VIENNA — Physicians are called to record clinical details of patients with asthma undergoing biologic therapy to monitor clinical remission and keep an eye on eosinophilic granulomatosis with polyangiitis (EGPA) symptoms as patients come off the medications, according to pulmonary experts presenting at the European Respiratory Society (ERS) 2024 International Congress.

Biologics have revolutionized the treatment of severe asthma, significantly improving patient outcomes. However, the focus has recently shifted toward achieving more comprehensive disease control. Remission, already a well-established goal in conditions like rheumatoid arthritis and inflammatory bowel disease, is now being explored in patients with asthma receiving biologics.

Peter Howarth, medical director at Global Medical, Specialty Medicine, GSK, in Brentford, England, said that new clinical remission criteria in asthma may be overly rigid and of little use. He said that more attainable limits must be created. Meanwhile, clinicians should collect clinical data more thoroughly.

In parallel, studies have also raised questions about the role of biologics in the emergence of EGPA.
 

Defining Clinical Remission in Asthma

Last year, a working group, including members from the American Thoracic Society and the American College and Academy of Allergy, Asthma, and Immunology, proposed new guidelines to define clinical remission in asthma. These guidelines extended beyond the typical outcomes of no severe exacerbations, no maintenance oral corticosteroid use, good asthma control, and stable lung function. The additional recommendations included no missed work or school due to asthma, limited use of rescue medication (no more than once a month), and reduced inhaled corticosteroid use to low or medium doses.

To explore the feasibility of achieving these clinical remission outcomes, GSK partnered with the Mayo Clinic for a retrospective analysis of the medical records of 700 patients with asthma undergoing various biologic therapies. The study revealed that essential data for determining clinical remission, such as asthma control and exacerbation records, were inconsistently documented. While some data were recorded, such as maintenance corticosteroid use in 50%-60% of cases, other key measures, like asthma control, were recorded in less than a quarter of the patients.

GSK researchers analyzed available data and found that around 30% of patients on any biologic therapy met three components of remission. Mepolizumab performed better than other corticosteroids, with over 40% of those receiving the drug meeting these criteria. However, when stricter definitions were applied, such as requiring four or more remission components, fewer patients achieved remission — less than 10% for four components, with no patients meeting the full seven-point criteria proposed by the working group.

An ongoing ERS Task Force is now exploring what clinical remission outcomes are practical to achieve, as the current definitions may be too aspirational, said Mr. Howarth. “It’s a matter of defying what is practical to achieve because if you can’t achieve it, then it won’t be valuable.”

He also pointed out that biologics are often used for the most severe cases of asthma after other treatments have failed. Evidence suggests that introducing biologics earlier in the disease, before chronic damage occurs, may result in better patient outcomes.
 

Biologics and EGPA

In a retrospective study, clinical details of 27 patients with adult-onset asthma from 28 countries, all on biologic therapy, were analyzed. The study, a multicounty collaboration, was led by ERS Severe Heterogeneous Asthma Research Collaboration, Patient-centred (SHARP), and aimed to understand the role of biologics in the emergence of EGPA.

The most significant finding presented at the ERS 2024 International Congress was that EGPA was not associated with maintenance corticosteroids; instead, it often emerged when corticosteroid doses were reduced or tapered off. “This might suggest that steroid withdrawal may unmask the underlying disease,” said Hitasha Rupani, MD, a consultant respiratory physician at the University Hospital Southampton, in Southampton, England. Importantly, the rate at which steroids were tapered did not influence the onset of EGPA, indicating that the tapering process, rather than its speed, may be the critical factor. However, due to the small sample size, this remains a hypothesis, Dr. Rupani explained.

The study also found that when clinicians had a clinical suspicion of EGPA before starting biologic therapy, the diagnosis was made earlier than in cases without such suspicion. Dr. Rupani concluded that this underscores the importance of clinical vigilance and the need to monitor patients closely for EGPA symptoms, especially during corticosteroid tapering.

The study was funded by GSK. Mr. Howarth is an employee at GSK. Dr. Rupani reports no relevant financial relationships. 

A version of this article appeared on Medscape.com.

VIENNA — Physicians are called to record clinical details of patients with asthma undergoing biologic therapy to monitor clinical remission and keep an eye on eosinophilic granulomatosis with polyangiitis (EGPA) symptoms as patients come off the medications, according to pulmonary experts presenting at the European Respiratory Society (ERS) 2024 International Congress.

Biologics have revolutionized the treatment of severe asthma, significantly improving patient outcomes. However, the focus has recently shifted toward achieving more comprehensive disease control. Remission, already a well-established goal in conditions like rheumatoid arthritis and inflammatory bowel disease, is now being explored in patients with asthma receiving biologics.

Peter Howarth, medical director at Global Medical, Specialty Medicine, GSK, in Brentford, England, said that new clinical remission criteria in asthma may be overly rigid and of little use. He said that more attainable limits must be created. Meanwhile, clinicians should collect clinical data more thoroughly.

In parallel, studies have also raised questions about the role of biologics in the emergence of EGPA.
 

Defining Clinical Remission in Asthma

Last year, a working group, including members from the American Thoracic Society and the American College and Academy of Allergy, Asthma, and Immunology, proposed new guidelines to define clinical remission in asthma. These guidelines extended beyond the typical outcomes of no severe exacerbations, no maintenance oral corticosteroid use, good asthma control, and stable lung function. The additional recommendations included no missed work or school due to asthma, limited use of rescue medication (no more than once a month), and reduced inhaled corticosteroid use to low or medium doses.

To explore the feasibility of achieving these clinical remission outcomes, GSK partnered with the Mayo Clinic for a retrospective analysis of the medical records of 700 patients with asthma undergoing various biologic therapies. The study revealed that essential data for determining clinical remission, such as asthma control and exacerbation records, were inconsistently documented. While some data were recorded, such as maintenance corticosteroid use in 50%-60% of cases, other key measures, like asthma control, were recorded in less than a quarter of the patients.

GSK researchers analyzed available data and found that around 30% of patients on any biologic therapy met three components of remission. Mepolizumab performed better than other corticosteroids, with over 40% of those receiving the drug meeting these criteria. However, when stricter definitions were applied, such as requiring four or more remission components, fewer patients achieved remission — less than 10% for four components, with no patients meeting the full seven-point criteria proposed by the working group.

An ongoing ERS Task Force is now exploring what clinical remission outcomes are practical to achieve, as the current definitions may be too aspirational, said Mr. Howarth. “It’s a matter of defying what is practical to achieve because if you can’t achieve it, then it won’t be valuable.”

He also pointed out that biologics are often used for the most severe cases of asthma after other treatments have failed. Evidence suggests that introducing biologics earlier in the disease, before chronic damage occurs, may result in better patient outcomes.
 

Biologics and EGPA

In a retrospective study, clinical details of 27 patients with adult-onset asthma from 28 countries, all on biologic therapy, were analyzed. The study, a multicounty collaboration, was led by ERS Severe Heterogeneous Asthma Research Collaboration, Patient-centred (SHARP), and aimed to understand the role of biologics in the emergence of EGPA.

The most significant finding presented at the ERS 2024 International Congress was that EGPA was not associated with maintenance corticosteroids; instead, it often emerged when corticosteroid doses were reduced or tapered off. “This might suggest that steroid withdrawal may unmask the underlying disease,” said Hitasha Rupani, MD, a consultant respiratory physician at the University Hospital Southampton, in Southampton, England. Importantly, the rate at which steroids were tapered did not influence the onset of EGPA, indicating that the tapering process, rather than its speed, may be the critical factor. However, due to the small sample size, this remains a hypothesis, Dr. Rupani explained.

The study also found that when clinicians had a clinical suspicion of EGPA before starting biologic therapy, the diagnosis was made earlier than in cases without such suspicion. Dr. Rupani concluded that this underscores the importance of clinical vigilance and the need to monitor patients closely for EGPA symptoms, especially during corticosteroid tapering.

The study was funded by GSK. Mr. Howarth is an employee at GSK. Dr. Rupani reports no relevant financial relationships. 

A version of this article appeared on Medscape.com.

VIENNA — Physicians are called to record clinical details of patients with asthma undergoing biologic therapy to monitor clinical remission and keep an eye on eosinophilic granulomatosis with polyangiitis (EGPA) symptoms as patients come off the medications, according to pulmonary experts presenting at the European Respiratory Society (ERS) 2024 International Congress.

Biologics have revolutionized the treatment of severe asthma, significantly improving patient outcomes. However, the focus has recently shifted toward achieving more comprehensive disease control. Remission, already a well-established goal in conditions like rheumatoid arthritis and inflammatory bowel disease, is now being explored in patients with asthma receiving biologics.

Peter Howarth, medical director at Global Medical, Specialty Medicine, GSK, in Brentford, England, said that new clinical remission criteria in asthma may be overly rigid and of little use. He said that more attainable limits must be created. Meanwhile, clinicians should collect clinical data more thoroughly.

In parallel, studies have also raised questions about the role of biologics in the emergence of EGPA.
 

Defining Clinical Remission in Asthma

Last year, a working group, including members from the American Thoracic Society and the American College and Academy of Allergy, Asthma, and Immunology, proposed new guidelines to define clinical remission in asthma. These guidelines extended beyond the typical outcomes of no severe exacerbations, no maintenance oral corticosteroid use, good asthma control, and stable lung function. The additional recommendations included no missed work or school due to asthma, limited use of rescue medication (no more than once a month), and reduced inhaled corticosteroid use to low or medium doses.

To explore the feasibility of achieving these clinical remission outcomes, GSK partnered with the Mayo Clinic for a retrospective analysis of the medical records of 700 patients with asthma undergoing various biologic therapies. The study revealed that essential data for determining clinical remission, such as asthma control and exacerbation records, were inconsistently documented. While some data were recorded, such as maintenance corticosteroid use in 50%-60% of cases, other key measures, like asthma control, were recorded in less than a quarter of the patients.

GSK researchers analyzed available data and found that around 30% of patients on any biologic therapy met three components of remission. Mepolizumab performed better than other corticosteroids, with over 40% of those receiving the drug meeting these criteria. However, when stricter definitions were applied, such as requiring four or more remission components, fewer patients achieved remission — less than 10% for four components, with no patients meeting the full seven-point criteria proposed by the working group.

An ongoing ERS Task Force is now exploring what clinical remission outcomes are practical to achieve, as the current definitions may be too aspirational, said Mr. Howarth. “It’s a matter of defying what is practical to achieve because if you can’t achieve it, then it won’t be valuable.”

He also pointed out that biologics are often used for the most severe cases of asthma after other treatments have failed. Evidence suggests that introducing biologics earlier in the disease, before chronic damage occurs, may result in better patient outcomes.
 

Biologics and EGPA

In a retrospective study, clinical details of 27 patients with adult-onset asthma from 28 countries, all on biologic therapy, were analyzed. The study, a multicounty collaboration, was led by ERS Severe Heterogeneous Asthma Research Collaboration, Patient-centred (SHARP), and aimed to understand the role of biologics in the emergence of EGPA.

The most significant finding presented at the ERS 2024 International Congress was that EGPA was not associated with maintenance corticosteroids; instead, it often emerged when corticosteroid doses were reduced or tapered off. “This might suggest that steroid withdrawal may unmask the underlying disease,” said Hitasha Rupani, MD, a consultant respiratory physician at the University Hospital Southampton, in Southampton, England. Importantly, the rate at which steroids were tapered did not influence the onset of EGPA, indicating that the tapering process, rather than its speed, may be the critical factor. However, due to the small sample size, this remains a hypothesis, Dr. Rupani explained.

The study also found that when clinicians had a clinical suspicion of EGPA before starting biologic therapy, the diagnosis was made earlier than in cases without such suspicion. Dr. Rupani concluded that this underscores the importance of clinical vigilance and the need to monitor patients closely for EGPA symptoms, especially during corticosteroid tapering.

The study was funded by GSK. Mr. Howarth is an employee at GSK. Dr. Rupani reports no relevant financial relationships. 

A version of this article appeared on Medscape.com.

MADRID — Night owls — individuals with late chronotypes — may be at an increased risk for type 2 diabetes (T2D), beyond the risks conferred by an unhealthy lifestyle, research presented at the annual meeting of the European Association for the Study of Diabetes suggested.

In the study, night owls were almost 50% more likely to develop T2D than those who went to sleep earlier.

“The magnitude of this risk was more than I expected, [although] residual confounding may have occurred,” said Jeroen van der Velde, PhD, Leiden University Medical Center in the Netherlands, who presented the study.

“Late chronotype has previously been associated with unhealthy lifestyle and overweight or obesity and, subsequently, cardiometabolic diseases,” he said in an interview. However, although the current study found that individuals with late chronotypes did indeed have larger waists and more visceral fat, “we (and others) believe that lifestyle cannot fully explain the relation between late chronotype and metabolic disorders.”

“In addition,” he noted, “previous studies that observed that late chronotype is associated with overweight or obesity mainly focused on body mass index [BMI]. However, BMI alone does not provide accurate information regarding fat distribution in the body. People with similar BMI may have different underlying fat distribution, and this may be more relevant than BMI for metabolic risk.”

The researchers examined associations between chronotype and BMI, waist circumference, visceral fat, liver fat, and the risk for T2D in a middle-aged population from the Netherlands Epidemiology of Obesity study. Among the 5026 participants, the mean age was 56 years, 54% were women, and mean BMI was 30.

Using data from the study, the study investigators calculated the midpoint of sleep (MPS) and divided participants into three chronotypes: Early MPS < 2:30 PM (20% of participants); intermediate MPS 2:30–4:00 PM (reference category; 60% of participants); and late MPS ≥ 4:00 PM (20% of participants). BMI and waist circumference were measured in all participants, and visceral fat and liver fat were measured in 1576 participants using MRI scans and MR spectroscopy, respectively.

During a median follow-up of 6.6 years, 225 participants were diagnosed with T2D. After adjustment for age, sex, education, physical activity, smoking, alcohol intake, diet quality, sleep quality and duration, and total body fat, participants with a late chronotype had a 46% increased risk for T2D.

Further, those with a late chronotype had 0.7 higher BMI, 1.9-cm larger waist circumference, 7 cm² more visceral fat, and 14% more liver fat.
 

Body Clock Out of Sync?

“Late chronotype was associated with increased ectopic body fat and with an increased risk of T2D independent of lifestyle factors and is an emerging risk factor for metabolic diseases,” the researchers concluded.

“A likely explanation is that the circadian rhythm or body clock in late chronotypes is out of sync with the work and social schedules followed by society,” Dr. van der Velde suggested. “This can lead to circadian misalignment, which we know can lead to metabolic disturbances and ultimately type 2 diabetes.”

Might trying to adjust chronotype earlier in life have an effect on risk?

“Chronotype, as measured via midpoint of sleep, does change a lot in the first 30 years or so in life,” he said. “After that it seems to stabilize. I suppose that if you adapt an intermediate or early chronotype around the age of 30 years, this will help to maintain an earlier chronotype later in life, although we cannot answer this from our study.”

Nevertheless, with respect to T2D risk, “chronotype is likely only part of the puzzle,” he noted.

“People with late chronotypes typically eat late in the evening, and this has also been associated with adverse metabolic effects. At this stage, we do not know if a person changes his/her chronotype that this will also lead to metabolic improvements. More research is needed before we can make recommendations regarding chronotype and timing of other lifestyle behaviors.”

Commenting on the study, Gianluca Iacobellis, MD, PhD, director of the University of Miami Hospital Diabetes Service, Coral Gables, Florida, said: “Interesting data. Altering the physiological circadian rhythm can affect the complex hormonal system — including cortisol, ghrelin, leptin, and serotonin — that regulates insulin sensitivity, glucose, and blood pressure control. The night owl may become more insulin resistant and therefore at higher risk of developing diabetes.”

Like Dr. van der Velde, he noted that “late sleep may be associated with night binging that can cause weight gain and ultimately obesity, further increasing the risk of diabetes.”

Dr. Iacobellis’s group recently showed that vital exhaustion, which is characterized by fatigue and loss of vigor, is associated with a higher cardiovascular risk for and markers of visceral adiposity.

“Abnormal circadian rhythms can be easily associated with vital exhaustion,” he said. Therefore, night owls with more visceral than peripheral fat accumulation might also be at higher cardiometabolic risk through that mechanism.

“However environmental factors and family history can play an important role too,” he added.

Regardless of the mechanisms involved, “preventive actions should be taken to educate teenagers and individuals at higher risk to have healthy sleep habits,” Dr. Iacobellis concluded.

No information regarding funding was provided; Dr. van der Velde and Dr. Iacobellis reported no conflicts of interest.

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

MADRID — Night owls — individuals with late chronotypes — may be at an increased risk for type 2 diabetes (T2D), beyond the risks conferred by an unhealthy lifestyle, research presented at the annual meeting of the European Association for the Study of Diabetes suggested.

In the study, night owls were almost 50% more likely to develop T2D than those who went to sleep earlier.

“The magnitude of this risk was more than I expected, [although] residual confounding may have occurred,” said Jeroen van der Velde, PhD, Leiden University Medical Center in the Netherlands, who presented the study.

“Late chronotype has previously been associated with unhealthy lifestyle and overweight or obesity and, subsequently, cardiometabolic diseases,” he said in an interview. However, although the current study found that individuals with late chronotypes did indeed have larger waists and more visceral fat, “we (and others) believe that lifestyle cannot fully explain the relation between late chronotype and metabolic disorders.”

“In addition,” he noted, “previous studies that observed that late chronotype is associated with overweight or obesity mainly focused on body mass index [BMI]. However, BMI alone does not provide accurate information regarding fat distribution in the body. People with similar BMI may have different underlying fat distribution, and this may be more relevant than BMI for metabolic risk.”

The researchers examined associations between chronotype and BMI, waist circumference, visceral fat, liver fat, and the risk for T2D in a middle-aged population from the Netherlands Epidemiology of Obesity study. Among the 5026 participants, the mean age was 56 years, 54% were women, and mean BMI was 30.

Using data from the study, the study investigators calculated the midpoint of sleep (MPS) and divided participants into three chronotypes: Early MPS < 2:30 PM (20% of participants); intermediate MPS 2:30–4:00 PM (reference category; 60% of participants); and late MPS ≥ 4:00 PM (20% of participants). BMI and waist circumference were measured in all participants, and visceral fat and liver fat were measured in 1576 participants using MRI scans and MR spectroscopy, respectively.

During a median follow-up of 6.6 years, 225 participants were diagnosed with T2D. After adjustment for age, sex, education, physical activity, smoking, alcohol intake, diet quality, sleep quality and duration, and total body fat, participants with a late chronotype had a 46% increased risk for T2D.

Further, those with a late chronotype had 0.7 higher BMI, 1.9-cm larger waist circumference, 7 cm² more visceral fat, and 14% more liver fat.
 

Body Clock Out of Sync?

“Late chronotype was associated with increased ectopic body fat and with an increased risk of T2D independent of lifestyle factors and is an emerging risk factor for metabolic diseases,” the researchers concluded.

“A likely explanation is that the circadian rhythm or body clock in late chronotypes is out of sync with the work and social schedules followed by society,” Dr. van der Velde suggested. “This can lead to circadian misalignment, which we know can lead to metabolic disturbances and ultimately type 2 diabetes.”

Might trying to adjust chronotype earlier in life have an effect on risk?

“Chronotype, as measured via midpoint of sleep, does change a lot in the first 30 years or so in life,” he said. “After that it seems to stabilize. I suppose that if you adapt an intermediate or early chronotype around the age of 30 years, this will help to maintain an earlier chronotype later in life, although we cannot answer this from our study.”

Nevertheless, with respect to T2D risk, “chronotype is likely only part of the puzzle,” he noted.

“People with late chronotypes typically eat late in the evening, and this has also been associated with adverse metabolic effects. At this stage, we do not know if a person changes his/her chronotype that this will also lead to metabolic improvements. More research is needed before we can make recommendations regarding chronotype and timing of other lifestyle behaviors.”

Commenting on the study, Gianluca Iacobellis, MD, PhD, director of the University of Miami Hospital Diabetes Service, Coral Gables, Florida, said: “Interesting data. Altering the physiological circadian rhythm can affect the complex hormonal system — including cortisol, ghrelin, leptin, and serotonin — that regulates insulin sensitivity, glucose, and blood pressure control. The night owl may become more insulin resistant and therefore at higher risk of developing diabetes.”

Like Dr. van der Velde, he noted that “late sleep may be associated with night binging that can cause weight gain and ultimately obesity, further increasing the risk of diabetes.”

Dr. Iacobellis’s group recently showed that vital exhaustion, which is characterized by fatigue and loss of vigor, is associated with a higher cardiovascular risk for and markers of visceral adiposity.

“Abnormal circadian rhythms can be easily associated with vital exhaustion,” he said. Therefore, night owls with more visceral than peripheral fat accumulation might also be at higher cardiometabolic risk through that mechanism.

“However environmental factors and family history can play an important role too,” he added.

Regardless of the mechanisms involved, “preventive actions should be taken to educate teenagers and individuals at higher risk to have healthy sleep habits,” Dr. Iacobellis concluded.

No information regarding funding was provided; Dr. van der Velde and Dr. Iacobellis reported no conflicts of interest.

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

MADRID — Night owls — individuals with late chronotypes — may be at an increased risk for type 2 diabetes (T2D), beyond the risks conferred by an unhealthy lifestyle, research presented at the annual meeting of the European Association for the Study of Diabetes suggested.

In the study, night owls were almost 50% more likely to develop T2D than those who went to sleep earlier.

“The magnitude of this risk was more than I expected, [although] residual confounding may have occurred,” said Jeroen van der Velde, PhD, Leiden University Medical Center in the Netherlands, who presented the study.

“Late chronotype has previously been associated with unhealthy lifestyle and overweight or obesity and, subsequently, cardiometabolic diseases,” he said in an interview. However, although the current study found that individuals with late chronotypes did indeed have larger waists and more visceral fat, “we (and others) believe that lifestyle cannot fully explain the relation between late chronotype and metabolic disorders.”

“In addition,” he noted, “previous studies that observed that late chronotype is associated with overweight or obesity mainly focused on body mass index [BMI]. However, BMI alone does not provide accurate information regarding fat distribution in the body. People with similar BMI may have different underlying fat distribution, and this may be more relevant than BMI for metabolic risk.”

The researchers examined associations between chronotype and BMI, waist circumference, visceral fat, liver fat, and the risk for T2D in a middle-aged population from the Netherlands Epidemiology of Obesity study. Among the 5026 participants, the mean age was 56 years, 54% were women, and mean BMI was 30.

Using data from the study, the study investigators calculated the midpoint of sleep (MPS) and divided participants into three chronotypes: Early MPS < 2:30 PM (20% of participants); intermediate MPS 2:30–4:00 PM (reference category; 60% of participants); and late MPS ≥ 4:00 PM (20% of participants). BMI and waist circumference were measured in all participants, and visceral fat and liver fat were measured in 1576 participants using MRI scans and MR spectroscopy, respectively.

During a median follow-up of 6.6 years, 225 participants were diagnosed with T2D. After adjustment for age, sex, education, physical activity, smoking, alcohol intake, diet quality, sleep quality and duration, and total body fat, participants with a late chronotype had a 46% increased risk for T2D.

Further, those with a late chronotype had 0.7 higher BMI, 1.9-cm larger waist circumference, 7 cm² more visceral fat, and 14% more liver fat.
 

Body Clock Out of Sync?

“Late chronotype was associated with increased ectopic body fat and with an increased risk of T2D independent of lifestyle factors and is an emerging risk factor for metabolic diseases,” the researchers concluded.

“A likely explanation is that the circadian rhythm or body clock in late chronotypes is out of sync with the work and social schedules followed by society,” Dr. van der Velde suggested. “This can lead to circadian misalignment, which we know can lead to metabolic disturbances and ultimately type 2 diabetes.”

Might trying to adjust chronotype earlier in life have an effect on risk?

“Chronotype, as measured via midpoint of sleep, does change a lot in the first 30 years or so in life,” he said. “After that it seems to stabilize. I suppose that if you adapt an intermediate or early chronotype around the age of 30 years, this will help to maintain an earlier chronotype later in life, although we cannot answer this from our study.”

Nevertheless, with respect to T2D risk, “chronotype is likely only part of the puzzle,” he noted.

“People with late chronotypes typically eat late in the evening, and this has also been associated with adverse metabolic effects. At this stage, we do not know if a person changes his/her chronotype that this will also lead to metabolic improvements. More research is needed before we can make recommendations regarding chronotype and timing of other lifestyle behaviors.”

Commenting on the study, Gianluca Iacobellis, MD, PhD, director of the University of Miami Hospital Diabetes Service, Coral Gables, Florida, said: “Interesting data. Altering the physiological circadian rhythm can affect the complex hormonal system — including cortisol, ghrelin, leptin, and serotonin — that regulates insulin sensitivity, glucose, and blood pressure control. The night owl may become more insulin resistant and therefore at higher risk of developing diabetes.”

Like Dr. van der Velde, he noted that “late sleep may be associated with night binging that can cause weight gain and ultimately obesity, further increasing the risk of diabetes.”

Dr. Iacobellis’s group recently showed that vital exhaustion, which is characterized by fatigue and loss of vigor, is associated with a higher cardiovascular risk for and markers of visceral adiposity.

