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Job market for physicians, advanced practitioners rebounds after COVID-19 slump: Report
After a year of uncertainty and decline because of the COVID-19 pandemic, according to a recently released report from Merritt Hawkins, the physician search division of AMN Healthcare.
The study is based on an analysis of job search and consulting assignments that the firm conducted on behalf of its health care organization clients from April 1, 2021, to March 31, 2022.
“Search engagements were down a little over 30% in 2020, but by the end of 2021, everything started spiking dramatically to the point of where we were at a 34-year high,” Michael Belkin, divisional vice president with Merritt Hawkins, told this news organization. “The pendulum has gone all the way back. People are more interested in going out and seeing their physicians.”
Demand for physicians was suppressed during the peak of the pandemic, as many hospitals curtailed elective procedures and many patients refrained from entering a medical facility. A large backlog of patients needing care subsequently developed.
This, combined with an aging population and widespread chronic medical conditions, has caused a strong surge in demand for physicians and advanced practitioners, according to the report.
In addition to the volume of searches increasing, physician starting salaries have rebounded from the COVID-19 downturn.
Average starting salaries of 14 physician specialties tracked in 2021/2022 increased, while only 3 decreased. Orthopedic surgeons were offered an average of $565,000 to start, exclusive of signing bonuses and other incentives, up from $546,000 the previous year. Urologists were offered an average of $510,000 to start, up from $497,000; gastroenterologists were offered $474,000, up from $453,000; while radiologists were offered $455,000, up from $401,000.
Similarly, a recent Medscape study based on responses from more than 13,000 U.S. physicians across 29 specialties found that income for all physician specialists increased, with otolaryngologists, gastroenterologists, and dermatologists experiencing the greatest gains.
A new reality
While the job market for physicians and advanced practitioners has seemingly recovered, there are many differences between today’s working environment for clinicians and what existed during the pandemic.
First, specialists are now stepping into the spotlight, a position that primary care clinicians previously held. The majority of Merritt Hawkins’ search engagements (64%) in 2021/2022 were for physician specialists, including cardiologists, gastroenterologists, orthopedic surgeons, neurologists, oncologists, and others. Only 17% of the search engagements were for primary care physicians, down from 18% in 2020/2021 and 20% in 2019/2020.
“We’ve seen specialties bounce back faster. Of course, you’ve got the aging population; you’ve got people that want that specialized care,” Mr. Belkin said.
Advanced practitioners also are playing a more significant role in the postpandemic word. In fact, 19% of Merritt Hawkins’ search engagements were for advanced practitioners, including nurse practitioners (NPs), physician assistants, and certified registered nurse anesthetists, up from 18% the previous year and just 13% the year prior to that, indicating growing demand for nonphysician providers.
NPs, in fact, topped the list of most requested search engagements, underscoring a shift from traditional physician office-based primary care delivery settings toward “convenient care” settings such as urgent care centers and retail clinics that are largely staffed by NPs and other advanced practitioners.
Advanced practitioners are taking on more responsibility for primary care simply because there is a large number of these professionals ready to take on the challenge.
The health care industry was “not able to produce enough primary care physicians over the last decade. So advanced practitioners, I believe, have slowly started to work alongside those primary care physicians. In a lot of areas such as your retail space, your CVS, your Walmart, your Walgreens, your standalone urgent cares, they’ve stepped up,” Mr. Belkin said.
Advanced practitioners also are providing the convenience that consumers are increasingly demanding.
“We are a society that wants things immediately ... but it’s still a challenge to schedule an appointment with a physician. However, it’s less of a challenge to get into a retail clinic or an urgent care center or to schedule something through telehealth,” Mr. Belkin noted.
More than just money
With the job market strong, the challenge for health care organizations is to create competitive recruiting packages. Sure enough, 92% of candidates were offered signing bonuses in 2021/2022 compared with just 61% in 2020/2021.
The financial incentives, however, might not be enough. In this environment, health care organizations need to go beyond simply offering competitive salaries to new recruits. For example, clinicians are seeking flexibility, as many potential hires are seeking remote positions. In fact, 18% of radiology search engagements were for teleradiologists, while 15% of its search engagements for psychiatrists were for telepsychiatrists in 2021/2022.
“Right now, quality of life is a very important factor. It’s work-life balance. It’s sensitivity to the stresses that we just experienced over the last 2.5 years,” Mr. Belkin concluded. “There’s more sensitivity around the culture of the organizations. What’s the leadership like? How did the organization handle the pandemic? How do they respond?”
A version of this article first appeared on Medscape.com.
After a year of uncertainty and decline because of the COVID-19 pandemic, according to a recently released report from Merritt Hawkins, the physician search division of AMN Healthcare.
The study is based on an analysis of job search and consulting assignments that the firm conducted on behalf of its health care organization clients from April 1, 2021, to March 31, 2022.
“Search engagements were down a little over 30% in 2020, but by the end of 2021, everything started spiking dramatically to the point of where we were at a 34-year high,” Michael Belkin, divisional vice president with Merritt Hawkins, told this news organization. “The pendulum has gone all the way back. People are more interested in going out and seeing their physicians.”
Demand for physicians was suppressed during the peak of the pandemic, as many hospitals curtailed elective procedures and many patients refrained from entering a medical facility. A large backlog of patients needing care subsequently developed.
This, combined with an aging population and widespread chronic medical conditions, has caused a strong surge in demand for physicians and advanced practitioners, according to the report.
In addition to the volume of searches increasing, physician starting salaries have rebounded from the COVID-19 downturn.
Average starting salaries of 14 physician specialties tracked in 2021/2022 increased, while only 3 decreased. Orthopedic surgeons were offered an average of $565,000 to start, exclusive of signing bonuses and other incentives, up from $546,000 the previous year. Urologists were offered an average of $510,000 to start, up from $497,000; gastroenterologists were offered $474,000, up from $453,000; while radiologists were offered $455,000, up from $401,000.
Similarly, a recent Medscape study based on responses from more than 13,000 U.S. physicians across 29 specialties found that income for all physician specialists increased, with otolaryngologists, gastroenterologists, and dermatologists experiencing the greatest gains.
A new reality
While the job market for physicians and advanced practitioners has seemingly recovered, there are many differences between today’s working environment for clinicians and what existed during the pandemic.
First, specialists are now stepping into the spotlight, a position that primary care clinicians previously held. The majority of Merritt Hawkins’ search engagements (64%) in 2021/2022 were for physician specialists, including cardiologists, gastroenterologists, orthopedic surgeons, neurologists, oncologists, and others. Only 17% of the search engagements were for primary care physicians, down from 18% in 2020/2021 and 20% in 2019/2020.
“We’ve seen specialties bounce back faster. Of course, you’ve got the aging population; you’ve got people that want that specialized care,” Mr. Belkin said.
Advanced practitioners also are playing a more significant role in the postpandemic word. In fact, 19% of Merritt Hawkins’ search engagements were for advanced practitioners, including nurse practitioners (NPs), physician assistants, and certified registered nurse anesthetists, up from 18% the previous year and just 13% the year prior to that, indicating growing demand for nonphysician providers.
NPs, in fact, topped the list of most requested search engagements, underscoring a shift from traditional physician office-based primary care delivery settings toward “convenient care” settings such as urgent care centers and retail clinics that are largely staffed by NPs and other advanced practitioners.
Advanced practitioners are taking on more responsibility for primary care simply because there is a large number of these professionals ready to take on the challenge.
The health care industry was “not able to produce enough primary care physicians over the last decade. So advanced practitioners, I believe, have slowly started to work alongside those primary care physicians. In a lot of areas such as your retail space, your CVS, your Walmart, your Walgreens, your standalone urgent cares, they’ve stepped up,” Mr. Belkin said.
Advanced practitioners also are providing the convenience that consumers are increasingly demanding.
“We are a society that wants things immediately ... but it’s still a challenge to schedule an appointment with a physician. However, it’s less of a challenge to get into a retail clinic or an urgent care center or to schedule something through telehealth,” Mr. Belkin noted.
More than just money
With the job market strong, the challenge for health care organizations is to create competitive recruiting packages. Sure enough, 92% of candidates were offered signing bonuses in 2021/2022 compared with just 61% in 2020/2021.
The financial incentives, however, might not be enough. In this environment, health care organizations need to go beyond simply offering competitive salaries to new recruits. For example, clinicians are seeking flexibility, as many potential hires are seeking remote positions. In fact, 18% of radiology search engagements were for teleradiologists, while 15% of its search engagements for psychiatrists were for telepsychiatrists in 2021/2022.
“Right now, quality of life is a very important factor. It’s work-life balance. It’s sensitivity to the stresses that we just experienced over the last 2.5 years,” Mr. Belkin concluded. “There’s more sensitivity around the culture of the organizations. What’s the leadership like? How did the organization handle the pandemic? How do they respond?”
A version of this article first appeared on Medscape.com.
After a year of uncertainty and decline because of the COVID-19 pandemic, according to a recently released report from Merritt Hawkins, the physician search division of AMN Healthcare.
The study is based on an analysis of job search and consulting assignments that the firm conducted on behalf of its health care organization clients from April 1, 2021, to March 31, 2022.
“Search engagements were down a little over 30% in 2020, but by the end of 2021, everything started spiking dramatically to the point of where we were at a 34-year high,” Michael Belkin, divisional vice president with Merritt Hawkins, told this news organization. “The pendulum has gone all the way back. People are more interested in going out and seeing their physicians.”
Demand for physicians was suppressed during the peak of the pandemic, as many hospitals curtailed elective procedures and many patients refrained from entering a medical facility. A large backlog of patients needing care subsequently developed.
This, combined with an aging population and widespread chronic medical conditions, has caused a strong surge in demand for physicians and advanced practitioners, according to the report.
In addition to the volume of searches increasing, physician starting salaries have rebounded from the COVID-19 downturn.
Average starting salaries of 14 physician specialties tracked in 2021/2022 increased, while only 3 decreased. Orthopedic surgeons were offered an average of $565,000 to start, exclusive of signing bonuses and other incentives, up from $546,000 the previous year. Urologists were offered an average of $510,000 to start, up from $497,000; gastroenterologists were offered $474,000, up from $453,000; while radiologists were offered $455,000, up from $401,000.
Similarly, a recent Medscape study based on responses from more than 13,000 U.S. physicians across 29 specialties found that income for all physician specialists increased, with otolaryngologists, gastroenterologists, and dermatologists experiencing the greatest gains.
A new reality
While the job market for physicians and advanced practitioners has seemingly recovered, there are many differences between today’s working environment for clinicians and what existed during the pandemic.
First, specialists are now stepping into the spotlight, a position that primary care clinicians previously held. The majority of Merritt Hawkins’ search engagements (64%) in 2021/2022 were for physician specialists, including cardiologists, gastroenterologists, orthopedic surgeons, neurologists, oncologists, and others. Only 17% of the search engagements were for primary care physicians, down from 18% in 2020/2021 and 20% in 2019/2020.
“We’ve seen specialties bounce back faster. Of course, you’ve got the aging population; you’ve got people that want that specialized care,” Mr. Belkin said.
Advanced practitioners also are playing a more significant role in the postpandemic word. In fact, 19% of Merritt Hawkins’ search engagements were for advanced practitioners, including nurse practitioners (NPs), physician assistants, and certified registered nurse anesthetists, up from 18% the previous year and just 13% the year prior to that, indicating growing demand for nonphysician providers.
NPs, in fact, topped the list of most requested search engagements, underscoring a shift from traditional physician office-based primary care delivery settings toward “convenient care” settings such as urgent care centers and retail clinics that are largely staffed by NPs and other advanced practitioners.
Advanced practitioners are taking on more responsibility for primary care simply because there is a large number of these professionals ready to take on the challenge.
The health care industry was “not able to produce enough primary care physicians over the last decade. So advanced practitioners, I believe, have slowly started to work alongside those primary care physicians. In a lot of areas such as your retail space, your CVS, your Walmart, your Walgreens, your standalone urgent cares, they’ve stepped up,” Mr. Belkin said.
Advanced practitioners also are providing the convenience that consumers are increasingly demanding.
“We are a society that wants things immediately ... but it’s still a challenge to schedule an appointment with a physician. However, it’s less of a challenge to get into a retail clinic or an urgent care center or to schedule something through telehealth,” Mr. Belkin noted.
More than just money
With the job market strong, the challenge for health care organizations is to create competitive recruiting packages. Sure enough, 92% of candidates were offered signing bonuses in 2021/2022 compared with just 61% in 2020/2021.
The financial incentives, however, might not be enough. In this environment, health care organizations need to go beyond simply offering competitive salaries to new recruits. For example, clinicians are seeking flexibility, as many potential hires are seeking remote positions. In fact, 18% of radiology search engagements were for teleradiologists, while 15% of its search engagements for psychiatrists were for telepsychiatrists in 2021/2022.
“Right now, quality of life is a very important factor. It’s work-life balance. It’s sensitivity to the stresses that we just experienced over the last 2.5 years,” Mr. Belkin concluded. “There’s more sensitivity around the culture of the organizations. What’s the leadership like? How did the organization handle the pandemic? How do they respond?”
A version of this article first appeared on Medscape.com.
What are your weaknesses?
In a video posted to TikTok by the comedian Will Flanary, MD, better known to his followers as Dr. Glaucomflecken, he imitates a neurosurgical residency interview. With glasses perched on the bridge of his nose, Dr. Glaucomflecken poses as the attending, asking: “What are your weaknesses?”
The residency applicant answers without hesitation: “My physiological need for sleep.” “What are your strengths?” The resident replies with the hard, steely stare of the determined and uninitiated: “My desire to eliminate my physiological need for sleep.”
If you follow Dr. Glaucomflecken on Twitter, you might know the skit I’m referencing. For many physicians and physicians-in-training, what makes the satire successful is its reflection of reality.
Many things have changed in medicine since his time, but the tired trope of the sleepless surgeon hangs on. Undaunted, I spent my second and third year of medical school accumulating accolades, conducting research, and connecting with mentors with the singular goal of joining the surgical ranks.
Midway through my third year, I completed a month-long surgical subinternship designed to give students a taste of what life would look like as an intern. I loved the operating room; it felt like the difference between being on dry land and being underwater. There were fewer distractions – your patient in the spotlight while everything else receded to the shadows.
However, as the month wore on, something stronger took hold. I couldn’t keep my eyes open in the darkened operating rooms and had to decline stools, fearing that I would fall asleep if I sat down.
On early morning prerounds, it’s 4:50 a.m. when I glance at the clock and pull back the curtain, already apologizing. My patient rolls over, flashing a wry smile. “Do you ever go home?” I’ve seen residents respond to this exact question in various ways. I live here. Yes. No. Soon. Not enough. My partner doesn’t think so.
There are days and, yes, years when we are led to believe this is what we live for: to be constantly available to our patients. It feels like a hollow victory when the patient, 2 days out from a total colectomy, begins to worry about your personal life. I ask her how she slept (not enough), any fevers (no), vomiting (no), urinating (I pause – she has a catheter).
My favorite part of these early morning rounds is the pause in my scripted litany of questions to listen to heart and lungs. It never fails to feel sacred: Patients become so quiet and still that I can’t help but think they have faith in me. Without prompting, she slides the back of her hospital gown forward like a curtain, already taking deep breaths so I can hear her lungs.
I look outside. The streetlights are still on, and from the seventh-floor window, I can watch staff making their way through the sliding double-doors, just beyond the yellowed pools of streetlight. I smile. I love medicine. I’m so tired.
For many in medicine, we are treated, and thus behave, as though our ability to manipulate physiology should also apply within the borders of our bodies: commanding less sleep, food, or bathroom breaks.
It places health care workers solidly in the realm of superhuman, living beyond one’s corporeal needs. The pandemic only heightened this misappropriation – adding hero and setting out a pedestal for health care workers to make their ungainly ascent. This kind of unsolicited admiration implicitly implies inhumanness, an otherness.
What would it look like if we started treating ourselves less like physicians and more like patients? I wish I was offering a solution, but really this is just a story.
To students rising through the ranks of medical training, identify what it is you need early and often. I can count on one hand how many physicians I’ve seen take a lunch break – even 10 minutes. Embrace hard work and self-preservation equally. My hope is that if enough of us take this path, it just might become a matter of course.
Dr. Meffert is a resident in the department of emergency medicine, MedStar Georgetown University Hospital, Washington Hospital Center, Washington. Dr. Meffert disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In a video posted to TikTok by the comedian Will Flanary, MD, better known to his followers as Dr. Glaucomflecken, he imitates a neurosurgical residency interview. With glasses perched on the bridge of his nose, Dr. Glaucomflecken poses as the attending, asking: “What are your weaknesses?”
The residency applicant answers without hesitation: “My physiological need for sleep.” “What are your strengths?” The resident replies with the hard, steely stare of the determined and uninitiated: “My desire to eliminate my physiological need for sleep.”
If you follow Dr. Glaucomflecken on Twitter, you might know the skit I’m referencing. For many physicians and physicians-in-training, what makes the satire successful is its reflection of reality.
Many things have changed in medicine since his time, but the tired trope of the sleepless surgeon hangs on. Undaunted, I spent my second and third year of medical school accumulating accolades, conducting research, and connecting with mentors with the singular goal of joining the surgical ranks.
Midway through my third year, I completed a month-long surgical subinternship designed to give students a taste of what life would look like as an intern. I loved the operating room; it felt like the difference between being on dry land and being underwater. There were fewer distractions – your patient in the spotlight while everything else receded to the shadows.
However, as the month wore on, something stronger took hold. I couldn’t keep my eyes open in the darkened operating rooms and had to decline stools, fearing that I would fall asleep if I sat down.
On early morning prerounds, it’s 4:50 a.m. when I glance at the clock and pull back the curtain, already apologizing. My patient rolls over, flashing a wry smile. “Do you ever go home?” I’ve seen residents respond to this exact question in various ways. I live here. Yes. No. Soon. Not enough. My partner doesn’t think so.
There are days and, yes, years when we are led to believe this is what we live for: to be constantly available to our patients. It feels like a hollow victory when the patient, 2 days out from a total colectomy, begins to worry about your personal life. I ask her how she slept (not enough), any fevers (no), vomiting (no), urinating (I pause – she has a catheter).
My favorite part of these early morning rounds is the pause in my scripted litany of questions to listen to heart and lungs. It never fails to feel sacred: Patients become so quiet and still that I can’t help but think they have faith in me. Without prompting, she slides the back of her hospital gown forward like a curtain, already taking deep breaths so I can hear her lungs.
I look outside. The streetlights are still on, and from the seventh-floor window, I can watch staff making their way through the sliding double-doors, just beyond the yellowed pools of streetlight. I smile. I love medicine. I’m so tired.
For many in medicine, we are treated, and thus behave, as though our ability to manipulate physiology should also apply within the borders of our bodies: commanding less sleep, food, or bathroom breaks.
It places health care workers solidly in the realm of superhuman, living beyond one’s corporeal needs. The pandemic only heightened this misappropriation – adding hero and setting out a pedestal for health care workers to make their ungainly ascent. This kind of unsolicited admiration implicitly implies inhumanness, an otherness.
What would it look like if we started treating ourselves less like physicians and more like patients? I wish I was offering a solution, but really this is just a story.
To students rising through the ranks of medical training, identify what it is you need early and often. I can count on one hand how many physicians I’ve seen take a lunch break – even 10 minutes. Embrace hard work and self-preservation equally. My hope is that if enough of us take this path, it just might become a matter of course.
Dr. Meffert is a resident in the department of emergency medicine, MedStar Georgetown University Hospital, Washington Hospital Center, Washington. Dr. Meffert disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In a video posted to TikTok by the comedian Will Flanary, MD, better known to his followers as Dr. Glaucomflecken, he imitates a neurosurgical residency interview. With glasses perched on the bridge of his nose, Dr. Glaucomflecken poses as the attending, asking: “What are your weaknesses?”
The residency applicant answers without hesitation: “My physiological need for sleep.” “What are your strengths?” The resident replies with the hard, steely stare of the determined and uninitiated: “My desire to eliminate my physiological need for sleep.”
If you follow Dr. Glaucomflecken on Twitter, you might know the skit I’m referencing. For many physicians and physicians-in-training, what makes the satire successful is its reflection of reality.
