This transcript has been edited for clarity.

I am far from the only doctor, and certainly far from the only oncologist, to recently comment on the topic of Maintenance of Certification. Of course, this is happening in a wider debate about our relationship as subspecialists to the American Board of Internal Medicine, and what they deem acceptable for the recertification of doctors in practice.

My take is that every oncologist is already engaged in lifelong learning. One of the things I tell my patients is that if I practiced exactly the way I was trained to practice — and I had a very good fellowship program with superb faculty – if I practiced the way they taught me, it would now be malpractice. I finished my fellowship in 2012, just over a decade ago. The rate of progress in the interim is simply staggering. It looks so different now than it did then.

For instance, 2011 was my first experience ever using a form of immunotherapy. It was an anti-CTLA4 agent, ipilimumab, and I was treating metastatic melanoma. I learned in that instance just how effective these drugs can be, but also how toxic they can be. Ever since then, I’ve been refining my use of immunotherapy. We do that iteratively. We do that as we encounter patients and as we try to meet their needs.

I do understand that the ABIM is saying they want an independent governing body to legislate that process. I think the reason this is stuck in the craw of so many oncologists is that we demonstrate our commitment to continuing medical education all the time.

I’m recording this in my office, which is separate from the space where I see patients. I see patients in a different group of exam rooms for their privacy and it’s a better setup for aspects of the physical encounter. Not a single patient has ever asked to come into my office and see my diplomas, and I sometimes wonder if I keep them here mostly as a visual cue to myself, sort of an antidote to ward off imposter syndrome and remind myself, Oh yeah – I earned these. I earned these through formal training.

Then something happens once you finish your training, whether it’s residency or fellowship, and you become an attending. I think you feel a weight of responsibility, the responsibility of independent learning. All of us are doing this. We have to do this. The field is moving along at such a rapid clip that it’s essentially built into what we do that we are going to keep up. In fact, channels such as the various aspects of social media are a way I curate my own information feed so I can stay up to speed and not feel like I’m drowning in a deluge of new data.

But what’s hard to demonstrate to the ABIM is that [this learning] is already happening. I think we can do it if we submit our records of CME credits that we formally accrue. The reason this is such an almost insult to oncologists in practice is because it is a necessary part of our day-to-day existence to keep apprised of developments so we can apply them to patient care.

One litmus test of attending a medical conference like the annual meeting of the American Society of Clinical Oncology is to ask oneself, When I go back to clinic, is this meeting going to change the way that I take care of patients? The answer almost invariably these days is yes. I go to multiple meetings per year, and I think it’s the exception, not the rule, that I return home and nothing changes in my management patterns. Again, this process is happening whether the ABIM recognizes it or not.

Lastly, I sat down in the fall of 2022 and I did my recertification. I looked at the span of all the things that had happened between 2012, when I first sat for my board examination in medical oncology, and 2022. It was staggering. I think the reason that it wasn’t such an overwhelming amount of information to review is that I had actually been accreting it slowly and gradually, month by month, year by year throughout that decade.

Again, it’s necessary that the ABIM hear us, hear oncologists, and know that of all the medical subspecialties they govern, it is basically already an essential task of our day-to-day professional existence that we engage in lifelong learning. To suggest otherwise really paints us as outdated. The reason that matters so much is that if we’re not up-to-date, then we are underserving our patients.

Mark A. Lewis, MD, is director of gastrointestinal oncology at Intermountain Healthcare in Salt Lake City. He reported no relevant conflicts of interest.

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

This transcript has been edited for clarity.

I am far from the only doctor, and certainly far from the only oncologist, to recently comment on the topic of Maintenance of Certification. Of course, this is happening in a wider debate about our relationship as subspecialists to the American Board of Internal Medicine, and what they deem acceptable for the recertification of doctors in practice.

My take is that every oncologist is already engaged in lifelong learning. One of the things I tell my patients is that if I practiced exactly the way I was trained to practice — and I had a very good fellowship program with superb faculty – if I practiced the way they taught me, it would now be malpractice. I finished my fellowship in 2012, just over a decade ago. The rate of progress in the interim is simply staggering. It looks so different now than it did then.

For instance, 2011 was my first experience ever using a form of immunotherapy. It was an anti-CTLA4 agent, ipilimumab, and I was treating metastatic melanoma. I learned in that instance just how effective these drugs can be, but also how toxic they can be. Ever since then, I’ve been refining my use of immunotherapy. We do that iteratively. We do that as we encounter patients and as we try to meet their needs.

I do understand that the ABIM is saying they want an independent governing body to legislate that process. I think the reason this is stuck in the craw of so many oncologists is that we demonstrate our commitment to continuing medical education all the time.

I’m recording this in my office, which is separate from the space where I see patients. I see patients in a different group of exam rooms for their privacy and it’s a better setup for aspects of the physical encounter. Not a single patient has ever asked to come into my office and see my diplomas, and I sometimes wonder if I keep them here mostly as a visual cue to myself, sort of an antidote to ward off imposter syndrome and remind myself, Oh yeah – I earned these. I earned these through formal training.

Then something happens once you finish your training, whether it’s residency or fellowship, and you become an attending. I think you feel a weight of responsibility, the responsibility of independent learning. All of us are doing this. We have to do this. The field is moving along at such a rapid clip that it’s essentially built into what we do that we are going to keep up. In fact, channels such as the various aspects of social media are a way I curate my own information feed so I can stay up to speed and not feel like I’m drowning in a deluge of new data.

But what’s hard to demonstrate to the ABIM is that [this learning] is already happening. I think we can do it if we submit our records of CME credits that we formally accrue. The reason this is such an almost insult to oncologists in practice is because it is a necessary part of our day-to-day existence to keep apprised of developments so we can apply them to patient care.

One litmus test of attending a medical conference like the annual meeting of the American Society of Clinical Oncology is to ask oneself, When I go back to clinic, is this meeting going to change the way that I take care of patients? The answer almost invariably these days is yes. I go to multiple meetings per year, and I think it’s the exception, not the rule, that I return home and nothing changes in my management patterns. Again, this process is happening whether the ABIM recognizes it or not.

Lastly, I sat down in the fall of 2022 and I did my recertification. I looked at the span of all the things that had happened between 2012, when I first sat for my board examination in medical oncology, and 2022. It was staggering. I think the reason that it wasn’t such an overwhelming amount of information to review is that I had actually been accreting it slowly and gradually, month by month, year by year throughout that decade.

Again, it’s necessary that the ABIM hear us, hear oncologists, and know that of all the medical subspecialties they govern, it is basically already an essential task of our day-to-day professional existence that we engage in lifelong learning. To suggest otherwise really paints us as outdated. The reason that matters so much is that if we’re not up-to-date, then we are underserving our patients.

Mark A. Lewis, MD, is director of gastrointestinal oncology at Intermountain Healthcare in Salt Lake City. He reported no relevant conflicts of interest.

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

This transcript has been edited for clarity.

I am far from the only doctor, and certainly far from the only oncologist, to recently comment on the topic of Maintenance of Certification. Of course, this is happening in a wider debate about our relationship as subspecialists to the American Board of Internal Medicine, and what they deem acceptable for the recertification of doctors in practice.

My take is that every oncologist is already engaged in lifelong learning. One of the things I tell my patients is that if I practiced exactly the way I was trained to practice — and I had a very good fellowship program with superb faculty – if I practiced the way they taught me, it would now be malpractice. I finished my fellowship in 2012, just over a decade ago. The rate of progress in the interim is simply staggering. It looks so different now than it did then.

For instance, 2011 was my first experience ever using a form of immunotherapy. It was an anti-CTLA4 agent, ipilimumab, and I was treating metastatic melanoma. I learned in that instance just how effective these drugs can be, but also how toxic they can be. Ever since then, I’ve been refining my use of immunotherapy. We do that iteratively. We do that as we encounter patients and as we try to meet their needs.

I do understand that the ABIM is saying they want an independent governing body to legislate that process. I think the reason this is stuck in the craw of so many oncologists is that we demonstrate our commitment to continuing medical education all the time.

I’m recording this in my office, which is separate from the space where I see patients. I see patients in a different group of exam rooms for their privacy and it’s a better setup for aspects of the physical encounter. Not a single patient has ever asked to come into my office and see my diplomas, and I sometimes wonder if I keep them here mostly as a visual cue to myself, sort of an antidote to ward off imposter syndrome and remind myself, Oh yeah – I earned these. I earned these through formal training.

Then something happens once you finish your training, whether it’s residency or fellowship, and you become an attending. I think you feel a weight of responsibility, the responsibility of independent learning. All of us are doing this. We have to do this. The field is moving along at such a rapid clip that it’s essentially built into what we do that we are going to keep up. In fact, channels such as the various aspects of social media are a way I curate my own information feed so I can stay up to speed and not feel like I’m drowning in a deluge of new data.

But what’s hard to demonstrate to the ABIM is that [this learning] is already happening. I think we can do it if we submit our records of CME credits that we formally accrue. The reason this is such an almost insult to oncologists in practice is because it is a necessary part of our day-to-day existence to keep apprised of developments so we can apply them to patient care.

One litmus test of attending a medical conference like the annual meeting of the American Society of Clinical Oncology is to ask oneself, When I go back to clinic, is this meeting going to change the way that I take care of patients? The answer almost invariably these days is yes. I go to multiple meetings per year, and I think it’s the exception, not the rule, that I return home and nothing changes in my management patterns. Again, this process is happening whether the ABIM recognizes it or not.

Lastly, I sat down in the fall of 2022 and I did my recertification. I looked at the span of all the things that had happened between 2012, when I first sat for my board examination in medical oncology, and 2022. It was staggering. I think the reason that it wasn’t such an overwhelming amount of information to review is that I had actually been accreting it slowly and gradually, month by month, year by year throughout that decade.

Again, it’s necessary that the ABIM hear us, hear oncologists, and know that of all the medical subspecialties they govern, it is basically already an essential task of our day-to-day professional existence that we engage in lifelong learning. To suggest otherwise really paints us as outdated. The reason that matters so much is that if we’re not up-to-date, then we are underserving our patients.

Mark A. Lewis, MD, is director of gastrointestinal oncology at Intermountain Healthcare in Salt Lake City. He reported no relevant conflicts of interest.

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

WASHINGTON – Multiple biologic failure in a minority of patients with psoriasis may have several causes, from genetic endotypes and immunologic factors to lower serum drug levels, the presence of anti-drug antibody levels, female sex, and certain comorbidities, Wilson Liao, MD, said at the annual research symposium of the National Psoriasis Foundation.

“Tough-to-treat psoriasis remains a challenge despite newer therapies ... Why do we still have this sub-population of patients who seem to be refractory?” said Dr. Liao, professor and associate vice chair of research in the department of dermatology at the University of California, San Francisco, who coauthored a 2015-2022 prospective cohort analysis that documented about 6% of patients failing two or more biologic agents of different mechanistic classes.

“These patients are really suffering,” he said. “We need to have better guidelines and treatment algorithms for these patients.”

A significant number of patients with psoriatic arthritis (PsA), meanwhile, are inadequate responders to tumor necrosis factor (TNF) inhibition, Christopher T. Ritchlin, MD, PhD, professor of medicine in the division of allergy/immunology and rheumatology and the Center of Musculoskeletal Research at the University of Rochester (N.Y.), said during another session at the meeting.

The long-term “persistence,” or usage, of first-line biologics in patients with PsA – and of second-line biologics in patients who failed one TNF-inhibitor – is low, but the literature offers little information on the reasons for TNF-inhibitor discontinuation, said Dr. Ritchlin, who coauthored a perspective piece in Arthritis & Rheumatology on managing the patient with PsA who fails one TNF inhibitor.

Dr. Ritchlin and his coauthors were asked to provide evidence-informed advice and algorithms, but the task was difficult. “It’s hard to know what to recommend for the next step if we don’t know why patients failed the first,” he said. “The point is, we need more data. [Clinical trials] are not recording the kind of information we need.”
 

Anti-drug antibodies, genetics, other factors in psoriasis

Research shows that in large cohorts, “all the biologics do seem to lose efficacy over time,” said Dr. Liao, who directs the UCSF Psoriasis and Skin Treatment Center. “Some are better than others, but we do see a loss of effectiveness over time.”

A cohort study published in 2022 in JAMA Dermatology, for instance, documented declining “drug survival” associated with ineffectiveness during 2 years of treatment for each of five biologics studied (adalimumab [Humira], ustekinumab [Stelara], secukinumab [Cosentyx], guselkumab [Tremfya], and ixekizumab [Taltz]).

“There have been a number of theories put forward” as to why that’s the case, including lower serum drug levels, “which of course can be related to anti-drug antibody production,” he said.

He pointed to two studies of ustekinumab: One prospective observational cohort study that reported an association of lower early drug levels of the IL-12/23 receptor antagonist with lower Psoriasis Area and Severity Index (PASI) scores, and another observational study that documented an association between anti-drug antibody positivity with lower ustekinumab levels and impaired clinical response.

“We also now know ... that there are genetic endotypes in psoriasis, and that patients who are [HLA-C*06:02]-positive tend to respond a little better to drugs like ustekinumab, and those who are [HLA-C*06:02]-negative tend to do a little better with the TNF inhibitors,” Dr. Liao said. The human leukocyte antigen (HLA) allele HLA-C*06:02 is associated with susceptibility to psoriasis.

