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High CD86+pDC counts may predict CML relapses
Patients with chronic myeloid leukemia (CML) with high CD86+pDC counts had a higher risk of relapse after discontinuing tyrosine kinase inhibitor (TKI) therapy, according to new findings published in Leukemia.
Of patients who achieve a deep molecular remission, only a minority are able to sustain it and remain off therapy. Even when deep remission is achieved, TKI therapy fails to eradicate CML stem cells, which can perpetuate disease.
“This is clinically reflected by the long-term persistence of BCR-ABL messenger RNA (mRNA) in the majority of patients,” wrote C. Schütz, MD, of the University Hospital Marburg (Germany) and colleagues (Leukemia. 2017 Apr;31[4]:829-36). “Even with undetectable BCR-ABL mRNA levels, patients frequently relapse after TKI cessation.”
The researchers investigated whether the expression of the T-cell inhibitory receptor (CTLA-4)-ligand CD86 (B7.2) on plasmacytoid dendritic cells (pDC) could have an effect on the risk of relapse in CML patients who discontinue TKI therapy after achieving remission.
The frequency of CD86+pDC was analyzed in 14 CML patients who were in treatment-free remission, in 130 patients in molecular remission who were part of the CML-V study, and prospectively in 122 EURO-SKI patients right before they discontinued TKI therapy.
The authors found that CML patients in molecular remission had a significantly higher frequency of CD86+pDC expression, compared with normal donors (P less than .0024). In contrast, those who were in treatment-free remission had consistently low CD86+pDC.
These results suggest that low CD86+pDC could be predictive of treatment-free remission.
To test the hypothesis that low CD86+pDC frequencies during TKI-induced molecular remission were associated with a lower risk of molecular relapse after stopping TKI therapy, the study authors measured CD86+pDC levels in the 122 EURO-SKI patients before they stopped therapy, and then prospectively monitored them for relapse.
Findings showed that the 122 EURO-SKI patients had a significantly higher CD86+pDC frequency than did 8 healthy donors (median, 20.8% vs. 7.3%; P = .0024).
When matched with the treatment-free remission patients, the 73 patients in the EURO-SKI group who did not relapse within the first 12 months after stopping therapy had a significantly lower median frequency of CD86+pDC at baseline, compared with the 49 patients who did relapse (P = .014).
Patients who relapsed also demonstrated higher absolute CD86+pDC counts (CD86+pDC per 105 lymphocytes) at baseline (median, 86.1 vs. 50.6; P = .0147).
Based on the findings, the authors noted that they provided “for the first time evidence that relapse biology after TKI discontinuation depends on the quantity of activated pDC and a T-cell exhaustion phenotype, rather than TKI pretreatment duration per se.”
The Clinical Research Group of the German Research Foundation and the German José Carreras Leukaemia Foundation funded the study. Several of the authors report relationships with Ariad, Bristol-Myers Squibb, Novartis, and Pfizer.
Patients with chronic myeloid leukemia (CML) with high CD86+pDC counts had a higher risk of relapse after discontinuing tyrosine kinase inhibitor (TKI) therapy, according to new findings published in Leukemia.
Of patients who achieve a deep molecular remission, only a minority are able to sustain it and remain off therapy. Even when deep remission is achieved, TKI therapy fails to eradicate CML stem cells, which can perpetuate disease.
“This is clinically reflected by the long-term persistence of BCR-ABL messenger RNA (mRNA) in the majority of patients,” wrote C. Schütz, MD, of the University Hospital Marburg (Germany) and colleagues (Leukemia. 2017 Apr;31[4]:829-36). “Even with undetectable BCR-ABL mRNA levels, patients frequently relapse after TKI cessation.”
The researchers investigated whether the expression of the T-cell inhibitory receptor (CTLA-4)-ligand CD86 (B7.2) on plasmacytoid dendritic cells (pDC) could have an effect on the risk of relapse in CML patients who discontinue TKI therapy after achieving remission.
The frequency of CD86+pDC was analyzed in 14 CML patients who were in treatment-free remission, in 130 patients in molecular remission who were part of the CML-V study, and prospectively in 122 EURO-SKI patients right before they discontinued TKI therapy.
The authors found that CML patients in molecular remission had a significantly higher frequency of CD86+pDC expression, compared with normal donors (P less than .0024). In contrast, those who were in treatment-free remission had consistently low CD86+pDC.
These results suggest that low CD86+pDC could be predictive of treatment-free remission.
To test the hypothesis that low CD86+pDC frequencies during TKI-induced molecular remission were associated with a lower risk of molecular relapse after stopping TKI therapy, the study authors measured CD86+pDC levels in the 122 EURO-SKI patients before they stopped therapy, and then prospectively monitored them for relapse.
Findings showed that the 122 EURO-SKI patients had a significantly higher CD86+pDC frequency than did 8 healthy donors (median, 20.8% vs. 7.3%; P = .0024).
When matched with the treatment-free remission patients, the 73 patients in the EURO-SKI group who did not relapse within the first 12 months after stopping therapy had a significantly lower median frequency of CD86+pDC at baseline, compared with the 49 patients who did relapse (P = .014).
Patients who relapsed also demonstrated higher absolute CD86+pDC counts (CD86+pDC per 105 lymphocytes) at baseline (median, 86.1 vs. 50.6; P = .0147).
Based on the findings, the authors noted that they provided “for the first time evidence that relapse biology after TKI discontinuation depends on the quantity of activated pDC and a T-cell exhaustion phenotype, rather than TKI pretreatment duration per se.”
The Clinical Research Group of the German Research Foundation and the German José Carreras Leukaemia Foundation funded the study. Several of the authors report relationships with Ariad, Bristol-Myers Squibb, Novartis, and Pfizer.
Patients with chronic myeloid leukemia (CML) with high CD86+pDC counts had a higher risk of relapse after discontinuing tyrosine kinase inhibitor (TKI) therapy, according to new findings published in Leukemia.
Of patients who achieve a deep molecular remission, only a minority are able to sustain it and remain off therapy. Even when deep remission is achieved, TKI therapy fails to eradicate CML stem cells, which can perpetuate disease.
“This is clinically reflected by the long-term persistence of BCR-ABL messenger RNA (mRNA) in the majority of patients,” wrote C. Schütz, MD, of the University Hospital Marburg (Germany) and colleagues (Leukemia. 2017 Apr;31[4]:829-36). “Even with undetectable BCR-ABL mRNA levels, patients frequently relapse after TKI cessation.”
The researchers investigated whether the expression of the T-cell inhibitory receptor (CTLA-4)-ligand CD86 (B7.2) on plasmacytoid dendritic cells (pDC) could have an effect on the risk of relapse in CML patients who discontinue TKI therapy after achieving remission.
The frequency of CD86+pDC was analyzed in 14 CML patients who were in treatment-free remission, in 130 patients in molecular remission who were part of the CML-V study, and prospectively in 122 EURO-SKI patients right before they discontinued TKI therapy.
The authors found that CML patients in molecular remission had a significantly higher frequency of CD86+pDC expression, compared with normal donors (P less than .0024). In contrast, those who were in treatment-free remission had consistently low CD86+pDC.
These results suggest that low CD86+pDC could be predictive of treatment-free remission.
To test the hypothesis that low CD86+pDC frequencies during TKI-induced molecular remission were associated with a lower risk of molecular relapse after stopping TKI therapy, the study authors measured CD86+pDC levels in the 122 EURO-SKI patients before they stopped therapy, and then prospectively monitored them for relapse.
Findings showed that the 122 EURO-SKI patients had a significantly higher CD86+pDC frequency than did 8 healthy donors (median, 20.8% vs. 7.3%; P = .0024).
When matched with the treatment-free remission patients, the 73 patients in the EURO-SKI group who did not relapse within the first 12 months after stopping therapy had a significantly lower median frequency of CD86+pDC at baseline, compared with the 49 patients who did relapse (P = .014).
Patients who relapsed also demonstrated higher absolute CD86+pDC counts (CD86+pDC per 105 lymphocytes) at baseline (median, 86.1 vs. 50.6; P = .0147).
Based on the findings, the authors noted that they provided “for the first time evidence that relapse biology after TKI discontinuation depends on the quantity of activated pDC and a T-cell exhaustion phenotype, rather than TKI pretreatment duration per se.”
The Clinical Research Group of the German Research Foundation and the German José Carreras Leukaemia Foundation funded the study. Several of the authors report relationships with Ariad, Bristol-Myers Squibb, Novartis, and Pfizer.
FROM LEUKEMIA
Key clinical point: High CD86+pDC counts predicted relapses in CML patients who stopped TKI therapy.
Major finding: CML patients in molecular remission had significantly higher CD86+pDC frequencies, while patients in treatment-free remission had consistently low CD86+pDC.
Data source: A study that used patient cohorts (n = 14, n = 130, n = 122) at different stages of TKI discontinuation and remission.
Disclosures: The Clinical Research Group of the German Research Foundation and the German José Carreras Leukaemia Foundation funded the study. Several of the authors report relationships with Ariad, Bristol-Myers Squibb, Novartis, and Pfizer.
Proper UTI diagnosis, treatment relies on cautious approach
LAS VEGAS – Prudent use of catheters, cultures, and antibiotics are three keys to proper urinary tract diagnosis and management, according to a speaker at this year’s annual meeting of the Society of Hospital Medicine.
“We have not done very well with decreasing catheter-associated urinary tract infections,” said Jennifer Hanrahan, DO, an assistant professor of infectious disease medicine at Case Western Reserve University in Cleveland, Ohio, and an infectious disease physician at MetroHealth Medical Center, where she is the medical director for infection prevention. “The main reason is people don’t really think of i
The main way to reduce catheter-associated urinary tract infections is to avoid catheters, she said, noting “that’s obvious, but unnecessary catheters get put in all the time.”
Dr. Hanrahan recommended only putting them in when absolutely necessary, doing so in a sterile manner, and then continually monitoring whether the patient still needs the catheter.
Knowing when to obtain a urine culture is key to ensuring proper diagnosing and treatment for UTIs. A person who is asymptomatic does not need a culture, Dr. Hanrahan said during the well-attended, rapid-fire session. Those who do need a culture include septic patients with no apparent cause for their symptomatic presentation, despite a careful history taking and physical exam. Also, patients with pelvic pain, or flank tenderness for whom no cause can otherwise be determined should be cultured. It is also appropriate to screen for asymptomatic bacteriuria for pregnant patients, since it can be a sign of premature labor, and for patients about to undergo any invasive urologic procedure, Dr Hanrahan said.
“An awful lot of people have asymptomatic bacteriuria all the time,” she added, “and it doesn’t mean anything.”
Reasons to not culture include urine that smells “off” or that is cloudy or has sediment. “Anyone who has eaten asparagus knows that, after you eat it, your urine smells weird. It doesn’t mean you have a UTI,” she said.
She recommended against “pan culturing” in sepsis, and culturing “just because” when there is a clearly identifiable cause for the fever.
Once a diagnosis is made, Dr. Hanrahan urged physicians to avoid the overuse of antibiotics, suggesting that, whenever possible, the shortest possible course should be used. In order to help preserve antibiotic resistance, she also recommended using antibiotics that are not as prevalent, in order to help preserve antibiotic resistance. These could include nitrofurantoin and fosfomycin.
Dr. Hanrahan had no relevant financial disclosures.
[email protected]
On Twitter @whitneymcknight
LAS VEGAS – Prudent use of catheters, cultures, and antibiotics are three keys to proper urinary tract diagnosis and management, according to a speaker at this year’s annual meeting of the Society of Hospital Medicine.
“We have not done very well with decreasing catheter-associated urinary tract infections,” said Jennifer Hanrahan, DO, an assistant professor of infectious disease medicine at Case Western Reserve University in Cleveland, Ohio, and an infectious disease physician at MetroHealth Medical Center, where she is the medical director for infection prevention. “The main reason is people don’t really think of i
The main way to reduce catheter-associated urinary tract infections is to avoid catheters, she said, noting “that’s obvious, but unnecessary catheters get put in all the time.”
Dr. Hanrahan recommended only putting them in when absolutely necessary, doing so in a sterile manner, and then continually monitoring whether the patient still needs the catheter.
Knowing when to obtain a urine culture is key to ensuring proper diagnosing and treatment for UTIs. A person who is asymptomatic does not need a culture, Dr. Hanrahan said during the well-attended, rapid-fire session. Those who do need a culture include septic patients with no apparent cause for their symptomatic presentation, despite a careful history taking and physical exam. Also, patients with pelvic pain, or flank tenderness for whom no cause can otherwise be determined should be cultured. It is also appropriate to screen for asymptomatic bacteriuria for pregnant patients, since it can be a sign of premature labor, and for patients about to undergo any invasive urologic procedure, Dr Hanrahan said.
“An awful lot of people have asymptomatic bacteriuria all the time,” she added, “and it doesn’t mean anything.”
Reasons to not culture include urine that smells “off” or that is cloudy or has sediment. “Anyone who has eaten asparagus knows that, after you eat it, your urine smells weird. It doesn’t mean you have a UTI,” she said.
She recommended against “pan culturing” in sepsis, and culturing “just because” when there is a clearly identifiable cause for the fever.
Once a diagnosis is made, Dr. Hanrahan urged physicians to avoid the overuse of antibiotics, suggesting that, whenever possible, the shortest possible course should be used. In order to help preserve antibiotic resistance, she also recommended using antibiotics that are not as prevalent, in order to help preserve antibiotic resistance. These could include nitrofurantoin and fosfomycin.
Dr. Hanrahan had no relevant financial disclosures.
[email protected]
On Twitter @whitneymcknight
LAS VEGAS – Prudent use of catheters, cultures, and antibiotics are three keys to proper urinary tract diagnosis and management, according to a speaker at this year’s annual meeting of the Society of Hospital Medicine.
“We have not done very well with decreasing catheter-associated urinary tract infections,” said Jennifer Hanrahan, DO, an assistant professor of infectious disease medicine at Case Western Reserve University in Cleveland, Ohio, and an infectious disease physician at MetroHealth Medical Center, where she is the medical director for infection prevention. “The main reason is people don’t really think of i
The main way to reduce catheter-associated urinary tract infections is to avoid catheters, she said, noting “that’s obvious, but unnecessary catheters get put in all the time.”
Dr. Hanrahan recommended only putting them in when absolutely necessary, doing so in a sterile manner, and then continually monitoring whether the patient still needs the catheter.
