate for the introduction of nevus anemicus as part of the diagnostic criteria for NF1, especially because it can be an early finding seen in babies, which can aid in early diagnosis of NF1.

Dr. Matiz is a pediatric dermatologist at Southern California Permanente Medical Group, San Diego. She has no relevant financial disclosures. Email Dr. Matiz at [email protected].

References

1. Pediatrics. 2000 Mar. doi: 10.1542/peds.105.3.608.

2. Nevus Anemicus. StatPearls [Internet] (Treasure Island, Fla.: StatPearls Publishing; 2020 Jan).

3. J Am Acad Dermatol. 2013 Nov. doi: 10.1016/j.jaad.2013.06.039.

4. Pediatr Dermatol. 2015 May-Jun. doi: 10.1111/pde.12525.

5. JAAD Case Rep. 2018 Apr 5. doi: 10.1016/j.jdcr.2017.09.037.
 

On close evaluation of the picture on her chest, she has pale macules and patches surrounded by erythematous ill-defined patches consistent with nevus anemicus. She also has several brown macules and light brown patches on the neck suggestive of café au lait macules. The findings of the picture raise the suspicion for neurofibromatosis, and it was recommended for her to be evaluated in person.

She comes several days later to the clinic. The caretaker, who is her aunt, reports she does not know much of the girl’s medical history as she recently moved from South America to live with her. The girl is a very nice and pleasant 8-year-old. She reports noticing the spots on her chest for about a year and that they seem to get a little itchier and more noticeable when she is hot or when she is running. She also reports increasing headaches for several months. She is being home schooled, and according to her aunt she is at par with her cousins who are about the same age. There is no history of seizures. She has had back surgery in the past. There is no history of hypertension. There is no family history of any genetic disorder or similar lesions.

On physical exam, her vital signs are normal, but her head circumference is over the 90th percentile. She is pleasant and interactive. On skin examination, she has slightly noticeable pale macules and patches on the chest and back that become more apparent after rubbing her skin. She has multiple light brown macules and oval patches on the chest, back, and neck. She has no axillary or inguinal freckling. She has scars on the back from her prior surgery.

As she was having worsening headaches, an MRI of the brain was ordered, which showed a left optic glioma. She was then referred to ophthalmology, neurology, and genetics.

Neurofibromatosis type 1 (NF1) is a common genetic autosomal dominant disorder cause by mutations on the NF1 gene on chromosome 17, which encodes for the protein neurofibromin. This protein works in the Ras-mitogen–activated protein kinase pathway as a negative regulator. Based on the National Institute of Health criteria, children need two or more of the following to be diagnosed with NF1: more than six café au lait macules larger than 5 mm in prepubescent children and 2.5 cm after puberty; axillary or inguinal freckling; two or more Lisch nodules; optic gliomas; two or more neurofibromas or one plexiform neurofibroma; or a first degree relative with a diagnosis of NF1. With these criteria, about 70% of the children can be diagnosed before the age of 1 year.¹

Nevus anemicus is an uncommon birthmark, sometimes overlooked, that is characterized by pale, hypopigmented, well-defined macules and patches that do not turn red after trauma or changes in temperature. Nevus anemicus is usually localized on the torso but can be seen on the face, neck, and extremities. These lesions are present in 1%-2% of the general population. They are thought to occur because of increased sensitivity of the affected blood vessels to catecholamines, which causes permanent vasoconstriction, which leads to hypopigmentation on the area.² These lesions are usually present at birth and have been described in patients with tuberous sclerosis, neurofibromatosis, and phakomatosis pigmentovascularis.

Recent studies of patients with neurofibromatosis and other RASopathies have noticed that nevus anemicus is present in about 8.8%-51% of the patients studied with a diagnosis NF1, compared with only 2% of the controls.^3,4 The studies failed to report any cases of nevus anemicus in patients with other RASopathies associated with café au lait macules. Bulteel and colleagues recently reported two cases of non-NF1 RASopathies also associated with nevus anemicus in a patient with Legius syndrome and a patient with Noonan syndrome with multiple lentigines.⁵ The nevus anemicus was reported to occur most commonly on the anterior chest and be multiple, as seen in our patient.

The authors of the published studies advocate for the introduction of nevus anemicus as part of the diagnostic criteria for NF1, especially because it can be an early finding seen in babies, which can aid in early diagnosis of NF1.

Dr. Matiz is a pediatric dermatologist at Southern California Permanente Medical Group, San Diego. She has no relevant financial disclosures. Email Dr. Matiz at [email protected].

References

1. Pediatrics. 2000 Mar. doi: 10.1542/peds.105.3.608.

2. Nevus Anemicus. StatPearls [Internet] (Treasure Island, Fla.: StatPearls Publishing; 2020 Jan).

3. J Am Acad Dermatol. 2013 Nov. doi: 10.1016/j.jaad.2013.06.039.

4. Pediatr Dermatol. 2015 May-Jun. doi: 10.1111/pde.12525.

5. JAAD Case Rep. 2018 Apr 5. doi: 10.1016/j.jdcr.2017.09.037.
 

On close evaluation of the picture on her chest, she has pale macules and patches surrounded by erythematous ill-defined patches consistent with nevus anemicus. She also has several brown macules and light brown patches on the neck suggestive of café au lait macules. The findings of the picture raise the suspicion for neurofibromatosis, and it was recommended for her to be evaluated in person.

She comes several days later to the clinic. The caretaker, who is her aunt, reports she does not know much of the girl’s medical history as she recently moved from South America to live with her. The girl is a very nice and pleasant 8-year-old. She reports noticing the spots on her chest for about a year and that they seem to get a little itchier and more noticeable when she is hot or when she is running. She also reports increasing headaches for several months. She is being home schooled, and according to her aunt she is at par with her cousins who are about the same age. There is no history of seizures. She has had back surgery in the past. There is no history of hypertension. There is no family history of any genetic disorder or similar lesions.

On physical exam, her vital signs are normal, but her head circumference is over the 90th percentile. She is pleasant and interactive. On skin examination, she has slightly noticeable pale macules and patches on the chest and back that become more apparent after rubbing her skin. She has multiple light brown macules and oval patches on the chest, back, and neck. She has no axillary or inguinal freckling. She has scars on the back from her prior surgery.

As she was having worsening headaches, an MRI of the brain was ordered, which showed a left optic glioma. She was then referred to ophthalmology, neurology, and genetics.

Neurofibromatosis type 1 (NF1) is a common genetic autosomal dominant disorder cause by mutations on the NF1 gene on chromosome 17, which encodes for the protein neurofibromin. This protein works in the Ras-mitogen–activated protein kinase pathway as a negative regulator. Based on the National Institute of Health criteria, children need two or more of the following to be diagnosed with NF1: more than six café au lait macules larger than 5 mm in prepubescent children and 2.5 cm after puberty; axillary or inguinal freckling; two or more Lisch nodules; optic gliomas; two or more neurofibromas or one plexiform neurofibroma; or a first degree relative with a diagnosis of NF1. With these criteria, about 70% of the children can be diagnosed before the age of 1 year.¹

Nevus anemicus is an uncommon birthmark, sometimes overlooked, that is characterized by pale, hypopigmented, well-defined macules and patches that do not turn red after trauma or changes in temperature. Nevus anemicus is usually localized on the torso but can be seen on the face, neck, and extremities. These lesions are present in 1%-2% of the general population. They are thought to occur because of increased sensitivity of the affected blood vessels to catecholamines, which causes permanent vasoconstriction, which leads to hypopigmentation on the area.² These lesions are usually present at birth and have been described in patients with tuberous sclerosis, neurofibromatosis, and phakomatosis pigmentovascularis.

Recent studies of patients with neurofibromatosis and other RASopathies have noticed that nevus anemicus is present in about 8.8%-51% of the patients studied with a diagnosis NF1, compared with only 2% of the controls.^3,4 The studies failed to report any cases of nevus anemicus in patients with other RASopathies associated with café au lait macules. Bulteel and colleagues recently reported two cases of non-NF1 RASopathies also associated with nevus anemicus in a patient with Legius syndrome and a patient with Noonan syndrome with multiple lentigines.⁵ The nevus anemicus was reported to occur most commonly on the anterior chest and be multiple, as seen in our patient.

The authors of the published studies advocate for the introduction of nevus anemicus as part of the diagnostic criteria for NF1, especially because it can be an early finding seen in babies, which can aid in early diagnosis of NF1.

Dr. Matiz is a pediatric dermatologist at Southern California Permanente Medical Group, San Diego. She has no relevant financial disclosures. Email Dr. Matiz at [email protected].

References

1. Pediatrics. 2000 Mar. doi: 10.1542/peds.105.3.608.

2. Nevus Anemicus. StatPearls [Internet] (Treasure Island, Fla.: StatPearls Publishing; 2020 Jan).

3. J Am Acad Dermatol. 2013 Nov. doi: 10.1016/j.jaad.2013.06.039.

4. Pediatr Dermatol. 2015 May-Jun. doi: 10.1111/pde.12525.

5. JAAD Case Rep. 2018 Apr 5. doi: 10.1016/j.jdcr.2017.09.037.
 

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 [email protected]. 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 [email protected]. 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 [email protected]. They had no relevant disclosures.

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 [email protected].

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 [email protected].

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 [email protected].

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.

The Centers for Disease Control and Prevention (CDC) advisory committee recommended on December 12 the recently authorized Pfizer-BioNTech COVID-19 vaccine for people age 16 and over in the United States, stating they found it was safe and effective.

The agency said it will quickly issue guidance to clinicians so they can determine when and when not to give the vaccine, and to help them communicate the risks and benefits to patients.

CDC staff gave a preview of those clinical considerations at the agency’s Advisory Committee on Immunization Practices (ACIP) meeting on December 12 and said it would be holding calls with clinicians on December 13 and 14.

The CDC will also issue guidance December 13 on how organizations can handle the workforce problems that might arise as health care workers experience side effects from vaccination.

ACIP voted 11-0, with three recusals, to recommend use of the Pfizer-BioNTech mRNA vaccine in individuals 16 years or older according to the guidelines of the Food and Drug Administration’s (FDA’s) emergency use authorization issued December 11.

The panel also voted unanimously to include the vaccine in 2021 immunization schedules. All panel members said the recommendation should go hand-in-hand with ACIP’s previous recommendation on December 1 that allocation of the vaccine be phased-in, with health care workers and residents and staff of long-term care facilities in phase 1a.

Allergies, pregnant women?

ACIP panelists said clinicians need more guidance on whether to use the vaccine in pregnant or breastfeeding women, the immunocompromised, or those who have a history of allergies.

The FDA health care provider information sheet said there is not enough data to recommend vaccinating those women or the immunocompromised, and also advises against giving the vaccine to individuals who have a history of serious allergic reaction to any component of the vaccine.

Peter Marks, MD, PhD, director of the FDA’s Center for Biologic Evaluation and Research (CBER) clarified this in a briefing on December 12, noting that women who are pregnant or lactating can make the decision in consultation with their physician. And, he said, patients with any other history of allergy should be able to safely get the vaccine.

The CDC — in its soon-to-be-released guidance — will make the same recommendations. For any woman considering vaccination, she should consider the level of COVID-19 in the community, her personal risk of contracting the virus, the risks to her or her fetus of developing the disease, and the vaccine’s known side effects, Sarah Mbaeyi, MD, MPH, a medical officer at the agency, said during the panel meeting December 12.

She added that the CDC will also urge physicians to advise women to take acetaminophen if they develop a fever after vaccination — to protect the developing fetus from fever.

Sandra Fryhofer, MD, representing the American Medical Association, commended the CDC for these recommendations. But she also called on Pfizer, the FDA, and the CDC to make data from the developmental and reproductive toxicity (DART) studies public as soon as possible.

“We really need to put those results on warp speed and get them out there to give our physicians and pregnant women more information,” said Fryhofer, an adjunct associate professor of medicine at Emory University School of Medicine in Atlanta, Georgia.

The American College of Obstetricians and Gynecologists (ACOG) will also soon release guidance for vaccinating pregnant and breastfeeding women, said Linda Eckert, MD, FACOG, an ACOG representative on the panel.

ACOG and the CDC met the morning of December 12 to discuss risks and benefits with experts in immunology, placental pathology, and vaccine kinetics, she said.