In a study using a national psoriasis registry, HLA-C*06:02-negative patients were 3 times more likely to achieve PASI90 status in response to adalimumab, a TNF-alpha inhibitor, than with ustekinumab treatment. And in a meta-analysis covering eight studies with more than 1,000 patients with psoriasis, the median PASI75 response rate after 6 months of ustekinumab therapy was 92% in the HLA-C*06:02-positive group and 67% in HLA-C*06:02-negative patients.

The recently published cohort study showing a 6% rate of multiple biologic failure evaluated patients in the multicenter CorEvitas Psoriasis Registry who initiated their first biologic between 2015 and 2020 and were followed for 2 or more years. Investigators looked for sociodemographic and clinical differences between the patients who continued use of their first biologic for at least 2 years (“good response”), and those who discontinued two or more biologics of different classes, each used for at least 90 days, because of inadequate efficacy.

Of 1,039 evaluated patients, 490 (47.2%) had good clinical response to their first biologic and 65 (6.3%) had multiple biologic failure. All biologic classes were represented among those who failed multiple biologics. The first and second biologic classes used were attempted for a mean duration of 10 months – “an adequate trial” of each, Dr. Liao said.

In multivariable regression analysis, six variables were significantly associated with multiple biologic failure: female sex at birth, shorter disease duration, earlier year of biologic initiation, prior nonbiologic systemic therapy, having Medicaid insurance, and a history of hyperlipidemia. The latter is “interesting because other studies have shown that metabolic syndrome, of which hyperlipidemia is a component, can also relate to poor response to biologics,” Dr. Liao said.

The most common sequences of first-to-second biologics among those with multiple biologic failure were TNF inhibitor to IL-17 inhibitor (30.8%); IL-12/23 inhibitor to IL-17 inhibitor (21.5%); TNF inhibitor to IL-12/23 inhibitor (12.3%); and IL-17 inhibitor to IL-23 inhibitor (10.8%).

The vast majority of patients failed more than two biologics, however, and “more than 20% had five or more biologics tried over a relatively short period,” Dr. Liao said.
 

Comorbidities and biologic failure in psoriasis, PsA

In practice, it was said during a discussion period, biologic failures in psoriasis can be of two types: a primary inadequate response or initial failure, or a secondary failure with initial improvement followed by declining or no response. “I agree 100% that these probably represent two different endotypes,” Dr. Liao said. “There’s research emerging that psoriasis isn’t necessarily a clean phenotype.”

The option of focusing on comorbidities in the face of biologic failure was another point of discussion. “Maybe the next biologic is not the answer,” a meeting participant said. “Maybe we should focus on metabolic syndrome.”

“I agree,” Dr. Liao said. “In clinic, there are people who may not respond to therapies but have other comorbidities and factors that make it difficult to manage [their psoriasis] ... that may be causative for psoriasis. Maybe if we treat the comorbidities, it will make it easier to treat the psoriasis.”

Addressing comorbidities and “extra-articular traits” such as poorly controlled diabetes, centralized pain, anxiety and depression, and obesity is something Dr. Ritchlin advocates for PsA. “Centralized pain, I believe, is a major driver of nonresponse,” he said at the meeting. “We have to be careful about blaming nonresponse and lack of efficacy of biologics when it could be a wholly different mechanism the biologic won’t treat ... for example, centralized pain.”

As with psoriasis, the emergence of antidrug antibodies may be one reason for the secondary failure of biologic agents for PsA, Dr. Ritchlin and his coauthors wrote in their paper on management of PsA after failure of one TNF inhibitor. Other areas to consider in evaluating failure, they wrote, are compliance and time of dosing, and financial barriers.

Low long-term persistence of second-line biologics for patients with PsA was demonstrated in a national cohort study utilizing the French health insurance database, Dr. Ritchlin noted at the research meeting. 

The French study covered almost 3,000 patients who started a second biologic after discontinuing a TNF inhibitor during 2015-2020. Overall, 1-year and 3-year persistence rates were 42% and 17%, respectively.

Dr. Liao disclosed research grant funding from AbbVie, Amgen, Janssen, Leo, Novartis, Pfizer, Regeneron, and Trex Bio. Dr. Ritchlin reported no disclosures.

WASHINGTON – Multiple biologic failure in a minority of patients with psoriasis may have several causes, from genetic endotypes and immunologic factors to lower serum drug levels, the presence of anti-drug antibody levels, female sex, and certain comorbidities, Wilson Liao, MD, said at the annual research symposium of the National Psoriasis Foundation.

“Tough-to-treat psoriasis remains a challenge despite newer therapies ... Why do we still have this sub-population of patients who seem to be refractory?” said Dr. Liao, professor and associate vice chair of research in the department of dermatology at the University of California, San Francisco, who coauthored a 2015-2022 prospective cohort analysis that documented about 6% of patients failing two or more biologic agents of different mechanistic classes.

“These patients are really suffering,” he said. “We need to have better guidelines and treatment algorithms for these patients.”

A significant number of patients with psoriatic arthritis (PsA), meanwhile, are inadequate responders to tumor necrosis factor (TNF) inhibition, Christopher T. Ritchlin, MD, PhD, professor of medicine in the division of allergy/immunology and rheumatology and the Center of Musculoskeletal Research at the University of Rochester (N.Y.), said during another session at the meeting.

The long-term “persistence,” or usage, of first-line biologics in patients with PsA – and of second-line biologics in patients who failed one TNF-inhibitor – is low, but the literature offers little information on the reasons for TNF-inhibitor discontinuation, said Dr. Ritchlin, who coauthored a perspective piece in Arthritis & Rheumatology on managing the patient with PsA who fails one TNF inhibitor.

Dr. Ritchlin and his coauthors were asked to provide evidence-informed advice and algorithms, but the task was difficult. “It’s hard to know what to recommend for the next step if we don’t know why patients failed the first,” he said. “The point is, we need more data. [Clinical trials] are not recording the kind of information we need.”
 

Anti-drug antibodies, genetics, other factors in psoriasis

Research shows that in large cohorts, “all the biologics do seem to lose efficacy over time,” said Dr. Liao, who directs the UCSF Psoriasis and Skin Treatment Center. “Some are better than others, but we do see a loss of effectiveness over time.”

A cohort study published in 2022 in JAMA Dermatology, for instance, documented declining “drug survival” associated with ineffectiveness during 2 years of treatment for each of five biologics studied (adalimumab [Humira], ustekinumab [Stelara], secukinumab [Cosentyx], guselkumab [Tremfya], and ixekizumab [Taltz]).

“There have been a number of theories put forward” as to why that’s the case, including lower serum drug levels, “which of course can be related to anti-drug antibody production,” he said.

He pointed to two studies of ustekinumab: One prospective observational cohort study that reported an association of lower early drug levels of the IL-12/23 receptor antagonist with lower Psoriasis Area and Severity Index (PASI) scores, and another observational study that documented an association between anti-drug antibody positivity with lower ustekinumab levels and impaired clinical response.

“We also now know ... that there are genetic endotypes in psoriasis, and that patients who are [HLA-C*06:02]-positive tend to respond a little better to drugs like ustekinumab, and those who are [HLA-C*06:02]-negative tend to do a little better with the TNF inhibitors,” Dr. Liao said. The human leukocyte antigen (HLA) allele HLA-C*06:02 is associated with susceptibility to psoriasis.

In a study using a national psoriasis registry, HLA-C*06:02-negative patients were 3 times more likely to achieve PASI90 status in response to adalimumab, a TNF-alpha inhibitor, than with ustekinumab treatment. And in a meta-analysis covering eight studies with more than 1,000 patients with psoriasis, the median PASI75 response rate after 6 months of ustekinumab therapy was 92% in the HLA-C*06:02-positive group and 67% in HLA-C*06:02-negative patients.

The recently published cohort study showing a 6% rate of multiple biologic failure evaluated patients in the multicenter CorEvitas Psoriasis Registry who initiated their first biologic between 2015 and 2020 and were followed for 2 or more years. Investigators looked for sociodemographic and clinical differences between the patients who continued use of their first biologic for at least 2 years (“good response”), and those who discontinued two or more biologics of different classes, each used for at least 90 days, because of inadequate efficacy.

Of 1,039 evaluated patients, 490 (47.2%) had good clinical response to their first biologic and 65 (6.3%) had multiple biologic failure. All biologic classes were represented among those who failed multiple biologics. The first and second biologic classes used were attempted for a mean duration of 10 months – “an adequate trial” of each, Dr. Liao said.

In multivariable regression analysis, six variables were significantly associated with multiple biologic failure: female sex at birth, shorter disease duration, earlier year of biologic initiation, prior nonbiologic systemic therapy, having Medicaid insurance, and a history of hyperlipidemia. The latter is “interesting because other studies have shown that metabolic syndrome, of which hyperlipidemia is a component, can also relate to poor response to biologics,” Dr. Liao said.

The most common sequences of first-to-second biologics among those with multiple biologic failure were TNF inhibitor to IL-17 inhibitor (30.8%); IL-12/23 inhibitor to IL-17 inhibitor (21.5%); TNF inhibitor to IL-12/23 inhibitor (12.3%); and IL-17 inhibitor to IL-23 inhibitor (10.8%).

The vast majority of patients failed more than two biologics, however, and “more than 20% had five or more biologics tried over a relatively short period,” Dr. Liao said.
 

Comorbidities and biologic failure in psoriasis, PsA

In practice, it was said during a discussion period, biologic failures in psoriasis can be of two types: a primary inadequate response or initial failure, or a secondary failure with initial improvement followed by declining or no response. “I agree 100% that these probably represent two different endotypes,” Dr. Liao said. “There’s research emerging that psoriasis isn’t necessarily a clean phenotype.”

The option of focusing on comorbidities in the face of biologic failure was another point of discussion. “Maybe the next biologic is not the answer,” a meeting participant said. “Maybe we should focus on metabolic syndrome.”

“I agree,” Dr. Liao said. “In clinic, there are people who may not respond to therapies but have other comorbidities and factors that make it difficult to manage [their psoriasis] ... that may be causative for psoriasis. Maybe if we treat the comorbidities, it will make it easier to treat the psoriasis.”

Addressing comorbidities and “extra-articular traits” such as poorly controlled diabetes, centralized pain, anxiety and depression, and obesity is something Dr. Ritchlin advocates for PsA. “Centralized pain, I believe, is a major driver of nonresponse,” he said at the meeting. “We have to be careful about blaming nonresponse and lack of efficacy of biologics when it could be a wholly different mechanism the biologic won’t treat ... for example, centralized pain.”

As with psoriasis, the emergence of antidrug antibodies may be one reason for the secondary failure of biologic agents for PsA, Dr. Ritchlin and his coauthors wrote in their paper on management of PsA after failure of one TNF inhibitor. Other areas to consider in evaluating failure, they wrote, are compliance and time of dosing, and financial barriers.

Low long-term persistence of second-line biologics for patients with PsA was demonstrated in a national cohort study utilizing the French health insurance database, Dr. Ritchlin noted at the research meeting. 

The French study covered almost 3,000 patients who started a second biologic after discontinuing a TNF inhibitor during 2015-2020. Overall, 1-year and 3-year persistence rates were 42% and 17%, respectively.

Dr. Liao disclosed research grant funding from AbbVie, Amgen, Janssen, Leo, Novartis, Pfizer, Regeneron, and Trex Bio. Dr. Ritchlin reported no disclosures.

WASHINGTON – Multiple biologic failure in a minority of patients with psoriasis may have several causes, from genetic endotypes and immunologic factors to lower serum drug levels, the presence of anti-drug antibody levels, female sex, and certain comorbidities, Wilson Liao, MD, said at the annual research symposium of the National Psoriasis Foundation.

“Tough-to-treat psoriasis remains a challenge despite newer therapies ... Why do we still have this sub-population of patients who seem to be refractory?” said Dr. Liao, professor and associate vice chair of research in the department of dermatology at the University of California, San Francisco, who coauthored a 2015-2022 prospective cohort analysis that documented about 6% of patients failing two or more biologic agents of different mechanistic classes.

“These patients are really suffering,” he said. “We need to have better guidelines and treatment algorithms for these patients.”

A significant number of patients with psoriatic arthritis (PsA), meanwhile, are inadequate responders to tumor necrosis factor (TNF) inhibition, Christopher T. Ritchlin, MD, PhD, professor of medicine in the division of allergy/immunology and rheumatology and the Center of Musculoskeletal Research at the University of Rochester (N.Y.), said during another session at the meeting.

The long-term “persistence,” or usage, of first-line biologics in patients with PsA – and of second-line biologics in patients who failed one TNF-inhibitor – is low, but the literature offers little information on the reasons for TNF-inhibitor discontinuation, said Dr. Ritchlin, who coauthored a perspective piece in Arthritis & Rheumatology on managing the patient with PsA who fails one TNF inhibitor.

Dr. Ritchlin and his coauthors were asked to provide evidence-informed advice and algorithms, but the task was difficult. “It’s hard to know what to recommend for the next step if we don’t know why patients failed the first,” he said. “The point is, we need more data. [Clinical trials] are not recording the kind of information we need.”
 