“Abnormal circadian rhythms can be easily associated with vital exhaustion,” he said. Therefore, night owls with more visceral than peripheral fat accumulation might also be at higher cardiometabolic risk through that mechanism.

“However environmental factors and family history can play an important role too,” he added.

Regardless of the mechanisms involved, “preventive actions should be taken to educate teenagers and individuals at higher risk to have healthy sleep habits,” Dr. Iacobellis concluded.

No information regarding funding was provided; Dr. van der Velde and Dr. Iacobellis reported no conflicts of interest.

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

Bruton’s tyrosine kinase inhibitors such as ibrutinib, acalabrutinib, and zanubrutinib have revolutionized the treatment of chronic lymphocytic leukemia (CLL). But should patients take a break from them?

At the annual meeting of the Society of Hematologic Oncology, two hematologist-oncologists — Inhye Ahn, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts, and Kerry A. Rogers, MD, of Ohio State University in Columbus — faced off in a debate. Ahn said the drugs can indeed be discontinued, while Rogers argued against stopping the medications.

“When I talk to my own patient about standard of care options in CLL, I use the analogy of a marathon and a sprint,” Dr. Ahn said. A marathon refers to continuous treatment with Bruton’s kinase inhibitors given daily for years, while the sprint refers to the combination of venetoclax with an anti-CD20 monoclonal antibody given over 12 cycles for the frontline regimen and 2 years for refractory CLL.

“I tell them these are both considered very efficacious regimens and well tolerated, one is by IV [the venetoclax regimen] and the other isn’t [Bruton’s kinase inhibitors], and they have different toxicity profile. I ask them what would you do? The most common question that I get from my patient is, ‘why would anyone do a marathon?’ ”

It’s not solely the length of treatment that’s important, Dr. Ahn said, as toxicities from the long-term use of Bruton’s kinase inhibitors build up over time and can lead to hypertension, arrhythmia, and sudden cardiac death.

In addition, she said, infections can occur, as well as hampered vaccine response, an important risk in the era of the COVID-19 pandemic. The cost of the drugs is high and adds up over time, and continuous use can boost resistance.

Is there a way to turn the marathon of Bruton’s kinase inhibitor use into a sprint without hurting patients? The answer is yes, through temporary discontinuation, Dr. Ahn said, although she cautioned that early cessation could lead to disease flare. “We dipped into our own database of 84 CLL patients treated with ibrutinib, and our conclusion was that temporary dose interruption or dose reduction did not impact progression-free survival”

Moving forward, she said, “more research is needed to define the optimal regimen that would lead to treatment cessation, the optimal patient population, who would benefit most from the cessation strategy, treatment duration, and how we define success.” For her part, Dr. Rogers argued that the continuous use of Bruton’s kinase inhibitors is “really the most effective treatment we have in CLL.”

It’s clear that “responses deepen with continued treatment,” Dr. Rogers said, noting that remission times grow over years of treatment. She highlighted a 2022 study of patients with CLL who took ibrutinib that found complete remission or complete remission with incomplete hematologic recovery was 7% at 12 months and 34% at 7 years. When patients quit taking the drugs, “you don’t get to maximize your patient’s response to this treatment.”

Dr. Rogers also noted that the RESONATE-2 trial found that ibrutinib is linked to the longest median progression-free survival of any CLL treatment at 8.9 years. “That really struck me a very effective initial therapy.”

Indeed, “when you’re offering someone initial therapy with a Bruton’s kinase inhibitor as a continuous treatment strategy, you can tell people that they can expect a normal lifespan with this approach. That’s extremely important when you’re talking to patients about whether they might want to alter their leukemia treatment.”

Finally, she noted that discontinuation of ibrutinib was linked to shorter survival in early research. “This was the first suggestion that discontinuation is not good.”

Dr. Rogers said that discontinuing the drugs is sometimes necessary because of adverse events, but patients can “certainly switch to a more tolerable Bruton’s kinase inhibitor. With the options available today, that should be a strategy that’s considered.”

Audience members at the debate were invited to respond to a live online survey about whether Bruton’s kinase inhibitors can be discontinued. Among 49 respondents, most (52.3%) said no, 42.8% said yes, and the rest were undecided/other.

Disclosures for the speakers were not provided. Dr. Ahn disclosed consulting for BeiGene and AstraZeneca. Dr. Rogers disclosed receiving research funding from Genentech, AbbVie, Janssen, and Novartis; consulting for AstraZeneca, BeiGene, Janssen, Pharmacyclics, AbbVie, Genentech, and LOXO@Lilly; and receiving travel funding from AstraZeneca.

A version of this article appeared on Medscape.com.

Bruton’s tyrosine kinase inhibitors such as ibrutinib, acalabrutinib, and zanubrutinib have revolutionized the treatment of chronic lymphocytic leukemia (CLL). But should patients take a break from them?

At the annual meeting of the Society of Hematologic Oncology, two hematologist-oncologists — Inhye Ahn, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts, and Kerry A. Rogers, MD, of Ohio State University in Columbus — faced off in a debate. Ahn said the drugs can indeed be discontinued, while Rogers argued against stopping the medications.

“When I talk to my own patient about standard of care options in CLL, I use the analogy of a marathon and a sprint,” Dr. Ahn said. A marathon refers to continuous treatment with Bruton’s kinase inhibitors given daily for years, while the sprint refers to the combination of venetoclax with an anti-CD20 monoclonal antibody given over 12 cycles for the frontline regimen and 2 years for refractory CLL.

“I tell them these are both considered very efficacious regimens and well tolerated, one is by IV [the venetoclax regimen] and the other isn’t [Bruton’s kinase inhibitors], and they have different toxicity profile. I ask them what would you do? The most common question that I get from my patient is, ‘why would anyone do a marathon?’ ”

It’s not solely the length of treatment that’s important, Dr. Ahn said, as toxicities from the long-term use of Bruton’s kinase inhibitors build up over time and can lead to hypertension, arrhythmia, and sudden cardiac death.

In addition, she said, infections can occur, as well as hampered vaccine response, an important risk in the era of the COVID-19 pandemic. The cost of the drugs is high and adds up over time, and continuous use can boost resistance.

Is there a way to turn the marathon of Bruton’s kinase inhibitor use into a sprint without hurting patients? The answer is yes, through temporary discontinuation, Dr. Ahn said, although she cautioned that early cessation could lead to disease flare. “We dipped into our own database of 84 CLL patients treated with ibrutinib, and our conclusion was that temporary dose interruption or dose reduction did not impact progression-free survival”

Moving forward, she said, “more research is needed to define the optimal regimen that would lead to treatment cessation, the optimal patient population, who would benefit most from the cessation strategy, treatment duration, and how we define success.” For her part, Dr. Rogers argued that the continuous use of Bruton’s kinase inhibitors is “really the most effective treatment we have in CLL.”

It’s clear that “responses deepen with continued treatment,” Dr. Rogers said, noting that remission times grow over years of treatment. She highlighted a 2022 study of patients with CLL who took ibrutinib that found complete remission or complete remission with incomplete hematologic recovery was 7% at 12 months and 34% at 7 years. When patients quit taking the drugs, “you don’t get to maximize your patient’s response to this treatment.”

Dr. Rogers also noted that the RESONATE-2 trial found that ibrutinib is linked to the longest median progression-free survival of any CLL treatment at 8.9 years. “That really struck me a very effective initial therapy.”

Indeed, “when you’re offering someone initial therapy with a Bruton’s kinase inhibitor as a continuous treatment strategy, you can tell people that they can expect a normal lifespan with this approach. That’s extremely important when you’re talking to patients about whether they might want to alter their leukemia treatment.”

Finally, she noted that discontinuation of ibrutinib was linked to shorter survival in early research. “This was the first suggestion that discontinuation is not good.”

Dr. Rogers said that discontinuing the drugs is sometimes necessary because of adverse events, but patients can “certainly switch to a more tolerable Bruton’s kinase inhibitor. With the options available today, that should be a strategy that’s considered.”

Audience members at the debate were invited to respond to a live online survey about whether Bruton’s kinase inhibitors can be discontinued. Among 49 respondents, most (52.3%) said no, 42.8% said yes, and the rest were undecided/other.

Disclosures for the speakers were not provided. Dr. Ahn disclosed consulting for BeiGene and AstraZeneca. Dr. Rogers disclosed receiving research funding from Genentech, AbbVie, Janssen, and Novartis; consulting for AstraZeneca, BeiGene, Janssen, Pharmacyclics, AbbVie, Genentech, and LOXO@Lilly; and receiving travel funding from AstraZeneca.

A version of this article appeared on Medscape.com.

Bruton’s tyrosine kinase inhibitors such as ibrutinib, acalabrutinib, and zanubrutinib have revolutionized the treatment of chronic lymphocytic leukemia (CLL). But should patients take a break from them?

At the annual meeting of the Society of Hematologic Oncology, two hematologist-oncologists — Inhye Ahn, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts, and Kerry A. Rogers, MD, of Ohio State University in Columbus — faced off in a debate. Ahn said the drugs can indeed be discontinued, while Rogers argued against stopping the medications.

“When I talk to my own patient about standard of care options in CLL, I use the analogy of a marathon and a sprint,” Dr. Ahn said. A marathon refers to continuous treatment with Bruton’s kinase inhibitors given daily for years, while the sprint refers to the combination of venetoclax with an anti-CD20 monoclonal antibody given over 12 cycles for the frontline regimen and 2 years for refractory CLL.

“I tell them these are both considered very efficacious regimens and well tolerated, one is by IV [the venetoclax regimen] and the other isn’t [Bruton’s kinase inhibitors], and they have different toxicity profile. I ask them what would you do? The most common question that I get from my patient is, ‘why would anyone do a marathon?’ ”

It’s not solely the length of treatment that’s important, Dr. Ahn said, as toxicities from the long-term use of Bruton’s kinase inhibitors build up over time and can lead to hypertension, arrhythmia, and sudden cardiac death.

In addition, she said, infections can occur, as well as hampered vaccine response, an important risk in the era of the COVID-19 pandemic. The cost of the drugs is high and adds up over time, and continuous use can boost resistance.

Is there a way to turn the marathon of Bruton’s kinase inhibitor use into a sprint without hurting patients? The answer is yes, through temporary discontinuation, Dr. Ahn said, although she cautioned that early cessation could lead to disease flare. “We dipped into our own database of 84 CLL patients treated with ibrutinib, and our conclusion was that temporary dose interruption or dose reduction did not impact progression-free survival”

Moving forward, she said, “more research is needed to define the optimal regimen that would lead to treatment cessation, the optimal patient population, who would benefit most from the cessation strategy, treatment duration, and how we define success.” For her part, Dr. Rogers argued that the continuous use of Bruton’s kinase inhibitors is “really the most effective treatment we have in CLL.”

It’s clear that “responses deepen with continued treatment,” Dr. Rogers said, noting that remission times grow over years of treatment. She highlighted a 2022 study of patients with CLL who took ibrutinib that found complete remission or complete remission with incomplete hematologic recovery was 7% at 12 months and 34% at 7 years. When patients quit taking the drugs, “you don’t get to maximize your patient’s response to this treatment.”

Dr. Rogers also noted that the RESONATE-2 trial found that ibrutinib is linked to the longest median progression-free survival of any CLL treatment at 8.9 years. “That really struck me a very effective initial therapy.”

Indeed, “when you’re offering someone initial therapy with a Bruton’s kinase inhibitor as a continuous treatment strategy, you can tell people that they can expect a normal lifespan with this approach. That’s extremely important when you’re talking to patients about whether they might want to alter their leukemia treatment.”

Finally, she noted that discontinuation of ibrutinib was linked to shorter survival in early research. “This was the first suggestion that discontinuation is not good.”

Dr. Rogers said that discontinuing the drugs is sometimes necessary because of adverse events, but patients can “certainly switch to a more tolerable Bruton’s kinase inhibitor. With the options available today, that should be a strategy that’s considered.”

Audience members at the debate were invited to respond to a live online survey about whether Bruton’s kinase inhibitors can be discontinued. Among 49 respondents, most (52.3%) said no, 42.8% said yes, and the rest were undecided/other.

Disclosures for the speakers were not provided. Dr. Ahn disclosed consulting for BeiGene and AstraZeneca. Dr. Rogers disclosed receiving research funding from Genentech, AbbVie, Janssen, and Novartis; consulting for AstraZeneca, BeiGene, Janssen, Pharmacyclics, AbbVie, Genentech, and LOXO@Lilly; and receiving travel funding from AstraZeneca.

A version of this article appeared on Medscape.com.

Diversity, equity, and inclusion (DEI) programs seek to improve dermatologic education and clinical care for an increasingly diverse patient population as well as to recruit and sustain a physician workforce that reflects the diversity of the patients they serve.^1,2 In dermatology, only 4.2% and 3.0% of practicing dermatologists self-identify as being of Hispanic and African American ethnicity, respectively, compared with 18.5% and 13.4% of the general population, respectively.³ Creating an educational system that works to meet the goals of DEI is essential to improve health outcomes and address disparities. The lack of robust DEI-related curricula during residency training may limit the ability of practicing dermatologists to provide comprehensive and culturally sensitive care. It has been shown that racial concordance between patients and physicians has a positive impact on patient satisfaction by fostering a trusting patient-physician relationship.⁴

It is the responsibility of all dermatologists to create an environment where patients from any background can feel comfortable, which can be cultivated by establishing patient-centered communication and cultural humility.⁵ These skills can be strengthened via the implementation of DEI-related curricula during residency training. Augmenting exposure of these topics during training can optimize the delivery of dermatologic care by providing residents with the tools and confidence needed to care for patients of culturally diverse backgrounds. Enhancing DEI education is crucial to not only improve the recognition and treatment of dermatologic conditions in all skin and hair types but also to minimize misconceptions, stigma, health disparities, and discrimination faced by historically marginalized communities. Creating a culture of inclusion is of paramount importance to build successful relationships with patients and colleagues of culturally diverse backgrounds.⁶

There are multiple efforts underway to increase DEI education across the field of dermatology, including the development of DEI task forces in professional organizations and societies that serve to expand DEI-related research, mentorship, and education. The American Academy of Dermatology has been leading efforts to create a curriculum focused on skin of color, particularly addressing inadequate educational training on how dermatologic conditions manifest in this population.⁷ The Skin of Color Society has similar efforts underway and is developing a speakers bureau to give leading experts a platform to lecture dermatology trainees as well as patient and community audiences on various topics in skin of color.⁸ These are just 2 of many professional dermatology organizations that are advocating for expanded education on DEI; however, consistently integrating DEI-related topics into dermatology residency training curricula remains a gap in pedagogy. To identify the DEI-related topics of greatest relevance to the dermatology resident curricula, we implemented a modified electronic Delphi (e-Delphi) consensus process to provide standardized recommendations.

Methods

A 2-round modified e-Delphi method was utilized (Figure). An initial list of potential curricular topics was formulated by an expert panel consisting of 5 dermatologists from the Association of Professors of Dermatology DEI subcommittee and the American Academy of Dermatology Diversity Task Force (A.M.A., S.B., R.V., S.D.W., J.I.S.). Initial topics were selected via several meetings among the panel members to discuss existing DEI concerns and issues that were deemed relevant due to education gaps in residency training. The list of topics was further expanded with recommendations obtained via an email sent to dermatology program directors on the Association of Professors of Dermatology listserve, which solicited voluntary participation of academic dermatologists, including program directors and dermatology residents.

There were 2 voting rounds, with each round consisting of questions scored on a Likert scale ranging from 1 to 5 (1=not essential, 2=probably not essential, 3=neutral, 4=probably essential, 5=definitely essential). The inclusion criteria to classify a topic as necessary for integration into the dermatology residency curriculum included 95% (18/19) or more of respondents rating the topic as probably essential or definitely essential; if more than 90% (17/19) of respondents rated the topic as probably essential or definitely essential and less than 10% (2/19) rated it as not essential or probably not essential, the topic was still included as part of the suggested curriculum. Topics that received ratings of probably essential or definitely essential by less than 80% (15/19) of respondents were removed from consideration. The topics that did not meet inclusion or exclusion criteria during the first round of voting were refined by the e-Delphi steering committee (V.S.E-C. and F-A.R.) based on open-ended feedback from the voting group provided at the end of the survey and subsequently passed to the second round of voting.

Results

Participants—A total of 19 respondents participated in both voting rounds, the majority (80% [15/19]) of whom were program directors or dermatologists affiliated with academia or development of DEI education; the remaining 20% [4/19]) were dermatology residents.

Open-Ended Feedback—Voting group members were able to provide open-ended feedback for each of the sets of topics after the survey, which the steering committee utilized to modify the topics as needed for the final voting round. For example, “structural racism/discrimination” was originally mentioned as a topic, but several participants suggested including specific types of racism; therefore, the wording was changed to “racism: types, definitions” to encompass broader definitions and types of racism.

Survey Results—Two genres of topics were surveyed in each voting round: clinical and nonclinical. Participants voted on a total of 61 topics, with 23 ultimately selected in the final list of consensus curricular topics. Of those, 9 were clinical and 14 nonclinical. All topics deemed necessary for inclusion in residency curricula are presented in eTables 1 and 2.

During the first round of voting, the e-Delphi panel reached a consensus to include the following 17 topics as essential to dermatology residency training (along with the percentage of voters who classified them as probably essential or definitely essential): how to mitigate bias in clinical and workplace settings (100% [40/40]); social determinants of health-related disparities in dermatology (100% [40/40]); hairstyling practices across different hair textures (100% [40/40]); definitions and examples of microaggressions (97.50% [39/40]); definition, background, and types of bias (97.50% [39/40]); manifestations of bias in the clinical setting (97.44% [38/39]); racial and ethnic disparities in dermatology (97.44% [38/39]); keloids (97.37% [37/38]); differences in dermoscopic presentations in skin of color (97.30% [36/37]); skin cancer in patients with skin of color (97.30% [36/37]); disparities due to bias (95.00% [38/40]); how to apply cultural humility and safety to patients of different cultural backgrounds (94.87% [37/40]); best practices in providing care to patients with limited English proficiency (94.87% [37/40]); hair loss in patients with textured hair (94.74% [36/38]); pseudofolliculitis barbae and acne keloidalis nuchae (94.60% [35/37]); disparities regarding people experiencing homelessness (92.31% [36/39]); and definitions and types of racism and other forms of discrimination (92.31% [36/39]). eTable 1 provides a list of suggested resources to incorporate these topics into the educational components of residency curricula. The resources provided were not part of the voting process, and they were not considered in the consensus analysis; they are included here as suggested educational catalysts.

During the second round of voting, 25 topics were evaluated. Of those, the following 6 topics were proposed to be included as essential in residency training: differences in prevalence and presentation of common inflammatory disorders (100% [29/29]); manifestations of bias in the learning environment (96.55%); antiracist action and how to decrease the effects of structural racism in clinical and educational settings (96.55% [28/29]); diversity of images in dermatology education (96.55% [28/29]); pigmentary disorders and their psychological effects (96.55% [28/29]); and LGBTQ (lesbian, gay, bisexual, transgender, and queer) dermatologic health care (96.55% [28/29]). eTable 2 includes these topics as well as suggested resources to help incorporate them into training.

Comment

This study utilized a modified e-Delphi technique to identify relevant clinical and nonclinical DEI topics that should be incorporated into dermatology residency curricula. The panel members reached a consensus for 9 clinical DEI-related topics. The respondents agreed that the topics related to skin and hair conditions in patients with skin of color as well as textured hair were crucial to residency education. Skin cancer, hair loss, pseudofolliculitis barbae, acne keloidalis nuchae, keloids, pigmentary disorders, and their varying presentations in patients with skin of color were among the recommended topics. The panel also recommended educating residents on the variable visual presentations of inflammatory conditions in skin of color. Addressing the needs of diverse patients—for example, those belonging to the LGBTQ community—also was deemed important for inclusion.

The remaining 14 chosen topics were nonclinical items addressing concepts such as bias and health care disparities as well as cultural humility and safety.⁹ Cultural humility and safety focus on developing cultural awareness by creating a safe setting for patients rather than encouraging power relationships between them and their physicians. Various topics related to racism also were recommended to be included in residency curricula, including education on implementation of antiracist action in the workplace.

Many of the nonclinical topics are intertwined; for instance, learning about health care disparities in patients with limited English proficiency allows for improved best practices in delivering care to patients from this population. The first step in overcoming bias and subsequent disparities is acknowledging how the perpetuation of bias leads to disparities after being taught tools to recognize it.

Our group’s guidance on DEI topics should help dermatology residency program leaders as they design and refine program curricula. There are multiple avenues for incorporating education on these topics, including lectures, interactive workshops, role-playing sessions, book or journal clubs, and discussion circles. Many of these topics/programs may already be included in programs’ didactic curricula, which would minimize the burden of finding space to educate on these topics. Institutional cultural change is key to ensuring truly diverse, equitable, and inclusive workplaces. Educating tomorrow’s dermatologists on these topics is a first step toward achieving that cultural change.

Limitations—A limitation of this e-Delphi survey is that only a selection of experts in this field was included. Additionally, we were concerned that the Likert scale format and the bar we set for inclusion and exclusion may have failed to adequately capture participants’ nuanced opinions. As such, participants were able to provide open-ended feedback, and suggestions for alternate wording or other changes were considered by the steering committee. Finally, inclusion recommendations identified in this survey were developed specifically for US dermatology residents.

Conclusion

In this e-Delphi consensus assessment of DEI-related topics, we recommend the inclusion of 23 topics into dermatology residency program curricula to improve medical training and the patient-physician relationship as well as to create better health outcomes. We also provide specific sample resource recommendations in eTables 1 and 2 to facilitate inclusion of these topics into residency curricula across the country.

Diversity, equity, and inclusion (DEI) programs seek to improve dermatologic education and clinical care for an increasingly diverse patient population as well as to recruit and sustain a physician workforce that reflects the diversity of the patients they serve.^1,2 In dermatology, only 4.2% and 3.0% of practicing dermatologists self-identify as being of Hispanic and African American ethnicity, respectively, compared with 18.5% and 13.4% of the general population, respectively.³ Creating an educational system that works to meet the goals of DEI is essential to improve health outcomes and address disparities. The lack of robust DEI-related curricula during residency training may limit the ability of practicing dermatologists to provide comprehensive and culturally sensitive care. It has been shown that racial concordance between patients and physicians has a positive impact on patient satisfaction by fostering a trusting patient-physician relationship.⁴

It is the responsibility of all dermatologists to create an environment where patients from any background can feel comfortable, which can be cultivated by establishing patient-centered communication and cultural humility.⁵ These skills can be strengthened via the implementation of DEI-related curricula during residency training. Augmenting exposure of these topics during training can optimize the delivery of dermatologic care by providing residents with the tools and confidence needed to care for patients of culturally diverse backgrounds. Enhancing DEI education is crucial to not only improve the recognition and treatment of dermatologic conditions in all skin and hair types but also to minimize misconceptions, stigma, health disparities, and discrimination faced by historically marginalized communities. Creating a culture of inclusion is of paramount importance to build successful relationships with patients and colleagues of culturally diverse backgrounds.⁶

There are multiple efforts underway to increase DEI education across the field of dermatology, including the development of DEI task forces in professional organizations and societies that serve to expand DEI-related research, mentorship, and education. The American Academy of Dermatology has been leading efforts to create a curriculum focused on skin of color, particularly addressing inadequate educational training on how dermatologic conditions manifest in this population.⁷ The Skin of Color Society has similar efforts underway and is developing a speakers bureau to give leading experts a platform to lecture dermatology trainees as well as patient and community audiences on various topics in skin of color.⁸ These are just 2 of many professional dermatology organizations that are advocating for expanded education on DEI; however, consistently integrating DEI-related topics into dermatology residency training curricula remains a gap in pedagogy. To identify the DEI-related topics of greatest relevance to the dermatology resident curricula, we implemented a modified electronic Delphi (e-Delphi) consensus process to provide standardized recommendations.

Methods

A 2-round modified e-Delphi method was utilized (Figure). An initial list of potential curricular topics was formulated by an expert panel consisting of 5 dermatologists from the Association of Professors of Dermatology DEI subcommittee and the American Academy of Dermatology Diversity Task Force (A.M.A., S.B., R.V., S.D.W., J.I.S.). Initial topics were selected via several meetings among the panel members to discuss existing DEI concerns and issues that were deemed relevant due to education gaps in residency training. The list of topics was further expanded with recommendations obtained via an email sent to dermatology program directors on the Association of Professors of Dermatology listserve, which solicited voluntary participation of academic dermatologists, including program directors and dermatology residents.

There were 2 voting rounds, with each round consisting of questions scored on a Likert scale ranging from 1 to 5 (1=not essential, 2=probably not essential, 3=neutral, 4=probably essential, 5=definitely essential). The inclusion criteria to classify a topic as necessary for integration into the dermatology residency curriculum included 95% (18/19) or more of respondents rating the topic as probably essential or definitely essential; if more than 90% (17/19) of respondents rated the topic as probably essential or definitely essential and less than 10% (2/19) rated it as not essential or probably not essential, the topic was still included as part of the suggested curriculum. Topics that received ratings of probably essential or definitely essential by less than 80% (15/19) of respondents were removed from consideration. The topics that did not meet inclusion or exclusion criteria during the first round of voting were refined by the e-Delphi steering committee (V.S.E-C. and F-A.R.) based on open-ended feedback from the voting group provided at the end of the survey and subsequently passed to the second round of voting.

