MDedge Dermatology

Life expectancy in the United States plateaued in recent years, and persistent racial disparities vary by state, according to an analysis of death records and Census data from 1990 to 2019.

“Life expectancy is an important measure of the health of the entire population,” corresponding author Gregory Roth, MD, a cardiologist at the University of Washington, Seattle, said in an interview. “We know race, ethnicity and where you live all affect health, but we wanted to look at the long arc over many decades to understand where subpopulations have been, and where they are headed. Also, it is important to understand how race and place interact, so we looked at race/ethnicity groups within each state to see where disparities exist that need to be addressed.”

In the study, published in Annals of Internal Medicine, researchers led by Catherine O. Johnson, PhD, of the University of Washington, Seattle, reviewed data from 23 states, using regression models based on Census data and deidentified death records. They examined life expectancy for subgroups of individuals reporting Hispanic, non-Hispanic Black, or non-Hispanic White race or ethnicity.

Overall, most states showed an improvement in life expectancy between 1990 and 2019. For women, the mean life expectancy across states increased from 79.3 years in 1990 to 81.3 years in 2019. For men, the mean life expectancy across states increased from 72.6 years in 1990 to 76.3 years in 2019.

However, the researchers found significant disparities across the three racial subgroups between and within states when life expectancy was examined by race/ethnicity, independent of the average life expectancy for an entire state overall. They defined disparity as the difference in life expectancy between states for those in different racial/ethnic groups.

Without considering race/ethnicity, disparities in life expectancy across states decreased from 8.0 years and 12.2 years in 1990 to 7.9 and 7.8 years in 2019, for females and males, respectively.

When race/ethnicity was taken into account, disparities in life expectancy decreased, but the differences across states were greater than when race was not considered; 20.7 years for females and 24.5 years for males in 1990, decreasing to 18.5 years for females and 23.7 years for males in 2019.

Despite the overall improvements, disparities in life expectancy persisted across all states within each race/ethnicity group.

Among females, for example, non-Hispanic Black females had the lowest mean life expectancy across states in 1990 (74.2 years) but had the greatest improvement on average (6.9% increase) by 2019. However, the mean LE for non-Hispanic Black females remained lower than it did for non-Hispanic White and Hispanic females.

Among males, the researchers found differences in life expectancies across states between the people of the three different ethnicities they studied. The greatest difference in life expectancies in 1990 was 24.5 years. This occurred between non-Hispanic Black males in the District of Columbia and Hispanic males in Georgia. The life expectancy for these non-Hispanic Black males was 59.4 years, versus 83.8 years for these Hispanic males that year.

This reduced life expectancy for non-Hispanic Black males persisted, although it improved slightly by 2019. That year, the largest race-based disparity – which was approximately 24 years – occurred between non-Hispanic Black males in the District of Columbia and Hispanic males in Virginia. For the Hispanic males in Virgina, the LE was 90.7 years versus 66.9 years for non-Hispanic Black males in the District of Columbia.

The findings were limited by several factors including the review of data from only 23 states, the focus on life expectancy from birth versus other ages, and the challenges of defining Hispanic ethnicity, the researchers noted. However, the results support that the potential use of state-level analysis that includes race/ethnicity could be a valuable tool for measuring health inequity as part of national average trends, they said.
 

Health has truly stagnated for some in certain states

“Subpopulations in some states have much longer life expectancy now than 30 years ago. But in some states, we were struck by how health has truly stagnated for some,” Dr. Roth said in an interview. “We were surprised by the scale of the overall gap; a difference of about 8 years between states is more than twice that if you drill down to race/ethnicity groups in each state.”

A key message from the study is the need for all clinicians to advocate for improved access to primary care, “which is increasingly hard to obtain for many people,” said Dr. Roth. “So much of health is determined by key risk factors such as high blood pressure, high cholesterol, obesity, diabetes, alcohol use, tobacco use. But many of the determinants of health are not in the healthcare system, and include efforts to improve education, interrupt cycles of poverty, and teach healthy behaviors at a very young age. “Racism remains a underdiscussed part of these disparities, and we need better ways to measure the impact of social policies that end up impacting health down the road,” he said.

Looking ahead: “There is a lot to be learned from the states that have improved life expectancy the most. We need researchers to work together to identify and communicate what are those best practices, and what state governments can do to play their part.”

State-level differences reveal variations in health care

“The findings add to our growing knowledge of large and persistent racial/ethnic health disparities and changes in disparities during recent stagnation in U.S. life expectancy,” wrote Hedwig Lee, PhD, of Washington University in St. Louis, and Kathleen M. Harris, PhD, of the University of North Carolina at Chapel Hill, in an accompanying editorial.

The focus on state-level differences provides a unique window into the huge variation in life expectancy by race/ethnicity across the United States. The data suggest that “a person’s life expectancy in the United States may depend more on where you live than it has in the past,” they noted. For example, the editorialists highlighted that life expectancy for non-Hispanic Black men in 2019 averaged 81.1 years in Rhode Island, but 66.9 years in the District of Columbia.

They also noted the study’s lack of data for many states with high mortality rates and high proportions of non-Hispanic Black persons, Hispanic persons, and those with low socioeconomic states. Including data from these areas may have yielded even greater disparities in life expectancy.

“Despite substantial declines in mortality among Black persons during the study period, a non-Hispanic Black person’s life expectancy remained persistently lower than that of non-Hispanic White and Hispanic persons, both within and across states,” the editorialists wrote. “Future research needs to unpack the complex web of factors driving health and well-being by enabling better understanding of the places where we see persistent health disadvantage and advantage and the state-based explanations for these increasingly important differences determining population risk and resilience. We should be outraged by disparities in longevity and called to act to eliminate them.”
 

Identifying the problem is the first step

“In order to address or fix a problem we should first identify and quantify the problem,” Noel Deep, MD, an internal medicine physician in private practice in Antigo, Wisc., said in an interview.

“This study provides us with the information regarding the trends in life expectancy within states and the disparities in life expectancy when race/ ethnicity and gender are factored into the equation,” said Dr. Deep, who was not involved in the study. “Based on previously available data, we are aware of the increase in life expectancy in the United States over the last few decades, as well as differences in life expectancy for the different ethnicities/races and genders, but these data provide averages, not state or geographical differences. By having this knowledge at a state level, we can use that data to make health policies that address those health inequities and allocate appropriate resources at a state or local level.”

Several studies have identified disparities in health care and life expectancy based on the zip codes, such as the U.S. Small-Area Life Expectancy Estimates Project in 2018. The current study “provides further information for health care professionals and policy makers about the disparities in health outcomes and life expectancy based on race as well as gender, and it is quite detailed,” he said. 

“As clinicians, we should strive to ensure that we are addressing these health inequities through our provision of clinical care and through our advocacy on behalf of our patients so that our nation’s health will improve overall,” he said.

“I would like to see future studies look at the socioeconomic status (income), urban versus rural residence, and place of birth (especially for immigrants),” said Dr. Deep. He also emphasized a need for studies to include the demographics for Hispanic populations; given the possible selection error “because of only healthy individuals immigrating to the United States or the older sicker Hispanics who might be migrating back to their homelands and not being included in the data and falsely increasing the life expectancy for this race/ ethnic groups.

“I would also like to see some research into the cultural and social factors that might explain why Hispanic populations might have a higher life expectancy even if their socioeconomic status is poor,” he said.

The study was supported by the National Heart, Lung, and Blood Institute. The researchers had no financial conflicts to disclose. The editorialists had no financial conflicts to disclose. Dr. Deep had no financial conflicts to disclose, but serves on the editorial advisory board of Internal Medicine News and as chair of the AMA’s Council on Science and Public Health.

Life expectancy in the United States plateaued in recent years, and persistent racial disparities vary by state, according to an analysis of death records and Census data from 1990 to 2019.

“Life expectancy is an important measure of the health of the entire population,” corresponding author Gregory Roth, MD, a cardiologist at the University of Washington, Seattle, said in an interview. “We know race, ethnicity and where you live all affect health, but we wanted to look at the long arc over many decades to understand where subpopulations have been, and where they are headed. Also, it is important to understand how race and place interact, so we looked at race/ethnicity groups within each state to see where disparities exist that need to be addressed.”

In the study, published in Annals of Internal Medicine, researchers led by Catherine O. Johnson, PhD, of the University of Washington, Seattle, reviewed data from 23 states, using regression models based on Census data and deidentified death records. They examined life expectancy for subgroups of individuals reporting Hispanic, non-Hispanic Black, or non-Hispanic White race or ethnicity.

Overall, most states showed an improvement in life expectancy between 1990 and 2019. For women, the mean life expectancy across states increased from 79.3 years in 1990 to 81.3 years in 2019. For men, the mean life expectancy across states increased from 72.6 years in 1990 to 76.3 years in 2019.

However, the researchers found significant disparities across the three racial subgroups between and within states when life expectancy was examined by race/ethnicity, independent of the average life expectancy for an entire state overall. They defined disparity as the difference in life expectancy between states for those in different racial/ethnic groups.

Without considering race/ethnicity, disparities in life expectancy across states decreased from 8.0 years and 12.2 years in 1990 to 7.9 and 7.8 years in 2019, for females and males, respectively.

When race/ethnicity was taken into account, disparities in life expectancy decreased, but the differences across states were greater than when race was not considered; 20.7 years for females and 24.5 years for males in 1990, decreasing to 18.5 years for females and 23.7 years for males in 2019.

Despite the overall improvements, disparities in life expectancy persisted across all states within each race/ethnicity group.

Among females, for example, non-Hispanic Black females had the lowest mean life expectancy across states in 1990 (74.2 years) but had the greatest improvement on average (6.9% increase) by 2019. However, the mean LE for non-Hispanic Black females remained lower than it did for non-Hispanic White and Hispanic females.

Among males, the researchers found differences in life expectancies across states between the people of the three different ethnicities they studied. The greatest difference in life expectancies in 1990 was 24.5 years. This occurred between non-Hispanic Black males in the District of Columbia and Hispanic males in Georgia. The life expectancy for these non-Hispanic Black males was 59.4 years, versus 83.8 years for these Hispanic males that year.

This reduced life expectancy for non-Hispanic Black males persisted, although it improved slightly by 2019. That year, the largest race-based disparity – which was approximately 24 years – occurred between non-Hispanic Black males in the District of Columbia and Hispanic males in Virginia. For the Hispanic males in Virgina, the LE was 90.7 years versus 66.9 years for non-Hispanic Black males in the District of Columbia.

The findings were limited by several factors including the review of data from only 23 states, the focus on life expectancy from birth versus other ages, and the challenges of defining Hispanic ethnicity, the researchers noted. However, the results support that the potential use of state-level analysis that includes race/ethnicity could be a valuable tool for measuring health inequity as part of national average trends, they said.
 

Health has truly stagnated for some in certain states

“Subpopulations in some states have much longer life expectancy now than 30 years ago. But in some states, we were struck by how health has truly stagnated for some,” Dr. Roth said in an interview. “We were surprised by the scale of the overall gap; a difference of about 8 years between states is more than twice that if you drill down to race/ethnicity groups in each state.”

A key message from the study is the need for all clinicians to advocate for improved access to primary care, “which is increasingly hard to obtain for many people,” said Dr. Roth. “So much of health is determined by key risk factors such as high blood pressure, high cholesterol, obesity, diabetes, alcohol use, tobacco use. But many of the determinants of health are not in the healthcare system, and include efforts to improve education, interrupt cycles of poverty, and teach healthy behaviors at a very young age. “Racism remains a underdiscussed part of these disparities, and we need better ways to measure the impact of social policies that end up impacting health down the road,” he said.

Looking ahead: “There is a lot to be learned from the states that have improved life expectancy the most. We need researchers to work together to identify and communicate what are those best practices, and what state governments can do to play their part.”

State-level differences reveal variations in health care

“The findings add to our growing knowledge of large and persistent racial/ethnic health disparities and changes in disparities during recent stagnation in U.S. life expectancy,” wrote Hedwig Lee, PhD, of Washington University in St. Louis, and Kathleen M. Harris, PhD, of the University of North Carolina at Chapel Hill, in an accompanying editorial.

The focus on state-level differences provides a unique window into the huge variation in life expectancy by race/ethnicity across the United States. The data suggest that “a person’s life expectancy in the United States may depend more on where you live than it has in the past,” they noted. For example, the editorialists highlighted that life expectancy for non-Hispanic Black men in 2019 averaged 81.1 years in Rhode Island, but 66.9 years in the District of Columbia.

They also noted the study’s lack of data for many states with high mortality rates and high proportions of non-Hispanic Black persons, Hispanic persons, and those with low socioeconomic states. Including data from these areas may have yielded even greater disparities in life expectancy.

“Despite substantial declines in mortality among Black persons during the study period, a non-Hispanic Black person’s life expectancy remained persistently lower than that of non-Hispanic White and Hispanic persons, both within and across states,” the editorialists wrote. “Future research needs to unpack the complex web of factors driving health and well-being by enabling better understanding of the places where we see persistent health disadvantage and advantage and the state-based explanations for these increasingly important differences determining population risk and resilience. We should be outraged by disparities in longevity and called to act to eliminate them.”
 

Identifying the problem is the first step

“In order to address or fix a problem we should first identify and quantify the problem,” Noel Deep, MD, an internal medicine physician in private practice in Antigo, Wisc., said in an interview.

“This study provides us with the information regarding the trends in life expectancy within states and the disparities in life expectancy when race/ ethnicity and gender are factored into the equation,” said Dr. Deep, who was not involved in the study. “Based on previously available data, we are aware of the increase in life expectancy in the United States over the last few decades, as well as differences in life expectancy for the different ethnicities/races and genders, but these data provide averages, not state or geographical differences. By having this knowledge at a state level, we can use that data to make health policies that address those health inequities and allocate appropriate resources at a state or local level.”

Several studies have identified disparities in health care and life expectancy based on the zip codes, such as the U.S. Small-Area Life Expectancy Estimates Project in 2018. The current study “provides further information for health care professionals and policy makers about the disparities in health outcomes and life expectancy based on race as well as gender, and it is quite detailed,” he said. 

“As clinicians, we should strive to ensure that we are addressing these health inequities through our provision of clinical care and through our advocacy on behalf of our patients so that our nation’s health will improve overall,” he said.

“I would like to see future studies look at the socioeconomic status (income), urban versus rural residence, and place of birth (especially for immigrants),” said Dr. Deep. He also emphasized a need for studies to include the demographics for Hispanic populations; given the possible selection error “because of only healthy individuals immigrating to the United States or the older sicker Hispanics who might be migrating back to their homelands and not being included in the data and falsely increasing the life expectancy for this race/ ethnic groups.

“I would also like to see some research into the cultural and social factors that might explain why Hispanic populations might have a higher life expectancy even if their socioeconomic status is poor,” he said.

The study was supported by the National Heart, Lung, and Blood Institute. The researchers had no financial conflicts to disclose. The editorialists had no financial conflicts to disclose. Dr. Deep had no financial conflicts to disclose, but serves on the editorial advisory board of Internal Medicine News and as chair of the AMA’s Council on Science and Public Health.

Life expectancy in the United States plateaued in recent years, and persistent racial disparities vary by state, according to an analysis of death records and Census data from 1990 to 2019.

“Life expectancy is an important measure of the health of the entire population,” corresponding author Gregory Roth, MD, a cardiologist at the University of Washington, Seattle, said in an interview. “We know race, ethnicity and where you live all affect health, but we wanted to look at the long arc over many decades to understand where subpopulations have been, and where they are headed. Also, it is important to understand how race and place interact, so we looked at race/ethnicity groups within each state to see where disparities exist that need to be addressed.”

In the study, published in Annals of Internal Medicine, researchers led by Catherine O. Johnson, PhD, of the University of Washington, Seattle, reviewed data from 23 states, using regression models based on Census data and deidentified death records. They examined life expectancy for subgroups of individuals reporting Hispanic, non-Hispanic Black, or non-Hispanic White race or ethnicity.

Overall, most states showed an improvement in life expectancy between 1990 and 2019. For women, the mean life expectancy across states increased from 79.3 years in 1990 to 81.3 years in 2019. For men, the mean life expectancy across states increased from 72.6 years in 1990 to 76.3 years in 2019.

However, the researchers found significant disparities across the three racial subgroups between and within states when life expectancy was examined by race/ethnicity, independent of the average life expectancy for an entire state overall. They defined disparity as the difference in life expectancy between states for those in different racial/ethnic groups.

Without considering race/ethnicity, disparities in life expectancy across states decreased from 8.0 years and 12.2 years in 1990 to 7.9 and 7.8 years in 2019, for females and males, respectively.

When race/ethnicity was taken into account, disparities in life expectancy decreased, but the differences across states were greater than when race was not considered; 20.7 years for females and 24.5 years for males in 1990, decreasing to 18.5 years for females and 23.7 years for males in 2019.

Despite the overall improvements, disparities in life expectancy persisted across all states within each race/ethnicity group.

Among females, for example, non-Hispanic Black females had the lowest mean life expectancy across states in 1990 (74.2 years) but had the greatest improvement on average (6.9% increase) by 2019. However, the mean LE for non-Hispanic Black females remained lower than it did for non-Hispanic White and Hispanic females.

Among males, the researchers found differences in life expectancies across states between the people of the three different ethnicities they studied. The greatest difference in life expectancies in 1990 was 24.5 years. This occurred between non-Hispanic Black males in the District of Columbia and Hispanic males in Georgia. The life expectancy for these non-Hispanic Black males was 59.4 years, versus 83.8 years for these Hispanic males that year.

This reduced life expectancy for non-Hispanic Black males persisted, although it improved slightly by 2019. That year, the largest race-based disparity – which was approximately 24 years – occurred between non-Hispanic Black males in the District of Columbia and Hispanic males in Virginia. For the Hispanic males in Virgina, the LE was 90.7 years versus 66.9 years for non-Hispanic Black males in the District of Columbia.

The findings were limited by several factors including the review of data from only 23 states, the focus on life expectancy from birth versus other ages, and the challenges of defining Hispanic ethnicity, the researchers noted. However, the results support that the potential use of state-level analysis that includes race/ethnicity could be a valuable tool for measuring health inequity as part of national average trends, they said.
 

Health has truly stagnated for some in certain states

“Subpopulations in some states have much longer life expectancy now than 30 years ago. But in some states, we were struck by how health has truly stagnated for some,” Dr. Roth said in an interview. “We were surprised by the scale of the overall gap; a difference of about 8 years between states is more than twice that if you drill down to race/ethnicity groups in each state.”

A key message from the study is the need for all clinicians to advocate for improved access to primary care, “which is increasingly hard to obtain for many people,” said Dr. Roth. “So much of health is determined by key risk factors such as high blood pressure, high cholesterol, obesity, diabetes, alcohol use, tobacco use. But many of the determinants of health are not in the healthcare system, and include efforts to improve education, interrupt cycles of poverty, and teach healthy behaviors at a very young age. “Racism remains a underdiscussed part of these disparities, and we need better ways to measure the impact of social policies that end up impacting health down the road,” he said.

Looking ahead: “There is a lot to be learned from the states that have improved life expectancy the most. We need researchers to work together to identify and communicate what are those best practices, and what state governments can do to play their part.”

State-level differences reveal variations in health care

“The findings add to our growing knowledge of large and persistent racial/ethnic health disparities and changes in disparities during recent stagnation in U.S. life expectancy,” wrote Hedwig Lee, PhD, of Washington University in St. Louis, and Kathleen M. Harris, PhD, of the University of North Carolina at Chapel Hill, in an accompanying editorial.

The focus on state-level differences provides a unique window into the huge variation in life expectancy by race/ethnicity across the United States. The data suggest that “a person’s life expectancy in the United States may depend more on where you live than it has in the past,” they noted. For example, the editorialists highlighted that life expectancy for non-Hispanic Black men in 2019 averaged 81.1 years in Rhode Island, but 66.9 years in the District of Columbia.

They also noted the study’s lack of data for many states with high mortality rates and high proportions of non-Hispanic Black persons, Hispanic persons, and those with low socioeconomic states. Including data from these areas may have yielded even greater disparities in life expectancy.

“Despite substantial declines in mortality among Black persons during the study period, a non-Hispanic Black person’s life expectancy remained persistently lower than that of non-Hispanic White and Hispanic persons, both within and across states,” the editorialists wrote. “Future research needs to unpack the complex web of factors driving health and well-being by enabling better understanding of the places where we see persistent health disadvantage and advantage and the state-based explanations for these increasingly important differences determining population risk and resilience. We should be outraged by disparities in longevity and called to act to eliminate them.”
 