“The overall complete consensus was that we don’t see biological plausibility at this time for placental transfer of the mRNA and that we see that direct fetal exposure or the possibility of fetal inflammatory response is extremely unlikely,” said Eckert, professor of obstetrics and gynecology at the University of Washington, Seattle. “Clearly we are waiting on the data.”

A Pfizer official told the ACIP panel that preliminary data “show no indication of either developmental or reproductive toxicity,” and that the company plans to send the final DART data to the FDA at the end of December.

On the potential for allergic reactions, the CDC concurred with the FDA that the vaccine should not be given to people with a history of serious reactions. The agency added that the category should include anyone who has had a reaction to any vaccine or injectable drug product because injectables may contain the same ingredients as the Pfizer vaccine, said Mbaeyi.

The CDC will also urge clinicians to observe patients with a history of anaphylaxis for 30 minutes after vaccination and all patients for at least 15 minutes afterward.

Should teens be a special population?

At least one ACIP panel member — Henry Bernstein, DO, MHCM, FAAP — said he was concerned that backing use of the vaccine in 16- and 17-year-olds was a leap of faith, given that Pfizer had extremely limited data on this cohort.

Bernstein, professor of pediatrics at the Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York, also said that systemic reactions were more common in that age group.

He argued for making the 16- and 17-year-olds a “special population” that would get specific attention and guidance for vaccination from the federal agencies and professional societies.

Bernstein said he did not want to sow any more doubts in parents’ minds about vaccination, noting that hesitancy was a growing concern. “A successful pediatric vaccination program depends on creating and sustaining parental confidence in both the safety and effectiveness of this vaccine,” he said.

Many panelists, however, noted that there has been no evidence to suggest that the vaccine is not safe or less effective in that younger age group.

Yvonne Maldonado, MD, the American Academy of Pediatrics representative on the panel, said that this age group should not be denied the vaccine as they often have essential or front-line jobs that put them at higher risk for infection.

“I am very concerned about this message being sent out that this vaccine will not be safe in children,” said Maldonado, professor of pediatrics and health research and policy at Stanford University School of Medicine in California.

“We currently have no evidence that that is the case,” she said, adding there is also no indication younger children are biologically or physiologically different in their response or safety risk than 18-year-olds.

Vaccine = hope

Committee members breathed a sigh of relief at the end of the 2-day meeting, saying that although the Pfizer vaccine is not perfect, it represents a scientific milestone and a significant advance against the continuing march of the SARS-CoV-2 pandemic.

“This vaccine and future vaccines do provide a promise for a lot of progress in the future,” said panelist Beth P. Bell, MD, MPH, clinical professor of global health at the University of Washington School of Public Health in Seattle.

Peter Szilagyi, MD, MPH, executive vice-chair and vice-chair for research at the University of California, Los Angeles pediatrics department, said, “I’m really hopeful that this is the beginning of the end of the coronavirus pandemic.”

“The need for this vaccine is profound,” said Veronica McNally, president and CEO of the Franny Strong Foundation in West Bloomfield, Michigan.

The ACIP panel also made the argument that while the at least $10 billion spent on vaccine development by the federal government’s Operation Warp Speed alone has been a good investment, more spending is needed to actually get Americans vaccinated.

The imbalance between the two is “shocking and needs to be corrected,” said Bell. “We are not going to be able to protect the American public if we don’t have a way to deliver the vaccine to them.”

This article first appeared on Medscape.com.

The Centers for Disease Control and Prevention (CDC) advisory committee recommended on December 12 the recently authorized Pfizer-BioNTech COVID-19 vaccine for people age 16 and over in the United States, stating they found it was safe and effective.

The agency said it will quickly issue guidance to clinicians so they can determine when and when not to give the vaccine, and to help them communicate the risks and benefits to patients.

CDC staff gave a preview of those clinical considerations at the agency’s Advisory Committee on Immunization Practices (ACIP) meeting on December 12 and said it would be holding calls with clinicians on December 13 and 14.

The CDC will also issue guidance December 13 on how organizations can handle the workforce problems that might arise as health care workers experience side effects from vaccination.

ACIP voted 11-0, with three recusals, to recommend use of the Pfizer-BioNTech mRNA vaccine in individuals 16 years or older according to the guidelines of the Food and Drug Administration’s (FDA’s) emergency use authorization issued December 11.

The panel also voted unanimously to include the vaccine in 2021 immunization schedules. All panel members said the recommendation should go hand-in-hand with ACIP’s previous recommendation on December 1 that allocation of the vaccine be phased-in, with health care workers and residents and staff of long-term care facilities in phase 1a.

Allergies, pregnant women?

ACIP panelists said clinicians need more guidance on whether to use the vaccine in pregnant or breastfeeding women, the immunocompromised, or those who have a history of allergies.

The FDA health care provider information sheet said there is not enough data to recommend vaccinating those women or the immunocompromised, and also advises against giving the vaccine to individuals who have a history of serious allergic reaction to any component of the vaccine.

Peter Marks, MD, PhD, director of the FDA’s Center for Biologic Evaluation and Research (CBER) clarified this in a briefing on December 12, noting that women who are pregnant or lactating can make the decision in consultation with their physician. And, he said, patients with any other history of allergy should be able to safely get the vaccine.

The CDC — in its soon-to-be-released guidance — will make the same recommendations. For any woman considering vaccination, she should consider the level of COVID-19 in the community, her personal risk of contracting the virus, the risks to her or her fetus of developing the disease, and the vaccine’s known side effects, Sarah Mbaeyi, MD, MPH, a medical officer at the agency, said during the panel meeting December 12.

She added that the CDC will also urge physicians to advise women to take acetaminophen if they develop a fever after vaccination — to protect the developing fetus from fever.

Sandra Fryhofer, MD, representing the American Medical Association, commended the CDC for these recommendations. But she also called on Pfizer, the FDA, and the CDC to make data from the developmental and reproductive toxicity (DART) studies public as soon as possible.

“We really need to put those results on warp speed and get them out there to give our physicians and pregnant women more information,” said Fryhofer, an adjunct associate professor of medicine at Emory University School of Medicine in Atlanta, Georgia.

The American College of Obstetricians and Gynecologists (ACOG) will also soon release guidance for vaccinating pregnant and breastfeeding women, said Linda Eckert, MD, FACOG, an ACOG representative on the panel.

ACOG and the CDC met the morning of December 12 to discuss risks and benefits with experts in immunology, placental pathology, and vaccine kinetics, she said.

“The overall complete consensus was that we don’t see biological plausibility at this time for placental transfer of the mRNA and that we see that direct fetal exposure or the possibility of fetal inflammatory response is extremely unlikely,” said Eckert, professor of obstetrics and gynecology at the University of Washington, Seattle. “Clearly we are waiting on the data.”

A Pfizer official told the ACIP panel that preliminary data “show no indication of either developmental or reproductive toxicity,” and that the company plans to send the final DART data to the FDA at the end of December.

On the potential for allergic reactions, the CDC concurred with the FDA that the vaccine should not be given to people with a history of serious reactions. The agency added that the category should include anyone who has had a reaction to any vaccine or injectable drug product because injectables may contain the same ingredients as the Pfizer vaccine, said Mbaeyi.

The CDC will also urge clinicians to observe patients with a history of anaphylaxis for 30 minutes after vaccination and all patients for at least 15 minutes afterward.

Should teens be a special population?

At least one ACIP panel member — Henry Bernstein, DO, MHCM, FAAP — said he was concerned that backing use of the vaccine in 16- and 17-year-olds was a leap of faith, given that Pfizer had extremely limited data on this cohort.

Bernstein, professor of pediatrics at the Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York, also said that systemic reactions were more common in that age group.

He argued for making the 16- and 17-year-olds a “special population” that would get specific attention and guidance for vaccination from the federal agencies and professional societies.

Bernstein said he did not want to sow any more doubts in parents’ minds about vaccination, noting that hesitancy was a growing concern. “A successful pediatric vaccination program depends on creating and sustaining parental confidence in both the safety and effectiveness of this vaccine,” he said.

Many panelists, however, noted that there has been no evidence to suggest that the vaccine is not safe or less effective in that younger age group.

Yvonne Maldonado, MD, the American Academy of Pediatrics representative on the panel, said that this age group should not be denied the vaccine as they often have essential or front-line jobs that put them at higher risk for infection.

“I am very concerned about this message being sent out that this vaccine will not be safe in children,” said Maldonado, professor of pediatrics and health research and policy at Stanford University School of Medicine in California.

“We currently have no evidence that that is the case,” she said, adding there is also no indication younger children are biologically or physiologically different in their response or safety risk than 18-year-olds.

Vaccine = hope

Committee members breathed a sigh of relief at the end of the 2-day meeting, saying that although the Pfizer vaccine is not perfect, it represents a scientific milestone and a significant advance against the continuing march of the SARS-CoV-2 pandemic.

“This vaccine and future vaccines do provide a promise for a lot of progress in the future,” said panelist Beth P. Bell, MD, MPH, clinical professor of global health at the University of Washington School of Public Health in Seattle.

Peter Szilagyi, MD, MPH, executive vice-chair and vice-chair for research at the University of California, Los Angeles pediatrics department, said, “I’m really hopeful that this is the beginning of the end of the coronavirus pandemic.”

“The need for this vaccine is profound,” said Veronica McNally, president and CEO of the Franny Strong Foundation in West Bloomfield, Michigan.

The ACIP panel also made the argument that while the at least $10 billion spent on vaccine development by the federal government’s Operation Warp Speed alone has been a good investment, more spending is needed to actually get Americans vaccinated.

The imbalance between the two is “shocking and needs to be corrected,” said Bell. “We are not going to be able to protect the American public if we don’t have a way to deliver the vaccine to them.”

This article first appeared on Medscape.com.

The Centers for Disease Control and Prevention (CDC) advisory committee recommended on December 12 the recently authorized Pfizer-BioNTech COVID-19 vaccine for people age 16 and over in the United States, stating they found it was safe and effective.

The agency said it will quickly issue guidance to clinicians so they can determine when and when not to give the vaccine, and to help them communicate the risks and benefits to patients.

CDC staff gave a preview of those clinical considerations at the agency’s Advisory Committee on Immunization Practices (ACIP) meeting on December 12 and said it would be holding calls with clinicians on December 13 and 14.

The CDC will also issue guidance December 13 on how organizations can handle the workforce problems that might arise as health care workers experience side effects from vaccination.

ACIP voted 11-0, with three recusals, to recommend use of the Pfizer-BioNTech mRNA vaccine in individuals 16 years or older according to the guidelines of the Food and Drug Administration’s (FDA’s) emergency use authorization issued December 11.

The panel also voted unanimously to include the vaccine in 2021 immunization schedules. All panel members said the recommendation should go hand-in-hand with ACIP’s previous recommendation on December 1 that allocation of the vaccine be phased-in, with health care workers and residents and staff of long-term care facilities in phase 1a.

Allergies, pregnant women?

ACIP panelists said clinicians need more guidance on whether to use the vaccine in pregnant or breastfeeding women, the immunocompromised, or those who have a history of allergies.

The FDA health care provider information sheet said there is not enough data to recommend vaccinating those women or the immunocompromised, and also advises against giving the vaccine to individuals who have a history of serious allergic reaction to any component of the vaccine.

Peter Marks, MD, PhD, director of the FDA’s Center for Biologic Evaluation and Research (CBER) clarified this in a briefing on December 12, noting that women who are pregnant or lactating can make the decision in consultation with their physician. And, he said, patients with any other history of allergy should be able to safely get the vaccine.

The CDC — in its soon-to-be-released guidance — will make the same recommendations. For any woman considering vaccination, she should consider the level of COVID-19 in the community, her personal risk of contracting the virus, the risks to her or her fetus of developing the disease, and the vaccine’s known side effects, Sarah Mbaeyi, MD, MPH, a medical officer at the agency, said during the panel meeting December 12.

She added that the CDC will also urge physicians to advise women to take acetaminophen if they develop a fever after vaccination — to protect the developing fetus from fever.

Sandra Fryhofer, MD, representing the American Medical Association, commended the CDC for these recommendations. But she also called on Pfizer, the FDA, and the CDC to make data from the developmental and reproductive toxicity (DART) studies public as soon as possible.

“We really need to put those results on warp speed and get them out there to give our physicians and pregnant women more information,” said Fryhofer, an adjunct associate professor of medicine at Emory University School of Medicine in Atlanta, Georgia.