Results

Participants—A total of 19 respondents participated in both voting rounds, the majority (80% [15/19]) of whom were program directors or dermatologists affiliated with academia or development of DEI education; the remaining 20% [4/19]) were dermatology residents.

Open-Ended Feedback—Voting group members were able to provide open-ended feedback for each of the sets of topics after the survey, which the steering committee utilized to modify the topics as needed for the final voting round. For example, “structural racism/discrimination” was originally mentioned as a topic, but several participants suggested including specific types of racism; therefore, the wording was changed to “racism: types, definitions” to encompass broader definitions and types of racism.

Survey Results—Two genres of topics were surveyed in each voting round: clinical and nonclinical. Participants voted on a total of 61 topics, with 23 ultimately selected in the final list of consensus curricular topics. Of those, 9 were clinical and 14 nonclinical. All topics deemed necessary for inclusion in residency curricula are presented in eTables 1 and 2.

During the first round of voting, the e-Delphi panel reached a consensus to include the following 17 topics as essential to dermatology residency training (along with the percentage of voters who classified them as probably essential or definitely essential): how to mitigate bias in clinical and workplace settings (100% [40/40]); social determinants of health-related disparities in dermatology (100% [40/40]); hairstyling practices across different hair textures (100% [40/40]); definitions and examples of microaggressions (97.50% [39/40]); definition, background, and types of bias (97.50% [39/40]); manifestations of bias in the clinical setting (97.44% [38/39]); racial and ethnic disparities in dermatology (97.44% [38/39]); keloids (97.37% [37/38]); differences in dermoscopic presentations in skin of color (97.30% [36/37]); skin cancer in patients with skin of color (97.30% [36/37]); disparities due to bias (95.00% [38/40]); how to apply cultural humility and safety to patients of different cultural backgrounds (94.87% [37/40]); best practices in providing care to patients with limited English proficiency (94.87% [37/40]); hair loss in patients with textured hair (94.74% [36/38]); pseudofolliculitis barbae and acne keloidalis nuchae (94.60% [35/37]); disparities regarding people experiencing homelessness (92.31% [36/39]); and definitions and types of racism and other forms of discrimination (92.31% [36/39]). eTable 1 provides a list of suggested resources to incorporate these topics into the educational components of residency curricula. The resources provided were not part of the voting process, and they were not considered in the consensus analysis; they are included here as suggested educational catalysts.

During the second round of voting, 25 topics were evaluated. Of those, the following 6 topics were proposed to be included as essential in residency training: differences in prevalence and presentation of common inflammatory disorders (100% [29/29]); manifestations of bias in the learning environment (96.55%); antiracist action and how to decrease the effects of structural racism in clinical and educational settings (96.55% [28/29]); diversity of images in dermatology education (96.55% [28/29]); pigmentary disorders and their psychological effects (96.55% [28/29]); and LGBTQ (lesbian, gay, bisexual, transgender, and queer) dermatologic health care (96.55% [28/29]). eTable 2 includes these topics as well as suggested resources to help incorporate them into training.

Comment

This study utilized a modified e-Delphi technique to identify relevant clinical and nonclinical DEI topics that should be incorporated into dermatology residency curricula. The panel members reached a consensus for 9 clinical DEI-related topics. The respondents agreed that the topics related to skin and hair conditions in patients with skin of color as well as textured hair were crucial to residency education. Skin cancer, hair loss, pseudofolliculitis barbae, acne keloidalis nuchae, keloids, pigmentary disorders, and their varying presentations in patients with skin of color were among the recommended topics. The panel also recommended educating residents on the variable visual presentations of inflammatory conditions in skin of color. Addressing the needs of diverse patients—for example, those belonging to the LGBTQ community—also was deemed important for inclusion.

The remaining 14 chosen topics were nonclinical items addressing concepts such as bias and health care disparities as well as cultural humility and safety.⁹ Cultural humility and safety focus on developing cultural awareness by creating a safe setting for patients rather than encouraging power relationships between them and their physicians. Various topics related to racism also were recommended to be included in residency curricula, including education on implementation of antiracist action in the workplace.

Many of the nonclinical topics are intertwined; for instance, learning about health care disparities in patients with limited English proficiency allows for improved best practices in delivering care to patients from this population. The first step in overcoming bias and subsequent disparities is acknowledging how the perpetuation of bias leads to disparities after being taught tools to recognize it.

Our group’s guidance on DEI topics should help dermatology residency program leaders as they design and refine program curricula. There are multiple avenues for incorporating education on these topics, including lectures, interactive workshops, role-playing sessions, book or journal clubs, and discussion circles. Many of these topics/programs may already be included in programs’ didactic curricula, which would minimize the burden of finding space to educate on these topics. Institutional cultural change is key to ensuring truly diverse, equitable, and inclusive workplaces. Educating tomorrow’s dermatologists on these topics is a first step toward achieving that cultural change.

Limitations—A limitation of this e-Delphi survey is that only a selection of experts in this field was included. Additionally, we were concerned that the Likert scale format and the bar we set for inclusion and exclusion may have failed to adequately capture participants’ nuanced opinions. As such, participants were able to provide open-ended feedback, and suggestions for alternate wording or other changes were considered by the steering committee. Finally, inclusion recommendations identified in this survey were developed specifically for US dermatology residents.

Conclusion

In this e-Delphi consensus assessment of DEI-related topics, we recommend the inclusion of 23 topics into dermatology residency program curricula to improve medical training and the patient-physician relationship as well as to create better health outcomes. We also provide specific sample resource recommendations in eTables 1 and 2 to facilitate inclusion of these topics into residency curricula across the country.

Diversity, equity, and inclusion (DEI) programs seek to improve dermatologic education and clinical care for an increasingly diverse patient population as well as to recruit and sustain a physician workforce that reflects the diversity of the patients they serve.^1,2 In dermatology, only 4.2% and 3.0% of practicing dermatologists self-identify as being of Hispanic and African American ethnicity, respectively, compared with 18.5% and 13.4% of the general population, respectively.³ Creating an educational system that works to meet the goals of DEI is essential to improve health outcomes and address disparities. The lack of robust DEI-related curricula during residency training may limit the ability of practicing dermatologists to provide comprehensive and culturally sensitive care. It has been shown that racial concordance between patients and physicians has a positive impact on patient satisfaction by fostering a trusting patient-physician relationship.⁴

It is the responsibility of all dermatologists to create an environment where patients from any background can feel comfortable, which can be cultivated by establishing patient-centered communication and cultural humility.⁵ These skills can be strengthened via the implementation of DEI-related curricula during residency training. Augmenting exposure of these topics during training can optimize the delivery of dermatologic care by providing residents with the tools and confidence needed to care for patients of culturally diverse backgrounds. Enhancing DEI education is crucial to not only improve the recognition and treatment of dermatologic conditions in all skin and hair types but also to minimize misconceptions, stigma, health disparities, and discrimination faced by historically marginalized communities. Creating a culture of inclusion is of paramount importance to build successful relationships with patients and colleagues of culturally diverse backgrounds.⁶

There are multiple efforts underway to increase DEI education across the field of dermatology, including the development of DEI task forces in professional organizations and societies that serve to expand DEI-related research, mentorship, and education. The American Academy of Dermatology has been leading efforts to create a curriculum focused on skin of color, particularly addressing inadequate educational training on how dermatologic conditions manifest in this population.⁷ The Skin of Color Society has similar efforts underway and is developing a speakers bureau to give leading experts a platform to lecture dermatology trainees as well as patient and community audiences on various topics in skin of color.⁸ These are just 2 of many professional dermatology organizations that are advocating for expanded education on DEI; however, consistently integrating DEI-related topics into dermatology residency training curricula remains a gap in pedagogy. To identify the DEI-related topics of greatest relevance to the dermatology resident curricula, we implemented a modified electronic Delphi (e-Delphi) consensus process to provide standardized recommendations.

Methods

A 2-round modified e-Delphi method was utilized (Figure). An initial list of potential curricular topics was formulated by an expert panel consisting of 5 dermatologists from the Association of Professors of Dermatology DEI subcommittee and the American Academy of Dermatology Diversity Task Force (A.M.A., S.B., R.V., S.D.W., J.I.S.). Initial topics were selected via several meetings among the panel members to discuss existing DEI concerns and issues that were deemed relevant due to education gaps in residency training. The list of topics was further expanded with recommendations obtained via an email sent to dermatology program directors on the Association of Professors of Dermatology listserve, which solicited voluntary participation of academic dermatologists, including program directors and dermatology residents.

There were 2 voting rounds, with each round consisting of questions scored on a Likert scale ranging from 1 to 5 (1=not essential, 2=probably not essential, 3=neutral, 4=probably essential, 5=definitely essential). The inclusion criteria to classify a topic as necessary for integration into the dermatology residency curriculum included 95% (18/19) or more of respondents rating the topic as probably essential or definitely essential; if more than 90% (17/19) of respondents rated the topic as probably essential or definitely essential and less than 10% (2/19) rated it as not essential or probably not essential, the topic was still included as part of the suggested curriculum. Topics that received ratings of probably essential or definitely essential by less than 80% (15/19) of respondents were removed from consideration. The topics that did not meet inclusion or exclusion criteria during the first round of voting were refined by the e-Delphi steering committee (V.S.E-C. and F-A.R.) based on open-ended feedback from the voting group provided at the end of the survey and subsequently passed to the second round of voting.

Results

Participants—A total of 19 respondents participated in both voting rounds, the majority (80% [15/19]) of whom were program directors or dermatologists affiliated with academia or development of DEI education; the remaining 20% [4/19]) were dermatology residents.

Open-Ended Feedback—Voting group members were able to provide open-ended feedback for each of the sets of topics after the survey, which the steering committee utilized to modify the topics as needed for the final voting round. For example, “structural racism/discrimination” was originally mentioned as a topic, but several participants suggested including specific types of racism; therefore, the wording was changed to “racism: types, definitions” to encompass broader definitions and types of racism.

Survey Results—Two genres of topics were surveyed in each voting round: clinical and nonclinical. Participants voted on a total of 61 topics, with 23 ultimately selected in the final list of consensus curricular topics. Of those, 9 were clinical and 14 nonclinical. All topics deemed necessary for inclusion in residency curricula are presented in eTables 1 and 2.

During the first round of voting, the e-Delphi panel reached a consensus to include the following 17 topics as essential to dermatology residency training (along with the percentage of voters who classified them as probably essential or definitely essential): how to mitigate bias in clinical and workplace settings (100% [40/40]); social determinants of health-related disparities in dermatology (100% [40/40]); hairstyling practices across different hair textures (100% [40/40]); definitions and examples of microaggressions (97.50% [39/40]); definition, background, and types of bias (97.50% [39/40]); manifestations of bias in the clinical setting (97.44% [38/39]); racial and ethnic disparities in dermatology (97.44% [38/39]); keloids (97.37% [37/38]); differences in dermoscopic presentations in skin of color (97.30% [36/37]); skin cancer in patients with skin of color (97.30% [36/37]); disparities due to bias (95.00% [38/40]); how to apply cultural humility and safety to patients of different cultural backgrounds (94.87% [37/40]); best practices in providing care to patients with limited English proficiency (94.87% [37/40]); hair loss in patients with textured hair (94.74% [36/38]); pseudofolliculitis barbae and acne keloidalis nuchae (94.60% [35/37]); disparities regarding people experiencing homelessness (92.31% [36/39]); and definitions and types of racism and other forms of discrimination (92.31% [36/39]). eTable 1 provides a list of suggested resources to incorporate these topics into the educational components of residency curricula. The resources provided were not part of the voting process, and they were not considered in the consensus analysis; they are included here as suggested educational catalysts.

During the second round of voting, 25 topics were evaluated. Of those, the following 6 topics were proposed to be included as essential in residency training: differences in prevalence and presentation of common inflammatory disorders (100% [29/29]); manifestations of bias in the learning environment (96.55%); antiracist action and how to decrease the effects of structural racism in clinical and educational settings (96.55% [28/29]); diversity of images in dermatology education (96.55% [28/29]); pigmentary disorders and their psychological effects (96.55% [28/29]); and LGBTQ (lesbian, gay, bisexual, transgender, and queer) dermatologic health care (96.55% [28/29]). eTable 2 includes these topics as well as suggested resources to help incorporate them into training.

Comment

This study utilized a modified e-Delphi technique to identify relevant clinical and nonclinical DEI topics that should be incorporated into dermatology residency curricula. The panel members reached a consensus for 9 clinical DEI-related topics. The respondents agreed that the topics related to skin and hair conditions in patients with skin of color as well as textured hair were crucial to residency education. Skin cancer, hair loss, pseudofolliculitis barbae, acne keloidalis nuchae, keloids, pigmentary disorders, and their varying presentations in patients with skin of color were among the recommended topics. The panel also recommended educating residents on the variable visual presentations of inflammatory conditions in skin of color. Addressing the needs of diverse patients—for example, those belonging to the LGBTQ community—also was deemed important for inclusion.

The remaining 14 chosen topics were nonclinical items addressing concepts such as bias and health care disparities as well as cultural humility and safety.⁹ Cultural humility and safety focus on developing cultural awareness by creating a safe setting for patients rather than encouraging power relationships between them and their physicians. Various topics related to racism also were recommended to be included in residency curricula, including education on implementation of antiracist action in the workplace.

Many of the nonclinical topics are intertwined; for instance, learning about health care disparities in patients with limited English proficiency allows for improved best practices in delivering care to patients from this population. The first step in overcoming bias and subsequent disparities is acknowledging how the perpetuation of bias leads to disparities after being taught tools to recognize it.

Our group’s guidance on DEI topics should help dermatology residency program leaders as they design and refine program curricula. There are multiple avenues for incorporating education on these topics, including lectures, interactive workshops, role-playing sessions, book or journal clubs, and discussion circles. Many of these topics/programs may already be included in programs’ didactic curricula, which would minimize the burden of finding space to educate on these topics. Institutional cultural change is key to ensuring truly diverse, equitable, and inclusive workplaces. Educating tomorrow’s dermatologists on these topics is a first step toward achieving that cultural change.

Limitations—A limitation of this e-Delphi survey is that only a selection of experts in this field was included. Additionally, we were concerned that the Likert scale format and the bar we set for inclusion and exclusion may have failed to adequately capture participants’ nuanced opinions. As such, participants were able to provide open-ended feedback, and suggestions for alternate wording or other changes were considered by the steering committee. Finally, inclusion recommendations identified in this survey were developed specifically for US dermatology residents.

Conclusion

In this e-Delphi consensus assessment of DEI-related topics, we recommend the inclusion of 23 topics into dermatology residency program curricula to improve medical training and the patient-physician relationship as well as to create better health outcomes. We also provide specific sample resource recommendations in eTables 1 and 2 to facilitate inclusion of these topics into residency curricula across the country.

A task force established by the American College of Gastroenterology (ACG) and the American Society for Gastrointestinal Endoscopy (ASGE) issued updated recommendations highlighting what they consider to be the highest priority quality indicators for colonoscopy, a list that, for the first time, includes adequate bowel preparation and sessile serrated lesion detection rate (SSLDR).

“Endoscopy teams now have an updated set of guidelines which can be used to enhance the quality of their colonoscopies and should certainly use these current quality measures to ‘raise the bar’ on behalf of their patients,” task force member Nicholas J. Shaheen, MD, MPH, Division of Gastroenterology and Hepatology, The University of North Carolina at Chapel Hill, said in a statement.

The task force published the recommendations online August 21 in The American Journal of Gastroenterology and in Gastrointestinal Endoscopy. It represents the third iteration of the ACG/ASGE quality indicators on colonoscopy recommendations and incorporates new evidence published since 2015.

“The last set of quality indicators from this group was 9 years ago. Since then, there has been a tremendous amount of new data published in colonoscopy quality,” Ziad F. Gellad, MD, MPH, professor of medicine, Duke University Medical Center, Durham, North Carolina, said in an interview.

“Keeping up with that data is a challenge, and so guidelines such as these are important in helping clinicians synthesize data on quality of care and implement best practices,” said Dr. Gellad, who was not involved with the task force.
 

Two New Priority Indicators 

The task force identified 15 quality indicators, divided into preprocedure, intraprocedure, and postprocedure. It includes five “priority” indicators — two of which are new.

One is the rate of adequate bowel preparation, preferably defined as a Boston Bowel Preparation Scale score ≥ 2 in each of three colon segments or by description of the preparation as excellent, good, or adequate. It has a performance target > 90%.

“Inadequate bowel preparation substantially increases the cost of colonoscopy delivery and creates risk and inconvenience for patients, thus warranting a ranking as a priority indicator,” the task force wrote.

Dr. Gellad explained that the addition of this priority indicator is “notable because it highlights the importance of bowel prep in high-quality colonoscopy. It also shifts more of the responsibility of bowel prep from the patient to the practice.”

The second new quality indicator is the SSLDR, which was selected due to its ability to contribute to cancer prevention.

Based on available evidence, the task force recommends a current minimum threshold for the SSLDR of 6%. “This is expected to be revised upward as evidence of increasing detection occurs,” they wrote.

Duke University

Dr. Gellad said the addition of SSLDR is “an important advance in these recommendations. We know that serrated adenomas are a precursor for colorectal cancer and that the detection of these subtle lesions is variable.

“Providing a benchmark encourages practices to measure the detection of serrated adenomas and intervene when rates are below benchmarks. Prior to these benchmarks, it was difficult to know where to peg our expectations,” Dr. Gellad added.
 

Changes to the Adenoma Detection Rate (ADR)

The ADR remains a priority indicator in the update, albeit with changes.

To keep the ADR measurement consistent with current screening guidelines, the task force now recommends that the ADR be measured starting at age 45 rather than 50 years.

“ADR plays a critical role in evaluating the performance of the colonoscopists,” task force lead Douglas K. Rex, MD, a gastroenterologist at Indiana University School of Medicine in Indianapolis, said in the statement.

“It is recommended that ADR calculations include screening, surveillance, and diagnostic colonoscopy but exclude indications of a positive noncolonoscopy screening test and therapeutic procedures for resection or treatment of known neoplasia, genetic cancer syndromes, and inflammatory bowel disease,” Dr. Rex explained.

The task force recommends a minimum ADR threshold of 35% (40% in men and 30% in women) and that colonoscopists with ADRs below 35% “undertake remedial measures to improve and to achieve acceptable performance.”
 

Additional Priorities 

The cecal intubation rate (CIR) — the percentage of patients undergoing colonoscopy with intact colons who have full intubation of the cecum with photo documentation of cecal landmarks — remains a priority quality indicator and has a performance target ≥ 95%.

“A trained colonoscopist should achieve a high CIR with a very high level of safety,” the task force wrote. “Low CIRs have been associated with higher PCCRC [postcolonoscopy colorectal cancer] rates.” 

The final priority indicator is the rate of using recommended screening and surveillance intervals, which carries a performance target ≥ 90%.

“We recommend that quality improvement efforts initially focus on high-priority indicators and then progress to other indicators once it is ascertained that endoscopists are performing above recommended thresholds, either at baseline or after corrective interventions,” the task force wrote.

“The priority indicators are absolutely important for practices to implement,” Dr. Gellad said.

“There is compelling evidence that these measures are correlated with clinically important outcomes, particularly ADR,” he added. “Many practices already capture this data, and the changes in ADR calculation make measurement less burdensome. Hopefully, this will encourage more practices to collect and report these measures.” 

Dr. Rex is a consultant for Olympus, Boston Scientific, Braintree Laboratories, Norgine, GI Supply, Medtronic, and Acacia Pharmaceuticals; receives research support from Olympus, Medivators, Erbe USA, and Braintree Laboratories; and is a shareholder in Satisfai Health. Dr. Shaheen had no relevant disclosures. Dr. Gellad has consulted for Merck & Co. and Novo Nordisk and is a cofounder of Higgs Boson.
 

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

A task force established by the American College of Gastroenterology (ACG) and the American Society for Gastrointestinal Endoscopy (ASGE) issued updated recommendations highlighting what they consider to be the highest priority quality indicators for colonoscopy, a list that, for the first time, includes adequate bowel preparation and sessile serrated lesion detection rate (SSLDR).

“Endoscopy teams now have an updated set of guidelines which can be used to enhance the quality of their colonoscopies and should certainly use these current quality measures to ‘raise the bar’ on behalf of their patients,” task force member Nicholas J. Shaheen, MD, MPH, Division of Gastroenterology and Hepatology, The University of North Carolina at Chapel Hill, said in a statement.

The task force published the recommendations online August 21 in The American Journal of Gastroenterology and in Gastrointestinal Endoscopy. It represents the third iteration of the ACG/ASGE quality indicators on colonoscopy recommendations and incorporates new evidence published since 2015.

“The last set of quality indicators from this group was 9 years ago. Since then, there has been a tremendous amount of new data published in colonoscopy quality,” Ziad F. Gellad, MD, MPH, professor of medicine, Duke University Medical Center, Durham, North Carolina, said in an interview.

“Keeping up with that data is a challenge, and so guidelines such as these are important in helping clinicians synthesize data on quality of care and implement best practices,” said Dr. Gellad, who was not involved with the task force.
 

Two New Priority Indicators 

The task force identified 15 quality indicators, divided into preprocedure, intraprocedure, and postprocedure. It includes five “priority” indicators — two of which are new.

One is the rate of adequate bowel preparation, preferably defined as a Boston Bowel Preparation Scale score ≥ 2 in each of three colon segments or by description of the preparation as excellent, good, or adequate. It has a performance target > 90%.

“Inadequate bowel preparation substantially increases the cost of colonoscopy delivery and creates risk and inconvenience for patients, thus warranting a ranking as a priority indicator,” the task force wrote.

Dr. Gellad explained that the addition of this priority indicator is “notable because it highlights the importance of bowel prep in high-quality colonoscopy. It also shifts more of the responsibility of bowel prep from the patient to the practice.”

The second new quality indicator is the SSLDR, which was selected due to its ability to contribute to cancer prevention.

Based on available evidence, the task force recommends a current minimum threshold for the SSLDR of 6%. “This is expected to be revised upward as evidence of increasing detection occurs,” they wrote.

Duke University

Dr. Gellad said the addition of SSLDR is “an important advance in these recommendations. We know that serrated adenomas are a precursor for colorectal cancer and that the detection of these subtle lesions is variable.

“Providing a benchmark encourages practices to measure the detection of serrated adenomas and intervene when rates are below benchmarks. Prior to these benchmarks, it was difficult to know where to peg our expectations,” Dr. Gellad added.
 

Changes to the Adenoma Detection Rate (ADR)

The ADR remains a priority indicator in the update, albeit with changes.

To keep the ADR measurement consistent with current screening guidelines, the task force now recommends that the ADR be measured starting at age 45 rather than 50 years.

“ADR plays a critical role in evaluating the performance of the colonoscopists,” task force lead Douglas K. Rex, MD, a gastroenterologist at Indiana University School of Medicine in Indianapolis, said in the statement.

“It is recommended that ADR calculations include screening, surveillance, and diagnostic colonoscopy but exclude indications of a positive noncolonoscopy screening test and therapeutic procedures for resection or treatment of known neoplasia, genetic cancer syndromes, and inflammatory bowel disease,” Dr. Rex explained.

The task force recommends a minimum ADR threshold of 35% (40% in men and 30% in women) and that colonoscopists with ADRs below 35% “undertake remedial measures to improve and to achieve acceptable performance.”
 

Additional Priorities 

The cecal intubation rate (CIR) — the percentage of patients undergoing colonoscopy with intact colons who have full intubation of the cecum with photo documentation of cecal landmarks — remains a priority quality indicator and has a performance target ≥ 95%.

“A trained colonoscopist should achieve a high CIR with a very high level of safety,” the task force wrote. “Low CIRs have been associated with higher PCCRC [postcolonoscopy colorectal cancer] rates.” 

The final priority indicator is the rate of using recommended screening and surveillance intervals, which carries a performance target ≥ 90%.

“We recommend that quality improvement efforts initially focus on high-priority indicators and then progress to other indicators once it is ascertained that endoscopists are performing above recommended thresholds, either at baseline or after corrective interventions,” the task force wrote.

“The priority indicators are absolutely important for practices to implement,” Dr. Gellad said.

“There is compelling evidence that these measures are correlated with clinically important outcomes, particularly ADR,” he added. “Many practices already capture this data, and the changes in ADR calculation make measurement less burdensome. Hopefully, this will encourage more practices to collect and report these measures.” 

Dr. Rex is a consultant for Olympus, Boston Scientific, Braintree Laboratories, Norgine, GI Supply, Medtronic, and Acacia Pharmaceuticals; receives research support from Olympus, Medivators, Erbe USA, and Braintree Laboratories; and is a shareholder in Satisfai Health. Dr. Shaheen had no relevant disclosures. Dr. Gellad has consulted for Merck & Co. and Novo Nordisk and is a cofounder of Higgs Boson.
 

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

A task force established by the American College of Gastroenterology (ACG) and the American Society for Gastrointestinal Endoscopy (ASGE) issued updated recommendations highlighting what they consider to be the highest priority quality indicators for colonoscopy, a list that, for the first time, includes adequate bowel preparation and sessile serrated lesion detection rate (SSLDR).