Anti-drug antibodies, genetics, other factors in psoriasis

Research shows that in large cohorts, “all the biologics do seem to lose efficacy over time,” said Dr. Liao, who directs the UCSF Psoriasis and Skin Treatment Center. “Some are better than others, but we do see a loss of effectiveness over time.”

A cohort study published in 2022 in JAMA Dermatology, for instance, documented declining “drug survival” associated with ineffectiveness during 2 years of treatment for each of five biologics studied (adalimumab [Humira], ustekinumab [Stelara], secukinumab [Cosentyx], guselkumab [Tremfya], and ixekizumab [Taltz]).

“There have been a number of theories put forward” as to why that’s the case, including lower serum drug levels, “which of course can be related to anti-drug antibody production,” he said.

He pointed to two studies of ustekinumab: One prospective observational cohort study that reported an association of lower early drug levels of the IL-12/23 receptor antagonist with lower Psoriasis Area and Severity Index (PASI) scores, and another observational study that documented an association between anti-drug antibody positivity with lower ustekinumab levels and impaired clinical response.

“We also now know ... that there are genetic endotypes in psoriasis, and that patients who are [HLA-C*06:02]-positive tend to respond a little better to drugs like ustekinumab, and those who are [HLA-C*06:02]-negative tend to do a little better with the TNF inhibitors,” Dr. Liao said. The human leukocyte antigen (HLA) allele HLA-C*06:02 is associated with susceptibility to psoriasis.

In a study using a national psoriasis registry, HLA-C*06:02-negative patients were 3 times more likely to achieve PASI90 status in response to adalimumab, a TNF-alpha inhibitor, than with ustekinumab treatment. And in a meta-analysis covering eight studies with more than 1,000 patients with psoriasis, the median PASI75 response rate after 6 months of ustekinumab therapy was 92% in the HLA-C*06:02-positive group and 67% in HLA-C*06:02-negative patients.

The recently published cohort study showing a 6% rate of multiple biologic failure evaluated patients in the multicenter CorEvitas Psoriasis Registry who initiated their first biologic between 2015 and 2020 and were followed for 2 or more years. Investigators looked for sociodemographic and clinical differences between the patients who continued use of their first biologic for at least 2 years (“good response”), and those who discontinued two or more biologics of different classes, each used for at least 90 days, because of inadequate efficacy.

Of 1,039 evaluated patients, 490 (47.2%) had good clinical response to their first biologic and 65 (6.3%) had multiple biologic failure. All biologic classes were represented among those who failed multiple biologics. The first and second biologic classes used were attempted for a mean duration of 10 months – “an adequate trial” of each, Dr. Liao said.

In multivariable regression analysis, six variables were significantly associated with multiple biologic failure: female sex at birth, shorter disease duration, earlier year of biologic initiation, prior nonbiologic systemic therapy, having Medicaid insurance, and a history of hyperlipidemia. The latter is “interesting because other studies have shown that metabolic syndrome, of which hyperlipidemia is a component, can also relate to poor response to biologics,” Dr. Liao said.

The most common sequences of first-to-second biologics among those with multiple biologic failure were TNF inhibitor to IL-17 inhibitor (30.8%); IL-12/23 inhibitor to IL-17 inhibitor (21.5%); TNF inhibitor to IL-12/23 inhibitor (12.3%); and IL-17 inhibitor to IL-23 inhibitor (10.8%).

The vast majority of patients failed more than two biologics, however, and “more than 20% had five or more biologics tried over a relatively short period,” Dr. Liao said.
 

Comorbidities and biologic failure in psoriasis, PsA

In practice, it was said during a discussion period, biologic failures in psoriasis can be of two types: a primary inadequate response or initial failure, or a secondary failure with initial improvement followed by declining or no response. “I agree 100% that these probably represent two different endotypes,” Dr. Liao said. “There’s research emerging that psoriasis isn’t necessarily a clean phenotype.”

The option of focusing on comorbidities in the face of biologic failure was another point of discussion. “Maybe the next biologic is not the answer,” a meeting participant said. “Maybe we should focus on metabolic syndrome.”

“I agree,” Dr. Liao said. “In clinic, there are people who may not respond to therapies but have other comorbidities and factors that make it difficult to manage [their psoriasis] ... that may be causative for psoriasis. Maybe if we treat the comorbidities, it will make it easier to treat the psoriasis.”

Addressing comorbidities and “extra-articular traits” such as poorly controlled diabetes, centralized pain, anxiety and depression, and obesity is something Dr. Ritchlin advocates for PsA. “Centralized pain, I believe, is a major driver of nonresponse,” he said at the meeting. “We have to be careful about blaming nonresponse and lack of efficacy of biologics when it could be a wholly different mechanism the biologic won’t treat ... for example, centralized pain.”

As with psoriasis, the emergence of antidrug antibodies may be one reason for the secondary failure of biologic agents for PsA, Dr. Ritchlin and his coauthors wrote in their paper on management of PsA after failure of one TNF inhibitor. Other areas to consider in evaluating failure, they wrote, are compliance and time of dosing, and financial barriers.

Low long-term persistence of second-line biologics for patients with PsA was demonstrated in a national cohort study utilizing the French health insurance database, Dr. Ritchlin noted at the research meeting. 

The French study covered almost 3,000 patients who started a second biologic after discontinuing a TNF inhibitor during 2015-2020. Overall, 1-year and 3-year persistence rates were 42% and 17%, respectively.

Dr. Liao disclosed research grant funding from AbbVie, Amgen, Janssen, Leo, Novartis, Pfizer, Regeneron, and Trex Bio. Dr. Ritchlin reported no disclosures.

Knowing the sex of a developing fetus is a common question many expectant parents ask at their prenatal appointments. While the sex of a fetus has minimal clinical significance to obstetrician/gynecologists, technology has made ascertaining the answer to this question much more accessible.

In addition to detecting certain genetic abnormalities, both noninvasive prenatal testing (NIPT) and preimplantation genetic testing (PGT) can discern the chromosomal sex of a fetus prior to birth. At the 20-week anatomy scan, the ultrasonographer can detect the presence of external genitalia to determine the sex. In fact, when a baby is first born, obstetrician/gynecologists are consistently asked “do I have a boy or a girl?” Assigning the sex of a newborn is one of the many tasks we complete in the delivery room. However, some of you reading this article would disagree.

“You cannot assign sex at birth.” “Sex is fixed, you cannot change biology.” These are examples of statements that frequent the comments section of my medical articles and plague professionals who treat gender diverse patients. I would argue, as would many biologists, scientists, and physicians, that these statements oversimplify biologic reality.

The term “sex” has multiple meanings: It can allude to the act of reproduction itself, but in the context of sexual determination and sexual differentiation, it can refer to the biologic and structural composition of a developing human. Within this paradigm, there exist three definitions for sex: chromosomal, gonadal, and phenotypic.

Chromosomal sex refers to the genetic makeup of a human, typically XX or XY chromosomes. There are also variations within this seemingly binary system. Embryos can have an extra sex chromosome, as seen in Klinefelter syndrome, which is characterized by XXY karyotype. Embryos can also be devoid of a sex chromosome, as observed in Turner’s syndrome, which is characterized by an XO karyotype. These variations can impact fertility and expression of secondary sexual characteristics as the type of sex chromosomes present results in primary sex determination, or the development of gonads.

Most often, individuals with a chromosomal makeup of XX are considered female and will subsequently develop ovaries that produce oocytes (eggs). Individuals with XY chromosomes are deemed male and will go on to develop testes, which are responsible for spermatogenesis (sperm production).

Gonadal sex is the presence of either testes or ovaries. The primary function of testes is to produce sperm for reproduction and to secrete testosterone, the primary male sex hormone. Similarly, ovaries produce oocytes and secrete estrogen as the primary female sex hormone. Gonads can be surgically removed either via orchiectomy (the removal of testes), or oophorectomy (the removal of ovaries) for a variety of reasons. There is no current medical technology that can replace the function of these structures, although patients can be placed on hormone replacement to counter the negative physiologic consequences resulting from their removal.

Secondary sex determination, or sexual differentiation, is the development of external genitalia and internal genital tracts because of the hormones produced from the gonads. At puberty, further differentiation occurs with the development of pubic and axillary hair and breast growth. This process determines phenotypic sex – the visible distinction between male and female.

When opponents of gender affirming care state that individuals cannot change sex, are they correct or false? The answer to this question is entirely dependent on which definition of sex they are using. Chromosomal? Gonadal? Phenotypic? It is an immutable fact that humans cannot change chromosomal sex. No one in the transgender community, either provider or patient, would dispute this. However, we can remove gonadal structures and alter phenotypic sex.

The goal of gender affirming hormone therapy and surgery isn’t to change chromosomal sex, but to alter one’s phenotypic sex so the physical body a patient sees, and others see, is reflective of how the patient feels. In fact, many cisgender individuals also revise their phenotypic sex when they undergo augmentation mammaplasty, penile enlargement, or vulvoplasty procedures for the exact same reason.

Circling back to the debate about whether we can “assign sex at birth,” it all depends on what definition of sex you are referencing. At birth, obstetrician/gynecologists most often look at the phenotypic sex and make assumptions about the genetic and gonadal sex based on the secondary sexual characteristics. So yes, we can, and we do assign sex at birth. However, in the case of intersex individuals, these physical characteristics may not align with their gonadal and chromosomal composition.

In the case of an infant that has a known XY karyotype prior to birth but a female phenotype at birth (as seen in a condition called complete androgen insensitivity syndrome), what sex should be assigned to that baby? Should the infant be raised male or female? A lot of unintended but significant harm has resulted from providers and parents trying to answer that very question. The mistreatment of intersex patients through forced and coercive medical and surgical treatments, often in infancy, should serve as a dark reminder that sex and gender are not as biologically binary as we would like to believe.

Dr. Brandt is an ob.gyn. and fellowship-trained gender-affirming surgeon in West Reading, Pa. She has no relevant disclosures.

References

Moore KL and Persaud TVN. The urogenital system. In: Before we are born: essentials of embryology and birth defects. 7th ed. Philadelphia: Saunders Elsevier;2008:163-89.

Standring S. Development of the urogenital system. In: Gray’s Anatomy, 42nd ed. Philadelphia: Elsevier;2021:341-64.

Escobar O et al. Pediatric endocrinology. In: Zitelli BJ, ed. Zitelli and Davis’ atlas of pediatric physical diagnosis 8th edition. Philadelphia: Elsevier;2023:342-81.

Knowing the sex of a developing fetus is a common question many expectant parents ask at their prenatal appointments. While the sex of a fetus has minimal clinical significance to obstetrician/gynecologists, technology has made ascertaining the answer to this question much more accessible.

In addition to detecting certain genetic abnormalities, both noninvasive prenatal testing (NIPT) and preimplantation genetic testing (PGT) can discern the chromosomal sex of a fetus prior to birth. At the 20-week anatomy scan, the ultrasonographer can detect the presence of external genitalia to determine the sex. In fact, when a baby is first born, obstetrician/gynecologists are consistently asked “do I have a boy or a girl?” Assigning the sex of a newborn is one of the many tasks we complete in the delivery room. However, some of you reading this article would disagree.

“You cannot assign sex at birth.” “Sex is fixed, you cannot change biology.” These are examples of statements that frequent the comments section of my medical articles and plague professionals who treat gender diverse patients. I would argue, as would many biologists, scientists, and physicians, that these statements oversimplify biologic reality.

The term “sex” has multiple meanings: It can allude to the act of reproduction itself, but in the context of sexual determination and sexual differentiation, it can refer to the biologic and structural composition of a developing human. Within this paradigm, there exist three definitions for sex: chromosomal, gonadal, and phenotypic.

Chromosomal sex refers to the genetic makeup of a human, typically XX or XY chromosomes. There are also variations within this seemingly binary system. Embryos can have an extra sex chromosome, as seen in Klinefelter syndrome, which is characterized by XXY karyotype. Embryos can also be devoid of a sex chromosome, as observed in Turner’s syndrome, which is characterized by an XO karyotype. These variations can impact fertility and expression of secondary sexual characteristics as the type of sex chromosomes present results in primary sex determination, or the development of gonads.

Most often, individuals with a chromosomal makeup of XX are considered female and will subsequently develop ovaries that produce oocytes (eggs). Individuals with XY chromosomes are deemed male and will go on to develop testes, which are responsible for spermatogenesis (sperm production).

Gonadal sex is the presence of either testes or ovaries. The primary function of testes is to produce sperm for reproduction and to secrete testosterone, the primary male sex hormone. Similarly, ovaries produce oocytes and secrete estrogen as the primary female sex hormone. Gonads can be surgically removed either via orchiectomy (the removal of testes), or oophorectomy (the removal of ovaries) for a variety of reasons. There is no current medical technology that can replace the function of these structures, although patients can be placed on hormone replacement to counter the negative physiologic consequences resulting from their removal.

Secondary sex determination, or sexual differentiation, is the development of external genitalia and internal genital tracts because of the hormones produced from the gonads. At puberty, further differentiation occurs with the development of pubic and axillary hair and breast growth. This process determines phenotypic sex – the visible distinction between male and female.