The American College of Obstetricians and Gynecologists (ACOG) will also soon release guidance for vaccinating pregnant and breastfeeding women, said Linda Eckert, MD, FACOG, an ACOG representative on the panel.

ACOG and the CDC met the morning of December 12 to discuss risks and benefits with experts in immunology, placental pathology, and vaccine kinetics, she said.

“The overall complete consensus was that we don’t see biological plausibility at this time for placental transfer of the mRNA and that we see that direct fetal exposure or the possibility of fetal inflammatory response is extremely unlikely,” said Eckert, professor of obstetrics and gynecology at the University of Washington, Seattle. “Clearly we are waiting on the data.”

A Pfizer official told the ACIP panel that preliminary data “show no indication of either developmental or reproductive toxicity,” and that the company plans to send the final DART data to the FDA at the end of December.

On the potential for allergic reactions, the CDC concurred with the FDA that the vaccine should not be given to people with a history of serious reactions. The agency added that the category should include anyone who has had a reaction to any vaccine or injectable drug product because injectables may contain the same ingredients as the Pfizer vaccine, said Mbaeyi.

The CDC will also urge clinicians to observe patients with a history of anaphylaxis for 30 minutes after vaccination and all patients for at least 15 minutes afterward.

Should teens be a special population?

At least one ACIP panel member — Henry Bernstein, DO, MHCM, FAAP — said he was concerned that backing use of the vaccine in 16- and 17-year-olds was a leap of faith, given that Pfizer had extremely limited data on this cohort.

Bernstein, professor of pediatrics at the Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York, also said that systemic reactions were more common in that age group.

He argued for making the 16- and 17-year-olds a “special population” that would get specific attention and guidance for vaccination from the federal agencies and professional societies.

Bernstein said he did not want to sow any more doubts in parents’ minds about vaccination, noting that hesitancy was a growing concern. “A successful pediatric vaccination program depends on creating and sustaining parental confidence in both the safety and effectiveness of this vaccine,” he said.

Many panelists, however, noted that there has been no evidence to suggest that the vaccine is not safe or less effective in that younger age group.

Yvonne Maldonado, MD, the American Academy of Pediatrics representative on the panel, said that this age group should not be denied the vaccine as they often have essential or front-line jobs that put them at higher risk for infection.

“I am very concerned about this message being sent out that this vaccine will not be safe in children,” said Maldonado, professor of pediatrics and health research and policy at Stanford University School of Medicine in California.

“We currently have no evidence that that is the case,” she said, adding there is also no indication younger children are biologically or physiologically different in their response or safety risk than 18-year-olds.

Vaccine = hope

Committee members breathed a sigh of relief at the end of the 2-day meeting, saying that although the Pfizer vaccine is not perfect, it represents a scientific milestone and a significant advance against the continuing march of the SARS-CoV-2 pandemic.

“This vaccine and future vaccines do provide a promise for a lot of progress in the future,” said panelist Beth P. Bell, MD, MPH, clinical professor of global health at the University of Washington School of Public Health in Seattle.

Peter Szilagyi, MD, MPH, executive vice-chair and vice-chair for research at the University of California, Los Angeles pediatrics department, said, “I’m really hopeful that this is the beginning of the end of the coronavirus pandemic.”

“The need for this vaccine is profound,” said Veronica McNally, president and CEO of the Franny Strong Foundation in West Bloomfield, Michigan.

The ACIP panel also made the argument that while the at least $10 billion spent on vaccine development by the federal government’s Operation Warp Speed alone has been a good investment, more spending is needed to actually get Americans vaccinated.

The imbalance between the two is “shocking and needs to be corrected,” said Bell. “We are not going to be able to protect the American public if we don’t have a way to deliver the vaccine to them.”

This article first appeared on Medscape.com.

The US Food and Drug Administration (FDA) has authorized Pfizer/BioNTech’s COVID-19 vaccine for emergency use in people 16 years of age and older. 

The much-anticipated emergency use authorization (EUA) of this vaccine — the first such approval in the United States — was greeted with optimism by infectious disease and pulmonary experts, although unanswered questions remain regarding use in people with allergic hypersensitivity, safety in pregnant women, and how smooth distribution will be.

“I am delighted. This is a first, firm step on a long path to getting this COVID pandemic under control,” William Schaffner, MD, professor of infectious diseases at the Vanderbilt University School of Medicine in Nashville, Tennessee, said in an interview.

The FDA gave the green light after the December 10 recommendation from the agency’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) meeting. The committee voted 17-4 in favor of the emergency authorization.

Allergic reactions reported in the UK

After vaccinations with the Pfizer vaccine began in the UK on December 8, reports surfaced of two healthcare workers who experienced allergic reactions. They have since recovered, but officials warned that people with a history of severe allergic reactions should not receive the Pfizer vaccine at this time.

“For the moment, they are asking people who have had notable allergic reactions to step aside while this is investigated. It shows you that the system is working,” Schaffner said.

Both vaccine recipients who experienced anaphylaxis carried EpiPens, as they were at high risk for allergic reactions, Hewlett said. Also, if other COVID-19 vaccines are approved for use in the future, people allergic to the Pfizer vaccine might have another option, he added.

Reassuring role models

Schaffner supports the CDC Advisory Committee on Immunization Practices (ACIP) decision to start vaccinations with healthcare workers and residents of long-term care facilities.

“Vaccinating healthcare workers, in particular, will be a model for the general public,” said Schaffner, who is also a former member of the IDSA board of directors. “If they see those of us in white coats and blue scrubs lining up for the vaccine, that will provide confidence.”

To further increase acceptance of the COVID-19 vaccine, public health officials need to provide information and reassure the general public, Schaffner said.

Hewlett agreed. “I know there are a lot of people in the population who are very hesitant about vaccines. As infection disease specialists and people in public health, we are trying to allay a lot of concerns people have.”

Reassurance will be especially important in minority communities. “They have been disproportionately affected by the virus, and they have a traditional history of not being optimally vaccinated,” Schaffner said. “We need to reach them in particular with good information and reassurance…so they can make good decisions for themselves and their families.”

No vaccine is 100% effective or completely free of side effects. “There is always a chance there can be adverse reactions, but we think for the most part this is going to be a safe and effective vaccine,” said Hewlett, medical director at the Division of Disease Control and deputy to commissioner of health at the Westchester County Department of Health in White Plains, New York.

Distribution: Smooth or full of strife?

In addition to the concern that some people will not take advantage of vaccination against COVID-19, there could be vaccine supply issues down the road, Schaffner said.

Culver agreed. “In the early phases, I expect that there will be some kinks to work out, but because the numbers are relatively small, this should be okay,” he said.

“I think when we start to get into larger-scale vaccination programs — the supply chain, transport, and storage will be a Herculean undertaking,” Culver added. “It will take careful coordination between healthcare providers, distributors, suppliers, and public health officials to pull this off.”

Planning and distribution also should focus beyond US borders. Any issues in vaccine distribution or administration in the United States “will only be multiplied in several other parts of the world,” Culver said. Because COVID-19 is a pandemic, “we need to think about vaccinating globally.”

Investigating adverse events

Adverse events common to vaccinations in general — injection site pain, headaches, and fever — would not be unexpected with the COVID-19 vaccines. However, experts remain concerned that other, unrelated adverse events might be erroneously attributed to vaccination. For example, if a fall, heart attack, or death occurs within days of immunization, some might immediately blame the vaccine product.

“It’s important to remember that any new, highly touted medical therapy like this will receive a lot of scrutiny, so it would be unusual not to hear about something happening to somebody,” Culver said. Vaccine companies and health agencies will be carefully evaluating any reported adverse events to ensure no safety signal was missed in the trials.

“Fortunately, there are systems in place to investigate these events immediately,” Schaffner said.

Pregnancy recommendations pending

One question still looms: Is the COVID-19 vaccination safe for pregnant women? This isn’t just a question for the general public, either, Schaffner said. He estimated that about 70 percent of healthcare workers are women, and data suggests about 300,000 of these healthcare workers are pregnant.

“The CDC’s Advisory Committee on Immunization Practices will speak to that just as soon as the EUA is issued,” he added.

Patients are asking Culver about the priority order for vaccination. He said it’s difficult to provide firm guidance at this point.

People also have “lingering skepticism” about whether vaccine development was done in a prudent way, Culver said. Some people question whether the Pfizer vaccine and others were rushed to market. “So we try to spend time with the patients, reassuring them that all the usual safety evaluations were carefully done,” he said.

Another concern is whether mRNA vaccines can interact with human DNA. “The quick, short, and definitive answer is no,” Schaffner said. The m stands for messenger — the vaccines transmit information. "Once it gets into a cell, the mRNA does not go anywhere near the DNA, and once it transmits its information to the cell appropriately, it gets metabolized, and we excrete all the remnants."

Hewlett pointed out that investigations and surveillance will continue. Because this is an EUA and not full approval, “that essentially means they will still be obligated to collect a lot more data than they would ordinarily,” he said.

How long immunoprotection will last also remains an unknown. “The big question left on the table now is the durability,” Culver said. “Of course, we won’t know the answer to that for quite some time.”

Schaffner and Culver have disclosed no relevant financial relationships. Hewlett was an employee of Pfizer until mid-2019. His previous work as Pfizer’s senior medical director of global medical product evaluation was not associated with development of the COVID-19 vaccine.

This article first appeared on Medscape.com.

The US Food and Drug Administration (FDA) has authorized Pfizer/BioNTech’s COVID-19 vaccine for emergency use in people 16 years of age and older. 

The much-anticipated emergency use authorization (EUA) of this vaccine — the first such approval in the United States — was greeted with optimism by infectious disease and pulmonary experts, although unanswered questions remain regarding use in people with allergic hypersensitivity, safety in pregnant women, and how smooth distribution will be.

“I am delighted. This is a first, firm step on a long path to getting this COVID pandemic under control,” William Schaffner, MD, professor of infectious diseases at the Vanderbilt University School of Medicine in Nashville, Tennessee, said in an interview.

The FDA gave the green light after the December 10 recommendation from the agency’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) meeting. The committee voted 17-4 in favor of the emergency authorization.

Allergic reactions reported in the UK

After vaccinations with the Pfizer vaccine began in the UK on December 8, reports surfaced of two healthcare workers who experienced allergic reactions. They have since recovered, but officials warned that people with a history of severe allergic reactions should not receive the Pfizer vaccine at this time.

“For the moment, they are asking people who have had notable allergic reactions to step aside while this is investigated. It shows you that the system is working,” Schaffner said.

Both vaccine recipients who experienced anaphylaxis carried EpiPens, as they were at high risk for allergic reactions, Hewlett said. Also, if other COVID-19 vaccines are approved for use in the future, people allergic to the Pfizer vaccine might have another option, he added.

Reassuring role models

Schaffner supports the CDC Advisory Committee on Immunization Practices (ACIP) decision to start vaccinations with healthcare workers and residents of long-term care facilities.

“Vaccinating healthcare workers, in particular, will be a model for the general public,” said Schaffner, who is also a former member of the IDSA board of directors. “If they see those of us in white coats and blue scrubs lining up for the vaccine, that will provide confidence.”

To further increase acceptance of the COVID-19 vaccine, public health officials need to provide information and reassure the general public, Schaffner said.

Hewlett agreed. “I know there are a lot of people in the population who are very hesitant about vaccines. As infection disease specialists and people in public health, we are trying to allay a lot of concerns people have.”

Reassurance will be especially important in minority communities. “They have been disproportionately affected by the virus, and they have a traditional history of not being optimally vaccinated,” Schaffner said. “We need to reach them in particular with good information and reassurance…so they can make good decisions for themselves and their families.”

No vaccine is 100% effective or completely free of side effects. “There is always a chance there can be adverse reactions, but we think for the most part this is going to be a safe and effective vaccine,” said Hewlett, medical director at the Division of Disease Control and deputy to commissioner of health at the Westchester County Department of Health in White Plains, New York.

Distribution: Smooth or full of strife?

In addition to the concern that some people will not take advantage of vaccination against COVID-19, there could be vaccine supply issues down the road, Schaffner said.

Culver agreed. “In the early phases, I expect that there will be some kinks to work out, but because the numbers are relatively small, this should be okay,” he said.