“Endoscopy teams now have an updated set of guidelines which can be used to enhance the quality of their colonoscopies and should certainly use these current quality measures to ‘raise the bar’ on behalf of their patients,” task force member Nicholas J. Shaheen, MD, MPH, Division of Gastroenterology and Hepatology, The University of North Carolina at Chapel Hill, said in a statement.

The task force published the recommendations online August 21 in The American Journal of Gastroenterology and in Gastrointestinal Endoscopy. It represents the third iteration of the ACG/ASGE quality indicators on colonoscopy recommendations and incorporates new evidence published since 2015.

“The last set of quality indicators from this group was 9 years ago. Since then, there has been a tremendous amount of new data published in colonoscopy quality,” Ziad F. Gellad, MD, MPH, professor of medicine, Duke University Medical Center, Durham, North Carolina, said in an interview.

“Keeping up with that data is a challenge, and so guidelines such as these are important in helping clinicians synthesize data on quality of care and implement best practices,” said Dr. Gellad, who was not involved with the task force.
 

Two New Priority Indicators 

The task force identified 15 quality indicators, divided into preprocedure, intraprocedure, and postprocedure. It includes five “priority” indicators — two of which are new.

One is the rate of adequate bowel preparation, preferably defined as a Boston Bowel Preparation Scale score ≥ 2 in each of three colon segments or by description of the preparation as excellent, good, or adequate. It has a performance target > 90%.

“Inadequate bowel preparation substantially increases the cost of colonoscopy delivery and creates risk and inconvenience for patients, thus warranting a ranking as a priority indicator,” the task force wrote.

Dr. Gellad explained that the addition of this priority indicator is “notable because it highlights the importance of bowel prep in high-quality colonoscopy. It also shifts more of the responsibility of bowel prep from the patient to the practice.”

The second new quality indicator is the SSLDR, which was selected due to its ability to contribute to cancer prevention.

Based on available evidence, the task force recommends a current minimum threshold for the SSLDR of 6%. “This is expected to be revised upward as evidence of increasing detection occurs,” they wrote.

Duke University

Dr. Gellad said the addition of SSLDR is “an important advance in these recommendations. We know that serrated adenomas are a precursor for colorectal cancer and that the detection of these subtle lesions is variable.

“Providing a benchmark encourages practices to measure the detection of serrated adenomas and intervene when rates are below benchmarks. Prior to these benchmarks, it was difficult to know where to peg our expectations,” Dr. Gellad added.
 

Changes to the Adenoma Detection Rate (ADR)

The ADR remains a priority indicator in the update, albeit with changes.

To keep the ADR measurement consistent with current screening guidelines, the task force now recommends that the ADR be measured starting at age 45 rather than 50 years.

“ADR plays a critical role in evaluating the performance of the colonoscopists,” task force lead Douglas K. Rex, MD, a gastroenterologist at Indiana University School of Medicine in Indianapolis, said in the statement.

“It is recommended that ADR calculations include screening, surveillance, and diagnostic colonoscopy but exclude indications of a positive noncolonoscopy screening test and therapeutic procedures for resection or treatment of known neoplasia, genetic cancer syndromes, and inflammatory bowel disease,” Dr. Rex explained.

The task force recommends a minimum ADR threshold of 35% (40% in men and 30% in women) and that colonoscopists with ADRs below 35% “undertake remedial measures to improve and to achieve acceptable performance.”
 

Additional Priorities 

The cecal intubation rate (CIR) — the percentage of patients undergoing colonoscopy with intact colons who have full intubation of the cecum with photo documentation of cecal landmarks — remains a priority quality indicator and has a performance target ≥ 95%.

“A trained colonoscopist should achieve a high CIR with a very high level of safety,” the task force wrote. “Low CIRs have been associated with higher PCCRC [postcolonoscopy colorectal cancer] rates.” 

The final priority indicator is the rate of using recommended screening and surveillance intervals, which carries a performance target ≥ 90%.

“We recommend that quality improvement efforts initially focus on high-priority indicators and then progress to other indicators once it is ascertained that endoscopists are performing above recommended thresholds, either at baseline or after corrective interventions,” the task force wrote.

“The priority indicators are absolutely important for practices to implement,” Dr. Gellad said.

“There is compelling evidence that these measures are correlated with clinically important outcomes, particularly ADR,” he added. “Many practices already capture this data, and the changes in ADR calculation make measurement less burdensome. Hopefully, this will encourage more practices to collect and report these measures.” 

Dr. Rex is a consultant for Olympus, Boston Scientific, Braintree Laboratories, Norgine, GI Supply, Medtronic, and Acacia Pharmaceuticals; receives research support from Olympus, Medivators, Erbe USA, and Braintree Laboratories; and is a shareholder in Satisfai Health. Dr. Shaheen had no relevant disclosures. Dr. Gellad has consulted for Merck & Co. and Novo Nordisk and is a cofounder of Higgs Boson.
 

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

Hormone therapy (HT) can help women manage menopause symptoms into their 80s and the reasons are varied, according to a retrospective analysis being presented at the annual meeting of The Menopause Society.

“It’s important to know that this is a preselected group of women who had no contraindications to continuing their hormone therapy,” senior author Wendy Wolfman, MD, director of the Menopause Clinic and The Premature Ovarian Insufficiency Clinic at Mount Sinai Hospital in Toronto, Ontario, Canada, said in an interview. “They had the initiation of hormone therapy closer to menopause and carried on their hormones. We followed them for a long time and basically saw no real concerns about taking the hormones and the patients did very well. It’s important to emphasize this was not the new initiation of hormone therapy in elderly women.”

She said that, in her large tertiary referral center, “I still see patients who are referred who are told that they have to stop their hormones after 5 years based on a false assumption. Everybody ages at different rates and everybody has different risk factors.”

About 70%-80% of women experience menopause symptoms that restrict quality of life and productivity, the authors noted. HT has consistently been the most effective means for managing many of the side effects, especially hot flashes.

Hot flashes last on average 7-11 years. But they continue in up to 40% of women in their 60s and 10%-15% in their 70s, the authors wrote. 

The analysis included more than 100 women in Canada older than 65 who continue to use HT and explored the motivations of the women to use them.

The average age of the women was 71 and nearly 8% were age 80 or older. The mean age for starting HT was 52 years and the women continued HT for an average 18 years, though 42% used it regularly for more than 20 years. Most of the women (nearly 88%) used a transdermal form of estrogen; only 12% used oral estrogen pills. Fewer than 5% of participants used synthetic progestins.

Controlling hot flashes was the No. 1 reason the women continued HT beyond age 65 (55%), followed by a desire for a better quality of life (29%), and to reduce chronic pain and arthritis symptoms (7%).

Some adverse effects were reported – postmenopausal bleeding was the most common – but no strokes, myocardial infarctions, or uterine cancers were documented.

More than one fourth (26.4%) of the women tried stopping HT once, but 87% reported that the return of hot flashes was the main reason to restart HT.

In addition, “many women choose to continue hormone therapy long term for relief of nonvasomotor symptoms, preservation of bone density, and a desire to benefit from potential long-term cardiovascular protection,” said Lauren F. Streicher, MD, Professor of Obstetrics and Gynecology at Feinberg School of Medicine at Northwestern University in Chicago, who was not part of the research.

In 2022, The Menopause Society position statement on hormone therapy acknowledged that, on an individual basis, it is appropriate for women to continue hormone therapy long term with counseling on benefits and risks.

“However, few studies have evaluated the outcomes of using hormone therapy for more than 10 years, and individual motivation for doing so,” Dr. Streicher said. She pointed to a study that analyzed the insurance records of more than 10 million women who continued their HT past the age of 65 and reassuringly found that there were significant risk reductions in all-cause mortality, breast cancer, lung cancer, colorectal cancer, heart failure, venous thromboembolism, atrial fibrillation, acute myocardial infarction, and dementia. In that study, however, the reasons women chose to continue hormone therapy were not specified. 

“In this retrospective Canadian study,” she noted, “the outcomes were again reassuring, with no increase in strokes, myocardial infarctions, or uterine cancers. The reasons cited for continuing hormone therapy were not just to treat ongoing vasomotor symptoms, but also other menopause symptoms such as musculoskeletal aches and pains, and overall quality of life.

Dr. Streicher said that, while long-term longitudinal studies are needed to make definitive recommendations, “It is reassuring that women who choose to extend hormone therapy can safely do so. It is irresponsible, cruel, and nonsensical to continue to make blanket statements that hormone therapy should be discontinued based on age or years of use and commit women to enduring symptoms and depriving them of possible long-term benefits.”

Dr. Streicher gives lectures for Midi Health and owns Sermonix stock. Dr. Wolfman has been on the advisory boards for many pharmaceutical companies. She is the past president of the Canadian Menopause Society and is on the board of the International Menopause Society.

Hormone therapy (HT) can help women manage menopause symptoms into their 80s and the reasons are varied, according to a retrospective analysis being presented at the annual meeting of The Menopause Society.

“It’s important to know that this is a preselected group of women who had no contraindications to continuing their hormone therapy,” senior author Wendy Wolfman, MD, director of the Menopause Clinic and The Premature Ovarian Insufficiency Clinic at Mount Sinai Hospital in Toronto, Ontario, Canada, said in an interview. “They had the initiation of hormone therapy closer to menopause and carried on their hormones. We followed them for a long time and basically saw no real concerns about taking the hormones and the patients did very well. It’s important to emphasize this was not the new initiation of hormone therapy in elderly women.”

She said that, in her large tertiary referral center, “I still see patients who are referred who are told that they have to stop their hormones after 5 years based on a false assumption. Everybody ages at different rates and everybody has different risk factors.”

About 70%-80% of women experience menopause symptoms that restrict quality of life and productivity, the authors noted. HT has consistently been the most effective means for managing many of the side effects, especially hot flashes.

Hot flashes last on average 7-11 years. But they continue in up to 40% of women in their 60s and 10%-15% in their 70s, the authors wrote. 

The analysis included more than 100 women in Canada older than 65 who continue to use HT and explored the motivations of the women to use them.

The average age of the women was 71 and nearly 8% were age 80 or older. The mean age for starting HT was 52 years and the women continued HT for an average 18 years, though 42% used it regularly for more than 20 years. Most of the women (nearly 88%) used a transdermal form of estrogen; only 12% used oral estrogen pills. Fewer than 5% of participants used synthetic progestins.

Controlling hot flashes was the No. 1 reason the women continued HT beyond age 65 (55%), followed by a desire for a better quality of life (29%), and to reduce chronic pain and arthritis symptoms (7%).

Some adverse effects were reported – postmenopausal bleeding was the most common – but no strokes, myocardial infarctions, or uterine cancers were documented.

More than one fourth (26.4%) of the women tried stopping HT once, but 87% reported that the return of hot flashes was the main reason to restart HT.

In addition, “many women choose to continue hormone therapy long term for relief of nonvasomotor symptoms, preservation of bone density, and a desire to benefit from potential long-term cardiovascular protection,” said Lauren F. Streicher, MD, Professor of Obstetrics and Gynecology at Feinberg School of Medicine at Northwestern University in Chicago, who was not part of the research.

In 2022, The Menopause Society position statement on hormone therapy acknowledged that, on an individual basis, it is appropriate for women to continue hormone therapy long term with counseling on benefits and risks.

“However, few studies have evaluated the outcomes of using hormone therapy for more than 10 years, and individual motivation for doing so,” Dr. Streicher said. She pointed to a study that analyzed the insurance records of more than 10 million women who continued their HT past the age of 65 and reassuringly found that there were significant risk reductions in all-cause mortality, breast cancer, lung cancer, colorectal cancer, heart failure, venous thromboembolism, atrial fibrillation, acute myocardial infarction, and dementia. In that study, however, the reasons women chose to continue hormone therapy were not specified. 

“In this retrospective Canadian study,” she noted, “the outcomes were again reassuring, with no increase in strokes, myocardial infarctions, or uterine cancers. The reasons cited for continuing hormone therapy were not just to treat ongoing vasomotor symptoms, but also other menopause symptoms such as musculoskeletal aches and pains, and overall quality of life.

Dr. Streicher said that, while long-term longitudinal studies are needed to make definitive recommendations, “It is reassuring that women who choose to extend hormone therapy can safely do so. It is irresponsible, cruel, and nonsensical to continue to make blanket statements that hormone therapy should be discontinued based on age or years of use and commit women to enduring symptoms and depriving them of possible long-term benefits.”

Dr. Streicher gives lectures for Midi Health and owns Sermonix stock. Dr. Wolfman has been on the advisory boards for many pharmaceutical companies. She is the past president of the Canadian Menopause Society and is on the board of the International Menopause Society.

Hormone therapy (HT) can help women manage menopause symptoms into their 80s and the reasons are varied, according to a retrospective analysis being presented at the annual meeting of The Menopause Society.

“It’s important to know that this is a preselected group of women who had no contraindications to continuing their hormone therapy,” senior author Wendy Wolfman, MD, director of the Menopause Clinic and The Premature Ovarian Insufficiency Clinic at Mount Sinai Hospital in Toronto, Ontario, Canada, said in an interview. “They had the initiation of hormone therapy closer to menopause and carried on their hormones. We followed them for a long time and basically saw no real concerns about taking the hormones and the patients did very well. It’s important to emphasize this was not the new initiation of hormone therapy in elderly women.”

She said that, in her large tertiary referral center, “I still see patients who are referred who are told that they have to stop their hormones after 5 years based on a false assumption. Everybody ages at different rates and everybody has different risk factors.”

About 70%-80% of women experience menopause symptoms that restrict quality of life and productivity, the authors noted. HT has consistently been the most effective means for managing many of the side effects, especially hot flashes.

Hot flashes last on average 7-11 years. But they continue in up to 40% of women in their 60s and 10%-15% in their 70s, the authors wrote. 

The analysis included more than 100 women in Canada older than 65 who continue to use HT and explored the motivations of the women to use them.

The average age of the women was 71 and nearly 8% were age 80 or older. The mean age for starting HT was 52 years and the women continued HT for an average 18 years, though 42% used it regularly for more than 20 years. Most of the women (nearly 88%) used a transdermal form of estrogen; only 12% used oral estrogen pills. Fewer than 5% of participants used synthetic progestins.

Controlling hot flashes was the No. 1 reason the women continued HT beyond age 65 (55%), followed by a desire for a better quality of life (29%), and to reduce chronic pain and arthritis symptoms (7%).

Some adverse effects were reported – postmenopausal bleeding was the most common – but no strokes, myocardial infarctions, or uterine cancers were documented.

More than one fourth (26.4%) of the women tried stopping HT once, but 87% reported that the return of hot flashes was the main reason to restart HT.

In addition, “many women choose to continue hormone therapy long term for relief of nonvasomotor symptoms, preservation of bone density, and a desire to benefit from potential long-term cardiovascular protection,” said Lauren F. Streicher, MD, Professor of Obstetrics and Gynecology at Feinberg School of Medicine at Northwestern University in Chicago, who was not part of the research.

In 2022, The Menopause Society position statement on hormone therapy acknowledged that, on an individual basis, it is appropriate for women to continue hormone therapy long term with counseling on benefits and risks.

“However, few studies have evaluated the outcomes of using hormone therapy for more than 10 years, and individual motivation for doing so,” Dr. Streicher said. She pointed to a study that analyzed the insurance records of more than 10 million women who continued their HT past the age of 65 and reassuringly found that there were significant risk reductions in all-cause mortality, breast cancer, lung cancer, colorectal cancer, heart failure, venous thromboembolism, atrial fibrillation, acute myocardial infarction, and dementia. In that study, however, the reasons women chose to continue hormone therapy were not specified. 

“In this retrospective Canadian study,” she noted, “the outcomes were again reassuring, with no increase in strokes, myocardial infarctions, or uterine cancers. The reasons cited for continuing hormone therapy were not just to treat ongoing vasomotor symptoms, but also other menopause symptoms such as musculoskeletal aches and pains, and overall quality of life.

Dr. Streicher said that, while long-term longitudinal studies are needed to make definitive recommendations, “It is reassuring that women who choose to extend hormone therapy can safely do so. It is irresponsible, cruel, and nonsensical to continue to make blanket statements that hormone therapy should be discontinued based on age or years of use and commit women to enduring symptoms and depriving them of possible long-term benefits.”

Dr. Streicher gives lectures for Midi Health and owns Sermonix stock. Dr. Wolfman has been on the advisory boards for many pharmaceutical companies. She is the past president of the Canadian Menopause Society and is on the board of the International Menopause Society.

To the Editor:

Melasma (also known as chloasma) is characterized by symmetric hyperpigmented patches affecting sun-exposed areas. Women commonly develop this condition during pregnancy, suggesting a connection between melasma and increased female sex hormone levels.¹ Other hypothesized risk factors include sun exposure, genetic susceptibility, estrogen and/or progesterone therapy, and thyroid abnormalities but have not been corroborated.² Treatment options are limited because the pathogenesis is poorly understood; thus, we aimed to analyze melasma risk factors using a national database with a nested case-control approach.

We conducted a matched case-control study using the Registered Tier dataset (version 7) from the National Institute of Health’s All of Us Research Program (https://allofus.nih.gov/), which is available to authorized users through the program’s Researcher Workbench and includes more than 413,000 total participants enrolled from May 1, 2018, through July 1, 2022. Cases included patients 18 years and older with a diagnosis of melasma (International Classification of Diseases, Tenth Revision, Clinical Modification code L81.1 [Chloasma]; concept ID 4264234 [Chloasma]; and Systematized Nomenclature of Medicine [SNOMED] code 36209000 [Chloasma]), and controls without a diagnosis of melasma were matched in a 1:10 ratio based on age, sex, and self-reported race. Concept IDs and SNOMED codes were used to identify individuals in each cohort with a diagnosis of alcohol dependence (concept IDs 433753, 435243, 4218106; SNOMED codes 15167005, 66590003, 7200002), depression (concept ID 440383; SNOMED code 35489007), hypothyroidism (concept ID 140673; SNOMED code 40930008), hyperthyroidism (concept ID 4142479; SNOMED code 34486009), anxiety (concept IDs 441542, 442077, 434613; SNOMED codes 48694002, 197480006, 21897009), tobacco dependence (concept IDs 37109023, 437264, 4099811; SNOMED codes 16077091000119107, 89765005, 191887008), or obesity (concept IDs 433736 and 434005; SNOMED codes 414916001 and 238136002), or with a history of radiation therapy (concept IDs 4085340, 4311117, 4061844, 4029715; SNOMED codes 24803000, 85983004, 200861004, 108290001) or hormonal medications containing estrogen and/or progesterone, including oral medications and implants (concept IDs 21602445, 40254009, 21602514, 21603814, 19049228, 21602529, 1549080, 1551673, 1549254, 21602472, 21602446, 21602450, 21602515, 21602566, 21602473, 21602567, 21602488, 21602585, 1596779, 1586808, 21602524). In our case cohort, diagnoses and exposures to treatments were only considered for analysis if they occurred prior to melasma diagnosis.

Multivariate logistic regression was performed to calculate odds ratios and P values between melasma and each comorbidity or exposure to the treatments specified. Statistical significance was set at P<.05.

We identified 744 melasma cases (mean age, 55.20 years; 95.43% female; 12.10% Black) and 7440 controls with similar demographics (ie, age, sex, race/ethnicity) between groups (all P>.05 [Table 1]). Patients with a melasma diagnosis were more likely to have a pre-existing diagnosis of depression (OR, 1.87; 95% CI, 1.51-2.31 [P<.001]) or hypothyroidism (OR, 1.31; 95% CI, 1.04-1.65 [P<.05]), or a history of radiation therapy (OR, 19.08; 95% CI, 10.20-35.69 [P<.001]) and/or estrogen and/or progesterone therapy (OR, 2.01; 95% CI, 1.69-2.40 [P<.001]) prior to melasma diagnosis. A diagnosis of anxiety prior to melasma diagnosis trended toward an association with melasma (P=.067). Pre-existing alcohol dependence, obesity, and hyperthyroidism were not associated with melasma (P=.98, P=.28, and P=.29, respectively). A diagnosis of tobacco dependence was associated with a decreased melasma risk (OR, 0.53, 95% CI, 0.37-0.76)[P<.001])(Table 2).

Our study results suggest that pre-existing depression was a risk factor for subsequent melasma diagnosis. Depression may exacerbate stress, leading to increased activation of the hypothalamic-pituitary-adrenal axis as well as increased levels of cortisol and adrenocorticotropic hormone, which subsequently act on melanocytes to increase melanogenesis.³ A retrospective study of 254 participants, including 127 with melasma, showed that increased melasma severity was associated with higher rates of depression (P=.002)²; however, the risk for melasma following a depression diagnosis has not been reported.

Our results also showed that hypothyroidism was associated with an increased risk for melasma. On a cellular level, hypothyroidism can cause systemic inflammation, potentailly leading to increased stress and melanogenesis via activation of the hypothalamic-pituitary-adrenal axis.⁴ These findings are similar to a systematic review and meta-analysis reporting increased thyroid-stimulating hormone, anti–thyroid peroxidase, and antithyroglobulin antibody levels associated with increased melasma risk (mean difference between cases and controls, 0.33 [95% CI, 0.18-0.47]; pooled association, P=.020; mean difference between cases and controls, 0.28 [95% CI, 0.01-0.55], respectively).⁵

Patients in our cohort who had a history of radiation therapy were 19 times more likely to develop melasma, similar to findings of a survey-based study of 421 breast cancer survivors in which 336 (79.81%) reported hyperpigmentation in irradiated areas.⁶ Patients in our cohort who had a history of estrogen and/or progesterone therapy were 2 times more likely to develop melasma, similar to a case-control study of 207 patients with melasma and 207 controls that showed combined oral contraceptives increased risk for melasma (OR, 1.23 [95% CI, 1.08-1.41; P<.01).³

Tobacco use is not a well-known protective factor against melasma. Prior studies have indicated that tobacco smoking activates melanocytes via the Wnt/β-Catenin pathway, leading to hyperpigmentation.⁷ Although exposure to cigarette smoke decreases angiogenesis and would more likely lead to hyperpigmentation, nicotine exposure has been shown to increase angiogenesis, which could lead to increased blood flow and partially explain the protection against melasma demonstrated in our cohort.⁸ Future studies are needed to explore this relationship.

Limitations of our study include lack of information about melasma severity and information about prior melasma treatment in our cohort as well as possible misdiagnosis reported in the dataset.

Our results demonstrated that pre-existing depression and hypothyroidism as well as a history of radiation or estrogen and/or progesterone therapies are potential risk factors for melasma. Therefore, we recommend that patients with melasma be screened for depression and thyroid dysfunction, and patients undergoing radiation therapy or starting estrogen and/or progesterone therapy should be counseled on their increased risk for melasma. Future studies are needed to determine whether treatment of comorbidities such as hypothyroidism and depression improve melasma severity. The decreased risk for melasma associated with tobacco use also requires further investigation.

Acknowledgments—The All of Us Research Program is supported by the National Institutes of Health, Office of the Director: Regional Medical Centers: 1 OT2 OD026549; 1 OT2 OD026554; 1 OT2 OD026557; 1 OT2 OD026556; 1 OT2 OD026550; 1 OT2 OD 026552; 1 OT2 OD026553; 1 OT2 OD026548; 1 OT2 OD026551; 1 OT2 OD026555; IAA #: AOD 16037; Federally Qualified Health Centers: HHSN 263201600085U; Data and Research Center: 5 U2C OD023196; Biobank: 1 U24 OD023121; The Participant Center: U24 OD023176; Participant Technology Systems Center: 1 U24 OD023163; Communications and Engagement: 3 OT2 OD023205; 3 OT2 OD023206; and Community Partners: 1 OT2 OD025277; 3 OT2 OD025315; 1 OT2 OD025337; 1 OT2 OD025276.

In addition, the All of Us Research Program would not be possible without the partnership of its participants, who we gratefully acknowledge for their contributions and without whom this research would not have been possible. We also thank the All of Us Research Program for making the participant data examined in this study available to us.

To the Editor:

Melasma (also known as chloasma) is characterized by symmetric hyperpigmented patches affecting sun-exposed areas. Women commonly develop this condition during pregnancy, suggesting a connection between melasma and increased female sex hormone levels.¹ Other hypothesized risk factors include sun exposure, genetic susceptibility, estrogen and/or progesterone therapy, and thyroid abnormalities but have not been corroborated.² Treatment options are limited because the pathogenesis is poorly understood; thus, we aimed to analyze melasma risk factors using a national database with a nested case-control approach.

