Paxlovid, an antiviral approved in 2023 to treat acute infections of COVID-19, is showing great potential as a new treatment for long COVID and may be the most promising experimental therapy now being studied for treating the condition.

New research offers strong evidence that Paxlovid provides significant benefits for COVID-19 patients who are at high risk for severe or prolonged disease, particularly older adults and those who are immunocompromised, said Lisa Sanders, MD, medical director of Yale’s Long COVID Multidisciplinary Care Center, New Haven, Connecticut. 

“We all know that long COVID is a disease smorgasbord of illnesses that have been somehow triggered by COVID. So, the question is, are there some types of these disorders that can respond to Paxlovid?” Dr. Sanders said. 

Some patients have also benefited from supplements such as N-acetyl cysteine (NAC), as well as vitamins B, C, D and alpha lipoic acid, in which the risks are low and there are potential benefits, Dr. Sanders said.

As researchers continue to study new treatments for long COVID, for which there are no standard approved therapies, Dr. Sanders suggested doctors might turn to Paxlovid and other promising therapeutics that have shown benefits in preliminary study findings.

A study published in 2023 by JAMA Internal Medicine reviewed the charts of nearly 300,000 veterans with severe acute COVID infections. The study found that Paxlovid treatment reduced the likelihood of developing long COVID. But a more recent study at Stanford University, Palo Alto, California — the STOP-PASC trial— did not find Paxlovid improved symptoms when given to 155 patients who had already recovered from acute infection. Participants with long COVID symptoms — and who had on average recovered from acute infection around 16 months earlier — were given a 15-day course of Paxlovid. Common symptoms like fog, fatigue, and cardiovascular or gastrointestinal symptoms did not improve.

However, long COVID likely has multiple drivers. Viral persistence may still be at play for a subset of patients. This means that, despite the fact that patients recover from acute infection, hidden reservoirs of SARS-CoV-2 are still present in the body, possibly bringing on long COVID symptoms. Which means Paxlovid may help some long COVID patients but not others, Dr. Sanders explained. That’s why research needs to continue to identify the best cases for Paxlovid’s use and to identify other treatments for those who do not benefit from Paxlovid.

The PAX LC trial at Yale suggests there may not be a one-size-fits-all treatment for the condition, but a range of factors that may determine the best therapy for individual patients. Led by Yale School of Medicine’s Harlan Krumholz, MD, and Akiko Iwasaki, PhD, the study tested the effects of Paxlovid overall and was designed to determine who is most likely to benefit from antiviral treatment and gain further understanding of the immune response in long COVID. Results should be reported soon. 

“This acknowledges one line of thinking that long COVID is caused by viral persistence,” Dr. Sanders said. “Do these people have hidden reservoirs of the virus? The question is, are there people who seem to respond [to Paxlovid]? And if so, what characterizes these people?”
 

Low-Risk, High-Reward Supplements

Some of Dr. Sanders’ colleagues at Yale are focusing on long COVID’s neurological symptoms and neuropathogenesis. There’s evidence showing these symptoms — notably brain fog — can be treated with supplements. 

In 2022, a Yale study by Arman Fesharaki-Zadeh, MD, PhD, found promise in treating brain fog through a combination supplement of NAC and guanfacine — the latter developed by Yale neuroscientist, Amy Arnsten, PhD. 

The two published their study in Neuroimmunology Reports in November 2023. NAC is available over the counter and patients can get a prescription for guanfacine off label from their physician. Guanfacine is approved to treat high blood pressure by decreasing heart rate and relaxing blood vessels. But it’s also been shown to treat attention-deficit/hyperactivity disorder (ADHD) and other cognitive issues. 

Though NAC can treat respiratory problems, it’s also commonly used to treat postconcussion symptoms. Dr. Fesharaki-Zadeh found that it helps treat brain fog, increases energy, and improves memory. When paired with guanfacine, substantial benefits were reported, such as better multitasking abilities and markedly improved organizational skills. 

Dr. Sanders is now using NAC and guanfacine for patients in her clinic. 
 

‘Mitochondrial Enhancement’ Through Vitamins

Dr. Sanders has also used a combination of alpha lipoic acid and vitamin C, and a combo of B vitamins that make up what’s called a “mitochondrial enhancement regimen.”

To treat a very common symptom like fatigue, Dr. Sanders prefers supplement combinations over other drugs like Modafinil or Adderall. 

Modafinil is a central nervous system stimulant used to reduce extreme sleepiness caused by narcolepsy or other sleep disorders. Adderall is an amphetamine also used to treat narcolepsy as well as ADHD. Both work on your sleep and alertness, but long COVID affects the whole body, causing a physical fatigue similar to postexertional malaise (PEM) that isn’t remedied by those kinds of drugs, as studies suggest what’s involved in PEM is mitochondria, Dr. Sanders said. 

PEM is a worsening of symptoms that occurs after minimal physical or mental exertion. These are activities that should be well tolerated, but PEM causes extreme fatigue and flu-like symptoms. It’s become a hallmark symptom of long COVID after having already been a key diagnostic factor in myalgic encephalomyelitis/chronic fatigue syndrome.

As Dr. Sanders noted in her long COVID blog, which tracks the latest research and treatment options for doctors who treat long COVID patients, previous studies have shown low vitamin D levels may not only increase the risk for severe COVID-19 but delay recovery from long COVID. Those without long COVID had higher levels of vitamin D, compared with long COVID patients. Vitamin D is known to boost the immune system.

Dr. Sanders found that those with vitamin D deficiencies are most likely to benefit from this approach. For people who don’t have sufficient sun exposure, which prompts the production of vitamin D, she says supplementation with 1000 IUs of vitamin D3 daily is enough for most adults.

Research is also currently being underway on the use of the diabetes drug metformin in people with acute COVID infections to determine if it may reduce the likelihood of developing long COVID. In a recent long COVID clinical trial, early outpatient COVID-19 treatment with metformin decreased the subsequent risk for long COVID by 41.3% during 10-month follow-up. 
 

Other New Treatments Under Study

Dr. Sanders believes the foundation for many of long COVID’s symptoms could be neurological. 

“I think that long COVID is probably a neurologic disorder,” Dr. Sanders said. 

Lindsey McAlpine, MD, director of the Yale Medicine NeuroCovid Clinic, is focusing on neuropsychiatric long COVID and the causes of neurologic post-acute sequelae of SARS-CoV-2 infection (neuro-PASC). Symptoms of neuro-PASC include cognitive impairment, headaches, and dizziness.

“Lindsey is trying to see which parts of the brain are involved and see if there are phenotypes of brain abnormalities that match up with clinical abnormalities,” Dr. Sanders said.

The National Institute of Neurological Disorders and Stroke recently awarded her a 5-year K23 grant to support her ongoing study, “Magnetic Resonance Imaging Biomarkers of Post-COVID-19 Cerebral Microvascular Dysfunction.”

Utilizing advanced MRI techniques to identify microvascular dysfunction biomarkers in the brain, Dr. McAlpine hopes to unearth and better understand the pathophysiology behind neurological issues post COVID.

Many of Dr. McAlpine’s patients with cognitive symptoms have responded well to NAC and guanfacine. 

Still, the hope is that her brain-imaging studies will bear fruit that leads to a better understanding of long COVID and new treatment methods.

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

Paxlovid, an antiviral approved in 2023 to treat acute infections of COVID-19, is showing great potential as a new treatment for long COVID and may be the most promising experimental therapy now being studied for treating the condition.

New research offers strong evidence that Paxlovid provides significant benefits for COVID-19 patients who are at high risk for severe or prolonged disease, particularly older adults and those who are immunocompromised, said Lisa Sanders, MD, medical director of Yale’s Long COVID Multidisciplinary Care Center, New Haven, Connecticut. 

“We all know that long COVID is a disease smorgasbord of illnesses that have been somehow triggered by COVID. So, the question is, are there some types of these disorders that can respond to Paxlovid?” Dr. Sanders said. 

Some patients have also benefited from supplements such as N-acetyl cysteine (NAC), as well as vitamins B, C, D and alpha lipoic acid, in which the risks are low and there are potential benefits, Dr. Sanders said.

As researchers continue to study new treatments for long COVID, for which there are no standard approved therapies, Dr. Sanders suggested doctors might turn to Paxlovid and other promising therapeutics that have shown benefits in preliminary study findings.

A study published in 2023 by JAMA Internal Medicine reviewed the charts of nearly 300,000 veterans with severe acute COVID infections. The study found that Paxlovid treatment reduced the likelihood of developing long COVID. But a more recent study at Stanford University, Palo Alto, California — the STOP-PASC trial— did not find Paxlovid improved symptoms when given to 155 patients who had already recovered from acute infection. Participants with long COVID symptoms — and who had on average recovered from acute infection around 16 months earlier — were given a 15-day course of Paxlovid. Common symptoms like fog, fatigue, and cardiovascular or gastrointestinal symptoms did not improve.

However, long COVID likely has multiple drivers. Viral persistence may still be at play for a subset of patients. This means that, despite the fact that patients recover from acute infection, hidden reservoirs of SARS-CoV-2 are still present in the body, possibly bringing on long COVID symptoms. Which means Paxlovid may help some long COVID patients but not others, Dr. Sanders explained. That’s why research needs to continue to identify the best cases for Paxlovid’s use and to identify other treatments for those who do not benefit from Paxlovid.

The PAX LC trial at Yale suggests there may not be a one-size-fits-all treatment for the condition, but a range of factors that may determine the best therapy for individual patients. Led by Yale School of Medicine’s Harlan Krumholz, MD, and Akiko Iwasaki, PhD, the study tested the effects of Paxlovid overall and was designed to determine who is most likely to benefit from antiviral treatment and gain further understanding of the immune response in long COVID. Results should be reported soon. 

“This acknowledges one line of thinking that long COVID is caused by viral persistence,” Dr. Sanders said. “Do these people have hidden reservoirs of the virus? The question is, are there people who seem to respond [to Paxlovid]? And if so, what characterizes these people?”
 

Low-Risk, High-Reward Supplements

Some of Dr. Sanders’ colleagues at Yale are focusing on long COVID’s neurological symptoms and neuropathogenesis. There’s evidence showing these symptoms — notably brain fog — can be treated with supplements. 

In 2022, a Yale study by Arman Fesharaki-Zadeh, MD, PhD, found promise in treating brain fog through a combination supplement of NAC and guanfacine — the latter developed by Yale neuroscientist, Amy Arnsten, PhD. 

The two published their study in Neuroimmunology Reports in November 2023. NAC is available over the counter and patients can get a prescription for guanfacine off label from their physician. Guanfacine is approved to treat high blood pressure by decreasing heart rate and relaxing blood vessels. But it’s also been shown to treat attention-deficit/hyperactivity disorder (ADHD) and other cognitive issues. 

Though NAC can treat respiratory problems, it’s also commonly used to treat postconcussion symptoms. Dr. Fesharaki-Zadeh found that it helps treat brain fog, increases energy, and improves memory. When paired with guanfacine, substantial benefits were reported, such as better multitasking abilities and markedly improved organizational skills. 

Dr. Sanders is now using NAC and guanfacine for patients in her clinic. 
 

‘Mitochondrial Enhancement’ Through Vitamins

Dr. Sanders has also used a combination of alpha lipoic acid and vitamin C, and a combo of B vitamins that make up what’s called a “mitochondrial enhancement regimen.”

To treat a very common symptom like fatigue, Dr. Sanders prefers supplement combinations over other drugs like Modafinil or Adderall. 

Modafinil is a central nervous system stimulant used to reduce extreme sleepiness caused by narcolepsy or other sleep disorders. Adderall is an amphetamine also used to treat narcolepsy as well as ADHD. Both work on your sleep and alertness, but long COVID affects the whole body, causing a physical fatigue similar to postexertional malaise (PEM) that isn’t remedied by those kinds of drugs, as studies suggest what’s involved in PEM is mitochondria, Dr. Sanders said. 

PEM is a worsening of symptoms that occurs after minimal physical or mental exertion. These are activities that should be well tolerated, but PEM causes extreme fatigue and flu-like symptoms. It’s become a hallmark symptom of long COVID after having already been a key diagnostic factor in myalgic encephalomyelitis/chronic fatigue syndrome.

As Dr. Sanders noted in her long COVID blog, which tracks the latest research and treatment options for doctors who treat long COVID patients, previous studies have shown low vitamin D levels may not only increase the risk for severe COVID-19 but delay recovery from long COVID. Those without long COVID had higher levels of vitamin D, compared with long COVID patients. Vitamin D is known to boost the immune system.

Dr. Sanders found that those with vitamin D deficiencies are most likely to benefit from this approach. For people who don’t have sufficient sun exposure, which prompts the production of vitamin D, she says supplementation with 1000 IUs of vitamin D3 daily is enough for most adults.

Research is also currently being underway on the use of the diabetes drug metformin in people with acute COVID infections to determine if it may reduce the likelihood of developing long COVID. In a recent long COVID clinical trial, early outpatient COVID-19 treatment with metformin decreased the subsequent risk for long COVID by 41.3% during 10-month follow-up. 
 

Other New Treatments Under Study

Dr. Sanders believes the foundation for many of long COVID’s symptoms could be neurological. 

“I think that long COVID is probably a neurologic disorder,” Dr. Sanders said. 

Lindsey McAlpine, MD, director of the Yale Medicine NeuroCovid Clinic, is focusing on neuropsychiatric long COVID and the causes of neurologic post-acute sequelae of SARS-CoV-2 infection (neuro-PASC). Symptoms of neuro-PASC include cognitive impairment, headaches, and dizziness.

“Lindsey is trying to see which parts of the brain are involved and see if there are phenotypes of brain abnormalities that match up with clinical abnormalities,” Dr. Sanders said.

The National Institute of Neurological Disorders and Stroke recently awarded her a 5-year K23 grant to support her ongoing study, “Magnetic Resonance Imaging Biomarkers of Post-COVID-19 Cerebral Microvascular Dysfunction.”

Utilizing advanced MRI techniques to identify microvascular dysfunction biomarkers in the brain, Dr. McAlpine hopes to unearth and better understand the pathophysiology behind neurological issues post COVID.

Many of Dr. McAlpine’s patients with cognitive symptoms have responded well to NAC and guanfacine. 

Still, the hope is that her brain-imaging studies will bear fruit that leads to a better understanding of long COVID and new treatment methods.

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

Paxlovid, an antiviral approved in 2023 to treat acute infections of COVID-19, is showing great potential as a new treatment for long COVID and may be the most promising experimental therapy now being studied for treating the condition.

New research offers strong evidence that Paxlovid provides significant benefits for COVID-19 patients who are at high risk for severe or prolonged disease, particularly older adults and those who are immunocompromised, said Lisa Sanders, MD, medical director of Yale’s Long COVID Multidisciplinary Care Center, New Haven, Connecticut. 

“We all know that long COVID is a disease smorgasbord of illnesses that have been somehow triggered by COVID. So, the question is, are there some types of these disorders that can respond to Paxlovid?” Dr. Sanders said. 

Some patients have also benefited from supplements such as N-acetyl cysteine (NAC), as well as vitamins B, C, D and alpha lipoic acid, in which the risks are low and there are potential benefits, Dr. Sanders said.

As researchers continue to study new treatments for long COVID, for which there are no standard approved therapies, Dr. Sanders suggested doctors might turn to Paxlovid and other promising therapeutics that have shown benefits in preliminary study findings.

A study published in 2023 by JAMA Internal Medicine reviewed the charts of nearly 300,000 veterans with severe acute COVID infections. The study found that Paxlovid treatment reduced the likelihood of developing long COVID. But a more recent study at Stanford University, Palo Alto, California — the STOP-PASC trial— did not find Paxlovid improved symptoms when given to 155 patients who had already recovered from acute infection. Participants with long COVID symptoms — and who had on average recovered from acute infection around 16 months earlier — were given a 15-day course of Paxlovid. Common symptoms like fog, fatigue, and cardiovascular or gastrointestinal symptoms did not improve.

However, long COVID likely has multiple drivers. Viral persistence may still be at play for a subset of patients. This means that, despite the fact that patients recover from acute infection, hidden reservoirs of SARS-CoV-2 are still present in the body, possibly bringing on long COVID symptoms. Which means Paxlovid may help some long COVID patients but not others, Dr. Sanders explained. That’s why research needs to continue to identify the best cases for Paxlovid’s use and to identify other treatments for those who do not benefit from Paxlovid.

The PAX LC trial at Yale suggests there may not be a one-size-fits-all treatment for the condition, but a range of factors that may determine the best therapy for individual patients. Led by Yale School of Medicine’s Harlan Krumholz, MD, and Akiko Iwasaki, PhD, the study tested the effects of Paxlovid overall and was designed to determine who is most likely to benefit from antiviral treatment and gain further understanding of the immune response in long COVID. Results should be reported soon. 

“This acknowledges one line of thinking that long COVID is caused by viral persistence,” Dr. Sanders said. “Do these people have hidden reservoirs of the virus? The question is, are there people who seem to respond [to Paxlovid]? And if so, what characterizes these people?”
 

Low-Risk, High-Reward Supplements

Some of Dr. Sanders’ colleagues at Yale are focusing on long COVID’s neurological symptoms and neuropathogenesis. There’s evidence showing these symptoms — notably brain fog — can be treated with supplements. 

In 2022, a Yale study by Arman Fesharaki-Zadeh, MD, PhD, found promise in treating brain fog through a combination supplement of NAC and guanfacine — the latter developed by Yale neuroscientist, Amy Arnsten, PhD. 

The two published their study in Neuroimmunology Reports in November 2023. NAC is available over the counter and patients can get a prescription for guanfacine off label from their physician. Guanfacine is approved to treat high blood pressure by decreasing heart rate and relaxing blood vessels. But it’s also been shown to treat attention-deficit/hyperactivity disorder (ADHD) and other cognitive issues. 

Though NAC can treat respiratory problems, it’s also commonly used to treat postconcussion symptoms. Dr. Fesharaki-Zadeh found that it helps treat brain fog, increases energy, and improves memory. When paired with guanfacine, substantial benefits were reported, such as better multitasking abilities and markedly improved organizational skills. 

Dr. Sanders is now using NAC and guanfacine for patients in her clinic. 
 

‘Mitochondrial Enhancement’ Through Vitamins

Dr. Sanders has also used a combination of alpha lipoic acid and vitamin C, and a combo of B vitamins that make up what’s called a “mitochondrial enhancement regimen.”

To treat a very common symptom like fatigue, Dr. Sanders prefers supplement combinations over other drugs like Modafinil or Adderall. 

Modafinil is a central nervous system stimulant used to reduce extreme sleepiness caused by narcolepsy or other sleep disorders. Adderall is an amphetamine also used to treat narcolepsy as well as ADHD. Both work on your sleep and alertness, but long COVID affects the whole body, causing a physical fatigue similar to postexertional malaise (PEM) that isn’t remedied by those kinds of drugs, as studies suggest what’s involved in PEM is mitochondria, Dr. Sanders said. 

PEM is a worsening of symptoms that occurs after minimal physical or mental exertion. These are activities that should be well tolerated, but PEM causes extreme fatigue and flu-like symptoms. It’s become a hallmark symptom of long COVID after having already been a key diagnostic factor in myalgic encephalomyelitis/chronic fatigue syndrome.

As Dr. Sanders noted in her long COVID blog, which tracks the latest research and treatment options for doctors who treat long COVID patients, previous studies have shown low vitamin D levels may not only increase the risk for severe COVID-19 but delay recovery from long COVID. Those without long COVID had higher levels of vitamin D, compared with long COVID patients. Vitamin D is known to boost the immune system.

Dr. Sanders found that those with vitamin D deficiencies are most likely to benefit from this approach. For people who don’t have sufficient sun exposure, which prompts the production of vitamin D, she says supplementation with 1000 IUs of vitamin D3 daily is enough for most adults.

Research is also currently being underway on the use of the diabetes drug metformin in people with acute COVID infections to determine if it may reduce the likelihood of developing long COVID. In a recent long COVID clinical trial, early outpatient COVID-19 treatment with metformin decreased the subsequent risk for long COVID by 41.3% during 10-month follow-up. 
 

Other New Treatments Under Study

Dr. Sanders believes the foundation for many of long COVID’s symptoms could be neurological. 

“I think that long COVID is probably a neurologic disorder,” Dr. Sanders said. 

Lindsey McAlpine, MD, director of the Yale Medicine NeuroCovid Clinic, is focusing on neuropsychiatric long COVID and the causes of neurologic post-acute sequelae of SARS-CoV-2 infection (neuro-PASC). Symptoms of neuro-PASC include cognitive impairment, headaches, and dizziness.

“Lindsey is trying to see which parts of the brain are involved and see if there are phenotypes of brain abnormalities that match up with clinical abnormalities,” Dr. Sanders said.

The National Institute of Neurological Disorders and Stroke recently awarded her a 5-year K23 grant to support her ongoing study, “Magnetic Resonance Imaging Biomarkers of Post-COVID-19 Cerebral Microvascular Dysfunction.”

Utilizing advanced MRI techniques to identify microvascular dysfunction biomarkers in the brain, Dr. McAlpine hopes to unearth and better understand the pathophysiology behind neurological issues post COVID.

Many of Dr. McAlpine’s patients with cognitive symptoms have responded well to NAC and guanfacine. 

Still, the hope is that her brain-imaging studies will bear fruit that leads to a better understanding of long COVID and new treatment methods.

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

The escalating costs of medications and the prevalence of medical bankruptcy in our country have drawn criticism from governments, regulators, and the media. Federal and state governments are exploring various strategies to mitigate this issue, including the Inflation Reduction Act (IRA) for drug price negotiations and the establishment of state Pharmaceutical Drug Affordability Boards (PDABs). However, it’s uncertain whether these measures will effectively reduce patients’ medication expenses, given the tendency of pharmacy benefit managers (PBMs) to favor more expensive drugs on their formularies and the implementation challenges faced by PDABs.

The question then arises: How can we promptly assist patients, especially those with multiple chronic conditions, in affording their healthcare? Many of these patients are enrolled in high-deductible plans and struggle to cover all their medical and pharmacy costs.

A significant obstacle to healthcare affordability emerged in 2018 with the introduction of Copay Accumulator Programs by PBMs. These programs prevent patients from applying manufacturer copay cards toward their deductible and maximum out-of-pocket (OOP) costs. The impact of these policies has been devastating, leading to decreased adherence to medications and delayed necessary medical procedures, such as colonoscopies. Copay accumulators do nothing to address the high cost of medical care. They merely shift the burden from insurance companies to patients.