When opponents of gender affirming care state that individuals cannot change sex, are they correct or false? The answer to this question is entirely dependent on which definition of sex they are using. Chromosomal? Gonadal? Phenotypic? It is an immutable fact that humans cannot change chromosomal sex. No one in the transgender community, either provider or patient, would dispute this. However, we can remove gonadal structures and alter phenotypic sex.

The goal of gender affirming hormone therapy and surgery isn’t to change chromosomal sex, but to alter one’s phenotypic sex so the physical body a patient sees, and others see, is reflective of how the patient feels. In fact, many cisgender individuals also revise their phenotypic sex when they undergo augmentation mammaplasty, penile enlargement, or vulvoplasty procedures for the exact same reason.

Circling back to the debate about whether we can “assign sex at birth,” it all depends on what definition of sex you are referencing. At birth, obstetrician/gynecologists most often look at the phenotypic sex and make assumptions about the genetic and gonadal sex based on the secondary sexual characteristics. So yes, we can, and we do assign sex at birth. However, in the case of intersex individuals, these physical characteristics may not align with their gonadal and chromosomal composition.

In the case of an infant that has a known XY karyotype prior to birth but a female phenotype at birth (as seen in a condition called complete androgen insensitivity syndrome), what sex should be assigned to that baby? Should the infant be raised male or female? A lot of unintended but significant harm has resulted from providers and parents trying to answer that very question. The mistreatment of intersex patients through forced and coercive medical and surgical treatments, often in infancy, should serve as a dark reminder that sex and gender are not as biologically binary as we would like to believe.

Dr. Brandt is an ob.gyn. and fellowship-trained gender-affirming surgeon in West Reading, Pa. She has no relevant disclosures.

References

Moore KL and Persaud TVN. The urogenital system. In: Before we are born: essentials of embryology and birth defects. 7th ed. Philadelphia: Saunders Elsevier;2008:163-89.

Standring S. Development of the urogenital system. In: Gray’s Anatomy, 42nd ed. Philadelphia: Elsevier;2021:341-64.

Escobar O et al. Pediatric endocrinology. In: Zitelli BJ, ed. Zitelli and Davis’ atlas of pediatric physical diagnosis 8th edition. Philadelphia: Elsevier;2023:342-81.

Knowing the sex of a developing fetus is a common question many expectant parents ask at their prenatal appointments. While the sex of a fetus has minimal clinical significance to obstetrician/gynecologists, technology has made ascertaining the answer to this question much more accessible.

In addition to detecting certain genetic abnormalities, both noninvasive prenatal testing (NIPT) and preimplantation genetic testing (PGT) can discern the chromosomal sex of a fetus prior to birth. At the 20-week anatomy scan, the ultrasonographer can detect the presence of external genitalia to determine the sex. In fact, when a baby is first born, obstetrician/gynecologists are consistently asked “do I have a boy or a girl?” Assigning the sex of a newborn is one of the many tasks we complete in the delivery room. However, some of you reading this article would disagree.

“You cannot assign sex at birth.” “Sex is fixed, you cannot change biology.” These are examples of statements that frequent the comments section of my medical articles and plague professionals who treat gender diverse patients. I would argue, as would many biologists, scientists, and physicians, that these statements oversimplify biologic reality.

The term “sex” has multiple meanings: It can allude to the act of reproduction itself, but in the context of sexual determination and sexual differentiation, it can refer to the biologic and structural composition of a developing human. Within this paradigm, there exist three definitions for sex: chromosomal, gonadal, and phenotypic.

Chromosomal sex refers to the genetic makeup of a human, typically XX or XY chromosomes. There are also variations within this seemingly binary system. Embryos can have an extra sex chromosome, as seen in Klinefelter syndrome, which is characterized by XXY karyotype. Embryos can also be devoid of a sex chromosome, as observed in Turner’s syndrome, which is characterized by an XO karyotype. These variations can impact fertility and expression of secondary sexual characteristics as the type of sex chromosomes present results in primary sex determination, or the development of gonads.

Most often, individuals with a chromosomal makeup of XX are considered female and will subsequently develop ovaries that produce oocytes (eggs). Individuals with XY chromosomes are deemed male and will go on to develop testes, which are responsible for spermatogenesis (sperm production).

Gonadal sex is the presence of either testes or ovaries. The primary function of testes is to produce sperm for reproduction and to secrete testosterone, the primary male sex hormone. Similarly, ovaries produce oocytes and secrete estrogen as the primary female sex hormone. Gonads can be surgically removed either via orchiectomy (the removal of testes), or oophorectomy (the removal of ovaries) for a variety of reasons. There is no current medical technology that can replace the function of these structures, although patients can be placed on hormone replacement to counter the negative physiologic consequences resulting from their removal.

Secondary sex determination, or sexual differentiation, is the development of external genitalia and internal genital tracts because of the hormones produced from the gonads. At puberty, further differentiation occurs with the development of pubic and axillary hair and breast growth. This process determines phenotypic sex – the visible distinction between male and female.

When opponents of gender affirming care state that individuals cannot change sex, are they correct or false? The answer to this question is entirely dependent on which definition of sex they are using. Chromosomal? Gonadal? Phenotypic? It is an immutable fact that humans cannot change chromosomal sex. No one in the transgender community, either provider or patient, would dispute this. However, we can remove gonadal structures and alter phenotypic sex.

The goal of gender affirming hormone therapy and surgery isn’t to change chromosomal sex, but to alter one’s phenotypic sex so the physical body a patient sees, and others see, is reflective of how the patient feels. In fact, many cisgender individuals also revise their phenotypic sex when they undergo augmentation mammaplasty, penile enlargement, or vulvoplasty procedures for the exact same reason.

Circling back to the debate about whether we can “assign sex at birth,” it all depends on what definition of sex you are referencing. At birth, obstetrician/gynecologists most often look at the phenotypic sex and make assumptions about the genetic and gonadal sex based on the secondary sexual characteristics. So yes, we can, and we do assign sex at birth. However, in the case of intersex individuals, these physical characteristics may not align with their gonadal and chromosomal composition.

In the case of an infant that has a known XY karyotype prior to birth but a female phenotype at birth (as seen in a condition called complete androgen insensitivity syndrome), what sex should be assigned to that baby? Should the infant be raised male or female? A lot of unintended but significant harm has resulted from providers and parents trying to answer that very question. The mistreatment of intersex patients through forced and coercive medical and surgical treatments, often in infancy, should serve as a dark reminder that sex and gender are not as biologically binary as we would like to believe.

Dr. Brandt is an ob.gyn. and fellowship-trained gender-affirming surgeon in West Reading, Pa. She has no relevant disclosures.

References

Moore KL and Persaud TVN. The urogenital system. In: Before we are born: essentials of embryology and birth defects. 7th ed. Philadelphia: Saunders Elsevier;2008:163-89.

Standring S. Development of the urogenital system. In: Gray’s Anatomy, 42nd ed. Philadelphia: Elsevier;2021:341-64.

Escobar O et al. Pediatric endocrinology. In: Zitelli BJ, ed. Zitelli and Davis’ atlas of pediatric physical diagnosis 8th edition. Philadelphia: Elsevier;2023:342-81.

Cognitive issues in children with Duchenne muscular dystrophy (DMD) are linked to worse outcomes, but limited access to specialists and limited resources make this problem difficult to address. A new tool from the National Institutes of Health, called NIH Toolbox, could improve that outcome, according to Mathula Thangarajh, MD, PhD, who has conducted research in the field.

“When we talk to families and parents, they are able to identify that even during infancy that [children with DMD] have delayed cognitive function. This includes speech delay, but also language and adaptive skills. We also know that those children with speech delay, which is really a very commonly reported phenotype in up to 50%, go on to have school-based needs. They may repeat [grades] in elementary years, but they also use more resources at school,” said Dr. Thangarajh, who is an assistant professor of neurology at the Children’s Hospital of Richmond at Virginia Commonwealth University, Richmond, during a talk at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).

Children’s Hospital of Richmond at Virginia Commonwealth University

A previous natural history study that utilized the Pediatric Quality of Life assessment also showed that DMD patients reported the lowest scores in brain health, including emotional health and school performance.

Other research has shown a correlation between cognitive function and survival in DMD. “This suggests that health maintenance may play an important role [in outcomes],” said Dr. Thangarajh. Another study found a correlation between psychomotor delay that required school-based interventions and earlier loss of ambulation, lower cardiac ejection fraction, and worse pulmonary function. The researchers also found that boys with cognitive delay were diagnosed at an earlier age, and yet had delays in diagnosis and worse motor function, pulmonary health, and cardiac health outcomes. On average, they lost ambulatory ability 2 years earlier.

A study by Dr. Thangarajh’s group showed that patients with speech delay and lower IQ had lower performance in timed tests, including 6-minute walk test distance and scored an average of 2 points lower on the North Star Ambulatory Assessment.
 

A tool for continuous cognitive assessment

The Centers for Disease Control and Prevention–supported DMD CARE guidelines only say that neuropsychological evaluations should be considered at diagnosis, but is essential if concerns arise about developmental progress. However, the Muscular Dystrophy Association has found barriers both in access to specialists, with an average wait time of 1-2 years, and burdensome out-of-pocket costs.

Those issues prompted Dr. Thangarajh to look for an alternative solution. At the time that she embarked on this work, the NIH was interested in technologies to assess neurobehavioral issues across different diseases. The resulting NIH Toolbox iPad app was driven largely by failed clinical trials in dementia, and the aim was to be able to provide continuous assessment over time. “It will allow for assessments across the lifespan, so you can use the same construct from age 3 to 80-plus,” said Dr. Thangarajh. It can also normalize population factors, such as annual household income and mother’s IQ.

She set out to validate the NIH Toolbox in children with DMD. The toolbox includes measures of crystalized cognition and fluid cognition. The former encompasses vocabulary and reading ability, which are strongly predicted by socioeconomic status and maternal IQ. On the other hand, fluid cognition includes cognitive features that develop across the lifespan and is directly related to academic underperformance in DMD patients.

Dr. Thangarajh’s group assessed 30 boys with DMD and found that crystallized cognition was normal, but they had a deficit in fluid cognition. They found deficits within several subdomains of fluid cognition. “This tells us that the NIH Toolbox was able to replicate what we had known in the literature, that these boys really have lower intellectual capacity, but they also have significant weakness in fluid cognition,” she said.

She also wanted to examine changes over time by testing the boys at a 1-year interview. “What we found was that they are not making as much gain in fluid cognition as we would like. They are just making marginal improvements over time. This has implications on how often we should screen them, but also not be over reliant on using school-based resources for them to get tested,” said Dr. Thangarajh.

Her group’s analysis of a dataset of 55 boys provided by PTC Therapeutics revealed a difference by age in a test of working memory. “What we found was that boys who are actually greater than 9 years, compared with those who are less than 9 years, they actually had a reversal of development-based improvement. The older they get, they were not making as much gains as you would expect,” said Dr. Thangarajh.

She went on to discuss psychosocial determinants of cognitive health in DMD. It is known that women who are carriers of the dystrophin mutation can underperform in cognitively stressful tasks, leading her to wonder if this could lead to transgenerational risk to offspring with DMD. Her group tested women who were carriers of the mutation with the NIH Toolbox and found that they had lower fluid cognition than noncarriers. They then tested 65 dyads of mothers and children, and found a correlation, but only when it came to inhibitory control, which required the individual to note the direction of an arrow while ignoring surrounding arrows pointing in various directions.

Next, the researchers examined neighborhoods and their impact on cognitive health, which can be affected by the presence of green spaces, access to public transportation and good nutrition, and other factors. There were significant deficits associated with residence zip codes. “We were pretty shocked. Someone who is not in a socially vulnerable region is scoring slightly below average, but someone who is in a very socially vulnerable neighborhood is only scoring 75 [age-adjusted score] on the NIH toolbox. So with this, we can conclude that carrier women are vulnerable in certain cognitive domains, but also children who come from socially vulnerable [situations] have poor cognitive control. This, again, has implications on how often we should screen and how much we should overly rely on school-based resources for these individuals,” said Dr. Thangarajh.
 

Overcoming a significant barrier

The NIH Toolbox has a lot of potential to improve DMD care, according to Dianna Quan, MD, who is the incoming president of AANEM, and professor of neurology at the University of Colorado at Denver, Aurora. “There’s this huge problem in terms of getting people in to see neuropsychologists and having formal evaluations. I think that’s a huge barrier. If we have people able to access this toolkit, which is simple and easily and universally accessible, how wonderful is that? I think that will be a really great improvement on what’s going on right now. It allows people to easily screen for these cognitive disabilities and make sure that we address them,” Dr. Quan said in an interview.

Asked how the tool could specifically improve care, Dr. Quan suggested that the first step is to understand the contributing factors to cognitive issues, whether they are biological, social, or a combination. “Some of them we can modify, potentially, through addressing the social environment. Some of those biologic factors may also be modifiable with many of the new drug studies that are coming.”

Dr. Thangarajh has received speaker honoraria from NS Pharma and PTC Therapeutics. Dr. Quan has received funding from Alnylam, Pfizer, Cytokinetics, Momenta, and Argenx.

