Endocrinologists report steady increases in pay in the Medscape Endocrinologist Compensation Report 2023, but more doctors dropped insurers that pay the least, compared with last year, and only about two-thirds of respondents say they would choose medicine again as a career if given the chance.

In the survey of more than 10,000 physicians in over 29 specialties, endocrinologists’ annual salaries were up by about 4% from last year’s average of $257,000, to $267,000.

Those earnings still place them in the lowest five specialties in terms of pay, above infectious diseases, family medicine, pediatrics, and public health and preventive medicine. The latter is at the bottom of the list, with average annual earnings of $249,000.

Conversely, the top three specialties were plastic surgery, at an average of $619,000 per annum, followed by orthopedics, at $573,000, and cardiology, at $507,000.

Specialties in which the most significant changes in annual compensation occurred were led by oncology, with a 13% increase from 2022, followed by gastroenterology, with an 11% increase. On the opposite end, ophthalmologists experienced a 7% decline in earnings, while emergency medicine had a 6% decrease from 2022.

Since Medscape’s 2015 report, annual salaries for endocrinologists have increased by 36%. Similar patterns in compensation increases since 2015 occurred across all specialties. In contrast to some other specialties, endocrinologists did not experience a significant decline in earnings during the pandemic.

Across all specialties, men still earned more than women in the 2023 report – with a gap of 19% ($386,000 vs. $300,000). However, there appears to be progress, as the difference represents the lowest gender pay gap in 5 years.

This gradual improvement should likely continue as awareness of pay discrepancies grows and new generations emerge, said Theresa Rohr-Kirchgraber, MD, president of the American Medical Women’s Association and professor of medicine at AU/USA Medical Partnership, Athens, Ga., in the report.

“Due to efforts by many, some institutions and health care organizations have reviewed their salary lines and recognized the discrepancies not only between the sexes but also between new hires” and more established workers, she explained in the report.

“[The new hires] can be offered significantly more than those more senior physicians who have been working there for years and hired under a different pay structure,” she noted.

Nearly half of endocrinologists (45%) reported taking on extra work outside of their profession, up from 39% in the 2022 report. Among them, 31% reported other medical-related work, 8% reported “medical moonlighting,” 7% reported non–medical-related work, and 2% added more hours to their primary job as a physician.

Endocrinologists were in the lowest third of specialties in terms of their impressions of fair compensation, with only 45% reporting that they felt adequately paid. On the lowest end was infectious disease, with only 35% feeling their compensation is fair. By contrast, the highest response, 68%, was among psychiatrists.

Nevertheless, 85% of endocrinologists report that they would choose the same specialty again if given the chance. Responses ranged from 61% in internal medicine to 97% in plastic surgery.

Of note, fewer – 71% of endocrinologists – responded that they would choose medicine again, down from the 76% of endocrinologists who answered yes to the same question in 2022. At the bottom of the list was emergency medicine, with only 61% saying they would choose medicine again. The highest rates were in dermatology, at 86%, and allergy and immunology, at 84%.

In terms of time spent seeing patients, endocrinologists are more likely to see patients less than 30 hours per week, at 24%, compared with physicians overall, at 19%; 61% of endocrinologists report seeing patients 30-40 hours per week, versus 53% of all physicians.

Only 12% report seeing patients 41-50 hours per week, compared with 16% of all physicians. And 4% reported seeing patients 51 hours or more weekly, versus 11% of physicians overall.

The proportion of endocrinologists who reported that they would drop insurers that pay the least was notably up in the current report, at 25%, versus just 15% in the 2022 report; 22% indicated they would not drop insurers because “I need all payers”; 16% said no because “it’s inappropriate”; and the remainder responded no for other reasons.

Overall, the leading response by physicians for the most rewarding aspects of their job were “being good at what I am doing/finding answers, diagnoses,” reported by 32%, followed by “gratitude from/relationships with patients” (24%) and “making the world a better place (for example, helping others),” at 22%.

Conversely, the most challenging aspect, described by 20%, is “having so many rules and regulations,” followed by “difficulties getting fair reimbursement from or dealing with Medicare and/or other insurers (17%).”

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

Endocrinologists report steady increases in pay in the Medscape Endocrinologist Compensation Report 2023, but more doctors dropped insurers that pay the least, compared with last year, and only about two-thirds of respondents say they would choose medicine again as a career if given the chance.

In the survey of more than 10,000 physicians in over 29 specialties, endocrinologists’ annual salaries were up by about 4% from last year’s average of $257,000, to $267,000.

Those earnings still place them in the lowest five specialties in terms of pay, above infectious diseases, family medicine, pediatrics, and public health and preventive medicine. The latter is at the bottom of the list, with average annual earnings of $249,000.

Conversely, the top three specialties were plastic surgery, at an average of $619,000 per annum, followed by orthopedics, at $573,000, and cardiology, at $507,000.

Specialties in which the most significant changes in annual compensation occurred were led by oncology, with a 13% increase from 2022, followed by gastroenterology, with an 11% increase. On the opposite end, ophthalmologists experienced a 7% decline in earnings, while emergency medicine had a 6% decrease from 2022.

Since Medscape’s 2015 report, annual salaries for endocrinologists have increased by 36%. Similar patterns in compensation increases since 2015 occurred across all specialties. In contrast to some other specialties, endocrinologists did not experience a significant decline in earnings during the pandemic.

Across all specialties, men still earned more than women in the 2023 report – with a gap of 19% ($386,000 vs. $300,000). However, there appears to be progress, as the difference represents the lowest gender pay gap in 5 years.

This gradual improvement should likely continue as awareness of pay discrepancies grows and new generations emerge, said Theresa Rohr-Kirchgraber, MD, president of the American Medical Women’s Association and professor of medicine at AU/USA Medical Partnership, Athens, Ga., in the report.

“Due to efforts by many, some institutions and health care organizations have reviewed their salary lines and recognized the discrepancies not only between the sexes but also between new hires” and more established workers, she explained in the report.

“[The new hires] can be offered significantly more than those more senior physicians who have been working there for years and hired under a different pay structure,” she noted.

Nearly half of endocrinologists (45%) reported taking on extra work outside of their profession, up from 39% in the 2022 report. Among them, 31% reported other medical-related work, 8% reported “medical moonlighting,” 7% reported non–medical-related work, and 2% added more hours to their primary job as a physician.

Endocrinologists were in the lowest third of specialties in terms of their impressions of fair compensation, with only 45% reporting that they felt adequately paid. On the lowest end was infectious disease, with only 35% feeling their compensation is fair. By contrast, the highest response, 68%, was among psychiatrists.

Nevertheless, 85% of endocrinologists report that they would choose the same specialty again if given the chance. Responses ranged from 61% in internal medicine to 97% in plastic surgery.

Of note, fewer – 71% of endocrinologists – responded that they would choose medicine again, down from the 76% of endocrinologists who answered yes to the same question in 2022. At the bottom of the list was emergency medicine, with only 61% saying they would choose medicine again. The highest rates were in dermatology, at 86%, and allergy and immunology, at 84%.

In terms of time spent seeing patients, endocrinologists are more likely to see patients less than 30 hours per week, at 24%, compared with physicians overall, at 19%; 61% of endocrinologists report seeing patients 30-40 hours per week, versus 53% of all physicians.

Only 12% report seeing patients 41-50 hours per week, compared with 16% of all physicians. And 4% reported seeing patients 51 hours or more weekly, versus 11% of physicians overall.

The proportion of endocrinologists who reported that they would drop insurers that pay the least was notably up in the current report, at 25%, versus just 15% in the 2022 report; 22% indicated they would not drop insurers because “I need all payers”; 16% said no because “it’s inappropriate”; and the remainder responded no for other reasons.

Overall, the leading response by physicians for the most rewarding aspects of their job were “being good at what I am doing/finding answers, diagnoses,” reported by 32%, followed by “gratitude from/relationships with patients” (24%) and “making the world a better place (for example, helping others),” at 22%.

Conversely, the most challenging aspect, described by 20%, is “having so many rules and regulations,” followed by “difficulties getting fair reimbursement from or dealing with Medicare and/or other insurers (17%).”

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

Endocrinologists report steady increases in pay in the Medscape Endocrinologist Compensation Report 2023, but more doctors dropped insurers that pay the least, compared with last year, and only about two-thirds of respondents say they would choose medicine again as a career if given the chance.

In the survey of more than 10,000 physicians in over 29 specialties, endocrinologists’ annual salaries were up by about 4% from last year’s average of $257,000, to $267,000.

Those earnings still place them in the lowest five specialties in terms of pay, above infectious diseases, family medicine, pediatrics, and public health and preventive medicine. The latter is at the bottom of the list, with average annual earnings of $249,000.

Conversely, the top three specialties were plastic surgery, at an average of $619,000 per annum, followed by orthopedics, at $573,000, and cardiology, at $507,000.

Specialties in which the most significant changes in annual compensation occurred were led by oncology, with a 13% increase from 2022, followed by gastroenterology, with an 11% increase. On the opposite end, ophthalmologists experienced a 7% decline in earnings, while emergency medicine had a 6% decrease from 2022.

Since Medscape’s 2015 report, annual salaries for endocrinologists have increased by 36%. Similar patterns in compensation increases since 2015 occurred across all specialties. In contrast to some other specialties, endocrinologists did not experience a significant decline in earnings during the pandemic.

Across all specialties, men still earned more than women in the 2023 report – with a gap of 19% ($386,000 vs. $300,000). However, there appears to be progress, as the difference represents the lowest gender pay gap in 5 years.

This gradual improvement should likely continue as awareness of pay discrepancies grows and new generations emerge, said Theresa Rohr-Kirchgraber, MD, president of the American Medical Women’s Association and professor of medicine at AU/USA Medical Partnership, Athens, Ga., in the report.

“Due to efforts by many, some institutions and health care organizations have reviewed their salary lines and recognized the discrepancies not only between the sexes but also between new hires” and more established workers, she explained in the report.

“[The new hires] can be offered significantly more than those more senior physicians who have been working there for years and hired under a different pay structure,” she noted.

Nearly half of endocrinologists (45%) reported taking on extra work outside of their profession, up from 39% in the 2022 report. Among them, 31% reported other medical-related work, 8% reported “medical moonlighting,” 7% reported non–medical-related work, and 2% added more hours to their primary job as a physician.

Endocrinologists were in the lowest third of specialties in terms of their impressions of fair compensation, with only 45% reporting that they felt adequately paid. On the lowest end was infectious disease, with only 35% feeling their compensation is fair. By contrast, the highest response, 68%, was among psychiatrists.

Nevertheless, 85% of endocrinologists report that they would choose the same specialty again if given the chance. Responses ranged from 61% in internal medicine to 97% in plastic surgery.

Of note, fewer – 71% of endocrinologists – responded that they would choose medicine again, down from the 76% of endocrinologists who answered yes to the same question in 2022. At the bottom of the list was emergency medicine, with only 61% saying they would choose medicine again. The highest rates were in dermatology, at 86%, and allergy and immunology, at 84%.

In terms of time spent seeing patients, endocrinologists are more likely to see patients less than 30 hours per week, at 24%, compared with physicians overall, at 19%; 61% of endocrinologists report seeing patients 30-40 hours per week, versus 53% of all physicians.

Only 12% report seeing patients 41-50 hours per week, compared with 16% of all physicians. And 4% reported seeing patients 51 hours or more weekly, versus 11% of physicians overall.

The proportion of endocrinologists who reported that they would drop insurers that pay the least was notably up in the current report, at 25%, versus just 15% in the 2022 report; 22% indicated they would not drop insurers because “I need all payers”; 16% said no because “it’s inappropriate”; and the remainder responded no for other reasons.

Overall, the leading response by physicians for the most rewarding aspects of their job were “being good at what I am doing/finding answers, diagnoses,” reported by 32%, followed by “gratitude from/relationships with patients” (24%) and “making the world a better place (for example, helping others),” at 22%.

Conversely, the most challenging aspect, described by 20%, is “having so many rules and regulations,” followed by “difficulties getting fair reimbursement from or dealing with Medicare and/or other insurers (17%).”

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

The phenolic compound intake (PCI) of traditional Mexican food positively affects health conditions and supports the hypothesis that specific nutritional foods have a particular effect on certain diseases, according to researchers from the Institute of Sciences at Benemérita Autonomous University of Puebla, Puebla, Mexico.

Their study, published in the journal Foods, is the first to produce tables showing the phenolic content of Mexican dishes. Physicians and nutritionists can use this information as a reference tool when drawing up diet recommendations for patients who could benefit from a higher intake of phenolic compounds (PC).

“Up until now, there hasn’t been a table that we – nutritionists and physicians – could look at and see exactly which foods were richest in these compounds. In the United States, European countries, Asian countries – they’ve all had food tables; in Mexico, we didn’t,” said lead author Julia Alatorre-Cruz, PhD, a biological scientist and postdoctoral researcher at BUAP. “So, it’s a fairly innovative contribution. As a bonus, the information can be used to analyze the relationship between diet and noncommunicable diseases in the Mexican population.”

In recent years, nutrition science has focused on counteracting nutrient deficiency and some diseases by identifying active-food components. Diet offers the possibility to improve the patient’s health conditions by using these components or functional food.

PCs are a diverse group of plant micronutrients, some of which modulate physiologic and molecular pathways involved in energy metabolism. They can act by different mechanisms; the most important of them are conducted by anti-inflammatory, antioxidant activities, and are antiallergic.

Moreover, recent studies explain how PCs positively affect certain illnesses, such as obesity, diabetes, cardiovascular diseases, thrombocytopenia, and metabolic syndrome. Several common features characterize these pathologies – among them are the redox balance and a notable inflammatory response that strongly alters the biochemical and functional characteristics of the affected tissues.

Traditional Mexican food is characterized by grains, tubers, legumes, vegetables, and spices, most of which are rich in PCs. However, the Mexican diet has changed over the past decades because traditional food has been replaced with ultraprocessed food with high-caloric values. Moreover, some vegetables and fruits are preferably consumed after processing, which affects the quantity, quality, and bioavailability of the PCs. In addition, diseases associated with eating habits have increased by more than 27% in the Mexican population.

The objective of the study was to determine whether participants with a higher PC intake from beverages or Mexican dishes have better health conditions than those with a lower intake.

A total of 973 adults (798 females, 175 males) aged 18-79 years were enrolled in this cross-sectional study. The data were obtained from a validated, self-administered food consumption survey that was posted on social media (Facebook) or sent via WhatsApp or email. In one section, there was a list of fruits, vegetables, cereals, legumes, seeds, spices, beverages, and Mexican dishes. The participants were asked to indicate how often in the past month they had consumed these items. There were also sections for providing identification data (for example, age, sex, marital status), height and weight information, and medical history.

“The study was carried out during the pandemic, so that limited contact with the participants,” said Dr. Alatorre-Cruz. “Not being able to directly interact with them was a challenge. For example, we would have liked to have taken those anthropometric measurements ourselves.”

The researchers performed K-means clustering to determine the participant’s health-condition level, resulting in two groups: those with less diseases (LD, n = 649) and those with more diseases (MD, n = 324).

Using the food biochemistry composition reported in multiple papers, the researchers computed the average total phenolic compounds (TPC) for each item listed in the survey. For Mexican dishes, they added the TPC of each recipe’s ingredient, then recalculated to come up with TPC for an individual portion of each recipe (TPCr). To analyze the results of the LD group and of the MD group, phenolic compounds intake of recipe was calculated for each participant.

To Dr. Alatorre-Cruz, the biggest challenge was determining the content of compounds in traditional dishes. “Extensive, in-depth research was done to gather as much information as possible about all of the foods – especially about local and regional ones, because we have such a wide variety – looking to see where that information would match up with the exact method with which the compounds of interest were extracted.”

As expected, the team found that food with high PC was associated with a better health condition. However, the consumption of beverages and Mexican dishes was lower than their expectations. As noted in the article, the Mexican diet has changed over the last decades because traditional food has been replaced with ultraprocessed food with high-caloric values.

The authors suggest that their data confirm the alarming changes previously reported in the Mexican diet – changes possibly attributable to the increased influence of other countries via social media and economic globalization. However, they also found that beans, corn (mainly tortilla), and nopal intake remained preserved in the Mexican eating habits.

Their statistical analyses revealed that sex, age, and education seem to play a role in the presence or absence of diseases in the Mexican cohort. Men, participants over age 29 years, and those with lower levels of education had more diseases.

Dr. Alatorre-Cruz told this news organization that the Foods article opens new lines of research for the group to pursue. “One future proposal looks to enroll patients with conditions where there’s an increase in oxidative stress – which we know has quite a detrimental effect – and look into possible links with their diet. But now, maybe the focus can be on patients with a single condition and using these traditional-food tables to find links. We also want to know more about the molecular or biochemical mechanisms that are modulating the association that we saw first in animal models.”

Laura Álvarez, MD, a specialist in clinical nutrition, is the founder of the NUTRIENT project, which focuses on nutrition and strength training. In her opinion, the study extols the benefits of Mexican food. “I’ve always thought that people have this idea that Mexican food isn’t good. For example, thinking that it’s very high in fat. But in reality, Mexican food is very rich in nutrients.”

She added that research should be broadened, by enrolling a larger group of participants and evaluating not only a greater number and a greater variety of Mexican dishes, and new variables as well. “I think that body composition could be taken into account. In this study, they took the BMI into account to assess overweight and obesity, but ... the BMI doesn’t tell us much. Overweight can be due to fat or due to muscle. If we could get even more specific and find out what type of fat, that would give us more information about other [possible] diseases that ... need to be taken into account.”

This research was funded by the Institute of Sciences, Benemérita Autonomous University of Puebla. The funders had no role in the design of the study; in the collection, analyses, or interpretation of the data; in the writing of the manuscript; or in the decision to publish the results. Dr. Alatorre-Cruz and Dr. Álvarez have disclosed no relevant financial relationships.

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

The phenolic compound intake (PCI) of traditional Mexican food positively affects health conditions and supports the hypothesis that specific nutritional foods have a particular effect on certain diseases, according to researchers from the Institute of Sciences at Benemérita Autonomous University of Puebla, Puebla, Mexico.

Their study, published in the journal Foods, is the first to produce tables showing the phenolic content of Mexican dishes. Physicians and nutritionists can use this information as a reference tool when drawing up diet recommendations for patients who could benefit from a higher intake of phenolic compounds (PC).

“Up until now, there hasn’t been a table that we – nutritionists and physicians – could look at and see exactly which foods were richest in these compounds. In the United States, European countries, Asian countries – they’ve all had food tables; in Mexico, we didn’t,” said lead author Julia Alatorre-Cruz, PhD, a biological scientist and postdoctoral researcher at BUAP. “So, it’s a fairly innovative contribution. As a bonus, the information can be used to analyze the relationship between diet and noncommunicable diseases in the Mexican population.”

In recent years, nutrition science has focused on counteracting nutrient deficiency and some diseases by identifying active-food components. Diet offers the possibility to improve the patient’s health conditions by using these components or functional food.

PCs are a diverse group of plant micronutrients, some of which modulate physiologic and molecular pathways involved in energy metabolism. They can act by different mechanisms; the most important of them are conducted by anti-inflammatory, antioxidant activities, and are antiallergic.

Moreover, recent studies explain how PCs positively affect certain illnesses, such as obesity, diabetes, cardiovascular diseases, thrombocytopenia, and metabolic syndrome. Several common features characterize these pathologies – among them are the redox balance and a notable inflammatory response that strongly alters the biochemical and functional characteristics of the affected tissues.

Traditional Mexican food is characterized by grains, tubers, legumes, vegetables, and spices, most of which are rich in PCs. However, the Mexican diet has changed over the past decades because traditional food has been replaced with ultraprocessed food with high-caloric values. Moreover, some vegetables and fruits are preferably consumed after processing, which affects the quantity, quality, and bioavailability of the PCs. In addition, diseases associated with eating habits have increased by more than 27% in the Mexican population.

The objective of the study was to determine whether participants with a higher PC intake from beverages or Mexican dishes have better health conditions than those with a lower intake.

A total of 973 adults (798 females, 175 males) aged 18-79 years were enrolled in this cross-sectional study. The data were obtained from a validated, self-administered food consumption survey that was posted on social media (Facebook) or sent via WhatsApp or email. In one section, there was a list of fruits, vegetables, cereals, legumes, seeds, spices, beverages, and Mexican dishes. The participants were asked to indicate how often in the past month they had consumed these items. There were also sections for providing identification data (for example, age, sex, marital status), height and weight information, and medical history.

“The study was carried out during the pandemic, so that limited contact with the participants,” said Dr. Alatorre-Cruz. “Not being able to directly interact with them was a challenge. For example, we would have liked to have taken those anthropometric measurements ourselves.”

The researchers performed K-means clustering to determine the participant’s health-condition level, resulting in two groups: those with less diseases (LD, n = 649) and those with more diseases (MD, n = 324).

Using the food biochemistry composition reported in multiple papers, the researchers computed the average total phenolic compounds (TPC) for each item listed in the survey. For Mexican dishes, they added the TPC of each recipe’s ingredient, then recalculated to come up with TPC for an individual portion of each recipe (TPCr). To analyze the results of the LD group and of the MD group, phenolic compounds intake of recipe was calculated for each participant.

To Dr. Alatorre-Cruz, the biggest challenge was determining the content of compounds in traditional dishes. “Extensive, in-depth research was done to gather as much information as possible about all of the foods – especially about local and regional ones, because we have such a wide variety – looking to see where that information would match up with the exact method with which the compounds of interest were extracted.”

As expected, the team found that food with high PC was associated with a better health condition. However, the consumption of beverages and Mexican dishes was lower than their expectations. As noted in the article, the Mexican diet has changed over the last decades because traditional food has been replaced with ultraprocessed food with high-caloric values.