Knowing when to obtain a urine culture is key to ensuring proper diagnosing and treatment for UTIs. A person who is asymptomatic does not need a culture, Dr. Hanrahan said during the well-attended, rapid-fire session. Those who do need a culture include septic patients with no apparent cause for their symptomatic presentation, despite a careful history taking and physical exam. Also, patients with pelvic pain, or flank tenderness for whom no cause can otherwise be determined should be cultured. It is also appropriate to screen for asymptomatic bacteriuria for pregnant patients, since it can be a sign of premature labor, and for patients about to undergo any invasive urologic procedure, Dr Hanrahan said.
“An awful lot of people have asymptomatic bacteriuria all the time,” she added, “and it doesn’t mean anything.”
Reasons to not culture include urine that smells “off” or that is cloudy or has sediment. “Anyone who has eaten asparagus knows that, after you eat it, your urine smells weird. It doesn’t mean you have a UTI,” she said.
She recommended against “pan culturing” in sepsis, and culturing “just because” when there is a clearly identifiable cause for the fever.
Once a diagnosis is made, Dr. Hanrahan urged physicians to avoid the overuse of antibiotics, suggesting that, whenever possible, the shortest possible course should be used. In order to help preserve antibiotic resistance, she also recommended using antibiotics that are not as prevalent, in order to help preserve antibiotic resistance. These could include nitrofurantoin and fosfomycin.
Dr. Hanrahan had no relevant financial disclosures.
[email protected]
On Twitter @whitneymcknight
Hospitalists offer tips on QI projects
Anjala Tess, MD, a hospitalist at Beth Israel Deaconess Medical Center and assistant professor of medicine at Harvard Medical School, Boston, asked the audience how many of them had done a quality improvement project that had failed. It was not a time to be bashful: Almost half the hospitalists in the room admitted that it had happened to them.
Dr. Tess and Darlene Tad-y, MD, chair of the Physicians-in-Training Committee and an assistant professor of medicine at the University of Colorado, were there to offer help in their session, “Adding to Your QI Toolbox.”
They highlighted three tools that they say are crucial to a project’s success: Creating a process map for clearly outlining how the project will work, interacting with stakeholders productively, and displaying data in a meaningful way.
Process mapping is a way of visualizing work or a process as distinct, ordered, and related steps, Dr. Tess said. Arranged on Post-It notes or written on a white board, the process should be one that can easily be updated. Seen objectively as a set of steps, it helps remove bias in how a process is viewed, she said.
“I would encourage you to do this on every QI project that you do where you are trying to accomplish something, because it makes a huge difference in understanding the work,” she said.
Stakeholder analysis – understanding the key people whose support could determine the success of the project – is also critical, she said. This can help get buy-in for the change, and it make a project stronger – and without it, you could doom your project, Dr. Tess said.
Doing this well involves understanding their financial and emotional interests, all the way down to whether they prefer face-to-face communication or e-mail, she said.
Then there’s the data. For it to matter, it must be presented well, and that requires context, Dr. Tad-y said.
“Data are just raw facts and figures,” she said. “Data are not the same as information.”
She suggested using run charts, in which data are plotted in some kind of order, usually chronological order. This kind of chart will typically include a median line, showing practice patterns before the QI project began, as well as a “goal line” to aim for, and notations on the timeline when changes were made, she said.
Others will be looking to the project manager for the meaning behind the data, she said.
“The story is going to come from you,” she said. “Otherwise, it’s just numbers.”
Anjala Tess, MD, a hospitalist at Beth Israel Deaconess Medical Center and assistant professor of medicine at Harvard Medical School, Boston, asked the audience how many of them had done a quality improvement project that had failed. It was not a time to be bashful: Almost half the hospitalists in the room admitted that it had happened to them.
Dr. Tess and Darlene Tad-y, MD, chair of the Physicians-in-Training Committee and an assistant professor of medicine at the University of Colorado, were there to offer help in their session, “Adding to Your QI Toolbox.”
They highlighted three tools that they say are crucial to a project’s success: Creating a process map for clearly outlining how the project will work, interacting with stakeholders productively, and displaying data in a meaningful way.
Process mapping is a way of visualizing work or a process as distinct, ordered, and related steps, Dr. Tess said. Arranged on Post-It notes or written on a white board, the process should be one that can easily be updated. Seen objectively as a set of steps, it helps remove bias in how a process is viewed, she said.
“I would encourage you to do this on every QI project that you do where you are trying to accomplish something, because it makes a huge difference in understanding the work,” she said.
Stakeholder analysis – understanding the key people whose support could determine the success of the project – is also critical, she said. This can help get buy-in for the change, and it make a project stronger – and without it, you could doom your project, Dr. Tess said.
Doing this well involves understanding their financial and emotional interests, all the way down to whether they prefer face-to-face communication or e-mail, she said.
Then there’s the data. For it to matter, it must be presented well, and that requires context, Dr. Tad-y said.
“Data are just raw facts and figures,” she said. “Data are not the same as information.”
She suggested using run charts, in which data are plotted in some kind of order, usually chronological order. This kind of chart will typically include a median line, showing practice patterns before the QI project began, as well as a “goal line” to aim for, and notations on the timeline when changes were made, she said.
Others will be looking to the project manager for the meaning behind the data, she said.
“The story is going to come from you,” she said. “Otherwise, it’s just numbers.”
Anjala Tess, MD, a hospitalist at Beth Israel Deaconess Medical Center and assistant professor of medicine at Harvard Medical School, Boston, asked the audience how many of them had done a quality improvement project that had failed. It was not a time to be bashful: Almost half the hospitalists in the room admitted that it had happened to them.
Dr. Tess and Darlene Tad-y, MD, chair of the Physicians-in-Training Committee and an assistant professor of medicine at the University of Colorado, were there to offer help in their session, “Adding to Your QI Toolbox.”
They highlighted three tools that they say are crucial to a project’s success: Creating a process map for clearly outlining how the project will work, interacting with stakeholders productively, and displaying data in a meaningful way.
Process mapping is a way of visualizing work or a process as distinct, ordered, and related steps, Dr. Tess said. Arranged on Post-It notes or written on a white board, the process should be one that can easily be updated. Seen objectively as a set of steps, it helps remove bias in how a process is viewed, she said.
“I would encourage you to do this on every QI project that you do where you are trying to accomplish something, because it makes a huge difference in understanding the work,” she said.
Stakeholder analysis – understanding the key people whose support could determine the success of the project – is also critical, she said. This can help get buy-in for the change, and it make a project stronger – and without it, you could doom your project, Dr. Tess said.
Doing this well involves understanding their financial and emotional interests, all the way down to whether they prefer face-to-face communication or e-mail, she said.
Then there’s the data. For it to matter, it must be presented well, and that requires context, Dr. Tad-y said.
“Data are just raw facts and figures,” she said. “Data are not the same as information.”
She suggested using run charts, in which data are plotted in some kind of order, usually chronological order. This kind of chart will typically include a median line, showing practice patterns before the QI project began, as well as a “goal line” to aim for, and notations on the timeline when changes were made, she said.
Others will be looking to the project manager for the meaning behind the data, she said.
“The story is going to come from you,” she said. “Otherwise, it’s just numbers.”
Work-life balance is not a ‘thing’ but alignment is
We are destined to fail at achieving work-life balance because it does not exist, nor has it ever existed, according to an expert on how people experience time.
The field of chronemics studies the space between people, namely how they communicate with others and with themselves as they experience life in a matrix, not just linearly.
“When we talk about time, we need to remember that context and communication really matter,” Dawna Ballard, PhD, a chronemics expert and associate professor of communication at the University of Texas at Austin, said during a session Tuesday. “We think of our concept of time as ‘truth,’ but when we experience other cultures, often we see they don’t function according to our idea of time.”
The modern concept of time as told by a clock was invented during the Industrial Age to control people and events by forcing a direct line between their lives outside the factory and the farm, according to Dr. Ballard. That is not to say that industrial time is bad. It is efficient and perhaps even necessary for organizing large groups of people, she said.
Time management as a concept evolved out of the ethos of “punching the clock” at the factory, but has carried over to the office where in fact, according to Dr. Ballard, people do not tend to be as effective if they are expected to work in a linear way, since that is not the experience in today’s digital world where interruptions are common. In a survey of 1,000 people, after researchers subtracted the time people spend on email, social media, and other digital interruptions, only 3½ hours of the typical 8-hour work day were left for actual work, and these remaining hours were not consecutive, Dr. Ballard noted.
“In reality, we operate in relationship to time more like we did in preindustrial times than we did during industrial times,” said Dr. Ballard. “Medicine has always had that approach, but the management of it is by people who are still being trained according to industrial [notions] of time.”
The resulting cognitive dissonance contributes to people experiencing guilt for not “balancing” their day properly, according to Dr. Ballard. Because to balance something means separating the pieces and quantifying them separately, people whose lives interrupt them throughout the work day find themselves thinking they have “failed” at achieving a work/life balance, when what they really have done is experience their life as it actually is. “No one likes to feel like a failure, particularly people who are high achievers and who expect to have agency over their lives.”
Dr. Ballard said that an alternative to seeing work and life as components that must be balanced is to instead view these things as being in an alignment that can shift over time. She also suggested challenging the accepted notions of what being productive really means in the context of how one’s life actually is, and to occasionally put down the smartphone and consciously practice experiencing time in an unstructured way.
We are destined to fail at achieving work-life balance because it does not exist, nor has it ever existed, according to an expert on how people experience time.
The field of chronemics studies the space between people, namely how they communicate with others and with themselves as they experience life in a matrix, not just linearly.
“When we talk about time, we need to remember that context and communication really matter,” Dawna Ballard, PhD, a chronemics expert and associate professor of communication at the University of Texas at Austin, said during a session Tuesday. “We think of our concept of time as ‘truth,’ but when we experience other cultures, often we see they don’t function according to our idea of time.”
The modern concept of time as told by a clock was invented during the Industrial Age to control people and events by forcing a direct line between their lives outside the factory and the farm, according to Dr. Ballard. That is not to say that industrial time is bad. It is efficient and perhaps even necessary for organizing large groups of people, she said.
Time management as a concept evolved out of the ethos of “punching the clock” at the factory, but has carried over to the office where in fact, according to Dr. Ballard, people do not tend to be as effective if they are expected to work in a linear way, since that is not the experience in today’s digital world where interruptions are common. In a survey of 1,000 people, after researchers subtracted the time people spend on email, social media, and other digital interruptions, only 3½ hours of the typical 8-hour work day were left for actual work, and these remaining hours were not consecutive, Dr. Ballard noted.
“In reality, we operate in relationship to time more like we did in preindustrial times than we did during industrial times,” said Dr. Ballard. “Medicine has always had that approach, but the management of it is by people who are still being trained according to industrial [notions] of time.”
The resulting cognitive dissonance contributes to people experiencing guilt for not “balancing” their day properly, according to Dr. Ballard. Because to balance something means separating the pieces and quantifying them separately, people whose lives interrupt them throughout the work day find themselves thinking they have “failed” at achieving a work/life balance, when what they really have done is experience their life as it actually is. “No one likes to feel like a failure, particularly people who are high achievers and who expect to have agency over their lives.”
Dr. Ballard said that an alternative to seeing work and life as components that must be balanced is to instead view these things as being in an alignment that can shift over time. She also suggested challenging the accepted notions of what being productive really means in the context of how one’s life actually is, and to occasionally put down the smartphone and consciously practice experiencing time in an unstructured way.
We are destined to fail at achieving work-life balance because it does not exist, nor has it ever existed, according to an expert on how people experience time.
The field of chronemics studies the space between people, namely how they communicate with others and with themselves as they experience life in a matrix, not just linearly.
“When we talk about time, we need to remember that context and communication really matter,” Dawna Ballard, PhD, a chronemics expert and associate professor of communication at the University of Texas at Austin, said during a session Tuesday. “We think of our concept of time as ‘truth,’ but when we experience other cultures, often we see they don’t function according to our idea of time.”
The modern concept of time as told by a clock was invented during the Industrial Age to control people and events by forcing a direct line between their lives outside the factory and the farm, according to Dr. Ballard. That is not to say that industrial time is bad. It is efficient and perhaps even necessary for organizing large groups of people, she said.
Time management as a concept evolved out of the ethos of “punching the clock” at the factory, but has carried over to the office where in fact, according to Dr. Ballard, people do not tend to be as effective if they are expected to work in a linear way, since that is not the experience in today’s digital world where interruptions are common. In a survey of 1,000 people, after researchers subtracted the time people spend on email, social media, and other digital interruptions, only 3½ hours of the typical 8-hour work day were left for actual work, and these remaining hours were not consecutive, Dr. Ballard noted.
“In reality, we operate in relationship to time more like we did in preindustrial times than we did during industrial times,” said Dr. Ballard. “Medicine has always had that approach, but the management of it is by people who are still being trained according to industrial [notions] of time.”
The resulting cognitive dissonance contributes to people experiencing guilt for not “balancing” their day properly, according to Dr. Ballard. Because to balance something means separating the pieces and quantifying them separately, people whose lives interrupt them throughout the work day find themselves thinking they have “failed” at achieving a work/life balance, when what they really have done is experience their life as it actually is. “No one likes to feel like a failure, particularly people who are high achievers and who expect to have agency over their lives.”
Dr. Ballard said that an alternative to seeing work and life as components that must be balanced is to instead view these things as being in an alignment that can shift over time. She also suggested challenging the accepted notions of what being productive really means in the context of how one’s life actually is, and to occasionally put down the smartphone and consciously practice experiencing time in an unstructured way.
VIDEO: SHM seeks sites to test pediatric transition tool
Would you like to help the Society of Hospital Medicine translate its award-winning Project BOOST® Mentored Implementation Program into the pediatric setting?
“We’re hoping to get six sites to help us implement this project so we can collect data and see how well it works for pediatrics,” James O’Callaghan, MD, medical director, EvergreenHealth, Seattle Children’s, said in an interview.
In this video, recorded during HM17 , Dr. O’Callaghan describes how Pedi-BOOST is intended to work, and what types of pediatric transition concerns it is intended to address.
For more information, please visit the SHM website.
Dr. O’Callaghan had no relevant disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Would you like to help the Society of Hospital Medicine translate its award-winning Project BOOST® Mentored Implementation Program into the pediatric setting?