Cognitive issues in children with Duchenne muscular dystrophy (DMD) are linked to worse outcomes, but limited access to specialists and limited resources make this problem difficult to address. A new tool from the National Institutes of Health, called NIH Toolbox, could improve that outcome, according to Mathula Thangarajh, MD, PhD, who has conducted research in the field.

“When we talk to families and parents, they are able to identify that even during infancy that [children with DMD] have delayed cognitive function. This includes speech delay, but also language and adaptive skills. We also know that those children with speech delay, which is really a very commonly reported phenotype in up to 50%, go on to have school-based needs. They may repeat [grades] in elementary years, but they also use more resources at school,” said Dr. Thangarajh, who is an assistant professor of neurology at the Children’s Hospital of Richmond at Virginia Commonwealth University, Richmond, during a talk at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).

Children’s Hospital of Richmond at Virginia Commonwealth University

A previous natural history study that utilized the Pediatric Quality of Life assessment also showed that DMD patients reported the lowest scores in brain health, including emotional health and school performance.

Other research has shown a correlation between cognitive function and survival in DMD. “This suggests that health maintenance may play an important role [in outcomes],” said Dr. Thangarajh. Another study found a correlation between psychomotor delay that required school-based interventions and earlier loss of ambulation, lower cardiac ejection fraction, and worse pulmonary function. The researchers also found that boys with cognitive delay were diagnosed at an earlier age, and yet had delays in diagnosis and worse motor function, pulmonary health, and cardiac health outcomes. On average, they lost ambulatory ability 2 years earlier.

A study by Dr. Thangarajh’s group showed that patients with speech delay and lower IQ had lower performance in timed tests, including 6-minute walk test distance and scored an average of 2 points lower on the North Star Ambulatory Assessment.
 

A tool for continuous cognitive assessment

The Centers for Disease Control and Prevention–supported DMD CARE guidelines only say that neuropsychological evaluations should be considered at diagnosis, but is essential if concerns arise about developmental progress. However, the Muscular Dystrophy Association has found barriers both in access to specialists, with an average wait time of 1-2 years, and burdensome out-of-pocket costs.

Those issues prompted Dr. Thangarajh to look for an alternative solution. At the time that she embarked on this work, the NIH was interested in technologies to assess neurobehavioral issues across different diseases. The resulting NIH Toolbox iPad app was driven largely by failed clinical trials in dementia, and the aim was to be able to provide continuous assessment over time. “It will allow for assessments across the lifespan, so you can use the same construct from age 3 to 80-plus,” said Dr. Thangarajh. It can also normalize population factors, such as annual household income and mother’s IQ.

She set out to validate the NIH Toolbox in children with DMD. The toolbox includes measures of crystalized cognition and fluid cognition. The former encompasses vocabulary and reading ability, which are strongly predicted by socioeconomic status and maternal IQ. On the other hand, fluid cognition includes cognitive features that develop across the lifespan and is directly related to academic underperformance in DMD patients.

Dr. Thangarajh’s group assessed 30 boys with DMD and found that crystallized cognition was normal, but they had a deficit in fluid cognition. They found deficits within several subdomains of fluid cognition. “This tells us that the NIH Toolbox was able to replicate what we had known in the literature, that these boys really have lower intellectual capacity, but they also have significant weakness in fluid cognition,” she said.

She also wanted to examine changes over time by testing the boys at a 1-year interview. “What we found was that they are not making as much gain in fluid cognition as we would like. They are just making marginal improvements over time. This has implications on how often we should screen them, but also not be over reliant on using school-based resources for them to get tested,” said Dr. Thangarajh.

Her group’s analysis of a dataset of 55 boys provided by PTC Therapeutics revealed a difference by age in a test of working memory. “What we found was that boys who are actually greater than 9 years, compared with those who are less than 9 years, they actually had a reversal of development-based improvement. The older they get, they were not making as much gains as you would expect,” said Dr. Thangarajh.

She went on to discuss psychosocial determinants of cognitive health in DMD. It is known that women who are carriers of the dystrophin mutation can underperform in cognitively stressful tasks, leading her to wonder if this could lead to transgenerational risk to offspring with DMD. Her group tested women who were carriers of the mutation with the NIH Toolbox and found that they had lower fluid cognition than noncarriers. They then tested 65 dyads of mothers and children, and found a correlation, but only when it came to inhibitory control, which required the individual to note the direction of an arrow while ignoring surrounding arrows pointing in various directions.

Next, the researchers examined neighborhoods and their impact on cognitive health, which can be affected by the presence of green spaces, access to public transportation and good nutrition, and other factors. There were significant deficits associated with residence zip codes. “We were pretty shocked. Someone who is not in a socially vulnerable region is scoring slightly below average, but someone who is in a very socially vulnerable neighborhood is only scoring 75 [age-adjusted score] on the NIH toolbox. So with this, we can conclude that carrier women are vulnerable in certain cognitive domains, but also children who come from socially vulnerable [situations] have poor cognitive control. This, again, has implications on how often we should screen and how much we should overly rely on school-based resources for these individuals,” said Dr. Thangarajh.
 

Overcoming a significant barrier

The NIH Toolbox has a lot of potential to improve DMD care, according to Dianna Quan, MD, who is the incoming president of AANEM, and professor of neurology at the University of Colorado at Denver, Aurora. “There’s this huge problem in terms of getting people in to see neuropsychologists and having formal evaluations. I think that’s a huge barrier. If we have people able to access this toolkit, which is simple and easily and universally accessible, how wonderful is that? I think that will be a really great improvement on what’s going on right now. It allows people to easily screen for these cognitive disabilities and make sure that we address them,” Dr. Quan said in an interview.

Asked how the tool could specifically improve care, Dr. Quan suggested that the first step is to understand the contributing factors to cognitive issues, whether they are biological, social, or a combination. “Some of them we can modify, potentially, through addressing the social environment. Some of those biologic factors may also be modifiable with many of the new drug studies that are coming.”

Dr. Thangarajh has received speaker honoraria from NS Pharma and PTC Therapeutics. Dr. Quan has received funding from Alnylam, Pfizer, Cytokinetics, Momenta, and Argenx.

Cognitive issues in children with Duchenne muscular dystrophy (DMD) are linked to worse outcomes, but limited access to specialists and limited resources make this problem difficult to address. A new tool from the National Institutes of Health, called NIH Toolbox, could improve that outcome, according to Mathula Thangarajh, MD, PhD, who has conducted research in the field.

“When we talk to families and parents, they are able to identify that even during infancy that [children with DMD] have delayed cognitive function. This includes speech delay, but also language and adaptive skills. We also know that those children with speech delay, which is really a very commonly reported phenotype in up to 50%, go on to have school-based needs. They may repeat [grades] in elementary years, but they also use more resources at school,” said Dr. Thangarajh, who is an assistant professor of neurology at the Children’s Hospital of Richmond at Virginia Commonwealth University, Richmond, during a talk at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).

Children’s Hospital of Richmond at Virginia Commonwealth University

A previous natural history study that utilized the Pediatric Quality of Life assessment also showed that DMD patients reported the lowest scores in brain health, including emotional health and school performance.

Other research has shown a correlation between cognitive function and survival in DMD. “This suggests that health maintenance may play an important role [in outcomes],” said Dr. Thangarajh. Another study found a correlation between psychomotor delay that required school-based interventions and earlier loss of ambulation, lower cardiac ejection fraction, and worse pulmonary function. The researchers also found that boys with cognitive delay were diagnosed at an earlier age, and yet had delays in diagnosis and worse motor function, pulmonary health, and cardiac health outcomes. On average, they lost ambulatory ability 2 years earlier.

A study by Dr. Thangarajh’s group showed that patients with speech delay and lower IQ had lower performance in timed tests, including 6-minute walk test distance and scored an average of 2 points lower on the North Star Ambulatory Assessment.
 

A tool for continuous cognitive assessment

The Centers for Disease Control and Prevention–supported DMD CARE guidelines only say that neuropsychological evaluations should be considered at diagnosis, but is essential if concerns arise about developmental progress. However, the Muscular Dystrophy Association has found barriers both in access to specialists, with an average wait time of 1-2 years, and burdensome out-of-pocket costs.

Those issues prompted Dr. Thangarajh to look for an alternative solution. At the time that she embarked on this work, the NIH was interested in technologies to assess neurobehavioral issues across different diseases. The resulting NIH Toolbox iPad app was driven largely by failed clinical trials in dementia, and the aim was to be able to provide continuous assessment over time. “It will allow for assessments across the lifespan, so you can use the same construct from age 3 to 80-plus,” said Dr. Thangarajh. It can also normalize population factors, such as annual household income and mother’s IQ.

She set out to validate the NIH Toolbox in children with DMD. The toolbox includes measures of crystalized cognition and fluid cognition. The former encompasses vocabulary and reading ability, which are strongly predicted by socioeconomic status and maternal IQ. On the other hand, fluid cognition includes cognitive features that develop across the lifespan and is directly related to academic underperformance in DMD patients.

Dr. Thangarajh’s group assessed 30 boys with DMD and found that crystallized cognition was normal, but they had a deficit in fluid cognition. They found deficits within several subdomains of fluid cognition. “This tells us that the NIH Toolbox was able to replicate what we had known in the literature, that these boys really have lower intellectual capacity, but they also have significant weakness in fluid cognition,” she said.

She also wanted to examine changes over time by testing the boys at a 1-year interview. “What we found was that they are not making as much gain in fluid cognition as we would like. They are just making marginal improvements over time. This has implications on how often we should screen them, but also not be over reliant on using school-based resources for them to get tested,” said Dr. Thangarajh.

Her group’s analysis of a dataset of 55 boys provided by PTC Therapeutics revealed a difference by age in a test of working memory. “What we found was that boys who are actually greater than 9 years, compared with those who are less than 9 years, they actually had a reversal of development-based improvement. The older they get, they were not making as much gains as you would expect,” said Dr. Thangarajh.

She went on to discuss psychosocial determinants of cognitive health in DMD. It is known that women who are carriers of the dystrophin mutation can underperform in cognitively stressful tasks, leading her to wonder if this could lead to transgenerational risk to offspring with DMD. Her group tested women who were carriers of the mutation with the NIH Toolbox and found that they had lower fluid cognition than noncarriers. They then tested 65 dyads of mothers and children, and found a correlation, but only when it came to inhibitory control, which required the individual to note the direction of an arrow while ignoring surrounding arrows pointing in various directions.

Next, the researchers examined neighborhoods and their impact on cognitive health, which can be affected by the presence of green spaces, access to public transportation and good nutrition, and other factors. There were significant deficits associated with residence zip codes. “We were pretty shocked. Someone who is not in a socially vulnerable region is scoring slightly below average, but someone who is in a very socially vulnerable neighborhood is only scoring 75 [age-adjusted score] on the NIH toolbox. So with this, we can conclude that carrier women are vulnerable in certain cognitive domains, but also children who come from socially vulnerable [situations] have poor cognitive control. This, again, has implications on how often we should screen and how much we should overly rely on school-based resources for these individuals,” said Dr. Thangarajh.
 

Overcoming a significant barrier

The NIH Toolbox has a lot of potential to improve DMD care, according to Dianna Quan, MD, who is the incoming president of AANEM, and professor of neurology at the University of Colorado at Denver, Aurora. “There’s this huge problem in terms of getting people in to see neuropsychologists and having formal evaluations. I think that’s a huge barrier. If we have people able to access this toolkit, which is simple and easily and universally accessible, how wonderful is that? I think that will be a really great improvement on what’s going on right now. It allows people to easily screen for these cognitive disabilities and make sure that we address them,” Dr. Quan said in an interview.

Asked how the tool could specifically improve care, Dr. Quan suggested that the first step is to understand the contributing factors to cognitive issues, whether they are biological, social, or a combination. “Some of them we can modify, potentially, through addressing the social environment. Some of those biologic factors may also be modifiable with many of the new drug studies that are coming.”

Dr. Thangarajh has received speaker honoraria from NS Pharma and PTC Therapeutics. Dr. Quan has received funding from Alnylam, Pfizer, Cytokinetics, Momenta, and Argenx.

Trastuzumab deruxtecan (T-DXd) provided sustained clinically meaningful improvement versus physician’s choice of treatment (TPC) for patients with advanced breast cancer and low HER2 expression in the randomized phase 3 DESTINY-Breast04 study, according to 32-month follow-up data.

The overall safety profile of the HER2-directed antibody drug conjugate was also comparable to that observed at the primary analysis in 2022, and longer exposure did not appear to increase toxicity, Shanu Modi, MD, reported on behalf of the DESTINY-Breast04 investigators at the European Society of Medical Oncology (ESMO) Congress 2023.

“These results continue to support the use of T-DXd as the new standard of care after one line of chemotherapy in patients with HER2-low metastatic breast cancer,” said Dr. Modi, a breast oncologist and attending physician at Memorial Sloan Kettering Cancer Center, New York.

DESTINY-Breast04 enrolled 557 patients 2:1 to receive 5.4 mg/kg of T-DXd every 3 weeks or physicians’ choice of capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel, and established HER2-low mBC as “a new targetable patient population with T-DXd as a new standard of care,” she explained.

