MDedge Dermatology

Fluorescence-optical imaging (FOI) identified early signs of psoriatic arthritis, based on data from 2 years of follow-up of a cohort of 389 adults at 14 rheumatology centers.

Approximately 25% of individuals with psoriasis go on to develop psoriatic arthritis (PsA), but there are no validated biomarkers to identify patients at risk for progression to PsA, Michaela Koehm, MD, of Goethe University, Frankfurt am Main, Germany, and colleagues wrote in RMD Open.

FOI is a technique that allows assessment of changes in microvascularization and subdermal skin inflammation, and because individuals with psoriasis who develop PsA have shown changes in blood vessel formation in the early stages of disease, the researchers sought to determine if FOI could be used to predict early PsA.

The researchers conducted a multicenter, two-part observational cohort study. The two parts, known as XCITING and XTEND, included 389 adults aged 18-75 years with plaque psoriasis deemed at increased risk for PsA. The patients were seen at rheumatology sites in Germany between Jan. 28, 2014, and March 16, 2017. The XTEND study included clinic visits 18-24 months after the XCITING study.

Participants underwent a complete clinical examination, with musculoskeletal ultrasound (MSUS) and FOI on both hands at a single visit. Those with positive FOI findings not seen with clinical exam or MSUS underwent MRI within 7 days. Patients with positive FOI but negative findings on clinical exam, MSUS, and MRI were followed for 2 years in the XTEND study.

The primary outcome was the ability of FOI to detect musculoskeletal inflammation, compared with clinical examination and MSUS.

Overall, 50% of the patients were diagnosed with PsA. A total of 116 (30%) had positive FOI findings; complete MRI data were available for 108 of these patients, including 68 negative MRIs and 40 positive MRIs.

In the XTEND study, another 12% of patients who were positive on FOI but not on MRI also developed PsA by the end of the 2-year follow-up. In comparison, the researchers noted that “literature data on yearly incidence rates [of PsA] in different national cohorts indicate an incidence rate of approximately 4.3% per year.”

A total of 149 of the 196 patients with PsA confirmed by either clinical exam or MSUS were also positive on FOI, yielding a sensitivity of 76.0%. The specificity of FOI was 39.5%.

The sensitive visualization of musculoskeletal inflammation possible with FOI “may exceed its ability to detect clinically manifest PsA at high sensitivity or specificity, but early visualization is arguably of greater value as other imaging methods are currently available for detection of later stages of PsA,” the researchers wrote in their discussion. “A technique allowing early identification of PsA may be especially valuable for nonrheumatologists, including dermatologists and general practitioners, and help expedite more efficient referral to specialists.”

The findings were limited by several factors, including the nonrandomized design and small subgroup numbers, the researchers noted. Other limitations include the presence of alternative conditions such as osteoarthritis that might have complicated the imaging; the focus only on the hands; and potential variation in FOI assessment related to technical standards such as temperature and positioning.

However, the results support FOI as a safe and effective method of detecting early signs of joint inflammation that could predict increased risk for PsA in psoriasis patients, the researchers said.

The researchers added that more work is needed to evaluate FOI in clinical practice, but FOI has the potential to identify vascularization changes earlier than other imaging modalities and in advance of clinical symptoms.

“Accordingly, FOI may have the potential to improve patient outcomes in PsA by reducing the time to initiation of early treatment,” they concluded.

The study was supported by Fraunhofer ITMP, a nonprofit organization, and a research grant from Pfizer Germany. Some of the researchers disclosed financial relationships with many pharmaceutical companies, including Pfizer.

Fluorescence-optical imaging (FOI) identified early signs of psoriatic arthritis, based on data from 2 years of follow-up of a cohort of 389 adults at 14 rheumatology centers.

Approximately 25% of individuals with psoriasis go on to develop psoriatic arthritis (PsA), but there are no validated biomarkers to identify patients at risk for progression to PsA, Michaela Koehm, MD, of Goethe University, Frankfurt am Main, Germany, and colleagues wrote in RMD Open.

FOI is a technique that allows assessment of changes in microvascularization and subdermal skin inflammation, and because individuals with psoriasis who develop PsA have shown changes in blood vessel formation in the early stages of disease, the researchers sought to determine if FOI could be used to predict early PsA.

The researchers conducted a multicenter, two-part observational cohort study. The two parts, known as XCITING and XTEND, included 389 adults aged 18-75 years with plaque psoriasis deemed at increased risk for PsA. The patients were seen at rheumatology sites in Germany between Jan. 28, 2014, and March 16, 2017. The XTEND study included clinic visits 18-24 months after the XCITING study.

Participants underwent a complete clinical examination, with musculoskeletal ultrasound (MSUS) and FOI on both hands at a single visit. Those with positive FOI findings not seen with clinical exam or MSUS underwent MRI within 7 days. Patients with positive FOI but negative findings on clinical exam, MSUS, and MRI were followed for 2 years in the XTEND study.

The primary outcome was the ability of FOI to detect musculoskeletal inflammation, compared with clinical examination and MSUS.

Overall, 50% of the patients were diagnosed with PsA. A total of 116 (30%) had positive FOI findings; complete MRI data were available for 108 of these patients, including 68 negative MRIs and 40 positive MRIs.

In the XTEND study, another 12% of patients who were positive on FOI but not on MRI also developed PsA by the end of the 2-year follow-up. In comparison, the researchers noted that “literature data on yearly incidence rates [of PsA] in different national cohorts indicate an incidence rate of approximately 4.3% per year.”

A total of 149 of the 196 patients with PsA confirmed by either clinical exam or MSUS were also positive on FOI, yielding a sensitivity of 76.0%. The specificity of FOI was 39.5%.

The sensitive visualization of musculoskeletal inflammation possible with FOI “may exceed its ability to detect clinically manifest PsA at high sensitivity or specificity, but early visualization is arguably of greater value as other imaging methods are currently available for detection of later stages of PsA,” the researchers wrote in their discussion. “A technique allowing early identification of PsA may be especially valuable for nonrheumatologists, including dermatologists and general practitioners, and help expedite more efficient referral to specialists.”

The findings were limited by several factors, including the nonrandomized design and small subgroup numbers, the researchers noted. Other limitations include the presence of alternative conditions such as osteoarthritis that might have complicated the imaging; the focus only on the hands; and potential variation in FOI assessment related to technical standards such as temperature and positioning.

However, the results support FOI as a safe and effective method of detecting early signs of joint inflammation that could predict increased risk for PsA in psoriasis patients, the researchers said.

The researchers added that more work is needed to evaluate FOI in clinical practice, but FOI has the potential to identify vascularization changes earlier than other imaging modalities and in advance of clinical symptoms.

“Accordingly, FOI may have the potential to improve patient outcomes in PsA by reducing the time to initiation of early treatment,” they concluded.

The study was supported by Fraunhofer ITMP, a nonprofit organization, and a research grant from Pfizer Germany. Some of the researchers disclosed financial relationships with many pharmaceutical companies, including Pfizer.

Fluorescence-optical imaging (FOI) identified early signs of psoriatic arthritis, based on data from 2 years of follow-up of a cohort of 389 adults at 14 rheumatology centers.

Approximately 25% of individuals with psoriasis go on to develop psoriatic arthritis (PsA), but there are no validated biomarkers to identify patients at risk for progression to PsA, Michaela Koehm, MD, of Goethe University, Frankfurt am Main, Germany, and colleagues wrote in RMD Open.

FOI is a technique that allows assessment of changes in microvascularization and subdermal skin inflammation, and because individuals with psoriasis who develop PsA have shown changes in blood vessel formation in the early stages of disease, the researchers sought to determine if FOI could be used to predict early PsA.

The researchers conducted a multicenter, two-part observational cohort study. The two parts, known as XCITING and XTEND, included 389 adults aged 18-75 years with plaque psoriasis deemed at increased risk for PsA. The patients were seen at rheumatology sites in Germany between Jan. 28, 2014, and March 16, 2017. The XTEND study included clinic visits 18-24 months after the XCITING study.

Participants underwent a complete clinical examination, with musculoskeletal ultrasound (MSUS) and FOI on both hands at a single visit. Those with positive FOI findings not seen with clinical exam or MSUS underwent MRI within 7 days. Patients with positive FOI but negative findings on clinical exam, MSUS, and MRI were followed for 2 years in the XTEND study.

The primary outcome was the ability of FOI to detect musculoskeletal inflammation, compared with clinical examination and MSUS.

Overall, 50% of the patients were diagnosed with PsA. A total of 116 (30%) had positive FOI findings; complete MRI data were available for 108 of these patients, including 68 negative MRIs and 40 positive MRIs.

In the XTEND study, another 12% of patients who were positive on FOI but not on MRI also developed PsA by the end of the 2-year follow-up. In comparison, the researchers noted that “literature data on yearly incidence rates [of PsA] in different national cohorts indicate an incidence rate of approximately 4.3% per year.”

A total of 149 of the 196 patients with PsA confirmed by either clinical exam or MSUS were also positive on FOI, yielding a sensitivity of 76.0%. The specificity of FOI was 39.5%.

The sensitive visualization of musculoskeletal inflammation possible with FOI “may exceed its ability to detect clinically manifest PsA at high sensitivity or specificity, but early visualization is arguably of greater value as other imaging methods are currently available for detection of later stages of PsA,” the researchers wrote in their discussion. “A technique allowing early identification of PsA may be especially valuable for nonrheumatologists, including dermatologists and general practitioners, and help expedite more efficient referral to specialists.”

The findings were limited by several factors, including the nonrandomized design and small subgroup numbers, the researchers noted. Other limitations include the presence of alternative conditions such as osteoarthritis that might have complicated the imaging; the focus only on the hands; and potential variation in FOI assessment related to technical standards such as temperature and positioning.

However, the results support FOI as a safe and effective method of detecting early signs of joint inflammation that could predict increased risk for PsA in psoriasis patients, the researchers said.

The researchers added that more work is needed to evaluate FOI in clinical practice, but FOI has the potential to identify vascularization changes earlier than other imaging modalities and in advance of clinical symptoms.

“Accordingly, FOI may have the potential to improve patient outcomes in PsA by reducing the time to initiation of early treatment,” they concluded.

The study was supported by Fraunhofer ITMP, a nonprofit organization, and a research grant from Pfizer Germany. Some of the researchers disclosed financial relationships with many pharmaceutical companies, including Pfizer.

When you became a doctor, you may have moved to one city for med school, another for residency, and a third to be an attending. All that moving can make it hard to maintain friendships. Factor in the challenges from the pandemic, and a physician’s life can be lonely. So, when a patient invites you for coffee or a game of pickleball, do you accept? For almost one-third of the physicians who responded to the Medscape Physician Friendships: The Joys and Challenges 2022, the answer might be yes.

About 29% said they develop friendships with patients. However, a lot depends on the circumstances. As one physician in the report said: “I have been a pediatrician for 35 years, and my patients have grown up and become productive adults in our small, rural, isolated area. You can’t help but know almost everyone.”

As the daughter of a cardiologist, Nishi Mehta, MD, a radiologist and founder of the largest physician-only Facebook group in the country, grew up with that small-town-everyone-knows-the-doctor model.

“When I was a kid, I’d go to the mall, and my friends and I would play a game: How long before a patient [of my dad’s] comes up to me?” she said. At the time, Dr. Mehta was embarrassed, but now she marvels that her dad knew his patients so well that they would recognize his daughter in crowded suburban mall.

In other instances, a physician may develop a friendly relationship after a patient leaves their care. For example, Leo Nissola, MD, now a full-time researcher and immunotherapy scientist in San Francisco, has stayed in touch with some of the patients he treated while at the University of Texas MD Anderson Cancer Center, Houston.

Dr. Nissola said it was important to stay connected with the patients he had meaningful relationships with. “It becomes challenging, though, when a former patient asks for medical advice.” At that moment, “you have to be explicitly clear that the relationship has changed.”
 

A hard line in the sand

The blurring of lines is one reason many doctors refuse to befriend patients, even after they are no longer treating them. The American College of Physicians Ethics Manual advises against treating anyone with whom you have a close relationship, including family and friends.

“Friendships can get in the way of patients being honest with you, which can interfere with medical care,” Dr. Mehta said. “If a patient has a concern related to something they wouldn’t want you to know as friends, it can get awkward. They may elect not to tell you.”

And on the flip side, friendship can provide a view into your private life that you may not welcome in the exam room.