The authors suggest that their data confirm the alarming changes previously reported in the Mexican diet – changes possibly attributable to the increased influence of other countries via social media and economic globalization. However, they also found that beans, corn (mainly tortilla), and nopal intake remained preserved in the Mexican eating habits.

Their statistical analyses revealed that sex, age, and education seem to play a role in the presence or absence of diseases in the Mexican cohort. Men, participants over age 29 years, and those with lower levels of education had more diseases.

Dr. Alatorre-Cruz told this news organization that the Foods article opens new lines of research for the group to pursue. “One future proposal looks to enroll patients with conditions where there’s an increase in oxidative stress – which we know has quite a detrimental effect – and look into possible links with their diet. But now, maybe the focus can be on patients with a single condition and using these traditional-food tables to find links. We also want to know more about the molecular or biochemical mechanisms that are modulating the association that we saw first in animal models.”

Laura Álvarez, MD, a specialist in clinical nutrition, is the founder of the NUTRIENT project, which focuses on nutrition and strength training. In her opinion, the study extols the benefits of Mexican food. “I’ve always thought that people have this idea that Mexican food isn’t good. For example, thinking that it’s very high in fat. But in reality, Mexican food is very rich in nutrients.”

She added that research should be broadened, by enrolling a larger group of participants and evaluating not only a greater number and a greater variety of Mexican dishes, and new variables as well. “I think that body composition could be taken into account. In this study, they took the BMI into account to assess overweight and obesity, but ... the BMI doesn’t tell us much. Overweight can be due to fat or due to muscle. If we could get even more specific and find out what type of fat, that would give us more information about other [possible] diseases that ... need to be taken into account.”

This research was funded by the Institute of Sciences, Benemérita Autonomous University of Puebla. The funders had no role in the design of the study; in the collection, analyses, or interpretation of the data; in the writing of the manuscript; or in the decision to publish the results. Dr. Alatorre-Cruz and Dr. Álvarez have disclosed no relevant financial relationships.

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

The phenolic compound intake (PCI) of traditional Mexican food positively affects health conditions and supports the hypothesis that specific nutritional foods have a particular effect on certain diseases, according to researchers from the Institute of Sciences at Benemérita Autonomous University of Puebla, Puebla, Mexico.

Their study, published in the journal Foods, is the first to produce tables showing the phenolic content of Mexican dishes. Physicians and nutritionists can use this information as a reference tool when drawing up diet recommendations for patients who could benefit from a higher intake of phenolic compounds (PC).

“Up until now, there hasn’t been a table that we – nutritionists and physicians – could look at and see exactly which foods were richest in these compounds. In the United States, European countries, Asian countries – they’ve all had food tables; in Mexico, we didn’t,” said lead author Julia Alatorre-Cruz, PhD, a biological scientist and postdoctoral researcher at BUAP. “So, it’s a fairly innovative contribution. As a bonus, the information can be used to analyze the relationship between diet and noncommunicable diseases in the Mexican population.”

In recent years, nutrition science has focused on counteracting nutrient deficiency and some diseases by identifying active-food components. Diet offers the possibility to improve the patient’s health conditions by using these components or functional food.

PCs are a diverse group of plant micronutrients, some of which modulate physiologic and molecular pathways involved in energy metabolism. They can act by different mechanisms; the most important of them are conducted by anti-inflammatory, antioxidant activities, and are antiallergic.

Moreover, recent studies explain how PCs positively affect certain illnesses, such as obesity, diabetes, cardiovascular diseases, thrombocytopenia, and metabolic syndrome. Several common features characterize these pathologies – among them are the redox balance and a notable inflammatory response that strongly alters the biochemical and functional characteristics of the affected tissues.

Traditional Mexican food is characterized by grains, tubers, legumes, vegetables, and spices, most of which are rich in PCs. However, the Mexican diet has changed over the past decades because traditional food has been replaced with ultraprocessed food with high-caloric values. Moreover, some vegetables and fruits are preferably consumed after processing, which affects the quantity, quality, and bioavailability of the PCs. In addition, diseases associated with eating habits have increased by more than 27% in the Mexican population.

The objective of the study was to determine whether participants with a higher PC intake from beverages or Mexican dishes have better health conditions than those with a lower intake.

A total of 973 adults (798 females, 175 males) aged 18-79 years were enrolled in this cross-sectional study. The data were obtained from a validated, self-administered food consumption survey that was posted on social media (Facebook) or sent via WhatsApp or email. In one section, there was a list of fruits, vegetables, cereals, legumes, seeds, spices, beverages, and Mexican dishes. The participants were asked to indicate how often in the past month they had consumed these items. There were also sections for providing identification data (for example, age, sex, marital status), height and weight information, and medical history.

“The study was carried out during the pandemic, so that limited contact with the participants,” said Dr. Alatorre-Cruz. “Not being able to directly interact with them was a challenge. For example, we would have liked to have taken those anthropometric measurements ourselves.”

The researchers performed K-means clustering to determine the participant’s health-condition level, resulting in two groups: those with less diseases (LD, n = 649) and those with more diseases (MD, n = 324).

Using the food biochemistry composition reported in multiple papers, the researchers computed the average total phenolic compounds (TPC) for each item listed in the survey. For Mexican dishes, they added the TPC of each recipe’s ingredient, then recalculated to come up with TPC for an individual portion of each recipe (TPCr). To analyze the results of the LD group and of the MD group, phenolic compounds intake of recipe was calculated for each participant.

To Dr. Alatorre-Cruz, the biggest challenge was determining the content of compounds in traditional dishes. “Extensive, in-depth research was done to gather as much information as possible about all of the foods – especially about local and regional ones, because we have such a wide variety – looking to see where that information would match up with the exact method with which the compounds of interest were extracted.”

As expected, the team found that food with high PC was associated with a better health condition. However, the consumption of beverages and Mexican dishes was lower than their expectations. As noted in the article, the Mexican diet has changed over the last decades because traditional food has been replaced with ultraprocessed food with high-caloric values.

The authors suggest that their data confirm the alarming changes previously reported in the Mexican diet – changes possibly attributable to the increased influence of other countries via social media and economic globalization. However, they also found that beans, corn (mainly tortilla), and nopal intake remained preserved in the Mexican eating habits.

Their statistical analyses revealed that sex, age, and education seem to play a role in the presence or absence of diseases in the Mexican cohort. Men, participants over age 29 years, and those with lower levels of education had more diseases.

Dr. Alatorre-Cruz told this news organization that the Foods article opens new lines of research for the group to pursue. “One future proposal looks to enroll patients with conditions where there’s an increase in oxidative stress – which we know has quite a detrimental effect – and look into possible links with their diet. But now, maybe the focus can be on patients with a single condition and using these traditional-food tables to find links. We also want to know more about the molecular or biochemical mechanisms that are modulating the association that we saw first in animal models.”

Laura Álvarez, MD, a specialist in clinical nutrition, is the founder of the NUTRIENT project, which focuses on nutrition and strength training. In her opinion, the study extols the benefits of Mexican food. “I’ve always thought that people have this idea that Mexican food isn’t good. For example, thinking that it’s very high in fat. But in reality, Mexican food is very rich in nutrients.”

She added that research should be broadened, by enrolling a larger group of participants and evaluating not only a greater number and a greater variety of Mexican dishes, and new variables as well. “I think that body composition could be taken into account. In this study, they took the BMI into account to assess overweight and obesity, but ... the BMI doesn’t tell us much. Overweight can be due to fat or due to muscle. If we could get even more specific and find out what type of fat, that would give us more information about other [possible] diseases that ... need to be taken into account.”

This research was funded by the Institute of Sciences, Benemérita Autonomous University of Puebla. The funders had no role in the design of the study; in the collection, analyses, or interpretation of the data; in the writing of the manuscript; or in the decision to publish the results. Dr. Alatorre-Cruz and Dr. Álvarez have disclosed no relevant financial relationships.

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

MUNICH, GERMANY – Intensive systolic blood pressure (SBP) management in the 24 hours after successful recanalization with intra-arterial thrombectomy (IAT) substantially increases the risk of a poor outcome at 3 months, suggests results from the OPTIMAL-BP trial.

The research, presented at the annual European Stroke Organisation Conference, supports the latest U.S. and European guidelines, which recommend a relatively high upper SBP limit.

For the trial, which was halted early, more than 300 patients who successfully underwent IAT for acute ischemic stroke were randomly assigned to intensive or conventional BP management within 2 hours of recanalization.

Patients in the intensive group were 44% less likely than those assigned to conventional management to have a favorable outcome of a modified Rankin Scale (mRS) score of 0-2 at 3 months, while having similar rates of adverse outcomes.

The results suggest that intensive BP lowering in the 24 hours after recanalization leads to an increased risk of disability without decreasing the risk of intracerebral hemorrhage (ICH) or death, said study presenter Hyo Suk Nam, MD, PhD, department of neurology, Yonsei (South Korea) University.

Consequently, the trial “does not support intensive blood pressure management” in that early post-IAT period, although the “optimal blood pressure range remains unclear and requires more investigation,” he said.

Dr. Nam added that the results suggest, “despite recanalization, some areas in the ischemic brain may have already been damaged,” or that surrounding areas continue to have reduced blood circulation.

He believes that these areas may have reduced capacity for autoregulation and so “may not effectively counteract sudden drops in blood pressure.

“Thus, intensive blood pressure lowering may further reduce blood flow ... and exacerbate ischemic injury.”

On the other hand, the conventional group confirmed prior studies indicating that high SBP is associated with poor outcomes.

Dr. Nam suggested that increased BP “may be a physiological response to the acute stress of stroke,” but that the adverse outcomes in some patients “might reflect stroke severity rather than being a direct effect of raised blood pressure.”

Session cochair Carlos Molina, MD, director of the stroke unit and brain hemodynamics at Vall d’Hebron Hospital, Barcelona, commented that “it’s very important to remember that the guidances are endorsed by the results of this study.

He said in an interview that “intensive blood pressure lowering harms the brain, especially just after reperfusion.

“So, the results are in line with the previous concept that we need to be careful, as intensive blood pressure lowering is associated with clinical deterioration and poor outcomes.”

He agreed with Dr. Nam that, with high BP also being harmful, the optimal range is currently unclear.

Dr. Molina underlined, however, that, in the absence of further studies, “we have to stick to the guidelines.”

Dr. Nam pointed out that, while high BP can result in reperfusion injury or ICH, “too low blood pressure can worsen cerebral ischemia.”

Yet the management of BP after successful recanalization with IAT is “largely unknown.”

He noted that, while both the European Stroke Organisation and American Heart Association/American Stroke Association guidelines recommend that BP should be kept below 180/105 mm Hg in patients who have undergone successful recanalization, the evidence class for this recommendation is “weak.”

Furthermore, observational studies have indicated that higher maximum or average SBP is associated with poor outcomes, but two multicenter clinical trials of intensive BP lowering after IAT, BP-TARGET and ENCHANTED2/MT, had conflicting results.

The researchers therefore investigated whether intensive BP management would result in better clinical outcomes in the 24 hours after successful recanalization with IAT.

They conducted a multicenter, open-label trial in which patients aged 20 years and older who underwent IAT for acute ischemic stroke with large cerebrovascular occlusion and had an SBP of at least 140 mm Hg were recruited from 19 centers in South Korea between June 2020 and November 2022.

The patients were randomly assigned within 2 hours of successful recanalization to intensive BP management, targeting an SBP less than 140 mm Hg, or conventional management, targeting an SBP of 140-180 mm Hg.

Clinicians could use local treatment protocols based on available intravenous BP-lowering drugs. BP was measured every 15 minutes for the first hour after randomization and then hourly for 24 hours.

The trial was terminated early because of safety concerns after the ENCHANTED2/MT trial revealed a negative impact on mRS scores at 3 months with intensive BP management.

Of 1,606 potentially eligible patients with acute ischemic stroke treated with IAT, 306 were randomly assigned, with 155 in the intensive group and 150 in the conventional group included in the primary analysis.

The mean age was 73.1 years, and 40.3% were women. The average National Institutes of Health Stroke Scale (NIHSS) score prior to IAT was 13. The mean time from stroke onset to randomization was 480 minutes (interquartile range, 320-820 minutes).

At 24 hours, the mean SBP in the intensive group was 129.2 mm Hg versus 138.0 mm Hg in the conventional group, for a between-group difference of 9.6 mm Hg (95% confidence interval, –12.2 to –6.9, P < .001).

Patients in the intensive group spent 80.3% of the first 24 hours with SBP less than 140 mm Hg versus 54.2% in the conventional group (P < .001). In contrast, conventional group patients spent 42.1% of the first 24 hours with SBP 140-180 mm Hg versus 14.2% in the intensive group.

Crucially, Dr. Nam showed that patients in the intensive BP-lowering group were significantly less likely than those in the conventional group to have a favorable outcome, defined as an mRS score of 0-2, at 3 months, at 39.4% versus 54.4%, or an adjusted odds ratio of 0.56 (95% CI, 0.33-0.96, P = .034).

Moreover, a poor outcome was 1.84 (95% CI, 1.17-2.91) times more common in the intervention group than the conventional group, Dr. Nam reported, with a number needed to harm of 6.6.

In terms of safety, there was no significant difference in rates of symptomatic ICH between the groups, at 9% in the intensive versus 8.1% in the conventional groups, or an aOR of 1.10 (95% CI, 0.48-2.53, P = .816).

There was also no difference in the rate of death related to the index stroke within 90 days, at 7.7% versus 5.4% (AOR, 1.73; 95% CI, 0.61-4.92, P = .307).

There were also no significant differences between the groups in key secondary outcomes, such as NIHSS score at 24 hours, recanalization at 24 hours, favorable outcome on the mRS at 1 month, and the EQ-5D-3L quality of life score.

However, patients in the intensive group were substantially more likely to experience malignant brain edema, at 7.7% versus 1.3% in the conventional group (aOR, 7.88; 95% CI, 1.57-39.39, P = .012).

Restricted cubic spline regression analysis indicated that there was a U-shaped relationship between mean SBP during the 24 hours following IAT and the odds ratio of a poor outcome, in which both a low and a high BPe were unfavorable.

Dr. Nam cautioned that, when interpreting the results, the early termination of the study may have reduced its statistical power and increased the likelihood of random and exaggerated treatment effects.

He also noted that the study was conducted in South Korea, and so the results may not be generalizable to other populations.

The study received a grant from the Patient-Centered Clinical Research Coordinating Center, funded by the Ministry of Health and Welfare. No relevant financial relationships were declared.

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

MUNICH, GERMANY – Intensive systolic blood pressure (SBP) management in the 24 hours after successful recanalization with intra-arterial thrombectomy (IAT) substantially increases the risk of a poor outcome at 3 months, suggests results from the OPTIMAL-BP trial.

The research, presented at the annual European Stroke Organisation Conference, supports the latest U.S. and European guidelines, which recommend a relatively high upper SBP limit.

For the trial, which was halted early, more than 300 patients who successfully underwent IAT for acute ischemic stroke were randomly assigned to intensive or conventional BP management within 2 hours of recanalization.

Patients in the intensive group were 44% less likely than those assigned to conventional management to have a favorable outcome of a modified Rankin Scale (mRS) score of 0-2 at 3 months, while having similar rates of adverse outcomes.

The results suggest that intensive BP lowering in the 24 hours after recanalization leads to an increased risk of disability without decreasing the risk of intracerebral hemorrhage (ICH) or death, said study presenter Hyo Suk Nam, MD, PhD, department of neurology, Yonsei (South Korea) University.

Consequently, the trial “does not support intensive blood pressure management” in that early post-IAT period, although the “optimal blood pressure range remains unclear and requires more investigation,” he said.

Dr. Nam added that the results suggest, “despite recanalization, some areas in the ischemic brain may have already been damaged,” or that surrounding areas continue to have reduced blood circulation.

He believes that these areas may have reduced capacity for autoregulation and so “may not effectively counteract sudden drops in blood pressure.

“Thus, intensive blood pressure lowering may further reduce blood flow ... and exacerbate ischemic injury.”

On the other hand, the conventional group confirmed prior studies indicating that high SBP is associated with poor outcomes.

Dr. Nam suggested that increased BP “may be a physiological response to the acute stress of stroke,” but that the adverse outcomes in some patients “might reflect stroke severity rather than being a direct effect of raised blood pressure.”

Session cochair Carlos Molina, MD, director of the stroke unit and brain hemodynamics at Vall d’Hebron Hospital, Barcelona, commented that “it’s very important to remember that the guidances are endorsed by the results of this study.

He said in an interview that “intensive blood pressure lowering harms the brain, especially just after reperfusion.

“So, the results are in line with the previous concept that we need to be careful, as intensive blood pressure lowering is associated with clinical deterioration and poor outcomes.”

He agreed with Dr. Nam that, with high BP also being harmful, the optimal range is currently unclear.

Dr. Molina underlined, however, that, in the absence of further studies, “we have to stick to the guidelines.”

Dr. Nam pointed out that, while high BP can result in reperfusion injury or ICH, “too low blood pressure can worsen cerebral ischemia.”

Yet the management of BP after successful recanalization with IAT is “largely unknown.”

He noted that, while both the European Stroke Organisation and American Heart Association/American Stroke Association guidelines recommend that BP should be kept below 180/105 mm Hg in patients who have undergone successful recanalization, the evidence class for this recommendation is “weak.”

Furthermore, observational studies have indicated that higher maximum or average SBP is associated with poor outcomes, but two multicenter clinical trials of intensive BP lowering after IAT, BP-TARGET and ENCHANTED2/MT, had conflicting results.

The researchers therefore investigated whether intensive BP management would result in better clinical outcomes in the 24 hours after successful recanalization with IAT.

They conducted a multicenter, open-label trial in which patients aged 20 years and older who underwent IAT for acute ischemic stroke with large cerebrovascular occlusion and had an SBP of at least 140 mm Hg were recruited from 19 centers in South Korea between June 2020 and November 2022.

The patients were randomly assigned within 2 hours of successful recanalization to intensive BP management, targeting an SBP less than 140 mm Hg, or conventional management, targeting an SBP of 140-180 mm Hg.

Clinicians could use local treatment protocols based on available intravenous BP-lowering drugs. BP was measured every 15 minutes for the first hour after randomization and then hourly for 24 hours.

The trial was terminated early because of safety concerns after the ENCHANTED2/MT trial revealed a negative impact on mRS scores at 3 months with intensive BP management.

Of 1,606 potentially eligible patients with acute ischemic stroke treated with IAT, 306 were randomly assigned, with 155 in the intensive group and 150 in the conventional group included in the primary analysis.

The mean age was 73.1 years, and 40.3% were women. The average National Institutes of Health Stroke Scale (NIHSS) score prior to IAT was 13. The mean time from stroke onset to randomization was 480 minutes (interquartile range, 320-820 minutes).

At 24 hours, the mean SBP in the intensive group was 129.2 mm Hg versus 138.0 mm Hg in the conventional group, for a between-group difference of 9.6 mm Hg (95% confidence interval, –12.2 to –6.9, P < .001).

Patients in the intensive group spent 80.3% of the first 24 hours with SBP less than 140 mm Hg versus 54.2% in the conventional group (P < .001). In contrast, conventional group patients spent 42.1% of the first 24 hours with SBP 140-180 mm Hg versus 14.2% in the intensive group.

Crucially, Dr. Nam showed that patients in the intensive BP-lowering group were significantly less likely than those in the conventional group to have a favorable outcome, defined as an mRS score of 0-2, at 3 months, at 39.4% versus 54.4%, or an adjusted odds ratio of 0.56 (95% CI, 0.33-0.96, P = .034).

Moreover, a poor outcome was 1.84 (95% CI, 1.17-2.91) times more common in the intervention group than the conventional group, Dr. Nam reported, with a number needed to harm of 6.6.

In terms of safety, there was no significant difference in rates of symptomatic ICH between the groups, at 9% in the intensive versus 8.1% in the conventional groups, or an aOR of 1.10 (95% CI, 0.48-2.53, P = .816).

There was also no difference in the rate of death related to the index stroke within 90 days, at 7.7% versus 5.4% (AOR, 1.73; 95% CI, 0.61-4.92, P = .307).

There were also no significant differences between the groups in key secondary outcomes, such as NIHSS score at 24 hours, recanalization at 24 hours, favorable outcome on the mRS at 1 month, and the EQ-5D-3L quality of life score.

However, patients in the intensive group were substantially more likely to experience malignant brain edema, at 7.7% versus 1.3% in the conventional group (aOR, 7.88; 95% CI, 1.57-39.39, P = .012).

Restricted cubic spline regression analysis indicated that there was a U-shaped relationship between mean SBP during the 24 hours following IAT and the odds ratio of a poor outcome, in which both a low and a high BPe were unfavorable.

Dr. Nam cautioned that, when interpreting the results, the early termination of the study may have reduced its statistical power and increased the likelihood of random and exaggerated treatment effects.

He also noted that the study was conducted in South Korea, and so the results may not be generalizable to other populations.

The study received a grant from the Patient-Centered Clinical Research Coordinating Center, funded by the Ministry of Health and Welfare. No relevant financial relationships were declared.

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

MUNICH, GERMANY – Intensive systolic blood pressure (SBP) management in the 24 hours after successful recanalization with intra-arterial thrombectomy (IAT) substantially increases the risk of a poor outcome at 3 months, suggests results from the OPTIMAL-BP trial.

The research, presented at the annual European Stroke Organisation Conference, supports the latest U.S. and European guidelines, which recommend a relatively high upper SBP limit.

For the trial, which was halted early, more than 300 patients who successfully underwent IAT for acute ischemic stroke were randomly assigned to intensive or conventional BP management within 2 hours of recanalization.

Patients in the intensive group were 44% less likely than those assigned to conventional management to have a favorable outcome of a modified Rankin Scale (mRS) score of 0-2 at 3 months, while having similar rates of adverse outcomes.