Many things have changed in medicine since his time, but the tired trope of the sleepless surgeon hangs on. Undaunted, I spent my second and third year of medical school accumulating accolades, conducting research, and connecting with mentors with the singular goal of joining the surgical ranks.
Midway through my third year, I completed a month-long surgical subinternship designed to give students a taste of what life would look like as an intern. I loved the operating room; it felt like the difference between being on dry land and being underwater. There were fewer distractions – your patient in the spotlight while everything else receded to the shadows.
However, as the month wore on, something stronger took hold. I couldn’t keep my eyes open in the darkened operating rooms and had to decline stools, fearing that I would fall asleep if I sat down.
On early morning prerounds, it’s 4:50 a.m. when I glance at the clock and pull back the curtain, already apologizing. My patient rolls over, flashing a wry smile. “Do you ever go home?” I’ve seen residents respond to this exact question in various ways. I live here. Yes. No. Soon. Not enough. My partner doesn’t think so.
There are days and, yes, years when we are led to believe this is what we live for: to be constantly available to our patients. It feels like a hollow victory when the patient, 2 days out from a total colectomy, begins to worry about your personal life. I ask her how she slept (not enough), any fevers (no), vomiting (no), urinating (I pause – she has a catheter).
My favorite part of these early morning rounds is the pause in my scripted litany of questions to listen to heart and lungs. It never fails to feel sacred: Patients become so quiet and still that I can’t help but think they have faith in me. Without prompting, she slides the back of her hospital gown forward like a curtain, already taking deep breaths so I can hear her lungs.
I look outside. The streetlights are still on, and from the seventh-floor window, I can watch staff making their way through the sliding double-doors, just beyond the yellowed pools of streetlight. I smile. I love medicine. I’m so tired.
For many in medicine, we are treated, and thus behave, as though our ability to manipulate physiology should also apply within the borders of our bodies: commanding less sleep, food, or bathroom breaks.
It places health care workers solidly in the realm of superhuman, living beyond one’s corporeal needs. The pandemic only heightened this misappropriation – adding hero and setting out a pedestal for health care workers to make their ungainly ascent. This kind of unsolicited admiration implicitly implies inhumanness, an otherness.
What would it look like if we started treating ourselves less like physicians and more like patients? I wish I was offering a solution, but really this is just a story.
To students rising through the ranks of medical training, identify what it is you need early and often. I can count on one hand how many physicians I’ve seen take a lunch break – even 10 minutes. Embrace hard work and self-preservation equally. My hope is that if enough of us take this path, it just might become a matter of course.
Dr. Meffert is a resident in the department of emergency medicine, MedStar Georgetown University Hospital, Washington Hospital Center, Washington. Dr. Meffert disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Charcoal could be the cure for the common high-fat diet
Charcoal won’t let high-fat diet weigh you down
Do you want to be the funniest person alive? Of course you do. It’s really simple too, just one joke can make you the greatest comedian of all time. All you have to do is go camping and cook food over a roaring campfire. When someone drops food into the fire (which they always will), get ready. Once they fish out the offending food, which is almost certainly coated in hot coals, tell them: “Ah, eat it anyway. A little texture never hurt!” Trust us, most hilarious and original gag of all time.
But before your hapless friend brushes off his hot dog and forces a laugh, consider this: Japanese researchers have found that a charcoal supplement can prevent weight gain in mice consuming a high-fat diet. Charcoal is actually quite the helpful substance, and not just for grilling. It’s been used as medicine for hundreds of years and even today is used as a treatment for drug overdose and excess gas and flatulence.
The study involved two groups of mice: One was fed a normal diet, the other a high-fat diet. After 12 weeks, the high-fat diet mice had gained weight. At that point, edible activated charcoal was added to their diet. From that point, weight gain was similar between the two groups, and the amount of bile acid, cholesterol, triglyceride, and fatty acid excreted by the high-fat mice increased by two to four times.
The researchers supported the notion that consuming an activated charcoal supplement before or while eating fatty food could prevent weight gain from said fatty food. Which works out well for the classic American barbecue, which is traditionally both high in fat and charcoal. All you have to do is buy some extra charcoal briquettes to pass around and munch on with your friends. Now that’s a party we can get behind.
There’s awake, and then there’s neurologically awake
Time to toss another urban legend onto the trash heap of history. Say goodbye to the benefits of uninterrupted sleep. It’s a fraud, a fake, a myth, a hit or myth, a swing and a myth, an old wives’ tale. You can stuff it and put it on a shelf next to Bigfoot, the Slender Man, and Twinkies.
We all thought we needed 8 hours of uninterrupted sleep every night, but guess who we forgot to tell? Our brains. They’ve been doing exactly the opposite all along, laughing at us the whole time. Smug SOBs.
To straighten out this mess, let’s bring in a scientist, Celia Kjaerby of the Center for Translational Neuromedicine at the University of Copenhagen: “You may think that sleep is a constant state that you are in, and then you wake up. But there is a lot more to sleep than meets the eye. We have learned that noradrenaline causes you to wake up more than 100 times a night. And that is during perfectly normal sleep.”
Those 100 or so sleep interruptions are so brief that we don’t even notice, but they are very important, according to a study conducted at the university. Those tiny little wake-up calls are “the essence for the part of sleep that makes us wake up rested and which enables us to remember what we learned the day before. ... The very short awakenings are created by waves of norepinephrine [and they] reset the brain so that it is ready to store memory when you dive back into sleep,” lead author Maiken Nedergaard, MD, explained.
The investigators compared the level of noradrenaline in sleeping mice with their electrical activity and found that the hormone constantly increased and decreased in a wavelike pattern. A high level meant that the animal was neurologically awake. Deeper valleys between the high points meant better sleep, and the mice with the “highest number of deep noradrenaline valleys were also the ones with the best memory,” the team said in their written statement.
Not just the best memory, they said, but “super memory.” That, of course, was enough to get the attention of Marvel Comics, so the next Disney superhero blockbuster will feature Nocturna, the queen of the night. Her power? Never forgets. Her archnemesis? The Insomniac. Her catchphrase? “Let me sleep on it.”
Words can hurt, literally
Growing up, we’re sure you heard the “sticks and stones” rhyme. Maybe you’ve even recited it once or twice to defend yourself. Well, forget it, because words can hurt and your brain knows it.
In a new study published in Frontiers in Communication, Marijn Struiksma, PhD, of Utrecht University, and colleagues incorporated the use of electroencephalography (EEG) and skin conductance on 79 women to see how words (specifically insults) actually affect the human body.
Each subject was asked to read three different types of statements: an insult, a compliment, and something factual but neutral. Half of the statements contained the subject’s name and half used somebody else’s. The participants were told that these statements were collected from three men.
Nobody interacted with each other, and the setting was completely clinical, yet the results were unmistakable. The EEG showed an effect in P2 amplitude with repetitive insults, no matter who it was about. Even though the insults weren’t real and the participants were aware of it, the brain still recognized them as hurtful, coming across as “mini slaps in the face,” Dr. Struiksma noted in a written statement.
The researchers noted that more needs to be done to better understand the long-term effects that insults can have and create a deeper understanding between words and emotion, but studying the effects of insults in a real-life setting is ethically tricky. This study is a start.
So, yeah, sticks and stones can break your bones, but words will actually hurt you.
This article was updated 7/21/22.
Charcoal won’t let high-fat diet weigh you down
Do you want to be the funniest person alive? Of course you do. It’s really simple too, just one joke can make you the greatest comedian of all time. All you have to do is go camping and cook food over a roaring campfire. When someone drops food into the fire (which they always will), get ready. Once they fish out the offending food, which is almost certainly coated in hot coals, tell them: “Ah, eat it anyway. A little texture never hurt!” Trust us, most hilarious and original gag of all time.
But before your hapless friend brushes off his hot dog and forces a laugh, consider this: Japanese researchers have found that a charcoal supplement can prevent weight gain in mice consuming a high-fat diet. Charcoal is actually quite the helpful substance, and not just for grilling. It’s been used as medicine for hundreds of years and even today is used as a treatment for drug overdose and excess gas and flatulence.
The study involved two groups of mice: One was fed a normal diet, the other a high-fat diet. After 12 weeks, the high-fat diet mice had gained weight. At that point, edible activated charcoal was added to their diet. From that point, weight gain was similar between the two groups, and the amount of bile acid, cholesterol, triglyceride, and fatty acid excreted by the high-fat mice increased by two to four times.
The researchers supported the notion that consuming an activated charcoal supplement before or while eating fatty food could prevent weight gain from said fatty food. Which works out well for the classic American barbecue, which is traditionally both high in fat and charcoal. All you have to do is buy some extra charcoal briquettes to pass around and munch on with your friends. Now that’s a party we can get behind.
There’s awake, and then there’s neurologically awake
Time to toss another urban legend onto the trash heap of history. Say goodbye to the benefits of uninterrupted sleep. It’s a fraud, a fake, a myth, a hit or myth, a swing and a myth, an old wives’ tale. You can stuff it and put it on a shelf next to Bigfoot, the Slender Man, and Twinkies.
We all thought we needed 8 hours of uninterrupted sleep every night, but guess who we forgot to tell? Our brains. They’ve been doing exactly the opposite all along, laughing at us the whole time. Smug SOBs.
To straighten out this mess, let’s bring in a scientist, Celia Kjaerby of the Center for Translational Neuromedicine at the University of Copenhagen: “You may think that sleep is a constant state that you are in, and then you wake up. But there is a lot more to sleep than meets the eye. We have learned that noradrenaline causes you to wake up more than 100 times a night. And that is during perfectly normal sleep.”
Those 100 or so sleep interruptions are so brief that we don’t even notice, but they are very important, according to a study conducted at the university. Those tiny little wake-up calls are “the essence for the part of sleep that makes us wake up rested and which enables us to remember what we learned the day before. ... The very short awakenings are created by waves of norepinephrine [and they] reset the brain so that it is ready to store memory when you dive back into sleep,” lead author Maiken Nedergaard, MD, explained.
The investigators compared the level of noradrenaline in sleeping mice with their electrical activity and found that the hormone constantly increased and decreased in a wavelike pattern. A high level meant that the animal was neurologically awake. Deeper valleys between the high points meant better sleep, and the mice with the “highest number of deep noradrenaline valleys were also the ones with the best memory,” the team said in their written statement.
Not just the best memory, they said, but “super memory.” That, of course, was enough to get the attention of Marvel Comics, so the next Disney superhero blockbuster will feature Nocturna, the queen of the night. Her power? Never forgets. Her archnemesis? The Insomniac. Her catchphrase? “Let me sleep on it.”
Words can hurt, literally
Growing up, we’re sure you heard the “sticks and stones” rhyme. Maybe you’ve even recited it once or twice to defend yourself. Well, forget it, because words can hurt and your brain knows it.
In a new study published in Frontiers in Communication, Marijn Struiksma, PhD, of Utrecht University, and colleagues incorporated the use of electroencephalography (EEG) and skin conductance on 79 women to see how words (specifically insults) actually affect the human body.
Each subject was asked to read three different types of statements: an insult, a compliment, and something factual but neutral. Half of the statements contained the subject’s name and half used somebody else’s. The participants were told that these statements were collected from three men.
Nobody interacted with each other, and the setting was completely clinical, yet the results were unmistakable. The EEG showed an effect in P2 amplitude with repetitive insults, no matter who it was about. Even though the insults weren’t real and the participants were aware of it, the brain still recognized them as hurtful, coming across as “mini slaps in the face,” Dr. Struiksma noted in a written statement.
The researchers noted that more needs to be done to better understand the long-term effects that insults can have and create a deeper understanding between words and emotion, but studying the effects of insults in a real-life setting is ethically tricky. This study is a start.
So, yeah, sticks and stones can break your bones, but words will actually hurt you.
This article was updated 7/21/22.
Charcoal won’t let high-fat diet weigh you down
Do you want to be the funniest person alive? Of course you do. It’s really simple too, just one joke can make you the greatest comedian of all time. All you have to do is go camping and cook food over a roaring campfire. When someone drops food into the fire (which they always will), get ready. Once they fish out the offending food, which is almost certainly coated in hot coals, tell them: “Ah, eat it anyway. A little texture never hurt!” Trust us, most hilarious and original gag of all time.
But before your hapless friend brushes off his hot dog and forces a laugh, consider this: Japanese researchers have found that a charcoal supplement can prevent weight gain in mice consuming a high-fat diet. Charcoal is actually quite the helpful substance, and not just for grilling. It’s been used as medicine for hundreds of years and even today is used as a treatment for drug overdose and excess gas and flatulence.
The study involved two groups of mice: One was fed a normal diet, the other a high-fat diet. After 12 weeks, the high-fat diet mice had gained weight. At that point, edible activated charcoal was added to their diet. From that point, weight gain was similar between the two groups, and the amount of bile acid, cholesterol, triglyceride, and fatty acid excreted by the high-fat mice increased by two to four times.
The researchers supported the notion that consuming an activated charcoal supplement before or while eating fatty food could prevent weight gain from said fatty food. Which works out well for the classic American barbecue, which is traditionally both high in fat and charcoal. All you have to do is buy some extra charcoal briquettes to pass around and munch on with your friends. Now that’s a party we can get behind.
There’s awake, and then there’s neurologically awake
Time to toss another urban legend onto the trash heap of history. Say goodbye to the benefits of uninterrupted sleep. It’s a fraud, a fake, a myth, a hit or myth, a swing and a myth, an old wives’ tale. You can stuff it and put it on a shelf next to Bigfoot, the Slender Man, and Twinkies.
We all thought we needed 8 hours of uninterrupted sleep every night, but guess who we forgot to tell? Our brains. They’ve been doing exactly the opposite all along, laughing at us the whole time. Smug SOBs.
To straighten out this mess, let’s bring in a scientist, Celia Kjaerby of the Center for Translational Neuromedicine at the University of Copenhagen: “You may think that sleep is a constant state that you are in, and then you wake up. But there is a lot more to sleep than meets the eye. We have learned that noradrenaline causes you to wake up more than 100 times a night. And that is during perfectly normal sleep.”
Those 100 or so sleep interruptions are so brief that we don’t even notice, but they are very important, according to a study conducted at the university. Those tiny little wake-up calls are “the essence for the part of sleep that makes us wake up rested and which enables us to remember what we learned the day before. ... The very short awakenings are created by waves of norepinephrine [and they] reset the brain so that it is ready to store memory when you dive back into sleep,” lead author Maiken Nedergaard, MD, explained.
The investigators compared the level of noradrenaline in sleeping mice with their electrical activity and found that the hormone constantly increased and decreased in a wavelike pattern. A high level meant that the animal was neurologically awake. Deeper valleys between the high points meant better sleep, and the mice with the “highest number of deep noradrenaline valleys were also the ones with the best memory,” the team said in their written statement.
Not just the best memory, they said, but “super memory.” That, of course, was enough to get the attention of Marvel Comics, so the next Disney superhero blockbuster will feature Nocturna, the queen of the night. Her power? Never forgets. Her archnemesis? The Insomniac. Her catchphrase? “Let me sleep on it.”
Words can hurt, literally
Growing up, we’re sure you heard the “sticks and stones” rhyme. Maybe you’ve even recited it once or twice to defend yourself. Well, forget it, because words can hurt and your brain knows it.
In a new study published in Frontiers in Communication, Marijn Struiksma, PhD, of Utrecht University, and colleagues incorporated the use of electroencephalography (EEG) and skin conductance on 79 women to see how words (specifically insults) actually affect the human body.
Each subject was asked to read three different types of statements: an insult, a compliment, and something factual but neutral. Half of the statements contained the subject’s name and half used somebody else’s. The participants were told that these statements were collected from three men.
Nobody interacted with each other, and the setting was completely clinical, yet the results were unmistakable. The EEG showed an effect in P2 amplitude with repetitive insults, no matter who it was about. Even though the insults weren’t real and the participants were aware of it, the brain still recognized them as hurtful, coming across as “mini slaps in the face,” Dr. Struiksma noted in a written statement.
The researchers noted that more needs to be done to better understand the long-term effects that insults can have and create a deeper understanding between words and emotion, but studying the effects of insults in a real-life setting is ethically tricky. This study is a start.
So, yeah, sticks and stones can break your bones, but words will actually hurt you.
This article was updated 7/21/22.
‘I shall harm’
I was quite sure I had multiple sclerosis when I was a medical student. I first noticed symptoms during my neurology rotation. All the signs were there: Fatigue that was getting worse in the North Carolina heat (Uhthoff sign!). A tingle running down my neck (Lhermitte sign!). Blurry vision late at night while studying pathways in Lange Neurology. “Didn’t cousin Amy have MS?” I asked my Mom. I started researching which medical specialties didn’t require dexterity. My left eyelid began twitching and didn’t stop until I rotated to ob.gyn.
Fortunately, it was not multiple sclerosis I had, but rather nosophobia, also known as Medical Student’s Disease. The combination of intense study of symptoms, spotty knowledge of diagnoses, and grade anxiety makes nosophobia common in med students. Despite its name, it doesn’t afflict only doctors. Patients often come to us convinced they have a disease but without reason. So unshakable is their belief that multiple visits are often required to disabuse them of their self-diagnosis. I sometimes have to remind myself to appear concerned even when a “melanoma” is a freckle so small I can barely see it with a dermatoscope. Or a “genital wart” is a hair follicle that looks exactly like the hundreds on the patient’s scrotum. Tougher though, are the treatment-avoiders: patients whose imagined side effects lead them to stop or refuse treatment.
I recently saw a middle-aged man with erythroderma so severe he looked like a ghillie suit of scale. He had a lifelong history of atopic dermatitis and a 2-year history of avoiding treatments. At some point, he tried all the usual remedies: cyclosporine, methotrexate, azathioprine, light therapy, boxes of topicals. The last treatment had been dupilumab, which he tried for a few weeks. “Why did you stop that one?” I asked. The injections were making him go blind, he explained. “Not blurry? Blind?” I asked. Yes, he could not see at all after each injection. Perhaps he might have dry eyes or keratitis? Sure. But blindness? It seemed an unreasonable concern. Further discussion revealed that intolerance to medication side effects was why he had stopped all his other treatments.
Nocebo, from the Latin “I shall harm,” is the dark counterpart to the placebo. Patients experience imagined, or even real, adverse effects because they believe the treatment is causing them harm. This is true even though that treatment might not be having any unwanted physiologic effect. Statins are a good example. Studies have shown that most patient-reported side effects of statins are in fact nocebo effects rather than a result of pharmacologic causes.
Yet, many patients on statins report muscle pain or other concerns as unbearable. As a consequence, some patients who might have benefited from statins might be missing out on the protective gains. as compared with bad outcomes that occurred from not taking action. It’s frustrating when there’s a standard of care treatment, but our patient can’t get past their fear of harm to try it.
Despite my recommendations, my eczema patient insisted on continuing his nontreatment rather than take any risks with treatments for now. There are ways I might help, but I expect it will require additional visits to build trust. Today, the best I can do is to understand and respect him. At least he doesn’t think he has a genital wart – I’m not sure how I’d treat it if he did.
Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at [email protected].
I was quite sure I had multiple sclerosis when I was a medical student. I first noticed symptoms during my neurology rotation. All the signs were there: Fatigue that was getting worse in the North Carolina heat (Uhthoff sign!). A tingle running down my neck (Lhermitte sign!). Blurry vision late at night while studying pathways in Lange Neurology. “Didn’t cousin Amy have MS?” I asked my Mom. I started researching which medical specialties didn’t require dexterity. My left eyelid began twitching and didn’t stop until I rotated to ob.gyn.
Fortunately, it was not multiple sclerosis I had, but rather nosophobia, also known as Medical Student’s Disease. The combination of intense study of symptoms, spotty knowledge of diagnoses, and grade anxiety makes nosophobia common in med students. Despite its name, it doesn’t afflict only doctors. Patients often come to us convinced they have a disease but without reason. So unshakable is their belief that multiple visits are often required to disabuse them of their self-diagnosis. I sometimes have to remind myself to appear concerned even when a “melanoma” is a freckle so small I can barely see it with a dermatoscope. Or a “genital wart” is a hair follicle that looks exactly like the hundreds on the patient’s scrotum. Tougher though, are the treatment-avoiders: patients whose imagined side effects lead them to stop or refuse treatment.