“Let’s say you go out for drinks [with a patient], and you’re up late, but you have surgery the next day,” said Brandi Ring, MD, an ob.gyn. and the associate medical director at the Center for Children and Women in Houston. Now, one of your patients knows you were out until midnight when you had to be in the OR at 5:00 a.m.

Worse still, your relationship could color your decisions about a patient’s care, even unconsciously. It can be hard to maintain objectivity when you have an emotional investment in someone’s well-being.

“We don’t necessarily treat family and friends to the standards of medical care,” said Dr. Ring. “We go above and beyond. We might order more tests and more scans. We don’t always follow the guidelines, especially in critical illness.”

For all these reasons and more, the ACP advises against treating friends.
 

Put physician before friend

But adhering to those guidelines can lead physicians to make some painful decisions. Cutting yourself off from the possibility of friendship is never easy, and the Medscape report found that physicians tend to have fewer friends than the average American.

“Especially earlier in my practice, when I was a young parent, and I would see a lot of other young parents in the same stage in life, I’d think, ‘In other circumstances, I would be hanging out at the park with this person,’ “ said Kathleen Rowland, MD, a family medicine physician and vice chair of education in the department of family medicine at Rush University, Chicago. “But the hard part is, the doctor-patient relationship always comes first.”

To a certain extent, one’s specialty may determine the feasibility of becoming friends with a patient. While Dr. Mehta has never done so, as a radiologist, she doesn’t usually see patients repeatedly. Likewise, a young gerontologist may have little in common with his octogenarian patients. And an older pediatrician is not in the same life stage as his patients’ sleep-deprived new parents, possibly making them less attractive friends.

However, practicing family medicine is all about long-term physician-patient relationships. Getting to know patients and their families over many years can lead to a certain intimacy. Dr. Rowland said that, while a wonderful part of being a physician is getting that unique trust whereby patients tell you all sorts of things about their lives, she’s never gone down the friendship path.

“There’s the assumption I’ll take care of someone for a long period of time, and their partner and their kids, maybe another generation or two,” Dr. Rowland said. “People really do rely on that relationship to contribute to their health.”

Worse, nowadays, when people may be starved for connection, many patients want to feel emotionally close and cared for by their doctor, so it’d be easy to cross the line. While patients deserve a compassionate, caring doctor, the physician is left to walk the line between those boundaries. Dr. Rowland said, “It’s up to the clinician to say: ‘My role is as a doctor. You deserve caring friends, but I have to order your mammogram and your blood counts. My role is different.’ ”
 

Friendly but not friends

It can be tricky to navigate the boundary between a cordial, warm relationship with a patient and that patient inviting you to their daughter’s wedding.

“People may mistake being pleasant and friendly for being friends,” said Larry Blosser, MD, chief medical officer at Central Ohio Primary Care, Westerville. In his position, he sometimes hears from patients who have misunderstood their relationship with a doctor in the practice. When that happens, he advises the physician to consider the persona they’re presenting to the patient. If you’re overly friendly, there’s the potential for confusion, but you can’t be aloof and cold, he said.

Maintaining that awareness helps to prevent a patient’s offhand invitation to catch a movie or go on a hike. And verbalizing it to your patients can make your relationship clear from the get-go.

“I tell patients we’re a team. I’m the captain, and they’re my MVP. When the match is over, whatever the results, we’re done,” said Karenne Fru, MD, PhD, a fertility specialist at Oma Fertility Atlanta. Making deep connections is essential to her practice, so Dr. Fru structures her patient interactions carefully. “Infertility is such an isolating experience. While you’re with us, we care about what’s going on in your life, your pets, and your mom’s chemo. We need mutual trust for you to be compliant with the care.”

However, that approach won’t work when you see patients regularly, as with family practice or specialties that see the same patients repeatedly throughout the year. In those circumstances, the match is never over but one in which the onus is on the physician to establish a friendly yet professional rapport without letting your self-interest, loneliness, or lack of friends interfere.

“It’s been a very difficult couple of years for a lot of us. Depending on what kind of clinical work we do, some of us took care of healthy people that got very sick or passed away,” Dr. Rowland said. “Having the chance to reconnect with people and reestablish some of that closeness, both physical and emotional, is going to be good for us.”

Just continue conveying warm, trusting compassion for your patients without blurring the friend lines.

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

When you became a doctor, you may have moved to one city for med school, another for residency, and a third to be an attending. All that moving can make it hard to maintain friendships. Factor in the challenges from the pandemic, and a physician’s life can be lonely. So, when a patient invites you for coffee or a game of pickleball, do you accept? For almost one-third of the physicians who responded to the Medscape Physician Friendships: The Joys and Challenges 2022, the answer might be yes.

About 29% said they develop friendships with patients. However, a lot depends on the circumstances. As one physician in the report said: “I have been a pediatrician for 35 years, and my patients have grown up and become productive adults in our small, rural, isolated area. You can’t help but know almost everyone.”

As the daughter of a cardiologist, Nishi Mehta, MD, a radiologist and founder of the largest physician-only Facebook group in the country, grew up with that small-town-everyone-knows-the-doctor model.

“When I was a kid, I’d go to the mall, and my friends and I would play a game: How long before a patient [of my dad’s] comes up to me?” she said. At the time, Dr. Mehta was embarrassed, but now she marvels that her dad knew his patients so well that they would recognize his daughter in crowded suburban mall.

In other instances, a physician may develop a friendly relationship after a patient leaves their care. For example, Leo Nissola, MD, now a full-time researcher and immunotherapy scientist in San Francisco, has stayed in touch with some of the patients he treated while at the University of Texas MD Anderson Cancer Center, Houston.

Dr. Nissola said it was important to stay connected with the patients he had meaningful relationships with. “It becomes challenging, though, when a former patient asks for medical advice.” At that moment, “you have to be explicitly clear that the relationship has changed.”
 

A hard line in the sand

The blurring of lines is one reason many doctors refuse to befriend patients, even after they are no longer treating them. The American College of Physicians Ethics Manual advises against treating anyone with whom you have a close relationship, including family and friends.

“Friendships can get in the way of patients being honest with you, which can interfere with medical care,” Dr. Mehta said. “If a patient has a concern related to something they wouldn’t want you to know as friends, it can get awkward. They may elect not to tell you.”

And on the flip side, friendship can provide a view into your private life that you may not welcome in the exam room.

“Let’s say you go out for drinks [with a patient], and you’re up late, but you have surgery the next day,” said Brandi Ring, MD, an ob.gyn. and the associate medical director at the Center for Children and Women in Houston. Now, one of your patients knows you were out until midnight when you had to be in the OR at 5:00 a.m.

Worse still, your relationship could color your decisions about a patient’s care, even unconsciously. It can be hard to maintain objectivity when you have an emotional investment in someone’s well-being.

“We don’t necessarily treat family and friends to the standards of medical care,” said Dr. Ring. “We go above and beyond. We might order more tests and more scans. We don’t always follow the guidelines, especially in critical illness.”

For all these reasons and more, the ACP advises against treating friends.
 

Put physician before friend

But adhering to those guidelines can lead physicians to make some painful decisions. Cutting yourself off from the possibility of friendship is never easy, and the Medscape report found that physicians tend to have fewer friends than the average American.

“Especially earlier in my practice, when I was a young parent, and I would see a lot of other young parents in the same stage in life, I’d think, ‘In other circumstances, I would be hanging out at the park with this person,’ “ said Kathleen Rowland, MD, a family medicine physician and vice chair of education in the department of family medicine at Rush University, Chicago. “But the hard part is, the doctor-patient relationship always comes first.”

To a certain extent, one’s specialty may determine the feasibility of becoming friends with a patient. While Dr. Mehta has never done so, as a radiologist, she doesn’t usually see patients repeatedly. Likewise, a young gerontologist may have little in common with his octogenarian patients. And an older pediatrician is not in the same life stage as his patients’ sleep-deprived new parents, possibly making them less attractive friends.

However, practicing family medicine is all about long-term physician-patient relationships. Getting to know patients and their families over many years can lead to a certain intimacy. Dr. Rowland said that, while a wonderful part of being a physician is getting that unique trust whereby patients tell you all sorts of things about their lives, she’s never gone down the friendship path.

“There’s the assumption I’ll take care of someone for a long period of time, and their partner and their kids, maybe another generation or two,” Dr. Rowland said. “People really do rely on that relationship to contribute to their health.”

Worse, nowadays, when people may be starved for connection, many patients want to feel emotionally close and cared for by their doctor, so it’d be easy to cross the line. While patients deserve a compassionate, caring doctor, the physician is left to walk the line between those boundaries. Dr. Rowland said, “It’s up to the clinician to say: ‘My role is as a doctor. You deserve caring friends, but I have to order your mammogram and your blood counts. My role is different.’ ”
 

Friendly but not friends

It can be tricky to navigate the boundary between a cordial, warm relationship with a patient and that patient inviting you to their daughter’s wedding.

“People may mistake being pleasant and friendly for being friends,” said Larry Blosser, MD, chief medical officer at Central Ohio Primary Care, Westerville. In his position, he sometimes hears from patients who have misunderstood their relationship with a doctor in the practice. When that happens, he advises the physician to consider the persona they’re presenting to the patient. If you’re overly friendly, there’s the potential for confusion, but you can’t be aloof and cold, he said.

Maintaining that awareness helps to prevent a patient’s offhand invitation to catch a movie or go on a hike. And verbalizing it to your patients can make your relationship clear from the get-go.

“I tell patients we’re a team. I’m the captain, and they’re my MVP. When the match is over, whatever the results, we’re done,” said Karenne Fru, MD, PhD, a fertility specialist at Oma Fertility Atlanta. Making deep connections is essential to her practice, so Dr. Fru structures her patient interactions carefully. “Infertility is such an isolating experience. While you’re with us, we care about what’s going on in your life, your pets, and your mom’s chemo. We need mutual trust for you to be compliant with the care.”

However, that approach won’t work when you see patients regularly, as with family practice or specialties that see the same patients repeatedly throughout the year. In those circumstances, the match is never over but one in which the onus is on the physician to establish a friendly yet professional rapport without letting your self-interest, loneliness, or lack of friends interfere.

“It’s been a very difficult couple of years for a lot of us. Depending on what kind of clinical work we do, some of us took care of healthy people that got very sick or passed away,” Dr. Rowland said. “Having the chance to reconnect with people and reestablish some of that closeness, both physical and emotional, is going to be good for us.”

Just continue conveying warm, trusting compassion for your patients without blurring the friend lines.

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

When you became a doctor, you may have moved to one city for med school, another for residency, and a third to be an attending. All that moving can make it hard to maintain friendships. Factor in the challenges from the pandemic, and a physician’s life can be lonely. So, when a patient invites you for coffee or a game of pickleball, do you accept? For almost one-third of the physicians who responded to the Medscape Physician Friendships: The Joys and Challenges 2022, the answer might be yes.

About 29% said they develop friendships with patients. However, a lot depends on the circumstances. As one physician in the report said: “I have been a pediatrician for 35 years, and my patients have grown up and become productive adults in our small, rural, isolated area. You can’t help but know almost everyone.”

As the daughter of a cardiologist, Nishi Mehta, MD, a radiologist and founder of the largest physician-only Facebook group in the country, grew up with that small-town-everyone-knows-the-doctor model.

“When I was a kid, I’d go to the mall, and my friends and I would play a game: How long before a patient [of my dad’s] comes up to me?” she said. At the time, Dr. Mehta was embarrassed, but now she marvels that her dad knew his patients so well that they would recognize his daughter in crowded suburban mall.

In other instances, a physician may develop a friendly relationship after a patient leaves their care. For example, Leo Nissola, MD, now a full-time researcher and immunotherapy scientist in San Francisco, has stayed in touch with some of the patients he treated while at the University of Texas MD Anderson Cancer Center, Houston.

Dr. Nissola said it was important to stay connected with the patients he had meaningful relationships with. “It becomes challenging, though, when a former patient asks for medical advice.” At that moment, “you have to be explicitly clear that the relationship has changed.”
 

A hard line in the sand

The blurring of lines is one reason many doctors refuse to befriend patients, even after they are no longer treating them. The American College of Physicians Ethics Manual advises against treating anyone with whom you have a close relationship, including family and friends.

“Friendships can get in the way of patients being honest with you, which can interfere with medical care,” Dr. Mehta said. “If a patient has a concern related to something they wouldn’t want you to know as friends, it can get awkward. They may elect not to tell you.”

And on the flip side, friendship can provide a view into your private life that you may not welcome in the exam room.

