Rare Diseases

An experimental brain-computer interface has allowed a man with amyotrophic lateral sclerosis (ALS) who was unable to speak or move to communicate.

Using a commercially available implant and newly designed software, the patient, who was in the advanced stages of Lou Gehrig’s disease and unable to move his eyes, was able to interact with researchers and caregivers, requesting goulash, beer, and music from the band Tool, thanking the researchers who developed the technology and inviting his 4-year-old son to watch a Disney film.

The investigators note the study shows for the first time that communication is possible in patients in a completely locked-in state (CLIS) and offers hope for a better quality of life in this population.

“It should encourage them to live after artificial respiration and to ask for brain-computer interfaces before they become CLIS,” study investigator Niels Birbaumer, PhD, a professor emeritus of the University of Tübingen, Germany, said in an interview. The study was published online March 22 in Nature Communications.

Although the findings appear promising, they build on previous research that was the subject of a 2019 investigation by the largest grant-funding agency in Germany. This controversy prompted the institute that led the current research to appoint an independent expert to audit and monitor the new study.
 

Mechanism a ‘mystery’

Use of brain-computer interface (BCI) technology to allow ALS patients to communicate has increased in recent years. BCIs capture brain signals, transmit them to a computer, and convert them into a command that the computer carries out.

Previous research shows patients with ALS who retain eye movement and control have been able to use BCIs to communicate. However, until now, the technology has not worked as well in CLIS patients, who have full-body paralysis.

In 2019, German and Swiss researchers implanted two 64-microde arrays in the brain of a 34-year-old patient who was diagnosed with ALS in 2015.

The electrodes measure neuronal activity while an amplifier located on the outside of the patient’s skull amplifies the signals to a computer. Software created by the research team decodes the signals and translates them into commands.

Using an auditory feedback system, the patient was able to use his mind to modulate the pitch of a tone to either high (meaning “yes”) or low (meaning “no.”) Just how the brain does this is a mystery, Dr. Birbaumer said.

A speller program reads letters aloud, first in groups and then individually. When a group contained letters the patient needed to spell a word, he used auditory feedback to select the high-pitch tone.

Initially, the patient was able to correctly spell his name. Ultimately, he was able to form complete sentences. The patient correctly spelled words on 44 of the 107 days in that phase of the experiment, spelling an average of just one character per minute.

Still, the researchers note he was able to interact with his caretakers, family, and researchers, even offering input on changes to make the device more effective.
 

Controversial history

In 2017, Dr. Birbaumer and Ujwal Chaudhary, PhD, who is the lead author on this current study, published a study in PLOS Biology. That research analyzed a brain-monitoring technique that the scientists claimed enabled patients with ALS who were completely locked in to answer yes or no questions correctly.

Allegations from a whistleblower at the University of Tübingen, where Dr. Birbaumer was a senior professor and Dr. Chaudhary was a postdoctoral researcher, prompted an investigation by the Deutsche Forschungsgemeinschaft, or German Research Foundation (DFG).

The whistleblower claimed that the 2017 paper and a second study published in 2019 contained incomplete data and misrepresented the findings. The DFG investigation found evidence of scientific misconduct and required that Dr. Birbaumer return the grant he had received for the research. The agency also banned Dr. Birbaumer from applying for grants or serving as a grant reviewer for 5 years. Dr. Chaudhary was banned for 3 years. PLOS Biology later retracted the papers.

Both researchers have refuted the allegations and have reportedly sued the German Research Foundation.

“We have no information about the status of our lawsuit against the DFG; it’s still pending,” Dr. Birbaumer told this news organization. “I hope they investigate our present study because the study of 2017 they did not investigate carefully enough.”
 

Results ‘not stunningly good’

The controversial history prompted the Wyss Center, Geneva, which led this new study, to seek out at an independent BCI expert to audit and monitor the study.

Nick Ramsey, PhD, a professor of cognitive neuroscience at the Brain Center of the University Medical Center Utrecht, the Netherlands, agreed to take on the assignment in March 2020.

Dr. Ramsey has also conducted research on BCI in patients with ALS, but his work has not included patients in CLIS.

“I judged the study to be compliant with universal standards of scientific integrity,” Dr. Ramsey told this news organization. “I am confident that the data and results presented in the paper are valid and will withstand academic and medical scrutiny.”

Commenting on the new findings, Dr. Ramsey noted that the results of the study are “not stunningly good, as the user could only communicate during a limited number of days, and even then with considerable slowness,” Dr. Ramsey said. However, he added that the study does provide proof of principle that communication is possible in CLIS patients.

“The question remains whether a BCI implant continues to work well in these patients, as there are some indications that people in such a state may lose their mental capabilities within months or a few years as a result of the disease and can thus no longer generate a wish to communicate,” Dr. Ramsey said.

Responding to a query from this news organization, a spokesperson for Nature Communications declined to comment on the new study but said that journal editors are “are alert to controversies within each field and take care when considering submissions during the peer-review process.”

“We have rigorous policies to safeguard the integrity of the research we publish,” the spokesperson continued, “including to ensure that research has been conducted to a high ethical standard and is reported transparently.”

The research was funded by Wyss Center for Bio and Neuroengineering, Geneva and Deutsche Forschungsgemeinschaft. The authors have disclosed no relevant financial relationships. Dr. Ramsey received payment from the Wyss Center for his advisory role in this project.

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

An experimental brain-computer interface has allowed a man with amyotrophic lateral sclerosis (ALS) who was unable to speak or move to communicate.

Using a commercially available implant and newly designed software, the patient, who was in the advanced stages of Lou Gehrig’s disease and unable to move his eyes, was able to interact with researchers and caregivers, requesting goulash, beer, and music from the band Tool, thanking the researchers who developed the technology and inviting his 4-year-old son to watch a Disney film.

The investigators note the study shows for the first time that communication is possible in patients in a completely locked-in state (CLIS) and offers hope for a better quality of life in this population.

“It should encourage them to live after artificial respiration and to ask for brain-computer interfaces before they become CLIS,” study investigator Niels Birbaumer, PhD, a professor emeritus of the University of Tübingen, Germany, said in an interview. The study was published online March 22 in Nature Communications.

Although the findings appear promising, they build on previous research that was the subject of a 2019 investigation by the largest grant-funding agency in Germany. This controversy prompted the institute that led the current research to appoint an independent expert to audit and monitor the new study.
 

Mechanism a ‘mystery’

Use of brain-computer interface (BCI) technology to allow ALS patients to communicate has increased in recent years. BCIs capture brain signals, transmit them to a computer, and convert them into a command that the computer carries out.

Previous research shows patients with ALS who retain eye movement and control have been able to use BCIs to communicate. However, until now, the technology has not worked as well in CLIS patients, who have full-body paralysis.

In 2019, German and Swiss researchers implanted two 64-microde arrays in the brain of a 34-year-old patient who was diagnosed with ALS in 2015.

The electrodes measure neuronal activity while an amplifier located on the outside of the patient’s skull amplifies the signals to a computer. Software created by the research team decodes the signals and translates them into commands.

Using an auditory feedback system, the patient was able to use his mind to modulate the pitch of a tone to either high (meaning “yes”) or low (meaning “no.”) Just how the brain does this is a mystery, Dr. Birbaumer said.

A speller program reads letters aloud, first in groups and then individually. When a group contained letters the patient needed to spell a word, he used auditory feedback to select the high-pitch tone.

Initially, the patient was able to correctly spell his name. Ultimately, he was able to form complete sentences. The patient correctly spelled words on 44 of the 107 days in that phase of the experiment, spelling an average of just one character per minute.

Still, the researchers note he was able to interact with his caretakers, family, and researchers, even offering input on changes to make the device more effective.
 

Controversial history

In 2017, Dr. Birbaumer and Ujwal Chaudhary, PhD, who is the lead author on this current study, published a study in PLOS Biology. That research analyzed a brain-monitoring technique that the scientists claimed enabled patients with ALS who were completely locked in to answer yes or no questions correctly.

Allegations from a whistleblower at the University of Tübingen, where Dr. Birbaumer was a senior professor and Dr. Chaudhary was a postdoctoral researcher, prompted an investigation by the Deutsche Forschungsgemeinschaft, or German Research Foundation (DFG).

The whistleblower claimed that the 2017 paper and a second study published in 2019 contained incomplete data and misrepresented the findings. The DFG investigation found evidence of scientific misconduct and required that Dr. Birbaumer return the grant he had received for the research. The agency also banned Dr. Birbaumer from applying for grants or serving as a grant reviewer for 5 years. Dr. Chaudhary was banned for 3 years. PLOS Biology later retracted the papers.

Both researchers have refuted the allegations and have reportedly sued the German Research Foundation.

“We have no information about the status of our lawsuit against the DFG; it’s still pending,” Dr. Birbaumer told this news organization. “I hope they investigate our present study because the study of 2017 they did not investigate carefully enough.”
 

Results ‘not stunningly good’

The controversial history prompted the Wyss Center, Geneva, which led this new study, to seek out at an independent BCI expert to audit and monitor the study.

Nick Ramsey, PhD, a professor of cognitive neuroscience at the Brain Center of the University Medical Center Utrecht, the Netherlands, agreed to take on the assignment in March 2020.

Dr. Ramsey has also conducted research on BCI in patients with ALS, but his work has not included patients in CLIS.

“I judged the study to be compliant with universal standards of scientific integrity,” Dr. Ramsey told this news organization. “I am confident that the data and results presented in the paper are valid and will withstand academic and medical scrutiny.”

Commenting on the new findings, Dr. Ramsey noted that the results of the study are “not stunningly good, as the user could only communicate during a limited number of days, and even then with considerable slowness,” Dr. Ramsey said. However, he added that the study does provide proof of principle that communication is possible in CLIS patients.

“The question remains whether a BCI implant continues to work well in these patients, as there are some indications that people in such a state may lose their mental capabilities within months or a few years as a result of the disease and can thus no longer generate a wish to communicate,” Dr. Ramsey said.

Responding to a query from this news organization, a spokesperson for Nature Communications declined to comment on the new study but said that journal editors are “are alert to controversies within each field and take care when considering submissions during the peer-review process.”

“We have rigorous policies to safeguard the integrity of the research we publish,” the spokesperson continued, “including to ensure that research has been conducted to a high ethical standard and is reported transparently.”

The research was funded by Wyss Center for Bio and Neuroengineering, Geneva and Deutsche Forschungsgemeinschaft. The authors have disclosed no relevant financial relationships. Dr. Ramsey received payment from the Wyss Center for his advisory role in this project.

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

An experimental brain-computer interface has allowed a man with amyotrophic lateral sclerosis (ALS) who was unable to speak or move to communicate.

Using a commercially available implant and newly designed software, the patient, who was in the advanced stages of Lou Gehrig’s disease and unable to move his eyes, was able to interact with researchers and caregivers, requesting goulash, beer, and music from the band Tool, thanking the researchers who developed the technology and inviting his 4-year-old son to watch a Disney film.

The investigators note the study shows for the first time that communication is possible in patients in a completely locked-in state (CLIS) and offers hope for a better quality of life in this population.

“It should encourage them to live after artificial respiration and to ask for brain-computer interfaces before they become CLIS,” study investigator Niels Birbaumer, PhD, a professor emeritus of the University of Tübingen, Germany, said in an interview. The study was published online March 22 in Nature Communications.

Although the findings appear promising, they build on previous research that was the subject of a 2019 investigation by the largest grant-funding agency in Germany. This controversy prompted the institute that led the current research to appoint an independent expert to audit and monitor the new study.
 

Mechanism a ‘mystery’

Use of brain-computer interface (BCI) technology to allow ALS patients to communicate has increased in recent years. BCIs capture brain signals, transmit them to a computer, and convert them into a command that the computer carries out.

Previous research shows patients with ALS who retain eye movement and control have been able to use BCIs to communicate. However, until now, the technology has not worked as well in CLIS patients, who have full-body paralysis.

In 2019, German and Swiss researchers implanted two 64-microde arrays in the brain of a 34-year-old patient who was diagnosed with ALS in 2015.

The electrodes measure neuronal activity while an amplifier located on the outside of the patient’s skull amplifies the signals to a computer. Software created by the research team decodes the signals and translates them into commands.

Using an auditory feedback system, the patient was able to use his mind to modulate the pitch of a tone to either high (meaning “yes”) or low (meaning “no.”) Just how the brain does this is a mystery, Dr. Birbaumer said.

A speller program reads letters aloud, first in groups and then individually. When a group contained letters the patient needed to spell a word, he used auditory feedback to select the high-pitch tone.

Initially, the patient was able to correctly spell his name. Ultimately, he was able to form complete sentences. The patient correctly spelled words on 44 of the 107 days in that phase of the experiment, spelling an average of just one character per minute.

Still, the researchers note he was able to interact with his caretakers, family, and researchers, even offering input on changes to make the device more effective.
 

Controversial history

In 2017, Dr. Birbaumer and Ujwal Chaudhary, PhD, who is the lead author on this current study, published a study in PLOS Biology. That research analyzed a brain-monitoring technique that the scientists claimed enabled patients with ALS who were completely locked in to answer yes or no questions correctly.

Allegations from a whistleblower at the University of Tübingen, where Dr. Birbaumer was a senior professor and Dr. Chaudhary was a postdoctoral researcher, prompted an investigation by the Deutsche Forschungsgemeinschaft, or German Research Foundation (DFG).

The whistleblower claimed that the 2017 paper and a second study published in 2019 contained incomplete data and misrepresented the findings. The DFG investigation found evidence of scientific misconduct and required that Dr. Birbaumer return the grant he had received for the research. The agency also banned Dr. Birbaumer from applying for grants or serving as a grant reviewer for 5 years. Dr. Chaudhary was banned for 3 years. PLOS Biology later retracted the papers.

Both researchers have refuted the allegations and have reportedly sued the German Research Foundation.

“We have no information about the status of our lawsuit against the DFG; it’s still pending,” Dr. Birbaumer told this news organization. “I hope they investigate our present study because the study of 2017 they did not investigate carefully enough.”
 

Results ‘not stunningly good’

The controversial history prompted the Wyss Center, Geneva, which led this new study, to seek out at an independent BCI expert to audit and monitor the study.

Nick Ramsey, PhD, a professor of cognitive neuroscience at the Brain Center of the University Medical Center Utrecht, the Netherlands, agreed to take on the assignment in March 2020.

Dr. Ramsey has also conducted research on BCI in patients with ALS, but his work has not included patients in CLIS.

“I judged the study to be compliant with universal standards of scientific integrity,” Dr. Ramsey told this news organization. “I am confident that the data and results presented in the paper are valid and will withstand academic and medical scrutiny.”

Commenting on the new findings, Dr. Ramsey noted that the results of the study are “not stunningly good, as the user could only communicate during a limited number of days, and even then with considerable slowness,” Dr. Ramsey said. However, he added that the study does provide proof of principle that communication is possible in CLIS patients.

“The question remains whether a BCI implant continues to work well in these patients, as there are some indications that people in such a state may lose their mental capabilities within months or a few years as a result of the disease and can thus no longer generate a wish to communicate,” Dr. Ramsey said.

Responding to a query from this news organization, a spokesperson for Nature Communications declined to comment on the new study but said that journal editors are “are alert to controversies within each field and take care when considering submissions during the peer-review process.”

“We have rigorous policies to safeguard the integrity of the research we publish,” the spokesperson continued, “including to ensure that research has been conducted to a high ethical standard and is reported transparently.”

The research was funded by Wyss Center for Bio and Neuroengineering, Geneva and Deutsche Forschungsgemeinschaft. The authors have disclosed no relevant financial relationships. Dr. Ramsey received payment from the Wyss Center for his advisory role in this project.

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

All Kawasaki disease (KD) patients should be treated first with intravenous immunoglobulin, according to an updated guideline issued jointly by the American College of Rheumatology and the Vasculitis Foundation.

KD has low mortality when treated appropriately, guideline first author Mark Gorelik, MD, assistant professor of pediatrics at Columbia University, New York, and colleagues wrote.

The update is important at this time because new evidence continues to emerge in the clinical management of KD, Dr. Gorelik said in an interview.

“In addition, this guideline approaches Kawasaki disease from a perspective of acting as an adjunct to the already existing and excellent American Heart Association guidelines by adding information in areas that rheumatologists may play a role,” Dr. Gorelik said. “This is specifically regarding patients who may require additional therapy beyond standard IVIg, such as patients who may be at higher risk of morbidity from disease and patients who have refractory disease,” he explained.

The guideline, published in Arthritis & Rheumatology, includes 11 recommendations, 1 good practice statement, and 1 ungraded position statement. The good practice statement emphasizes that all patients with KD should be initially treated with IVIg.

The position statement advises that either nonglucocorticoid immunosuppressive therapy or glucocorticoids may be used for patients with acute KD whose fever persists despite repeated IVIg treatment. No clinical evidence currently supports the superiority of either nonglucocorticoid immunosuppressive therapy or glucocorticoids; therefore, the authors support the use of either based on what is appropriate in any given clinical situation. Although optimal dosage and duration of glucocorticoids have yet to be determined in a U.S. population, the authors described a typical glucocorticoid dosage as starting prednisone at 2 mg/kg per day, with a maximum of 60 mg/day, and dose tapering over 15 days.

The 11 recommendations consist of 7 strong and 4 conditional recommendations. The strong recommendations focus on prompt treatment of incomplete KD, treatment with aspirin, and obtaining an echocardiogram in patients with unexplained macrophage activation syndrome or shock. The conditional recommendations support using established therapy promptly at disease onset, then identifying cases in which additional therapy is needed.

Dr. Gorelik highlighted four clinical takeaways from the guideline. First, “patients with higher risk for complications do exist in Kawasaki disease, and that these patients can be treated more aggressively,” he said. “Specifically, patients with aneurysms seen at first ultrasound, and patients who are under 6 months, are more likely to have progressive and/or refractory disease; these patients can be treated with an adjunctive short course of corticosteroids.”

Second, “the use of high-dose aspirin for patients with Kawasaki disease does not have strong basis in evidence. While aspirin itself of some dose is necessary for patients with Kawasaki disease, use of either high- or low-dose aspirin has the same outcome for patients, and a physician may choose either of these in practice,” he said.

Third, “we continue to recommend that refractory patients with Kawasaki disease be treated with a second dose of IVIg; however, there are many scenarios in which a physician may choose either corticosteroids [either a single high dose of >10 mg/kg, or a short moderate-dose course of 2 mg/kg per day for 5-7 days] or a biologic agent such as infliximab. ... These are valid choices for therapy in patients with refractory Kawasaki disease,” he emphasized.

Fourth, “physicians should discard the idea of treating before [and conversely, not treating after] 10 days of fever,” Dr. Gorelik said. “Patients with Kawasaki disease should be treated as soon as the diagnosis is made, regardless of whether this patient is on day 5, day 12, or day 20 of symptoms.”

Update incorporates emerging evidence

Potential barriers to implementing the guideline in practice include the challenge of weaning doctors from practices that are habitual in medicine, Dr. Gorelik said. “One of these is the use of high-dose aspirin for Kawasaki disease; a number of studies have shown over the past decade or more that high-dose aspirin has no greater effect than lower-dose aspirin for Kawasaki disease. Despite all of these studies, the use of high-dose aspirin continued. High-dose aspirin for Kawasaki disease was used in the era prior to use of IVIg as an anti-inflammatory agent. However, it has poor efficacy in this regard, and the true benefit for aspirin is for anticoagulation for patients at risk of a clot, and this is just as effective in lower doses. Expressing this in a guideline could help to change practices by helping physicians understand not only what they are guided to do, but why.”

Additional research is needed to better identify high-risk patients in non-Japanese populations, he noted. “While studies from Japan suggest that higher-risk patients can be identified based on various parameters, these have not been well replicated in non-Japanese populations. Good research that identifies which patients may be more at risk in other populations would be helpful to more precisely target high-risk therapy.”

Other research needs include a clearer understanding of the best therapies for refractory patients, Dr. Gorelik said. “One area of the most difficulty was determining whether patients with refractory disease should have repeated IVIg or a switch to glucocorticoids and biologic agents. Some of this research is underway, and some was published just as these guidelines were being drawn, and this particular area is one that is likely to change significantly. While currently we recommend a repeated dose of IVIg, it is likely that over the very near term, the use of repeated IVIg in KD will be curtailed” because of concerns such as the relatively high rate of hemolysis. Research to identify which therapy has a noninferior effect with a superior risk profile is needed; such research “will likely result in a future iteration of these guidelines specifically related to this question,” he concluded.

The KD guideline is the final companion to three additional ACR/VF vasculitis guidelines that were released in July 2021. The guideline research received no outside funding. The researchers had no financial conflicts to disclose.

All Kawasaki disease (KD) patients should be treated first with intravenous immunoglobulin, according to an updated guideline issued jointly by the American College of Rheumatology and the Vasculitis Foundation.

KD has low mortality when treated appropriately, guideline first author Mark Gorelik, MD, assistant professor of pediatrics at Columbia University, New York, and colleagues wrote.

The update is important at this time because new evidence continues to emerge in the clinical management of KD, Dr. Gorelik said in an interview.

“In addition, this guideline approaches Kawasaki disease from a perspective of acting as an adjunct to the already existing and excellent American Heart Association guidelines by adding information in areas that rheumatologists may play a role,” Dr. Gorelik said. “This is specifically regarding patients who may require additional therapy beyond standard IVIg, such as patients who may be at higher risk of morbidity from disease and patients who have refractory disease,” he explained.

The guideline, published in Arthritis & Rheumatology, includes 11 recommendations, 1 good practice statement, and 1 ungraded position statement. The good practice statement emphasizes that all patients with KD should be initially treated with IVIg.

The position statement advises that either nonglucocorticoid immunosuppressive therapy or glucocorticoids may be used for patients with acute KD whose fever persists despite repeated IVIg treatment. No clinical evidence currently supports the superiority of either nonglucocorticoid immunosuppressive therapy or glucocorticoids; therefore, the authors support the use of either based on what is appropriate in any given clinical situation. Although optimal dosage and duration of glucocorticoids have yet to be determined in a U.S. population, the authors described a typical glucocorticoid dosage as starting prednisone at 2 mg/kg per day, with a maximum of 60 mg/day, and dose tapering over 15 days.