There is a direct solution to help patients, particularly those burdened with high pharmacy bills, afford their medical care. It would be that all payments from patients, including manufacturer copay cards, count toward their deductible and maximum OOP costs. This should apply regardless of whether the insurance plan is fully funded or a self-insured employer plan. This would be an immediate step toward making healthcare more affordable for patients.
 

Copay Accumulator Programs

How did these detrimental policies, which have been proven to harm patients, originate? It’s interesting that health insurance policies for federal employees do not allow these programs and yet the federal government has done little to protect its citizens from these egregious policies. More on that later.

In 2018, insurance companies and PBMs conceived an idea to introduce what they called copay accumulator adjustment programs. These programs would prevent the use of manufacturer copay cards from counting toward patient deductibles or OOP maximums. They justified this by arguing that manufacturer copay cards encouraged patients to opt for higher-priced brand drugs when lower-cost generics were available.

However, data from IQVIA contradicts this claim. An analysis of copay card usage from 2013 to 2017 revealed that a mere 0.4% of these cards were used for brand-name drugs that had already lost their exclusivity. This indicates that the vast majority of copay cards were not being used to purchase more expensive brand-name drugs when cheaper, generic alternatives were available.

Another argument put forth by one of the large PBMs was that patients with high deductibles don’t have enough “skin in the game” due to their low premiums, and therefore don’t deserve to have their deductible covered by a copay card. This raises the question, “Does a patient with hemophilia or systemic lupus who can’t afford a low deductible plan not have ‘skin in the game’? Is that a fair assessment?” It’s disconcerting to see a multibillion-dollar company dictating who deserves to have their deductible covered. These policies clearly disproportionately harm patients with chronic illnesses, especially those with high deductibles. As a result, many organizations have labeled these policies as discriminatory.

Following the implementation of accumulator programs in 2018 and 2019, many patients were unaware that their copay cards weren’t contributing toward their deductibles. They were taken aback when specialty pharmacies informed them of owing substantial amounts because of unmet deductibles. Consequently, patients discontinued their medications, leading to disease progression and increased costs. The only downside for health insurers and PBMs was the negative publicity associated with patients losing medication access.
 

Maximizer Programs

By the end of 2019, the three major PBMs had devised a strategy to keep patients on their medication throughout the year, without counting copay cards toward the deductible, and found a way to profit more from these cards, sometimes quadrupling their value. This was the birth of the maximizer programs.

Maximizers exploit a “loophole” in the Affordable Care Act (ACA). The ACA defines Essential Healthcare Benefits (EHB); anything not listed as an EHB is deemed “non-essential.” As a result, neither personal payments nor copay cards count toward deductibles or OOP maximums. Patients were informed that neither their own money nor manufacturer copay cards would count toward their deductible/OOP max.

One of my patients was warned that without enrolling in the maximizer program through SaveOnSP (owned by Express Scripts), she would bear the full cost of the drug, and nothing would count toward her OOP max. Frightened, she enrolled and surrendered her manufacturer copay card to SaveOnSP. Maximizers pocket the maximum value of the copay card, even if it exceeds the insurance plan’s yearly cost share by threefold or more. To do this legally, PBMs increase the patient’s original cost share amount during the plan year to match the value of the manufacturer copay card.
 

Combating These Programs

Nineteen states, the District of Columbia, and Puerto Rico have outlawed copay accumulators in health plans under state jurisdiction. I personally testified in Louisiana, leading to a ban in our state. CSRO’s award-winning map tool can show if your state has passed the ban on copay accumulator programs. However, many states have not passed bans on copay accumulators and self-insured employer groups, which fall under the Department of Labor and not state regulation, are still unaffected. There is also proposed federal legislation, the “Help Ensure Lower Patient Copays Act,” that would prohibit the use of copay accumulators in exchange plans. Despite having bipartisan support, it is having a hard time getting across the finish line in Congress.

In 2020, the Department of Health and Human Services (HHS) issued a rule prohibiting accumulator programs in all plans if the product was a brand name without a generic alternative. Unfortunately, this rule was rescinded in 2021, allowing copay accumulators even if a lower-cost generic was available.

In a positive turn of events, the US District Court of the District of Columbia overturned the 2021 rule in late 2023, reinstating the 2020 ban on copay accumulators. However, HHS has yet to enforce this ban.
 

Double Standard

Why is it that our federal government refrains from enforcing bans on copay accumulators for the American public, yet the US Office of Personnel Management (OPM) in its 2024 health plan for federal employees has explicitly stated that it “will decline any arrangements which may manipulate the prescription drug benefit design or incorporate any programs such as copay maximizers, copay optimizers, or other similar programs as these types of benefit designs are not in the best interest of enrollees or the Government.”

If such practices are deemed unsuitable for federal employees, why are they considered acceptable for the rest of the American population? This discrepancy raises important questions about healthcare equity.

In conclusion, the prevalence of medical bankruptcy in our country is a pressing issue that requires immediate attention. The introduction of copay accumulator programs and maximizers by PBMs has led to decreased adherence to needed medications, as well as delay in important medical procedures, exacerbating this situation. An across-the-board ban on these programs would offer immediate relief to many families that no longer can afford needed care.

It is clear that more needs to be done to ensure that all patients, regardless of their financial situation or the nature of their health insurance plan, can afford the healthcare they need. This includes ensuring that patients are not penalized for using manufacturer copay cards to help cover their costs. As we move forward, it is crucial that we continue to advocate for policies that prioritize the health and well-being of all patients.
 

Dr. Feldman is a rheumatologist in private practice with The Rheumatology Group in New Orleans. She is the CSRO’s vice president of Advocacy and Government Affairs and its immediate past president, as well as past chair of the Alliance for Safe Biologic Medicines and a past member of the American College of Rheumatology insurance subcommittee. You can reach her at [email protected].

The escalating costs of medications and the prevalence of medical bankruptcy in our country have drawn criticism from governments, regulators, and the media. Federal and state governments are exploring various strategies to mitigate this issue, including the Inflation Reduction Act (IRA) for drug price negotiations and the establishment of state Pharmaceutical Drug Affordability Boards (PDABs). However, it’s uncertain whether these measures will effectively reduce patients’ medication expenses, given the tendency of pharmacy benefit managers (PBMs) to favor more expensive drugs on their formularies and the implementation challenges faced by PDABs.

The question then arises: How can we promptly assist patients, especially those with multiple chronic conditions, in affording their healthcare? Many of these patients are enrolled in high-deductible plans and struggle to cover all their medical and pharmacy costs.

A significant obstacle to healthcare affordability emerged in 2018 with the introduction of Copay Accumulator Programs by PBMs. These programs prevent patients from applying manufacturer copay cards toward their deductible and maximum out-of-pocket (OOP) costs. The impact of these policies has been devastating, leading to decreased adherence to medications and delayed necessary medical procedures, such as colonoscopies. Copay accumulators do nothing to address the high cost of medical care. They merely shift the burden from insurance companies to patients.

There is a direct solution to help patients, particularly those burdened with high pharmacy bills, afford their medical care. It would be that all payments from patients, including manufacturer copay cards, count toward their deductible and maximum OOP costs. This should apply regardless of whether the insurance plan is fully funded or a self-insured employer plan. This would be an immediate step toward making healthcare more affordable for patients.
 

Copay Accumulator Programs

How did these detrimental policies, which have been proven to harm patients, originate? It’s interesting that health insurance policies for federal employees do not allow these programs and yet the federal government has done little to protect its citizens from these egregious policies. More on that later.

In 2018, insurance companies and PBMs conceived an idea to introduce what they called copay accumulator adjustment programs. These programs would prevent the use of manufacturer copay cards from counting toward patient deductibles or OOP maximums. They justified this by arguing that manufacturer copay cards encouraged patients to opt for higher-priced brand drugs when lower-cost generics were available.

However, data from IQVIA contradicts this claim. An analysis of copay card usage from 2013 to 2017 revealed that a mere 0.4% of these cards were used for brand-name drugs that had already lost their exclusivity. This indicates that the vast majority of copay cards were not being used to purchase more expensive brand-name drugs when cheaper, generic alternatives were available.

Another argument put forth by one of the large PBMs was that patients with high deductibles don’t have enough “skin in the game” due to their low premiums, and therefore don’t deserve to have their deductible covered by a copay card. This raises the question, “Does a patient with hemophilia or systemic lupus who can’t afford a low deductible plan not have ‘skin in the game’? Is that a fair assessment?” It’s disconcerting to see a multibillion-dollar company dictating who deserves to have their deductible covered. These policies clearly disproportionately harm patients with chronic illnesses, especially those with high deductibles. As a result, many organizations have labeled these policies as discriminatory.

Following the implementation of accumulator programs in 2018 and 2019, many patients were unaware that their copay cards weren’t contributing toward their deductibles. They were taken aback when specialty pharmacies informed them of owing substantial amounts because of unmet deductibles. Consequently, patients discontinued their medications, leading to disease progression and increased costs. The only downside for health insurers and PBMs was the negative publicity associated with patients losing medication access.
 

Maximizer Programs

By the end of 2019, the three major PBMs had devised a strategy to keep patients on their medication throughout the year, without counting copay cards toward the deductible, and found a way to profit more from these cards, sometimes quadrupling their value. This was the birth of the maximizer programs.

Maximizers exploit a “loophole” in the Affordable Care Act (ACA). The ACA defines Essential Healthcare Benefits (EHB); anything not listed as an EHB is deemed “non-essential.” As a result, neither personal payments nor copay cards count toward deductibles or OOP maximums. Patients were informed that neither their own money nor manufacturer copay cards would count toward their deductible/OOP max.

One of my patients was warned that without enrolling in the maximizer program through SaveOnSP (owned by Express Scripts), she would bear the full cost of the drug, and nothing would count toward her OOP max. Frightened, she enrolled and surrendered her manufacturer copay card to SaveOnSP. Maximizers pocket the maximum value of the copay card, even if it exceeds the insurance plan’s yearly cost share by threefold or more. To do this legally, PBMs increase the patient’s original cost share amount during the plan year to match the value of the manufacturer copay card.
 

Combating These Programs

Nineteen states, the District of Columbia, and Puerto Rico have outlawed copay accumulators in health plans under state jurisdiction. I personally testified in Louisiana, leading to a ban in our state. CSRO’s award-winning map tool can show if your state has passed the ban on copay accumulator programs. However, many states have not passed bans on copay accumulators and self-insured employer groups, which fall under the Department of Labor and not state regulation, are still unaffected. There is also proposed federal legislation, the “Help Ensure Lower Patient Copays Act,” that would prohibit the use of copay accumulators in exchange plans. Despite having bipartisan support, it is having a hard time getting across the finish line in Congress.

In 2020, the Department of Health and Human Services (HHS) issued a rule prohibiting accumulator programs in all plans if the product was a brand name without a generic alternative. Unfortunately, this rule was rescinded in 2021, allowing copay accumulators even if a lower-cost generic was available.

In a positive turn of events, the US District Court of the District of Columbia overturned the 2021 rule in late 2023, reinstating the 2020 ban on copay accumulators. However, HHS has yet to enforce this ban.
 

Double Standard

Why is it that our federal government refrains from enforcing bans on copay accumulators for the American public, yet the US Office of Personnel Management (OPM) in its 2024 health plan for federal employees has explicitly stated that it “will decline any arrangements which may manipulate the prescription drug benefit design or incorporate any programs such as copay maximizers, copay optimizers, or other similar programs as these types of benefit designs are not in the best interest of enrollees or the Government.”

If such practices are deemed unsuitable for federal employees, why are they considered acceptable for the rest of the American population? This discrepancy raises important questions about healthcare equity.

In conclusion, the prevalence of medical bankruptcy in our country is a pressing issue that requires immediate attention. The introduction of copay accumulator programs and maximizers by PBMs has led to decreased adherence to needed medications, as well as delay in important medical procedures, exacerbating this situation. An across-the-board ban on these programs would offer immediate relief to many families that no longer can afford needed care.

It is clear that more needs to be done to ensure that all patients, regardless of their financial situation or the nature of their health insurance plan, can afford the healthcare they need. This includes ensuring that patients are not penalized for using manufacturer copay cards to help cover their costs. As we move forward, it is crucial that we continue to advocate for policies that prioritize the health and well-being of all patients.
 

Dr. Feldman is a rheumatologist in private practice with The Rheumatology Group in New Orleans. She is the CSRO’s vice president of Advocacy and Government Affairs and its immediate past president, as well as past chair of the Alliance for Safe Biologic Medicines and a past member of the American College of Rheumatology insurance subcommittee. You can reach her at [email protected].

The escalating costs of medications and the prevalence of medical bankruptcy in our country have drawn criticism from governments, regulators, and the media. Federal and state governments are exploring various strategies to mitigate this issue, including the Inflation Reduction Act (IRA) for drug price negotiations and the establishment of state Pharmaceutical Drug Affordability Boards (PDABs). However, it’s uncertain whether these measures will effectively reduce patients’ medication expenses, given the tendency of pharmacy benefit managers (PBMs) to favor more expensive drugs on their formularies and the implementation challenges faced by PDABs.

The question then arises: How can we promptly assist patients, especially those with multiple chronic conditions, in affording their healthcare? Many of these patients are enrolled in high-deductible plans and struggle to cover all their medical and pharmacy costs.

A significant obstacle to healthcare affordability emerged in 2018 with the introduction of Copay Accumulator Programs by PBMs. These programs prevent patients from applying manufacturer copay cards toward their deductible and maximum out-of-pocket (OOP) costs. The impact of these policies has been devastating, leading to decreased adherence to medications and delayed necessary medical procedures, such as colonoscopies. Copay accumulators do nothing to address the high cost of medical care. They merely shift the burden from insurance companies to patients.

There is a direct solution to help patients, particularly those burdened with high pharmacy bills, afford their medical care. It would be that all payments from patients, including manufacturer copay cards, count toward their deductible and maximum OOP costs. This should apply regardless of whether the insurance plan is fully funded or a self-insured employer plan. This would be an immediate step toward making healthcare more affordable for patients.
 

Copay Accumulator Programs

How did these detrimental policies, which have been proven to harm patients, originate? It’s interesting that health insurance policies for federal employees do not allow these programs and yet the federal government has done little to protect its citizens from these egregious policies. More on that later.

In 2018, insurance companies and PBMs conceived an idea to introduce what they called copay accumulator adjustment programs. These programs would prevent the use of manufacturer copay cards from counting toward patient deductibles or OOP maximums. They justified this by arguing that manufacturer copay cards encouraged patients to opt for higher-priced brand drugs when lower-cost generics were available.

However, data from IQVIA contradicts this claim. An analysis of copay card usage from 2013 to 2017 revealed that a mere 0.4% of these cards were used for brand-name drugs that had already lost their exclusivity. This indicates that the vast majority of copay cards were not being used to purchase more expensive brand-name drugs when cheaper, generic alternatives were available.

Another argument put forth by one of the large PBMs was that patients with high deductibles don’t have enough “skin in the game” due to their low premiums, and therefore don’t deserve to have their deductible covered by a copay card. This raises the question, “Does a patient with hemophilia or systemic lupus who can’t afford a low deductible plan not have ‘skin in the game’? Is that a fair assessment?” It’s disconcerting to see a multibillion-dollar company dictating who deserves to have their deductible covered. These policies clearly disproportionately harm patients with chronic illnesses, especially those with high deductibles. As a result, many organizations have labeled these policies as discriminatory.

Following the implementation of accumulator programs in 2018 and 2019, many patients were unaware that their copay cards weren’t contributing toward their deductibles. They were taken aback when specialty pharmacies informed them of owing substantial amounts because of unmet deductibles. Consequently, patients discontinued their medications, leading to disease progression and increased costs. The only downside for health insurers and PBMs was the negative publicity associated with patients losing medication access.
 

Maximizer Programs

By the end of 2019, the three major PBMs had devised a strategy to keep patients on their medication throughout the year, without counting copay cards toward the deductible, and found a way to profit more from these cards, sometimes quadrupling their value. This was the birth of the maximizer programs.

Maximizers exploit a “loophole” in the Affordable Care Act (ACA). The ACA defines Essential Healthcare Benefits (EHB); anything not listed as an EHB is deemed “non-essential.” As a result, neither personal payments nor copay cards count toward deductibles or OOP maximums. Patients were informed that neither their own money nor manufacturer copay cards would count toward their deductible/OOP max.

One of my patients was warned that without enrolling in the maximizer program through SaveOnSP (owned by Express Scripts), she would bear the full cost of the drug, and nothing would count toward her OOP max. Frightened, she enrolled and surrendered her manufacturer copay card to SaveOnSP. Maximizers pocket the maximum value of the copay card, even if it exceeds the insurance plan’s yearly cost share by threefold or more. To do this legally, PBMs increase the patient’s original cost share amount during the plan year to match the value of the manufacturer copay card.
 

Combating These Programs

Nineteen states, the District of Columbia, and Puerto Rico have outlawed copay accumulators in health plans under state jurisdiction. I personally testified in Louisiana, leading to a ban in our state. CSRO’s award-winning map tool can show if your state has passed the ban on copay accumulator programs. However, many states have not passed bans on copay accumulators and self-insured employer groups, which fall under the Department of Labor and not state regulation, are still unaffected. There is also proposed federal legislation, the “Help Ensure Lower Patient Copays Act,” that would prohibit the use of copay accumulators in exchange plans. Despite having bipartisan support, it is having a hard time getting across the finish line in Congress.

In 2020, the Department of Health and Human Services (HHS) issued a rule prohibiting accumulator programs in all plans if the product was a brand name without a generic alternative. Unfortunately, this rule was rescinded in 2021, allowing copay accumulators even if a lower-cost generic was available.

In a positive turn of events, the US District Court of the District of Columbia overturned the 2021 rule in late 2023, reinstating the 2020 ban on copay accumulators. However, HHS has yet to enforce this ban.
 

Double Standard

Why is it that our federal government refrains from enforcing bans on copay accumulators for the American public, yet the US Office of Personnel Management (OPM) in its 2024 health plan for federal employees has explicitly stated that it “will decline any arrangements which may manipulate the prescription drug benefit design or incorporate any programs such as copay maximizers, copay optimizers, or other similar programs as these types of benefit designs are not in the best interest of enrollees or the Government.”

If such practices are deemed unsuitable for federal employees, why are they considered acceptable for the rest of the American population? This discrepancy raises important questions about healthcare equity.

In conclusion, the prevalence of medical bankruptcy in our country is a pressing issue that requires immediate attention. The introduction of copay accumulator programs and maximizers by PBMs has led to decreased adherence to needed medications, as well as delay in important medical procedures, exacerbating this situation. An across-the-board ban on these programs would offer immediate relief to many families that no longer can afford needed care.

It is clear that more needs to be done to ensure that all patients, regardless of their financial situation or the nature of their health insurance plan, can afford the healthcare they need. This includes ensuring that patients are not penalized for using manufacturer copay cards to help cover their costs. As we move forward, it is crucial that we continue to advocate for policies that prioritize the health and well-being of all patients.
 

Dr. Feldman is a rheumatologist in private practice with The Rheumatology Group in New Orleans. She is the CSRO’s vice president of Advocacy and Government Affairs and its immediate past president, as well as past chair of the Alliance for Safe Biologic Medicines and a past member of the American College of Rheumatology insurance subcommittee. You can reach her at [email protected].

CHICAGO — Being hormone receptor positive is generally a favorable prognostic factor in breast cancer, but that doesn’t seem to be the case in women with BRCA-associated tumors, according to a study presented at the American Society of Clinical Oncology annual meeting.

The conclusion is based on a large international study on how hormone receptor status impacts breast cancer outcomes in young women with germline BRCA pathological variants (PVs).

Overall, “hormone receptor positivity did not seem to have a strong positive prognostic value in young BRCA carriers” with early breast cancer, lead investigator Luca Arecco, MD, an oncology resident at the University of Genoa, Italy, said at the meeting.

Investigators reviewed the records of 4709 women ages 40 years or younger with stage 1-3 BRCA-associated invasive breast cancer treated from 2000 to 2020 at 78 centers in 28 countries across four continents. Median follow-up was about 8 years.
 

Weaker Prognostic Value in Hormone Receptor Status

They found, in general, that hormone receptor–positive breast cancer appears to be biologically more aggressive in patients with BRCA PVs than in the general breast cancer population, generating outcomes similar to those with hormone receptor-negative BRCA tumors.

Specifically, among patients with germline BRCA PVs, while hormone receptor–positive patients had a higher distant recurrence rate (13.1% vs. 9.6%) than hormone receptor–negative patients, 8-year disease free survival (65.8% and 63.4% respectively) and overall survival (a bit under 90% in both groups) were similar.

Hormone receptor–positive patients did have a lower rate of second primary breast cancers (9.1% versus 14.7%).

In the formal write-up of the results published shortly after the meeting in Annals of Oncology, the investigators concluded that “in young BRCA carriers, differences in recurrence pattern and second primary breast cancer among hormone receptor–positive versus negative disease warrant consideration in counseling patients on treatment, follow-up, and risk-reducing surgery.”

The team also found other differences between BRCA-associated breast cancer and sporadic disease. For instance, in the BRCA cohort, luminal A-like breast cancer had a worse long-term prognosis in their BRCA cohort than triple-negative or HER2-positive disease. Luminal A-like tumors are generally considered less aggressive, but in patients with BRCA PVs, “improving neoadjuvant chemotherapy … could be worthwhile,” the investigators said.

Also, although the risk of recurrence for sporadic hormone receptor–negative tumors is highest in the first few years, the team found that the risk in the hormone negative BRCA cohort progressively increased with longer follow-up, driven by the occurrence of second primary breast cancers, especially in patients with BRCA 1 PVs.
 

Greater Clarity in Prognosis in BRCA-Associated Breast Cancer

Overall, study discussant Lisa A. Carey, MD, a breast cancer specialist at the University of North Carolina at Chapel Hill, said, “we now know much more clearly the issues of prognosis in women who are very young and have germline BRCA-associated breast cancer,” about 12% of newly diagnosed cases.

“Young patients with germline BRCA-associated breast cancers have high relapse and high new primary risks, warranting comprehensive multimodality therapy,” she said.

A bit fewer than half of women in the study were hormone receptor–positive, and they tended to be patients with BRCA 2 PVs. The rest were hormone receptor–negative and tended to have BRCA 1 PVs.

Patients with hormone receptor–positive disease had grade 3 cancers in about 50% of cases, while patients with hormone receptor–negative disease had a grade 3 disease in over 80%.

Hormone receptor–positive patients were more likely to have nodal involvement and undergo mastectomies but less likely to receive chemotherapy than hormone receptor–negative patients. It’s likely that few patients in the review received PARP inhibitors, Dr. Carey noted.