Identifying the problem is the first step

“In order to address or fix a problem we should first identify and quantify the problem,” Noel Deep, MD, an internal medicine physician in private practice in Antigo, Wisc., said in an interview.

“This study provides us with the information regarding the trends in life expectancy within states and the disparities in life expectancy when race/ ethnicity and gender are factored into the equation,” said Dr. Deep, who was not involved in the study. “Based on previously available data, we are aware of the increase in life expectancy in the United States over the last few decades, as well as differences in life expectancy for the different ethnicities/races and genders, but these data provide averages, not state or geographical differences. By having this knowledge at a state level, we can use that data to make health policies that address those health inequities and allocate appropriate resources at a state or local level.”

Several studies have identified disparities in health care and life expectancy based on the zip codes, such as the U.S. Small-Area Life Expectancy Estimates Project in 2018. The current study “provides further information for health care professionals and policy makers about the disparities in health outcomes and life expectancy based on race as well as gender, and it is quite detailed,” he said. 

“As clinicians, we should strive to ensure that we are addressing these health inequities through our provision of clinical care and through our advocacy on behalf of our patients so that our nation’s health will improve overall,” he said.

“I would like to see future studies look at the socioeconomic status (income), urban versus rural residence, and place of birth (especially for immigrants),” said Dr. Deep. He also emphasized a need for studies to include the demographics for Hispanic populations; given the possible selection error “because of only healthy individuals immigrating to the United States or the older sicker Hispanics who might be migrating back to their homelands and not being included in the data and falsely increasing the life expectancy for this race/ ethnic groups.

“I would also like to see some research into the cultural and social factors that might explain why Hispanic populations might have a higher life expectancy even if their socioeconomic status is poor,” he said.

The study was supported by the National Heart, Lung, and Blood Institute. The researchers had no financial conflicts to disclose. The editorialists had no financial conflicts to disclose. Dr. Deep had no financial conflicts to disclose, but serves on the editorial advisory board of Internal Medicine News and as chair of the AMA’s Council on Science and Public Health.

A large study showing an increased risk of keratinocyte carcinoma (KC) in children who receive a solid-organ transplant highlights the need for early education about risk reduction and more research to determine optimal timing for screening, say an investigator and two dermatologists with expertise in transplant-related skin issues.

The increased incidence of KC in pediatric transplant recipients is “really high, so we definitely know there’s risk there,” just as there is for adult recipients of solid-organ transplants, said Cathryn Sibbald, MD, MSc, a dermatologist at the Hospital for Sick Children in Toronto and coauthor of a research letter published in June in JAMA Dermatology.

For their study, Dr. Sibbald and her coinvestigators turned to the Ontario Health Insurance plan database, which covers health care for Canadian citizens and qualified residents in the province. They identified 951 patients younger than the age of 18 who received a solid-organ transplant between 1991 and 2004 at an Ontario hospital

They then used a validated health insurance claims–based algorithm to identify diagnoses of KC for the transplant recipients and for more than 5 million age-matched controls. KC, including squamous and basal cell carcinoma, is the most prevalent skin cancer for people who have had a solid-organ transplant.

Fifteen posttransplant KCs (10 patients, 1.1%) were reported a mean of 13.1 years after transplant, with none reported in the first 4 years. The mean age at transplant was 7.8 years, and the mean age at KC diagnosis was 25.2 years. Kidney transplants were the most common (42.1% of transplantations). Most of the transplants recipients (eight patients) who developed KC had kidney transplantation, and most of them had functional graft at the time of KC diagnosis.

Researchers found an increased incidence of KC compared with that of the general population (standardized incidence ratio, 9.09; 95% confidence interval, 5.48-15.08). And the risk for KC increased with time since transplant, with adjusted hazard ratios for KC of 3.63 (95% CI, 0.51-25.77) for 1-5 years, 5.14 (95% CI, 1.28-20.55) for 5-10 years, and 4.80 (95% CI, 2.29-10.08) for 10 years or more, compared with the control population.

Several years ago, another research team performed a similar population-based cohort study of adult transplant recipients in Ontario and found a 6.6-times increased risk of KC in transplant recipients compared with the general population.

Sun protection and skin cancer screening

In commenting on the study, Sarah Arron, MD, PhD, a San Francisco Bay area dermatologist and immediate past president of the International Immunosuppression and Transplant Skin Cancer Collaborative (www.itscc.org), said she feels “reassured” that young transplant patients tend not to develop the skin cancer until young adulthood.

A ”large study like this is important because the overall rate of KC is low in this age group,” she noted.

The findings “suggest that we can focus our efforts on prevention during childhood, with sun protection and skin cancer education,” she said. “Then, as these children move into adulthood, we can begin screening with skin examinations. Of course, [any child] with a skin lesion or mole that concerns their parents or transplant team should be referred to dermatology for evaluation.”

Pediatric transplant recipients and their parents are most interested in learning about skin cancer prevention either before or immediately after transplantation, according to a survey by other researchers.

Intervention studies needed

The increased risk of KC probably stems largely from immunosuppression, said Dr. Sibbald in an interview. “We know [this is the case] in the older population, and it’s likely true in the younger population as well that it’s one of the primary drivers,” she said.

More research to extensively analyze risk factors should come next, she said. This includes “the granularity of what [immunosuppressants and other] medications are received, and at what dose and for what periods of time, so we can calculate cumulative exposure and its relation to risk,” she said.

Kristin Bibee, MD, PhD, assistant professor of dermatology at Johns Hopkins University in Baltimore, said she’d like to see further studies “evaluate appropriate interventions, like sun-protective behavior in childhood and adolescence or immunosuppression modulation, to prevent malignancy development.”

The optimal time and intensity of screening for young transplant recipients must still be determined, both Dr. Bibee and Dr. Arron said. Patients deemed through further research to be at higher risk may need earlier and/or more intensive surveillance.

The role of race in skin cancer risk in this population is “one question the study leaves open,” said Dr. Arron. U.S. studies have shown that among adult transplant recipients White patients are “at highest risk for the ultraviolet-associated melanoma and squamous cell carcinoma, followed by Asian and Latino patients. African Americans have had the lowest risk, but some still developed skin cancer after transplant,” she said.

Prior studies of cancer in pediatric transplant recipients have reported primarily on internal malignant neoplasms, with limited data on KC, Dr. Sibbald and coauthors wrote. It is possible the incidence of KS is underestimated in the new study because of “undiagnosed or unreported KCs,” they noted.

The new study was funded by a grant from the Pediatric Dermatology Research Alliance and a Hospital for Sick Children grant. In disclosures, Dr. Sibbald reported to JAMA Dermatology receiving grants from the alliance and from Paediatric Consultants Partnership during the conduct of the study. Dr. Arron and Dr. Bibee both said they have no disclosures relevant to the study and its content.

A large study showing an increased risk of keratinocyte carcinoma (KC) in children who receive a solid-organ transplant highlights the need for early education about risk reduction and more research to determine optimal timing for screening, say an investigator and two dermatologists with expertise in transplant-related skin issues.

The increased incidence of KC in pediatric transplant recipients is “really high, so we definitely know there’s risk there,” just as there is for adult recipients of solid-organ transplants, said Cathryn Sibbald, MD, MSc, a dermatologist at the Hospital for Sick Children in Toronto and coauthor of a research letter published in June in JAMA Dermatology.

For their study, Dr. Sibbald and her coinvestigators turned to the Ontario Health Insurance plan database, which covers health care for Canadian citizens and qualified residents in the province. They identified 951 patients younger than the age of 18 who received a solid-organ transplant between 1991 and 2004 at an Ontario hospital

They then used a validated health insurance claims–based algorithm to identify diagnoses of KC for the transplant recipients and for more than 5 million age-matched controls. KC, including squamous and basal cell carcinoma, is the most prevalent skin cancer for people who have had a solid-organ transplant.

Fifteen posttransplant KCs (10 patients, 1.1%) were reported a mean of 13.1 years after transplant, with none reported in the first 4 years. The mean age at transplant was 7.8 years, and the mean age at KC diagnosis was 25.2 years. Kidney transplants were the most common (42.1% of transplantations). Most of the transplants recipients (eight patients) who developed KC had kidney transplantation, and most of them had functional graft at the time of KC diagnosis.

Researchers found an increased incidence of KC compared with that of the general population (standardized incidence ratio, 9.09; 95% confidence interval, 5.48-15.08). And the risk for KC increased with time since transplant, with adjusted hazard ratios for KC of 3.63 (95% CI, 0.51-25.77) for 1-5 years, 5.14 (95% CI, 1.28-20.55) for 5-10 years, and 4.80 (95% CI, 2.29-10.08) for 10 years or more, compared with the control population.

Several years ago, another research team performed a similar population-based cohort study of adult transplant recipients in Ontario and found a 6.6-times increased risk of KC in transplant recipients compared with the general population.

Sun protection and skin cancer screening

In commenting on the study, Sarah Arron, MD, PhD, a San Francisco Bay area dermatologist and immediate past president of the International Immunosuppression and Transplant Skin Cancer Collaborative (www.itscc.org), said she feels “reassured” that young transplant patients tend not to develop the skin cancer until young adulthood.

A ”large study like this is important because the overall rate of KC is low in this age group,” she noted.

The findings “suggest that we can focus our efforts on prevention during childhood, with sun protection and skin cancer education,” she said. “Then, as these children move into adulthood, we can begin screening with skin examinations. Of course, [any child] with a skin lesion or mole that concerns their parents or transplant team should be referred to dermatology for evaluation.”

Pediatric transplant recipients and their parents are most interested in learning about skin cancer prevention either before or immediately after transplantation, according to a survey by other researchers.

Intervention studies needed

The increased risk of KC probably stems largely from immunosuppression, said Dr. Sibbald in an interview. “We know [this is the case] in the older population, and it’s likely true in the younger population as well that it’s one of the primary drivers,” she said.

More research to extensively analyze risk factors should come next, she said. This includes “the granularity of what [immunosuppressants and other] medications are received, and at what dose and for what periods of time, so we can calculate cumulative exposure and its relation to risk,” she said.

Kristin Bibee, MD, PhD, assistant professor of dermatology at Johns Hopkins University in Baltimore, said she’d like to see further studies “evaluate appropriate interventions, like sun-protective behavior in childhood and adolescence or immunosuppression modulation, to prevent malignancy development.”

The optimal time and intensity of screening for young transplant recipients must still be determined, both Dr. Bibee and Dr. Arron said. Patients deemed through further research to be at higher risk may need earlier and/or more intensive surveillance.

The role of race in skin cancer risk in this population is “one question the study leaves open,” said Dr. Arron. U.S. studies have shown that among adult transplant recipients White patients are “at highest risk for the ultraviolet-associated melanoma and squamous cell carcinoma, followed by Asian and Latino patients. African Americans have had the lowest risk, but some still developed skin cancer after transplant,” she said.

Prior studies of cancer in pediatric transplant recipients have reported primarily on internal malignant neoplasms, with limited data on KC, Dr. Sibbald and coauthors wrote. It is possible the incidence of KS is underestimated in the new study because of “undiagnosed or unreported KCs,” they noted.

The new study was funded by a grant from the Pediatric Dermatology Research Alliance and a Hospital for Sick Children grant. In disclosures, Dr. Sibbald reported to JAMA Dermatology receiving grants from the alliance and from Paediatric Consultants Partnership during the conduct of the study. Dr. Arron and Dr. Bibee both said they have no disclosures relevant to the study and its content.

A large study showing an increased risk of keratinocyte carcinoma (KC) in children who receive a solid-organ transplant highlights the need for early education about risk reduction and more research to determine optimal timing for screening, say an investigator and two dermatologists with expertise in transplant-related skin issues.

The increased incidence of KC in pediatric transplant recipients is “really high, so we definitely know there’s risk there,” just as there is for adult recipients of solid-organ transplants, said Cathryn Sibbald, MD, MSc, a dermatologist at the Hospital for Sick Children in Toronto and coauthor of a research letter published in June in JAMA Dermatology.

For their study, Dr. Sibbald and her coinvestigators turned to the Ontario Health Insurance plan database, which covers health care for Canadian citizens and qualified residents in the province. They identified 951 patients younger than the age of 18 who received a solid-organ transplant between 1991 and 2004 at an Ontario hospital

They then used a validated health insurance claims–based algorithm to identify diagnoses of KC for the transplant recipients and for more than 5 million age-matched controls. KC, including squamous and basal cell carcinoma, is the most prevalent skin cancer for people who have had a solid-organ transplant.

Fifteen posttransplant KCs (10 patients, 1.1%) were reported a mean of 13.1 years after transplant, with none reported in the first 4 years. The mean age at transplant was 7.8 years, and the mean age at KC diagnosis was 25.2 years. Kidney transplants were the most common (42.1% of transplantations). Most of the transplants recipients (eight patients) who developed KC had kidney transplantation, and most of them had functional graft at the time of KC diagnosis.

Researchers found an increased incidence of KC compared with that of the general population (standardized incidence ratio, 9.09; 95% confidence interval, 5.48-15.08). And the risk for KC increased with time since transplant, with adjusted hazard ratios for KC of 3.63 (95% CI, 0.51-25.77) for 1-5 years, 5.14 (95% CI, 1.28-20.55) for 5-10 years, and 4.80 (95% CI, 2.29-10.08) for 10 years or more, compared with the control population.

Several years ago, another research team performed a similar population-based cohort study of adult transplant recipients in Ontario and found a 6.6-times increased risk of KC in transplant recipients compared with the general population.

Sun protection and skin cancer screening

In commenting on the study, Sarah Arron, MD, PhD, a San Francisco Bay area dermatologist and immediate past president of the International Immunosuppression and Transplant Skin Cancer Collaborative (www.itscc.org), said she feels “reassured” that young transplant patients tend not to develop the skin cancer until young adulthood.

A ”large study like this is important because the overall rate of KC is low in this age group,” she noted.

The findings “suggest that we can focus our efforts on prevention during childhood, with sun protection and skin cancer education,” she said. “Then, as these children move into adulthood, we can begin screening with skin examinations. Of course, [any child] with a skin lesion or mole that concerns their parents or transplant team should be referred to dermatology for evaluation.”

Pediatric transplant recipients and their parents are most interested in learning about skin cancer prevention either before or immediately after transplantation, according to a survey by other researchers.

Intervention studies needed

The increased risk of KC probably stems largely from immunosuppression, said Dr. Sibbald in an interview. “We know [this is the case] in the older population, and it’s likely true in the younger population as well that it’s one of the primary drivers,” she said.

More research to extensively analyze risk factors should come next, she said. This includes “the granularity of what [immunosuppressants and other] medications are received, and at what dose and for what periods of time, so we can calculate cumulative exposure and its relation to risk,” she said.

Kristin Bibee, MD, PhD, assistant professor of dermatology at Johns Hopkins University in Baltimore, said she’d like to see further studies “evaluate appropriate interventions, like sun-protective behavior in childhood and adolescence or immunosuppression modulation, to prevent malignancy development.”

The optimal time and intensity of screening for young transplant recipients must still be determined, both Dr. Bibee and Dr. Arron said. Patients deemed through further research to be at higher risk may need earlier and/or more intensive surveillance.

The role of race in skin cancer risk in this population is “one question the study leaves open,” said Dr. Arron. U.S. studies have shown that among adult transplant recipients White patients are “at highest risk for the ultraviolet-associated melanoma and squamous cell carcinoma, followed by Asian and Latino patients. African Americans have had the lowest risk, but some still developed skin cancer after transplant,” she said.

Prior studies of cancer in pediatric transplant recipients have reported primarily on internal malignant neoplasms, with limited data on KC, Dr. Sibbald and coauthors wrote. It is possible the incidence of KS is underestimated in the new study because of “undiagnosed or unreported KCs,” they noted.

The new study was funded by a grant from the Pediatric Dermatology Research Alliance and a Hospital for Sick Children grant. In disclosures, Dr. Sibbald reported to JAMA Dermatology receiving grants from the alliance and from Paediatric Consultants Partnership during the conduct of the study. Dr. Arron and Dr. Bibee both said they have no disclosures relevant to the study and its content.

To the Editor:

Intravascular large cell lymphoma (ILCL) is a rare B-cell lymphoma that is defined by the presence of large neoplastic B cells in the lumen of blood vessels.¹ At least 3 variants of ILCL have been described based on case reports and a small case series: classic, cutaneous, and hemophagocytic. The classic variant presents in elderly patients as nonspecific constitutional symptoms (fever or pain, or less frequently weight loss) or as signs of multiorgan failure (most commonly of the central nervous system). Skin involvement, which is present in nearly half of these patients, can take on multiple morphologies, including retiform purpura, ulcerated nodules, or pseudocellulitis. The cutaneous variant typically presents in middle-aged women with normal hematologic studies. Systemic involvement is less common in this variant of disease than the classic variant, which may partly explain why overall survival is superior in this variant. The hemophagocytic variant manifests as intravascular lymphoma accompanied by hemophagocytic syndrome (fever, hepatosplenomegaly, thrombocytopenia, and bone marrow involvement). Of the 3 variants, the hemophagocytic variant presents with the most rapid, aggressive decline, primarily in patients in Asian countries.¹ We describe a fatal case of classic ILCL, highlighting the importance of maintaining a high index of suspicion with false-negative biopsies.

A 69-year-old man presented to the emergency department for failure to thrive and nonhealing wounds of 1 year’s duration. His medical history was notable for poorly controlled diabetes mellitus, progressive multifocal ischemic and hemorrhagic cerebral infarcts, and bilateral deep venous thromboses. Physical examination revealed large purpuric to brown plaques in a retiform configuration with central necrotic eschars on the thighs and abdomen (Figure 1). There was no palpable lymphadenopathy. Laboratory tests revealed normocytic anemia with a hemoglobin level of 10.5 g/dL (reference range, 12–18 g/dL), elevated lactate dehydrogenase level of 525 U/L (reference range, 118–242 U/L), elevated erythrocyte sedimentation rate of 73 mm/h (reference range, <20 mm/h), antinuclear antibody (ANA) titer of 1:2560 (reference range, <1:80), and polyclonal hypergammaglobulinemia. The patient’s white blood cell and platelet counts, creatinine level, and liver function tests were within reference range. Cryoglobulins, coagulation studies, and cardiolipin antibodies were negative. Chest and abdominal imaging also were negative. An incisional skin biopsy and skin punch biopsy showed thrombotic coagulopathy and dilated vessels. A bone marrow biopsy revealed a hypercellular marrow but no plasma cell neoplasm. A repeat incisional skin biopsy demonstrated large CD20⁺ and CD45⁺ atypical lymphocytes within the small capillaries of the deep dermis and subcutaneous fat (Figure 2), which confirmed ILCL. Too deconditioned to tolerate chemotherapy, the patient opted for palliative care and died 18 months after initial presentation.

The diagnosis of ILCL often is delayed for several reasons.² Patients can present with a variety of signs and symptoms related to small vessel occlusion that can be misattributed to other conditions.^3,4 In our case, the patient’s recurrent infarcts were thought to be due to his poorly controlled diabetes mellitus, which was diagnosed a few weeks prior, and a positive ANA, even though the workup for antiphospholipid syndrome was negative. Interestingly, a positive ANA (without signs or symptoms of lupus or other autoimmune conditions) has been reported in patients with lymphoma.³ A positive antineutrophil cytoplasmic antibody level (without symptoms or other signs of vasculitis) has been reported in patients with ILCL.^4,5 Therefore, distractors are common.

Multiple incisional skin biopsies in the absence of clinical findings (ie, random skin biopsy) are moderately sensitive (77.8%) for the diagnosis of ILCL.² In a study by Matsue et al,² 111 suspected cases of ILCL underwent 3 incisional biopsies of fat-containing areas of the skin, such as the thigh, abdomen, and upper arm. Intravascular large cell lymphoma was confirmed in 26 cases. Seven additional cases were diagnosed as ILCL, 2 by additional skin biopsies (1 by a second round and 1 by a third round) and 5 by internal organ biopsy (4 bone marrow and 1 adrenal gland). The remaining cases ultimately were found to be a diagnostic mimicker of ILCL, including non-ILCL.² Although random skin biopsies are reasonably sensitive for ILCL, multiple biopsies are needed, and in some cases, sampling of an internal organ may be required to establish the diagnosis of ILCL.