The 11 recommendations consist of 7 strong and 4 conditional recommendations. The strong recommendations focus on prompt treatment of incomplete KD, treatment with aspirin, and obtaining an echocardiogram in patients with unexplained macrophage activation syndrome or shock. The conditional recommendations support using established therapy promptly at disease onset, then identifying cases in which additional therapy is needed.

Dr. Gorelik highlighted four clinical takeaways from the guideline. First, “patients with higher risk for complications do exist in Kawasaki disease, and that these patients can be treated more aggressively,” he said. “Specifically, patients with aneurysms seen at first ultrasound, and patients who are under 6 months, are more likely to have progressive and/or refractory disease; these patients can be treated with an adjunctive short course of corticosteroids.”

Second, “the use of high-dose aspirin for patients with Kawasaki disease does not have strong basis in evidence. While aspirin itself of some dose is necessary for patients with Kawasaki disease, use of either high- or low-dose aspirin has the same outcome for patients, and a physician may choose either of these in practice,” he said.

Third, “we continue to recommend that refractory patients with Kawasaki disease be treated with a second dose of IVIg; however, there are many scenarios in which a physician may choose either corticosteroids [either a single high dose of >10 mg/kg, or a short moderate-dose course of 2 mg/kg per day for 5-7 days] or a biologic agent such as infliximab. ... These are valid choices for therapy in patients with refractory Kawasaki disease,” he emphasized.

Fourth, “physicians should discard the idea of treating before [and conversely, not treating after] 10 days of fever,” Dr. Gorelik said. “Patients with Kawasaki disease should be treated as soon as the diagnosis is made, regardless of whether this patient is on day 5, day 12, or day 20 of symptoms.”

Update incorporates emerging evidence

Potential barriers to implementing the guideline in practice include the challenge of weaning doctors from practices that are habitual in medicine, Dr. Gorelik said. “One of these is the use of high-dose aspirin for Kawasaki disease; a number of studies have shown over the past decade or more that high-dose aspirin has no greater effect than lower-dose aspirin for Kawasaki disease. Despite all of these studies, the use of high-dose aspirin continued. High-dose aspirin for Kawasaki disease was used in the era prior to use of IVIg as an anti-inflammatory agent. However, it has poor efficacy in this regard, and the true benefit for aspirin is for anticoagulation for patients at risk of a clot, and this is just as effective in lower doses. Expressing this in a guideline could help to change practices by helping physicians understand not only what they are guided to do, but why.”

Additional research is needed to better identify high-risk patients in non-Japanese populations, he noted. “While studies from Japan suggest that higher-risk patients can be identified based on various parameters, these have not been well replicated in non-Japanese populations. Good research that identifies which patients may be more at risk in other populations would be helpful to more precisely target high-risk therapy.”

Other research needs include a clearer understanding of the best therapies for refractory patients, Dr. Gorelik said. “One area of the most difficulty was determining whether patients with refractory disease should have repeated IVIg or a switch to glucocorticoids and biologic agents. Some of this research is underway, and some was published just as these guidelines were being drawn, and this particular area is one that is likely to change significantly. While currently we recommend a repeated dose of IVIg, it is likely that over the very near term, the use of repeated IVIg in KD will be curtailed” because of concerns such as the relatively high rate of hemolysis. Research to identify which therapy has a noninferior effect with a superior risk profile is needed; such research “will likely result in a future iteration of these guidelines specifically related to this question,” he concluded.

The KD guideline is the final companion to three additional ACR/VF vasculitis guidelines that were released in July 2021. The guideline research received no outside funding. The researchers had no financial conflicts to disclose.

All Kawasaki disease (KD) patients should be treated first with intravenous immunoglobulin, according to an updated guideline issued jointly by the American College of Rheumatology and the Vasculitis Foundation.

KD has low mortality when treated appropriately, guideline first author Mark Gorelik, MD, assistant professor of pediatrics at Columbia University, New York, and colleagues wrote.

The update is important at this time because new evidence continues to emerge in the clinical management of KD, Dr. Gorelik said in an interview.

“In addition, this guideline approaches Kawasaki disease from a perspective of acting as an adjunct to the already existing and excellent American Heart Association guidelines by adding information in areas that rheumatologists may play a role,” Dr. Gorelik said. “This is specifically regarding patients who may require additional therapy beyond standard IVIg, such as patients who may be at higher risk of morbidity from disease and patients who have refractory disease,” he explained.

The guideline, published in Arthritis & Rheumatology, includes 11 recommendations, 1 good practice statement, and 1 ungraded position statement. The good practice statement emphasizes that all patients with KD should be initially treated with IVIg.

The position statement advises that either nonglucocorticoid immunosuppressive therapy or glucocorticoids may be used for patients with acute KD whose fever persists despite repeated IVIg treatment. No clinical evidence currently supports the superiority of either nonglucocorticoid immunosuppressive therapy or glucocorticoids; therefore, the authors support the use of either based on what is appropriate in any given clinical situation. Although optimal dosage and duration of glucocorticoids have yet to be determined in a U.S. population, the authors described a typical glucocorticoid dosage as starting prednisone at 2 mg/kg per day, with a maximum of 60 mg/day, and dose tapering over 15 days.

The 11 recommendations consist of 7 strong and 4 conditional recommendations. The strong recommendations focus on prompt treatment of incomplete KD, treatment with aspirin, and obtaining an echocardiogram in patients with unexplained macrophage activation syndrome or shock. The conditional recommendations support using established therapy promptly at disease onset, then identifying cases in which additional therapy is needed.

Dr. Gorelik highlighted four clinical takeaways from the guideline. First, “patients with higher risk for complications do exist in Kawasaki disease, and that these patients can be treated more aggressively,” he said. “Specifically, patients with aneurysms seen at first ultrasound, and patients who are under 6 months, are more likely to have progressive and/or refractory disease; these patients can be treated with an adjunctive short course of corticosteroids.”

Second, “the use of high-dose aspirin for patients with Kawasaki disease does not have strong basis in evidence. While aspirin itself of some dose is necessary for patients with Kawasaki disease, use of either high- or low-dose aspirin has the same outcome for patients, and a physician may choose either of these in practice,” he said.

Third, “we continue to recommend that refractory patients with Kawasaki disease be treated with a second dose of IVIg; however, there are many scenarios in which a physician may choose either corticosteroids [either a single high dose of >10 mg/kg, or a short moderate-dose course of 2 mg/kg per day for 5-7 days] or a biologic agent such as infliximab. ... These are valid choices for therapy in patients with refractory Kawasaki disease,” he emphasized.

Fourth, “physicians should discard the idea of treating before [and conversely, not treating after] 10 days of fever,” Dr. Gorelik said. “Patients with Kawasaki disease should be treated as soon as the diagnosis is made, regardless of whether this patient is on day 5, day 12, or day 20 of symptoms.”

Update incorporates emerging evidence

Potential barriers to implementing the guideline in practice include the challenge of weaning doctors from practices that are habitual in medicine, Dr. Gorelik said. “One of these is the use of high-dose aspirin for Kawasaki disease; a number of studies have shown over the past decade or more that high-dose aspirin has no greater effect than lower-dose aspirin for Kawasaki disease. Despite all of these studies, the use of high-dose aspirin continued. High-dose aspirin for Kawasaki disease was used in the era prior to use of IVIg as an anti-inflammatory agent. However, it has poor efficacy in this regard, and the true benefit for aspirin is for anticoagulation for patients at risk of a clot, and this is just as effective in lower doses. Expressing this in a guideline could help to change practices by helping physicians understand not only what they are guided to do, but why.”

Additional research is needed to better identify high-risk patients in non-Japanese populations, he noted. “While studies from Japan suggest that higher-risk patients can be identified based on various parameters, these have not been well replicated in non-Japanese populations. Good research that identifies which patients may be more at risk in other populations would be helpful to more precisely target high-risk therapy.”

Other research needs include a clearer understanding of the best therapies for refractory patients, Dr. Gorelik said. “One area of the most difficulty was determining whether patients with refractory disease should have repeated IVIg or a switch to glucocorticoids and biologic agents. Some of this research is underway, and some was published just as these guidelines were being drawn, and this particular area is one that is likely to change significantly. While currently we recommend a repeated dose of IVIg, it is likely that over the very near term, the use of repeated IVIg in KD will be curtailed” because of concerns such as the relatively high rate of hemolysis. Research to identify which therapy has a noninferior effect with a superior risk profile is needed; such research “will likely result in a future iteration of these guidelines specifically related to this question,” he concluded.

The KD guideline is the final companion to three additional ACR/VF vasculitis guidelines that were released in July 2021. The guideline research received no outside funding. The researchers had no financial conflicts to disclose.

Mycosis fungoides (MF) and Sézary syndrome (SS) are non-Hodgkin T-cell lymphomas that make up the majority of cutaneous T-cell lymphomas. These conditions commonly affect Black patients, with an incidence rate of 12.6 cases of cutaneous T-cell lymphomas per million individuals vs 9.8 per million individuals in non–skin of color (SoC) patients.¹ However, educational resources tend to focus on the clinical manifestations of MF/SS in lighter skin types, describing MF as erythematous patches, plaques, or tumors presenting in non–sun-exposed areas of the skin and SS as generalized erythroderma.² Skin of color, comprised of Fitzpatrick skin types (FSTs) IV to VI,³ is poorly represented across dermatology textbooks,^4,5 medical student resources,⁶ and peer-reviewed publications,⁷ raising awareness for the need to address this disparity.

Skin of color patients with MF/SS display variable morphologies, including features such as hyperpigmentation and hypopigmentation,⁸ the latter being exceedingly rare in non-SoC patients.⁹ Familiarity with these differences among providers is essential to allow for equitable diagnosis and treatment across all skin types, especially in light of data predicting that by 2044 more than 50% of the US population will be people of color.¹⁰ Patients with SoC are of many ethnic and racial backgrounds, including Black, Hispanic, American Indian, Pacific Islander, and Asian.¹¹

Along with morphologic differences, there also are several racial disparities in the prognosis and survival of patients with MF/SS. Black patients diagnosed with MF present with greater body surface area affected, and Black women with MF have reduced survival rates compared to their White counterparts.¹² Given these racial disparities in survival and representation in educational resources, we aimed to quantify the frequency of various morphologic characteristics of MF/SS in patients with SoC vs non-SoC patients to facilitate better recognition of early MF/SS in SoC patients by medical providers.

Methods

We performed a retrospective chart review following approval from the institutional review board at Northwestern University (Chicago, Illinois). We identified all patients with FSTs IV to VI and biopsy-proven MF/SS who had been clinically photographed in our clinic from January 1998 to December 2019. Only photographs that were high quality enough to review morphologic features were included in our review. Fitzpatrick skin type was determined based on electronic medical record documentation. If photographs were available from multiple visits for the same patient, only those showing posttreatment nonactive lesions were included. Additionally, 36 patients with FSTs I to III (non-SoC) and biopsy-proven MF/SS were included in our review as a comparison with the SoC cohort. The primary outcomes for this study included the presence of scale, erythema, hyperpigmentation, hypopigmentation, violaceous color, lichenification, silver hue, dyschromia, alopecia, poikiloderma, atrophy, and ulceration in active lesions. Dyschromia was defined by the presence of both hypopigmentation and hyperpigmentation. Poikiloderma was defined by hypopigmentation and hyperpigmentation, telangiectasia, and atrophy. Secondary outcomes included evaluation of those same characteristics in posttreatment nonactive lesions. All photographs were independently assessed by 3 authors (M.L.E., C.J.W., J.M.M.), and discrepancies were resolved by further review of the photograph in question and discussion.

Statistical Analysis—Summary statistics were applied to describe demographic and clinical characteristics. The χ² test was used for categorical variables. Results achieving P<.05 were considered statistically significant.

Results

We reviewed photographs of 111 patients across all skin types (8, FST I; 12, FST II; 16, FST III; 17, FST IV; 44, FST V; 14, FST VI). The cohort was 47% female, and the mean age was 49.7 years (range, 15–86 years). The majority of the cohort had early-stage MF (stage IA or IB). There were more cases of SS in the SoC cohort than the non-SoC cohort (Table). Only 5 photographs had discrepancies and required discussion among the reviewers to achieve consensus.

Regarding morphologic characteristics in active lesions (Figure 1), scale was present in almost all patients (99% in SoC, 94% in non-SoC). Erythema was present in nearly all non-SoC patients (94%) but only in 69% of SoC patients (P=.003). Poikiloderma also was found to be present at higher frequencies in non-SoC patients compared with SoC patients (19% and 4%, respectively [P=.008]). However, hyperpigmentation (80% vs 39%), lichenification (43% vs 17%), and silver hue (25% vs 3%) were more common in SoC patients than non-SoC patients (P<.05). There were no significant differences in the remaining features, including hypopigmentation (39% vs 25%), dyschromia (24% vs 19%), violaceous color (44% vs 25%), atrophy (11% vs 22%), alopecia (23% vs 31%), and ulceration (16% vs 8%) between SoC and non-SoC patients (P>.05). Photographs of MF in patients with SoC can be seen in Figure 2.

Posttreatment (nonactive) photographs were available for 26 patients (6 non-SoC, 20 SoC). We found that across all FST groups, hyperpigmentation was more common than hypopigmentation in areas of previously active disease. Statistical analysis was not completed given that few non-SoC photographs were available for comparison.

Comment

This qualitative review demonstrates the heterogeneity of MF/SS in SoC patients and that these conditions do not present in this population with the classic erythematous patches and plaques found in non-SoC patients. We found that hyperpigmentation, lichenification, and silver hue were present at higher rates in patients with FSTs IV to VI compared to those with FSTs I to III, which had higher rates of erythema and poikiloderma. Familiarity with these morphologic features along with increased exposure to clinical photographs of MF/SS in SoC patients will aid in the visual recognition required for this diagnosis, since erythema is harder to identify in darker skin types. Recognizing the unique findings of MF in patients with SoC as well as in patients with lighter skin types will enable earlier diagnosis and treatment of MF/SS across all skin types. If MF is diagnosed and treated early, life expectancy is similar to that of patients without MF.¹³ However, the 5-year survival rate for advanced-stage MF/SS is 52% across all skin types, and studies have found that Black patients with advanced-stage disease have worse outcomes despite accounting for demographic factors and tumor stage.^14,15 Given the worse outcomes in SoC patients with advanced-stage MF/SS, earlier diagnosis could help address this disparity.^8,13,14 Similar morphologic features could be used in diagnosing other inflammatory conditions; studies have shown that the lack of recognition of erythema in Black children has led to delayed diagnosis of atopic dermatitis and subsequent inadequate treatment.^16,17

The morphologic presentation of MF/SS in SoC patients also can influence an optimal treatment plan for this population. Hypopigmented MF responds better to phototherapy than hyperpigmented MF, as phototherapy has been shown to have decreased efficacy with increasing FST.¹⁸ Therefore, for patients with FSTs IV to VI, topical agents such as nitrogen mustard or bexarotene may be more suitable treatment options, as the efficacy of these treatments is independent of skin color.⁸ However, nitrogen mustard commonly leads to postinflammatory hyperpigmentation, and topical bexarotene may lead to erythema or irritation; therefore, providers must counsel patients on these possible side effects. For refractory disease, adjunct systemic treatments such as oral bexarotene, subcutaneous interferon, methotrexate, or radiation therapy may be considered.⁸

In addition to aiding in the prompt diagnosis and treatment of MF/SS in SoC patients, our findings may be used to better assess the extent of disease and distinguish between active MF/SS lesions vs xerosis cutis or residual dyschromia from previously treated lesions. It is important to note that these morphologic features must be taken into account with a complete history and work-up. The differential diagnosis of MF/SS includes conditions such as atopic dermatitis, psoriasis, tinea corporis, and drug reactions, which may have similar morphology in SoC.¹⁹

Limitations of our study include the single-center design and the use of photographs instead of in-person examination; however, our cutaneous lymphoma clinic serves a diverse patient population, and our 3 reviewers rated the photographs independently. Discussion amongst the reviewers to address discrepancies was only required for 5 photographs, indicating the high inter-reviewer reliability. Additionally, the original purpose of FST was to assess for the propensity of the skin to burn when undergoing phototherapy, not to serve as a marker for skin color. We recommend trainees and clinicians be mindful about the purpose of FST and to use inclusive language (eg, using the terms skin irritation, skin tenderness, or skin becoming darker from the sun instead of tanning) when determining FST in darker-skinned individuals.²⁰ Future directions include examining if certain treatments are associated with prolonged dyschromia.

Conclusion

In our single-institution retrospective study, we found differences in the morphologic presentation of MF/SS in SoC patients vs non-SoC patients. While erythema is a common feature in non-SoC patients, clinical features of hyperpigmentation, lichenification, and silver hue should be carefully evaluated in the diagnosis of MF/SS in SoC patients. Knowledge of the heterogenous presentation of MF/SS in patients with SoC allows for expedited diagnosis and treatment, leading to better clinical outcomes. Valuable resources, including Taylor and Kelly’s Dermatology for Skin of Color, the Skin of Color Society, and VisualDx educate providers on how dermatologic conditions present in darker skin types. However, there is still work to be done to enhance diversity in educational resources in order to provide equitable care to patients of all skin types.

Mycosis fungoides (MF) and Sézary syndrome (SS) are non-Hodgkin T-cell lymphomas that make up the majority of cutaneous T-cell lymphomas. These conditions commonly affect Black patients, with an incidence rate of 12.6 cases of cutaneous T-cell lymphomas per million individuals vs 9.8 per million individuals in non–skin of color (SoC) patients.¹ However, educational resources tend to focus on the clinical manifestations of MF/SS in lighter skin types, describing MF as erythematous patches, plaques, or tumors presenting in non–sun-exposed areas of the skin and SS as generalized erythroderma.² Skin of color, comprised of Fitzpatrick skin types (FSTs) IV to VI,³ is poorly represented across dermatology textbooks,^4,5 medical student resources,⁶ and peer-reviewed publications,⁷ raising awareness for the need to address this disparity.

Skin of color patients with MF/SS display variable morphologies, including features such as hyperpigmentation and hypopigmentation,⁸ the latter being exceedingly rare in non-SoC patients.⁹ Familiarity with these differences among providers is essential to allow for equitable diagnosis and treatment across all skin types, especially in light of data predicting that by 2044 more than 50% of the US population will be people of color.¹⁰ Patients with SoC are of many ethnic and racial backgrounds, including Black, Hispanic, American Indian, Pacific Islander, and Asian.¹¹

Along with morphologic differences, there also are several racial disparities in the prognosis and survival of patients with MF/SS. Black patients diagnosed with MF present with greater body surface area affected, and Black women with MF have reduced survival rates compared to their White counterparts.¹² Given these racial disparities in survival and representation in educational resources, we aimed to quantify the frequency of various morphologic characteristics of MF/SS in patients with SoC vs non-SoC patients to facilitate better recognition of early MF/SS in SoC patients by medical providers.

Methods

We performed a retrospective chart review following approval from the institutional review board at Northwestern University (Chicago, Illinois). We identified all patients with FSTs IV to VI and biopsy-proven MF/SS who had been clinically photographed in our clinic from January 1998 to December 2019. Only photographs that were high quality enough to review morphologic features were included in our review. Fitzpatrick skin type was determined based on electronic medical record documentation. If photographs were available from multiple visits for the same patient, only those showing posttreatment nonactive lesions were included. Additionally, 36 patients with FSTs I to III (non-SoC) and biopsy-proven MF/SS were included in our review as a comparison with the SoC cohort. The primary outcomes for this study included the presence of scale, erythema, hyperpigmentation, hypopigmentation, violaceous color, lichenification, silver hue, dyschromia, alopecia, poikiloderma, atrophy, and ulceration in active lesions. Dyschromia was defined by the presence of both hypopigmentation and hyperpigmentation. Poikiloderma was defined by hypopigmentation and hyperpigmentation, telangiectasia, and atrophy. Secondary outcomes included evaluation of those same characteristics in posttreatment nonactive lesions. All photographs were independently assessed by 3 authors (M.L.E., C.J.W., J.M.M.), and discrepancies were resolved by further review of the photograph in question and discussion.

Statistical Analysis—Summary statistics were applied to describe demographic and clinical characteristics. The χ² test was used for categorical variables. Results achieving P<.05 were considered statistically significant.

Results

We reviewed photographs of 111 patients across all skin types (8, FST I; 12, FST II; 16, FST III; 17, FST IV; 44, FST V; 14, FST VI). The cohort was 47% female, and the mean age was 49.7 years (range, 15–86 years). The majority of the cohort had early-stage MF (stage IA or IB). There were more cases of SS in the SoC cohort than the non-SoC cohort (Table). Only 5 photographs had discrepancies and required discussion among the reviewers to achieve consensus.

Regarding morphologic characteristics in active lesions (Figure 1), scale was present in almost all patients (99% in SoC, 94% in non-SoC). Erythema was present in nearly all non-SoC patients (94%) but only in 69% of SoC patients (P=.003). Poikiloderma also was found to be present at higher frequencies in non-SoC patients compared with SoC patients (19% and 4%, respectively [P=.008]). However, hyperpigmentation (80% vs 39%), lichenification (43% vs 17%), and silver hue (25% vs 3%) were more common in SoC patients than non-SoC patients (P<.05). There were no significant differences in the remaining features, including hypopigmentation (39% vs 25%), dyschromia (24% vs 19%), violaceous color (44% vs 25%), atrophy (11% vs 22%), alopecia (23% vs 31%), and ulceration (16% vs 8%) between SoC and non-SoC patients (P>.05). Photographs of MF in patients with SoC can be seen in Figure 2.

Posttreatment (nonactive) photographs were available for 26 patients (6 non-SoC, 20 SoC). We found that across all FST groups, hyperpigmentation was more common than hypopigmentation in areas of previously active disease. Statistical analysis was not completed given that few non-SoC photographs were available for comparison.