Although overall survival at 8 years was similar in both groups, after that point “the prognosis of patients with hormone receptor–positive disease appeared to be worse … This appeared to occur earlier than that described in sporadic disease,” in which the worsening of survival in hormone receptor–positive disease occurs after a follow-up of at least 14-15 years, the investigators noted in their journal report.

The work was funded by the Italian Association for Cancer Research, Institut Jules Bordet, Korea Health Industry Development Institute, Australian National Health and Medical Council, Cancer Australia, US National Institute of Health, and others. Dr. Arecco had no disclosures. Dr. Carey and other coauthors disclosed research funding, speaker honoraria, and other financial relationships with AstraZeneca, Genentech/Roche, Lilly, and other pharmaceutical companies.

CHICAGO — Being hormone receptor positive is generally a favorable prognostic factor in breast cancer, but that doesn’t seem to be the case in women with BRCA-associated tumors, according to a study presented at the American Society of Clinical Oncology annual meeting.

The conclusion is based on a large international study on how hormone receptor status impacts breast cancer outcomes in young women with germline BRCA pathological variants (PVs).

Overall, “hormone receptor positivity did not seem to have a strong positive prognostic value in young BRCA carriers” with early breast cancer, lead investigator Luca Arecco, MD, an oncology resident at the University of Genoa, Italy, said at the meeting.

Investigators reviewed the records of 4709 women ages 40 years or younger with stage 1-3 BRCA-associated invasive breast cancer treated from 2000 to 2020 at 78 centers in 28 countries across four continents. Median follow-up was about 8 years.
 

Weaker Prognostic Value in Hormone Receptor Status

They found, in general, that hormone receptor–positive breast cancer appears to be biologically more aggressive in patients with BRCA PVs than in the general breast cancer population, generating outcomes similar to those with hormone receptor-negative BRCA tumors.

Specifically, among patients with germline BRCA PVs, while hormone receptor–positive patients had a higher distant recurrence rate (13.1% vs. 9.6%) than hormone receptor–negative patients, 8-year disease free survival (65.8% and 63.4% respectively) and overall survival (a bit under 90% in both groups) were similar.

Hormone receptor–positive patients did have a lower rate of second primary breast cancers (9.1% versus 14.7%).

In the formal write-up of the results published shortly after the meeting in Annals of Oncology, the investigators concluded that “in young BRCA carriers, differences in recurrence pattern and second primary breast cancer among hormone receptor–positive versus negative disease warrant consideration in counseling patients on treatment, follow-up, and risk-reducing surgery.”

The team also found other differences between BRCA-associated breast cancer and sporadic disease. For instance, in the BRCA cohort, luminal A-like breast cancer had a worse long-term prognosis in their BRCA cohort than triple-negative or HER2-positive disease. Luminal A-like tumors are generally considered less aggressive, but in patients with BRCA PVs, “improving neoadjuvant chemotherapy … could be worthwhile,” the investigators said.

Also, although the risk of recurrence for sporadic hormone receptor–negative tumors is highest in the first few years, the team found that the risk in the hormone negative BRCA cohort progressively increased with longer follow-up, driven by the occurrence of second primary breast cancers, especially in patients with BRCA 1 PVs.
 

Greater Clarity in Prognosis in BRCA-Associated Breast Cancer

Overall, study discussant Lisa A. Carey, MD, a breast cancer specialist at the University of North Carolina at Chapel Hill, said, “we now know much more clearly the issues of prognosis in women who are very young and have germline BRCA-associated breast cancer,” about 12% of newly diagnosed cases.

“Young patients with germline BRCA-associated breast cancers have high relapse and high new primary risks, warranting comprehensive multimodality therapy,” she said.

A bit fewer than half of women in the study were hormone receptor–positive, and they tended to be patients with BRCA 2 PVs. The rest were hormone receptor–negative and tended to have BRCA 1 PVs.

Patients with hormone receptor–positive disease had grade 3 cancers in about 50% of cases, while patients with hormone receptor–negative disease had a grade 3 disease in over 80%.

Hormone receptor–positive patients were more likely to have nodal involvement and undergo mastectomies but less likely to receive chemotherapy than hormone receptor–negative patients. It’s likely that few patients in the review received PARP inhibitors, Dr. Carey noted.

Although overall survival at 8 years was similar in both groups, after that point “the prognosis of patients with hormone receptor–positive disease appeared to be worse … This appeared to occur earlier than that described in sporadic disease,” in which the worsening of survival in hormone receptor–positive disease occurs after a follow-up of at least 14-15 years, the investigators noted in their journal report.

The work was funded by the Italian Association for Cancer Research, Institut Jules Bordet, Korea Health Industry Development Institute, Australian National Health and Medical Council, Cancer Australia, US National Institute of Health, and others. Dr. Arecco had no disclosures. Dr. Carey and other coauthors disclosed research funding, speaker honoraria, and other financial relationships with AstraZeneca, Genentech/Roche, Lilly, and other pharmaceutical companies.

CHICAGO — Being hormone receptor positive is generally a favorable prognostic factor in breast cancer, but that doesn’t seem to be the case in women with BRCA-associated tumors, according to a study presented at the American Society of Clinical Oncology annual meeting.

The conclusion is based on a large international study on how hormone receptor status impacts breast cancer outcomes in young women with germline BRCA pathological variants (PVs).

Overall, “hormone receptor positivity did not seem to have a strong positive prognostic value in young BRCA carriers” with early breast cancer, lead investigator Luca Arecco, MD, an oncology resident at the University of Genoa, Italy, said at the meeting.

Investigators reviewed the records of 4709 women ages 40 years or younger with stage 1-3 BRCA-associated invasive breast cancer treated from 2000 to 2020 at 78 centers in 28 countries across four continents. Median follow-up was about 8 years.
 

Weaker Prognostic Value in Hormone Receptor Status

They found, in general, that hormone receptor–positive breast cancer appears to be biologically more aggressive in patients with BRCA PVs than in the general breast cancer population, generating outcomes similar to those with hormone receptor-negative BRCA tumors.

Specifically, among patients with germline BRCA PVs, while hormone receptor–positive patients had a higher distant recurrence rate (13.1% vs. 9.6%) than hormone receptor–negative patients, 8-year disease free survival (65.8% and 63.4% respectively) and overall survival (a bit under 90% in both groups) were similar.

Hormone receptor–positive patients did have a lower rate of second primary breast cancers (9.1% versus 14.7%).

In the formal write-up of the results published shortly after the meeting in Annals of Oncology, the investigators concluded that “in young BRCA carriers, differences in recurrence pattern and second primary breast cancer among hormone receptor–positive versus negative disease warrant consideration in counseling patients on treatment, follow-up, and risk-reducing surgery.”

The team also found other differences between BRCA-associated breast cancer and sporadic disease. For instance, in the BRCA cohort, luminal A-like breast cancer had a worse long-term prognosis in their BRCA cohort than triple-negative or HER2-positive disease. Luminal A-like tumors are generally considered less aggressive, but in patients with BRCA PVs, “improving neoadjuvant chemotherapy … could be worthwhile,” the investigators said.

Also, although the risk of recurrence for sporadic hormone receptor–negative tumors is highest in the first few years, the team found that the risk in the hormone negative BRCA cohort progressively increased with longer follow-up, driven by the occurrence of second primary breast cancers, especially in patients with BRCA 1 PVs.
 

Greater Clarity in Prognosis in BRCA-Associated Breast Cancer

Overall, study discussant Lisa A. Carey, MD, a breast cancer specialist at the University of North Carolina at Chapel Hill, said, “we now know much more clearly the issues of prognosis in women who are very young and have germline BRCA-associated breast cancer,” about 12% of newly diagnosed cases.

“Young patients with germline BRCA-associated breast cancers have high relapse and high new primary risks, warranting comprehensive multimodality therapy,” she said.

A bit fewer than half of women in the study were hormone receptor–positive, and they tended to be patients with BRCA 2 PVs. The rest were hormone receptor–negative and tended to have BRCA 1 PVs.

Patients with hormone receptor–positive disease had grade 3 cancers in about 50% of cases, while patients with hormone receptor–negative disease had a grade 3 disease in over 80%.

Hormone receptor–positive patients were more likely to have nodal involvement and undergo mastectomies but less likely to receive chemotherapy than hormone receptor–negative patients. It’s likely that few patients in the review received PARP inhibitors, Dr. Carey noted.

Although overall survival at 8 years was similar in both groups, after that point “the prognosis of patients with hormone receptor–positive disease appeared to be worse … This appeared to occur earlier than that described in sporadic disease,” in which the worsening of survival in hormone receptor–positive disease occurs after a follow-up of at least 14-15 years, the investigators noted in their journal report.

The work was funded by the Italian Association for Cancer Research, Institut Jules Bordet, Korea Health Industry Development Institute, Australian National Health and Medical Council, Cancer Australia, US National Institute of Health, and others. Dr. Arecco had no disclosures. Dr. Carey and other coauthors disclosed research funding, speaker honoraria, and other financial relationships with AstraZeneca, Genentech/Roche, Lilly, and other pharmaceutical companies.

TOPLINE:

Smartphone apps, including those using cognitive-behavioral therapy (CBT) and mindfulness techniques, showed comparable efficacy in reducing depression, anxiety, and suicidality in patients with psychiatric conditions waiting for appointments with psychiatrists or therapists.

METHODOLOGY:

• Participants were adults aged 18 years or older seeking outpatient psychiatric services from several mental and behavioral health clinics within the University of Michigan Health System.
• Eligible participants were those with either a scheduled future mental health appointment or an initial appointment completed within the past 60 days and daily access to a smartphone.
• After completing a baseline survey that gathered data on participants’ depression, anxiety, and suicidality scores, 2080 participants were randomly assigned to one of five groups:
• Enhanced personalized feedback (EPF) only (n = 690)
• SilverCloud only (SilverCloud, a mobile application designed to deliver CBT strategies; n = 345)
• SilverCloud plus EPF (n = 346)
• Headspace only (Headspace, a mobile application designed to train users in mindfulness practices; n = 349)
• Headspace plus EPF (n = 349)

TAKEAWAY:

• The mean baseline Patient Health Questionnaire-9 depression score was 12.7 (6.4% patients). Overall, depression scores significantly decreased by 2.5 points from baseline to the 6-week follow-up for all five arms, with marginal mean differences in mean change ranging from −2.1 to −2.9 (P < .001).
• The magnitude of change was not significantly different across the five arms on most measures (P = .31). Additionally, the groups did not differ in decrease of anxiety or substance use symptoms.
• The Headspace arms reported significantly greater improvements on a suicidality measure subscale than the SilverCloud arms (mean difference in mean change, 0.63; P = .004).

IN PRACTICE:

“Having this type of option, especially for people who are motivated enough to seek an appointment and wait for it, could be very valuable when providers have long wait lists,” lead author Adam Horwitz, PhD, University of Michigan, Ann Arbor, said in a press release.

“These individuals want to be doing something about their mental health but don’t yet have access, so this suggests that providing them with some sort of digital option when their motivation is already high, and they are ready to do something, could begin to make a difference.”
 

SOURCE:

Dr. Horwitz led the study, which was published online in JAMA Network Open.

LIMITATIONS:

There may have been aspects of formal or in-person care that contributed to the improvement in symptoms across groups and diluted the ability to identify differences between applications in effects on symptom reduction.

DISCLOSURES:

This study was funded by a grant from Precision Health, the Eisenberg Family Depression Center, and the National Institute of Mental Health. Disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.A version of this article first appeared on Medscape.com.

TOPLINE:

Smartphone apps, including those using cognitive-behavioral therapy (CBT) and mindfulness techniques, showed comparable efficacy in reducing depression, anxiety, and suicidality in patients with psychiatric conditions waiting for appointments with psychiatrists or therapists.

METHODOLOGY:

• Participants were adults aged 18 years or older seeking outpatient psychiatric services from several mental and behavioral health clinics within the University of Michigan Health System.
• Eligible participants were those with either a scheduled future mental health appointment or an initial appointment completed within the past 60 days and daily access to a smartphone.
• After completing a baseline survey that gathered data on participants’ depression, anxiety, and suicidality scores, 2080 participants were randomly assigned to one of five groups:
• Enhanced personalized feedback (EPF) only (n = 690)
• SilverCloud only (SilverCloud, a mobile application designed to deliver CBT strategies; n = 345)
• SilverCloud plus EPF (n = 346)
• Headspace only (Headspace, a mobile application designed to train users in mindfulness practices; n = 349)
• Headspace plus EPF (n = 349)

TAKEAWAY:

• The mean baseline Patient Health Questionnaire-9 depression score was 12.7 (6.4% patients). Overall, depression scores significantly decreased by 2.5 points from baseline to the 6-week follow-up for all five arms, with marginal mean differences in mean change ranging from −2.1 to −2.9 (P < .001).
• The magnitude of change was not significantly different across the five arms on most measures (P = .31). Additionally, the groups did not differ in decrease of anxiety or substance use symptoms.
• The Headspace arms reported significantly greater improvements on a suicidality measure subscale than the SilverCloud arms (mean difference in mean change, 0.63; P = .004).

IN PRACTICE:

“Having this type of option, especially for people who are motivated enough to seek an appointment and wait for it, could be very valuable when providers have long wait lists,” lead author Adam Horwitz, PhD, University of Michigan, Ann Arbor, said in a press release.

“These individuals want to be doing something about their mental health but don’t yet have access, so this suggests that providing them with some sort of digital option when their motivation is already high, and they are ready to do something, could begin to make a difference.”
 

SOURCE:

Dr. Horwitz led the study, which was published online in JAMA Network Open.

LIMITATIONS:

There may have been aspects of formal or in-person care that contributed to the improvement in symptoms across groups and diluted the ability to identify differences between applications in effects on symptom reduction.

DISCLOSURES:

This study was funded by a grant from Precision Health, the Eisenberg Family Depression Center, and the National Institute of Mental Health. Disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.A version of this article first appeared on Medscape.com.

TOPLINE:

Smartphone apps, including those using cognitive-behavioral therapy (CBT) and mindfulness techniques, showed comparable efficacy in reducing depression, anxiety, and suicidality in patients with psychiatric conditions waiting for appointments with psychiatrists or therapists.

METHODOLOGY:

• Participants were adults aged 18 years or older seeking outpatient psychiatric services from several mental and behavioral health clinics within the University of Michigan Health System.
• Eligible participants were those with either a scheduled future mental health appointment or an initial appointment completed within the past 60 days and daily access to a smartphone.
• After completing a baseline survey that gathered data on participants’ depression, anxiety, and suicidality scores, 2080 participants were randomly assigned to one of five groups:
• Enhanced personalized feedback (EPF) only (n = 690)
• SilverCloud only (SilverCloud, a mobile application designed to deliver CBT strategies; n = 345)
• SilverCloud plus EPF (n = 346)
• Headspace only (Headspace, a mobile application designed to train users in mindfulness practices; n = 349)
• Headspace plus EPF (n = 349)

TAKEAWAY:

• The mean baseline Patient Health Questionnaire-9 depression score was 12.7 (6.4% patients). Overall, depression scores significantly decreased by 2.5 points from baseline to the 6-week follow-up for all five arms, with marginal mean differences in mean change ranging from −2.1 to −2.9 (P < .001).
• The magnitude of change was not significantly different across the five arms on most measures (P = .31). Additionally, the groups did not differ in decrease of anxiety or substance use symptoms.
• The Headspace arms reported significantly greater improvements on a suicidality measure subscale than the SilverCloud arms (mean difference in mean change, 0.63; P = .004).

IN PRACTICE:

“Having this type of option, especially for people who are motivated enough to seek an appointment and wait for it, could be very valuable when providers have long wait lists,” lead author Adam Horwitz, PhD, University of Michigan, Ann Arbor, said in a press release.

“These individuals want to be doing something about their mental health but don’t yet have access, so this suggests that providing them with some sort of digital option when their motivation is already high, and they are ready to do something, could begin to make a difference.”
 

SOURCE:

Dr. Horwitz led the study, which was published online in JAMA Network Open.

LIMITATIONS:

There may have been aspects of formal or in-person care that contributed to the improvement in symptoms across groups and diluted the ability to identify differences between applications in effects on symptom reduction.

DISCLOSURES:

This study was funded by a grant from Precision Health, the Eisenberg Family Depression Center, and the National Institute of Mental Health. Disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.A version of this article first appeared on Medscape.com.

Marybeth Spanarkel, MD, a Duke University School of Medicine alumna (1979), completed her internal medicine and gastroenterology training at the University of Pennsylvania, National Institutes of Health, and Johns Hopkins. Initially groomed for an academic role, she chose a clinical position in private practice at Duke Regional Hospital in Durham, North Carolina, where she worked for 25 years.

At age 59, Dr. Spanarkel suffered a neck injury leading to permanent C5-6 radiculopathy, which abruptly ended her career as a clinical gastroenterologist. Since then, she has been a passionate advocate for ergonomic reform in endoscopy. Currently, she is the senior medical adviser and cofounder of ColoWrap, a device designed to improve colonoscopy procedures and reduce ergonomic risk.

Dr. Spanarkel

Would you share with the readers your experience with maternity leave in private practice?

As a mother of four, I had two children during my GI fellowship, and received my full salary each time for a 3-month maternity leave. My third child arrived in the time period between leaving my academic position and starting in private practice. My fourth child was born after 2 years in private practice, and I took 3 weeks off. Fortunately, I was not asked to pay upfront overhead fees in my 15-person practice. However, my reduced productivity during that time was factored into my salary calculations, leading to a decreased income for the following 6 months.

How does pregnancy affect your performance and productivity as a GI physician?

“We” may be having a baby, but “You” are pregnant. While some may experience few symptoms, most pregnant doctors deal with problems such as nausea and extreme fatigue, especially in the first trimester. The third trimester may result in reduced physical agility, particularly when performing procedures. Even in uncomplicated pregnancies, balancing the physiologic changes with the demands of a full-time GI role can be strenuous. And this doesn’t even take into account potential infertility issues, pregnancy complications, or newborn concerns that physicians may encounter.

And after childbirth?

Post childbirth, despite a supportive partner, the primary responsibilities such as feeding, nursing support, and bonding often fall on the biological mother. These duties are superimposed on the doctor’s own recovery and postpartum changes. While the United States commonly recognizes 3 months as a standard maternity leave, some European countries advocate for up to 12 months, demonstrating again that this is not an “overnight” transition.

In the past, GI doctors were mostly male, but now there’s a growing number of females in the field. Despite this shift, studies still highlight continued gender disparities in salaries and leadership opportunities, and support for pregnancy-related issues has been largely under-addressed.^1,2,3

How do academic centers manage maternity leave?

In academic centers or large healthcare settings, maternity leave policies are more standardized compared with private practice. Doctors are salaried depending on their level of training and experience and then they are assigned a mix of clinical, research, teaching, and/or administrative duties.

Typically, maternity leave in these centers is a standard 3-month period, often combining paid time off (PTO) with unpaid or paid leave. In some cases, short- or long-term disability payments are available, especially for complications. But, the financial impact of a doctor’s maternity leave on the overall unit is usually minimal due to the number of participants in the system. The extra workload is diffused over a larger number of doctors, so the new schedule is generally manageable.⁴ And since the salary of the employee/physician includes a portion of nonclinical time (administrative, teaching, research), the actual decrease in revenue isn’t that dramatic.
 

How about maternity leave in private practice?

Maternity leave in private practice, especially if there is only a small number of partners, is handled entirely differently. Think of a household budget (rent, utilities, salaries, benefits, insurance) that is shared by “roommates,” the other partners in the group. To understand how maternity leave affects a private practice, you have to understand how your private practice operates.

Typically, newly hired private practice physicians receive a set salary, with the expectation that their patient revenue will eventually cover both their share of overhead and their salary. The practice might set a monthly quota, offering a bonus for exceeding it, or they may retain the extra revenue until the physician becomes a full partner.

Income in private practice is almost entirely generated by seeing patients and performing procedures, as opposed to non-reimbursable activities such as committee meetings or lectures. Physicians learn to be highly efficient with their time, a standard also expected of their employees. They have more control over their schedules, vacation time, and patient/procedure load. Since income is affected only after overhead costs are covered, each doctor’s approach to workload and pace doesn’t typically concern the other partners. Some physicians may be highly aggressive and efficient (and thus increase their salaries), while others may prefer a slower pace due to external responsibilities.

This arrangement is often seen as fair because the established practice helps you get started by providing the environment for you to generate revenue. This includes patient referrals, office space, and staff. In return, the practice not only hopes you will achieve its goals/quotas but may expect a return on its investment in you.

Additionally, access to shared passive revenue streams, such as a pathology lab, clinical research trials, or facility fees from an endoscopy center, may only be available once a certain level of productivity or full partnership is reached.

The initial years in private practice can be seen as a trial period. Your professional reputation, liability, and patient population are more directly in your own hands. Decision-making, patient management, and potential complications are more wholly your responsibility, which can feel isolating. However, providing excellent care can build your reputation, as satisfied patients will seek you out and generate more referrals. During this time, you need to demonstrate to your prospective partners your commitment to delivering high-quality patient care and to meeting certain minimum standards of volume. If clinical medicine is your passion, the right private practice role can be a fulfilling platform where you do what you love to do and simultaneously are well compensated for it.
 

How does taking maternity affect shared overhead?

Any physician requiring “leave” will affect the overall revenue of a practice. Issues regarding maternity leave in private practice can also be applied to adoption, paternity, surrogacy, foster care, or medical leave. For instance, if the cumulative overhead is $100k per month in a practice with five doctors, each doctor contributes $20k monthly, totaling $240k each annually.

For example, Dr. “Jones” generates $480k in charges/collections, so after paying his share of overhead, his salary is $240k for the year. In contrast, Dr. “Smith” works more intensely, doubling the patients and procedures of Dr. “Jones,” and generates $960k. After deducting the overhead, his salary is $720k, more than twice his partner’s salary.

Let’s say the practice is considering hiring a new doctor who is 2 months pregnant. If he/she generates $380k in charges in the first year but owes $240k in shared overhead, his/her salary would be $140k, which is not very attractive as a “starting salary” for a highly competent, well-trained GI physician. In extreme cases, with high overhead and low productivity, there might be no revenue for salary once the overhead is paid.
 

In private practice, is there hesitancy hiring a pregnant person?

While it’s illegal to inquire about pregnancy during employment interviews, partners in private practice might still hesitate to hire a pregnant person. Concerns include sharing overhead costs, handling extra calls or emergencies, and wanting new physicians to contribute equally.

However, this viewpoint can be shortsighted. Three months of maternity leave is a minor “blip” in a 30-year career. Supporting a partner during maternity leave can lead to reciprocal benefits later, as older partners might also face personal or medical needs. Adopting a flexible, empathetic approach toward partners can foster goodwill, potentially enhancing revenue, teamwork, and patient care over a long-term career. The value of empathy should not be underestimated.
 