“We’re hoping to get six sites to help us implement this project so we can collect data and see how well it works for pediatrics,” James O’Callaghan, MD, medical director, EvergreenHealth, Seattle Children’s, said in an interview.
In this video, recorded during HM17 , Dr. O’Callaghan describes how Pedi-BOOST is intended to work, and what types of pediatric transition concerns it is intended to address.
For more information, please visit the SHM website.
Dr. O’Callaghan had no relevant disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Would you like to help the Society of Hospital Medicine translate its award-winning Project BOOST® Mentored Implementation Program into the pediatric setting?
“We’re hoping to get six sites to help us implement this project so we can collect data and see how well it works for pediatrics,” James O’Callaghan, MD, medical director, EvergreenHealth, Seattle Children’s, said in an interview.
In this video, recorded during HM17 , Dr. O’Callaghan describes how Pedi-BOOST is intended to work, and what types of pediatric transition concerns it is intended to address.
For more information, please visit the SHM website.
Dr. O’Callaghan had no relevant disclosures.
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Digestive Disease Week® – always the biggest GI meeting in the world
GI & Hepatology News will be in Chicago this week at the McCormick Place Convention Center reporting the latest news and perspective across gastroenterology. Studies at this year’s meeting have a decidedly genetic slant as the genetic bases for many GI and liver diseases are being determined and studied for their use in treatments.
Our reporters will cover comparative effectiveness studies and controversies in inflammatory bowel disease; Clostridium difficile colitis; and prevention and treatment of clinical hepatitis, among many other topics, as well as an NIH Consortium presentation on chronic pancreatitis, diabetes, and pancreatic cancer.
Highly anticipated presentations include:
- Genetic markers could improve treatment of hepatitis C.
- Nonsurgical weight-loss treatment could help patients with limited options.
- First-ever autonomously controlled “capsule robot” explores colon.
- Enzyme could be a game-changer for gluten-sensitive patients.
Our team will provide daily coverage, starting Saturday, May 6.
GI & Hepatology News will be in Chicago this week at the McCormick Place Convention Center reporting the latest news and perspective across gastroenterology. Studies at this year’s meeting have a decidedly genetic slant as the genetic bases for many GI and liver diseases are being determined and studied for their use in treatments.
Our reporters will cover comparative effectiveness studies and controversies in inflammatory bowel disease; Clostridium difficile colitis; and prevention and treatment of clinical hepatitis, among many other topics, as well as an NIH Consortium presentation on chronic pancreatitis, diabetes, and pancreatic cancer.
Highly anticipated presentations include:
- Genetic markers could improve treatment of hepatitis C.
- Nonsurgical weight-loss treatment could help patients with limited options.
- First-ever autonomously controlled “capsule robot” explores colon.
- Enzyme could be a game-changer for gluten-sensitive patients.
Our team will provide daily coverage, starting Saturday, May 6.
GI & Hepatology News will be in Chicago this week at the McCormick Place Convention Center reporting the latest news and perspective across gastroenterology. Studies at this year’s meeting have a decidedly genetic slant as the genetic bases for many GI and liver diseases are being determined and studied for their use in treatments.
Our reporters will cover comparative effectiveness studies and controversies in inflammatory bowel disease; Clostridium difficile colitis; and prevention and treatment of clinical hepatitis, among many other topics, as well as an NIH Consortium presentation on chronic pancreatitis, diabetes, and pancreatic cancer.
Highly anticipated presentations include:
- Genetic markers could improve treatment of hepatitis C.
- Nonsurgical weight-loss treatment could help patients with limited options.
- First-ever autonomously controlled “capsule robot” explores colon.
- Enzyme could be a game-changer for gluten-sensitive patients.
Our team will provide daily coverage, starting Saturday, May 6.
FROM DDW
Top Acthar prescribers reap hefty payments from drug maker
BOSTON – A new analysis finds that some of the biggest neurologist prescribers of repository corticotropin gel (Acthar) – the extraordinarily expensive multiple sclerosis (MS) relapse drug – reaped extensive payments from its manufacturer, with one taking in $130,307 in a single year.
Together, 51 neurologists accounted for 980 Medicare claims worth more than $39 million in Acthar spending in 2014, almost half of the entire estimated $83 million in Medicare spending on neurologist-prescribed Acthar that year.
“There is a small group of neurologists – less than 1% – who are prescribing Acthar at considerable cost to Medicare and may do this in part because of financial relationships with the company that sells Acthar,” said study lead author Dennis Bourdette, MD, chair and research professor of neurology at Oregon Health and Science University, Portland.
Dr. Bourdette acknowledges that the research doesn’t prove a causal relationship between payments and prescriptions. In response to questions, Acthar manufacturer Mallinckrodt Pharmaceuticals, already under fire for the $34,000-per-vial cost of the drug, questioned the study design and denied wrongdoing in a statement: “Mallinckrodt is committed to following the highest standards for integrity and compliance in all of our business practices, including our collaboration with physicians.”
Acthar, also known as H.P. Acthar, is the poster child for stunningly expensive medication. According to the Federal Trade Commission, the cost of the drug rose from $40 per vial in 2001 to more than $34,000 this year. The New York Times reports that Medicare spending on Acthar topped half a billion in 2015.
Earlier this year, Mallinckrodt ARD (formerly Questcor) and its parent company agreed to pay a $100 million fine to settle charges that it created an illegal monopoly over the drug.
Dr. Bourdette and colleagues released their findings at the annual meeting of the American Academy of Neurology.
In an interview, Dr. Bourdette said the study’s roots lie in his concern about the medication, whose transformation from an inexpensive 1950s-era medication for pulmonary sarcoidosis to high-priced MS treatment has drawn national media attention.
“I believe that Acthar is tremendously overpriced and a waste of health care money,” Dr. Bourdette said. “I wanted to find out how extensive an economic problem it was and how much money Medicare was spending on it since this data was easily accessible.”
According to the study, Medicare spent $1.3 billion from 2011 to 2015 on Acthar, with about 25% of the cost due to prescriptions from neurologists. “When I discovered that a relatively small number of neurologists was prescribing it commonly at a cost of $40-$50 million a year to Medicare, I was interested in determining why they were prescribing this expensive therapy and postulated that it might be related to financial support they were receiving from the manufacturer,” Dr. Bourdette said.
The researchers examined the Medicare Part D Public Use File to determine which neurologists prescribed Acthar frequently in 2014. They identified 51 who prescribed Acthar 10 or more times that year and were frequent prescribers of MS disease-modifying therapy, indicating they treated many people with MS.
The 51 neurologists accounted for a mean of 19 Acthar claims each in 2014 (range, 11-50) totaling a mean annual cost of $770,145 (range, $354,479-$3,623,509). Together, the neurologists accounted for total Medicare spending on Acthar of $39,277,380.
The researchers also chose a control group – 51 neurologists who prescribed glatiramer acetate (Copaxone) more than 10 times in 2014 and also prescribed a similar frequency of all MS disease-modifying therapies as the high-frequency Acthar group.
“Acthar is used episodically to treat MS relapses, and glatiramer acetate is taken chronically to prevent relapses and disability,” Dr. Bourdette said. He added that glatiramer acetate is now available in a generic, but it wasn’t in 2014.
The Acthar and Copaxone groups were nearly identical in terms of gender (about two-thirds men) and years since graduation (a mean of 26), but the Acthar prescribers were more likely to work in small practices (1-10 doctors), file more prescription claims, see more Medicare patients, and practice in the South or West. The demographic information came from CMS Physician Compare.
In terms of overall drug maker payments, neurologists in the Acthar group accepted much more (median, $54,270; range, $623-$369,847) than did the Copaxone group (median, $1,747, range, $0-$256,305, P less than .001). Payment information came from the federal Open Payments database.
As for payments directly from the manufacturers of the two drugs, the Acthar prescribers accepted a median of $5,344 (range, $0-$130,307) from its manufacturer, while the Copaxone prescribers accepted a median of $137 (range, $0-$168,373) from Teva (P = .003).
“The payments are primarily for giving lectures or serving on advisory boards,” Dr. Bourdette said. “These types of payments are commonly made by pharmaceutical companies to physicians who participate in these types of activities.”
In a statement, Mallinckrodt Pharmaceuticals contends that the study inappropriately compares Acthar, often a later-line therapy, to Copaxone, which it says is often a first-line therapy.
Dr. Bourdette responded that the researchers chose a comparison group of top prescribers of Copaxone “as a marker of neurologists who treated a significant number of patients with MS.”
Mallinckrodt also notes that “there may be unmeasured confounding factors in the matching process between the comparator physician groups. These could include differences in the patient characteristics managed by these physicians including disease severity affecting prescribing patterns.”
The researchers agree that there may be differences between the groups, Dr. Bourdette said. However, he added, “the fact remains that the two groups differed in the amount of money they received as open-source payments from pharmaceutical companies. We doubt that the severity of their case mixes should lead to one group receiving more pharmaceutical open-source payments than another.”
Finally, Mallinckrodt says there’s no proof of a causal connection between the payments and the prescriptions; the study authors agree. And, the company says, “this pattern of correlation would be expected in any scenario where a small number of prescribers are the experts in the use of a later-line drug to treat a limited subset of patients.”
Dr. Bourdette rejects this contention. Few of the high Acthar prescribers practice at academic centers, he said, and few are recognized for their MS expertise. “So to suggest that they are experts in the use of Acthar for the treatment of MS when they are not as a group recognized as being experts on the treatment of MS in general is incredible,” he said. “Why a small group of neurologists prescribe Acthar remains a mystery, but it is not because the majority are leaders in the field of MS therapeutics.”
In an interview, Eric G. Campbell, PhD, professor of medicine and director of research at the Mongan Institute Health Policy Center at Harvard Medical School, Boston, said the study findings fit in with previous research that has found that “the more money that people get, the more they use the drug.
“Any reasonable person looking at this data would assume or at least consider very strongly that there is a causal relationship here,” he said.
What should be done? “There are lots of ways to stop this,” Dr. Campbell said. “One could simply impose rules that forbid doctors who accept payments for marketing drugs from billing Medicare or private payers for the care they provide. Large provider organizations could pass rules that forbid this kind of behavior. Finally, the government could vigorously pursue stiff penalties against physicians who accept payments that are really nothing more than incentives to encourage or sustain prescribing practices.”
The study was supported by a National Multiple Sclerosis Society grant. Dr. Bourdette said that he provides consulting to Magellan Healthcare, a company that provides recommendations to insurance companies on the approval of high-cost therapies. Dr. Campbell disclosed that he serves as an expert witness on law cases related to conflicts of interest in medicine.
BOSTON – A new analysis finds that some of the biggest neurologist prescribers of repository corticotropin gel (Acthar) – the extraordinarily expensive multiple sclerosis (MS) relapse drug – reaped extensive payments from its manufacturer, with one taking in $130,307 in a single year.
Together, 51 neurologists accounted for 980 Medicare claims worth more than $39 million in Acthar spending in 2014, almost half of the entire estimated $83 million in Medicare spending on neurologist-prescribed Acthar that year.
“There is a small group of neurologists – less than 1% – who are prescribing Acthar at considerable cost to Medicare and may do this in part because of financial relationships with the company that sells Acthar,” said study lead author Dennis Bourdette, MD, chair and research professor of neurology at Oregon Health and Science University, Portland.
Dr. Bourdette acknowledges that the research doesn’t prove a causal relationship between payments and prescriptions. In response to questions, Acthar manufacturer Mallinckrodt Pharmaceuticals, already under fire for the $34,000-per-vial cost of the drug, questioned the study design and denied wrongdoing in a statement: “Mallinckrodt is committed to following the highest standards for integrity and compliance in all of our business practices, including our collaboration with physicians.”
Acthar, also known as H.P. Acthar, is the poster child for stunningly expensive medication. According to the Federal Trade Commission, the cost of the drug rose from $40 per vial in 2001 to more than $34,000 this year. The New York Times reports that Medicare spending on Acthar topped half a billion in 2015.
Earlier this year, Mallinckrodt ARD (formerly Questcor) and its parent company agreed to pay a $100 million fine to settle charges that it created an illegal monopoly over the drug.
Dr. Bourdette and colleagues released their findings at the annual meeting of the American Academy of Neurology.
In an interview, Dr. Bourdette said the study’s roots lie in his concern about the medication, whose transformation from an inexpensive 1950s-era medication for pulmonary sarcoidosis to high-priced MS treatment has drawn national media attention.
“I believe that Acthar is tremendously overpriced and a waste of health care money,” Dr. Bourdette said. “I wanted to find out how extensive an economic problem it was and how much money Medicare was spending on it since this data was easily accessible.”
According to the study, Medicare spent $1.3 billion from 2011 to 2015 on Acthar, with about 25% of the cost due to prescriptions from neurologists. “When I discovered that a relatively small number of neurologists was prescribing it commonly at a cost of $40-$50 million a year to Medicare, I was interested in determining why they were prescribing this expensive therapy and postulated that it might be related to financial support they were receiving from the manufacturer,” Dr. Bourdette said.
The researchers examined the Medicare Part D Public Use File to determine which neurologists prescribed Acthar frequently in 2014. They identified 51 who prescribed Acthar 10 or more times that year and were frequent prescribers of MS disease-modifying therapy, indicating they treated many people with MS.
The 51 neurologists accounted for a mean of 19 Acthar claims each in 2014 (range, 11-50) totaling a mean annual cost of $770,145 (range, $354,479-$3,623,509). Together, the neurologists accounted for total Medicare spending on Acthar of $39,277,380.
The researchers also chose a control group – 51 neurologists who prescribed glatiramer acetate (Copaxone) more than 10 times in 2014 and also prescribed a similar frequency of all MS disease-modifying therapies as the high-frequency Acthar group.
“Acthar is used episodically to treat MS relapses, and glatiramer acetate is taken chronically to prevent relapses and disability,” Dr. Bourdette said. He added that glatiramer acetate is now available in a generic, but it wasn’t in 2014.
The Acthar and Copaxone groups were nearly identical in terms of gender (about two-thirds men) and years since graduation (a mean of 26), but the Acthar prescribers were more likely to work in small practices (1-10 doctors), file more prescription claims, see more Medicare patients, and practice in the South or West. The demographic information came from CMS Physician Compare.