“Let’s say you go out for drinks [with a patient], and you’re up late, but you have surgery the next day,” said Brandi Ring, MD, an ob.gyn. and the associate medical director at the Center for Children and Women in Houston. Now, one of your patients knows you were out until midnight when you had to be in the OR at 5:00 a.m.

Worse still, your relationship could color your decisions about a patient’s care, even unconsciously. It can be hard to maintain objectivity when you have an emotional investment in someone’s well-being.

“We don’t necessarily treat family and friends to the standards of medical care,” said Dr. Ring. “We go above and beyond. We might order more tests and more scans. We don’t always follow the guidelines, especially in critical illness.”

For all these reasons and more, the ACP advises against treating friends.
 

Put physician before friend

But adhering to those guidelines can lead physicians to make some painful decisions. Cutting yourself off from the possibility of friendship is never easy, and the Medscape report found that physicians tend to have fewer friends than the average American.

“Especially earlier in my practice, when I was a young parent, and I would see a lot of other young parents in the same stage in life, I’d think, ‘In other circumstances, I would be hanging out at the park with this person,’ “ said Kathleen Rowland, MD, a family medicine physician and vice chair of education in the department of family medicine at Rush University, Chicago. “But the hard part is, the doctor-patient relationship always comes first.”

To a certain extent, one’s specialty may determine the feasibility of becoming friends with a patient. While Dr. Mehta has never done so, as a radiologist, she doesn’t usually see patients repeatedly. Likewise, a young gerontologist may have little in common with his octogenarian patients. And an older pediatrician is not in the same life stage as his patients’ sleep-deprived new parents, possibly making them less attractive friends.

However, practicing family medicine is all about long-term physician-patient relationships. Getting to know patients and their families over many years can lead to a certain intimacy. Dr. Rowland said that, while a wonderful part of being a physician is getting that unique trust whereby patients tell you all sorts of things about their lives, she’s never gone down the friendship path.

“There’s the assumption I’ll take care of someone for a long period of time, and their partner and their kids, maybe another generation or two,” Dr. Rowland said. “People really do rely on that relationship to contribute to their health.”

Worse, nowadays, when people may be starved for connection, many patients want to feel emotionally close and cared for by their doctor, so it’d be easy to cross the line. While patients deserve a compassionate, caring doctor, the physician is left to walk the line between those boundaries. Dr. Rowland said, “It’s up to the clinician to say: ‘My role is as a doctor. You deserve caring friends, but I have to order your mammogram and your blood counts. My role is different.’ ”
 

Friendly but not friends

It can be tricky to navigate the boundary between a cordial, warm relationship with a patient and that patient inviting you to their daughter’s wedding.

“People may mistake being pleasant and friendly for being friends,” said Larry Blosser, MD, chief medical officer at Central Ohio Primary Care, Westerville. In his position, he sometimes hears from patients who have misunderstood their relationship with a doctor in the practice. When that happens, he advises the physician to consider the persona they’re presenting to the patient. If you’re overly friendly, there’s the potential for confusion, but you can’t be aloof and cold, he said.

Maintaining that awareness helps to prevent a patient’s offhand invitation to catch a movie or go on a hike. And verbalizing it to your patients can make your relationship clear from the get-go.

“I tell patients we’re a team. I’m the captain, and they’re my MVP. When the match is over, whatever the results, we’re done,” said Karenne Fru, MD, PhD, a fertility specialist at Oma Fertility Atlanta. Making deep connections is essential to her practice, so Dr. Fru structures her patient interactions carefully. “Infertility is such an isolating experience. While you’re with us, we care about what’s going on in your life, your pets, and your mom’s chemo. We need mutual trust for you to be compliant with the care.”

However, that approach won’t work when you see patients regularly, as with family practice or specialties that see the same patients repeatedly throughout the year. In those circumstances, the match is never over but one in which the onus is on the physician to establish a friendly yet professional rapport without letting your self-interest, loneliness, or lack of friends interfere.

“It’s been a very difficult couple of years for a lot of us. Depending on what kind of clinical work we do, some of us took care of healthy people that got very sick or passed away,” Dr. Rowland said. “Having the chance to reconnect with people and reestablish some of that closeness, both physical and emotional, is going to be good for us.”

Just continue conveying warm, trusting compassion for your patients without blurring the friend lines.

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

SAN DIEGO – As with many markers for the evaluation of challenging melanocytic lesions, preferentially expressed antigen in melanoma (PRAME) has its benefits and drawbacks, according to Cora Humberson, MD.

“I’m a fan, but there are issues with it,” Dr. Humberson, dermatopathology coordinator in the department of pathology at Scripps MD Anderson Cancer Center, San Diego, said at the annual Cutaneous Malignancy Update. “It’s all in how you use it.”

PRAME is part of the cancer/testis (CT) antigens, of which more than 40 have now been identified. They are encoded by genes that are normally expressed only in the human germ line, but are also expressed in various tumor types, including melanoma and carcinomas of the bladder, lung, and liver. “The biological function of these antigens is not fully understood, but they may act as a repressor of retinoic acid, potentially inhibiting differentiation, inhibiting proliferation arrest – things that we associate with malignancy,” she said at the meeting, which was hosted by Scripps MD Anderson Cancer Center. “These immunogenic proteins are being pursued as targets for therapeutic cancer vaccines,” she noted.

CT antigens are also being evaluated for their role in oncogenesis, she added. Recapitulation of portions of the germline gene-expression might contribute characteristic features to the neoplastic phenotype, including immortality, invasiveness, immune evasion, and metastatic capacity.

According to Dr. Humberson, PRAME can be used to differentiate comingled nevus and melanoma, to distinguish between nevoid melanoma and nevus, and for melanoma margin assessment in sun-damaged skin. One potential pitfall is that sun-damaged melanocytes may express PRAME. “The older the person and the more sun damage [they have], the more likely you are to see this, but the melanocytes won’t be grouped, they’ll be scattered,” she said.

Another pitfall is that less than 15% of nevi may express PRAME. “PRAME can be expressed in scars, so if you’re looking at a spindle cell lesion, be aware that you might be looking at a scar if you’re seeing PRAME expression,” she added. She also noted that PRAME immunohistochemistry (IHC) expression is not a prognostic biomarker in thin melanomas.

If fewer than 25% of cells in a melanocytic lesion express PRAME, most published assessments of PRAME IHC favor nevi as the diagnosis. “If more than 75% are expressing it, it favors melanoma,” Dr. Humberson said. “There’s a big category in between. It’s not that 30% is more likely benign or that 60% is more likely malignant; you can’t really depend upon [PRAME] if you’re in this range.”

A diagnostic accuracy study found that when more than 75% of cells express PRAME, the marker has a sensitivity of 0.63 and a specificity of 0.97.

Selected PRAME-related published references she recommended include: J Cutan Pathol. 2021;48(9):1115-23; Diagnostics. 2022 Sep 9; 12(9):2197, and J Cutan Pathol. 2022;49(9):829-32.

Dr. Humberson reported having no relevant disclosures.

SAN DIEGO – As with many markers for the evaluation of challenging melanocytic lesions, preferentially expressed antigen in melanoma (PRAME) has its benefits and drawbacks, according to Cora Humberson, MD.

“I’m a fan, but there are issues with it,” Dr. Humberson, dermatopathology coordinator in the department of pathology at Scripps MD Anderson Cancer Center, San Diego, said at the annual Cutaneous Malignancy Update. “It’s all in how you use it.”

PRAME is part of the cancer/testis (CT) antigens, of which more than 40 have now been identified. They are encoded by genes that are normally expressed only in the human germ line, but are also expressed in various tumor types, including melanoma and carcinomas of the bladder, lung, and liver. “The biological function of these antigens is not fully understood, but they may act as a repressor of retinoic acid, potentially inhibiting differentiation, inhibiting proliferation arrest – things that we associate with malignancy,” she said at the meeting, which was hosted by Scripps MD Anderson Cancer Center. “These immunogenic proteins are being pursued as targets for therapeutic cancer vaccines,” she noted.

CT antigens are also being evaluated for their role in oncogenesis, she added. Recapitulation of portions of the germline gene-expression might contribute characteristic features to the neoplastic phenotype, including immortality, invasiveness, immune evasion, and metastatic capacity.

According to Dr. Humberson, PRAME can be used to differentiate comingled nevus and melanoma, to distinguish between nevoid melanoma and nevus, and for melanoma margin assessment in sun-damaged skin. One potential pitfall is that sun-damaged melanocytes may express PRAME. “The older the person and the more sun damage [they have], the more likely you are to see this, but the melanocytes won’t be grouped, they’ll be scattered,” she said.

Another pitfall is that less than 15% of nevi may express PRAME. “PRAME can be expressed in scars, so if you’re looking at a spindle cell lesion, be aware that you might be looking at a scar if you’re seeing PRAME expression,” she added. She also noted that PRAME immunohistochemistry (IHC) expression is not a prognostic biomarker in thin melanomas.

If fewer than 25% of cells in a melanocytic lesion express PRAME, most published assessments of PRAME IHC favor nevi as the diagnosis. “If more than 75% are expressing it, it favors melanoma,” Dr. Humberson said. “There’s a big category in between. It’s not that 30% is more likely benign or that 60% is more likely malignant; you can’t really depend upon [PRAME] if you’re in this range.”

A diagnostic accuracy study found that when more than 75% of cells express PRAME, the marker has a sensitivity of 0.63 and a specificity of 0.97.

Selected PRAME-related published references she recommended include: J Cutan Pathol. 2021;48(9):1115-23; Diagnostics. 2022 Sep 9; 12(9):2197, and J Cutan Pathol. 2022;49(9):829-32.

Dr. Humberson reported having no relevant disclosures.

SAN DIEGO – As with many markers for the evaluation of challenging melanocytic lesions, preferentially expressed antigen in melanoma (PRAME) has its benefits and drawbacks, according to Cora Humberson, MD.

“I’m a fan, but there are issues with it,” Dr. Humberson, dermatopathology coordinator in the department of pathology at Scripps MD Anderson Cancer Center, San Diego, said at the annual Cutaneous Malignancy Update. “It’s all in how you use it.”

PRAME is part of the cancer/testis (CT) antigens, of which more than 40 have now been identified. They are encoded by genes that are normally expressed only in the human germ line, but are also expressed in various tumor types, including melanoma and carcinomas of the bladder, lung, and liver. “The biological function of these antigens is not fully understood, but they may act as a repressor of retinoic acid, potentially inhibiting differentiation, inhibiting proliferation arrest – things that we associate with malignancy,” she said at the meeting, which was hosted by Scripps MD Anderson Cancer Center. “These immunogenic proteins are being pursued as targets for therapeutic cancer vaccines,” she noted.

CT antigens are also being evaluated for their role in oncogenesis, she added. Recapitulation of portions of the germline gene-expression might contribute characteristic features to the neoplastic phenotype, including immortality, invasiveness, immune evasion, and metastatic capacity.

According to Dr. Humberson, PRAME can be used to differentiate comingled nevus and melanoma, to distinguish between nevoid melanoma and nevus, and for melanoma margin assessment in sun-damaged skin. One potential pitfall is that sun-damaged melanocytes may express PRAME. “The older the person and the more sun damage [they have], the more likely you are to see this, but the melanocytes won’t be grouped, they’ll be scattered,” she said.

Another pitfall is that less than 15% of nevi may express PRAME. “PRAME can be expressed in scars, so if you’re looking at a spindle cell lesion, be aware that you might be looking at a scar if you’re seeing PRAME expression,” she added. She also noted that PRAME immunohistochemistry (IHC) expression is not a prognostic biomarker in thin melanomas.

If fewer than 25% of cells in a melanocytic lesion express PRAME, most published assessments of PRAME IHC favor nevi as the diagnosis. “If more than 75% are expressing it, it favors melanoma,” Dr. Humberson said. “There’s a big category in between. It’s not that 30% is more likely benign or that 60% is more likely malignant; you can’t really depend upon [PRAME] if you’re in this range.”

A diagnostic accuracy study found that when more than 75% of cells express PRAME, the marker has a sensitivity of 0.63 and a specificity of 0.97.

Selected PRAME-related published references she recommended include: J Cutan Pathol. 2021;48(9):1115-23; Diagnostics. 2022 Sep 9; 12(9):2197, and J Cutan Pathol. 2022;49(9):829-32.

Dr. Humberson reported having no relevant disclosures.

A panel of advisers to the Food and Drug Administration unanimously supported an effort to simplify COVID-19 vaccinations, with the aim of developing a one-dose approach – perhaps annually – for the general population.