I recently saw a middle-aged man with erythroderma so severe he looked like a ghillie suit of scale. He had a lifelong history of atopic dermatitis and a 2-year history of avoiding treatments. At some point, he tried all the usual remedies: cyclosporine, methotrexate, azathioprine, light therapy, boxes of topicals. The last treatment had been dupilumab, which he tried for a few weeks. “Why did you stop that one?” I asked. The injections were making him go blind, he explained. “Not blurry? Blind?” I asked. Yes, he could not see at all after each injection. Perhaps he might have dry eyes or keratitis? Sure. But blindness? It seemed an unreasonable concern. Further discussion revealed that intolerance to medication side effects was why he had stopped all his other treatments.
Nocebo, from the Latin “I shall harm,” is the dark counterpart to the placebo. Patients experience imagined, or even real, adverse effects because they believe the treatment is causing them harm. This is true even though that treatment might not be having any unwanted physiologic effect. Statins are a good example. Studies have shown that most patient-reported side effects of statins are in fact nocebo effects rather than a result of pharmacologic causes.
Yet, many patients on statins report muscle pain or other concerns as unbearable. As a consequence, some patients who might have benefited from statins might be missing out on the protective gains. as compared with bad outcomes that occurred from not taking action. It’s frustrating when there’s a standard of care treatment, but our patient can’t get past their fear of harm to try it.
Despite my recommendations, my eczema patient insisted on continuing his nontreatment rather than take any risks with treatments for now. There are ways I might help, but I expect it will require additional visits to build trust. Today, the best I can do is to understand and respect him. At least he doesn’t think he has a genital wart – I’m not sure how I’d treat it if he did.
Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at [email protected].
I was quite sure I had multiple sclerosis when I was a medical student. I first noticed symptoms during my neurology rotation. All the signs were there: Fatigue that was getting worse in the North Carolina heat (Uhthoff sign!). A tingle running down my neck (Lhermitte sign!). Blurry vision late at night while studying pathways in Lange Neurology. “Didn’t cousin Amy have MS?” I asked my Mom. I started researching which medical specialties didn’t require dexterity. My left eyelid began twitching and didn’t stop until I rotated to ob.gyn.
Fortunately, it was not multiple sclerosis I had, but rather nosophobia, also known as Medical Student’s Disease. The combination of intense study of symptoms, spotty knowledge of diagnoses, and grade anxiety makes nosophobia common in med students. Despite its name, it doesn’t afflict only doctors. Patients often come to us convinced they have a disease but without reason. So unshakable is their belief that multiple visits are often required to disabuse them of their self-diagnosis. I sometimes have to remind myself to appear concerned even when a “melanoma” is a freckle so small I can barely see it with a dermatoscope. Or a “genital wart” is a hair follicle that looks exactly like the hundreds on the patient’s scrotum. Tougher though, are the treatment-avoiders: patients whose imagined side effects lead them to stop or refuse treatment.
I recently saw a middle-aged man with erythroderma so severe he looked like a ghillie suit of scale. He had a lifelong history of atopic dermatitis and a 2-year history of avoiding treatments. At some point, he tried all the usual remedies: cyclosporine, methotrexate, azathioprine, light therapy, boxes of topicals. The last treatment had been dupilumab, which he tried for a few weeks. “Why did you stop that one?” I asked. The injections were making him go blind, he explained. “Not blurry? Blind?” I asked. Yes, he could not see at all after each injection. Perhaps he might have dry eyes or keratitis? Sure. But blindness? It seemed an unreasonable concern. Further discussion revealed that intolerance to medication side effects was why he had stopped all his other treatments.
Nocebo, from the Latin “I shall harm,” is the dark counterpart to the placebo. Patients experience imagined, or even real, adverse effects because they believe the treatment is causing them harm. This is true even though that treatment might not be having any unwanted physiologic effect. Statins are a good example. Studies have shown that most patient-reported side effects of statins are in fact nocebo effects rather than a result of pharmacologic causes.
Yet, many patients on statins report muscle pain or other concerns as unbearable. As a consequence, some patients who might have benefited from statins might be missing out on the protective gains. as compared with bad outcomes that occurred from not taking action. It’s frustrating when there’s a standard of care treatment, but our patient can’t get past their fear of harm to try it.
Despite my recommendations, my eczema patient insisted on continuing his nontreatment rather than take any risks with treatments for now. There are ways I might help, but I expect it will require additional visits to build trust. Today, the best I can do is to understand and respect him. At least he doesn’t think he has a genital wart – I’m not sure how I’d treat it if he did.
Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at [email protected].
NAFLD strongly correlated with psoriasis, PsA; risk linked to severity
NEW YORK – – and probably in those with psoriatic arthritis (PsA) as well, according to a systematic review and meta-analysis presented at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis.
“Our findings imply that psoriatic patients should be screened with an ultrasonographic exam in cases where there are metabolic features that are associated with NAFLD,” reported Francesco Bellinato, MD, a researcher in the section of dermatology and venereology, University of Verona (Italy).
The data are strong. Of 76 nonduplicate publications found in the literature, the 11 observational studies included in the meta-analysis met stringent criteria, including a diagnosis of psoriasis and PsA based on objective criteria, NAFLD confirmed with liver biopsy or imaging, and odds rates calculated with 95% confidence intervals.
From these 11 studies, aggregate data were available for 249,333 psoriatic patients, of which 49% had NAFLD, and 1,491,402 were healthy controls. Among the controls, 36% had NAFLD. Four of the studies were from North America, four from Europe, and three from Asia.
In the pooled data, the risk of NAFLD among those with psoriasis relative to healthy controls fell just short of a twofold increase (odds ratio, 1.96; 95% CI, 1.70-2.26; P < .001). When stratified by studies that confirmed NAFLD by biopsy relative to ultrasonography, there was no significant heterogeneity.
Eight of the studies included an analysis of relative risk in the context of skin lesion severity defined by Psoriasis Area and Severity Index (PASI) score. Relative to those without NAFLD, psoriatic patients with NAFLD had a significant greater mean PASI score on a pooled weighted mean difference analysis (OR, 3.93; 95% CI, 2.01-5.84; P < .0001).
For PsA relative to no PsA in the five studies that compared risk between these two groups, the risk of NAFLD was again nearly twofold higher. This fell short of conventional definition of statistical significance, but it was associated with a strong trend (OR, 1.83; 95% CI, 0.98-3.43; P = .06).
The risk of NAFLD among patients with psoriasis was not found to vary significantly when assessed by univariable meta-regressions across numerous characteristics, such as sex and body mass index.
In one of the largest of the observational studies included in the meta-analysis by Alexis Ogdie, MD, associate professor of medicine and epidemiology at the University of Pennsylvania, Philadelphia, and colleagues, data were analyzed in more than 1.5 million patients, which included 54,251 patients with rheumatoid arthritis. While the hazard ratio of NAFLD was increased for both psoriasis (HR, 2.23) and PsA (HR, 2.11), it was not elevated in those with RA (HR, 0.96).
Risk by severity, possible mechanisms
This study also included an analysis of NAFLD risk according to psoriasis severity. While risk was still significant among those with mild disease (HR, 1.18; 95% CI, 1.07-1.30), it was almost twofold greater in those with moderate to severe psoriasis (HR, 2.23; 95% CI, 1.73-2.87).
Dr. Bellinato conceded that the mechanisms underlying the association between psoriasis and NAFLD are unknown, but he said “metaflammation” is suspected.
“The secretion of proinflammatory, prothrombotic, and oxidative stress mediators in both psoriatic skin and adipose tissue might act systemically and promote insulin resistance and other metabolic derangements that promote the development and progression of NAFLD,” Dr. Bellinato explained.
He thinks that noninvasive screening methods, such as currently used methods to calculate fibrosis score, might be useful for evaluating patients with psoriasis for NAFLD and referring them to a hepatologist when appropriate.
Given the strong association with NAFLD, Dr. Bellinato suggested that “the findings of this meta-analysis pave the way for novel, large, prospective, and histologically based studies.”
The association between psoriasis and NAFLD is clinically relevant, agreed Joel M. Gelfand, MD, vice-chair of clinical research and medical director of the clinical studies unit, department of dermatology, University of Pennsylvania, Philadelphia.
“It is not clear if psoriasis causes fatty liver disease or vice versa, but clinicians should be aware of this association,” he said in an interview. Dr. Gelfand was a coauthor of the study by Dr. Ogdie and colleagues and led another more recent population-based study that implicated methotrexate as a factor in psoriasis-related hepatotoxicity.
If NAFLD is identified in a patient with psoriasis, treatments are limited, but Dr. Gelfand suggested that patients should be made aware of the risk. “Clinicians should encourage patients with psoriasis to take measures to protect their liver, such as avoiding drinking alcohol to excess and trying to maintain a healthy body weight,” he said.
Dr. Bellinato reported no conflicts of interest. Dr. Gelfand has financial relationships with more than 10 pharmaceutical companies, including those that make therapies for psoriasis.
NEW YORK – – and probably in those with psoriatic arthritis (PsA) as well, according to a systematic review and meta-analysis presented at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis.
“Our findings imply that psoriatic patients should be screened with an ultrasonographic exam in cases where there are metabolic features that are associated with NAFLD,” reported Francesco Bellinato, MD, a researcher in the section of dermatology and venereology, University of Verona (Italy).
The data are strong. Of 76 nonduplicate publications found in the literature, the 11 observational studies included in the meta-analysis met stringent criteria, including a diagnosis of psoriasis and PsA based on objective criteria, NAFLD confirmed with liver biopsy or imaging, and odds rates calculated with 95% confidence intervals.
From these 11 studies, aggregate data were available for 249,333 psoriatic patients, of which 49% had NAFLD, and 1,491,402 were healthy controls. Among the controls, 36% had NAFLD. Four of the studies were from North America, four from Europe, and three from Asia.
In the pooled data, the risk of NAFLD among those with psoriasis relative to healthy controls fell just short of a twofold increase (odds ratio, 1.96; 95% CI, 1.70-2.26; P < .001). When stratified by studies that confirmed NAFLD by biopsy relative to ultrasonography, there was no significant heterogeneity.
Eight of the studies included an analysis of relative risk in the context of skin lesion severity defined by Psoriasis Area and Severity Index (PASI) score. Relative to those without NAFLD, psoriatic patients with NAFLD had a significant greater mean PASI score on a pooled weighted mean difference analysis (OR, 3.93; 95% CI, 2.01-5.84; P < .0001).
For PsA relative to no PsA in the five studies that compared risk between these two groups, the risk of NAFLD was again nearly twofold higher. This fell short of conventional definition of statistical significance, but it was associated with a strong trend (OR, 1.83; 95% CI, 0.98-3.43; P = .06).
The risk of NAFLD among patients with psoriasis was not found to vary significantly when assessed by univariable meta-regressions across numerous characteristics, such as sex and body mass index.
In one of the largest of the observational studies included in the meta-analysis by Alexis Ogdie, MD, associate professor of medicine and epidemiology at the University of Pennsylvania, Philadelphia, and colleagues, data were analyzed in more than 1.5 million patients, which included 54,251 patients with rheumatoid arthritis. While the hazard ratio of NAFLD was increased for both psoriasis (HR, 2.23) and PsA (HR, 2.11), it was not elevated in those with RA (HR, 0.96).
Risk by severity, possible mechanisms
This study also included an analysis of NAFLD risk according to psoriasis severity. While risk was still significant among those with mild disease (HR, 1.18; 95% CI, 1.07-1.30), it was almost twofold greater in those with moderate to severe psoriasis (HR, 2.23; 95% CI, 1.73-2.87).
Dr. Bellinato conceded that the mechanisms underlying the association between psoriasis and NAFLD are unknown, but he said “metaflammation” is suspected.
“The secretion of proinflammatory, prothrombotic, and oxidative stress mediators in both psoriatic skin and adipose tissue might act systemically and promote insulin resistance and other metabolic derangements that promote the development and progression of NAFLD,” Dr. Bellinato explained.
He thinks that noninvasive screening methods, such as currently used methods to calculate fibrosis score, might be useful for evaluating patients with psoriasis for NAFLD and referring them to a hepatologist when appropriate.
Given the strong association with NAFLD, Dr. Bellinato suggested that “the findings of this meta-analysis pave the way for novel, large, prospective, and histologically based studies.”
The association between psoriasis and NAFLD is clinically relevant, agreed Joel M. Gelfand, MD, vice-chair of clinical research and medical director of the clinical studies unit, department of dermatology, University of Pennsylvania, Philadelphia.
“It is not clear if psoriasis causes fatty liver disease or vice versa, but clinicians should be aware of this association,” he said in an interview. Dr. Gelfand was a coauthor of the study by Dr. Ogdie and colleagues and led another more recent population-based study that implicated methotrexate as a factor in psoriasis-related hepatotoxicity.
If NAFLD is identified in a patient with psoriasis, treatments are limited, but Dr. Gelfand suggested that patients should be made aware of the risk. “Clinicians should encourage patients with psoriasis to take measures to protect their liver, such as avoiding drinking alcohol to excess and trying to maintain a healthy body weight,” he said.
Dr. Bellinato reported no conflicts of interest. Dr. Gelfand has financial relationships with more than 10 pharmaceutical companies, including those that make therapies for psoriasis.
NEW YORK – – and probably in those with psoriatic arthritis (PsA) as well, according to a systematic review and meta-analysis presented at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis.
“Our findings imply that psoriatic patients should be screened with an ultrasonographic exam in cases where there are metabolic features that are associated with NAFLD,” reported Francesco Bellinato, MD, a researcher in the section of dermatology and venereology, University of Verona (Italy).
The data are strong. Of 76 nonduplicate publications found in the literature, the 11 observational studies included in the meta-analysis met stringent criteria, including a diagnosis of psoriasis and PsA based on objective criteria, NAFLD confirmed with liver biopsy or imaging, and odds rates calculated with 95% confidence intervals.
From these 11 studies, aggregate data were available for 249,333 psoriatic patients, of which 49% had NAFLD, and 1,491,402 were healthy controls. Among the controls, 36% had NAFLD. Four of the studies were from North America, four from Europe, and three from Asia.
In the pooled data, the risk of NAFLD among those with psoriasis relative to healthy controls fell just short of a twofold increase (odds ratio, 1.96; 95% CI, 1.70-2.26; P < .001). When stratified by studies that confirmed NAFLD by biopsy relative to ultrasonography, there was no significant heterogeneity.
Eight of the studies included an analysis of relative risk in the context of skin lesion severity defined by Psoriasis Area and Severity Index (PASI) score. Relative to those without NAFLD, psoriatic patients with NAFLD had a significant greater mean PASI score on a pooled weighted mean difference analysis (OR, 3.93; 95% CI, 2.01-5.84; P < .0001).
For PsA relative to no PsA in the five studies that compared risk between these two groups, the risk of NAFLD was again nearly twofold higher. This fell short of conventional definition of statistical significance, but it was associated with a strong trend (OR, 1.83; 95% CI, 0.98-3.43; P = .06).
The risk of NAFLD among patients with psoriasis was not found to vary significantly when assessed by univariable meta-regressions across numerous characteristics, such as sex and body mass index.
In one of the largest of the observational studies included in the meta-analysis by Alexis Ogdie, MD, associate professor of medicine and epidemiology at the University of Pennsylvania, Philadelphia, and colleagues, data were analyzed in more than 1.5 million patients, which included 54,251 patients with rheumatoid arthritis. While the hazard ratio of NAFLD was increased for both psoriasis (HR, 2.23) and PsA (HR, 2.11), it was not elevated in those with RA (HR, 0.96).
Risk by severity, possible mechanisms
This study also included an analysis of NAFLD risk according to psoriasis severity. While risk was still significant among those with mild disease (HR, 1.18; 95% CI, 1.07-1.30), it was almost twofold greater in those with moderate to severe psoriasis (HR, 2.23; 95% CI, 1.73-2.87).
Dr. Bellinato conceded that the mechanisms underlying the association between psoriasis and NAFLD are unknown, but he said “metaflammation” is suspected.
“The secretion of proinflammatory, prothrombotic, and oxidative stress mediators in both psoriatic skin and adipose tissue might act systemically and promote insulin resistance and other metabolic derangements that promote the development and progression of NAFLD,” Dr. Bellinato explained.
He thinks that noninvasive screening methods, such as currently used methods to calculate fibrosis score, might be useful for evaluating patients with psoriasis for NAFLD and referring them to a hepatologist when appropriate.
Given the strong association with NAFLD, Dr. Bellinato suggested that “the findings of this meta-analysis pave the way for novel, large, prospective, and histologically based studies.”
The association between psoriasis and NAFLD is clinically relevant, agreed Joel M. Gelfand, MD, vice-chair of clinical research and medical director of the clinical studies unit, department of dermatology, University of Pennsylvania, Philadelphia.
“It is not clear if psoriasis causes fatty liver disease or vice versa, but clinicians should be aware of this association,” he said in an interview. Dr. Gelfand was a coauthor of the study by Dr. Ogdie and colleagues and led another more recent population-based study that implicated methotrexate as a factor in psoriasis-related hepatotoxicity.
If NAFLD is identified in a patient with psoriasis, treatments are limited, but Dr. Gelfand suggested that patients should be made aware of the risk. “Clinicians should encourage patients with psoriasis to take measures to protect their liver, such as avoiding drinking alcohol to excess and trying to maintain a healthy body weight,” he said.
Dr. Bellinato reported no conflicts of interest. Dr. Gelfand has financial relationships with more than 10 pharmaceutical companies, including those that make therapies for psoriasis.
AT GRAPPA 2022
Focal Palmoplantar Keratoderma and Gingival Keratosis Caused by a KRT16 Mutation
To the Editor:
Focal palmoplantar keratoderma and gingival keratosis (FPGK)(Online Mendelian Inheritance in Man [OMIM] 148730) is a rare autosomal-dominant syndrome featuring focal, pressure-related, painful palmoplantar keratoderma and gingival hyperkeratosis presenting as leukokeratosis. Focal palmoplantar keratoderma and gingival keratosis was first defined by Gorlin1 in 1976. Since then, only a few cases have been reported, but no causative mutations have been identified.2
Focal pressure-related palmoplantar keratoderma (PPK) and oral hyperkeratosis also are seen in pachyonychia congenita (PC)(OMIM 167200, 615726, 615728, 167210), a rare autosomal-dominant disorder of keratinization characterized by PPK and nail dystrophy. Patients with PC often present with plantar pain; more variable features include oral leukokeratosis, follicular hyperkeratosis, pilosebaceous and epidermal inclusion cysts, hoarseness, hyperhidrosis, and natal teeth. Pachyonychia congenita is caused by mutation in keratin genes KRT6A, KRT6B, KRT16, or KRT17.
Focal palmoplantar keratoderma and gingival keratosis as well as PC are distinct from other forms of PPK with gingival involvement such as
Despite the common features of FPGK and PC, they are considered distinct disorders due to absence of nail changes in FPGK and no prior evidence of a common genetic cause. We present a patient with familial FPGK found by whole exome sequencing to be caused by a mutation in KRT16.
The proband was a 57-year-old man born to unrelated parents (Figure 1). He had no skin problems at birth, and his development was normal. He had painful focal keratoderma since childhood that were most prominent at pressure points on the soles and toes (Figure 2A), in addition to gingival hyperkeratosis and oral leukokeratosis (Figure 2B). He had no associated abnormalities of the skin, hair, or teeth and no nail findings (Figure 2C). He reported that his father and 2 of his 3 sisters were affected with similar symptoms. A punch biopsy of the right fifth toe was consistent with verrucous epidermal hyperplasia with perinuclear keratinization in the spinous layer (Figure 3A). A gingival biopsy showed perinuclear eosinophilic globules and basophilic stranding in the cytoplasm (Figure 3B). His older sister had more severe and painful focal keratoderma of the soles, punctate keratoderma of the palms, gingival hyperkeratosis, and leukokeratosis of the tongue.
Whole exome sequencing of the proband revealed a heterozygous missense mutation in KRT16 (c.380G>A, p.R127H, rs57424749). Sanger sequencing confirmed this mutation and showed that it was heterozygous in both of his affected sisters and absent in his unaffected niece (Figure 1). The patient was treated with topical and systemic retinoids, keratolytics, and mechanical removal to moderate effect, with noted improvement in the appearance and associated pain of the plantar keratoderma.