In terms of overall drug maker payments, neurologists in the Acthar group accepted much more (median, $54,270; range, $623-$369,847) than did the Copaxone group (median, $1,747, range, $0-$256,305, P less than .001). Payment information came from the federal Open Payments database.
As for payments directly from the manufacturers of the two drugs, the Acthar prescribers accepted a median of $5,344 (range, $0-$130,307) from its manufacturer, while the Copaxone prescribers accepted a median of $137 (range, $0-$168,373) from Teva (P = .003).
“The payments are primarily for giving lectures or serving on advisory boards,” Dr. Bourdette said. “These types of payments are commonly made by pharmaceutical companies to physicians who participate in these types of activities.”
In a statement, Mallinckrodt Pharmaceuticals contends that the study inappropriately compares Acthar, often a later-line therapy, to Copaxone, which it says is often a first-line therapy.
Dr. Bourdette responded that the researchers chose a comparison group of top prescribers of Copaxone “as a marker of neurologists who treated a significant number of patients with MS.”
Mallinckrodt also notes that “there may be unmeasured confounding factors in the matching process between the comparator physician groups. These could include differences in the patient characteristics managed by these physicians including disease severity affecting prescribing patterns.”
The researchers agree that there may be differences between the groups, Dr. Bourdette said. However, he added, “the fact remains that the two groups differed in the amount of money they received as open-source payments from pharmaceutical companies. We doubt that the severity of their case mixes should lead to one group receiving more pharmaceutical open-source payments than another.”
Finally, Mallinckrodt says there’s no proof of a causal connection between the payments and the prescriptions; the study authors agree. And, the company says, “this pattern of correlation would be expected in any scenario where a small number of prescribers are the experts in the use of a later-line drug to treat a limited subset of patients.”
Dr. Bourdette rejects this contention. Few of the high Acthar prescribers practice at academic centers, he said, and few are recognized for their MS expertise. “So to suggest that they are experts in the use of Acthar for the treatment of MS when they are not as a group recognized as being experts on the treatment of MS in general is incredible,” he said. “Why a small group of neurologists prescribe Acthar remains a mystery, but it is not because the majority are leaders in the field of MS therapeutics.”
In an interview, Eric G. Campbell, PhD, professor of medicine and director of research at the Mongan Institute Health Policy Center at Harvard Medical School, Boston, said the study findings fit in with previous research that has found that “the more money that people get, the more they use the drug.
“Any reasonable person looking at this data would assume or at least consider very strongly that there is a causal relationship here,” he said.
What should be done? “There are lots of ways to stop this,” Dr. Campbell said. “One could simply impose rules that forbid doctors who accept payments for marketing drugs from billing Medicare or private payers for the care they provide. Large provider organizations could pass rules that forbid this kind of behavior. Finally, the government could vigorously pursue stiff penalties against physicians who accept payments that are really nothing more than incentives to encourage or sustain prescribing practices.”
The study was supported by a National Multiple Sclerosis Society grant. Dr. Bourdette said that he provides consulting to Magellan Healthcare, a company that provides recommendations to insurance companies on the approval of high-cost therapies. Dr. Campbell disclosed that he serves as an expert witness on law cases related to conflicts of interest in medicine.
BOSTON – A new analysis finds that some of the biggest neurologist prescribers of repository corticotropin gel (Acthar) – the extraordinarily expensive multiple sclerosis (MS) relapse drug – reaped extensive payments from its manufacturer, with one taking in $130,307 in a single year.
Together, 51 neurologists accounted for 980 Medicare claims worth more than $39 million in Acthar spending in 2014, almost half of the entire estimated $83 million in Medicare spending on neurologist-prescribed Acthar that year.
“There is a small group of neurologists – less than 1% – who are prescribing Acthar at considerable cost to Medicare and may do this in part because of financial relationships with the company that sells Acthar,” said study lead author Dennis Bourdette, MD, chair and research professor of neurology at Oregon Health and Science University, Portland.
Dr. Bourdette acknowledges that the research doesn’t prove a causal relationship between payments and prescriptions. In response to questions, Acthar manufacturer Mallinckrodt Pharmaceuticals, already under fire for the $34,000-per-vial cost of the drug, questioned the study design and denied wrongdoing in a statement: “Mallinckrodt is committed to following the highest standards for integrity and compliance in all of our business practices, including our collaboration with physicians.”
Acthar, also known as H.P. Acthar, is the poster child for stunningly expensive medication. According to the Federal Trade Commission, the cost of the drug rose from $40 per vial in 2001 to more than $34,000 this year. The New York Times reports that Medicare spending on Acthar topped half a billion in 2015.
Earlier this year, Mallinckrodt ARD (formerly Questcor) and its parent company agreed to pay a $100 million fine to settle charges that it created an illegal monopoly over the drug.
Dr. Bourdette and colleagues released their findings at the annual meeting of the American Academy of Neurology.
In an interview, Dr. Bourdette said the study’s roots lie in his concern about the medication, whose transformation from an inexpensive 1950s-era medication for pulmonary sarcoidosis to high-priced MS treatment has drawn national media attention.
“I believe that Acthar is tremendously overpriced and a waste of health care money,” Dr. Bourdette said. “I wanted to find out how extensive an economic problem it was and how much money Medicare was spending on it since this data was easily accessible.”
According to the study, Medicare spent $1.3 billion from 2011 to 2015 on Acthar, with about 25% of the cost due to prescriptions from neurologists. “When I discovered that a relatively small number of neurologists was prescribing it commonly at a cost of $40-$50 million a year to Medicare, I was interested in determining why they were prescribing this expensive therapy and postulated that it might be related to financial support they were receiving from the manufacturer,” Dr. Bourdette said.
The researchers examined the Medicare Part D Public Use File to determine which neurologists prescribed Acthar frequently in 2014. They identified 51 who prescribed Acthar 10 or more times that year and were frequent prescribers of MS disease-modifying therapy, indicating they treated many people with MS.
The 51 neurologists accounted for a mean of 19 Acthar claims each in 2014 (range, 11-50) totaling a mean annual cost of $770,145 (range, $354,479-$3,623,509). Together, the neurologists accounted for total Medicare spending on Acthar of $39,277,380.
The researchers also chose a control group – 51 neurologists who prescribed glatiramer acetate (Copaxone) more than 10 times in 2014 and also prescribed a similar frequency of all MS disease-modifying therapies as the high-frequency Acthar group.
“Acthar is used episodically to treat MS relapses, and glatiramer acetate is taken chronically to prevent relapses and disability,” Dr. Bourdette said. He added that glatiramer acetate is now available in a generic, but it wasn’t in 2014.
The Acthar and Copaxone groups were nearly identical in terms of gender (about two-thirds men) and years since graduation (a mean of 26), but the Acthar prescribers were more likely to work in small practices (1-10 doctors), file more prescription claims, see more Medicare patients, and practice in the South or West. The demographic information came from CMS Physician Compare.
In terms of overall drug maker payments, neurologists in the Acthar group accepted much more (median, $54,270; range, $623-$369,847) than did the Copaxone group (median, $1,747, range, $0-$256,305, P less than .001). Payment information came from the federal Open Payments database.
As for payments directly from the manufacturers of the two drugs, the Acthar prescribers accepted a median of $5,344 (range, $0-$130,307) from its manufacturer, while the Copaxone prescribers accepted a median of $137 (range, $0-$168,373) from Teva (P = .003).
“The payments are primarily for giving lectures or serving on advisory boards,” Dr. Bourdette said. “These types of payments are commonly made by pharmaceutical companies to physicians who participate in these types of activities.”
In a statement, Mallinckrodt Pharmaceuticals contends that the study inappropriately compares Acthar, often a later-line therapy, to Copaxone, which it says is often a first-line therapy.
Dr. Bourdette responded that the researchers chose a comparison group of top prescribers of Copaxone “as a marker of neurologists who treated a significant number of patients with MS.”
Mallinckrodt also notes that “there may be unmeasured confounding factors in the matching process between the comparator physician groups. These could include differences in the patient characteristics managed by these physicians including disease severity affecting prescribing patterns.”
The researchers agree that there may be differences between the groups, Dr. Bourdette said. However, he added, “the fact remains that the two groups differed in the amount of money they received as open-source payments from pharmaceutical companies. We doubt that the severity of their case mixes should lead to one group receiving more pharmaceutical open-source payments than another.”
Finally, Mallinckrodt says there’s no proof of a causal connection between the payments and the prescriptions; the study authors agree. And, the company says, “this pattern of correlation would be expected in any scenario where a small number of prescribers are the experts in the use of a later-line drug to treat a limited subset of patients.”
Dr. Bourdette rejects this contention. Few of the high Acthar prescribers practice at academic centers, he said, and few are recognized for their MS expertise. “So to suggest that they are experts in the use of Acthar for the treatment of MS when they are not as a group recognized as being experts on the treatment of MS in general is incredible,” he said. “Why a small group of neurologists prescribe Acthar remains a mystery, but it is not because the majority are leaders in the field of MS therapeutics.”
In an interview, Eric G. Campbell, PhD, professor of medicine and director of research at the Mongan Institute Health Policy Center at Harvard Medical School, Boston, said the study findings fit in with previous research that has found that “the more money that people get, the more they use the drug.
“Any reasonable person looking at this data would assume or at least consider very strongly that there is a causal relationship here,” he said.
What should be done? “There are lots of ways to stop this,” Dr. Campbell said. “One could simply impose rules that forbid doctors who accept payments for marketing drugs from billing Medicare or private payers for the care they provide. Large provider organizations could pass rules that forbid this kind of behavior. Finally, the government could vigorously pursue stiff penalties against physicians who accept payments that are really nothing more than incentives to encourage or sustain prescribing practices.”
The study was supported by a National Multiple Sclerosis Society grant. Dr. Bourdette said that he provides consulting to Magellan Healthcare, a company that provides recommendations to insurance companies on the approval of high-cost therapies. Dr. Campbell disclosed that he serves as an expert witness on law cases related to conflicts of interest in medicine.
AT AAN 2017
Key clinical point:
Major finding: The top Acthar prescribers reaped much more in payments from drug makers overall in 2014 than did a control group of top prescribers of another MS drug (median of $54,270 vs. $1,747; P less than .001) and from the manufacturer of each drug (median of $5,344 vs. $137; P = .003).
Data source: Medicare Part D Public Use File, CMS Physician Compare, Open Payments database, 2014.
Disclosures: The work was supported by a National Multiple Sclerosis Society grant. Dr. Bourdette provides consulting to Magellan Healthcare, a company that provides recommendations to insurance companies on the approval of high-cost therapies.
Serpentine Supravenous Hyperpigmentation Following Cisplatin and Pemetrexed Chemotherapy
To the Editor:
Serpentine supravenous hyperpigmentation (SSH) is a rare phenomenon characterized by linear hyperpigmentation of the skin overlying veins secondary to intravenous antineoplastic therapy. The term was first suggested by Hrushesky1 in 1976 as an uncommon side effect of administering intravenous 5-fluorouracil (5-FU). Although 5-FU is the most frequent offending agent, cases involving treatment with actinomycin, cyclophosphamide, docetaxel, fotemustine, nitrogen mustard, nitrosoureas, taxanes, and triazinate, as well as various combinations of chemotherapeutic agents, also have been observed.2,3 We present the case of SSH following a cisplatin and pemetrexed chemotherapy regimen.
A 52-year-old man with newly diagnosed inoperable adenocarcinoma in the left upper lung lobe received 2 cycles of treatment with cisplatin 138 mg and pemetrexed 920 mg 21 days apart. The first cycle of chemotherapy was delivered intravenously through the left forearm and the second cycle through the right forearm. Each infusion was followed by a 20-cc 0.9% saline flush. The patient developed nausea, vomiting, diarrhea, and hyperpigmentation tracing the path of infusion on the right arm as well as a slight darkness on the left arm that were noted by medical staff. At that time, cisplatin was discontinued from the chemotherapeutic regimen.
A port-a-cath was inserted into the patient’s right upper chest 4 weeks later and was used for subsequent infusions. Carboplatin 450 mg was initiated with pemetrexed thereafter. The patient was seen in the dermatology clinic 3 weeks after the insertion of the port-a-cath for evaluation of diffuse tinea versicolor of the trunk. Further examination of the arms revealed asymptomatic serpiginous hyperpigmentation overlying the superficial venous network tracing from the prior intravenous access points in the bilateral forearms to the upper arms (Figure). There was no evidence of extravasation or phlebitis prior to the hyperpigmentation. The patient was continued on pemetrexed and was subsequently lost to follow-up.
Cisplatin was the first member of the platinum-based chemotherapeutic agent class and is now one of the most potent and widely used in the treatment of solid malignancies. The cytotoxic mode of action is primarily mediated through interaction with DNA to form intrastrand cross-link adducts leading to aberrant mitosis and culminating in the activation of apoptosis. A variety of dermatologic complications have been reported with cisplatin chemotherapy including melanonychia, oral mucosal hyperpigmentation, hypersensitivity reactions, extravasation,4 Raynaud phenomenon, and flushing.5
Two cases of SSH have been reported following combination chemotherapy with cisplatin included in the regimen. A 61-year-old man with inoperable esophageal squamous cell carcinoma received cisplatin and 5-FU in addition to concurrent radiotherapy.6 After worsening renal function, cisplatin promptly was replaced with leucovorin. The patient developed SSH after the eighth infusion of 5-FU–leucovorin delivered through a peripheral catheter over a 24-hour period. The cutaneous side effect was attributed to the use of intravenous 5-FU.6 The second case involved a 48-year-old woman diagnosed with Paget disease of the breast who received adjuvant therapy with 12 courses of once-daily 5-FU and docetaxel for 5 years as well as 2 courses of vinorelbine and 1 course of cisplatin and etoposide for lung metastases.7 Serpentine supravenous hyperpigmentation lesions slowly developed over approximately 6 months. Based on the literature, the authors speculated that 5-FU and vinorelbine were most likely to be responsible. They noted, however, the inability to clarify the relationship between the onset of skin lesions and the time course of the chemotherapy.7 Although these cases do not directly implicate cisplatin as the cause of SSH, the possibility of a delayed reaction or augmentation of another drug’s effect cannot be excluded.