The results suggest that intensive BP lowering in the 24 hours after recanalization leads to an increased risk of disability without decreasing the risk of intracerebral hemorrhage (ICH) or death, said study presenter Hyo Suk Nam, MD, PhD, department of neurology, Yonsei (South Korea) University.

Consequently, the trial “does not support intensive blood pressure management” in that early post-IAT period, although the “optimal blood pressure range remains unclear and requires more investigation,” he said.

Dr. Nam added that the results suggest, “despite recanalization, some areas in the ischemic brain may have already been damaged,” or that surrounding areas continue to have reduced blood circulation.

He believes that these areas may have reduced capacity for autoregulation and so “may not effectively counteract sudden drops in blood pressure.

“Thus, intensive blood pressure lowering may further reduce blood flow ... and exacerbate ischemic injury.”

On the other hand, the conventional group confirmed prior studies indicating that high SBP is associated with poor outcomes.

Dr. Nam suggested that increased BP “may be a physiological response to the acute stress of stroke,” but that the adverse outcomes in some patients “might reflect stroke severity rather than being a direct effect of raised blood pressure.”

Session cochair Carlos Molina, MD, director of the stroke unit and brain hemodynamics at Vall d’Hebron Hospital, Barcelona, commented that “it’s very important to remember that the guidances are endorsed by the results of this study.

He said in an interview that “intensive blood pressure lowering harms the brain, especially just after reperfusion.

“So, the results are in line with the previous concept that we need to be careful, as intensive blood pressure lowering is associated with clinical deterioration and poor outcomes.”

He agreed with Dr. Nam that, with high BP also being harmful, the optimal range is currently unclear.

Dr. Molina underlined, however, that, in the absence of further studies, “we have to stick to the guidelines.”

Dr. Nam pointed out that, while high BP can result in reperfusion injury or ICH, “too low blood pressure can worsen cerebral ischemia.”

Yet the management of BP after successful recanalization with IAT is “largely unknown.”

He noted that, while both the European Stroke Organisation and American Heart Association/American Stroke Association guidelines recommend that BP should be kept below 180/105 mm Hg in patients who have undergone successful recanalization, the evidence class for this recommendation is “weak.”

Furthermore, observational studies have indicated that higher maximum or average SBP is associated with poor outcomes, but two multicenter clinical trials of intensive BP lowering after IAT, BP-TARGET and ENCHANTED2/MT, had conflicting results.

The researchers therefore investigated whether intensive BP management would result in better clinical outcomes in the 24 hours after successful recanalization with IAT.

They conducted a multicenter, open-label trial in which patients aged 20 years and older who underwent IAT for acute ischemic stroke with large cerebrovascular occlusion and had an SBP of at least 140 mm Hg were recruited from 19 centers in South Korea between June 2020 and November 2022.

The patients were randomly assigned within 2 hours of successful recanalization to intensive BP management, targeting an SBP less than 140 mm Hg, or conventional management, targeting an SBP of 140-180 mm Hg.

Clinicians could use local treatment protocols based on available intravenous BP-lowering drugs. BP was measured every 15 minutes for the first hour after randomization and then hourly for 24 hours.

The trial was terminated early because of safety concerns after the ENCHANTED2/MT trial revealed a negative impact on mRS scores at 3 months with intensive BP management.

Of 1,606 potentially eligible patients with acute ischemic stroke treated with IAT, 306 were randomly assigned, with 155 in the intensive group and 150 in the conventional group included in the primary analysis.

The mean age was 73.1 years, and 40.3% were women. The average National Institutes of Health Stroke Scale (NIHSS) score prior to IAT was 13. The mean time from stroke onset to randomization was 480 minutes (interquartile range, 320-820 minutes).

At 24 hours, the mean SBP in the intensive group was 129.2 mm Hg versus 138.0 mm Hg in the conventional group, for a between-group difference of 9.6 mm Hg (95% confidence interval, –12.2 to –6.9, P < .001).

Patients in the intensive group spent 80.3% of the first 24 hours with SBP less than 140 mm Hg versus 54.2% in the conventional group (P < .001). In contrast, conventional group patients spent 42.1% of the first 24 hours with SBP 140-180 mm Hg versus 14.2% in the intensive group.

Crucially, Dr. Nam showed that patients in the intensive BP-lowering group were significantly less likely than those in the conventional group to have a favorable outcome, defined as an mRS score of 0-2, at 3 months, at 39.4% versus 54.4%, or an adjusted odds ratio of 0.56 (95% CI, 0.33-0.96, P = .034).

Moreover, a poor outcome was 1.84 (95% CI, 1.17-2.91) times more common in the intervention group than the conventional group, Dr. Nam reported, with a number needed to harm of 6.6.

In terms of safety, there was no significant difference in rates of symptomatic ICH between the groups, at 9% in the intensive versus 8.1% in the conventional groups, or an aOR of 1.10 (95% CI, 0.48-2.53, P = .816).

There was also no difference in the rate of death related to the index stroke within 90 days, at 7.7% versus 5.4% (AOR, 1.73; 95% CI, 0.61-4.92, P = .307).

There were also no significant differences between the groups in key secondary outcomes, such as NIHSS score at 24 hours, recanalization at 24 hours, favorable outcome on the mRS at 1 month, and the EQ-5D-3L quality of life score.

However, patients in the intensive group were substantially more likely to experience malignant brain edema, at 7.7% versus 1.3% in the conventional group (aOR, 7.88; 95% CI, 1.57-39.39, P = .012).

Restricted cubic spline regression analysis indicated that there was a U-shaped relationship between mean SBP during the 24 hours following IAT and the odds ratio of a poor outcome, in which both a low and a high BPe were unfavorable.

Dr. Nam cautioned that, when interpreting the results, the early termination of the study may have reduced its statistical power and increased the likelihood of random and exaggerated treatment effects.

He also noted that the study was conducted in South Korea, and so the results may not be generalizable to other populations.

The study received a grant from the Patient-Centered Clinical Research Coordinating Center, funded by the Ministry of Health and Welfare. No relevant financial relationships were declared.

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

Giving very late thrombolysis to patients with large-vessel occlusion small core strokes did not show a significant benefit in the TIMELESS trial.

However, there were some encouraging trends, and there did not appear to be an increase in intracranial hemorrhage (ICH), leading to hope that the option of late thrombolysis in this group of patients may still have potential.

The TIMELESS study tested the approach of giving thrombolysis with tenecteplase (TNK) to patients with a large-vessel occlusion stroke up to 24 hours after symptom onset. Patients were selected by perfusion imaging, and those who had a stroke with a small core and large amount of salvageable brain tissue were included in the placebo-controlled study.

“This is first trial to try giving a thrombolytic so late – up to 24 hours after last known well. While we did not meet the primary outcome, there were some promising findings,” lead author, Gregory Albers, MD, director of the Stanford (Calif.) Stroke Center and professor of neurology at Stanford University, said in an interview.

“The most encouraging observation was that we did not show any safety issues with giving TNK to this population at such a late time. Many people thought this would be too high risk but there was no increase in ICH, which was very low and the same in both groups,” Dr. Albers said.

“And we saw some evidence of drug effect. There appeared to be a benefit in patients with M1 occlusions, the most common type of large-vessel occlusion, who represented half the patients in the study,” he added.

The researchers also gained information on the logistics and timing of TNK administration in this late period which they hope can guide the design of a future trial.

Dr. Albers presented the TIMELESS trial at the annual European Stroke Organisation Conference.

He explained that there is increasing evidence that intravenous thrombolysis can improve outcome in selected patients even beyond the traditional 4.5-hour time window.

The phase 3, double-blind, randomized, placebo-controlled TIMELESS study sought to investigate whether tenecteplase administered to patients with ischemic stroke with large-vessel occlusion presenting between 4.5 and 24 hours after last known well would improve clinical outcome as measured by modified Rankin Scale (mRS) at day 90.

The trial included 458 patients with an internal carotid artery occlusion or middle cerebral artery segment 1 or 2 occlusion and presenting with salvageable tissue on imaging. They were randomly assigned 1:1 to either intravenous tenecteplase (0.25 mg/kg; maximum, 25 mg) or placebo.

The proportion of patients treated with mechanical thrombectomy were similar between the two treatment arms (around 77%). The study completion rate was higher than 96% in both treatment arms.

The primary endpoint analyses showed no significant difference in the odds of a lower mRS score at day 90, but there was a slight trend toward benefit in the TNK group in the shift analysis, with a common odds ratio of 1.13 (95% confidence interval, 0.81-1.56; P = .48).

The percentage of patients achieving a favorable outcome, defined as an mRS of 0-2, was not significantly different between the treatment groups: 46% in the TNK group versus 42% in the placebo group (nominal P = .41).


 

Promising safety data

There were no significant safety issues, and the risk for bleeding was not significantly increased in the tenecteplase group. Symptomatic ICH occurred in 3.2% of the TNK group versus 2.3% of the placebo group, a nonsignificant difference.

“The low rate of ICH with TNK at this late time point is very reassuring,” Dr. Albers said. “We believe the reason for the low ICH rate is probably because these patients were selected for small core strokes. We also found that there was a trend towards the most benefit from TNK in patients with the smallest cores, supporting the use of imaging to select patients.”

The secondary endpoint of complete recanalization at 24-hours post randomization was higher in the TNK group at 76.7%, compared with 63.9% in the placebo group (P = .006).
 

Benefit in M1 occlusions?

Subgroup analysis showed that there appeared to be a benefit of TNK in the 227 patients included who had an M1 occlusion. In this group, the common odds ratio for a more favorable outcome in the mRS shift analysis with TNK was 1.59 (95% CI, 1.00-2.52; adjusted nominal P = .051).

The percentage of patients with a favorable outcome (mRS, 0-2) at 90 days in the M1 occlusion subgroup was 45.9% for TNK versus 31.4% for placebo, giving an adjusted odds ratio of 2.03 (95% CI, 1.14-3.66; nominal P = .017).

But Dr. Albers cautioned that this was an exploratory analysis, and no formal conclusions should be drawn from these data.

“We saw very strong results in favor of giving thrombolysis in the patients with M1 occlusions. We had preliminary pilot data suggesting this approach may work in these patients,” he commented.

“But we included the smaller M2 occlusions as well, because we thought that as there should be less clot in an M2 occlusion it might be easier to dissolve with thrombolysis,” he added. “But surprisingly, the M2 occlusion patients seemed to do worse with TNK than placebo, and the M1 patients did better.”
 

Timing of TNK

Dr. Albers said that there was also information from in the study on the timing of TNK administration.

In patients who also received thrombectomy, who made up of the majority of those in the study, the average time of TNK administration was only 20 minutes before the thrombectomy procedure.

“We had hoped to have a longer time between thrombolysis and thrombectomy so the drug would have more time to work. The idea was that patients would be given TNK at the primary stroke center before being transferred for thrombectomy, but actually only a few patients received TNK at the primary stroke center,” Dr. Albers explained.

“But, again surprisingly, we found that patients given TNK right at the time of the thrombectomy procedure seemed to show a trend toward benefit over placebo,” he reported.

He suggested that this may be caused by the thrombolytic dissolving the small fragments that can sometimes break off and cause further occlusions when the clot is removed by thrombectomy.

“We have learned a lot from this study, and we are planning to go forward with the information gained to plan a second study, in which we will focus on patients with M1 occlusions and try to get the drug on board at primary stroke centers, so it has more time to work before thrombectomy,” he added.

Commenting on the TIMELESS study at the ESOC meeting, Georgios Tsivgoulis, MD, professor of neurology, University of Athens, said that he thought the trial had shown three important results: “Firstly, TNK appeared to be safe in this late window in these selected patients – that is a very important observation. Secondly, reperfusion rates at 24 hours were increased with TNK and we know that this translates into clinical benefit. And thirdly, there was a neutral effect on primary outcomes, but I think the sample size of 438 patients was not large enough to show efficacy.”

Dr. Tsivgoulis concluded that these points need to be addressed in future trials.

The TIMELESS trial was funded by Genentech.

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

Giving very late thrombolysis to patients with large-vessel occlusion small core strokes did not show a significant benefit in the TIMELESS trial.

However, there were some encouraging trends, and there did not appear to be an increase in intracranial hemorrhage (ICH), leading to hope that the option of late thrombolysis in this group of patients may still have potential.

The TIMELESS study tested the approach of giving thrombolysis with tenecteplase (TNK) to patients with a large-vessel occlusion stroke up to 24 hours after symptom onset. Patients were selected by perfusion imaging, and those who had a stroke with a small core and large amount of salvageable brain tissue were included in the placebo-controlled study.

“This is first trial to try giving a thrombolytic so late – up to 24 hours after last known well. While we did not meet the primary outcome, there were some promising findings,” lead author, Gregory Albers, MD, director of the Stanford (Calif.) Stroke Center and professor of neurology at Stanford University, said in an interview.

“The most encouraging observation was that we did not show any safety issues with giving TNK to this population at such a late time. Many people thought this would be too high risk but there was no increase in ICH, which was very low and the same in both groups,” Dr. Albers said.

“And we saw some evidence of drug effect. There appeared to be a benefit in patients with M1 occlusions, the most common type of large-vessel occlusion, who represented half the patients in the study,” he added.

The researchers also gained information on the logistics and timing of TNK administration in this late period which they hope can guide the design of a future trial.

Dr. Albers presented the TIMELESS trial at the annual European Stroke Organisation Conference.

He explained that there is increasing evidence that intravenous thrombolysis can improve outcome in selected patients even beyond the traditional 4.5-hour time window.

The phase 3, double-blind, randomized, placebo-controlled TIMELESS study sought to investigate whether tenecteplase administered to patients with ischemic stroke with large-vessel occlusion presenting between 4.5 and 24 hours after last known well would improve clinical outcome as measured by modified Rankin Scale (mRS) at day 90.

The trial included 458 patients with an internal carotid artery occlusion or middle cerebral artery segment 1 or 2 occlusion and presenting with salvageable tissue on imaging. They were randomly assigned 1:1 to either intravenous tenecteplase (0.25 mg/kg; maximum, 25 mg) or placebo.

The proportion of patients treated with mechanical thrombectomy were similar between the two treatment arms (around 77%). The study completion rate was higher than 96% in both treatment arms.

The primary endpoint analyses showed no significant difference in the odds of a lower mRS score at day 90, but there was a slight trend toward benefit in the TNK group in the shift analysis, with a common odds ratio of 1.13 (95% confidence interval, 0.81-1.56; P = .48).

The percentage of patients achieving a favorable outcome, defined as an mRS of 0-2, was not significantly different between the treatment groups: 46% in the TNK group versus 42% in the placebo group (nominal P = .41).


 

Promising safety data

There were no significant safety issues, and the risk for bleeding was not significantly increased in the tenecteplase group. Symptomatic ICH occurred in 3.2% of the TNK group versus 2.3% of the placebo group, a nonsignificant difference.

“The low rate of ICH with TNK at this late time point is very reassuring,” Dr. Albers said. “We believe the reason for the low ICH rate is probably because these patients were selected for small core strokes. We also found that there was a trend towards the most benefit from TNK in patients with the smallest cores, supporting the use of imaging to select patients.”

The secondary endpoint of complete recanalization at 24-hours post randomization was higher in the TNK group at 76.7%, compared with 63.9% in the placebo group (P = .006).
 

Benefit in M1 occlusions?

Subgroup analysis showed that there appeared to be a benefit of TNK in the 227 patients included who had an M1 occlusion. In this group, the common odds ratio for a more favorable outcome in the mRS shift analysis with TNK was 1.59 (95% CI, 1.00-2.52; adjusted nominal P = .051).

The percentage of patients with a favorable outcome (mRS, 0-2) at 90 days in the M1 occlusion subgroup was 45.9% for TNK versus 31.4% for placebo, giving an adjusted odds ratio of 2.03 (95% CI, 1.14-3.66; nominal P = .017).

But Dr. Albers cautioned that this was an exploratory analysis, and no formal conclusions should be drawn from these data.

“We saw very strong results in favor of giving thrombolysis in the patients with M1 occlusions. We had preliminary pilot data suggesting this approach may work in these patients,” he commented.

“But we included the smaller M2 occlusions as well, because we thought that as there should be less clot in an M2 occlusion it might be easier to dissolve with thrombolysis,” he added. “But surprisingly, the M2 occlusion patients seemed to do worse with TNK than placebo, and the M1 patients did better.”
 

Timing of TNK

Dr. Albers said that there was also information from in the study on the timing of TNK administration.

In patients who also received thrombectomy, who made up of the majority of those in the study, the average time of TNK administration was only 20 minutes before the thrombectomy procedure.

“We had hoped to have a longer time between thrombolysis and thrombectomy so the drug would have more time to work. The idea was that patients would be given TNK at the primary stroke center before being transferred for thrombectomy, but actually only a few patients received TNK at the primary stroke center,” Dr. Albers explained.

“But, again surprisingly, we found that patients given TNK right at the time of the thrombectomy procedure seemed to show a trend toward benefit over placebo,” he reported.

He suggested that this may be caused by the thrombolytic dissolving the small fragments that can sometimes break off and cause further occlusions when the clot is removed by thrombectomy.

“We have learned a lot from this study, and we are planning to go forward with the information gained to plan a second study, in which we will focus on patients with M1 occlusions and try to get the drug on board at primary stroke centers, so it has more time to work before thrombectomy,” he added.

Commenting on the TIMELESS study at the ESOC meeting, Georgios Tsivgoulis, MD, professor of neurology, University of Athens, said that he thought the trial had shown three important results: “Firstly, TNK appeared to be safe in this late window in these selected patients – that is a very important observation. Secondly, reperfusion rates at 24 hours were increased with TNK and we know that this translates into clinical benefit. And thirdly, there was a neutral effect on primary outcomes, but I think the sample size of 438 patients was not large enough to show efficacy.”

Dr. Tsivgoulis concluded that these points need to be addressed in future trials.

The TIMELESS trial was funded by Genentech.

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

Giving very late thrombolysis to patients with large-vessel occlusion small core strokes did not show a significant benefit in the TIMELESS trial.

However, there were some encouraging trends, and there did not appear to be an increase in intracranial hemorrhage (ICH), leading to hope that the option of late thrombolysis in this group of patients may still have potential.

The TIMELESS study tested the approach of giving thrombolysis with tenecteplase (TNK) to patients with a large-vessel occlusion stroke up to 24 hours after symptom onset. Patients were selected by perfusion imaging, and those who had a stroke with a small core and large amount of salvageable brain tissue were included in the placebo-controlled study.

“This is first trial to try giving a thrombolytic so late – up to 24 hours after last known well. While we did not meet the primary outcome, there were some promising findings,” lead author, Gregory Albers, MD, director of the Stanford (Calif.) Stroke Center and professor of neurology at Stanford University, said in an interview.

“The most encouraging observation was that we did not show any safety issues with giving TNK to this population at such a late time. Many people thought this would be too high risk but there was no increase in ICH, which was very low and the same in both groups,” Dr. Albers said.

“And we saw some evidence of drug effect. There appeared to be a benefit in patients with M1 occlusions, the most common type of large-vessel occlusion, who represented half the patients in the study,” he added.

The researchers also gained information on the logistics and timing of TNK administration in this late period which they hope can guide the design of a future trial.

Dr. Albers presented the TIMELESS trial at the annual European Stroke Organisation Conference.

He explained that there is increasing evidence that intravenous thrombolysis can improve outcome in selected patients even beyond the traditional 4.5-hour time window.

The phase 3, double-blind, randomized, placebo-controlled TIMELESS study sought to investigate whether tenecteplase administered to patients with ischemic stroke with large-vessel occlusion presenting between 4.5 and 24 hours after last known well would improve clinical outcome as measured by modified Rankin Scale (mRS) at day 90.

The trial included 458 patients with an internal carotid artery occlusion or middle cerebral artery segment 1 or 2 occlusion and presenting with salvageable tissue on imaging. They were randomly assigned 1:1 to either intravenous tenecteplase (0.25 mg/kg; maximum, 25 mg) or placebo.

The proportion of patients treated with mechanical thrombectomy were similar between the two treatment arms (around 77%). The study completion rate was higher than 96% in both treatment arms.

The primary endpoint analyses showed no significant difference in the odds of a lower mRS score at day 90, but there was a slight trend toward benefit in the TNK group in the shift analysis, with a common odds ratio of 1.13 (95% confidence interval, 0.81-1.56; P = .48).

The percentage of patients achieving a favorable outcome, defined as an mRS of 0-2, was not significantly different between the treatment groups: 46% in the TNK group versus 42% in the placebo group (nominal P = .41).


 

Promising safety data

There were no significant safety issues, and the risk for bleeding was not significantly increased in the tenecteplase group. Symptomatic ICH occurred in 3.2% of the TNK group versus 2.3% of the placebo group, a nonsignificant difference.

“The low rate of ICH with TNK at this late time point is very reassuring,” Dr. Albers said. “We believe the reason for the low ICH rate is probably because these patients were selected for small core strokes. We also found that there was a trend towards the most benefit from TNK in patients with the smallest cores, supporting the use of imaging to select patients.”

The secondary endpoint of complete recanalization at 24-hours post randomization was higher in the TNK group at 76.7%, compared with 63.9% in the placebo group (P = .006).
 

Benefit in M1 occlusions?

Subgroup analysis showed that there appeared to be a benefit of TNK in the 227 patients included who had an M1 occlusion. In this group, the common odds ratio for a more favorable outcome in the mRS shift analysis with TNK was 1.59 (95% CI, 1.00-2.52; adjusted nominal P = .051).

The percentage of patients with a favorable outcome (mRS, 0-2) at 90 days in the M1 occlusion subgroup was 45.9% for TNK versus 31.4% for placebo, giving an adjusted odds ratio of 2.03 (95% CI, 1.14-3.66; nominal P = .017).