What should you consider when you are applying for a new private practice job?

When applying for a private practice position, here are some key points to consider:

• If possible, have your children while employed by a large healthcare system with an established leave policy.
• In a private practice job, ensure the employment contract clearly outlines the terms of medical leave (maternity, paternity, adoption, illness), including details on overhead, benefits, salary, call schedule, and the path to full partnership. Consider having a lawyer review the contract.
• Inquire about how other types of leave, like sabbatical, personal, family, military, or medical, are managed. Understand the implications for salary and overhead, for example, in cases of a partner needing extended leave for surgery or rehabilitation.
• Review the requirements for becoming a full partner, particularly if this includes potential future passive income sources. Does maternity leave (or other types of leave) alter this path?
• Examine the entire benefit package, with a focus on long-term disability policies, considering the statistics on both temporary and permanent disability among GI doctors.⁵
• Negotiate terms for overhead during leave. Options might include a long term or interest-free loan to cover the 3-month sum, a 50% reduction in overhead charges, or “overhead protection insurance” where a designated policy covers overhead for partners on medical leave.

Remember, a brief leave in a 30-year career is relatively minor. Prioritize taking enough time for yourself and your child. Concentrate on long term fairness when engaged in salary negotiations. Don’t rush back; there will be time later to compensate for a temporary decrease in salary, but limited opportunities to spend age-specific time with your young child.

References

1. Butkus R, et al. Achieving Gender Equity in Physician Compensation and Career Advancement: A Position Paper of the American College of Physicians. Ann Intern Med. 2018 May 15. doi: 10.7326/M17-3438.

2. American Medical Association. Advancing Gender Equity in Medicine: Resources for physicians. 2024 Feb 28.

3. Devi J, et al. Fixing the leaky pipeline: gender imbalance in gastroenterology in Asia-Pacific region. J Gastroenterol Hepatol. 2023 Sept. doi: 10.1111/jgh.16353.

4. Mahadevan U, et al. Closing the gender gap: building a successful career and leadership in research as a female gastroenterologist. Lancet Gastroenterol Hepatol. 2022 Jun. doi: 10.1016/S2468-1253(22)00135-2.

5. Murphy R. Know your maternity leave options. 2024 Apr 4.

Marybeth Spanarkel, MD, a Duke University School of Medicine alumna (1979), completed her internal medicine and gastroenterology training at the University of Pennsylvania, National Institutes of Health, and Johns Hopkins. Initially groomed for an academic role, she chose a clinical position in private practice at Duke Regional Hospital in Durham, North Carolina, where she worked for 25 years.

At age 59, Dr. Spanarkel suffered a neck injury leading to permanent C5-6 radiculopathy, which abruptly ended her career as a clinical gastroenterologist. Since then, she has been a passionate advocate for ergonomic reform in endoscopy. Currently, she is the senior medical adviser and cofounder of ColoWrap, a device designed to improve colonoscopy procedures and reduce ergonomic risk.

Dr. Spanarkel

Would you share with the readers your experience with maternity leave in private practice?

As a mother of four, I had two children during my GI fellowship, and received my full salary each time for a 3-month maternity leave. My third child arrived in the time period between leaving my academic position and starting in private practice. My fourth child was born after 2 years in private practice, and I took 3 weeks off. Fortunately, I was not asked to pay upfront overhead fees in my 15-person practice. However, my reduced productivity during that time was factored into my salary calculations, leading to a decreased income for the following 6 months.

How does pregnancy affect your performance and productivity as a GI physician?

“We” may be having a baby, but “You” are pregnant. While some may experience few symptoms, most pregnant doctors deal with problems such as nausea and extreme fatigue, especially in the first trimester. The third trimester may result in reduced physical agility, particularly when performing procedures. Even in uncomplicated pregnancies, balancing the physiologic changes with the demands of a full-time GI role can be strenuous. And this doesn’t even take into account potential infertility issues, pregnancy complications, or newborn concerns that physicians may encounter.

And after childbirth?

Post childbirth, despite a supportive partner, the primary responsibilities such as feeding, nursing support, and bonding often fall on the biological mother. These duties are superimposed on the doctor’s own recovery and postpartum changes. While the United States commonly recognizes 3 months as a standard maternity leave, some European countries advocate for up to 12 months, demonstrating again that this is not an “overnight” transition.

In the past, GI doctors were mostly male, but now there’s a growing number of females in the field. Despite this shift, studies still highlight continued gender disparities in salaries and leadership opportunities, and support for pregnancy-related issues has been largely under-addressed.^1,2,3

How do academic centers manage maternity leave?

In academic centers or large healthcare settings, maternity leave policies are more standardized compared with private practice. Doctors are salaried depending on their level of training and experience and then they are assigned a mix of clinical, research, teaching, and/or administrative duties.

Typically, maternity leave in these centers is a standard 3-month period, often combining paid time off (PTO) with unpaid or paid leave. In some cases, short- or long-term disability payments are available, especially for complications. But, the financial impact of a doctor’s maternity leave on the overall unit is usually minimal due to the number of participants in the system. The extra workload is diffused over a larger number of doctors, so the new schedule is generally manageable.⁴ And since the salary of the employee/physician includes a portion of nonclinical time (administrative, teaching, research), the actual decrease in revenue isn’t that dramatic.
 

How about maternity leave in private practice?

Maternity leave in private practice, especially if there is only a small number of partners, is handled entirely differently. Think of a household budget (rent, utilities, salaries, benefits, insurance) that is shared by “roommates,” the other partners in the group. To understand how maternity leave affects a private practice, you have to understand how your private practice operates.

Typically, newly hired private practice physicians receive a set salary, with the expectation that their patient revenue will eventually cover both their share of overhead and their salary. The practice might set a monthly quota, offering a bonus for exceeding it, or they may retain the extra revenue until the physician becomes a full partner.

Income in private practice is almost entirely generated by seeing patients and performing procedures, as opposed to non-reimbursable activities such as committee meetings or lectures. Physicians learn to be highly efficient with their time, a standard also expected of their employees. They have more control over their schedules, vacation time, and patient/procedure load. Since income is affected only after overhead costs are covered, each doctor’s approach to workload and pace doesn’t typically concern the other partners. Some physicians may be highly aggressive and efficient (and thus increase their salaries), while others may prefer a slower pace due to external responsibilities.

This arrangement is often seen as fair because the established practice helps you get started by providing the environment for you to generate revenue. This includes patient referrals, office space, and staff. In return, the practice not only hopes you will achieve its goals/quotas but may expect a return on its investment in you.

Additionally, access to shared passive revenue streams, such as a pathology lab, clinical research trials, or facility fees from an endoscopy center, may only be available once a certain level of productivity or full partnership is reached.

The initial years in private practice can be seen as a trial period. Your professional reputation, liability, and patient population are more directly in your own hands. Decision-making, patient management, and potential complications are more wholly your responsibility, which can feel isolating. However, providing excellent care can build your reputation, as satisfied patients will seek you out and generate more referrals. During this time, you need to demonstrate to your prospective partners your commitment to delivering high-quality patient care and to meeting certain minimum standards of volume. If clinical medicine is your passion, the right private practice role can be a fulfilling platform where you do what you love to do and simultaneously are well compensated for it.
 

How does taking maternity affect shared overhead?

Any physician requiring “leave” will affect the overall revenue of a practice. Issues regarding maternity leave in private practice can also be applied to adoption, paternity, surrogacy, foster care, or medical leave. For instance, if the cumulative overhead is $100k per month in a practice with five doctors, each doctor contributes $20k monthly, totaling $240k each annually.

For example, Dr. “Jones” generates $480k in charges/collections, so after paying his share of overhead, his salary is $240k for the year. In contrast, Dr. “Smith” works more intensely, doubling the patients and procedures of Dr. “Jones,” and generates $960k. After deducting the overhead, his salary is $720k, more than twice his partner’s salary.

Let’s say the practice is considering hiring a new doctor who is 2 months pregnant. If he/she generates $380k in charges in the first year but owes $240k in shared overhead, his/her salary would be $140k, which is not very attractive as a “starting salary” for a highly competent, well-trained GI physician. In extreme cases, with high overhead and low productivity, there might be no revenue for salary once the overhead is paid.
 

In private practice, is there hesitancy hiring a pregnant person?

While it’s illegal to inquire about pregnancy during employment interviews, partners in private practice might still hesitate to hire a pregnant person. Concerns include sharing overhead costs, handling extra calls or emergencies, and wanting new physicians to contribute equally.

However, this viewpoint can be shortsighted. Three months of maternity leave is a minor “blip” in a 30-year career. Supporting a partner during maternity leave can lead to reciprocal benefits later, as older partners might also face personal or medical needs. Adopting a flexible, empathetic approach toward partners can foster goodwill, potentially enhancing revenue, teamwork, and patient care over a long-term career. The value of empathy should not be underestimated.
 

What should you consider when you are applying for a new private practice job?

When applying for a private practice position, here are some key points to consider:

• If possible, have your children while employed by a large healthcare system with an established leave policy.
• In a private practice job, ensure the employment contract clearly outlines the terms of medical leave (maternity, paternity, adoption, illness), including details on overhead, benefits, salary, call schedule, and the path to full partnership. Consider having a lawyer review the contract.
• Inquire about how other types of leave, like sabbatical, personal, family, military, or medical, are managed. Understand the implications for salary and overhead, for example, in cases of a partner needing extended leave for surgery or rehabilitation.
• Review the requirements for becoming a full partner, particularly if this includes potential future passive income sources. Does maternity leave (or other types of leave) alter this path?
• Examine the entire benefit package, with a focus on long-term disability policies, considering the statistics on both temporary and permanent disability among GI doctors.⁵
• Negotiate terms for overhead during leave. Options might include a long term or interest-free loan to cover the 3-month sum, a 50% reduction in overhead charges, or “overhead protection insurance” where a designated policy covers overhead for partners on medical leave.

Remember, a brief leave in a 30-year career is relatively minor. Prioritize taking enough time for yourself and your child. Concentrate on long term fairness when engaged in salary negotiations. Don’t rush back; there will be time later to compensate for a temporary decrease in salary, but limited opportunities to spend age-specific time with your young child.

References

1. Butkus R, et al. Achieving Gender Equity in Physician Compensation and Career Advancement: A Position Paper of the American College of Physicians. Ann Intern Med. 2018 May 15. doi: 10.7326/M17-3438.

2. American Medical Association. Advancing Gender Equity in Medicine: Resources for physicians. 2024 Feb 28.

3. Devi J, et al. Fixing the leaky pipeline: gender imbalance in gastroenterology in Asia-Pacific region. J Gastroenterol Hepatol. 2023 Sept. doi: 10.1111/jgh.16353.

4. Mahadevan U, et al. Closing the gender gap: building a successful career and leadership in research as a female gastroenterologist. Lancet Gastroenterol Hepatol. 2022 Jun. doi: 10.1016/S2468-1253(22)00135-2.

5. Murphy R. Know your maternity leave options. 2024 Apr 4.

Marybeth Spanarkel, MD, a Duke University School of Medicine alumna (1979), completed her internal medicine and gastroenterology training at the University of Pennsylvania, National Institutes of Health, and Johns Hopkins. Initially groomed for an academic role, she chose a clinical position in private practice at Duke Regional Hospital in Durham, North Carolina, where she worked for 25 years.

At age 59, Dr. Spanarkel suffered a neck injury leading to permanent C5-6 radiculopathy, which abruptly ended her career as a clinical gastroenterologist. Since then, she has been a passionate advocate for ergonomic reform in endoscopy. Currently, she is the senior medical adviser and cofounder of ColoWrap, a device designed to improve colonoscopy procedures and reduce ergonomic risk.

Dr. Spanarkel

Would you share with the readers your experience with maternity leave in private practice?

As a mother of four, I had two children during my GI fellowship, and received my full salary each time for a 3-month maternity leave. My third child arrived in the time period between leaving my academic position and starting in private practice. My fourth child was born after 2 years in private practice, and I took 3 weeks off. Fortunately, I was not asked to pay upfront overhead fees in my 15-person practice. However, my reduced productivity during that time was factored into my salary calculations, leading to a decreased income for the following 6 months.

How does pregnancy affect your performance and productivity as a GI physician?

“We” may be having a baby, but “You” are pregnant. While some may experience few symptoms, most pregnant doctors deal with problems such as nausea and extreme fatigue, especially in the first trimester. The third trimester may result in reduced physical agility, particularly when performing procedures. Even in uncomplicated pregnancies, balancing the physiologic changes with the demands of a full-time GI role can be strenuous. And this doesn’t even take into account potential infertility issues, pregnancy complications, or newborn concerns that physicians may encounter.

And after childbirth?

Post childbirth, despite a supportive partner, the primary responsibilities such as feeding, nursing support, and bonding often fall on the biological mother. These duties are superimposed on the doctor’s own recovery and postpartum changes. While the United States commonly recognizes 3 months as a standard maternity leave, some European countries advocate for up to 12 months, demonstrating again that this is not an “overnight” transition.

In the past, GI doctors were mostly male, but now there’s a growing number of females in the field. Despite this shift, studies still highlight continued gender disparities in salaries and leadership opportunities, and support for pregnancy-related issues has been largely under-addressed.^1,2,3

How do academic centers manage maternity leave?

In academic centers or large healthcare settings, maternity leave policies are more standardized compared with private practice. Doctors are salaried depending on their level of training and experience and then they are assigned a mix of clinical, research, teaching, and/or administrative duties.

Typically, maternity leave in these centers is a standard 3-month period, often combining paid time off (PTO) with unpaid or paid leave. In some cases, short- or long-term disability payments are available, especially for complications. But, the financial impact of a doctor’s maternity leave on the overall unit is usually minimal due to the number of participants in the system. The extra workload is diffused over a larger number of doctors, so the new schedule is generally manageable.⁴ And since the salary of the employee/physician includes a portion of nonclinical time (administrative, teaching, research), the actual decrease in revenue isn’t that dramatic.
 

How about maternity leave in private practice?

Maternity leave in private practice, especially if there is only a small number of partners, is handled entirely differently. Think of a household budget (rent, utilities, salaries, benefits, insurance) that is shared by “roommates,” the other partners in the group. To understand how maternity leave affects a private practice, you have to understand how your private practice operates.

Typically, newly hired private practice physicians receive a set salary, with the expectation that their patient revenue will eventually cover both their share of overhead and their salary. The practice might set a monthly quota, offering a bonus for exceeding it, or they may retain the extra revenue until the physician becomes a full partner.

Income in private practice is almost entirely generated by seeing patients and performing procedures, as opposed to non-reimbursable activities such as committee meetings or lectures. Physicians learn to be highly efficient with their time, a standard also expected of their employees. They have more control over their schedules, vacation time, and patient/procedure load. Since income is affected only after overhead costs are covered, each doctor’s approach to workload and pace doesn’t typically concern the other partners. Some physicians may be highly aggressive and efficient (and thus increase their salaries), while others may prefer a slower pace due to external responsibilities.

This arrangement is often seen as fair because the established practice helps you get started by providing the environment for you to generate revenue. This includes patient referrals, office space, and staff. In return, the practice not only hopes you will achieve its goals/quotas but may expect a return on its investment in you.

Additionally, access to shared passive revenue streams, such as a pathology lab, clinical research trials, or facility fees from an endoscopy center, may only be available once a certain level of productivity or full partnership is reached.

The initial years in private practice can be seen as a trial period. Your professional reputation, liability, and patient population are more directly in your own hands. Decision-making, patient management, and potential complications are more wholly your responsibility, which can feel isolating. However, providing excellent care can build your reputation, as satisfied patients will seek you out and generate more referrals. During this time, you need to demonstrate to your prospective partners your commitment to delivering high-quality patient care and to meeting certain minimum standards of volume. If clinical medicine is your passion, the right private practice role can be a fulfilling platform where you do what you love to do and simultaneously are well compensated for it.
 

How does taking maternity affect shared overhead?

Any physician requiring “leave” will affect the overall revenue of a practice. Issues regarding maternity leave in private practice can also be applied to adoption, paternity, surrogacy, foster care, or medical leave. For instance, if the cumulative overhead is $100k per month in a practice with five doctors, each doctor contributes $20k monthly, totaling $240k each annually.

For example, Dr. “Jones” generates $480k in charges/collections, so after paying his share of overhead, his salary is $240k for the year. In contrast, Dr. “Smith” works more intensely, doubling the patients and procedures of Dr. “Jones,” and generates $960k. After deducting the overhead, his salary is $720k, more than twice his partner’s salary.

Let’s say the practice is considering hiring a new doctor who is 2 months pregnant. If he/she generates $380k in charges in the first year but owes $240k in shared overhead, his/her salary would be $140k, which is not very attractive as a “starting salary” for a highly competent, well-trained GI physician. In extreme cases, with high overhead and low productivity, there might be no revenue for salary once the overhead is paid.
 

In private practice, is there hesitancy hiring a pregnant person?

While it’s illegal to inquire about pregnancy during employment interviews, partners in private practice might still hesitate to hire a pregnant person. Concerns include sharing overhead costs, handling extra calls or emergencies, and wanting new physicians to contribute equally.

However, this viewpoint can be shortsighted. Three months of maternity leave is a minor “blip” in a 30-year career. Supporting a partner during maternity leave can lead to reciprocal benefits later, as older partners might also face personal or medical needs. Adopting a flexible, empathetic approach toward partners can foster goodwill, potentially enhancing revenue, teamwork, and patient care over a long-term career. The value of empathy should not be underestimated.
 

What should you consider when you are applying for a new private practice job?

When applying for a private practice position, here are some key points to consider:

• If possible, have your children while employed by a large healthcare system with an established leave policy.
• In a private practice job, ensure the employment contract clearly outlines the terms of medical leave (maternity, paternity, adoption, illness), including details on overhead, benefits, salary, call schedule, and the path to full partnership. Consider having a lawyer review the contract.
• Inquire about how other types of leave, like sabbatical, personal, family, military, or medical, are managed. Understand the implications for salary and overhead, for example, in cases of a partner needing extended leave for surgery or rehabilitation.
• Review the requirements for becoming a full partner, particularly if this includes potential future passive income sources. Does maternity leave (or other types of leave) alter this path?
• Examine the entire benefit package, with a focus on long-term disability policies, considering the statistics on both temporary and permanent disability among GI doctors.⁵
• Negotiate terms for overhead during leave. Options might include a long term or interest-free loan to cover the 3-month sum, a 50% reduction in overhead charges, or “overhead protection insurance” where a designated policy covers overhead for partners on medical leave.

Remember, a brief leave in a 30-year career is relatively minor. Prioritize taking enough time for yourself and your child. Concentrate on long term fairness when engaged in salary negotiations. Don’t rush back; there will be time later to compensate for a temporary decrease in salary, but limited opportunities to spend age-specific time with your young child.

References

1. Butkus R, et al. Achieving Gender Equity in Physician Compensation and Career Advancement: A Position Paper of the American College of Physicians. Ann Intern Med. 2018 May 15. doi: 10.7326/M17-3438.

2. American Medical Association. Advancing Gender Equity in Medicine: Resources for physicians. 2024 Feb 28.

3. Devi J, et al. Fixing the leaky pipeline: gender imbalance in gastroenterology in Asia-Pacific region. J Gastroenterol Hepatol. 2023 Sept. doi: 10.1111/jgh.16353.

4. Mahadevan U, et al. Closing the gender gap: building a successful career and leadership in research as a female gastroenterologist. Lancet Gastroenterol Hepatol. 2022 Jun. doi: 10.1016/S2468-1253(22)00135-2.

5. Murphy R. Know your maternity leave options. 2024 Apr 4.

Older adults with relapsed/refractory large B-cell lymphoma (R/R LBCL) treated with CD19-directed chimeric antigen receptor (CAR) T-cell therapy show no significant differences in key survival outcomes versus younger patients, suggesting important benefits for the age group of patients that commonly are diagnosed with this subtype of non-Hodgkin lymphoma.

“This real-world study demonstrates that CD19 CAR-T cell therapy is feasible in a population of patients aged 75 years and older,” said senior author Pierre Bories, MD, PhD, of the Institute for Cancer Strasbourg-Europe, in Alsace, France. He presented the findings at the annual meeting of the European Hematology Association, held in Madrid, Spain.

Patients with R/R LBCL are often older, with many aged over 75, yet patients in those age groups are frequently underrepresented in clinical trials of CD19-directed CAR T-cell therapy, which has significantly improved outcomes for patients with R/R LBCL.

To further investigate differences in outcomes between older and younger patients with R/R LBCL treated with CAR-T cell therapy, Dr. Bories and colleagues conducted a retrospective analysis of 1,524 patients in the French DESCAR-T registry who were treated at treated at 31 centers in France and had at least two previous infusions of CAR-T cell therapy between April 2018 and September 2023.

Of the patients, 69.8% (n = 1065) were treated with axicabtagene ciloleucel (axi-cel), while 30.1% (n = 459) were treated with tisagenlecleucel (tisa-cel).

Among those patients, 125 were 75 years old or older, with a median age of 76, and the remaining 1399 were under the age of 75, with a median age of 62.

The two age groups had significant differences in terms of characteristics including gender, LBCL subset, number of prior lines of therapy, performance status, age-adjusted International Prognostic Index (IPI), rate of patients receiving a bridging therapy, response to the bridging therapy, and LDH at time of infusion.

Compared with patients aged 75 or younger, those who were 75 years or older had a higher hematopoietic cell transplantation–specific comorbidity index (HCT-CI) score, (31.2% high HCT-CI versus 16.8%, respectively; P < .001).

Patients over 75 also had fewer prior transplants than those under 75 (4.8% versus 21.8%, respectively; P < .001), and they more commonly received tisa-cel CAR-T cell therapy (43.2% versus 28.9%, respectively; P < .001).

Among 1457 patients with response data available, with a median follow-up of 12.7 months, there were no significant differences in terms of the best overall response rate (ORR) and complete response rates (CRR) between the two age groups, with rates of 74.8% for ORR and 62.6% for CRR among those 75 or older, compared with 78.0% and 60.8%, respectively, in the under 75 group (P = .425 and P = .699, respectively).

Likewise, the estimated median overall survival (OS) was 18.3 months in the 75 and older group and 24.0 months in the under 75 group (P = .12).

There were also no significant difference in terms of the estimated median progression-free survival, of 8.2 months in the 75 and older group versus 6.1 months in the under 75 group (P = .73).

In terms of safety, there were no significant differences in terms of grade 3 or higher cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) among patients 75 and older versus under 75, with 7.3% versus 7.4% developing CRS, respectively (P = .97), and 9.8% versus 12.4% developing ICANS (P = .39).