“I think when we start to get into larger-scale vaccination programs — the supply chain, transport, and storage will be a Herculean undertaking,” Culver added. “It will take careful coordination between healthcare providers, distributors, suppliers, and public health officials to pull this off.”

Planning and distribution also should focus beyond US borders. Any issues in vaccine distribution or administration in the United States “will only be multiplied in several other parts of the world,” Culver said. Because COVID-19 is a pandemic, “we need to think about vaccinating globally.”

Investigating adverse events

Adverse events common to vaccinations in general — injection site pain, headaches, and fever — would not be unexpected with the COVID-19 vaccines. However, experts remain concerned that other, unrelated adverse events might be erroneously attributed to vaccination. For example, if a fall, heart attack, or death occurs within days of immunization, some might immediately blame the vaccine product.

“It’s important to remember that any new, highly touted medical therapy like this will receive a lot of scrutiny, so it would be unusual not to hear about something happening to somebody,” Culver said. Vaccine companies and health agencies will be carefully evaluating any reported adverse events to ensure no safety signal was missed in the trials.

“Fortunately, there are systems in place to investigate these events immediately,” Schaffner said.

Pregnancy recommendations pending

One question still looms: Is the COVID-19 vaccination safe for pregnant women? This isn’t just a question for the general public, either, Schaffner said. He estimated that about 70 percent of healthcare workers are women, and data suggests about 300,000 of these healthcare workers are pregnant.

“The CDC’s Advisory Committee on Immunization Practices will speak to that just as soon as the EUA is issued,” he added.

Patients are asking Culver about the priority order for vaccination. He said it’s difficult to provide firm guidance at this point.

People also have “lingering skepticism” about whether vaccine development was done in a prudent way, Culver said. Some people question whether the Pfizer vaccine and others were rushed to market. “So we try to spend time with the patients, reassuring them that all the usual safety evaluations were carefully done,” he said.

Another concern is whether mRNA vaccines can interact with human DNA. “The quick, short, and definitive answer is no,” Schaffner said. The m stands for messenger — the vaccines transmit information. "Once it gets into a cell, the mRNA does not go anywhere near the DNA, and once it transmits its information to the cell appropriately, it gets metabolized, and we excrete all the remnants."

Hewlett pointed out that investigations and surveillance will continue. Because this is an EUA and not full approval, “that essentially means they will still be obligated to collect a lot more data than they would ordinarily,” he said.

How long immunoprotection will last also remains an unknown. “The big question left on the table now is the durability,” Culver said. “Of course, we won’t know the answer to that for quite some time.”

Schaffner and Culver have disclosed no relevant financial relationships. Hewlett was an employee of Pfizer until mid-2019. His previous work as Pfizer’s senior medical director of global medical product evaluation was not associated with development of the COVID-19 vaccine.

This article first appeared on Medscape.com.

The US Food and Drug Administration (FDA) has authorized Pfizer/BioNTech’s COVID-19 vaccine for emergency use in people 16 years of age and older. 

The much-anticipated emergency use authorization (EUA) of this vaccine — the first such approval in the United States — was greeted with optimism by infectious disease and pulmonary experts, although unanswered questions remain regarding use in people with allergic hypersensitivity, safety in pregnant women, and how smooth distribution will be.

“I am delighted. This is a first, firm step on a long path to getting this COVID pandemic under control,” William Schaffner, MD, professor of infectious diseases at the Vanderbilt University School of Medicine in Nashville, Tennessee, said in an interview.

The FDA gave the green light after the December 10 recommendation from the agency’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) meeting. The committee voted 17-4 in favor of the emergency authorization.

Allergic reactions reported in the UK

After vaccinations with the Pfizer vaccine began in the UK on December 8, reports surfaced of two healthcare workers who experienced allergic reactions. They have since recovered, but officials warned that people with a history of severe allergic reactions should not receive the Pfizer vaccine at this time.

“For the moment, they are asking people who have had notable allergic reactions to step aside while this is investigated. It shows you that the system is working,” Schaffner said.

Both vaccine recipients who experienced anaphylaxis carried EpiPens, as they were at high risk for allergic reactions, Hewlett said. Also, if other COVID-19 vaccines are approved for use in the future, people allergic to the Pfizer vaccine might have another option, he added.

Reassuring role models

Schaffner supports the CDC Advisory Committee on Immunization Practices (ACIP) decision to start vaccinations with healthcare workers and residents of long-term care facilities.

“Vaccinating healthcare workers, in particular, will be a model for the general public,” said Schaffner, who is also a former member of the IDSA board of directors. “If they see those of us in white coats and blue scrubs lining up for the vaccine, that will provide confidence.”

To further increase acceptance of the COVID-19 vaccine, public health officials need to provide information and reassure the general public, Schaffner said.

Hewlett agreed. “I know there are a lot of people in the population who are very hesitant about vaccines. As infection disease specialists and people in public health, we are trying to allay a lot of concerns people have.”

Reassurance will be especially important in minority communities. “They have been disproportionately affected by the virus, and they have a traditional history of not being optimally vaccinated,” Schaffner said. “We need to reach them in particular with good information and reassurance…so they can make good decisions for themselves and their families.”

No vaccine is 100% effective or completely free of side effects. “There is always a chance there can be adverse reactions, but we think for the most part this is going to be a safe and effective vaccine,” said Hewlett, medical director at the Division of Disease Control and deputy to commissioner of health at the Westchester County Department of Health in White Plains, New York.

Distribution: Smooth or full of strife?

In addition to the concern that some people will not take advantage of vaccination against COVID-19, there could be vaccine supply issues down the road, Schaffner said.

Culver agreed. “In the early phases, I expect that there will be some kinks to work out, but because the numbers are relatively small, this should be okay,” he said.

“I think when we start to get into larger-scale vaccination programs — the supply chain, transport, and storage will be a Herculean undertaking,” Culver added. “It will take careful coordination between healthcare providers, distributors, suppliers, and public health officials to pull this off.”

Planning and distribution also should focus beyond US borders. Any issues in vaccine distribution or administration in the United States “will only be multiplied in several other parts of the world,” Culver said. Because COVID-19 is a pandemic, “we need to think about vaccinating globally.”

Investigating adverse events

Adverse events common to vaccinations in general — injection site pain, headaches, and fever — would not be unexpected with the COVID-19 vaccines. However, experts remain concerned that other, unrelated adverse events might be erroneously attributed to vaccination. For example, if a fall, heart attack, or death occurs within days of immunization, some might immediately blame the vaccine product.

“It’s important to remember that any new, highly touted medical therapy like this will receive a lot of scrutiny, so it would be unusual not to hear about something happening to somebody,” Culver said. Vaccine companies and health agencies will be carefully evaluating any reported adverse events to ensure no safety signal was missed in the trials.

“Fortunately, there are systems in place to investigate these events immediately,” Schaffner said.

Pregnancy recommendations pending

One question still looms: Is the COVID-19 vaccination safe for pregnant women? This isn’t just a question for the general public, either, Schaffner said. He estimated that about 70 percent of healthcare workers are women, and data suggests about 300,000 of these healthcare workers are pregnant.

“The CDC’s Advisory Committee on Immunization Practices will speak to that just as soon as the EUA is issued,” he added.

Patients are asking Culver about the priority order for vaccination. He said it’s difficult to provide firm guidance at this point.

People also have “lingering skepticism” about whether vaccine development was done in a prudent way, Culver said. Some people question whether the Pfizer vaccine and others were rushed to market. “So we try to spend time with the patients, reassuring them that all the usual safety evaluations were carefully done,” he said.

Another concern is whether mRNA vaccines can interact with human DNA. “The quick, short, and definitive answer is no,” Schaffner said. The m stands for messenger — the vaccines transmit information. "Once it gets into a cell, the mRNA does not go anywhere near the DNA, and once it transmits its information to the cell appropriately, it gets metabolized, and we excrete all the remnants."

Hewlett pointed out that investigations and surveillance will continue. Because this is an EUA and not full approval, “that essentially means they will still be obligated to collect a lot more data than they would ordinarily,” he said.

How long immunoprotection will last also remains an unknown. “The big question left on the table now is the durability,” Culver said. “Of course, we won’t know the answer to that for quite some time.”

Schaffner and Culver have disclosed no relevant financial relationships. Hewlett was an employee of Pfizer until mid-2019. His previous work as Pfizer’s senior medical director of global medical product evaluation was not associated with development of the COVID-19 vaccine.

This article first appeared on Medscape.com.

Differences in gene expression between the skin and synovial tissues of individuals with psoriatic arthritis could explain why treatments targeting proinflammatory mechanisms don’t improve joint symptoms in some patients.

SilverV/Thinkstock

A paper published in Annals of the Rheumatic Diseases presents the results of an observational, open-label study involving 27 patients with active psoriatic arthritis, 18 of whom were treated with anti–tumor necrosis factor (anti-TNF) therapies and 9 with the monoclonal antibody ustekinumab (Stelara). This drug targets the axis of proinflammatory cytokine interleukin-23 and effector cytokine IL-12, which are believed to play an important role both in skin and nail psoriasis, and psoriatic arthritis.

However, while anti–IL-23 antibodies seem to work well to address skin manifestations of psoriasis, they tend to improve joint symptoms only in selected patients.

“The lack of a clear mechanism to explain such divergent responses prompted this study,” said Dr. Alessandra Nerviani, lead author of the study, from the Barts and The London School of Medicine & Dentistry.

Participants also had biopsies taken from the synovium – in particular, from joints that were clinically and ultrasonographically active – and from lesional and nonlesional skin for gene expression analysis.

In terms of treatment response, the ustekinumab-treated group showed significantly higher scores for erythrocyte sedimentation rate, joint pain, and disease activity, compared with the anti–TNF-treated group. Psoriasis Area and Severity Index scores were similar in both treatment arms, but significantly more patients in the anti-TNF group met the EULAR Disease Activity Score for response (70.6% vs. 22.2%).

The gene expression analysis, which assessed the activity of 80 genes related to inflammation in 14 patient samples from synovial tissue, lesional skin, and nonlesional skin, found that patterns of expression in the synovium clustered away from those from skin.

This was particularly the case when it came to genes related to drug targets. The targets for anti-TNF showed similar levels of expression in both skin and synovial tissue. However, the targets for ustekinumab – namely interleukin (IL)–23A, IL-23R and, IL-12B – showed higher levels of expression in lesional skin than in nonlesional skin and synovial tissue.

“Interestingly, we observed that, while some patients did express IL-23 cytokines/receptor in both skin and joint, others had discordant expression, that is, active IL-23 pathway in the lesional skin but not in the synovium,” the authors wrote.

When researchers then stratified patients according to how much synovial inflammation they had, they found that patients who had higher scores also showed higher expression of genes for IL-12B and IL-23R, but not IL-23A, despite showing no other major clinical differences.

The authors also looked at the protein expression levels for IL-23p40, IL-23p19 and IL-23R, and found that while the percentage of cells positive for these proteins was significantly higher in lesional, compared with nonlesional skin, it was also higher in the synovium among patients with more inflammation.

“Except for the LIKERT patient score, we did not detect other significant correlations between IL-23 axis expression and clinical parameters at baseline, suggesting that patients with comparable disease severity may have, in fact, heterogeneous histopathological features and expression of drug targets within the diseased synovium,” they wrote.

More selective expression of IL-23 in synovium

Commenting on the findings, the authors highlighted that the expression of targets for anti-TNF was much more homogeneous across skin and synovial tissue, but the IL-23A/IL-12B/IL-23R genes generally showed higher levels of expression in lesional skin. compared with either nonlesional skin or synovium. However, even within the synovium, expression of these genes varied enormously, from levels similar to those seen in paired lesional skin to levels well below those.

“It is plausible to speculate that an overall higher presence of IL-23 in the psoriatic skin supports the concept of a generally better response in terms of skin manifestations, including almost complete clearance of psoriatic lesions,” Dr. Nerviani said in an interview. “While, on the other hand, the more selective expression of IL-23 in the synovium, namely in histologically more inflamed synovium characterized by immune cells infiltration, may explain the overall more modest success to meet stringent response criteria in the joints.“

Of particular significance was the observation that IL-12B and IL-23R transcription levels were higher in patients with higher levels of synovial tissue inflammation.

“We confirmed that IL-23 axis expression relates to the synovial histopathology not only in PsA at different stages of the disease, including early treatment-naive patients, but also in the early phase of RA, investigated as disease control,” they wrote.