We conducted a matched case-control study using the Registered Tier dataset (version 7) from the National Institute of Health’s All of Us Research Program (https://allofus.nih.gov/), which is available to authorized users through the program’s Researcher Workbench and includes more than 413,000 total participants enrolled from May 1, 2018, through July 1, 2022. Cases included patients 18 years and older with a diagnosis of melasma (International Classification of Diseases, Tenth Revision, Clinical Modification code L81.1 [Chloasma]; concept ID 4264234 [Chloasma]; and Systematized Nomenclature of Medicine [SNOMED] code 36209000 [Chloasma]), and controls without a diagnosis of melasma were matched in a 1:10 ratio based on age, sex, and self-reported race. Concept IDs and SNOMED codes were used to identify individuals in each cohort with a diagnosis of alcohol dependence (concept IDs 433753, 435243, 4218106; SNOMED codes 15167005, 66590003, 7200002), depression (concept ID 440383; SNOMED code 35489007), hypothyroidism (concept ID 140673; SNOMED code 40930008), hyperthyroidism (concept ID 4142479; SNOMED code 34486009), anxiety (concept IDs 441542, 442077, 434613; SNOMED codes 48694002, 197480006, 21897009), tobacco dependence (concept IDs 37109023, 437264, 4099811; SNOMED codes 16077091000119107, 89765005, 191887008), or obesity (concept IDs 433736 and 434005; SNOMED codes 414916001 and 238136002), or with a history of radiation therapy (concept IDs 4085340, 4311117, 4061844, 4029715; SNOMED codes 24803000, 85983004, 200861004, 108290001) or hormonal medications containing estrogen and/or progesterone, including oral medications and implants (concept IDs 21602445, 40254009, 21602514, 21603814, 19049228, 21602529, 1549080, 1551673, 1549254, 21602472, 21602446, 21602450, 21602515, 21602566, 21602473, 21602567, 21602488, 21602585, 1596779, 1586808, 21602524). In our case cohort, diagnoses and exposures to treatments were only considered for analysis if they occurred prior to melasma diagnosis.

Multivariate logistic regression was performed to calculate odds ratios and P values between melasma and each comorbidity or exposure to the treatments specified. Statistical significance was set at P<.05.

We identified 744 melasma cases (mean age, 55.20 years; 95.43% female; 12.10% Black) and 7440 controls with similar demographics (ie, age, sex, race/ethnicity) between groups (all P>.05 [Table 1]). Patients with a melasma diagnosis were more likely to have a pre-existing diagnosis of depression (OR, 1.87; 95% CI, 1.51-2.31 [P<.001]) or hypothyroidism (OR, 1.31; 95% CI, 1.04-1.65 [P<.05]), or a history of radiation therapy (OR, 19.08; 95% CI, 10.20-35.69 [P<.001]) and/or estrogen and/or progesterone therapy (OR, 2.01; 95% CI, 1.69-2.40 [P<.001]) prior to melasma diagnosis. A diagnosis of anxiety prior to melasma diagnosis trended toward an association with melasma (P=.067). Pre-existing alcohol dependence, obesity, and hyperthyroidism were not associated with melasma (P=.98, P=.28, and P=.29, respectively). A diagnosis of tobacco dependence was associated with a decreased melasma risk (OR, 0.53, 95% CI, 0.37-0.76)[P<.001])(Table 2).

Our study results suggest that pre-existing depression was a risk factor for subsequent melasma diagnosis. Depression may exacerbate stress, leading to increased activation of the hypothalamic-pituitary-adrenal axis as well as increased levels of cortisol and adrenocorticotropic hormone, which subsequently act on melanocytes to increase melanogenesis.³ A retrospective study of 254 participants, including 127 with melasma, showed that increased melasma severity was associated with higher rates of depression (P=.002)²; however, the risk for melasma following a depression diagnosis has not been reported.

Our results also showed that hypothyroidism was associated with an increased risk for melasma. On a cellular level, hypothyroidism can cause systemic inflammation, potentailly leading to increased stress and melanogenesis via activation of the hypothalamic-pituitary-adrenal axis.⁴ These findings are similar to a systematic review and meta-analysis reporting increased thyroid-stimulating hormone, anti–thyroid peroxidase, and antithyroglobulin antibody levels associated with increased melasma risk (mean difference between cases and controls, 0.33 [95% CI, 0.18-0.47]; pooled association, P=.020; mean difference between cases and controls, 0.28 [95% CI, 0.01-0.55], respectively).⁵

Patients in our cohort who had a history of radiation therapy were 19 times more likely to develop melasma, similar to findings of a survey-based study of 421 breast cancer survivors in which 336 (79.81%) reported hyperpigmentation in irradiated areas.⁶ Patients in our cohort who had a history of estrogen and/or progesterone therapy were 2 times more likely to develop melasma, similar to a case-control study of 207 patients with melasma and 207 controls that showed combined oral contraceptives increased risk for melasma (OR, 1.23 [95% CI, 1.08-1.41; P<.01).³

Tobacco use is not a well-known protective factor against melasma. Prior studies have indicated that tobacco smoking activates melanocytes via the Wnt/β-Catenin pathway, leading to hyperpigmentation.⁷ Although exposure to cigarette smoke decreases angiogenesis and would more likely lead to hyperpigmentation, nicotine exposure has been shown to increase angiogenesis, which could lead to increased blood flow and partially explain the protection against melasma demonstrated in our cohort.⁸ Future studies are needed to explore this relationship.

Limitations of our study include lack of information about melasma severity and information about prior melasma treatment in our cohort as well as possible misdiagnosis reported in the dataset.

Our results demonstrated that pre-existing depression and hypothyroidism as well as a history of radiation or estrogen and/or progesterone therapies are potential risk factors for melasma. Therefore, we recommend that patients with melasma be screened for depression and thyroid dysfunction, and patients undergoing radiation therapy or starting estrogen and/or progesterone therapy should be counseled on their increased risk for melasma. Future studies are needed to determine whether treatment of comorbidities such as hypothyroidism and depression improve melasma severity. The decreased risk for melasma associated with tobacco use also requires further investigation.

Acknowledgments—The All of Us Research Program is supported by the National Institutes of Health, Office of the Director: Regional Medical Centers: 1 OT2 OD026549; 1 OT2 OD026554; 1 OT2 OD026557; 1 OT2 OD026556; 1 OT2 OD026550; 1 OT2 OD 026552; 1 OT2 OD026553; 1 OT2 OD026548; 1 OT2 OD026551; 1 OT2 OD026555; IAA #: AOD 16037; Federally Qualified Health Centers: HHSN 263201600085U; Data and Research Center: 5 U2C OD023196; Biobank: 1 U24 OD023121; The Participant Center: U24 OD023176; Participant Technology Systems Center: 1 U24 OD023163; Communications and Engagement: 3 OT2 OD023205; 3 OT2 OD023206; and Community Partners: 1 OT2 OD025277; 3 OT2 OD025315; 1 OT2 OD025337; 1 OT2 OD025276.

In addition, the All of Us Research Program would not be possible without the partnership of its participants, who we gratefully acknowledge for their contributions and without whom this research would not have been possible. We also thank the All of Us Research Program for making the participant data examined in this study available to us.

To the Editor:

Melasma (also known as chloasma) is characterized by symmetric hyperpigmented patches affecting sun-exposed areas. Women commonly develop this condition during pregnancy, suggesting a connection between melasma and increased female sex hormone levels.¹ Other hypothesized risk factors include sun exposure, genetic susceptibility, estrogen and/or progesterone therapy, and thyroid abnormalities but have not been corroborated.² Treatment options are limited because the pathogenesis is poorly understood; thus, we aimed to analyze melasma risk factors using a national database with a nested case-control approach.

We conducted a matched case-control study using the Registered Tier dataset (version 7) from the National Institute of Health’s All of Us Research Program (https://allofus.nih.gov/), which is available to authorized users through the program’s Researcher Workbench and includes more than 413,000 total participants enrolled from May 1, 2018, through July 1, 2022. Cases included patients 18 years and older with a diagnosis of melasma (International Classification of Diseases, Tenth Revision, Clinical Modification code L81.1 [Chloasma]; concept ID 4264234 [Chloasma]; and Systematized Nomenclature of Medicine [SNOMED] code 36209000 [Chloasma]), and controls without a diagnosis of melasma were matched in a 1:10 ratio based on age, sex, and self-reported race. Concept IDs and SNOMED codes were used to identify individuals in each cohort with a diagnosis of alcohol dependence (concept IDs 433753, 435243, 4218106; SNOMED codes 15167005, 66590003, 7200002), depression (concept ID 440383; SNOMED code 35489007), hypothyroidism (concept ID 140673; SNOMED code 40930008), hyperthyroidism (concept ID 4142479; SNOMED code 34486009), anxiety (concept IDs 441542, 442077, 434613; SNOMED codes 48694002, 197480006, 21897009), tobacco dependence (concept IDs 37109023, 437264, 4099811; SNOMED codes 16077091000119107, 89765005, 191887008), or obesity (concept IDs 433736 and 434005; SNOMED codes 414916001 and 238136002), or with a history of radiation therapy (concept IDs 4085340, 4311117, 4061844, 4029715; SNOMED codes 24803000, 85983004, 200861004, 108290001) or hormonal medications containing estrogen and/or progesterone, including oral medications and implants (concept IDs 21602445, 40254009, 21602514, 21603814, 19049228, 21602529, 1549080, 1551673, 1549254, 21602472, 21602446, 21602450, 21602515, 21602566, 21602473, 21602567, 21602488, 21602585, 1596779, 1586808, 21602524). In our case cohort, diagnoses and exposures to treatments were only considered for analysis if they occurred prior to melasma diagnosis.

Multivariate logistic regression was performed to calculate odds ratios and P values between melasma and each comorbidity or exposure to the treatments specified. Statistical significance was set at P<.05.

We identified 744 melasma cases (mean age, 55.20 years; 95.43% female; 12.10% Black) and 7440 controls with similar demographics (ie, age, sex, race/ethnicity) between groups (all P>.05 [Table 1]). Patients with a melasma diagnosis were more likely to have a pre-existing diagnosis of depression (OR, 1.87; 95% CI, 1.51-2.31 [P<.001]) or hypothyroidism (OR, 1.31; 95% CI, 1.04-1.65 [P<.05]), or a history of radiation therapy (OR, 19.08; 95% CI, 10.20-35.69 [P<.001]) and/or estrogen and/or progesterone therapy (OR, 2.01; 95% CI, 1.69-2.40 [P<.001]) prior to melasma diagnosis. A diagnosis of anxiety prior to melasma diagnosis trended toward an association with melasma (P=.067). Pre-existing alcohol dependence, obesity, and hyperthyroidism were not associated with melasma (P=.98, P=.28, and P=.29, respectively). A diagnosis of tobacco dependence was associated with a decreased melasma risk (OR, 0.53, 95% CI, 0.37-0.76)[P<.001])(Table 2).

Our study results suggest that pre-existing depression was a risk factor for subsequent melasma diagnosis. Depression may exacerbate stress, leading to increased activation of the hypothalamic-pituitary-adrenal axis as well as increased levels of cortisol and adrenocorticotropic hormone, which subsequently act on melanocytes to increase melanogenesis.³ A retrospective study of 254 participants, including 127 with melasma, showed that increased melasma severity was associated with higher rates of depression (P=.002)²; however, the risk for melasma following a depression diagnosis has not been reported.

Our results also showed that hypothyroidism was associated with an increased risk for melasma. On a cellular level, hypothyroidism can cause systemic inflammation, potentailly leading to increased stress and melanogenesis via activation of the hypothalamic-pituitary-adrenal axis.⁴ These findings are similar to a systematic review and meta-analysis reporting increased thyroid-stimulating hormone, anti–thyroid peroxidase, and antithyroglobulin antibody levels associated with increased melasma risk (mean difference between cases and controls, 0.33 [95% CI, 0.18-0.47]; pooled association, P=.020; mean difference between cases and controls, 0.28 [95% CI, 0.01-0.55], respectively).⁵

Patients in our cohort who had a history of radiation therapy were 19 times more likely to develop melasma, similar to findings of a survey-based study of 421 breast cancer survivors in which 336 (79.81%) reported hyperpigmentation in irradiated areas.⁶ Patients in our cohort who had a history of estrogen and/or progesterone therapy were 2 times more likely to develop melasma, similar to a case-control study of 207 patients with melasma and 207 controls that showed combined oral contraceptives increased risk for melasma (OR, 1.23 [95% CI, 1.08-1.41; P<.01).³

Tobacco use is not a well-known protective factor against melasma. Prior studies have indicated that tobacco smoking activates melanocytes via the Wnt/β-Catenin pathway, leading to hyperpigmentation.⁷ Although exposure to cigarette smoke decreases angiogenesis and would more likely lead to hyperpigmentation, nicotine exposure has been shown to increase angiogenesis, which could lead to increased blood flow and partially explain the protection against melasma demonstrated in our cohort.⁸ Future studies are needed to explore this relationship.

Limitations of our study include lack of information about melasma severity and information about prior melasma treatment in our cohort as well as possible misdiagnosis reported in the dataset.

Our results demonstrated that pre-existing depression and hypothyroidism as well as a history of radiation or estrogen and/or progesterone therapies are potential risk factors for melasma. Therefore, we recommend that patients with melasma be screened for depression and thyroid dysfunction, and patients undergoing radiation therapy or starting estrogen and/or progesterone therapy should be counseled on their increased risk for melasma. Future studies are needed to determine whether treatment of comorbidities such as hypothyroidism and depression improve melasma severity. The decreased risk for melasma associated with tobacco use also requires further investigation.

Acknowledgments—The All of Us Research Program is supported by the National Institutes of Health, Office of the Director: Regional Medical Centers: 1 OT2 OD026549; 1 OT2 OD026554; 1 OT2 OD026557; 1 OT2 OD026556; 1 OT2 OD026550; 1 OT2 OD 026552; 1 OT2 OD026553; 1 OT2 OD026548; 1 OT2 OD026551; 1 OT2 OD026555; IAA #: AOD 16037; Federally Qualified Health Centers: HHSN 263201600085U; Data and Research Center: 5 U2C OD023196; Biobank: 1 U24 OD023121; The Participant Center: U24 OD023176; Participant Technology Systems Center: 1 U24 OD023163; Communications and Engagement: 3 OT2 OD023205; 3 OT2 OD023206; and Community Partners: 1 OT2 OD025277; 3 OT2 OD025315; 1 OT2 OD025337; 1 OT2 OD025276.

In addition, the All of Us Research Program would not be possible without the partnership of its participants, who we gratefully acknowledge for their contributions and without whom this research would not have been possible. We also thank the All of Us Research Program for making the participant data examined in this study available to us.

The Comparison

A A 25-year-old man of Hispanic ethnicity with pink papules, pustules, and large keloidal tumors on the occipital scalp characteristic of acne keloidalis nuchae (AKN). There is hair loss and some tufting of remaining hairs.

B A 17-year-old adolescent boy of African descent with small papules on the occipital scalp and some hair loss from AKN.

C A 19-year-old man of African descent with extensive papules and keloidal tumors on the occipital scalp as well as scarring hair loss and tufting of hairs from AKN.

Acne keloidalis nuchae (AKN) is a chronic inflammatory condition commonly affecting the occipital scalp and posterior neck. It causes discrete or extensive fibrosing papules that may coalesce to form pronounced ­tumorlike masses^1,2 with scarring alopecia (Figure, A–C).³ Pustules, hair tufts, secondary bacterial infections, abscesses, and sinus tracts also may occur.¹ The pathogenesis of AKN has been characterized as varying stages of follicular inflammation at the infundibular and isthmus levels followed by fibrotic occlusion of the ­follicular lumen.⁴ Pruritus, pain, bleeding, oozing, and a feeling of scalp tightness may occur.^1,5

Umar et al⁶ performed a retrospective review of 108 men with AKN—58% of African descent, 37% Hispanic, 3% Asian, and 2% Middle Eastern—and proposed a 3-tier classification system for AKN. Tier 1 focused on the distribution and sagittal spread of AKN lesions between the clinical demarcation lines of the occipital notch and posterior hairline. Tier 2 focused on the type of lesions present—discrete papules or nodules, coalescing/abutting lesions, plaques (raised, atrophic, or indurated), or dome-shaped tumoral masses. Tier 3 focused on the presence or absence of co-existing dissecting cellulitis or folliculitis decalvans.⁶

Epidemiology

Acne keloidalis nuchae primarily manifests in adolescent and adult men of African or Afro-Caribbean descent.⁷ Among African American men, the prevalence of AKN ranges from 0.5% to 13.6%.⁸ Similar ranges have been reported among Nigerian, South African, and West African men.¹ Acne keloidalis nuchae also affects Asian and Hispanic men but rarely is seen in non-Hispanic White men or in women of any ethnicity.^9,10 The male to female ratio is 20:1.^1,11 Hair texture, hairstyling practices such as closely shaved or faded haircuts, and genetics likely contribute to development of AKN. Sports and occupations that require the use of headgear or a tight collar may increase the risk for AKN.¹²

Key clinical features in people with darker skin tones

• The lesions of AKN range in color from pink to dark brown or black. Postinflammatory hyperpigmentation or hyperchromia may be present around AKN lesions.
• Chronicity of AKN may lead to extended use of high-potency topical or intralesional corticosteroids, which causes transient or long-lasting hypopigmentation, especially in those with darker skin tones.

Worth noting

• Acne keloidalis nuchae can be disfiguring, which negatively impacts quality of life and self-esteem.¹²
• Some occupations (eg, military, police) have hair policies that may not be favorable to those with or at risk for AKN.
• Patients with AKN are 2 to 3 times more likely to present with metabolic syndrome, hypertension, type 2 diabetes mellitus, or obesity.¹³

Treatment

There are no treatments approved by the US Food and Drug Administration specifically for AKN. Treatment approaches are based on the pathophysiology, secondary impacts on the skin, and disease severity. Growing out the hair may prevent worsening and/or decrease the risk for new lesions.⁶

• Options include but are not limited to topical and systemic therapies (eg, topical corticosteroids, oral or topical antibiotics, isotretinoin, topical retinoids, imiquimod, pimecrolimus), light devices (eg, phototherapy, laser), ablative therapies (eg, laser, cryotherapy, radiotherapy), and surgery (eg, excision, follicular unit excision), often in combination.^6,14,15
• Intralesional triamcinolone injections are considered standard of care. Adotama et al¹⁶ found that injecting ­triamcinolone into the deep dermis in the area of flat or papular AKN yielded better control of inflammation and decreased appearance of lesions compared with injecting individual lesions.
• For extensive AKN lesions that do not respond to ­less-invasive therapies, consider surgical techniques,^6,17 such as follicular unit excision¹⁸ and more extensive surgical excisions building on approaches from pioneers Drs. John Kenney and Harold Pierce.¹⁹ An innovative surgical approach for removal of large AKNs is the bat excision technique—wound shape resembles a bat in a spread-eagled position—with secondary intention healing with or without debridement and/or tension sutures. The resulting linear scar acts as a new posterior hair line.²⁰

Health disparity highlights

Access to a dermatologic or plastic surgeon with expertise in the surgical treatment of large AKNs may be challenging but is needed to reduce risk for recurrence and adverse events.

Close-cropped haircuts on the occipital scalp, which are particularly popular among men of African descent, increase the risk for AKN.⁵ Although this grooming style may be a personal preference, other hairstyles commonly worn by those with tightly coiled hair may be deemed “unprofessional” in society or the workplace,²¹ which leads to hairstyling practices that may increase the risk for AKN.

Acne keloidalis nuchae remains an understudied entity that adversely affects patients with skin of color.

The Comparison

A A 25-year-old man of Hispanic ethnicity with pink papules, pustules, and large keloidal tumors on the occipital scalp characteristic of acne keloidalis nuchae (AKN). There is hair loss and some tufting of remaining hairs.

B A 17-year-old adolescent boy of African descent with small papules on the occipital scalp and some hair loss from AKN.

C A 19-year-old man of African descent with extensive papules and keloidal tumors on the occipital scalp as well as scarring hair loss and tufting of hairs from AKN.

Acne keloidalis nuchae (AKN) is a chronic inflammatory condition commonly affecting the occipital scalp and posterior neck. It causes discrete or extensive fibrosing papules that may coalesce to form pronounced ­tumorlike masses^1,2 with scarring alopecia (Figure, A–C).³ Pustules, hair tufts, secondary bacterial infections, abscesses, and sinus tracts also may occur.¹ The pathogenesis of AKN has been characterized as varying stages of follicular inflammation at the infundibular and isthmus levels followed by fibrotic occlusion of the ­follicular lumen.⁴ Pruritus, pain, bleeding, oozing, and a feeling of scalp tightness may occur.^1,5

Umar et al⁶ performed a retrospective review of 108 men with AKN—58% of African descent, 37% Hispanic, 3% Asian, and 2% Middle Eastern—and proposed a 3-tier classification system for AKN. Tier 1 focused on the distribution and sagittal spread of AKN lesions between the clinical demarcation lines of the occipital notch and posterior hairline. Tier 2 focused on the type of lesions present—discrete papules or nodules, coalescing/abutting lesions, plaques (raised, atrophic, or indurated), or dome-shaped tumoral masses. Tier 3 focused on the presence or absence of co-existing dissecting cellulitis or folliculitis decalvans.⁶

Epidemiology

Acne keloidalis nuchae primarily manifests in adolescent and adult men of African or Afro-Caribbean descent.⁷ Among African American men, the prevalence of AKN ranges from 0.5% to 13.6%.⁸ Similar ranges have been reported among Nigerian, South African, and West African men.¹ Acne keloidalis nuchae also affects Asian and Hispanic men but rarely is seen in non-Hispanic White men or in women of any ethnicity.^9,10 The male to female ratio is 20:1.^1,11 Hair texture, hairstyling practices such as closely shaved or faded haircuts, and genetics likely contribute to development of AKN. Sports and occupations that require the use of headgear or a tight collar may increase the risk for AKN.¹²

Key clinical features in people with darker skin tones

• The lesions of AKN range in color from pink to dark brown or black. Postinflammatory hyperpigmentation or hyperchromia may be present around AKN lesions.
• Chronicity of AKN may lead to extended use of high-potency topical or intralesional corticosteroids, which causes transient or long-lasting hypopigmentation, especially in those with darker skin tones.

Worth noting

• Acne keloidalis nuchae can be disfiguring, which negatively impacts quality of life and self-esteem.¹²
• Some occupations (eg, military, police) have hair policies that may not be favorable to those with or at risk for AKN.
• Patients with AKN are 2 to 3 times more likely to present with metabolic syndrome, hypertension, type 2 diabetes mellitus, or obesity.¹³

Treatment

There are no treatments approved by the US Food and Drug Administration specifically for AKN. Treatment approaches are based on the pathophysiology, secondary impacts on the skin, and disease severity. Growing out the hair may prevent worsening and/or decrease the risk for new lesions.⁶

• Options include but are not limited to topical and systemic therapies (eg, topical corticosteroids, oral or topical antibiotics, isotretinoin, topical retinoids, imiquimod, pimecrolimus), light devices (eg, phototherapy, laser), ablative therapies (eg, laser, cryotherapy, radiotherapy), and surgery (eg, excision, follicular unit excision), often in combination.^6,14,15
• Intralesional triamcinolone injections are considered standard of care. Adotama et al¹⁶ found that injecting ­triamcinolone into the deep dermis in the area of flat or papular AKN yielded better control of inflammation and decreased appearance of lesions compared with injecting individual lesions.
• For extensive AKN lesions that do not respond to ­less-invasive therapies, consider surgical techniques,^6,17 such as follicular unit excision¹⁸ and more extensive surgical excisions building on approaches from pioneers Drs. John Kenney and Harold Pierce.¹⁹ An innovative surgical approach for removal of large AKNs is the bat excision technique—wound shape resembles a bat in a spread-eagled position—with secondary intention healing with or without debridement and/or tension sutures. The resulting linear scar acts as a new posterior hair line.²⁰

Health disparity highlights

Access to a dermatologic or plastic surgeon with expertise in the surgical treatment of large AKNs may be challenging but is needed to reduce risk for recurrence and adverse events.

Close-cropped haircuts on the occipital scalp, which are particularly popular among men of African descent, increase the risk for AKN.⁵ Although this grooming style may be a personal preference, other hairstyles commonly worn by those with tightly coiled hair may be deemed “unprofessional” in society or the workplace,²¹ which leads to hairstyling practices that may increase the risk for AKN.

Acne keloidalis nuchae remains an understudied entity that adversely affects patients with skin of color.

The Comparison

A A 25-year-old man of Hispanic ethnicity with pink papules, pustules, and large keloidal tumors on the occipital scalp characteristic of acne keloidalis nuchae (AKN). There is hair loss and some tufting of remaining hairs.

B A 17-year-old adolescent boy of African descent with small papules on the occipital scalp and some hair loss from AKN.

C A 19-year-old man of African descent with extensive papules and keloidal tumors on the occipital scalp as well as scarring hair loss and tufting of hairs from AKN.

Acne keloidalis nuchae (AKN) is a chronic inflammatory condition commonly affecting the occipital scalp and posterior neck. It causes discrete or extensive fibrosing papules that may coalesce to form pronounced ­tumorlike masses^1,2 with scarring alopecia (Figure, A–C).³ Pustules, hair tufts, secondary bacterial infections, abscesses, and sinus tracts also may occur.¹ The pathogenesis of AKN has been characterized as varying stages of follicular inflammation at the infundibular and isthmus levels followed by fibrotic occlusion of the ­follicular lumen.⁴ Pruritus, pain, bleeding, oozing, and a feeling of scalp tightness may occur.^1,5

Umar et al⁶ performed a retrospective review of 108 men with AKN—58% of African descent, 37% Hispanic, 3% Asian, and 2% Middle Eastern—and proposed a 3-tier classification system for AKN. Tier 1 focused on the distribution and sagittal spread of AKN lesions between the clinical demarcation lines of the occipital notch and posterior hairline. Tier 2 focused on the type of lesions present—discrete papules or nodules, coalescing/abutting lesions, plaques (raised, atrophic, or indurated), or dome-shaped tumoral masses. Tier 3 focused on the presence or absence of co-existing dissecting cellulitis or folliculitis decalvans.⁶

Epidemiology

Acne keloidalis nuchae primarily manifests in adolescent and adult men of African or Afro-Caribbean descent.⁷ Among African American men, the prevalence of AKN ranges from 0.5% to 13.6%.⁸ Similar ranges have been reported among Nigerian, South African, and West African men.¹ Acne keloidalis nuchae also affects Asian and Hispanic men but rarely is seen in non-Hispanic White men or in women of any ethnicity.^9,10 The male to female ratio is 20:1.^1,11 Hair texture, hairstyling practices such as closely shaved or faded haircuts, and genetics likely contribute to development of AKN. Sports and occupations that require the use of headgear or a tight collar may increase the risk for AKN.¹²

Key clinical features in people with darker skin tones

• The lesions of AKN range in color from pink to dark brown or black. Postinflammatory hyperpigmentation or hyperchromia may be present around AKN lesions.
• Chronicity of AKN may lead to extended use of high-potency topical or intralesional corticosteroids, which causes transient or long-lasting hypopigmentation, especially in those with darker skin tones.