The prognosis of ILCL is poor; the 3-year overall survival rate for classic and cutaneous variants is 22% and 56%, respectively.⁶ Anthracycline-based chemotherapy, such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), is considered first-line treatment, and the addition of rituximab to the CHOP regimen may improve remission rates and survival.⁷

To the Editor:

Intravascular large cell lymphoma (ILCL) is a rare B-cell lymphoma that is defined by the presence of large neoplastic B cells in the lumen of blood vessels.¹ At least 3 variants of ILCL have been described based on case reports and a small case series: classic, cutaneous, and hemophagocytic. The classic variant presents in elderly patients as nonspecific constitutional symptoms (fever or pain, or less frequently weight loss) or as signs of multiorgan failure (most commonly of the central nervous system). Skin involvement, which is present in nearly half of these patients, can take on multiple morphologies, including retiform purpura, ulcerated nodules, or pseudocellulitis. The cutaneous variant typically presents in middle-aged women with normal hematologic studies. Systemic involvement is less common in this variant of disease than the classic variant, which may partly explain why overall survival is superior in this variant. The hemophagocytic variant manifests as intravascular lymphoma accompanied by hemophagocytic syndrome (fever, hepatosplenomegaly, thrombocytopenia, and bone marrow involvement). Of the 3 variants, the hemophagocytic variant presents with the most rapid, aggressive decline, primarily in patients in Asian countries.¹ We describe a fatal case of classic ILCL, highlighting the importance of maintaining a high index of suspicion with false-negative biopsies.

A 69-year-old man presented to the emergency department for failure to thrive and nonhealing wounds of 1 year’s duration. His medical history was notable for poorly controlled diabetes mellitus, progressive multifocal ischemic and hemorrhagic cerebral infarcts, and bilateral deep venous thromboses. Physical examination revealed large purpuric to brown plaques in a retiform configuration with central necrotic eschars on the thighs and abdomen (Figure 1). There was no palpable lymphadenopathy. Laboratory tests revealed normocytic anemia with a hemoglobin level of 10.5 g/dL (reference range, 12–18 g/dL), elevated lactate dehydrogenase level of 525 U/L (reference range, 118–242 U/L), elevated erythrocyte sedimentation rate of 73 mm/h (reference range, <20 mm/h), antinuclear antibody (ANA) titer of 1:2560 (reference range, <1:80), and polyclonal hypergammaglobulinemia. The patient’s white blood cell and platelet counts, creatinine level, and liver function tests were within reference range. Cryoglobulins, coagulation studies, and cardiolipin antibodies were negative. Chest and abdominal imaging also were negative. An incisional skin biopsy and skin punch biopsy showed thrombotic coagulopathy and dilated vessels. A bone marrow biopsy revealed a hypercellular marrow but no plasma cell neoplasm. A repeat incisional skin biopsy demonstrated large CD20⁺ and CD45⁺ atypical lymphocytes within the small capillaries of the deep dermis and subcutaneous fat (Figure 2), which confirmed ILCL. Too deconditioned to tolerate chemotherapy, the patient opted for palliative care and died 18 months after initial presentation.

The diagnosis of ILCL often is delayed for several reasons.² Patients can present with a variety of signs and symptoms related to small vessel occlusion that can be misattributed to other conditions.^3,4 In our case, the patient’s recurrent infarcts were thought to be due to his poorly controlled diabetes mellitus, which was diagnosed a few weeks prior, and a positive ANA, even though the workup for antiphospholipid syndrome was negative. Interestingly, a positive ANA (without signs or symptoms of lupus or other autoimmune conditions) has been reported in patients with lymphoma.³ A positive antineutrophil cytoplasmic antibody level (without symptoms or other signs of vasculitis) has been reported in patients with ILCL.^4,5 Therefore, distractors are common.

Multiple incisional skin biopsies in the absence of clinical findings (ie, random skin biopsy) are moderately sensitive (77.8%) for the diagnosis of ILCL.² In a study by Matsue et al,² 111 suspected cases of ILCL underwent 3 incisional biopsies of fat-containing areas of the skin, such as the thigh, abdomen, and upper arm. Intravascular large cell lymphoma was confirmed in 26 cases. Seven additional cases were diagnosed as ILCL, 2 by additional skin biopsies (1 by a second round and 1 by a third round) and 5 by internal organ biopsy (4 bone marrow and 1 adrenal gland). The remaining cases ultimately were found to be a diagnostic mimicker of ILCL, including non-ILCL.² Although random skin biopsies are reasonably sensitive for ILCL, multiple biopsies are needed, and in some cases, sampling of an internal organ may be required to establish the diagnosis of ILCL.

The prognosis of ILCL is poor; the 3-year overall survival rate for classic and cutaneous variants is 22% and 56%, respectively.⁶ Anthracycline-based chemotherapy, such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), is considered first-line treatment, and the addition of rituximab to the CHOP regimen may improve remission rates and survival.⁷

To the Editor:

Intravascular large cell lymphoma (ILCL) is a rare B-cell lymphoma that is defined by the presence of large neoplastic B cells in the lumen of blood vessels.¹ At least 3 variants of ILCL have been described based on case reports and a small case series: classic, cutaneous, and hemophagocytic. The classic variant presents in elderly patients as nonspecific constitutional symptoms (fever or pain, or less frequently weight loss) or as signs of multiorgan failure (most commonly of the central nervous system). Skin involvement, which is present in nearly half of these patients, can take on multiple morphologies, including retiform purpura, ulcerated nodules, or pseudocellulitis. The cutaneous variant typically presents in middle-aged women with normal hematologic studies. Systemic involvement is less common in this variant of disease than the classic variant, which may partly explain why overall survival is superior in this variant. The hemophagocytic variant manifests as intravascular lymphoma accompanied by hemophagocytic syndrome (fever, hepatosplenomegaly, thrombocytopenia, and bone marrow involvement). Of the 3 variants, the hemophagocytic variant presents with the most rapid, aggressive decline, primarily in patients in Asian countries.¹ We describe a fatal case of classic ILCL, highlighting the importance of maintaining a high index of suspicion with false-negative biopsies.

A 69-year-old man presented to the emergency department for failure to thrive and nonhealing wounds of 1 year’s duration. His medical history was notable for poorly controlled diabetes mellitus, progressive multifocal ischemic and hemorrhagic cerebral infarcts, and bilateral deep venous thromboses. Physical examination revealed large purpuric to brown plaques in a retiform configuration with central necrotic eschars on the thighs and abdomen (Figure 1). There was no palpable lymphadenopathy. Laboratory tests revealed normocytic anemia with a hemoglobin level of 10.5 g/dL (reference range, 12–18 g/dL), elevated lactate dehydrogenase level of 525 U/L (reference range, 118–242 U/L), elevated erythrocyte sedimentation rate of 73 mm/h (reference range, <20 mm/h), antinuclear antibody (ANA) titer of 1:2560 (reference range, <1:80), and polyclonal hypergammaglobulinemia. The patient’s white blood cell and platelet counts, creatinine level, and liver function tests were within reference range. Cryoglobulins, coagulation studies, and cardiolipin antibodies were negative. Chest and abdominal imaging also were negative. An incisional skin biopsy and skin punch biopsy showed thrombotic coagulopathy and dilated vessels. A bone marrow biopsy revealed a hypercellular marrow but no plasma cell neoplasm. A repeat incisional skin biopsy demonstrated large CD20⁺ and CD45⁺ atypical lymphocytes within the small capillaries of the deep dermis and subcutaneous fat (Figure 2), which confirmed ILCL. Too deconditioned to tolerate chemotherapy, the patient opted for palliative care and died 18 months after initial presentation.

The diagnosis of ILCL often is delayed for several reasons.² Patients can present with a variety of signs and symptoms related to small vessel occlusion that can be misattributed to other conditions.^3,4 In our case, the patient’s recurrent infarcts were thought to be due to his poorly controlled diabetes mellitus, which was diagnosed a few weeks prior, and a positive ANA, even though the workup for antiphospholipid syndrome was negative. Interestingly, a positive ANA (without signs or symptoms of lupus or other autoimmune conditions) has been reported in patients with lymphoma.³ A positive antineutrophil cytoplasmic antibody level (without symptoms or other signs of vasculitis) has been reported in patients with ILCL.^4,5 Therefore, distractors are common.

Multiple incisional skin biopsies in the absence of clinical findings (ie, random skin biopsy) are moderately sensitive (77.8%) for the diagnosis of ILCL.² In a study by Matsue et al,² 111 suspected cases of ILCL underwent 3 incisional biopsies of fat-containing areas of the skin, such as the thigh, abdomen, and upper arm. Intravascular large cell lymphoma was confirmed in 26 cases. Seven additional cases were diagnosed as ILCL, 2 by additional skin biopsies (1 by a second round and 1 by a third round) and 5 by internal organ biopsy (4 bone marrow and 1 adrenal gland). The remaining cases ultimately were found to be a diagnostic mimicker of ILCL, including non-ILCL.² Although random skin biopsies are reasonably sensitive for ILCL, multiple biopsies are needed, and in some cases, sampling of an internal organ may be required to establish the diagnosis of ILCL.

The prognosis of ILCL is poor; the 3-year overall survival rate for classic and cutaneous variants is 22% and 56%, respectively.⁶ Anthracycline-based chemotherapy, such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), is considered first-line treatment, and the addition of rituximab to the CHOP regimen may improve remission rates and survival.⁷

To the Editor:

Tumor necrosis factor α (TNF-α) inhibitor–induced lupuslike syndrome (TAILS) is a newly described entity that refers to the onset of subacute cutaneous lupus erythematosus (SCLE) during drug therapy with TNF-α antagonists. The condition is unique because it is thought to occur via a separate pathophysiologic mechanism than all other agents implicated in the development of drug-induced lupus erythematosus (DILE). Infliximab and etanercept are the 2 most common TNF-α antagonists associated with TAILS. Although rare, adalimumab, golimumab, and certolizumab pegol have been reported to induce this state of autoimmunity. We report an uncommon presentation of TAILS in a patient taking certolizumab pegol with a brief discussion of the pathogenesis underlying TAILS.

A 71-year-old woman presented to the dermatology clinic with a rash located on the arms, face, and trunk that she reported as having been present for months. She had a medical history of rheumatoid arthritis and currently was receiving certolizumab pegol injections. Physical examination revealed erythematous patches and plaques with overlying scaling and evidence of atrophic scarring on sun-exposed areas of the body. The lesions predominantly were in a symmetrical distribution across the extensor surfaces of both outer arms as well as the posterior superior thoracic region extending anteriorly along the bilateral supraclavicular area (Figures 1 and 2). A 4-mm punch biopsy was obtained and sent for histologic analysis, along with a sample of the patient’s serum for antinuclear antibody (ANA) testing.

Hematoxylin and eosin–stained tissue sections of the right superior thoracic lesions revealed epidermal atrophy, hyperkeratosis, and vacuolar alteration of the basal layer with apoptosis, consistent with a lichenoid tissue reaction. In addition, both superficial and deep perivascular and periadnexal lymphocytic infiltrates were observed as well as increased dermal mucin. Serologic testing was performed with a comprehensive ANA panel of the patient’s serum (Table). Of note, there was a speckled ANA pattern (1:1280), with elevated anti–double-stranded DNA (anti-dsDNA) and anti–Sjögren syndrome–related antigen A (anti-SSA)(also called anti-Ro antibodies) levels. The patient’s rheumatologist was consulted; certolizumab pegol was removed from the current drug regimen and switched to a daily regimen of hydroxychloroquine and prednisone. Seven weeks after discontinuation of certolizumab pegol, the patient was symptom free and without any cutaneous involvement. Based on the histologic analysis, presence of anti-SSA (Ro) autoantibodies, and the resolution of symptoms following withdrawal of anti–TNF-α therapy, a diagnosis of TAILS was made.

Subacute cutaneous lupus erythematosus, the most common subset of DILE, typically presents with annular polycyclic or papulosquamous skin eruptions on the legs; patients often test positive for anti-SSA/Ro and/or anti–Sjögren syndrome–related antigen B (also called anti-La) antibodies. Pharmaceutical agents linked to the development of SCLE are calcium channel blockers, angiotensin-converting enzyme inhibitors, thiazide diuretics, terbinafine, the chemotherapeutic agent gemcitabine, and TNF-α antagonists.^1,2 Tumor necrosis factor α antagonists are biologic agents that commonly are used in the management of systemic inflammatory diseases such as ulcerative colitis, Crohn disease, seronegative spondyloarthropathies, and rheumatoid arthritis. Among this family of therapeutics includes adalimumab (humanized monoclonal antibody), infliximab (chimeric monoclonal TNF-α antagonist), etanercept (soluble receptor fusion protein), certolizumab pegol (Fab fraction of a human IgG monoclonal antibody), and golimumab (humanized monoclonal antibody).

Tumor necrosis factor α inhibitor–induced lupuslike syndrome most commonly occurs in women in the fifth decade of life, and it is seen more often in those using infliximab or entanercept.³ Although reports do exist, TAILS rarely complicates treatment with adalimumab, golimumab, or certolizumab.^4,5 Due to the lack of reports, there are no diagnostic criteria nor an acceptable theory regarding the pathogenesis. In one study in France, the estimated incidence was thought to be 0.19% for infliximab and 0.18% for etanercept.⁶ Tumor necrosis factor α inhibitor–induced lupuslike syndrome is unique in that it is thought to occur by a different mechanism than that of other known offending agents in the development of DILE. Molecular mimicry, direct cytotoxicity, altered T-cell gene expression, and disruption of central immune tolerance have all been hypothesized to cause drug-induced systemic lupus erythematosus, SCLE, and chronic cutaneous lupus erythematosus. Tumor necrosis factor α inhibitors, are postulated to cause the induction of SCLE via an independent route separate from not only other drugs that cause SCLE but also all forms of DILE as a whole, making it a distinctive player within the realm of agents known to cause a lupuslike syndrome. The following hypotheses may explain this occurrence:

1. Increased humoral autoimmunity: Under normal circumstances, TNF-α activation leads to upregulation in the production of cytotoxic CD8⁺ T lymphocytes. The upregulation of CD8⁺ T lymphocytes concurrently leads to a simultaneous suppression of B lymphocytes. Inhibiting the effects of TNF-α on the other hand promotes cytotoxic T-lymphocyte suppression, leading to an increased synthesis of B cells and subsequently a state of increased humoral autoimmunity.⁷

2. Infection: The immunosuppressive effects of TNF-α inhibitors are well known, and the propensity to develop microbial infections, such as tuberculosis, is markedly increased on the use of these agents. Infections brought on by TNF-α inhibitor usage are hypothesized to induce a widespread activation of polyclonal B lymphocytes, eventually leading to the formation of antibodies against these polyclonal B lymphocytes and subsequently SCLE.⁸

3. Helper T cell (TH2) response: The inhibition of T_H1 CD4⁺ lymphocytes by TNF-α inversely leads to an increased production of T_H2 CD4⁺ lymphocytes. This increase in the levels of circulating T_H2 CD4⁺ lymphocytes brought on by the action of anti–TNF-α agents is thought to promote the development of SCLE.^9,10

4. Apoptosis theory: Molecules of TNF-α inhibitors are capable of binding to TNF-α receptors on the cell surface. In doing so, cellular apoptosis is triggered, resulting in the release of nucleosomal autoantigens from the apoptotic cells. In susceptible individuals, autoantibodies then begin to form against the nucleosomal autoantigens, leading to an autoimmune reaction that is characterized by SCLE.^11,12

Major histone compatibility (MHC) antigen testing performed by Sontheimer et al¹² established the presence of the HLA class I, HLA-B8, and/or HLA-DR3 haplotypes in patients with SCLE.^13,14 Furthermore, there is a well-known association between the antinuclear profile of known SCLE patients and the presence of anti-SSA (Ro) antibodies.¹³ Therefore, we propose that in susceptible individuals, such as those with the HLA class I, HLA-B8, or HLA-DR3 haplotypes, the initiation of a TNF-α inhibitor causes cellular apoptosis with the subsequent release of nucleosomal and cytoplasmic components (namely that of the Ro autoantigens), inducing a state of autoimmunity. An ensuing immunogenic response is then initiated in predisposed individuals for which anti-SSA (Ro) autoantibodies are produced against these previously mentioned autoantigens.

Drug-induced SCLE is most common in females (71%), with a median age of 58 years. The most common site of cutaneous manifestations is the legs.¹⁵ Although our patient was in the eighth decade of life with predominant cutaneous involvement of the upper extremity, the erythematous plaques with a symmetric, annular, polycyclic appearance in photosensitive regions raised a heightened suspicion for lupus erythematosus. Histology classically involves an interface dermatitis with vacuolar or hydropic change and lymphocytic infiltrates,¹⁶ consistent with the analysis of tissue sections from our patient. Moreover, the speckled ANA profile with positive anti-dsDNA and anti-SSA (Ro) antibodies in the absence of a negative rheumatoid factor and anticyclic citrullinated peptide antibodies strongly favored the diagnosis of SCLE over alternative diagnoses.²

The supraclavicular rash in our patient raises clinical suspicion for the shawl sign of dermatomyositis, which also is associated with musculoskeletal pain and photosensitivity. In addition, skin biopsy revealed vacuolar alteration of the basement membrane zoneand dermal mucin in both lupus erythematosus and dermatomyositis; therefore, skin biopsy is of little use in distinguishing the 2 conditions, and antibody testing must be performed. Although anti-SSA (Ro) antibodies commonly are associated with SCLE, there are reports involving positivity for the extractable nuclear antigen in cases of dermatomyositis.¹⁷ Based on our patient’s current drug regimen, including that of a known offending agent for SCLE, a presumptive diagnosis of TAILS was made. Following withdrawal of certolizumab pegol injections and subsequent resolution of the skin lesions, our patient was given a definitive diagnosis of TAILS based on clinical and pathological assessments.

The clinical diagnosis of TAILS should be made according to the triad of at least 1 serologic and 1 nonserologic American College of Rheumatology criteria, such as anti-SSA (Ro) antibodies and a photosensitive rash, respectively, as well as a relationship between the onset of symptoms and TNF-α inhibitor therapy.¹⁸ Both the definitive diagnosis and the treatment of TAILS can be made via withdrawal of the TNF-α inhibitor, which was true in our case whereby chronologically the onset of use with a TNF-α inhibitor was associated with disease onset. Furthermore, withdrawal led to complete improvement of all signs and symptoms, collectively supporting a diagnosis of TAILS. Notably, switching to a different TNF-α inhibitor has been shown to be safe and effective.¹⁹

To the Editor:

Tumor necrosis factor α (TNF-α) inhibitor–induced lupuslike syndrome (TAILS) is a newly described entity that refers to the onset of subacute cutaneous lupus erythematosus (SCLE) during drug therapy with TNF-α antagonists. The condition is unique because it is thought to occur via a separate pathophysiologic mechanism than all other agents implicated in the development of drug-induced lupus erythematosus (DILE). Infliximab and etanercept are the 2 most common TNF-α antagonists associated with TAILS. Although rare, adalimumab, golimumab, and certolizumab pegol have been reported to induce this state of autoimmunity. We report an uncommon presentation of TAILS in a patient taking certolizumab pegol with a brief discussion of the pathogenesis underlying TAILS.

A 71-year-old woman presented to the dermatology clinic with a rash located on the arms, face, and trunk that she reported as having been present for months. She had a medical history of rheumatoid arthritis and currently was receiving certolizumab pegol injections. Physical examination revealed erythematous patches and plaques with overlying scaling and evidence of atrophic scarring on sun-exposed areas of the body. The lesions predominantly were in a symmetrical distribution across the extensor surfaces of both outer arms as well as the posterior superior thoracic region extending anteriorly along the bilateral supraclavicular area (Figures 1 and 2). A 4-mm punch biopsy was obtained and sent for histologic analysis, along with a sample of the patient’s serum for antinuclear antibody (ANA) testing.