There were no significant differences between the age groups regarding ICU admissions, which occurred in about 24% of the cohorts, or the need for mechanical ventilation, which was necessary in about 3% of the entire cohort.

Of note, the overall rates of non-relapse mortality were more common in the 75 years and older group, among whom 19.5% of deaths were not related to lymphoma progression or relapse, compared with 8.1% in the under 75 group (P < .0001).

Early mortalities not related to relapse, defined as occurring before day 28 post-infusion, occurred among 3 patients aged 75 and older (2.4% of all patients 75 and older, representing 12.0% of all non-relapse mortality cases) compared with 16 patients under 75 (1.2% of those patients and 13.1% of all non-relapse mortality).

Infection was the main cause of non-relapse mortality in both groups, representing the cause in 57.7% of those under 75 and 54.2% of those aged 75 and older.

Patients 75 and older had a significantly higher risk of non-relapse mortality from infection (P = .0003), CRS (P = .022) or other causes, compared with those under 75 (P = .0004), but not from ICANS (P = .524).

“Our findings show a higher non-relapse mortality in this older population, which mainly relied on late infectious events, occurring after 28 days,” Dr. Bories said.

“There was also a higher rate of non-relapse mortality from infections, CRS or other causes in those 75 or older, but that did not translate to a lower overall survival in our patient sample,” he said.

Asked at the session about the implications of the higher infection risk in elderly patients, Dr. Bories said, “I think this deserves special attention and we have to be more careful with frail patients.

“This should obviously encourage the use of prophylaxis for a longer period of time.”

Dr. Bories noted that he and his team are currently conducting a more detailed propensity-matched comparison between axi-cel and tisa-cel in an older population.

The findings are consistent with those of other studies, among the latest including a 2024 real-world multicenter study of 172 diffuse LBCL (DLBCL) patients treated with CAR-T cell therapy (mostly axi-cel).

That study showed comparable median progression-free and OS rates between those over and under the age of 70, however, in contrast to the current study, that study showed no significant differences in non-relapse mortality.

The ORR in that study also did not differ between age groups, exceeding 75%.

Of note, in that study, tisa‐cel treatment was associated with an approximately 60% higher risk of relapse and/or death compared with axi‐cel treatment, which the authors report was driven primarily by less favorable survival outcomes among tisa‐cel patients younger than age 70 years.

“In this context, some reports showed that axi‐cel may offer enhanced effectiveness compared to tisa‐cel in patients aged 65 and older, despite higher rates of neurotoxicity,” they wrote.

Nevertheless, the study’s overall findings indicate that “CAR T-cell therapy should be not withheld for elderly patients with r/r DLBCL,” the authors concluded.
 

Low CAR T Utilization in Elderly Patients

Overall, utilization of CAR-T cell therapy among older patients reportedly remains low, as demonstrated in one recent real-world study on the issue, involving 551 older patients with DLBCL.

The study showed that 19% of patients aged 65-69 and 22% of those aged 70-74 years received CAR-T cell therapy, compared with only 13% of those aged 75 and older.

“While CAR T-cell therapy in older patients is associated with favorable event-free survival comparable to outcomes in younger patients, CAR T-cell usage is low in older patients with DLBCL, which suggests an unmet need for more accessible, effective, and tolerable therapy,” reported first author Dia Chihara, MD, PhD, of the Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, in Houston, Texas, and colleagues.

Noting that “the use of current CAR-T cell therapy products seemed to be limited to selected patients,” the authors added that “this may change in the future with next-generation CAR T-cell therapy products.”

Dr. Bories disclosed relationships with Kite Gilead, Novartis, BMD-Celgene, Abbvie, Servier, Janssen and the BMS foundation.

Older adults with relapsed/refractory large B-cell lymphoma (R/R LBCL) treated with CD19-directed chimeric antigen receptor (CAR) T-cell therapy show no significant differences in key survival outcomes versus younger patients, suggesting important benefits for the age group of patients that commonly are diagnosed with this subtype of non-Hodgkin lymphoma.

“This real-world study demonstrates that CD19 CAR-T cell therapy is feasible in a population of patients aged 75 years and older,” said senior author Pierre Bories, MD, PhD, of the Institute for Cancer Strasbourg-Europe, in Alsace, France. He presented the findings at the annual meeting of the European Hematology Association, held in Madrid, Spain.

Patients with R/R LBCL are often older, with many aged over 75, yet patients in those age groups are frequently underrepresented in clinical trials of CD19-directed CAR T-cell therapy, which has significantly improved outcomes for patients with R/R LBCL.

To further investigate differences in outcomes between older and younger patients with R/R LBCL treated with CAR-T cell therapy, Dr. Bories and colleagues conducted a retrospective analysis of 1,524 patients in the French DESCAR-T registry who were treated at treated at 31 centers in France and had at least two previous infusions of CAR-T cell therapy between April 2018 and September 2023.

Of the patients, 69.8% (n = 1065) were treated with axicabtagene ciloleucel (axi-cel), while 30.1% (n = 459) were treated with tisagenlecleucel (tisa-cel).

Among those patients, 125 were 75 years old or older, with a median age of 76, and the remaining 1399 were under the age of 75, with a median age of 62.

The two age groups had significant differences in terms of characteristics including gender, LBCL subset, number of prior lines of therapy, performance status, age-adjusted International Prognostic Index (IPI), rate of patients receiving a bridging therapy, response to the bridging therapy, and LDH at time of infusion.

Compared with patients aged 75 or younger, those who were 75 years or older had a higher hematopoietic cell transplantation–specific comorbidity index (HCT-CI) score, (31.2% high HCT-CI versus 16.8%, respectively; P < .001).

Patients over 75 also had fewer prior transplants than those under 75 (4.8% versus 21.8%, respectively; P < .001), and they more commonly received tisa-cel CAR-T cell therapy (43.2% versus 28.9%, respectively; P < .001).

Among 1457 patients with response data available, with a median follow-up of 12.7 months, there were no significant differences in terms of the best overall response rate (ORR) and complete response rates (CRR) between the two age groups, with rates of 74.8% for ORR and 62.6% for CRR among those 75 or older, compared with 78.0% and 60.8%, respectively, in the under 75 group (P = .425 and P = .699, respectively).

Likewise, the estimated median overall survival (OS) was 18.3 months in the 75 and older group and 24.0 months in the under 75 group (P = .12).

There were also no significant difference in terms of the estimated median progression-free survival, of 8.2 months in the 75 and older group versus 6.1 months in the under 75 group (P = .73).

In terms of safety, there were no significant differences in terms of grade 3 or higher cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) among patients 75 and older versus under 75, with 7.3% versus 7.4% developing CRS, respectively (P = .97), and 9.8% versus 12.4% developing ICANS (P = .39).

There were no significant differences between the age groups regarding ICU admissions, which occurred in about 24% of the cohorts, or the need for mechanical ventilation, which was necessary in about 3% of the entire cohort.

Of note, the overall rates of non-relapse mortality were more common in the 75 years and older group, among whom 19.5% of deaths were not related to lymphoma progression or relapse, compared with 8.1% in the under 75 group (P < .0001).

Early mortalities not related to relapse, defined as occurring before day 28 post-infusion, occurred among 3 patients aged 75 and older (2.4% of all patients 75 and older, representing 12.0% of all non-relapse mortality cases) compared with 16 patients under 75 (1.2% of those patients and 13.1% of all non-relapse mortality).

Infection was the main cause of non-relapse mortality in both groups, representing the cause in 57.7% of those under 75 and 54.2% of those aged 75 and older.

Patients 75 and older had a significantly higher risk of non-relapse mortality from infection (P = .0003), CRS (P = .022) or other causes, compared with those under 75 (P = .0004), but not from ICANS (P = .524).

“Our findings show a higher non-relapse mortality in this older population, which mainly relied on late infectious events, occurring after 28 days,” Dr. Bories said.

“There was also a higher rate of non-relapse mortality from infections, CRS or other causes in those 75 or older, but that did not translate to a lower overall survival in our patient sample,” he said.

Asked at the session about the implications of the higher infection risk in elderly patients, Dr. Bories said, “I think this deserves special attention and we have to be more careful with frail patients.

“This should obviously encourage the use of prophylaxis for a longer period of time.”

Dr. Bories noted that he and his team are currently conducting a more detailed propensity-matched comparison between axi-cel and tisa-cel in an older population.

The findings are consistent with those of other studies, among the latest including a 2024 real-world multicenter study of 172 diffuse LBCL (DLBCL) patients treated with CAR-T cell therapy (mostly axi-cel).

That study showed comparable median progression-free and OS rates between those over and under the age of 70, however, in contrast to the current study, that study showed no significant differences in non-relapse mortality.

The ORR in that study also did not differ between age groups, exceeding 75%.

Of note, in that study, tisa‐cel treatment was associated with an approximately 60% higher risk of relapse and/or death compared with axi‐cel treatment, which the authors report was driven primarily by less favorable survival outcomes among tisa‐cel patients younger than age 70 years.

“In this context, some reports showed that axi‐cel may offer enhanced effectiveness compared to tisa‐cel in patients aged 65 and older, despite higher rates of neurotoxicity,” they wrote.

Nevertheless, the study’s overall findings indicate that “CAR T-cell therapy should be not withheld for elderly patients with r/r DLBCL,” the authors concluded.
 

Low CAR T Utilization in Elderly Patients

Overall, utilization of CAR-T cell therapy among older patients reportedly remains low, as demonstrated in one recent real-world study on the issue, involving 551 older patients with DLBCL.

The study showed that 19% of patients aged 65-69 and 22% of those aged 70-74 years received CAR-T cell therapy, compared with only 13% of those aged 75 and older.

“While CAR T-cell therapy in older patients is associated with favorable event-free survival comparable to outcomes in younger patients, CAR T-cell usage is low in older patients with DLBCL, which suggests an unmet need for more accessible, effective, and tolerable therapy,” reported first author Dia Chihara, MD, PhD, of the Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, in Houston, Texas, and colleagues.

Noting that “the use of current CAR-T cell therapy products seemed to be limited to selected patients,” the authors added that “this may change in the future with next-generation CAR T-cell therapy products.”

Dr. Bories disclosed relationships with Kite Gilead, Novartis, BMD-Celgene, Abbvie, Servier, Janssen and the BMS foundation.

Older adults with relapsed/refractory large B-cell lymphoma (R/R LBCL) treated with CD19-directed chimeric antigen receptor (CAR) T-cell therapy show no significant differences in key survival outcomes versus younger patients, suggesting important benefits for the age group of patients that commonly are diagnosed with this subtype of non-Hodgkin lymphoma.

“This real-world study demonstrates that CD19 CAR-T cell therapy is feasible in a population of patients aged 75 years and older,” said senior author Pierre Bories, MD, PhD, of the Institute for Cancer Strasbourg-Europe, in Alsace, France. He presented the findings at the annual meeting of the European Hematology Association, held in Madrid, Spain.

Patients with R/R LBCL are often older, with many aged over 75, yet patients in those age groups are frequently underrepresented in clinical trials of CD19-directed CAR T-cell therapy, which has significantly improved outcomes for patients with R/R LBCL.

To further investigate differences in outcomes between older and younger patients with R/R LBCL treated with CAR-T cell therapy, Dr. Bories and colleagues conducted a retrospective analysis of 1,524 patients in the French DESCAR-T registry who were treated at treated at 31 centers in France and had at least two previous infusions of CAR-T cell therapy between April 2018 and September 2023.

Of the patients, 69.8% (n = 1065) were treated with axicabtagene ciloleucel (axi-cel), while 30.1% (n = 459) were treated with tisagenlecleucel (tisa-cel).

Among those patients, 125 were 75 years old or older, with a median age of 76, and the remaining 1399 were under the age of 75, with a median age of 62.

The two age groups had significant differences in terms of characteristics including gender, LBCL subset, number of prior lines of therapy, performance status, age-adjusted International Prognostic Index (IPI), rate of patients receiving a bridging therapy, response to the bridging therapy, and LDH at time of infusion.

Compared with patients aged 75 or younger, those who were 75 years or older had a higher hematopoietic cell transplantation–specific comorbidity index (HCT-CI) score, (31.2% high HCT-CI versus 16.8%, respectively; P < .001).

Patients over 75 also had fewer prior transplants than those under 75 (4.8% versus 21.8%, respectively; P < .001), and they more commonly received tisa-cel CAR-T cell therapy (43.2% versus 28.9%, respectively; P < .001).

Among 1457 patients with response data available, with a median follow-up of 12.7 months, there were no significant differences in terms of the best overall response rate (ORR) and complete response rates (CRR) between the two age groups, with rates of 74.8% for ORR and 62.6% for CRR among those 75 or older, compared with 78.0% and 60.8%, respectively, in the under 75 group (P = .425 and P = .699, respectively).

Likewise, the estimated median overall survival (OS) was 18.3 months in the 75 and older group and 24.0 months in the under 75 group (P = .12).

There were also no significant difference in terms of the estimated median progression-free survival, of 8.2 months in the 75 and older group versus 6.1 months in the under 75 group (P = .73).

In terms of safety, there were no significant differences in terms of grade 3 or higher cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) among patients 75 and older versus under 75, with 7.3% versus 7.4% developing CRS, respectively (P = .97), and 9.8% versus 12.4% developing ICANS (P = .39).

There were no significant differences between the age groups regarding ICU admissions, which occurred in about 24% of the cohorts, or the need for mechanical ventilation, which was necessary in about 3% of the entire cohort.

Of note, the overall rates of non-relapse mortality were more common in the 75 years and older group, among whom 19.5% of deaths were not related to lymphoma progression or relapse, compared with 8.1% in the under 75 group (P < .0001).

Early mortalities not related to relapse, defined as occurring before day 28 post-infusion, occurred among 3 patients aged 75 and older (2.4% of all patients 75 and older, representing 12.0% of all non-relapse mortality cases) compared with 16 patients under 75 (1.2% of those patients and 13.1% of all non-relapse mortality).

Infection was the main cause of non-relapse mortality in both groups, representing the cause in 57.7% of those under 75 and 54.2% of those aged 75 and older.

Patients 75 and older had a significantly higher risk of non-relapse mortality from infection (P = .0003), CRS (P = .022) or other causes, compared with those under 75 (P = .0004), but not from ICANS (P = .524).

“Our findings show a higher non-relapse mortality in this older population, which mainly relied on late infectious events, occurring after 28 days,” Dr. Bories said.

“There was also a higher rate of non-relapse mortality from infections, CRS or other causes in those 75 or older, but that did not translate to a lower overall survival in our patient sample,” he said.

Asked at the session about the implications of the higher infection risk in elderly patients, Dr. Bories said, “I think this deserves special attention and we have to be more careful with frail patients.

“This should obviously encourage the use of prophylaxis for a longer period of time.”

Dr. Bories noted that he and his team are currently conducting a more detailed propensity-matched comparison between axi-cel and tisa-cel in an older population.

The findings are consistent with those of other studies, among the latest including a 2024 real-world multicenter study of 172 diffuse LBCL (DLBCL) patients treated with CAR-T cell therapy (mostly axi-cel).

That study showed comparable median progression-free and OS rates between those over and under the age of 70, however, in contrast to the current study, that study showed no significant differences in non-relapse mortality.

The ORR in that study also did not differ between age groups, exceeding 75%.

Of note, in that study, tisa‐cel treatment was associated with an approximately 60% higher risk of relapse and/or death compared with axi‐cel treatment, which the authors report was driven primarily by less favorable survival outcomes among tisa‐cel patients younger than age 70 years.

“In this context, some reports showed that axi‐cel may offer enhanced effectiveness compared to tisa‐cel in patients aged 65 and older, despite higher rates of neurotoxicity,” they wrote.

Nevertheless, the study’s overall findings indicate that “CAR T-cell therapy should be not withheld for elderly patients with r/r DLBCL,” the authors concluded.
 

Low CAR T Utilization in Elderly Patients

Overall, utilization of CAR-T cell therapy among older patients reportedly remains low, as demonstrated in one recent real-world study on the issue, involving 551 older patients with DLBCL.

The study showed that 19% of patients aged 65-69 and 22% of those aged 70-74 years received CAR-T cell therapy, compared with only 13% of those aged 75 and older.

“While CAR T-cell therapy in older patients is associated with favorable event-free survival comparable to outcomes in younger patients, CAR T-cell usage is low in older patients with DLBCL, which suggests an unmet need for more accessible, effective, and tolerable therapy,” reported first author Dia Chihara, MD, PhD, of the Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, in Houston, Texas, and colleagues.

Noting that “the use of current CAR-T cell therapy products seemed to be limited to selected patients,” the authors added that “this may change in the future with next-generation CAR T-cell therapy products.”

Dr. Bories disclosed relationships with Kite Gilead, Novartis, BMD-Celgene, Abbvie, Servier, Janssen and the BMS foundation.

WASHINGTON — Advancing treatment for what has been variably called chronic Lyme and posttreatment Lyme disease (PTLD) is under the eyes of a National Academies of Science, Engineering, and Medicine (NASEM) committee of experts for the first time — a year after the NASEM shone a spotlight on the need to accelerate research on chronic illnesses that follow known or suspected infections.

The committee will not make recommendations on specific approaches to diagnosis and treatment when it issues a report in early 2025 but will instead present “consensus findings” on treatment for chronic illness associated with Lyme disease, including recommendations for advancing treatment.

There have been only a few randomized controlled trials (RCTs) conducted on what the committee is calling Lyme Infection-Associated Chronic Illness (Lyme IACI) for now, and no National Institutes of Health (NIH)-funded RCTs in the past 20 years or so. It’s an area void of the US Food and Drug Administration–approved therapies, void of any consensus on the off-label use of medications, and without any current standard of care or proven mechanisms and pathophysiology, said John Aucott, MD, director of the Johns Hopkins Medicine Lyme Disease Clinical Research Center, Baltimore, one of the invited speakers at a public meeting held by the NASEM in Washington, DC.

“The best way to look at this illness is not from the silos of infectious disease or the silos of rheumatology; you have to look across disciplines,” Dr. Aucott, also associate professor of medicine in the Division of Rheumatology, told the committee. “The story doesn’t fit anything I trained for in my infectious disease fellowship. Even today, I’d posit that PTLD is like an island — it’s still not connected to a lot of the mainstream of medicine.”

Rhisa Parera, who wrote and directed a 2021 documentary, Your Labs Are Normal, was one of several invited speakers who amplified the patient voice. Starting around age 7, she had pain in her knees, spine, and hips and vivid nightmares. In high school, she developed gastrointestinal issues, and in college, she developed debilitating neurologic symptoms.

Depression was her eventual diagnosis after having seen “every specialist in the book,” she said. At age 29, she received a positive western blot test and a Lyme disease diagnosis, at which point “I was prescribed 4 weeks of doxycycline and left in the dark,” the 34-year-old Black patient told the committee. Her health improved only after she began working with an “LLMD,” or Lyme-literate medical doctor (a term used in the patient community), while she lived with her mother and did not work, she said.

“I don’t share my Lyme disease history with other doctors. It’s pointless when you have those who will laugh at you, say you’re fine if you were treated, or just deny the disease completely,” Ms. Parera said. “We need this to be taught in medical school. It’s a literal emergency.”
 

Incidence and Potential Mechanisms

Limited research has suggested that 10%-20% of patients with Lyme disease develop persistent symptoms after standard antibiotic treatment advised by the Infectious Diseases Society of America (IDSA), Dr. Aucott said. (On its web page on chronic symptoms, the Centers for Disease Control and Prevention presents a more conservative range of 5%-10%.)

His own prospective cohort study at Johns Hopkins, published in 2022, found that 13.7% of 234 patients with prior Lyme disease met symptom and functional impact criteria for PTLD, compared with 4.1% of 49 participants without a history of Lyme disease — a statistically significant difference that he said should “put to rest” the question of “is it real?”

PTLD is the research case definition proposed by the IDSA in 2006; it requires that patients have prior documented Lyme disease, no other specific comorbidities, and specific symptoms (fatigue, widespread musculoskeletal pain, and/or cognitive difficulties) causing significant functional impact at least 6 months from their initial diagnosis and treatment.

In the real world, however, where diagnostics for acute Lyme disease are often inaccurate, erythema migrans is often absent, and the symptomatology of Lyme IACI is variable (and where there is no approved laboratory test or objective biomarker for diagnosing Lyme IACI), PTLD represents only a subset of a broader, heterogeneous population with persistent symptoms.

The term “Lyme IACI,” pronounced “Lyme eye-ACK-ee” at the meeting, builds on conversations at the 2023 NASEM workshop on infection-associated chronic illnesses and “encompasses a variety of terms that are used,” including PTLD, PTLD syndrome, persistent Lyme disease, and chronic Lyme disease, according to committee documents. Symptoms are distinct from the known complications of Lyme disease, such as arthritis or carditis.

The findings from Dr. Aucott’s SLICE cohort likely represent “the best outcome,” he said. They’re “probably not generalizable to a community setting where we see lots of missed diagnoses and delayed diagnoses,” as well as other tick-borne coinfections.

One of the challenges in designing future trials, in fact, relates to enrollment criteria and whether to use strict inclusion and exclusion criteria associated with the IDSA definition or take a broader approach to trial enrollment, he and others said. “You want to enroll patients for whom there’s no controversy that they’ve had Lyme infection ... for a study people believe in,” Dr. Aucott said during a discussion period, noting that it’s typical to screen over 100 patients to find one enrollee. “But it’s a tension we’re having.”

Timothy Sellati, PhD, chief scientific officer of the Global Lyme Alliance, urged change. “It’s really important to try to figure out how to alter our thinking on identifying and diagnosing chronic Lyme patients because they need to be recruited into clinical trials,” he said during his presentation.

“We think the best way to do this is to [develop and] employ composite diagnostic testing” that looks at unique Borrelia signatures (eg, protein, DNA, RNA, or metabolites), genetic and/or epigenetic signatures, inflammation signatures, T-cell-independent antibody signatures, and other elements, Dr. Sellati said.

Researchers designing treatment trials also face unknowns, Dr. Aucott and others said, about the role of potential mechanisms of Lyme IACI, from persistent Borrelia burgdorferi (or Borrelia mayonii) infection or the persistence of bacterial remnants (eg, nucleic acids or peptidoglycans) to infection-triggered pathology such as persistent immune dysregulation, chronic inflammation, autoimmunity, microbiome alterations, and dysautonomia and other neural network alterations.

The NASEM’s spotlight on Lyme IACI follows its long COVID-driven push last year to advance a common research agenda in infection-associated chronic illnesses. Investigators see common symptoms and potential shared mechanisms between long COVID, Lyme IACI, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and other complex chronic illnesses following infections.