The FDA is looking to give clearer direction to vaccine makers about future development of COVID-19 vaccines. The plan is to narrow down the current complex landscape of options for vaccinations, and thus help increase use of these shots. 

COVID remains a serious threat, causing about 4,000 deaths a week recently, according to the Centers for Disease Control and Prevention. The 21 members of the Vaccines and Related Biological Products Advisory Committee (VRBPAC) on Jan. 26 voted unanimously “yes” on a single question posed by the FDA: 

“Does the committee recommend harmonizing the vaccine strain composition of primary series and booster doses in the U.S. to a single composition, e.g., the composition for all vaccines administered currently would be a bivalent vaccine (Original plus Omicron BA.4/BA.5)?”

In other words, would it be better to have one vaccine potentially combining multiple strains of the virus, instead of multiple vaccines – such as a two-shot primary series then a booster containing different combinations of viral strains.

The FDA will consider the panel’s advice as it outlines new strategies for keeping ahead of the evolving virus.

In explaining their support for the FDA plan, panel members said they hoped that a simpler regime would aid in persuading more people to get COVID vaccines.

Pamela McInnes, DDS, MSc, noted that it’s difficult to explain to many people that the vaccine works to protect them from more severe illness if they contract COVID after getting vaccinated. 

“That is a real challenge,” said Dr. McInness, retired deputy director of the National Center for Advancing Translational Sciences at the National Institutes of Health.

“The message that you would have gotten more sick and landed in the hospital resonates with me, but I’m not sure if it resonates with” many people who become infected, she said.
 

The plan

In the briefing document for the meeting, the FDA outlined a plan for transitioning from the current complex landscape of COVID-19 vaccines to a single vaccine composition for the primary series and booster vaccination. 

This would require harmonizing the strain composition of all COVID-19 vaccines; simplifying the immunization schedule for future vaccination campaigns to administer a two-dose series in certain young children and in older adults and persons with compromised immunity, and only one dose in all other individuals; and establishing a process for vaccine strain selection recommendations, similar in many ways to that used for seasonal influenza vaccines, based on prevailing and predicted variants that would take place by June to allow for vaccine production by September.

During the discussion, though, questions arose about the June target date. Given the production schedule for some vaccines, that date might need to shift, said Jerry Weir, PhD, director of the division of viral products at FDA’s Center for Biologics Evaluation and Research. 

“We’re all just going to have to maintain flexibility,” Dr. Weir said, adding that there is not yet a “good pattern” established for updating these vaccines. 
 

Increasing vaccination rates

There was broad consensus about the need to boost public support for COVID-19 vaccinations. While about 81% of the U.S. population has had at least one dose of this vaccine, only 15.3% have had an updated bivalent booster dose, according to the CDC.

“Anything that results in better public communication would be extremely valuable,” said committee member Henry H. Bernstein, DO, MHCM, of the Zucker School of Medicine at Hofstra/Northwell Health in Hempstead, N.Y.

But it’s unclear what expectations will be prioritized for the COVID vaccine program, he said. 

“Realistically, I don’t think we can have it all – less infection, less transmission, less severe disease, and less long COVID,” Dr. Bernstein said. “And that seems to be a major challenge for public messaging.” 
 

Panelists press for more data 

Other committee members also pressed for clearer targets in evaluating the goals for COVID vaccines, and for more robust data. 

Like his fellow VRBPAC members, Cody Meissner, MD, of Dartmouth’s Geisel School of Medicine, Hanover, N.H., supported a move toward harmonizing the strains used in different companies’ vaccines. But he added that it wasn’t clear yet how frequently they should be administered. 

“We need to see what happens with disease burden,” Dr. Meissner said. “We may or may not need annual vaccination. It’s just awfully early, it seems to me, in this process to answer that question.”

Among those serving on VRBPAC was one of the FDA’s more vocal critics on these points, Paul A. Offit, MD, a vaccine expert from Children’s Hospital of Philadelphia. Dr. Offit, for example, joined former FDA officials in writing a November opinion article for the Washington Post, arguing that the evidence for boosters for healthy younger adults was not strong.

At the Jan. 26 meeting, he supported the drive toward simplification of COVID vaccine schedules, while arguing for more data about how well these products are working.

“This virus is going to be with us for years, if not decades, and there will always be vulnerable groups who are going to be hospitalized and killed by the virus,” Dr. Offit said.

The CDC needs to provide more information about the characteristics of people being hospitalized with COVID infections, including their ages and comorbidities as well as details about their vaccine history, he said. In addition, academic researchers should provide a clearer picture of what immunological predictors are at play in increasing people’s risk from COVID.

“Then and only then can we really best make the decision about who gets vaccinated with what and when,” Dr. Offit said. 

VRBPAC member Ofer Levy, MD, PhD, also urged the FDA to press for a collection of more robust and detailed information about the immune response to COVID-19 vaccinations, such as a deeper look at what’s happening with antibodies.

“I hope FDA will continue to reflect on how to best take this information forward, and encourage – or require – sponsors to gather more information in a standardized way across these different arms of the human immune system,” Dr. Levy said. “So we keep learning and keep doing this better.”

In recapping the panel’s suggestions at the end of the meeting, Peter Marks, MD, PhD, the director of the FDA’s Center for Biologics Evaluation and Research, addressed the requests made during the day’s meeting about better data on how the vaccines work. 

“We heard loud and clear that we need to use a data-driven approach to get to the simplest possible scheme that we can for vaccination,” Dr. Marks said. “And it should be as simple as possible but not oversimplified, a little bit like they say about Mozart’s music.”

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

A panel of advisers to the Food and Drug Administration unanimously supported an effort to simplify COVID-19 vaccinations, with the aim of developing a one-dose approach – perhaps annually – for the general population.

The FDA is looking to give clearer direction to vaccine makers about future development of COVID-19 vaccines. The plan is to narrow down the current complex landscape of options for vaccinations, and thus help increase use of these shots. 

COVID remains a serious threat, causing about 4,000 deaths a week recently, according to the Centers for Disease Control and Prevention. The 21 members of the Vaccines and Related Biological Products Advisory Committee (VRBPAC) on Jan. 26 voted unanimously “yes” on a single question posed by the FDA: 

“Does the committee recommend harmonizing the vaccine strain composition of primary series and booster doses in the U.S. to a single composition, e.g., the composition for all vaccines administered currently would be a bivalent vaccine (Original plus Omicron BA.4/BA.5)?”

In other words, would it be better to have one vaccine potentially combining multiple strains of the virus, instead of multiple vaccines – such as a two-shot primary series then a booster containing different combinations of viral strains.

The FDA will consider the panel’s advice as it outlines new strategies for keeping ahead of the evolving virus.

In explaining their support for the FDA plan, panel members said they hoped that a simpler regime would aid in persuading more people to get COVID vaccines.

Pamela McInnes, DDS, MSc, noted that it’s difficult to explain to many people that the vaccine works to protect them from more severe illness if they contract COVID after getting vaccinated. 

“That is a real challenge,” said Dr. McInness, retired deputy director of the National Center for Advancing Translational Sciences at the National Institutes of Health.

“The message that you would have gotten more sick and landed in the hospital resonates with me, but I’m not sure if it resonates with” many people who become infected, she said.
 

The plan

In the briefing document for the meeting, the FDA outlined a plan for transitioning from the current complex landscape of COVID-19 vaccines to a single vaccine composition for the primary series and booster vaccination. 

This would require harmonizing the strain composition of all COVID-19 vaccines; simplifying the immunization schedule for future vaccination campaigns to administer a two-dose series in certain young children and in older adults and persons with compromised immunity, and only one dose in all other individuals; and establishing a process for vaccine strain selection recommendations, similar in many ways to that used for seasonal influenza vaccines, based on prevailing and predicted variants that would take place by June to allow for vaccine production by September.

During the discussion, though, questions arose about the June target date. Given the production schedule for some vaccines, that date might need to shift, said Jerry Weir, PhD, director of the division of viral products at FDA’s Center for Biologics Evaluation and Research. 

“We’re all just going to have to maintain flexibility,” Dr. Weir said, adding that there is not yet a “good pattern” established for updating these vaccines. 
 

Increasing vaccination rates

There was broad consensus about the need to boost public support for COVID-19 vaccinations. While about 81% of the U.S. population has had at least one dose of this vaccine, only 15.3% have had an updated bivalent booster dose, according to the CDC.

“Anything that results in better public communication would be extremely valuable,” said committee member Henry H. Bernstein, DO, MHCM, of the Zucker School of Medicine at Hofstra/Northwell Health in Hempstead, N.Y.

But it’s unclear what expectations will be prioritized for the COVID vaccine program, he said. 

“Realistically, I don’t think we can have it all – less infection, less transmission, less severe disease, and less long COVID,” Dr. Bernstein said. “And that seems to be a major challenge for public messaging.” 
 

Panelists press for more data 

Other committee members also pressed for clearer targets in evaluating the goals for COVID vaccines, and for more robust data. 

Like his fellow VRBPAC members, Cody Meissner, MD, of Dartmouth’s Geisel School of Medicine, Hanover, N.H., supported a move toward harmonizing the strains used in different companies’ vaccines. But he added that it wasn’t clear yet how frequently they should be administered. 

“We need to see what happens with disease burden,” Dr. Meissner said. “We may or may not need annual vaccination. It’s just awfully early, it seems to me, in this process to answer that question.”

Among those serving on VRBPAC was one of the FDA’s more vocal critics on these points, Paul A. Offit, MD, a vaccine expert from Children’s Hospital of Philadelphia. Dr. Offit, for example, joined former FDA officials in writing a November opinion article for the Washington Post, arguing that the evidence for boosters for healthy younger adults was not strong.

At the Jan. 26 meeting, he supported the drive toward simplification of COVID vaccine schedules, while arguing for more data about how well these products are working.

“This virus is going to be with us for years, if not decades, and there will always be vulnerable groups who are going to be hospitalized and killed by the virus,” Dr. Offit said.

The CDC needs to provide more information about the characteristics of people being hospitalized with COVID infections, including their ages and comorbidities as well as details about their vaccine history, he said. In addition, academic researchers should provide a clearer picture of what immunological predictors are at play in increasing people’s risk from COVID.

“Then and only then can we really best make the decision about who gets vaccinated with what and when,” Dr. Offit said. 

VRBPAC member Ofer Levy, MD, PhD, also urged the FDA to press for a collection of more robust and detailed information about the immune response to COVID-19 vaccinations, such as a deeper look at what’s happening with antibodies.

“I hope FDA will continue to reflect on how to best take this information forward, and encourage – or require – sponsors to gather more information in a standardized way across these different arms of the human immune system,” Dr. Levy said. “So we keep learning and keep doing this better.”

In recapping the panel’s suggestions at the end of the meeting, Peter Marks, MD, PhD, the director of the FDA’s Center for Biologics Evaluation and Research, addressed the requests made during the day’s meeting about better data on how the vaccines work. 

“We heard loud and clear that we need to use a data-driven approach to get to the simplest possible scheme that we can for vaccination,” Dr. Marks said. “And it should be as simple as possible but not oversimplified, a little bit like they say about Mozart’s music.”

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

A panel of advisers to the Food and Drug Administration unanimously supported an effort to simplify COVID-19 vaccinations, with the aim of developing a one-dose approach – perhaps annually – for the general population.

The FDA is looking to give clearer direction to vaccine makers about future development of COVID-19 vaccines. The plan is to narrow down the current complex landscape of options for vaccinations, and thus help increase use of these shots. 

COVID remains a serious threat, causing about 4,000 deaths a week recently, according to the Centers for Disease Control and Prevention. The 21 members of the Vaccines and Related Biological Products Advisory Committee (VRBPAC) on Jan. 26 voted unanimously “yes” on a single question posed by the FDA: 

“Does the committee recommend harmonizing the vaccine strain composition of primary series and booster doses in the U.S. to a single composition, e.g., the composition for all vaccines administered currently would be a bivalent vaccine (Original plus Omicron BA.4/BA.5)?”

In other words, would it be better to have one vaccine potentially combining multiple strains of the virus, instead of multiple vaccines – such as a two-shot primary series then a booster containing different combinations of viral strains.

The FDA will consider the panel’s advice as it outlines new strategies for keeping ahead of the evolving virus.

In explaining their support for the FDA plan, panel members said they hoped that a simpler regime would aid in persuading more people to get COVID vaccines.

Pamela McInnes, DDS, MSc, noted that it’s difficult to explain to many people that the vaccine works to protect them from more severe illness if they contract COVID after getting vaccinated. 