Hematoxylin and eosin–stained tissue sections of the right superior thoracic lesions revealed epidermal atrophy, hyperkeratosis, and vacuolar alteration of the basal layer with apoptosis, consistent with a lichenoid tissue reaction. In addition, both superficial and deep perivascular and periadnexal lymphocytic infiltrates were observed as well as increased dermal mucin. Serologic testing was performed with a comprehensive ANA panel of the patient’s serum (Table). Of note, there was a speckled ANA pattern (1:1280), with elevated anti–double-stranded DNA (anti-dsDNA) and anti–Sjögren syndrome–related antigen A (anti-SSA)(also called anti-Ro antibodies) levels. The patient’s rheumatologist was consulted; certolizumab pegol was removed from the current drug regimen and switched to a daily regimen of hydroxychloroquine and prednisone. Seven weeks after discontinuation of certolizumab pegol, the patient was symptom free and without any cutaneous involvement. Based on the histologic analysis, presence of anti-SSA (Ro) autoantibodies, and the resolution of symptoms following withdrawal of anti–TNF-α therapy, a diagnosis of TAILS was made.

Subacute cutaneous lupus erythematosus, the most common subset of DILE, typically presents with annular polycyclic or papulosquamous skin eruptions on the legs; patients often test positive for anti-SSA/Ro and/or anti–Sjögren syndrome–related antigen B (also called anti-La) antibodies. Pharmaceutical agents linked to the development of SCLE are calcium channel blockers, angiotensin-converting enzyme inhibitors, thiazide diuretics, terbinafine, the chemotherapeutic agent gemcitabine, and TNF-α antagonists.^1,2 Tumor necrosis factor α antagonists are biologic agents that commonly are used in the management of systemic inflammatory diseases such as ulcerative colitis, Crohn disease, seronegative spondyloarthropathies, and rheumatoid arthritis. Among this family of therapeutics includes adalimumab (humanized monoclonal antibody), infliximab (chimeric monoclonal TNF-α antagonist), etanercept (soluble receptor fusion protein), certolizumab pegol (Fab fraction of a human IgG monoclonal antibody), and golimumab (humanized monoclonal antibody).

Tumor necrosis factor α inhibitor–induced lupuslike syndrome most commonly occurs in women in the fifth decade of life, and it is seen more often in those using infliximab or entanercept.³ Although reports do exist, TAILS rarely complicates treatment with adalimumab, golimumab, or certolizumab.^4,5 Due to the lack of reports, there are no diagnostic criteria nor an acceptable theory regarding the pathogenesis. In one study in France, the estimated incidence was thought to be 0.19% for infliximab and 0.18% for etanercept.⁶ Tumor necrosis factor α inhibitor–induced lupuslike syndrome is unique in that it is thought to occur by a different mechanism than that of other known offending agents in the development of DILE. Molecular mimicry, direct cytotoxicity, altered T-cell gene expression, and disruption of central immune tolerance have all been hypothesized to cause drug-induced systemic lupus erythematosus, SCLE, and chronic cutaneous lupus erythematosus. Tumor necrosis factor α inhibitors, are postulated to cause the induction of SCLE via an independent route separate from not only other drugs that cause SCLE but also all forms of DILE as a whole, making it a distinctive player within the realm of agents known to cause a lupuslike syndrome. The following hypotheses may explain this occurrence:

1. Increased humoral autoimmunity: Under normal circumstances, TNF-α activation leads to upregulation in the production of cytotoxic CD8⁺ T lymphocytes. The upregulation of CD8⁺ T lymphocytes concurrently leads to a simultaneous suppression of B lymphocytes. Inhibiting the effects of TNF-α on the other hand promotes cytotoxic T-lymphocyte suppression, leading to an increased synthesis of B cells and subsequently a state of increased humoral autoimmunity.⁷

2. Infection: The immunosuppressive effects of TNF-α inhibitors are well known, and the propensity to develop microbial infections, such as tuberculosis, is markedly increased on the use of these agents. Infections brought on by TNF-α inhibitor usage are hypothesized to induce a widespread activation of polyclonal B lymphocytes, eventually leading to the formation of antibodies against these polyclonal B lymphocytes and subsequently SCLE.⁸

3. Helper T cell (TH2) response: The inhibition of T_H1 CD4⁺ lymphocytes by TNF-α inversely leads to an increased production of T_H2 CD4⁺ lymphocytes. This increase in the levels of circulating T_H2 CD4⁺ lymphocytes brought on by the action of anti–TNF-α agents is thought to promote the development of SCLE.^9,10

4. Apoptosis theory: Molecules of TNF-α inhibitors are capable of binding to TNF-α receptors on the cell surface. In doing so, cellular apoptosis is triggered, resulting in the release of nucleosomal autoantigens from the apoptotic cells. In susceptible individuals, autoantibodies then begin to form against the nucleosomal autoantigens, leading to an autoimmune reaction that is characterized by SCLE.^11,12

Major histone compatibility (MHC) antigen testing performed by Sontheimer et al¹² established the presence of the HLA class I, HLA-B8, and/or HLA-DR3 haplotypes in patients with SCLE.^13,14 Furthermore, there is a well-known association between the antinuclear profile of known SCLE patients and the presence of anti-SSA (Ro) antibodies.¹³ Therefore, we propose that in susceptible individuals, such as those with the HLA class I, HLA-B8, or HLA-DR3 haplotypes, the initiation of a TNF-α inhibitor causes cellular apoptosis with the subsequent release of nucleosomal and cytoplasmic components (namely that of the Ro autoantigens), inducing a state of autoimmunity. An ensuing immunogenic response is then initiated in predisposed individuals for which anti-SSA (Ro) autoantibodies are produced against these previously mentioned autoantigens.

Drug-induced SCLE is most common in females (71%), with a median age of 58 years. The most common site of cutaneous manifestations is the legs.¹⁵ Although our patient was in the eighth decade of life with predominant cutaneous involvement of the upper extremity, the erythematous plaques with a symmetric, annular, polycyclic appearance in photosensitive regions raised a heightened suspicion for lupus erythematosus. Histology classically involves an interface dermatitis with vacuolar or hydropic change and lymphocytic infiltrates,¹⁶ consistent with the analysis of tissue sections from our patient. Moreover, the speckled ANA profile with positive anti-dsDNA and anti-SSA (Ro) antibodies in the absence of a negative rheumatoid factor and anticyclic citrullinated peptide antibodies strongly favored the diagnosis of SCLE over alternative diagnoses.²

The supraclavicular rash in our patient raises clinical suspicion for the shawl sign of dermatomyositis, which also is associated with musculoskeletal pain and photosensitivity. In addition, skin biopsy revealed vacuolar alteration of the basement membrane zoneand dermal mucin in both lupus erythematosus and dermatomyositis; therefore, skin biopsy is of little use in distinguishing the 2 conditions, and antibody testing must be performed. Although anti-SSA (Ro) antibodies commonly are associated with SCLE, there are reports involving positivity for the extractable nuclear antigen in cases of dermatomyositis.¹⁷ Based on our patient’s current drug regimen, including that of a known offending agent for SCLE, a presumptive diagnosis of TAILS was made. Following withdrawal of certolizumab pegol injections and subsequent resolution of the skin lesions, our patient was given a definitive diagnosis of TAILS based on clinical and pathological assessments.

The clinical diagnosis of TAILS should be made according to the triad of at least 1 serologic and 1 nonserologic American College of Rheumatology criteria, such as anti-SSA (Ro) antibodies and a photosensitive rash, respectively, as well as a relationship between the onset of symptoms and TNF-α inhibitor therapy.¹⁸ Both the definitive diagnosis and the treatment of TAILS can be made via withdrawal of the TNF-α inhibitor, which was true in our case whereby chronologically the onset of use with a TNF-α inhibitor was associated with disease onset. Furthermore, withdrawal led to complete improvement of all signs and symptoms, collectively supporting a diagnosis of TAILS. Notably, switching to a different TNF-α inhibitor has been shown to be safe and effective.¹⁹

To the Editor:

Tumor necrosis factor α (TNF-α) inhibitor–induced lupuslike syndrome (TAILS) is a newly described entity that refers to the onset of subacute cutaneous lupus erythematosus (SCLE) during drug therapy with TNF-α antagonists. The condition is unique because it is thought to occur via a separate pathophysiologic mechanism than all other agents implicated in the development of drug-induced lupus erythematosus (DILE). Infliximab and etanercept are the 2 most common TNF-α antagonists associated with TAILS. Although rare, adalimumab, golimumab, and certolizumab pegol have been reported to induce this state of autoimmunity. We report an uncommon presentation of TAILS in a patient taking certolizumab pegol with a brief discussion of the pathogenesis underlying TAILS.

A 71-year-old woman presented to the dermatology clinic with a rash located on the arms, face, and trunk that she reported as having been present for months. She had a medical history of rheumatoid arthritis and currently was receiving certolizumab pegol injections. Physical examination revealed erythematous patches and plaques with overlying scaling and evidence of atrophic scarring on sun-exposed areas of the body. The lesions predominantly were in a symmetrical distribution across the extensor surfaces of both outer arms as well as the posterior superior thoracic region extending anteriorly along the bilateral supraclavicular area (Figures 1 and 2). A 4-mm punch biopsy was obtained and sent for histologic analysis, along with a sample of the patient’s serum for antinuclear antibody (ANA) testing.

Hematoxylin and eosin–stained tissue sections of the right superior thoracic lesions revealed epidermal atrophy, hyperkeratosis, and vacuolar alteration of the basal layer with apoptosis, consistent with a lichenoid tissue reaction. In addition, both superficial and deep perivascular and periadnexal lymphocytic infiltrates were observed as well as increased dermal mucin. Serologic testing was performed with a comprehensive ANA panel of the patient’s serum (Table). Of note, there was a speckled ANA pattern (1:1280), with elevated anti–double-stranded DNA (anti-dsDNA) and anti–Sjögren syndrome–related antigen A (anti-SSA)(also called anti-Ro antibodies) levels. The patient’s rheumatologist was consulted; certolizumab pegol was removed from the current drug regimen and switched to a daily regimen of hydroxychloroquine and prednisone. Seven weeks after discontinuation of certolizumab pegol, the patient was symptom free and without any cutaneous involvement. Based on the histologic analysis, presence of anti-SSA (Ro) autoantibodies, and the resolution of symptoms following withdrawal of anti–TNF-α therapy, a diagnosis of TAILS was made.

Subacute cutaneous lupus erythematosus, the most common subset of DILE, typically presents with annular polycyclic or papulosquamous skin eruptions on the legs; patients often test positive for anti-SSA/Ro and/or anti–Sjögren syndrome–related antigen B (also called anti-La) antibodies. Pharmaceutical agents linked to the development of SCLE are calcium channel blockers, angiotensin-converting enzyme inhibitors, thiazide diuretics, terbinafine, the chemotherapeutic agent gemcitabine, and TNF-α antagonists.^1,2 Tumor necrosis factor α antagonists are biologic agents that commonly are used in the management of systemic inflammatory diseases such as ulcerative colitis, Crohn disease, seronegative spondyloarthropathies, and rheumatoid arthritis. Among this family of therapeutics includes adalimumab (humanized monoclonal antibody), infliximab (chimeric monoclonal TNF-α antagonist), etanercept (soluble receptor fusion protein), certolizumab pegol (Fab fraction of a human IgG monoclonal antibody), and golimumab (humanized monoclonal antibody).

Tumor necrosis factor α inhibitor–induced lupuslike syndrome most commonly occurs in women in the fifth decade of life, and it is seen more often in those using infliximab or entanercept.³ Although reports do exist, TAILS rarely complicates treatment with adalimumab, golimumab, or certolizumab.^4,5 Due to the lack of reports, there are no diagnostic criteria nor an acceptable theory regarding the pathogenesis. In one study in France, the estimated incidence was thought to be 0.19% for infliximab and 0.18% for etanercept.⁶ Tumor necrosis factor α inhibitor–induced lupuslike syndrome is unique in that it is thought to occur by a different mechanism than that of other known offending agents in the development of DILE. Molecular mimicry, direct cytotoxicity, altered T-cell gene expression, and disruption of central immune tolerance have all been hypothesized to cause drug-induced systemic lupus erythematosus, SCLE, and chronic cutaneous lupus erythematosus. Tumor necrosis factor α inhibitors, are postulated to cause the induction of SCLE via an independent route separate from not only other drugs that cause SCLE but also all forms of DILE as a whole, making it a distinctive player within the realm of agents known to cause a lupuslike syndrome. The following hypotheses may explain this occurrence:

1. Increased humoral autoimmunity: Under normal circumstances, TNF-α activation leads to upregulation in the production of cytotoxic CD8⁺ T lymphocytes. The upregulation of CD8⁺ T lymphocytes concurrently leads to a simultaneous suppression of B lymphocytes. Inhibiting the effects of TNF-α on the other hand promotes cytotoxic T-lymphocyte suppression, leading to an increased synthesis of B cells and subsequently a state of increased humoral autoimmunity.⁷

2. Infection: The immunosuppressive effects of TNF-α inhibitors are well known, and the propensity to develop microbial infections, such as tuberculosis, is markedly increased on the use of these agents. Infections brought on by TNF-α inhibitor usage are hypothesized to induce a widespread activation of polyclonal B lymphocytes, eventually leading to the formation of antibodies against these polyclonal B lymphocytes and subsequently SCLE.⁸

3. Helper T cell (TH2) response: The inhibition of T_H1 CD4⁺ lymphocytes by TNF-α inversely leads to an increased production of T_H2 CD4⁺ lymphocytes. This increase in the levels of circulating T_H2 CD4⁺ lymphocytes brought on by the action of anti–TNF-α agents is thought to promote the development of SCLE.^9,10

4. Apoptosis theory: Molecules of TNF-α inhibitors are capable of binding to TNF-α receptors on the cell surface. In doing so, cellular apoptosis is triggered, resulting in the release of nucleosomal autoantigens from the apoptotic cells. In susceptible individuals, autoantibodies then begin to form against the nucleosomal autoantigens, leading to an autoimmune reaction that is characterized by SCLE.^11,12

Major histone compatibility (MHC) antigen testing performed by Sontheimer et al¹² established the presence of the HLA class I, HLA-B8, and/or HLA-DR3 haplotypes in patients with SCLE.^13,14 Furthermore, there is a well-known association between the antinuclear profile of known SCLE patients and the presence of anti-SSA (Ro) antibodies.¹³ Therefore, we propose that in susceptible individuals, such as those with the HLA class I, HLA-B8, or HLA-DR3 haplotypes, the initiation of a TNF-α inhibitor causes cellular apoptosis with the subsequent release of nucleosomal and cytoplasmic components (namely that of the Ro autoantigens), inducing a state of autoimmunity. An ensuing immunogenic response is then initiated in predisposed individuals for which anti-SSA (Ro) autoantibodies are produced against these previously mentioned autoantigens.

Drug-induced SCLE is most common in females (71%), with a median age of 58 years. The most common site of cutaneous manifestations is the legs.¹⁵ Although our patient was in the eighth decade of life with predominant cutaneous involvement of the upper extremity, the erythematous plaques with a symmetric, annular, polycyclic appearance in photosensitive regions raised a heightened suspicion for lupus erythematosus. Histology classically involves an interface dermatitis with vacuolar or hydropic change and lymphocytic infiltrates,¹⁶ consistent with the analysis of tissue sections from our patient. Moreover, the speckled ANA profile with positive anti-dsDNA and anti-SSA (Ro) antibodies in the absence of a negative rheumatoid factor and anticyclic citrullinated peptide antibodies strongly favored the diagnosis of SCLE over alternative diagnoses.²

The supraclavicular rash in our patient raises clinical suspicion for the shawl sign of dermatomyositis, which also is associated with musculoskeletal pain and photosensitivity. In addition, skin biopsy revealed vacuolar alteration of the basement membrane zoneand dermal mucin in both lupus erythematosus and dermatomyositis; therefore, skin biopsy is of little use in distinguishing the 2 conditions, and antibody testing must be performed. Although anti-SSA (Ro) antibodies commonly are associated with SCLE, there are reports involving positivity for the extractable nuclear antigen in cases of dermatomyositis.¹⁷ Based on our patient’s current drug regimen, including that of a known offending agent for SCLE, a presumptive diagnosis of TAILS was made. Following withdrawal of certolizumab pegol injections and subsequent resolution of the skin lesions, our patient was given a definitive diagnosis of TAILS based on clinical and pathological assessments.

The clinical diagnosis of TAILS should be made according to the triad of at least 1 serologic and 1 nonserologic American College of Rheumatology criteria, such as anti-SSA (Ro) antibodies and a photosensitive rash, respectively, as well as a relationship between the onset of symptoms and TNF-α inhibitor therapy.¹⁸ Both the definitive diagnosis and the treatment of TAILS can be made via withdrawal of the TNF-α inhibitor, which was true in our case whereby chronologically the onset of use with a TNF-α inhibitor was associated with disease onset. Furthermore, withdrawal led to complete improvement of all signs and symptoms, collectively supporting a diagnosis of TAILS. Notably, switching to a different TNF-α inhibitor has been shown to be safe and effective.¹⁹

Poly-L-lactic acid (PLLA) is a synthetic biologic polymer that is suspended in solution and can be injected for soft-tissue augmentation. The stimulatory molecule functions to increase collagen synthesis as a by-product of its degradation.¹ Poly-L-lactic acid measures 40 to 63 μm and is irregularly shaped, which inhibits product mobility and allows for precise tissue augmentation.² Clinical trials of injectable PLLA have proven its safety with no reported cases of infection, allergies, or serious adverse reactions.^3-5 The most common patient concerns generally are transient in nature, such as swelling, tenderness, pain, bruising, and bleeding. Persistent adverse events of PLLA primarily are papule and nodule formation.⁶ Clinical trials showed a variable incidence of papule/nodule formation between 6% and 44%.² Nodule formation remains a major challenge to achieving optimal results from injectable PLLA. We present a case in which a hyperdiluted formulation of PLLA produced a relatively acute (3-week) onset of multiple nodule formations dispersed on the anterior neck. The nodules were resistant to less-invasive treatment modalities and were further requested to be surgically excised.

Case Report

A 38-year-old woman presented for soft-tissue augmentation of the anterior neck using PLLA to achieve correction of skin laxity and static rhytides. She had a history of successful PLLA injections in the temples, knees, chest, and buttocks over a 5-year period. Forty-eight hours prior to injection, 1 PLLA vial was hydrated with 7 cc bacteriostatic water by using a continuous rotation suspension method over the 48 hours. On the day of injection, the PLLA was further hyperdiluted with 2 cc of 2% lidocaine and an additional 7 cc of bacteriostatic water, for a total of 16 cc diluent. The product was injected using a cannula in the anterior and lateral neck. According to the patient, 3 weeks after the procedure she noticed that some nodules began to form at the cannula insertion sites, while others formed distant from those sites; a total of 10 nodules had formed on the anterior neck (Figure 1).

The bacteriostatic water, lidocaine, and PLLA vial were all confirmed not to be expired. The manufacturer was contacted, and no other adverse reactions have been reported with this particular lot number of PLLA. The nodules initially were treated with injections of large boluses of bacteriostatic saline, which was ineffective. Treatment was then attempted using injections of a solution containing 1.0 mL of 5-fluorouracil (5-FU) 50 mg/mL, 0.4 mL of dexamethasone 4 mg/mL, 0.1 mL of triamcinolone 10 mg/mL, and 0.3 mL hyaluronidase. A series of 4 injections was performed in 2- to 4-week intervals. Two of the nodules resolved completely with this treatment. The remaining 8 nodules subjectively improved in size and softened to palpation but did not resolve completely. At 2 of the injection sites, treatment was complicated with steroid atrophy of the overlying skin. At the patient’s request, the remaining nodules were surgically excised (Figure 2). Histopathology revealed exogenous foreign material consistent with dermal filler (Figure 3).

Comment

Causes of Nodule Formation—Two factors that could contribute to nodule formation are inadequate dispersion of molecules and an insufficient volume of dilution. One study demonstrated that hydration for at least 24 hours is required for adequate PLLA dispersion. Furthermore, sonification for 5 minutes after a 2-hour hydration disperses molecules similarly to the 48-hour hydration.⁷ The PLLA in the current case was hydrated for 48 hours using a continuous rotation suspension method. Therefore, this likely did not play a role in our patient’s nodule formation. The volume of dilution has been shown to impact the incidence of nodule formation.⁸ At present, most injectors (60.4%) reconstitute each vial of PLLA with 9 to 10 mL of diluent.⁹ The PLLA in our patient was reconstituted with 16 mL; therefore, we believe that the anatomic location was the main contributor of nodule formation.