Phenotypic heterogeneity is common in PC, though PC due to KRT6A mutations demonstrates more severe nail disease with oral lesions, cysts, and follicular hyperkeratosis, while PC caused by KRT16 mutations generally presents with more extensive and painful PPK.4KRT16 mutations affecting p.R127 are frequent causes of PC, and genotype-phenotype correlations have been observed. Individuals with p.R127P mutations exhibit more severe disease with earlier age of onset, more extensive nail involvement and oral leukokeratosis, and greater impact on daily quality of life than in individuals with p.R127C mutations.5 Cases of PC with KRT16 p.R127S and p.R127G mutations also have been observed. The KRT16 c.380G>A, p.R127H mutation we documented has been reported in one kindred with PC who presented with PPK, oral leukokeratosis, toenail thickening, and pilosebaceous and follicular hyperkeratosis.6
Although patients with FPGK lack the thickening of fingernails and/or toenails considered a defining feature of PC, the disorders otherwise are phenotypically similar, suggesting the possibility of common pathogenesis. One linkage study of familial FPGK excluded genetic intervals containing type I and type II keratins but was limited to a single small kindred.2 This study and our data together suggest that, similar to PC, there are multiple genes in which mutations cause FPGK.
Murine Krt16 knockouts show distinct phenotypes depending on the mouse strain in which they are propagated, ranging from perinatal lethality to differences in the severity of oral and PPK lesions.7 These observations provide evidence that additional genetic variants contribute to Krt16 phenotypes in mice and suggest the same could be true for humans.
We propose that some cases of FPGK are due to mutations in KRT16 and thus share a genetic pathogenesis with PC, underscoring the utility of whole exome sequencing in providing genetic diagnoses for disorders that are genetically and clinically heterogeneous. Further biologic investigation of phenotypes caused by KRT16 mutation may reveal respective contributions of additional genetic variation and environmental effects to the variable clinical presentations.
- Gorlin RJ. Focal palmoplantar and marginal gingival hyperkeratosis—a syndrome. Birth Defects Orig Artic Ser. 1976;12:239-242.
- Kolde G, Hennies HC, Bethke G, et al. Focal palmoplantar and gingival keratosis: a distinct palmoplantar ectodermal dysplasia with epidermolytic alterations but lack of mutations in known keratins. J Am Acad Dermatol. 2005;52(3 pt 1):403-409.
- Duchatelet S, Hovnanian A. Olmsted syndrome: clinical, molecular and therapeutic aspects. Orphanet J Rare Dis. 2015;10:33.
- Spaunhurst KM, Hogendorf AM, Smith FJ, et al. Pachyonychia congenita patients with mutations in KRT6A have more extensive disease compared with patients who have mutations in KRT16. Br J Dermatol. 2012;166:875-878.
- Fu T, Leachman SA, Wilson NJ, et al. Genotype-phenotype correlations among pachyonychia congenita patients with K16 mutations. J Invest Dermatol. 2011;131:1025-1028.
- Wilson NJ, O’Toole EA, Milstone LM, et al. The molecular genetic analysis of the expanding pachyonychia congenita case collection. Br J Dermatol. 2014;171:343-355.
- Zieman A, Coulombe PA. The keratin 16 null phenotype is modestly impacted by genetic strain background in mice. Exp Dermatol. 2018;27:672-674.
To the Editor:
Focal palmoplantar keratoderma and gingival keratosis (FPGK)(Online Mendelian Inheritance in Man [OMIM] 148730) is a rare autosomal-dominant syndrome featuring focal, pressure-related, painful palmoplantar keratoderma and gingival hyperkeratosis presenting as leukokeratosis. Focal palmoplantar keratoderma and gingival keratosis was first defined by Gorlin1 in 1976. Since then, only a few cases have been reported, but no causative mutations have been identified.2
Focal pressure-related palmoplantar keratoderma (PPK) and oral hyperkeratosis also are seen in pachyonychia congenita (PC)(OMIM 167200, 615726, 615728, 167210), a rare autosomal-dominant disorder of keratinization characterized by PPK and nail dystrophy. Patients with PC often present with plantar pain; more variable features include oral leukokeratosis, follicular hyperkeratosis, pilosebaceous and epidermal inclusion cysts, hoarseness, hyperhidrosis, and natal teeth. Pachyonychia congenita is caused by mutation in keratin genes KRT6A, KRT6B, KRT16, or KRT17.
Focal palmoplantar keratoderma and gingival keratosis as well as PC are distinct from other forms of PPK with gingival involvement such as
Despite the common features of FPGK and PC, they are considered distinct disorders due to absence of nail changes in FPGK and no prior evidence of a common genetic cause. We present a patient with familial FPGK found by whole exome sequencing to be caused by a mutation in KRT16.
The proband was a 57-year-old man born to unrelated parents (Figure 1). He had no skin problems at birth, and his development was normal. He had painful focal keratoderma since childhood that were most prominent at pressure points on the soles and toes (Figure 2A), in addition to gingival hyperkeratosis and oral leukokeratosis (Figure 2B). He had no associated abnormalities of the skin, hair, or teeth and no nail findings (Figure 2C). He reported that his father and 2 of his 3 sisters were affected with similar symptoms. A punch biopsy of the right fifth toe was consistent with verrucous epidermal hyperplasia with perinuclear keratinization in the spinous layer (Figure 3A). A gingival biopsy showed perinuclear eosinophilic globules and basophilic stranding in the cytoplasm (Figure 3B). His older sister had more severe and painful focal keratoderma of the soles, punctate keratoderma of the palms, gingival hyperkeratosis, and leukokeratosis of the tongue.
Whole exome sequencing of the proband revealed a heterozygous missense mutation in KRT16 (c.380G>A, p.R127H, rs57424749). Sanger sequencing confirmed this mutation and showed that it was heterozygous in both of his affected sisters and absent in his unaffected niece (Figure 1). The patient was treated with topical and systemic retinoids, keratolytics, and mechanical removal to moderate effect, with noted improvement in the appearance and associated pain of the plantar keratoderma.
Phenotypic heterogeneity is common in PC, though PC due to KRT6A mutations demonstrates more severe nail disease with oral lesions, cysts, and follicular hyperkeratosis, while PC caused by KRT16 mutations generally presents with more extensive and painful PPK.4KRT16 mutations affecting p.R127 are frequent causes of PC, and genotype-phenotype correlations have been observed. Individuals with p.R127P mutations exhibit more severe disease with earlier age of onset, more extensive nail involvement and oral leukokeratosis, and greater impact on daily quality of life than in individuals with p.R127C mutations.5 Cases of PC with KRT16 p.R127S and p.R127G mutations also have been observed. The KRT16 c.380G>A, p.R127H mutation we documented has been reported in one kindred with PC who presented with PPK, oral leukokeratosis, toenail thickening, and pilosebaceous and follicular hyperkeratosis.6
Although patients with FPGK lack the thickening of fingernails and/or toenails considered a defining feature of PC, the disorders otherwise are phenotypically similar, suggesting the possibility of common pathogenesis. One linkage study of familial FPGK excluded genetic intervals containing type I and type II keratins but was limited to a single small kindred.2 This study and our data together suggest that, similar to PC, there are multiple genes in which mutations cause FPGK.
Murine Krt16 knockouts show distinct phenotypes depending on the mouse strain in which they are propagated, ranging from perinatal lethality to differences in the severity of oral and PPK lesions.7 These observations provide evidence that additional genetic variants contribute to Krt16 phenotypes in mice and suggest the same could be true for humans.
We propose that some cases of FPGK are due to mutations in KRT16 and thus share a genetic pathogenesis with PC, underscoring the utility of whole exome sequencing in providing genetic diagnoses for disorders that are genetically and clinically heterogeneous. Further biologic investigation of phenotypes caused by KRT16 mutation may reveal respective contributions of additional genetic variation and environmental effects to the variable clinical presentations.
To the Editor:
Focal palmoplantar keratoderma and gingival keratosis (FPGK)(Online Mendelian Inheritance in Man [OMIM] 148730) is a rare autosomal-dominant syndrome featuring focal, pressure-related, painful palmoplantar keratoderma and gingival hyperkeratosis presenting as leukokeratosis. Focal palmoplantar keratoderma and gingival keratosis was first defined by Gorlin1 in 1976. Since then, only a few cases have been reported, but no causative mutations have been identified.2
Focal pressure-related palmoplantar keratoderma (PPK) and oral hyperkeratosis also are seen in pachyonychia congenita (PC)(OMIM 167200, 615726, 615728, 167210), a rare autosomal-dominant disorder of keratinization characterized by PPK and nail dystrophy. Patients with PC often present with plantar pain; more variable features include oral leukokeratosis, follicular hyperkeratosis, pilosebaceous and epidermal inclusion cysts, hoarseness, hyperhidrosis, and natal teeth. Pachyonychia congenita is caused by mutation in keratin genes KRT6A, KRT6B, KRT16, or KRT17.
Focal palmoplantar keratoderma and gingival keratosis as well as PC are distinct from other forms of PPK with gingival involvement such as
Despite the common features of FPGK and PC, they are considered distinct disorders due to absence of nail changes in FPGK and no prior evidence of a common genetic cause. We present a patient with familial FPGK found by whole exome sequencing to be caused by a mutation in KRT16.
The proband was a 57-year-old man born to unrelated parents (Figure 1). He had no skin problems at birth, and his development was normal. He had painful focal keratoderma since childhood that were most prominent at pressure points on the soles and toes (Figure 2A), in addition to gingival hyperkeratosis and oral leukokeratosis (Figure 2B). He had no associated abnormalities of the skin, hair, or teeth and no nail findings (Figure 2C). He reported that his father and 2 of his 3 sisters were affected with similar symptoms. A punch biopsy of the right fifth toe was consistent with verrucous epidermal hyperplasia with perinuclear keratinization in the spinous layer (Figure 3A). A gingival biopsy showed perinuclear eosinophilic globules and basophilic stranding in the cytoplasm (Figure 3B). His older sister had more severe and painful focal keratoderma of the soles, punctate keratoderma of the palms, gingival hyperkeratosis, and leukokeratosis of the tongue.
Whole exome sequencing of the proband revealed a heterozygous missense mutation in KRT16 (c.380G>A, p.R127H, rs57424749). Sanger sequencing confirmed this mutation and showed that it was heterozygous in both of his affected sisters and absent in his unaffected niece (Figure 1). The patient was treated with topical and systemic retinoids, keratolytics, and mechanical removal to moderate effect, with noted improvement in the appearance and associated pain of the plantar keratoderma.
Phenotypic heterogeneity is common in PC, though PC due to KRT6A mutations demonstrates more severe nail disease with oral lesions, cysts, and follicular hyperkeratosis, while PC caused by KRT16 mutations generally presents with more extensive and painful PPK.4KRT16 mutations affecting p.R127 are frequent causes of PC, and genotype-phenotype correlations have been observed. Individuals with p.R127P mutations exhibit more severe disease with earlier age of onset, more extensive nail involvement and oral leukokeratosis, and greater impact on daily quality of life than in individuals with p.R127C mutations.5 Cases of PC with KRT16 p.R127S and p.R127G mutations also have been observed. The KRT16 c.380G>A, p.R127H mutation we documented has been reported in one kindred with PC who presented with PPK, oral leukokeratosis, toenail thickening, and pilosebaceous and follicular hyperkeratosis.6
Although patients with FPGK lack the thickening of fingernails and/or toenails considered a defining feature of PC, the disorders otherwise are phenotypically similar, suggesting the possibility of common pathogenesis. One linkage study of familial FPGK excluded genetic intervals containing type I and type II keratins but was limited to a single small kindred.2 This study and our data together suggest that, similar to PC, there are multiple genes in which mutations cause FPGK.
Murine Krt16 knockouts show distinct phenotypes depending on the mouse strain in which they are propagated, ranging from perinatal lethality to differences in the severity of oral and PPK lesions.7 These observations provide evidence that additional genetic variants contribute to Krt16 phenotypes in mice and suggest the same could be true for humans.
We propose that some cases of FPGK are due to mutations in KRT16 and thus share a genetic pathogenesis with PC, underscoring the utility of whole exome sequencing in providing genetic diagnoses for disorders that are genetically and clinically heterogeneous. Further biologic investigation of phenotypes caused by KRT16 mutation may reveal respective contributions of additional genetic variation and environmental effects to the variable clinical presentations.
- Gorlin RJ. Focal palmoplantar and marginal gingival hyperkeratosis—a syndrome. Birth Defects Orig Artic Ser. 1976;12:239-242.
- Kolde G, Hennies HC, Bethke G, et al. Focal palmoplantar and gingival keratosis: a distinct palmoplantar ectodermal dysplasia with epidermolytic alterations but lack of mutations in known keratins. J Am Acad Dermatol. 2005;52(3 pt 1):403-409.
- Duchatelet S, Hovnanian A. Olmsted syndrome: clinical, molecular and therapeutic aspects. Orphanet J Rare Dis. 2015;10:33.
- Spaunhurst KM, Hogendorf AM, Smith FJ, et al. Pachyonychia congenita patients with mutations in KRT6A have more extensive disease compared with patients who have mutations in KRT16. Br J Dermatol. 2012;166:875-878.
- Fu T, Leachman SA, Wilson NJ, et al. Genotype-phenotype correlations among pachyonychia congenita patients with K16 mutations. J Invest Dermatol. 2011;131:1025-1028.
- Wilson NJ, O’Toole EA, Milstone LM, et al. The molecular genetic analysis of the expanding pachyonychia congenita case collection. Br J Dermatol. 2014;171:343-355.
- Zieman A, Coulombe PA. The keratin 16 null phenotype is modestly impacted by genetic strain background in mice. Exp Dermatol. 2018;27:672-674.
- Gorlin RJ. Focal palmoplantar and marginal gingival hyperkeratosis—a syndrome. Birth Defects Orig Artic Ser. 1976;12:239-242.
- Kolde G, Hennies HC, Bethke G, et al. Focal palmoplantar and gingival keratosis: a distinct palmoplantar ectodermal dysplasia with epidermolytic alterations but lack of mutations in known keratins. J Am Acad Dermatol. 2005;52(3 pt 1):403-409.
- Duchatelet S, Hovnanian A. Olmsted syndrome: clinical, molecular and therapeutic aspects. Orphanet J Rare Dis. 2015;10:33.
- Spaunhurst KM, Hogendorf AM, Smith FJ, et al. Pachyonychia congenita patients with mutations in KRT6A have more extensive disease compared with patients who have mutations in KRT16. Br J Dermatol. 2012;166:875-878.
- Fu T, Leachman SA, Wilson NJ, et al. Genotype-phenotype correlations among pachyonychia congenita patients with K16 mutations. J Invest Dermatol. 2011;131:1025-1028.
- Wilson NJ, O’Toole EA, Milstone LM, et al. The molecular genetic analysis of the expanding pachyonychia congenita case collection. Br J Dermatol. 2014;171:343-355.
- Zieman A, Coulombe PA. The keratin 16 null phenotype is modestly impacted by genetic strain background in mice. Exp Dermatol. 2018;27:672-674.
Practice Points
- Focal palmoplantar keratoderma and gingival keratosis (FPGK) is a rare autosomal-dominant syndrome featuring focal, pressure-related, painful palmoplantar keratoderma (PPK) and gingival hyperkeratosis presenting as leukokeratosis.
- Focal pressure-related PPK and oral hyperkeratosis also are seen in pachyonychia congenita (PC), which is caused by mutations in keratin genes and is distinguished from FPGK by characteristic nail changes.
- A shared causative gene suggests that FPGK should be considered part of the PC spectrum.
Meet Argireline, the neurotoxinlike cosmeceutical
Acetyl hexapeptide-8 (or -3), better known by its brand name, Argireline (Lubrizol; Wickliffe, Ohio), is a synthetic peptide gaining popularity in cosmeceutical products for its antiaging benefits. Argireline was developed by the company Lipotec in 2001. Media, beauty bloggers, and product claims have likened this product to a “Botox [or other neurotoxin] alternative,” or “Botox mimicker.”
Mechanism of action
Understanding how Argireline works requires a brief refresher on the mechanism of action of botulinum neurotoxin (BoNT). BoNT relaxes facial muscles and smooths expression lines by inhibiting acetylcholine release at the neuromuscular junction.1 More specifically, the various serotypes of BoNT are single-chain polypeptides that target members of the SNARE complex: SNAP-25, syntaxin, and Vamp. The proteins within the SNARE complex are involved in the docking and fusion of presynaptic vesicles to the presynaptic membrane, necessary steps for acetylcholine release into the neuromuscular junction and muscle contraction. By blocking the action of the SNARE complex proteins, BoNT inhibits release of acetylcholine in the neuromuscular junction and prevents muscle contraction.
Argireline is a synthetic peptide with the sequence Ac-EEMQRR-NH2.2 It is patterned after the N-terminal domain of SNAP-25, one of the members of the SNARE complex targeted by BoNT, and functions to interfere with the assembly of the SNARE complex. In this manner, Argireline would theoretically inhibit fusion of presynaptic vesicles and release of acetylcholine into the neuromuscular junction, thus impeding muscle movement. For this reason, it has been likened to topical Botox. Unlike Botox and other neurotoxins, Argireline was developed for topical application rather than injection.
Preclinical studies
In vitro work done 20 years ago demonstrated that Argireline can prevent assembly of the SNARE complex and inhibit neurotransmitter release with a potency similar to that of BoNT A (Botox).2
In 2013, Wang et al. evaluated the histologic effects of Argireline in aged mouse skin induced by D-galactose. For 6 weeks, Argireline was applied twice daily, and histological changes were assessed using hematoxylin and eosin (H&E) and picrosirius–polarization (PSP) stains. The researchers found elevated levels of type I collagen (P < .01) and reduced type III collagen (P < .05) with the Argireline treatment. These results demonstrated that Argireline could histologically enhance collagen in a manner consistent with skin rejuvenation.3
Clinical studies
In 2002, Blanes et al. assessed the antiwrinkle activity of Argireline by measuring skin topography from silicone implants in the lateral periorbital region of an oil/water (O/W) emulsion containing 10% of the acetyl-hexapeptide in 10 healthy women volunteers. The hexapeptide emulsion was applied twice daily in one lateral periorbital area, and the emulsion vehicle alone was applied twice daily on the contralateral side. Over 30 days of treatment, wrinkle depth was found to have decreased by 30%. The investigators also found that Argireline significantly hindered neurotransmitter release in vitro as robustly as BoNT A, though with notably lower efficacy. No toxicity or irritation was associated with this treatment.2 However, it should be noted that this small study conducted 2 decades ago evaluated only silicone implants with confocal microscopy to evaluate wrinkle depth. There was no subjective clinical assessment of dynamic facial wrinkles. As such, their study is an insufficient basis for drawing conclusions that Argireline is a BoNT mimic. Botox and other types of BoNT affect dynamic facial wrinkles mostly (i.e., wrinkles created by moving muscles of facial expression). This study primarily considers static wrinkles on periorbital skin. While static wrinkles may result from longstanding dynamic wrinkles, BoNT mainly targets dynamic wrinkles, again not comparing apples to apples.
At the same time that Wang et al. conducted their experiment on the skin of aged mice as noted above, they performed a multicenter clinical trial in 60 human subjects who received a randomized treatment of Argireline or placebo in a ratio of 3:1 to assess its safety and efficacy. For 4 weeks, the test product or placebo was applied to periorbital wrinkles twice daily. The researchers found the total antiwrinkle efficacy in the Argireline group to be 48.9% based on the subjective evaluation, compared with 0% in the placebo group. The objective evaluation indicated that all parameters of roughness were diminished in the Argireline group (P < .01), with no reduction observed in the placebo group (P < .05).4 There was a little more to appreciate from this study compared with the one reported by Blanes et al., insofar as subjective evaluations and objective evaluations with silica replicas were done. However, this study was not blinded, so the 48.9% wrinkle reduction in the Argireline group vs. 0% in the control group seems suspicious. Additionally, there was a greater focus on static rather than dynamic wrinkles.
In 2017, Raikou et al. conducted a prospective, randomized controlled study to assess the effects of acetyl hexapeptide-3 (Argireline) and tripeptide-10 citrulline in 24 healthy female volunteers (aged 30-60 years) and determine if there was any synergistic action between the peptides. Subjects were randomized to receive a combination of the peptides, tripeptide-10 citrulline only, acetyl hexapeptide-3 only, or neither peptide for 60 days. The researchers found a significant reduction in transepidermal water loss (TEWL) in the Argireline group, compared with the placebo group.5 The result of this study makes me question if the decrease in depth of the wrinkles measured in the former studies is really just a measure of increased skin hydration from the Argireline, rather than a neurotoxic effect of Argireline.