Median overall survival (mOS) with a median of 18.4 months of follow-up at the Jan. 11, 2022, primary data cut-off was 23.4 months in the T-DXd arm versus 16.8 months in the TPC arm and 23.9 versus 17.5 months, respectively, in the hormone receptor–positive (HR+) cohort (hazard ratio, 0.64 for both groups). At the preplanned extended follow-up with data cut-off on March 1, 2023, the mOS was 22.9 versus 16.8 months for T-DXd versus TPC, and 23.9 versus 17.6 months for the HR+ cohort, respectively (HR, 0.69 for both).

Median progression-free survival (PFS) by investigator assessment was 8.8 versus 4.2 months for the full cohort, and 9.6 versus 4.2 months for the HR+ cohort (HR, 0.36 and 0.37, respectively). PFS was consistent with the results from the primary analysis.

The benefits in the HR+ patients were consistent across all patient subgroups, Dr. Modi noted.

“I do think it’s interesting to point out that at the landmark 2-year point, all patients on standard chemotherapy discontinued study treatment, whereas 15% on T-DXd remain [on treatment] without any evidence of disease progression, Dr. Modi added

An exploratory analysis in the hormone receptor–negative (HR–) cohort showed mOS of 18.2 versus 8.3 months at the primary analysis (HR, 0.48), and a “clinically meaningful and numerical advantage for T-DXd” persisted at the planned follow-up (mOS, 17.1 vs. 8.3; HR, 0.58), she said.

PFS in the HR- cohort was 8.5 versus 2.9 months at the primary analysis, and 6.3 versus 2.9 months at the update (HR, 0.46 and 0.29, respectively).

An assessment of post-study therapies received by patients showed that those therapies did not account for the significant survival advantage conferred by T-DXd, Dr. Modi said.

She noted, however, that while no new safety signals were observed at follow-up, lung toxicity remains a “toxicity of special interest,” having occurred in 12.1% of cases at the time of the primary analysis.

Most cases were grade 1 or 2, and no new cases were observed at follow-up, but one patient with lung toxicity and an initial grade 3 event experienced clinical deterioration and later died from lung toxicity, which underscores the importance of remaining vigilant and intervening promptly in all cases of lung toxicity, Dr. Modi stressed.

Invited discussant Giampaolo Bianchini, MD, reiterated that T-DXd is an effective treatment option and said, “we must accurately identify patients and avoid improperly denying this important therapeutic option.”

Although HER2-low disease is not a unique biological disease entity, it is a “practical and pragmatic definition used to select patients with ‘some degree’ of HER2 protein expression adopting a test and a scoring system already implemented in the routine clinical practice,” said Dr. Bianchini, head of the breast cancer group and head of clinical translational and immunotherapy research at IRCCS Ospedale, San Raffaele, Milan.

However, the current definition may be inadequate, he said, explaining that the ongoing DESTINY-Breast06 study “will challenge the current definition of what we consider HER2-low definition,” potentially extending the T-DXd indication to HER2 ultra-low.

Furthermore, current HER2 testing was designed to discriminate cases with high abundant protein – not for the low HER2 dynamic range, which leads to technical inaccuracy.

Given these considerations, he suggested considering a new biopsy, if feasible, in patients with an immunohistochemistry (IHC) score of 0 in all tumor biopsies, and having a revision performed by the pathologist.

In patients with an IHC score of 1 or greater only in one biopsy, there is no need to confirm the HER2-low status, he said.

DESTINY-Breast04 is funded by Daiichi Sankyo Inc. and AstraZeneca. Dr. Modi reported relationships with Daiichi Sankyo, Genentech, AstraZeneca, Seagen, and MacroGenics. Dr. Bianchini reported relationships with AstraZeneca, Daiichi Sankyo, Gilead, MSD, Seagen, Roche, Sanofi, Lilly, EISAI, Novartis, Pfizer, Stemline, Exact Science, and Agendia.

Trastuzumab deruxtecan (T-DXd) provided sustained clinically meaningful improvement versus physician’s choice of treatment (TPC) for patients with advanced breast cancer and low HER2 expression in the randomized phase 3 DESTINY-Breast04 study, according to 32-month follow-up data.

The overall safety profile of the HER2-directed antibody drug conjugate was also comparable to that observed at the primary analysis in 2022, and longer exposure did not appear to increase toxicity, Shanu Modi, MD, reported on behalf of the DESTINY-Breast04 investigators at the European Society of Medical Oncology (ESMO) Congress 2023.

“These results continue to support the use of T-DXd as the new standard of care after one line of chemotherapy in patients with HER2-low metastatic breast cancer,” said Dr. Modi, a breast oncologist and attending physician at Memorial Sloan Kettering Cancer Center, New York.

DESTINY-Breast04 enrolled 557 patients 2:1 to receive 5.4 mg/kg of T-DXd every 3 weeks or physicians’ choice of capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel, and established HER2-low mBC as “a new targetable patient population with T-DXd as a new standard of care,” she explained.

Median overall survival (mOS) with a median of 18.4 months of follow-up at the Jan. 11, 2022, primary data cut-off was 23.4 months in the T-DXd arm versus 16.8 months in the TPC arm and 23.9 versus 17.5 months, respectively, in the hormone receptor–positive (HR+) cohort (hazard ratio, 0.64 for both groups). At the preplanned extended follow-up with data cut-off on March 1, 2023, the mOS was 22.9 versus 16.8 months for T-DXd versus TPC, and 23.9 versus 17.6 months for the HR+ cohort, respectively (HR, 0.69 for both).

Median progression-free survival (PFS) by investigator assessment was 8.8 versus 4.2 months for the full cohort, and 9.6 versus 4.2 months for the HR+ cohort (HR, 0.36 and 0.37, respectively). PFS was consistent with the results from the primary analysis.

The benefits in the HR+ patients were consistent across all patient subgroups, Dr. Modi noted.

“I do think it’s interesting to point out that at the landmark 2-year point, all patients on standard chemotherapy discontinued study treatment, whereas 15% on T-DXd remain [on treatment] without any evidence of disease progression, Dr. Modi added

An exploratory analysis in the hormone receptor–negative (HR–) cohort showed mOS of 18.2 versus 8.3 months at the primary analysis (HR, 0.48), and a “clinically meaningful and numerical advantage for T-DXd” persisted at the planned follow-up (mOS, 17.1 vs. 8.3; HR, 0.58), she said.

PFS in the HR- cohort was 8.5 versus 2.9 months at the primary analysis, and 6.3 versus 2.9 months at the update (HR, 0.46 and 0.29, respectively).

An assessment of post-study therapies received by patients showed that those therapies did not account for the significant survival advantage conferred by T-DXd, Dr. Modi said.

She noted, however, that while no new safety signals were observed at follow-up, lung toxicity remains a “toxicity of special interest,” having occurred in 12.1% of cases at the time of the primary analysis.

Most cases were grade 1 or 2, and no new cases were observed at follow-up, but one patient with lung toxicity and an initial grade 3 event experienced clinical deterioration and later died from lung toxicity, which underscores the importance of remaining vigilant and intervening promptly in all cases of lung toxicity, Dr. Modi stressed.

Invited discussant Giampaolo Bianchini, MD, reiterated that T-DXd is an effective treatment option and said, “we must accurately identify patients and avoid improperly denying this important therapeutic option.”

Although HER2-low disease is not a unique biological disease entity, it is a “practical and pragmatic definition used to select patients with ‘some degree’ of HER2 protein expression adopting a test and a scoring system already implemented in the routine clinical practice,” said Dr. Bianchini, head of the breast cancer group and head of clinical translational and immunotherapy research at IRCCS Ospedale, San Raffaele, Milan.

However, the current definition may be inadequate, he said, explaining that the ongoing DESTINY-Breast06 study “will challenge the current definition of what we consider HER2-low definition,” potentially extending the T-DXd indication to HER2 ultra-low.

Furthermore, current HER2 testing was designed to discriminate cases with high abundant protein – not for the low HER2 dynamic range, which leads to technical inaccuracy.

Given these considerations, he suggested considering a new biopsy, if feasible, in patients with an immunohistochemistry (IHC) score of 0 in all tumor biopsies, and having a revision performed by the pathologist.

In patients with an IHC score of 1 or greater only in one biopsy, there is no need to confirm the HER2-low status, he said.

DESTINY-Breast04 is funded by Daiichi Sankyo Inc. and AstraZeneca. Dr. Modi reported relationships with Daiichi Sankyo, Genentech, AstraZeneca, Seagen, and MacroGenics. Dr. Bianchini reported relationships with AstraZeneca, Daiichi Sankyo, Gilead, MSD, Seagen, Roche, Sanofi, Lilly, EISAI, Novartis, Pfizer, Stemline, Exact Science, and Agendia.

Trastuzumab deruxtecan (T-DXd) provided sustained clinically meaningful improvement versus physician’s choice of treatment (TPC) for patients with advanced breast cancer and low HER2 expression in the randomized phase 3 DESTINY-Breast04 study, according to 32-month follow-up data.

The overall safety profile of the HER2-directed antibody drug conjugate was also comparable to that observed at the primary analysis in 2022, and longer exposure did not appear to increase toxicity, Shanu Modi, MD, reported on behalf of the DESTINY-Breast04 investigators at the European Society of Medical Oncology (ESMO) Congress 2023.

“These results continue to support the use of T-DXd as the new standard of care after one line of chemotherapy in patients with HER2-low metastatic breast cancer,” said Dr. Modi, a breast oncologist and attending physician at Memorial Sloan Kettering Cancer Center, New York.

DESTINY-Breast04 enrolled 557 patients 2:1 to receive 5.4 mg/kg of T-DXd every 3 weeks or physicians’ choice of capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel, and established HER2-low mBC as “a new targetable patient population with T-DXd as a new standard of care,” she explained.

Median overall survival (mOS) with a median of 18.4 months of follow-up at the Jan. 11, 2022, primary data cut-off was 23.4 months in the T-DXd arm versus 16.8 months in the TPC arm and 23.9 versus 17.5 months, respectively, in the hormone receptor–positive (HR+) cohort (hazard ratio, 0.64 for both groups). At the preplanned extended follow-up with data cut-off on March 1, 2023, the mOS was 22.9 versus 16.8 months for T-DXd versus TPC, and 23.9 versus 17.6 months for the HR+ cohort, respectively (HR, 0.69 for both).

Median progression-free survival (PFS) by investigator assessment was 8.8 versus 4.2 months for the full cohort, and 9.6 versus 4.2 months for the HR+ cohort (HR, 0.36 and 0.37, respectively). PFS was consistent with the results from the primary analysis.

The benefits in the HR+ patients were consistent across all patient subgroups, Dr. Modi noted.

“I do think it’s interesting to point out that at the landmark 2-year point, all patients on standard chemotherapy discontinued study treatment, whereas 15% on T-DXd remain [on treatment] without any evidence of disease progression, Dr. Modi added

An exploratory analysis in the hormone receptor–negative (HR–) cohort showed mOS of 18.2 versus 8.3 months at the primary analysis (HR, 0.48), and a “clinically meaningful and numerical advantage for T-DXd” persisted at the planned follow-up (mOS, 17.1 vs. 8.3; HR, 0.58), she said.

PFS in the HR- cohort was 8.5 versus 2.9 months at the primary analysis, and 6.3 versus 2.9 months at the update (HR, 0.46 and 0.29, respectively).

An assessment of post-study therapies received by patients showed that those therapies did not account for the significant survival advantage conferred by T-DXd, Dr. Modi said.

She noted, however, that while no new safety signals were observed at follow-up, lung toxicity remains a “toxicity of special interest,” having occurred in 12.1% of cases at the time of the primary analysis.

Most cases were grade 1 or 2, and no new cases were observed at follow-up, but one patient with lung toxicity and an initial grade 3 event experienced clinical deterioration and later died from lung toxicity, which underscores the importance of remaining vigilant and intervening promptly in all cases of lung toxicity, Dr. Modi stressed.

Invited discussant Giampaolo Bianchini, MD, reiterated that T-DXd is an effective treatment option and said, “we must accurately identify patients and avoid improperly denying this important therapeutic option.”

Although HER2-low disease is not a unique biological disease entity, it is a “practical and pragmatic definition used to select patients with ‘some degree’ of HER2 protein expression adopting a test and a scoring system already implemented in the routine clinical practice,” said Dr. Bianchini, head of the breast cancer group and head of clinical translational and immunotherapy research at IRCCS Ospedale, San Raffaele, Milan.

However, the current definition may be inadequate, he said, explaining that the ongoing DESTINY-Breast06 study “will challenge the current definition of what we consider HER2-low definition,” potentially extending the T-DXd indication to HER2 ultra-low.

Furthermore, current HER2 testing was designed to discriminate cases with high abundant protein – not for the low HER2 dynamic range, which leads to technical inaccuracy.

Given these considerations, he suggested considering a new biopsy, if feasible, in patients with an immunohistochemistry (IHC) score of 0 in all tumor biopsies, and having a revision performed by the pathologist.

In patients with an IHC score of 1 or greater only in one biopsy, there is no need to confirm the HER2-low status, he said.

DESTINY-Breast04 is funded by Daiichi Sankyo Inc. and AstraZeneca. Dr. Modi reported relationships with Daiichi Sankyo, Genentech, AstraZeneca, Seagen, and MacroGenics. Dr. Bianchini reported relationships with AstraZeneca, Daiichi Sankyo, Gilead, MSD, Seagen, Roche, Sanofi, Lilly, EISAI, Novartis, Pfizer, Stemline, Exact Science, and Agendia.