Pemetrexed, on the other hand, has not been associated with SSH. Several cutaneous adverse reactions have been reported, including acute generalized exanthematous pustulosis, alopecia, pityriasis lichenoides, radiation recall dermatitis, toxic epidermal necrolysis, and urticarial vasculitis.8 Three cases of pemetrexed-induced skin hyperpigmentation including the palms of the hands and soles of the feet as well as diffuse hyperpigmentation sparing only the palms and soles have been reported.8-10
Similar cases of SSH have demonstrated histopathologic findings with increased basal melanin synthesis and occasional melanophages in the papillary dermis without inflammatory changes.7,11 Although the unique serpentine pattern of hyperpigmentation is instantly recognizable, clinical differential diagnosis may include thrombophlebitis, cutis marmorata, erythema ab igne, livedo reticularis, and lichen planus.2,12
The exact mechanism of SSH has not been conclusively elucidated. Several studies postulate that direct cytotoxic damage causes loss of endothelial integrity permitting the extravasation of the agent to the overlying epidermis and interfering with melanogenesis.2,6,11 Other hypotheses include direct stimulation of melanocytes, depletion of reduced thioredoxin leading to tyrosinase stimulation, hyperthermia-related changes including reduced cytokine production and/or increased expression of melanocyte-stimulating hormone receptor, subclinical phlebitis leading to postinflammatory hyperpigmentation, or hyperpigmentation secondary to increased blood flow in certain areas and therefore increased drug deposition.12,13
Currently, there is no specific therapy recommended for SSH and the pigment may persist anywhere from a few months to more than a year after completing chemotherapy.2,7 Although discontinuing the offending agent would certainly prevent further development, due to the benign nature of the reaction, modifying therapy based on cutaneous findings alone is not recommended.12 Several authors have suggested avoiding peripheral infusions of chemotherapeutic agents known to cause SSH or have recommended using a permanent central venous catheter.6,7 Another option, which needs further investigation, is the administration of an abundant flush following chemotherapy. This technique was described in a case report of a 47-year-old man who developed persistent SSH in the right forearm following docetaxel injection.13 Copious venous washing with 1000 mL of isotonic saline solution following the second infusion in the unaffected arm prevented discoloration. The lack of subsequent reaction may support the theory that direct toxic effect on the vascular endothelium results in hyperpigmentation of the supravenous skin.13
Serpentine supravenous hyperpigmentation is an uncommon cutaneous reaction secondary to antineoplastic therapies. Given the widespread use of chemotherapeutic regimens, dermatologists should be aware of the reaction. Additional studies are warranted to better elucidate the pathogenesis and investigate how infusion techniques might aid in the prevention of skin discoloration. Although this side effect originally was described in relation to 5-FU, subsequent observations have included other chemotherapeutic agents. In light of the findings presented in this report, cisplatin and pemetrexed should be considered on the list of offending agents. Ultimately, patients should be reassured that the lesions are benign, self-limiting, and gradually resolve on their own in most cases.12
- Hrushesky WJ. Letter: serpentine supravenous fluorouracil hyperpigmentation. JAMA. 1976;236:138.
- Ghosh SK, Bandyopadhyay D, Ghoshal L, et al. Letter: docetaxel-induced supravenous serpentine dermatitis. Dermatol Online J. 2011;17:16.
- Pujol RM, Rocamora V, Lopez-Pousa A, et al. Persistent supravenous erythematous eruption: a rare local complication of intravenous 5-fluorouracil therapy. J Am Acad Dermatol. 1998;39:839-842.
- Kufe DW, Pollock RE, Weichsebaum RR, et al, eds. Holland-Frei Cancer Medicine. 6th ed. Hamilton, Ontario, Canada: BC Decker Inc; 2000.
- Mann MW, Berk DR, Popkin DL, et al. Handbook of Dermatology: A Practical Manual. Hoboken, NJ: Wiley-Blackwell; 2009.
- Chan CC, Lin SJ. Serpentine supravenous hyperpigmentation. N Engl J Med. 2010;29:363.
- Ouyang Y-H, Chu C-Y, Hu S-L. Linear hyperpigmentation of the left hand following chemotherapy. Dermatol Sinica. 2004;22:262-263.
- Piérard-Franchimont C, Quatresooz P, Reginster MA, et al. Revisiting cutaneous adverse reactions to pemetrexed. Oncol Lett. 2011;2:769-772.
- Buchinger K, Stahel R, Niggemeier V, et al. Pemetrexed-induced neutropenic enteritis and severe cutaneous hyperpigmentation in a patient with malignant pleural mesothelioma. Lung Cancer. 2013;80:347-349.
- Schallier D, Decoster L, De Greve J. Pemetrexed-induced hyperpigmentation of the skin. Anticancer Res. 2011;31:1753-1755.
- Rao R, Balachandran C. Serpentine supravenous pigmentation. a rare vasculocutaneous effect induced by systemic 5-fluoruracil. Indian J Dermatol Venereol Leprol. 2010;76:714-715.
- Geddes ER, Cohen PR. Antineoplastic agent-associated serpentine supravenous hyperpigmentation: superficial venous system hyperpigmentation following intravenous chemotherapy. South Med J. 2010;103:231-235.
- Ayodogan I, Kavak A, Parlak AH, et al. Persistent serpentine supravenous hyperpigmented eruption associated with docetaxel. J Eur Acad Dermatol Venereol. 2005;19:345-347.
To the Editor:
Serpentine supravenous hyperpigmentation (SSH) is a rare phenomenon characterized by linear hyperpigmentation of the skin overlying veins secondary to intravenous antineoplastic therapy. The term was first suggested by Hrushesky1 in 1976 as an uncommon side effect of administering intravenous 5-fluorouracil (5-FU). Although 5-FU is the most frequent offending agent, cases involving treatment with actinomycin, cyclophosphamide, docetaxel, fotemustine, nitrogen mustard, nitrosoureas, taxanes, and triazinate, as well as various combinations of chemotherapeutic agents, also have been observed.2,3 We present the case of SSH following a cisplatin and pemetrexed chemotherapy regimen.
A 52-year-old man with newly diagnosed inoperable adenocarcinoma in the left upper lung lobe received 2 cycles of treatment with cisplatin 138 mg and pemetrexed 920 mg 21 days apart. The first cycle of chemotherapy was delivered intravenously through the left forearm and the second cycle through the right forearm. Each infusion was followed by a 20-cc 0.9% saline flush. The patient developed nausea, vomiting, diarrhea, and hyperpigmentation tracing the path of infusion on the right arm as well as a slight darkness on the left arm that were noted by medical staff. At that time, cisplatin was discontinued from the chemotherapeutic regimen.
A port-a-cath was inserted into the patient’s right upper chest 4 weeks later and was used for subsequent infusions. Carboplatin 450 mg was initiated with pemetrexed thereafter. The patient was seen in the dermatology clinic 3 weeks after the insertion of the port-a-cath for evaluation of diffuse tinea versicolor of the trunk. Further examination of the arms revealed asymptomatic serpiginous hyperpigmentation overlying the superficial venous network tracing from the prior intravenous access points in the bilateral forearms to the upper arms (Figure). There was no evidence of extravasation or phlebitis prior to the hyperpigmentation. The patient was continued on pemetrexed and was subsequently lost to follow-up.
Cisplatin was the first member of the platinum-based chemotherapeutic agent class and is now one of the most potent and widely used in the treatment of solid malignancies. The cytotoxic mode of action is primarily mediated through interaction with DNA to form intrastrand cross-link adducts leading to aberrant mitosis and culminating in the activation of apoptosis. A variety of dermatologic complications have been reported with cisplatin chemotherapy including melanonychia, oral mucosal hyperpigmentation, hypersensitivity reactions, extravasation,4 Raynaud phenomenon, and flushing.5
Two cases of SSH have been reported following combination chemotherapy with cisplatin included in the regimen. A 61-year-old man with inoperable esophageal squamous cell carcinoma received cisplatin and 5-FU in addition to concurrent radiotherapy.6 After worsening renal function, cisplatin promptly was replaced with leucovorin. The patient developed SSH after the eighth infusion of 5-FU–leucovorin delivered through a peripheral catheter over a 24-hour period. The cutaneous side effect was attributed to the use of intravenous 5-FU.6 The second case involved a 48-year-old woman diagnosed with Paget disease of the breast who received adjuvant therapy with 12 courses of once-daily 5-FU and docetaxel for 5 years as well as 2 courses of vinorelbine and 1 course of cisplatin and etoposide for lung metastases.7 Serpentine supravenous hyperpigmentation lesions slowly developed over approximately 6 months. Based on the literature, the authors speculated that 5-FU and vinorelbine were most likely to be responsible. They noted, however, the inability to clarify the relationship between the onset of skin lesions and the time course of the chemotherapy.7 Although these cases do not directly implicate cisplatin as the cause of SSH, the possibility of a delayed reaction or augmentation of another drug’s effect cannot be excluded.
Pemetrexed, on the other hand, has not been associated with SSH. Several cutaneous adverse reactions have been reported, including acute generalized exanthematous pustulosis, alopecia, pityriasis lichenoides, radiation recall dermatitis, toxic epidermal necrolysis, and urticarial vasculitis.8 Three cases of pemetrexed-induced skin hyperpigmentation including the palms of the hands and soles of the feet as well as diffuse hyperpigmentation sparing only the palms and soles have been reported.8-10
Similar cases of SSH have demonstrated histopathologic findings with increased basal melanin synthesis and occasional melanophages in the papillary dermis without inflammatory changes.7,11 Although the unique serpentine pattern of hyperpigmentation is instantly recognizable, clinical differential diagnosis may include thrombophlebitis, cutis marmorata, erythema ab igne, livedo reticularis, and lichen planus.2,12
The exact mechanism of SSH has not been conclusively elucidated. Several studies postulate that direct cytotoxic damage causes loss of endothelial integrity permitting the extravasation of the agent to the overlying epidermis and interfering with melanogenesis.2,6,11 Other hypotheses include direct stimulation of melanocytes, depletion of reduced thioredoxin leading to tyrosinase stimulation, hyperthermia-related changes including reduced cytokine production and/or increased expression of melanocyte-stimulating hormone receptor, subclinical phlebitis leading to postinflammatory hyperpigmentation, or hyperpigmentation secondary to increased blood flow in certain areas and therefore increased drug deposition.12,13
Currently, there is no specific therapy recommended for SSH and the pigment may persist anywhere from a few months to more than a year after completing chemotherapy.2,7 Although discontinuing the offending agent would certainly prevent further development, due to the benign nature of the reaction, modifying therapy based on cutaneous findings alone is not recommended.12 Several authors have suggested avoiding peripheral infusions of chemotherapeutic agents known to cause SSH or have recommended using a permanent central venous catheter.6,7 Another option, which needs further investigation, is the administration of an abundant flush following chemotherapy. This technique was described in a case report of a 47-year-old man who developed persistent SSH in the right forearm following docetaxel injection.13 Copious venous washing with 1000 mL of isotonic saline solution following the second infusion in the unaffected arm prevented discoloration. The lack of subsequent reaction may support the theory that direct toxic effect on the vascular endothelium results in hyperpigmentation of the supravenous skin.13
Serpentine supravenous hyperpigmentation is an uncommon cutaneous reaction secondary to antineoplastic therapies. Given the widespread use of chemotherapeutic regimens, dermatologists should be aware of the reaction. Additional studies are warranted to better elucidate the pathogenesis and investigate how infusion techniques might aid in the prevention of skin discoloration. Although this side effect originally was described in relation to 5-FU, subsequent observations have included other chemotherapeutic agents. In light of the findings presented in this report, cisplatin and pemetrexed should be considered on the list of offending agents. Ultimately, patients should be reassured that the lesions are benign, self-limiting, and gradually resolve on their own in most cases.12
To the Editor:
Serpentine supravenous hyperpigmentation (SSH) is a rare phenomenon characterized by linear hyperpigmentation of the skin overlying veins secondary to intravenous antineoplastic therapy. The term was first suggested by Hrushesky1 in 1976 as an uncommon side effect of administering intravenous 5-fluorouracil (5-FU). Although 5-FU is the most frequent offending agent, cases involving treatment with actinomycin, cyclophosphamide, docetaxel, fotemustine, nitrogen mustard, nitrosoureas, taxanes, and triazinate, as well as various combinations of chemotherapeutic agents, also have been observed.2,3 We present the case of SSH following a cisplatin and pemetrexed chemotherapy regimen.
A 52-year-old man with newly diagnosed inoperable adenocarcinoma in the left upper lung lobe received 2 cycles of treatment with cisplatin 138 mg and pemetrexed 920 mg 21 days apart. The first cycle of chemotherapy was delivered intravenously through the left forearm and the second cycle through the right forearm. Each infusion was followed by a 20-cc 0.9% saline flush. The patient developed nausea, vomiting, diarrhea, and hyperpigmentation tracing the path of infusion on the right arm as well as a slight darkness on the left arm that were noted by medical staff. At that time, cisplatin was discontinued from the chemotherapeutic regimen.
A port-a-cath was inserted into the patient’s right upper chest 4 weeks later and was used for subsequent infusions. Carboplatin 450 mg was initiated with pemetrexed thereafter. The patient was seen in the dermatology clinic 3 weeks after the insertion of the port-a-cath for evaluation of diffuse tinea versicolor of the trunk. Further examination of the arms revealed asymptomatic serpiginous hyperpigmentation overlying the superficial venous network tracing from the prior intravenous access points in the bilateral forearms to the upper arms (Figure). There was no evidence of extravasation or phlebitis prior to the hyperpigmentation. The patient was continued on pemetrexed and was subsequently lost to follow-up.
Cisplatin was the first member of the platinum-based chemotherapeutic agent class and is now one of the most potent and widely used in the treatment of solid malignancies. The cytotoxic mode of action is primarily mediated through interaction with DNA to form intrastrand cross-link adducts leading to aberrant mitosis and culminating in the activation of apoptosis. A variety of dermatologic complications have been reported with cisplatin chemotherapy including melanonychia, oral mucosal hyperpigmentation, hypersensitivity reactions, extravasation,4 Raynaud phenomenon, and flushing.5
Two cases of SSH have been reported following combination chemotherapy with cisplatin included in the regimen. A 61-year-old man with inoperable esophageal squamous cell carcinoma received cisplatin and 5-FU in addition to concurrent radiotherapy.6 After worsening renal function, cisplatin promptly was replaced with leucovorin. The patient developed SSH after the eighth infusion of 5-FU–leucovorin delivered through a peripheral catheter over a 24-hour period. The cutaneous side effect was attributed to the use of intravenous 5-FU.6 The second case involved a 48-year-old woman diagnosed with Paget disease of the breast who received adjuvant therapy with 12 courses of once-daily 5-FU and docetaxel for 5 years as well as 2 courses of vinorelbine and 1 course of cisplatin and etoposide for lung metastases.7 Serpentine supravenous hyperpigmentation lesions slowly developed over approximately 6 months. Based on the literature, the authors speculated that 5-FU and vinorelbine were most likely to be responsible. They noted, however, the inability to clarify the relationship between the onset of skin lesions and the time course of the chemotherapy.7 Although these cases do not directly implicate cisplatin as the cause of SSH, the possibility of a delayed reaction or augmentation of another drug’s effect cannot be excluded.