Fillers should be injected in the subcutaneous or deep dermal plane of tissue.¹⁰ The platysma is a superficial muscle that is intimately involved with the overlying skin of the anterior neck, and injections in this area could inadvertently be intramuscular. Intramuscular injections have a higher incidence of nodule formation.¹ Our patient had prior PLLA injections without adverse reactions in numerous other sites, supporting the claim that the anterior neck is prone to nodule formation from PLLA injections.

Management of Noninflammatory Nodules—Initial treatment of nodules with injections of saline was ineffective. This treatment can be used in an attempt to disperse the product. Treatment was then attempted with injections of a solution containing 5-FU, dexamethasone, triamcinolone, and hyaluronidase. Combination steroid therapy may be superior to monotherapy.¹¹ Dexamethasone may exhibit a cytoprotective effect on cells such as fibroblasts when used in combination with triamcinolone; monotherapy steroid use with triamcinolone alone induced fibroblast apoptosis at a much higher level.¹² Hyaluronidase works by breaking cross-links in hyaluronic acid, a glycosaminoglycan polysaccharide prevalent in the skin and connective tissue, which increases tissue permeability and aids in delivery of the other injected fluids.¹³ 5-Fluorouracil is an antimetabolite that may aid in treating nodules by discouraging additional fibroblast activity and fibrosis.¹⁴

The combination of 5-FU, dexamethasone, and triamcinolone has been shown to be successful in treating noninflammatory nodules in as few as 1 treatment.¹⁴ In our patient, hyaluronidase also was used in an attempt to aid delivery of the other injected fluids. If nodules do not resolve with 1 injection, it is recommended to wait at least 8 weeks before repeating the injection to prevent steroid atrophy of the overlying skin. In our patient, the intramuscular placement of the filler contributed to the nodules being resistant to this treatment. During excision, the nodules were tightly embedded in the underlying tissue, which may have prevented the solution from being delivered to the nodule (Figure 2).

Conclusion

Injectable PLLA is approved by the US Food and Drug Administration for soft-tissue augmentation of deep nasolabial folds and facial wrinkles. Off-label use of this product may cause higher incidence of nodule formation. Injectors should be cautious of injecting into the anterior neck. If nodules do form, treatment can be attempted with injections of saline. If that treatment fails, another treatment option is injection(s) of a mixture of 5-FU, dexamethasone, triamcinolone, and hyaluronidase separated by 8-week intervals. Finally, surgical excision is a viable treatment option, as presented in our case.

Poly-L-lactic acid (PLLA) is a synthetic biologic polymer that is suspended in solution and can be injected for soft-tissue augmentation. The stimulatory molecule functions to increase collagen synthesis as a by-product of its degradation.¹ Poly-L-lactic acid measures 40 to 63 μm and is irregularly shaped, which inhibits product mobility and allows for precise tissue augmentation.² Clinical trials of injectable PLLA have proven its safety with no reported cases of infection, allergies, or serious adverse reactions.^3-5 The most common patient concerns generally are transient in nature, such as swelling, tenderness, pain, bruising, and bleeding. Persistent adverse events of PLLA primarily are papule and nodule formation.⁶ Clinical trials showed a variable incidence of papule/nodule formation between 6% and 44%.² Nodule formation remains a major challenge to achieving optimal results from injectable PLLA. We present a case in which a hyperdiluted formulation of PLLA produced a relatively acute (3-week) onset of multiple nodule formations dispersed on the anterior neck. The nodules were resistant to less-invasive treatment modalities and were further requested to be surgically excised.

Case Report

A 38-year-old woman presented for soft-tissue augmentation of the anterior neck using PLLA to achieve correction of skin laxity and static rhytides. She had a history of successful PLLA injections in the temples, knees, chest, and buttocks over a 5-year period. Forty-eight hours prior to injection, 1 PLLA vial was hydrated with 7 cc bacteriostatic water by using a continuous rotation suspension method over the 48 hours. On the day of injection, the PLLA was further hyperdiluted with 2 cc of 2% lidocaine and an additional 7 cc of bacteriostatic water, for a total of 16 cc diluent. The product was injected using a cannula in the anterior and lateral neck. According to the patient, 3 weeks after the procedure she noticed that some nodules began to form at the cannula insertion sites, while others formed distant from those sites; a total of 10 nodules had formed on the anterior neck (Figure 1).

The bacteriostatic water, lidocaine, and PLLA vial were all confirmed not to be expired. The manufacturer was contacted, and no other adverse reactions have been reported with this particular lot number of PLLA. The nodules initially were treated with injections of large boluses of bacteriostatic saline, which was ineffective. Treatment was then attempted using injections of a solution containing 1.0 mL of 5-fluorouracil (5-FU) 50 mg/mL, 0.4 mL of dexamethasone 4 mg/mL, 0.1 mL of triamcinolone 10 mg/mL, and 0.3 mL hyaluronidase. A series of 4 injections was performed in 2- to 4-week intervals. Two of the nodules resolved completely with this treatment. The remaining 8 nodules subjectively improved in size and softened to palpation but did not resolve completely. At 2 of the injection sites, treatment was complicated with steroid atrophy of the overlying skin. At the patient’s request, the remaining nodules were surgically excised (Figure 2). Histopathology revealed exogenous foreign material consistent with dermal filler (Figure 3).

Comment

Causes of Nodule Formation—Two factors that could contribute to nodule formation are inadequate dispersion of molecules and an insufficient volume of dilution. One study demonstrated that hydration for at least 24 hours is required for adequate PLLA dispersion. Furthermore, sonification for 5 minutes after a 2-hour hydration disperses molecules similarly to the 48-hour hydration.⁷ The PLLA in the current case was hydrated for 48 hours using a continuous rotation suspension method. Therefore, this likely did not play a role in our patient’s nodule formation. The volume of dilution has been shown to impact the incidence of nodule formation.⁸ At present, most injectors (60.4%) reconstitute each vial of PLLA with 9 to 10 mL of diluent.⁹ The PLLA in our patient was reconstituted with 16 mL; therefore, we believe that the anatomic location was the main contributor of nodule formation.

Fillers should be injected in the subcutaneous or deep dermal plane of tissue.¹⁰ The platysma is a superficial muscle that is intimately involved with the overlying skin of the anterior neck, and injections in this area could inadvertently be intramuscular. Intramuscular injections have a higher incidence of nodule formation.¹ Our patient had prior PLLA injections without adverse reactions in numerous other sites, supporting the claim that the anterior neck is prone to nodule formation from PLLA injections.

Management of Noninflammatory Nodules—Initial treatment of nodules with injections of saline was ineffective. This treatment can be used in an attempt to disperse the product. Treatment was then attempted with injections of a solution containing 5-FU, dexamethasone, triamcinolone, and hyaluronidase. Combination steroid therapy may be superior to monotherapy.¹¹ Dexamethasone may exhibit a cytoprotective effect on cells such as fibroblasts when used in combination with triamcinolone; monotherapy steroid use with triamcinolone alone induced fibroblast apoptosis at a much higher level.¹² Hyaluronidase works by breaking cross-links in hyaluronic acid, a glycosaminoglycan polysaccharide prevalent in the skin and connective tissue, which increases tissue permeability and aids in delivery of the other injected fluids.¹³ 5-Fluorouracil is an antimetabolite that may aid in treating nodules by discouraging additional fibroblast activity and fibrosis.¹⁴

The combination of 5-FU, dexamethasone, and triamcinolone has been shown to be successful in treating noninflammatory nodules in as few as 1 treatment.¹⁴ In our patient, hyaluronidase also was used in an attempt to aid delivery of the other injected fluids. If nodules do not resolve with 1 injection, it is recommended to wait at least 8 weeks before repeating the injection to prevent steroid atrophy of the overlying skin. In our patient, the intramuscular placement of the filler contributed to the nodules being resistant to this treatment. During excision, the nodules were tightly embedded in the underlying tissue, which may have prevented the solution from being delivered to the nodule (Figure 2).

Conclusion

Injectable PLLA is approved by the US Food and Drug Administration for soft-tissue augmentation of deep nasolabial folds and facial wrinkles. Off-label use of this product may cause higher incidence of nodule formation. Injectors should be cautious of injecting into the anterior neck. If nodules do form, treatment can be attempted with injections of saline. If that treatment fails, another treatment option is injection(s) of a mixture of 5-FU, dexamethasone, triamcinolone, and hyaluronidase separated by 8-week intervals. Finally, surgical excision is a viable treatment option, as presented in our case.

Poly-L-lactic acid (PLLA) is a synthetic biologic polymer that is suspended in solution and can be injected for soft-tissue augmentation. The stimulatory molecule functions to increase collagen synthesis as a by-product of its degradation.¹ Poly-L-lactic acid measures 40 to 63 μm and is irregularly shaped, which inhibits product mobility and allows for precise tissue augmentation.² Clinical trials of injectable PLLA have proven its safety with no reported cases of infection, allergies, or serious adverse reactions.^3-5 The most common patient concerns generally are transient in nature, such as swelling, tenderness, pain, bruising, and bleeding. Persistent adverse events of PLLA primarily are papule and nodule formation.⁶ Clinical trials showed a variable incidence of papule/nodule formation between 6% and 44%.² Nodule formation remains a major challenge to achieving optimal results from injectable PLLA. We present a case in which a hyperdiluted formulation of PLLA produced a relatively acute (3-week) onset of multiple nodule formations dispersed on the anterior neck. The nodules were resistant to less-invasive treatment modalities and were further requested to be surgically excised.

Case Report

A 38-year-old woman presented for soft-tissue augmentation of the anterior neck using PLLA to achieve correction of skin laxity and static rhytides. She had a history of successful PLLA injections in the temples, knees, chest, and buttocks over a 5-year period. Forty-eight hours prior to injection, 1 PLLA vial was hydrated with 7 cc bacteriostatic water by using a continuous rotation suspension method over the 48 hours. On the day of injection, the PLLA was further hyperdiluted with 2 cc of 2% lidocaine and an additional 7 cc of bacteriostatic water, for a total of 16 cc diluent. The product was injected using a cannula in the anterior and lateral neck. According to the patient, 3 weeks after the procedure she noticed that some nodules began to form at the cannula insertion sites, while others formed distant from those sites; a total of 10 nodules had formed on the anterior neck (Figure 1).

The bacteriostatic water, lidocaine, and PLLA vial were all confirmed not to be expired. The manufacturer was contacted, and no other adverse reactions have been reported with this particular lot number of PLLA. The nodules initially were treated with injections of large boluses of bacteriostatic saline, which was ineffective. Treatment was then attempted using injections of a solution containing 1.0 mL of 5-fluorouracil (5-FU) 50 mg/mL, 0.4 mL of dexamethasone 4 mg/mL, 0.1 mL of triamcinolone 10 mg/mL, and 0.3 mL hyaluronidase. A series of 4 injections was performed in 2- to 4-week intervals. Two of the nodules resolved completely with this treatment. The remaining 8 nodules subjectively improved in size and softened to palpation but did not resolve completely. At 2 of the injection sites, treatment was complicated with steroid atrophy of the overlying skin. At the patient’s request, the remaining nodules were surgically excised (Figure 2). Histopathology revealed exogenous foreign material consistent with dermal filler (Figure 3).

Comment

Causes of Nodule Formation—Two factors that could contribute to nodule formation are inadequate dispersion of molecules and an insufficient volume of dilution. One study demonstrated that hydration for at least 24 hours is required for adequate PLLA dispersion. Furthermore, sonification for 5 minutes after a 2-hour hydration disperses molecules similarly to the 48-hour hydration.⁷ The PLLA in the current case was hydrated for 48 hours using a continuous rotation suspension method. Therefore, this likely did not play a role in our patient’s nodule formation. The volume of dilution has been shown to impact the incidence of nodule formation.⁸ At present, most injectors (60.4%) reconstitute each vial of PLLA with 9 to 10 mL of diluent.⁹ The PLLA in our patient was reconstituted with 16 mL; therefore, we believe that the anatomic location was the main contributor of nodule formation.

Fillers should be injected in the subcutaneous or deep dermal plane of tissue.¹⁰ The platysma is a superficial muscle that is intimately involved with the overlying skin of the anterior neck, and injections in this area could inadvertently be intramuscular. Intramuscular injections have a higher incidence of nodule formation.¹ Our patient had prior PLLA injections without adverse reactions in numerous other sites, supporting the claim that the anterior neck is prone to nodule formation from PLLA injections.

Management of Noninflammatory Nodules—Initial treatment of nodules with injections of saline was ineffective. This treatment can be used in an attempt to disperse the product. Treatment was then attempted with injections of a solution containing 5-FU, dexamethasone, triamcinolone, and hyaluronidase. Combination steroid therapy may be superior to monotherapy.¹¹ Dexamethasone may exhibit a cytoprotective effect on cells such as fibroblasts when used in combination with triamcinolone; monotherapy steroid use with triamcinolone alone induced fibroblast apoptosis at a much higher level.¹² Hyaluronidase works by breaking cross-links in hyaluronic acid, a glycosaminoglycan polysaccharide prevalent in the skin and connective tissue, which increases tissue permeability and aids in delivery of the other injected fluids.¹³ 5-Fluorouracil is an antimetabolite that may aid in treating nodules by discouraging additional fibroblast activity and fibrosis.¹⁴

The combination of 5-FU, dexamethasone, and triamcinolone has been shown to be successful in treating noninflammatory nodules in as few as 1 treatment.¹⁴ In our patient, hyaluronidase also was used in an attempt to aid delivery of the other injected fluids. If nodules do not resolve with 1 injection, it is recommended to wait at least 8 weeks before repeating the injection to prevent steroid atrophy of the overlying skin. In our patient, the intramuscular placement of the filler contributed to the nodules being resistant to this treatment. During excision, the nodules were tightly embedded in the underlying tissue, which may have prevented the solution from being delivered to the nodule (Figure 2).

Conclusion

Injectable PLLA is approved by the US Food and Drug Administration for soft-tissue augmentation of deep nasolabial folds and facial wrinkles. Off-label use of this product may cause higher incidence of nodule formation. Injectors should be cautious of injecting into the anterior neck. If nodules do form, treatment can be attempted with injections of saline. If that treatment fails, another treatment option is injection(s) of a mixture of 5-FU, dexamethasone, triamcinolone, and hyaluronidase separated by 8-week intervals. Finally, surgical excision is a viable treatment option, as presented in our case.

CHICAGO – Mortality rates from melanoma have fallen in recent years, likely due to the introduction of checkpoint inhibitors, according to a new analysis of the National Cancer Institute SEER database between 1975 and 2019.

“This is very encouraging data and represents the real-world effectiveness of these therapies. The cost of these therapies can be prohibitive for universal treatment access, so the ways to address the accessibility of these treatments and the health care costs need to be supported,” said lead author Navkirat Kaur Kahlon MD, a hematology/oncology fellow at the University of Toledo (Ohio). The study was presented at the annual meeting of the American Society of Clinical Oncology.

According to the American Cancer Society, the 5-year mortality for regional melanoma metastasis is 68%, and 30% for distant metastasis. However, these numbers may underestimate current survival. “People now being diagnosed with melanoma may have a better outlook than these numbers show. Treatments have improved over time, and these numbers are based on people who were diagnosed and treated at least 5 years earlier,” the American Cancer Society wrote.

Other studies have found similar trends. According to Cancer Research UK, 5-year melanoma skin cancer survival approximately doubled, from 46% to 90%, between 1971 and 2010. And, 1-year survival increased from 74% to 96%, but these improvements predated immune checkpoint inhibitors. An analysis of the Canadian Cancer Registry and Canadian Vital Statistics found an increasing incidence of melanoma, but a drop in mortality since 2013. A study of melanoma outcomes in Hungary also found increased incidence, while mortality declined by 16.55% between 2011 and 2019 (P =.013).

“These new drugs, which include immunotherapies and targeted therapies, are effective treatments in the clinical trial data, so the magnitude of drop seen in population mortality was not surprising but very exciting,” Dr. Kahlon said.

The findings are encouraging, but prevention remains the most important strategy. “The utility of sun-protective strategies and policies should be encouraged,” she added.

Cytotoxic chemotherapy has poor efficacy against metastatic melanoma, but novel therapies such as checkpoint inhibitors increased expected survival from months to years. “Given the magnitude of benefit compared to traditional chemotherapy in clinical trials, we decided to see if the real-world population is deriving the same benefit,” Dr. Kahlon said.

The researchers found that the annual percentage change (APC) melanoma mortality rate (MMR) was +1.65% between 1975 and 1988 (P < .01). The APC was 0.01% between 1988 and 2013, which was not statistically significant (P = .85). Between 2013 and 2017, APC was –6.24% (P < .01), and it was –1.56% between 2017 and 2019 (P = .53).

The increase in melanoma mortality between 1975 and 1988 may be due to changes in the way that SEER data was collected. “It is possible that this increase was at least in part due to better capturing of the data. There may also be a contribution of increased mortality due to increased incidence of diagnoses related to increased UV exposure. From the 1920s, increased sun exposure and bronzed skin became fashionable. In the 1940s-1960s, tanning oils and lotions became more popular, and there may have been an increase in UV exposure during that time, which later led to an increase in diagnosis and, without effective therapies, mortality. Further, the use of indoor tanning beds from the 1970s onward may have contributed to increased UV exposure, incidence, and mortality,” she said.

On the other hand, the researchers noted a slowing of mortality reduction between 2017 and 2019. This was not a surprise, Dr. Kahlon said, since by that time most novel therapies were being introduced in the adjuvant setting. “The mortality benefit, if any, from adjuvant treatments is seen over a longer period and may not yet be captured in SEER data. Even the clinical trial data for most of these treatments have not shown an overall survival advantage and require more time for the data to mature. It will be interesting to see how these trends change in the near future,” Dr. Kahlon said.

The study was limited by its retrospective nature. Dr. Kahlon has no relevant financial disclosures.

CHICAGO – Mortality rates from melanoma have fallen in recent years, likely due to the introduction of checkpoint inhibitors, according to a new analysis of the National Cancer Institute SEER database between 1975 and 2019.

“This is very encouraging data and represents the real-world effectiveness of these therapies. The cost of these therapies can be prohibitive for universal treatment access, so the ways to address the accessibility of these treatments and the health care costs need to be supported,” said lead author Navkirat Kaur Kahlon MD, a hematology/oncology fellow at the University of Toledo (Ohio). The study was presented at the annual meeting of the American Society of Clinical Oncology.

According to the American Cancer Society, the 5-year mortality for regional melanoma metastasis is 68%, and 30% for distant metastasis. However, these numbers may underestimate current survival. “People now being diagnosed with melanoma may have a better outlook than these numbers show. Treatments have improved over time, and these numbers are based on people who were diagnosed and treated at least 5 years earlier,” the American Cancer Society wrote.

Other studies have found similar trends. According to Cancer Research UK, 5-year melanoma skin cancer survival approximately doubled, from 46% to 90%, between 1971 and 2010. And, 1-year survival increased from 74% to 96%, but these improvements predated immune checkpoint inhibitors. An analysis of the Canadian Cancer Registry and Canadian Vital Statistics found an increasing incidence of melanoma, but a drop in mortality since 2013. A study of melanoma outcomes in Hungary also found increased incidence, while mortality declined by 16.55% between 2011 and 2019 (P =.013).

“These new drugs, which include immunotherapies and targeted therapies, are effective treatments in the clinical trial data, so the magnitude of drop seen in population mortality was not surprising but very exciting,” Dr. Kahlon said.

The findings are encouraging, but prevention remains the most important strategy. “The utility of sun-protective strategies and policies should be encouraged,” she added.

Cytotoxic chemotherapy has poor efficacy against metastatic melanoma, but novel therapies such as checkpoint inhibitors increased expected survival from months to years. “Given the magnitude of benefit compared to traditional chemotherapy in clinical trials, we decided to see if the real-world population is deriving the same benefit,” Dr. Kahlon said.

The researchers found that the annual percentage change (APC) melanoma mortality rate (MMR) was +1.65% between 1975 and 1988 (P < .01). The APC was 0.01% between 1988 and 2013, which was not statistically significant (P = .85). Between 2013 and 2017, APC was –6.24% (P < .01), and it was –1.56% between 2017 and 2019 (P = .53).