Comment

This qualitative review demonstrates the heterogeneity of MF/SS in SoC patients and that these conditions do not present in this population with the classic erythematous patches and plaques found in non-SoC patients. We found that hyperpigmentation, lichenification, and silver hue were present at higher rates in patients with FSTs IV to VI compared to those with FSTs I to III, which had higher rates of erythema and poikiloderma. Familiarity with these morphologic features along with increased exposure to clinical photographs of MF/SS in SoC patients will aid in the visual recognition required for this diagnosis, since erythema is harder to identify in darker skin types. Recognizing the unique findings of MF in patients with SoC as well as in patients with lighter skin types will enable earlier diagnosis and treatment of MF/SS across all skin types. If MF is diagnosed and treated early, life expectancy is similar to that of patients without MF.¹³ However, the 5-year survival rate for advanced-stage MF/SS is 52% across all skin types, and studies have found that Black patients with advanced-stage disease have worse outcomes despite accounting for demographic factors and tumor stage.^14,15 Given the worse outcomes in SoC patients with advanced-stage MF/SS, earlier diagnosis could help address this disparity.^8,13,14 Similar morphologic features could be used in diagnosing other inflammatory conditions; studies have shown that the lack of recognition of erythema in Black children has led to delayed diagnosis of atopic dermatitis and subsequent inadequate treatment.^16,17

The morphologic presentation of MF/SS in SoC patients also can influence an optimal treatment plan for this population. Hypopigmented MF responds better to phototherapy than hyperpigmented MF, as phototherapy has been shown to have decreased efficacy with increasing FST.¹⁸ Therefore, for patients with FSTs IV to VI, topical agents such as nitrogen mustard or bexarotene may be more suitable treatment options, as the efficacy of these treatments is independent of skin color.⁸ However, nitrogen mustard commonly leads to postinflammatory hyperpigmentation, and topical bexarotene may lead to erythema or irritation; therefore, providers must counsel patients on these possible side effects. For refractory disease, adjunct systemic treatments such as oral bexarotene, subcutaneous interferon, methotrexate, or radiation therapy may be considered.⁸

In addition to aiding in the prompt diagnosis and treatment of MF/SS in SoC patients, our findings may be used to better assess the extent of disease and distinguish between active MF/SS lesions vs xerosis cutis or residual dyschromia from previously treated lesions. It is important to note that these morphologic features must be taken into account with a complete history and work-up. The differential diagnosis of MF/SS includes conditions such as atopic dermatitis, psoriasis, tinea corporis, and drug reactions, which may have similar morphology in SoC.¹⁹

Limitations of our study include the single-center design and the use of photographs instead of in-person examination; however, our cutaneous lymphoma clinic serves a diverse patient population, and our 3 reviewers rated the photographs independently. Discussion amongst the reviewers to address discrepancies was only required for 5 photographs, indicating the high inter-reviewer reliability. Additionally, the original purpose of FST was to assess for the propensity of the skin to burn when undergoing phototherapy, not to serve as a marker for skin color. We recommend trainees and clinicians be mindful about the purpose of FST and to use inclusive language (eg, using the terms skin irritation, skin tenderness, or skin becoming darker from the sun instead of tanning) when determining FST in darker-skinned individuals.²⁰ Future directions include examining if certain treatments are associated with prolonged dyschromia.

Conclusion

In our single-institution retrospective study, we found differences in the morphologic presentation of MF/SS in SoC patients vs non-SoC patients. While erythema is a common feature in non-SoC patients, clinical features of hyperpigmentation, lichenification, and silver hue should be carefully evaluated in the diagnosis of MF/SS in SoC patients. Knowledge of the heterogenous presentation of MF/SS in patients with SoC allows for expedited diagnosis and treatment, leading to better clinical outcomes. Valuable resources, including Taylor and Kelly’s Dermatology for Skin of Color, the Skin of Color Society, and VisualDx educate providers on how dermatologic conditions present in darker skin types. However, there is still work to be done to enhance diversity in educational resources in order to provide equitable care to patients of all skin types.

Mycosis fungoides (MF) and Sézary syndrome (SS) are non-Hodgkin T-cell lymphomas that make up the majority of cutaneous T-cell lymphomas. These conditions commonly affect Black patients, with an incidence rate of 12.6 cases of cutaneous T-cell lymphomas per million individuals vs 9.8 per million individuals in non–skin of color (SoC) patients.¹ However, educational resources tend to focus on the clinical manifestations of MF/SS in lighter skin types, describing MF as erythematous patches, plaques, or tumors presenting in non–sun-exposed areas of the skin and SS as generalized erythroderma.² Skin of color, comprised of Fitzpatrick skin types (FSTs) IV to VI,³ is poorly represented across dermatology textbooks,^4,5 medical student resources,⁶ and peer-reviewed publications,⁷ raising awareness for the need to address this disparity.

Skin of color patients with MF/SS display variable morphologies, including features such as hyperpigmentation and hypopigmentation,⁸ the latter being exceedingly rare in non-SoC patients.⁹ Familiarity with these differences among providers is essential to allow for equitable diagnosis and treatment across all skin types, especially in light of data predicting that by 2044 more than 50% of the US population will be people of color.¹⁰ Patients with SoC are of many ethnic and racial backgrounds, including Black, Hispanic, American Indian, Pacific Islander, and Asian.¹¹

Along with morphologic differences, there also are several racial disparities in the prognosis and survival of patients with MF/SS. Black patients diagnosed with MF present with greater body surface area affected, and Black women with MF have reduced survival rates compared to their White counterparts.¹² Given these racial disparities in survival and representation in educational resources, we aimed to quantify the frequency of various morphologic characteristics of MF/SS in patients with SoC vs non-SoC patients to facilitate better recognition of early MF/SS in SoC patients by medical providers.

Methods

We performed a retrospective chart review following approval from the institutional review board at Northwestern University (Chicago, Illinois). We identified all patients with FSTs IV to VI and biopsy-proven MF/SS who had been clinically photographed in our clinic from January 1998 to December 2019. Only photographs that were high quality enough to review morphologic features were included in our review. Fitzpatrick skin type was determined based on electronic medical record documentation. If photographs were available from multiple visits for the same patient, only those showing posttreatment nonactive lesions were included. Additionally, 36 patients with FSTs I to III (non-SoC) and biopsy-proven MF/SS were included in our review as a comparison with the SoC cohort. The primary outcomes for this study included the presence of scale, erythema, hyperpigmentation, hypopigmentation, violaceous color, lichenification, silver hue, dyschromia, alopecia, poikiloderma, atrophy, and ulceration in active lesions. Dyschromia was defined by the presence of both hypopigmentation and hyperpigmentation. Poikiloderma was defined by hypopigmentation and hyperpigmentation, telangiectasia, and atrophy. Secondary outcomes included evaluation of those same characteristics in posttreatment nonactive lesions. All photographs were independently assessed by 3 authors (M.L.E., C.J.W., J.M.M.), and discrepancies were resolved by further review of the photograph in question and discussion.

Statistical Analysis—Summary statistics were applied to describe demographic and clinical characteristics. The χ² test was used for categorical variables. Results achieving P<.05 were considered statistically significant.

Results

We reviewed photographs of 111 patients across all skin types (8, FST I; 12, FST II; 16, FST III; 17, FST IV; 44, FST V; 14, FST VI). The cohort was 47% female, and the mean age was 49.7 years (range, 15–86 years). The majority of the cohort had early-stage MF (stage IA or IB). There were more cases of SS in the SoC cohort than the non-SoC cohort (Table). Only 5 photographs had discrepancies and required discussion among the reviewers to achieve consensus.

Regarding morphologic characteristics in active lesions (Figure 1), scale was present in almost all patients (99% in SoC, 94% in non-SoC). Erythema was present in nearly all non-SoC patients (94%) but only in 69% of SoC patients (P=.003). Poikiloderma also was found to be present at higher frequencies in non-SoC patients compared with SoC patients (19% and 4%, respectively [P=.008]). However, hyperpigmentation (80% vs 39%), lichenification (43% vs 17%), and silver hue (25% vs 3%) were more common in SoC patients than non-SoC patients (P<.05). There were no significant differences in the remaining features, including hypopigmentation (39% vs 25%), dyschromia (24% vs 19%), violaceous color (44% vs 25%), atrophy (11% vs 22%), alopecia (23% vs 31%), and ulceration (16% vs 8%) between SoC and non-SoC patients (P>.05). Photographs of MF in patients with SoC can be seen in Figure 2.

Posttreatment (nonactive) photographs were available for 26 patients (6 non-SoC, 20 SoC). We found that across all FST groups, hyperpigmentation was more common than hypopigmentation in areas of previously active disease. Statistical analysis was not completed given that few non-SoC photographs were available for comparison.

Comment

This qualitative review demonstrates the heterogeneity of MF/SS in SoC patients and that these conditions do not present in this population with the classic erythematous patches and plaques found in non-SoC patients. We found that hyperpigmentation, lichenification, and silver hue were present at higher rates in patients with FSTs IV to VI compared to those with FSTs I to III, which had higher rates of erythema and poikiloderma. Familiarity with these morphologic features along with increased exposure to clinical photographs of MF/SS in SoC patients will aid in the visual recognition required for this diagnosis, since erythema is harder to identify in darker skin types. Recognizing the unique findings of MF in patients with SoC as well as in patients with lighter skin types will enable earlier diagnosis and treatment of MF/SS across all skin types. If MF is diagnosed and treated early, life expectancy is similar to that of patients without MF.¹³ However, the 5-year survival rate for advanced-stage MF/SS is 52% across all skin types, and studies have found that Black patients with advanced-stage disease have worse outcomes despite accounting for demographic factors and tumor stage.^14,15 Given the worse outcomes in SoC patients with advanced-stage MF/SS, earlier diagnosis could help address this disparity.^8,13,14 Similar morphologic features could be used in diagnosing other inflammatory conditions; studies have shown that the lack of recognition of erythema in Black children has led to delayed diagnosis of atopic dermatitis and subsequent inadequate treatment.^16,17

The morphologic presentation of MF/SS in SoC patients also can influence an optimal treatment plan for this population. Hypopigmented MF responds better to phototherapy than hyperpigmented MF, as phototherapy has been shown to have decreased efficacy with increasing FST.¹⁸ Therefore, for patients with FSTs IV to VI, topical agents such as nitrogen mustard or bexarotene may be more suitable treatment options, as the efficacy of these treatments is independent of skin color.⁸ However, nitrogen mustard commonly leads to postinflammatory hyperpigmentation, and topical bexarotene may lead to erythema or irritation; therefore, providers must counsel patients on these possible side effects. For refractory disease, adjunct systemic treatments such as oral bexarotene, subcutaneous interferon, methotrexate, or radiation therapy may be considered.⁸

In addition to aiding in the prompt diagnosis and treatment of MF/SS in SoC patients, our findings may be used to better assess the extent of disease and distinguish between active MF/SS lesions vs xerosis cutis or residual dyschromia from previously treated lesions. It is important to note that these morphologic features must be taken into account with a complete history and work-up. The differential diagnosis of MF/SS includes conditions such as atopic dermatitis, psoriasis, tinea corporis, and drug reactions, which may have similar morphology in SoC.¹⁹

Limitations of our study include the single-center design and the use of photographs instead of in-person examination; however, our cutaneous lymphoma clinic serves a diverse patient population, and our 3 reviewers rated the photographs independently. Discussion amongst the reviewers to address discrepancies was only required for 5 photographs, indicating the high inter-reviewer reliability. Additionally, the original purpose of FST was to assess for the propensity of the skin to burn when undergoing phototherapy, not to serve as a marker for skin color. We recommend trainees and clinicians be mindful about the purpose of FST and to use inclusive language (eg, using the terms skin irritation, skin tenderness, or skin becoming darker from the sun instead of tanning) when determining FST in darker-skinned individuals.²⁰ Future directions include examining if certain treatments are associated with prolonged dyschromia.

Conclusion

In our single-institution retrospective study, we found differences in the morphologic presentation of MF/SS in SoC patients vs non-SoC patients. While erythema is a common feature in non-SoC patients, clinical features of hyperpigmentation, lichenification, and silver hue should be carefully evaluated in the diagnosis of MF/SS in SoC patients. Knowledge of the heterogenous presentation of MF/SS in patients with SoC allows for expedited diagnosis and treatment, leading to better clinical outcomes. Valuable resources, including Taylor and Kelly’s Dermatology for Skin of Color, the Skin of Color Society, and VisualDx educate providers on how dermatologic conditions present in darker skin types. However, there is still work to be done to enhance diversity in educational resources in order to provide equitable care to patients of all skin types.

Treatment of systemic juvenile idiopathic arthritis (sJIA) should emphasize early use of conventional synthetic and biologic disease-modifying antirheumatic drugs (DMARDs), compared with the previous reliance on NSAIDs and glucocorticoids, according to new guidelines from the American College of Rheumatology. The recently published 2021 guidelines focus on therapeutic approaches for oligoarthritis, temporomandibular joint (TMJ) arthritis, and sJIA.

“Systemic JIA should be treated early with biologics to rapidly bring disease under control and to avoid long-term use of glucocorticoids,” Karen Onel, MD, chief of the division of pediatric rheumatology at Weill Cornell Medicine, New York, and lead author of the guidelines, told this news organization. “Unfortunately, biologics can and are frequently denied for first-line use. For this reason, the guidelines are critically important as they demonstrate that first-line use of biologics are standard of care for the treatment of sJIA.”

The new publication is the second part of the ACR’s process to update JIA guidelines that began in 2017 and complements the release in 2019 of guidelines on the management of nonsystemic polyarthritis, sacroiliitis, and enthesitis, as well as a separate guidance on JIA-associated uveitis. The new guidelines include a second publication focused on nonpharmacologic therapies, medication monitoring, immunizations, and imaging. Both sets of guidelines grew out of a 15-member panel that included young adults with JIA and caregivers of children with JIA, and which required at least 70% agreement on recommendations.

“Though the scope of the two guidelines differed, one thing they had in common is the recognition of the importance of shared decision-making with the patient/caregiver,” Dr. Onel said. “Not every decision will be appropriate for every patient, which is why it was so instrumental to receive input from both patients and caregivers when creating these recommendations.”
 

Oligoarticular and TMJ arthritis

Oligoarticular and TMJ arthritis have similar recommendations, beginning with NSAIDs conditionally recommended and intra-articular glucocorticoids (IAGCs) strongly recommended as part of initial therapy. For oligoarticular arthritis, the guidelines specifically include a strong recommendation of triamcinolone hexacetonide as the preferred agent; no preferred agent is recommended for TMJ arthritis.

“The one thing that the panel was unanimous about was the use of triamcinolone hexacetonide for intra-articular steroid injections in oligoarticular kids,” Susan Shenoi, MBBS, MS, an associate professor and clinical director of pediatric rheumatology at Seattle Children’s Hospital and Research Center, said in an interview. “Triamcinolone hexacetonide has not been available recently, and through advocacy efforts, there is now a pathway to get that medication,” added Dr. Shenoi, a coauthor on the guidelines.

Dr. Onel said that “triamcinolone hexacetonide has been shown to be superior to alternative injectable glucocorticoids in achieving and maintaining remission in children with JIA,” but its unavailability meant physicians had to consider less effective, more potent, or more costly alternatives.” To address the shortage, “the FDA allowed the importation of one particular formulation of triamcinolone hexacetonide [Hexatrione 2%] specifically for joint injections in patients with JIA.”

The guidelines conditionally recommend against oral glucocorticoids for initial therapy for both oligoarticular and TMJ arthritis. In fact, throughout the guidelines it’s clear that the authors emphasize using steroids as little as possible, Dr. Shenoi said.

“Steroids are great anti-inflammatories, but in kids we worry about the long-term effects on growth and metabolism, and now we have many more DMARDs available,” Dr. Shenoi said.

The guidelines strongly recommend conventional synthetic DMARDs for patients with either of these diseases who cannot tolerate or do not respond to NSAIDs or IAGCs, with methotrexate conditionally recommended over leflunomide (Arava) for TMJ and over leflunomide, sulfasalazine (Azulfidine, Sulfazine), and hydroxychloroquine, respectively, for oligoarticular arthritis.

“NSAIDs remain widely used despite evidence supporting early use of DMARDs,” Dr. Onel said. “NSAIDs are readily available and familiar; however, they will not prevent disease progression. These guidelines should encourage short courses of NSAIDs only.”

If patients do not respond to or cannot tolerate NSAIDs, IAGCs, and at least one conventional DMARD, the guidelines strongly recommend a biologic DMARD for oligoarticular arthritis and conditionally recommend one for TMJ arthritis, without any preferences to the specific agent.

The guidelines also advise using validated disease activity measures to guide treatment decisions.

“The most important thing when you’re looking at these patients is to determine, do they have active disease or not?” Dr. Shenoi said. “If they have active disease, then you really want to step up therapy.” Using the relatively new concept of treat-to-target, Dr. Shenoi added that a crucial part of shared decision-making with the family is identifying the most appropriate target for that family “and then really trying hard to achieve that target.”

The guidelines also list risk factors for poor outcome that can be used to guide treatment decisions.

“Specific involvement of key joints, such as TMJ, wrist, sacroiliac, hip, and ankle, and other features were considered reasonable justification for early escalation of therapy,” Dr. Onel said. Other features included presence of erosive disease or enthesitis, delay in diagnosis, elevated levels of inflammation markers, and symmetric disease. “Moving quickly may be needed for a patient who is rapidly worsening, while moving slower may be appropriate for somebody who has improved substantially, but not fully.”

Systemic JIA with and without macrophage activation syndrome

For systemic JIA without macrophage activation syndrome (MAS), the guidelines similarly advise against oral glucocorticoids as initial monotherapy while conditionally recommending NSAIDs for initial monotherapy. Where the guidelines differ most from those for oligoarticular and TMJ arthritis is in progression of DMARD use, with a strong recommendation against conventional synthetic DMARDs as an initial monotherapy and interleukin-1 and IL-6 inhibitors conditionally recommended for initial monotherapy.

For patients who don’t adequately respond to NSAIDs or glucocorticoids, IL-1 and IL-6 inhibitors are strongly recommended over a single or combination of conventional DMARDs. Residual arthritis or an incomplete response to IL-1 or IL-6 inhibitors should lead next to biologic or conventional DMARDs instead of long-term glucocorticoids.

For patients with MAS, the guidelines conditionally recommend IL-1 and IL-6 inhibitors over calcineurin inhibitor monotherapy to reach inactive disease and MAS resolution, with glucocorticoids conditionally recommended in initial treatment. Again, however, for patients with incomplete responses to IL-1 or IL-6 inhibitors or with residual arthritis, the guidelines advise biologic or conventional DMARDs over long-term glucocorticoids.

In patients with sJIA with or without a history of MAS who have inactive disease, practitioners should taper and discontinue glucocorticoids (a strong recommendation). A conditional recommendation for tapering and discontinuing biologic DMARDs follows attainment of inactive disease.

Beyond pharmacology

Although many of the nonpharmacologic recommendations did not have strong evidence based on assessment with Grading of Recommendations Assessment, Development, and Evaluation methodology, consensus was more often the case than not, Dr. Onel said, such as with vaccination.

“There was strong support for the use of immunizations in children with JIA and specific guidance for children with JIA receiving immunosuppression, not on immunosuppression, and children who are underimmunized or unimmunized,” she said. “Although the supportive evidence was very low as per GRADE, panel members were strongly in favor [of immunizations], given risk of infection for immunosuppressed children as well as the preponderance of evidence in similar disease states, such as IBD [inflammatory bowel disease].”

An area with less consensus was whether to check antibody titers for vaccine-preventable childhood infections before beginning immunosuppressive medication, but more panelists opposed the practice than supported it, Dr. Onel said.

“Some panelists felt that the information might be useful for risk management in case of an outbreak or exposure,” she said. “Most believed that screening a fully immunized child was of low benefit and might delay treatment and incur unnecessary cost.”

The process of developing the documents also reveals where the biggest gaps are in research. 

“One of the things that we should strive for in the future is really to do more systematic studies so we have better quality of evidence going forward,” Dr. Shenoi said. Overall, however, the guidelines also reveal the progress made in treatment of JIA.

“We now know some of the key cytokines that are involved in the disease pathogenesis, and we have effective therapies for some of these pathways,” Dr. Shenoi said. “We used to use a lot more toxic medication for systemic JIA, and in past decades, these patients used to be on steroids forever. Now we have targeted therapies, and we have some patients who don’t ever need steroids because people are moving toward targeted therapies and having good results. That’s a huge step forward in the field.”

The research was funded by the ACR. Dr. Shenoi has been a consultant for Pfizer. Dr. Onel disclosed no relevant financial relationships.

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

Treatment of systemic juvenile idiopathic arthritis (sJIA) should emphasize early use of conventional synthetic and biologic disease-modifying antirheumatic drugs (DMARDs), compared with the previous reliance on NSAIDs and glucocorticoids, according to new guidelines from the American College of Rheumatology. The recently published 2021 guidelines focus on therapeutic approaches for oligoarthritis, temporomandibular joint (TMJ) arthritis, and sJIA.

“Systemic JIA should be treated early with biologics to rapidly bring disease under control and to avoid long-term use of glucocorticoids,” Karen Onel, MD, chief of the division of pediatric rheumatology at Weill Cornell Medicine, New York, and lead author of the guidelines, told this news organization. “Unfortunately, biologics can and are frequently denied for first-line use. For this reason, the guidelines are critically important as they demonstrate that first-line use of biologics are standard of care for the treatment of sJIA.”

The new publication is the second part of the ACR’s process to update JIA guidelines that began in 2017 and complements the release in 2019 of guidelines on the management of nonsystemic polyarthritis, sacroiliitis, and enthesitis, as well as a separate guidance on JIA-associated uveitis. The new guidelines include a second publication focused on nonpharmacologic therapies, medication monitoring, immunizations, and imaging. Both sets of guidelines grew out of a 15-member panel that included young adults with JIA and caregivers of children with JIA, and which required at least 70% agreement on recommendations.

“Though the scope of the two guidelines differed, one thing they had in common is the recognition of the importance of shared decision-making with the patient/caregiver,” Dr. Onel said. “Not every decision will be appropriate for every patient, which is why it was so instrumental to receive input from both patients and caregivers when creating these recommendations.”
 

Oligoarticular and TMJ arthritis

Oligoarticular and TMJ arthritis have similar recommendations, beginning with NSAIDs conditionally recommended and intra-articular glucocorticoids (IAGCs) strongly recommended as part of initial therapy. For oligoarticular arthritis, the guidelines specifically include a strong recommendation of triamcinolone hexacetonide as the preferred agent; no preferred agent is recommended for TMJ arthritis.