Pemetrexed, on the other hand, has not been associated with SSH. Several cutaneous adverse reactions have been reported, including acute generalized exanthematous pustulosis, alopecia, pityriasis lichenoides, radiation recall dermatitis, toxic epidermal necrolysis, and urticarial vasculitis.8 Three cases of pemetrexed-induced skin hyperpigmentation including the palms of the hands and soles of the feet as well as diffuse hyperpigmentation sparing only the palms and soles have been reported.8-10
Similar cases of SSH have demonstrated histopathologic findings with increased basal melanin synthesis and occasional melanophages in the papillary dermis without inflammatory changes.7,11 Although the unique serpentine pattern of hyperpigmentation is instantly recognizable, clinical differential diagnosis may include thrombophlebitis, cutis marmorata, erythema ab igne, livedo reticularis, and lichen planus.2,12
The exact mechanism of SSH has not been conclusively elucidated. Several studies postulate that direct cytotoxic damage causes loss of endothelial integrity permitting the extravasation of the agent to the overlying epidermis and interfering with melanogenesis.2,6,11 Other hypotheses include direct stimulation of melanocytes, depletion of reduced thioredoxin leading to tyrosinase stimulation, hyperthermia-related changes including reduced cytokine production and/or increased expression of melanocyte-stimulating hormone receptor, subclinical phlebitis leading to postinflammatory hyperpigmentation, or hyperpigmentation secondary to increased blood flow in certain areas and therefore increased drug deposition.12,13
Currently, there is no specific therapy recommended for SSH and the pigment may persist anywhere from a few months to more than a year after completing chemotherapy.2,7 Although discontinuing the offending agent would certainly prevent further development, due to the benign nature of the reaction, modifying therapy based on cutaneous findings alone is not recommended.12 Several authors have suggested avoiding peripheral infusions of chemotherapeutic agents known to cause SSH or have recommended using a permanent central venous catheter.6,7 Another option, which needs further investigation, is the administration of an abundant flush following chemotherapy. This technique was described in a case report of a 47-year-old man who developed persistent SSH in the right forearm following docetaxel injection.13 Copious venous washing with 1000 mL of isotonic saline solution following the second infusion in the unaffected arm prevented discoloration. The lack of subsequent reaction may support the theory that direct toxic effect on the vascular endothelium results in hyperpigmentation of the supravenous skin.13
Serpentine supravenous hyperpigmentation is an uncommon cutaneous reaction secondary to antineoplastic therapies. Given the widespread use of chemotherapeutic regimens, dermatologists should be aware of the reaction. Additional studies are warranted to better elucidate the pathogenesis and investigate how infusion techniques might aid in the prevention of skin discoloration. Although this side effect originally was described in relation to 5-FU, subsequent observations have included other chemotherapeutic agents. In light of the findings presented in this report, cisplatin and pemetrexed should be considered on the list of offending agents. Ultimately, patients should be reassured that the lesions are benign, self-limiting, and gradually resolve on their own in most cases.12
- Hrushesky WJ. Letter: serpentine supravenous fluorouracil hyperpigmentation. JAMA. 1976;236:138.
- Ghosh SK, Bandyopadhyay D, Ghoshal L, et al. Letter: docetaxel-induced supravenous serpentine dermatitis. Dermatol Online J. 2011;17:16.
- Pujol RM, Rocamora V, Lopez-Pousa A, et al. Persistent supravenous erythematous eruption: a rare local complication of intravenous 5-fluorouracil therapy. J Am Acad Dermatol. 1998;39:839-842.
- Kufe DW, Pollock RE, Weichsebaum RR, et al, eds. Holland-Frei Cancer Medicine. 6th ed. Hamilton, Ontario, Canada: BC Decker Inc; 2000.
- Mann MW, Berk DR, Popkin DL, et al. Handbook of Dermatology: A Practical Manual. Hoboken, NJ: Wiley-Blackwell; 2009.
- Chan CC, Lin SJ. Serpentine supravenous hyperpigmentation. N Engl J Med. 2010;29:363.
- Ouyang Y-H, Chu C-Y, Hu S-L. Linear hyperpigmentation of the left hand following chemotherapy. Dermatol Sinica. 2004;22:262-263.
- Piérard-Franchimont C, Quatresooz P, Reginster MA, et al. Revisiting cutaneous adverse reactions to pemetrexed. Oncol Lett. 2011;2:769-772.
- Buchinger K, Stahel R, Niggemeier V, et al. Pemetrexed-induced neutropenic enteritis and severe cutaneous hyperpigmentation in a patient with malignant pleural mesothelioma. Lung Cancer. 2013;80:347-349.
- Schallier D, Decoster L, De Greve J. Pemetrexed-induced hyperpigmentation of the skin. Anticancer Res. 2011;31:1753-1755.
- Rao R, Balachandran C. Serpentine supravenous pigmentation. a rare vasculocutaneous effect induced by systemic 5-fluoruracil. Indian J Dermatol Venereol Leprol. 2010;76:714-715.
- Geddes ER, Cohen PR. Antineoplastic agent-associated serpentine supravenous hyperpigmentation: superficial venous system hyperpigmentation following intravenous chemotherapy. South Med J. 2010;103:231-235.
- Ayodogan I, Kavak A, Parlak AH, et al. Persistent serpentine supravenous hyperpigmented eruption associated with docetaxel. J Eur Acad Dermatol Venereol. 2005;19:345-347.
- Hrushesky WJ. Letter: serpentine supravenous fluorouracil hyperpigmentation. JAMA. 1976;236:138.
- Ghosh SK, Bandyopadhyay D, Ghoshal L, et al. Letter: docetaxel-induced supravenous serpentine dermatitis. Dermatol Online J. 2011;17:16.
- Pujol RM, Rocamora V, Lopez-Pousa A, et al. Persistent supravenous erythematous eruption: a rare local complication of intravenous 5-fluorouracil therapy. J Am Acad Dermatol. 1998;39:839-842.
- Kufe DW, Pollock RE, Weichsebaum RR, et al, eds. Holland-Frei Cancer Medicine. 6th ed. Hamilton, Ontario, Canada: BC Decker Inc; 2000.
- Mann MW, Berk DR, Popkin DL, et al. Handbook of Dermatology: A Practical Manual. Hoboken, NJ: Wiley-Blackwell; 2009.
- Chan CC, Lin SJ. Serpentine supravenous hyperpigmentation. N Engl J Med. 2010;29:363.
- Ouyang Y-H, Chu C-Y, Hu S-L. Linear hyperpigmentation of the left hand following chemotherapy. Dermatol Sinica. 2004;22:262-263.
- Piérard-Franchimont C, Quatresooz P, Reginster MA, et al. Revisiting cutaneous adverse reactions to pemetrexed. Oncol Lett. 2011;2:769-772.
- Buchinger K, Stahel R, Niggemeier V, et al. Pemetrexed-induced neutropenic enteritis and severe cutaneous hyperpigmentation in a patient with malignant pleural mesothelioma. Lung Cancer. 2013;80:347-349.
- Schallier D, Decoster L, De Greve J. Pemetrexed-induced hyperpigmentation of the skin. Anticancer Res. 2011;31:1753-1755.
- Rao R, Balachandran C. Serpentine supravenous pigmentation. a rare vasculocutaneous effect induced by systemic 5-fluoruracil. Indian J Dermatol Venereol Leprol. 2010;76:714-715.
- Geddes ER, Cohen PR. Antineoplastic agent-associated serpentine supravenous hyperpigmentation: superficial venous system hyperpigmentation following intravenous chemotherapy. South Med J. 2010;103:231-235.
- Ayodogan I, Kavak A, Parlak AH, et al. Persistent serpentine supravenous hyperpigmented eruption associated with docetaxel. J Eur Acad Dermatol Venereol. 2005;19:345-347.
Practice Points
- A variety of dermatologic complications have been reported with cisplatin chemotherapy, including serpentine supravenous hyperpigmentation (SSH); however, pemetrexed has not been associated with SSH.
- Although discontinuing the offending agent would certainly prevent further development, due to the benign nature of the reaction, modifying therapy based on cutaneous findings alone is not recommended.
Lasers may be effective for treating xanthelasma
SAN DIEGO – Laser treatments may be effective for xanthelasma palpebrarum lesions, based on a systematic review of existing studies, although the research is limited.
“The number of cases we looked at was relatively small, so you can’t come up with any definite conclusions,” said review coauthor Christopher J. Huerter, MD, head of the division of dermatology at Creighton University, Omaha. “But it’s promising since the lasers we examined all work with some efficacy, with the CO2 and Er:YAG [erbium:YAG] lasers probably having the best results.”
Xanthelasma lesions appear as small yellowish plaques on the eyelids. “About half the people who have it have some blood lipid abnormality,” Dr. Huerter said in an interview. “If a person has it, it’s worthwhile to do a cholesterol screen or a lipid profile.”
Treatment with trichloroacetic acid is one option, although it was more common before lasers began to be used. In addition, “surgical incision can be very effective,” he said, although the review notes that it can create undesirable scarring.
Researchers have studied laser treatment for xanthelasma for at least 30 years. Dr. Huerter and his colleagues examined 21 studies published since 1987, with the following lasers: CO2 laser (three studies), argon laser (one study), Er:YAG laser (four studies), ultrapulse CO2 laser (five studies), 1,450-nm diode laser (one study), pulsed dye laser (PDL, two studies), superpulsed or fractional CO2 laser (one study), and Q-switched neodymium:YAG laser (three studies). An additional study examined both argon and Er:YAG lasers.
The number of treated patients in the studies ranged from 1 to 50, and the number of treated lesions ranged from 1 to 76. (Patients often had more than one lesion.) “It would be nice to have bigger studies and bigger numbers,” Dr. Huerter said at the annual meeting of the American Society for Laser Medicine and Surgery.
Although the studies were limited by small cohorts, short follow-up, and lack of comparison groups, the findings did reveal signs of effectiveness: Clearance rates were 100% in CO2, argon, and PDL cases and about 85% with Er:YAG lasers. Clearance rates were lower with Nd:YAG (about 55%) and 1,450-nm diode (about 48%) lasers.
Edema was reported in all PDL cases and erythema in almost 20% of CO2 cases. Dyspigmentation was most common – at about 30% – in Er:YAG and 1,450-nm diode cases. Visible scars were reported in more than 5% of Er:YAG cases.
The review concluded that “sufficient evidence is available to suggest laser therapies to be a cosmetically excellent treatment option for xanthelasma , particularly applicable in patients who are not good candidates for surgical excision,” he said.
As for advice to dermatologists, Dr. Huerter pointed to the positive results for CO2 and Er:YAG lasers. He said PDL lasers could also be used. As for argon lasers, he noted that it’s not as likely for dermatologists to have them on hand, he said.
In regard to choosing which xanthelasma lesions to treat with laser, he said thicker ones may not be as amenable. “But if you do laser treatment and don’t get the results you want, you can always excise.”
No funding for the study was reported. Dr. Huerter reported no disclosures.
SAN DIEGO – Laser treatments may be effective for xanthelasma palpebrarum lesions, based on a systematic review of existing studies, although the research is limited.
“The number of cases we looked at was relatively small, so you can’t come up with any definite conclusions,” said review coauthor Christopher J. Huerter, MD, head of the division of dermatology at Creighton University, Omaha. “But it’s promising since the lasers we examined all work with some efficacy, with the CO2 and Er:YAG [erbium:YAG] lasers probably having the best results.”
Xanthelasma lesions appear as small yellowish plaques on the eyelids. “About half the people who have it have some blood lipid abnormality,” Dr. Huerter said in an interview. “If a person has it, it’s worthwhile to do a cholesterol screen or a lipid profile.”
Treatment with trichloroacetic acid is one option, although it was more common before lasers began to be used. In addition, “surgical incision can be very effective,” he said, although the review notes that it can create undesirable scarring.
Researchers have studied laser treatment for xanthelasma for at least 30 years. Dr. Huerter and his colleagues examined 21 studies published since 1987, with the following lasers: CO2 laser (three studies), argon laser (one study), Er:YAG laser (four studies), ultrapulse CO2 laser (five studies), 1,450-nm diode laser (one study), pulsed dye laser (PDL, two studies), superpulsed or fractional CO2 laser (one study), and Q-switched neodymium:YAG laser (three studies). An additional study examined both argon and Er:YAG lasers.
The number of treated patients in the studies ranged from 1 to 50, and the number of treated lesions ranged from 1 to 76. (Patients often had more than one lesion.) “It would be nice to have bigger studies and bigger numbers,” Dr. Huerter said at the annual meeting of the American Society for Laser Medicine and Surgery.
Although the studies were limited by small cohorts, short follow-up, and lack of comparison groups, the findings did reveal signs of effectiveness: Clearance rates were 100% in CO2, argon, and PDL cases and about 85% with Er:YAG lasers. Clearance rates were lower with Nd:YAG (about 55%) and 1,450-nm diode (about 48%) lasers.
Edema was reported in all PDL cases and erythema in almost 20% of CO2 cases. Dyspigmentation was most common – at about 30% – in Er:YAG and 1,450-nm diode cases. Visible scars were reported in more than 5% of Er:YAG cases.
The review concluded that “sufficient evidence is available to suggest laser therapies to be a cosmetically excellent treatment option for xanthelasma , particularly applicable in patients who are not good candidates for surgical excision,” he said.
As for advice to dermatologists, Dr. Huerter pointed to the positive results for CO2 and Er:YAG lasers. He said PDL lasers could also be used. As for argon lasers, he noted that it’s not as likely for dermatologists to have them on hand, he said.