At the Lyme IACI meeting, invited speakers described parts of the research landscape. Avindra Nath, MD, of the National Institute of Neurological Disorders and Stroke, for instance, described a recently published deep phenotyping study of 17 patients with ME/CFS that found decreased central catecholamine synthesis, circuit dysfunction of integrative brain regions, and immune profiling differences (eg, defects in B-cell maturation or T-cell exhaustion), compared with matched controls, that suggest the persistence of microbial antigens.

And John Leong, MD, PhD, of Tufts University, Boston, described his lab’s focus on understanding the microbe-host interactions that enable bloodstream dissemination and tissue invasion of B burgdorferi to take hold, increasing the risk for persistent symptoms. Other research at Tufts, he noted during a discussion period, has demonstrated the persistence of B burgdorferi to antibiotics in microtiter dishes. “Those organisms that survive are really difficult to eradicate in vitro,” Dr. Leong said.

Other physician investigators described research on nociplastic pain — a category of pain that can be triggered by infections, causing both amplified sensory processing and augmented central nervous system pain — and on whether reactivation of the Epstein-Barr virus could potentiate autoimmunity in the context of Borrelia infection.

Researchers are ready to test therapies while pathophysiology is unraveled — provided there is funding, Dr. Aucott said. The Clinical Trials Network for Lyme and Other Tick-Borne Diseases, coordinated by Brian Fallon, MD, of Columbia University, New York City, and funded several years ago by the Steven & Alexandra Cohen Foundation, has a slate of small pilot studies underway or being planned that address potential mechanisms (eg, studies of pulse intravenous ceftriaxone, tetracycline, transauricular vagus nerve stimulation, and mast cell modulation). And should full multisite trials be designed and funded, the network is ready with an infrastructure.
 

Need for Patient-Centered Outcomes

Persistent symptomatology is on the NIH’s radar screen. Efforts to understand causes were part of a strategic tick-borne disease research plan developed by the NIH in 2019. And in 2023, the National Institute of Allergy and Infectious Diseases (NIAID) funded seven projects addressing persistent symptoms that will run through 2028, C. Benjamin Beard, PhD, deputy division director of the CDC’s Division of Vector-Borne Disease, said at the NASEM committee meeting.

Patient advocates maintained that too much emphasis is placed on tick biology and pathophysiology. When Wendy Adams, research grant director and advisory board member of the Bay Area Lyme Foundation, and a colleague analyzed NIAID tick-borne disease funding from 2013 to 2021, they found that 75% of the funding went toward basic research, 15% to translational research, and “only 3% went to clinical research,” Ms. Adams told the committee.

Only 3% of the basic research budget was spent on coinfections, she said, and only 1% was spent on neurologic disease associated with tick-borne infections, both of which are survey-defined patient priorities. Moreover, “12% of the overall NIAID [tick-borne diseases] budget was spent on tick biology,” she said.

Research needs to involve community physicians who are utilizing the guidelines and approaches of the International Lyme and Associated Diseases Society to treat most patients with Lyme IACI, Ms. Adams said. “They have data to be mined,” she said, as does LymeDisease.org, which maintains a patient registry, MyLymeData, with over 18,000 patients. The organization has published two treatment studies, including one on antibiotic treatment response.

Lorraine Johnson, JD, MBA, CEO of LymeDisease.org and principal investigator of MyLymeData, stressed the importance of using patient-centered outcomes that incorporate minimal clinically important differences (MCIDs). “A change in the SF-36 score [without consideration of MCIDs] is not inherently important or meaningful to patients,” she said, referring to the SF-36 survey of health-related quality of life.

“This may seem like an esoteric issue, but two of the four clinical trials done [on retreatment of] persistent Lyme disease used the SF-36 as their outcome measure, and those studies, led by [Mark] Klempner, concluded that retreatment was not effective,” Ms. Johnson said. “Patients have been and continue to be harmed by [this research] because they’re told by physicians that antibiotics don’t work.”

A 2012 biostatistical review of these four RCTs — trials that helped inform the 2006 IDSA treatment guidelines — concluded that the Klempner studies “set the bar for treatment success too high,” Ms. Johnson said. Three of the four trials were likely underpowered to detect clinically meaningful treatment effects, the review also found.

The NASEM committee will hold additional public meetings and review a wide range of literature through this year. The formation of the committee was recommended by the US Department of Health and Human Services Tick-Borne Disease Working Group that was established by Congress in 2016 and concluded its work in 2022. The committee’s work is funded by the Cohen Foundation.
 

A version of this article appeared on Medscape.com.

WASHINGTON — Advancing treatment for what has been variably called chronic Lyme and posttreatment Lyme disease (PTLD) is under the eyes of a National Academies of Science, Engineering, and Medicine (NASEM) committee of experts for the first time — a year after the NASEM shone a spotlight on the need to accelerate research on chronic illnesses that follow known or suspected infections.

The committee will not make recommendations on specific approaches to diagnosis and treatment when it issues a report in early 2025 but will instead present “consensus findings” on treatment for chronic illness associated with Lyme disease, including recommendations for advancing treatment.

There have been only a few randomized controlled trials (RCTs) conducted on what the committee is calling Lyme Infection-Associated Chronic Illness (Lyme IACI) for now, and no National Institutes of Health (NIH)-funded RCTs in the past 20 years or so. It’s an area void of the US Food and Drug Administration–approved therapies, void of any consensus on the off-label use of medications, and without any current standard of care or proven mechanisms and pathophysiology, said John Aucott, MD, director of the Johns Hopkins Medicine Lyme Disease Clinical Research Center, Baltimore, one of the invited speakers at a public meeting held by the NASEM in Washington, DC.

“The best way to look at this illness is not from the silos of infectious disease or the silos of rheumatology; you have to look across disciplines,” Dr. Aucott, also associate professor of medicine in the Division of Rheumatology, told the committee. “The story doesn’t fit anything I trained for in my infectious disease fellowship. Even today, I’d posit that PTLD is like an island — it’s still not connected to a lot of the mainstream of medicine.”

Rhisa Parera, who wrote and directed a 2021 documentary, Your Labs Are Normal, was one of several invited speakers who amplified the patient voice. Starting around age 7, she had pain in her knees, spine, and hips and vivid nightmares. In high school, she developed gastrointestinal issues, and in college, she developed debilitating neurologic symptoms.

Depression was her eventual diagnosis after having seen “every specialist in the book,” she said. At age 29, she received a positive western blot test and a Lyme disease diagnosis, at which point “I was prescribed 4 weeks of doxycycline and left in the dark,” the 34-year-old Black patient told the committee. Her health improved only after she began working with an “LLMD,” or Lyme-literate medical doctor (a term used in the patient community), while she lived with her mother and did not work, she said.

“I don’t share my Lyme disease history with other doctors. It’s pointless when you have those who will laugh at you, say you’re fine if you were treated, or just deny the disease completely,” Ms. Parera said. “We need this to be taught in medical school. It’s a literal emergency.”
 

Incidence and Potential Mechanisms

Limited research has suggested that 10%-20% of patients with Lyme disease develop persistent symptoms after standard antibiotic treatment advised by the Infectious Diseases Society of America (IDSA), Dr. Aucott said. (On its web page on chronic symptoms, the Centers for Disease Control and Prevention presents a more conservative range of 5%-10%.)

His own prospective cohort study at Johns Hopkins, published in 2022, found that 13.7% of 234 patients with prior Lyme disease met symptom and functional impact criteria for PTLD, compared with 4.1% of 49 participants without a history of Lyme disease — a statistically significant difference that he said should “put to rest” the question of “is it real?”

PTLD is the research case definition proposed by the IDSA in 2006; it requires that patients have prior documented Lyme disease, no other specific comorbidities, and specific symptoms (fatigue, widespread musculoskeletal pain, and/or cognitive difficulties) causing significant functional impact at least 6 months from their initial diagnosis and treatment.

In the real world, however, where diagnostics for acute Lyme disease are often inaccurate, erythema migrans is often absent, and the symptomatology of Lyme IACI is variable (and where there is no approved laboratory test or objective biomarker for diagnosing Lyme IACI), PTLD represents only a subset of a broader, heterogeneous population with persistent symptoms.

The term “Lyme IACI,” pronounced “Lyme eye-ACK-ee” at the meeting, builds on conversations at the 2023 NASEM workshop on infection-associated chronic illnesses and “encompasses a variety of terms that are used,” including PTLD, PTLD syndrome, persistent Lyme disease, and chronic Lyme disease, according to committee documents. Symptoms are distinct from the known complications of Lyme disease, such as arthritis or carditis.

The findings from Dr. Aucott’s SLICE cohort likely represent “the best outcome,” he said. They’re “probably not generalizable to a community setting where we see lots of missed diagnoses and delayed diagnoses,” as well as other tick-borne coinfections.

One of the challenges in designing future trials, in fact, relates to enrollment criteria and whether to use strict inclusion and exclusion criteria associated with the IDSA definition or take a broader approach to trial enrollment, he and others said. “You want to enroll patients for whom there’s no controversy that they’ve had Lyme infection ... for a study people believe in,” Dr. Aucott said during a discussion period, noting that it’s typical to screen over 100 patients to find one enrollee. “But it’s a tension we’re having.”

Timothy Sellati, PhD, chief scientific officer of the Global Lyme Alliance, urged change. “It’s really important to try to figure out how to alter our thinking on identifying and diagnosing chronic Lyme patients because they need to be recruited into clinical trials,” he said during his presentation.

“We think the best way to do this is to [develop and] employ composite diagnostic testing” that looks at unique Borrelia signatures (eg, protein, DNA, RNA, or metabolites), genetic and/or epigenetic signatures, inflammation signatures, T-cell-independent antibody signatures, and other elements, Dr. Sellati said.

Researchers designing treatment trials also face unknowns, Dr. Aucott and others said, about the role of potential mechanisms of Lyme IACI, from persistent Borrelia burgdorferi (or Borrelia mayonii) infection or the persistence of bacterial remnants (eg, nucleic acids or peptidoglycans) to infection-triggered pathology such as persistent immune dysregulation, chronic inflammation, autoimmunity, microbiome alterations, and dysautonomia and other neural network alterations.

The NASEM’s spotlight on Lyme IACI follows its long COVID-driven push last year to advance a common research agenda in infection-associated chronic illnesses. Investigators see common symptoms and potential shared mechanisms between long COVID, Lyme IACI, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and other complex chronic illnesses following infections.

At the Lyme IACI meeting, invited speakers described parts of the research landscape. Avindra Nath, MD, of the National Institute of Neurological Disorders and Stroke, for instance, described a recently published deep phenotyping study of 17 patients with ME/CFS that found decreased central catecholamine synthesis, circuit dysfunction of integrative brain regions, and immune profiling differences (eg, defects in B-cell maturation or T-cell exhaustion), compared with matched controls, that suggest the persistence of microbial antigens.

And John Leong, MD, PhD, of Tufts University, Boston, described his lab’s focus on understanding the microbe-host interactions that enable bloodstream dissemination and tissue invasion of B burgdorferi to take hold, increasing the risk for persistent symptoms. Other research at Tufts, he noted during a discussion period, has demonstrated the persistence of B burgdorferi to antibiotics in microtiter dishes. “Those organisms that survive are really difficult to eradicate in vitro,” Dr. Leong said.

Other physician investigators described research on nociplastic pain — a category of pain that can be triggered by infections, causing both amplified sensory processing and augmented central nervous system pain — and on whether reactivation of the Epstein-Barr virus could potentiate autoimmunity in the context of Borrelia infection.

Researchers are ready to test therapies while pathophysiology is unraveled — provided there is funding, Dr. Aucott said. The Clinical Trials Network for Lyme and Other Tick-Borne Diseases, coordinated by Brian Fallon, MD, of Columbia University, New York City, and funded several years ago by the Steven & Alexandra Cohen Foundation, has a slate of small pilot studies underway or being planned that address potential mechanisms (eg, studies of pulse intravenous ceftriaxone, tetracycline, transauricular vagus nerve stimulation, and mast cell modulation). And should full multisite trials be designed and funded, the network is ready with an infrastructure.
 

Need for Patient-Centered Outcomes

Persistent symptomatology is on the NIH’s radar screen. Efforts to understand causes were part of a strategic tick-borne disease research plan developed by the NIH in 2019. And in 2023, the National Institute of Allergy and Infectious Diseases (NIAID) funded seven projects addressing persistent symptoms that will run through 2028, C. Benjamin Beard, PhD, deputy division director of the CDC’s Division of Vector-Borne Disease, said at the NASEM committee meeting.

Patient advocates maintained that too much emphasis is placed on tick biology and pathophysiology. When Wendy Adams, research grant director and advisory board member of the Bay Area Lyme Foundation, and a colleague analyzed NIAID tick-borne disease funding from 2013 to 2021, they found that 75% of the funding went toward basic research, 15% to translational research, and “only 3% went to clinical research,” Ms. Adams told the committee.

Only 3% of the basic research budget was spent on coinfections, she said, and only 1% was spent on neurologic disease associated with tick-borne infections, both of which are survey-defined patient priorities. Moreover, “12% of the overall NIAID [tick-borne diseases] budget was spent on tick biology,” she said.

Research needs to involve community physicians who are utilizing the guidelines and approaches of the International Lyme and Associated Diseases Society to treat most patients with Lyme IACI, Ms. Adams said. “They have data to be mined,” she said, as does LymeDisease.org, which maintains a patient registry, MyLymeData, with over 18,000 patients. The organization has published two treatment studies, including one on antibiotic treatment response.

Lorraine Johnson, JD, MBA, CEO of LymeDisease.org and principal investigator of MyLymeData, stressed the importance of using patient-centered outcomes that incorporate minimal clinically important differences (MCIDs). “A change in the SF-36 score [without consideration of MCIDs] is not inherently important or meaningful to patients,” she said, referring to the SF-36 survey of health-related quality of life.

“This may seem like an esoteric issue, but two of the four clinical trials done [on retreatment of] persistent Lyme disease used the SF-36 as their outcome measure, and those studies, led by [Mark] Klempner, concluded that retreatment was not effective,” Ms. Johnson said. “Patients have been and continue to be harmed by [this research] because they’re told by physicians that antibiotics don’t work.”

A 2012 biostatistical review of these four RCTs — trials that helped inform the 2006 IDSA treatment guidelines — concluded that the Klempner studies “set the bar for treatment success too high,” Ms. Johnson said. Three of the four trials were likely underpowered to detect clinically meaningful treatment effects, the review also found.

The NASEM committee will hold additional public meetings and review a wide range of literature through this year. The formation of the committee was recommended by the US Department of Health and Human Services Tick-Borne Disease Working Group that was established by Congress in 2016 and concluded its work in 2022. The committee’s work is funded by the Cohen Foundation.
 

A version of this article appeared on Medscape.com.

WASHINGTON — Advancing treatment for what has been variably called chronic Lyme and posttreatment Lyme disease (PTLD) is under the eyes of a National Academies of Science, Engineering, and Medicine (NASEM) committee of experts for the first time — a year after the NASEM shone a spotlight on the need to accelerate research on chronic illnesses that follow known or suspected infections.

The committee will not make recommendations on specific approaches to diagnosis and treatment when it issues a report in early 2025 but will instead present “consensus findings” on treatment for chronic illness associated with Lyme disease, including recommendations for advancing treatment.

There have been only a few randomized controlled trials (RCTs) conducted on what the committee is calling Lyme Infection-Associated Chronic Illness (Lyme IACI) for now, and no National Institutes of Health (NIH)-funded RCTs in the past 20 years or so. It’s an area void of the US Food and Drug Administration–approved therapies, void of any consensus on the off-label use of medications, and without any current standard of care or proven mechanisms and pathophysiology, said John Aucott, MD, director of the Johns Hopkins Medicine Lyme Disease Clinical Research Center, Baltimore, one of the invited speakers at a public meeting held by the NASEM in Washington, DC.

“The best way to look at this illness is not from the silos of infectious disease or the silos of rheumatology; you have to look across disciplines,” Dr. Aucott, also associate professor of medicine in the Division of Rheumatology, told the committee. “The story doesn’t fit anything I trained for in my infectious disease fellowship. Even today, I’d posit that PTLD is like an island — it’s still not connected to a lot of the mainstream of medicine.”

Rhisa Parera, who wrote and directed a 2021 documentary, Your Labs Are Normal, was one of several invited speakers who amplified the patient voice. Starting around age 7, she had pain in her knees, spine, and hips and vivid nightmares. In high school, she developed gastrointestinal issues, and in college, she developed debilitating neurologic symptoms.

Depression was her eventual diagnosis after having seen “every specialist in the book,” she said. At age 29, she received a positive western blot test and a Lyme disease diagnosis, at which point “I was prescribed 4 weeks of doxycycline and left in the dark,” the 34-year-old Black patient told the committee. Her health improved only after she began working with an “LLMD,” or Lyme-literate medical doctor (a term used in the patient community), while she lived with her mother and did not work, she said.

“I don’t share my Lyme disease history with other doctors. It’s pointless when you have those who will laugh at you, say you’re fine if you were treated, or just deny the disease completely,” Ms. Parera said. “We need this to be taught in medical school. It’s a literal emergency.”
 

Incidence and Potential Mechanisms

Limited research has suggested that 10%-20% of patients with Lyme disease develop persistent symptoms after standard antibiotic treatment advised by the Infectious Diseases Society of America (IDSA), Dr. Aucott said. (On its web page on chronic symptoms, the Centers for Disease Control and Prevention presents a more conservative range of 5%-10%.)

His own prospective cohort study at Johns Hopkins, published in 2022, found that 13.7% of 234 patients with prior Lyme disease met symptom and functional impact criteria for PTLD, compared with 4.1% of 49 participants without a history of Lyme disease — a statistically significant difference that he said should “put to rest” the question of “is it real?”

PTLD is the research case definition proposed by the IDSA in 2006; it requires that patients have prior documented Lyme disease, no other specific comorbidities, and specific symptoms (fatigue, widespread musculoskeletal pain, and/or cognitive difficulties) causing significant functional impact at least 6 months from their initial diagnosis and treatment.

In the real world, however, where diagnostics for acute Lyme disease are often inaccurate, erythema migrans is often absent, and the symptomatology of Lyme IACI is variable (and where there is no approved laboratory test or objective biomarker for diagnosing Lyme IACI), PTLD represents only a subset of a broader, heterogeneous population with persistent symptoms.

The term “Lyme IACI,” pronounced “Lyme eye-ACK-ee” at the meeting, builds on conversations at the 2023 NASEM workshop on infection-associated chronic illnesses and “encompasses a variety of terms that are used,” including PTLD, PTLD syndrome, persistent Lyme disease, and chronic Lyme disease, according to committee documents. Symptoms are distinct from the known complications of Lyme disease, such as arthritis or carditis.

The findings from Dr. Aucott’s SLICE cohort likely represent “the best outcome,” he said. They’re “probably not generalizable to a community setting where we see lots of missed diagnoses and delayed diagnoses,” as well as other tick-borne coinfections.

One of the challenges in designing future trials, in fact, relates to enrollment criteria and whether to use strict inclusion and exclusion criteria associated with the IDSA definition or take a broader approach to trial enrollment, he and others said. “You want to enroll patients for whom there’s no controversy that they’ve had Lyme infection ... for a study people believe in,” Dr. Aucott said during a discussion period, noting that it’s typical to screen over 100 patients to find one enrollee. “But it’s a tension we’re having.”

Timothy Sellati, PhD, chief scientific officer of the Global Lyme Alliance, urged change. “It’s really important to try to figure out how to alter our thinking on identifying and diagnosing chronic Lyme patients because they need to be recruited into clinical trials,” he said during his presentation.

“We think the best way to do this is to [develop and] employ composite diagnostic testing” that looks at unique Borrelia signatures (eg, protein, DNA, RNA, or metabolites), genetic and/or epigenetic signatures, inflammation signatures, T-cell-independent antibody signatures, and other elements, Dr. Sellati said.

Researchers designing treatment trials also face unknowns, Dr. Aucott and others said, about the role of potential mechanisms of Lyme IACI, from persistent Borrelia burgdorferi (or Borrelia mayonii) infection or the persistence of bacterial remnants (eg, nucleic acids or peptidoglycans) to infection-triggered pathology such as persistent immune dysregulation, chronic inflammation, autoimmunity, microbiome alterations, and dysautonomia and other neural network alterations.

The NASEM’s spotlight on Lyme IACI follows its long COVID-driven push last year to advance a common research agenda in infection-associated chronic illnesses. Investigators see common symptoms and potential shared mechanisms between long COVID, Lyme IACI, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and other complex chronic illnesses following infections.

At the Lyme IACI meeting, invited speakers described parts of the research landscape. Avindra Nath, MD, of the National Institute of Neurological Disorders and Stroke, for instance, described a recently published deep phenotyping study of 17 patients with ME/CFS that found decreased central catecholamine synthesis, circuit dysfunction of integrative brain regions, and immune profiling differences (eg, defects in B-cell maturation or T-cell exhaustion), compared with matched controls, that suggest the persistence of microbial antigens.

And John Leong, MD, PhD, of Tufts University, Boston, described his lab’s focus on understanding the microbe-host interactions that enable bloodstream dissemination and tissue invasion of B burgdorferi to take hold, increasing the risk for persistent symptoms. Other research at Tufts, he noted during a discussion period, has demonstrated the persistence of B burgdorferi to antibiotics in microtiter dishes. “Those organisms that survive are really difficult to eradicate in vitro,” Dr. Leong said.

Other physician investigators described research on nociplastic pain — a category of pain that can be triggered by infections, causing both amplified sensory processing and augmented central nervous system pain — and on whether reactivation of the Epstein-Barr virus could potentiate autoimmunity in the context of Borrelia infection.

Researchers are ready to test therapies while pathophysiology is unraveled — provided there is funding, Dr. Aucott said. The Clinical Trials Network for Lyme and Other Tick-Borne Diseases, coordinated by Brian Fallon, MD, of Columbia University, New York City, and funded several years ago by the Steven & Alexandra Cohen Foundation, has a slate of small pilot studies underway or being planned that address potential mechanisms (eg, studies of pulse intravenous ceftriaxone, tetracycline, transauricular vagus nerve stimulation, and mast cell modulation). And should full multisite trials be designed and funded, the network is ready with an infrastructure.
 

Need for Patient-Centered Outcomes

Persistent symptomatology is on the NIH’s radar screen. Efforts to understand causes were part of a strategic tick-borne disease research plan developed by the NIH in 2019. And in 2023, the National Institute of Allergy and Infectious Diseases (NIAID) funded seven projects addressing persistent symptoms that will run through 2028, C. Benjamin Beard, PhD, deputy division director of the CDC’s Division of Vector-Borne Disease, said at the NASEM committee meeting.