“The one thing that the panel was unanimous about was the use of triamcinolone hexacetonide for intra-articular steroid injections in oligoarticular kids,” Susan Shenoi, MBBS, MS, an associate professor and clinical director of pediatric rheumatology at Seattle Children’s Hospital and Research Center, said in an interview. “Triamcinolone hexacetonide has not been available recently, and through advocacy efforts, there is now a pathway to get that medication,” added Dr. Shenoi, a coauthor on the guidelines.

Dr. Onel said that “triamcinolone hexacetonide has been shown to be superior to alternative injectable glucocorticoids in achieving and maintaining remission in children with JIA,” but its unavailability meant physicians had to consider less effective, more potent, or more costly alternatives.” To address the shortage, “the FDA allowed the importation of one particular formulation of triamcinolone hexacetonide [Hexatrione 2%] specifically for joint injections in patients with JIA.”

The guidelines conditionally recommend against oral glucocorticoids for initial therapy for both oligoarticular and TMJ arthritis. In fact, throughout the guidelines it’s clear that the authors emphasize using steroids as little as possible, Dr. Shenoi said.

“Steroids are great anti-inflammatories, but in kids we worry about the long-term effects on growth and metabolism, and now we have many more DMARDs available,” Dr. Shenoi said.

The guidelines strongly recommend conventional synthetic DMARDs for patients with either of these diseases who cannot tolerate or do not respond to NSAIDs or IAGCs, with methotrexate conditionally recommended over leflunomide (Arava) for TMJ and over leflunomide, sulfasalazine (Azulfidine, Sulfazine), and hydroxychloroquine, respectively, for oligoarticular arthritis.

“NSAIDs remain widely used despite evidence supporting early use of DMARDs,” Dr. Onel said. “NSAIDs are readily available and familiar; however, they will not prevent disease progression. These guidelines should encourage short courses of NSAIDs only.”

If patients do not respond to or cannot tolerate NSAIDs, IAGCs, and at least one conventional DMARD, the guidelines strongly recommend a biologic DMARD for oligoarticular arthritis and conditionally recommend one for TMJ arthritis, without any preferences to the specific agent.

The guidelines also advise using validated disease activity measures to guide treatment decisions.

“The most important thing when you’re looking at these patients is to determine, do they have active disease or not?” Dr. Shenoi said. “If they have active disease, then you really want to step up therapy.” Using the relatively new concept of treat-to-target, Dr. Shenoi added that a crucial part of shared decision-making with the family is identifying the most appropriate target for that family “and then really trying hard to achieve that target.”

The guidelines also list risk factors for poor outcome that can be used to guide treatment decisions.

“Specific involvement of key joints, such as TMJ, wrist, sacroiliac, hip, and ankle, and other features were considered reasonable justification for early escalation of therapy,” Dr. Onel said. Other features included presence of erosive disease or enthesitis, delay in diagnosis, elevated levels of inflammation markers, and symmetric disease. “Moving quickly may be needed for a patient who is rapidly worsening, while moving slower may be appropriate for somebody who has improved substantially, but not fully.”

Systemic JIA with and without macrophage activation syndrome

For systemic JIA without macrophage activation syndrome (MAS), the guidelines similarly advise against oral glucocorticoids as initial monotherapy while conditionally recommending NSAIDs for initial monotherapy. Where the guidelines differ most from those for oligoarticular and TMJ arthritis is in progression of DMARD use, with a strong recommendation against conventional synthetic DMARDs as an initial monotherapy and interleukin-1 and IL-6 inhibitors conditionally recommended for initial monotherapy.

For patients who don’t adequately respond to NSAIDs or glucocorticoids, IL-1 and IL-6 inhibitors are strongly recommended over a single or combination of conventional DMARDs. Residual arthritis or an incomplete response to IL-1 or IL-6 inhibitors should lead next to biologic or conventional DMARDs instead of long-term glucocorticoids.

For patients with MAS, the guidelines conditionally recommend IL-1 and IL-6 inhibitors over calcineurin inhibitor monotherapy to reach inactive disease and MAS resolution, with glucocorticoids conditionally recommended in initial treatment. Again, however, for patients with incomplete responses to IL-1 or IL-6 inhibitors or with residual arthritis, the guidelines advise biologic or conventional DMARDs over long-term glucocorticoids.

In patients with sJIA with or without a history of MAS who have inactive disease, practitioners should taper and discontinue glucocorticoids (a strong recommendation). A conditional recommendation for tapering and discontinuing biologic DMARDs follows attainment of inactive disease.

Beyond pharmacology

Although many of the nonpharmacologic recommendations did not have strong evidence based on assessment with Grading of Recommendations Assessment, Development, and Evaluation methodology, consensus was more often the case than not, Dr. Onel said, such as with vaccination.

“There was strong support for the use of immunizations in children with JIA and specific guidance for children with JIA receiving immunosuppression, not on immunosuppression, and children who are underimmunized or unimmunized,” she said. “Although the supportive evidence was very low as per GRADE, panel members were strongly in favor [of immunizations], given risk of infection for immunosuppressed children as well as the preponderance of evidence in similar disease states, such as IBD [inflammatory bowel disease].”

An area with less consensus was whether to check antibody titers for vaccine-preventable childhood infections before beginning immunosuppressive medication, but more panelists opposed the practice than supported it, Dr. Onel said.

“Some panelists felt that the information might be useful for risk management in case of an outbreak or exposure,” she said. “Most believed that screening a fully immunized child was of low benefit and might delay treatment and incur unnecessary cost.”

The process of developing the documents also reveals where the biggest gaps are in research. 

“One of the things that we should strive for in the future is really to do more systematic studies so we have better quality of evidence going forward,” Dr. Shenoi said. Overall, however, the guidelines also reveal the progress made in treatment of JIA.

“We now know some of the key cytokines that are involved in the disease pathogenesis, and we have effective therapies for some of these pathways,” Dr. Shenoi said. “We used to use a lot more toxic medication for systemic JIA, and in past decades, these patients used to be on steroids forever. Now we have targeted therapies, and we have some patients who don’t ever need steroids because people are moving toward targeted therapies and having good results. That’s a huge step forward in the field.”

The research was funded by the ACR. Dr. Shenoi has been a consultant for Pfizer. Dr. Onel disclosed no relevant financial relationships.

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

Treatment of systemic juvenile idiopathic arthritis (sJIA) should emphasize early use of conventional synthetic and biologic disease-modifying antirheumatic drugs (DMARDs), compared with the previous reliance on NSAIDs and glucocorticoids, according to new guidelines from the American College of Rheumatology. The recently published 2021 guidelines focus on therapeutic approaches for oligoarthritis, temporomandibular joint (TMJ) arthritis, and sJIA.

“Systemic JIA should be treated early with biologics to rapidly bring disease under control and to avoid long-term use of glucocorticoids,” Karen Onel, MD, chief of the division of pediatric rheumatology at Weill Cornell Medicine, New York, and lead author of the guidelines, told this news organization. “Unfortunately, biologics can and are frequently denied for first-line use. For this reason, the guidelines are critically important as they demonstrate that first-line use of biologics are standard of care for the treatment of sJIA.”

The new publication is the second part of the ACR’s process to update JIA guidelines that began in 2017 and complements the release in 2019 of guidelines on the management of nonsystemic polyarthritis, sacroiliitis, and enthesitis, as well as a separate guidance on JIA-associated uveitis. The new guidelines include a second publication focused on nonpharmacologic therapies, medication monitoring, immunizations, and imaging. Both sets of guidelines grew out of a 15-member panel that included young adults with JIA and caregivers of children with JIA, and which required at least 70% agreement on recommendations.

“Though the scope of the two guidelines differed, one thing they had in common is the recognition of the importance of shared decision-making with the patient/caregiver,” Dr. Onel said. “Not every decision will be appropriate for every patient, which is why it was so instrumental to receive input from both patients and caregivers when creating these recommendations.”
 

Oligoarticular and TMJ arthritis

Oligoarticular and TMJ arthritis have similar recommendations, beginning with NSAIDs conditionally recommended and intra-articular glucocorticoids (IAGCs) strongly recommended as part of initial therapy. For oligoarticular arthritis, the guidelines specifically include a strong recommendation of triamcinolone hexacetonide as the preferred agent; no preferred agent is recommended for TMJ arthritis.

“The one thing that the panel was unanimous about was the use of triamcinolone hexacetonide for intra-articular steroid injections in oligoarticular kids,” Susan Shenoi, MBBS, MS, an associate professor and clinical director of pediatric rheumatology at Seattle Children’s Hospital and Research Center, said in an interview. “Triamcinolone hexacetonide has not been available recently, and through advocacy efforts, there is now a pathway to get that medication,” added Dr. Shenoi, a coauthor on the guidelines.

Dr. Onel said that “triamcinolone hexacetonide has been shown to be superior to alternative injectable glucocorticoids in achieving and maintaining remission in children with JIA,” but its unavailability meant physicians had to consider less effective, more potent, or more costly alternatives.” To address the shortage, “the FDA allowed the importation of one particular formulation of triamcinolone hexacetonide [Hexatrione 2%] specifically for joint injections in patients with JIA.”

The guidelines conditionally recommend against oral glucocorticoids for initial therapy for both oligoarticular and TMJ arthritis. In fact, throughout the guidelines it’s clear that the authors emphasize using steroids as little as possible, Dr. Shenoi said.

“Steroids are great anti-inflammatories, but in kids we worry about the long-term effects on growth and metabolism, and now we have many more DMARDs available,” Dr. Shenoi said.

The guidelines strongly recommend conventional synthetic DMARDs for patients with either of these diseases who cannot tolerate or do not respond to NSAIDs or IAGCs, with methotrexate conditionally recommended over leflunomide (Arava) for TMJ and over leflunomide, sulfasalazine (Azulfidine, Sulfazine), and hydroxychloroquine, respectively, for oligoarticular arthritis.

“NSAIDs remain widely used despite evidence supporting early use of DMARDs,” Dr. Onel said. “NSAIDs are readily available and familiar; however, they will not prevent disease progression. These guidelines should encourage short courses of NSAIDs only.”

If patients do not respond to or cannot tolerate NSAIDs, IAGCs, and at least one conventional DMARD, the guidelines strongly recommend a biologic DMARD for oligoarticular arthritis and conditionally recommend one for TMJ arthritis, without any preferences to the specific agent.

The guidelines also advise using validated disease activity measures to guide treatment decisions.

“The most important thing when you’re looking at these patients is to determine, do they have active disease or not?” Dr. Shenoi said. “If they have active disease, then you really want to step up therapy.” Using the relatively new concept of treat-to-target, Dr. Shenoi added that a crucial part of shared decision-making with the family is identifying the most appropriate target for that family “and then really trying hard to achieve that target.”

The guidelines also list risk factors for poor outcome that can be used to guide treatment decisions.

“Specific involvement of key joints, such as TMJ, wrist, sacroiliac, hip, and ankle, and other features were considered reasonable justification for early escalation of therapy,” Dr. Onel said. Other features included presence of erosive disease or enthesitis, delay in diagnosis, elevated levels of inflammation markers, and symmetric disease. “Moving quickly may be needed for a patient who is rapidly worsening, while moving slower may be appropriate for somebody who has improved substantially, but not fully.”

Systemic JIA with and without macrophage activation syndrome

For systemic JIA without macrophage activation syndrome (MAS), the guidelines similarly advise against oral glucocorticoids as initial monotherapy while conditionally recommending NSAIDs for initial monotherapy. Where the guidelines differ most from those for oligoarticular and TMJ arthritis is in progression of DMARD use, with a strong recommendation against conventional synthetic DMARDs as an initial monotherapy and interleukin-1 and IL-6 inhibitors conditionally recommended for initial monotherapy.

For patients who don’t adequately respond to NSAIDs or glucocorticoids, IL-1 and IL-6 inhibitors are strongly recommended over a single or combination of conventional DMARDs. Residual arthritis or an incomplete response to IL-1 or IL-6 inhibitors should lead next to biologic or conventional DMARDs instead of long-term glucocorticoids.

For patients with MAS, the guidelines conditionally recommend IL-1 and IL-6 inhibitors over calcineurin inhibitor monotherapy to reach inactive disease and MAS resolution, with glucocorticoids conditionally recommended in initial treatment. Again, however, for patients with incomplete responses to IL-1 or IL-6 inhibitors or with residual arthritis, the guidelines advise biologic or conventional DMARDs over long-term glucocorticoids.

In patients with sJIA with or without a history of MAS who have inactive disease, practitioners should taper and discontinue glucocorticoids (a strong recommendation). A conditional recommendation for tapering and discontinuing biologic DMARDs follows attainment of inactive disease.

Beyond pharmacology

Although many of the nonpharmacologic recommendations did not have strong evidence based on assessment with Grading of Recommendations Assessment, Development, and Evaluation methodology, consensus was more often the case than not, Dr. Onel said, such as with vaccination.

“There was strong support for the use of immunizations in children with JIA and specific guidance for children with JIA receiving immunosuppression, not on immunosuppression, and children who are underimmunized or unimmunized,” she said. “Although the supportive evidence was very low as per GRADE, panel members were strongly in favor [of immunizations], given risk of infection for immunosuppressed children as well as the preponderance of evidence in similar disease states, such as IBD [inflammatory bowel disease].”

An area with less consensus was whether to check antibody titers for vaccine-preventable childhood infections before beginning immunosuppressive medication, but more panelists opposed the practice than supported it, Dr. Onel said.

“Some panelists felt that the information might be useful for risk management in case of an outbreak or exposure,” she said. “Most believed that screening a fully immunized child was of low benefit and might delay treatment and incur unnecessary cost.”

The process of developing the documents also reveals where the biggest gaps are in research. 

“One of the things that we should strive for in the future is really to do more systematic studies so we have better quality of evidence going forward,” Dr. Shenoi said. Overall, however, the guidelines also reveal the progress made in treatment of JIA.

“We now know some of the key cytokines that are involved in the disease pathogenesis, and we have effective therapies for some of these pathways,” Dr. Shenoi said. “We used to use a lot more toxic medication for systemic JIA, and in past decades, these patients used to be on steroids forever. Now we have targeted therapies, and we have some patients who don’t ever need steroids because people are moving toward targeted therapies and having good results. That’s a huge step forward in the field.”

The research was funded by the ACR. Dr. Shenoi has been a consultant for Pfizer. Dr. Onel disclosed no relevant financial relationships.

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

The rate of recurrence of the rare but aggressive skin cancer Merkel cell carcinoma (MCC) is markedly higher than that for invasive melanoma, squamous cell carcinoma, or basal cell carcinoma, and more than half of all patients with stage IV disease will have a recurrence within 1 year of definitive therapy, results of a new study show.

A study of 618 patients with MCC who were enrolled in a Seattle-based data repository shows that among all patients the 5-year recurrence rate was 40%. The risk of recurrence within the first year was 11% for patients with pathologic stage I disease, 33% for those with stage IIA/IIB disease, 45% for those with stage IIIB disease, and 58% for patients with pathologic stage IV MCC.

Approximately 95% of all recurrences happened within 3 years of the initial diagnosis, report Aubriana McEvoy, MD, from the University of Washington in Seattle, and colleagues.

“This cohort study indicates that the highest yield (and likely most cost-effective) time period for detecting MCC recurrence is 1-3 years after diagnosis,” they write in a study published online in JAMA Dermatology.

The estimated annual incidence of MCC in the United States in 2018 was 2,000 according to the American Cancer Society. The annual incidence rate is rising rapidly, however, and is estimated to reach 3,284 by 2025, McEvoy and colleagues write.

Although MCC is known to have high recurrence rates and is associated with a higher mortality rate than malignant melanoma, recurrence rate data are not captured by either the Surveillance, Epidemiology, and End Results (SEER) database or by the National Cancer Database. As a result, estimates of recurrence rates with MCC have been all over the map, ranging from 27% to 77%, depending on the population studied.

But as senior author Paul Nghiem, MD, PhD, professor and chair of dermatology at the University of Washington, Seattle, told this news organization, recurrence rates over time in their study were remarkably consistent.

“The biggest surprise to me was that, when we broke our nearly 20-year cohort into three 5- or 6-year chunks, every one of the groups had a 40% recurrence rate, within 1%. So we feel really confident that’s the right number,” he said.

Dr. Nghiem and colleagues report that, in contrast to patients with MCC, approximately 19% of patients with melanoma will have a recurrence, as will an estimated 5%-9% of patients with squamous cell carcinoma and 1%-10% of patients with basal cell carcinoma.

The fact that recurrence rates of MCC have remained stable over time despite presumed improvements in definitive therapy is disappointing, Dr. Nghiem acknowledged. He noted that it’s still unclear whether immunotherapy will have the same dramatic effect on survival rates for patients with MCC as it has for patients with malignant melanoma.

The high recurrence rates following definitive therapy for patients with early-stage disease was a novel finding, commented Shawn Demehri, MD, PhD, director of the high-risk skin cancer clinic at Massachusetts General Hospital in Boston.

“When you’re looking at patients with stage I or stage II, and they have definitive surgery but still have recurrences at a higher rate than melanoma, it brings home the point that these are among the most aggressive tumors of the skin,” he said in an interview.

The high recurrence rates seen with MCC are attributable to a variety of factors.

“This is a rare cancer of mostly older individuals with a lot of comorbidities, and also a cancer that, even though it is a primary cancer, might be detected a little later than even a melanoma primary tumor, just because of the nature of the neuroendocrine tumor cells,” he said.

Dr. Demehri was not involved in the study.
 

Prospective cohort

The study cohort consisted of 618 patients with MCC. The median age of the patients was 69, and 227 (37%) were women. The patients were enrolled within 6 months of their diagnosis in the prospective data repository from 2003 through 2019. Of this group, 223 had a recurrence of MCC.

As noted, there was a high risk of recurrence within 1 year, ranging from 11% for patients with pathologic stage I tumors to 58% for those with stage IV disease, and 95% of all recurrences occurred within 3 years of definitive therapy.

To get a better picture of the natural history of MCC recurrence, the investigators studied a cohort of patients with pathologically confirmed MCC who were prospectively enrolled from January 2003 through April 2019 in a data repository maintained at the University of Washington.

In addition to disease stage, factors associated with increased recurrence risk in univariable analyses include immunosuppression (hazard ratio, 2.4; P < .001), male sex (HR, 1.9; P < .001), known primary lesion among patients with clinically detectable nodal disease (HR, 2.3; P = .001), and older age (HR, 1.1, P = .06 for each 10-year increase).

Of the 187 patients in the cohort who died during the study, 121 died from MCC. At 4 years after diagnosis, MCC-specific survival rates were 95% for patients with pathologic stage I, 84% with stage IIA/IIB, 80% with stage IIIA, 58% with stage IIIB, and 41% with stage IV.

Evidence supports close monitoring within the first 3 years for patients with stage I-II MCC. Local recurrence within or adjacent to the primary tumor scar was associated with a 5-year MCC-specific survival rate of 85%, compared with 88% of patients with stage I or II disease who did not have recurrences.

“Because more than 90% of MCC recurrences arise within 3 years, it is appropriate to adjust surveillance intensity accordingly. Stage- and time-specific recurrence data can assist in appropriately focusing surveillance resources on patients and time intervals in which recurrence risk is highest,” the authors wrote.

“If you’re a patient who has not had your cancer come back for 3, 4, or 5 years, you can really cut down on the intensity of your follow-up and scans,” Dr. Nghiem said.

“We do now have two excellent blood tests that are working very well, and we have really good ways to detect the cancer coming back early, and that’s important, because we have potentially curative therapies that tend to work better if you catch the cancer early,” he said.

The study was supported by the National Institutes of Health. Dr. Nghiem reported personal fees and institutional support outside the study from several companies and patents for Merkel cell therapies with the University of Washington and University of Denmark. Dr. Demehri has disclosed no relevant financial relationships.

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

The rate of recurrence of the rare but aggressive skin cancer Merkel cell carcinoma (MCC) is markedly higher than that for invasive melanoma, squamous cell carcinoma, or basal cell carcinoma, and more than half of all patients with stage IV disease will have a recurrence within 1 year of definitive therapy, results of a new study show.

A study of 618 patients with MCC who were enrolled in a Seattle-based data repository shows that among all patients the 5-year recurrence rate was 40%. The risk of recurrence within the first year was 11% for patients with pathologic stage I disease, 33% for those with stage IIA/IIB disease, 45% for those with stage IIIB disease, and 58% for patients with pathologic stage IV MCC.

Approximately 95% of all recurrences happened within 3 years of the initial diagnosis, report Aubriana McEvoy, MD, from the University of Washington in Seattle, and colleagues.

“This cohort study indicates that the highest yield (and likely most cost-effective) time period for detecting MCC recurrence is 1-3 years after diagnosis,” they write in a study published online in JAMA Dermatology.

The estimated annual incidence of MCC in the United States in 2018 was 2,000 according to the American Cancer Society. The annual incidence rate is rising rapidly, however, and is estimated to reach 3,284 by 2025, McEvoy and colleagues write.

Although MCC is known to have high recurrence rates and is associated with a higher mortality rate than malignant melanoma, recurrence rate data are not captured by either the Surveillance, Epidemiology, and End Results (SEER) database or by the National Cancer Database. As a result, estimates of recurrence rates with MCC have been all over the map, ranging from 27% to 77%, depending on the population studied.

But as senior author Paul Nghiem, MD, PhD, professor and chair of dermatology at the University of Washington, Seattle, told this news organization, recurrence rates over time in their study were remarkably consistent.

“The biggest surprise to me was that, when we broke our nearly 20-year cohort into three 5- or 6-year chunks, every one of the groups had a 40% recurrence rate, within 1%. So we feel really confident that’s the right number,” he said.

Dr. Nghiem and colleagues report that, in contrast to patients with MCC, approximately 19% of patients with melanoma will have a recurrence, as will an estimated 5%-9% of patients with squamous cell carcinoma and 1%-10% of patients with basal cell carcinoma.

The fact that recurrence rates of MCC have remained stable over time despite presumed improvements in definitive therapy is disappointing, Dr. Nghiem acknowledged. He noted that it’s still unclear whether immunotherapy will have the same dramatic effect on survival rates for patients with MCC as it has for patients with malignant melanoma.

The high recurrence rates following definitive therapy for patients with early-stage disease was a novel finding, commented Shawn Demehri, MD, PhD, director of the high-risk skin cancer clinic at Massachusetts General Hospital in Boston.