Worth noting

• Acne keloidalis nuchae can be disfiguring, which negatively impacts quality of life and self-esteem.¹²
• Some occupations (eg, military, police) have hair policies that may not be favorable to those with or at risk for AKN.
• Patients with AKN are 2 to 3 times more likely to present with metabolic syndrome, hypertension, type 2 diabetes mellitus, or obesity.¹³

Treatment

There are no treatments approved by the US Food and Drug Administration specifically for AKN. Treatment approaches are based on the pathophysiology, secondary impacts on the skin, and disease severity. Growing out the hair may prevent worsening and/or decrease the risk for new lesions.⁶

• Options include but are not limited to topical and systemic therapies (eg, topical corticosteroids, oral or topical antibiotics, isotretinoin, topical retinoids, imiquimod, pimecrolimus), light devices (eg, phototherapy, laser), ablative therapies (eg, laser, cryotherapy, radiotherapy), and surgery (eg, excision, follicular unit excision), often in combination.^6,14,15
• Intralesional triamcinolone injections are considered standard of care. Adotama et al¹⁶ found that injecting ­triamcinolone into the deep dermis in the area of flat or papular AKN yielded better control of inflammation and decreased appearance of lesions compared with injecting individual lesions.
• For extensive AKN lesions that do not respond to ­less-invasive therapies, consider surgical techniques,^6,17 such as follicular unit excision¹⁸ and more extensive surgical excisions building on approaches from pioneers Drs. John Kenney and Harold Pierce.¹⁹ An innovative surgical approach for removal of large AKNs is the bat excision technique—wound shape resembles a bat in a spread-eagled position—with secondary intention healing with or without debridement and/or tension sutures. The resulting linear scar acts as a new posterior hair line.²⁰

Health disparity highlights

Access to a dermatologic or plastic surgeon with expertise in the surgical treatment of large AKNs may be challenging but is needed to reduce risk for recurrence and adverse events.

Close-cropped haircuts on the occipital scalp, which are particularly popular among men of African descent, increase the risk for AKN.⁵ Although this grooming style may be a personal preference, other hairstyles commonly worn by those with tightly coiled hair may be deemed “unprofessional” in society or the workplace,²¹ which leads to hairstyling practices that may increase the risk for AKN.

Acne keloidalis nuchae remains an understudied entity that adversely affects patients with skin of color.

Vitamin D (VD) regulates keratinocyte proliferation and differentiation, modulates inflammatory pathways, and protects against cellular damage in the skin. ¹ In the setting of tissue injury and acute skin inflammation, active vitamin D—1,25(OH) ₂ D—suppresses signaling from pro-inflammatory chemokines and cytokines such as IFN- γ and IL-17. ^2,3 This suppression reduces proliferation of helper T cells (T _H 1, T _H 17) and B cells, decreasing tissue damage from reactive oxygen species release while enhancing secretion of the anti-inflammatory cytokine IL-10 by antigen-presenting cells. ^2-4

Suboptimal VD levels have been associated with numerous health consequences including malignancy, prompting interest in VD supplementation for improving cancer-related outcomes.⁵ Beyond disease prognosis, high-dose VD supplementation has been suggested as a potential therapy for adverse events (AEs) related to cancer treatments. In one study, mice that received oral vitamin D₃ supplementation of 11,500 IU/kg daily had fewer doxorubicin-induced cardiotoxic effects on ejection fraction (P<.0001) and stroke volume (P<.01) than mice that received VD supplementation of 1500 IU/kg daily.⁶

In this review, we examine the impact of chemoradiation on 25(OH)D levels—which more accurately reflects VD stores than 1,25(OH)₂D levels—and the impact of suboptimal VD on cutaneous toxicities related to chemoradiation. To define the suboptimal VD threshold, we used the Endocrine Society’s clinical practice guidelines, which characterize suboptimal 25(OH)D levels as insufficiency (21–29 ng/mL [52.5–72.5 nmol/L]) or deficiency (<20 ng/mL [50 nmol/L])⁷; deficiency can be further categorized as severe deficiency (<12 ng/mL [30 nmol/L]).⁸ This review also evaluates the evidence for vitamin D₃ supplementation to alleviate the cutaneous AEs of chemotherapy and radiation treatments.

Effects of Chemotherapy on Vitamin D Levels

A high prevalence of VD deficiency is seen in various cancers. In a retrospective review of 25(OH)D levels in 2098 adults with solid tumors of any stage (6% had metastatic disease [n=124]), suboptimal levels were found in 69% of patients with breast cancer (n=617), 75% with colorectal cancer (n=84), 72% with gynecologic cancer (n=65), 79% with kidney and bladder cancer (n=145), 83% with pancreatic and upper gastrointestinal tract cancer (n=178), 73% with lung cancer (n=73), 69% with prostate cancer (n=225), 61% with skin cancer (n=399), and 63% with thyroid cancer (n=172).⁵ Suboptimal VD also has been found in hematologic malignancies. In a prospective cohort study, mean serum 25(OH)D levels in 23 patients with recently diagnosed acute myeloid leukemia demonstrated VD deficiency (mean [SD], 18.6 [6.6] nmol/L).⁹ Given that many patients already exhibit a baseline VD deficiency at cancer diagnosis, it is important to understand the relationship between VD and cancer treatment modalities.⁵

In the United States, breast and colorectal cancers were estimated to be the first and fourth most common cancers, with 313,510 and 152,810 predicted new cases in 2024, respectively.¹⁰ This review will focus on breast and colorectal cancer when describing VD variation associated with chemotherapy exposure due to their high prevalence.

Effects of Chemotherapy on Vitamin D Levels in Breast Cancer—Breast cancer studies have shown suboptimal VD levels in 76% of females 75 years or younger with any T1, T2, or T3; N0 or N1; and M0 breast cancer, in which 38.5% (n=197) had insufficient and 37.5% (n=192) had deficient 25(OH)D levels.¹¹ In a study of female patients with primary breast cancer (stage I, II, or III and T1 with high Ki67 expression [≥30%], T2, or T3), VD deficiency was seen in 60% of patients not receiving VD supplementation.^12,13 A systematic review that included 7 studies of different types of breast cancer suggested that circulating 25(OH)D may be associated with improved prognosis.¹⁴ Thus, studies have investigated risk factors associated with poor or worsening VD status in individuals with breast cancer, including exposure to chemotherapy and/or radiation treatment.^12,15-18

A prospective cohort study assessed 25(OH)D levels in 95 patients with any breast cancer (stages I, II, IIIA, IIIB) before and after initiating chemotherapy with docetaxel, doxorubicin, epirubicin, 5-fluorouracil, or cyclophosphamide, compared with a group of 52 females without cancer.¹⁷ In the breast cancer group, approximately 80% (76/95) had suboptimal and 50% (47/95) had deficient VD levels before chemotherapy initiation (mean [SD], 54.1 [22.8] nmol/L). In the comparison group, 60% (31/52) had suboptimal and 30% (15/52) had deficient VD at baseline (mean [SD], 66.1 [23.5] nmol/L), which was higher than the breast cancer group (P=.03). A subgroup analysis excluded participants who started, stopped, or lacked data on dietary supplements containing VD (n=39); in the remaining 56 participants, a significant decrease in 25(OH)D levels was observed shortly after finishing chemotherapy compared with the prechemotherapy baseline value (mean, −7.9 nmol/L; P=.004). Notably, 6 months after chemotherapy completion, 25(OH)D levels increased (mean, +12.8 nmol/L; P<.001). Vitamin D levels remained stable in the comparison group (P=.987).¹⁷

Consistent with these findings, a cross-sectional study assessing VD status in 394 female patients with primary breast cancer (stage I, II, or III and T1 with high Ki67 expression [≥30%], T2, or T3), found that a history of chemotherapy was associated with increased odds of 25(OH)D levels less than 20 ng/mL compared with breast cancer patients with no prior chemotherapy (odds ratio, 1.86; 95% CI, 1.03-3.38).¹² Although the study data included chemotherapy history, no information was provided on specific chemotherapy agents or regimens used in this cohort, limiting the ability to detect the drugs most often implicated.

Both studies indicated a complex interplay between chemotherapy and VD levels in breast cancer patients. Although Kok et al¹⁷ suggested a transient decrease in VD levels during chemotherapy with a subsequent recovery after cessation, Fassio et al¹² highlighted the increased odds of VD deficiency associated with chemotherapy. Ultimately, larger randomized controlled trials are needed to better understand the relationship between chemotherapy and VD status in breast cancer patients.

Effects of Chemotherapy on Vitamin D Levels in Colorectal Cancer—Similar to patterns seen in breast cancer, a systematic review with 6 studies of different types of colorectal cancer suggested that circulating 25(OH)D levels may be associated with prognosis.¹⁴ Studies also have investigated the relationship between colorectal chemotherapy regimens and VD status.^15,16,18,19

A retrospective study assessed 25(OH)D levels in 315 patients with any colorectal cancer (stage I–IV).¹⁵ Patients were included in the analysis if they received less than 400 IU daily of VD supplementation at baseline. For the whole study sample, the mean (SD) VD level was 23.7 (13.71) ng/mL. Patients who had not received chemotherapy within 3 months of the VD level assessment were categorized as the no chemotherapy group, and the others were designated as the chemotherapy group; the latter group was exposed to various chemotherapy regimens, including combinations of irinotecan, oxaliplatin, 5-fluorouracil, leucovorin, bevacizumab, or cetuximab. Multivariate analysis showed that the chemotherapy group was 3.7 times more likely to have very low VD levels (≤15 ng/mL) compared with those in the no chemotherapy group (P<.0001).¹⁵

A separate cross-sectional study examined serum 25(OH)D concentrations in 1201 patients with any newly diagnosed colorectal carcinoma (stage I–III); 91% of cases were adenocarcinoma.¹⁸ In a multivariate analysis, chemotherapy plus surgery was associated with lower VD levels than surgery alone 6 months after diagnosis (mean, −8.74 nmol/L; 95% CI, −11.30 to −6.18 nmol/L), specifically decreasing by a mean of 6.7 nmol/L (95% CI, −9.8 to −3.8 nmol/L) after adjusting for demographic and lifestyle factors.¹⁸ However, a prospective cohort study demonstrated different findings.¹⁹ Comparing 58 patients with newly diagnosed colorectal adenocarcinoma (stages I–IV) who underwent chemotherapy and 36 patients who did not receive chemotherapy, there was no significant change in 25(OH)D levels from the time of diagnosis to 6 months later. Median VD levels decreased by 0.7 ng/mL in those who received chemotherapy, while a minimal (and not significant) increase of 1.6 ng/mL was observed in those without chemotherapy intervention (P=.26). Notably, supplementation was not restricted in this cohort, which may have resulted in higher VD levels in those taking supplements.¹⁹

Since time of year and geographic location can influence VD levels, one prospective cohort study controlled for differential sun exposure due to these factors in their analysis.¹⁶ Assessment of 25(OH)D levels was completed in 81 chemotherapy-naïve cancer patients immediately before beginning chemotherapy as well as 6 and 12 weeks into treatment. More than 8 primary cancer types were represented in this study, with breast (34% [29/81]) and colorectal (14% [12/81]) cancer being the most common, but the cancer stages of the participants were not detailed. Vitamin D levels decreased after commencing chemotherapy, with the largest drop occurring 6 weeks into treatment. From the 6- to 12-week end points, VD increased but remained below the original baseline level (baseline: mean [SD], 49.2 [22.3] nmol/L; 6 weeks: mean [SD], 40.9 [19.0] nmol/L; 12 weeks: mean [SD], 45.9 [19.7] nmol/L; P=.05).¹⁶

Although focused on breast and colorectal cancers, these studies suggest that various chemotherapy regimens may confer a higher risk for VD deficiency compared with VD status at diagnosis and/or prior to chemotherapy treatment. However, most of these studies only discussed stage-based differences, excluding analysis of the variety of cancer subtypes that comprise breast and colorectal malignancies, which may limit our ability to extrapolate from these data. Ultimately, larger randomized controlled trials are needed to better understand the relationship between chemotherapy and VD status across various primary cancer types.

Effects of Radiation Therapy on Vitamin D Levels

Unlike chemotherapy, studies on the association between radiation therapy and VD levels are minimal, with most reports in the literature discussing the use of VD to potentiate the effects of radiation therapy. In one cross-sectional analysis of 1201 patients with newly diagnosed stage I, II, or III colorectal cancer of any type (94% were adenocarcinoma), radiation plus surgery was associated with slightly lower 25(OH)D levels than surgery alone for tumor treatment 6 months after diagnosis (mean, −3.17; 95% CI, −6.07 to −0.28 nmol/L). However, after adjustment for demographic and lifestyle factors, this decrease in VD levels attributable to radiotherapy was not statistically significant compared with the surgery-only cohort (mean, −1.78; 95% CI, −5.07 to 1.52 nmol/L).¹⁸

Similarly, a cross-sectional study assessing VD status in 394 female patients with primary breast cancer (stage I, II, or III and T1 with high Ki67 expression [≥30%], T2, or T3), found that a history of radiotherapy was not associated with a difference in serum 25(OH)D levels compared with those with breast cancer without prior radiotherapy (odds ratio, 0.90; 95% CI, 0.52-1.54).¹² From the limited existing literature specifically addressing variations of VD levels with radiation, radiation therapy does not appear to significantly impact VD levels.

Vitamin D Levels and the Severity of Chemotherapy- or Radiation Therapy–Induced AEs

A prospective cohort of 241 patients did not find an increase in the incidence or severity of chemotherapy-induced cutaneous toxicities in those with suboptimal 1,25(OH)₂D₃ levels (≤75 nmol/L).²⁰ Eight different primary cancer types were represented, including breast and colorectal cancer; the tumor stages of the participants were not detailed. Forty-one patients had normal 1,25(OH)₂D₃ levels, while the remaining 200 had suboptimal levels. There was no significant association between serum VD levels and the following dermatologic toxicities: desquamation (P=.26), xerosis (P=.15), mucositis (P=.30), or painful rash (P=.87). Surprisingly, nail changes and hand-foot reactions occurred with greater frequency in patients with normal VD levels (P=.01 and P=.03, respectively).²⁰ Hand-foot reaction is part of the toxic erythema of chemotherapy (TEC) spectrum, which is comprised of a range of cytotoxic skin injuries that typically manifest within 2 to 3 weeks of exposure to the offending chemotherapeutic agents, often characterized by erythema, pain, swelling, and blistering, particularly in intertriginous and acral areas.^21-23 Recovery from TEC generally takes at least 2 to 4 weeks and may necessitate cessation of the offending chemotherapeutic agent.^21,24 Notably, this study measured 1,25(OH)₂D₃ levels instead of 25(OH)D levels, which may not reliably indicate body stores of VD.^7,20 These results underscore the complex nature between chemotherapy and VD; however, VD levels alone do not appear to be a sufficient biomarker for predicting chemotherapy-associated cutaneous AEs.

Interestingly, radiation therapy–induced AEs may be associated with VD levels. A prospective cohort study of 98 patients with prostate, bladder, or gynecologic cancers (tumor stages were not detailed) undergoing pelvic radiotherapy found that females and males with 25(OH)D levels below a threshold of 35 and 40 nmol/L, respectively, were more likely to experience higher Radiation Therapy Oncology Group (RTOG) grade acute proctitis compared with those with VD above these thresholds.²⁵ Specifically, VD below these thresholds was associated with increased odds of RTOG grade 2 or higher radiation-induced proctitis (OR, 3.07; 95% CI, 1.27-7.50 [P=.013]). Additionally, a weak correlation was noted between VD below these thresholds and the RTOG grade, with a Spearman correlation value of −0.189 (P=.031).²⁵

One prospective cohort study included 28 patients with any cancer of the oral cavity, oropharynx, hypopharynx, or larynx stages II, III, or IVA; 93% (26/28) were stage III or IVA.²⁶ The 20 (71%) patients with suboptimal 25(OH)D levels (≤75 nmol/L) experienced a higher prevalence of grade II radiation dermatitis compared with the 8 (29%) patients with optimal VD levels (χ²₂=5.973; P=.0505). This pattern persisted with the severity of mucositis; patients from the suboptimal VD group presented with higher rates of grades II and III mucositis compared with the VD optimal group (χ²₂=13.627; P=.0011).²⁶ Recognizing the small cohort evaluated in the study, we highlight the importance of further studies to clarify these associations.

Chemotherapy-Induced Cutaneous Events Treated with High-Dose Vitamin D

Chemotherapeutic agents are known to induce cellular damage, resulting in a range of cutaneous AEs that can invoke discontinuation of otherwise effective chemotherapeutic interventions.^27,28 Recent research has explored the potential of high-dose vitamin D₃ as a therapeutic agent to mitigate cutaneous reactions.^29,30

A randomized, double-blind, placebo-controlled trial investigated the use of a single high dose of oral ­25(OH)D to treat topical nitrogen mustard (NM)–induced rash.²⁹ To characterize baseline inflammatory responses from NM injury without intervention, clinical measures, serum studies, and tissue analyses from skin biopsies were performed on 28 healthy adults after exposure to topical NM—a chemotherapeutic agent classified as a DNA alkylator. Two weeks later, participants were exposed to topical NM a second time and were split into 2 groups: 14 patients received a single 200,000-IU dose of oral 25(OH)D while the other 14 participants were given a placebo. Using the inflammatory markers induced from baseline exposure to NM alone, posttreatment analysis revealed that the punch biopsies from the 25(OH)D group expressed fewer NM-induced inflammatory markers compared with the placebo group at both 72 hours and 6 weeks following NM injury (72 hours: 12 vs 17 inflammatory markers; 6 weeks: 4 vs 11 inflammatory markers). Notably, NM inflammatory markers were enriched for IL-17 signaling pathways in the placebo biopsies but not in the 25(OH)D intervention group. This study also identified mild and severe patterns of inflammatory responses to NM that were independent of the 25(OH)D intervention. Biomarkers specific to skin biopsies from participants with the severe response included CCL20, CCL2, and CXCL8 (adjusted P<.05). At 6 weeks posttreatment, the 25(OH)D group showed a 67% reduction in NM injury markers compared with a 35% reduction in the placebo group. Despite a reduction in tissue inflammatory markers, there were no clinically significant changes observed in skin redness, swelling, or histologic structure when comparing the 25(OH)D- supplemented group to the placebo group at any time during the study, necessitating further research into the mechanistic roles of high doses VD supplementation.²⁹

Although Ernst et al²⁹ did not observe any clinically significant improvements with VD treatment, a case series of 6 patients with either glioblastoma multiforme, acute myeloid leukemia, or aplastic anemia did demonstrate clinical improvement of TEC after receiving high-dose vitamin D₃.³⁰ The mean time to onset of TEC was noted at 8.5 days following administration of the inciting chemotherapeutic agent, which included combinations of anthracycline, antimetabolite, kinase inhibitor, B-cell lymphoma 2 inhibitor, purine analogue, and alkylating agents. A combination of clinical and histologic findings was used to diagnose TEC. Baseline 25(OH)D levels were not established prior to treatment. The treatment regimen for 1 patient included 2 doses of 50,000 IU of VD spaced 1 week apart, totaling 100,000 IU, while the remaining 5 patients received a total of 200,000 IU, also split into 2 doses given 1 week apart. All patients received their first dose of VD within a week of the cutaneous eruption. Following the initial VD dose, there was a notable improvement in pain, pruritus, or swelling by the next day. Reduction in erythema also was observed within 1 to 4 days.³⁰

No AEs associated with VD supplementation were reported, suggesting a potential beneficial role of high-dose VD in accelerating recovery from chemotherapy-induced rashes without evident safety concerns.

Radiation Therapy–Induced Cutaneous Events Treated with High-Dose Vitamin D

Radiation dermatitis is a common and often severe complication of radiation therapy that affects more than 90% of patients undergoing treatment, with half of these individuals experiencing grade 2 toxicity, according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events.^31,32 Radiation damage to basal keratinocytes and hair follicle stem cells disrupts the renewal of the skin’s outer layer, while a surge of free radicals causes irreversible DNA damage.³³ Symptoms of radiation dermatitis can vary from mild pink erythema to tissue ulceration and necrosis, typically within 1 to 4 weeks of radiation exposure.³⁴ The resulting dermatitis can take 2 to 4 weeks to heal, notably impacting patient quality of life and often necessitating modifications or interruptions in cancer therapy.³³

Prior studies have demonstrated the use of high-dose VD to improve the healing of UV-irradiated skin. A randomized controlled trial investigated high-dose vitamin D₃ to treat experimentally induced sunburn in 20 healthy adults. Compared with those who received a placebo, participants receiving the oral dose of 200,000 IU of vitamin D₃ demonstrated suppression of the pro-inflammatory mediators tumor necrosis factor α (P=.04) and inducible nitric oxide synthase (P=.02), while expression of tissue repair enhancer arginase 1 was increased (P<.005).³⁵ The mechanism of this enhanced tissue repair was investigated using a mouse model, in which intraperitoneal 25(OH)D was administered following severe UV-induced skin injury. On immunofluorescence microscopy, mice treated with VD showed enhanced autophagy within the macrophages infiltrating UV-irradiated skin.³⁶ The use of high-dose VD to treat UV-irradiated skin in these studies established a precedent for using VD to heal cutaneous injury caused by ionizing radiation therapy.

Some studies have focused on the role of VD for treating acute radiation dermatitis. A study of 23 patients with ductal carcinoma in situ or localized invasive ductal carcinoma breast cancer compared the effectiveness of topical calcipotriol to that of a standard hydrating ointment.³⁷ Participants were randomized to 1 of 2 treatments before starting adjuvant radiotherapy to evaluate their potential in preventing radiation dermatitis. In 87% (20/23) of these patients, no difference in skin reaction was observed between the 2 treatments, suggesting that topical VD application may not offer any advantage over the standard hydrating ointment for the prevention of radiation dermatitis.³⁷

Benefits of high-dose oral VD for treating radiation dermatitis also have been reported. Nguyen et al³⁸ documented 3 cases in which patients with neuroendocrine carcinoma of the pancreas, tonsillar carcinoma, and breast cancer received 200,000 IU of oral ergocalciferol distributed over 2 doses given 7 days apart for radiation dermatitis. These patients experienced substantial improvements in pain, swelling, and redness within a week of the initial dose. Additionally, a case of radiation recall dermatitis, which occurred a week after vinorelbine chemotherapy, was treated with 2 doses totaling 100,000 IU of oral ergocalciferol. This patient also had improvement in pain and swelling but continued to have tumor-related induration and ulceration.³⁹

Although topical VD did not show significant benefits over standard treatments for radiation dermatitis, high-dose oral VD appears promising in improving patient outcomes of pain and swelling more rapidly than current practices. Further research is needed to confirm these findings and establish standardized treatment protocols.

Final Thoughts

Suboptimal VD levels are prevalent in numerous cancer types. Chemotherapy often is associated with acute, potentially transient worsening of VD status in patients with breast and colorectal cancer. Although 25(OH)D levels have not corresponded with increased frequency of ­chemotherapy-related dermatologic AEs, suboptimal 25(OH)D levels appear to be associated with increased severity of radiation-induced mucositis and dermatitis.^20,25,26 The use of high-dose VD as a therapeutic agent shows promise in mitigating chemotherapy-induced and radiation therapy–induced rashes in multiple cancer types with reduction of inflammatory markers and a durable anti-inflammatory impact. Although the mechanisms of cellular injury vary among chemotherapeutic agents, the anti-inflammatory and tissue repair properties of VD may make it an effective treatment for chemotherapy-induced cutaneous damage regardless of injury mechanism.^2-4,35 However, reports of clinical improvement vary, and further objective studies to classify optimal dosing, administration, and outcome measures are needed. The absence of reported AEs associated with high-dose VD supplementation is encouraging, but selection of a safe and optimal dosing regimen can only occur with dedicated clinical trials.