Dr. Nerviani said the results could inform a more tailored “precision medicine” approach to treating patients with psoriatic arthritis.

“While randomized synovial biopsy–driven clinical trials are now a reality in rheumatoid arthritis, in psoriatic arthritis, these kinds of studies have not been performed yet but may become actual in the future,” she said. “An in-depth characterization of the synovial tissue represents the first essential step towards addressing current unmet clinical needs and, potentially, changing our practice.”

However, she stressed that the study was not powered to test the correlation between the expression level of these pathways in disease tissue and clinical response to treatment.

“Further dedicated clinical trials should be designed to look at the relationship between synovial pathology and molecular characteristics, and response to targeted treatment to address this question,” Dr. Nerviani said.

The study was supported by the Queen Mary University of London and the Fondazione Ceschina, and in part by grants from Versus Arthritis. No conflicts of interest were declared.

SOURCE: Nerviani A et al. Ann Rheum Dis. 2020 Nov 26. doi: 10.1136/annrheumdis-2020-218186.

Nerviani A et al. Ann Rheum Dis. 2020 Nov 26. doi: 10.1136/annrheumdis-2020-218186.

Differences in gene expression between the skin and synovial tissues of individuals with psoriatic arthritis could explain why treatments targeting proinflammatory mechanisms don’t improve joint symptoms in some patients.

SilverV/Thinkstock

A paper published in Annals of the Rheumatic Diseases presents the results of an observational, open-label study involving 27 patients with active psoriatic arthritis, 18 of whom were treated with anti–tumor necrosis factor (anti-TNF) therapies and 9 with the monoclonal antibody ustekinumab (Stelara). This drug targets the axis of proinflammatory cytokine interleukin-23 and effector cytokine IL-12, which are believed to play an important role both in skin and nail psoriasis, and psoriatic arthritis.

However, while anti–IL-23 antibodies seem to work well to address skin manifestations of psoriasis, they tend to improve joint symptoms only in selected patients.

“The lack of a clear mechanism to explain such divergent responses prompted this study,” said Dr. Alessandra Nerviani, lead author of the study, from the Barts and The London School of Medicine & Dentistry.

Participants also had biopsies taken from the synovium – in particular, from joints that were clinically and ultrasonographically active – and from lesional and nonlesional skin for gene expression analysis.

In terms of treatment response, the ustekinumab-treated group showed significantly higher scores for erythrocyte sedimentation rate, joint pain, and disease activity, compared with the anti–TNF-treated group. Psoriasis Area and Severity Index scores were similar in both treatment arms, but significantly more patients in the anti-TNF group met the EULAR Disease Activity Score for response (70.6% vs. 22.2%).

The gene expression analysis, which assessed the activity of 80 genes related to inflammation in 14 patient samples from synovial tissue, lesional skin, and nonlesional skin, found that patterns of expression in the synovium clustered away from those from skin.

This was particularly the case when it came to genes related to drug targets. The targets for anti-TNF showed similar levels of expression in both skin and synovial tissue. However, the targets for ustekinumab – namely interleukin (IL)–23A, IL-23R and, IL-12B – showed higher levels of expression in lesional skin than in nonlesional skin and synovial tissue.

“Interestingly, we observed that, while some patients did express IL-23 cytokines/receptor in both skin and joint, others had discordant expression, that is, active IL-23 pathway in the lesional skin but not in the synovium,” the authors wrote.

When researchers then stratified patients according to how much synovial inflammation they had, they found that patients who had higher scores also showed higher expression of genes for IL-12B and IL-23R, but not IL-23A, despite showing no other major clinical differences.

The authors also looked at the protein expression levels for IL-23p40, IL-23p19 and IL-23R, and found that while the percentage of cells positive for these proteins was significantly higher in lesional, compared with nonlesional skin, it was also higher in the synovium among patients with more inflammation.

“Except for the LIKERT patient score, we did not detect other significant correlations between IL-23 axis expression and clinical parameters at baseline, suggesting that patients with comparable disease severity may have, in fact, heterogeneous histopathological features and expression of drug targets within the diseased synovium,” they wrote.

More selective expression of IL-23 in synovium

Commenting on the findings, the authors highlighted that the expression of targets for anti-TNF was much more homogeneous across skin and synovial tissue, but the IL-23A/IL-12B/IL-23R genes generally showed higher levels of expression in lesional skin. compared with either nonlesional skin or synovium. However, even within the synovium, expression of these genes varied enormously, from levels similar to those seen in paired lesional skin to levels well below those.

“It is plausible to speculate that an overall higher presence of IL-23 in the psoriatic skin supports the concept of a generally better response in terms of skin manifestations, including almost complete clearance of psoriatic lesions,” Dr. Nerviani said in an interview. “While, on the other hand, the more selective expression of IL-23 in the synovium, namely in histologically more inflamed synovium characterized by immune cells infiltration, may explain the overall more modest success to meet stringent response criteria in the joints.“

Of particular significance was the observation that IL-12B and IL-23R transcription levels were higher in patients with higher levels of synovial tissue inflammation.

“We confirmed that IL-23 axis expression relates to the synovial histopathology not only in PsA at different stages of the disease, including early treatment-naive patients, but also in the early phase of RA, investigated as disease control,” they wrote.

Dr. Nerviani said the results could inform a more tailored “precision medicine” approach to treating patients with psoriatic arthritis.

“While randomized synovial biopsy–driven clinical trials are now a reality in rheumatoid arthritis, in psoriatic arthritis, these kinds of studies have not been performed yet but may become actual in the future,” she said. “An in-depth characterization of the synovial tissue represents the first essential step towards addressing current unmet clinical needs and, potentially, changing our practice.”

However, she stressed that the study was not powered to test the correlation between the expression level of these pathways in disease tissue and clinical response to treatment.

“Further dedicated clinical trials should be designed to look at the relationship between synovial pathology and molecular characteristics, and response to targeted treatment to address this question,” Dr. Nerviani said.

The study was supported by the Queen Mary University of London and the Fondazione Ceschina, and in part by grants from Versus Arthritis. No conflicts of interest were declared.

SOURCE: Nerviani A et al. Ann Rheum Dis. 2020 Nov 26. doi: 10.1136/annrheumdis-2020-218186.

Nerviani A et al. Ann Rheum Dis. 2020 Nov 26. doi: 10.1136/annrheumdis-2020-218186.

Differences in gene expression between the skin and synovial tissues of individuals with psoriatic arthritis could explain why treatments targeting proinflammatory mechanisms don’t improve joint symptoms in some patients.

SilverV/Thinkstock

A paper published in Annals of the Rheumatic Diseases presents the results of an observational, open-label study involving 27 patients with active psoriatic arthritis, 18 of whom were treated with anti–tumor necrosis factor (anti-TNF) therapies and 9 with the monoclonal antibody ustekinumab (Stelara). This drug targets the axis of proinflammatory cytokine interleukin-23 and effector cytokine IL-12, which are believed to play an important role both in skin and nail psoriasis, and psoriatic arthritis.

However, while anti–IL-23 antibodies seem to work well to address skin manifestations of psoriasis, they tend to improve joint symptoms only in selected patients.

“The lack of a clear mechanism to explain such divergent responses prompted this study,” said Dr. Alessandra Nerviani, lead author of the study, from the Barts and The London School of Medicine & Dentistry.

Participants also had biopsies taken from the synovium – in particular, from joints that were clinically and ultrasonographically active – and from lesional and nonlesional skin for gene expression analysis.

In terms of treatment response, the ustekinumab-treated group showed significantly higher scores for erythrocyte sedimentation rate, joint pain, and disease activity, compared with the anti–TNF-treated group. Psoriasis Area and Severity Index scores were similar in both treatment arms, but significantly more patients in the anti-TNF group met the EULAR Disease Activity Score for response (70.6% vs. 22.2%).

The gene expression analysis, which assessed the activity of 80 genes related to inflammation in 14 patient samples from synovial tissue, lesional skin, and nonlesional skin, found that patterns of expression in the synovium clustered away from those from skin.

This was particularly the case when it came to genes related to drug targets. The targets for anti-TNF showed similar levels of expression in both skin and synovial tissue. However, the targets for ustekinumab – namely interleukin (IL)–23A, IL-23R and, IL-12B – showed higher levels of expression in lesional skin than in nonlesional skin and synovial tissue.

“Interestingly, we observed that, while some patients did express IL-23 cytokines/receptor in both skin and joint, others had discordant expression, that is, active IL-23 pathway in the lesional skin but not in the synovium,” the authors wrote.

When researchers then stratified patients according to how much synovial inflammation they had, they found that patients who had higher scores also showed higher expression of genes for IL-12B and IL-23R, but not IL-23A, despite showing no other major clinical differences.

The authors also looked at the protein expression levels for IL-23p40, IL-23p19 and IL-23R, and found that while the percentage of cells positive for these proteins was significantly higher in lesional, compared with nonlesional skin, it was also higher in the synovium among patients with more inflammation.

“Except for the LIKERT patient score, we did not detect other significant correlations between IL-23 axis expression and clinical parameters at baseline, suggesting that patients with comparable disease severity may have, in fact, heterogeneous histopathological features and expression of drug targets within the diseased synovium,” they wrote.

More selective expression of IL-23 in synovium

Commenting on the findings, the authors highlighted that the expression of targets for anti-TNF was much more homogeneous across skin and synovial tissue, but the IL-23A/IL-12B/IL-23R genes generally showed higher levels of expression in lesional skin. compared with either nonlesional skin or synovium. However, even within the synovium, expression of these genes varied enormously, from levels similar to those seen in paired lesional skin to levels well below those.

“It is plausible to speculate that an overall higher presence of IL-23 in the psoriatic skin supports the concept of a generally better response in terms of skin manifestations, including almost complete clearance of psoriatic lesions,” Dr. Nerviani said in an interview. “While, on the other hand, the more selective expression of IL-23 in the synovium, namely in histologically more inflamed synovium characterized by immune cells infiltration, may explain the overall more modest success to meet stringent response criteria in the joints.“

Of particular significance was the observation that IL-12B and IL-23R transcription levels were higher in patients with higher levels of synovial tissue inflammation.

“We confirmed that IL-23 axis expression relates to the synovial histopathology not only in PsA at different stages of the disease, including early treatment-naive patients, but also in the early phase of RA, investigated as disease control,” they wrote.

Dr. Nerviani said the results could inform a more tailored “precision medicine” approach to treating patients with psoriatic arthritis.

“While randomized synovial biopsy–driven clinical trials are now a reality in rheumatoid arthritis, in psoriatic arthritis, these kinds of studies have not been performed yet but may become actual in the future,” she said. “An in-depth characterization of the synovial tissue represents the first essential step towards addressing current unmet clinical needs and, potentially, changing our practice.”

However, she stressed that the study was not powered to test the correlation between the expression level of these pathways in disease tissue and clinical response to treatment.

“Further dedicated clinical trials should be designed to look at the relationship between synovial pathology and molecular characteristics, and response to targeted treatment to address this question,” Dr. Nerviani said.

The study was supported by the Queen Mary University of London and the Fondazione Ceschina, and in part by grants from Versus Arthritis. No conflicts of interest were declared.

SOURCE: Nerviani A et al. Ann Rheum Dis. 2020 Nov 26. doi: 10.1136/annrheumdis-2020-218186.

Nerviani A et al. Ann Rheum Dis. 2020 Nov 26. doi: 10.1136/annrheumdis-2020-218186.

With U.S. approval of one coronavirus vaccine likely imminent and approval of a second one expected soon after, physicians will likely be deluged with questions. Public attitudes about the vaccines vary by demographics, with a recent poll showing that men and older adults are more likely to choose vaccination, and women and people of color evincing more wariness.

Although the reasons for reluctance may vary, questions from patient will likely be similar. Some are related to the “warp speed” language about the vaccines. Other concerns arise from the fact that the platform – mRNA – has not been used in human vaccines before. And as with any vaccine, there are rumors and false claims making the rounds on social media.

In anticipation of the most common questions physicians may encounter, two experts, Krutika Kuppalli, MD, assistant professor of medicine in the division of infectious diseases at the Medical University of South Carolina, Charleston, and Angela Rasmussen, PhD, virologist and nonresident affiliate at Georgetown University’s Center for Global Health Science and Security, Washington, talked in an interview about what clinicians can expect and what evidence-based – as well as compassionate – answers might look like.
 