The increase in melanoma mortality between 1975 and 1988 may be due to changes in the way that SEER data was collected. “It is possible that this increase was at least in part due to better capturing of the data. There may also be a contribution of increased mortality due to increased incidence of diagnoses related to increased UV exposure. From the 1920s, increased sun exposure and bronzed skin became fashionable. In the 1940s-1960s, tanning oils and lotions became more popular, and there may have been an increase in UV exposure during that time, which later led to an increase in diagnosis and, without effective therapies, mortality. Further, the use of indoor tanning beds from the 1970s onward may have contributed to increased UV exposure, incidence, and mortality,” she said.

On the other hand, the researchers noted a slowing of mortality reduction between 2017 and 2019. This was not a surprise, Dr. Kahlon said, since by that time most novel therapies were being introduced in the adjuvant setting. “The mortality benefit, if any, from adjuvant treatments is seen over a longer period and may not yet be captured in SEER data. Even the clinical trial data for most of these treatments have not shown an overall survival advantage and require more time for the data to mature. It will be interesting to see how these trends change in the near future,” Dr. Kahlon said.

The study was limited by its retrospective nature. Dr. Kahlon has no relevant financial disclosures.

CHICAGO – Mortality rates from melanoma have fallen in recent years, likely due to the introduction of checkpoint inhibitors, according to a new analysis of the National Cancer Institute SEER database between 1975 and 2019.

“This is very encouraging data and represents the real-world effectiveness of these therapies. The cost of these therapies can be prohibitive for universal treatment access, so the ways to address the accessibility of these treatments and the health care costs need to be supported,” said lead author Navkirat Kaur Kahlon MD, a hematology/oncology fellow at the University of Toledo (Ohio). The study was presented at the annual meeting of the American Society of Clinical Oncology.

According to the American Cancer Society, the 5-year mortality for regional melanoma metastasis is 68%, and 30% for distant metastasis. However, these numbers may underestimate current survival. “People now being diagnosed with melanoma may have a better outlook than these numbers show. Treatments have improved over time, and these numbers are based on people who were diagnosed and treated at least 5 years earlier,” the American Cancer Society wrote.

Other studies have found similar trends. According to Cancer Research UK, 5-year melanoma skin cancer survival approximately doubled, from 46% to 90%, between 1971 and 2010. And, 1-year survival increased from 74% to 96%, but these improvements predated immune checkpoint inhibitors. An analysis of the Canadian Cancer Registry and Canadian Vital Statistics found an increasing incidence of melanoma, but a drop in mortality since 2013. A study of melanoma outcomes in Hungary also found increased incidence, while mortality declined by 16.55% between 2011 and 2019 (P =.013).

“These new drugs, which include immunotherapies and targeted therapies, are effective treatments in the clinical trial data, so the magnitude of drop seen in population mortality was not surprising but very exciting,” Dr. Kahlon said.

The findings are encouraging, but prevention remains the most important strategy. “The utility of sun-protective strategies and policies should be encouraged,” she added.

Cytotoxic chemotherapy has poor efficacy against metastatic melanoma, but novel therapies such as checkpoint inhibitors increased expected survival from months to years. “Given the magnitude of benefit compared to traditional chemotherapy in clinical trials, we decided to see if the real-world population is deriving the same benefit,” Dr. Kahlon said.

The researchers found that the annual percentage change (APC) melanoma mortality rate (MMR) was +1.65% between 1975 and 1988 (P < .01). The APC was 0.01% between 1988 and 2013, which was not statistically significant (P = .85). Between 2013 and 2017, APC was –6.24% (P < .01), and it was –1.56% between 2017 and 2019 (P = .53).

The increase in melanoma mortality between 1975 and 1988 may be due to changes in the way that SEER data was collected. “It is possible that this increase was at least in part due to better capturing of the data. There may also be a contribution of increased mortality due to increased incidence of diagnoses related to increased UV exposure. From the 1920s, increased sun exposure and bronzed skin became fashionable. In the 1940s-1960s, tanning oils and lotions became more popular, and there may have been an increase in UV exposure during that time, which later led to an increase in diagnosis and, without effective therapies, mortality. Further, the use of indoor tanning beds from the 1970s onward may have contributed to increased UV exposure, incidence, and mortality,” she said.

On the other hand, the researchers noted a slowing of mortality reduction between 2017 and 2019. This was not a surprise, Dr. Kahlon said, since by that time most novel therapies were being introduced in the adjuvant setting. “The mortality benefit, if any, from adjuvant treatments is seen over a longer period and may not yet be captured in SEER data. Even the clinical trial data for most of these treatments have not shown an overall survival advantage and require more time for the data to mature. It will be interesting to see how these trends change in the near future,” Dr. Kahlon said.

The study was limited by its retrospective nature. Dr. Kahlon has no relevant financial disclosures.

On the 50th anniversary of Title IX’s inception, the Biden administration has proposed changes to the law that would protect transgender students and assault survivors on college and university campuses.

With these changes, the protections provided by Title IX – a civil rights law that prohibits sex-based discrimination in schools that receive federal funding – would now be extended to students who identify as trans. The update would ensure that government-funded schools make proper accommodations for a trans student population, such as allowing students to use bathrooms and other facilities that align with their gender identity, and enforcing the use of students’ correct pronouns.

The revisions also seek to undo amendments made to the law by Betsy DeVos, who was secretary of education during the Trump presidency, which strengthened due process protections for students accused of sexual assault and narrowed the definition of sexual harassment. These rules “weakened protections for survivors of sexual assault and diminished the promise of an education free from discrimination,” the Biden administration said.

“Our proposed changes will allow us to continue that progress and ensure all our nation’s students – no matter where they live, who they are, or whom they love – can learn, grow, and thrive in school,” Education Secretary Miguel Cardona, PhD, said in a news release. “We welcome public comment on these critical regulations so we can further the Biden-Harris Administration’s mission of creating educational environments free from sex discrimination and sexual violence.”

The revisions will go through a long period of public comment before they are set into law. Still, the proposed changes mark a way forward for trans students who are not explicitly protected under Title IX, and they offer solace to assault survivors who may have felt discouraged to come forward and report under Ms. DeVos’s rules.

“The proposed regulations reflect the [Education] Department’s commitment to give full effect to Title IX, ensuring that no person experiences sex discrimination in education, and that school procedures for addressing complaints of sex discrimination, including sexual violence and other forms of sex-based harassment, are clear, effective, and fair to all involved,” said Catherine Lhamon, JD, assistant secretary for the Education Department’s Office Of Civil Rights.

More specific rules about transgender students’ participation in school sports are still to come.

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

On the 50th anniversary of Title IX’s inception, the Biden administration has proposed changes to the law that would protect transgender students and assault survivors on college and university campuses.

With these changes, the protections provided by Title IX – a civil rights law that prohibits sex-based discrimination in schools that receive federal funding – would now be extended to students who identify as trans. The update would ensure that government-funded schools make proper accommodations for a trans student population, such as allowing students to use bathrooms and other facilities that align with their gender identity, and enforcing the use of students’ correct pronouns.

The revisions also seek to undo amendments made to the law by Betsy DeVos, who was secretary of education during the Trump presidency, which strengthened due process protections for students accused of sexual assault and narrowed the definition of sexual harassment. These rules “weakened protections for survivors of sexual assault and diminished the promise of an education free from discrimination,” the Biden administration said.

“Our proposed changes will allow us to continue that progress and ensure all our nation’s students – no matter where they live, who they are, or whom they love – can learn, grow, and thrive in school,” Education Secretary Miguel Cardona, PhD, said in a news release. “We welcome public comment on these critical regulations so we can further the Biden-Harris Administration’s mission of creating educational environments free from sex discrimination and sexual violence.”

The revisions will go through a long period of public comment before they are set into law. Still, the proposed changes mark a way forward for trans students who are not explicitly protected under Title IX, and they offer solace to assault survivors who may have felt discouraged to come forward and report under Ms. DeVos’s rules.

“The proposed regulations reflect the [Education] Department’s commitment to give full effect to Title IX, ensuring that no person experiences sex discrimination in education, and that school procedures for addressing complaints of sex discrimination, including sexual violence and other forms of sex-based harassment, are clear, effective, and fair to all involved,” said Catherine Lhamon, JD, assistant secretary for the Education Department’s Office Of Civil Rights.

More specific rules about transgender students’ participation in school sports are still to come.

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

On the 50th anniversary of Title IX’s inception, the Biden administration has proposed changes to the law that would protect transgender students and assault survivors on college and university campuses.

With these changes, the protections provided by Title IX – a civil rights law that prohibits sex-based discrimination in schools that receive federal funding – would now be extended to students who identify as trans. The update would ensure that government-funded schools make proper accommodations for a trans student population, such as allowing students to use bathrooms and other facilities that align with their gender identity, and enforcing the use of students’ correct pronouns.

The revisions also seek to undo amendments made to the law by Betsy DeVos, who was secretary of education during the Trump presidency, which strengthened due process protections for students accused of sexual assault and narrowed the definition of sexual harassment. These rules “weakened protections for survivors of sexual assault and diminished the promise of an education free from discrimination,” the Biden administration said.

“Our proposed changes will allow us to continue that progress and ensure all our nation’s students – no matter where they live, who they are, or whom they love – can learn, grow, and thrive in school,” Education Secretary Miguel Cardona, PhD, said in a news release. “We welcome public comment on these critical regulations so we can further the Biden-Harris Administration’s mission of creating educational environments free from sex discrimination and sexual violence.”

The revisions will go through a long period of public comment before they are set into law. Still, the proposed changes mark a way forward for trans students who are not explicitly protected under Title IX, and they offer solace to assault survivors who may have felt discouraged to come forward and report under Ms. DeVos’s rules.

“The proposed regulations reflect the [Education] Department’s commitment to give full effect to Title IX, ensuring that no person experiences sex discrimination in education, and that school procedures for addressing complaints of sex discrimination, including sexual violence and other forms of sex-based harassment, are clear, effective, and fair to all involved,” said Catherine Lhamon, JD, assistant secretary for the Education Department’s Office Of Civil Rights.

More specific rules about transgender students’ participation in school sports are still to come.

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

Treating keloid scars by combining excision and contact cryosurgery is a plausible way to decrease the volume of scars, results from a single-center observational study suggest.

“There is currently no consensus regarding the best treatment of keloid scars,” corresponding author Manon Artz, of the department of plastic, reconstructive, and aesthetic surgery at University Hospital of Brest (France), and colleagues wrote in a research letter published online in JAMA Dermatology.

Prompilove/Getty Images

“Earlier studies report a decreased scar volume and a substantial reduction of recurrence in keloid scars treated by cryosurgery,” they wrote. “In this study, our objective was to assess whether intramarginal excision (shaving) of the keloid scar followed by an immediate single session of contact cryosurgery is associated with decreased scar volume.”

Between March 2014 and May 2020, the researchers evaluated the approach in 31 patients with 40 keloid scars who were treated at University Hospital of Brest. Of these study participants, four were lost to follow-up, leaving 27 patients with 35 keloid scars in the final analysis. Their mean age was 24 years, 60% were female, and there was fairly even distribution of Fitzpatrick skin types II-VI.

Most of the keloid scars were located on the ear (69%) and the chest (23%), while the rest were on the head and neck. The primary outcome was reduction of keloid scar volume after 12 months, which was measured with the Vancouver scar scale. The researchers defined 80%-100% reduction in scar volume as “major,” a 50%-80% reduction as “substantial,” and a 0%-50% reduction or recurrence as “moderate.”

After 12 months, 19 scars (54%) showed a major reduction in volume, while 6 (17%) had a substantial reduction, and seven (20%) experienced no reduction. Across all keloid scars, the median scar volume decreased significantly by 81.9%.

Scar volume reduction differed by anatomical location. Specifically, 84% of ear scars showed major or substantial reduction, while 60% of scars on the chest showed a moderate reduction in scar volume or recurrence. In another key finding, the Vancouver scar scale score was reduced overall in 25 scars by 71.4%, from 7 before treatment to 5 after treatment.

“There remains no silver bullet for the treatment of keloids, but this study adds invaluable evidence that tangential excision followed by contact cryosurgery can be a viable treatment regimen with low recurrence rates,” said Marcus G. Tan, MD, who recently completed his dermatology residency at the University of Ottawa and who was asked to comment on the study. “Clinicians should exercise caution especially when treating individuals with darker skin phototypes due to their increased risk of scarring and dyspigmentation.”

Limitations of this study, he said, include a smaller study population with some patient dropouts and a lack of adverse effects reported.

The researchers and Dr. Tan reported having no financial conflicts.

Treating keloid scars by combining excision and contact cryosurgery is a plausible way to decrease the volume of scars, results from a single-center observational study suggest.

“There is currently no consensus regarding the best treatment of keloid scars,” corresponding author Manon Artz, of the department of plastic, reconstructive, and aesthetic surgery at University Hospital of Brest (France), and colleagues wrote in a research letter published online in JAMA Dermatology.

Prompilove/Getty Images

“Earlier studies report a decreased scar volume and a substantial reduction of recurrence in keloid scars treated by cryosurgery,” they wrote. “In this study, our objective was to assess whether intramarginal excision (shaving) of the keloid scar followed by an immediate single session of contact cryosurgery is associated with decreased scar volume.”

Between March 2014 and May 2020, the researchers evaluated the approach in 31 patients with 40 keloid scars who were treated at University Hospital of Brest. Of these study participants, four were lost to follow-up, leaving 27 patients with 35 keloid scars in the final analysis. Their mean age was 24 years, 60% were female, and there was fairly even distribution of Fitzpatrick skin types II-VI.

Most of the keloid scars were located on the ear (69%) and the chest (23%), while the rest were on the head and neck. The primary outcome was reduction of keloid scar volume after 12 months, which was measured with the Vancouver scar scale. The researchers defined 80%-100% reduction in scar volume as “major,” a 50%-80% reduction as “substantial,” and a 0%-50% reduction or recurrence as “moderate.”

After 12 months, 19 scars (54%) showed a major reduction in volume, while 6 (17%) had a substantial reduction, and seven (20%) experienced no reduction. Across all keloid scars, the median scar volume decreased significantly by 81.9%.

Scar volume reduction differed by anatomical location. Specifically, 84% of ear scars showed major or substantial reduction, while 60% of scars on the chest showed a moderate reduction in scar volume or recurrence. In another key finding, the Vancouver scar scale score was reduced overall in 25 scars by 71.4%, from 7 before treatment to 5 after treatment.

“There remains no silver bullet for the treatment of keloids, but this study adds invaluable evidence that tangential excision followed by contact cryosurgery can be a viable treatment regimen with low recurrence rates,” said Marcus G. Tan, MD, who recently completed his dermatology residency at the University of Ottawa and who was asked to comment on the study. “Clinicians should exercise caution especially when treating individuals with darker skin phototypes due to their increased risk of scarring and dyspigmentation.”

Limitations of this study, he said, include a smaller study population with some patient dropouts and a lack of adverse effects reported.

The researchers and Dr. Tan reported having no financial conflicts.

Treating keloid scars by combining excision and contact cryosurgery is a plausible way to decrease the volume of scars, results from a single-center observational study suggest.

“There is currently no consensus regarding the best treatment of keloid scars,” corresponding author Manon Artz, of the department of plastic, reconstructive, and aesthetic surgery at University Hospital of Brest (France), and colleagues wrote in a research letter published online in JAMA Dermatology.

Prompilove/Getty Images

“Earlier studies report a decreased scar volume and a substantial reduction of recurrence in keloid scars treated by cryosurgery,” they wrote. “In this study, our objective was to assess whether intramarginal excision (shaving) of the keloid scar followed by an immediate single session of contact cryosurgery is associated with decreased scar volume.”

Between March 2014 and May 2020, the researchers evaluated the approach in 31 patients with 40 keloid scars who were treated at University Hospital of Brest. Of these study participants, four were lost to follow-up, leaving 27 patients with 35 keloid scars in the final analysis. Their mean age was 24 years, 60% were female, and there was fairly even distribution of Fitzpatrick skin types II-VI.

Most of the keloid scars were located on the ear (69%) and the chest (23%), while the rest were on the head and neck. The primary outcome was reduction of keloid scar volume after 12 months, which was measured with the Vancouver scar scale. The researchers defined 80%-100% reduction in scar volume as “major,” a 50%-80% reduction as “substantial,” and a 0%-50% reduction or recurrence as “moderate.”

After 12 months, 19 scars (54%) showed a major reduction in volume, while 6 (17%) had a substantial reduction, and seven (20%) experienced no reduction. Across all keloid scars, the median scar volume decreased significantly by 81.9%.

Scar volume reduction differed by anatomical location. Specifically, 84% of ear scars showed major or substantial reduction, while 60% of scars on the chest showed a moderate reduction in scar volume or recurrence. In another key finding, the Vancouver scar scale score was reduced overall in 25 scars by 71.4%, from 7 before treatment to 5 after treatment.

“There remains no silver bullet for the treatment of keloids, but this study adds invaluable evidence that tangential excision followed by contact cryosurgery can be a viable treatment regimen with low recurrence rates,” said Marcus G. Tan, MD, who recently completed his dermatology residency at the University of Ottawa and who was asked to comment on the study. “Clinicians should exercise caution especially when treating individuals with darker skin phototypes due to their increased risk of scarring and dyspigmentation.”

Limitations of this study, he said, include a smaller study population with some patient dropouts and a lack of adverse effects reported.

The researchers and Dr. Tan reported having no financial conflicts.

Aiming for a disease activity target while reducing biologic therapy could be a winning approach for patients with psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA), according to the results of a new study presented at the annual European Congress of Rheumatology.

The findings show that a treat-to-target (T2T) strategy with tapering using a tumor necrosis factor (TNF) inhibitor produces results that are noninferior to a T2T strategy that doesn’t include tapering in these patients.

“Our study has for the first time shown that a treat-to-target tapering strategy is just as good as full-dose continuation, while reducing medication use substantially,” first author Celia Michielsens, MD, a PhD student and researcher at Sint Maartenskliniek in Nijmegen, the Netherlands, said in an interview before her presentation of the study during an oral abstract session at the congress. “Stepwise tapering is also better than fixed-dose reduction or discontinuation, since it is much more individualized.”

The study is now published in Annals of the Rheumatic Diseases.

In the randomized, controlled, open-label, noninferiority study, researchers enrolled patients with PsA or axSpA who were using a TNF inhibitor such as etanercept, adalimumab, or infliximab, and had stable low disease activity for at least 6 months. Patients needed to have a Psoriatic Arthritis Disease Activity Score (PASDAS) of 3.2 or less, or an Ankylosing Spondylitis Disease Activity Score (ASDAS) of at 2.1 or less. In cases of flare, patients were treated with NSAIDs and/or glucorticoids, and if they still had not reached low disease activity after a month, their previous TNF inhibitor dose was reinstated to the last effective interval or dosage, which was maintained throughout the study period. When the patient was already using a full TNF-inhibitor dose or if dose adjustment did not suffice, patients were switched to another biologic or targeted synthetic disease-modifying antirheumatic drug (DMARD).

Participants were randomized, from January 2019 to June 2021, to a tapering or a nontapering T2T strategy in a 2:1 fashion. Then researchers then followed them for 12 months and aimed to determine if the tapering strategy proved noninferior to not tapering within a predefined 20% margin for noninferiority, which Dr. Michielsens said was derived from other studies and what her group determined to be “an acceptable risk.”

Results show strategy is ‘feasible in daily clinical care’

A total of 81 patients – 42 with PsA and 39 with axSpA – were in the group with tapering, and 41 were in the group without tapering: 22 with PsA and 19 with axSpA.

At 12 months, researchers found that 69% of the patients in the group with tapering had low disease activity, measured via the PASDAS and ASDAS, compared with 73% in patients who did not taper. And those in the tapering group saw their medication use dramatically reduced. At the 12-month mark, they were taking just 53% of the defined daily dose for maintenance, compared with 91% of the defined daily dose for the group that didn’t taper.

The researchers were able to successfully taper 72% of the patients in the tapering group, with 28% of them discontinuing their TNF-inhibitor medication entirely. The incidence of flares was 85% in the tapering group and 78% in the nontapering group, a nonsignificant difference (P = .32).

The start of a new medication or an increase in use of an existing medication was more frequent in the tapering group, and significantly so for NSAIDs. An increase in NSAID use was seen in 54% of the tapering group and in just 24% of the nontapering group (P = .002).