But Dr. Albers cautioned that this was an exploratory analysis, and no formal conclusions should be drawn from these data.

“We saw very strong results in favor of giving thrombolysis in the patients with M1 occlusions. We had preliminary pilot data suggesting this approach may work in these patients,” he commented.

“But we included the smaller M2 occlusions as well, because we thought that as there should be less clot in an M2 occlusion it might be easier to dissolve with thrombolysis,” he added. “But surprisingly, the M2 occlusion patients seemed to do worse with TNK than placebo, and the M1 patients did better.”
 

Timing of TNK

Dr. Albers said that there was also information from in the study on the timing of TNK administration.

In patients who also received thrombectomy, who made up of the majority of those in the study, the average time of TNK administration was only 20 minutes before the thrombectomy procedure.

“We had hoped to have a longer time between thrombolysis and thrombectomy so the drug would have more time to work. The idea was that patients would be given TNK at the primary stroke center before being transferred for thrombectomy, but actually only a few patients received TNK at the primary stroke center,” Dr. Albers explained.

“But, again surprisingly, we found that patients given TNK right at the time of the thrombectomy procedure seemed to show a trend toward benefit over placebo,” he reported.

He suggested that this may be caused by the thrombolytic dissolving the small fragments that can sometimes break off and cause further occlusions when the clot is removed by thrombectomy.

“We have learned a lot from this study, and we are planning to go forward with the information gained to plan a second study, in which we will focus on patients with M1 occlusions and try to get the drug on board at primary stroke centers, so it has more time to work before thrombectomy,” he added.

Commenting on the TIMELESS study at the ESOC meeting, Georgios Tsivgoulis, MD, professor of neurology, University of Athens, said that he thought the trial had shown three important results: “Firstly, TNK appeared to be safe in this late window in these selected patients – that is a very important observation. Secondly, reperfusion rates at 24 hours were increased with TNK and we know that this translates into clinical benefit. And thirdly, there was a neutral effect on primary outcomes, but I think the sample size of 438 patients was not large enough to show efficacy.”

Dr. Tsivgoulis concluded that these points need to be addressed in future trials.

The TIMELESS trial was funded by Genentech.

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

Around 5% of patients treated with dupilumab (Dupixent) for moderate-to-severe atopic dermatitis experience musculoskeletal (MSK) symptoms, according to the results of a descriptive study.

The main MSK symptom seen in the observational cohort was enthesitis, but some patients also experienced arthritis and tenosynovitis a median of 17 weeks after starting dupilumab treatment. Together these symptoms represent a new MSK syndrome, say researchers from the United Kingdom.

“The pattern of MSK symptoms and signs is characteristic of psoriatic arthritis/peripheral spondyloarthritis,” Bruce Kirkham, MD, and collaborators report in Arthritis & Rheumatology.

“We started a few years ago and have been following the patients for quite a long time,” Dr. Kirkham, a consultant rheumatologist at Guy’s and St. Thomas’ NHS Foundation Trust, London, told this news organization.

Characterizing the MSK symptoms

Of 470 patients with atopic dermatitis who started treatment with dupilumab at Guy’s and St. Thomas’ NHS Foundation Trust between October 2018 and February 2021, 36 (7.65%) developed rheumatic symptoms and were referred to the rheumatology department. These individuals had their family history assessed and thorough MSK evaluations, which included antibody and inflammatory markers, ultrasound of the peripheral small joints, and MRI of the large joints and spine.

A total of 26 (5.5%) patients – 14 of whom were male – had inflammatory enthesitis, arthritis, and/or tenosynovitis. Of the others, seven had osteoarthritis and three had degenerative spine disease.

Enthesitis was the most common finding in those with rheumatic symptoms, occurring on its own in 11 patients, with arthritis in three patients, and tenosynovitis in two patients.  

These symptoms appeared 2-48 weeks after starting dupilumab treatment and were categorized as mild in 16 (61%) cases, moderate in six cases, and severe in four cases.

No specific predictors of the MSK symptoms seen were noted. Patient age, sex, duration of their atopic dermatitis, or how their skin condition had been previously treated did not help identify those who might develop rheumatic problems.
 

Conservative management approach

All patients had “outstanding” responses to treatment, Dr. Kirkham noted: The mean Eczema Area and Severity Index score before dupilumab treatment was 21, falling to 4.2 with treatment, indicating a mean 80% improvement.

Co-author Joseph Nathan, MBChB, of London North West Healthcare NHS Trust, who collaborated on the research while working within Dr. Kirkham’s group, said separately: “The concern that patients have is that when they start a medication and develop a side effect is that the medication is going to be stopped.”

Clinicians treating the patients took a conservative approach, prescribing NSAIDs such as cyclooxygenase-2 inhibitors or altering the frequency with which dupilumab was given.

With this approach, MSK symptoms resolved in 15 patients who remained on treatment and in seven who had to stop dupilumab. There were four patients, however, who had unresolved symptoms even once dupilumab treatment had been stopped.
 

Altering the local cytokine balance

Dupilumab is a monoclonal antibody that binds to the alpha subunit of the interleukin-4 receptor. This results in blocking the function of not only IL-4 but also IL-13.

Dr. Kirkham and colleagues think this might not only alter the balance of cytokines in the skin but also in the joints and entheses with IL-17, IL-23, or even tumor necrosis factor playing a possible role. Another thought is that many circulating T-cells in the skin move to the joints and entheses to trigger symptoms.

IL-13 inhibition does seem to be important, as another British research team, from the Centre for Epidemiology Versus Arthritis at the University of Manchester (England), has found.

At the recent annual meeting of the British Society for Rheumatology, Sizheng Steven Zhao, MBChB, PhD, and colleagues reported that among people who carried a genetic variant predisposing them to having low IL-13 function, there was a higher risk for inflammatory diseases such as psoriatic arthritis and other spondyloarthropathy-related diseases.

Sara Freeman/Frontline Medical News

Dermatology perspective

Approved by the U.S. Food and Drug Administration in 2017, dupilumab has since been hailed as a “breakthrough” in atopic dermatitis treatment. Given as a subcutaneous injection every 2 weeks, it provides a much-needed option for people who have moderate-to-severe disease and have tried other available treatments, including corticosteroids.

Dupilumab has since also been approved for asthma, chronic sinusitis with nasal polyposis, eosinophilic esophagitis, and prurigo nodularis and is used off-label for other skin conditions such as contact dermatitis, chronic spontaneous urticaria, and alopecia areata.

“Dupilumab, like a lot of medications for atopic dermatitis, is a relatively new drug, and we are still learning about its safety,” Joel M. Gelfand, MD, MSCE, of the University of Pennsylvania Perelman School of Medicine, Philadelphia, told this news organization.

“Inflammatory arthritis has been reported in patients treated with dupilumab, and this new study provides some useful estimates,” added Dr. Gelfand, who is a professor of dermatology and epidemiology and directs the Psoriasis and Phototherapy Treatment Center, Philadelphia.

“There was no control group,” Dr. Gelfand said, so “a causal relationship cannot be well established based on these data alone. The mechanism is not known but may result from a shifting of the immune system.”

Dr. Zhao observed: “We don’t know what the natural history of these adverse events is. We don’t know if stopping the drug early will prevent long-term adverse events. So, we don’t know if people will ultimately develop permanent psoriatic arthritis if we don’t intervene quick enough when we observe an adverse event.”

Being aware of the possibility of rheumatic side effects occurring with dupilumab and similar agents is key, Dr. Gelfand and Dr. Kirkham both said independently.

“I have personally seen this entity in my practice,” Dr. Gelfand said. “It is important to clinicians prescribing dupilumab to alert patients about this potential side effect and ask about joint symptoms in follow-up.”

Dr. Kirkham said: “Prescribers need to be aware of it, because up until now it’s been just very vaguely discussed as sort of aches and pains, arthralgias, and it’s a much more specific of a kind of syndrome of enthesitis, arthritis, tenosynovitis – a little like psoriatic arthritis.”

Not everyone has come across these side effects, however, as Steven Daveluy, MD, associate professor and dermatology program director at Wayne State University, Detroit, said in an interview.

“This article and the other case series both noted the musculoskeletal symptoms occurred in about 5% of patients, which surprised me since I haven’t seen it in my practice and have enough patients being treated with dupilumab that I would expect to see a case at that rate,” Dr. Daveluy said.

“The majority of cases are mild and respond to treatment with anti-inflammatories like naproxen, which is available over the counter. It’s likely that patients with a mild case could simply treat their pain with naproxen that’s already in their medicine cabinet until it resolves, never bringing it to the doctor’s attention,” he suggested.

“Dupilumab is still a safe and effective medication that can change the lives of patients suffering from atopic dermatitis,” he said.

“Awareness of this potential side effect can help dermatologists recognize it early and work together with patients to determine the best course of action.”

All research mentioned in this article was independently supported. Dr. Kirkham, Mr. Nathan, Dr. Zhao, and Dr. Daveluy report no relevant financial relationships. Dr. Gelfand has served as a consultant for numerous pharmaceutical companies and receives research grants from Amgen, Boehringer Ingelheim, and Pfizer. He is a co-patent holder of resiquimod for treatment of cutaneous T-cell lymphoma.

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

Around 5% of patients treated with dupilumab (Dupixent) for moderate-to-severe atopic dermatitis experience musculoskeletal (MSK) symptoms, according to the results of a descriptive study.

The main MSK symptom seen in the observational cohort was enthesitis, but some patients also experienced arthritis and tenosynovitis a median of 17 weeks after starting dupilumab treatment. Together these symptoms represent a new MSK syndrome, say researchers from the United Kingdom.

“The pattern of MSK symptoms and signs is characteristic of psoriatic arthritis/peripheral spondyloarthritis,” Bruce Kirkham, MD, and collaborators report in Arthritis & Rheumatology.

“We started a few years ago and have been following the patients for quite a long time,” Dr. Kirkham, a consultant rheumatologist at Guy’s and St. Thomas’ NHS Foundation Trust, London, told this news organization.

Characterizing the MSK symptoms

Of 470 patients with atopic dermatitis who started treatment with dupilumab at Guy’s and St. Thomas’ NHS Foundation Trust between October 2018 and February 2021, 36 (7.65%) developed rheumatic symptoms and were referred to the rheumatology department. These individuals had their family history assessed and thorough MSK evaluations, which included antibody and inflammatory markers, ultrasound of the peripheral small joints, and MRI of the large joints and spine.

A total of 26 (5.5%) patients – 14 of whom were male – had inflammatory enthesitis, arthritis, and/or tenosynovitis. Of the others, seven had osteoarthritis and three had degenerative spine disease.

Enthesitis was the most common finding in those with rheumatic symptoms, occurring on its own in 11 patients, with arthritis in three patients, and tenosynovitis in two patients.  

These symptoms appeared 2-48 weeks after starting dupilumab treatment and were categorized as mild in 16 (61%) cases, moderate in six cases, and severe in four cases.

No specific predictors of the MSK symptoms seen were noted. Patient age, sex, duration of their atopic dermatitis, or how their skin condition had been previously treated did not help identify those who might develop rheumatic problems.
 

Conservative management approach

All patients had “outstanding” responses to treatment, Dr. Kirkham noted: The mean Eczema Area and Severity Index score before dupilumab treatment was 21, falling to 4.2 with treatment, indicating a mean 80% improvement.

Co-author Joseph Nathan, MBChB, of London North West Healthcare NHS Trust, who collaborated on the research while working within Dr. Kirkham’s group, said separately: “The concern that patients have is that when they start a medication and develop a side effect is that the medication is going to be stopped.”

Clinicians treating the patients took a conservative approach, prescribing NSAIDs such as cyclooxygenase-2 inhibitors or altering the frequency with which dupilumab was given.

With this approach, MSK symptoms resolved in 15 patients who remained on treatment and in seven who had to stop dupilumab. There were four patients, however, who had unresolved symptoms even once dupilumab treatment had been stopped.
 

Altering the local cytokine balance

Dupilumab is a monoclonal antibody that binds to the alpha subunit of the interleukin-4 receptor. This results in blocking the function of not only IL-4 but also IL-13.

Dr. Kirkham and colleagues think this might not only alter the balance of cytokines in the skin but also in the joints and entheses with IL-17, IL-23, or even tumor necrosis factor playing a possible role. Another thought is that many circulating T-cells in the skin move to the joints and entheses to trigger symptoms.

IL-13 inhibition does seem to be important, as another British research team, from the Centre for Epidemiology Versus Arthritis at the University of Manchester (England), has found.

At the recent annual meeting of the British Society for Rheumatology, Sizheng Steven Zhao, MBChB, PhD, and colleagues reported that among people who carried a genetic variant predisposing them to having low IL-13 function, there was a higher risk for inflammatory diseases such as psoriatic arthritis and other spondyloarthropathy-related diseases.

Sara Freeman/Frontline Medical News

Dermatology perspective

Approved by the U.S. Food and Drug Administration in 2017, dupilumab has since been hailed as a “breakthrough” in atopic dermatitis treatment. Given as a subcutaneous injection every 2 weeks, it provides a much-needed option for people who have moderate-to-severe disease and have tried other available treatments, including corticosteroids.

Dupilumab has since also been approved for asthma, chronic sinusitis with nasal polyposis, eosinophilic esophagitis, and prurigo nodularis and is used off-label for other skin conditions such as contact dermatitis, chronic spontaneous urticaria, and alopecia areata.

“Dupilumab, like a lot of medications for atopic dermatitis, is a relatively new drug, and we are still learning about its safety,” Joel M. Gelfand, MD, MSCE, of the University of Pennsylvania Perelman School of Medicine, Philadelphia, told this news organization.

“Inflammatory arthritis has been reported in patients treated with dupilumab, and this new study provides some useful estimates,” added Dr. Gelfand, who is a professor of dermatology and epidemiology and directs the Psoriasis and Phototherapy Treatment Center, Philadelphia.

“There was no control group,” Dr. Gelfand said, so “a causal relationship cannot be well established based on these data alone. The mechanism is not known but may result from a shifting of the immune system.”

Dr. Zhao observed: “We don’t know what the natural history of these adverse events is. We don’t know if stopping the drug early will prevent long-term adverse events. So, we don’t know if people will ultimately develop permanent psoriatic arthritis if we don’t intervene quick enough when we observe an adverse event.”

Being aware of the possibility of rheumatic side effects occurring with dupilumab and similar agents is key, Dr. Gelfand and Dr. Kirkham both said independently.

“I have personally seen this entity in my practice,” Dr. Gelfand said. “It is important to clinicians prescribing dupilumab to alert patients about this potential side effect and ask about joint symptoms in follow-up.”

Dr. Kirkham said: “Prescribers need to be aware of it, because up until now it’s been just very vaguely discussed as sort of aches and pains, arthralgias, and it’s a much more specific of a kind of syndrome of enthesitis, arthritis, tenosynovitis – a little like psoriatic arthritis.”

Not everyone has come across these side effects, however, as Steven Daveluy, MD, associate professor and dermatology program director at Wayne State University, Detroit, said in an interview.

“This article and the other case series both noted the musculoskeletal symptoms occurred in about 5% of patients, which surprised me since I haven’t seen it in my practice and have enough patients being treated with dupilumab that I would expect to see a case at that rate,” Dr. Daveluy said.

“The majority of cases are mild and respond to treatment with anti-inflammatories like naproxen, which is available over the counter. It’s likely that patients with a mild case could simply treat their pain with naproxen that’s already in their medicine cabinet until it resolves, never bringing it to the doctor’s attention,” he suggested.

“Dupilumab is still a safe and effective medication that can change the lives of patients suffering from atopic dermatitis,” he said.

“Awareness of this potential side effect can help dermatologists recognize it early and work together with patients to determine the best course of action.”

All research mentioned in this article was independently supported. Dr. Kirkham, Mr. Nathan, Dr. Zhao, and Dr. Daveluy report no relevant financial relationships. Dr. Gelfand has served as a consultant for numerous pharmaceutical companies and receives research grants from Amgen, Boehringer Ingelheim, and Pfizer. He is a co-patent holder of resiquimod for treatment of cutaneous T-cell lymphoma.

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

Around 5% of patients treated with dupilumab (Dupixent) for moderate-to-severe atopic dermatitis experience musculoskeletal (MSK) symptoms, according to the results of a descriptive study.

The main MSK symptom seen in the observational cohort was enthesitis, but some patients also experienced arthritis and tenosynovitis a median of 17 weeks after starting dupilumab treatment. Together these symptoms represent a new MSK syndrome, say researchers from the United Kingdom.

“The pattern of MSK symptoms and signs is characteristic of psoriatic arthritis/peripheral spondyloarthritis,” Bruce Kirkham, MD, and collaborators report in Arthritis & Rheumatology.

“We started a few years ago and have been following the patients for quite a long time,” Dr. Kirkham, a consultant rheumatologist at Guy’s and St. Thomas’ NHS Foundation Trust, London, told this news organization.

Characterizing the MSK symptoms

Of 470 patients with atopic dermatitis who started treatment with dupilumab at Guy’s and St. Thomas’ NHS Foundation Trust between October 2018 and February 2021, 36 (7.65%) developed rheumatic symptoms and were referred to the rheumatology department. These individuals had their family history assessed and thorough MSK evaluations, which included antibody and inflammatory markers, ultrasound of the peripheral small joints, and MRI of the large joints and spine.

A total of 26 (5.5%) patients – 14 of whom were male – had inflammatory enthesitis, arthritis, and/or tenosynovitis. Of the others, seven had osteoarthritis and three had degenerative spine disease.

Enthesitis was the most common finding in those with rheumatic symptoms, occurring on its own in 11 patients, with arthritis in three patients, and tenosynovitis in two patients.  

These symptoms appeared 2-48 weeks after starting dupilumab treatment and were categorized as mild in 16 (61%) cases, moderate in six cases, and severe in four cases.

No specific predictors of the MSK symptoms seen were noted. Patient age, sex, duration of their atopic dermatitis, or how their skin condition had been previously treated did not help identify those who might develop rheumatic problems.
 

Conservative management approach

All patients had “outstanding” responses to treatment, Dr. Kirkham noted: The mean Eczema Area and Severity Index score before dupilumab treatment was 21, falling to 4.2 with treatment, indicating a mean 80% improvement.

Co-author Joseph Nathan, MBChB, of London North West Healthcare NHS Trust, who collaborated on the research while working within Dr. Kirkham’s group, said separately: “The concern that patients have is that when they start a medication and develop a side effect is that the medication is going to be stopped.”

Clinicians treating the patients took a conservative approach, prescribing NSAIDs such as cyclooxygenase-2 inhibitors or altering the frequency with which dupilumab was given.

With this approach, MSK symptoms resolved in 15 patients who remained on treatment and in seven who had to stop dupilumab. There were four patients, however, who had unresolved symptoms even once dupilumab treatment had been stopped.
 

Altering the local cytokine balance

Dupilumab is a monoclonal antibody that binds to the alpha subunit of the interleukin-4 receptor. This results in blocking the function of not only IL-4 but also IL-13.

Dr. Kirkham and colleagues think this might not only alter the balance of cytokines in the skin but also in the joints and entheses with IL-17, IL-23, or even tumor necrosis factor playing a possible role. Another thought is that many circulating T-cells in the skin move to the joints and entheses to trigger symptoms.

IL-13 inhibition does seem to be important, as another British research team, from the Centre for Epidemiology Versus Arthritis at the University of Manchester (England), has found.

At the recent annual meeting of the British Society for Rheumatology, Sizheng Steven Zhao, MBChB, PhD, and colleagues reported that among people who carried a genetic variant predisposing them to having low IL-13 function, there was a higher risk for inflammatory diseases such as psoriatic arthritis and other spondyloarthropathy-related diseases.

Sara Freeman/Frontline Medical News

Dermatology perspective

Approved by the U.S. Food and Drug Administration in 2017, dupilumab has since been hailed as a “breakthrough” in atopic dermatitis treatment. Given as a subcutaneous injection every 2 weeks, it provides a much-needed option for people who have moderate-to-severe disease and have tried other available treatments, including corticosteroids.

Dupilumab has since also been approved for asthma, chronic sinusitis with nasal polyposis, eosinophilic esophagitis, and prurigo nodularis and is used off-label for other skin conditions such as contact dermatitis, chronic spontaneous urticaria, and alopecia areata.

“Dupilumab, like a lot of medications for atopic dermatitis, is a relatively new drug, and we are still learning about its safety,” Joel M. Gelfand, MD, MSCE, of the University of Pennsylvania Perelman School of Medicine, Philadelphia, told this news organization.

“Inflammatory arthritis has been reported in patients treated with dupilumab, and this new study provides some useful estimates,” added Dr. Gelfand, who is a professor of dermatology and epidemiology and directs the Psoriasis and Phototherapy Treatment Center, Philadelphia.

“There was no control group,” Dr. Gelfand said, so “a causal relationship cannot be well established based on these data alone. The mechanism is not known but may result from a shifting of the immune system.”

Dr. Zhao observed: “We don’t know what the natural history of these adverse events is. We don’t know if stopping the drug early will prevent long-term adverse events. So, we don’t know if people will ultimately develop permanent psoriatic arthritis if we don’t intervene quick enough when we observe an adverse event.”

Being aware of the possibility of rheumatic side effects occurring with dupilumab and similar agents is key, Dr. Gelfand and Dr. Kirkham both said independently.

“I have personally seen this entity in my practice,” Dr. Gelfand said. “It is important to clinicians prescribing dupilumab to alert patients about this potential side effect and ask about joint symptoms in follow-up.”

Dr. Kirkham said: “Prescribers need to be aware of it, because up until now it’s been just very vaguely discussed as sort of aches and pains, arthralgias, and it’s a much more specific of a kind of syndrome of enthesitis, arthritis, tenosynovitis – a little like psoriatic arthritis.”