Patient advocates maintained that too much emphasis is placed on tick biology and pathophysiology. When Wendy Adams, research grant director and advisory board member of the Bay Area Lyme Foundation, and a colleague analyzed NIAID tick-borne disease funding from 2013 to 2021, they found that 75% of the funding went toward basic research, 15% to translational research, and “only 3% went to clinical research,” Ms. Adams told the committee.

Only 3% of the basic research budget was spent on coinfections, she said, and only 1% was spent on neurologic disease associated with tick-borne infections, both of which are survey-defined patient priorities. Moreover, “12% of the overall NIAID [tick-borne diseases] budget was spent on tick biology,” she said.

Research needs to involve community physicians who are utilizing the guidelines and approaches of the International Lyme and Associated Diseases Society to treat most patients with Lyme IACI, Ms. Adams said. “They have data to be mined,” she said, as does LymeDisease.org, which maintains a patient registry, MyLymeData, with over 18,000 patients. The organization has published two treatment studies, including one on antibiotic treatment response.

Lorraine Johnson, JD, MBA, CEO of LymeDisease.org and principal investigator of MyLymeData, stressed the importance of using patient-centered outcomes that incorporate minimal clinically important differences (MCIDs). “A change in the SF-36 score [without consideration of MCIDs] is not inherently important or meaningful to patients,” she said, referring to the SF-36 survey of health-related quality of life.

“This may seem like an esoteric issue, but two of the four clinical trials done [on retreatment of] persistent Lyme disease used the SF-36 as their outcome measure, and those studies, led by [Mark] Klempner, concluded that retreatment was not effective,” Ms. Johnson said. “Patients have been and continue to be harmed by [this research] because they’re told by physicians that antibiotics don’t work.”

A 2012 biostatistical review of these four RCTs — trials that helped inform the 2006 IDSA treatment guidelines — concluded that the Klempner studies “set the bar for treatment success too high,” Ms. Johnson said. Three of the four trials were likely underpowered to detect clinically meaningful treatment effects, the review also found.

The NASEM committee will hold additional public meetings and review a wide range of literature through this year. The formation of the committee was recommended by the US Department of Health and Human Services Tick-Borne Disease Working Group that was established by Congress in 2016 and concluded its work in 2022. The committee’s work is funded by the Cohen Foundation.
 

A version of this article appeared on Medscape.com.

On World Brain Day (July 22, 2024), the German Society of Neurology (DGN) and the German Brain Foundation pointed out that too much sugar can harm the brain. The current results of the Global Burden of Diseases study shows that stroke and dementia are among the top 10 causes of death. A healthy, active lifestyle with sufficient exercise and sleep, along with the avoidance of harmful substances like alcohol, nicotine, or excessive sugar, protects the brain.

“Of course, the dose makes the poison as the brain, being the body’s powerhouse, needs glucose to function,” said Frank Erbguth, MD, PhD, president of the German Brain Foundation, in a press release from DGN and the German Brain Foundation. “However, with a permanent increase in blood sugar levels due to too many, too lavish meals and constant snacking on the side, we overload the system and fuel the development of neurologic diseases, particularly dementia and stroke.”

The per capita consumption of sugar was 33.2 kg in 2021/2022, which is almost twice the recommended amount. The German Nutrition Society recommends that no more than 10% of energy come from sugar. With a goal of 2000 kilocalories, that’s 50 g per day, or 18 kg per year. This total includes not only added sugar but also naturally occurring sugar, such as in fruits, honey, or juices.
 

What’s the Mechanism?

High blood sugar levels damage brain blood vessels and promote deposits on the vessel walls, thus reducing blood flow and nutrient supply to brain cells. This process can cause various limitations, as well as vascular dementia.

In Germany, around 250,000 people are diagnosed with dementia annually, and 15%-25% have vascular dementia. That proportion represents between 40,000 and 60,000 new cases each year.

In addition, glycosaminoglycans, which are complex sugar molecules, can directly impair cognition. They affect the function of synapses between nerve cells and, thus, affect neuronal plasticity. Experimental data presented at the 2023 American Chemical Society Congress have shown this phenomenon.

Twenty years ago, a study provided evidence that a diet high in fat and sugar disrupts neuronal plasticity and can impair the function of the hippocampus in the long term. A recent meta-analysis confirms these findings: Although mental performance improves at 2-12 hours after sugar consumption, sustained sugar intake can permanently damage cognitive function.

Diabetes mellitus can indirectly cause brain damage. Since the 1990s, it has been known that patients with type 2 diabetes have a significantly higher risk for dementia. It is suspected that glucose metabolism is also disrupted in neurons, thus contributing to the development of Alzheimer’s disease. Insulin also plays a role in the formation of Alzheimer’s plaques.

The Max Planck Institute for Metabolism Research demonstrated in 2023 that regular consumption of high-sugar and high-fat foods can change the brain. This leads to an increased craving for high-sugar and high-fat foods, which in turn promotes the development of obesity and type 2 diabetes.
 

Reduce Sugar Consumption

DGN and the German Brain Foundation advise minimizing sugar consumption. This process is often challenging, as even a small dose of sugar can trigger the gut to send signals to the brain via the vagus nerve, thus causing a strong craving for more sugar. “This could be the reason why some people quickly eat a whole chocolate bar after just one piece,” said Dr. Erbguth. In addition, dopamine, a “feel-good hormone,” is released in the brain when consuming sugar, thus leading to a desire for more.

“It is wise to break free from this cycle by largely avoiding sugar,” said Peter Berlit, MD, secretary general and spokesperson for DGN. “The effort is worth it, as 40% of all dementia cases and 90% of all strokes are preventable, with many of them linked to industrial sugar,” said Dr. Berlit. DGN and the German Brain Foundation support the call for a tax on particularly sugary beverages. They also pointed out that foods like yogurt or tomato ketchup contain sugar, and alcohol can also significantly raise blood sugar levels.

This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

On World Brain Day (July 22, 2024), the German Society of Neurology (DGN) and the German Brain Foundation pointed out that too much sugar can harm the brain. The current results of the Global Burden of Diseases study shows that stroke and dementia are among the top 10 causes of death. A healthy, active lifestyle with sufficient exercise and sleep, along with the avoidance of harmful substances like alcohol, nicotine, or excessive sugar, protects the brain.

“Of course, the dose makes the poison as the brain, being the body’s powerhouse, needs glucose to function,” said Frank Erbguth, MD, PhD, president of the German Brain Foundation, in a press release from DGN and the German Brain Foundation. “However, with a permanent increase in blood sugar levels due to too many, too lavish meals and constant snacking on the side, we overload the system and fuel the development of neurologic diseases, particularly dementia and stroke.”

The per capita consumption of sugar was 33.2 kg in 2021/2022, which is almost twice the recommended amount. The German Nutrition Society recommends that no more than 10% of energy come from sugar. With a goal of 2000 kilocalories, that’s 50 g per day, or 18 kg per year. This total includes not only added sugar but also naturally occurring sugar, such as in fruits, honey, or juices.
 

What’s the Mechanism?

High blood sugar levels damage brain blood vessels and promote deposits on the vessel walls, thus reducing blood flow and nutrient supply to brain cells. This process can cause various limitations, as well as vascular dementia.

In Germany, around 250,000 people are diagnosed with dementia annually, and 15%-25% have vascular dementia. That proportion represents between 40,000 and 60,000 new cases each year.

In addition, glycosaminoglycans, which are complex sugar molecules, can directly impair cognition. They affect the function of synapses between nerve cells and, thus, affect neuronal plasticity. Experimental data presented at the 2023 American Chemical Society Congress have shown this phenomenon.

Twenty years ago, a study provided evidence that a diet high in fat and sugar disrupts neuronal plasticity and can impair the function of the hippocampus in the long term. A recent meta-analysis confirms these findings: Although mental performance improves at 2-12 hours after sugar consumption, sustained sugar intake can permanently damage cognitive function.

Diabetes mellitus can indirectly cause brain damage. Since the 1990s, it has been known that patients with type 2 diabetes have a significantly higher risk for dementia. It is suspected that glucose metabolism is also disrupted in neurons, thus contributing to the development of Alzheimer’s disease. Insulin also plays a role in the formation of Alzheimer’s plaques.

The Max Planck Institute for Metabolism Research demonstrated in 2023 that regular consumption of high-sugar and high-fat foods can change the brain. This leads to an increased craving for high-sugar and high-fat foods, which in turn promotes the development of obesity and type 2 diabetes.
 

Reduce Sugar Consumption

DGN and the German Brain Foundation advise minimizing sugar consumption. This process is often challenging, as even a small dose of sugar can trigger the gut to send signals to the brain via the vagus nerve, thus causing a strong craving for more sugar. “This could be the reason why some people quickly eat a whole chocolate bar after just one piece,” said Dr. Erbguth. In addition, dopamine, a “feel-good hormone,” is released in the brain when consuming sugar, thus leading to a desire for more.

“It is wise to break free from this cycle by largely avoiding sugar,” said Peter Berlit, MD, secretary general and spokesperson for DGN. “The effort is worth it, as 40% of all dementia cases and 90% of all strokes are preventable, with many of them linked to industrial sugar,” said Dr. Berlit. DGN and the German Brain Foundation support the call for a tax on particularly sugary beverages. They also pointed out that foods like yogurt or tomato ketchup contain sugar, and alcohol can also significantly raise blood sugar levels.

This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

On World Brain Day (July 22, 2024), the German Society of Neurology (DGN) and the German Brain Foundation pointed out that too much sugar can harm the brain. The current results of the Global Burden of Diseases study shows that stroke and dementia are among the top 10 causes of death. A healthy, active lifestyle with sufficient exercise and sleep, along with the avoidance of harmful substances like alcohol, nicotine, or excessive sugar, protects the brain.

“Of course, the dose makes the poison as the brain, being the body’s powerhouse, needs glucose to function,” said Frank Erbguth, MD, PhD, president of the German Brain Foundation, in a press release from DGN and the German Brain Foundation. “However, with a permanent increase in blood sugar levels due to too many, too lavish meals and constant snacking on the side, we overload the system and fuel the development of neurologic diseases, particularly dementia and stroke.”

The per capita consumption of sugar was 33.2 kg in 2021/2022, which is almost twice the recommended amount. The German Nutrition Society recommends that no more than 10% of energy come from sugar. With a goal of 2000 kilocalories, that’s 50 g per day, or 18 kg per year. This total includes not only added sugar but also naturally occurring sugar, such as in fruits, honey, or juices.
 

What’s the Mechanism?

High blood sugar levels damage brain blood vessels and promote deposits on the vessel walls, thus reducing blood flow and nutrient supply to brain cells. This process can cause various limitations, as well as vascular dementia.

In Germany, around 250,000 people are diagnosed with dementia annually, and 15%-25% have vascular dementia. That proportion represents between 40,000 and 60,000 new cases each year.

In addition, glycosaminoglycans, which are complex sugar molecules, can directly impair cognition. They affect the function of synapses between nerve cells and, thus, affect neuronal plasticity. Experimental data presented at the 2023 American Chemical Society Congress have shown this phenomenon.

Twenty years ago, a study provided evidence that a diet high in fat and sugar disrupts neuronal plasticity and can impair the function of the hippocampus in the long term. A recent meta-analysis confirms these findings: Although mental performance improves at 2-12 hours after sugar consumption, sustained sugar intake can permanently damage cognitive function.

Diabetes mellitus can indirectly cause brain damage. Since the 1990s, it has been known that patients with type 2 diabetes have a significantly higher risk for dementia. It is suspected that glucose metabolism is also disrupted in neurons, thus contributing to the development of Alzheimer’s disease. Insulin also plays a role in the formation of Alzheimer’s plaques.

The Max Planck Institute for Metabolism Research demonstrated in 2023 that regular consumption of high-sugar and high-fat foods can change the brain. This leads to an increased craving for high-sugar and high-fat foods, which in turn promotes the development of obesity and type 2 diabetes.
 

Reduce Sugar Consumption

DGN and the German Brain Foundation advise minimizing sugar consumption. This process is often challenging, as even a small dose of sugar can trigger the gut to send signals to the brain via the vagus nerve, thus causing a strong craving for more sugar. “This could be the reason why some people quickly eat a whole chocolate bar after just one piece,” said Dr. Erbguth. In addition, dopamine, a “feel-good hormone,” is released in the brain when consuming sugar, thus leading to a desire for more.

“It is wise to break free from this cycle by largely avoiding sugar,” said Peter Berlit, MD, secretary general and spokesperson for DGN. “The effort is worth it, as 40% of all dementia cases and 90% of all strokes are preventable, with many of them linked to industrial sugar,” said Dr. Berlit. DGN and the German Brain Foundation support the call for a tax on particularly sugary beverages. They also pointed out that foods like yogurt or tomato ketchup contain sugar, and alcohol can also significantly raise blood sugar levels.

This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Black metastatic breast cancer patients with PIK3CA mutations were less likely to receive targeted therapy and less likely to be enrolled in clinical trials than White patients and had shorter overall survival, according to a retrospective cohort study. Black and White patients were equally likely to receive other drugs that did not require genomic testing.

“These clinical inequities in the use of targeted therapies and clinical trials ... must be a focus going forward,” said lead investigator Emily Podany, MD, a clinical fellow in hematology-oncology at Washington University in St. Louis, Missouri. “Our consortium is looking for paths forward in order to try and decrease these striking inequities. And it’s a focus of future research for us and future implementation [of] science interventions, hopefully, across the country.”

The study results were presented at the annual meeting of the American Society of Clinical Oncology.
 

Black Women Underrepresented

Black women are generally underrepresented in clinical trials, noted Dr. Podany. “They make up about 2%-5% of the patients in breast cancer clinical trials, and there are documented inequities in treatment and in outcomes for Black patients with metastatic breast cancer. This includes longer treatment delays, it includes fewer sentinel lymph node biopsies, and unfortunately, they’re more likely to discontinue treatment early.”

In terms of PI3K inhibition, PIK3CA mutations are found in about 40% of patients with HR-positive HER2-negative metastatic breast cancer. Alpelisib is FDA-approved as a targeted therapy for these patients, she said.

The study evaluated records of 1327 patients with metastatic breast cancer who also had circulating tumor DNA (ctDNA) results and were treated at Washington University, Massachusetts General Hospital in Boston, and Northwestern University in Chicago. Of these, 795 had an ER-positive, HER2-negative subtype and were included in the analysis. Most (89%) of the patients were White (n = 708), while 11% (n = 87) were Black, and the only baseline difference between patients was that Black patients had significantly more de novo metastatic breast cancer (31% versus 22%).

Use of PI3K, CDK4/6, or mTOR inhibitors was evaluated using manual electronic medical review, and genomic differences were evaluated using logistic regression.

The analysis showed inequities in both treatment and clinical trial enrollment. There were no differences between groups in the use of CDK4/6 or mTOR inhibitors, which do not require a genomic profile, the researchers noted, but Black patients with PIK3CA single nucleotide variants (SNV) were significantly less likely than White patients to use PI3K inhibitors (5.9% versus 28.8%; P = .045), despite no difference in PIK3CA mutations between groups (36% and 34% respectively). Similarly, 11% of White patients with PIK3CA mutations were enrolled in clinical trials, but none of the Black patients was.

Genomic differences were also found, Dr. Podany reported. Black patients with estrogen/progesterone receptor (ER/PR) positive, HER2-negative disease were more likely to have a CCND1 copy number variant. And for ER-positive PR-negative HER2-negative patients, Black patients were more likely to have a GATA3 SNV, while White patients were more likely to have a KRAS copy number variant.
 

Black Survival Less Than Half

The analysis also found significant differences in overall survival from the time of the first liquid biopsy, with White ER-positive, PR-negative, HER2-negative patients living a median of 21 months, versus 9.1 months for Black patients.

There were several limitations to the study beyond its retrospective nature, “so, we may be underestimating the true inequity,” noted Dr. Podany. “These are large urban academic centers, so our patients have access to these treatments. They have access to care. They have access to ctDNA liquid biopsy testing. And the timing of ctDNA, especially the first ctDNA test, is variable and provider-dependant. We were also unable to assess receipt of PI3 kinase inhibitors at future time points after the end of this cohort study.”

Asked for comment, Giuseppe Del Priore, MD, MPH, from Morehouse School of Medicine in Atlanta, Georgia, approved of the study design “with subjects limited to three distinctive institutions. That parameter alone can control for several unknown variables among the studied comparison groups, ie, Black women versus others.”

However, Dr. Del Priore, who is adjunct professor of obstetrics and gynecology, with a specialty in oncology, added, “retrospective studies are not reliable except for generating hypotheses. Therefore, I would like to see a rapid implementation of an intervention trial at these same institutions to ensure equal consideration of, and access to, targeted therapies. Too often a retrospective correlation is reported, but the solution is elusive due to unknown factors. In this case, knowing there is a mutation is far from alleviating the disproportionate burden of disease that many communities face.”

Dr. Podany had no relevant disclosures. Dr. Del Priore reported no conflicts of interest and disclosed that he is chief medical officer at BriaCell.

Black metastatic breast cancer patients with PIK3CA mutations were less likely to receive targeted therapy and less likely to be enrolled in clinical trials than White patients and had shorter overall survival, according to a retrospective cohort study. Black and White patients were equally likely to receive other drugs that did not require genomic testing.

“These clinical inequities in the use of targeted therapies and clinical trials ... must be a focus going forward,” said lead investigator Emily Podany, MD, a clinical fellow in hematology-oncology at Washington University in St. Louis, Missouri. “Our consortium is looking for paths forward in order to try and decrease these striking inequities. And it’s a focus of future research for us and future implementation [of] science interventions, hopefully, across the country.”

The study results were presented at the annual meeting of the American Society of Clinical Oncology.
 

Black Women Underrepresented

Black women are generally underrepresented in clinical trials, noted Dr. Podany. “They make up about 2%-5% of the patients in breast cancer clinical trials, and there are documented inequities in treatment and in outcomes for Black patients with metastatic breast cancer. This includes longer treatment delays, it includes fewer sentinel lymph node biopsies, and unfortunately, they’re more likely to discontinue treatment early.”

In terms of PI3K inhibition, PIK3CA mutations are found in about 40% of patients with HR-positive HER2-negative metastatic breast cancer. Alpelisib is FDA-approved as a targeted therapy for these patients, she said.

The study evaluated records of 1327 patients with metastatic breast cancer who also had circulating tumor DNA (ctDNA) results and were treated at Washington University, Massachusetts General Hospital in Boston, and Northwestern University in Chicago. Of these, 795 had an ER-positive, HER2-negative subtype and were included in the analysis. Most (89%) of the patients were White (n = 708), while 11% (n = 87) were Black, and the only baseline difference between patients was that Black patients had significantly more de novo metastatic breast cancer (31% versus 22%).

Use of PI3K, CDK4/6, or mTOR inhibitors was evaluated using manual electronic medical review, and genomic differences were evaluated using logistic regression.

The analysis showed inequities in both treatment and clinical trial enrollment. There were no differences between groups in the use of CDK4/6 or mTOR inhibitors, which do not require a genomic profile, the researchers noted, but Black patients with PIK3CA single nucleotide variants (SNV) were significantly less likely than White patients to use PI3K inhibitors (5.9% versus 28.8%; P = .045), despite no difference in PIK3CA mutations between groups (36% and 34% respectively). Similarly, 11% of White patients with PIK3CA mutations were enrolled in clinical trials, but none of the Black patients was.

Genomic differences were also found, Dr. Podany reported. Black patients with estrogen/progesterone receptor (ER/PR) positive, HER2-negative disease were more likely to have a CCND1 copy number variant. And for ER-positive PR-negative HER2-negative patients, Black patients were more likely to have a GATA3 SNV, while White patients were more likely to have a KRAS copy number variant.
 

Black Survival Less Than Half

The analysis also found significant differences in overall survival from the time of the first liquid biopsy, with White ER-positive, PR-negative, HER2-negative patients living a median of 21 months, versus 9.1 months for Black patients.

There were several limitations to the study beyond its retrospective nature, “so, we may be underestimating the true inequity,” noted Dr. Podany. “These are large urban academic centers, so our patients have access to these treatments. They have access to care. They have access to ctDNA liquid biopsy testing. And the timing of ctDNA, especially the first ctDNA test, is variable and provider-dependant. We were also unable to assess receipt of PI3 kinase inhibitors at future time points after the end of this cohort study.”

Asked for comment, Giuseppe Del Priore, MD, MPH, from Morehouse School of Medicine in Atlanta, Georgia, approved of the study design “with subjects limited to three distinctive institutions. That parameter alone can control for several unknown variables among the studied comparison groups, ie, Black women versus others.”

However, Dr. Del Priore, who is adjunct professor of obstetrics and gynecology, with a specialty in oncology, added, “retrospective studies are not reliable except for generating hypotheses. Therefore, I would like to see a rapid implementation of an intervention trial at these same institutions to ensure equal consideration of, and access to, targeted therapies. Too often a retrospective correlation is reported, but the solution is elusive due to unknown factors. In this case, knowing there is a mutation is far from alleviating the disproportionate burden of disease that many communities face.”

Dr. Podany had no relevant disclosures. Dr. Del Priore reported no conflicts of interest and disclosed that he is chief medical officer at BriaCell.

Black metastatic breast cancer patients with PIK3CA mutations were less likely to receive targeted therapy and less likely to be enrolled in clinical trials than White patients and had shorter overall survival, according to a retrospective cohort study. Black and White patients were equally likely to receive other drugs that did not require genomic testing.

“These clinical inequities in the use of targeted therapies and clinical trials ... must be a focus going forward,” said lead investigator Emily Podany, MD, a clinical fellow in hematology-oncology at Washington University in St. Louis, Missouri. “Our consortium is looking for paths forward in order to try and decrease these striking inequities. And it’s a focus of future research for us and future implementation [of] science interventions, hopefully, across the country.”

The study results were presented at the annual meeting of the American Society of Clinical Oncology.
 

Black Women Underrepresented

Black women are generally underrepresented in clinical trials, noted Dr. Podany. “They make up about 2%-5% of the patients in breast cancer clinical trials, and there are documented inequities in treatment and in outcomes for Black patients with metastatic breast cancer. This includes longer treatment delays, it includes fewer sentinel lymph node biopsies, and unfortunately, they’re more likely to discontinue treatment early.”

In terms of PI3K inhibition, PIK3CA mutations are found in about 40% of patients with HR-positive HER2-negative metastatic breast cancer. Alpelisib is FDA-approved as a targeted therapy for these patients, she said.