Q: Will this vaccine give me COVID-19?

“There is not an intact virus in there,” Dr. Rasmussen said. The mRNA-based vaccines cannot cause COVID-19 because they don’t use any part of the coronavirus itself. Instead, the Moderna and Pfizer vaccines contain manufactured mRNA molecules that carry the instructions for building the virus’ spike protein. After vaccine administration, the recipient’s own cells take up this mRNA, use it to build this bit of protein, and display it on their surfaces. The foreign protein flag triggers the immune system response.

The mRNA does not enter the cell nucleus or interact with the recipient’s DNA. And because it’s so fragile, it degrades quite quickly. To keep that from happening before cell entry, the mRNAs are cushioned in protective fats.

Q: Was this vaccine made too quickly?

“People have been working on this platform for 30 years, so it’s not that this is brand new,” Dr. Kuppalli said.

Researchers began working on mRNA vaccines in the 1990s. Technological developments in the last decade have meant that their use has become feasible, and they have been tested in animals against many viral diseases. The mRNA vaccines are attractive because they’re expected to be safe and easily manufactured from common materials. That’s what we’ve seen in the COVID-19 pandemic, the  Centers for Disease Control and Prevention says on its website. Design of the spike protein mRNA component began as soon as the viral genome became available in January.

Usually, rolling out a vaccine takes years, so less than a year under a program called Operation Warp Speed can seem like moving too fast, Dr. Rasmussen acknowledged. “The name has given people the impression that by going at warp speed, we’re cutting all the corners. [But] the reality is that Operation Warp Speed is mostly for manufacturing and distribution.”

What underlies the speed is a restructuring of the normal vaccine development process, Dr. Kuppalli said. The same phases of development – animal testing, a small initial human phase, a second for safety testing, a third large phase for efficacy – were all conducted as for any vaccine. But in this case, some phases were completed in parallel, rather than sequentially. This approach has proved so successful that there is already talk about making it the model for developing future vaccines.

Two other factors contributed to the speed, said Dr. Kuppalli and Dr. Rasmussen. First, gearing up production can slow a rollout, but with these vaccines, companies ramped up production even before anyone knew if the vaccines would work – the “warp speed” part. The second factor has been the large number of cases, making exposures more likely and thus accelerating the results of the efficacy trials. “There is so much COVID being transmitted everywhere in the United States that it did not take long to hit the threshold of events to read out phase 3,” Dr. Rasmussen said.

Q: This vaccine has never been used in humans. How do we know it’s safe?

The Pfizer phase 3 trial included more than 43,000 people, and Moderna’s had more than 30,000. The first humans received mRNA-based COVID-19 vaccines in March. The most common adverse events emerge right after a vaccination, Dr. Kuppalli said.

As with any vaccine that gains approval, monitoring will continue.

UK health officials have reported that two health care workers vaccinated in the initial rollout of the Pfizer vaccine had what seems to have been a severe allergic response. Both recipients had a history of anaphylactic allergic responses and carried EpiPens, and both recovered. During the trial, allergic reaction rates were 0.63% in the vaccine group and 0.51% in the placebo group.

As a result of the two reactions, UK regulators are now recommending that patients with a history of severe allergies not receive the vaccine at the current time.

Q: What are the likely side effects?

So far, the most common side effects are pain at the injection site and an achy, flu-like feeling, Dr. Kuppalli said. More severe reactions have been reported, but were not common in the trials.

Dr. Rasmussen noted that the common side effects are a good sign, and signal that the recipient is generating “a robust immune response.”

“Everybody I’ve talked to who’s had the response has said they would go through it again,” Dr. Kruppalli said. “I definitely plan on lining up and being one of the first people to get the vaccine.”

Q: I already had COVID-19 or had a positive antibody test. Do I still need to get the vaccine?

Dr. Rasmussen said that there are “too many unknowns” to say if a history of COVID-19 would make a difference. “We don’t know how long neutralizing antibodies last” after infection, she said. “What we know is that the vaccine tends to produce antibody titers towards the higher end of the spectrum,” suggesting better immunity with vaccination than after natural infection.

Q: Can patients of color feel safe getting the vaccine?

“People of color might be understandably reluctant to take a vaccine that was developed in a way that appears to be faster [than past development],” said Dr. Rasmussen. She said physicians should acknowledge and understand the history that has led them to feel that way, “everything from Tuskegee to Henrietta Lacks to today.”

Empathy is key, and “providers should meet patients where they are and not condescend to them.”

Dr. Kuppalli agreed. “Clinicians really need to work on trying to strip away their biases.”

Thus far there are no safety signals that differ by race or ethnicity, according to the companies. The Pfizer phase 3 trial enrolled just over 9% Black participants, 0.5% Native American/Alaska Native, 0.2% Native Hawaiian/Pacific Islander, 2.3% multiracial participants, and 28% Hispanic/Latinx. For its part, Moderna says that approximately 37% of participants in its phase 3 trial come from communities of color.

Q: What about children and pregnant women?

Although the trials included participants from many different age groups and backgrounds, children and pregnant or lactating women were not among them. Pfizer gained approval in October to include participants as young as age 12 years, and a Moderna spokesperson said in an interview that the company planned pediatric inclusion at the end of 2020, pending approval.

“Unfortunately, we don’t have data on pregnant and lactating women,” Dr. Kuppalli said. She said she hopes that public health organizations such as the CDC will address that in the coming weeks. Dr. Rasmussen called the lack of data in pregnant women and children “a big oversight.”

Dr. Rasmussen has disclosed no relevant financial relationships. Dr. Kuppalli is a consultant with GlaxoSmithKline.

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

With U.S. approval of one coronavirus vaccine likely imminent and approval of a second one expected soon after, physicians will likely be deluged with questions. Public attitudes about the vaccines vary by demographics, with a recent poll showing that men and older adults are more likely to choose vaccination, and women and people of color evincing more wariness.

Although the reasons for reluctance may vary, questions from patient will likely be similar. Some are related to the “warp speed” language about the vaccines. Other concerns arise from the fact that the platform – mRNA – has not been used in human vaccines before. And as with any vaccine, there are rumors and false claims making the rounds on social media.

In anticipation of the most common questions physicians may encounter, two experts, Krutika Kuppalli, MD, assistant professor of medicine in the division of infectious diseases at the Medical University of South Carolina, Charleston, and Angela Rasmussen, PhD, virologist and nonresident affiliate at Georgetown University’s Center for Global Health Science and Security, Washington, talked in an interview about what clinicians can expect and what evidence-based – as well as compassionate – answers might look like.
 

Q: Will this vaccine give me COVID-19?

“There is not an intact virus in there,” Dr. Rasmussen said. The mRNA-based vaccines cannot cause COVID-19 because they don’t use any part of the coronavirus itself. Instead, the Moderna and Pfizer vaccines contain manufactured mRNA molecules that carry the instructions for building the virus’ spike protein. After vaccine administration, the recipient’s own cells take up this mRNA, use it to build this bit of protein, and display it on their surfaces. The foreign protein flag triggers the immune system response.

The mRNA does not enter the cell nucleus or interact with the recipient’s DNA. And because it’s so fragile, it degrades quite quickly. To keep that from happening before cell entry, the mRNAs are cushioned in protective fats.

Q: Was this vaccine made too quickly?

“People have been working on this platform for 30 years, so it’s not that this is brand new,” Dr. Kuppalli said.

Researchers began working on mRNA vaccines in the 1990s. Technological developments in the last decade have meant that their use has become feasible, and they have been tested in animals against many viral diseases. The mRNA vaccines are attractive because they’re expected to be safe and easily manufactured from common materials. That’s what we’ve seen in the COVID-19 pandemic, the  Centers for Disease Control and Prevention says on its website. Design of the spike protein mRNA component began as soon as the viral genome became available in January.

Usually, rolling out a vaccine takes years, so less than a year under a program called Operation Warp Speed can seem like moving too fast, Dr. Rasmussen acknowledged. “The name has given people the impression that by going at warp speed, we’re cutting all the corners. [But] the reality is that Operation Warp Speed is mostly for manufacturing and distribution.”

What underlies the speed is a restructuring of the normal vaccine development process, Dr. Kuppalli said. The same phases of development – animal testing, a small initial human phase, a second for safety testing, a third large phase for efficacy – were all conducted as for any vaccine. But in this case, some phases were completed in parallel, rather than sequentially. This approach has proved so successful that there is already talk about making it the model for developing future vaccines.

Two other factors contributed to the speed, said Dr. Kuppalli and Dr. Rasmussen. First, gearing up production can slow a rollout, but with these vaccines, companies ramped up production even before anyone knew if the vaccines would work – the “warp speed” part. The second factor has been the large number of cases, making exposures more likely and thus accelerating the results of the efficacy trials. “There is so much COVID being transmitted everywhere in the United States that it did not take long to hit the threshold of events to read out phase 3,” Dr. Rasmussen said.

Q: This vaccine has never been used in humans. How do we know it’s safe?

The Pfizer phase 3 trial included more than 43,000 people, and Moderna’s had more than 30,000. The first humans received mRNA-based COVID-19 vaccines in March. The most common adverse events emerge right after a vaccination, Dr. Kuppalli said.

As with any vaccine that gains approval, monitoring will continue.

UK health officials have reported that two health care workers vaccinated in the initial rollout of the Pfizer vaccine had what seems to have been a severe allergic response. Both recipients had a history of anaphylactic allergic responses and carried EpiPens, and both recovered. During the trial, allergic reaction rates were 0.63% in the vaccine group and 0.51% in the placebo group.

As a result of the two reactions, UK regulators are now recommending that patients with a history of severe allergies not receive the vaccine at the current time.

Q: What are the likely side effects?

So far, the most common side effects are pain at the injection site and an achy, flu-like feeling, Dr. Kuppalli said. More severe reactions have been reported, but were not common in the trials.

Dr. Rasmussen noted that the common side effects are a good sign, and signal that the recipient is generating “a robust immune response.”

“Everybody I’ve talked to who’s had the response has said they would go through it again,” Dr. Kruppalli said. “I definitely plan on lining up and being one of the first people to get the vaccine.”

Q: I already had COVID-19 or had a positive antibody test. Do I still need to get the vaccine?

Dr. Rasmussen said that there are “too many unknowns” to say if a history of COVID-19 would make a difference. “We don’t know how long neutralizing antibodies last” after infection, she said. “What we know is that the vaccine tends to produce antibody titers towards the higher end of the spectrum,” suggesting better immunity with vaccination than after natural infection.

Q: Can patients of color feel safe getting the vaccine?

“People of color might be understandably reluctant to take a vaccine that was developed in a way that appears to be faster [than past development],” said Dr. Rasmussen. She said physicians should acknowledge and understand the history that has led them to feel that way, “everything from Tuskegee to Henrietta Lacks to today.”

Empathy is key, and “providers should meet patients where they are and not condescend to them.”

Dr. Kuppalli agreed. “Clinicians really need to work on trying to strip away their biases.”

Thus far there are no safety signals that differ by race or ethnicity, according to the companies. The Pfizer phase 3 trial enrolled just over 9% Black participants, 0.5% Native American/Alaska Native, 0.2% Native Hawaiian/Pacific Islander, 2.3% multiracial participants, and 28% Hispanic/Latinx. For its part, Moderna says that approximately 37% of participants in its phase 3 trial come from communities of color.

Q: What about children and pregnant women?

Although the trials included participants from many different age groups and backgrounds, children and pregnant or lactating women were not among them. Pfizer gained approval in October to include participants as young as age 12 years, and a Moderna spokesperson said in an interview that the company planned pediatric inclusion at the end of 2020, pending approval.

“Unfortunately, we don’t have data on pregnant and lactating women,” Dr. Kuppalli said. She said she hopes that public health organizations such as the CDC will address that in the coming weeks. Dr. Rasmussen called the lack of data in pregnant women and children “a big oversight.”

Dr. Rasmussen has disclosed no relevant financial relationships. Dr. Kuppalli is a consultant with GlaxoSmithKline.

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

With U.S. approval of one coronavirus vaccine likely imminent and approval of a second one expected soon after, physicians will likely be deluged with questions. Public attitudes about the vaccines vary by demographics, with a recent poll showing that men and older adults are more likely to choose vaccination, and women and people of color evincing more wariness.