Conventional synthetic DMARD use went up in the tapering group, compared with the nontapering group, but this was only among the PsA patients and the change in use was not statistically significant. There were also more frequent increases in glucocorticoid use in the tapering group, compared with the nontapering group, but this was not significant.

Dr. Michielsens said the findings show the value of an individualized approach in treating patients with PsA or axSpA.

“Our study – and those [studies] in rheumatoid arthritis earlier – deliver the highest quality of evidence that disease activity–guided dose personalization can, and in fact should, be used in clinical practice,” she said. “Our pragmatic treat-to-target tapering strategy is feasible in daily clinical care, although treat-to-target using PASDAS and ASDAS needs some implementation. In shared decision-making with patients, a 50% reduction in TNFi use is obtainable, while maintaining low disease activity.”

The increase in the use of NSAIDs is something to be aware of, but it is “not concerning,” Dr. Michielsens added. She pointed out that the NSAID use was typically temporary, used when flares arose, and that the drugs are effective, safe, and inexpensive. She also noted that the use of TNF blockers decreased more than the use of NSAIDs increased.

“This seems a perfectly acceptable trade-off that can be discussed with your patient,” she said.

The 12-month duration of the study is likely long enough to show that the tapering strategy works, Dr. Michielsens said. In rheumatoid arthritis studies, for example, differences in strategies didn’t change after 1 year.

“That said, we are doing an observational extension study to provide more insights in the long-term effects of this treat-to-target strategy,” she said. “At the end of this summer, all patients will have completed their extended follow-up period – a 12-month observational period – so hopefully we can present the results next year at EULAR.”

This study received funding from ReumaNederland. Dr. Michielsens did not have any financial interests to disclose. Two coauthors reported financial relationships with numerous pharmaceutical companies.

Aiming for a disease activity target while reducing biologic therapy could be a winning approach for patients with psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA), according to the results of a new study presented at the annual European Congress of Rheumatology.

The findings show that a treat-to-target (T2T) strategy with tapering using a tumor necrosis factor (TNF) inhibitor produces results that are noninferior to a T2T strategy that doesn’t include tapering in these patients.

“Our study has for the first time shown that a treat-to-target tapering strategy is just as good as full-dose continuation, while reducing medication use substantially,” first author Celia Michielsens, MD, a PhD student and researcher at Sint Maartenskliniek in Nijmegen, the Netherlands, said in an interview before her presentation of the study during an oral abstract session at the congress. “Stepwise tapering is also better than fixed-dose reduction or discontinuation, since it is much more individualized.”

The study is now published in Annals of the Rheumatic Diseases.

In the randomized, controlled, open-label, noninferiority study, researchers enrolled patients with PsA or axSpA who were using a TNF inhibitor such as etanercept, adalimumab, or infliximab, and had stable low disease activity for at least 6 months. Patients needed to have a Psoriatic Arthritis Disease Activity Score (PASDAS) of 3.2 or less, or an Ankylosing Spondylitis Disease Activity Score (ASDAS) of at 2.1 or less. In cases of flare, patients were treated with NSAIDs and/or glucorticoids, and if they still had not reached low disease activity after a month, their previous TNF inhibitor dose was reinstated to the last effective interval or dosage, which was maintained throughout the study period. When the patient was already using a full TNF-inhibitor dose or if dose adjustment did not suffice, patients were switched to another biologic or targeted synthetic disease-modifying antirheumatic drug (DMARD).

Participants were randomized, from January 2019 to June 2021, to a tapering or a nontapering T2T strategy in a 2:1 fashion. Then researchers then followed them for 12 months and aimed to determine if the tapering strategy proved noninferior to not tapering within a predefined 20% margin for noninferiority, which Dr. Michielsens said was derived from other studies and what her group determined to be “an acceptable risk.”

Results show strategy is ‘feasible in daily clinical care’

A total of 81 patients – 42 with PsA and 39 with axSpA – were in the group with tapering, and 41 were in the group without tapering: 22 with PsA and 19 with axSpA.

At 12 months, researchers found that 69% of the patients in the group with tapering had low disease activity, measured via the PASDAS and ASDAS, compared with 73% in patients who did not taper. And those in the tapering group saw their medication use dramatically reduced. At the 12-month mark, they were taking just 53% of the defined daily dose for maintenance, compared with 91% of the defined daily dose for the group that didn’t taper.

The researchers were able to successfully taper 72% of the patients in the tapering group, with 28% of them discontinuing their TNF-inhibitor medication entirely. The incidence of flares was 85% in the tapering group and 78% in the nontapering group, a nonsignificant difference (P = .32).

The start of a new medication or an increase in use of an existing medication was more frequent in the tapering group, and significantly so for NSAIDs. An increase in NSAID use was seen in 54% of the tapering group and in just 24% of the nontapering group (P = .002).

Conventional synthetic DMARD use went up in the tapering group, compared with the nontapering group, but this was only among the PsA patients and the change in use was not statistically significant. There were also more frequent increases in glucocorticoid use in the tapering group, compared with the nontapering group, but this was not significant.

Dr. Michielsens said the findings show the value of an individualized approach in treating patients with PsA or axSpA.

“Our study – and those [studies] in rheumatoid arthritis earlier – deliver the highest quality of evidence that disease activity–guided dose personalization can, and in fact should, be used in clinical practice,” she said. “Our pragmatic treat-to-target tapering strategy is feasible in daily clinical care, although treat-to-target using PASDAS and ASDAS needs some implementation. In shared decision-making with patients, a 50% reduction in TNFi use is obtainable, while maintaining low disease activity.”

The increase in the use of NSAIDs is something to be aware of, but it is “not concerning,” Dr. Michielsens added. She pointed out that the NSAID use was typically temporary, used when flares arose, and that the drugs are effective, safe, and inexpensive. She also noted that the use of TNF blockers decreased more than the use of NSAIDs increased.

“This seems a perfectly acceptable trade-off that can be discussed with your patient,” she said.

The 12-month duration of the study is likely long enough to show that the tapering strategy works, Dr. Michielsens said. In rheumatoid arthritis studies, for example, differences in strategies didn’t change after 1 year.

“That said, we are doing an observational extension study to provide more insights in the long-term effects of this treat-to-target strategy,” she said. “At the end of this summer, all patients will have completed their extended follow-up period – a 12-month observational period – so hopefully we can present the results next year at EULAR.”

This study received funding from ReumaNederland. Dr. Michielsens did not have any financial interests to disclose. Two coauthors reported financial relationships with numerous pharmaceutical companies.

Aiming for a disease activity target while reducing biologic therapy could be a winning approach for patients with psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA), according to the results of a new study presented at the annual European Congress of Rheumatology.

The findings show that a treat-to-target (T2T) strategy with tapering using a tumor necrosis factor (TNF) inhibitor produces results that are noninferior to a T2T strategy that doesn’t include tapering in these patients.

“Our study has for the first time shown that a treat-to-target tapering strategy is just as good as full-dose continuation, while reducing medication use substantially,” first author Celia Michielsens, MD, a PhD student and researcher at Sint Maartenskliniek in Nijmegen, the Netherlands, said in an interview before her presentation of the study during an oral abstract session at the congress. “Stepwise tapering is also better than fixed-dose reduction or discontinuation, since it is much more individualized.”

The study is now published in Annals of the Rheumatic Diseases.

In the randomized, controlled, open-label, noninferiority study, researchers enrolled patients with PsA or axSpA who were using a TNF inhibitor such as etanercept, adalimumab, or infliximab, and had stable low disease activity for at least 6 months. Patients needed to have a Psoriatic Arthritis Disease Activity Score (PASDAS) of 3.2 or less, or an Ankylosing Spondylitis Disease Activity Score (ASDAS) of at 2.1 or less. In cases of flare, patients were treated with NSAIDs and/or glucorticoids, and if they still had not reached low disease activity after a month, their previous TNF inhibitor dose was reinstated to the last effective interval or dosage, which was maintained throughout the study period. When the patient was already using a full TNF-inhibitor dose or if dose adjustment did not suffice, patients were switched to another biologic or targeted synthetic disease-modifying antirheumatic drug (DMARD).

Participants were randomized, from January 2019 to June 2021, to a tapering or a nontapering T2T strategy in a 2:1 fashion. Then researchers then followed them for 12 months and aimed to determine if the tapering strategy proved noninferior to not tapering within a predefined 20% margin for noninferiority, which Dr. Michielsens said was derived from other studies and what her group determined to be “an acceptable risk.”

Results show strategy is ‘feasible in daily clinical care’

A total of 81 patients – 42 with PsA and 39 with axSpA – were in the group with tapering, and 41 were in the group without tapering: 22 with PsA and 19 with axSpA.

At 12 months, researchers found that 69% of the patients in the group with tapering had low disease activity, measured via the PASDAS and ASDAS, compared with 73% in patients who did not taper. And those in the tapering group saw their medication use dramatically reduced. At the 12-month mark, they were taking just 53% of the defined daily dose for maintenance, compared with 91% of the defined daily dose for the group that didn’t taper.

The researchers were able to successfully taper 72% of the patients in the tapering group, with 28% of them discontinuing their TNF-inhibitor medication entirely. The incidence of flares was 85% in the tapering group and 78% in the nontapering group, a nonsignificant difference (P = .32).

The start of a new medication or an increase in use of an existing medication was more frequent in the tapering group, and significantly so for NSAIDs. An increase in NSAID use was seen in 54% of the tapering group and in just 24% of the nontapering group (P = .002).

Conventional synthetic DMARD use went up in the tapering group, compared with the nontapering group, but this was only among the PsA patients and the change in use was not statistically significant. There were also more frequent increases in glucocorticoid use in the tapering group, compared with the nontapering group, but this was not significant.

Dr. Michielsens said the findings show the value of an individualized approach in treating patients with PsA or axSpA.

“Our study – and those [studies] in rheumatoid arthritis earlier – deliver the highest quality of evidence that disease activity–guided dose personalization can, and in fact should, be used in clinical practice,” she said. “Our pragmatic treat-to-target tapering strategy is feasible in daily clinical care, although treat-to-target using PASDAS and ASDAS needs some implementation. In shared decision-making with patients, a 50% reduction in TNFi use is obtainable, while maintaining low disease activity.”

The increase in the use of NSAIDs is something to be aware of, but it is “not concerning,” Dr. Michielsens added. She pointed out that the NSAID use was typically temporary, used when flares arose, and that the drugs are effective, safe, and inexpensive. She also noted that the use of TNF blockers decreased more than the use of NSAIDs increased.

“This seems a perfectly acceptable trade-off that can be discussed with your patient,” she said.

The 12-month duration of the study is likely long enough to show that the tapering strategy works, Dr. Michielsens said. In rheumatoid arthritis studies, for example, differences in strategies didn’t change after 1 year.

“That said, we are doing an observational extension study to provide more insights in the long-term effects of this treat-to-target strategy,” she said. “At the end of this summer, all patients will have completed their extended follow-up period – a 12-month observational period – so hopefully we can present the results next year at EULAR.”

This study received funding from ReumaNederland. Dr. Michielsens did not have any financial interests to disclose. Two coauthors reported financial relationships with numerous pharmaceutical companies.

Kip Wenger, DO, an emergency physician and systems medical director of Team Health, Knoxville, Tenn., was asked to see a patient in the emergency department. He was shocked when he realized who the patient was – a 33-year-old female physician friend and colleague.

She was bleeding from multiple self-inflicted injuries and ultimately died. “I was devastated and couldn’t wrap my head around what had just happened,” Dr. Wenger told this news organization.

It’s important for physicians to be aware of warning signs in their colleagues, such as showing up late, being irritable and short-tempered with staff, missing shifts, making mistakes, or receiving an increasing number of patient complaints, Dr. Wenger says.

Dr. Wenger had had dinner with her several weeks earlier and saw some subtle changes. He had known her as a “positive, upbeat person,” but her demeanor was different during dinner.

“There were no typical telltale signs – she was talking about her plans for the future, including buying a new bicycle – but she wasn’t herself and seemed to become tearful when I hugged her at the end of the evening,” he said. He later heard from another colleague that she had shared feeling “hopeless.”
 

The scope of the problem

According to the American Society for Suicide Prevention, roughly 300-400 physicians die by suicide annually. Although one study suggests a lower number, official reports likely underestimate suicides, study author Katherine Gold, MD, MSW, associate professor of family medicine, obstetrics, and gynecology, Michigan Medicine, University of Michigan, Ann Arbor, said in an interview.

Peter Yellowlees, MD, MBBS, professor of psychiatry, University of California, Davis, concurs, suggesting that some single-car accidents involving physicians might be suicides. Perry Lin, MD, assistant clinical professor, Heritage College of Osteopathic Medicine, Ohio University, Athens, and national co-chair of the Physician Suicide Awareness Committee of the American Association of Suicidology, says that some death certificates state that the deceased died of “accidental causes” because the physician who completes the certificate, possibly a colleague, is reluctant to list the actual cause of death to protect his colleague’s memory or the family’s feelings.

In general, and among physicians, White men older than 65 “represent the largest percentage of people who die from suicide nationwide,” says Dr. Lin.

But younger people are also susceptible, Dr. Lin adds. One of the most vulnerable periods for potential suicide is during the first few months of residency. This dovetails with the findings of Medscape’s 2022 report Suicide: A Tragedy of the Profession. In that report, a difference was found between frequency of suicidal thoughts in younger physicians, compared with older physicians (14% in those < 35 years vs. 8% for those ≥ 45 years).
 

Hurdles to preventing physician suicide

“The best thing that can happen in our profession is upstream intervention – if people seek help before they get to the point of suicidality, recognizing they’re under stress and duress and that they might be going down a bad pathway,” says Dr. Lin. But research suggests that many physicians don’t do so.

Gary Price, MD, attending surgeon and clinical assistant professor of surgery, Yale–New Haven Hospital, Connecticut, and president of the Physicians Foundation, says his organization has identified barriers that prevent physicians from seeking help.

The major concern is that, in many states, licensing applications still ask whether the physician has been in treatment for a mental health condition. Physicians feel they may put their licensure at risk if they admit to receiving help for mental issues. These concerns were expressed by respondents in Medscape’s above mentioned 2022 report, many of whom didn’t seek treatment for depression, burnout, or suicidal thoughts lest it affect their professional standing when renewing their license or seeking credentialing.

Although organizations and societies are advocating against these questions, a recent study found that almost 70% of U.S. states and territories continue to ask physicians about their mental health, and 28% ask for diagnoses (beyond current impairments) – a violation of the Americans With Disabilities Act.

“Mental health illness is different from mental health impairment,” Ryan Mire, MD, a Nashville, Tenn.–based internist, said in an interview. “As physicians, we’re comfortable with licensing boards asking whether the physician has any condition that might impair their care for patients, but not about a history of mental illness.”

The second barrier, says Dr. Price, is that hospital credentialing committees sometimes ask similar questions, as do commercial and malpractice insurers.

Another roadblock is that in some states, undergoing treatment for a mental health problem could be subject to discovery by a plaintiff’s attorney in a malpractice case, even if the physician’s mental health history had no effect on patient care. But that’s uncommon, says Daniel Shapiro, PhD, author of “Delivering Doctor Amelia,” a book about his treatment of a suicidal physician who underwent a malpractice lawsuit. “I’ve never seen that happen.”

A final barrier is that many employers require employees to receive treatment within their own institution or health system. “Physicians may be reluctant to get help where they work, with colleagues and friends knowing about their illness or being involved with their care,” says Dr. Price.

In 2022, the American College of Physicians (ACP) issued a toolkit to help members encourage licensing and credentialing boards to remove questions about mental health on applications and include language that supports receiving treatment, Dr. Mire says.
 

Layers of vulnerability

There are few data regarding relative risk among particular races or ethnicities, “but we know racism is a social stressor,” says Dr. Mire. “Obviously, people from historically disadvantaged populations tend to have societal stressors like discrimination and racism that add an extra layer of burden.”

Intersectionality – having multiple intersecting risk factors – may confer even higher risk. “For example, if you’re a female physician from a historically marginalized race and a resident dealing with the ‘hidden curriculum’ of trying to be resilient, you have multiple layers of vulnerability.”

There are also limited data regarding which specialties or work environments are associated with highest risk. “Obviously, challenges exist in every segment of medicine and at different ages, stages, and work environments, and they intersect with each individual physician’s personal risk factors,” says Dr. Mire, president of the ACP and assistant clinical professor of clinical medical education, University of Tennessee Health Science Center, Memphis.

Pamela Wible, MD, is an Oregon-based retired physician who herself went through a suicidal period about 11 years into her career that motivated her to embrace a new vision of clinical practice and change her practice model. After a series of physician suicides in her area, she began to speak and write openly about physician suicide, and since her retirement from clinical practice, she makes herself available on a full-time basis to distressed physicians. “When I address a conference of a particular medical specialty or a group in a particular geographical region, I focus on the specific vulnerabilities in that specialty or region,” she says.
 

What increases the chances of suicide?

“Many factors, both within and outside the professional setting, affect someone’s decision to die by suicide – after all, physicians have the same stressors as other people, like family, finances, and their own health,” Dr. Mire says. When it comes to non–work-related factors, marital stressors and comorbid psychiatric illness particularly raise the risk, says Dr. Lin.

But certain drivers are specific to the practice of medicine, with burnout and depression first in line.

Dr. Shapiro, who is vice dean for faculty and administrative affairs, Penn State University, Hershey, and the Garner James Cline Professor of Medical Humanism, conducts burnout evaluations throughout the country. “Simple depression screeners prior to the pandemic showed about a 10% major depression rate in physicians,” he told this news organization. “Now, we’re seeing a 30%-33% depression rate, even in those who weren’t frontline providers during the pandemic.”

Dr. Price agrees, noting that burnout in physicians has gone from 40% to 60% since the pandemic. But burnout doesn’t always lead to suicide. It’s when burnout progresses to depression, becomes more severe, and is untreated that the suicidal risk arises, he emphasizes.

Additionally, being a doctor isn’t “just a profession” but a “calling and identity,” says Dr. Gold. Job-related problems (for example, a malpractice suit, complaints to the medical board, loss of autonomy, changing work demands) can raise suicidal risk.

And job-related problems can inform the location of suicide, says Dr. Wible, who is the author of “Physicians Suicide Letters – Answered.”

“A work-related catalyst makes it more likely that the person will attempt or complete suicide in the work setting. Physicians have stepped off hospital rooftops, shot or stabbed themselves in hospital parking lots, or [hanged] themselves in hospital chapels. Perhaps it’s because they’re choosing to die in the place where they’ve been most wounded.”
 

You are not at fault

“If you’re feeling suicidal, you might feel utterly alone, but if there’s one message I can give you, it’s that you’re not alone, and there are many things you can do to mitigate your pain and despair,” Dr. Wible says. “And you’re not defective. It’s the health care system that’s defective. You have nothing to be ashamed of.”

Some institutions have a “buddy system” that pairs clinicians to provide mutual peer support. A partner who notices concerning signs can refer the other partner for help. Physicians can also be paired with a “buddy,” even without a formal institutional structure.

A “buddy” is a step in the right direction, but Dr. Shapiro cautions it might be necessary to consult a trained professional for serious depression or suicidality. Several states provide connection to local resources. Employee assistance programs (EAPs) might be helpful, although many physicians don’t trust their institution’s EAP. Or physicians can ask colleagues to recommend a “doctor’s doctor” who specializes in treating physicians, suggests Dr. Yellowlees, author of “Physician Suicide: Cases and Commentaries.”

In Medscape’s 2022 report, almost all respondents who reported having suicidal colleagues said they offered help, including emotional support, practical assistance, referrals, speaking to family members, or even personally taking the colleague to the ED or to a therapist.

To enhance physicians’ ability to help each other, Dr. Lin recommends “gatekeeper training,” which has been shown to reduce suicide. “This strategy utilizes a peer-to-peer model, but, rather than a single ‘peer buddy,’ everyone is a ‘gatekeeper’ trained in approaches, such as QPR – Question, Persuade, Refer. ‘Gatekeepers’ are taught how to recognize warning signs of suicide, question the potentially suicidal individual, persuade him/her to get help, and provide referrals.”
 

Other ways to prevent suicide

Dr. Lin advises physicians to “create a personalized safety plan and write down signs and clues that they may be going down the wrong path and what they can do – like breathing exercises, relaxation – and identifying people to talk to, places to go, or phone numbers to call, if those initial measures aren’t enough.” The plan is private and allows the physician to determine at what point help is needed and who should be consulted. “Sometimes, when a person is in acute stress, even looking up a phone number can seem insurmountable. But having it on paper lowers the barrier, making it more achievable.”