In October, the Diversity, Equity, and Inclusion in GI section of Gastroenterology and Clinical Gastroenterology and Hepatology features the article, “Parental Leave and Return-to-Work Policies: A Practical Model for Implementation in Gastroenterology.” 

The authors note that this article can serve as a roadmap for institutions and practices to create a parental leave policy and return-to-work environment that attracts talent and supports a diverse and thriving workforce. 

Despite a joint statement by the four main gastroenterology societies more than 25 years ago, few structural changes have been implemented to mandate a minimum of 12 weeks of parental leave for gastroenterologists. 

We asked one of the article’s authors, Dr. Lauren D. Feld, a few questions about the motivation behind this article and the movement at large.
 

Q: What motivated you and your coauthors to write this article?

A: “It was a pleasure working with my coauthors – an incredible team of gender equity experts – Drs. Amy S. Oxentenko, Dawn Sears, Aline Charabaty, Loren G. Rabinowitz, and Julie K. Silver. 

I’m grateful to Dr. May and Dr. Quezada for the invitation to write about the important topic of creating family-friendly work environments. My coauthors and I have noticed increasing support for women in gastroenterology.”

UMass

Q: Why is this issue important?

A: “Nationwide, women are leaving clinical and academic medicine at alarming rates. The incompatibility of parenthood with a traditional medical career has been identified as a major driver of retention issues across specialties. In addition to impacting retention, incompatibility with pregnancy and parenthood also impacts recruitment. Survey studies of internal medicine residents have identified concerns about family life as a major barrier to choosing gastroenterology as a specialty. Women in medicine have worked too hard to get to where they are to be excluded from or driven out of our field. 

Beyond the impact on the physicians, there is a major impact on patients. Studies have identified that women patients’ preference for a woman endoscopist as well as the difficulty in finding women endoscopists has created a barrier to colon cancer screening for women. Areas of research have also gone understudied because they primarily impact women patients. We must work towards equity for the benefit of both physicians and patients.”
 

Q: What actions can practicing GI doctors take now to help support better parental leave and return to work policies?

A: “Start by reviewing this article and asking your human resources for your employer’s policies in this area. If your employer doesn’t have a parental leave policy, or if their policy is inadequate, discuss the importance of this with your leadership. Describing the cost impact of physicians leaving practice is a good way to justify the cost investment to support family friendly policies.”

The authors recommend policies outlined in the paper be consistent across genders with attention to equity for the LGBTQ+ community. The blueprint for parental leave and return to work department policies includes:  

• Specific policies to support physicians during pregnancy, including endoscopy ergonomic accommodations. 
• Components of a parental leave policy such as duration and adjusted RVUs to account for leave. 
• Coverage models to consider during leave.  
• How to create a family friendly return to work, including modified overnight call during postpartum and autonomy over schedule.

In October, the Diversity, Equity, and Inclusion in GI section of Gastroenterology and Clinical Gastroenterology and Hepatology features the article, “Parental Leave and Return-to-Work Policies: A Practical Model for Implementation in Gastroenterology.” 

The authors note that this article can serve as a roadmap for institutions and practices to create a parental leave policy and return-to-work environment that attracts talent and supports a diverse and thriving workforce. 

Despite a joint statement by the four main gastroenterology societies more than 25 years ago, few structural changes have been implemented to mandate a minimum of 12 weeks of parental leave for gastroenterologists. 

We asked one of the article’s authors, Dr. Lauren D. Feld, a few questions about the motivation behind this article and the movement at large.
 

Q: What motivated you and your coauthors to write this article?

A: “It was a pleasure working with my coauthors – an incredible team of gender equity experts – Drs. Amy S. Oxentenko, Dawn Sears, Aline Charabaty, Loren G. Rabinowitz, and Julie K. Silver. 

I’m grateful to Dr. May and Dr. Quezada for the invitation to write about the important topic of creating family-friendly work environments. My coauthors and I have noticed increasing support for women in gastroenterology.”

UMass

Q: Why is this issue important?

A: “Nationwide, women are leaving clinical and academic medicine at alarming rates. The incompatibility of parenthood with a traditional medical career has been identified as a major driver of retention issues across specialties. In addition to impacting retention, incompatibility with pregnancy and parenthood also impacts recruitment. Survey studies of internal medicine residents have identified concerns about family life as a major barrier to choosing gastroenterology as a specialty. Women in medicine have worked too hard to get to where they are to be excluded from or driven out of our field. 

Beyond the impact on the physicians, there is a major impact on patients. Studies have identified that women patients’ preference for a woman endoscopist as well as the difficulty in finding women endoscopists has created a barrier to colon cancer screening for women. Areas of research have also gone understudied because they primarily impact women patients. We must work towards equity for the benefit of both physicians and patients.”
 

Q: What actions can practicing GI doctors take now to help support better parental leave and return to work policies?

A: “Start by reviewing this article and asking your human resources for your employer’s policies in this area. If your employer doesn’t have a parental leave policy, or if their policy is inadequate, discuss the importance of this with your leadership. Describing the cost impact of physicians leaving practice is a good way to justify the cost investment to support family friendly policies.”

The authors recommend policies outlined in the paper be consistent across genders with attention to equity for the LGBTQ+ community. The blueprint for parental leave and return to work department policies includes:  

• Specific policies to support physicians during pregnancy, including endoscopy ergonomic accommodations. 
• Components of a parental leave policy such as duration and adjusted RVUs to account for leave. 
• Coverage models to consider during leave.  
• How to create a family friendly return to work, including modified overnight call during postpartum and autonomy over schedule.

In October, the Diversity, Equity, and Inclusion in GI section of Gastroenterology and Clinical Gastroenterology and Hepatology features the article, “Parental Leave and Return-to-Work Policies: A Practical Model for Implementation in Gastroenterology.” 

The authors note that this article can serve as a roadmap for institutions and practices to create a parental leave policy and return-to-work environment that attracts talent and supports a diverse and thriving workforce. 

Despite a joint statement by the four main gastroenterology societies more than 25 years ago, few structural changes have been implemented to mandate a minimum of 12 weeks of parental leave for gastroenterologists. 

We asked one of the article’s authors, Dr. Lauren D. Feld, a few questions about the motivation behind this article and the movement at large.
 

Q: What motivated you and your coauthors to write this article?

A: “It was a pleasure working with my coauthors – an incredible team of gender equity experts – Drs. Amy S. Oxentenko, Dawn Sears, Aline Charabaty, Loren G. Rabinowitz, and Julie K. Silver. 

I’m grateful to Dr. May and Dr. Quezada for the invitation to write about the important topic of creating family-friendly work environments. My coauthors and I have noticed increasing support for women in gastroenterology.”

UMass

Q: Why is this issue important?

A: “Nationwide, women are leaving clinical and academic medicine at alarming rates. The incompatibility of parenthood with a traditional medical career has been identified as a major driver of retention issues across specialties. In addition to impacting retention, incompatibility with pregnancy and parenthood also impacts recruitment. Survey studies of internal medicine residents have identified concerns about family life as a major barrier to choosing gastroenterology as a specialty. Women in medicine have worked too hard to get to where they are to be excluded from or driven out of our field. 

Beyond the impact on the physicians, there is a major impact on patients. Studies have identified that women patients’ preference for a woman endoscopist as well as the difficulty in finding women endoscopists has created a barrier to colon cancer screening for women. Areas of research have also gone understudied because they primarily impact women patients. We must work towards equity for the benefit of both physicians and patients.”
 

Q: What actions can practicing GI doctors take now to help support better parental leave and return to work policies?

A: “Start by reviewing this article and asking your human resources for your employer’s policies in this area. If your employer doesn’t have a parental leave policy, or if their policy is inadequate, discuss the importance of this with your leadership. Describing the cost impact of physicians leaving practice is a good way to justify the cost investment to support family friendly policies.”

The authors recommend policies outlined in the paper be consistent across genders with attention to equity for the LGBTQ+ community. The blueprint for parental leave and return to work department policies includes:  

• Specific policies to support physicians during pregnancy, including endoscopy ergonomic accommodations. 
• Components of a parental leave policy such as duration and adjusted RVUs to account for leave. 
• Coverage models to consider during leave.  
• How to create a family friendly return to work, including modified overnight call during postpartum and autonomy over schedule.

PHOENIX – Subcutaneous efgartigimod PH20 SC shows efficacy and tolerability in the treatment of chronic inflammatory demyelinating polyneuropathy (CIDP), providing a convenient alternative to intravenous and other older treatments for this rare disease.

“This was the largest study of CIDP that has been performed, with over 600 patients screened and 322 enrolled, and was the first to use an adjudication committee to confirm the diagnosis,” said study investigator Richard Lewis, MD, of the department of neurology, Cedars-Sinai Medical Center, Los Angeles.

Furthermore, “this is the first new treatment for CIDP in over 30 years, so it’s very exciting. It is a brief subcutaneous injection, which should be something that patients will appreciate,” he said.

The study was presented at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).
 

Filling an unmet need

A rare and often-debilitating autoimmune disorder, CIDP is characterized by weakness and numbness that can result in disability, pain, and fatigue and has been linked to IgG autoantibodies.

Treatments include corticosteroids, intravenous immunoglobulin (IVIg), subcutaneous immunoglobulin, and plasma exchange, but not all patients achieve meaningful benefits and many patients complain about safety risks, costs, and burdensome treatment regimens.

“There is an unmet need for a first-line treatment with long-term efficacy that maintains or improves quality of life, has an early onset of action, is well tolerated, is not dependent on plasma donation, and has greater convenience,” the investigators wrote in their abstract.

Efgartigimod, which is approved in its intravenous and subcutaneous forms for the treatment of myasthenia gravis, is a human IgG1 antibody Fc receptor blocker designed to reduce pathogenic IgG autoantibody levels, which may be drivers of pathogenesis in CIDP.

The therapy is a coformulation of efgartigimod and recombinant human hyaluronidase that allows for rapid subcutaneous administration of larger volumes and is administered as a 90-second subcutaneous injection once weekly.

For the ongoing phase 2 ADHERE trial, 322 patients with a diagnosis of CIDP and active disease who were either treatment naive or receiving standard treatments were withdrawn from their treatments prior to day 1 of a run-in period of up to 12 weeks.

They then entered stage A of the study, an open-label phase in which all were treated with 1,000-mg efgartigimod PH20 SC weekly for up to 12 weeks.

Of those patients, 66% showed evidence of clinical improvement and a rapid onset of effect with the efgartigimod PH20 SC treatment, and 70% of the patients were then entered into stage B, a double-blind randomized phase, with 111 of patients receiving continued efgartigimod PH20 SC weekly and 110 receiving placebo for 48 weeks.

Of those moving on to stage B, more than 70% were on IVIg prior to the time of enrollment.

The study met its primary endpoint, with the efgartigimod PH20 SC groups showing a 61% lower risk for relapse on the basis of time to a first adjusted Inflammatory Neuropathy Cause and Treatment deterioration, compared with placebo (hazard ratio, 0.39; P = .000039).

Clinical benefits were also observed on the Inflammatory Rasch-built Overall Disability Scale (I-RODS) and in measures of mean grip strength in all groups regardless of prior CIDP medication.

Specifically, efgartigimod patients had a mean improvement of 7.7 points on I-RODS and 12.3 kPa on mean grip strength in stage A, which was maintained in stage B. These were partially lost in patients receiving placebo.

In terms of safety, most adverse events were mild or moderate in severity, and no new safety signals were identified with up to 60 weeks of treatment. There were no increased infection rates with increased exposure.

The findings show that “efgartigimod-PH20, given as a 90-second subcutaneous injection once a week, was effective in treating patients with CIDP who had relapsed when taken off their previous treatment (IVIg or corticosteroids),” said Dr. Lewis.

“[The study] then showed that the majority of patients, over 70%, maintained that improvement, compared with placebo, where over 50% relapsed – most within 8 weeks, so the treatment, which reduces circulating immunoglobulin G by over 70%, is effective in treating CIDP,” he added.

Plans for this ongoing trial include recruiting up to 360 patients until 88 events of clinical deterioration have been observed in stage B.
 

Promising data

Commenting on the study, Karissa Gable, MD, an associate professor of neurology at Duke University, Durham, N.C., said that the “initial data reported from the ADHERE study is very promising and demonstrated significant efficacy.”

The study’s use of an adjudication committee in confirming the diagnosis is particularly notable, she said. “The trial design demonstrated confirmation of diagnosis and activity of disease and response to drug prior to randomization, which is a novel design that is particularly applicable to patients with CIDP given the rate of misdiagnosis and placebo effect found in other trials.”

Dr. Gable agreed that new options are important to address an unmet need in CIDP.

“The current first-line treatments are generally 80%-90% effective, however, there are limited options with respect to the first line treatments due to side effects and comorbid disease in patients,” she explained.

“Other treatments options are needed and so this is an unmet need in patients with CIDP,” Dr. Gable said. “This medication will be likely to be one that will provide a strong alternate option for treatment.”

Overall, “this is a novel mechanism for drug treatment for CIDP and seems to demonstrate efficacy and good safety and tolerability based on the initial report of the data,” Dr. Gable added.