Formulation and penetration: Can Argireline get through your skin?
One of the fundamental questions regarding Argireline is whether it can penetrate through the stratum corneum and find its target – the facial muscles – where it is intended to function. Argireline is a charged, hydrophilic, and large–molecular weight peptide, and each of these factors impairs penetration through the stratum corneum. Therefore, studies assessing penetration are particularly important.
In 2015, Kraeling et al. conducted an in vitro evaluation of the skin penetration of acetyl hexapeptide-8 in hairless guinea pig and human cadaver skin. An oil-in-water (O/W) emulsion containing 10% acetyl hexapeptide-8 was applied (2 mg/cm2) and penetration was quantified in skin layers via hydrophilic interaction liquid chromatography with tandem mass spectrometry. Most of the acetyl hexapeptide-8 was found to have been washed from human cadaver, as well as guinea pig, skin. Less than 1% of the peptide penetrated the guinea pig or human skin. Of this small amount that penetrated the skin, most stayed in the stratum corneum of guinea pigs (0.54%) and human cadavers (0.22%). The levels of acetyl hexapeptide-8 declined further with each layer of tape stripping removal. Epidermal levels of the peptide in tested skin were similar at 0.01%, and none of the peptide was found in the dermis.6 These results indicate negligible penetration by this highly touted peptide ingredient.
Some studies have shown that altering the formulation of acetyl hexapeptide-8 can enhance penetration. Hoppel et al. demonstrated that formulations of the peptide, especially in a water-oil-water (W/O/W emulsion [as compared with O/W and W/O emulsions] can increase penetration into the stratum corneum in porcine skin.7 Notably, this is still very superficial relative to the dermis and muscles. Irrespective of formulation, studies have shown that Argireline barely penetrates the stratum corneum, let alone the dermis. Therefore, I would give pause to attributing any clinical impact or benefit of Argireline to its neurotoxinlike effects measured in vitro.
Conclusion
Despite the growing popularity of this ingredient in cosmeceuticals and the praise it gets in media for acting as a topical neurotoxin, there are no rigorous clinical trials or data demonstrating its efficacy in suppressing dynamic facial wrinkles like BoNT does. Most importantly, without penetration into the stratum corneum and deeper layers of the skin, it seems unlikely that Argireline’s clinical benefit derives from a neurotoxiclike mechanism of action. It seems more likely that the Argireline-containing product enhances hydration or imparts some other quality to the skin surface. While there is certainly great appeal for a neurotoxinlike product without injections, I do not believe this ingredient will replace injections of BoNT in the foreseeable future, or at least until scientists can figure out how to enable these products to penetrate into the deeper layers of the skin.
Dr. Goldman is a dermatologist in private practice in Miami and specializes in cosmetic and general dermatology. She practices at Baumann Cosmetic & Research Institute and is also opening a general dermatology practice. Dr. Goldman has no relevant disclosures. Write to her at [email protected] or message her on Instagram @DrChloeGoldman.
References
1. Reddy BY et al. Exp Dermatol. 2012 Aug;21(8):569-75.
2. Blanes-Mira C et al. Int J Cosmet Sci. 2002 Oct;24(5):303-10.
3. Wang Y et al. J Cosmet Laser Ther. 2013 Aug;15(4):237-41.
4. Wang Y et al. J Cosmet Laser Ther. 2013;14(2):147-53.
5. Raikou V et al. J Cosmet Dermatol. 2017 Jun;16(2):271-8.
6. Kraeling ME et al. Cutan Ocul Toxicol. 2015 Mar;34(1):46-52.
7. Hoppel M et al. Eur J Pharm Sci. 2015 Feb 20;68:27-35.
Acetyl hexapeptide-8 (or -3), better known by its brand name, Argireline (Lubrizol; Wickliffe, Ohio), is a synthetic peptide gaining popularity in cosmeceutical products for its antiaging benefits. Argireline was developed by the company Lipotec in 2001. Media, beauty bloggers, and product claims have likened this product to a “Botox [or other neurotoxin] alternative,” or “Botox mimicker.”
Mechanism of action
Understanding how Argireline works requires a brief refresher on the mechanism of action of botulinum neurotoxin (BoNT). BoNT relaxes facial muscles and smooths expression lines by inhibiting acetylcholine release at the neuromuscular junction.1 More specifically, the various serotypes of BoNT are single-chain polypeptides that target members of the SNARE complex: SNAP-25, syntaxin, and Vamp. The proteins within the SNARE complex are involved in the docking and fusion of presynaptic vesicles to the presynaptic membrane, necessary steps for acetylcholine release into the neuromuscular junction and muscle contraction. By blocking the action of the SNARE complex proteins, BoNT inhibits release of acetylcholine in the neuromuscular junction and prevents muscle contraction.
Argireline is a synthetic peptide with the sequence Ac-EEMQRR-NH2.2 It is patterned after the N-terminal domain of SNAP-25, one of the members of the SNARE complex targeted by BoNT, and functions to interfere with the assembly of the SNARE complex. In this manner, Argireline would theoretically inhibit fusion of presynaptic vesicles and release of acetylcholine into the neuromuscular junction, thus impeding muscle movement. For this reason, it has been likened to topical Botox. Unlike Botox and other neurotoxins, Argireline was developed for topical application rather than injection.
Preclinical studies
In vitro work done 20 years ago demonstrated that Argireline can prevent assembly of the SNARE complex and inhibit neurotransmitter release with a potency similar to that of BoNT A (Botox).2
In 2013, Wang et al. evaluated the histologic effects of Argireline in aged mouse skin induced by D-galactose. For 6 weeks, Argireline was applied twice daily, and histological changes were assessed using hematoxylin and eosin (H&E) and picrosirius–polarization (PSP) stains. The researchers found elevated levels of type I collagen (P < .01) and reduced type III collagen (P < .05) with the Argireline treatment. These results demonstrated that Argireline could histologically enhance collagen in a manner consistent with skin rejuvenation.3
Clinical studies
In 2002, Blanes et al. assessed the antiwrinkle activity of Argireline by measuring skin topography from silicone implants in the lateral periorbital region of an oil/water (O/W) emulsion containing 10% of the acetyl-hexapeptide in 10 healthy women volunteers. The hexapeptide emulsion was applied twice daily in one lateral periorbital area, and the emulsion vehicle alone was applied twice daily on the contralateral side. Over 30 days of treatment, wrinkle depth was found to have decreased by 30%. The investigators also found that Argireline significantly hindered neurotransmitter release in vitro as robustly as BoNT A, though with notably lower efficacy. No toxicity or irritation was associated with this treatment.2 However, it should be noted that this small study conducted 2 decades ago evaluated only silicone implants with confocal microscopy to evaluate wrinkle depth. There was no subjective clinical assessment of dynamic facial wrinkles. As such, their study is an insufficient basis for drawing conclusions that Argireline is a BoNT mimic. Botox and other types of BoNT affect dynamic facial wrinkles mostly (i.e., wrinkles created by moving muscles of facial expression). This study primarily considers static wrinkles on periorbital skin. While static wrinkles may result from longstanding dynamic wrinkles, BoNT mainly targets dynamic wrinkles, again not comparing apples to apples.
At the same time that Wang et al. conducted their experiment on the skin of aged mice as noted above, they performed a multicenter clinical trial in 60 human subjects who received a randomized treatment of Argireline or placebo in a ratio of 3:1 to assess its safety and efficacy. For 4 weeks, the test product or placebo was applied to periorbital wrinkles twice daily. The researchers found the total antiwrinkle efficacy in the Argireline group to be 48.9% based on the subjective evaluation, compared with 0% in the placebo group. The objective evaluation indicated that all parameters of roughness were diminished in the Argireline group (P < .01), with no reduction observed in the placebo group (P < .05).4 There was a little more to appreciate from this study compared with the one reported by Blanes et al., insofar as subjective evaluations and objective evaluations with silica replicas were done. However, this study was not blinded, so the 48.9% wrinkle reduction in the Argireline group vs. 0% in the control group seems suspicious. Additionally, there was a greater focus on static rather than dynamic wrinkles.
In 2017, Raikou et al. conducted a prospective, randomized controlled study to assess the effects of acetyl hexapeptide-3 (Argireline) and tripeptide-10 citrulline in 24 healthy female volunteers (aged 30-60 years) and determine if there was any synergistic action between the peptides. Subjects were randomized to receive a combination of the peptides, tripeptide-10 citrulline only, acetyl hexapeptide-3 only, or neither peptide for 60 days. The researchers found a significant reduction in transepidermal water loss (TEWL) in the Argireline group, compared with the placebo group.5 The result of this study makes me question if the decrease in depth of the wrinkles measured in the former studies is really just a measure of increased skin hydration from the Argireline, rather than a neurotoxic effect of Argireline.
Formulation and penetration: Can Argireline get through your skin?
One of the fundamental questions regarding Argireline is whether it can penetrate through the stratum corneum and find its target – the facial muscles – where it is intended to function. Argireline is a charged, hydrophilic, and large–molecular weight peptide, and each of these factors impairs penetration through the stratum corneum. Therefore, studies assessing penetration are particularly important.
In 2015, Kraeling et al. conducted an in vitro evaluation of the skin penetration of acetyl hexapeptide-8 in hairless guinea pig and human cadaver skin. An oil-in-water (O/W) emulsion containing 10% acetyl hexapeptide-8 was applied (2 mg/cm2) and penetration was quantified in skin layers via hydrophilic interaction liquid chromatography with tandem mass spectrometry. Most of the acetyl hexapeptide-8 was found to have been washed from human cadaver, as well as guinea pig, skin. Less than 1% of the peptide penetrated the guinea pig or human skin. Of this small amount that penetrated the skin, most stayed in the stratum corneum of guinea pigs (0.54%) and human cadavers (0.22%). The levels of acetyl hexapeptide-8 declined further with each layer of tape stripping removal. Epidermal levels of the peptide in tested skin were similar at 0.01%, and none of the peptide was found in the dermis.6 These results indicate negligible penetration by this highly touted peptide ingredient.
Some studies have shown that altering the formulation of acetyl hexapeptide-8 can enhance penetration. Hoppel et al. demonstrated that formulations of the peptide, especially in a water-oil-water (W/O/W emulsion [as compared with O/W and W/O emulsions] can increase penetration into the stratum corneum in porcine skin.7 Notably, this is still very superficial relative to the dermis and muscles. Irrespective of formulation, studies have shown that Argireline barely penetrates the stratum corneum, let alone the dermis. Therefore, I would give pause to attributing any clinical impact or benefit of Argireline to its neurotoxinlike effects measured in vitro.
Conclusion
Despite the growing popularity of this ingredient in cosmeceuticals and the praise it gets in media for acting as a topical neurotoxin, there are no rigorous clinical trials or data demonstrating its efficacy in suppressing dynamic facial wrinkles like BoNT does. Most importantly, without penetration into the stratum corneum and deeper layers of the skin, it seems unlikely that Argireline’s clinical benefit derives from a neurotoxiclike mechanism of action. It seems more likely that the Argireline-containing product enhances hydration or imparts some other quality to the skin surface. While there is certainly great appeal for a neurotoxinlike product without injections, I do not believe this ingredient will replace injections of BoNT in the foreseeable future, or at least until scientists can figure out how to enable these products to penetrate into the deeper layers of the skin.
Dr. Goldman is a dermatologist in private practice in Miami and specializes in cosmetic and general dermatology. She practices at Baumann Cosmetic & Research Institute and is also opening a general dermatology practice. Dr. Goldman has no relevant disclosures. Write to her at [email protected] or message her on Instagram @DrChloeGoldman.
References
1. Reddy BY et al. Exp Dermatol. 2012 Aug;21(8):569-75.
2. Blanes-Mira C et al. Int J Cosmet Sci. 2002 Oct;24(5):303-10.
3. Wang Y et al. J Cosmet Laser Ther. 2013 Aug;15(4):237-41.
4. Wang Y et al. J Cosmet Laser Ther. 2013;14(2):147-53.
5. Raikou V et al. J Cosmet Dermatol. 2017 Jun;16(2):271-8.
6. Kraeling ME et al. Cutan Ocul Toxicol. 2015 Mar;34(1):46-52.
7. Hoppel M et al. Eur J Pharm Sci. 2015 Feb 20;68:27-35.
Acetyl hexapeptide-8 (or -3), better known by its brand name, Argireline (Lubrizol; Wickliffe, Ohio), is a synthetic peptide gaining popularity in cosmeceutical products for its antiaging benefits. Argireline was developed by the company Lipotec in 2001. Media, beauty bloggers, and product claims have likened this product to a “Botox [or other neurotoxin] alternative,” or “Botox mimicker.”
Mechanism of action
Understanding how Argireline works requires a brief refresher on the mechanism of action of botulinum neurotoxin (BoNT). BoNT relaxes facial muscles and smooths expression lines by inhibiting acetylcholine release at the neuromuscular junction.1 More specifically, the various serotypes of BoNT are single-chain polypeptides that target members of the SNARE complex: SNAP-25, syntaxin, and Vamp. The proteins within the SNARE complex are involved in the docking and fusion of presynaptic vesicles to the presynaptic membrane, necessary steps for acetylcholine release into the neuromuscular junction and muscle contraction. By blocking the action of the SNARE complex proteins, BoNT inhibits release of acetylcholine in the neuromuscular junction and prevents muscle contraction.
Argireline is a synthetic peptide with the sequence Ac-EEMQRR-NH2.2 It is patterned after the N-terminal domain of SNAP-25, one of the members of the SNARE complex targeted by BoNT, and functions to interfere with the assembly of the SNARE complex. In this manner, Argireline would theoretically inhibit fusion of presynaptic vesicles and release of acetylcholine into the neuromuscular junction, thus impeding muscle movement. For this reason, it has been likened to topical Botox. Unlike Botox and other neurotoxins, Argireline was developed for topical application rather than injection.
Preclinical studies
In vitro work done 20 years ago demonstrated that Argireline can prevent assembly of the SNARE complex and inhibit neurotransmitter release with a potency similar to that of BoNT A (Botox).2
In 2013, Wang et al. evaluated the histologic effects of Argireline in aged mouse skin induced by D-galactose. For 6 weeks, Argireline was applied twice daily, and histological changes were assessed using hematoxylin and eosin (H&E) and picrosirius–polarization (PSP) stains. The researchers found elevated levels of type I collagen (P < .01) and reduced type III collagen (P < .05) with the Argireline treatment. These results demonstrated that Argireline could histologically enhance collagen in a manner consistent with skin rejuvenation.3
Clinical studies
In 2002, Blanes et al. assessed the antiwrinkle activity of Argireline by measuring skin topography from silicone implants in the lateral periorbital region of an oil/water (O/W) emulsion containing 10% of the acetyl-hexapeptide in 10 healthy women volunteers. The hexapeptide emulsion was applied twice daily in one lateral periorbital area, and the emulsion vehicle alone was applied twice daily on the contralateral side. Over 30 days of treatment, wrinkle depth was found to have decreased by 30%. The investigators also found that Argireline significantly hindered neurotransmitter release in vitro as robustly as BoNT A, though with notably lower efficacy. No toxicity or irritation was associated with this treatment.2 However, it should be noted that this small study conducted 2 decades ago evaluated only silicone implants with confocal microscopy to evaluate wrinkle depth. There was no subjective clinical assessment of dynamic facial wrinkles. As such, their study is an insufficient basis for drawing conclusions that Argireline is a BoNT mimic. Botox and other types of BoNT affect dynamic facial wrinkles mostly (i.e., wrinkles created by moving muscles of facial expression). This study primarily considers static wrinkles on periorbital skin. While static wrinkles may result from longstanding dynamic wrinkles, BoNT mainly targets dynamic wrinkles, again not comparing apples to apples.
At the same time that Wang et al. conducted their experiment on the skin of aged mice as noted above, they performed a multicenter clinical trial in 60 human subjects who received a randomized treatment of Argireline or placebo in a ratio of 3:1 to assess its safety and efficacy. For 4 weeks, the test product or placebo was applied to periorbital wrinkles twice daily. The researchers found the total antiwrinkle efficacy in the Argireline group to be 48.9% based on the subjective evaluation, compared with 0% in the placebo group. The objective evaluation indicated that all parameters of roughness were diminished in the Argireline group (P < .01), with no reduction observed in the placebo group (P < .05).4 There was a little more to appreciate from this study compared with the one reported by Blanes et al., insofar as subjective evaluations and objective evaluations with silica replicas were done. However, this study was not blinded, so the 48.9% wrinkle reduction in the Argireline group vs. 0% in the control group seems suspicious. Additionally, there was a greater focus on static rather than dynamic wrinkles.
In 2017, Raikou et al. conducted a prospective, randomized controlled study to assess the effects of acetyl hexapeptide-3 (Argireline) and tripeptide-10 citrulline in 24 healthy female volunteers (aged 30-60 years) and determine if there was any synergistic action between the peptides. Subjects were randomized to receive a combination of the peptides, tripeptide-10 citrulline only, acetyl hexapeptide-3 only, or neither peptide for 60 days. The researchers found a significant reduction in transepidermal water loss (TEWL) in the Argireline group, compared with the placebo group.5 The result of this study makes me question if the decrease in depth of the wrinkles measured in the former studies is really just a measure of increased skin hydration from the Argireline, rather than a neurotoxic effect of Argireline.
Formulation and penetration: Can Argireline get through your skin?
One of the fundamental questions regarding Argireline is whether it can penetrate through the stratum corneum and find its target – the facial muscles – where it is intended to function. Argireline is a charged, hydrophilic, and large–molecular weight peptide, and each of these factors impairs penetration through the stratum corneum. Therefore, studies assessing penetration are particularly important.
In 2015, Kraeling et al. conducted an in vitro evaluation of the skin penetration of acetyl hexapeptide-8 in hairless guinea pig and human cadaver skin. An oil-in-water (O/W) emulsion containing 10% acetyl hexapeptide-8 was applied (2 mg/cm2) and penetration was quantified in skin layers via hydrophilic interaction liquid chromatography with tandem mass spectrometry. Most of the acetyl hexapeptide-8 was found to have been washed from human cadaver, as well as guinea pig, skin. Less than 1% of the peptide penetrated the guinea pig or human skin. Of this small amount that penetrated the skin, most stayed in the stratum corneum of guinea pigs (0.54%) and human cadavers (0.22%). The levels of acetyl hexapeptide-8 declined further with each layer of tape stripping removal. Epidermal levels of the peptide in tested skin were similar at 0.01%, and none of the peptide was found in the dermis.6 These results indicate negligible penetration by this highly touted peptide ingredient.
Some studies have shown that altering the formulation of acetyl hexapeptide-8 can enhance penetration. Hoppel et al. demonstrated that formulations of the peptide, especially in a water-oil-water (W/O/W emulsion [as compared with O/W and W/O emulsions] can increase penetration into the stratum corneum in porcine skin.7 Notably, this is still very superficial relative to the dermis and muscles. Irrespective of formulation, studies have shown that Argireline barely penetrates the stratum corneum, let alone the dermis. Therefore, I would give pause to attributing any clinical impact or benefit of Argireline to its neurotoxinlike effects measured in vitro.
Conclusion
Despite the growing popularity of this ingredient in cosmeceuticals and the praise it gets in media for acting as a topical neurotoxin, there are no rigorous clinical trials or data demonstrating its efficacy in suppressing dynamic facial wrinkles like BoNT does. Most importantly, without penetration into the stratum corneum and deeper layers of the skin, it seems unlikely that Argireline’s clinical benefit derives from a neurotoxiclike mechanism of action. It seems more likely that the Argireline-containing product enhances hydration or imparts some other quality to the skin surface. While there is certainly great appeal for a neurotoxinlike product without injections, I do not believe this ingredient will replace injections of BoNT in the foreseeable future, or at least until scientists can figure out how to enable these products to penetrate into the deeper layers of the skin.
Dr. Goldman is a dermatologist in private practice in Miami and specializes in cosmetic and general dermatology. She practices at Baumann Cosmetic & Research Institute and is also opening a general dermatology practice. Dr. Goldman has no relevant disclosures. Write to her at [email protected] or message her on Instagram @DrChloeGoldman.