Although the reasons for reluctance may vary, questions from patient will likely be similar. Some are related to the “warp speed” language about the vaccines. Other concerns arise from the fact that the platform – mRNA – has not been used in human vaccines before. And as with any vaccine, there are rumors and false claims making the rounds on social media.

In anticipation of the most common questions physicians may encounter, two experts, Krutika Kuppalli, MD, assistant professor of medicine in the division of infectious diseases at the Medical University of South Carolina, Charleston, and Angela Rasmussen, PhD, virologist and nonresident affiliate at Georgetown University’s Center for Global Health Science and Security, Washington, talked in an interview about what clinicians can expect and what evidence-based – as well as compassionate – answers might look like.
 

Q: Will this vaccine give me COVID-19?

“There is not an intact virus in there,” Dr. Rasmussen said. The mRNA-based vaccines cannot cause COVID-19 because they don’t use any part of the coronavirus itself. Instead, the Moderna and Pfizer vaccines contain manufactured mRNA molecules that carry the instructions for building the virus’ spike protein. After vaccine administration, the recipient’s own cells take up this mRNA, use it to build this bit of protein, and display it on their surfaces. The foreign protein flag triggers the immune system response.

The mRNA does not enter the cell nucleus or interact with the recipient’s DNA. And because it’s so fragile, it degrades quite quickly. To keep that from happening before cell entry, the mRNAs are cushioned in protective fats.

Q: Was this vaccine made too quickly?

“People have been working on this platform for 30 years, so it’s not that this is brand new,” Dr. Kuppalli said.

Researchers began working on mRNA vaccines in the 1990s. Technological developments in the last decade have meant that their use has become feasible, and they have been tested in animals against many viral diseases. The mRNA vaccines are attractive because they’re expected to be safe and easily manufactured from common materials. That’s what we’ve seen in the COVID-19 pandemic, the  Centers for Disease Control and Prevention says on its website. Design of the spike protein mRNA component began as soon as the viral genome became available in January.

Usually, rolling out a vaccine takes years, so less than a year under a program called Operation Warp Speed can seem like moving too fast, Dr. Rasmussen acknowledged. “The name has given people the impression that by going at warp speed, we’re cutting all the corners. [But] the reality is that Operation Warp Speed is mostly for manufacturing and distribution.”

What underlies the speed is a restructuring of the normal vaccine development process, Dr. Kuppalli said. The same phases of development – animal testing, a small initial human phase, a second for safety testing, a third large phase for efficacy – were all conducted as for any vaccine. But in this case, some phases were completed in parallel, rather than sequentially. This approach has proved so successful that there is already talk about making it the model for developing future vaccines.

Two other factors contributed to the speed, said Dr. Kuppalli and Dr. Rasmussen. First, gearing up production can slow a rollout, but with these vaccines, companies ramped up production even before anyone knew if the vaccines would work – the “warp speed” part. The second factor has been the large number of cases, making exposures more likely and thus accelerating the results of the efficacy trials. “There is so much COVID being transmitted everywhere in the United States that it did not take long to hit the threshold of events to read out phase 3,” Dr. Rasmussen said.

Q: This vaccine has never been used in humans. How do we know it’s safe?

The Pfizer phase 3 trial included more than 43,000 people, and Moderna’s had more than 30,000. The first humans received mRNA-based COVID-19 vaccines in March. The most common adverse events emerge right after a vaccination, Dr. Kuppalli said.

As with any vaccine that gains approval, monitoring will continue.

UK health officials have reported that two health care workers vaccinated in the initial rollout of the Pfizer vaccine had what seems to have been a severe allergic response. Both recipients had a history of anaphylactic allergic responses and carried EpiPens, and both recovered. During the trial, allergic reaction rates were 0.63% in the vaccine group and 0.51% in the placebo group.

As a result of the two reactions, UK regulators are now recommending that patients with a history of severe allergies not receive the vaccine at the current time.

Q: What are the likely side effects?

So far, the most common side effects are pain at the injection site and an achy, flu-like feeling, Dr. Kuppalli said. More severe reactions have been reported, but were not common in the trials.

Dr. Rasmussen noted that the common side effects are a good sign, and signal that the recipient is generating “a robust immune response.”

“Everybody I’ve talked to who’s had the response has said they would go through it again,” Dr. Kruppalli said. “I definitely plan on lining up and being one of the first people to get the vaccine.”

Q: I already had COVID-19 or had a positive antibody test. Do I still need to get the vaccine?

Dr. Rasmussen said that there are “too many unknowns” to say if a history of COVID-19 would make a difference. “We don’t know how long neutralizing antibodies last” after infection, she said. “What we know is that the vaccine tends to produce antibody titers towards the higher end of the spectrum,” suggesting better immunity with vaccination than after natural infection.

Q: Can patients of color feel safe getting the vaccine?

“People of color might be understandably reluctant to take a vaccine that was developed in a way that appears to be faster [than past development],” said Dr. Rasmussen. She said physicians should acknowledge and understand the history that has led them to feel that way, “everything from Tuskegee to Henrietta Lacks to today.”

Empathy is key, and “providers should meet patients where they are and not condescend to them.”

Dr. Kuppalli agreed. “Clinicians really need to work on trying to strip away their biases.”

Thus far there are no safety signals that differ by race or ethnicity, according to the companies. The Pfizer phase 3 trial enrolled just over 9% Black participants, 0.5% Native American/Alaska Native, 0.2% Native Hawaiian/Pacific Islander, 2.3% multiracial participants, and 28% Hispanic/Latinx. For its part, Moderna says that approximately 37% of participants in its phase 3 trial come from communities of color.

Q: What about children and pregnant women?

Although the trials included participants from many different age groups and backgrounds, children and pregnant or lactating women were not among them. Pfizer gained approval in October to include participants as young as age 12 years, and a Moderna spokesperson said in an interview that the company planned pediatric inclusion at the end of 2020, pending approval.

“Unfortunately, we don’t have data on pregnant and lactating women,” Dr. Kuppalli said. She said she hopes that public health organizations such as the CDC will address that in the coming weeks. Dr. Rasmussen called the lack of data in pregnant women and children “a big oversight.”

Dr. Rasmussen has disclosed no relevant financial relationships. Dr. Kuppalli is a consultant with GlaxoSmithKline.

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

The majority of human cells, including skin and hair cells, keep their own time; that is, they manifest autonomous clocks and the genes that regulate their functioning.¹ During the day, one primary function of the skin is protection; at night, repairing any damage (particularly DNA impairment) incurred during the day prevails.^2-4 These activities are driven through circadian rhythms using clock genes that exist in all cutaneous cells.² Important cutaneous functions such as blood flow, transepidermal water loss, and capacitance are affected by circadian rhythms.⁵ Hydration and inflammation are also among the several functions pertaining to epidermal homeostasis affected by circadian rhythms.⁶ In addition, some collagens and extracellular matrix proteases are diurnally regulated, and approximately 10% of the transcriptome, including the extracellular matrix, is thought to be controlled by circadian rhythms.⁷

Emerging research on the circadian rhythms displayed in the skin yield implications related to skin care. Cutaneous cell migration and proliferation, wound healing, and tissue vulnerability to harm from UV exposure, oxidative stress, and protease activity, for example, are affected by circadian rhythms, Sherratt et al. noted in suggesting that chronotherapy presents promise for enhancing skin therapy.⁷ Indeed, recent research has led to the understanding that cutaneous aging, cellular repair, optimal timing for drug delivery to the skin, and skin cancer development are all affected by the chronobiological functioning of the skin.⁸

We have known for several years that certain types of products should be used at different times of the day. For instance, antioxidants should be used in the morning to protect skin from sun exposure and retinols should be used in the evening because of its induction of light sensitivity. The remainder of this column focuses on research in the last 2 decades that reinforces the notion of circadian rhythms working in the skin, and may alter how we view the timing of skin care. Next month’s column, part two on the circadian rhythms of the skin, will address recent clinical trials and the implications for timing treatments for certain cutaneous conditions.
 

Emerging data on the circadian rhythms of the skin

In 2001, Le Fur et al. studied the cutaneous circadian rhythms in the facial and forearm skin of eight healthy White women during a 48-hour period. They were able to detect such rhythms in facial sebum excretion, transepidermal water loss (TEWL) in the face and forearm, pH in the face, forearm skin temperature, and forearm capacitance using cosinor or analysis of variance methods. The investigators also observed 8- and 12-hour rhythms in TEWL in both areas, and 12 hours for forearm skin temperature. They verified that such rhythms could be measured and that they vary between skin sites. In addition, they were the first to show that ultradian and/or component rhythms can also be found in TEWL, sebum excretion, and skin temperature.⁹

A year later, Kawara et al. showed that mRNA of the circadian clock genes Per1, Clock, and bmal1/mop3 are expressed in normal human-cultured keratinocytes and that low-dose UVB down-regulates these genes and changes their express in keratinocyte cell cultures. They concluded that UV targeting of keratinocytes could alter circadian rhythms.¹⁰

In 2011, Spörl and colleagues characterized an in vitro functional cell autonomous circadian clock in adult human low calcium temperature keratinocytes, demonstrating that the molecular composition of the keratinocyte clock was comparable with peripheral tissue clocks. Notably, they observed that temperature acts as a robust time cue for epidermal traits, such as cholesterol homeostasis and differentiation.¹¹

The next year, Sandu et al. investigated the kinetics of clock gene expression in epidermal and dermal cells collected from the same donor and compared their characteristics. They were able to reveal the presence of functional circadian machinery in primary cultures of fibroblasts, keratinocytes, and melanocytes, with oscillators identified in all skin cell types and thought to be involved in spurring cutaneous rhythmic functions as they exhibited discrete periods and phase relationships between clock genes.¹²

Three years later, Sandu et al. characterized the circadian clocks in rat skin and dermal fibroblasts. They found that skin has a self-sustaining circadian clock that experiences age-dependent alterations, and that dermal fibroblasts manifest circadian rhythms that can be modulated by endogenous (e.g., melatonin) and exogenous (e.g., temperature) influences.¹³

In 2019, Park et al. demonstrated that the diurnal expression of the gene TIMP3, which is thought to evince a circadian rhythm in synchronized human keratinocytes, experiences disruptions in such rhythms by UVB exposure. The inflammation that results can be blocked, they argued, by recovering the circadian expression of TIMP3 using synthetic TIMP3 peptides or bioactive natural ingredients, such as green tea extracts.⁶

Conclusion

Circadian rhythms and the biological clocks by which most cells, including skin and hair cells, regulate themselves represent a ripe and fascinating area of research. Applying evidence in this realm to skin care has been occurring over time and is likely to enhance our practice even more as we continue to elucidate the behavior of cutaneous cells based on the solar day. Based on this information, my recommendations are to use antioxidants and protective products in the morning, and use DNA repair enzymes, retinoids, and other repair products at night.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann has written two textbooks and a New York Times Best Sellers book for consumers. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Revance, Evolus, and Burt’s Bees. She is the CEO of Skin Type Solutions, a company that independently tests skin care products and makes recommendations to physicians on which skin care technologies are best. Write to her at [email protected].