“When you’re looking at patients with stage I or stage II, and they have definitive surgery but still have recurrences at a higher rate than melanoma, it brings home the point that these are among the most aggressive tumors of the skin,” he said in an interview.

The high recurrence rates seen with MCC are attributable to a variety of factors.

“This is a rare cancer of mostly older individuals with a lot of comorbidities, and also a cancer that, even though it is a primary cancer, might be detected a little later than even a melanoma primary tumor, just because of the nature of the neuroendocrine tumor cells,” he said.

Dr. Demehri was not involved in the study.
 

Prospective cohort

The study cohort consisted of 618 patients with MCC. The median age of the patients was 69, and 227 (37%) were women. The patients were enrolled within 6 months of their diagnosis in the prospective data repository from 2003 through 2019. Of this group, 223 had a recurrence of MCC.

As noted, there was a high risk of recurrence within 1 year, ranging from 11% for patients with pathologic stage I tumors to 58% for those with stage IV disease, and 95% of all recurrences occurred within 3 years of definitive therapy.

To get a better picture of the natural history of MCC recurrence, the investigators studied a cohort of patients with pathologically confirmed MCC who were prospectively enrolled from January 2003 through April 2019 in a data repository maintained at the University of Washington.

In addition to disease stage, factors associated with increased recurrence risk in univariable analyses include immunosuppression (hazard ratio, 2.4; P < .001), male sex (HR, 1.9; P < .001), known primary lesion among patients with clinically detectable nodal disease (HR, 2.3; P = .001), and older age (HR, 1.1, P = .06 for each 10-year increase).

Of the 187 patients in the cohort who died during the study, 121 died from MCC. At 4 years after diagnosis, MCC-specific survival rates were 95% for patients with pathologic stage I, 84% with stage IIA/IIB, 80% with stage IIIA, 58% with stage IIIB, and 41% with stage IV.

Evidence supports close monitoring within the first 3 years for patients with stage I-II MCC. Local recurrence within or adjacent to the primary tumor scar was associated with a 5-year MCC-specific survival rate of 85%, compared with 88% of patients with stage I or II disease who did not have recurrences.

“Because more than 90% of MCC recurrences arise within 3 years, it is appropriate to adjust surveillance intensity accordingly. Stage- and time-specific recurrence data can assist in appropriately focusing surveillance resources on patients and time intervals in which recurrence risk is highest,” the authors wrote.

“If you’re a patient who has not had your cancer come back for 3, 4, or 5 years, you can really cut down on the intensity of your follow-up and scans,” Dr. Nghiem said.

“We do now have two excellent blood tests that are working very well, and we have really good ways to detect the cancer coming back early, and that’s important, because we have potentially curative therapies that tend to work better if you catch the cancer early,” he said.

The study was supported by the National Institutes of Health. Dr. Nghiem reported personal fees and institutional support outside the study from several companies and patents for Merkel cell therapies with the University of Washington and University of Denmark. Dr. Demehri has disclosed no relevant financial relationships.

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

The rate of recurrence of the rare but aggressive skin cancer Merkel cell carcinoma (MCC) is markedly higher than that for invasive melanoma, squamous cell carcinoma, or basal cell carcinoma, and more than half of all patients with stage IV disease will have a recurrence within 1 year of definitive therapy, results of a new study show.

A study of 618 patients with MCC who were enrolled in a Seattle-based data repository shows that among all patients the 5-year recurrence rate was 40%. The risk of recurrence within the first year was 11% for patients with pathologic stage I disease, 33% for those with stage IIA/IIB disease, 45% for those with stage IIIB disease, and 58% for patients with pathologic stage IV MCC.

Approximately 95% of all recurrences happened within 3 years of the initial diagnosis, report Aubriana McEvoy, MD, from the University of Washington in Seattle, and colleagues.

“This cohort study indicates that the highest yield (and likely most cost-effective) time period for detecting MCC recurrence is 1-3 years after diagnosis,” they write in a study published online in JAMA Dermatology.

The estimated annual incidence of MCC in the United States in 2018 was 2,000 according to the American Cancer Society. The annual incidence rate is rising rapidly, however, and is estimated to reach 3,284 by 2025, McEvoy and colleagues write.

Although MCC is known to have high recurrence rates and is associated with a higher mortality rate than malignant melanoma, recurrence rate data are not captured by either the Surveillance, Epidemiology, and End Results (SEER) database or by the National Cancer Database. As a result, estimates of recurrence rates with MCC have been all over the map, ranging from 27% to 77%, depending on the population studied.

But as senior author Paul Nghiem, MD, PhD, professor and chair of dermatology at the University of Washington, Seattle, told this news organization, recurrence rates over time in their study were remarkably consistent.

“The biggest surprise to me was that, when we broke our nearly 20-year cohort into three 5- or 6-year chunks, every one of the groups had a 40% recurrence rate, within 1%. So we feel really confident that’s the right number,” he said.

Dr. Nghiem and colleagues report that, in contrast to patients with MCC, approximately 19% of patients with melanoma will have a recurrence, as will an estimated 5%-9% of patients with squamous cell carcinoma and 1%-10% of patients with basal cell carcinoma.

The fact that recurrence rates of MCC have remained stable over time despite presumed improvements in definitive therapy is disappointing, Dr. Nghiem acknowledged. He noted that it’s still unclear whether immunotherapy will have the same dramatic effect on survival rates for patients with MCC as it has for patients with malignant melanoma.

The high recurrence rates following definitive therapy for patients with early-stage disease was a novel finding, commented Shawn Demehri, MD, PhD, director of the high-risk skin cancer clinic at Massachusetts General Hospital in Boston.

“When you’re looking at patients with stage I or stage II, and they have definitive surgery but still have recurrences at a higher rate than melanoma, it brings home the point that these are among the most aggressive tumors of the skin,” he said in an interview.

The high recurrence rates seen with MCC are attributable to a variety of factors.

“This is a rare cancer of mostly older individuals with a lot of comorbidities, and also a cancer that, even though it is a primary cancer, might be detected a little later than even a melanoma primary tumor, just because of the nature of the neuroendocrine tumor cells,” he said.

Dr. Demehri was not involved in the study.
 

Prospective cohort

The study cohort consisted of 618 patients with MCC. The median age of the patients was 69, and 227 (37%) were women. The patients were enrolled within 6 months of their diagnosis in the prospective data repository from 2003 through 2019. Of this group, 223 had a recurrence of MCC.

As noted, there was a high risk of recurrence within 1 year, ranging from 11% for patients with pathologic stage I tumors to 58% for those with stage IV disease, and 95% of all recurrences occurred within 3 years of definitive therapy.

To get a better picture of the natural history of MCC recurrence, the investigators studied a cohort of patients with pathologically confirmed MCC who were prospectively enrolled from January 2003 through April 2019 in a data repository maintained at the University of Washington.

In addition to disease stage, factors associated with increased recurrence risk in univariable analyses include immunosuppression (hazard ratio, 2.4; P < .001), male sex (HR, 1.9; P < .001), known primary lesion among patients with clinically detectable nodal disease (HR, 2.3; P = .001), and older age (HR, 1.1, P = .06 for each 10-year increase).

Of the 187 patients in the cohort who died during the study, 121 died from MCC. At 4 years after diagnosis, MCC-specific survival rates were 95% for patients with pathologic stage I, 84% with stage IIA/IIB, 80% with stage IIIA, 58% with stage IIIB, and 41% with stage IV.

Evidence supports close monitoring within the first 3 years for patients with stage I-II MCC. Local recurrence within or adjacent to the primary tumor scar was associated with a 5-year MCC-specific survival rate of 85%, compared with 88% of patients with stage I or II disease who did not have recurrences.

“Because more than 90% of MCC recurrences arise within 3 years, it is appropriate to adjust surveillance intensity accordingly. Stage- and time-specific recurrence data can assist in appropriately focusing surveillance resources on patients and time intervals in which recurrence risk is highest,” the authors wrote.

“If you’re a patient who has not had your cancer come back for 3, 4, or 5 years, you can really cut down on the intensity of your follow-up and scans,” Dr. Nghiem said.

“We do now have two excellent blood tests that are working very well, and we have really good ways to detect the cancer coming back early, and that’s important, because we have potentially curative therapies that tend to work better if you catch the cancer early,” he said.

The study was supported by the National Institutes of Health. Dr. Nghiem reported personal fees and institutional support outside the study from several companies and patents for Merkel cell therapies with the University of Washington and University of Denmark. Dr. Demehri has disclosed no relevant financial relationships.

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

Updated guidance for health care providers on multisystem inflammatory syndrome in children (MIS-C) recognizes the evolving nature of the disease and offers strategies for pediatric rheumatologists, who also may be asked to recommend treatment for hyperinflammation in children with acute COVID-19.

Guidance is needed for many reasons, including the variable case definitions for MIS-C, the presence of MIS-C features in other infections and childhood rheumatic diseases, the extrapolation of treatment strategies from other conditions with similar presentations, and the issue of myocardial dysfunction, wrote Lauren A. Henderson, MD, MMSC, of Boston Children’s Hospital, and members of the American College of Rheumatology MIS-C and COVID-19–Related Hyperinflammation Task Force.

However, “modifications to treatment plans, particularly in patients with complex conditions, are highly disease, patient, geography, and time specific, and therefore must be individualized as part of a shared decision-making process,” the authors said. The updated guidance was published in Arthritis & Rheumatology.
 

Update needed in wake of Omicron

“We continue to see cases of MIS-C across the United States due to the spike in SARS-CoV-2 infections from the Omicron variant,” and therefore updated guidance is important at this time, Dr. Henderson told this news organization.

“MIS-C remains a serious complication of COVID-19 in children and the ACR wanted to continue to provide pediatricians with up-to-date recommendations for the management of MIS-C,” she said.

“Children began to present with MIS-C in April 2020. At that time, little was known about this entity. Most of the recommendations in the first version of the MIS-C guidance were based on expert opinion,” she explained. However, “over the last 2 years, pediatricians have worked very hard to conduct high-quality research studies to better understand MIS-C, so we now have more scientific evidence to guide our recommendations.

“In version three of the MIS-C guidance, there are new recommendations on treatment. Previously, it was unclear what medications should be used for first-line treatment in patients with MIS-C. Some children were given intravenous immunoglobulin while others were given IVIg and steroids together. Several new studies show that children with MIS-C who are treated with a combination of IVIg and steroids have better outcomes. Accordingly, the MIS-C guidance now recommends dual therapy with IVIg and steroids in children with MIS-C.”

Diagnostic evaluation

The guidance calls for maintaining a broad differential diagnosis of MIS-C, given that the condition remains rare, and that most children with COVID-19 present with mild symptoms and have excellent outcomes, the authors noted. The range of clinical features associated with MIS-C include fever, mucocutaneous findings, myocardial dysfunction, cardiac conduction abnormalities, shock, gastrointestinal symptoms, and lymphadenopathy.

Some patients also experience neurologic involvement in the form of severe headache, altered mental status, seizures, cranial nerve palsies, meningismus, cerebral edema, and ischemic or hemorrhagic stroke. Given the nonspecific nature of these symptoms, “it is imperative that a diagnostic evaluation for MIS-C include investigation for other possible causes, as deemed appropriate by the treating provider,” the authors emphasized. Other diagnostic considerations include the prevalence and chronology of COVID-19 in the community, which may change over time.
 

MIS-C and Kawasaki disease phenotypes

Earlier in the pandemic, when MIS-C first emerged, it was compared with Kawasaki disease (KD). “However, a closer examination of the literature shows that only about one-quarter to half of patients with a reported diagnosis of MIS-C meet the full diagnostic criteria for KD,” the authors wrote. Key features that separate MIS-C from KD include the greater incidence of KD among children in Japan and East Asia versus the higher incidence of MIS-C among non-Hispanic Black children. In addition, children with MIS-C have shown a wider age range, more prominent gastrointestinal and neurologic symptoms, and more frequent cardiac dysfunction, compared with those with KD.

Cardiac management

Close follow-up with cardiology is essential for children with MIS-C, according to the authors. The recommendations call for repeat echocardiograms for all children with MIS-C at a minimum of 7-14 days, then again at 4-6 weeks after the initial presentation. The authors also recommended additional echocardiograms for children with left ventricular dysfunction and cardiac aortic aneurysms. 

MIS-C treatment

Current treatment recommendations emphasize that patients under investigation for MIS-C with life-threatening manifestations may need immunomodulatory therapy before a full diagnostic evaluation is complete, the authors said. However, patients without life-threatening manifestations should be evaluated before starting immunomodulatory treatment to avoid potentially harmful therapies for pediatric patients who don’t need them.

When MIS-C is refractory to initial immunomodulatory treatment, a second dose of IVIg is not recommended, but intensification therapy is advised with either high-dose (10-30 mg/kg per day) glucocorticoids, anakinra, or infliximab. However, there is little evidence available for selecting a specific agent for intensification therapy.

The task force also advises giving low-dose aspirin (3-5 mg/kg per day, up to 81 mg once daily) to all MIS-C patients without active bleeding or significant bleeding risk until normalization of the platelet count and confirmed normal coronary arteries at least 4 weeks after diagnosis.
 

COVID-19 and hyperinflammation

The task force also noted a distinction between MIS-C and severe COVID-19 in children. Although many children with MIS-C are previously healthy, most children who develop severe COVID-19 during an initial infection have complex conditions or comorbidities such as developmental delay or genetic anomaly, or chronic conditions such as congenital heart disease, type 1 diabetes, or asthma, the authors said. They recommend that “hospitalized children with COVID-19 requiring supplemental oxygen or respiratory support should be considered for immunomodulatory therapy in addition to supportive care and antiviral medications.”

The authors acknowledged the limitations and evolving nature of the recommendations, which will continue to change and do not replace clinical judgment for the management of individual patients. In the meantime, the ACR will support the task force in reviewing new evidence and providing revised versions of the current document.

Many questions about MIS-C remain, Dr. Henderson said in an interview. “It can be very hard to diagnose children with MIS-C because many of the symptoms are similar to those seen in other febrile illness of childhood. We need to identify better biomarkers to help us make the diagnosis of MIS-C. In addition, we need studies to provide information about what treatments should be used if children fail to respond to IVIg and steroids. Finally, it appears that vaccination [against SARS-CoV-2] protects against severe forms of MIS-C, and studies are needed to see how vaccination protects children from MIS-C.”

The development of the guidance was supported by the American College of Rheumatology. Dr. Henderson disclosed relationships with companies including Sobi, Pfizer, and Adaptive Biotechnologies (less than $10,000) and research support from the Childhood Arthritis and Rheumatology Research Alliance and research grant support from Bristol-Myers Squibb.

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

Updated guidance for health care providers on multisystem inflammatory syndrome in children (MIS-C) recognizes the evolving nature of the disease and offers strategies for pediatric rheumatologists, who also may be asked to recommend treatment for hyperinflammation in children with acute COVID-19.

Guidance is needed for many reasons, including the variable case definitions for MIS-C, the presence of MIS-C features in other infections and childhood rheumatic diseases, the extrapolation of treatment strategies from other conditions with similar presentations, and the issue of myocardial dysfunction, wrote Lauren A. Henderson, MD, MMSC, of Boston Children’s Hospital, and members of the American College of Rheumatology MIS-C and COVID-19–Related Hyperinflammation Task Force.

However, “modifications to treatment plans, particularly in patients with complex conditions, are highly disease, patient, geography, and time specific, and therefore must be individualized as part of a shared decision-making process,” the authors said. The updated guidance was published in Arthritis & Rheumatology.
 

Update needed in wake of Omicron

“We continue to see cases of MIS-C across the United States due to the spike in SARS-CoV-2 infections from the Omicron variant,” and therefore updated guidance is important at this time, Dr. Henderson told this news organization.

“MIS-C remains a serious complication of COVID-19 in children and the ACR wanted to continue to provide pediatricians with up-to-date recommendations for the management of MIS-C,” she said.

“Children began to present with MIS-C in April 2020. At that time, little was known about this entity. Most of the recommendations in the first version of the MIS-C guidance were based on expert opinion,” she explained. However, “over the last 2 years, pediatricians have worked very hard to conduct high-quality research studies to better understand MIS-C, so we now have more scientific evidence to guide our recommendations.

“In version three of the MIS-C guidance, there are new recommendations on treatment. Previously, it was unclear what medications should be used for first-line treatment in patients with MIS-C. Some children were given intravenous immunoglobulin while others were given IVIg and steroids together. Several new studies show that children with MIS-C who are treated with a combination of IVIg and steroids have better outcomes. Accordingly, the MIS-C guidance now recommends dual therapy with IVIg and steroids in children with MIS-C.”

Diagnostic evaluation

The guidance calls for maintaining a broad differential diagnosis of MIS-C, given that the condition remains rare, and that most children with COVID-19 present with mild symptoms and have excellent outcomes, the authors noted. The range of clinical features associated with MIS-C include fever, mucocutaneous findings, myocardial dysfunction, cardiac conduction abnormalities, shock, gastrointestinal symptoms, and lymphadenopathy.

Some patients also experience neurologic involvement in the form of severe headache, altered mental status, seizures, cranial nerve palsies, meningismus, cerebral edema, and ischemic or hemorrhagic stroke. Given the nonspecific nature of these symptoms, “it is imperative that a diagnostic evaluation for MIS-C include investigation for other possible causes, as deemed appropriate by the treating provider,” the authors emphasized. Other diagnostic considerations include the prevalence and chronology of COVID-19 in the community, which may change over time.
 

MIS-C and Kawasaki disease phenotypes

Earlier in the pandemic, when MIS-C first emerged, it was compared with Kawasaki disease (KD). “However, a closer examination of the literature shows that only about one-quarter to half of patients with a reported diagnosis of MIS-C meet the full diagnostic criteria for KD,” the authors wrote. Key features that separate MIS-C from KD include the greater incidence of KD among children in Japan and East Asia versus the higher incidence of MIS-C among non-Hispanic Black children. In addition, children with MIS-C have shown a wider age range, more prominent gastrointestinal and neurologic symptoms, and more frequent cardiac dysfunction, compared with those with KD.

Cardiac management

Close follow-up with cardiology is essential for children with MIS-C, according to the authors. The recommendations call for repeat echocardiograms for all children with MIS-C at a minimum of 7-14 days, then again at 4-6 weeks after the initial presentation. The authors also recommended additional echocardiograms for children with left ventricular dysfunction and cardiac aortic aneurysms. 

MIS-C treatment

Current treatment recommendations emphasize that patients under investigation for MIS-C with life-threatening manifestations may need immunomodulatory therapy before a full diagnostic evaluation is complete, the authors said. However, patients without life-threatening manifestations should be evaluated before starting immunomodulatory treatment to avoid potentially harmful therapies for pediatric patients who don’t need them.

When MIS-C is refractory to initial immunomodulatory treatment, a second dose of IVIg is not recommended, but intensification therapy is advised with either high-dose (10-30 mg/kg per day) glucocorticoids, anakinra, or infliximab. However, there is little evidence available for selecting a specific agent for intensification therapy.

The task force also advises giving low-dose aspirin (3-5 mg/kg per day, up to 81 mg once daily) to all MIS-C patients without active bleeding or significant bleeding risk until normalization of the platelet count and confirmed normal coronary arteries at least 4 weeks after diagnosis.
 

COVID-19 and hyperinflammation

The task force also noted a distinction between MIS-C and severe COVID-19 in children. Although many children with MIS-C are previously healthy, most children who develop severe COVID-19 during an initial infection have complex conditions or comorbidities such as developmental delay or genetic anomaly, or chronic conditions such as congenital heart disease, type 1 diabetes, or asthma, the authors said. They recommend that “hospitalized children with COVID-19 requiring supplemental oxygen or respiratory support should be considered for immunomodulatory therapy in addition to supportive care and antiviral medications.”

The authors acknowledged the limitations and evolving nature of the recommendations, which will continue to change and do not replace clinical judgment for the management of individual patients. In the meantime, the ACR will support the task force in reviewing new evidence and providing revised versions of the current document.

Many questions about MIS-C remain, Dr. Henderson said in an interview. “It can be very hard to diagnose children with MIS-C because many of the symptoms are similar to those seen in other febrile illness of childhood. We need to identify better biomarkers to help us make the diagnosis of MIS-C. In addition, we need studies to provide information about what treatments should be used if children fail to respond to IVIg and steroids. Finally, it appears that vaccination [against SARS-CoV-2] protects against severe forms of MIS-C, and studies are needed to see how vaccination protects children from MIS-C.”

The development of the guidance was supported by the American College of Rheumatology. Dr. Henderson disclosed relationships with companies including Sobi, Pfizer, and Adaptive Biotechnologies (less than $10,000) and research support from the Childhood Arthritis and Rheumatology Research Alliance and research grant support from Bristol-Myers Squibb.

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

Updated guidance for health care providers on multisystem inflammatory syndrome in children (MIS-C) recognizes the evolving nature of the disease and offers strategies for pediatric rheumatologists, who also may be asked to recommend treatment for hyperinflammation in children with acute COVID-19.

Guidance is needed for many reasons, including the variable case definitions for MIS-C, the presence of MIS-C features in other infections and childhood rheumatic diseases, the extrapolation of treatment strategies from other conditions with similar presentations, and the issue of myocardial dysfunction, wrote Lauren A. Henderson, MD, MMSC, of Boston Children’s Hospital, and members of the American College of Rheumatology MIS-C and COVID-19–Related Hyperinflammation Task Force.

However, “modifications to treatment plans, particularly in patients with complex conditions, are highly disease, patient, geography, and time specific, and therefore must be individualized as part of a shared decision-making process,” the authors said. The updated guidance was published in Arthritis & Rheumatology.
 

Update needed in wake of Omicron

“We continue to see cases of MIS-C across the United States due to the spike in SARS-CoV-2 infections from the Omicron variant,” and therefore updated guidance is important at this time, Dr. Henderson told this news organization.

“MIS-C remains a serious complication of COVID-19 in children and the ACR wanted to continue to provide pediatricians with up-to-date recommendations for the management of MIS-C,” she said.

“Children began to present with MIS-C in April 2020. At that time, little was known about this entity. Most of the recommendations in the first version of the MIS-C guidance were based on expert opinion,” she explained. However, “over the last 2 years, pediatricians have worked very hard to conduct high-quality research studies to better understand MIS-C, so we now have more scientific evidence to guide our recommendations.