“That is a real challenge,” said Dr. McInness, retired deputy director of the National Center for Advancing Translational Sciences at the National Institutes of Health.

“The message that you would have gotten more sick and landed in the hospital resonates with me, but I’m not sure if it resonates with” many people who become infected, she said.
 

The plan

In the briefing document for the meeting, the FDA outlined a plan for transitioning from the current complex landscape of COVID-19 vaccines to a single vaccine composition for the primary series and booster vaccination. 

This would require harmonizing the strain composition of all COVID-19 vaccines; simplifying the immunization schedule for future vaccination campaigns to administer a two-dose series in certain young children and in older adults and persons with compromised immunity, and only one dose in all other individuals; and establishing a process for vaccine strain selection recommendations, similar in many ways to that used for seasonal influenza vaccines, based on prevailing and predicted variants that would take place by June to allow for vaccine production by September.

During the discussion, though, questions arose about the June target date. Given the production schedule for some vaccines, that date might need to shift, said Jerry Weir, PhD, director of the division of viral products at FDA’s Center for Biologics Evaluation and Research. 

“We’re all just going to have to maintain flexibility,” Dr. Weir said, adding that there is not yet a “good pattern” established for updating these vaccines. 
 

Increasing vaccination rates

There was broad consensus about the need to boost public support for COVID-19 vaccinations. While about 81% of the U.S. population has had at least one dose of this vaccine, only 15.3% have had an updated bivalent booster dose, according to the CDC.

“Anything that results in better public communication would be extremely valuable,” said committee member Henry H. Bernstein, DO, MHCM, of the Zucker School of Medicine at Hofstra/Northwell Health in Hempstead, N.Y.

But it’s unclear what expectations will be prioritized for the COVID vaccine program, he said. 

“Realistically, I don’t think we can have it all – less infection, less transmission, less severe disease, and less long COVID,” Dr. Bernstein said. “And that seems to be a major challenge for public messaging.” 
 

Panelists press for more data 

Other committee members also pressed for clearer targets in evaluating the goals for COVID vaccines, and for more robust data. 

Like his fellow VRBPAC members, Cody Meissner, MD, of Dartmouth’s Geisel School of Medicine, Hanover, N.H., supported a move toward harmonizing the strains used in different companies’ vaccines. But he added that it wasn’t clear yet how frequently they should be administered. 

“We need to see what happens with disease burden,” Dr. Meissner said. “We may or may not need annual vaccination. It’s just awfully early, it seems to me, in this process to answer that question.”

Among those serving on VRBPAC was one of the FDA’s more vocal critics on these points, Paul A. Offit, MD, a vaccine expert from Children’s Hospital of Philadelphia. Dr. Offit, for example, joined former FDA officials in writing a November opinion article for the Washington Post, arguing that the evidence for boosters for healthy younger adults was not strong.

At the Jan. 26 meeting, he supported the drive toward simplification of COVID vaccine schedules, while arguing for more data about how well these products are working.

“This virus is going to be with us for years, if not decades, and there will always be vulnerable groups who are going to be hospitalized and killed by the virus,” Dr. Offit said.

The CDC needs to provide more information about the characteristics of people being hospitalized with COVID infections, including their ages and comorbidities as well as details about their vaccine history, he said. In addition, academic researchers should provide a clearer picture of what immunological predictors are at play in increasing people’s risk from COVID.

“Then and only then can we really best make the decision about who gets vaccinated with what and when,” Dr. Offit said. 

VRBPAC member Ofer Levy, MD, PhD, also urged the FDA to press for a collection of more robust and detailed information about the immune response to COVID-19 vaccinations, such as a deeper look at what’s happening with antibodies.

“I hope FDA will continue to reflect on how to best take this information forward, and encourage – or require – sponsors to gather more information in a standardized way across these different arms of the human immune system,” Dr. Levy said. “So we keep learning and keep doing this better.”

In recapping the panel’s suggestions at the end of the meeting, Peter Marks, MD, PhD, the director of the FDA’s Center for Biologics Evaluation and Research, addressed the requests made during the day’s meeting about better data on how the vaccines work. 

“We heard loud and clear that we need to use a data-driven approach to get to the simplest possible scheme that we can for vaccination,” Dr. Marks said. “And it should be as simple as possible but not oversimplified, a little bit like they say about Mozart’s music.”

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

If you could go back in time 75 years and tell Dr. Sidney Farber, the developer of methotrexate for cancer therapy, that 21st-century medicine would utilize his specially designed drug more in rheumatology than oncology, he might be surprised. He might scratch his head even more, hearing of his drug sparking interest in still other medical fields, like cardiology.

But drug repurposing is not so uncommon. One classic example is aspirin. Once the most common pain medication and used also in rheumatology, aspirin now finds a range of applications, from colorectal cancer to the prevention of cardiovascular and cerebrovascular thrombosis. Minoxidil is another example, developed for hypertension but used today mostly to stop hair loss. Perhaps most ironic is thalidomide, utilized today for leprosy and multiple myeloma, yet actually contraindicated for its original application, nausea of pregnancy.

Courtesy NIH

Methotrexate, thus, has much in common with other medical treatments, and yet its origin story is as unique and as fascinating as the story of Dr. Farber himself. While this is a rheumatology article, it’s also a story about the origin of a particular rheumatologic treatment, and so the story of that origin will take us mostly through a discussion of hematologic malignancy and of the clinical researcher who dared search for a cure.

Born in 1903, in Buffalo, New York, third of fourteen children of Jewish immigrants from Poland, Dr. Farber grew up in a household that was crowded but academically rigorous. His father, Simon, routinely brought home textbooks, assigning each child a book to read and on which to write a report. His mother, Matilda, was as devoted as her husband to raising the children to succeed in their adopted new country. Upstairs, the children were permitted to speak Yiddish, but downstairs they were required to use only English and German.

As a teen, Dr. Farber lived through the 1918 influenza pandemic that killed at least 50 million people worldwide, including more than 2,000 Buffalonians. This probably helped motivate him to study medicine, but with antisemitism overt in the America of the early 1920s, securing admission to a U.S. medical school was close to impossible. So, in what now seems like the greatest of ironies, Dr. Farber began medical studies in Germany, then transferred for the second year to a U.S. program that seemed adequate – Harvard Medical School, from which he graduated in 1927. From there, he trained as a pathologist, focusing ultimately on pediatric pathology. But, frustrated by case after case of malignancy, whose young victims he’d often have to autopsy, Dr. Farber decided that he wanted to advance the pitiful state of cancer therapeutics, especially for hematologic malignancy.

This was a tall order in the 1930s and early 1940s, when cancer therapeutics consisted only of surgical resection and very primitive forms of radiation therapy. Applicable only to neoplasia that was localized, these options were useless against malignancies in the blood, like acute lymphoblastic leukemia (ALL), but by January 1948 there was at least one glimmer of hope. At that time, one patient with ALL, 2-year-old Robert Sandler, was too ill to join his twin brother Elliott for snow play outside their home in the Dorchester section of Boston. Diagnosed back in August, Robert had suffered multiple episodes of fever, anemia, and thrombocytopenia. His illness had enlarged his spleen dramatically and caused pathologic bone fractures with excruciating bone pain, and for a while he couldn’t walk because of pressure on his lower spinal cord. All of this was the result of uncontrolled mitosis and cell division of lymphoblasts, immature lymphocytes. By December, these out-of-control cells had elevated the boy’s white blood cell count to a peak of 70,000/mcL, more than six times the high end of the normal range (4,500-11,000/mcL). This had happened despite treatment with an experimental drug, developed at Boston Children’s Hospital by Dr. Farber and his team, working on the assumption that inhibition of folate metabolism should slow the growth of tumor cells. On Dec. 28, however, Dr. Farber had switched the child to a new drug with a chemical structure just slightly different from the other agent’s.

Merely another chemical modification in a series of attempts by the research team, the new drug, aminopterin, was not expected to do anything dramatic, but Dr. Farber and the team had come such a long way since the middle of 1947, when he’d actually done the opposite of what he was doing now. On the basis of British research from India showing folic acid deficiency as the basis of a common type of anemia in malnourished people, Dr. Farber had reasoned that children with leukemia, who also suffered from anemia, might also benefit from folic acid supplementation. Even without prior rodent testing, Dr. Farber had tried giving the nutrient to patients with ALL, a strategy made possible by the presence of a spectacular chemist working on folic acid synthesis at Farber’s own hospital to help combat folate deficiency. Born into a poor Brahmin family in India, the chemist, Dr. Yellapragada SubbaRow, had begun life with so much stacked against him as to appear even less likely during childhood than the young Dr. Farber to grow up to make major contributions to medicine. Going through childhood with death all around him, Dr. SubbaRow was motivated to study medicine, but getting into medical school had been an uphill fight, given his family’s economic difficulty. Knowing that he’d also face discrimination on account of his low status after receiving admission to a medical program, SubbaRow could have made things a bit easier for himself by living within the norms of the British Imperial system, but as a supporter of Mohandas Gandhi’s nationalist movement, he boycotted British goods. As a medical student, this meant doing things like wearing Indian-made surgical gloves, instead of the English products that were expected of the students. Such actions led Dr. SubbaRow to receive a kind of second-rate medical degree, rather than the prestigious MBBS.

The political situation also led Dr. SubbaRow to emigrate to the United States, where, ironically, his medical degree initially was taken less seriously than it had been taken in his British-occupied homeland. He thus worked in the capacity of a hospital night porter at Peter Bent Brigham Hospital (the future Brigham and Women’s Hospital), doing menial tasks like changing sheets to make ends meet. He studied, however, and made enough of an impression to gain admission to the same institution that also admitted Farber through the backdoor, Harvard Medical School. This launched him into a research career in which he not only would be instrumental in developing folate antagonists and other classes of drugs, but also would make him the codiscoverer of the role of creatine phosphate and ATP in cellular energy metabolism. Sadly, even after obtaining his top-notch American credentials and contributing through his research to what you might say is a good chunk of the biochemistry pathways that first year medical students memorize without ever learning who discovered them, Dr. SubbaRow still faced prejudice for the rest of his life, which turned out to last only until the age of 53. To add insult to injury, he is rarely remembered for his role.

Dr. Farber proceeded with the folic acid supplementation idea in patients with ALL, even though ALL caused a hypoproliferative anemia, whereas anemia from folate deficiency was megaloblastic, meaning that erythrocytes were produced but they were oversized and dysfunctional. Tragically, folic acid had accelerated the disease process in children with ALL, but the process of chemical experimentation aimed at synthesizing folate also produced some compounds that mimicked chemical precursors of folate in a way that made them antifolates, inhibitors of folate metabolism. If folic acid made lymphoblasts grow faster, Dr. Farber had reasoned that antifolates should inhibit their growth. He thus asked the chemistry lab to focus on folate inhibitors. Testing aminopterin, beginning with young Robert Sandler at the end of December, is what proved his hypothesis correct. By late January, aminopterin had brought the child’s WBC count down to the realm of 12,000, just slightly above normal, with symptoms and signs abating as well, and by February, the child could play with his twin brother. It was not a cure; malignant lymphoblasts still showed on microscopy of Robert’s blood. While he and some 15 other children whom Dr. Farber treated in this early trial would all succumb to ALL, they experienced remission lasting several months.

This was a big deal because the concept of chemotherapy was based only on serendipitous observations of WBC counts dropping in soldiers exposed to nitrogen mustard gas during World War I and during an incident in World War II, yet aminopterin had been designed from the ground up. Though difficult to synthesize in quantities, there was no reason for Dr. Farber’s team not to keep tweaking the drug, and so they did. Replacing one hydrogen atom with a methyl group, they turned it into methotrexate.

Proving easier to synthesize and less toxic, methotrexate would become a workhorse for chemotherapy over the next couple of decades, but the capability of both methotrexate and aminopterin to blunt the growth of white blood cells and other cells did not go unnoticed outside the realm of oncology. As early as the 1950s, dermatologists were using aminopterin to treat psoriasis. This led to the approval of methotrexate for psoriasis in 1972.

Meanwhile, like oncology, infectious diseases, aviation medicine, and so many other areas of practice, rheumatology had gotten a major boost from research stemming from World War II. During the war, Dr. Philip Hench of the Mayo Clinic developed cortisone, which pilots used to stay alert and energetic during trans-Atlantic flights. But it turned out that cortisone had a powerful immunosuppressive effect that dramatically improved rheumatoid arthritis, leading Dr. Hench to receive the Nobel Prize in Physiology or Medicine in 1950. By the end of the 1950s, however, the significant side effects of long-term corticosteroid therapy were very clear, so over the next few decades there was a major effort to develop different treatments for RA and other rheumatologic diseases.