References
1. Reddy BY et al. Exp Dermatol. 2012 Aug;21(8):569-75.
2. Blanes-Mira C et al. Int J Cosmet Sci. 2002 Oct;24(5):303-10.
3. Wang Y et al. J Cosmet Laser Ther. 2013 Aug;15(4):237-41.
4. Wang Y et al. J Cosmet Laser Ther. 2013;14(2):147-53.
5. Raikou V et al. J Cosmet Dermatol. 2017 Jun;16(2):271-8.
6. Kraeling ME et al. Cutan Ocul Toxicol. 2015 Mar;34(1):46-52.
7. Hoppel M et al. Eur J Pharm Sci. 2015 Feb 20;68:27-35.
FDA approves topical ruxolitinib for nonsegmental vitiligo
The on July 18. The treatment, which was approved for treating mild to moderate atopic dermatitis in September 2021, is a cream formulation of ruxolitinib, a Janus kinase 1 (JAK1)/JAK2 inhibitor.
Previously, no treatment was approved to repigment patients with vitiligo, says David Rosmarin, MD, vice chair for research and education in the department of dermatology at Tufts Medical Center, Boston. “It’s important to have options that we can give to patients that are both safe and effective to get them the desired results,” Dr. Rosmarin, the lead investigator of the phase 3 clinical trials of topical ruxolitinib, said in an interview. Vitiligo is “a disease that can really affect quality of life. Some people [with vitiligo] feel as if they’re being stared at or they’re being bullied; they don’t feel confident. It can affect relationships and intimacy.”
Approval was based on the results of two phase 3 trials (TruE-V1 and TruE-V2) in 674 patients with nonsegmental vitiligo aged 12 years or older. At 24 weeks, about 30% of the patients on treatment, applied twice a day, achieved at least a 75% improvement in the facial Vitiligo Area Scoring Index (F-VASI75), compared with about 8% and 13% among those in the vehicle groups in the two trials.
At 52 weeks, about 50% of the patients treated with topical ruxolitinib achieved F-VASI75.
Also, using self-reporting as measured by the Vitiligo Noticeability Scale, about 30%-40% of patients described their vitiligo as being “a lot less noticeable” or “no longer noticeable” at week 52. Dr. Rosmarin reported the 52-week results at the 2022 annual meeting of the American Academy of Dermatology.
The trial group used 1.5% ruxolitinib cream twice daily for the full year. The vehicle group began using ruxolitinib halfway through the trial. In this group, 26.8% and 29.6% achieved F-VASI 75 at 52 weeks in the two trials.
For treating vitiligo, patients are advised to apply a thin layer of topical ruxolitinib to affected areas twice a day, “up to 10% body surface area,” according to the prescribing information, which adds: “Satisfactory patient response may require treatment … for more than 24 weeks. If the patient does not find the repigmentation meaningful by 24 weeks, the patient should be reevaluated by the health care provider.”
The most common side effects during the vehicle-controlled part of the trials were development of acne and pruritus at the application site, headache, urinary tract infections, erythema at the application site, and pyrexia, according to the company.
The approved label for topical ruxolitinib includes a boxed warning about serious infections, mortality, cancer, major adverse cardiovascular events, and thrombosis – which, the warning notes, is based on reports in patients treated with oral JAK inhibitors for inflammatory conditions.
Dr. Rosmarin believes that using this drug with other therapies, like light treatment, might yield even better responses. The available data are in patients treated with ruxolitinib as monotherapy, without complementary therapies.
William Damsky, MD, PhD, professor of dermatology and dermatopathology at Yale University, New Haven, who was not involved in the trials, said what is most exciting about this drug is its novelty. Although some topical steroids are used off-label to treat vitiligo, their efficacy is far from what’s been observed in these trials of topical ruxolitinib, he told this news organization. “It’s huge for a number of reasons. … One very big reason is it just provides some hope” for the many patients with vitiligo who, over the years, have been told “that there’s nothing that could be done for their disease, and this really changes that.”
Dr. Rosmarin reports financial relationships with over 20 pharmaceutical companies. Dr. Damsky disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The on July 18. The treatment, which was approved for treating mild to moderate atopic dermatitis in September 2021, is a cream formulation of ruxolitinib, a Janus kinase 1 (JAK1)/JAK2 inhibitor.
Previously, no treatment was approved to repigment patients with vitiligo, says David Rosmarin, MD, vice chair for research and education in the department of dermatology at Tufts Medical Center, Boston. “It’s important to have options that we can give to patients that are both safe and effective to get them the desired results,” Dr. Rosmarin, the lead investigator of the phase 3 clinical trials of topical ruxolitinib, said in an interview. Vitiligo is “a disease that can really affect quality of life. Some people [with vitiligo] feel as if they’re being stared at or they’re being bullied; they don’t feel confident. It can affect relationships and intimacy.”
Approval was based on the results of two phase 3 trials (TruE-V1 and TruE-V2) in 674 patients with nonsegmental vitiligo aged 12 years or older. At 24 weeks, about 30% of the patients on treatment, applied twice a day, achieved at least a 75% improvement in the facial Vitiligo Area Scoring Index (F-VASI75), compared with about 8% and 13% among those in the vehicle groups in the two trials.
At 52 weeks, about 50% of the patients treated with topical ruxolitinib achieved F-VASI75.
Also, using self-reporting as measured by the Vitiligo Noticeability Scale, about 30%-40% of patients described their vitiligo as being “a lot less noticeable” or “no longer noticeable” at week 52. Dr. Rosmarin reported the 52-week results at the 2022 annual meeting of the American Academy of Dermatology.
The trial group used 1.5% ruxolitinib cream twice daily for the full year. The vehicle group began using ruxolitinib halfway through the trial. In this group, 26.8% and 29.6% achieved F-VASI 75 at 52 weeks in the two trials.
For treating vitiligo, patients are advised to apply a thin layer of topical ruxolitinib to affected areas twice a day, “up to 10% body surface area,” according to the prescribing information, which adds: “Satisfactory patient response may require treatment … for more than 24 weeks. If the patient does not find the repigmentation meaningful by 24 weeks, the patient should be reevaluated by the health care provider.”
The most common side effects during the vehicle-controlled part of the trials were development of acne and pruritus at the application site, headache, urinary tract infections, erythema at the application site, and pyrexia, according to the company.
The approved label for topical ruxolitinib includes a boxed warning about serious infections, mortality, cancer, major adverse cardiovascular events, and thrombosis – which, the warning notes, is based on reports in patients treated with oral JAK inhibitors for inflammatory conditions.
Dr. Rosmarin believes that using this drug with other therapies, like light treatment, might yield even better responses. The available data are in patients treated with ruxolitinib as monotherapy, without complementary therapies.
William Damsky, MD, PhD, professor of dermatology and dermatopathology at Yale University, New Haven, who was not involved in the trials, said what is most exciting about this drug is its novelty. Although some topical steroids are used off-label to treat vitiligo, their efficacy is far from what’s been observed in these trials of topical ruxolitinib, he told this news organization. “It’s huge for a number of reasons. … One very big reason is it just provides some hope” for the many patients with vitiligo who, over the years, have been told “that there’s nothing that could be done for their disease, and this really changes that.”
Dr. Rosmarin reports financial relationships with over 20 pharmaceutical companies. Dr. Damsky disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The on July 18. The treatment, which was approved for treating mild to moderate atopic dermatitis in September 2021, is a cream formulation of ruxolitinib, a Janus kinase 1 (JAK1)/JAK2 inhibitor.
Previously, no treatment was approved to repigment patients with vitiligo, says David Rosmarin, MD, vice chair for research and education in the department of dermatology at Tufts Medical Center, Boston. “It’s important to have options that we can give to patients that are both safe and effective to get them the desired results,” Dr. Rosmarin, the lead investigator of the phase 3 clinical trials of topical ruxolitinib, said in an interview. Vitiligo is “a disease that can really affect quality of life. Some people [with vitiligo] feel as if they’re being stared at or they’re being bullied; they don’t feel confident. It can affect relationships and intimacy.”
Approval was based on the results of two phase 3 trials (TruE-V1 and TruE-V2) in 674 patients with nonsegmental vitiligo aged 12 years or older. At 24 weeks, about 30% of the patients on treatment, applied twice a day, achieved at least a 75% improvement in the facial Vitiligo Area Scoring Index (F-VASI75), compared with about 8% and 13% among those in the vehicle groups in the two trials.
At 52 weeks, about 50% of the patients treated with topical ruxolitinib achieved F-VASI75.
Also, using self-reporting as measured by the Vitiligo Noticeability Scale, about 30%-40% of patients described their vitiligo as being “a lot less noticeable” or “no longer noticeable” at week 52. Dr. Rosmarin reported the 52-week results at the 2022 annual meeting of the American Academy of Dermatology.
The trial group used 1.5% ruxolitinib cream twice daily for the full year. The vehicle group began using ruxolitinib halfway through the trial. In this group, 26.8% and 29.6% achieved F-VASI 75 at 52 weeks in the two trials.
For treating vitiligo, patients are advised to apply a thin layer of topical ruxolitinib to affected areas twice a day, “up to 10% body surface area,” according to the prescribing information, which adds: “Satisfactory patient response may require treatment … for more than 24 weeks. If the patient does not find the repigmentation meaningful by 24 weeks, the patient should be reevaluated by the health care provider.”
The most common side effects during the vehicle-controlled part of the trials were development of acne and pruritus at the application site, headache, urinary tract infections, erythema at the application site, and pyrexia, according to the company.
The approved label for topical ruxolitinib includes a boxed warning about serious infections, mortality, cancer, major adverse cardiovascular events, and thrombosis – which, the warning notes, is based on reports in patients treated with oral JAK inhibitors for inflammatory conditions.
Dr. Rosmarin believes that using this drug with other therapies, like light treatment, might yield even better responses. The available data are in patients treated with ruxolitinib as monotherapy, without complementary therapies.
William Damsky, MD, PhD, professor of dermatology and dermatopathology at Yale University, New Haven, who was not involved in the trials, said what is most exciting about this drug is its novelty. Although some topical steroids are used off-label to treat vitiligo, their efficacy is far from what’s been observed in these trials of topical ruxolitinib, he told this news organization. “It’s huge for a number of reasons. … One very big reason is it just provides some hope” for the many patients with vitiligo who, over the years, have been told “that there’s nothing that could be done for their disease, and this really changes that.”
Dr. Rosmarin reports financial relationships with over 20 pharmaceutical companies. Dr. Damsky disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Methotrexate’s impact on COVID-19 vaccination: New insights made
Patients who take methotrexate for a variety of immune-mediated inflammatory diseases and pause taking the drug following receipt of a COVID-19 vaccine dose did not have a higher risk of disease flare and had higher antireceptor binding domain (anti-RBD) antibody titers and increased immunogenicity when compared with continuing the drug, three recent studies suggest.
In one study, British researchers examined the effects of a 2-week break in methotrexate therapy on anti-RBD titers following receipt of a third COVID-19 vaccine dose. In their paper published in The Lancet: Respiratory Medicine, they reported results from a randomized, open-label, superiority trial that suggested pausing the drug improved immunogenicity, compared with no break.
In two trials presented at the European Alliance of Associations for Rheumatology (EULAR) 2022 Congress, a team from India set out to determine whether holding methotrexate after receiving both doses of a COVID-19 vaccine, or holding it only after the second dose, was safe and effective. They found that pausing methotrexate only following the second dose contributed to a lower flare risk, and that patients had higher anti-RBD titers when holding methotrexate for 2 weeks following each dose.
Pausing methotrexate after booster
The 2-week methotrexate break and booster vaccine dose data in the Vaccine Response On Off Methotrexate (VROOM) trial showed that after a month, the geometric mean antispike 1 (S1)-RBD antibody titer was 10,798 U/mL (95% confidence interval [CI], 8,970-12,997) in the group that continued methotrexate and 22,750 U/mL (95% CI, 19,314-26,796) in the group that suspended methotrexate; the geometric mean ratio was 2.19 (P < .0001; mixed-effects model), reported Abhishek Abhishek, MD, PhD, professor of rheumatology at the University of Nottingham in Nottingham, England, and colleagues.
Prior research showed that stopping methotrexate therapy for 2 weeks following the seasonal influenza vaccine contributed to better vaccine immunity among patients with rheumatoid arthritis, but there was no impact of stopping the drug for up to 4 weeks before vaccination on vaccine-related immunity, the researchers noted.
It is crucial in maximizing long-lasting vaccine protection in people who are possibly susceptible through immune suppression at this point in the COVID-19 vaccination regimen, the study team noted.
“Evidence from this study will be useful for policymakers, national immunization advisory committees, and specialist societies formulating recommendations on the use of methotrexate around the time of COVID-19 vaccination. This evidence will help patients and clinicians make informed choices about the risks and benefits of interrupting methotrexate treatment around the time of COVID-19 vaccination, with implications for the potential to extend such approaches to other therapeutics,” they wrote.
In American College of Rheumatology (ACR) guidance for COVID-19 vaccination, the organization advised against using standard synthetic disease-modifying antirheumatic medicines such as methotrexate “for 1-2 weeks (as disease activity allows) after each COVID-19 vaccine dose,” given the at-risk population and public health concerns, Jeffrey A. Sparks, MD, MMSc, assistant professor of medicine and associate physician at Brigham and Women’s Hospital and Harvard Medical School, Boston, and Sara K. Tedeschi, MD, MPH, assistant professor of medicine at Harvard Medical School, noted in an accompanying editorial in The Lancet: Respiratory Medicine.
However, when the ACR developed this statement, there was only one trial involving patients with rheumatoid arthritis who paused methotrexate following seasonal influenza vaccination, the editorialists said.
“Although this finding adds to the evidence base to support interruption of methotrexate after vaccination, a shared decision process is needed to weigh the possible benefit of optimizing protection from COVID-19 and the possible risk of underlying disease flare,” they added.
Dr. Abhishek and colleagues assessed 254 patients with immune-mediated inflammatory disease from dermatology and rheumatology clinics across 26 hospitals in the United Kingdom. Participants had been diagnosed with systemic lupus erythematosus, rheumatoid arthritis, atopic dermatitis, polymyalgia rheumatica, axial spondyloarthritis, and psoriasis without or with arthritis. They had also been taking up to 25 mg of methotrexate per week for 3 months or longer and had received two doses of either the Pfizer/BioNTech BNT162b2 vaccine or AstraZeneca/Oxford viral vector vaccine. The booster dose was most often the Pfizer BNT162b2 vaccine (82%). The patients’ mean age was 59 years, with females comprising 61% of the cohort. Participants were randomly assigned 1:1 to either group.
Investigators performing laboratory analysis were masked to cohort assignment, and clinical research staff, data analysts, participants, and researchers were unmasked.
The elevated antibody response of patients who suspended methotrexate was the same across different kinds of immune-mediated inflammatory disease, primary vaccination platform, SARS-CoV-2 infection history, and age.
Notably, no intervention-associated adverse events were reported, the study team noted.
The conclusions that could be drawn from the booster-dose study were limited by the trial’s modest cohort size, the small number of patients in exploratory subgroup analyses, a lack of information about differences in prescription drug behavior, and early termination’s effect on the researchers’ ability to identify differences between subgroups and in secondary outcomes, the authors noted.
Other limitations included a lack of generalizability to patients with active disease who couldn’t stop therapy and were not included in the investigation, and participants were not blinded to what group they were in, the researchers said.
Expert commentary
This current study is consistent with other studies over the last several months showing that methotrexate harms both humoral and cell-mediated COVID-19 responses, noted Kevin Winthrop, MD, MPH, professor of infectious disease and public health at Oregon Health & Science University, Portland, who was not involved in the study. “And so now the new wave of studies are like this one, where they are holding methotrexate experimentally and seeing if it makes a difference,” he said.
“The one shortcoming of this study – and so far, the studies to date – is that no one has looked at whether the experimental hold has resulted in a change in T-cell responses, which ... we are [now] recognizing [the importance of] more and more in long-term protection, particularly in severe disease. Theoretically, holding [methotrexate] might help enhance T-cell responses, but that hasn’t been shown experimentally.”
Dr. Winthrop pointed out that one might get the same benefit from holding methotrexate for 1 week instead of 2 and that there likely is a reduced risk of flare-up from underlying autoimmune disease.
It is still not certain that this benefit extends to other vaccines, Dr. Winthrop noted. “It is probably true for most vaccines that if you hold methotrexate for 1 or 2 weeks, you might see some short-term benefit in responsiveness, but you don’t know that there is any clinical meaningfulness of this. That’s going to take other long-term studies. You don’t know how long this benefit lasts.”
Pausing methotrexate during initial COVID vaccine doses
Patients with either rheumatoid arthritis or psoriatic arthritis had higher anti-RBD antibody titers when methotrexate was stopped after both doses of the AstraZeneca vaccine, or simply after the second dose, than when methotrexate was continued, according to results from two single-center, randomized controlled trials called MIVAC I and II, Anu Sreekanth, MD, of Sree Sudheendra Medical Mission in Kochi, Kerala, India, and colleagues reported at EULAR 2022.
Results from MIVAC I indicated that there was a higher flare rate when methotrexate was stopped after both vaccine doses, but there was no difference in flare rate in MIVAC II when methotrexate was stopped only after the second dose as opposed to stopping it after both doses.
In the MIVAC I trial, 158 unvaccinated patients were randomized 1:1 to a cohort in which methotrexate was held for 2 weeks after both doses and a cohort in which methotrexate was continued despite the vaccine. In MIVAC II, 157 patients continued methotrexate while receiving the first vaccine dose. These patients were subsequently randomized either to continue or to stop methotrexate for 2 weeks following the second dose.
The findings from MIVAC I demonstrated the flare rate was lower in the methotrexate-continue group than in the methotrexate-pause group (8% vs. 25%; P = .005) and that the median anti-RBD titer was significantly higher for the methotrexate-pause group than the methotrexate-continue group (2,484 vs. 1,147; P = .001).
The results from MIVAC II trial indicated that there was no difference in flare rates between the two study groups (7.9% vs. 11.8%; P = .15). Yet, the median anti-RBD titer was significantly higher in the methotrexate-pause cohort than in the methotrexate-continue cohort (2,553 vs. 990; P = .001).
The report suggests there is a flare risk when methotrexate is stopped, Dr. Sreekanth noted. “It appears more logical to hold only after the second dose, as comparable anti-RBD titers are generated” with either approach, Dr. Sreekanth said.
Expert commentary: MIVAC I and II
Inés Colmegna, MD, associate professor at McGill University in Montreal, noted that it was intriguing that the risk of flares in MIVAC II is half of that reported after each of the doses of MIVAC I. “It is also worth emphasizing that despite the reported frequency of flares, the actual disease activity [as measured by the Disease Activity Score in 28 joints] in patients who did or did not withhold methotrexate was similar.
“MIVAC I and II have practical implications as they help to adequately inform patients about the risk and benefit trade of withholding methotrexate post–COVID-19 vaccination,” Dr. Colmegna told this news organization.
“Additional information would help to [further] interpret the findings of these studies, including whether any of the participants were taking any other DMARDs; data on the severity of the flares and functional impact; analysis of factors that predict the risk of flares, such as higher doses of methotrexate; [and change in] disease activity scores pre- and postvaccination,” Dr. Colmegna concluded.
Dr. Abhishek disclosed relationships with Springer, UpTodate, Oxford, Immunotec, AstraZeneca, Inflazome, NGM Biopharmaceuticals, Menarini Pharmaceuticals, and Cadila Pharmaceuticals. Dr. Abhishek is cochair of the ACR/EULAR CPPD Classification Criteria Working Group and the OMERACT CPPD Working Group. Dr. Sparks disclosed relationships with Gilead, Boehringer Ingelheim, Amgen, Bristol-Myers Squibb, and AbbVie, unrelated to this study. Dr. Tedeschi disclosed relationships with ModernaTx and NGM Biopharmaceuticals. Dr. Winthrop disclosed a research grant and serving as a scientific consultant for Pfizer. Dr. Sreekanth and Dr. Colmegna have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Patients who take methotrexate for a variety of immune-mediated inflammatory diseases and pause taking the drug following receipt of a COVID-19 vaccine dose did not have a higher risk of disease flare and had higher antireceptor binding domain (anti-RBD) antibody titers and increased immunogenicity when compared with continuing the drug, three recent studies suggest.