In regard to choosing which xanthelasma lesions to treat with laser, he said thicker ones may not be as amenable. “But if you do laser treatment and don’t get the results you want, you can always excise.”
No funding for the study was reported. Dr. Huerter reported no disclosures.
SAN DIEGO – Laser treatments may be effective for xanthelasma palpebrarum lesions, based on a systematic review of existing studies, although the research is limited.
“The number of cases we looked at was relatively small, so you can’t come up with any definite conclusions,” said review coauthor Christopher J. Huerter, MD, head of the division of dermatology at Creighton University, Omaha. “But it’s promising since the lasers we examined all work with some efficacy, with the CO2 and Er:YAG [erbium:YAG] lasers probably having the best results.”
Xanthelasma lesions appear as small yellowish plaques on the eyelids. “About half the people who have it have some blood lipid abnormality,” Dr. Huerter said in an interview. “If a person has it, it’s worthwhile to do a cholesterol screen or a lipid profile.”
Treatment with trichloroacetic acid is one option, although it was more common before lasers began to be used. In addition, “surgical incision can be very effective,” he said, although the review notes that it can create undesirable scarring.
Researchers have studied laser treatment for xanthelasma for at least 30 years. Dr. Huerter and his colleagues examined 21 studies published since 1987, with the following lasers: CO2 laser (three studies), argon laser (one study), Er:YAG laser (four studies), ultrapulse CO2 laser (five studies), 1,450-nm diode laser (one study), pulsed dye laser (PDL, two studies), superpulsed or fractional CO2 laser (one study), and Q-switched neodymium:YAG laser (three studies). An additional study examined both argon and Er:YAG lasers.
The number of treated patients in the studies ranged from 1 to 50, and the number of treated lesions ranged from 1 to 76. (Patients often had more than one lesion.) “It would be nice to have bigger studies and bigger numbers,” Dr. Huerter said at the annual meeting of the American Society for Laser Medicine and Surgery.
Although the studies were limited by small cohorts, short follow-up, and lack of comparison groups, the findings did reveal signs of effectiveness: Clearance rates were 100% in CO2, argon, and PDL cases and about 85% with Er:YAG lasers. Clearance rates were lower with Nd:YAG (about 55%) and 1,450-nm diode (about 48%) lasers.
Edema was reported in all PDL cases and erythema in almost 20% of CO2 cases. Dyspigmentation was most common – at about 30% – in Er:YAG and 1,450-nm diode cases. Visible scars were reported in more than 5% of Er:YAG cases.
The review concluded that “sufficient evidence is available to suggest laser therapies to be a cosmetically excellent treatment option for xanthelasma , particularly applicable in patients who are not good candidates for surgical excision,” he said.
As for advice to dermatologists, Dr. Huerter pointed to the positive results for CO2 and Er:YAG lasers. He said PDL lasers could also be used. As for argon lasers, he noted that it’s not as likely for dermatologists to have them on hand, he said.
In regard to choosing which xanthelasma lesions to treat with laser, he said thicker ones may not be as amenable. “But if you do laser treatment and don’t get the results you want, you can always excise.”
No funding for the study was reported. Dr. Huerter reported no disclosures.
Key clinical point:
Major finding: Clearance rates of about 85%-100% were reported for xanthelasma treatment with CO2, argon, pulsed dye, and Er:YAG laser treatments.
Data source: A systematic review of 21 studies evaluating different laser treatments for xanthelasma.
Disclosures: No funding was reported. Dr. Huerter reported no disclosures.
Expanding Uses of Propranolol in Dermatology
Since the serendipitous discovery of expedited involution of infantile hemangiomas (IHs) with propranolol in 2008,1 current research has proliferated to discern the mechanism of action of beta-blockers in the care of IHs. Propranolol is a nonselective beta-blocker with a structure similar to catecholamines and thus competes for β-adrenergic receptors. Blocking β1-receptors is cardioselective, leading to decreased heart rate and myocardial contractility, while blocking β2-receptors leads to inhibition of smooth muscle relaxation and decreased glycogenolysis. The endothelial cells of IH express β2-adrenergic receptors; the mechanistic role of propranolol in these lesions is surmised to be due to vasoconstriction, decreased angiogenesis through inhibition of vascular endothelial growth factor, and subsequent endothelial cell apoptosis.2
After this breakthrough finding, a subsequent novel development was made when an ophthalmologist demonstrated that timolol, a topical beta-blocker, could be utilized to expedite IH involution and prevent ocular complications such as amblyopia secondary to the mass effect of the lesion. Guo and Ni3 prescribed the commercially available ophthalmologic solution of timolol maleate 0.5% for twice-daily use for 5 weeks. Remarkable reduction in the periorbital IH without rebound phenomenon was observed.3 A recent multicenter retrospective cohort of more than 700 patients with IH were treated with topical timolol with a 70% success rate, corresponding to 10% improvement from baseline; this study highlights the efficacy of timolol while confirming the safety of the medication.4
Systemic beta-blockers for IH have been used predominately for critical sites such as the nasal tip, lip, ear, perineum, and periocular area; ulcerated lesions or those that may be prone to leave a fibrofatty tissue residue after involution also have been targeted. Contraindications for use include premature infants younger than 5 weeks, infants weighing less than 2 kg, history of asthma or bronchospasm, heart rate less than 80 beats per minute, blood pressure less than 50/30 mm Hg, or hypersensitivity to the medication.5 Current guidelines for propranolol initiation vary; some dermatologists consult cardiology prior to initiation, while others perform routine vitals and an indication-driven electrocardiogram as needed based on family history of cardiac disease, maternal history of connective tissue disease, congenital heart block, or abnormal vital signs.
Given the demonstrated long-term safety of propranolol and the acceptable side-effect profile, the use of beta-blockers for IH has become increasingly mainstream. Three randomized controlled trials (RCTs) have evaluated the efficacy and minimal adverse effects of propranolol for IH. The first RCT evaluated 40 patients who received either placebo or propranolol 2 mg/kg daily (divided into 3 doses) for 6 months; IH growth stopped by week 4 in the treatment group and the largest volume difference in IH was seen at week 12.6 Léauté-Labrèze et al7 demonstrated that propranolol could be given earlier to patients and at higher doses; the treatment group included 7 patients at 3 mg/kg daily of propranolol for 15 days, followed by 15 additional days of 4 mg/kg daily of propranolol. A statistically significant (P=.004) decrease in IH volume, quantified by use of ultrasonography, was exhibited by the propranolol group.7 Lastly, the largest RCT (N=456) established the efficacy of propranolol 3 mg/kg daily for 6 months with a 60% successful treatment rate compared to 4% for patients receiving placebo.8
Given the efficacy of propranolol for IH, other investigators have experimented with nonselective beta-blockers for other dermatologic conditions. In addition to second-line use for flushing, hyperhidrosis, and adrenergic urticaria, the future of propranolol is expanding for vascular lesions in particular.9 Chow et al10 highlighted a case of progressive angiosarcoma of the scalp that responded to propranolol hydrochloride therapy at 40 mg 3 times daily with extensive regression; propranolol was given in addition to chemotherapy and radiation. The tumor was biopsied before and after propranolol therapy and exhibited a 34% decrease in the proliferative index (Ki-67).10 Interestingly, Chisholm et al11 evaluated the expression of β-adrenergic expression in 141 vascular lesions; endothelial cell expression of β2-adrenergic receptors was found positive in 100% of IHs, 67% of kaposiform hemangioendotheliomas, 41% of angiosarcomas, 50% of pyogenic granulomas, and 75% of Kaposi sarcomas, to name merely a few studied lesions.
These data have spurred physicians to further seek beta-blocker dermatologic use in specific patient populations. For example, Meseguer-Yebra et al12 employed timolol solution 0.5% twice daily for 12 weeks for 2 human immunodeficiency virus–negative patients with limited Kaposi sarcoma of the right thigh and foot; no clinical evidence of recurrence was seen at 20 months, and one of the patients had a subsequent biopsy performed with negative human herpesvirus 8 staining after therapy. In the pediatric arena, topical timolol has been used for both port-wine stains and pyogenic granulomas.13-15 Two lesions of pyogenic granulomas on the scalp of a child were treated with timolol ophthalmic solution 0.5% under occlusion for 4 weeks with resolution.15 Propranolol also has been utilized as adjunctive therapy for aggressive pediatric vascular lesions such as kaposiform hemangioendothelioma with promising results and additionally reducing the duration of therapy needed with vincristine.2
In summary, propranolol and timolol have made an indelible impression on the field of pediatric dermatology and have demonstrated a burgeoning role in the dermatologic arena. The use of nonselective beta-blockers for the management of vascular lesions can serve as adjunctive or monotherapy for certain patient populations. The relatively low adverse risk profile of propranolol makes it a versatile tool to use both systemically and topically. Although the authors of the study assessing the β2-adrenergic expression in vascular lesions admittedly stated that the positivity of the receptors does not necessarily correlate with therapeutic management, it is an interesting subject area with much potential in the future.11 This review serves to illuminate the expanding role of beta-blockers in dermatology.
- Léauté-Labrèze C, Dumas de la Roque E, Hubiche T, et al. Propranolol for severe hemangiomas of infancy. N Engl J Med. 2008;358:2649-2651.
- Hermans DJ, van Beynum IM, van der Vijver RJ, et al. Kaposiform hemangioendothelioma with Kasabach-Merritt syndrome: a new indication for propranolol treatment. J Pediatr Hematol Oncol. 2011;33:E171-E173.
- Guo S, Ni N. Topical treatment for capillary hemangioma of the eyelid using beta-blocker solution. Arch Ophthalmol. 2010;128:255-256.
- Püttgen K, Lucky A, Adams D, et al. Topical timolol maleate treatment of infantile hemangiomas. Pediatrics. 2016;138:3.
- Drolet BA, Frommelt PC, Chamlin SL, et al. Initiation and use of propranolol for infantile hemangioma: report of a consensus conference. Pediatrics. 2013;131:128-140.
- Hogeling M, Adams S, Wargon O. A randomized controlled trial of propranolol for infantile hemangiomas [published online July 25, 2011]. Pediatrics. 2011;128:E259-E266.
- Léauté-Labrèze C, Dumas de la Roque E, Nacka F, et al. Doubleblind randomized pilot trial evaluating the efficacy of oral propranolol on infantile haemangiomas in infants < 4 months of age. Br J Dermatol. 2013;169:181-183.
- Léauté-Labrèze C, Hoeger P, Mazereeuw-Hautier J, et al. A randomized, controlled trial of oral propranolol in infantile hemangioma. N Engl J Med. 2015;372:735-746.
- Shelley WB, Shelley ED. Adrenergic urticaria: a new form of stress induced hives. Lancet. 1985;2:1031-1033.
- Chow W, Amaya CN, Rains S, et al. Growth attenuation of cutaneous angiosarcoma with propranolol-mediated β-blockade. JAMA Dermatol. 2015;151:1226-1229.
- Chisholm KM, Chang KW, Truong MT, et al. β-adrenergic receptor expression in vascular tumors. Mod Pathol. 2012;25:1446-1451.
- Meseguer-Yebra C, Cardeñoso-Álvarez, ME, Bordel-Gómez MT, et al. Successful treatment of classic Kaposi sarcoma with topical timolol: report of two cases. Br J Dermatol. 2015;173:860-862.
- Passeron T, Maza A, Fontas E, et al. Treatment of port wine stains and pulsed dye laser and topical timolol: a multicenter randomized controlled trial. Br J Dermatol. 2014;170:1350-1353.
- Wine LL, Goff KL, Lam JM, et al. Treatment of pediatric pyogenic granulomas using β-adrenergic receptor antagonist. Pediatr Dermatol. 2014;31:203-207.
- Knöpfel N, Escudero-Góngora Mdel M, Bauzà A, et al. Timolol for the treatment of pyogenic granuloma (PG) in children. J Am Acad Dermatol. 2016;75:E105-E106.
Since the serendipitous discovery of expedited involution of infantile hemangiomas (IHs) with propranolol in 2008,1 current research has proliferated to discern the mechanism of action of beta-blockers in the care of IHs. Propranolol is a nonselective beta-blocker with a structure similar to catecholamines and thus competes for β-adrenergic receptors. Blocking β1-receptors is cardioselective, leading to decreased heart rate and myocardial contractility, while blocking β2-receptors leads to inhibition of smooth muscle relaxation and decreased glycogenolysis. The endothelial cells of IH express β2-adrenergic receptors; the mechanistic role of propranolol in these lesions is surmised to be due to vasoconstriction, decreased angiogenesis through inhibition of vascular endothelial growth factor, and subsequent endothelial cell apoptosis.2
After this breakthrough finding, a subsequent novel development was made when an ophthalmologist demonstrated that timolol, a topical beta-blocker, could be utilized to expedite IH involution and prevent ocular complications such as amblyopia secondary to the mass effect of the lesion. Guo and Ni3 prescribed the commercially available ophthalmologic solution of timolol maleate 0.5% for twice-daily use for 5 weeks. Remarkable reduction in the periorbital IH without rebound phenomenon was observed.3 A recent multicenter retrospective cohort of more than 700 patients with IH were treated with topical timolol with a 70% success rate, corresponding to 10% improvement from baseline; this study highlights the efficacy of timolol while confirming the safety of the medication.4
Systemic beta-blockers for IH have been used predominately for critical sites such as the nasal tip, lip, ear, perineum, and periocular area; ulcerated lesions or those that may be prone to leave a fibrofatty tissue residue after involution also have been targeted. Contraindications for use include premature infants younger than 5 weeks, infants weighing less than 2 kg, history of asthma or bronchospasm, heart rate less than 80 beats per minute, blood pressure less than 50/30 mm Hg, or hypersensitivity to the medication.5 Current guidelines for propranolol initiation vary; some dermatologists consult cardiology prior to initiation, while others perform routine vitals and an indication-driven electrocardiogram as needed based on family history of cardiac disease, maternal history of connective tissue disease, congenital heart block, or abnormal vital signs.