Not everyone has come across these side effects, however, as Steven Daveluy, MD, associate professor and dermatology program director at Wayne State University, Detroit, said in an interview.

“This article and the other case series both noted the musculoskeletal symptoms occurred in about 5% of patients, which surprised me since I haven’t seen it in my practice and have enough patients being treated with dupilumab that I would expect to see a case at that rate,” Dr. Daveluy said.

“The majority of cases are mild and respond to treatment with anti-inflammatories like naproxen, which is available over the counter. It’s likely that patients with a mild case could simply treat their pain with naproxen that’s already in their medicine cabinet until it resolves, never bringing it to the doctor’s attention,” he suggested.

“Dupilumab is still a safe and effective medication that can change the lives of patients suffering from atopic dermatitis,” he said.

“Awareness of this potential side effect can help dermatologists recognize it early and work together with patients to determine the best course of action.”

All research mentioned in this article was independently supported. Dr. Kirkham, Mr. Nathan, Dr. Zhao, and Dr. Daveluy report no relevant financial relationships. Dr. Gelfand has served as a consultant for numerous pharmaceutical companies and receives research grants from Amgen, Boehringer Ingelheim, and Pfizer. He is a co-patent holder of resiquimod for treatment of cutaneous T-cell lymphoma.

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

MILAN – Secukinumab (Cosentyx) and biosimilar adalimumab-adaz (Hyrimoz) injection proved to have similar efficacy for limiting spinal radiographic progression over a 2-year period in patients with radiographic axial spondyloarthritis (r-axSpA) in the SURPASS study, a phase 3b, randomized controlled trial.

The study, presented at the annual European Congress of Rheumatology, represents the first head-to-head trial comparing the effects of two biologic disease-modifying antirheumatic drugs (bDMARDs) in axSpA. Notably, secukinumab and adalimumab-adaz target different pathways as an interleukin-17A inhibitor and a tumor necrosis factor (TNF) inhibitor, respectively.

Both TNF and IL-17A have been implicated in the pathogenesis of axSpA. Anti-TNF agents and the IL-17A inhibitor secukinumab have demonstrated effectiveness in improving symptoms, signs, and physical function in patients with axSpA and are approved therapies for the disease. However, limited data exist regarding the effect of bDMARDs in slowing radiographic progression, which is a key therapeutic goal in axSpA to prevent irreversible structural damage.

The SURPASS trial, funded by Novartis, enrolled 859 biologic-naive adult patients with moderate to severe r-axSpA. Participants were randomly assigned (1:1:1) to receive secukinumab 150 mg (n = 287), secukinumab 300 mg (n = 286), or adalimumab-adaz 40 mg (n = 286). The primary endpoint was the proportion of patients with no radiographic progression at the 2-year mark (week 104). Radiographic progression was defined as a change from baseline in modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS; range, 0-72) of 0.5 or less. The radiographic assessments were conducted by three independent evaluators who were blinded to treatment and the chronology of images.

Baseline characteristics indicated that the study population (78.5% male; mean age, 42.1 years) had a high risk of radiographic progression. The proportion of patients with no radiographic progression at week 104 was 66.1% in the secukinumab 150-mg arm, 66.9% in the secukinumab 300-mg arm, and 65.6% in the adalimumab-adaz arm. The mean change from baseline in mSASSS was 0.54, 0.55, and 0.72, respectively.

Notably, more than half of the patients (56.9%, 53.8%, and 53.3%, respectively) with at least one syndesmophyte at baseline did not develop new syndesmophytes over the 2-year period. The observed reductions in sacroiliac joint and spinal edema were comparable across all treatment groups. The safety profile of secukinumab and adalimumab-adaz was consistent with their well-established profiles.

No significant differences were observed between the treatment groups in terms of the primary and secondary endpoints. Study presenter and lead author Xenofon Baraliakos, MD, PhD, medical director of the Rheumatism Centre and professor of internal medicine and rheumatology at Ruhr University Bochum (Germany), stated: “Anti-TNF therapy has been considered the gold-standard treatment for axial spondyloarthritis in terms of slowing or halting radiographic progression. Our aim was to investigate whether other modes of action, such as IL-17 inhibition, achieve the same results. The primary hypothesis was that IL-17 inhibition could be even more effective than TNF blockade. However, our data indicate that secukinumab is at least as good as TNF blockers.

“Several risk factors, including high C-reactive protein [CRP] levels, male gender, high disease activity, and baseline radiographic damage (e.g., presence of syndesmophytes), are associated with structural progression,” Dr. Baraliakos explained. “We performed subgroup analyses and found no differences. This is a positive outcome as it suggests that there is no need to select patients based on either secukinumab or anti-TNF agents.”

When making treatment decisions, other factors must be taken into consideration. “Our study specifically examined radiographic progression. The clinical outcomes, indications, and contraindications for anti-TNF agents and secukinumab differ,” Dr. Baraliakos explained. “For instance, secukinumab may be preferred for patients with psoriasis, while adalimumab is more suitable for those with inflammatory bowel disease. Although these bDMARDs are not interchangeable, they have the same positive effect on radiographic progression.”
 

Not a definitive answer about structural progression

An open question remains. Alexandre Sepriano, MD, PhD, a rheumatologist at Hospital Egas Moniz and researcher at NOVA Medical School, both in Lisbon, commented: “The study was designed to maximize the chances of detecting a difference, if any, in spinal radiographic progression between secukinumab 150 mg and 300 mg and adalimumab. The included patients had a high risk of progression at baseline; in addition to back pain, they either had elevated CRP or at least one syndesmophyte on spine radiographs. Consequently, baseline structural damage was high [mean mSASSS, 17].”

“After 2 years, no difference was observed in the percentage of patients with no progression across the study arms. This finding does not definitively answer whether bDMARDs can modify structural progression or if secukinumab and adalimumab are equally effective in this regard,” explained Dr. Sepriano, who was not involved in the study. “However, there is good news for patients. Both secukinumab and adalimumab are potent anti-inflammatory drugs that effectively alleviate axial inflammation caused by the disease. This was demonstrated by the reduction in inflammatory scores on MRI in the SURPASS study. It aligns with robust evidence that both IL-17 inhibitors and TNF inhibitors are effective in improving symptoms in individuals with axSpA.

“Researchers continue to make significant efforts to understand how axial inflammation contributes to pathological new bone formation in axSpA,” Dr. Sepriano continued. “Understanding these mechanisms can guide future research aimed at interfering with disease progression. Furthermore, the use of new methods to quantify structural progression in axSpA, such as low-dose CT, which has shown greater sensitivity to change than traditional methods, can pave the way for new studies with fewer patients and shorter follow-up periods, thereby increasing the likelihood of detecting treatment effects.”

Dr. Baraliakos has received speaking and consulting fees and grant/research support from AbbVie, Bristol-Myers Squibb, Celgene, Chugai, Merck Sharp & Dohme, Novartis, Pfizer, and UCB. Dr. Sepriano has received speaking and/or consulting fees from AbbVie, Novartis, UCB, and Lilly. The trial was sponsored by Novartis.

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

MILAN – Secukinumab (Cosentyx) and biosimilar adalimumab-adaz (Hyrimoz) injection proved to have similar efficacy for limiting spinal radiographic progression over a 2-year period in patients with radiographic axial spondyloarthritis (r-axSpA) in the SURPASS study, a phase 3b, randomized controlled trial.

The study, presented at the annual European Congress of Rheumatology, represents the first head-to-head trial comparing the effects of two biologic disease-modifying antirheumatic drugs (bDMARDs) in axSpA. Notably, secukinumab and adalimumab-adaz target different pathways as an interleukin-17A inhibitor and a tumor necrosis factor (TNF) inhibitor, respectively.

Both TNF and IL-17A have been implicated in the pathogenesis of axSpA. Anti-TNF agents and the IL-17A inhibitor secukinumab have demonstrated effectiveness in improving symptoms, signs, and physical function in patients with axSpA and are approved therapies for the disease. However, limited data exist regarding the effect of bDMARDs in slowing radiographic progression, which is a key therapeutic goal in axSpA to prevent irreversible structural damage.

The SURPASS trial, funded by Novartis, enrolled 859 biologic-naive adult patients with moderate to severe r-axSpA. Participants were randomly assigned (1:1:1) to receive secukinumab 150 mg (n = 287), secukinumab 300 mg (n = 286), or adalimumab-adaz 40 mg (n = 286). The primary endpoint was the proportion of patients with no radiographic progression at the 2-year mark (week 104). Radiographic progression was defined as a change from baseline in modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS; range, 0-72) of 0.5 or less. The radiographic assessments were conducted by three independent evaluators who were blinded to treatment and the chronology of images.

Baseline characteristics indicated that the study population (78.5% male; mean age, 42.1 years) had a high risk of radiographic progression. The proportion of patients with no radiographic progression at week 104 was 66.1% in the secukinumab 150-mg arm, 66.9% in the secukinumab 300-mg arm, and 65.6% in the adalimumab-adaz arm. The mean change from baseline in mSASSS was 0.54, 0.55, and 0.72, respectively.

Notably, more than half of the patients (56.9%, 53.8%, and 53.3%, respectively) with at least one syndesmophyte at baseline did not develop new syndesmophytes over the 2-year period. The observed reductions in sacroiliac joint and spinal edema were comparable across all treatment groups. The safety profile of secukinumab and adalimumab-adaz was consistent with their well-established profiles.

No significant differences were observed between the treatment groups in terms of the primary and secondary endpoints. Study presenter and lead author Xenofon Baraliakos, MD, PhD, medical director of the Rheumatism Centre and professor of internal medicine and rheumatology at Ruhr University Bochum (Germany), stated: “Anti-TNF therapy has been considered the gold-standard treatment for axial spondyloarthritis in terms of slowing or halting radiographic progression. Our aim was to investigate whether other modes of action, such as IL-17 inhibition, achieve the same results. The primary hypothesis was that IL-17 inhibition could be even more effective than TNF blockade. However, our data indicate that secukinumab is at least as good as TNF blockers.

“Several risk factors, including high C-reactive protein [CRP] levels, male gender, high disease activity, and baseline radiographic damage (e.g., presence of syndesmophytes), are associated with structural progression,” Dr. Baraliakos explained. “We performed subgroup analyses and found no differences. This is a positive outcome as it suggests that there is no need to select patients based on either secukinumab or anti-TNF agents.”

When making treatment decisions, other factors must be taken into consideration. “Our study specifically examined radiographic progression. The clinical outcomes, indications, and contraindications for anti-TNF agents and secukinumab differ,” Dr. Baraliakos explained. “For instance, secukinumab may be preferred for patients with psoriasis, while adalimumab is more suitable for those with inflammatory bowel disease. Although these bDMARDs are not interchangeable, they have the same positive effect on radiographic progression.”
 

Not a definitive answer about structural progression

An open question remains. Alexandre Sepriano, MD, PhD, a rheumatologist at Hospital Egas Moniz and researcher at NOVA Medical School, both in Lisbon, commented: “The study was designed to maximize the chances of detecting a difference, if any, in spinal radiographic progression between secukinumab 150 mg and 300 mg and adalimumab. The included patients had a high risk of progression at baseline; in addition to back pain, they either had elevated CRP or at least one syndesmophyte on spine radiographs. Consequently, baseline structural damage was high [mean mSASSS, 17].”

“After 2 years, no difference was observed in the percentage of patients with no progression across the study arms. This finding does not definitively answer whether bDMARDs can modify structural progression or if secukinumab and adalimumab are equally effective in this regard,” explained Dr. Sepriano, who was not involved in the study. “However, there is good news for patients. Both secukinumab and adalimumab are potent anti-inflammatory drugs that effectively alleviate axial inflammation caused by the disease. This was demonstrated by the reduction in inflammatory scores on MRI in the SURPASS study. It aligns with robust evidence that both IL-17 inhibitors and TNF inhibitors are effective in improving symptoms in individuals with axSpA.

“Researchers continue to make significant efforts to understand how axial inflammation contributes to pathological new bone formation in axSpA,” Dr. Sepriano continued. “Understanding these mechanisms can guide future research aimed at interfering with disease progression. Furthermore, the use of new methods to quantify structural progression in axSpA, such as low-dose CT, which has shown greater sensitivity to change than traditional methods, can pave the way for new studies with fewer patients and shorter follow-up periods, thereby increasing the likelihood of detecting treatment effects.”

Dr. Baraliakos has received speaking and consulting fees and grant/research support from AbbVie, Bristol-Myers Squibb, Celgene, Chugai, Merck Sharp & Dohme, Novartis, Pfizer, and UCB. Dr. Sepriano has received speaking and/or consulting fees from AbbVie, Novartis, UCB, and Lilly. The trial was sponsored by Novartis.

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

MILAN – Secukinumab (Cosentyx) and biosimilar adalimumab-adaz (Hyrimoz) injection proved to have similar efficacy for limiting spinal radiographic progression over a 2-year period in patients with radiographic axial spondyloarthritis (r-axSpA) in the SURPASS study, a phase 3b, randomized controlled trial.

The study, presented at the annual European Congress of Rheumatology, represents the first head-to-head trial comparing the effects of two biologic disease-modifying antirheumatic drugs (bDMARDs) in axSpA. Notably, secukinumab and adalimumab-adaz target different pathways as an interleukin-17A inhibitor and a tumor necrosis factor (TNF) inhibitor, respectively.

Both TNF and IL-17A have been implicated in the pathogenesis of axSpA. Anti-TNF agents and the IL-17A inhibitor secukinumab have demonstrated effectiveness in improving symptoms, signs, and physical function in patients with axSpA and are approved therapies for the disease. However, limited data exist regarding the effect of bDMARDs in slowing radiographic progression, which is a key therapeutic goal in axSpA to prevent irreversible structural damage.

The SURPASS trial, funded by Novartis, enrolled 859 biologic-naive adult patients with moderate to severe r-axSpA. Participants were randomly assigned (1:1:1) to receive secukinumab 150 mg (n = 287), secukinumab 300 mg (n = 286), or adalimumab-adaz 40 mg (n = 286). The primary endpoint was the proportion of patients with no radiographic progression at the 2-year mark (week 104). Radiographic progression was defined as a change from baseline in modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS; range, 0-72) of 0.5 or less. The radiographic assessments were conducted by three independent evaluators who were blinded to treatment and the chronology of images.

Baseline characteristics indicated that the study population (78.5% male; mean age, 42.1 years) had a high risk of radiographic progression. The proportion of patients with no radiographic progression at week 104 was 66.1% in the secukinumab 150-mg arm, 66.9% in the secukinumab 300-mg arm, and 65.6% in the adalimumab-adaz arm. The mean change from baseline in mSASSS was 0.54, 0.55, and 0.72, respectively.

Notably, more than half of the patients (56.9%, 53.8%, and 53.3%, respectively) with at least one syndesmophyte at baseline did not develop new syndesmophytes over the 2-year period. The observed reductions in sacroiliac joint and spinal edema were comparable across all treatment groups. The safety profile of secukinumab and adalimumab-adaz was consistent with their well-established profiles.

No significant differences were observed between the treatment groups in terms of the primary and secondary endpoints. Study presenter and lead author Xenofon Baraliakos, MD, PhD, medical director of the Rheumatism Centre and professor of internal medicine and rheumatology at Ruhr University Bochum (Germany), stated: “Anti-TNF therapy has been considered the gold-standard treatment for axial spondyloarthritis in terms of slowing or halting radiographic progression. Our aim was to investigate whether other modes of action, such as IL-17 inhibition, achieve the same results. The primary hypothesis was that IL-17 inhibition could be even more effective than TNF blockade. However, our data indicate that secukinumab is at least as good as TNF blockers.

“Several risk factors, including high C-reactive protein [CRP] levels, male gender, high disease activity, and baseline radiographic damage (e.g., presence of syndesmophytes), are associated with structural progression,” Dr. Baraliakos explained. “We performed subgroup analyses and found no differences. This is a positive outcome as it suggests that there is no need to select patients based on either secukinumab or anti-TNF agents.”

When making treatment decisions, other factors must be taken into consideration. “Our study specifically examined radiographic progression. The clinical outcomes, indications, and contraindications for anti-TNF agents and secukinumab differ,” Dr. Baraliakos explained. “For instance, secukinumab may be preferred for patients with psoriasis, while adalimumab is more suitable for those with inflammatory bowel disease. Although these bDMARDs are not interchangeable, they have the same positive effect on radiographic progression.”
 

Not a definitive answer about structural progression

An open question remains. Alexandre Sepriano, MD, PhD, a rheumatologist at Hospital Egas Moniz and researcher at NOVA Medical School, both in Lisbon, commented: “The study was designed to maximize the chances of detecting a difference, if any, in spinal radiographic progression between secukinumab 150 mg and 300 mg and adalimumab. The included patients had a high risk of progression at baseline; in addition to back pain, they either had elevated CRP or at least one syndesmophyte on spine radiographs. Consequently, baseline structural damage was high [mean mSASSS, 17].”

“After 2 years, no difference was observed in the percentage of patients with no progression across the study arms. This finding does not definitively answer whether bDMARDs can modify structural progression or if secukinumab and adalimumab are equally effective in this regard,” explained Dr. Sepriano, who was not involved in the study. “However, there is good news for patients. Both secukinumab and adalimumab are potent anti-inflammatory drugs that effectively alleviate axial inflammation caused by the disease. This was demonstrated by the reduction in inflammatory scores on MRI in the SURPASS study. It aligns with robust evidence that both IL-17 inhibitors and TNF inhibitors are effective in improving symptoms in individuals with axSpA.

“Researchers continue to make significant efforts to understand how axial inflammation contributes to pathological new bone formation in axSpA,” Dr. Sepriano continued. “Understanding these mechanisms can guide future research aimed at interfering with disease progression. Furthermore, the use of new methods to quantify structural progression in axSpA, such as low-dose CT, which has shown greater sensitivity to change than traditional methods, can pave the way for new studies with fewer patients and shorter follow-up periods, thereby increasing the likelihood of detecting treatment effects.”

Dr. Baraliakos has received speaking and consulting fees and grant/research support from AbbVie, Bristol-Myers Squibb, Celgene, Chugai, Merck Sharp & Dohme, Novartis, Pfizer, and UCB. Dr. Sepriano has received speaking and/or consulting fees from AbbVie, Novartis, UCB, and Lilly. The trial was sponsored by Novartis.

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

MILAN – The oral Janus kinase (JAK) 1/2 inhibitor baricitinib (Olumiant) demonstrated significantly better efficacy than cyclophosphamide infusions in the treatment of lupus nephritis in a small, independently funded, phase 3, double-blind clinical trial, Manal Hassanien, MD, reported at the annual European Congress of Rheumatology.

Baricitinib, licensed by Eli Lilly, has been recognized as a potential therapeutic option in systemic lupus, and is approved in the United States to treat RA, alopecia areata, and COVID-19 in certain hospitalized adults. It is also approved to treat atopic dermatitis in Europe. However, it previously yielded disappointing results in phase 3 clinical trials SLE-BRAVE-I and SLE-BRAVE-II for systemic lupus erythematosus. The trial results presented at EULAR suggest that baricitinib could be beneficial in the treatment of lupus nephritis, further establishing the role of JAK inhibitors in autoimmune disease therapy.

“Lupus nephritis typically develops within 5 years of initial lupus symptoms,” said Dr. Hassanien, of the rheumatology research and advanced therapeutics department at Assiut (Egypt) University. “Research has shown that up to 60% of lupus patients will eventually develop lupus nephritis. The management of proliferative lupus nephritis usually involves an initial phase focused on preventing the development of irreversible damage, followed by a maintenance phase to control lupus activity. Despite significant progress, lupus nephritis still carries an increased risk of end-stage renal disease and mortality.”

The study’s primary endpoint of 24-hour proteinuria response rate (≥ 50% reduction from baseline) at week 12 was significantly greater with baricitinib 4 mg daily, compared with monthly cyclophosphamide infusions at 0.7 mg/m² (70% vs. 43%; P < .0001). At week 24, 76.6% of the baricitinib group met the primary endpoint, compared with 50% in the cyclophosphamide group. Two multiplicity-controlled secondary endpoints, C3 serum level and the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), also showed statistical significance at 12 weeks (P < .01).

The 6-month trial included 60 adult patients (age 18 years and older) with a clinical diagnosis of lupus nephritis fulfilling classification criteria for LN grade III and IV. Patients needed to demonstrate objective signs of active nephritis consistent with persistent proteinuria greater than 0.5 g/day and/or cellular casts at screening to be included. Additional inclusion criteria were SLEDAI-2K greater than 4 and assessment of anti–double-stranded DNA and C3 serum levels at study entry. The patients were randomly assigned to two equal-sized groups, with one group receiving baricitinib 4 mg daily and a monthly placebo saline infusion, and the other group receiving monthly cyclophosphamide infusions and oral placebo tablets.

The incidence of adverse events was comparable between the two treatment groups, with 48% of patients in the baricitinib group and 46% in the cyclophosphamide group experiencing adverse events. Only three serious adverse events, specifically serious infection or herpes zoster, were recorded, leading to treatment discontinuation.

Two patients (6.6%) in the baricitinib group and one patient (3.3%) in the cyclophosphamide group were affected. The researchers recorded no major adverse cardiovascular or venous thromboembolic events, which are known to occur at higher rates among some users of baricitinib and other JAK inhibitors. The safety profile of baricitinib was consistent with observations made in other inflammatory musculoskeletal diseases, and no new risks were identified.

However, there were some concerns expressed by audience members during the presentation.