In one study, British researchers examined the effects of a 2-week break in methotrexate therapy on anti-RBD titers following receipt of a third COVID-19 vaccine dose. In their paper published in The Lancet: Respiratory Medicine, they reported results from a randomized, open-label, superiority trial that suggested pausing the drug improved immunogenicity, compared with no break.
In two trials presented at the European Alliance of Associations for Rheumatology (EULAR) 2022 Congress, a team from India set out to determine whether holding methotrexate after receiving both doses of a COVID-19 vaccine, or holding it only after the second dose, was safe and effective. They found that pausing methotrexate only following the second dose contributed to a lower flare risk, and that patients had higher anti-RBD titers when holding methotrexate for 2 weeks following each dose.
Pausing methotrexate after booster
The 2-week methotrexate break and booster vaccine dose data in the Vaccine Response On Off Methotrexate (VROOM) trial showed that after a month, the geometric mean antispike 1 (S1)-RBD antibody titer was 10,798 U/mL (95% confidence interval [CI], 8,970-12,997) in the group that continued methotrexate and 22,750 U/mL (95% CI, 19,314-26,796) in the group that suspended methotrexate; the geometric mean ratio was 2.19 (P < .0001; mixed-effects model), reported Abhishek Abhishek, MD, PhD, professor of rheumatology at the University of Nottingham in Nottingham, England, and colleagues.
Prior research showed that stopping methotrexate therapy for 2 weeks following the seasonal influenza vaccine contributed to better vaccine immunity among patients with rheumatoid arthritis, but there was no impact of stopping the drug for up to 4 weeks before vaccination on vaccine-related immunity, the researchers noted.
It is crucial in maximizing long-lasting vaccine protection in people who are possibly susceptible through immune suppression at this point in the COVID-19 vaccination regimen, the study team noted.
“Evidence from this study will be useful for policymakers, national immunization advisory committees, and specialist societies formulating recommendations on the use of methotrexate around the time of COVID-19 vaccination. This evidence will help patients and clinicians make informed choices about the risks and benefits of interrupting methotrexate treatment around the time of COVID-19 vaccination, with implications for the potential to extend such approaches to other therapeutics,” they wrote.
In American College of Rheumatology (ACR) guidance for COVID-19 vaccination, the organization advised against using standard synthetic disease-modifying antirheumatic medicines such as methotrexate “for 1-2 weeks (as disease activity allows) after each COVID-19 vaccine dose,” given the at-risk population and public health concerns, Jeffrey A. Sparks, MD, MMSc, assistant professor of medicine and associate physician at Brigham and Women’s Hospital and Harvard Medical School, Boston, and Sara K. Tedeschi, MD, MPH, assistant professor of medicine at Harvard Medical School, noted in an accompanying editorial in The Lancet: Respiratory Medicine.
However, when the ACR developed this statement, there was only one trial involving patients with rheumatoid arthritis who paused methotrexate following seasonal influenza vaccination, the editorialists said.
“Although this finding adds to the evidence base to support interruption of methotrexate after vaccination, a shared decision process is needed to weigh the possible benefit of optimizing protection from COVID-19 and the possible risk of underlying disease flare,” they added.
Dr. Abhishek and colleagues assessed 254 patients with immune-mediated inflammatory disease from dermatology and rheumatology clinics across 26 hospitals in the United Kingdom. Participants had been diagnosed with systemic lupus erythematosus, rheumatoid arthritis, atopic dermatitis, polymyalgia rheumatica, axial spondyloarthritis, and psoriasis without or with arthritis. They had also been taking up to 25 mg of methotrexate per week for 3 months or longer and had received two doses of either the Pfizer/BioNTech BNT162b2 vaccine or AstraZeneca/Oxford viral vector vaccine. The booster dose was most often the Pfizer BNT162b2 vaccine (82%). The patients’ mean age was 59 years, with females comprising 61% of the cohort. Participants were randomly assigned 1:1 to either group.
Investigators performing laboratory analysis were masked to cohort assignment, and clinical research staff, data analysts, participants, and researchers were unmasked.
The elevated antibody response of patients who suspended methotrexate was the same across different kinds of immune-mediated inflammatory disease, primary vaccination platform, SARS-CoV-2 infection history, and age.
Notably, no intervention-associated adverse events were reported, the study team noted.
The conclusions that could be drawn from the booster-dose study were limited by the trial’s modest cohort size, the small number of patients in exploratory subgroup analyses, a lack of information about differences in prescription drug behavior, and early termination’s effect on the researchers’ ability to identify differences between subgroups and in secondary outcomes, the authors noted.
Other limitations included a lack of generalizability to patients with active disease who couldn’t stop therapy and were not included in the investigation, and participants were not blinded to what group they were in, the researchers said.
Expert commentary
This current study is consistent with other studies over the last several months showing that methotrexate harms both humoral and cell-mediated COVID-19 responses, noted Kevin Winthrop, MD, MPH, professor of infectious disease and public health at Oregon Health & Science University, Portland, who was not involved in the study. “And so now the new wave of studies are like this one, where they are holding methotrexate experimentally and seeing if it makes a difference,” he said.
“The one shortcoming of this study – and so far, the studies to date – is that no one has looked at whether the experimental hold has resulted in a change in T-cell responses, which ... we are [now] recognizing [the importance of] more and more in long-term protection, particularly in severe disease. Theoretically, holding [methotrexate] might help enhance T-cell responses, but that hasn’t been shown experimentally.”
Dr. Winthrop pointed out that one might get the same benefit from holding methotrexate for 1 week instead of 2 and that there likely is a reduced risk of flare-up from underlying autoimmune disease.
It is still not certain that this benefit extends to other vaccines, Dr. Winthrop noted. “It is probably true for most vaccines that if you hold methotrexate for 1 or 2 weeks, you might see some short-term benefit in responsiveness, but you don’t know that there is any clinical meaningfulness of this. That’s going to take other long-term studies. You don’t know how long this benefit lasts.”
Pausing methotrexate during initial COVID vaccine doses
Patients with either rheumatoid arthritis or psoriatic arthritis had higher anti-RBD antibody titers when methotrexate was stopped after both doses of the AstraZeneca vaccine, or simply after the second dose, than when methotrexate was continued, according to results from two single-center, randomized controlled trials called MIVAC I and II, Anu Sreekanth, MD, of Sree Sudheendra Medical Mission in Kochi, Kerala, India, and colleagues reported at EULAR 2022.
Results from MIVAC I indicated that there was a higher flare rate when methotrexate was stopped after both vaccine doses, but there was no difference in flare rate in MIVAC II when methotrexate was stopped only after the second dose as opposed to stopping it after both doses.
In the MIVAC I trial, 158 unvaccinated patients were randomized 1:1 to a cohort in which methotrexate was held for 2 weeks after both doses and a cohort in which methotrexate was continued despite the vaccine. In MIVAC II, 157 patients continued methotrexate while receiving the first vaccine dose. These patients were subsequently randomized either to continue or to stop methotrexate for 2 weeks following the second dose.
The findings from MIVAC I demonstrated the flare rate was lower in the methotrexate-continue group than in the methotrexate-pause group (8% vs. 25%; P = .005) and that the median anti-RBD titer was significantly higher for the methotrexate-pause group than the methotrexate-continue group (2,484 vs. 1,147; P = .001).
The results from MIVAC II trial indicated that there was no difference in flare rates between the two study groups (7.9% vs. 11.8%; P = .15). Yet, the median anti-RBD titer was significantly higher in the methotrexate-pause cohort than in the methotrexate-continue cohort (2,553 vs. 990; P = .001).
The report suggests there is a flare risk when methotrexate is stopped, Dr. Sreekanth noted. “It appears more logical to hold only after the second dose, as comparable anti-RBD titers are generated” with either approach, Dr. Sreekanth said.
Expert commentary: MIVAC I and II
Inés Colmegna, MD, associate professor at McGill University in Montreal, noted that it was intriguing that the risk of flares in MIVAC II is half of that reported after each of the doses of MIVAC I. “It is also worth emphasizing that despite the reported frequency of flares, the actual disease activity [as measured by the Disease Activity Score in 28 joints] in patients who did or did not withhold methotrexate was similar.
“MIVAC I and II have practical implications as they help to adequately inform patients about the risk and benefit trade of withholding methotrexate post–COVID-19 vaccination,” Dr. Colmegna told this news organization.
“Additional information would help to [further] interpret the findings of these studies, including whether any of the participants were taking any other DMARDs; data on the severity of the flares and functional impact; analysis of factors that predict the risk of flares, such as higher doses of methotrexate; [and change in] disease activity scores pre- and postvaccination,” Dr. Colmegna concluded.
Dr. Abhishek disclosed relationships with Springer, UpTodate, Oxford, Immunotec, AstraZeneca, Inflazome, NGM Biopharmaceuticals, Menarini Pharmaceuticals, and Cadila Pharmaceuticals. Dr. Abhishek is cochair of the ACR/EULAR CPPD Classification Criteria Working Group and the OMERACT CPPD Working Group. Dr. Sparks disclosed relationships with Gilead, Boehringer Ingelheim, Amgen, Bristol-Myers Squibb, and AbbVie, unrelated to this study. Dr. Tedeschi disclosed relationships with ModernaTx and NGM Biopharmaceuticals. Dr. Winthrop disclosed a research grant and serving as a scientific consultant for Pfizer. Dr. Sreekanth and Dr. Colmegna have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Patients who take methotrexate for a variety of immune-mediated inflammatory diseases and pause taking the drug following receipt of a COVID-19 vaccine dose did not have a higher risk of disease flare and had higher antireceptor binding domain (anti-RBD) antibody titers and increased immunogenicity when compared with continuing the drug, three recent studies suggest.
In one study, British researchers examined the effects of a 2-week break in methotrexate therapy on anti-RBD titers following receipt of a third COVID-19 vaccine dose. In their paper published in The Lancet: Respiratory Medicine, they reported results from a randomized, open-label, superiority trial that suggested pausing the drug improved immunogenicity, compared with no break.
In two trials presented at the European Alliance of Associations for Rheumatology (EULAR) 2022 Congress, a team from India set out to determine whether holding methotrexate after receiving both doses of a COVID-19 vaccine, or holding it only after the second dose, was safe and effective. They found that pausing methotrexate only following the second dose contributed to a lower flare risk, and that patients had higher anti-RBD titers when holding methotrexate for 2 weeks following each dose.
Pausing methotrexate after booster
The 2-week methotrexate break and booster vaccine dose data in the Vaccine Response On Off Methotrexate (VROOM) trial showed that after a month, the geometric mean antispike 1 (S1)-RBD antibody titer was 10,798 U/mL (95% confidence interval [CI], 8,970-12,997) in the group that continued methotrexate and 22,750 U/mL (95% CI, 19,314-26,796) in the group that suspended methotrexate; the geometric mean ratio was 2.19 (P < .0001; mixed-effects model), reported Abhishek Abhishek, MD, PhD, professor of rheumatology at the University of Nottingham in Nottingham, England, and colleagues.
Prior research showed that stopping methotrexate therapy for 2 weeks following the seasonal influenza vaccine contributed to better vaccine immunity among patients with rheumatoid arthritis, but there was no impact of stopping the drug for up to 4 weeks before vaccination on vaccine-related immunity, the researchers noted.
It is crucial in maximizing long-lasting vaccine protection in people who are possibly susceptible through immune suppression at this point in the COVID-19 vaccination regimen, the study team noted.
“Evidence from this study will be useful for policymakers, national immunization advisory committees, and specialist societies formulating recommendations on the use of methotrexate around the time of COVID-19 vaccination. This evidence will help patients and clinicians make informed choices about the risks and benefits of interrupting methotrexate treatment around the time of COVID-19 vaccination, with implications for the potential to extend such approaches to other therapeutics,” they wrote.
In American College of Rheumatology (ACR) guidance for COVID-19 vaccination, the organization advised against using standard synthetic disease-modifying antirheumatic medicines such as methotrexate “for 1-2 weeks (as disease activity allows) after each COVID-19 vaccine dose,” given the at-risk population and public health concerns, Jeffrey A. Sparks, MD, MMSc, assistant professor of medicine and associate physician at Brigham and Women’s Hospital and Harvard Medical School, Boston, and Sara K. Tedeschi, MD, MPH, assistant professor of medicine at Harvard Medical School, noted in an accompanying editorial in The Lancet: Respiratory Medicine.
However, when the ACR developed this statement, there was only one trial involving patients with rheumatoid arthritis who paused methotrexate following seasonal influenza vaccination, the editorialists said.
“Although this finding adds to the evidence base to support interruption of methotrexate after vaccination, a shared decision process is needed to weigh the possible benefit of optimizing protection from COVID-19 and the possible risk of underlying disease flare,” they added.
Dr. Abhishek and colleagues assessed 254 patients with immune-mediated inflammatory disease from dermatology and rheumatology clinics across 26 hospitals in the United Kingdom. Participants had been diagnosed with systemic lupus erythematosus, rheumatoid arthritis, atopic dermatitis, polymyalgia rheumatica, axial spondyloarthritis, and psoriasis without or with arthritis. They had also been taking up to 25 mg of methotrexate per week for 3 months or longer and had received two doses of either the Pfizer/BioNTech BNT162b2 vaccine or AstraZeneca/Oxford viral vector vaccine. The booster dose was most often the Pfizer BNT162b2 vaccine (82%). The patients’ mean age was 59 years, with females comprising 61% of the cohort. Participants were randomly assigned 1:1 to either group.
Investigators performing laboratory analysis were masked to cohort assignment, and clinical research staff, data analysts, participants, and researchers were unmasked.
The elevated antibody response of patients who suspended methotrexate was the same across different kinds of immune-mediated inflammatory disease, primary vaccination platform, SARS-CoV-2 infection history, and age.
Notably, no intervention-associated adverse events were reported, the study team noted.
The conclusions that could be drawn from the booster-dose study were limited by the trial’s modest cohort size, the small number of patients in exploratory subgroup analyses, a lack of information about differences in prescription drug behavior, and early termination’s effect on the researchers’ ability to identify differences between subgroups and in secondary outcomes, the authors noted.
Other limitations included a lack of generalizability to patients with active disease who couldn’t stop therapy and were not included in the investigation, and participants were not blinded to what group they were in, the researchers said.
Expert commentary
This current study is consistent with other studies over the last several months showing that methotrexate harms both humoral and cell-mediated COVID-19 responses, noted Kevin Winthrop, MD, MPH, professor of infectious disease and public health at Oregon Health & Science University, Portland, who was not involved in the study. “And so now the new wave of studies are like this one, where they are holding methotrexate experimentally and seeing if it makes a difference,” he said.
“The one shortcoming of this study – and so far, the studies to date – is that no one has looked at whether the experimental hold has resulted in a change in T-cell responses, which ... we are [now] recognizing [the importance of] more and more in long-term protection, particularly in severe disease. Theoretically, holding [methotrexate] might help enhance T-cell responses, but that hasn’t been shown experimentally.”
Dr. Winthrop pointed out that one might get the same benefit from holding methotrexate for 1 week instead of 2 and that there likely is a reduced risk of flare-up from underlying autoimmune disease.
It is still not certain that this benefit extends to other vaccines, Dr. Winthrop noted. “It is probably true for most vaccines that if you hold methotrexate for 1 or 2 weeks, you might see some short-term benefit in responsiveness, but you don’t know that there is any clinical meaningfulness of this. That’s going to take other long-term studies. You don’t know how long this benefit lasts.”
Pausing methotrexate during initial COVID vaccine doses
Patients with either rheumatoid arthritis or psoriatic arthritis had higher anti-RBD antibody titers when methotrexate was stopped after both doses of the AstraZeneca vaccine, or simply after the second dose, than when methotrexate was continued, according to results from two single-center, randomized controlled trials called MIVAC I and II, Anu Sreekanth, MD, of Sree Sudheendra Medical Mission in Kochi, Kerala, India, and colleagues reported at EULAR 2022.
Results from MIVAC I indicated that there was a higher flare rate when methotrexate was stopped after both vaccine doses, but there was no difference in flare rate in MIVAC II when methotrexate was stopped only after the second dose as opposed to stopping it after both doses.
In the MIVAC I trial, 158 unvaccinated patients were randomized 1:1 to a cohort in which methotrexate was held for 2 weeks after both doses and a cohort in which methotrexate was continued despite the vaccine. In MIVAC II, 157 patients continued methotrexate while receiving the first vaccine dose. These patients were subsequently randomized either to continue or to stop methotrexate for 2 weeks following the second dose.
The findings from MIVAC I demonstrated the flare rate was lower in the methotrexate-continue group than in the methotrexate-pause group (8% vs. 25%; P = .005) and that the median anti-RBD titer was significantly higher for the methotrexate-pause group than the methotrexate-continue group (2,484 vs. 1,147; P = .001).
The results from MIVAC II trial indicated that there was no difference in flare rates between the two study groups (7.9% vs. 11.8%; P = .15). Yet, the median anti-RBD titer was significantly higher in the methotrexate-pause cohort than in the methotrexate-continue cohort (2,553 vs. 990; P = .001).
The report suggests there is a flare risk when methotrexate is stopped, Dr. Sreekanth noted. “It appears more logical to hold only after the second dose, as comparable anti-RBD titers are generated” with either approach, Dr. Sreekanth said.
Expert commentary: MIVAC I and II
Inés Colmegna, MD, associate professor at McGill University in Montreal, noted that it was intriguing that the risk of flares in MIVAC II is half of that reported after each of the doses of MIVAC I. “It is also worth emphasizing that despite the reported frequency of flares, the actual disease activity [as measured by the Disease Activity Score in 28 joints] in patients who did or did not withhold methotrexate was similar.
“MIVAC I and II have practical implications as they help to adequately inform patients about the risk and benefit trade of withholding methotrexate post–COVID-19 vaccination,” Dr. Colmegna told this news organization.
“Additional information would help to [further] interpret the findings of these studies, including whether any of the participants were taking any other DMARDs; data on the severity of the flares and functional impact; analysis of factors that predict the risk of flares, such as higher doses of methotrexate; [and change in] disease activity scores pre- and postvaccination,” Dr. Colmegna concluded.
Dr. Abhishek disclosed relationships with Springer, UpTodate, Oxford, Immunotec, AstraZeneca, Inflazome, NGM Biopharmaceuticals, Menarini Pharmaceuticals, and Cadila Pharmaceuticals. Dr. Abhishek is cochair of the ACR/EULAR CPPD Classification Criteria Working Group and the OMERACT CPPD Working Group. Dr. Sparks disclosed relationships with Gilead, Boehringer Ingelheim, Amgen, Bristol-Myers Squibb, and AbbVie, unrelated to this study. Dr. Tedeschi disclosed relationships with ModernaTx and NGM Biopharmaceuticals. Dr. Winthrop disclosed a research grant and serving as a scientific consultant for Pfizer. Dr. Sreekanth and Dr. Colmegna have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Think of pediatric morphea as a systemic, chronic disease, expert advises
INDIANAPOLIS – In the opinion of Elena Pope, MD, MSc,
“There is no correlation between the extent and activity of skin lesions and the presence, severity, and activity of extracutaneous manifestations,” Dr. Pope, professor of pediatrics at the University of Toronto and division head of pediatric dermatology at the Hospital for Sick Children in Toronto, said during the annual meeting of the Society for Pediatric Dermatology. “Treatment needs to be tailored to the extent of cutaneous manifestations, and I think we need to be aware of and address the impact on patients’ quality of life,” she added. There is also a need for more research “on targeted and better-tolerated therapies to put a stop to the progression of disease.”
Congenital morphea is a form of localized scleroderma that presents at birth but can be confused with port wine stain. Results from a multicenter retrospective review of 25 cases conducted by Dr. Pope and colleagues found that the median age at diagnosis was 2.9 years and 76% had linear-type lesions. In addition, 48% had extracutaneous involvement (all of these patients had linear morphea), most commonly of the central nervous system.
“It’s important to realize these lesions may become active over time,” Dr. Pope said. “In my experience, there are two different courses. Either you have innocuous lesions when the patients are born and they may become active around 3-4 years of age, or you have early intrauterine involvement, with lesions inactive at birth but with potential for significant damage in utero.”