The study evaluated records of 1327 patients with metastatic breast cancer who also had circulating tumor DNA (ctDNA) results and were treated at Washington University, Massachusetts General Hospital in Boston, and Northwestern University in Chicago. Of these, 795 had an ER-positive, HER2-negative subtype and were included in the analysis. Most (89%) of the patients were White (n = 708), while 11% (n = 87) were Black, and the only baseline difference between patients was that Black patients had significantly more de novo metastatic breast cancer (31% versus 22%).

Use of PI3K, CDK4/6, or mTOR inhibitors was evaluated using manual electronic medical review, and genomic differences were evaluated using logistic regression.

The analysis showed inequities in both treatment and clinical trial enrollment. There were no differences between groups in the use of CDK4/6 or mTOR inhibitors, which do not require a genomic profile, the researchers noted, but Black patients with PIK3CA single nucleotide variants (SNV) were significantly less likely than White patients to use PI3K inhibitors (5.9% versus 28.8%; P = .045), despite no difference in PIK3CA mutations between groups (36% and 34% respectively). Similarly, 11% of White patients with PIK3CA mutations were enrolled in clinical trials, but none of the Black patients was.

Genomic differences were also found, Dr. Podany reported. Black patients with estrogen/progesterone receptor (ER/PR) positive, HER2-negative disease were more likely to have a CCND1 copy number variant. And for ER-positive PR-negative HER2-negative patients, Black patients were more likely to have a GATA3 SNV, while White patients were more likely to have a KRAS copy number variant.
 

Black Survival Less Than Half

The analysis also found significant differences in overall survival from the time of the first liquid biopsy, with White ER-positive, PR-negative, HER2-negative patients living a median of 21 months, versus 9.1 months for Black patients.

There were several limitations to the study beyond its retrospective nature, “so, we may be underestimating the true inequity,” noted Dr. Podany. “These are large urban academic centers, so our patients have access to these treatments. They have access to care. They have access to ctDNA liquid biopsy testing. And the timing of ctDNA, especially the first ctDNA test, is variable and provider-dependant. We were also unable to assess receipt of PI3 kinase inhibitors at future time points after the end of this cohort study.”

Asked for comment, Giuseppe Del Priore, MD, MPH, from Morehouse School of Medicine in Atlanta, Georgia, approved of the study design “with subjects limited to three distinctive institutions. That parameter alone can control for several unknown variables among the studied comparison groups, ie, Black women versus others.”

However, Dr. Del Priore, who is adjunct professor of obstetrics and gynecology, with a specialty in oncology, added, “retrospective studies are not reliable except for generating hypotheses. Therefore, I would like to see a rapid implementation of an intervention trial at these same institutions to ensure equal consideration of, and access to, targeted therapies. Too often a retrospective correlation is reported, but the solution is elusive due to unknown factors. In this case, knowing there is a mutation is far from alleviating the disproportionate burden of disease that many communities face.”

Dr. Podany had no relevant disclosures. Dr. Del Priore reported no conflicts of interest and disclosed that he is chief medical officer at BriaCell.

Gluconolactone, 3,4,5-trihydroxy-6-(hydroxymethyl) oxan-2-one (C₆H₁₀O₆), is known to display antioxidant, moisturizing, and soothing activity as well as enhance skin barrier function and protect elastin fibers from UV-engendered damage.¹ This derivative of oxidized glucose lactone is present naturally in bread, cheese, fruit juices, honey, tofu, and wine, and is used as a food additive in Europe.^1,2 In dermatology, it is most often used in chemical peels.

Polyhydroxy acids (PHAs) were discovered about 3 decades ago to exert similar functions as alpha hydroxy acids without provoking sensory irritation reactions. Gluconolactone along with lactobionic acid were the identified PHAs and further characterized as delivering more humectant and moisturizing activity than alpha hydroxy acids and effective in combination with retinoic acid to treat adult acne and with retinyl acetate to confer antiaging benefits.³ It is typically added to products for its skin-conditioning qualities, resulting in smoother, brighter, more toned skin.⁴ This column focuses on recent studies using this bioactive agent for dermatologic purposes.
 

Split-Face Studies Show Various Benefits

peepo/E+/Getty Images

In 2023, Jarząbek-Perz and colleagues conducted a split-face evaluation to assess the effects on various skin parameters (ie, hydration, pH, sebum, and transepidermal water loss [TEWL]) of gluconolactone and oxybrasion, compared with gluconolactone and microneedling. Twenty-one White women underwent a series of three split-face treatments at 1-week intervals. Chemical peels with 10% gluconolactone were performed on the whole face. The right side of the face was also treated with oxybrasion and the left with microneedle mesotherapy. Skin parameters were measured before the first and third treatments and 2 weeks following the final treatment. Photos were taken before and after the study. Both treatments resulted in improved hydration and reductions in sebum, pH, and TEWL. No statistically significant differences were noted between the treatment protocols. The researchers concluded that gluconolactone peels can be effectively combined with oxybrasion or microneedle mesotherapy to enhance skin hydration and to secure the hydrolipid barrier.⁵

Later that year, the same team evaluated pH, sebum levels, and TEWL before, during, and after several applications of 10% and 30% gluconolactone chemical peels in a split-face model in 16 female participants. The investigators conducted three procedures on both sides of the face, taking measurements on the forehead, periorbital area, on the cheek, and on the nose wing before, during, and 7 days after the final treatment. They found statistically significant improvements in sebum levels in the cheeks after the treatment series. Also, pH values were lower at each measurement site after each procedure. TEWL levels were significantly diminished around the eyes, as well as the left forehead and right cheek, with no significant discrepancy between gluconolactone concentrations. The researchers concluded that gluconolactone plays a major role in reducing cutaneous pH and TEWL and imparts a regulatory effect on sebum.¹

Two years earlier, Jarząbek-Perz and colleagues assessed skin moisture in a split-face model in 16 healthy women after the application of 10% and 30% gluconolactone. Investigators measured skin moisture before and after each of three treatments and a week after the final treatment from the forehead, periorbital area, and on the cheek. They observed no significant discrepancies between the 10% and 30% formulations, but a significant elevation in facial skin hydration was found to be promoted by gluconolactone. The investigators concluded that gluconolactone is an effective moisturizer for care of dry skin.⁶

Topical Formulation

In 2023, Zerbinati and colleagues determined that a gluconolactone-based lotion that they had begun testing 2 years earlier was safe and effective for dermatologic applications, with the noncomedogenic formulation found suitable as an antiaging agent, particularly as it treats aging-related pore dilatation.^7,8

Acne Treatment

In 2019, Kantikosum and colleagues conducted a double-blind, within-person comparative study to assess the efficacy of various cosmeceutical ingredients, including gluconolactone, glycolic acid, licochalcone A, and salicylic acid, combined with the acne treatment adapalene vs adapalene monotherapy for mild to moderate acne. Each of 25 subjects over 28 days applied a product mixed with 0.1% adapalene on one side of the face, and 0.1% adapalene alone on the other side of the face once nightly. The VISIA camera system spot score pointed to a statistically significant improvement on the combination sides. Differences in lesion reduction and severity were within acceptable margins, the authors reported. They concluded that the cosmeceutical combinations yielded similar benefits as adapalene alone, with the combination formulations decreasing acne complications.⁹

Potential Use as an Antifibrotic Agent

Baumann Cosmetic &amp; Research Institute

In 2018, Jayamani and colleagues investigated the antifibrotic characteristics of glucono-delta-lactone, a known acidifier, to ascertain if it could directly suppress collagen fibrils or even cause them to disintegrate. The researchers noted that collagen fibrillation is pH dependent, and that glucono-delta-lactone was found to exert a concentration-dependent suppression of fibrils and disintegration of preformed collagen fibrils with the antifibrotic function of the compound ascribed to its capacity to decrease pH. Further, glucono-delta-lactone appeared to emerge as an ideal antifibrotic agent as it left intact the triple helical structure of collagen after treatment. The investigators concluded that glucono-delta-lactone provides the foundation for developing antifibrotic agents intended to treat disorders characterized by collagen deposition.¹⁰

Conclusion

Gluconolactone emerged in the 1990s as a PHA useful in skin peels as an alternative to alpha hydroxy acids because of its nonirritating qualities. Since then, its soothing, hydrating, and, in particular, antiacne and antiaging qualities have become established. Wider applications of this versatile agent for dermatologic purposes are likely to be further investigated.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur in Miami. She founded the division of cosmetic dermatology at the University of Miami in 1997. The third edition of her bestselling textbook, “Cosmetic Dermatology,” was published in 2022. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Johnson & Johnson, and Burt’s Bees. She is the CEO of Skin Type Solutions, a SaaS company used to generate skin care routines in office and as a ecommerce solution. Write to her at [email protected].

References

1. Jarząbek-Perz S et al. J Cosmet Dermatol. 2023 Dec;22(12):3305-3312..

2. Qin X et al. Front Physiol. 2022 Mar 14;13:856699.

3. Grimes PE et al. Cutis. 2004 Feb;73(2 Suppl):3-13.

4. Glaser DA. Facial Plast Surg Clin North Am. 2003 May;11(2):219-227.

5. Jarząbek-Perz S et al. Skin Res Technol. 2023 Jun;29(6):e13353.

6. Jarząbek-Perz S et al. Skin Res Technol. 2021 Sep;27(5):925-930.

7. Zerbinati N et al. Molecules. 2021 Dec 15;26(24):7592.

8. Zerbinati Net al. Pharmaceuticals (Basel). 2023 Apr 27;16(5):655.

9. Kantikosum K et al. Clin Cosmet Investig Dermatol. 2019 Feb 19;12:151-161.

10. Jayamani J et al. Int J Biol Macromol. 2018 Feb;107(Pt A):175-185.

Gluconolactone, 3,4,5-trihydroxy-6-(hydroxymethyl) oxan-2-one (C₆H₁₀O₆), is known to display antioxidant, moisturizing, and soothing activity as well as enhance skin barrier function and protect elastin fibers from UV-engendered damage.¹ This derivative of oxidized glucose lactone is present naturally in bread, cheese, fruit juices, honey, tofu, and wine, and is used as a food additive in Europe.^1,2 In dermatology, it is most often used in chemical peels.

Polyhydroxy acids (PHAs) were discovered about 3 decades ago to exert similar functions as alpha hydroxy acids without provoking sensory irritation reactions. Gluconolactone along with lactobionic acid were the identified PHAs and further characterized as delivering more humectant and moisturizing activity than alpha hydroxy acids and effective in combination with retinoic acid to treat adult acne and with retinyl acetate to confer antiaging benefits.³ It is typically added to products for its skin-conditioning qualities, resulting in smoother, brighter, more toned skin.⁴ This column focuses on recent studies using this bioactive agent for dermatologic purposes.
 

Split-Face Studies Show Various Benefits

peepo/E+/Getty Images

In 2023, Jarząbek-Perz and colleagues conducted a split-face evaluation to assess the effects on various skin parameters (ie, hydration, pH, sebum, and transepidermal water loss [TEWL]) of gluconolactone and oxybrasion, compared with gluconolactone and microneedling. Twenty-one White women underwent a series of three split-face treatments at 1-week intervals. Chemical peels with 10% gluconolactone were performed on the whole face. The right side of the face was also treated with oxybrasion and the left with microneedle mesotherapy. Skin parameters were measured before the first and third treatments and 2 weeks following the final treatment. Photos were taken before and after the study. Both treatments resulted in improved hydration and reductions in sebum, pH, and TEWL. No statistically significant differences were noted between the treatment protocols. The researchers concluded that gluconolactone peels can be effectively combined with oxybrasion or microneedle mesotherapy to enhance skin hydration and to secure the hydrolipid barrier.⁵

Later that year, the same team evaluated pH, sebum levels, and TEWL before, during, and after several applications of 10% and 30% gluconolactone chemical peels in a split-face model in 16 female participants. The investigators conducted three procedures on both sides of the face, taking measurements on the forehead, periorbital area, on the cheek, and on the nose wing before, during, and 7 days after the final treatment. They found statistically significant improvements in sebum levels in the cheeks after the treatment series. Also, pH values were lower at each measurement site after each procedure. TEWL levels were significantly diminished around the eyes, as well as the left forehead and right cheek, with no significant discrepancy between gluconolactone concentrations. The researchers concluded that gluconolactone plays a major role in reducing cutaneous pH and TEWL and imparts a regulatory effect on sebum.¹

Two years earlier, Jarząbek-Perz and colleagues assessed skin moisture in a split-face model in 16 healthy women after the application of 10% and 30% gluconolactone. Investigators measured skin moisture before and after each of three treatments and a week after the final treatment from the forehead, periorbital area, and on the cheek. They observed no significant discrepancies between the 10% and 30% formulations, but a significant elevation in facial skin hydration was found to be promoted by gluconolactone. The investigators concluded that gluconolactone is an effective moisturizer for care of dry skin.⁶

Topical Formulation

In 2023, Zerbinati and colleagues determined that a gluconolactone-based lotion that they had begun testing 2 years earlier was safe and effective for dermatologic applications, with the noncomedogenic formulation found suitable as an antiaging agent, particularly as it treats aging-related pore dilatation.^7,8

Acne Treatment

In 2019, Kantikosum and colleagues conducted a double-blind, within-person comparative study to assess the efficacy of various cosmeceutical ingredients, including gluconolactone, glycolic acid, licochalcone A, and salicylic acid, combined with the acne treatment adapalene vs adapalene monotherapy for mild to moderate acne. Each of 25 subjects over 28 days applied a product mixed with 0.1% adapalene on one side of the face, and 0.1% adapalene alone on the other side of the face once nightly. The VISIA camera system spot score pointed to a statistically significant improvement on the combination sides. Differences in lesion reduction and severity were within acceptable margins, the authors reported. They concluded that the cosmeceutical combinations yielded similar benefits as adapalene alone, with the combination formulations decreasing acne complications.⁹

Potential Use as an Antifibrotic Agent

Baumann Cosmetic &amp; Research Institute

In 2018, Jayamani and colleagues investigated the antifibrotic characteristics of glucono-delta-lactone, a known acidifier, to ascertain if it could directly suppress collagen fibrils or even cause them to disintegrate. The researchers noted that collagen fibrillation is pH dependent, and that glucono-delta-lactone was found to exert a concentration-dependent suppression of fibrils and disintegration of preformed collagen fibrils with the antifibrotic function of the compound ascribed to its capacity to decrease pH. Further, glucono-delta-lactone appeared to emerge as an ideal antifibrotic agent as it left intact the triple helical structure of collagen after treatment. The investigators concluded that glucono-delta-lactone provides the foundation for developing antifibrotic agents intended to treat disorders characterized by collagen deposition.¹⁰

Conclusion

Gluconolactone emerged in the 1990s as a PHA useful in skin peels as an alternative to alpha hydroxy acids because of its nonirritating qualities. Since then, its soothing, hydrating, and, in particular, antiacne and antiaging qualities have become established. Wider applications of this versatile agent for dermatologic purposes are likely to be further investigated.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur in Miami. She founded the division of cosmetic dermatology at the University of Miami in 1997. The third edition of her bestselling textbook, “Cosmetic Dermatology,” was published in 2022. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Johnson & Johnson, and Burt’s Bees. She is the CEO of Skin Type Solutions, a SaaS company used to generate skin care routines in office and as a ecommerce solution. Write to her at [email protected].

References

1. Jarząbek-Perz S et al. J Cosmet Dermatol. 2023 Dec;22(12):3305-3312..

2. Qin X et al. Front Physiol. 2022 Mar 14;13:856699.

3. Grimes PE et al. Cutis. 2004 Feb;73(2 Suppl):3-13.

4. Glaser DA. Facial Plast Surg Clin North Am. 2003 May;11(2):219-227.

5. Jarząbek-Perz S et al. Skin Res Technol. 2023 Jun;29(6):e13353.

6. Jarząbek-Perz S et al. Skin Res Technol. 2021 Sep;27(5):925-930.

7. Zerbinati N et al. Molecules. 2021 Dec 15;26(24):7592.

8. Zerbinati Net al. Pharmaceuticals (Basel). 2023 Apr 27;16(5):655.

9. Kantikosum K et al. Clin Cosmet Investig Dermatol. 2019 Feb 19;12:151-161.

10. Jayamani J et al. Int J Biol Macromol. 2018 Feb;107(Pt A):175-185.

Gluconolactone, 3,4,5-trihydroxy-6-(hydroxymethyl) oxan-2-one (C₆H₁₀O₆), is known to display antioxidant, moisturizing, and soothing activity as well as enhance skin barrier function and protect elastin fibers from UV-engendered damage.¹ This derivative of oxidized glucose lactone is present naturally in bread, cheese, fruit juices, honey, tofu, and wine, and is used as a food additive in Europe.^1,2 In dermatology, it is most often used in chemical peels.

Polyhydroxy acids (PHAs) were discovered about 3 decades ago to exert similar functions as alpha hydroxy acids without provoking sensory irritation reactions. Gluconolactone along with lactobionic acid were the identified PHAs and further characterized as delivering more humectant and moisturizing activity than alpha hydroxy acids and effective in combination with retinoic acid to treat adult acne and with retinyl acetate to confer antiaging benefits.³ It is typically added to products for its skin-conditioning qualities, resulting in smoother, brighter, more toned skin.⁴ This column focuses on recent studies using this bioactive agent for dermatologic purposes.
 

Split-Face Studies Show Various Benefits

peepo/E+/Getty Images

In 2023, Jarząbek-Perz and colleagues conducted a split-face evaluation to assess the effects on various skin parameters (ie, hydration, pH, sebum, and transepidermal water loss [TEWL]) of gluconolactone and oxybrasion, compared with gluconolactone and microneedling. Twenty-one White women underwent a series of three split-face treatments at 1-week intervals. Chemical peels with 10% gluconolactone were performed on the whole face. The right side of the face was also treated with oxybrasion and the left with microneedle mesotherapy. Skin parameters were measured before the first and third treatments and 2 weeks following the final treatment. Photos were taken before and after the study. Both treatments resulted in improved hydration and reductions in sebum, pH, and TEWL. No statistically significant differences were noted between the treatment protocols. The researchers concluded that gluconolactone peels can be effectively combined with oxybrasion or microneedle mesotherapy to enhance skin hydration and to secure the hydrolipid barrier.⁵

Later that year, the same team evaluated pH, sebum levels, and TEWL before, during, and after several applications of 10% and 30% gluconolactone chemical peels in a split-face model in 16 female participants. The investigators conducted three procedures on both sides of the face, taking measurements on the forehead, periorbital area, on the cheek, and on the nose wing before, during, and 7 days after the final treatment. They found statistically significant improvements in sebum levels in the cheeks after the treatment series. Also, pH values were lower at each measurement site after each procedure. TEWL levels were significantly diminished around the eyes, as well as the left forehead and right cheek, with no significant discrepancy between gluconolactone concentrations. The researchers concluded that gluconolactone plays a major role in reducing cutaneous pH and TEWL and imparts a regulatory effect on sebum.¹

Two years earlier, Jarząbek-Perz and colleagues assessed skin moisture in a split-face model in 16 healthy women after the application of 10% and 30% gluconolactone. Investigators measured skin moisture before and after each of three treatments and a week after the final treatment from the forehead, periorbital area, and on the cheek. They observed no significant discrepancies between the 10% and 30% formulations, but a significant elevation in facial skin hydration was found to be promoted by gluconolactone. The investigators concluded that gluconolactone is an effective moisturizer for care of dry skin.⁶

Topical Formulation

In 2023, Zerbinati and colleagues determined that a gluconolactone-based lotion that they had begun testing 2 years earlier was safe and effective for dermatologic applications, with the noncomedogenic formulation found suitable as an antiaging agent, particularly as it treats aging-related pore dilatation.^7,8

Acne Treatment

In 2019, Kantikosum and colleagues conducted a double-blind, within-person comparative study to assess the efficacy of various cosmeceutical ingredients, including gluconolactone, glycolic acid, licochalcone A, and salicylic acid, combined with the acne treatment adapalene vs adapalene monotherapy for mild to moderate acne. Each of 25 subjects over 28 days applied a product mixed with 0.1% adapalene on one side of the face, and 0.1% adapalene alone on the other side of the face once nightly. The VISIA camera system spot score pointed to a statistically significant improvement on the combination sides. Differences in lesion reduction and severity were within acceptable margins, the authors reported. They concluded that the cosmeceutical combinations yielded similar benefits as adapalene alone, with the combination formulations decreasing acne complications.⁹

Potential Use as an Antifibrotic Agent

Baumann Cosmetic &amp; Research Institute

In 2018, Jayamani and colleagues investigated the antifibrotic characteristics of glucono-delta-lactone, a known acidifier, to ascertain if it could directly suppress collagen fibrils or even cause them to disintegrate. The researchers noted that collagen fibrillation is pH dependent, and that glucono-delta-lactone was found to exert a concentration-dependent suppression of fibrils and disintegration of preformed collagen fibrils with the antifibrotic function of the compound ascribed to its capacity to decrease pH. Further, glucono-delta-lactone appeared to emerge as an ideal antifibrotic agent as it left intact the triple helical structure of collagen after treatment. The investigators concluded that glucono-delta-lactone provides the foundation for developing antifibrotic agents intended to treat disorders characterized by collagen deposition.¹⁰

Conclusion

Gluconolactone emerged in the 1990s as a PHA useful in skin peels as an alternative to alpha hydroxy acids because of its nonirritating qualities. Since then, its soothing, hydrating, and, in particular, antiacne and antiaging qualities have become established. Wider applications of this versatile agent for dermatologic purposes are likely to be further investigated.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur in Miami. She founded the division of cosmetic dermatology at the University of Miami in 1997. The third edition of her bestselling textbook, “Cosmetic Dermatology,” was published in 2022. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Johnson & Johnson, and Burt’s Bees. She is the CEO of Skin Type Solutions, a SaaS company used to generate skin care routines in office and as a ecommerce solution. Write to her at [email protected].

References

1. Jarząbek-Perz S et al. J Cosmet Dermatol. 2023 Dec;22(12):3305-3312..

2. Qin X et al. Front Physiol. 2022 Mar 14;13:856699.

3. Grimes PE et al. Cutis. 2004 Feb;73(2 Suppl):3-13.

4. Glaser DA. Facial Plast Surg Clin North Am. 2003 May;11(2):219-227.

5. Jarząbek-Perz S et al. Skin Res Technol. 2023 Jun;29(6):e13353.

6. Jarząbek-Perz S et al. Skin Res Technol. 2021 Sep;27(5):925-930.

7. Zerbinati N et al. Molecules. 2021 Dec 15;26(24):7592.

8. Zerbinati Net al. Pharmaceuticals (Basel). 2023 Apr 27;16(5):655.

9. Kantikosum K et al. Clin Cosmet Investig Dermatol. 2019 Feb 19;12:151-161.

10. Jayamani J et al. Int J Biol Macromol. 2018 Feb;107(Pt A):175-185.