Vitamin D (VD) regulates keratinocyte proliferation and differentiation, modulates inflammatory pathways, and protects against cellular damage in the skin. ¹ In the setting of tissue injury and acute skin inflammation, active vitamin D—1,25(OH) ₂ D—suppresses signaling from pro-inflammatory chemokines and cytokines such as IFN- γ and IL-17. ^2,3 This suppression reduces proliferation of helper T cells (T _H 1, T _H 17) and B cells, decreasing tissue damage from reactive oxygen species release while enhancing secretion of the anti-inflammatory cytokine IL-10 by antigen-presenting cells. ^2-4

Suboptimal VD levels have been associated with numerous health consequences including malignancy, prompting interest in VD supplementation for improving cancer-related outcomes.⁵ Beyond disease prognosis, high-dose VD supplementation has been suggested as a potential therapy for adverse events (AEs) related to cancer treatments. In one study, mice that received oral vitamin D₃ supplementation of 11,500 IU/kg daily had fewer doxorubicin-induced cardiotoxic effects on ejection fraction (P<.0001) and stroke volume (P<.01) than mice that received VD supplementation of 1500 IU/kg daily.⁶

In this review, we examine the impact of chemoradiation on 25(OH)D levels—which more accurately reflects VD stores than 1,25(OH)₂D levels—and the impact of suboptimal VD on cutaneous toxicities related to chemoradiation. To define the suboptimal VD threshold, we used the Endocrine Society’s clinical practice guidelines, which characterize suboptimal 25(OH)D levels as insufficiency (21–29 ng/mL [52.5–72.5 nmol/L]) or deficiency (<20 ng/mL [50 nmol/L])⁷; deficiency can be further categorized as severe deficiency (<12 ng/mL [30 nmol/L]).⁸ This review also evaluates the evidence for vitamin D₃ supplementation to alleviate the cutaneous AEs of chemotherapy and radiation treatments.

Effects of Chemotherapy on Vitamin D Levels

A high prevalence of VD deficiency is seen in various cancers. In a retrospective review of 25(OH)D levels in 2098 adults with solid tumors of any stage (6% had metastatic disease [n=124]), suboptimal levels were found in 69% of patients with breast cancer (n=617), 75% with colorectal cancer (n=84), 72% with gynecologic cancer (n=65), 79% with kidney and bladder cancer (n=145), 83% with pancreatic and upper gastrointestinal tract cancer (n=178), 73% with lung cancer (n=73), 69% with prostate cancer (n=225), 61% with skin cancer (n=399), and 63% with thyroid cancer (n=172).⁵ Suboptimal VD also has been found in hematologic malignancies. In a prospective cohort study, mean serum 25(OH)D levels in 23 patients with recently diagnosed acute myeloid leukemia demonstrated VD deficiency (mean [SD], 18.6 [6.6] nmol/L).⁹ Given that many patients already exhibit a baseline VD deficiency at cancer diagnosis, it is important to understand the relationship between VD and cancer treatment modalities.⁵

In the United States, breast and colorectal cancers were estimated to be the first and fourth most common cancers, with 313,510 and 152,810 predicted new cases in 2024, respectively.¹⁰ This review will focus on breast and colorectal cancer when describing VD variation associated with chemotherapy exposure due to their high prevalence.

Effects of Chemotherapy on Vitamin D Levels in Breast Cancer—Breast cancer studies have shown suboptimal VD levels in 76% of females 75 years or younger with any T1, T2, or T3; N0 or N1; and M0 breast cancer, in which 38.5% (n=197) had insufficient and 37.5% (n=192) had deficient 25(OH)D levels.¹¹ In a study of female patients with primary breast cancer (stage I, II, or III and T1 with high Ki67 expression [≥30%], T2, or T3), VD deficiency was seen in 60% of patients not receiving VD supplementation.^12,13 A systematic review that included 7 studies of different types of breast cancer suggested that circulating 25(OH)D may be associated with improved prognosis.¹⁴ Thus, studies have investigated risk factors associated with poor or worsening VD status in individuals with breast cancer, including exposure to chemotherapy and/or radiation treatment.^12,15-18

A prospective cohort study assessed 25(OH)D levels in 95 patients with any breast cancer (stages I, II, IIIA, IIIB) before and after initiating chemotherapy with docetaxel, doxorubicin, epirubicin, 5-fluorouracil, or cyclophosphamide, compared with a group of 52 females without cancer.¹⁷ In the breast cancer group, approximately 80% (76/95) had suboptimal and 50% (47/95) had deficient VD levels before chemotherapy initiation (mean [SD], 54.1 [22.8] nmol/L). In the comparison group, 60% (31/52) had suboptimal and 30% (15/52) had deficient VD at baseline (mean [SD], 66.1 [23.5] nmol/L), which was higher than the breast cancer group (P=.03). A subgroup analysis excluded participants who started, stopped, or lacked data on dietary supplements containing VD (n=39); in the remaining 56 participants, a significant decrease in 25(OH)D levels was observed shortly after finishing chemotherapy compared with the prechemotherapy baseline value (mean, −7.9 nmol/L; P=.004). Notably, 6 months after chemotherapy completion, 25(OH)D levels increased (mean, +12.8 nmol/L; P<.001). Vitamin D levels remained stable in the comparison group (P=.987).¹⁷

Consistent with these findings, a cross-sectional study assessing VD status in 394 female patients with primary breast cancer (stage I, II, or III and T1 with high Ki67 expression [≥30%], T2, or T3), found that a history of chemotherapy was associated with increased odds of 25(OH)D levels less than 20 ng/mL compared with breast cancer patients with no prior chemotherapy (odds ratio, 1.86; 95% CI, 1.03-3.38).¹² Although the study data included chemotherapy history, no information was provided on specific chemotherapy agents or regimens used in this cohort, limiting the ability to detect the drugs most often implicated.

Both studies indicated a complex interplay between chemotherapy and VD levels in breast cancer patients. Although Kok et al¹⁷ suggested a transient decrease in VD levels during chemotherapy with a subsequent recovery after cessation, Fassio et al¹² highlighted the increased odds of VD deficiency associated with chemotherapy. Ultimately, larger randomized controlled trials are needed to better understand the relationship between chemotherapy and VD status in breast cancer patients.

Effects of Chemotherapy on Vitamin D Levels in Colorectal Cancer—Similar to patterns seen in breast cancer, a systematic review with 6 studies of different types of colorectal cancer suggested that circulating 25(OH)D levels may be associated with prognosis.¹⁴ Studies also have investigated the relationship between colorectal chemotherapy regimens and VD status.^15,16,18,19

A retrospective study assessed 25(OH)D levels in 315 patients with any colorectal cancer (stage I–IV).¹⁵ Patients were included in the analysis if they received less than 400 IU daily of VD supplementation at baseline. For the whole study sample, the mean (SD) VD level was 23.7 (13.71) ng/mL. Patients who had not received chemotherapy within 3 months of the VD level assessment were categorized as the no chemotherapy group, and the others were designated as the chemotherapy group; the latter group was exposed to various chemotherapy regimens, including combinations of irinotecan, oxaliplatin, 5-fluorouracil, leucovorin, bevacizumab, or cetuximab. Multivariate analysis showed that the chemotherapy group was 3.7 times more likely to have very low VD levels (≤15 ng/mL) compared with those in the no chemotherapy group (P<.0001).¹⁵

A separate cross-sectional study examined serum 25(OH)D concentrations in 1201 patients with any newly diagnosed colorectal carcinoma (stage I–III); 91% of cases were adenocarcinoma.¹⁸ In a multivariate analysis, chemotherapy plus surgery was associated with lower VD levels than surgery alone 6 months after diagnosis (mean, −8.74 nmol/L; 95% CI, −11.30 to −6.18 nmol/L), specifically decreasing by a mean of 6.7 nmol/L (95% CI, −9.8 to −3.8 nmol/L) after adjusting for demographic and lifestyle factors.¹⁸ However, a prospective cohort study demonstrated different findings.¹⁹ Comparing 58 patients with newly diagnosed colorectal adenocarcinoma (stages I–IV) who underwent chemotherapy and 36 patients who did not receive chemotherapy, there was no significant change in 25(OH)D levels from the time of diagnosis to 6 months later. Median VD levels decreased by 0.7 ng/mL in those who received chemotherapy, while a minimal (and not significant) increase of 1.6 ng/mL was observed in those without chemotherapy intervention (P=.26). Notably, supplementation was not restricted in this cohort, which may have resulted in higher VD levels in those taking supplements.¹⁹

Since time of year and geographic location can influence VD levels, one prospective cohort study controlled for differential sun exposure due to these factors in their analysis.¹⁶ Assessment of 25(OH)D levels was completed in 81 chemotherapy-naïve cancer patients immediately before beginning chemotherapy as well as 6 and 12 weeks into treatment. More than 8 primary cancer types were represented in this study, with breast (34% [29/81]) and colorectal (14% [12/81]) cancer being the most common, but the cancer stages of the participants were not detailed. Vitamin D levels decreased after commencing chemotherapy, with the largest drop occurring 6 weeks into treatment. From the 6- to 12-week end points, VD increased but remained below the original baseline level (baseline: mean [SD], 49.2 [22.3] nmol/L; 6 weeks: mean [SD], 40.9 [19.0] nmol/L; 12 weeks: mean [SD], 45.9 [19.7] nmol/L; P=.05).¹⁶

Although focused on breast and colorectal cancers, these studies suggest that various chemotherapy regimens may confer a higher risk for VD deficiency compared with VD status at diagnosis and/or prior to chemotherapy treatment. However, most of these studies only discussed stage-based differences, excluding analysis of the variety of cancer subtypes that comprise breast and colorectal malignancies, which may limit our ability to extrapolate from these data. Ultimately, larger randomized controlled trials are needed to better understand the relationship between chemotherapy and VD status across various primary cancer types.

Effects of Radiation Therapy on Vitamin D Levels

Unlike chemotherapy, studies on the association between radiation therapy and VD levels are minimal, with most reports in the literature discussing the use of VD to potentiate the effects of radiation therapy. In one cross-sectional analysis of 1201 patients with newly diagnosed stage I, II, or III colorectal cancer of any type (94% were adenocarcinoma), radiation plus surgery was associated with slightly lower 25(OH)D levels than surgery alone for tumor treatment 6 months after diagnosis (mean, −3.17; 95% CI, −6.07 to −0.28 nmol/L). However, after adjustment for demographic and lifestyle factors, this decrease in VD levels attributable to radiotherapy was not statistically significant compared with the surgery-only cohort (mean, −1.78; 95% CI, −5.07 to 1.52 nmol/L).¹⁸

Similarly, a cross-sectional study assessing VD status in 394 female patients with primary breast cancer (stage I, II, or III and T1 with high Ki67 expression [≥30%], T2, or T3), found that a history of radiotherapy was not associated with a difference in serum 25(OH)D levels compared with those with breast cancer without prior radiotherapy (odds ratio, 0.90; 95% CI, 0.52-1.54).¹² From the limited existing literature specifically addressing variations of VD levels with radiation, radiation therapy does not appear to significantly impact VD levels.

Vitamin D Levels and the Severity of Chemotherapy- or Radiation Therapy–Induced AEs

A prospective cohort of 241 patients did not find an increase in the incidence or severity of chemotherapy-induced cutaneous toxicities in those with suboptimal 1,25(OH)₂D₃ levels (≤75 nmol/L).²⁰ Eight different primary cancer types were represented, including breast and colorectal cancer; the tumor stages of the participants were not detailed. Forty-one patients had normal 1,25(OH)₂D₃ levels, while the remaining 200 had suboptimal levels. There was no significant association between serum VD levels and the following dermatologic toxicities: desquamation (P=.26), xerosis (P=.15), mucositis (P=.30), or painful rash (P=.87). Surprisingly, nail changes and hand-foot reactions occurred with greater frequency in patients with normal VD levels (P=.01 and P=.03, respectively).²⁰ Hand-foot reaction is part of the toxic erythema of chemotherapy (TEC) spectrum, which is comprised of a range of cytotoxic skin injuries that typically manifest within 2 to 3 weeks of exposure to the offending chemotherapeutic agents, often characterized by erythema, pain, swelling, and blistering, particularly in intertriginous and acral areas.^21-23 Recovery from TEC generally takes at least 2 to 4 weeks and may necessitate cessation of the offending chemotherapeutic agent.^21,24 Notably, this study measured 1,25(OH)₂D₃ levels instead of 25(OH)D levels, which may not reliably indicate body stores of VD.^7,20 These results underscore the complex nature between chemotherapy and VD; however, VD levels alone do not appear to be a sufficient biomarker for predicting chemotherapy-associated cutaneous AEs.

Interestingly, radiation therapy–induced AEs may be associated with VD levels. A prospective cohort study of 98 patients with prostate, bladder, or gynecologic cancers (tumor stages were not detailed) undergoing pelvic radiotherapy found that females and males with 25(OH)D levels below a threshold of 35 and 40 nmol/L, respectively, were more likely to experience higher Radiation Therapy Oncology Group (RTOG) grade acute proctitis compared with those with VD above these thresholds.²⁵ Specifically, VD below these thresholds was associated with increased odds of RTOG grade 2 or higher radiation-induced proctitis (OR, 3.07; 95% CI, 1.27-7.50 [P=.013]). Additionally, a weak correlation was noted between VD below these thresholds and the RTOG grade, with a Spearman correlation value of −0.189 (P=.031).²⁵

One prospective cohort study included 28 patients with any cancer of the oral cavity, oropharynx, hypopharynx, or larynx stages II, III, or IVA; 93% (26/28) were stage III or IVA.²⁶ The 20 (71%) patients with suboptimal 25(OH)D levels (≤75 nmol/L) experienced a higher prevalence of grade II radiation dermatitis compared with the 8 (29%) patients with optimal VD levels (χ²₂=5.973; P=.0505). This pattern persisted with the severity of mucositis; patients from the suboptimal VD group presented with higher rates of grades II and III mucositis compared with the VD optimal group (χ²₂=13.627; P=.0011).²⁶ Recognizing the small cohort evaluated in the study, we highlight the importance of further studies to clarify these associations.

Chemotherapy-Induced Cutaneous Events Treated with High-Dose Vitamin D

Chemotherapeutic agents are known to induce cellular damage, resulting in a range of cutaneous AEs that can invoke discontinuation of otherwise effective chemotherapeutic interventions.^27,28 Recent research has explored the potential of high-dose vitamin D₃ as a therapeutic agent to mitigate cutaneous reactions.^29,30

A randomized, double-blind, placebo-controlled trial investigated the use of a single high dose of oral ­25(OH)D to treat topical nitrogen mustard (NM)–induced rash.²⁹ To characterize baseline inflammatory responses from NM injury without intervention, clinical measures, serum studies, and tissue analyses from skin biopsies were performed on 28 healthy adults after exposure to topical NM—a chemotherapeutic agent classified as a DNA alkylator. Two weeks later, participants were exposed to topical NM a second time and were split into 2 groups: 14 patients received a single 200,000-IU dose of oral 25(OH)D while the other 14 participants were given a placebo. Using the inflammatory markers induced from baseline exposure to NM alone, posttreatment analysis revealed that the punch biopsies from the 25(OH)D group expressed fewer NM-induced inflammatory markers compared with the placebo group at both 72 hours and 6 weeks following NM injury (72 hours: 12 vs 17 inflammatory markers; 6 weeks: 4 vs 11 inflammatory markers). Notably, NM inflammatory markers were enriched for IL-17 signaling pathways in the placebo biopsies but not in the 25(OH)D intervention group. This study also identified mild and severe patterns of inflammatory responses to NM that were independent of the 25(OH)D intervention. Biomarkers specific to skin biopsies from participants with the severe response included CCL20, CCL2, and CXCL8 (adjusted P<.05). At 6 weeks posttreatment, the 25(OH)D group showed a 67% reduction in NM injury markers compared with a 35% reduction in the placebo group. Despite a reduction in tissue inflammatory markers, there were no clinically significant changes observed in skin redness, swelling, or histologic structure when comparing the 25(OH)D- supplemented group to the placebo group at any time during the study, necessitating further research into the mechanistic roles of high doses VD supplementation.²⁹

Although Ernst et al²⁹ did not observe any clinically significant improvements with VD treatment, a case series of 6 patients with either glioblastoma multiforme, acute myeloid leukemia, or aplastic anemia did demonstrate clinical improvement of TEC after receiving high-dose vitamin D₃.³⁰ The mean time to onset of TEC was noted at 8.5 days following administration of the inciting chemotherapeutic agent, which included combinations of anthracycline, antimetabolite, kinase inhibitor, B-cell lymphoma 2 inhibitor, purine analogue, and alkylating agents. A combination of clinical and histologic findings was used to diagnose TEC. Baseline 25(OH)D levels were not established prior to treatment. The treatment regimen for 1 patient included 2 doses of 50,000 IU of VD spaced 1 week apart, totaling 100,000 IU, while the remaining 5 patients received a total of 200,000 IU, also split into 2 doses given 1 week apart. All patients received their first dose of VD within a week of the cutaneous eruption. Following the initial VD dose, there was a notable improvement in pain, pruritus, or swelling by the next day. Reduction in erythema also was observed within 1 to 4 days.³⁰

No AEs associated with VD supplementation were reported, suggesting a potential beneficial role of high-dose VD in accelerating recovery from chemotherapy-induced rashes without evident safety concerns.

Radiation Therapy–Induced Cutaneous Events Treated with High-Dose Vitamin D

Radiation dermatitis is a common and often severe complication of radiation therapy that affects more than 90% of patients undergoing treatment, with half of these individuals experiencing grade 2 toxicity, according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events.^31,32 Radiation damage to basal keratinocytes and hair follicle stem cells disrupts the renewal of the skin’s outer layer, while a surge of free radicals causes irreversible DNA damage.³³ Symptoms of radiation dermatitis can vary from mild pink erythema to tissue ulceration and necrosis, typically within 1 to 4 weeks of radiation exposure.³⁴ The resulting dermatitis can take 2 to 4 weeks to heal, notably impacting patient quality of life and often necessitating modifications or interruptions in cancer therapy.³³

Prior studies have demonstrated the use of high-dose VD to improve the healing of UV-irradiated skin. A randomized controlled trial investigated high-dose vitamin D₃ to treat experimentally induced sunburn in 20 healthy adults. Compared with those who received a placebo, participants receiving the oral dose of 200,000 IU of vitamin D₃ demonstrated suppression of the pro-inflammatory mediators tumor necrosis factor α (P=.04) and inducible nitric oxide synthase (P=.02), while expression of tissue repair enhancer arginase 1 was increased (P<.005).³⁵ The mechanism of this enhanced tissue repair was investigated using a mouse model, in which intraperitoneal 25(OH)D was administered following severe UV-induced skin injury. On immunofluorescence microscopy, mice treated with VD showed enhanced autophagy within the macrophages infiltrating UV-irradiated skin.³⁶ The use of high-dose VD to treat UV-irradiated skin in these studies established a precedent for using VD to heal cutaneous injury caused by ionizing radiation therapy.

Some studies have focused on the role of VD for treating acute radiation dermatitis. A study of 23 patients with ductal carcinoma in situ or localized invasive ductal carcinoma breast cancer compared the effectiveness of topical calcipotriol to that of a standard hydrating ointment.³⁷ Participants were randomized to 1 of 2 treatments before starting adjuvant radiotherapy to evaluate their potential in preventing radiation dermatitis. In 87% (20/23) of these patients, no difference in skin reaction was observed between the 2 treatments, suggesting that topical VD application may not offer any advantage over the standard hydrating ointment for the prevention of radiation dermatitis.³⁷

Benefits of high-dose oral VD for treating radiation dermatitis also have been reported. Nguyen et al³⁸ documented 3 cases in which patients with neuroendocrine carcinoma of the pancreas, tonsillar carcinoma, and breast cancer received 200,000 IU of oral ergocalciferol distributed over 2 doses given 7 days apart for radiation dermatitis. These patients experienced substantial improvements in pain, swelling, and redness within a week of the initial dose. Additionally, a case of radiation recall dermatitis, which occurred a week after vinorelbine chemotherapy, was treated with 2 doses totaling 100,000 IU of oral ergocalciferol. This patient also had improvement in pain and swelling but continued to have tumor-related induration and ulceration.³⁹

Although topical VD did not show significant benefits over standard treatments for radiation dermatitis, high-dose oral VD appears promising in improving patient outcomes of pain and swelling more rapidly than current practices. Further research is needed to confirm these findings and establish standardized treatment protocols.

Final Thoughts

Suboptimal VD levels are prevalent in numerous cancer types. Chemotherapy often is associated with acute, potentially transient worsening of VD status in patients with breast and colorectal cancer. Although 25(OH)D levels have not corresponded with increased frequency of ­chemotherapy-related dermatologic AEs, suboptimal 25(OH)D levels appear to be associated with increased severity of radiation-induced mucositis and dermatitis.^20,25,26 The use of high-dose VD as a therapeutic agent shows promise in mitigating chemotherapy-induced and radiation therapy–induced rashes in multiple cancer types with reduction of inflammatory markers and a durable anti-inflammatory impact. Although the mechanisms of cellular injury vary among chemotherapeutic agents, the anti-inflammatory and tissue repair properties of VD may make it an effective treatment for chemotherapy-induced cutaneous damage regardless of injury mechanism.^2-4,35 However, reports of clinical improvement vary, and further objective studies to classify optimal dosing, administration, and outcome measures are needed. The absence of reported AEs associated with high-dose VD supplementation is encouraging, but selection of a safe and optimal dosing regimen can only occur with dedicated clinical trials.

Vitamin D (VD) regulates keratinocyte proliferation and differentiation, modulates inflammatory pathways, and protects against cellular damage in the skin. ¹ In the setting of tissue injury and acute skin inflammation, active vitamin D—1,25(OH) ₂ D—suppresses signaling from pro-inflammatory chemokines and cytokines such as IFN- γ and IL-17. ^2,3 This suppression reduces proliferation of helper T cells (T _H 1, T _H 17) and B cells, decreasing tissue damage from reactive oxygen species release while enhancing secretion of the anti-inflammatory cytokine IL-10 by antigen-presenting cells. ^2-4

Suboptimal VD levels have been associated with numerous health consequences including malignancy, prompting interest in VD supplementation for improving cancer-related outcomes.⁵ Beyond disease prognosis, high-dose VD supplementation has been suggested as a potential therapy for adverse events (AEs) related to cancer treatments. In one study, mice that received oral vitamin D₃ supplementation of 11,500 IU/kg daily had fewer doxorubicin-induced cardiotoxic effects on ejection fraction (P<.0001) and stroke volume (P<.01) than mice that received VD supplementation of 1500 IU/kg daily.⁶

In this review, we examine the impact of chemoradiation on 25(OH)D levels—which more accurately reflects VD stores than 1,25(OH)₂D levels—and the impact of suboptimal VD on cutaneous toxicities related to chemoradiation. To define the suboptimal VD threshold, we used the Endocrine Society’s clinical practice guidelines, which characterize suboptimal 25(OH)D levels as insufficiency (21–29 ng/mL [52.5–72.5 nmol/L]) or deficiency (<20 ng/mL [50 nmol/L])⁷; deficiency can be further categorized as severe deficiency (<12 ng/mL [30 nmol/L]).⁸ This review also evaluates the evidence for vitamin D₃ supplementation to alleviate the cutaneous AEs of chemotherapy and radiation treatments.

Effects of Chemotherapy on Vitamin D Levels

A high prevalence of VD deficiency is seen in various cancers. In a retrospective review of 25(OH)D levels in 2098 adults with solid tumors of any stage (6% had metastatic disease [n=124]), suboptimal levels were found in 69% of patients with breast cancer (n=617), 75% with colorectal cancer (n=84), 72% with gynecologic cancer (n=65), 79% with kidney and bladder cancer (n=145), 83% with pancreatic and upper gastrointestinal tract cancer (n=178), 73% with lung cancer (n=73), 69% with prostate cancer (n=225), 61% with skin cancer (n=399), and 63% with thyroid cancer (n=172).⁵ Suboptimal VD also has been found in hematologic malignancies. In a prospective cohort study, mean serum 25(OH)D levels in 23 patients with recently diagnosed acute myeloid leukemia demonstrated VD deficiency (mean [SD], 18.6 [6.6] nmol/L).⁹ Given that many patients already exhibit a baseline VD deficiency at cancer diagnosis, it is important to understand the relationship between VD and cancer treatment modalities.⁵

In the United States, breast and colorectal cancers were estimated to be the first and fourth most common cancers, with 313,510 and 152,810 predicted new cases in 2024, respectively.¹⁰ This review will focus on breast and colorectal cancer when describing VD variation associated with chemotherapy exposure due to their high prevalence.