Given the demonstrated long-term safety of propranolol and the acceptable side-effect profile, the use of beta-blockers for IH has become increasingly mainstream. Three randomized controlled trials (RCTs) have evaluated the efficacy and minimal adverse effects of propranolol for IH. The first RCT evaluated 40 patients who received either placebo or propranolol 2 mg/kg daily (divided into 3 doses) for 6 months; IH growth stopped by week 4 in the treatment group and the largest volume difference in IH was seen at week 12.6 Léauté-Labrèze et al7 demonstrated that propranolol could be given earlier to patients and at higher doses; the treatment group included 7 patients at 3 mg/kg daily of propranolol for 15 days, followed by 15 additional days of 4 mg/kg daily of propranolol. A statistically significant (P=.004) decrease in IH volume, quantified by use of ultrasonography, was exhibited by the propranolol group.7 Lastly, the largest RCT (N=456) established the efficacy of propranolol 3 mg/kg daily for 6 months with a 60% successful treatment rate compared to 4% for patients receiving placebo.8
Given the efficacy of propranolol for IH, other investigators have experimented with nonselective beta-blockers for other dermatologic conditions. In addition to second-line use for flushing, hyperhidrosis, and adrenergic urticaria, the future of propranolol is expanding for vascular lesions in particular.9 Chow et al10 highlighted a case of progressive angiosarcoma of the scalp that responded to propranolol hydrochloride therapy at 40 mg 3 times daily with extensive regression; propranolol was given in addition to chemotherapy and radiation. The tumor was biopsied before and after propranolol therapy and exhibited a 34% decrease in the proliferative index (Ki-67).10 Interestingly, Chisholm et al11 evaluated the expression of β-adrenergic expression in 141 vascular lesions; endothelial cell expression of β2-adrenergic receptors was found positive in 100% of IHs, 67% of kaposiform hemangioendotheliomas, 41% of angiosarcomas, 50% of pyogenic granulomas, and 75% of Kaposi sarcomas, to name merely a few studied lesions.
These data have spurred physicians to further seek beta-blocker dermatologic use in specific patient populations. For example, Meseguer-Yebra et al12 employed timolol solution 0.5% twice daily for 12 weeks for 2 human immunodeficiency virus–negative patients with limited Kaposi sarcoma of the right thigh and foot; no clinical evidence of recurrence was seen at 20 months, and one of the patients had a subsequent biopsy performed with negative human herpesvirus 8 staining after therapy. In the pediatric arena, topical timolol has been used for both port-wine stains and pyogenic granulomas.13-15 Two lesions of pyogenic granulomas on the scalp of a child were treated with timolol ophthalmic solution 0.5% under occlusion for 4 weeks with resolution.15 Propranolol also has been utilized as adjunctive therapy for aggressive pediatric vascular lesions such as kaposiform hemangioendothelioma with promising results and additionally reducing the duration of therapy needed with vincristine.2
In summary, propranolol and timolol have made an indelible impression on the field of pediatric dermatology and have demonstrated a burgeoning role in the dermatologic arena. The use of nonselective beta-blockers for the management of vascular lesions can serve as adjunctive or monotherapy for certain patient populations. The relatively low adverse risk profile of propranolol makes it a versatile tool to use both systemically and topically. Although the authors of the study assessing the β2-adrenergic expression in vascular lesions admittedly stated that the positivity of the receptors does not necessarily correlate with therapeutic management, it is an interesting subject area with much potential in the future.11 This review serves to illuminate the expanding role of beta-blockers in dermatology.
Since the serendipitous discovery of expedited involution of infantile hemangiomas (IHs) with propranolol in 2008,1 current research has proliferated to discern the mechanism of action of beta-blockers in the care of IHs. Propranolol is a nonselective beta-blocker with a structure similar to catecholamines and thus competes for β-adrenergic receptors. Blocking β1-receptors is cardioselective, leading to decreased heart rate and myocardial contractility, while blocking β2-receptors leads to inhibition of smooth muscle relaxation and decreased glycogenolysis. The endothelial cells of IH express β2-adrenergic receptors; the mechanistic role of propranolol in these lesions is surmised to be due to vasoconstriction, decreased angiogenesis through inhibition of vascular endothelial growth factor, and subsequent endothelial cell apoptosis.2
After this breakthrough finding, a subsequent novel development was made when an ophthalmologist demonstrated that timolol, a topical beta-blocker, could be utilized to expedite IH involution and prevent ocular complications such as amblyopia secondary to the mass effect of the lesion. Guo and Ni3 prescribed the commercially available ophthalmologic solution of timolol maleate 0.5% for twice-daily use for 5 weeks. Remarkable reduction in the periorbital IH without rebound phenomenon was observed.3 A recent multicenter retrospective cohort of more than 700 patients with IH were treated with topical timolol with a 70% success rate, corresponding to 10% improvement from baseline; this study highlights the efficacy of timolol while confirming the safety of the medication.4
Systemic beta-blockers for IH have been used predominately for critical sites such as the nasal tip, lip, ear, perineum, and periocular area; ulcerated lesions or those that may be prone to leave a fibrofatty tissue residue after involution also have been targeted. Contraindications for use include premature infants younger than 5 weeks, infants weighing less than 2 kg, history of asthma or bronchospasm, heart rate less than 80 beats per minute, blood pressure less than 50/30 mm Hg, or hypersensitivity to the medication.5 Current guidelines for propranolol initiation vary; some dermatologists consult cardiology prior to initiation, while others perform routine vitals and an indication-driven electrocardiogram as needed based on family history of cardiac disease, maternal history of connective tissue disease, congenital heart block, or abnormal vital signs.
Given the demonstrated long-term safety of propranolol and the acceptable side-effect profile, the use of beta-blockers for IH has become increasingly mainstream. Three randomized controlled trials (RCTs) have evaluated the efficacy and minimal adverse effects of propranolol for IH. The first RCT evaluated 40 patients who received either placebo or propranolol 2 mg/kg daily (divided into 3 doses) for 6 months; IH growth stopped by week 4 in the treatment group and the largest volume difference in IH was seen at week 12.6 Léauté-Labrèze et al7 demonstrated that propranolol could be given earlier to patients and at higher doses; the treatment group included 7 patients at 3 mg/kg daily of propranolol for 15 days, followed by 15 additional days of 4 mg/kg daily of propranolol. A statistically significant (P=.004) decrease in IH volume, quantified by use of ultrasonography, was exhibited by the propranolol group.7 Lastly, the largest RCT (N=456) established the efficacy of propranolol 3 mg/kg daily for 6 months with a 60% successful treatment rate compared to 4% for patients receiving placebo.8
Given the efficacy of propranolol for IH, other investigators have experimented with nonselective beta-blockers for other dermatologic conditions. In addition to second-line use for flushing, hyperhidrosis, and adrenergic urticaria, the future of propranolol is expanding for vascular lesions in particular.9 Chow et al10 highlighted a case of progressive angiosarcoma of the scalp that responded to propranolol hydrochloride therapy at 40 mg 3 times daily with extensive regression; propranolol was given in addition to chemotherapy and radiation. The tumor was biopsied before and after propranolol therapy and exhibited a 34% decrease in the proliferative index (Ki-67).10 Interestingly, Chisholm et al11 evaluated the expression of β-adrenergic expression in 141 vascular lesions; endothelial cell expression of β2-adrenergic receptors was found positive in 100% of IHs, 67% of kaposiform hemangioendotheliomas, 41% of angiosarcomas, 50% of pyogenic granulomas, and 75% of Kaposi sarcomas, to name merely a few studied lesions.
These data have spurred physicians to further seek beta-blocker dermatologic use in specific patient populations. For example, Meseguer-Yebra et al12 employed timolol solution 0.5% twice daily for 12 weeks for 2 human immunodeficiency virus–negative patients with limited Kaposi sarcoma of the right thigh and foot; no clinical evidence of recurrence was seen at 20 months, and one of the patients had a subsequent biopsy performed with negative human herpesvirus 8 staining after therapy. In the pediatric arena, topical timolol has been used for both port-wine stains and pyogenic granulomas.13-15 Two lesions of pyogenic granulomas on the scalp of a child were treated with timolol ophthalmic solution 0.5% under occlusion for 4 weeks with resolution.15 Propranolol also has been utilized as adjunctive therapy for aggressive pediatric vascular lesions such as kaposiform hemangioendothelioma with promising results and additionally reducing the duration of therapy needed with vincristine.2
In summary, propranolol and timolol have made an indelible impression on the field of pediatric dermatology and have demonstrated a burgeoning role in the dermatologic arena. The use of nonselective beta-blockers for the management of vascular lesions can serve as adjunctive or monotherapy for certain patient populations. The relatively low adverse risk profile of propranolol makes it a versatile tool to use both systemically and topically. Although the authors of the study assessing the β2-adrenergic expression in vascular lesions admittedly stated that the positivity of the receptors does not necessarily correlate with therapeutic management, it is an interesting subject area with much potential in the future.11 This review serves to illuminate the expanding role of beta-blockers in dermatology.
- Léauté-Labrèze C, Dumas de la Roque E, Hubiche T, et al. Propranolol for severe hemangiomas of infancy. N Engl J Med. 2008;358:2649-2651.
- Hermans DJ, van Beynum IM, van der Vijver RJ, et al. Kaposiform hemangioendothelioma with Kasabach-Merritt syndrome: a new indication for propranolol treatment. J Pediatr Hematol Oncol. 2011;33:E171-E173.
- Guo S, Ni N. Topical treatment for capillary hemangioma of the eyelid using beta-blocker solution. Arch Ophthalmol. 2010;128:255-256.
- Püttgen K, Lucky A, Adams D, et al. Topical timolol maleate treatment of infantile hemangiomas. Pediatrics. 2016;138:3.
- Drolet BA, Frommelt PC, Chamlin SL, et al. Initiation and use of propranolol for infantile hemangioma: report of a consensus conference. Pediatrics. 2013;131:128-140.
- Hogeling M, Adams S, Wargon O. A randomized controlled trial of propranolol for infantile hemangiomas [published online July 25, 2011]. Pediatrics. 2011;128:E259-E266.
- Léauté-Labrèze C, Dumas de la Roque E, Nacka F, et al. Doubleblind randomized pilot trial evaluating the efficacy of oral propranolol on infantile haemangiomas in infants < 4 months of age. Br J Dermatol. 2013;169:181-183.
- Léauté-Labrèze C, Hoeger P, Mazereeuw-Hautier J, et al. A randomized, controlled trial of oral propranolol in infantile hemangioma. N Engl J Med. 2015;372:735-746.
- Shelley WB, Shelley ED. Adrenergic urticaria: a new form of stress induced hives. Lancet. 1985;2:1031-1033.
- Chow W, Amaya CN, Rains S, et al. Growth attenuation of cutaneous angiosarcoma with propranolol-mediated β-blockade. JAMA Dermatol. 2015;151:1226-1229.
- Chisholm KM, Chang KW, Truong MT, et al. β-adrenergic receptor expression in vascular tumors. Mod Pathol. 2012;25:1446-1451.
- Meseguer-Yebra C, Cardeñoso-Álvarez, ME, Bordel-Gómez MT, et al. Successful treatment of classic Kaposi sarcoma with topical timolol: report of two cases. Br J Dermatol. 2015;173:860-862.
- Passeron T, Maza A, Fontas E, et al. Treatment of port wine stains and pulsed dye laser and topical timolol: a multicenter randomized controlled trial. Br J Dermatol. 2014;170:1350-1353.
- Wine LL, Goff KL, Lam JM, et al. Treatment of pediatric pyogenic granulomas using β-adrenergic receptor antagonist. Pediatr Dermatol. 2014;31:203-207.
- Knöpfel N, Escudero-Góngora Mdel M, Bauzà A, et al. Timolol for the treatment of pyogenic granuloma (PG) in children. J Am Acad Dermatol. 2016;75:E105-E106.
- Léauté-Labrèze C, Dumas de la Roque E, Hubiche T, et al. Propranolol for severe hemangiomas of infancy. N Engl J Med. 2008;358:2649-2651.
- Hermans DJ, van Beynum IM, van der Vijver RJ, et al. Kaposiform hemangioendothelioma with Kasabach-Merritt syndrome: a new indication for propranolol treatment. J Pediatr Hematol Oncol. 2011;33:E171-E173.
- Guo S, Ni N. Topical treatment for capillary hemangioma of the eyelid using beta-blocker solution. Arch Ophthalmol. 2010;128:255-256.
- Püttgen K, Lucky A, Adams D, et al. Topical timolol maleate treatment of infantile hemangiomas. Pediatrics. 2016;138:3.
- Drolet BA, Frommelt PC, Chamlin SL, et al. Initiation and use of propranolol for infantile hemangioma: report of a consensus conference. Pediatrics. 2013;131:128-140.
- Hogeling M, Adams S, Wargon O. A randomized controlled trial of propranolol for infantile hemangiomas [published online July 25, 2011]. Pediatrics. 2011;128:E259-E266.
- Léauté-Labrèze C, Dumas de la Roque E, Nacka F, et al. Doubleblind randomized pilot trial evaluating the efficacy of oral propranolol on infantile haemangiomas in infants < 4 months of age. Br J Dermatol. 2013;169:181-183.
- Léauté-Labrèze C, Hoeger P, Mazereeuw-Hautier J, et al. A randomized, controlled trial of oral propranolol in infantile hemangioma. N Engl J Med. 2015;372:735-746.
- Shelley WB, Shelley ED. Adrenergic urticaria: a new form of stress induced hives. Lancet. 1985;2:1031-1033.
- Chow W, Amaya CN, Rains S, et al. Growth attenuation of cutaneous angiosarcoma with propranolol-mediated β-blockade. JAMA Dermatol. 2015;151:1226-1229.
- Chisholm KM, Chang KW, Truong MT, et al. β-adrenergic receptor expression in vascular tumors. Mod Pathol. 2012;25:1446-1451.
- Meseguer-Yebra C, Cardeñoso-Álvarez, ME, Bordel-Gómez MT, et al. Successful treatment of classic Kaposi sarcoma with topical timolol: report of two cases. Br J Dermatol. 2015;173:860-862.
- Passeron T, Maza A, Fontas E, et al. Treatment of port wine stains and pulsed dye laser and topical timolol: a multicenter randomized controlled trial. Br J Dermatol. 2014;170:1350-1353.
- Wine LL, Goff KL, Lam JM, et al. Treatment of pediatric pyogenic granulomas using β-adrenergic receptor antagonist. Pediatr Dermatol. 2014;31:203-207.
- Knöpfel N, Escudero-Góngora Mdel M, Bauzà A, et al. Timolol for the treatment of pyogenic granuloma (PG) in children. J Am Acad Dermatol. 2016;75:E105-E106.