“In version three of the MIS-C guidance, there are new recommendations on treatment. Previously, it was unclear what medications should be used for first-line treatment in patients with MIS-C. Some children were given intravenous immunoglobulin while others were given IVIg and steroids together. Several new studies show that children with MIS-C who are treated with a combination of IVIg and steroids have better outcomes. Accordingly, the MIS-C guidance now recommends dual therapy with IVIg and steroids in children with MIS-C.”

Diagnostic evaluation

The guidance calls for maintaining a broad differential diagnosis of MIS-C, given that the condition remains rare, and that most children with COVID-19 present with mild symptoms and have excellent outcomes, the authors noted. The range of clinical features associated with MIS-C include fever, mucocutaneous findings, myocardial dysfunction, cardiac conduction abnormalities, shock, gastrointestinal symptoms, and lymphadenopathy.

Some patients also experience neurologic involvement in the form of severe headache, altered mental status, seizures, cranial nerve palsies, meningismus, cerebral edema, and ischemic or hemorrhagic stroke. Given the nonspecific nature of these symptoms, “it is imperative that a diagnostic evaluation for MIS-C include investigation for other possible causes, as deemed appropriate by the treating provider,” the authors emphasized. Other diagnostic considerations include the prevalence and chronology of COVID-19 in the community, which may change over time.
 

MIS-C and Kawasaki disease phenotypes

Earlier in the pandemic, when MIS-C first emerged, it was compared with Kawasaki disease (KD). “However, a closer examination of the literature shows that only about one-quarter to half of patients with a reported diagnosis of MIS-C meet the full diagnostic criteria for KD,” the authors wrote. Key features that separate MIS-C from KD include the greater incidence of KD among children in Japan and East Asia versus the higher incidence of MIS-C among non-Hispanic Black children. In addition, children with MIS-C have shown a wider age range, more prominent gastrointestinal and neurologic symptoms, and more frequent cardiac dysfunction, compared with those with KD.

Cardiac management

Close follow-up with cardiology is essential for children with MIS-C, according to the authors. The recommendations call for repeat echocardiograms for all children with MIS-C at a minimum of 7-14 days, then again at 4-6 weeks after the initial presentation. The authors also recommended additional echocardiograms for children with left ventricular dysfunction and cardiac aortic aneurysms. 

MIS-C treatment

Current treatment recommendations emphasize that patients under investigation for MIS-C with life-threatening manifestations may need immunomodulatory therapy before a full diagnostic evaluation is complete, the authors said. However, patients without life-threatening manifestations should be evaluated before starting immunomodulatory treatment to avoid potentially harmful therapies for pediatric patients who don’t need them.

When MIS-C is refractory to initial immunomodulatory treatment, a second dose of IVIg is not recommended, but intensification therapy is advised with either high-dose (10-30 mg/kg per day) glucocorticoids, anakinra, or infliximab. However, there is little evidence available for selecting a specific agent for intensification therapy.

The task force also advises giving low-dose aspirin (3-5 mg/kg per day, up to 81 mg once daily) to all MIS-C patients without active bleeding or significant bleeding risk until normalization of the platelet count and confirmed normal coronary arteries at least 4 weeks after diagnosis.
 

COVID-19 and hyperinflammation

The task force also noted a distinction between MIS-C and severe COVID-19 in children. Although many children with MIS-C are previously healthy, most children who develop severe COVID-19 during an initial infection have complex conditions or comorbidities such as developmental delay or genetic anomaly, or chronic conditions such as congenital heart disease, type 1 diabetes, or asthma, the authors said. They recommend that “hospitalized children with COVID-19 requiring supplemental oxygen or respiratory support should be considered for immunomodulatory therapy in addition to supportive care and antiviral medications.”

The authors acknowledged the limitations and evolving nature of the recommendations, which will continue to change and do not replace clinical judgment for the management of individual patients. In the meantime, the ACR will support the task force in reviewing new evidence and providing revised versions of the current document.

Many questions about MIS-C remain, Dr. Henderson said in an interview. “It can be very hard to diagnose children with MIS-C because many of the symptoms are similar to those seen in other febrile illness of childhood. We need to identify better biomarkers to help us make the diagnosis of MIS-C. In addition, we need studies to provide information about what treatments should be used if children fail to respond to IVIg and steroids. Finally, it appears that vaccination [against SARS-CoV-2] protects against severe forms of MIS-C, and studies are needed to see how vaccination protects children from MIS-C.”

The development of the guidance was supported by the American College of Rheumatology. Dr. Henderson disclosed relationships with companies including Sobi, Pfizer, and Adaptive Biotechnologies (less than $10,000) and research support from the Childhood Arthritis and Rheumatology Research Alliance and research grant support from Bristol-Myers Squibb.

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

“Dr. Lilley, you’ll always be my favorite doctor; you helped me grow.”

These were the parting words from the last patient that I treated during my endocrinology fellowship. I had watched this young man grow from a prepubertal 17-year-old to a young man who had reached his predicted family height as I treated his delayed puberty caused by Kallmann syndrome, a problem that had been missed for years. It was the appropriate bookend for my chosen specialty.

Watching children grow and develop into who they were meant to be is one of my favorite things about endocrinology, as well as forming meaningful relationships with families. Treating detectable deficiencies in logical and measurable ways is also extremely satisfying.

Too little testosterone? That’s a problem I can solve. Too much thyroid hormone? There’s a blocker for that! Endocrinology can be a straightforward field, and when all goes well, everyone leaves happy.

Except when they don’t.
 

Gatekeepers for treatment for children’s growth

“Nice to meet you. We’re here to get growth hormone.”

“We’re here because his pediatrician made us come. We’ve already decided we’re not going to put hormones into his body.”

These are common statements I hear when I first meet new patients whose parents are concerned about their children’s growth. Pediatric endocrinologists, after all, are the usual gatekeepers for this treatment.

Growth hormone (GH) often makes the news for controversial reasons – most commonly for its abuse by elite athletes hoping to exploit its anabolic effects – causing parents to have varied opinions about its possible use in their children.

Some refuse endocrinology referrals at all owing to concerns that we will push daily injections on their children. Others demand referrals for their children of average height, hoping for every perceived advantage.

GH deficiency (GHD) – a condition where the pituitary gland fails to produce enough GH – can occur because of congenital pituitary malformations; anatomic, surgical, or traumatic interruptions to the gland; or enzyme deficiencies leading to faulty production.

GHD is just one reason for poor growth, however.

Growth is one of the most important indicators of health in children. A waning growth rate may be an early symptom of serious problems. In my clinic, I’ve diagnosed severe hypothyroidism in a marathon runner, a brain tumor, celiac disease in a teenager with no gastrointestinal complaints, autoimmune hepatitis, and several other diseases needing treatment in children who show no symptoms other than poor growth.
 

Barriers to normal growth

Sometimes, the die is cast for children to have barriers to normal growth. Several genetic conditions can lead to poor GH production or response, and GH treatment is often necessary to approximate normal height.

These may include:

• Turner syndrome (in females who are missing an X chromosome in whole or part) should be considered in every girl with abnormally short stature; mosaic forms of the condition may be subtle and lack classic features.
• Noonan syndrome is important to detect owing to the possibility of cardiac or renal malformations that may also occur in this condition, caused by a mutation in one of the genes in the RAS-MAPK pathway.
• Russell-Silver syndrome can cause intrauterine GH restriction and has been traced to uniparental disomy of chromosome 7 or duplications, mutations, or methylation defects in chromosome 11.
• Individuals with Prader-Willi syndrome, which is characterized by low muscle tone, hyperphagia, and hypogonadism, have demonstrated dramatic benefits from GH therapy, primarily in maintaining a normal body mass index.

Children who are small for their gestational age may be GH resistant, and those who do not catch up to their growth curve by the age of 2 years may require GH treatment to reach their height potential.

GH therapy isn’t entirely benign. Rare adverse effects of overtreatment can include slipped capital femoral epiphysis (a fracture to the growth plate) and pseudotumor cerebri (idiopathic intracranial hypertension).

Overtreatment can cause acromegaly, which results in coarsened features and large hands and feet.
 

When is GH therapy warranted?

“Growth hormone therapy has been denied by her insurer. They want you to fill out an appeal.”

Insurance approval in the United States can be a herculean effort because GH is expensive: Out-of-pocket costs are prohibitive for most people without insurance assistance, ranging from $7,000 to $30,000 annually.

Pediatric endocrinologists aren’t in the business of cosmetic endocrinology. Treatment of idiopathic short stature has been controversial since this became an indication for GH treatment.

GH isn’t always necessary. Diagnosing the underlying cause for poor growth is the most important step.

Often, we find constitutional delay of growth and puberty, or “late bloomers.” This condition is characterized by a delayed bone age (growth plates more open than expected for age) and delayed pubertal onset. These children will often reach a normal height despite starting as some of the smallest of their peers.

However, GH plays other roles in the body than simply propelling height. Children with congenital GHD will require GH treatment to prevent hypoglycemia, especially in infancy.

GH is needed even in adults with fused growth plates for normal lipid metabolism, bone accrual, and maintaining normal muscle mass.

I have noticed marked improvements in muscle tone in many children with developmental delays who are treated with GH, and research supports cognitive benefits for certain populations.

The most common regimens for GH focus on treatment via subcutaneous injection nightly, when GH is naturally produced; sometimes, injections are given six nights out of seven to provide a break or for splitting time between households.

Newer once-weekly formulations have recently received approval, as reported by this news organization, and are coming into use.

Pediatric endocrinologists measure height and follow growth factors closely with visits every 3-6 months. GH levels are not useful outside of provocative diagnostic (stimulation) testing.

Insulinlike growth factor 1 or insulinlike growth factor binding protein levels are analyzed per Tanner stage of puberty to assess appropriate response and to make dose adjustments.

Annual standardized films of the left hand help predict progress and anticipated adult height. Treatment usually persists through puberty until growth plates are closed; if true GHD is noticed, much smaller doses are continued through adulthood.

Regardless, conversations about GH happen with your friendly local pediatric endocrinologist.

We are thrilled to help shepherd patients through their growing age to meet their potential. For more information about GH treatment for children, the MAGIC Foundation is the perfect place to start.

Dr. Lilley is director of the pediatric diabetes and lipid program, Mississippi Center for Advanced Medicine, Madison. She disclosed no relevant conflicts of interest. A version of this article first appeared on Medscape.com.

“Dr. Lilley, you’ll always be my favorite doctor; you helped me grow.”

These were the parting words from the last patient that I treated during my endocrinology fellowship. I had watched this young man grow from a prepubertal 17-year-old to a young man who had reached his predicted family height as I treated his delayed puberty caused by Kallmann syndrome, a problem that had been missed for years. It was the appropriate bookend for my chosen specialty.

Watching children grow and develop into who they were meant to be is one of my favorite things about endocrinology, as well as forming meaningful relationships with families. Treating detectable deficiencies in logical and measurable ways is also extremely satisfying.

Too little testosterone? That’s a problem I can solve. Too much thyroid hormone? There’s a blocker for that! Endocrinology can be a straightforward field, and when all goes well, everyone leaves happy.

Except when they don’t.
 

Gatekeepers for treatment for children’s growth

“Nice to meet you. We’re here to get growth hormone.”

“We’re here because his pediatrician made us come. We’ve already decided we’re not going to put hormones into his body.”

These are common statements I hear when I first meet new patients whose parents are concerned about their children’s growth. Pediatric endocrinologists, after all, are the usual gatekeepers for this treatment.

Growth hormone (GH) often makes the news for controversial reasons – most commonly for its abuse by elite athletes hoping to exploit its anabolic effects – causing parents to have varied opinions about its possible use in their children.

Some refuse endocrinology referrals at all owing to concerns that we will push daily injections on their children. Others demand referrals for their children of average height, hoping for every perceived advantage.

GH deficiency (GHD) – a condition where the pituitary gland fails to produce enough GH – can occur because of congenital pituitary malformations; anatomic, surgical, or traumatic interruptions to the gland; or enzyme deficiencies leading to faulty production.

GHD is just one reason for poor growth, however.

Growth is one of the most important indicators of health in children. A waning growth rate may be an early symptom of serious problems. In my clinic, I’ve diagnosed severe hypothyroidism in a marathon runner, a brain tumor, celiac disease in a teenager with no gastrointestinal complaints, autoimmune hepatitis, and several other diseases needing treatment in children who show no symptoms other than poor growth.
 

Barriers to normal growth

Sometimes, the die is cast for children to have barriers to normal growth. Several genetic conditions can lead to poor GH production or response, and GH treatment is often necessary to approximate normal height.

These may include:

• Turner syndrome (in females who are missing an X chromosome in whole or part) should be considered in every girl with abnormally short stature; mosaic forms of the condition may be subtle and lack classic features.
• Noonan syndrome is important to detect owing to the possibility of cardiac or renal malformations that may also occur in this condition, caused by a mutation in one of the genes in the RAS-MAPK pathway.
• Russell-Silver syndrome can cause intrauterine GH restriction and has been traced to uniparental disomy of chromosome 7 or duplications, mutations, or methylation defects in chromosome 11.
• Individuals with Prader-Willi syndrome, which is characterized by low muscle tone, hyperphagia, and hypogonadism, have demonstrated dramatic benefits from GH therapy, primarily in maintaining a normal body mass index.

Children who are small for their gestational age may be GH resistant, and those who do not catch up to their growth curve by the age of 2 years may require GH treatment to reach their height potential.

GH therapy isn’t entirely benign. Rare adverse effects of overtreatment can include slipped capital femoral epiphysis (a fracture to the growth plate) and pseudotumor cerebri (idiopathic intracranial hypertension).

Overtreatment can cause acromegaly, which results in coarsened features and large hands and feet.
 

When is GH therapy warranted?

“Growth hormone therapy has been denied by her insurer. They want you to fill out an appeal.”

Insurance approval in the United States can be a herculean effort because GH is expensive: Out-of-pocket costs are prohibitive for most people without insurance assistance, ranging from $7,000 to $30,000 annually.

Pediatric endocrinologists aren’t in the business of cosmetic endocrinology. Treatment of idiopathic short stature has been controversial since this became an indication for GH treatment.

GH isn’t always necessary. Diagnosing the underlying cause for poor growth is the most important step.

Often, we find constitutional delay of growth and puberty, or “late bloomers.” This condition is characterized by a delayed bone age (growth plates more open than expected for age) and delayed pubertal onset. These children will often reach a normal height despite starting as some of the smallest of their peers.

However, GH plays other roles in the body than simply propelling height. Children with congenital GHD will require GH treatment to prevent hypoglycemia, especially in infancy.

GH is needed even in adults with fused growth plates for normal lipid metabolism, bone accrual, and maintaining normal muscle mass.

I have noticed marked improvements in muscle tone in many children with developmental delays who are treated with GH, and research supports cognitive benefits for certain populations.

The most common regimens for GH focus on treatment via subcutaneous injection nightly, when GH is naturally produced; sometimes, injections are given six nights out of seven to provide a break or for splitting time between households.

Newer once-weekly formulations have recently received approval, as reported by this news organization, and are coming into use.

Pediatric endocrinologists measure height and follow growth factors closely with visits every 3-6 months. GH levels are not useful outside of provocative diagnostic (stimulation) testing.

Insulinlike growth factor 1 or insulinlike growth factor binding protein levels are analyzed per Tanner stage of puberty to assess appropriate response and to make dose adjustments.

Annual standardized films of the left hand help predict progress and anticipated adult height. Treatment usually persists through puberty until growth plates are closed; if true GHD is noticed, much smaller doses are continued through adulthood.

Regardless, conversations about GH happen with your friendly local pediatric endocrinologist.

We are thrilled to help shepherd patients through their growing age to meet their potential. For more information about GH treatment for children, the MAGIC Foundation is the perfect place to start.

Dr. Lilley is director of the pediatric diabetes and lipid program, Mississippi Center for Advanced Medicine, Madison. She disclosed no relevant conflicts of interest. A version of this article first appeared on Medscape.com.

“Dr. Lilley, you’ll always be my favorite doctor; you helped me grow.”

These were the parting words from the last patient that I treated during my endocrinology fellowship. I had watched this young man grow from a prepubertal 17-year-old to a young man who had reached his predicted family height as I treated his delayed puberty caused by Kallmann syndrome, a problem that had been missed for years. It was the appropriate bookend for my chosen specialty.

Watching children grow and develop into who they were meant to be is one of my favorite things about endocrinology, as well as forming meaningful relationships with families. Treating detectable deficiencies in logical and measurable ways is also extremely satisfying.

Too little testosterone? That’s a problem I can solve. Too much thyroid hormone? There’s a blocker for that! Endocrinology can be a straightforward field, and when all goes well, everyone leaves happy.

Except when they don’t.
 

Gatekeepers for treatment for children’s growth

“Nice to meet you. We’re here to get growth hormone.”

“We’re here because his pediatrician made us come. We’ve already decided we’re not going to put hormones into his body.”

These are common statements I hear when I first meet new patients whose parents are concerned about their children’s growth. Pediatric endocrinologists, after all, are the usual gatekeepers for this treatment.

Growth hormone (GH) often makes the news for controversial reasons – most commonly for its abuse by elite athletes hoping to exploit its anabolic effects – causing parents to have varied opinions about its possible use in their children.

Some refuse endocrinology referrals at all owing to concerns that we will push daily injections on their children. Others demand referrals for their children of average height, hoping for every perceived advantage.

GH deficiency (GHD) – a condition where the pituitary gland fails to produce enough GH – can occur because of congenital pituitary malformations; anatomic, surgical, or traumatic interruptions to the gland; or enzyme deficiencies leading to faulty production.

GHD is just one reason for poor growth, however.

Growth is one of the most important indicators of health in children. A waning growth rate may be an early symptom of serious problems. In my clinic, I’ve diagnosed severe hypothyroidism in a marathon runner, a brain tumor, celiac disease in a teenager with no gastrointestinal complaints, autoimmune hepatitis, and several other diseases needing treatment in children who show no symptoms other than poor growth.
 

Barriers to normal growth

Sometimes, the die is cast for children to have barriers to normal growth. Several genetic conditions can lead to poor GH production or response, and GH treatment is often necessary to approximate normal height.

These may include:

• Turner syndrome (in females who are missing an X chromosome in whole or part) should be considered in every girl with abnormally short stature; mosaic forms of the condition may be subtle and lack classic features.
• Noonan syndrome is important to detect owing to the possibility of cardiac or renal malformations that may also occur in this condition, caused by a mutation in one of the genes in the RAS-MAPK pathway.
• Russell-Silver syndrome can cause intrauterine GH restriction and has been traced to uniparental disomy of chromosome 7 or duplications, mutations, or methylation defects in chromosome 11.
• Individuals with Prader-Willi syndrome, which is characterized by low muscle tone, hyperphagia, and hypogonadism, have demonstrated dramatic benefits from GH therapy, primarily in maintaining a normal body mass index.

Children who are small for their gestational age may be GH resistant, and those who do not catch up to their growth curve by the age of 2 years may require GH treatment to reach their height potential.

GH therapy isn’t entirely benign. Rare adverse effects of overtreatment can include slipped capital femoral epiphysis (a fracture to the growth plate) and pseudotumor cerebri (idiopathic intracranial hypertension).

Overtreatment can cause acromegaly, which results in coarsened features and large hands and feet.
 

When is GH therapy warranted?

“Growth hormone therapy has been denied by her insurer. They want you to fill out an appeal.”

Insurance approval in the United States can be a herculean effort because GH is expensive: Out-of-pocket costs are prohibitive for most people without insurance assistance, ranging from $7,000 to $30,000 annually.

Pediatric endocrinologists aren’t in the business of cosmetic endocrinology. Treatment of idiopathic short stature has been controversial since this became an indication for GH treatment.

GH isn’t always necessary. Diagnosing the underlying cause for poor growth is the most important step.

Often, we find constitutional delay of growth and puberty, or “late bloomers.” This condition is characterized by a delayed bone age (growth plates more open than expected for age) and delayed pubertal onset. These children will often reach a normal height despite starting as some of the smallest of their peers.

However, GH plays other roles in the body than simply propelling height. Children with congenital GHD will require GH treatment to prevent hypoglycemia, especially in infancy.

GH is needed even in adults with fused growth plates for normal lipid metabolism, bone accrual, and maintaining normal muscle mass.

I have noticed marked improvements in muscle tone in many children with developmental delays who are treated with GH, and research supports cognitive benefits for certain populations.

The most common regimens for GH focus on treatment via subcutaneous injection nightly, when GH is naturally produced; sometimes, injections are given six nights out of seven to provide a break or for splitting time between households.

Newer once-weekly formulations have recently received approval, as reported by this news organization, and are coming into use.

Pediatric endocrinologists measure height and follow growth factors closely with visits every 3-6 months. GH levels are not useful outside of provocative diagnostic (stimulation) testing.

Insulinlike growth factor 1 or insulinlike growth factor binding protein levels are analyzed per Tanner stage of puberty to assess appropriate response and to make dose adjustments.

Annual standardized films of the left hand help predict progress and anticipated adult height. Treatment usually persists through puberty until growth plates are closed; if true GHD is noticed, much smaller doses are continued through adulthood.

Regardless, conversations about GH happen with your friendly local pediatric endocrinologist.

We are thrilled to help shepherd patients through their growing age to meet their potential. For more information about GH treatment for children, the MAGIC Foundation is the perfect place to start.

Dr. Lilley is director of the pediatric diabetes and lipid program, Mississippi Center for Advanced Medicine, Madison. She disclosed no relevant conflicts of interest. A version of this article first appeared on Medscape.com.

In 1938, the year that cystic fibrosis (CF) was first described clinically, four of five children born with the disease did not live past their first birthdays.

In 2019, the median age at death for patients enrolled in the Cystic Fibrosis Foundation (CFF) registry was 32 years, and the predicted life expectancy for patients with CF who were born from 2015 through 2019 was 46 years.

Blausen.com staff (2014). &amp;quot;Medical gallery of Blausen Medical Blausen.com staff (2014). &amp;quot;Medical gallery of Blausen Medical 2014&amp;quot;. WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.010. ISSN 2002-4436.

Those numbers reflect the remarkable progress made in the past 4 decades in the care of patients with CF, but also highlight the obstacles ahead, given that the predicted life expectancy for the overall U.S. population in 2019 (pre–COVID-19) was 78.9 years.