Top on the list of such agents was methotrexate, developed for RA in part by Dr. Michael Weinblatt of Brigham and Women’s Hospital in Boston. In the 1980s, Dr. Weinblatt published the first clinical trial showing the benefits of methotrexate for RA patients. This has since developed into a standard treatment, noticeably different from the original malignancy application in that it is a low-dose regimen. Patients taking methotrexate for RA typically receive no more than 25 mg per week orally, and often much less. Rheumatology today includes expertise in keeping long-term methotrexate therapy safe by monitoring liver function and through other routine tests. The routine nature of the therapy has brought methotrexate to the point of beckoning in a realm that Dr. Farber might not have predicted in his wildest imagination: cardiology. This is on account of the growing appreciation of the inflammatory process in the pathophysiology of atherosclerotic heart disease.

Meanwhile, being an antimetabolite, harmful to rapidly dividing cells, the danger of methotrexate to the embryo and fetus was recognized early. This made methotrexate off-limits to pregnant women, yet it also has made the drug useful as an abortifacient. Though not as good for medication abortion in unwanted but thriving pregnancies, where mifepristone/misoprostol has become the regimen of choice, methotrexate has become a workhorse in other obstetrical settings, such as for ending ectopic pregnancy.

Looking at the present and into the future, the potential for this very old medication looks wide open, as if it could go in any direction, so let’s wind up the discussion with the thought that we may be in for some surprises. Rather than jumping deeply into any rheumatologic issue, we spent most of this article weaving through other medical issues, but does this not make today’s story fairly analogous to rheumatology itself?

Dr. Warmflash is a physician from Portland, Ore. He reported no conflicts of interest.

This story was updated 2/10/2023.

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

If you could go back in time 75 years and tell Dr. Sidney Farber, the developer of methotrexate for cancer therapy, that 21st-century medicine would utilize his specially designed drug more in rheumatology than oncology, he might be surprised. He might scratch his head even more, hearing of his drug sparking interest in still other medical fields, like cardiology.

But drug repurposing is not so uncommon. One classic example is aspirin. Once the most common pain medication and used also in rheumatology, aspirin now finds a range of applications, from colorectal cancer to the prevention of cardiovascular and cerebrovascular thrombosis. Minoxidil is another example, developed for hypertension but used today mostly to stop hair loss. Perhaps most ironic is thalidomide, utilized today for leprosy and multiple myeloma, yet actually contraindicated for its original application, nausea of pregnancy.

Courtesy NIH

Methotrexate, thus, has much in common with other medical treatments, and yet its origin story is as unique and as fascinating as the story of Dr. Farber himself. While this is a rheumatology article, it’s also a story about the origin of a particular rheumatologic treatment, and so the story of that origin will take us mostly through a discussion of hematologic malignancy and of the clinical researcher who dared search for a cure.

Born in 1903, in Buffalo, New York, third of fourteen children of Jewish immigrants from Poland, Dr. Farber grew up in a household that was crowded but academically rigorous. His father, Simon, routinely brought home textbooks, assigning each child a book to read and on which to write a report. His mother, Matilda, was as devoted as her husband to raising the children to succeed in their adopted new country. Upstairs, the children were permitted to speak Yiddish, but downstairs they were required to use only English and German.

As a teen, Dr. Farber lived through the 1918 influenza pandemic that killed at least 50 million people worldwide, including more than 2,000 Buffalonians. This probably helped motivate him to study medicine, but with antisemitism overt in the America of the early 1920s, securing admission to a U.S. medical school was close to impossible. So, in what now seems like the greatest of ironies, Dr. Farber began medical studies in Germany, then transferred for the second year to a U.S. program that seemed adequate – Harvard Medical School, from which he graduated in 1927. From there, he trained as a pathologist, focusing ultimately on pediatric pathology. But, frustrated by case after case of malignancy, whose young victims he’d often have to autopsy, Dr. Farber decided that he wanted to advance the pitiful state of cancer therapeutics, especially for hematologic malignancy.

This was a tall order in the 1930s and early 1940s, when cancer therapeutics consisted only of surgical resection and very primitive forms of radiation therapy. Applicable only to neoplasia that was localized, these options were useless against malignancies in the blood, like acute lymphoblastic leukemia (ALL), but by January 1948 there was at least one glimmer of hope. At that time, one patient with ALL, 2-year-old Robert Sandler, was too ill to join his twin brother Elliott for snow play outside their home in the Dorchester section of Boston. Diagnosed back in August, Robert had suffered multiple episodes of fever, anemia, and thrombocytopenia. His illness had enlarged his spleen dramatically and caused pathologic bone fractures with excruciating bone pain, and for a while he couldn’t walk because of pressure on his lower spinal cord. All of this was the result of uncontrolled mitosis and cell division of lymphoblasts, immature lymphocytes. By December, these out-of-control cells had elevated the boy’s white blood cell count to a peak of 70,000/mcL, more than six times the high end of the normal range (4,500-11,000/mcL). This had happened despite treatment with an experimental drug, developed at Boston Children’s Hospital by Dr. Farber and his team, working on the assumption that inhibition of folate metabolism should slow the growth of tumor cells. On Dec. 28, however, Dr. Farber had switched the child to a new drug with a chemical structure just slightly different from the other agent’s.

Merely another chemical modification in a series of attempts by the research team, the new drug, aminopterin, was not expected to do anything dramatic, but Dr. Farber and the team had come such a long way since the middle of 1947, when he’d actually done the opposite of what he was doing now. On the basis of British research from India showing folic acid deficiency as the basis of a common type of anemia in malnourished people, Dr. Farber had reasoned that children with leukemia, who also suffered from anemia, might also benefit from folic acid supplementation. Even without prior rodent testing, Dr. Farber had tried giving the nutrient to patients with ALL, a strategy made possible by the presence of a spectacular chemist working on folic acid synthesis at Farber’s own hospital to help combat folate deficiency. Born into a poor Brahmin family in India, the chemist, Dr. Yellapragada SubbaRow, had begun life with so much stacked against him as to appear even less likely during childhood than the young Dr. Farber to grow up to make major contributions to medicine. Going through childhood with death all around him, Dr. SubbaRow was motivated to study medicine, but getting into medical school had been an uphill fight, given his family’s economic difficulty. Knowing that he’d also face discrimination on account of his low status after receiving admission to a medical program, SubbaRow could have made things a bit easier for himself by living within the norms of the British Imperial system, but as a supporter of Mohandas Gandhi’s nationalist movement, he boycotted British goods. As a medical student, this meant doing things like wearing Indian-made surgical gloves, instead of the English products that were expected of the students. Such actions led Dr. SubbaRow to receive a kind of second-rate medical degree, rather than the prestigious MBBS.

The political situation also led Dr. SubbaRow to emigrate to the United States, where, ironically, his medical degree initially was taken less seriously than it had been taken in his British-occupied homeland. He thus worked in the capacity of a hospital night porter at Peter Bent Brigham Hospital (the future Brigham and Women’s Hospital), doing menial tasks like changing sheets to make ends meet. He studied, however, and made enough of an impression to gain admission to the same institution that also admitted Farber through the backdoor, Harvard Medical School. This launched him into a research career in which he not only would be instrumental in developing folate antagonists and other classes of drugs, but also would make him the codiscoverer of the role of creatine phosphate and ATP in cellular energy metabolism. Sadly, even after obtaining his top-notch American credentials and contributing through his research to what you might say is a good chunk of the biochemistry pathways that first year medical students memorize without ever learning who discovered them, Dr. SubbaRow still faced prejudice for the rest of his life, which turned out to last only until the age of 53. To add insult to injury, he is rarely remembered for his role.

Dr. Farber proceeded with the folic acid supplementation idea in patients with ALL, even though ALL caused a hypoproliferative anemia, whereas anemia from folate deficiency was megaloblastic, meaning that erythrocytes were produced but they were oversized and dysfunctional. Tragically, folic acid had accelerated the disease process in children with ALL, but the process of chemical experimentation aimed at synthesizing folate also produced some compounds that mimicked chemical precursors of folate in a way that made them antifolates, inhibitors of folate metabolism. If folic acid made lymphoblasts grow faster, Dr. Farber had reasoned that antifolates should inhibit their growth. He thus asked the chemistry lab to focus on folate inhibitors. Testing aminopterin, beginning with young Robert Sandler at the end of December, is what proved his hypothesis correct. By late January, aminopterin had brought the child’s WBC count down to the realm of 12,000, just slightly above normal, with symptoms and signs abating as well, and by February, the child could play with his twin brother. It was not a cure; malignant lymphoblasts still showed on microscopy of Robert’s blood. While he and some 15 other children whom Dr. Farber treated in this early trial would all succumb to ALL, they experienced remission lasting several months.

This was a big deal because the concept of chemotherapy was based only on serendipitous observations of WBC counts dropping in soldiers exposed to nitrogen mustard gas during World War I and during an incident in World War II, yet aminopterin had been designed from the ground up. Though difficult to synthesize in quantities, there was no reason for Dr. Farber’s team not to keep tweaking the drug, and so they did. Replacing one hydrogen atom with a methyl group, they turned it into methotrexate.

Proving easier to synthesize and less toxic, methotrexate would become a workhorse for chemotherapy over the next couple of decades, but the capability of both methotrexate and aminopterin to blunt the growth of white blood cells and other cells did not go unnoticed outside the realm of oncology. As early as the 1950s, dermatologists were using aminopterin to treat psoriasis. This led to the approval of methotrexate for psoriasis in 1972.

Meanwhile, like oncology, infectious diseases, aviation medicine, and so many other areas of practice, rheumatology had gotten a major boost from research stemming from World War II. During the war, Dr. Philip Hench of the Mayo Clinic developed cortisone, which pilots used to stay alert and energetic during trans-Atlantic flights. But it turned out that cortisone had a powerful immunosuppressive effect that dramatically improved rheumatoid arthritis, leading Dr. Hench to receive the Nobel Prize in Physiology or Medicine in 1950. By the end of the 1950s, however, the significant side effects of long-term corticosteroid therapy were very clear, so over the next few decades there was a major effort to develop different treatments for RA and other rheumatologic diseases.

Top on the list of such agents was methotrexate, developed for RA in part by Dr. Michael Weinblatt of Brigham and Women’s Hospital in Boston. In the 1980s, Dr. Weinblatt published the first clinical trial showing the benefits of methotrexate for RA patients. This has since developed into a standard treatment, noticeably different from the original malignancy application in that it is a low-dose regimen. Patients taking methotrexate for RA typically receive no more than 25 mg per week orally, and often much less. Rheumatology today includes expertise in keeping long-term methotrexate therapy safe by monitoring liver function and through other routine tests. The routine nature of the therapy has brought methotrexate to the point of beckoning in a realm that Dr. Farber might not have predicted in his wildest imagination: cardiology. This is on account of the growing appreciation of the inflammatory process in the pathophysiology of atherosclerotic heart disease.

Meanwhile, being an antimetabolite, harmful to rapidly dividing cells, the danger of methotrexate to the embryo and fetus was recognized early. This made methotrexate off-limits to pregnant women, yet it also has made the drug useful as an abortifacient. Though not as good for medication abortion in unwanted but thriving pregnancies, where mifepristone/misoprostol has become the regimen of choice, methotrexate has become a workhorse in other obstetrical settings, such as for ending ectopic pregnancy.

Looking at the present and into the future, the potential for this very old medication looks wide open, as if it could go in any direction, so let’s wind up the discussion with the thought that we may be in for some surprises. Rather than jumping deeply into any rheumatologic issue, we spent most of this article weaving through other medical issues, but does this not make today’s story fairly analogous to rheumatology itself?

Dr. Warmflash is a physician from Portland, Ore. He reported no conflicts of interest.

This story was updated 2/10/2023.

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

If you could go back in time 75 years and tell Dr. Sidney Farber, the developer of methotrexate for cancer therapy, that 21st-century medicine would utilize his specially designed drug more in rheumatology than oncology, he might be surprised. He might scratch his head even more, hearing of his drug sparking interest in still other medical fields, like cardiology.

But drug repurposing is not so uncommon. One classic example is aspirin. Once the most common pain medication and used also in rheumatology, aspirin now finds a range of applications, from colorectal cancer to the prevention of cardiovascular and cerebrovascular thrombosis. Minoxidil is another example, developed for hypertension but used today mostly to stop hair loss. Perhaps most ironic is thalidomide, utilized today for leprosy and multiple myeloma, yet actually contraindicated for its original application, nausea of pregnancy.