Resources should be posted in places where physicians gather so that those who don’t already have a safety plan have easy access to that information, he suggests.

In addition, consideration may be given to reaching out for support if a colleague has died by suicide, experts suggest. Whether offered by one’s institution, a peer arrangement, spiritual counseling, or psychotherapy, one may need help dealing with the trauma, guilt, and grief that often accompany this type of loss.

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

Kip Wenger, DO, an emergency physician and systems medical director of Team Health, Knoxville, Tenn., was asked to see a patient in the emergency department. He was shocked when he realized who the patient was – a 33-year-old female physician friend and colleague.

She was bleeding from multiple self-inflicted injuries and ultimately died. “I was devastated and couldn’t wrap my head around what had just happened,” Dr. Wenger told this news organization.

It’s important for physicians to be aware of warning signs in their colleagues, such as showing up late, being irritable and short-tempered with staff, missing shifts, making mistakes, or receiving an increasing number of patient complaints, Dr. Wenger says.

Dr. Wenger had had dinner with her several weeks earlier and saw some subtle changes. He had known her as a “positive, upbeat person,” but her demeanor was different during dinner.

“There were no typical telltale signs – she was talking about her plans for the future, including buying a new bicycle – but she wasn’t herself and seemed to become tearful when I hugged her at the end of the evening,” he said. He later heard from another colleague that she had shared feeling “hopeless.”
 

The scope of the problem

According to the American Society for Suicide Prevention, roughly 300-400 physicians die by suicide annually. Although one study suggests a lower number, official reports likely underestimate suicides, study author Katherine Gold, MD, MSW, associate professor of family medicine, obstetrics, and gynecology, Michigan Medicine, University of Michigan, Ann Arbor, said in an interview.

Peter Yellowlees, MD, MBBS, professor of psychiatry, University of California, Davis, concurs, suggesting that some single-car accidents involving physicians might be suicides. Perry Lin, MD, assistant clinical professor, Heritage College of Osteopathic Medicine, Ohio University, Athens, and national co-chair of the Physician Suicide Awareness Committee of the American Association of Suicidology, says that some death certificates state that the deceased died of “accidental causes” because the physician who completes the certificate, possibly a colleague, is reluctant to list the actual cause of death to protect his colleague’s memory or the family’s feelings.

In general, and among physicians, White men older than 65 “represent the largest percentage of people who die from suicide nationwide,” says Dr. Lin.

But younger people are also susceptible, Dr. Lin adds. One of the most vulnerable periods for potential suicide is during the first few months of residency. This dovetails with the findings of Medscape’s 2022 report Suicide: A Tragedy of the Profession. In that report, a difference was found between frequency of suicidal thoughts in younger physicians, compared with older physicians (14% in those < 35 years vs. 8% for those ≥ 45 years).
 

Hurdles to preventing physician suicide

“The best thing that can happen in our profession is upstream intervention – if people seek help before they get to the point of suicidality, recognizing they’re under stress and duress and that they might be going down a bad pathway,” says Dr. Lin. But research suggests that many physicians don’t do so.

Gary Price, MD, attending surgeon and clinical assistant professor of surgery, Yale–New Haven Hospital, Connecticut, and president of the Physicians Foundation, says his organization has identified barriers that prevent physicians from seeking help.

The major concern is that, in many states, licensing applications still ask whether the physician has been in treatment for a mental health condition. Physicians feel they may put their licensure at risk if they admit to receiving help for mental issues. These concerns were expressed by respondents in Medscape’s above mentioned 2022 report, many of whom didn’t seek treatment for depression, burnout, or suicidal thoughts lest it affect their professional standing when renewing their license or seeking credentialing.

Although organizations and societies are advocating against these questions, a recent study found that almost 70% of U.S. states and territories continue to ask physicians about their mental health, and 28% ask for diagnoses (beyond current impairments) – a violation of the Americans With Disabilities Act.

“Mental health illness is different from mental health impairment,” Ryan Mire, MD, a Nashville, Tenn.–based internist, said in an interview. “As physicians, we’re comfortable with licensing boards asking whether the physician has any condition that might impair their care for patients, but not about a history of mental illness.”

The second barrier, says Dr. Price, is that hospital credentialing committees sometimes ask similar questions, as do commercial and malpractice insurers.

Another roadblock is that in some states, undergoing treatment for a mental health problem could be subject to discovery by a plaintiff’s attorney in a malpractice case, even if the physician’s mental health history had no effect on patient care. But that’s uncommon, says Daniel Shapiro, PhD, author of “Delivering Doctor Amelia,” a book about his treatment of a suicidal physician who underwent a malpractice lawsuit. “I’ve never seen that happen.”

A final barrier is that many employers require employees to receive treatment within their own institution or health system. “Physicians may be reluctant to get help where they work, with colleagues and friends knowing about their illness or being involved with their care,” says Dr. Price.

In 2022, the American College of Physicians (ACP) issued a toolkit to help members encourage licensing and credentialing boards to remove questions about mental health on applications and include language that supports receiving treatment, Dr. Mire says.
 

Layers of vulnerability

There are few data regarding relative risk among particular races or ethnicities, “but we know racism is a social stressor,” says Dr. Mire. “Obviously, people from historically disadvantaged populations tend to have societal stressors like discrimination and racism that add an extra layer of burden.”

Intersectionality – having multiple intersecting risk factors – may confer even higher risk. “For example, if you’re a female physician from a historically marginalized race and a resident dealing with the ‘hidden curriculum’ of trying to be resilient, you have multiple layers of vulnerability.”

There are also limited data regarding which specialties or work environments are associated with highest risk. “Obviously, challenges exist in every segment of medicine and at different ages, stages, and work environments, and they intersect with each individual physician’s personal risk factors,” says Dr. Mire, president of the ACP and assistant clinical professor of clinical medical education, University of Tennessee Health Science Center, Memphis.

Pamela Wible, MD, is an Oregon-based retired physician who herself went through a suicidal period about 11 years into her career that motivated her to embrace a new vision of clinical practice and change her practice model. After a series of physician suicides in her area, she began to speak and write openly about physician suicide, and since her retirement from clinical practice, she makes herself available on a full-time basis to distressed physicians. “When I address a conference of a particular medical specialty or a group in a particular geographical region, I focus on the specific vulnerabilities in that specialty or region,” she says.
 

What increases the chances of suicide?

“Many factors, both within and outside the professional setting, affect someone’s decision to die by suicide – after all, physicians have the same stressors as other people, like family, finances, and their own health,” Dr. Mire says. When it comes to non–work-related factors, marital stressors and comorbid psychiatric illness particularly raise the risk, says Dr. Lin.

But certain drivers are specific to the practice of medicine, with burnout and depression first in line.

Dr. Shapiro, who is vice dean for faculty and administrative affairs, Penn State University, Hershey, and the Garner James Cline Professor of Medical Humanism, conducts burnout evaluations throughout the country. “Simple depression screeners prior to the pandemic showed about a 10% major depression rate in physicians,” he told this news organization. “Now, we’re seeing a 30%-33% depression rate, even in those who weren’t frontline providers during the pandemic.”

Dr. Price agrees, noting that burnout in physicians has gone from 40% to 60% since the pandemic. But burnout doesn’t always lead to suicide. It’s when burnout progresses to depression, becomes more severe, and is untreated that the suicidal risk arises, he emphasizes.

Additionally, being a doctor isn’t “just a profession” but a “calling and identity,” says Dr. Gold. Job-related problems (for example, a malpractice suit, complaints to the medical board, loss of autonomy, changing work demands) can raise suicidal risk.

And job-related problems can inform the location of suicide, says Dr. Wible, who is the author of “Physicians Suicide Letters – Answered.”

“A work-related catalyst makes it more likely that the person will attempt or complete suicide in the work setting. Physicians have stepped off hospital rooftops, shot or stabbed themselves in hospital parking lots, or [hanged] themselves in hospital chapels. Perhaps it’s because they’re choosing to die in the place where they’ve been most wounded.”
 

You are not at fault

“If you’re feeling suicidal, you might feel utterly alone, but if there’s one message I can give you, it’s that you’re not alone, and there are many things you can do to mitigate your pain and despair,” Dr. Wible says. “And you’re not defective. It’s the health care system that’s defective. You have nothing to be ashamed of.”

Some institutions have a “buddy system” that pairs clinicians to provide mutual peer support. A partner who notices concerning signs can refer the other partner for help. Physicians can also be paired with a “buddy,” even without a formal institutional structure.

A “buddy” is a step in the right direction, but Dr. Shapiro cautions it might be necessary to consult a trained professional for serious depression or suicidality. Several states provide connection to local resources. Employee assistance programs (EAPs) might be helpful, although many physicians don’t trust their institution’s EAP. Or physicians can ask colleagues to recommend a “doctor’s doctor” who specializes in treating physicians, suggests Dr. Yellowlees, author of “Physician Suicide: Cases and Commentaries.”

In Medscape’s 2022 report, almost all respondents who reported having suicidal colleagues said they offered help, including emotional support, practical assistance, referrals, speaking to family members, or even personally taking the colleague to the ED or to a therapist.

To enhance physicians’ ability to help each other, Dr. Lin recommends “gatekeeper training,” which has been shown to reduce suicide. “This strategy utilizes a peer-to-peer model, but, rather than a single ‘peer buddy,’ everyone is a ‘gatekeeper’ trained in approaches, such as QPR – Question, Persuade, Refer. ‘Gatekeepers’ are taught how to recognize warning signs of suicide, question the potentially suicidal individual, persuade him/her to get help, and provide referrals.”
 

Other ways to prevent suicide

Dr. Lin advises physicians to “create a personalized safety plan and write down signs and clues that they may be going down the wrong path and what they can do – like breathing exercises, relaxation – and identifying people to talk to, places to go, or phone numbers to call, if those initial measures aren’t enough.” The plan is private and allows the physician to determine at what point help is needed and who should be consulted. “Sometimes, when a person is in acute stress, even looking up a phone number can seem insurmountable. But having it on paper lowers the barrier, making it more achievable.”

Resources should be posted in places where physicians gather so that those who don’t already have a safety plan have easy access to that information, he suggests.

In addition, consideration may be given to reaching out for support if a colleague has died by suicide, experts suggest. Whether offered by one’s institution, a peer arrangement, spiritual counseling, or psychotherapy, one may need help dealing with the trauma, guilt, and grief that often accompany this type of loss.

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

Kip Wenger, DO, an emergency physician and systems medical director of Team Health, Knoxville, Tenn., was asked to see a patient in the emergency department. He was shocked when he realized who the patient was – a 33-year-old female physician friend and colleague.

She was bleeding from multiple self-inflicted injuries and ultimately died. “I was devastated and couldn’t wrap my head around what had just happened,” Dr. Wenger told this news organization.

It’s important for physicians to be aware of warning signs in their colleagues, such as showing up late, being irritable and short-tempered with staff, missing shifts, making mistakes, or receiving an increasing number of patient complaints, Dr. Wenger says.

Dr. Wenger had had dinner with her several weeks earlier and saw some subtle changes. He had known her as a “positive, upbeat person,” but her demeanor was different during dinner.

“There were no typical telltale signs – she was talking about her plans for the future, including buying a new bicycle – but she wasn’t herself and seemed to become tearful when I hugged her at the end of the evening,” he said. He later heard from another colleague that she had shared feeling “hopeless.”
 

The scope of the problem

According to the American Society for Suicide Prevention, roughly 300-400 physicians die by suicide annually. Although one study suggests a lower number, official reports likely underestimate suicides, study author Katherine Gold, MD, MSW, associate professor of family medicine, obstetrics, and gynecology, Michigan Medicine, University of Michigan, Ann Arbor, said in an interview.

Peter Yellowlees, MD, MBBS, professor of psychiatry, University of California, Davis, concurs, suggesting that some single-car accidents involving physicians might be suicides. Perry Lin, MD, assistant clinical professor, Heritage College of Osteopathic Medicine, Ohio University, Athens, and national co-chair of the Physician Suicide Awareness Committee of the American Association of Suicidology, says that some death certificates state that the deceased died of “accidental causes” because the physician who completes the certificate, possibly a colleague, is reluctant to list the actual cause of death to protect his colleague’s memory or the family’s feelings.

In general, and among physicians, White men older than 65 “represent the largest percentage of people who die from suicide nationwide,” says Dr. Lin.

But younger people are also susceptible, Dr. Lin adds. One of the most vulnerable periods for potential suicide is during the first few months of residency. This dovetails with the findings of Medscape’s 2022 report Suicide: A Tragedy of the Profession. In that report, a difference was found between frequency of suicidal thoughts in younger physicians, compared with older physicians (14% in those < 35 years vs. 8% for those ≥ 45 years).
 

Hurdles to preventing physician suicide

“The best thing that can happen in our profession is upstream intervention – if people seek help before they get to the point of suicidality, recognizing they’re under stress and duress and that they might be going down a bad pathway,” says Dr. Lin. But research suggests that many physicians don’t do so.

Gary Price, MD, attending surgeon and clinical assistant professor of surgery, Yale–New Haven Hospital, Connecticut, and president of the Physicians Foundation, says his organization has identified barriers that prevent physicians from seeking help.

The major concern is that, in many states, licensing applications still ask whether the physician has been in treatment for a mental health condition. Physicians feel they may put their licensure at risk if they admit to receiving help for mental issues. These concerns were expressed by respondents in Medscape’s above mentioned 2022 report, many of whom didn’t seek treatment for depression, burnout, or suicidal thoughts lest it affect their professional standing when renewing their license or seeking credentialing.

Although organizations and societies are advocating against these questions, a recent study found that almost 70% of U.S. states and territories continue to ask physicians about their mental health, and 28% ask for diagnoses (beyond current impairments) – a violation of the Americans With Disabilities Act.

“Mental health illness is different from mental health impairment,” Ryan Mire, MD, a Nashville, Tenn.–based internist, said in an interview. “As physicians, we’re comfortable with licensing boards asking whether the physician has any condition that might impair their care for patients, but not about a history of mental illness.”

The second barrier, says Dr. Price, is that hospital credentialing committees sometimes ask similar questions, as do commercial and malpractice insurers.

Another roadblock is that in some states, undergoing treatment for a mental health problem could be subject to discovery by a plaintiff’s attorney in a malpractice case, even if the physician’s mental health history had no effect on patient care. But that’s uncommon, says Daniel Shapiro, PhD, author of “Delivering Doctor Amelia,” a book about his treatment of a suicidal physician who underwent a malpractice lawsuit. “I’ve never seen that happen.”

A final barrier is that many employers require employees to receive treatment within their own institution or health system. “Physicians may be reluctant to get help where they work, with colleagues and friends knowing about their illness or being involved with their care,” says Dr. Price.

In 2022, the American College of Physicians (ACP) issued a toolkit to help members encourage licensing and credentialing boards to remove questions about mental health on applications and include language that supports receiving treatment, Dr. Mire says.
 

Layers of vulnerability

There are few data regarding relative risk among particular races or ethnicities, “but we know racism is a social stressor,” says Dr. Mire. “Obviously, people from historically disadvantaged populations tend to have societal stressors like discrimination and racism that add an extra layer of burden.”

Intersectionality – having multiple intersecting risk factors – may confer even higher risk. “For example, if you’re a female physician from a historically marginalized race and a resident dealing with the ‘hidden curriculum’ of trying to be resilient, you have multiple layers of vulnerability.”

There are also limited data regarding which specialties or work environments are associated with highest risk. “Obviously, challenges exist in every segment of medicine and at different ages, stages, and work environments, and they intersect with each individual physician’s personal risk factors,” says Dr. Mire, president of the ACP and assistant clinical professor of clinical medical education, University of Tennessee Health Science Center, Memphis.

Pamela Wible, MD, is an Oregon-based retired physician who herself went through a suicidal period about 11 years into her career that motivated her to embrace a new vision of clinical practice and change her practice model. After a series of physician suicides in her area, she began to speak and write openly about physician suicide, and since her retirement from clinical practice, she makes herself available on a full-time basis to distressed physicians. “When I address a conference of a particular medical specialty or a group in a particular geographical region, I focus on the specific vulnerabilities in that specialty or region,” she says.
 

What increases the chances of suicide?

“Many factors, both within and outside the professional setting, affect someone’s decision to die by suicide – after all, physicians have the same stressors as other people, like family, finances, and their own health,” Dr. Mire says. When it comes to non–work-related factors, marital stressors and comorbid psychiatric illness particularly raise the risk, says Dr. Lin.

But certain drivers are specific to the practice of medicine, with burnout and depression first in line.

Dr. Shapiro, who is vice dean for faculty and administrative affairs, Penn State University, Hershey, and the Garner James Cline Professor of Medical Humanism, conducts burnout evaluations throughout the country. “Simple depression screeners prior to the pandemic showed about a 10% major depression rate in physicians,” he told this news organization. “Now, we’re seeing a 30%-33% depression rate, even in those who weren’t frontline providers during the pandemic.”

Dr. Price agrees, noting that burnout in physicians has gone from 40% to 60% since the pandemic. But burnout doesn’t always lead to suicide. It’s when burnout progresses to depression, becomes more severe, and is untreated that the suicidal risk arises, he emphasizes.

Additionally, being a doctor isn’t “just a profession” but a “calling and identity,” says Dr. Gold. Job-related problems (for example, a malpractice suit, complaints to the medical board, loss of autonomy, changing work demands) can raise suicidal risk.

And job-related problems can inform the location of suicide, says Dr. Wible, who is the author of “Physicians Suicide Letters – Answered.”

“A work-related catalyst makes it more likely that the person will attempt or complete suicide in the work setting. Physicians have stepped off hospital rooftops, shot or stabbed themselves in hospital parking lots, or [hanged] themselves in hospital chapels. Perhaps it’s because they’re choosing to die in the place where they’ve been most wounded.”
 

You are not at fault

“If you’re feeling suicidal, you might feel utterly alone, but if there’s one message I can give you, it’s that you’re not alone, and there are many things you can do to mitigate your pain and despair,” Dr. Wible says. “And you’re not defective. It’s the health care system that’s defective. You have nothing to be ashamed of.”

Some institutions have a “buddy system” that pairs clinicians to provide mutual peer support. A partner who notices concerning signs can refer the other partner for help. Physicians can also be paired with a “buddy,” even without a formal institutional structure.

A “buddy” is a step in the right direction, but Dr. Shapiro cautions it might be necessary to consult a trained professional for serious depression or suicidality. Several states provide connection to local resources. Employee assistance programs (EAPs) might be helpful, although many physicians don’t trust their institution’s EAP. Or physicians can ask colleagues to recommend a “doctor’s doctor” who specializes in treating physicians, suggests Dr. Yellowlees, author of “Physician Suicide: Cases and Commentaries.”

In Medscape’s 2022 report, almost all respondents who reported having suicidal colleagues said they offered help, including emotional support, practical assistance, referrals, speaking to family members, or even personally taking the colleague to the ED or to a therapist.

To enhance physicians’ ability to help each other, Dr. Lin recommends “gatekeeper training,” which has been shown to reduce suicide. “This strategy utilizes a peer-to-peer model, but, rather than a single ‘peer buddy,’ everyone is a ‘gatekeeper’ trained in approaches, such as QPR – Question, Persuade, Refer. ‘Gatekeepers’ are taught how to recognize warning signs of suicide, question the potentially suicidal individual, persuade him/her to get help, and provide referrals.”
 

Other ways to prevent suicide

Dr. Lin advises physicians to “create a personalized safety plan and write down signs and clues that they may be going down the wrong path and what they can do – like breathing exercises, relaxation – and identifying people to talk to, places to go, or phone numbers to call, if those initial measures aren’t enough.” The plan is private and allows the physician to determine at what point help is needed and who should be consulted. “Sometimes, when a person is in acute stress, even looking up a phone number can seem insurmountable. But having it on paper lowers the barrier, making it more achievable.”

Resources should be posted in places where physicians gather so that those who don’t already have a safety plan have easy access to that information, he suggests.

In addition, consideration may be given to reaching out for support if a colleague has died by suicide, experts suggest. Whether offered by one’s institution, a peer arrangement, spiritual counseling, or psychotherapy, one may need help dealing with the trauma, guilt, and grief that often accompany this type of loss.

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