Julie Desch, MD, is a CF survivor who has beaten the odds and then some. At age 61, the retired surgical pathologist is a CF patient advocate, speaker, and a board member of the Cystic Fibrosis Research Institute, a not-for-profit organization that funds CF research and offers education, advocacy, and psychosocial support for persons with CF and their families and caregivers.

In an interview, Dr. Desch said that while there has been remarkable progress in her lifetime in the field of CF research and treatment, particularly in the development of drugs that modulate function of the underlying cause of approximately 90% of CF cases, there are still many CF patients who cannot benefit from these therapies.

“There are still 10% of people who don’t make a protein to be modified, so that’s a huge unmet need,” she said.
 

Genetic disorder

CF is a chronic autosomal recessive disorder with multiorgan and multisystem manifestations. It is caused by mutations in the CFTR gene, which codes for the protein CF transmembrane conductance regulator. CFTR controls transport of chloride ions across cell membranes, specifically the apical membrane of epithelial cells in tissues of the airways, intestinal tract, pancreas, kidneys, sweat glands, and the reproductive system, notably the vas deferens in males.

Emw/Wikimedia Commons/CC BY-SA 3.0

The F508 deletion (F508del) mutation is the most common, occurring in approximately 70% of persons with CF. It is a class 2-type protein processing mutation, leading to defects in cellular processing, protein stability, and chloride channel gating defects.

The CFTR protein also secretes bicarbonate to regulate the pH of airway surface liquid, and inhibits the epithelial sodium channel, which mediates passive sodium transport across apical membranes of sodium-absorbing epithelial cells in the kidneys, intestine, and airways.

CF typically presents with the buildup in the lungs of abnormally viscous and sticky mucus leading to frequent, severe infections, particularly with Pseudomonas aeruginosa, progressive lung damage and, prior to the development of effective disease management, to premature death. The phenotype often includes malnutrition due to malabsorption, and failure to thrive.
 

Diagnosis

In all 50 U.S. states and the District of Columbia, newborns are screened for CF with an assay for immunoreactive trypsinogen (IRT) an indirect marker for pancreatic injury that is elevated in serum in most newborns with CF, but also detected in premature infants or those delivered under stressful circumstances. In some states newborns are tested only for IRT, with a diagnosis confirmed with a sweat chloride test and/or a CFTR mutation panel.

Treatment

There is no cure for CF, but the discovery of the gene in 1989 by Canadian and U.S. investigators has led to life-prolonging therapeutic interventions, specifically the development of CFTR modulators.

CFTR modulators include potentiators such as ivacaftor (Kalydeco), and correctors such as lumacaftor and tezacaftor (available in the combination Orkambi), and most recently in the triple combination of elexacaftor, tezacaftor, and ivacaftor (Trikafta; ETI).

Neil Sweezey, MD, FRCPC, a CF expert at The Hospital for Sick Children (SickKids) in Toronto, told this news organization that the ideal therapy for CF, genetic correction of the underlying mutations, is still not feasible, but that CFTR modulators are a close second.

“For 90% of patients, the three-drug combination Trikafta has been shown to be quite safe, quite tolerable, and quite remarkably beneficial,” he said.

In a study reported at CHEST 2021 by investigators from Nationwide Children’s Hospital in Columbus, Ohio, 32 adults who were started on the triple combination had significantly improved in forced expiratory volume in 1 second (FEV₁), gain in body mass index, decreased sweat chloride and decreased colonization by Pseudomonas species. In addition, patients had significant improvements in blood inflammatory markers.

Christopher H. Goss, MD, FCCP, professor of pulmonary critical care and sleep medicine and professor of pediatrics at the University of Washington in Seattle, agreed that with the availability of the triple combination, “these are extraordinary times. An astounding fact is that most patients have complete resolution of cough, and the exacerbation rates have just plummeted,” he said in an interview.

Some of the reductions in exacerbations may be attributable to the COVID-19 pandemic, he noted, because patients in isolation have less exposure to circulating respiratory viruses.

“But it has been miraculous, and the clinical effect is certainly still more astounding than the effects of ivacaftor, which was the first truly breakthrough drug. Weight goes up, well-being increases, and the population lung function has shifted up to better grade lung function, in the entire population,” he said.

In addition, the need for lung and heart transplantation has sharply declined.

“I had a patient who had decided to forgo transplantation, despite absolutely horrible lung function, and he’s now bowling and leading a very productive life, when before he had been preparing for end of life,” Dr. Goss said.

Dr. Sweezey emphasized that as with all medications, patients being started on the triple combination require close monitoring for potential adverse events that might require dose modification or, for a small number of patients, withdrawal.


 

Burden of care

CFTR modulators have reduced but not eliminated the need for some patients to have mucolytic therapy, which may include dornase alfa, a recombinant human deoxyribonuclease (DNase) that reduces the viscosity of lung secretions, hypertonic saline inhaled twice daily (for patients 12 and older), mannitol, and physical manipulations to help patients clear mucus. This can include both manual percussion and the use of devices for high-frequency chest wall oscillation.

The complex nature of CF often requires a combination of other therapies to address comorbidities. These therapies may include infection prophylaxis and treatment with antibiotics and antifungals, nutrition support, and therapy for CF-related complications, including gastrointestinal issues, liver diseases, diabetes, and osteopenia that may be related to poor nutrient absorption, chronic inflammation, or other sequelae of CF.

In addition, patients often require frequent CF care center visits – ideally a minimum of every 3 months – which can result in significant loss of work or school time.

“Outcomes for patients in the long run have been absolutely proven to be best if they’re followed in big, established, multidisciplinary well-organized CF centers,” Dr. Sweezey said. “In the United States and Canada if you’re looked after on a regular basis, which means quarterly, every 3 months – whether you need it or not, you really do need it – and if the patients are seen and assessed and checked every 3 months all of their lives, they have small changes caught early, whether it’s an infection you can slap down with medication or a nutrition problem that may be affecting a child’s growth and development.”

“We’re really kind of at a pivotal moment in CF, where we realize things are changing,” said A. Whitney Brown, MD, senior director for clinical affairs at the Cystic Fibrosis Foundation, and an adult CF and lung transplant physician in the Inova Advanced Lung Disease Program in Falls Church, Va.

“Patient needs and interest have evolved, because of the pandemic and because of the highly effective modulator therapy, but we want to take great effort to study it in a rigorous way, to make sure that as we are agile and adapt the care model, that we can maintain the same quality outcomes that we have traditionally done,” she said in an interview.

The Lancet Respiratory Medicine Commission on the future of CF care states that models of care “need to consider management approaches (including disease monitoring) to maintain health and delay lung transplantation, while minimizing the burden of care for patients and their families.”
 

‘A great problem to have’

One of the most significant changes in CF care has been the growing population of CF patients like Dr. Desch who are living well into adulthood, with some approaching Medicare eligibility.

With the advent of triple therapy and CFTR modulators being started earlier in life, lung function can be preserved, damage to other organs can be minimized, and life expectancy for patients with CF will continue to improve.

“We’re anticipating that there may be some needs in the aging CF population that are different than what we have historically had,” Dr. Brown said. “Will there be geriatric providers that need to become experts in CF care? That’s a great problem to have,” she said.

Dr. Goss agreed, noting that CF is steadily shifting from a near uniformly fatal disease to a chronic disorder that in many cases can be managed “with a complex regimen of novel drugs, much like HIV.”

He noted that there are multiple drug interactions with the triple combination, “so it’s really important that people don’t start a CF patient on a drug without consulting a pharmacist, because you can totally inactivate ETI, or augment it dramatically, and we’ve seen both happen.”
 

Cost and access

All experts interviewed for this article agreed that while the care of patients with CF has improved exponentially over the last few decades, there are still troubling inequities in care.

One of the largest impediments is the cost of care, with the triple combination costing more than $300,000 per year.

“Clearly patients aren’t paying that, but insurance companies are, and that’s causing all kinds of trickle-down effects that definitely affect patients. The patients like myself who are able to have insurance that covers it benefit, but there are so many people that don’t,” Dr. Desch said.

Dr. Sweezey noted that prior to the advent of ETI, patients with CF in Canada had better outcomes and longer life expectancy than did similar patients in the United States because of universal access to care and coordinated services under Canada’s health care system, compared with the highly fragmented and inefficient U.S. system. He added that the wider availability of ETI in the United States vs. Canada may begin to narrow that gap, however.

As noted before, there is a substantial proportion of patients – an estimated 10% – who have CFTR mutations that are not correctable by currently available CFTR modulators, and these patients are at significant risk for irreversible airway complications and lung damage.

In addition, although CF occurs most frequently among people of White ancestry, the disease does not respect distinctions of race or ethnicity.

“It’s not just [Whites] – a lot of people from different racial backgrounds, ethnic backgrounds, are not being diagnosed or are not being diagnosed soon enough to have effective care early enough,” Dr. Desch said.

That statement is supported by the Lancet Respiratory Medicine Commission on the future of cystic fibrosis care, whose members noted in 2019 that “epidemiological studies in the past 2 decades have shown that cystic fibrosis occurs and is more frequent than was previously thought in populations of non-European descent, and the disease is now recognized in many regions of the world.”

The commission members noted that the costs of adequate CF care may be beyond the reach of many patients in developing nations.

Still, if the substantial barriers of cost and access can be overcome, the future will continue to look brighter for patients with CF. As Dr. Sweezey put it: “There are studies that are pushing lower age limits for using these modulators, and as the evidence builds for the efficacy and safety at younger ages, I think all of us are hoping that we’ll end up being able to use either the current or future modulators to actually prevent trouble in CF, rather than trying to come along and fix it after it’s been there.”

Dr. Brown disclosed advisory board activity for Vertex that ended prior to her joining the CF Foundation. Dr. Desch, Dr. Goss, and Dr. Sweezey reported no relevant conflicts of interest.

In 1938, the year that cystic fibrosis (CF) was first described clinically, four of five children born with the disease did not live past their first birthdays.

In 2019, the median age at death for patients enrolled in the Cystic Fibrosis Foundation (CFF) registry was 32 years, and the predicted life expectancy for patients with CF who were born from 2015 through 2019 was 46 years.

Blausen.com staff (2014). &amp;quot;Medical gallery of Blausen Medical Blausen.com staff (2014). &amp;quot;Medical gallery of Blausen Medical 2014&amp;quot;. WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.010. ISSN 2002-4436.

Those numbers reflect the remarkable progress made in the past 4 decades in the care of patients with CF, but also highlight the obstacles ahead, given that the predicted life expectancy for the overall U.S. population in 2019 (pre–COVID-19) was 78.9 years.

Julie Desch, MD, is a CF survivor who has beaten the odds and then some. At age 61, the retired surgical pathologist is a CF patient advocate, speaker, and a board member of the Cystic Fibrosis Research Institute, a not-for-profit organization that funds CF research and offers education, advocacy, and psychosocial support for persons with CF and their families and caregivers.

In an interview, Dr. Desch said that while there has been remarkable progress in her lifetime in the field of CF research and treatment, particularly in the development of drugs that modulate function of the underlying cause of approximately 90% of CF cases, there are still many CF patients who cannot benefit from these therapies.

“There are still 10% of people who don’t make a protein to be modified, so that’s a huge unmet need,” she said.
 

Genetic disorder

CF is a chronic autosomal recessive disorder with multiorgan and multisystem manifestations. It is caused by mutations in the CFTR gene, which codes for the protein CF transmembrane conductance regulator. CFTR controls transport of chloride ions across cell membranes, specifically the apical membrane of epithelial cells in tissues of the airways, intestinal tract, pancreas, kidneys, sweat glands, and the reproductive system, notably the vas deferens in males.

Emw/Wikimedia Commons/CC BY-SA 3.0

The F508 deletion (F508del) mutation is the most common, occurring in approximately 70% of persons with CF. It is a class 2-type protein processing mutation, leading to defects in cellular processing, protein stability, and chloride channel gating defects.

The CFTR protein also secretes bicarbonate to regulate the pH of airway surface liquid, and inhibits the epithelial sodium channel, which mediates passive sodium transport across apical membranes of sodium-absorbing epithelial cells in the kidneys, intestine, and airways.

CF typically presents with the buildup in the lungs of abnormally viscous and sticky mucus leading to frequent, severe infections, particularly with Pseudomonas aeruginosa, progressive lung damage and, prior to the development of effective disease management, to premature death. The phenotype often includes malnutrition due to malabsorption, and failure to thrive.
 

Diagnosis

In all 50 U.S. states and the District of Columbia, newborns are screened for CF with an assay for immunoreactive trypsinogen (IRT) an indirect marker for pancreatic injury that is elevated in serum in most newborns with CF, but also detected in premature infants or those delivered under stressful circumstances. In some states newborns are tested only for IRT, with a diagnosis confirmed with a sweat chloride test and/or a CFTR mutation panel.

Treatment

There is no cure for CF, but the discovery of the gene in 1989 by Canadian and U.S. investigators has led to life-prolonging therapeutic interventions, specifically the development of CFTR modulators.

CFTR modulators include potentiators such as ivacaftor (Kalydeco), and correctors such as lumacaftor and tezacaftor (available in the combination Orkambi), and most recently in the triple combination of elexacaftor, tezacaftor, and ivacaftor (Trikafta; ETI).

Neil Sweezey, MD, FRCPC, a CF expert at The Hospital for Sick Children (SickKids) in Toronto, told this news organization that the ideal therapy for CF, genetic correction of the underlying mutations, is still not feasible, but that CFTR modulators are a close second.

“For 90% of patients, the three-drug combination Trikafta has been shown to be quite safe, quite tolerable, and quite remarkably beneficial,” he said.

In a study reported at CHEST 2021 by investigators from Nationwide Children’s Hospital in Columbus, Ohio, 32 adults who were started on the triple combination had significantly improved in forced expiratory volume in 1 second (FEV₁), gain in body mass index, decreased sweat chloride and decreased colonization by Pseudomonas species. In addition, patients had significant improvements in blood inflammatory markers.

Christopher H. Goss, MD, FCCP, professor of pulmonary critical care and sleep medicine and professor of pediatrics at the University of Washington in Seattle, agreed that with the availability of the triple combination, “these are extraordinary times. An astounding fact is that most patients have complete resolution of cough, and the exacerbation rates have just plummeted,” he said in an interview.

Some of the reductions in exacerbations may be attributable to the COVID-19 pandemic, he noted, because patients in isolation have less exposure to circulating respiratory viruses.

“But it has been miraculous, and the clinical effect is certainly still more astounding than the effects of ivacaftor, which was the first truly breakthrough drug. Weight goes up, well-being increases, and the population lung function has shifted up to better grade lung function, in the entire population,” he said.

In addition, the need for lung and heart transplantation has sharply declined.

“I had a patient who had decided to forgo transplantation, despite absolutely horrible lung function, and he’s now bowling and leading a very productive life, when before he had been preparing for end of life,” Dr. Goss said.

Dr. Sweezey emphasized that as with all medications, patients being started on the triple combination require close monitoring for potential adverse events that might require dose modification or, for a small number of patients, withdrawal.


 

Burden of care

CFTR modulators have reduced but not eliminated the need for some patients to have mucolytic therapy, which may include dornase alfa, a recombinant human deoxyribonuclease (DNase) that reduces the viscosity of lung secretions, hypertonic saline inhaled twice daily (for patients 12 and older), mannitol, and physical manipulations to help patients clear mucus. This can include both manual percussion and the use of devices for high-frequency chest wall oscillation.

The complex nature of CF often requires a combination of other therapies to address comorbidities. These therapies may include infection prophylaxis and treatment with antibiotics and antifungals, nutrition support, and therapy for CF-related complications, including gastrointestinal issues, liver diseases, diabetes, and osteopenia that may be related to poor nutrient absorption, chronic inflammation, or other sequelae of CF.

In addition, patients often require frequent CF care center visits – ideally a minimum of every 3 months – which can result in significant loss of work or school time.

“Outcomes for patients in the long run have been absolutely proven to be best if they’re followed in big, established, multidisciplinary well-organized CF centers,” Dr. Sweezey said. “In the United States and Canada if you’re looked after on a regular basis, which means quarterly, every 3 months – whether you need it or not, you really do need it – and if the patients are seen and assessed and checked every 3 months all of their lives, they have small changes caught early, whether it’s an infection you can slap down with medication or a nutrition problem that may be affecting a child’s growth and development.”

“We’re really kind of at a pivotal moment in CF, where we realize things are changing,” said A. Whitney Brown, MD, senior director for clinical affairs at the Cystic Fibrosis Foundation, and an adult CF and lung transplant physician in the Inova Advanced Lung Disease Program in Falls Church, Va.

“Patient needs and interest have evolved, because of the pandemic and because of the highly effective modulator therapy, but we want to take great effort to study it in a rigorous way, to make sure that as we are agile and adapt the care model, that we can maintain the same quality outcomes that we have traditionally done,” she said in an interview.

The Lancet Respiratory Medicine Commission on the future of CF care states that models of care “need to consider management approaches (including disease monitoring) to maintain health and delay lung transplantation, while minimizing the burden of care for patients and their families.”
 

‘A great problem to have’

One of the most significant changes in CF care has been the growing population of CF patients like Dr. Desch who are living well into adulthood, with some approaching Medicare eligibility.

With the advent of triple therapy and CFTR modulators being started earlier in life, lung function can be preserved, damage to other organs can be minimized, and life expectancy for patients with CF will continue to improve.

“We’re anticipating that there may be some needs in the aging CF population that are different than what we have historically had,” Dr. Brown said. “Will there be geriatric providers that need to become experts in CF care? That’s a great problem to have,” she said.

Dr. Goss agreed, noting that CF is steadily shifting from a near uniformly fatal disease to a chronic disorder that in many cases can be managed “with a complex regimen of novel drugs, much like HIV.”

He noted that there are multiple drug interactions with the triple combination, “so it’s really important that people don’t start a CF patient on a drug without consulting a pharmacist, because you can totally inactivate ETI, or augment it dramatically, and we’ve seen both happen.”
 

Cost and access

All experts interviewed for this article agreed that while the care of patients with CF has improved exponentially over the last few decades, there are still troubling inequities in care.

One of the largest impediments is the cost of care, with the triple combination costing more than $300,000 per year.

“Clearly patients aren’t paying that, but insurance companies are, and that’s causing all kinds of trickle-down effects that definitely affect patients. The patients like myself who are able to have insurance that covers it benefit, but there are so many people that don’t,” Dr. Desch said.

Dr. Sweezey noted that prior to the advent of ETI, patients with CF in Canada had better outcomes and longer life expectancy than did similar patients in the United States because of universal access to care and coordinated services under Canada’s health care system, compared with the highly fragmented and inefficient U.S. system. He added that the wider availability of ETI in the United States vs. Canada may begin to narrow that gap, however.

As noted before, there is a substantial proportion of patients – an estimated 10% – who have CFTR mutations that are not correctable by currently available CFTR modulators, and these patients are at significant risk for irreversible airway complications and lung damage.

In addition, although CF occurs most frequently among people of White ancestry, the disease does not respect distinctions of race or ethnicity.

“It’s not just [Whites] – a lot of people from different racial backgrounds, ethnic backgrounds, are not being diagnosed or are not being diagnosed soon enough to have effective care early enough,” Dr. Desch said.

That statement is supported by the Lancet Respiratory Medicine Commission on the future of cystic fibrosis care, whose members noted in 2019 that “epidemiological studies in the past 2 decades have shown that cystic fibrosis occurs and is more frequent than was previously thought in populations of non-European descent, and the disease is now recognized in many regions of the world.”

The commission members noted that the costs of adequate CF care may be beyond the reach of many patients in developing nations.

Still, if the substantial barriers of cost and access can be overcome, the future will continue to look brighter for patients with CF. As Dr. Sweezey put it: “There are studies that are pushing lower age limits for using these modulators, and as the evidence builds for the efficacy and safety at younger ages, I think all of us are hoping that we’ll end up being able to use either the current or future modulators to actually prevent trouble in CF, rather than trying to come along and fix it after it’s been there.”

Dr. Brown disclosed advisory board activity for Vertex that ended prior to her joining the CF Foundation. Dr. Desch, Dr. Goss, and Dr. Sweezey reported no relevant conflicts of interest.

In 1938, the year that cystic fibrosis (CF) was first described clinically, four of five children born with the disease did not live past their first birthdays.

In 2019, the median age at death for patients enrolled in the Cystic Fibrosis Foundation (CFF) registry was 32 years, and the predicted life expectancy for patients with CF who were born from 2015 through 2019 was 46 years.

Blausen.com staff (2014). &amp;quot;Medical gallery of Blausen Medical Blausen.com staff (2014). &amp;quot;Medical gallery of Blausen Medical 2014&amp;quot;. WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.010. ISSN 2002-4436.

Those numbers reflect the remarkable progress made in the past 4 decades in the care of patients with CF, but also highlight the obstacles ahead, given that the predicted life expectancy for the overall U.S. population in 2019 (pre–COVID-19) was 78.9 years.

Julie Desch, MD, is a CF survivor who has beaten the odds and then some. At age 61, the retired surgical pathologist is a CF patient advocate, speaker, and a board member of the Cystic Fibrosis Research Institute, a not-for-profit organization that funds CF research and offers education, advocacy, and psychosocial support for persons with CF and their families and caregivers.

In an interview, Dr. Desch said that while there has been remarkable progress in her lifetime in the field of CF research and treatment, particularly in the development of drugs that modulate function of the underlying cause of approximately 90% of CF cases, there are still many CF patients who cannot benefit from these therapies.

“There are still 10% of people who don’t make a protein to be modified, so that’s a huge unmet need,” she said.
 

Genetic disorder

CF is a chronic autosomal recessive disorder with multiorgan and multisystem manifestations. It is caused by mutations in the CFTR gene, which codes for the protein CF transmembrane conductance regulator. CFTR controls transport of chloride ions across cell membranes, specifically the apical membrane of epithelial cells in tissues of the airways, intestinal tract, pancreas, kidneys, sweat glands, and the reproductive system, notably the vas deferens in males.

Emw/Wikimedia Commons/CC BY-SA 3.0

The F508 deletion (F508del) mutation is the most common, occurring in approximately 70% of persons with CF. It is a class 2-type protein processing mutation, leading to defects in cellular processing, protein stability, and chloride channel gating defects.