Courtesy NIH

Methotrexate, thus, has much in common with other medical treatments, and yet its origin story is as unique and as fascinating as the story of Dr. Farber himself. While this is a rheumatology article, it’s also a story about the origin of a particular rheumatologic treatment, and so the story of that origin will take us mostly through a discussion of hematologic malignancy and of the clinical researcher who dared search for a cure.

Born in 1903, in Buffalo, New York, third of fourteen children of Jewish immigrants from Poland, Dr. Farber grew up in a household that was crowded but academically rigorous. His father, Simon, routinely brought home textbooks, assigning each child a book to read and on which to write a report. His mother, Matilda, was as devoted as her husband to raising the children to succeed in their adopted new country. Upstairs, the children were permitted to speak Yiddish, but downstairs they were required to use only English and German.

As a teen, Dr. Farber lived through the 1918 influenza pandemic that killed at least 50 million people worldwide, including more than 2,000 Buffalonians. This probably helped motivate him to study medicine, but with antisemitism overt in the America of the early 1920s, securing admission to a U.S. medical school was close to impossible. So, in what now seems like the greatest of ironies, Dr. Farber began medical studies in Germany, then transferred for the second year to a U.S. program that seemed adequate – Harvard Medical School, from which he graduated in 1927. From there, he trained as a pathologist, focusing ultimately on pediatric pathology. But, frustrated by case after case of malignancy, whose young victims he’d often have to autopsy, Dr. Farber decided that he wanted to advance the pitiful state of cancer therapeutics, especially for hematologic malignancy.

This was a tall order in the 1930s and early 1940s, when cancer therapeutics consisted only of surgical resection and very primitive forms of radiation therapy. Applicable only to neoplasia that was localized, these options were useless against malignancies in the blood, like acute lymphoblastic leukemia (ALL), but by January 1948 there was at least one glimmer of hope. At that time, one patient with ALL, 2-year-old Robert Sandler, was too ill to join his twin brother Elliott for snow play outside their home in the Dorchester section of Boston. Diagnosed back in August, Robert had suffered multiple episodes of fever, anemia, and thrombocytopenia. His illness had enlarged his spleen dramatically and caused pathologic bone fractures with excruciating bone pain, and for a while he couldn’t walk because of pressure on his lower spinal cord. All of this was the result of uncontrolled mitosis and cell division of lymphoblasts, immature lymphocytes. By December, these out-of-control cells had elevated the boy’s white blood cell count to a peak of 70,000/mcL, more than six times the high end of the normal range (4,500-11,000/mcL). This had happened despite treatment with an experimental drug, developed at Boston Children’s Hospital by Dr. Farber and his team, working on the assumption that inhibition of folate metabolism should slow the growth of tumor cells. On Dec. 28, however, Dr. Farber had switched the child to a new drug with a chemical structure just slightly different from the other agent’s.

Merely another chemical modification in a series of attempts by the research team, the new drug, aminopterin, was not expected to do anything dramatic, but Dr. Farber and the team had come such a long way since the middle of 1947, when he’d actually done the opposite of what he was doing now. On the basis of British research from India showing folic acid deficiency as the basis of a common type of anemia in malnourished people, Dr. Farber had reasoned that children with leukemia, who also suffered from anemia, might also benefit from folic acid supplementation. Even without prior rodent testing, Dr. Farber had tried giving the nutrient to patients with ALL, a strategy made possible by the presence of a spectacular chemist working on folic acid synthesis at Farber’s own hospital to help combat folate deficiency. Born into a poor Brahmin family in India, the chemist, Dr. Yellapragada SubbaRow, had begun life with so much stacked against him as to appear even less likely during childhood than the young Dr. Farber to grow up to make major contributions to medicine. Going through childhood with death all around him, Dr. SubbaRow was motivated to study medicine, but getting into medical school had been an uphill fight, given his family’s economic difficulty. Knowing that he’d also face discrimination on account of his low status after receiving admission to a medical program, SubbaRow could have made things a bit easier for himself by living within the norms of the British Imperial system, but as a supporter of Mohandas Gandhi’s nationalist movement, he boycotted British goods. As a medical student, this meant doing things like wearing Indian-made surgical gloves, instead of the English products that were expected of the students. Such actions led Dr. SubbaRow to receive a kind of second-rate medical degree, rather than the prestigious MBBS.

The political situation also led Dr. SubbaRow to emigrate to the United States, where, ironically, his medical degree initially was taken less seriously than it had been taken in his British-occupied homeland. He thus worked in the capacity of a hospital night porter at Peter Bent Brigham Hospital (the future Brigham and Women’s Hospital), doing menial tasks like changing sheets to make ends meet. He studied, however, and made enough of an impression to gain admission to the same institution that also admitted Farber through the backdoor, Harvard Medical School. This launched him into a research career in which he not only would be instrumental in developing folate antagonists and other classes of drugs, but also would make him the codiscoverer of the role of creatine phosphate and ATP in cellular energy metabolism. Sadly, even after obtaining his top-notch American credentials and contributing through his research to what you might say is a good chunk of the biochemistry pathways that first year medical students memorize without ever learning who discovered them, Dr. SubbaRow still faced prejudice for the rest of his life, which turned out to last only until the age of 53. To add insult to injury, he is rarely remembered for his role.

Dr. Farber proceeded with the folic acid supplementation idea in patients with ALL, even though ALL caused a hypoproliferative anemia, whereas anemia from folate deficiency was megaloblastic, meaning that erythrocytes were produced but they were oversized and dysfunctional. Tragically, folic acid had accelerated the disease process in children with ALL, but the process of chemical experimentation aimed at synthesizing folate also produced some compounds that mimicked chemical precursors of folate in a way that made them antifolates, inhibitors of folate metabolism. If folic acid made lymphoblasts grow faster, Dr. Farber had reasoned that antifolates should inhibit their growth. He thus asked the chemistry lab to focus on folate inhibitors. Testing aminopterin, beginning with young Robert Sandler at the end of December, is what proved his hypothesis correct. By late January, aminopterin had brought the child’s WBC count down to the realm of 12,000, just slightly above normal, with symptoms and signs abating as well, and by February, the child could play with his twin brother. It was not a cure; malignant lymphoblasts still showed on microscopy of Robert’s blood. While he and some 15 other children whom Dr. Farber treated in this early trial would all succumb to ALL, they experienced remission lasting several months.

This was a big deal because the concept of chemotherapy was based only on serendipitous observations of WBC counts dropping in soldiers exposed to nitrogen mustard gas during World War I and during an incident in World War II, yet aminopterin had been designed from the ground up. Though difficult to synthesize in quantities, there was no reason for Dr. Farber’s team not to keep tweaking the drug, and so they did. Replacing one hydrogen atom with a methyl group, they turned it into methotrexate.

Proving easier to synthesize and less toxic, methotrexate would become a workhorse for chemotherapy over the next couple of decades, but the capability of both methotrexate and aminopterin to blunt the growth of white blood cells and other cells did not go unnoticed outside the realm of oncology. As early as the 1950s, dermatologists were using aminopterin to treat psoriasis. This led to the approval of methotrexate for psoriasis in 1972.

Meanwhile, like oncology, infectious diseases, aviation medicine, and so many other areas of practice, rheumatology had gotten a major boost from research stemming from World War II. During the war, Dr. Philip Hench of the Mayo Clinic developed cortisone, which pilots used to stay alert and energetic during trans-Atlantic flights. But it turned out that cortisone had a powerful immunosuppressive effect that dramatically improved rheumatoid arthritis, leading Dr. Hench to receive the Nobel Prize in Physiology or Medicine in 1950. By the end of the 1950s, however, the significant side effects of long-term corticosteroid therapy were very clear, so over the next few decades there was a major effort to develop different treatments for RA and other rheumatologic diseases.

Top on the list of such agents was methotrexate, developed for RA in part by Dr. Michael Weinblatt of Brigham and Women’s Hospital in Boston. In the 1980s, Dr. Weinblatt published the first clinical trial showing the benefits of methotrexate for RA patients. This has since developed into a standard treatment, noticeably different from the original malignancy application in that it is a low-dose regimen. Patients taking methotrexate for RA typically receive no more than 25 mg per week orally, and often much less. Rheumatology today includes expertise in keeping long-term methotrexate therapy safe by monitoring liver function and through other routine tests. The routine nature of the therapy has brought methotrexate to the point of beckoning in a realm that Dr. Farber might not have predicted in his wildest imagination: cardiology. This is on account of the growing appreciation of the inflammatory process in the pathophysiology of atherosclerotic heart disease.

Meanwhile, being an antimetabolite, harmful to rapidly dividing cells, the danger of methotrexate to the embryo and fetus was recognized early. This made methotrexate off-limits to pregnant women, yet it also has made the drug useful as an abortifacient. Though not as good for medication abortion in unwanted but thriving pregnancies, where mifepristone/misoprostol has become the regimen of choice, methotrexate has become a workhorse in other obstetrical settings, such as for ending ectopic pregnancy.

Looking at the present and into the future, the potential for this very old medication looks wide open, as if it could go in any direction, so let’s wind up the discussion with the thought that we may be in for some surprises. Rather than jumping deeply into any rheumatologic issue, we spent most of this article weaving through other medical issues, but does this not make today’s story fairly analogous to rheumatology itself?

Dr. Warmflash is a physician from Portland, Ore. He reported no conflicts of interest.

This story was updated 2/10/2023.

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

Key clinical point: The majority of topical and systemic therapies for atopic dermatitis (AD) effectively reduced pruritus, the most common patient-reported symptom.

Major finding: Topical and systemic treatments led to a mean reduction of 3.32 (99% CI 2.32-4.33) and 3.07 (99% CI 2.58-3.56) points in pruritus score, respectively. Wet-wrap therapy using halometasone (−4.75 points) was the most effective topical treatment, and 30 mg upadacitinib (−4.90 points) was the most effective systemic treatment.

Study details: This study analyzed 22 studies that included patients aged ≥ 10 years with AD who received topical or systemic treatments.

Disclosures: No information on the source of funding was provided. Two authors reported ties with various organizations.

Source: Rodriguez-Le Roy Y et al. Efficacy of topical and systemic treatments for atopic dermatitis on pruritus: A systematic literature review and meta-analysis. Front Med (Lausanne). 2022;9:1079323 (Dec 22). Doi: 10.3389/fmed.2022.1079323

Key clinical point: The majority of topical and systemic therapies for atopic dermatitis (AD) effectively reduced pruritus, the most common patient-reported symptom.

Major finding: Topical and systemic treatments led to a mean reduction of 3.32 (99% CI 2.32-4.33) and 3.07 (99% CI 2.58-3.56) points in pruritus score, respectively. Wet-wrap therapy using halometasone (−4.75 points) was the most effective topical treatment, and 30 mg upadacitinib (−4.90 points) was the most effective systemic treatment.

Study details: This study analyzed 22 studies that included patients aged ≥ 10 years with AD who received topical or systemic treatments.

Disclosures: No information on the source of funding was provided. Two authors reported ties with various organizations.

Source: Rodriguez-Le Roy Y et al. Efficacy of topical and systemic treatments for atopic dermatitis on pruritus: A systematic literature review and meta-analysis. Front Med (Lausanne). 2022;9:1079323 (Dec 22). Doi: 10.3389/fmed.2022.1079323

Key clinical point: The majority of topical and systemic therapies for atopic dermatitis (AD) effectively reduced pruritus, the most common patient-reported symptom.

Major finding: Topical and systemic treatments led to a mean reduction of 3.32 (99% CI 2.32-4.33) and 3.07 (99% CI 2.58-3.56) points in pruritus score, respectively. Wet-wrap therapy using halometasone (−4.75 points) was the most effective topical treatment, and 30 mg upadacitinib (−4.90 points) was the most effective systemic treatment.

Study details: This study analyzed 22 studies that included patients aged ≥ 10 years with AD who received topical or systemic treatments.

Disclosures: No information on the source of funding was provided. Two authors reported ties with various organizations.

Source: Rodriguez-Le Roy Y et al. Efficacy of topical and systemic treatments for atopic dermatitis on pruritus: A systematic literature review and meta-analysis. Front Med (Lausanne). 2022;9:1079323 (Dec 22). Doi: 10.3389/fmed.2022.1079323

Key clinical point: Children and adolescents with atopic dermatitis (AD) are at an increased risk of developing juvenile idiopathic arthritis (JIA).