“The primary endpoint is limited at proteinuria, while biopsy is considered the gold standard for measuring efficacy,” said Eric F. Morand, MD, head of the Monash Health rheumatology unit, Melbourne. This was not the only critical comment regarding the study that emerged during the discussion. The use of a 4-mg dosage regimen throughout the entire study duration (despite official recommendations suggesting a 2-mg dosage in the long run) and the positive outcomes observed in the control group treated with cyclophosphamide were also mentioned.

Dr. Hassanien acknowledged that this is a small and relatively short study and disclosed plans to extend the follow-up period to 1 year and conduct a renal biopsy.

Dr. Hassanien reported no relevant financial relationships. Assiut University funded the trial.

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

MILAN – The oral Janus kinase (JAK) 1/2 inhibitor baricitinib (Olumiant) demonstrated significantly better efficacy than cyclophosphamide infusions in the treatment of lupus nephritis in a small, independently funded, phase 3, double-blind clinical trial, Manal Hassanien, MD, reported at the annual European Congress of Rheumatology.

Baricitinib, licensed by Eli Lilly, has been recognized as a potential therapeutic option in systemic lupus, and is approved in the United States to treat RA, alopecia areata, and COVID-19 in certain hospitalized adults. It is also approved to treat atopic dermatitis in Europe. However, it previously yielded disappointing results in phase 3 clinical trials SLE-BRAVE-I and SLE-BRAVE-II for systemic lupus erythematosus. The trial results presented at EULAR suggest that baricitinib could be beneficial in the treatment of lupus nephritis, further establishing the role of JAK inhibitors in autoimmune disease therapy.

“Lupus nephritis typically develops within 5 years of initial lupus symptoms,” said Dr. Hassanien, of the rheumatology research and advanced therapeutics department at Assiut (Egypt) University. “Research has shown that up to 60% of lupus patients will eventually develop lupus nephritis. The management of proliferative lupus nephritis usually involves an initial phase focused on preventing the development of irreversible damage, followed by a maintenance phase to control lupus activity. Despite significant progress, lupus nephritis still carries an increased risk of end-stage renal disease and mortality.”

The study’s primary endpoint of 24-hour proteinuria response rate (≥ 50% reduction from baseline) at week 12 was significantly greater with baricitinib 4 mg daily, compared with monthly cyclophosphamide infusions at 0.7 mg/m² (70% vs. 43%; P < .0001). At week 24, 76.6% of the baricitinib group met the primary endpoint, compared with 50% in the cyclophosphamide group. Two multiplicity-controlled secondary endpoints, C3 serum level and the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), also showed statistical significance at 12 weeks (P < .01).

The 6-month trial included 60 adult patients (age 18 years and older) with a clinical diagnosis of lupus nephritis fulfilling classification criteria for LN grade III and IV. Patients needed to demonstrate objective signs of active nephritis consistent with persistent proteinuria greater than 0.5 g/day and/or cellular casts at screening to be included. Additional inclusion criteria were SLEDAI-2K greater than 4 and assessment of anti–double-stranded DNA and C3 serum levels at study entry. The patients were randomly assigned to two equal-sized groups, with one group receiving baricitinib 4 mg daily and a monthly placebo saline infusion, and the other group receiving monthly cyclophosphamide infusions and oral placebo tablets.

The incidence of adverse events was comparable between the two treatment groups, with 48% of patients in the baricitinib group and 46% in the cyclophosphamide group experiencing adverse events. Only three serious adverse events, specifically serious infection or herpes zoster, were recorded, leading to treatment discontinuation.

Two patients (6.6%) in the baricitinib group and one patient (3.3%) in the cyclophosphamide group were affected. The researchers recorded no major adverse cardiovascular or venous thromboembolic events, which are known to occur at higher rates among some users of baricitinib and other JAK inhibitors. The safety profile of baricitinib was consistent with observations made in other inflammatory musculoskeletal diseases, and no new risks were identified.

However, there were some concerns expressed by audience members during the presentation.

“The primary endpoint is limited at proteinuria, while biopsy is considered the gold standard for measuring efficacy,” said Eric F. Morand, MD, head of the Monash Health rheumatology unit, Melbourne. This was not the only critical comment regarding the study that emerged during the discussion. The use of a 4-mg dosage regimen throughout the entire study duration (despite official recommendations suggesting a 2-mg dosage in the long run) and the positive outcomes observed in the control group treated with cyclophosphamide were also mentioned.

Dr. Hassanien acknowledged that this is a small and relatively short study and disclosed plans to extend the follow-up period to 1 year and conduct a renal biopsy.

Dr. Hassanien reported no relevant financial relationships. Assiut University funded the trial.

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

MILAN – The oral Janus kinase (JAK) 1/2 inhibitor baricitinib (Olumiant) demonstrated significantly better efficacy than cyclophosphamide infusions in the treatment of lupus nephritis in a small, independently funded, phase 3, double-blind clinical trial, Manal Hassanien, MD, reported at the annual European Congress of Rheumatology.

Baricitinib, licensed by Eli Lilly, has been recognized as a potential therapeutic option in systemic lupus, and is approved in the United States to treat RA, alopecia areata, and COVID-19 in certain hospitalized adults. It is also approved to treat atopic dermatitis in Europe. However, it previously yielded disappointing results in phase 3 clinical trials SLE-BRAVE-I and SLE-BRAVE-II for systemic lupus erythematosus. The trial results presented at EULAR suggest that baricitinib could be beneficial in the treatment of lupus nephritis, further establishing the role of JAK inhibitors in autoimmune disease therapy.

“Lupus nephritis typically develops within 5 years of initial lupus symptoms,” said Dr. Hassanien, of the rheumatology research and advanced therapeutics department at Assiut (Egypt) University. “Research has shown that up to 60% of lupus patients will eventually develop lupus nephritis. The management of proliferative lupus nephritis usually involves an initial phase focused on preventing the development of irreversible damage, followed by a maintenance phase to control lupus activity. Despite significant progress, lupus nephritis still carries an increased risk of end-stage renal disease and mortality.”

The study’s primary endpoint of 24-hour proteinuria response rate (≥ 50% reduction from baseline) at week 12 was significantly greater with baricitinib 4 mg daily, compared with monthly cyclophosphamide infusions at 0.7 mg/m² (70% vs. 43%; P < .0001). At week 24, 76.6% of the baricitinib group met the primary endpoint, compared with 50% in the cyclophosphamide group. Two multiplicity-controlled secondary endpoints, C3 serum level and the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), also showed statistical significance at 12 weeks (P < .01).

The 6-month trial included 60 adult patients (age 18 years and older) with a clinical diagnosis of lupus nephritis fulfilling classification criteria for LN grade III and IV. Patients needed to demonstrate objective signs of active nephritis consistent with persistent proteinuria greater than 0.5 g/day and/or cellular casts at screening to be included. Additional inclusion criteria were SLEDAI-2K greater than 4 and assessment of anti–double-stranded DNA and C3 serum levels at study entry. The patients were randomly assigned to two equal-sized groups, with one group receiving baricitinib 4 mg daily and a monthly placebo saline infusion, and the other group receiving monthly cyclophosphamide infusions and oral placebo tablets.

The incidence of adverse events was comparable between the two treatment groups, with 48% of patients in the baricitinib group and 46% in the cyclophosphamide group experiencing adverse events. Only three serious adverse events, specifically serious infection or herpes zoster, were recorded, leading to treatment discontinuation.

Two patients (6.6%) in the baricitinib group and one patient (3.3%) in the cyclophosphamide group were affected. The researchers recorded no major adverse cardiovascular or venous thromboembolic events, which are known to occur at higher rates among some users of baricitinib and other JAK inhibitors. The safety profile of baricitinib was consistent with observations made in other inflammatory musculoskeletal diseases, and no new risks were identified.

However, there were some concerns expressed by audience members during the presentation.

“The primary endpoint is limited at proteinuria, while biopsy is considered the gold standard for measuring efficacy,” said Eric F. Morand, MD, head of the Monash Health rheumatology unit, Melbourne. This was not the only critical comment regarding the study that emerged during the discussion. The use of a 4-mg dosage regimen throughout the entire study duration (despite official recommendations suggesting a 2-mg dosage in the long run) and the positive outcomes observed in the control group treated with cyclophosphamide were also mentioned.

Dr. Hassanien acknowledged that this is a small and relatively short study and disclosed plans to extend the follow-up period to 1 year and conduct a renal biopsy.

Dr. Hassanien reported no relevant financial relationships. Assiut University funded the trial.

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

SAN FRANCISCO – As the opioid epidemic continues to grow and evolve, the federal government is trying to make it easier for clinicians to treat abusers with the drug buprenorphine, psychiatrists told colleagues at the annual meeting of the American Psychiatric Association. And an injectable version of the drug is making a big difference.

While overall overdose numbers are grim, “the work we’re doing to get people on buprenorphine is working, and our efforts to get people in treatment are paying off,” John A. Renner Jr., MD, of Boston University, said in a presentation at the APA meeting.

As Dr. Renner explained, the United States is now in the fourth wave of nearly a quarter-century of opioid overdose-related deaths. The outbreak began in 1999 as prescription opioids spurred deaths, and heroin overdoses began to rise in 2010. The third wave brought rises in deaths from synthetic opioids such as fentanyl in 2013. In 2015, the fourth wave – driven by deaths from combinations of synthetic opioids and psychostimulants like methamphetamines – started in 2015.

COVID-19 seems to have played a role too: In 2020, opioid overdose deaths spiked during the early months of the pandemic. In 2021, drug-related overdose deaths overall hit a high of 106,889, including 80,411 linked to opioids. In contrast, fewer than 20,000 drug-related overdose deaths were reported in 1999.

On the other hand, deaths from prescription drug overdoses are falling, Dr. Renner said, suggesting “improvement in terms of how clinicians are handling medications and our prescribing practices. But that’s being masked by what’s happened with fentanyl and methamphetamine.”

Buprenorphine (Subutex), used to treat opioid use withdrawal, is itself an opioid and can cause addiction and death in some cases. However, Dr. Renner highlighted a 2023 study that determined that efforts to increase its use from 2019 to 2021 didn’t appear to boost buprenorphine-related overdose deaths in the United States.

New federal regulations aim to make it easier to prescribe buprenorphine. Thanks to Congressional legislation, the Drug Enforcement Administration in January 2023 eliminated regulations requiring clinicians to undergo special training to get an “X-waiver” to be able to prescribe buprenorphine. But they’re not off the hook entirely: As of June 27, 2023, providers must have undergone training in order to apply for – or renew – a DEA license to prescribe certain controlled substances like buprenorphine.

“I’m afraid that people will be able to meet that requirement easily, and they’re not going to get good coordinated teaching,” Dr. Renner said. “I’m not sure that’s really going to improve the quality of care that we’re delivering.”

In regard to treatment, psychiatrist Dong Chan Park, MD, of Boston University, touted a long-acting injectable form of buprenorphine known by the brand name Sublocade. The FDA approved Sublocade in 2017 for patients who’ve been taking sublingual buprenorphine for at least 7 days, although Dr. Park said research suggests the 7-day period may not be necessary.

“We’ve utilized this about 2.5-plus years in my hospital, and it’s really been a game changer for some of our sickest, most challenging patients,” he said at the APA presentation. As he explained, one benefit is that patients can’t repeatedly avoid doses depending on how they feel, as they may do with the sublingual version. “On the first day of injection, you can actually stop the sublingual buprenorphine.”

Dr. Renner emphasized the importance of getting users on buprenorphine as fast as possible. If the treatment begins in the ED, he said, “they need to have a system that is going to be able to pick them up and continue the care.”

Otherwise, the risk is high. “We’re in a very dangerous era,” he said, “where the patient walks out the door, and then they die.”

Dr. Park had no disclosures, and Dr. Renner disclosed royalties from the APA.

SAN FRANCISCO – As the opioid epidemic continues to grow and evolve, the federal government is trying to make it easier for clinicians to treat abusers with the drug buprenorphine, psychiatrists told colleagues at the annual meeting of the American Psychiatric Association. And an injectable version of the drug is making a big difference.

While overall overdose numbers are grim, “the work we’re doing to get people on buprenorphine is working, and our efforts to get people in treatment are paying off,” John A. Renner Jr., MD, of Boston University, said in a presentation at the APA meeting.

As Dr. Renner explained, the United States is now in the fourth wave of nearly a quarter-century of opioid overdose-related deaths. The outbreak began in 1999 as prescription opioids spurred deaths, and heroin overdoses began to rise in 2010. The third wave brought rises in deaths from synthetic opioids such as fentanyl in 2013. In 2015, the fourth wave – driven by deaths from combinations of synthetic opioids and psychostimulants like methamphetamines – started in 2015.

COVID-19 seems to have played a role too: In 2020, opioid overdose deaths spiked during the early months of the pandemic. In 2021, drug-related overdose deaths overall hit a high of 106,889, including 80,411 linked to opioids. In contrast, fewer than 20,000 drug-related overdose deaths were reported in 1999.

On the other hand, deaths from prescription drug overdoses are falling, Dr. Renner said, suggesting “improvement in terms of how clinicians are handling medications and our prescribing practices. But that’s being masked by what’s happened with fentanyl and methamphetamine.”

Buprenorphine (Subutex), used to treat opioid use withdrawal, is itself an opioid and can cause addiction and death in some cases. However, Dr. Renner highlighted a 2023 study that determined that efforts to increase its use from 2019 to 2021 didn’t appear to boost buprenorphine-related overdose deaths in the United States.

New federal regulations aim to make it easier to prescribe buprenorphine. Thanks to Congressional legislation, the Drug Enforcement Administration in January 2023 eliminated regulations requiring clinicians to undergo special training to get an “X-waiver” to be able to prescribe buprenorphine. But they’re not off the hook entirely: As of June 27, 2023, providers must have undergone training in order to apply for – or renew – a DEA license to prescribe certain controlled substances like buprenorphine.

“I’m afraid that people will be able to meet that requirement easily, and they’re not going to get good coordinated teaching,” Dr. Renner said. “I’m not sure that’s really going to improve the quality of care that we’re delivering.”

In regard to treatment, psychiatrist Dong Chan Park, MD, of Boston University, touted a long-acting injectable form of buprenorphine known by the brand name Sublocade. The FDA approved Sublocade in 2017 for patients who’ve been taking sublingual buprenorphine for at least 7 days, although Dr. Park said research suggests the 7-day period may not be necessary.

“We’ve utilized this about 2.5-plus years in my hospital, and it’s really been a game changer for some of our sickest, most challenging patients,” he said at the APA presentation. As he explained, one benefit is that patients can’t repeatedly avoid doses depending on how they feel, as they may do with the sublingual version. “On the first day of injection, you can actually stop the sublingual buprenorphine.”

Dr. Renner emphasized the importance of getting users on buprenorphine as fast as possible. If the treatment begins in the ED, he said, “they need to have a system that is going to be able to pick them up and continue the care.”

Otherwise, the risk is high. “We’re in a very dangerous era,” he said, “where the patient walks out the door, and then they die.”

Dr. Park had no disclosures, and Dr. Renner disclosed royalties from the APA.

SAN FRANCISCO – As the opioid epidemic continues to grow and evolve, the federal government is trying to make it easier for clinicians to treat abusers with the drug buprenorphine, psychiatrists told colleagues at the annual meeting of the American Psychiatric Association. And an injectable version of the drug is making a big difference.

While overall overdose numbers are grim, “the work we’re doing to get people on buprenorphine is working, and our efforts to get people in treatment are paying off,” John A. Renner Jr., MD, of Boston University, said in a presentation at the APA meeting.

As Dr. Renner explained, the United States is now in the fourth wave of nearly a quarter-century of opioid overdose-related deaths. The outbreak began in 1999 as prescription opioids spurred deaths, and heroin overdoses began to rise in 2010. The third wave brought rises in deaths from synthetic opioids such as fentanyl in 2013. In 2015, the fourth wave – driven by deaths from combinations of synthetic opioids and psychostimulants like methamphetamines – started in 2015.

COVID-19 seems to have played a role too: In 2020, opioid overdose deaths spiked during the early months of the pandemic. In 2021, drug-related overdose deaths overall hit a high of 106,889, including 80,411 linked to opioids. In contrast, fewer than 20,000 drug-related overdose deaths were reported in 1999.

On the other hand, deaths from prescription drug overdoses are falling, Dr. Renner said, suggesting “improvement in terms of how clinicians are handling medications and our prescribing practices. But that’s being masked by what’s happened with fentanyl and methamphetamine.”

Buprenorphine (Subutex), used to treat opioid use withdrawal, is itself an opioid and can cause addiction and death in some cases. However, Dr. Renner highlighted a 2023 study that determined that efforts to increase its use from 2019 to 2021 didn’t appear to boost buprenorphine-related overdose deaths in the United States.

New federal regulations aim to make it easier to prescribe buprenorphine. Thanks to Congressional legislation, the Drug Enforcement Administration in January 2023 eliminated regulations requiring clinicians to undergo special training to get an “X-waiver” to be able to prescribe buprenorphine. But they’re not off the hook entirely: As of June 27, 2023, providers must have undergone training in order to apply for – or renew – a DEA license to prescribe certain controlled substances like buprenorphine.

“I’m afraid that people will be able to meet that requirement easily, and they’re not going to get good coordinated teaching,” Dr. Renner said. “I’m not sure that’s really going to improve the quality of care that we’re delivering.”

In regard to treatment, psychiatrist Dong Chan Park, MD, of Boston University, touted a long-acting injectable form of buprenorphine known by the brand name Sublocade. The FDA approved Sublocade in 2017 for patients who’ve been taking sublingual buprenorphine for at least 7 days, although Dr. Park said research suggests the 7-day period may not be necessary.

“We’ve utilized this about 2.5-plus years in my hospital, and it’s really been a game changer for some of our sickest, most challenging patients,” he said at the APA presentation. As he explained, one benefit is that patients can’t repeatedly avoid doses depending on how they feel, as they may do with the sublingual version. “On the first day of injection, you can actually stop the sublingual buprenorphine.”

Dr. Renner emphasized the importance of getting users on buprenorphine as fast as possible. If the treatment begins in the ED, he said, “they need to have a system that is going to be able to pick them up and continue the care.”

Otherwise, the risk is high. “We’re in a very dangerous era,” he said, “where the patient walks out the door, and then they die.”

Dr. Park had no disclosures, and Dr. Renner disclosed royalties from the APA.

Scabies is caused by cutaneous ectoparasitic infection by the mite Sarcoptes scabiei var hominis. The infection is highly contagious via direct skin-to-skin contact or indirectly through infested bedding, clothing or fomites.^1,2 Scabies occurs at all ages, in all ethnic groups, and at all socioeconomic levels.¹ Analysis by the Global Burden of Disease estimates that 200 million individuals have been infected with scabies worldwide. The World Health Organization has declared scabies a neglected tropical disease.³

Crusted scabies is a severe and rare form of scabies, with hyperinfestation of thousands to millions of mites, and more commonly is associated with immunosuppressed states, including HIV and hematologic malignancies.^1,2,4 Crusted scabies has a high mortality rate due to sepsis when left untreated.^3,5

Occasionally, iatrogenic immunosuppression contributes to the development of crusted scabies.^1,2 Iatrogenic immunosuppression leading to crusted scabies most commonly occurs secondary to immunosuppression after bone marrow or solid organ transplantation.⁶ Less often, crusted scabies is caused by iatrogenic immunosuppression from other clinical scenarios.^1,2

We describe a patient with iatrogenic immunosuppression due to azathioprine-induced myelosuppression for the treatment of granulomatosis with polyangiitis (GPA) who developed crusted scabies that clinically presented as erythroderma. Crusted scabies should be included in the differential diagnosis of erythroderma, especially in the setting of iatrogenic immunosuppression, for timely and appropriate management.

Case Report

An 84-year-old man presented with worsening pruritus, erythema, and thick yellow scale that progressed to erythroderma over the last 2 weeks. He was diagnosed with GPA 6 months prior to presentation and was treated with azathioprine 150 mg/d, prednisone 10 mg/d, and sulfamethoxazole 800 mg plus trimethoprim 160 mg twice weekly for prophylaxis against Pneumocystis jirovecii pneumonia.

Three weeks prior to presentation, the patient was hospitalized for pancytopenia attributed to azathioprine-induced myelosuppression (hemoglobin, 6.1 g/dL [reference range, 13.5–18.0 g/dL]; hematocrit, 17.5% [reference range, 42%–52%]; white blood cell count, 1.66×10³/μL [reference range, 4.0–10.5×10³/μL]; platelet count, 146×10³/μL [reference range, 150–450×10³/μL]; absolute neutrophil count, 1.29×10³/μL [reference range, 1.4–6.5×10³/μL]). He was transferred to a skilled nursing facility after discharge and referred to dermatology for evaluation of the worsening pruritic rash.

At the current presentation, the patient denied close contact with anyone who had a similar rash at home or at the skilled nursing facility. Physical examination revealed diffuse erythroderma with yellow scale on the scalp, trunk, arms, and legs (Figure 1). The palms showed scattered 2- to 3-mm pustules. The mucosal surfaces did not have lesions. A punch biopsy of a pustule from the right arm revealed focal spongiosis, parakeratosis, and acanthosis, as well as a perivascular and interstitial mixed inflammatory infiltrate with lymphocytes and eosinophils. Organisms morphologically compatible with scabies were found in the stratum corneum (Figure 2). Another punch biopsy of a pustule from the right arm was performed for direct immunofluorescence (DIF) and was negative for immunoglobulin deposition. Mineral oil preparation from pustules on the palm was positive for mites.

The patient was treated with permethrin cream 5% and oral ivermectin 200 μg/kg on day 1 and day 10. The prednisone dosage was increased from 10 mg/d to 50 mg/d and tapered over 2 weeks to treat the symptomatic rash and GPA. He remains on maintenance rituximab for GPA, without recurrence of scabies.