The CFTR protein also secretes bicarbonate to regulate the pH of airway surface liquid, and inhibits the epithelial sodium channel, which mediates passive sodium transport across apical membranes of sodium-absorbing epithelial cells in the kidneys, intestine, and airways.

CF typically presents with the buildup in the lungs of abnormally viscous and sticky mucus leading to frequent, severe infections, particularly with Pseudomonas aeruginosa, progressive lung damage and, prior to the development of effective disease management, to premature death. The phenotype often includes malnutrition due to malabsorption, and failure to thrive.
 

Diagnosis

In all 50 U.S. states and the District of Columbia, newborns are screened for CF with an assay for immunoreactive trypsinogen (IRT) an indirect marker for pancreatic injury that is elevated in serum in most newborns with CF, but also detected in premature infants or those delivered under stressful circumstances. In some states newborns are tested only for IRT, with a diagnosis confirmed with a sweat chloride test and/or a CFTR mutation panel.

Treatment

There is no cure for CF, but the discovery of the gene in 1989 by Canadian and U.S. investigators has led to life-prolonging therapeutic interventions, specifically the development of CFTR modulators.

CFTR modulators include potentiators such as ivacaftor (Kalydeco), and correctors such as lumacaftor and tezacaftor (available in the combination Orkambi), and most recently in the triple combination of elexacaftor, tezacaftor, and ivacaftor (Trikafta; ETI).

Neil Sweezey, MD, FRCPC, a CF expert at The Hospital for Sick Children (SickKids) in Toronto, told this news organization that the ideal therapy for CF, genetic correction of the underlying mutations, is still not feasible, but that CFTR modulators are a close second.

“For 90% of patients, the three-drug combination Trikafta has been shown to be quite safe, quite tolerable, and quite remarkably beneficial,” he said.

In a study reported at CHEST 2021 by investigators from Nationwide Children’s Hospital in Columbus, Ohio, 32 adults who were started on the triple combination had significantly improved in forced expiratory volume in 1 second (FEV₁), gain in body mass index, decreased sweat chloride and decreased colonization by Pseudomonas species. In addition, patients had significant improvements in blood inflammatory markers.

Christopher H. Goss, MD, FCCP, professor of pulmonary critical care and sleep medicine and professor of pediatrics at the University of Washington in Seattle, agreed that with the availability of the triple combination, “these are extraordinary times. An astounding fact is that most patients have complete resolution of cough, and the exacerbation rates have just plummeted,” he said in an interview.

Some of the reductions in exacerbations may be attributable to the COVID-19 pandemic, he noted, because patients in isolation have less exposure to circulating respiratory viruses.

“But it has been miraculous, and the clinical effect is certainly still more astounding than the effects of ivacaftor, which was the first truly breakthrough drug. Weight goes up, well-being increases, and the population lung function has shifted up to better grade lung function, in the entire population,” he said.

In addition, the need for lung and heart transplantation has sharply declined.

“I had a patient who had decided to forgo transplantation, despite absolutely horrible lung function, and he’s now bowling and leading a very productive life, when before he had been preparing for end of life,” Dr. Goss said.

Dr. Sweezey emphasized that as with all medications, patients being started on the triple combination require close monitoring for potential adverse events that might require dose modification or, for a small number of patients, withdrawal.


 

Burden of care

CFTR modulators have reduced but not eliminated the need for some patients to have mucolytic therapy, which may include dornase alfa, a recombinant human deoxyribonuclease (DNase) that reduces the viscosity of lung secretions, hypertonic saline inhaled twice daily (for patients 12 and older), mannitol, and physical manipulations to help patients clear mucus. This can include both manual percussion and the use of devices for high-frequency chest wall oscillation.

The complex nature of CF often requires a combination of other therapies to address comorbidities. These therapies may include infection prophylaxis and treatment with antibiotics and antifungals, nutrition support, and therapy for CF-related complications, including gastrointestinal issues, liver diseases, diabetes, and osteopenia that may be related to poor nutrient absorption, chronic inflammation, or other sequelae of CF.

In addition, patients often require frequent CF care center visits – ideally a minimum of every 3 months – which can result in significant loss of work or school time.

“Outcomes for patients in the long run have been absolutely proven to be best if they’re followed in big, established, multidisciplinary well-organized CF centers,” Dr. Sweezey said. “In the United States and Canada if you’re looked after on a regular basis, which means quarterly, every 3 months – whether you need it or not, you really do need it – and if the patients are seen and assessed and checked every 3 months all of their lives, they have small changes caught early, whether it’s an infection you can slap down with medication or a nutrition problem that may be affecting a child’s growth and development.”

“We’re really kind of at a pivotal moment in CF, where we realize things are changing,” said A. Whitney Brown, MD, senior director for clinical affairs at the Cystic Fibrosis Foundation, and an adult CF and lung transplant physician in the Inova Advanced Lung Disease Program in Falls Church, Va.

“Patient needs and interest have evolved, because of the pandemic and because of the highly effective modulator therapy, but we want to take great effort to study it in a rigorous way, to make sure that as we are agile and adapt the care model, that we can maintain the same quality outcomes that we have traditionally done,” she said in an interview.

The Lancet Respiratory Medicine Commission on the future of CF care states that models of care “need to consider management approaches (including disease monitoring) to maintain health and delay lung transplantation, while minimizing the burden of care for patients and their families.”
 

‘A great problem to have’

One of the most significant changes in CF care has been the growing population of CF patients like Dr. Desch who are living well into adulthood, with some approaching Medicare eligibility.

With the advent of triple therapy and CFTR modulators being started earlier in life, lung function can be preserved, damage to other organs can be minimized, and life expectancy for patients with CF will continue to improve.

“We’re anticipating that there may be some needs in the aging CF population that are different than what we have historically had,” Dr. Brown said. “Will there be geriatric providers that need to become experts in CF care? That’s a great problem to have,” she said.

Dr. Goss agreed, noting that CF is steadily shifting from a near uniformly fatal disease to a chronic disorder that in many cases can be managed “with a complex regimen of novel drugs, much like HIV.”

He noted that there are multiple drug interactions with the triple combination, “so it’s really important that people don’t start a CF patient on a drug without consulting a pharmacist, because you can totally inactivate ETI, or augment it dramatically, and we’ve seen both happen.”
 

Cost and access

All experts interviewed for this article agreed that while the care of patients with CF has improved exponentially over the last few decades, there are still troubling inequities in care.

One of the largest impediments is the cost of care, with the triple combination costing more than $300,000 per year.

“Clearly patients aren’t paying that, but insurance companies are, and that’s causing all kinds of trickle-down effects that definitely affect patients. The patients like myself who are able to have insurance that covers it benefit, but there are so many people that don’t,” Dr. Desch said.

Dr. Sweezey noted that prior to the advent of ETI, patients with CF in Canada had better outcomes and longer life expectancy than did similar patients in the United States because of universal access to care and coordinated services under Canada’s health care system, compared with the highly fragmented and inefficient U.S. system. He added that the wider availability of ETI in the United States vs. Canada may begin to narrow that gap, however.

As noted before, there is a substantial proportion of patients – an estimated 10% – who have CFTR mutations that are not correctable by currently available CFTR modulators, and these patients are at significant risk for irreversible airway complications and lung damage.

In addition, although CF occurs most frequently among people of White ancestry, the disease does not respect distinctions of race or ethnicity.

“It’s not just [Whites] – a lot of people from different racial backgrounds, ethnic backgrounds, are not being diagnosed or are not being diagnosed soon enough to have effective care early enough,” Dr. Desch said.

That statement is supported by the Lancet Respiratory Medicine Commission on the future of cystic fibrosis care, whose members noted in 2019 that “epidemiological studies in the past 2 decades have shown that cystic fibrosis occurs and is more frequent than was previously thought in populations of non-European descent, and the disease is now recognized in many regions of the world.”

The commission members noted that the costs of adequate CF care may be beyond the reach of many patients in developing nations.

Still, if the substantial barriers of cost and access can be overcome, the future will continue to look brighter for patients with CF. As Dr. Sweezey put it: “There are studies that are pushing lower age limits for using these modulators, and as the evidence builds for the efficacy and safety at younger ages, I think all of us are hoping that we’ll end up being able to use either the current or future modulators to actually prevent trouble in CF, rather than trying to come along and fix it after it’s been there.”

Dr. Brown disclosed advisory board activity for Vertex that ended prior to her joining the CF Foundation. Dr. Desch, Dr. Goss, and Dr. Sweezey reported no relevant conflicts of interest.

Lipedema – a disease that causes excess fat to accumulate primarily in the lower part of the body – is a condition “that most physicians in the U.S. don’t understand,” according to C. William Hanke, MD, MPH.

“This disease is well known in Europe, especially in the Netherlands, Germany, and Austria, but in this country, I believe most dermatologists have never heard of it,” Dr. Hanke said at the ODAC Dermatology, Aesthetic & Surgical Conference.

Clinically, patients with lipedema – also known as “two-body syndrome” – present with a symmetric, bilateral increase in subcutaneous fat, with “cuffs of fat” around the ankles. It usually affects the legs and thighs; the hands and feet are not affected.

“From the waist on up, the body looks like one person, and from the waist on down, it looks like an entirely different person,” said Dr. Hanke, a dermatologist who is program director for the micrographic surgery and dermatologic oncology fellowship training program at Ascension St. Vincent Hospital in Indianapolis. “Just think of the difficulty that the person has with their life in terms of buying clothes or social interactions. This is a devastating problem.”

Lipedema almost always affects women and is progressive from puberty. “Characteristically, patients have pain and bruise easily in the areas of lipedema,” said Dr. Hanke, who has served as president of the American Academy of Dermatology, the American Society for Dermatologic Surgery, the American College of Mohs Surgery, and the International Society for Dermatologic Surgery. The affected areas are painful to touch, making exercise uncomfortable for patients, he said.

Courtesy Dr. C. William Hanke.

Lipedema can be masked by obesity, “so, if you superimpose generalized obesity on lipedema, you have an even more difficult problem,” he added. “A physician who doesn’t understand the disease may perform standard nontumescent liposuction under general anesthesia, with cannulas, which traumatize lipedematous fat. Thereby, a patient with lipedema can then be inadvertently transformed into a patient with lympholipedema. Then you’ve got even an even worse problem.”

One might think that the rate of diabetes would be high among lipedema patients, “but diabetes is essentially nonexistent in this group,” he continued. However, patients with lipedema “may develop hypothyroidism, venous disease, joint pain, and fibrosis in the fat as the disease progresses.”
 

Lipedema stages, treatment

Lipedema is defined by three clinical stages: Stage one is characterized by an enlarged subcutaneous fat department, but the skin surface is smooth. In stage 2, the skin surface becomes wavy with irregularities and dents, and in stage 3, patients develop large deforming nodules and hanging flaps.

“If we can diagnose lipedema in the early stages and perform tumescent liposuction using tumescent local anesthesia, we can prevent the progression of the disease,” Dr. Hanke said. For patients who meet criteria for tumescent liposuction, three to six treatments may be required for stage 3 disease. “Tumescent local anesthesia should be used, because liposuction using tumescent local anesthesia is atraumatic to fat,” he said. “Usually, the most painful areas are treated first.”

In a single-center study from Germany that followed 85 patients who underwent tumescent liposuction for lipedema, researchers found that improvements in pain, bruising, and mobility were sustained at 4 and 8 years following the procedure. Patient quality of life and cosmetic appearance were also sustained.

In terms of liposuction’s cosmetic effects, “the goal of liposuction in lipedema patients is different,” Dr. Hanke said. “The goal is to get these people moving again, stabilize their weight, and minimize progression of the disease. Cosmetic improvement is secondary.”

A more recent follow-up study of 60 patients from the same single-center German study showed that the positive effects of liposuction lasted 12 years postoperatively without relevant progression of disease.

Following the first International Consensus Conference on Lipedema in Vienna in 2017, Dr. Hanke and colleagues published guidelines on preventing progression of lipedema with liposuction using tumescent local anesthesia.

“If patients with lipedema gain weight, the problem becomes even worse,” he said. “A sensible diet and nontraumatic exercise like water aerobics is ideal. If patients pursue yo-yo dieting, more and more fat stays in the legs after each cycle. Sometimes I’ll refer overweight patients with lipedema for a bariatric surgery consult.”

Dr. Hanke noted that Karen Herbst, MD, PhD, an endocrinologist at the University of Arizona, Tucson, who is widely considered an expert on the medical management of lipedema, has a website on lipedema care.

Dr. Hanke reported having no financial conflicts related to his presentation.
 

Lipedema – a disease that causes excess fat to accumulate primarily in the lower part of the body – is a condition “that most physicians in the U.S. don’t understand,” according to C. William Hanke, MD, MPH.

“This disease is well known in Europe, especially in the Netherlands, Germany, and Austria, but in this country, I believe most dermatologists have never heard of it,” Dr. Hanke said at the ODAC Dermatology, Aesthetic & Surgical Conference.

Clinically, patients with lipedema – also known as “two-body syndrome” – present with a symmetric, bilateral increase in subcutaneous fat, with “cuffs of fat” around the ankles. It usually affects the legs and thighs; the hands and feet are not affected.

“From the waist on up, the body looks like one person, and from the waist on down, it looks like an entirely different person,” said Dr. Hanke, a dermatologist who is program director for the micrographic surgery and dermatologic oncology fellowship training program at Ascension St. Vincent Hospital in Indianapolis. “Just think of the difficulty that the person has with their life in terms of buying clothes or social interactions. This is a devastating problem.”

Lipedema almost always affects women and is progressive from puberty. “Characteristically, patients have pain and bruise easily in the areas of lipedema,” said Dr. Hanke, who has served as president of the American Academy of Dermatology, the American Society for Dermatologic Surgery, the American College of Mohs Surgery, and the International Society for Dermatologic Surgery. The affected areas are painful to touch, making exercise uncomfortable for patients, he said.

Courtesy Dr. C. William Hanke.

Lipedema can be masked by obesity, “so, if you superimpose generalized obesity on lipedema, you have an even more difficult problem,” he added. “A physician who doesn’t understand the disease may perform standard nontumescent liposuction under general anesthesia, with cannulas, which traumatize lipedematous fat. Thereby, a patient with lipedema can then be inadvertently transformed into a patient with lympholipedema. Then you’ve got even an even worse problem.”

One might think that the rate of diabetes would be high among lipedema patients, “but diabetes is essentially nonexistent in this group,” he continued. However, patients with lipedema “may develop hypothyroidism, venous disease, joint pain, and fibrosis in the fat as the disease progresses.”
 

Lipedema stages, treatment

Lipedema is defined by three clinical stages: Stage one is characterized by an enlarged subcutaneous fat department, but the skin surface is smooth. In stage 2, the skin surface becomes wavy with irregularities and dents, and in stage 3, patients develop large deforming nodules and hanging flaps.

“If we can diagnose lipedema in the early stages and perform tumescent liposuction using tumescent local anesthesia, we can prevent the progression of the disease,” Dr. Hanke said. For patients who meet criteria for tumescent liposuction, three to six treatments may be required for stage 3 disease. “Tumescent local anesthesia should be used, because liposuction using tumescent local anesthesia is atraumatic to fat,” he said. “Usually, the most painful areas are treated first.”

In a single-center study from Germany that followed 85 patients who underwent tumescent liposuction for lipedema, researchers found that improvements in pain, bruising, and mobility were sustained at 4 and 8 years following the procedure. Patient quality of life and cosmetic appearance were also sustained.

In terms of liposuction’s cosmetic effects, “the goal of liposuction in lipedema patients is different,” Dr. Hanke said. “The goal is to get these people moving again, stabilize their weight, and minimize progression of the disease. Cosmetic improvement is secondary.”

A more recent follow-up study of 60 patients from the same single-center German study showed that the positive effects of liposuction lasted 12 years postoperatively without relevant progression of disease.

Following the first International Consensus Conference on Lipedema in Vienna in 2017, Dr. Hanke and colleagues published guidelines on preventing progression of lipedema with liposuction using tumescent local anesthesia.

“If patients with lipedema gain weight, the problem becomes even worse,” he said. “A sensible diet and nontraumatic exercise like water aerobics is ideal. If patients pursue yo-yo dieting, more and more fat stays in the legs after each cycle. Sometimes I’ll refer overweight patients with lipedema for a bariatric surgery consult.”

Dr. Hanke noted that Karen Herbst, MD, PhD, an endocrinologist at the University of Arizona, Tucson, who is widely considered an expert on the medical management of lipedema, has a website on lipedema care.

Dr. Hanke reported having no financial conflicts related to his presentation.
 

Lipedema – a disease that causes excess fat to accumulate primarily in the lower part of the body – is a condition “that most physicians in the U.S. don’t understand,” according to C. William Hanke, MD, MPH.

“This disease is well known in Europe, especially in the Netherlands, Germany, and Austria, but in this country, I believe most dermatologists have never heard of it,” Dr. Hanke said at the ODAC Dermatology, Aesthetic & Surgical Conference.

Clinically, patients with lipedema – also known as “two-body syndrome” – present with a symmetric, bilateral increase in subcutaneous fat, with “cuffs of fat” around the ankles. It usually affects the legs and thighs; the hands and feet are not affected.

“From the waist on up, the body looks like one person, and from the waist on down, it looks like an entirely different person,” said Dr. Hanke, a dermatologist who is program director for the micrographic surgery and dermatologic oncology fellowship training program at Ascension St. Vincent Hospital in Indianapolis. “Just think of the difficulty that the person has with their life in terms of buying clothes or social interactions. This is a devastating problem.”

Lipedema almost always affects women and is progressive from puberty. “Characteristically, patients have pain and bruise easily in the areas of lipedema,” said Dr. Hanke, who has served as president of the American Academy of Dermatology, the American Society for Dermatologic Surgery, the American College of Mohs Surgery, and the International Society for Dermatologic Surgery. The affected areas are painful to touch, making exercise uncomfortable for patients, he said.

Courtesy Dr. C. William Hanke.

Lipedema can be masked by obesity, “so, if you superimpose generalized obesity on lipedema, you have an even more difficult problem,” he added. “A physician who doesn’t understand the disease may perform standard nontumescent liposuction under general anesthesia, with cannulas, which traumatize lipedematous fat. Thereby, a patient with lipedema can then be inadvertently transformed into a patient with lympholipedema. Then you’ve got even an even worse problem.”

One might think that the rate of diabetes would be high among lipedema patients, “but diabetes is essentially nonexistent in this group,” he continued. However, patients with lipedema “may develop hypothyroidism, venous disease, joint pain, and fibrosis in the fat as the disease progresses.”
 

Lipedema stages, treatment

Lipedema is defined by three clinical stages: Stage one is characterized by an enlarged subcutaneous fat department, but the skin surface is smooth. In stage 2, the skin surface becomes wavy with irregularities and dents, and in stage 3, patients develop large deforming nodules and hanging flaps.

“If we can diagnose lipedema in the early stages and perform tumescent liposuction using tumescent local anesthesia, we can prevent the progression of the disease,” Dr. Hanke said. For patients who meet criteria for tumescent liposuction, three to six treatments may be required for stage 3 disease. “Tumescent local anesthesia should be used, because liposuction using tumescent local anesthesia is atraumatic to fat,” he said. “Usually, the most painful areas are treated first.”

In a single-center study from Germany that followed 85 patients who underwent tumescent liposuction for lipedema, researchers found that improvements in pain, bruising, and mobility were sustained at 4 and 8 years following the procedure. Patient quality of life and cosmetic appearance were also sustained.

In terms of liposuction’s cosmetic effects, “the goal of liposuction in lipedema patients is different,” Dr. Hanke said. “The goal is to get these people moving again, stabilize their weight, and minimize progression of the disease. Cosmetic improvement is secondary.”

A more recent follow-up study of 60 patients from the same single-center German study showed that the positive effects of liposuction lasted 12 years postoperatively without relevant progression of disease.

Following the first International Consensus Conference on Lipedema in Vienna in 2017, Dr. Hanke and colleagues published guidelines on preventing progression of lipedema with liposuction using tumescent local anesthesia.

“If patients with lipedema gain weight, the problem becomes even worse,” he said. “A sensible diet and nontraumatic exercise like water aerobics is ideal. If patients pursue yo-yo dieting, more and more fat stays in the legs after each cycle. Sometimes I’ll refer overweight patients with lipedema for a bariatric surgery consult.”

Dr. Hanke noted that Karen Herbst, MD, PhD, an endocrinologist at the University of Arizona, Tucson, who is widely considered an expert on the medical management of lipedema, has a website on lipedema care.

Dr. Hanke reported having no financial conflicts related to his presentation.
 

The Food and Drug Administration has approved levoketoconazole (Recorlev, Xeris Biopharma) for the treatment of endogenous hypercortisolemia in adults with Cushing syndrome for whom surgery is not possible or was not curative.

Endogenous Cushing syndrome is a relatively rare condition characterized by chronically elevated cortisol levels, typically arising from a benign pituitary tumor. Left untreated, it can lead to reproductive problems and hirsutism in women, as well as serious complications, including diabetes, hypertension, tissue fragility, and mood disorders. Half of patients will die within 5 years if left untreated.

Olivier Le Moal/Getty Images

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

The Food and Drug Administration has approved levoketoconazole (Recorlev, Xeris Biopharma) for the treatment of endogenous hypercortisolemia in adults with Cushing syndrome for whom surgery is not possible or was not curative.

Endogenous Cushing syndrome is a relatively rare condition characterized by chronically elevated cortisol levels, typically arising from a benign pituitary tumor. Left untreated, it can lead to reproductive problems and hirsutism in women, as well as serious complications, including diabetes, hypertension, tissue fragility, and mood disorders. Half of patients will die within 5 years if left untreated.

Olivier Le Moal/Getty Images

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

The Food and Drug Administration has approved levoketoconazole (Recorlev, Xeris Biopharma) for the treatment of endogenous hypercortisolemia in adults with Cushing syndrome for whom surgery is not possible or was not curative.

Endogenous Cushing syndrome is a relatively rare condition characterized by chronically elevated cortisol levels, typically arising from a benign pituitary tumor. Left untreated, it can lead to reproductive problems and hirsutism in women, as well as serious complications, including diabetes, hypertension, tissue fragility, and mood disorders. Half of patients will die within 5 years if left untreated.

Olivier Le Moal/Getty Images

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