Effects of Chemotherapy on Vitamin D Levels in Breast Cancer—Breast cancer studies have shown suboptimal VD levels in 76% of females 75 years or younger with any T1, T2, or T3; N0 or N1; and M0 breast cancer, in which 38.5% (n=197) had insufficient and 37.5% (n=192) had deficient 25(OH)D levels.¹¹ In a study of female patients with primary breast cancer (stage I, II, or III and T1 with high Ki67 expression [≥30%], T2, or T3), VD deficiency was seen in 60% of patients not receiving VD supplementation.^12,13 A systematic review that included 7 studies of different types of breast cancer suggested that circulating 25(OH)D may be associated with improved prognosis.¹⁴ Thus, studies have investigated risk factors associated with poor or worsening VD status in individuals with breast cancer, including exposure to chemotherapy and/or radiation treatment.^12,15-18

A prospective cohort study assessed 25(OH)D levels in 95 patients with any breast cancer (stages I, II, IIIA, IIIB) before and after initiating chemotherapy with docetaxel, doxorubicin, epirubicin, 5-fluorouracil, or cyclophosphamide, compared with a group of 52 females without cancer.¹⁷ In the breast cancer group, approximately 80% (76/95) had suboptimal and 50% (47/95) had deficient VD levels before chemotherapy initiation (mean [SD], 54.1 [22.8] nmol/L). In the comparison group, 60% (31/52) had suboptimal and 30% (15/52) had deficient VD at baseline (mean [SD], 66.1 [23.5] nmol/L), which was higher than the breast cancer group (P=.03). A subgroup analysis excluded participants who started, stopped, or lacked data on dietary supplements containing VD (n=39); in the remaining 56 participants, a significant decrease in 25(OH)D levels was observed shortly after finishing chemotherapy compared with the prechemotherapy baseline value (mean, −7.9 nmol/L; P=.004). Notably, 6 months after chemotherapy completion, 25(OH)D levels increased (mean, +12.8 nmol/L; P<.001). Vitamin D levels remained stable in the comparison group (P=.987).¹⁷

Consistent with these findings, a cross-sectional study assessing VD status in 394 female patients with primary breast cancer (stage I, II, or III and T1 with high Ki67 expression [≥30%], T2, or T3), found that a history of chemotherapy was associated with increased odds of 25(OH)D levels less than 20 ng/mL compared with breast cancer patients with no prior chemotherapy (odds ratio, 1.86; 95% CI, 1.03-3.38).¹² Although the study data included chemotherapy history, no information was provided on specific chemotherapy agents or regimens used in this cohort, limiting the ability to detect the drugs most often implicated.

Both studies indicated a complex interplay between chemotherapy and VD levels in breast cancer patients. Although Kok et al¹⁷ suggested a transient decrease in VD levels during chemotherapy with a subsequent recovery after cessation, Fassio et al¹² highlighted the increased odds of VD deficiency associated with chemotherapy. Ultimately, larger randomized controlled trials are needed to better understand the relationship between chemotherapy and VD status in breast cancer patients.

Effects of Chemotherapy on Vitamin D Levels in Colorectal Cancer—Similar to patterns seen in breast cancer, a systematic review with 6 studies of different types of colorectal cancer suggested that circulating 25(OH)D levels may be associated with prognosis.¹⁴ Studies also have investigated the relationship between colorectal chemotherapy regimens and VD status.^15,16,18,19

A retrospective study assessed 25(OH)D levels in 315 patients with any colorectal cancer (stage I–IV).¹⁵ Patients were included in the analysis if they received less than 400 IU daily of VD supplementation at baseline. For the whole study sample, the mean (SD) VD level was 23.7 (13.71) ng/mL. Patients who had not received chemotherapy within 3 months of the VD level assessment were categorized as the no chemotherapy group, and the others were designated as the chemotherapy group; the latter group was exposed to various chemotherapy regimens, including combinations of irinotecan, oxaliplatin, 5-fluorouracil, leucovorin, bevacizumab, or cetuximab. Multivariate analysis showed that the chemotherapy group was 3.7 times more likely to have very low VD levels (≤15 ng/mL) compared with those in the no chemotherapy group (P<.0001).¹⁵

A separate cross-sectional study examined serum 25(OH)D concentrations in 1201 patients with any newly diagnosed colorectal carcinoma (stage I–III); 91% of cases were adenocarcinoma.¹⁸ In a multivariate analysis, chemotherapy plus surgery was associated with lower VD levels than surgery alone 6 months after diagnosis (mean, −8.74 nmol/L; 95% CI, −11.30 to −6.18 nmol/L), specifically decreasing by a mean of 6.7 nmol/L (95% CI, −9.8 to −3.8 nmol/L) after adjusting for demographic and lifestyle factors.¹⁸ However, a prospective cohort study demonstrated different findings.¹⁹ Comparing 58 patients with newly diagnosed colorectal adenocarcinoma (stages I–IV) who underwent chemotherapy and 36 patients who did not receive chemotherapy, there was no significant change in 25(OH)D levels from the time of diagnosis to 6 months later. Median VD levels decreased by 0.7 ng/mL in those who received chemotherapy, while a minimal (and not significant) increase of 1.6 ng/mL was observed in those without chemotherapy intervention (P=.26). Notably, supplementation was not restricted in this cohort, which may have resulted in higher VD levels in those taking supplements.¹⁹

Since time of year and geographic location can influence VD levels, one prospective cohort study controlled for differential sun exposure due to these factors in their analysis.¹⁶ Assessment of 25(OH)D levels was completed in 81 chemotherapy-naïve cancer patients immediately before beginning chemotherapy as well as 6 and 12 weeks into treatment. More than 8 primary cancer types were represented in this study, with breast (34% [29/81]) and colorectal (14% [12/81]) cancer being the most common, but the cancer stages of the participants were not detailed. Vitamin D levels decreased after commencing chemotherapy, with the largest drop occurring 6 weeks into treatment. From the 6- to 12-week end points, VD increased but remained below the original baseline level (baseline: mean [SD], 49.2 [22.3] nmol/L; 6 weeks: mean [SD], 40.9 [19.0] nmol/L; 12 weeks: mean [SD], 45.9 [19.7] nmol/L; P=.05).¹⁶

Although focused on breast and colorectal cancers, these studies suggest that various chemotherapy regimens may confer a higher risk for VD deficiency compared with VD status at diagnosis and/or prior to chemotherapy treatment. However, most of these studies only discussed stage-based differences, excluding analysis of the variety of cancer subtypes that comprise breast and colorectal malignancies, which may limit our ability to extrapolate from these data. Ultimately, larger randomized controlled trials are needed to better understand the relationship between chemotherapy and VD status across various primary cancer types.

Effects of Radiation Therapy on Vitamin D Levels

Unlike chemotherapy, studies on the association between radiation therapy and VD levels are minimal, with most reports in the literature discussing the use of VD to potentiate the effects of radiation therapy. In one cross-sectional analysis of 1201 patients with newly diagnosed stage I, II, or III colorectal cancer of any type (94% were adenocarcinoma), radiation plus surgery was associated with slightly lower 25(OH)D levels than surgery alone for tumor treatment 6 months after diagnosis (mean, −3.17; 95% CI, −6.07 to −0.28 nmol/L). However, after adjustment for demographic and lifestyle factors, this decrease in VD levels attributable to radiotherapy was not statistically significant compared with the surgery-only cohort (mean, −1.78; 95% CI, −5.07 to 1.52 nmol/L).¹⁸

Similarly, a cross-sectional study assessing VD status in 394 female patients with primary breast cancer (stage I, II, or III and T1 with high Ki67 expression [≥30%], T2, or T3), found that a history of radiotherapy was not associated with a difference in serum 25(OH)D levels compared with those with breast cancer without prior radiotherapy (odds ratio, 0.90; 95% CI, 0.52-1.54).¹² From the limited existing literature specifically addressing variations of VD levels with radiation, radiation therapy does not appear to significantly impact VD levels.

Vitamin D Levels and the Severity of Chemotherapy- or Radiation Therapy–Induced AEs

A prospective cohort of 241 patients did not find an increase in the incidence or severity of chemotherapy-induced cutaneous toxicities in those with suboptimal 1,25(OH)₂D₃ levels (≤75 nmol/L).²⁰ Eight different primary cancer types were represented, including breast and colorectal cancer; the tumor stages of the participants were not detailed. Forty-one patients had normal 1,25(OH)₂D₃ levels, while the remaining 200 had suboptimal levels. There was no significant association between serum VD levels and the following dermatologic toxicities: desquamation (P=.26), xerosis (P=.15), mucositis (P=.30), or painful rash (P=.87). Surprisingly, nail changes and hand-foot reactions occurred with greater frequency in patients with normal VD levels (P=.01 and P=.03, respectively).²⁰ Hand-foot reaction is part of the toxic erythema of chemotherapy (TEC) spectrum, which is comprised of a range of cytotoxic skin injuries that typically manifest within 2 to 3 weeks of exposure to the offending chemotherapeutic agents, often characterized by erythema, pain, swelling, and blistering, particularly in intertriginous and acral areas.^21-23 Recovery from TEC generally takes at least 2 to 4 weeks and may necessitate cessation of the offending chemotherapeutic agent.^21,24 Notably, this study measured 1,25(OH)₂D₃ levels instead of 25(OH)D levels, which may not reliably indicate body stores of VD.^7,20 These results underscore the complex nature between chemotherapy and VD; however, VD levels alone do not appear to be a sufficient biomarker for predicting chemotherapy-associated cutaneous AEs.

Interestingly, radiation therapy–induced AEs may be associated with VD levels. A prospective cohort study of 98 patients with prostate, bladder, or gynecologic cancers (tumor stages were not detailed) undergoing pelvic radiotherapy found that females and males with 25(OH)D levels below a threshold of 35 and 40 nmol/L, respectively, were more likely to experience higher Radiation Therapy Oncology Group (RTOG) grade acute proctitis compared with those with VD above these thresholds.²⁵ Specifically, VD below these thresholds was associated with increased odds of RTOG grade 2 or higher radiation-induced proctitis (OR, 3.07; 95% CI, 1.27-7.50 [P=.013]). Additionally, a weak correlation was noted between VD below these thresholds and the RTOG grade, with a Spearman correlation value of −0.189 (P=.031).²⁵

One prospective cohort study included 28 patients with any cancer of the oral cavity, oropharynx, hypopharynx, or larynx stages II, III, or IVA; 93% (26/28) were stage III or IVA.²⁶ The 20 (71%) patients with suboptimal 25(OH)D levels (≤75 nmol/L) experienced a higher prevalence of grade II radiation dermatitis compared with the 8 (29%) patients with optimal VD levels (χ²₂=5.973; P=.0505). This pattern persisted with the severity of mucositis; patients from the suboptimal VD group presented with higher rates of grades II and III mucositis compared with the VD optimal group (χ²₂=13.627; P=.0011).²⁶ Recognizing the small cohort evaluated in the study, we highlight the importance of further studies to clarify these associations.

Chemotherapy-Induced Cutaneous Events Treated with High-Dose Vitamin D

Chemotherapeutic agents are known to induce cellular damage, resulting in a range of cutaneous AEs that can invoke discontinuation of otherwise effective chemotherapeutic interventions.^27,28 Recent research has explored the potential of high-dose vitamin D₃ as a therapeutic agent to mitigate cutaneous reactions.^29,30

A randomized, double-blind, placebo-controlled trial investigated the use of a single high dose of oral ­25(OH)D to treat topical nitrogen mustard (NM)–induced rash.²⁹ To characterize baseline inflammatory responses from NM injury without intervention, clinical measures, serum studies, and tissue analyses from skin biopsies were performed on 28 healthy adults after exposure to topical NM—a chemotherapeutic agent classified as a DNA alkylator. Two weeks later, participants were exposed to topical NM a second time and were split into 2 groups: 14 patients received a single 200,000-IU dose of oral 25(OH)D while the other 14 participants were given a placebo. Using the inflammatory markers induced from baseline exposure to NM alone, posttreatment analysis revealed that the punch biopsies from the 25(OH)D group expressed fewer NM-induced inflammatory markers compared with the placebo group at both 72 hours and 6 weeks following NM injury (72 hours: 12 vs 17 inflammatory markers; 6 weeks: 4 vs 11 inflammatory markers). Notably, NM inflammatory markers were enriched for IL-17 signaling pathways in the placebo biopsies but not in the 25(OH)D intervention group. This study also identified mild and severe patterns of inflammatory responses to NM that were independent of the 25(OH)D intervention. Biomarkers specific to skin biopsies from participants with the severe response included CCL20, CCL2, and CXCL8 (adjusted P<.05). At 6 weeks posttreatment, the 25(OH)D group showed a 67% reduction in NM injury markers compared with a 35% reduction in the placebo group. Despite a reduction in tissue inflammatory markers, there were no clinically significant changes observed in skin redness, swelling, or histologic structure when comparing the 25(OH)D- supplemented group to the placebo group at any time during the study, necessitating further research into the mechanistic roles of high doses VD supplementation.²⁹

Although Ernst et al²⁹ did not observe any clinically significant improvements with VD treatment, a case series of 6 patients with either glioblastoma multiforme, acute myeloid leukemia, or aplastic anemia did demonstrate clinical improvement of TEC after receiving high-dose vitamin D₃.³⁰ The mean time to onset of TEC was noted at 8.5 days following administration of the inciting chemotherapeutic agent, which included combinations of anthracycline, antimetabolite, kinase inhibitor, B-cell lymphoma 2 inhibitor, purine analogue, and alkylating agents. A combination of clinical and histologic findings was used to diagnose TEC. Baseline 25(OH)D levels were not established prior to treatment. The treatment regimen for 1 patient included 2 doses of 50,000 IU of VD spaced 1 week apart, totaling 100,000 IU, while the remaining 5 patients received a total of 200,000 IU, also split into 2 doses given 1 week apart. All patients received their first dose of VD within a week of the cutaneous eruption. Following the initial VD dose, there was a notable improvement in pain, pruritus, or swelling by the next day. Reduction in erythema also was observed within 1 to 4 days.³⁰

No AEs associated with VD supplementation were reported, suggesting a potential beneficial role of high-dose VD in accelerating recovery from chemotherapy-induced rashes without evident safety concerns.

Radiation Therapy–Induced Cutaneous Events Treated with High-Dose Vitamin D

Radiation dermatitis is a common and often severe complication of radiation therapy that affects more than 90% of patients undergoing treatment, with half of these individuals experiencing grade 2 toxicity, according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events.^31,32 Radiation damage to basal keratinocytes and hair follicle stem cells disrupts the renewal of the skin’s outer layer, while a surge of free radicals causes irreversible DNA damage.³³ Symptoms of radiation dermatitis can vary from mild pink erythema to tissue ulceration and necrosis, typically within 1 to 4 weeks of radiation exposure.³⁴ The resulting dermatitis can take 2 to 4 weeks to heal, notably impacting patient quality of life and often necessitating modifications or interruptions in cancer therapy.³³

Prior studies have demonstrated the use of high-dose VD to improve the healing of UV-irradiated skin. A randomized controlled trial investigated high-dose vitamin D₃ to treat experimentally induced sunburn in 20 healthy adults. Compared with those who received a placebo, participants receiving the oral dose of 200,000 IU of vitamin D₃ demonstrated suppression of the pro-inflammatory mediators tumor necrosis factor α (P=.04) and inducible nitric oxide synthase (P=.02), while expression of tissue repair enhancer arginase 1 was increased (P<.005).³⁵ The mechanism of this enhanced tissue repair was investigated using a mouse model, in which intraperitoneal 25(OH)D was administered following severe UV-induced skin injury. On immunofluorescence microscopy, mice treated with VD showed enhanced autophagy within the macrophages infiltrating UV-irradiated skin.³⁶ The use of high-dose VD to treat UV-irradiated skin in these studies established a precedent for using VD to heal cutaneous injury caused by ionizing radiation therapy.

Some studies have focused on the role of VD for treating acute radiation dermatitis. A study of 23 patients with ductal carcinoma in situ or localized invasive ductal carcinoma breast cancer compared the effectiveness of topical calcipotriol to that of a standard hydrating ointment.³⁷ Participants were randomized to 1 of 2 treatments before starting adjuvant radiotherapy to evaluate their potential in preventing radiation dermatitis. In 87% (20/23) of these patients, no difference in skin reaction was observed between the 2 treatments, suggesting that topical VD application may not offer any advantage over the standard hydrating ointment for the prevention of radiation dermatitis.³⁷

Benefits of high-dose oral VD for treating radiation dermatitis also have been reported. Nguyen et al³⁸ documented 3 cases in which patients with neuroendocrine carcinoma of the pancreas, tonsillar carcinoma, and breast cancer received 200,000 IU of oral ergocalciferol distributed over 2 doses given 7 days apart for radiation dermatitis. These patients experienced substantial improvements in pain, swelling, and redness within a week of the initial dose. Additionally, a case of radiation recall dermatitis, which occurred a week after vinorelbine chemotherapy, was treated with 2 doses totaling 100,000 IU of oral ergocalciferol. This patient also had improvement in pain and swelling but continued to have tumor-related induration and ulceration.³⁹

Although topical VD did not show significant benefits over standard treatments for radiation dermatitis, high-dose oral VD appears promising in improving patient outcomes of pain and swelling more rapidly than current practices. Further research is needed to confirm these findings and establish standardized treatment protocols.

Final Thoughts

Suboptimal VD levels are prevalent in numerous cancer types. Chemotherapy often is associated with acute, potentially transient worsening of VD status in patients with breast and colorectal cancer. Although 25(OH)D levels have not corresponded with increased frequency of ­chemotherapy-related dermatologic AEs, suboptimal 25(OH)D levels appear to be associated with increased severity of radiation-induced mucositis and dermatitis.^20,25,26 The use of high-dose VD as a therapeutic agent shows promise in mitigating chemotherapy-induced and radiation therapy–induced rashes in multiple cancer types with reduction of inflammatory markers and a durable anti-inflammatory impact. Although the mechanisms of cellular injury vary among chemotherapeutic agents, the anti-inflammatory and tissue repair properties of VD may make it an effective treatment for chemotherapy-induced cutaneous damage regardless of injury mechanism.^2-4,35 However, reports of clinical improvement vary, and further objective studies to classify optimal dosing, administration, and outcome measures are needed. The absence of reported AEs associated with high-dose VD supplementation is encouraging, but selection of a safe and optimal dosing regimen can only occur with dedicated clinical trials.

TOPLINE:

First-generation antihistamines are linked to a 22% higher risk for seizures in children, new research shows. The risk appears to be most pronounced in children aged 6-24 months.

METHODOLOGY:

• Researchers in Korea used a self-controlled case-crossover design to assess the risk for seizures associated with prescriptions of first-generation antihistamines.
• They analyzed data from 11,729 children who had a seizure event (an emergency department visit with a diagnosis of epilepsy, status epilepticus, or convulsion) and had previously received a prescription for a first-generation antihistamine, including chlorpheniramine maleate, mequitazine, oxatomide, piprinhydrinate, or hydroxyzine hydrochloride.
• Prescriptions during the 15 days before a seizure were considered to have been received during a hazard period, whereas earlier prescriptions were considered to have been received during a control period.
• The researchers excluded patients with febrile seizures.

TAKEAWAY:

• In an adjusted analysis, a prescription for an antihistamine during the hazard period was associated with a 22% higher risk for seizures in children (adjusted odds ratio, 1.22; 95% CI, 1.13-1.31).
• The seizure risk was significant in children aged 6-24 months, with an adjusted odds ratio of 1.49 (95% CI, 1.31-1.70).
• For older children, the risk was not statistically significant.

IN PRACTICE:

“The study underscores a substantial increase in seizure risk associated with antihistamine prescription among children aged 6-24 months,” the authors of the study wrote. “We are not aware of any other studies that have pointed out the increased risk of seizures with first-generation antihistamines in this particular age group. ... The benefits and risks of antihistamine use should always be carefully considered, especially when prescribing H1 antihistamines to vulnerable infants.”

The findings raise a host of questions for clinicians, including how a “relatively small risk” should translate into practice, and whether the risk may be attenuated with newer antihistamines, wrote Frank Max Charles Besag, MB, ChB, with East London NHS Foundation Trust in England, in an editorial accompanying the study. “It would be reasonable to inform families that at least one study has suggested a relatively small increase in the risk of seizures with first-generation antihistamines, adding that there are still too few data to draw any firm conclusions and also providing families with the information on what to do if the child were to have a seizure.” 
 

SOURCE:

Seonkyeong Rhie, MD, and Man Yong Han, MD, both with the Department of Pediatrics at CHA University School of Medicine, in Seongnam, South Korea, were the corresponding authors on the study. The research was published online in JAMA Network Open.

LIMITATIONS:

The researchers did not have details about seizure symptoms, did not include children seen in outpatient clinics, and were unable to verify the actual intake of the prescribed antihistamines. Although second-generation antihistamines may be less likely to cross the blood-brain barrier, one newer medication, desloratadine, has been associated with seizures.

DISCLOSURES:

The study was supported by grants from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, the Ministry of Health and Welfare, Republic of Korea.

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:

First-generation antihistamines are linked to a 22% higher risk for seizures in children, new research shows. The risk appears to be most pronounced in children aged 6-24 months.

METHODOLOGY:

• Researchers in Korea used a self-controlled case-crossover design to assess the risk for seizures associated with prescriptions of first-generation antihistamines.
• They analyzed data from 11,729 children who had a seizure event (an emergency department visit with a diagnosis of epilepsy, status epilepticus, or convulsion) and had previously received a prescription for a first-generation antihistamine, including chlorpheniramine maleate, mequitazine, oxatomide, piprinhydrinate, or hydroxyzine hydrochloride.
• Prescriptions during the 15 days before a seizure were considered to have been received during a hazard period, whereas earlier prescriptions were considered to have been received during a control period.
• The researchers excluded patients with febrile seizures.

TAKEAWAY:

• In an adjusted analysis, a prescription for an antihistamine during the hazard period was associated with a 22% higher risk for seizures in children (adjusted odds ratio, 1.22; 95% CI, 1.13-1.31).
• The seizure risk was significant in children aged 6-24 months, with an adjusted odds ratio of 1.49 (95% CI, 1.31-1.70).
• For older children, the risk was not statistically significant.

IN PRACTICE:

“The study underscores a substantial increase in seizure risk associated with antihistamine prescription among children aged 6-24 months,” the authors of the study wrote. “We are not aware of any other studies that have pointed out the increased risk of seizures with first-generation antihistamines in this particular age group. ... The benefits and risks of antihistamine use should always be carefully considered, especially when prescribing H1 antihistamines to vulnerable infants.”

The findings raise a host of questions for clinicians, including how a “relatively small risk” should translate into practice, and whether the risk may be attenuated with newer antihistamines, wrote Frank Max Charles Besag, MB, ChB, with East London NHS Foundation Trust in England, in an editorial accompanying the study. “It would be reasonable to inform families that at least one study has suggested a relatively small increase in the risk of seizures with first-generation antihistamines, adding that there are still too few data to draw any firm conclusions and also providing families with the information on what to do if the child were to have a seizure.” 
 

SOURCE:

Seonkyeong Rhie, MD, and Man Yong Han, MD, both with the Department of Pediatrics at CHA University School of Medicine, in Seongnam, South Korea, were the corresponding authors on the study. The research was published online in JAMA Network Open.

LIMITATIONS:

The researchers did not have details about seizure symptoms, did not include children seen in outpatient clinics, and were unable to verify the actual intake of the prescribed antihistamines. Although second-generation antihistamines may be less likely to cross the blood-brain barrier, one newer medication, desloratadine, has been associated with seizures.

DISCLOSURES:

The study was supported by grants from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, the Ministry of Health and Welfare, Republic of Korea.

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:

First-generation antihistamines are linked to a 22% higher risk for seizures in children, new research shows. The risk appears to be most pronounced in children aged 6-24 months.

METHODOLOGY:

• Researchers in Korea used a self-controlled case-crossover design to assess the risk for seizures associated with prescriptions of first-generation antihistamines.
• They analyzed data from 11,729 children who had a seizure event (an emergency department visit with a diagnosis of epilepsy, status epilepticus, or convulsion) and had previously received a prescription for a first-generation antihistamine, including chlorpheniramine maleate, mequitazine, oxatomide, piprinhydrinate, or hydroxyzine hydrochloride.
• Prescriptions during the 15 days before a seizure were considered to have been received during a hazard period, whereas earlier prescriptions were considered to have been received during a control period.
• The researchers excluded patients with febrile seizures.

TAKEAWAY:

• In an adjusted analysis, a prescription for an antihistamine during the hazard period was associated with a 22% higher risk for seizures in children (adjusted odds ratio, 1.22; 95% CI, 1.13-1.31).
• The seizure risk was significant in children aged 6-24 months, with an adjusted odds ratio of 1.49 (95% CI, 1.31-1.70).
• For older children, the risk was not statistically significant.

IN PRACTICE:

“The study underscores a substantial increase in seizure risk associated with antihistamine prescription among children aged 6-24 months,” the authors of the study wrote. “We are not aware of any other studies that have pointed out the increased risk of seizures with first-generation antihistamines in this particular age group. ... The benefits and risks of antihistamine use should always be carefully considered, especially when prescribing H1 antihistamines to vulnerable infants.”

The findings raise a host of questions for clinicians, including how a “relatively small risk” should translate into practice, and whether the risk may be attenuated with newer antihistamines, wrote Frank Max Charles Besag, MB, ChB, with East London NHS Foundation Trust in England, in an editorial accompanying the study. “It would be reasonable to inform families that at least one study has suggested a relatively small increase in the risk of seizures with first-generation antihistamines, adding that there are still too few data to draw any firm conclusions and also providing families with the information on what to do if the child were to have a seizure.” 
 

SOURCE:

Seonkyeong Rhie, MD, and Man Yong Han, MD, both with the Department of Pediatrics at CHA University School of Medicine, in Seongnam, South Korea, were the corresponding authors on the study. The research was published online in JAMA Network Open.

LIMITATIONS:

The researchers did not have details about seizure symptoms, did not include children seen in outpatient clinics, and were unable to verify the actual intake of the prescribed antihistamines. Although second-generation antihistamines may be less likely to cross the blood-brain barrier, one newer medication, desloratadine, has been associated with seizures.

DISCLOSURES:

The study was supported by grants from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, the Ministry of Health and Welfare, Republic of Korea.

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.