Comment

Pathogenesis—As an obligate parasite, S scabiei spends its entire life cycle within the host. Impregnated female mites burrow into the epidermis after mating and lay eggs daily for 1 to 2 months. Eggs hatch 2 or 3 days later. Larvae then migrate to the skin surface; burrow into the stratum corneum, where they mature into adults; and then mate on the skin surface.^1,4

Clinical Presentation and Sequelae—Typically, scabies presents 2 to 6 weeks after initial exposure with generalized and intense itching and inflammatory pruritic papules on the finger webs, wrists, elbows, axillae, buttocks, umbilicus, genitalia, and areolae.¹ Burrows are specific for scabies but may not always be present. Often, there are nonspecific secondary lesions, including excoriations, dermatitis, and impetiginization.

Complications of scabies can be severe, with initial colonization and infection of the skin resulting in impetigo and cellulitis. Systematic sequelae from local skin infection include post-streptococcal glomerulonephritis, rheumatic fever, and sepsis. Mortality from sepsis in scabies can be high.^3,5

Classic Crusted Scabies and Other Variants—Crusted scabies presents with psoriasiform hyperkeratotic plaques involving the hands and feet with potential nail involvement that can become more generalized.¹ Alterations in CD4⁺ T-cell function have been implicated in the development of crusted scabies, in which an excessive helper T cell (T_H2) response is elicited against the ectoparasite, which may help explain the intense pruritus of scabies.⁶ Occasionally, iatrogenic immunosuppression contributes to development of crusted scabies,¹ as was the case with our patient. However, it is rare for crusted scabies to present with erythroderma.⁷

Other atypical presentations of scabies include a seborrheic dermatitis–like presentation in infants, nodular lesions in the groin and axillae in more chronic scabies, and vesicles or bullous lesions.¹

Diagnosis—Identification of mites, eggs, or feces is necessary for definitive diagnosis of scabies.⁸ These materials can be obtained through skin scrapings with mineral oil and observed under light microscopy or direct dermoscopy. Multiple scrapings on many lesions should be performed because failure to identify mites can be common and does not rule out scabies. Dermoscopic examination of active lesions under low power also can be helpful, given that identification of dark brown triangular structures can correspond to visualization of the pigmented anterior section of the mite.^9-11 A skin biopsy can help identify mites, but histopathology often shows a nonspecific hypersensitivity reaction.¹² Therefore, empiric treatment often is necessary.

Differential Diagnosis—The differential diagnosis of erythroderma is broad and includes a drug eruption; Sézary syndrome; and pre-existing skin diseases, including psoriasis, atopic dermatitis, pityriasis rubra pilaris, pemphigus foliaceus, and bullous pemphigoid. Histopathology is critical to differentiate these diagnoses. Bullous pemphigoid and pemphigus foliaceus are immunobullous diseases that typically are positive for immunoglobulin deposition on DIF. In rare cases, scabies also can present with bullae and positive DIF test results.¹³

Treatment—First-line treatment of crusted scabies in the United States is permethrin cream 5%, followed by oral ivermectin 200 μg/kg.^4,5,14,15 Other scabicides include topicals such as benzyl benzoate 10% to 25%; precipitated sulfur 2% to 10%; crotamiton 10%; malathion 0.5%; and lindane 1%.⁵ The association of neurotoxicity with lindane has considerably reduced the drug’s use.¹

During treatment of scabies, it is important to isolate patients to mitigate the possibility of spread.⁴ Pruritus can persist for a few weeks after completion of therapy.⁵ Patients should be closely monitored to ensure that this symptom is secondary to skin inflammation and not incomplete treatment.

Treatment of crusted scabies may require repeated treatments to decrease the notable mite burden as well as the associated crusting and scale. Adding a keratolytic such as 5% to 10% salicylic acid in petrolatum to the treatment regimen may be useful for breaking up thick scale.⁵

Immunosuppression—With numerous immunomodulatory drugs for treating autoimmunity comes an increased risk for iatrogenic immunosuppression that may contribute to the development of crusted scabies.¹⁶ In a number of autoimmune diseases such as rheumatoid arthritis,^17-19 psoriasis,^20,21 pemphigus vulgaris,²² systemic lupus erythematosus,²³ systemic sclerosis,^22,24 bullous pemphigoid,^25,26 and dermatomyositis,²⁷ patients have developed crusted scabies secondary to treatment-related immunosuppression. These immunosuppressive therapies include systemic steroids,^22-24,26-31 methotrexate,²³ infliximab,¹⁸ adalimumab,²¹ toclizumab,¹⁹ and etanercept.²⁰ In a case of drug-induced Stevens-Johnson syndrome, the patient developed crusted scabies during long-term use of oral steroids.²²

Patients with a malignancy who are being treated with chemotherapy also can develop crusted scabies.²⁸ Crusted scabies has even been associated with long-term topical steroid^32-34 and topical calcineurin inhibitor use.¹⁶

Iatrogenic immunosuppression in our patient resulted from treatment of GPA with azathioprine, an immunosuppressive drug that acts as an antagonist of the breakdown of purines, leading to inhibition of DNA, RNA, and protein synthesis.³⁵ On occasion, azathioprine can induce immunosuppression in the form of myelosuppression and resulting pancytopenia, as was the case with our patient.

Conclusion

Although scabies is designated as a neglected tropical disease by the World Health Organization, it still causes a notable burden worldwide, regardless of the economics. Our case highlights an unusual presentation of scabies as erythroderma in the setting of iatrogenic immunosuppression from azathioprine use. Dermatologists should consider crusted scabies in the differential diagnosis of erythroderma, especially in immunocompromised patients, to avoid delays in diagnosis and treatment. Immunosuppressive therapy is an important mainstay in the treatment of many conditions, but it is important to consider that these medications can place patients at an increased risk for rare opportunistic infections. Therefore, patients receiving such treatment should be closely monitored.

Scabies is caused by cutaneous ectoparasitic infection by the mite Sarcoptes scabiei var hominis. The infection is highly contagious via direct skin-to-skin contact or indirectly through infested bedding, clothing or fomites.^1,2 Scabies occurs at all ages, in all ethnic groups, and at all socioeconomic levels.¹ Analysis by the Global Burden of Disease estimates that 200 million individuals have been infected with scabies worldwide. The World Health Organization has declared scabies a neglected tropical disease.³

Crusted scabies is a severe and rare form of scabies, with hyperinfestation of thousands to millions of mites, and more commonly is associated with immunosuppressed states, including HIV and hematologic malignancies.^1,2,4 Crusted scabies has a high mortality rate due to sepsis when left untreated.^3,5

Occasionally, iatrogenic immunosuppression contributes to the development of crusted scabies.^1,2 Iatrogenic immunosuppression leading to crusted scabies most commonly occurs secondary to immunosuppression after bone marrow or solid organ transplantation.⁶ Less often, crusted scabies is caused by iatrogenic immunosuppression from other clinical scenarios.^1,2

We describe a patient with iatrogenic immunosuppression due to azathioprine-induced myelosuppression for the treatment of granulomatosis with polyangiitis (GPA) who developed crusted scabies that clinically presented as erythroderma. Crusted scabies should be included in the differential diagnosis of erythroderma, especially in the setting of iatrogenic immunosuppression, for timely and appropriate management.

Case Report

An 84-year-old man presented with worsening pruritus, erythema, and thick yellow scale that progressed to erythroderma over the last 2 weeks. He was diagnosed with GPA 6 months prior to presentation and was treated with azathioprine 150 mg/d, prednisone 10 mg/d, and sulfamethoxazole 800 mg plus trimethoprim 160 mg twice weekly for prophylaxis against Pneumocystis jirovecii pneumonia.

Three weeks prior to presentation, the patient was hospitalized for pancytopenia attributed to azathioprine-induced myelosuppression (hemoglobin, 6.1 g/dL [reference range, 13.5–18.0 g/dL]; hematocrit, 17.5% [reference range, 42%–52%]; white blood cell count, 1.66×10³/μL [reference range, 4.0–10.5×10³/μL]; platelet count, 146×10³/μL [reference range, 150–450×10³/μL]; absolute neutrophil count, 1.29×10³/μL [reference range, 1.4–6.5×10³/μL]). He was transferred to a skilled nursing facility after discharge and referred to dermatology for evaluation of the worsening pruritic rash.

At the current presentation, the patient denied close contact with anyone who had a similar rash at home or at the skilled nursing facility. Physical examination revealed diffuse erythroderma with yellow scale on the scalp, trunk, arms, and legs (Figure 1). The palms showed scattered 2- to 3-mm pustules. The mucosal surfaces did not have lesions. A punch biopsy of a pustule from the right arm revealed focal spongiosis, parakeratosis, and acanthosis, as well as a perivascular and interstitial mixed inflammatory infiltrate with lymphocytes and eosinophils. Organisms morphologically compatible with scabies were found in the stratum corneum (Figure 2). Another punch biopsy of a pustule from the right arm was performed for direct immunofluorescence (DIF) and was negative for immunoglobulin deposition. Mineral oil preparation from pustules on the palm was positive for mites.

The patient was treated with permethrin cream 5% and oral ivermectin 200 μg/kg on day 1 and day 10. The prednisone dosage was increased from 10 mg/d to 50 mg/d and tapered over 2 weeks to treat the symptomatic rash and GPA. He remains on maintenance rituximab for GPA, without recurrence of scabies.

Comment

Pathogenesis—As an obligate parasite, S scabiei spends its entire life cycle within the host. Impregnated female mites burrow into the epidermis after mating and lay eggs daily for 1 to 2 months. Eggs hatch 2 or 3 days later. Larvae then migrate to the skin surface; burrow into the stratum corneum, where they mature into adults; and then mate on the skin surface.^1,4

Clinical Presentation and Sequelae—Typically, scabies presents 2 to 6 weeks after initial exposure with generalized and intense itching and inflammatory pruritic papules on the finger webs, wrists, elbows, axillae, buttocks, umbilicus, genitalia, and areolae.¹ Burrows are specific for scabies but may not always be present. Often, there are nonspecific secondary lesions, including excoriations, dermatitis, and impetiginization.

Complications of scabies can be severe, with initial colonization and infection of the skin resulting in impetigo and cellulitis. Systematic sequelae from local skin infection include post-streptococcal glomerulonephritis, rheumatic fever, and sepsis. Mortality from sepsis in scabies can be high.^3,5

Classic Crusted Scabies and Other Variants—Crusted scabies presents with psoriasiform hyperkeratotic plaques involving the hands and feet with potential nail involvement that can become more generalized.¹ Alterations in CD4⁺ T-cell function have been implicated in the development of crusted scabies, in which an excessive helper T cell (T_H2) response is elicited against the ectoparasite, which may help explain the intense pruritus of scabies.⁶ Occasionally, iatrogenic immunosuppression contributes to development of crusted scabies,¹ as was the case with our patient. However, it is rare for crusted scabies to present with erythroderma.⁷

Other atypical presentations of scabies include a seborrheic dermatitis–like presentation in infants, nodular lesions in the groin and axillae in more chronic scabies, and vesicles or bullous lesions.¹

Diagnosis—Identification of mites, eggs, or feces is necessary for definitive diagnosis of scabies.⁸ These materials can be obtained through skin scrapings with mineral oil and observed under light microscopy or direct dermoscopy. Multiple scrapings on many lesions should be performed because failure to identify mites can be common and does not rule out scabies. Dermoscopic examination of active lesions under low power also can be helpful, given that identification of dark brown triangular structures can correspond to visualization of the pigmented anterior section of the mite.^9-11 A skin biopsy can help identify mites, but histopathology often shows a nonspecific hypersensitivity reaction.¹² Therefore, empiric treatment often is necessary.

Differential Diagnosis—The differential diagnosis of erythroderma is broad and includes a drug eruption; Sézary syndrome; and pre-existing skin diseases, including psoriasis, atopic dermatitis, pityriasis rubra pilaris, pemphigus foliaceus, and bullous pemphigoid. Histopathology is critical to differentiate these diagnoses. Bullous pemphigoid and pemphigus foliaceus are immunobullous diseases that typically are positive for immunoglobulin deposition on DIF. In rare cases, scabies also can present with bullae and positive DIF test results.¹³

Treatment—First-line treatment of crusted scabies in the United States is permethrin cream 5%, followed by oral ivermectin 200 μg/kg.^4,5,14,15 Other scabicides include topicals such as benzyl benzoate 10% to 25%; precipitated sulfur 2% to 10%; crotamiton 10%; malathion 0.5%; and lindane 1%.⁵ The association of neurotoxicity with lindane has considerably reduced the drug’s use.¹

During treatment of scabies, it is important to isolate patients to mitigate the possibility of spread.⁴ Pruritus can persist for a few weeks after completion of therapy.⁵ Patients should be closely monitored to ensure that this symptom is secondary to skin inflammation and not incomplete treatment.

Treatment of crusted scabies may require repeated treatments to decrease the notable mite burden as well as the associated crusting and scale. Adding a keratolytic such as 5% to 10% salicylic acid in petrolatum to the treatment regimen may be useful for breaking up thick scale.⁵

Immunosuppression—With numerous immunomodulatory drugs for treating autoimmunity comes an increased risk for iatrogenic immunosuppression that may contribute to the development of crusted scabies.¹⁶ In a number of autoimmune diseases such as rheumatoid arthritis,^17-19 psoriasis,^20,21 pemphigus vulgaris,²² systemic lupus erythematosus,²³ systemic sclerosis,^22,24 bullous pemphigoid,^25,26 and dermatomyositis,²⁷ patients have developed crusted scabies secondary to treatment-related immunosuppression. These immunosuppressive therapies include systemic steroids,^22-24,26-31 methotrexate,²³ infliximab,¹⁸ adalimumab,²¹ toclizumab,¹⁹ and etanercept.²⁰ In a case of drug-induced Stevens-Johnson syndrome, the patient developed crusted scabies during long-term use of oral steroids.²²

Patients with a malignancy who are being treated with chemotherapy also can develop crusted scabies.²⁸ Crusted scabies has even been associated with long-term topical steroid^32-34 and topical calcineurin inhibitor use.¹⁶

Iatrogenic immunosuppression in our patient resulted from treatment of GPA with azathioprine, an immunosuppressive drug that acts as an antagonist of the breakdown of purines, leading to inhibition of DNA, RNA, and protein synthesis.³⁵ On occasion, azathioprine can induce immunosuppression in the form of myelosuppression and resulting pancytopenia, as was the case with our patient.

Conclusion

Although scabies is designated as a neglected tropical disease by the World Health Organization, it still causes a notable burden worldwide, regardless of the economics. Our case highlights an unusual presentation of scabies as erythroderma in the setting of iatrogenic immunosuppression from azathioprine use. Dermatologists should consider crusted scabies in the differential diagnosis of erythroderma, especially in immunocompromised patients, to avoid delays in diagnosis and treatment. Immunosuppressive therapy is an important mainstay in the treatment of many conditions, but it is important to consider that these medications can place patients at an increased risk for rare opportunistic infections. Therefore, patients receiving such treatment should be closely monitored.

Scabies is caused by cutaneous ectoparasitic infection by the mite Sarcoptes scabiei var hominis. The infection is highly contagious via direct skin-to-skin contact or indirectly through infested bedding, clothing or fomites.^1,2 Scabies occurs at all ages, in all ethnic groups, and at all socioeconomic levels.¹ Analysis by the Global Burden of Disease estimates that 200 million individuals have been infected with scabies worldwide. The World Health Organization has declared scabies a neglected tropical disease.³

Crusted scabies is a severe and rare form of scabies, with hyperinfestation of thousands to millions of mites, and more commonly is associated with immunosuppressed states, including HIV and hematologic malignancies.^1,2,4 Crusted scabies has a high mortality rate due to sepsis when left untreated.^3,5

Occasionally, iatrogenic immunosuppression contributes to the development of crusted scabies.^1,2 Iatrogenic immunosuppression leading to crusted scabies most commonly occurs secondary to immunosuppression after bone marrow or solid organ transplantation.⁶ Less often, crusted scabies is caused by iatrogenic immunosuppression from other clinical scenarios.^1,2

We describe a patient with iatrogenic immunosuppression due to azathioprine-induced myelosuppression for the treatment of granulomatosis with polyangiitis (GPA) who developed crusted scabies that clinically presented as erythroderma. Crusted scabies should be included in the differential diagnosis of erythroderma, especially in the setting of iatrogenic immunosuppression, for timely and appropriate management.

Case Report

An 84-year-old man presented with worsening pruritus, erythema, and thick yellow scale that progressed to erythroderma over the last 2 weeks. He was diagnosed with GPA 6 months prior to presentation and was treated with azathioprine 150 mg/d, prednisone 10 mg/d, and sulfamethoxazole 800 mg plus trimethoprim 160 mg twice weekly for prophylaxis against Pneumocystis jirovecii pneumonia.

Three weeks prior to presentation, the patient was hospitalized for pancytopenia attributed to azathioprine-induced myelosuppression (hemoglobin, 6.1 g/dL [reference range, 13.5–18.0 g/dL]; hematocrit, 17.5% [reference range, 42%–52%]; white blood cell count, 1.66×10³/μL [reference range, 4.0–10.5×10³/μL]; platelet count, 146×10³/μL [reference range, 150–450×10³/μL]; absolute neutrophil count, 1.29×10³/μL [reference range, 1.4–6.5×10³/μL]). He was transferred to a skilled nursing facility after discharge and referred to dermatology for evaluation of the worsening pruritic rash.

At the current presentation, the patient denied close contact with anyone who had a similar rash at home or at the skilled nursing facility. Physical examination revealed diffuse erythroderma with yellow scale on the scalp, trunk, arms, and legs (Figure 1). The palms showed scattered 2- to 3-mm pustules. The mucosal surfaces did not have lesions. A punch biopsy of a pustule from the right arm revealed focal spongiosis, parakeratosis, and acanthosis, as well as a perivascular and interstitial mixed inflammatory infiltrate with lymphocytes and eosinophils. Organisms morphologically compatible with scabies were found in the stratum corneum (Figure 2). Another punch biopsy of a pustule from the right arm was performed for direct immunofluorescence (DIF) and was negative for immunoglobulin deposition. Mineral oil preparation from pustules on the palm was positive for mites.

The patient was treated with permethrin cream 5% and oral ivermectin 200 μg/kg on day 1 and day 10. The prednisone dosage was increased from 10 mg/d to 50 mg/d and tapered over 2 weeks to treat the symptomatic rash and GPA. He remains on maintenance rituximab for GPA, without recurrence of scabies.

Comment

Pathogenesis—As an obligate parasite, S scabiei spends its entire life cycle within the host. Impregnated female mites burrow into the epidermis after mating and lay eggs daily for 1 to 2 months. Eggs hatch 2 or 3 days later. Larvae then migrate to the skin surface; burrow into the stratum corneum, where they mature into adults; and then mate on the skin surface.^1,4

Clinical Presentation and Sequelae—Typically, scabies presents 2 to 6 weeks after initial exposure with generalized and intense itching and inflammatory pruritic papules on the finger webs, wrists, elbows, axillae, buttocks, umbilicus, genitalia, and areolae.¹ Burrows are specific for scabies but may not always be present. Often, there are nonspecific secondary lesions, including excoriations, dermatitis, and impetiginization.

Complications of scabies can be severe, with initial colonization and infection of the skin resulting in impetigo and cellulitis. Systematic sequelae from local skin infection include post-streptococcal glomerulonephritis, rheumatic fever, and sepsis. Mortality from sepsis in scabies can be high.^3,5

Classic Crusted Scabies and Other Variants—Crusted scabies presents with psoriasiform hyperkeratotic plaques involving the hands and feet with potential nail involvement that can become more generalized.¹ Alterations in CD4⁺ T-cell function have been implicated in the development of crusted scabies, in which an excessive helper T cell (T_H2) response is elicited against the ectoparasite, which may help explain the intense pruritus of scabies.⁶ Occasionally, iatrogenic immunosuppression contributes to development of crusted scabies,¹ as was the case with our patient. However, it is rare for crusted scabies to present with erythroderma.⁷

Other atypical presentations of scabies include a seborrheic dermatitis–like presentation in infants, nodular lesions in the groin and axillae in more chronic scabies, and vesicles or bullous lesions.¹

Diagnosis—Identification of mites, eggs, or feces is necessary for definitive diagnosis of scabies.⁸ These materials can be obtained through skin scrapings with mineral oil and observed under light microscopy or direct dermoscopy. Multiple scrapings on many lesions should be performed because failure to identify mites can be common and does not rule out scabies. Dermoscopic examination of active lesions under low power also can be helpful, given that identification of dark brown triangular structures can correspond to visualization of the pigmented anterior section of the mite.^9-11 A skin biopsy can help identify mites, but histopathology often shows a nonspecific hypersensitivity reaction.¹² Therefore, empiric treatment often is necessary.

Differential Diagnosis—The differential diagnosis of erythroderma is broad and includes a drug eruption; Sézary syndrome; and pre-existing skin diseases, including psoriasis, atopic dermatitis, pityriasis rubra pilaris, pemphigus foliaceus, and bullous pemphigoid. Histopathology is critical to differentiate these diagnoses. Bullous pemphigoid and pemphigus foliaceus are immunobullous diseases that typically are positive for immunoglobulin deposition on DIF. In rare cases, scabies also can present with bullae and positive DIF test results.¹³

Treatment—First-line treatment of crusted scabies in the United States is permethrin cream 5%, followed by oral ivermectin 200 μg/kg.^4,5,14,15 Other scabicides include topicals such as benzyl benzoate 10% to 25%; precipitated sulfur 2% to 10%; crotamiton 10%; malathion 0.5%; and lindane 1%.⁵ The association of neurotoxicity with lindane has considerably reduced the drug’s use.¹

During treatment of scabies, it is important to isolate patients to mitigate the possibility of spread.⁴ Pruritus can persist for a few weeks after completion of therapy.⁵ Patients should be closely monitored to ensure that this symptom is secondary to skin inflammation and not incomplete treatment.