She cautioned against treating a suspected port wine stain lesion with laser until congenital morphea is ruled out. “I’m aware of at least one lawsuit of a child where someone used a laser in a child who had progression with significant sclerosis,” she said. “The parents assumed it was the use of the laser that led to the progression, not the actual disease.”
Extracutaneous manifestations are common in morphea patients. A multicenter study of 750 patients with juvenile scleroderma found that 22% had extracutaneous manifestations. Almost half of patients (47%) had arthritis, but 17% had neurologic findings such as seizures and headaches, 9% had vascular manifestations, and 8% had uveitis. Subsequent studies found that neurological disease affects between 11% and 19% of cases, especially in those involving the head and neck.
“There is a wide range of manifestations from headache and neuropsychiatric changes to brain atrophy, seizures, and CNS cavernoma,” Dr. Pope said. “There also can be orthodental involvement such as malocclusion. It’s important to do a brain MRI, eye exam for uveitis, and don’t forget the orthodental assessment.”
She recalled a 10-year-old boy who presented to the Hospital for Sick Children with tissue loss on the forehead and eyebrow and eyelashes. He had no other congenital morphea symptoms and the MRI was normal, but the eye exam revealed uveitis. “It’s important to remember that uveitis is asymptomatic, so unless you look for it, you’re not going to find it,” she said.
According to unpublished data in 42 congenital morphea patients with lesions limited to the head and neck, who underwent MRI imaging at the Hospital for Sick Children, 57% had CNS changes that were ipsilateral in 68% of cases. “White matter changes were the most common, and to our surprise, there were patients who had progressive CNS disease, including CNS vasculitis, new lesions, and enhancement of prior stable lesions,” Dr. Pope said.
She recalled the case of an 8-year-old boy who presented to the hospital with intractable seizures. Upon completion of the MRI, one of the radiologists noted that the imaging showed subtle thinning of the forehead, and he was referred to Dr. Pope and colleagues for assessment. In the span of 4 years, despite aggressive treatment, the boy’s CNS disease progressed. “There was more enhancement, more tissue loss, his seizures are very hard to control, and he has many neurodevelopmental changes,” she recalled. “What I learned from this case is that skin activity does not correlate with imaging. Don’t assume that just because the skin is burnt out that the CNS will be the same. Also, the extent of skin disease does not predict involvement or progression of the CNS.”
Linear lesions on the lower extremities are a harbinger of orthopedic complications, which can occur in about half of patients. Joint contractures in this subset of patients are seen in about 81% of cases, while other sequelae can include arthritis, limb atrophy, leg-leg discrepancy, and angular deformity. “About 14% of patients require intervention,” Dr. Pope said. “In terms of working those patients up, you need to do an MRI and assess the extent of muscle and fascial involvement. Early physiotherapy and an orthopedic evaluation are also recommended.”
As for possible markers of morphea, antinuclear antibody is positive in 22%-68% of cases and correlates with disease severity, extracutaneous manifestations, and disease flare-up. Antihistone antibodies (AHA) are positive in about 47% of cases, “and that tends to correlate with the extent of skin and muscle involvement,” Dr. Pope said. “Anti–double-stranded DNA correlates with extent of disease, but the only known biomarker to date that correlates with disease activity is CXCL9/10. This has been documented in the skin as well as in the blood. So, this marker may help us determine if the patient needs to be treated or not.”
Treatments
For treatment of active localized disease, topical medications are helpful in some cases. Options include topical steroids, calcipotriol with or without betamethasone, imiquimod, and tacrolimus. “In my experience the combination of calcipotriol with betamethasone is best,” she said. “It really shuts down the activity fairly soon, and you can scale down to calcipotriol alone. I don’t find imiquimod very helpful for active lesions, although it has a role for inactive lesions.”
For patients with linear or generalized/mixed disease, “the combination of methotrexate and corticosteroids or methotrexate alone is probably the way to go,” Dr. Pope said. “The addition of steroids really depends on where the lesion is and how worried you are about other problems.”
According to the best available literature, 88% of patients should respond to treatment with methotrexate (MTX) and/or steroids within 3-6 months, and 74% within 3 months. “If they don’t, you have to wonder if the patient’s taking the medication, or you need to think about other alternative treatments,” she said. “Complete remission is possible in most of the patients, and the longer you treat the more you will see that. On average, most of us treat patients for about 3 years, but there are treatment failures as well. This can occur in up to 16% of patients.”
As for second-line treatment agents for congenital morphea, clinicians often turn to mycophenolate mofetil (MMF). Results from a retrospective longitudinal study of juvenile localized scleroderma patients found that after a mean of 9 years 91% of patients on MMF and 100% of patients on MTX had inactive disease. “There were no differences in relapse rates, although MMF seems to have a more sustained long-term effect and overall is better tolerated,” said Dr. Pope, who was not involved with the study. “However, it’s more immunosuppressive than MTX, which is important, especially in the era of COVID-19. You also need to think about the potential for more hematological suppression with MMF use.” If standard therapy fails, there is anecdotal data supporting the use of abatacept (which suppresses the T-cell activity in affected patients), tofacitinib (which inhibits transforming growth factor–beta), or dupilumab (which inhibits interleukin-4).
Dr. Pope emphasized the effect congenital morphea has on quality of life. Remarks from patients with facial morphea and their parents who participated in a focus group on the topic organized by the Hospital for Sick Children included, “You just want to stay inside because you are afraid of what people will say,” “They laugh at her. They make fun of her, and it’s terrible,” and “MTX makes me feel weird. I would throw up, feel dizzy.”
“You have to take that into consideration, because we cannot make the treatment worse than the disease,” Dr. Pope said. “There are many domains where patients could be affected, including skin symptoms, physical functioning, body image and social support, side effects of medication, and presence of extracutaneous manifestations. Predictors of poor quality of life include female sex and involvement of hands and feet.”
Dr. Pope disclosed that she has received grants/research support from AbbVie, Centocor, and Amgen. She has also received consulting fees from AbbVie, Sanofi, Novartis, Boehringer-Ingelheim, Phoenix, Amryt Pharma, and Timber Pharmaceuticals.
INDIANAPOLIS – In the opinion of Elena Pope, MD, MSc,
“There is no correlation between the extent and activity of skin lesions and the presence, severity, and activity of extracutaneous manifestations,” Dr. Pope, professor of pediatrics at the University of Toronto and division head of pediatric dermatology at the Hospital for Sick Children in Toronto, said during the annual meeting of the Society for Pediatric Dermatology. “Treatment needs to be tailored to the extent of cutaneous manifestations, and I think we need to be aware of and address the impact on patients’ quality of life,” she added. There is also a need for more research “on targeted and better-tolerated therapies to put a stop to the progression of disease.”
Congenital morphea is a form of localized scleroderma that presents at birth but can be confused with port wine stain. Results from a multicenter retrospective review of 25 cases conducted by Dr. Pope and colleagues found that the median age at diagnosis was 2.9 years and 76% had linear-type lesions. In addition, 48% had extracutaneous involvement (all of these patients had linear morphea), most commonly of the central nervous system.
“It’s important to realize these lesions may become active over time,” Dr. Pope said. “In my experience, there are two different courses. Either you have innocuous lesions when the patients are born and they may become active around 3-4 years of age, or you have early intrauterine involvement, with lesions inactive at birth but with potential for significant damage in utero.”
She cautioned against treating a suspected port wine stain lesion with laser until congenital morphea is ruled out. “I’m aware of at least one lawsuit of a child where someone used a laser in a child who had progression with significant sclerosis,” she said. “The parents assumed it was the use of the laser that led to the progression, not the actual disease.”
Extracutaneous manifestations are common in morphea patients. A multicenter study of 750 patients with juvenile scleroderma found that 22% had extracutaneous manifestations. Almost half of patients (47%) had arthritis, but 17% had neurologic findings such as seizures and headaches, 9% had vascular manifestations, and 8% had uveitis. Subsequent studies found that neurological disease affects between 11% and 19% of cases, especially in those involving the head and neck.
“There is a wide range of manifestations from headache and neuropsychiatric changes to brain atrophy, seizures, and CNS cavernoma,” Dr. Pope said. “There also can be orthodental involvement such as malocclusion. It’s important to do a brain MRI, eye exam for uveitis, and don’t forget the orthodental assessment.”
She recalled a 10-year-old boy who presented to the Hospital for Sick Children with tissue loss on the forehead and eyebrow and eyelashes. He had no other congenital morphea symptoms and the MRI was normal, but the eye exam revealed uveitis. “It’s important to remember that uveitis is asymptomatic, so unless you look for it, you’re not going to find it,” she said.
According to unpublished data in 42 congenital morphea patients with lesions limited to the head and neck, who underwent MRI imaging at the Hospital for Sick Children, 57% had CNS changes that were ipsilateral in 68% of cases. “White matter changes were the most common, and to our surprise, there were patients who had progressive CNS disease, including CNS vasculitis, new lesions, and enhancement of prior stable lesions,” Dr. Pope said.
She recalled the case of an 8-year-old boy who presented to the hospital with intractable seizures. Upon completion of the MRI, one of the radiologists noted that the imaging showed subtle thinning of the forehead, and he was referred to Dr. Pope and colleagues for assessment. In the span of 4 years, despite aggressive treatment, the boy’s CNS disease progressed. “There was more enhancement, more tissue loss, his seizures are very hard to control, and he has many neurodevelopmental changes,” she recalled. “What I learned from this case is that skin activity does not correlate with imaging. Don’t assume that just because the skin is burnt out that the CNS will be the same. Also, the extent of skin disease does not predict involvement or progression of the CNS.”
Linear lesions on the lower extremities are a harbinger of orthopedic complications, which can occur in about half of patients. Joint contractures in this subset of patients are seen in about 81% of cases, while other sequelae can include arthritis, limb atrophy, leg-leg discrepancy, and angular deformity. “About 14% of patients require intervention,” Dr. Pope said. “In terms of working those patients up, you need to do an MRI and assess the extent of muscle and fascial involvement. Early physiotherapy and an orthopedic evaluation are also recommended.”
As for possible markers of morphea, antinuclear antibody is positive in 22%-68% of cases and correlates with disease severity, extracutaneous manifestations, and disease flare-up. Antihistone antibodies (AHA) are positive in about 47% of cases, “and that tends to correlate with the extent of skin and muscle involvement,” Dr. Pope said. “Anti–double-stranded DNA correlates with extent of disease, but the only known biomarker to date that correlates with disease activity is CXCL9/10. This has been documented in the skin as well as in the blood. So, this marker may help us determine if the patient needs to be treated or not.”
Treatments
For treatment of active localized disease, topical medications are helpful in some cases. Options include topical steroids, calcipotriol with or without betamethasone, imiquimod, and tacrolimus. “In my experience the combination of calcipotriol with betamethasone is best,” she said. “It really shuts down the activity fairly soon, and you can scale down to calcipotriol alone. I don’t find imiquimod very helpful for active lesions, although it has a role for inactive lesions.”
For patients with linear or generalized/mixed disease, “the combination of methotrexate and corticosteroids or methotrexate alone is probably the way to go,” Dr. Pope said. “The addition of steroids really depends on where the lesion is and how worried you are about other problems.”
According to the best available literature, 88% of patients should respond to treatment with methotrexate (MTX) and/or steroids within 3-6 months, and 74% within 3 months. “If they don’t, you have to wonder if the patient’s taking the medication, or you need to think about other alternative treatments,” she said. “Complete remission is possible in most of the patients, and the longer you treat the more you will see that. On average, most of us treat patients for about 3 years, but there are treatment failures as well. This can occur in up to 16% of patients.”
As for second-line treatment agents for congenital morphea, clinicians often turn to mycophenolate mofetil (MMF). Results from a retrospective longitudinal study of juvenile localized scleroderma patients found that after a mean of 9 years 91% of patients on MMF and 100% of patients on MTX had inactive disease. “There were no differences in relapse rates, although MMF seems to have a more sustained long-term effect and overall is better tolerated,” said Dr. Pope, who was not involved with the study. “However, it’s more immunosuppressive than MTX, which is important, especially in the era of COVID-19. You also need to think about the potential for more hematological suppression with MMF use.” If standard therapy fails, there is anecdotal data supporting the use of abatacept (which suppresses the T-cell activity in affected patients), tofacitinib (which inhibits transforming growth factor–beta), or dupilumab (which inhibits interleukin-4).
Dr. Pope emphasized the effect congenital morphea has on quality of life. Remarks from patients with facial morphea and their parents who participated in a focus group on the topic organized by the Hospital for Sick Children included, “You just want to stay inside because you are afraid of what people will say,” “They laugh at her. They make fun of her, and it’s terrible,” and “MTX makes me feel weird. I would throw up, feel dizzy.”
“You have to take that into consideration, because we cannot make the treatment worse than the disease,” Dr. Pope said. “There are many domains where patients could be affected, including skin symptoms, physical functioning, body image and social support, side effects of medication, and presence of extracutaneous manifestations. Predictors of poor quality of life include female sex and involvement of hands and feet.”
Dr. Pope disclosed that she has received grants/research support from AbbVie, Centocor, and Amgen. She has also received consulting fees from AbbVie, Sanofi, Novartis, Boehringer-Ingelheim, Phoenix, Amryt Pharma, and Timber Pharmaceuticals.
INDIANAPOLIS – In the opinion of Elena Pope, MD, MSc,
“There is no correlation between the extent and activity of skin lesions and the presence, severity, and activity of extracutaneous manifestations,” Dr. Pope, professor of pediatrics at the University of Toronto and division head of pediatric dermatology at the Hospital for Sick Children in Toronto, said during the annual meeting of the Society for Pediatric Dermatology. “Treatment needs to be tailored to the extent of cutaneous manifestations, and I think we need to be aware of and address the impact on patients’ quality of life,” she added. There is also a need for more research “on targeted and better-tolerated therapies to put a stop to the progression of disease.”
Congenital morphea is a form of localized scleroderma that presents at birth but can be confused with port wine stain. Results from a multicenter retrospective review of 25 cases conducted by Dr. Pope and colleagues found that the median age at diagnosis was 2.9 years and 76% had linear-type lesions. In addition, 48% had extracutaneous involvement (all of these patients had linear morphea), most commonly of the central nervous system.
“It’s important to realize these lesions may become active over time,” Dr. Pope said. “In my experience, there are two different courses. Either you have innocuous lesions when the patients are born and they may become active around 3-4 years of age, or you have early intrauterine involvement, with lesions inactive at birth but with potential for significant damage in utero.”
She cautioned against treating a suspected port wine stain lesion with laser until congenital morphea is ruled out. “I’m aware of at least one lawsuit of a child where someone used a laser in a child who had progression with significant sclerosis,” she said. “The parents assumed it was the use of the laser that led to the progression, not the actual disease.”
Extracutaneous manifestations are common in morphea patients. A multicenter study of 750 patients with juvenile scleroderma found that 22% had extracutaneous manifestations. Almost half of patients (47%) had arthritis, but 17% had neurologic findings such as seizures and headaches, 9% had vascular manifestations, and 8% had uveitis. Subsequent studies found that neurological disease affects between 11% and 19% of cases, especially in those involving the head and neck.
“There is a wide range of manifestations from headache and neuropsychiatric changes to brain atrophy, seizures, and CNS cavernoma,” Dr. Pope said. “There also can be orthodental involvement such as malocclusion. It’s important to do a brain MRI, eye exam for uveitis, and don’t forget the orthodental assessment.”
She recalled a 10-year-old boy who presented to the Hospital for Sick Children with tissue loss on the forehead and eyebrow and eyelashes. He had no other congenital morphea symptoms and the MRI was normal, but the eye exam revealed uveitis. “It’s important to remember that uveitis is asymptomatic, so unless you look for it, you’re not going to find it,” she said.
According to unpublished data in 42 congenital morphea patients with lesions limited to the head and neck, who underwent MRI imaging at the Hospital for Sick Children, 57% had CNS changes that were ipsilateral in 68% of cases. “White matter changes were the most common, and to our surprise, there were patients who had progressive CNS disease, including CNS vasculitis, new lesions, and enhancement of prior stable lesions,” Dr. Pope said.
She recalled the case of an 8-year-old boy who presented to the hospital with intractable seizures. Upon completion of the MRI, one of the radiologists noted that the imaging showed subtle thinning of the forehead, and he was referred to Dr. Pope and colleagues for assessment. In the span of 4 years, despite aggressive treatment, the boy’s CNS disease progressed. “There was more enhancement, more tissue loss, his seizures are very hard to control, and he has many neurodevelopmental changes,” she recalled. “What I learned from this case is that skin activity does not correlate with imaging. Don’t assume that just because the skin is burnt out that the CNS will be the same. Also, the extent of skin disease does not predict involvement or progression of the CNS.”
Linear lesions on the lower extremities are a harbinger of orthopedic complications, which can occur in about half of patients. Joint contractures in this subset of patients are seen in about 81% of cases, while other sequelae can include arthritis, limb atrophy, leg-leg discrepancy, and angular deformity. “About 14% of patients require intervention,” Dr. Pope said. “In terms of working those patients up, you need to do an MRI and assess the extent of muscle and fascial involvement. Early physiotherapy and an orthopedic evaluation are also recommended.”
As for possible markers of morphea, antinuclear antibody is positive in 22%-68% of cases and correlates with disease severity, extracutaneous manifestations, and disease flare-up. Antihistone antibodies (AHA) are positive in about 47% of cases, “and that tends to correlate with the extent of skin and muscle involvement,” Dr. Pope said. “Anti–double-stranded DNA correlates with extent of disease, but the only known biomarker to date that correlates with disease activity is CXCL9/10. This has been documented in the skin as well as in the blood. So, this marker may help us determine if the patient needs to be treated or not.”
Treatments
For treatment of active localized disease, topical medications are helpful in some cases. Options include topical steroids, calcipotriol with or without betamethasone, imiquimod, and tacrolimus. “In my experience the combination of calcipotriol with betamethasone is best,” she said. “It really shuts down the activity fairly soon, and you can scale down to calcipotriol alone. I don’t find imiquimod very helpful for active lesions, although it has a role for inactive lesions.”
For patients with linear or generalized/mixed disease, “the combination of methotrexate and corticosteroids or methotrexate alone is probably the way to go,” Dr. Pope said. “The addition of steroids really depends on where the lesion is and how worried you are about other problems.”
According to the best available literature, 88% of patients should respond to treatment with methotrexate (MTX) and/or steroids within 3-6 months, and 74% within 3 months. “If they don’t, you have to wonder if the patient’s taking the medication, or you need to think about other alternative treatments,” she said. “Complete remission is possible in most of the patients, and the longer you treat the more you will see that. On average, most of us treat patients for about 3 years, but there are treatment failures as well. This can occur in up to 16% of patients.”
As for second-line treatment agents for congenital morphea, clinicians often turn to mycophenolate mofetil (MMF). Results from a retrospective longitudinal study of juvenile localized scleroderma patients found that after a mean of 9 years 91% of patients on MMF and 100% of patients on MTX had inactive disease. “There were no differences in relapse rates, although MMF seems to have a more sustained long-term effect and overall is better tolerated,” said Dr. Pope, who was not involved with the study. “However, it’s more immunosuppressive than MTX, which is important, especially in the era of COVID-19. You also need to think about the potential for more hematological suppression with MMF use.” If standard therapy fails, there is anecdotal data supporting the use of abatacept (which suppresses the T-cell activity in affected patients), tofacitinib (which inhibits transforming growth factor–beta), or dupilumab (which inhibits interleukin-4).
Dr. Pope emphasized the effect congenital morphea has on quality of life. Remarks from patients with facial morphea and their parents who participated in a focus group on the topic organized by the Hospital for Sick Children included, “You just want to stay inside because you are afraid of what people will say,” “They laugh at her. They make fun of her, and it’s terrible,” and “MTX makes me feel weird. I would throw up, feel dizzy.”
“You have to take that into consideration, because we cannot make the treatment worse than the disease,” Dr. Pope said. “There are many domains where patients could be affected, including skin symptoms, physical functioning, body image and social support, side effects of medication, and presence of extracutaneous manifestations. Predictors of poor quality of life include female sex and involvement of hands and feet.”
Dr. Pope disclosed that she has received grants/research support from AbbVie, Centocor, and Amgen. She has also received consulting fees from AbbVie, Sanofi, Novartis, Boehringer-Ingelheim, Phoenix, Amryt Pharma, and Timber Pharmaceuticals.
AT SPD 2022