References

1. Dong K et al. Int J Mol Sci. 2020 Jan 3. doi: 10.3390/ijms21010326.

2. Dong K et al. Int J Cosmet Sci. 2019 Dec;41(6):558-62.

3. Lyons AB et al. J Clin Aesthet Dermatol. 2019 Sep;12(9):42-5.

4. Wu G et al. Proc Natl Acad Sci U S A. 2018 Nov 27;115(48):12313-8.

5. Vaughn AR et al. Pediatr Dermatol. 2018 Jan;35(1):152-7.

6. Park S et al. Int J Mol Sci. 2019 Feb 16. doi: 10.3390/ijms20040862.

7. Sherratt MJ et al. Matrix Biol. 2019 Nov;84:97-110.

8. Luber AJ et al. J Drugs Dermatol. 2014 Feb;13(2):130-4.

9. Le Fur I et al. J Invest Dermatol. 2001 Sep;117(3):718-24.

10. Kawara S et al. J Invest Dermatol. 2002 Dec;119(6):1220-3.

11. Spörl F et al. J Invest Dermatol. 2011 Feb;131(2):338-48.

12. Sandu C et al. Cell Mol Life Sci. 2012 Oct;69(19):3329-39.

13. Sandu C et al. Cell Mol Life Sci. 2015 Jun;72(11):2237-48.

The majority of human cells, including skin and hair cells, keep their own time; that is, they manifest autonomous clocks and the genes that regulate their functioning.¹ During the day, one primary function of the skin is protection; at night, repairing any damage (particularly DNA impairment) incurred during the day prevails.^2-4 These activities are driven through circadian rhythms using clock genes that exist in all cutaneous cells.² Important cutaneous functions such as blood flow, transepidermal water loss, and capacitance are affected by circadian rhythms.⁵ Hydration and inflammation are also among the several functions pertaining to epidermal homeostasis affected by circadian rhythms.⁶ In addition, some collagens and extracellular matrix proteases are diurnally regulated, and approximately 10% of the transcriptome, including the extracellular matrix, is thought to be controlled by circadian rhythms.⁷

Emerging research on the circadian rhythms displayed in the skin yield implications related to skin care. Cutaneous cell migration and proliferation, wound healing, and tissue vulnerability to harm from UV exposure, oxidative stress, and protease activity, for example, are affected by circadian rhythms, Sherratt et al. noted in suggesting that chronotherapy presents promise for enhancing skin therapy.⁷ Indeed, recent research has led to the understanding that cutaneous aging, cellular repair, optimal timing for drug delivery to the skin, and skin cancer development are all affected by the chronobiological functioning of the skin.⁸

We have known for several years that certain types of products should be used at different times of the day. For instance, antioxidants should be used in the morning to protect skin from sun exposure and retinols should be used in the evening because of its induction of light sensitivity. The remainder of this column focuses on research in the last 2 decades that reinforces the notion of circadian rhythms working in the skin, and may alter how we view the timing of skin care. Next month’s column, part two on the circadian rhythms of the skin, will address recent clinical trials and the implications for timing treatments for certain cutaneous conditions.
 

Emerging data on the circadian rhythms of the skin

In 2001, Le Fur et al. studied the cutaneous circadian rhythms in the facial and forearm skin of eight healthy White women during a 48-hour period. They were able to detect such rhythms in facial sebum excretion, transepidermal water loss (TEWL) in the face and forearm, pH in the face, forearm skin temperature, and forearm capacitance using cosinor or analysis of variance methods. The investigators also observed 8- and 12-hour rhythms in TEWL in both areas, and 12 hours for forearm skin temperature. They verified that such rhythms could be measured and that they vary between skin sites. In addition, they were the first to show that ultradian and/or component rhythms can also be found in TEWL, sebum excretion, and skin temperature.⁹

A year later, Kawara et al. showed that mRNA of the circadian clock genes Per1, Clock, and bmal1/mop3 are expressed in normal human-cultured keratinocytes and that low-dose UVB down-regulates these genes and changes their express in keratinocyte cell cultures. They concluded that UV targeting of keratinocytes could alter circadian rhythms.¹⁰

In 2011, Spörl and colleagues characterized an in vitro functional cell autonomous circadian clock in adult human low calcium temperature keratinocytes, demonstrating that the molecular composition of the keratinocyte clock was comparable with peripheral tissue clocks. Notably, they observed that temperature acts as a robust time cue for epidermal traits, such as cholesterol homeostasis and differentiation.¹¹

The next year, Sandu et al. investigated the kinetics of clock gene expression in epidermal and dermal cells collected from the same donor and compared their characteristics. They were able to reveal the presence of functional circadian machinery in primary cultures of fibroblasts, keratinocytes, and melanocytes, with oscillators identified in all skin cell types and thought to be involved in spurring cutaneous rhythmic functions as they exhibited discrete periods and phase relationships between clock genes.¹²

Three years later, Sandu et al. characterized the circadian clocks in rat skin and dermal fibroblasts. They found that skin has a self-sustaining circadian clock that experiences age-dependent alterations, and that dermal fibroblasts manifest circadian rhythms that can be modulated by endogenous (e.g., melatonin) and exogenous (e.g., temperature) influences.¹³

In 2019, Park et al. demonstrated that the diurnal expression of the gene TIMP3, which is thought to evince a circadian rhythm in synchronized human keratinocytes, experiences disruptions in such rhythms by UVB exposure. The inflammation that results can be blocked, they argued, by recovering the circadian expression of TIMP3 using synthetic TIMP3 peptides or bioactive natural ingredients, such as green tea extracts.⁶

Conclusion

Circadian rhythms and the biological clocks by which most cells, including skin and hair cells, regulate themselves represent a ripe and fascinating area of research. Applying evidence in this realm to skin care has been occurring over time and is likely to enhance our practice even more as we continue to elucidate the behavior of cutaneous cells based on the solar day. Based on this information, my recommendations are to use antioxidants and protective products in the morning, and use DNA repair enzymes, retinoids, and other repair products at night.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann has written two textbooks and a New York Times Best Sellers book for consumers. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Revance, Evolus, and Burt’s Bees. She is the CEO of Skin Type Solutions, a company that independently tests skin care products and makes recommendations to physicians on which skin care technologies are best. Write to her at [email protected].

References

1. Dong K et al. Int J Mol Sci. 2020 Jan 3. doi: 10.3390/ijms21010326.

2. Dong K et al. Int J Cosmet Sci. 2019 Dec;41(6):558-62.

3. Lyons AB et al. J Clin Aesthet Dermatol. 2019 Sep;12(9):42-5.

4. Wu G et al. Proc Natl Acad Sci U S A. 2018 Nov 27;115(48):12313-8.

5. Vaughn AR et al. Pediatr Dermatol. 2018 Jan;35(1):152-7.

6. Park S et al. Int J Mol Sci. 2019 Feb 16. doi: 10.3390/ijms20040862.

7. Sherratt MJ et al. Matrix Biol. 2019 Nov;84:97-110.

8. Luber AJ et al. J Drugs Dermatol. 2014 Feb;13(2):130-4.

9. Le Fur I et al. J Invest Dermatol. 2001 Sep;117(3):718-24.

10. Kawara S et al. J Invest Dermatol. 2002 Dec;119(6):1220-3.

11. Spörl F et al. J Invest Dermatol. 2011 Feb;131(2):338-48.

12. Sandu C et al. Cell Mol Life Sci. 2012 Oct;69(19):3329-39.

13. Sandu C et al. Cell Mol Life Sci. 2015 Jun;72(11):2237-48.

The majority of human cells, including skin and hair cells, keep their own time; that is, they manifest autonomous clocks and the genes that regulate their functioning.¹ During the day, one primary function of the skin is protection; at night, repairing any damage (particularly DNA impairment) incurred during the day prevails.^2-4 These activities are driven through circadian rhythms using clock genes that exist in all cutaneous cells.² Important cutaneous functions such as blood flow, transepidermal water loss, and capacitance are affected by circadian rhythms.⁵ Hydration and inflammation are also among the several functions pertaining to epidermal homeostasis affected by circadian rhythms.⁶ In addition, some collagens and extracellular matrix proteases are diurnally regulated, and approximately 10% of the transcriptome, including the extracellular matrix, is thought to be controlled by circadian rhythms.⁷

Emerging research on the circadian rhythms displayed in the skin yield implications related to skin care. Cutaneous cell migration and proliferation, wound healing, and tissue vulnerability to harm from UV exposure, oxidative stress, and protease activity, for example, are affected by circadian rhythms, Sherratt et al. noted in suggesting that chronotherapy presents promise for enhancing skin therapy.⁷ Indeed, recent research has led to the understanding that cutaneous aging, cellular repair, optimal timing for drug delivery to the skin, and skin cancer development are all affected by the chronobiological functioning of the skin.⁸

We have known for several years that certain types of products should be used at different times of the day. For instance, antioxidants should be used in the morning to protect skin from sun exposure and retinols should be used in the evening because of its induction of light sensitivity. The remainder of this column focuses on research in the last 2 decades that reinforces the notion of circadian rhythms working in the skin, and may alter how we view the timing of skin care. Next month’s column, part two on the circadian rhythms of the skin, will address recent clinical trials and the implications for timing treatments for certain cutaneous conditions.
 

Emerging data on the circadian rhythms of the skin

In 2001, Le Fur et al. studied the cutaneous circadian rhythms in the facial and forearm skin of eight healthy White women during a 48-hour period. They were able to detect such rhythms in facial sebum excretion, transepidermal water loss (TEWL) in the face and forearm, pH in the face, forearm skin temperature, and forearm capacitance using cosinor or analysis of variance methods. The investigators also observed 8- and 12-hour rhythms in TEWL in both areas, and 12 hours for forearm skin temperature. They verified that such rhythms could be measured and that they vary between skin sites. In addition, they were the first to show that ultradian and/or component rhythms can also be found in TEWL, sebum excretion, and skin temperature.⁹

A year later, Kawara et al. showed that mRNA of the circadian clock genes Per1, Clock, and bmal1/mop3 are expressed in normal human-cultured keratinocytes and that low-dose UVB down-regulates these genes and changes their express in keratinocyte cell cultures. They concluded that UV targeting of keratinocytes could alter circadian rhythms.¹⁰

In 2011, Spörl and colleagues characterized an in vitro functional cell autonomous circadian clock in adult human low calcium temperature keratinocytes, demonstrating that the molecular composition of the keratinocyte clock was comparable with peripheral tissue clocks. Notably, they observed that temperature acts as a robust time cue for epidermal traits, such as cholesterol homeostasis and differentiation.¹¹

The next year, Sandu et al. investigated the kinetics of clock gene expression in epidermal and dermal cells collected from the same donor and compared their characteristics. They were able to reveal the presence of functional circadian machinery in primary cultures of fibroblasts, keratinocytes, and melanocytes, with oscillators identified in all skin cell types and thought to be involved in spurring cutaneous rhythmic functions as they exhibited discrete periods and phase relationships between clock genes.¹²

Three years later, Sandu et al. characterized the circadian clocks in rat skin and dermal fibroblasts. They found that skin has a self-sustaining circadian clock that experiences age-dependent alterations, and that dermal fibroblasts manifest circadian rhythms that can be modulated by endogenous (e.g., melatonin) and exogenous (e.g., temperature) influences.¹³

In 2019, Park et al. demonstrated that the diurnal expression of the gene TIMP3, which is thought to evince a circadian rhythm in synchronized human keratinocytes, experiences disruptions in such rhythms by UVB exposure. The inflammation that results can be blocked, they argued, by recovering the circadian expression of TIMP3 using synthetic TIMP3 peptides or bioactive natural ingredients, such as green tea extracts.⁶

Conclusion

Circadian rhythms and the biological clocks by which most cells, including skin and hair cells, regulate themselves represent a ripe and fascinating area of research. Applying evidence in this realm to skin care has been occurring over time and is likely to enhance our practice even more as we continue to elucidate the behavior of cutaneous cells based on the solar day. Based on this information, my recommendations are to use antioxidants and protective products in the morning, and use DNA repair enzymes, retinoids, and other repair products at night.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann has written two textbooks and a New York Times Best Sellers book for consumers. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Revance, Evolus, and Burt’s Bees. She is the CEO of Skin Type Solutions, a company that independently tests skin care products and makes recommendations to physicians on which skin care technologies are best. Write to her at [email protected].

References

1. Dong K et al. Int J Mol Sci. 2020 Jan 3. doi: 10.3390/ijms21010326.

2. Dong K et al. Int J Cosmet Sci. 2019 Dec;41(6):558-62.

3. Lyons AB et al. J Clin Aesthet Dermatol. 2019 Sep;12(9):42-5.

4. Wu G et al. Proc Natl Acad Sci U S A. 2018 Nov 27;115(48):12313-8.

5. Vaughn AR et al. Pediatr Dermatol. 2018 Jan;35(1):152-7.

6. Park S et al. Int J Mol Sci. 2019 Feb 16. doi: 10.3390/ijms20040862.

7. Sherratt MJ et al. Matrix Biol. 2019 Nov;84:97-110.

8. Luber AJ et al. J Drugs Dermatol. 2014 Feb;13(2):130-4.

9. Le Fur I et al. J Invest Dermatol. 2001 Sep;117(3):718-24.

10. Kawara S et al. J Invest Dermatol. 2002 Dec;119(6):1220-3.

11. Spörl F et al. J Invest Dermatol. 2011 Feb;131(2):338-48.

12. Sandu C et al. Cell Mol Life Sci. 2012 Oct;69(19):3329-39.

13. Sandu C et al. Cell Mol Life Sci. 2015 Jun;72(11):2237-48.