Treatment of crusted scabies may require repeated treatments to decrease the notable mite burden as well as the associated crusting and scale. Adding a keratolytic such as 5% to 10% salicylic acid in petrolatum to the treatment regimen may be useful for breaking up thick scale.⁵

Immunosuppression—With numerous immunomodulatory drugs for treating autoimmunity comes an increased risk for iatrogenic immunosuppression that may contribute to the development of crusted scabies.¹⁶ In a number of autoimmune diseases such as rheumatoid arthritis,^17-19 psoriasis,^20,21 pemphigus vulgaris,²² systemic lupus erythematosus,²³ systemic sclerosis,^22,24 bullous pemphigoid,^25,26 and dermatomyositis,²⁷ patients have developed crusted scabies secondary to treatment-related immunosuppression. These immunosuppressive therapies include systemic steroids,^22-24,26-31 methotrexate,²³ infliximab,¹⁸ adalimumab,²¹ toclizumab,¹⁹ and etanercept.²⁰ In a case of drug-induced Stevens-Johnson syndrome, the patient developed crusted scabies during long-term use of oral steroids.²²

Patients with a malignancy who are being treated with chemotherapy also can develop crusted scabies.²⁸ Crusted scabies has even been associated with long-term topical steroid^32-34 and topical calcineurin inhibitor use.¹⁶

Iatrogenic immunosuppression in our patient resulted from treatment of GPA with azathioprine, an immunosuppressive drug that acts as an antagonist of the breakdown of purines, leading to inhibition of DNA, RNA, and protein synthesis.³⁵ On occasion, azathioprine can induce immunosuppression in the form of myelosuppression and resulting pancytopenia, as was the case with our patient.

Conclusion

Although scabies is designated as a neglected tropical disease by the World Health Organization, it still causes a notable burden worldwide, regardless of the economics. Our case highlights an unusual presentation of scabies as erythroderma in the setting of iatrogenic immunosuppression from azathioprine use. Dermatologists should consider crusted scabies in the differential diagnosis of erythroderma, especially in immunocompromised patients, to avoid delays in diagnosis and treatment. Immunosuppressive therapy is an important mainstay in the treatment of many conditions, but it is important to consider that these medications can place patients at an increased risk for rare opportunistic infections. Therefore, patients receiving such treatment should be closely monitored.

To the Editor:

A 47-year-old man presented to the dermatology service with an asymptomatic plaque on the right thigh of 2 months’ duration. He had a medical history of HIV and Kaposi sarcoma as well as a recently relapsed primary effusion lymphoma (PEL) subsequent to an allogeneic bone marrow transplant. He initially was diagnosed with PEL 3 years prior to the current presentation during a workup for fever and weight loss. Imaging at the time demonstrated a bladder mass, which was biopsied and demonstrated PEL. Further imaging demonstrated both sinus and bone marrow involvement. Prior to dermatologic consultation, he had been treated with 6 cycles of etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin (EPOCH); 6 cycles of brentuximab; 4 cycles of rituximab with gemcitabine and oxaliplatin; and 2 cycles of ifosfamide, carboplatin, and etoposide. Despite these therapies, he had 3 relapses, and oncology determined the need for a matched unrelated donor allogeneic stem cell transplant for his PEL.

At the time of dermatology consultation, the patient was being managed on daratumumab and bortezomib. Physical examination revealed an infiltrative plaque on the right inferomedial thigh measuring approximately 6.0 cm (largest dimension) with a small amount of peripheral scale (Figure 1). An ultrasound revealed notable subcutaneous tissue edema and increased vascularity without a discrete mass or fluid collection. A 4-mm punch biopsy demonstrated a dense infiltrate comprised of collections of histiocytes admixed with scattered plasma cells and mature lymphoid aggregates. Additionally, rare enlarged plasmablastic cells with scant basophilic cytoplasm and slightly irregular nuclear contours were visualized (Figure 2A). Immunohistochemistry was positive for CD3 with a normal CD4:CD8 ratio, CD68-highlighted histiocytes within the lymphoid aggregates, and human herpesvirus 8 (HHV-8)(or Kaposi sarcoma–associated herpesvirus) demonstrated stippled nuclear staining within the scattered large cells (Figure 2B). Epstein-Barr virus–encoded RNA staining was negative, though the area of interest was lost on deeper sectioning of the tissue block. The histopathologic findings were consistent with cutaneous extracavitary PEL. Shortly after this diagnosis, he died from disease complications.

Primary effusion lymphoma is an aggressive non-Hodgkin B-cell lymphoma that was first described by Knowles et al¹ in 1989. Primary effusion lymphoma occurs exclusively in the setting of HHV-8 infection and typically is associated with chronic immunosuppression related to HIV/AIDS. Cases that are negative for HIV-1 are rare but have been reported in organ transplant recipients and elderly men from areas with a high prevalence of HHV-8 infections. Most HIV-associated cases show concurrent Epstein-Barr virus infection, though the pathogenic meaning of this co-infection remains unclear.^2,3

Primary effusion lymphoma classically presents as an isolated effusion of malignant lymphoid cells within body cavities in the absence of solid tumor masses. The pleural, peritoneal, and pericardial spaces most commonly are involved. Extracavitary PEL, a rare variant, may present as a solid mass without effusion. In general, extracavitary tumors may occur in the setting of de novo malignancy or recurrent PEL.⁴ Cutaneous manifestations associated with extracavitary PEL are rare; 4 cases have been described in which skin lesions were the heralding sign of the disease.³ Interestingly, despite obligatory underlying HHV-8 infection, a review by Pielasinski et al³ noted only 2 patients with cutaneous PEL who had prior or concurrent Kaposi sarcoma. This heterogeneity in HHV-8–related phenotypes may be related to differences in microRNA expression, but further study is needed.⁵

The diagnosis of PEL relies on histologic, immunophenotypic, and molecular analysis of the affected tissue. The malignant cells typically are large with round to irregular nuclei. These cells may demonstrate a variety of appearances, including anaplastic, plasmablastic, and immunoblastic morphologies.^6,7 The immunophenotype displays CD45 positivity and markers of lymphocyte activation (CD30, CD38, CD71), while typical B-cell (CD19, CD20, CD79a) and T-cell (CD3, CD4, CD8) markers often are absent.^6-8 Human herpesvirus 8 detection by polymerase chain reaction testing of the peripheral blood or by immunohistochemistry staining of the affected tissue is required for diagnosis.^6,7 Epstein-Barr virus infection may be detected via in situ hybridization, though it is not required for diagnosis.

The overall prognosis for PEL is poor; Brimo et al⁶ reported a median survival of less than 6 months, and Guillet et al⁹ reported 5-year overall survival (OS) for PEL vs extracavitary PEL to be 43% vs 39%. Another review noted variation in survival contingent on the number of body cavities involved; patients with a single body cavity involved experienced a median OS of 18 months, whereas patients with multiple involved cavities experienced a median OS of 4 months,⁷ possibly due to the limited study of treatment regimens or disease aggressiveness. Even in cases of successful initial treatment, relapse within 6 to 8 months is common. Extracavitary PEL may have improved disease-free survival relative to classic PEL, though the data were less clear for OS.⁹ Limitations of the Guillet et al⁹ study included a small sample size, the impossibility to randomize to disease type, and loss of power on the log-rank test for OS in the setting of possible nonproportional hazards (crossing survival curves). Overall, prognostic differences between the groups may be challenging to ascertain until further data are obtained.

As with many HIV-associated neoplasms, antiretroviral treatment (ART) for HIV-positive patients affords a better prognosis when used in addition to therapy directed at malignancy.⁷ The general approach is for concurrent ART with systemic therapies such as rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone for the rare CD20⁺ cases, and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or dose-adjusted EPOCH therapy in the more common CD20⁻ PEL cases. Narkhede et al⁷ suggested avoidance of methotrexate in patients with effusions because of increased toxicity, but it is unclear if this recommendation is applicable in extracavitary PEL patients without an effusion. Additionally, second-line treatment modalities include radiation for solid PEL masses, HHV-8–targeted antivirals, and stem cell transplantation, though evidence is limited. Of note, there is a phase I-II trial (ClinicalTrials.gov identifier NCT02911142) ongoing for treatment-naïve PEL patients involving the experimental treatment DA-EPOCH-R plus lenalidomide, but the trial is ongoing.¹⁰

We report a case of cutaneous PEL in a patient with a history of Kaposi sarcoma. The patient’s deterioration and ultimate death despite initial treatment with EPOCH and bone marrow transplantation followed by final management with daratumumab and bortezomib confirm other reports that PEL has a poor prognosis and that optimal treatments are not well delineated for these patients. In general, the current approach is to utilize ART for HIV-positive patients and to then implement chemotherapy such as CHOP. Without continued research and careful planning of treatments, data will remain limited on how best to serve patients with PEL.

To the Editor:

A 47-year-old man presented to the dermatology service with an asymptomatic plaque on the right thigh of 2 months’ duration. He had a medical history of HIV and Kaposi sarcoma as well as a recently relapsed primary effusion lymphoma (PEL) subsequent to an allogeneic bone marrow transplant. He initially was diagnosed with PEL 3 years prior to the current presentation during a workup for fever and weight loss. Imaging at the time demonstrated a bladder mass, which was biopsied and demonstrated PEL. Further imaging demonstrated both sinus and bone marrow involvement. Prior to dermatologic consultation, he had been treated with 6 cycles of etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin (EPOCH); 6 cycles of brentuximab; 4 cycles of rituximab with gemcitabine and oxaliplatin; and 2 cycles of ifosfamide, carboplatin, and etoposide. Despite these therapies, he had 3 relapses, and oncology determined the need for a matched unrelated donor allogeneic stem cell transplant for his PEL.

At the time of dermatology consultation, the patient was being managed on daratumumab and bortezomib. Physical examination revealed an infiltrative plaque on the right inferomedial thigh measuring approximately 6.0 cm (largest dimension) with a small amount of peripheral scale (Figure 1). An ultrasound revealed notable subcutaneous tissue edema and increased vascularity without a discrete mass or fluid collection. A 4-mm punch biopsy demonstrated a dense infiltrate comprised of collections of histiocytes admixed with scattered plasma cells and mature lymphoid aggregates. Additionally, rare enlarged plasmablastic cells with scant basophilic cytoplasm and slightly irregular nuclear contours were visualized (Figure 2A). Immunohistochemistry was positive for CD3 with a normal CD4:CD8 ratio, CD68-highlighted histiocytes within the lymphoid aggregates, and human herpesvirus 8 (HHV-8)(or Kaposi sarcoma–associated herpesvirus) demonstrated stippled nuclear staining within the scattered large cells (Figure 2B). Epstein-Barr virus–encoded RNA staining was negative, though the area of interest was lost on deeper sectioning of the tissue block. The histopathologic findings were consistent with cutaneous extracavitary PEL. Shortly after this diagnosis, he died from disease complications.

Primary effusion lymphoma is an aggressive non-Hodgkin B-cell lymphoma that was first described by Knowles et al¹ in 1989. Primary effusion lymphoma occurs exclusively in the setting of HHV-8 infection and typically is associated with chronic immunosuppression related to HIV/AIDS. Cases that are negative for HIV-1 are rare but have been reported in organ transplant recipients and elderly men from areas with a high prevalence of HHV-8 infections. Most HIV-associated cases show concurrent Epstein-Barr virus infection, though the pathogenic meaning of this co-infection remains unclear.^2,3

Primary effusion lymphoma classically presents as an isolated effusion of malignant lymphoid cells within body cavities in the absence of solid tumor masses. The pleural, peritoneal, and pericardial spaces most commonly are involved. Extracavitary PEL, a rare variant, may present as a solid mass without effusion. In general, extracavitary tumors may occur in the setting of de novo malignancy or recurrent PEL.⁴ Cutaneous manifestations associated with extracavitary PEL are rare; 4 cases have been described in which skin lesions were the heralding sign of the disease.³ Interestingly, despite obligatory underlying HHV-8 infection, a review by Pielasinski et al³ noted only 2 patients with cutaneous PEL who had prior or concurrent Kaposi sarcoma. This heterogeneity in HHV-8–related phenotypes may be related to differences in microRNA expression, but further study is needed.⁵

The diagnosis of PEL relies on histologic, immunophenotypic, and molecular analysis of the affected tissue. The malignant cells typically are large with round to irregular nuclei. These cells may demonstrate a variety of appearances, including anaplastic, plasmablastic, and immunoblastic morphologies.^6,7 The immunophenotype displays CD45 positivity and markers of lymphocyte activation (CD30, CD38, CD71), while typical B-cell (CD19, CD20, CD79a) and T-cell (CD3, CD4, CD8) markers often are absent.^6-8 Human herpesvirus 8 detection by polymerase chain reaction testing of the peripheral blood or by immunohistochemistry staining of the affected tissue is required for diagnosis.^6,7 Epstein-Barr virus infection may be detected via in situ hybridization, though it is not required for diagnosis.

The overall prognosis for PEL is poor; Brimo et al⁶ reported a median survival of less than 6 months, and Guillet et al⁹ reported 5-year overall survival (OS) for PEL vs extracavitary PEL to be 43% vs 39%. Another review noted variation in survival contingent on the number of body cavities involved; patients with a single body cavity involved experienced a median OS of 18 months, whereas patients with multiple involved cavities experienced a median OS of 4 months,⁷ possibly due to the limited study of treatment regimens or disease aggressiveness. Even in cases of successful initial treatment, relapse within 6 to 8 months is common. Extracavitary PEL may have improved disease-free survival relative to classic PEL, though the data were less clear for OS.⁹ Limitations of the Guillet et al⁹ study included a small sample size, the impossibility to randomize to disease type, and loss of power on the log-rank test for OS in the setting of possible nonproportional hazards (crossing survival curves). Overall, prognostic differences between the groups may be challenging to ascertain until further data are obtained.

As with many HIV-associated neoplasms, antiretroviral treatment (ART) for HIV-positive patients affords a better prognosis when used in addition to therapy directed at malignancy.⁷ The general approach is for concurrent ART with systemic therapies such as rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone for the rare CD20⁺ cases, and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or dose-adjusted EPOCH therapy in the more common CD20⁻ PEL cases. Narkhede et al⁷ suggested avoidance of methotrexate in patients with effusions because of increased toxicity, but it is unclear if this recommendation is applicable in extracavitary PEL patients without an effusion. Additionally, second-line treatment modalities include radiation for solid PEL masses, HHV-8–targeted antivirals, and stem cell transplantation, though evidence is limited. Of note, there is a phase I-II trial (ClinicalTrials.gov identifier NCT02911142) ongoing for treatment-naïve PEL patients involving the experimental treatment DA-EPOCH-R plus lenalidomide, but the trial is ongoing.¹⁰

We report a case of cutaneous PEL in a patient with a history of Kaposi sarcoma. The patient’s deterioration and ultimate death despite initial treatment with EPOCH and bone marrow transplantation followed by final management with daratumumab and bortezomib confirm other reports that PEL has a poor prognosis and that optimal treatments are not well delineated for these patients. In general, the current approach is to utilize ART for HIV-positive patients and to then implement chemotherapy such as CHOP. Without continued research and careful planning of treatments, data will remain limited on how best to serve patients with PEL.

To the Editor:

A 47-year-old man presented to the dermatology service with an asymptomatic plaque on the right thigh of 2 months’ duration. He had a medical history of HIV and Kaposi sarcoma as well as a recently relapsed primary effusion lymphoma (PEL) subsequent to an allogeneic bone marrow transplant. He initially was diagnosed with PEL 3 years prior to the current presentation during a workup for fever and weight loss. Imaging at the time demonstrated a bladder mass, which was biopsied and demonstrated PEL. Further imaging demonstrated both sinus and bone marrow involvement. Prior to dermatologic consultation, he had been treated with 6 cycles of etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin (EPOCH); 6 cycles of brentuximab; 4 cycles of rituximab with gemcitabine and oxaliplatin; and 2 cycles of ifosfamide, carboplatin, and etoposide. Despite these therapies, he had 3 relapses, and oncology determined the need for a matched unrelated donor allogeneic stem cell transplant for his PEL.

At the time of dermatology consultation, the patient was being managed on daratumumab and bortezomib. Physical examination revealed an infiltrative plaque on the right inferomedial thigh measuring approximately 6.0 cm (largest dimension) with a small amount of peripheral scale (Figure 1). An ultrasound revealed notable subcutaneous tissue edema and increased vascularity without a discrete mass or fluid collection. A 4-mm punch biopsy demonstrated a dense infiltrate comprised of collections of histiocytes admixed with scattered plasma cells and mature lymphoid aggregates. Additionally, rare enlarged plasmablastic cells with scant basophilic cytoplasm and slightly irregular nuclear contours were visualized (Figure 2A). Immunohistochemistry was positive for CD3 with a normal CD4:CD8 ratio, CD68-highlighted histiocytes within the lymphoid aggregates, and human herpesvirus 8 (HHV-8)(or Kaposi sarcoma–associated herpesvirus) demonstrated stippled nuclear staining within the scattered large cells (Figure 2B). Epstein-Barr virus–encoded RNA staining was negative, though the area of interest was lost on deeper sectioning of the tissue block. The histopathologic findings were consistent with cutaneous extracavitary PEL. Shortly after this diagnosis, he died from disease complications.

Primary effusion lymphoma is an aggressive non-Hodgkin B-cell lymphoma that was first described by Knowles et al¹ in 1989. Primary effusion lymphoma occurs exclusively in the setting of HHV-8 infection and typically is associated with chronic immunosuppression related to HIV/AIDS. Cases that are negative for HIV-1 are rare but have been reported in organ transplant recipients and elderly men from areas with a high prevalence of HHV-8 infections. Most HIV-associated cases show concurrent Epstein-Barr virus infection, though the pathogenic meaning of this co-infection remains unclear.^2,3

Primary effusion lymphoma classically presents as an isolated effusion of malignant lymphoid cells within body cavities in the absence of solid tumor masses. The pleural, peritoneal, and pericardial spaces most commonly are involved. Extracavitary PEL, a rare variant, may present as a solid mass without effusion. In general, extracavitary tumors may occur in the setting of de novo malignancy or recurrent PEL.⁴ Cutaneous manifestations associated with extracavitary PEL are rare; 4 cases have been described in which skin lesions were the heralding sign of the disease.³ Interestingly, despite obligatory underlying HHV-8 infection, a review by Pielasinski et al³ noted only 2 patients with cutaneous PEL who had prior or concurrent Kaposi sarcoma. This heterogeneity in HHV-8–related phenotypes may be related to differences in microRNA expression, but further study is needed.⁵

The diagnosis of PEL relies on histologic, immunophenotypic, and molecular analysis of the affected tissue. The malignant cells typically are large with round to irregular nuclei. These cells may demonstrate a variety of appearances, including anaplastic, plasmablastic, and immunoblastic morphologies.^6,7 The immunophenotype displays CD45 positivity and markers of lymphocyte activation (CD30, CD38, CD71), while typical B-cell (CD19, CD20, CD79a) and T-cell (CD3, CD4, CD8) markers often are absent.^6-8 Human herpesvirus 8 detection by polymerase chain reaction testing of the peripheral blood or by immunohistochemistry staining of the affected tissue is required for diagnosis.^6,7 Epstein-Barr virus infection may be detected via in situ hybridization, though it is not required for diagnosis.

The overall prognosis for PEL is poor; Brimo et al⁶ reported a median survival of less than 6 months, and Guillet et al⁹ reported 5-year overall survival (OS) for PEL vs extracavitary PEL to be 43% vs 39%. Another review noted variation in survival contingent on the number of body cavities involved; patients with a single body cavity involved experienced a median OS of 18 months, whereas patients with multiple involved cavities experienced a median OS of 4 months,⁷ possibly due to the limited study of treatment regimens or disease aggressiveness. Even in cases of successful initial treatment, relapse within 6 to 8 months is common. Extracavitary PEL may have improved disease-free survival relative to classic PEL, though the data were less clear for OS.⁹ Limitations of the Guillet et al⁹ study included a small sample size, the impossibility to randomize to disease type, and loss of power on the log-rank test for OS in the setting of possible nonproportional hazards (crossing survival curves). Overall, prognostic differences between the groups may be challenging to ascertain until further data are obtained.

As with many HIV-associated neoplasms, antiretroviral treatment (ART) for HIV-positive patients affords a better prognosis when used in addition to therapy directed at malignancy.⁷ The general approach is for concurrent ART with systemic therapies such as rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone for the rare CD20⁺ cases, and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or dose-adjusted EPOCH therapy in the more common CD20⁻ PEL cases. Narkhede et al⁷ suggested avoidance of methotrexate in patients with effusions because of increased toxicity, but it is unclear if this recommendation is applicable in extracavitary PEL patients without an effusion. Additionally, second-line treatment modalities include radiation for solid PEL masses, HHV-8–targeted antivirals, and stem cell transplantation, though evidence is limited. Of note, there is a phase I-II trial (ClinicalTrials.gov identifier NCT02911142) ongoing for treatment-naïve PEL patients involving the experimental treatment DA-EPOCH-R plus lenalidomide, but the trial is ongoing.¹⁰

We report a case of cutaneous PEL in a patient with a history of Kaposi sarcoma. The patient’s deterioration and ultimate death despite initial treatment with EPOCH and bone marrow transplantation followed by final management with daratumumab and bortezomib confirm other reports that PEL has a poor prognosis and that optimal treatments are not well delineated for these patients. In general, the current approach is to utilize ART for HIV-positive patients and to then implement chemotherapy such as CHOP. Without continued research and careful planning of treatments, data will remain limited on how best to serve patients with PEL.