Major finding: Patients with AD vs control individuals had an increased risk for JIA (adjusted odds ratio [aOR] 1.58; 95% CI 1.41-1.77), especially for psoriatic JIA (aOR 2.75; 95% CI 1.64-4.60).

Study details: This population-based register study included 70,584 patients with AD aged <18 years at the time of the first AD diagnosis and 270,783 age- and sex-matched control individuals without AD.

Disclosures: This study did not receive any funding. Some authors declared serving as investigators for or receiving educational grants, speaker honoraria, or consultation honoraria from various organizations.

Source: Keskitalo PL et al. Juvenile idiopathic arthritis in children and adolescents with atopic dermatitis: A Finnish nationwide registry study. J Am Acad Dermatol. 2023 (Jan 3). Doi: 10.1016/j.jaad.2022.12.025

Key clinical point: Children and adolescents with atopic dermatitis (AD) are at an increased risk of developing juvenile idiopathic arthritis (JIA).

Major finding: Patients with AD vs control individuals had an increased risk for JIA (adjusted odds ratio [aOR] 1.58; 95% CI 1.41-1.77), especially for psoriatic JIA (aOR 2.75; 95% CI 1.64-4.60).

Study details: This population-based register study included 70,584 patients with AD aged <18 years at the time of the first AD diagnosis and 270,783 age- and sex-matched control individuals without AD.

Disclosures: This study did not receive any funding. Some authors declared serving as investigators for or receiving educational grants, speaker honoraria, or consultation honoraria from various organizations.

Source: Keskitalo PL et al. Juvenile idiopathic arthritis in children and adolescents with atopic dermatitis: A Finnish nationwide registry study. J Am Acad Dermatol. 2023 (Jan 3). Doi: 10.1016/j.jaad.2022.12.025

Key clinical point: Children and adolescents with atopic dermatitis (AD) are at an increased risk of developing juvenile idiopathic arthritis (JIA).

Major finding: Patients with AD vs control individuals had an increased risk for JIA (adjusted odds ratio [aOR] 1.58; 95% CI 1.41-1.77), especially for psoriatic JIA (aOR 2.75; 95% CI 1.64-4.60).

Study details: This population-based register study included 70,584 patients with AD aged <18 years at the time of the first AD diagnosis and 270,783 age- and sex-matched control individuals without AD.

Disclosures: This study did not receive any funding. Some authors declared serving as investigators for or receiving educational grants, speaker honoraria, or consultation honoraria from various organizations.

Source: Keskitalo PL et al. Juvenile idiopathic arthritis in children and adolescents with atopic dermatitis: A Finnish nationwide registry study. J Am Acad Dermatol. 2023 (Jan 3). Doi: 10.1016/j.jaad.2022.12.025

Key clinical point: Treatment of patients with atopic dermatitis (AD) with dupilumab is not associated with the development of primary or recurrent malignancy.

Major finding: Dupilumab-exposed and unexposed patients had comparable incidence rates of primary malignancies (adjusted hazard ratio [aHR], 1.010; P  =  .946), keratinocyte cancers (aHR, 0.994; P  =  .973), and recurrent cancers (aHR, 0.828; P  =  .758) per 1,000 person-years.

Study details: This single-center 5-year retrospective study included 9,707 patients with AD, of which 1,627 patients received dupilumab treatment.

Disclosures: This study did not receive any funding. Some authors declared serving as consultants for and/or receiving research funds from various organizations.

Source: Owji S et al. No association between dupilumab use and short-term cancer development in atopic dermatitis patients. J Allergy Clin Immunol Pract. 2022 (Dec 26). Doi: 10.1016/j.jaip.2022.12.018.

Key clinical point: Treatment of patients with atopic dermatitis (AD) with dupilumab is not associated with the development of primary or recurrent malignancy.

Major finding: Dupilumab-exposed and unexposed patients had comparable incidence rates of primary malignancies (adjusted hazard ratio [aHR], 1.010; P  =  .946), keratinocyte cancers (aHR, 0.994; P  =  .973), and recurrent cancers (aHR, 0.828; P  =  .758) per 1,000 person-years.

Study details: This single-center 5-year retrospective study included 9,707 patients with AD, of which 1,627 patients received dupilumab treatment.

Disclosures: This study did not receive any funding. Some authors declared serving as consultants for and/or receiving research funds from various organizations.

Source: Owji S et al. No association between dupilumab use and short-term cancer development in atopic dermatitis patients. J Allergy Clin Immunol Pract. 2022 (Dec 26). Doi: 10.1016/j.jaip.2022.12.018.

Key clinical point: Treatment of patients with atopic dermatitis (AD) with dupilumab is not associated with the development of primary or recurrent malignancy.

Major finding: Dupilumab-exposed and unexposed patients had comparable incidence rates of primary malignancies (adjusted hazard ratio [aHR], 1.010; P  =  .946), keratinocyte cancers (aHR, 0.994; P  =  .973), and recurrent cancers (aHR, 0.828; P  =  .758) per 1,000 person-years.

Study details: This single-center 5-year retrospective study included 9,707 patients with AD, of which 1,627 patients received dupilumab treatment.

Disclosures: This study did not receive any funding. Some authors declared serving as consultants for and/or receiving research funds from various organizations.

Source: Owji S et al. No association between dupilumab use and short-term cancer development in atopic dermatitis patients. J Allergy Clin Immunol Pract. 2022 (Dec 26). Doi: 10.1016/j.jaip.2022.12.018.

Key clinical point: Fatigue is a common symptom in children with atopic dermatitis (AD), particularly those with moderate-to-severe AD, and thus should be considered in clinical practice and trials.

Major finding: Most children had no (38.6%) or mild (32.1%) parent-proxy fatigue, but 27.2% had moderate fatigue and 2.0% had severe fatigue. Higher proportions of children with moderate-to-severe parent-proxy Patient-Reported Outcome Measurement Information System Pediatric fatigue scores were those with moderate (25.7%/1.4%) and severe (39.3%/5.4%) AD vs mild AD (18.0%/0.0%), as determined by Investigator’s Global Assessment, especially those with 5-6 (44.4%/0.0%) or 7 (44.2%/5.2%) nights of sleep disturbance from eczema.

Study details: This cross-sectional observational study included 248 children aged 0-17 years with AD.

Disclosures: This study was funded by the US National Institute of Arthritis and Musculoskeletal and Skin Diseases. The authors declared no conflicts of interest.

Source: Rangel SM et al. Prevalence and associations of fatigue in childhood atopic dermatitis: A cross-sectional study. J Eur Acad Dermatol Venereol. 2022 (Dec 21). Doi: 10.1111/jdv.18819

Key clinical point: Fatigue is a common symptom in children with atopic dermatitis (AD), particularly those with moderate-to-severe AD, and thus should be considered in clinical practice and trials.

Major finding: Most children had no (38.6%) or mild (32.1%) parent-proxy fatigue, but 27.2% had moderate fatigue and 2.0% had severe fatigue. Higher proportions of children with moderate-to-severe parent-proxy Patient-Reported Outcome Measurement Information System Pediatric fatigue scores were those with moderate (25.7%/1.4%) and severe (39.3%/5.4%) AD vs mild AD (18.0%/0.0%), as determined by Investigator’s Global Assessment, especially those with 5-6 (44.4%/0.0%) or 7 (44.2%/5.2%) nights of sleep disturbance from eczema.

Study details: This cross-sectional observational study included 248 children aged 0-17 years with AD.

Disclosures: This study was funded by the US National Institute of Arthritis and Musculoskeletal and Skin Diseases. The authors declared no conflicts of interest.

Source: Rangel SM et al. Prevalence and associations of fatigue in childhood atopic dermatitis: A cross-sectional study. J Eur Acad Dermatol Venereol. 2022 (Dec 21). Doi: 10.1111/jdv.18819

Key clinical point: Fatigue is a common symptom in children with atopic dermatitis (AD), particularly those with moderate-to-severe AD, and thus should be considered in clinical practice and trials.

Major finding: Most children had no (38.6%) or mild (32.1%) parent-proxy fatigue, but 27.2% had moderate fatigue and 2.0% had severe fatigue. Higher proportions of children with moderate-to-severe parent-proxy Patient-Reported Outcome Measurement Information System Pediatric fatigue scores were those with moderate (25.7%/1.4%) and severe (39.3%/5.4%) AD vs mild AD (18.0%/0.0%), as determined by Investigator’s Global Assessment, especially those with 5-6 (44.4%/0.0%) or 7 (44.2%/5.2%) nights of sleep disturbance from eczema.

Study details: This cross-sectional observational study included 248 children aged 0-17 years with AD.

Disclosures: This study was funded by the US National Institute of Arthritis and Musculoskeletal and Skin Diseases. The authors declared no conflicts of interest.

Source: Rangel SM et al. Prevalence and associations of fatigue in childhood atopic dermatitis: A cross-sectional study. J Eur Acad Dermatol Venereol. 2022 (Dec 21). Doi: 10.1111/jdv.18819

Key clinical point: Dupilumab maintained efficacy against moderate-to-severe atopic dermatitis (AD) with no new safety signals over 104 weeks; however, it was ineffective in treating head-and-neck AD.

Major finding: The median Eczema Area and Severity Index score decreased significantly from 18.0 at baseline to 2.0 at week 52 and 1.7 at week 104 (both P < .0001); 35% of patients reported an adverse event, with conjunctivitis being the most common (25%). Although the 104-week treatment persistence rate was 86%, the majority of patients still had AD in the head-and-neck area.

Study details: This real-world study included 347 adult patients with moderate-to-severe AD who received dupilumab and were registered in the prospective Severe and ChRonic Atopic dermatitis Treatment CoHort (SCRATCH) registry during 2017-2022.

Disclosures: The SCRATCH registry was supported by research grants from Sanofi-Genzyme and Pfizer. Some authors reported ties with various organizations, including Sanofi-Genzyme and Pfizer.

Source: Vittrup I et al. A nationwide 104 weeks real-world study of dupilumab in adults with atopic dermatitis: Ineffectiveness in head-and-neck dermatitis. J Eur Acad Dermatol Venereol. 2023 (Jan 6). Doi: 10.1111/jdv.18849

Key clinical point: Dupilumab maintained efficacy against moderate-to-severe atopic dermatitis (AD) with no new safety signals over 104 weeks; however, it was ineffective in treating head-and-neck AD.

Major finding: The median Eczema Area and Severity Index score decreased significantly from 18.0 at baseline to 2.0 at week 52 and 1.7 at week 104 (both P < .0001); 35% of patients reported an adverse event, with conjunctivitis being the most common (25%). Although the 104-week treatment persistence rate was 86%, the majority of patients still had AD in the head-and-neck area.

Study details: This real-world study included 347 adult patients with moderate-to-severe AD who received dupilumab and were registered in the prospective Severe and ChRonic Atopic dermatitis Treatment CoHort (SCRATCH) registry during 2017-2022.

Disclosures: The SCRATCH registry was supported by research grants from Sanofi-Genzyme and Pfizer. Some authors reported ties with various organizations, including Sanofi-Genzyme and Pfizer.

Source: Vittrup I et al. A nationwide 104 weeks real-world study of dupilumab in adults with atopic dermatitis: Ineffectiveness in head-and-neck dermatitis. J Eur Acad Dermatol Venereol. 2023 (Jan 6). Doi: 10.1111/jdv.18849

Key clinical point: Dupilumab maintained efficacy against moderate-to-severe atopic dermatitis (AD) with no new safety signals over 104 weeks; however, it was ineffective in treating head-and-neck AD.

Major finding: The median Eczema Area and Severity Index score decreased significantly from 18.0 at baseline to 2.0 at week 52 and 1.7 at week 104 (both P < .0001); 35% of patients reported an adverse event, with conjunctivitis being the most common (25%). Although the 104-week treatment persistence rate was 86%, the majority of patients still had AD in the head-and-neck area.

Study details: This real-world study included 347 adult patients with moderate-to-severe AD who received dupilumab and were registered in the prospective Severe and ChRonic Atopic dermatitis Treatment CoHort (SCRATCH) registry during 2017-2022.

Disclosures: The SCRATCH registry was supported by research grants from Sanofi-Genzyme and Pfizer. Some authors reported ties with various organizations, including Sanofi-Genzyme and Pfizer.

Source: Vittrup I et al. A nationwide 104 weeks real-world study of dupilumab in adults with atopic dermatitis: Ineffectiveness in head-and-neck dermatitis. J Eur Acad Dermatol Venereol. 2023 (Jan 6). Doi: 10.1111/jdv.18849