“It will likely be a promising medication to use for these patients to fill the unmet need for treatment of patients with CIDP.”

The study was sponsored by Argenx. Dr. Lewis disclosed relationships with Argenx and other companies involved in neuromuscular disease therapies. Dr. Gable is on the global medical advisory board steering committee for Argenx and she was the principal investigator at her site for the Adhere study. Dr. Gable has served as a consultant for Immunovant and Takeda as well as Sanofi for CIDP and she is on the Takeda speaker bureau for Huyquvia for treatment of CIDP.

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

PHOENIX – Subcutaneous efgartigimod PH20 SC shows efficacy and tolerability in the treatment of chronic inflammatory demyelinating polyneuropathy (CIDP), providing a convenient alternative to intravenous and other older treatments for this rare disease.

“This was the largest study of CIDP that has been performed, with over 600 patients screened and 322 enrolled, and was the first to use an adjudication committee to confirm the diagnosis,” said study investigator Richard Lewis, MD, of the department of neurology, Cedars-Sinai Medical Center, Los Angeles.

Furthermore, “this is the first new treatment for CIDP in over 30 years, so it’s very exciting. It is a brief subcutaneous injection, which should be something that patients will appreciate,” he said.

The study was presented at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).
 

Filling an unmet need

A rare and often-debilitating autoimmune disorder, CIDP is characterized by weakness and numbness that can result in disability, pain, and fatigue and has been linked to IgG autoantibodies.

Treatments include corticosteroids, intravenous immunoglobulin (IVIg), subcutaneous immunoglobulin, and plasma exchange, but not all patients achieve meaningful benefits and many patients complain about safety risks, costs, and burdensome treatment regimens.

“There is an unmet need for a first-line treatment with long-term efficacy that maintains or improves quality of life, has an early onset of action, is well tolerated, is not dependent on plasma donation, and has greater convenience,” the investigators wrote in their abstract.

Efgartigimod, which is approved in its intravenous and subcutaneous forms for the treatment of myasthenia gravis, is a human IgG1 antibody Fc receptor blocker designed to reduce pathogenic IgG autoantibody levels, which may be drivers of pathogenesis in CIDP.

The therapy is a coformulation of efgartigimod and recombinant human hyaluronidase that allows for rapid subcutaneous administration of larger volumes and is administered as a 90-second subcutaneous injection once weekly.

For the ongoing phase 2 ADHERE trial, 322 patients with a diagnosis of CIDP and active disease who were either treatment naive or receiving standard treatments were withdrawn from their treatments prior to day 1 of a run-in period of up to 12 weeks.

They then entered stage A of the study, an open-label phase in which all were treated with 1,000-mg efgartigimod PH20 SC weekly for up to 12 weeks.

Of those patients, 66% showed evidence of clinical improvement and a rapid onset of effect with the efgartigimod PH20 SC treatment, and 70% of the patients were then entered into stage B, a double-blind randomized phase, with 111 of patients receiving continued efgartigimod PH20 SC weekly and 110 receiving placebo for 48 weeks.

Of those moving on to stage B, more than 70% were on IVIg prior to the time of enrollment.

The study met its primary endpoint, with the efgartigimod PH20 SC groups showing a 61% lower risk for relapse on the basis of time to a first adjusted Inflammatory Neuropathy Cause and Treatment deterioration, compared with placebo (hazard ratio, 0.39; P = .000039).

Clinical benefits were also observed on the Inflammatory Rasch-built Overall Disability Scale (I-RODS) and in measures of mean grip strength in all groups regardless of prior CIDP medication.

Specifically, efgartigimod patients had a mean improvement of 7.7 points on I-RODS and 12.3 kPa on mean grip strength in stage A, which was maintained in stage B. These were partially lost in patients receiving placebo.

In terms of safety, most adverse events were mild or moderate in severity, and no new safety signals were identified with up to 60 weeks of treatment. There were no increased infection rates with increased exposure.

The findings show that “efgartigimod-PH20, given as a 90-second subcutaneous injection once a week, was effective in treating patients with CIDP who had relapsed when taken off their previous treatment (IVIg or corticosteroids),” said Dr. Lewis.

“[The study] then showed that the majority of patients, over 70%, maintained that improvement, compared with placebo, where over 50% relapsed – most within 8 weeks, so the treatment, which reduces circulating immunoglobulin G by over 70%, is effective in treating CIDP,” he added.

Plans for this ongoing trial include recruiting up to 360 patients until 88 events of clinical deterioration have been observed in stage B.
 

Promising data

Commenting on the study, Karissa Gable, MD, an associate professor of neurology at Duke University, Durham, N.C., said that the “initial data reported from the ADHERE study is very promising and demonstrated significant efficacy.”

The study’s use of an adjudication committee in confirming the diagnosis is particularly notable, she said. “The trial design demonstrated confirmation of diagnosis and activity of disease and response to drug prior to randomization, which is a novel design that is particularly applicable to patients with CIDP given the rate of misdiagnosis and placebo effect found in other trials.”

Dr. Gable agreed that new options are important to address an unmet need in CIDP.

“The current first-line treatments are generally 80%-90% effective, however, there are limited options with respect to the first line treatments due to side effects and comorbid disease in patients,” she explained.

“Other treatments options are needed and so this is an unmet need in patients with CIDP,” Dr. Gable said. “This medication will be likely to be one that will provide a strong alternate option for treatment.”

Overall, “this is a novel mechanism for drug treatment for CIDP and seems to demonstrate efficacy and good safety and tolerability based on the initial report of the data,” Dr. Gable added.

“It will likely be a promising medication to use for these patients to fill the unmet need for treatment of patients with CIDP.”

The study was sponsored by Argenx. Dr. Lewis disclosed relationships with Argenx and other companies involved in neuromuscular disease therapies. Dr. Gable is on the global medical advisory board steering committee for Argenx and she was the principal investigator at her site for the Adhere study. Dr. Gable has served as a consultant for Immunovant and Takeda as well as Sanofi for CIDP and she is on the Takeda speaker bureau for Huyquvia for treatment of CIDP.

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

PHOENIX – Subcutaneous efgartigimod PH20 SC shows efficacy and tolerability in the treatment of chronic inflammatory demyelinating polyneuropathy (CIDP), providing a convenient alternative to intravenous and other older treatments for this rare disease.

“This was the largest study of CIDP that has been performed, with over 600 patients screened and 322 enrolled, and was the first to use an adjudication committee to confirm the diagnosis,” said study investigator Richard Lewis, MD, of the department of neurology, Cedars-Sinai Medical Center, Los Angeles.

Furthermore, “this is the first new treatment for CIDP in over 30 years, so it’s very exciting. It is a brief subcutaneous injection, which should be something that patients will appreciate,” he said.

The study was presented at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).
 

Filling an unmet need

A rare and often-debilitating autoimmune disorder, CIDP is characterized by weakness and numbness that can result in disability, pain, and fatigue and has been linked to IgG autoantibodies.

Treatments include corticosteroids, intravenous immunoglobulin (IVIg), subcutaneous immunoglobulin, and plasma exchange, but not all patients achieve meaningful benefits and many patients complain about safety risks, costs, and burdensome treatment regimens.

“There is an unmet need for a first-line treatment with long-term efficacy that maintains or improves quality of life, has an early onset of action, is well tolerated, is not dependent on plasma donation, and has greater convenience,” the investigators wrote in their abstract.

Efgartigimod, which is approved in its intravenous and subcutaneous forms for the treatment of myasthenia gravis, is a human IgG1 antibody Fc receptor blocker designed to reduce pathogenic IgG autoantibody levels, which may be drivers of pathogenesis in CIDP.

The therapy is a coformulation of efgartigimod and recombinant human hyaluronidase that allows for rapid subcutaneous administration of larger volumes and is administered as a 90-second subcutaneous injection once weekly.

For the ongoing phase 2 ADHERE trial, 322 patients with a diagnosis of CIDP and active disease who were either treatment naive or receiving standard treatments were withdrawn from their treatments prior to day 1 of a run-in period of up to 12 weeks.

They then entered stage A of the study, an open-label phase in which all were treated with 1,000-mg efgartigimod PH20 SC weekly for up to 12 weeks.

Of those patients, 66% showed evidence of clinical improvement and a rapid onset of effect with the efgartigimod PH20 SC treatment, and 70% of the patients were then entered into stage B, a double-blind randomized phase, with 111 of patients receiving continued efgartigimod PH20 SC weekly and 110 receiving placebo for 48 weeks.

Of those moving on to stage B, more than 70% were on IVIg prior to the time of enrollment.

The study met its primary endpoint, with the efgartigimod PH20 SC groups showing a 61% lower risk for relapse on the basis of time to a first adjusted Inflammatory Neuropathy Cause and Treatment deterioration, compared with placebo (hazard ratio, 0.39; P = .000039).

Clinical benefits were also observed on the Inflammatory Rasch-built Overall Disability Scale (I-RODS) and in measures of mean grip strength in all groups regardless of prior CIDP medication.

Specifically, efgartigimod patients had a mean improvement of 7.7 points on I-RODS and 12.3 kPa on mean grip strength in stage A, which was maintained in stage B. These were partially lost in patients receiving placebo.

In terms of safety, most adverse events were mild or moderate in severity, and no new safety signals were identified with up to 60 weeks of treatment. There were no increased infection rates with increased exposure.

The findings show that “efgartigimod-PH20, given as a 90-second subcutaneous injection once a week, was effective in treating patients with CIDP who had relapsed when taken off their previous treatment (IVIg or corticosteroids),” said Dr. Lewis.

“[The study] then showed that the majority of patients, over 70%, maintained that improvement, compared with placebo, where over 50% relapsed – most within 8 weeks, so the treatment, which reduces circulating immunoglobulin G by over 70%, is effective in treating CIDP,” he added.

Plans for this ongoing trial include recruiting up to 360 patients until 88 events of clinical deterioration have been observed in stage B.
 

Promising data

Commenting on the study, Karissa Gable, MD, an associate professor of neurology at Duke University, Durham, N.C., said that the “initial data reported from the ADHERE study is very promising and demonstrated significant efficacy.”

The study’s use of an adjudication committee in confirming the diagnosis is particularly notable, she said. “The trial design demonstrated confirmation of diagnosis and activity of disease and response to drug prior to randomization, which is a novel design that is particularly applicable to patients with CIDP given the rate of misdiagnosis and placebo effect found in other trials.”

Dr. Gable agreed that new options are important to address an unmet need in CIDP.

“The current first-line treatments are generally 80%-90% effective, however, there are limited options with respect to the first line treatments due to side effects and comorbid disease in patients,” she explained.

“Other treatments options are needed and so this is an unmet need in patients with CIDP,” Dr. Gable said. “This medication will be likely to be one that will provide a strong alternate option for treatment.”

Overall, “this is a novel mechanism for drug treatment for CIDP and seems to demonstrate efficacy and good safety and tolerability based on the initial report of the data,” Dr. Gable added.

“It will likely be a promising medication to use for these patients to fill the unmet need for treatment of patients with CIDP.”

The study was sponsored by Argenx. Dr. Lewis disclosed relationships with Argenx and other companies involved in neuromuscular disease therapies. Dr. Gable is on the global medical advisory board steering committee for Argenx and she was the principal investigator at her site for the Adhere study. Dr. Gable has served as a consultant for Immunovant and Takeda as well as Sanofi for CIDP and she is on the Takeda speaker bureau for Huyquvia for treatment of CIDP.

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

In a significant move that will fundamentally change the way clinicians bill for telemedicine services, the American Medical Association has unveiled 17 new Evaluation and Management (E/M) Current Procedural Terminology (CPT) codes specifically for telemedicine visits scheduled for release in CPT 2025. The AMA says the new codes are designed to bring the coding system up to date with the changing landscape of health care and reflect the realities of modern medical practice.

The 17 new CPT codes will encompass a variety of telemedicine services. While the official language of the codes has not been released yet, codes for telemedicine visits using a real-time audio-visual platform could be organized similarly to existing office/outpatient E/M visits (99202-99205, 99212-99215). As part of these revisions, the current telephone E/M codes (99441-99443) will be deleted and replaced with new codes for audio-only E/M.

Implementation of so many codes will require health care providers and systems to adapt their documentation and coding practices. Typically, the exact language and code numbers for new and revised codes are not released to the public until fall of the preceding year, leaving only a few months for practices to educate their physicians and coding staff and prepare their internal systems for implementation starting Jan. 1, 2025. However, given the significant education and systems changes that will be necessary to prepare for so many new codes, we will advocate that the AMA release this information in early 2024.

Additionally, the reimbursement for telemedicine services may not ultimately be the same as for in-person E/M office visits. The AMA/Specialty Society RVS Update Committee (RUC) provides recommendations to the Centers for Medicare & Medicaid Services (CMS) for consideration in developing Relative Value Units (RVUs) for new procedures, including the telemedicine codes. The RUC’s recommendations for the telemedicine codes are not yet publicly available. However, it is important to note that regardless of the RUC recommendations, CMS makes all final decisions about Medicare payment. CMS could decide to set the payments for the telemedicine codes at parity with in-person office E/M visits or less than, more than, or some combination at the individual code level.

If payments for telemedicine visits are set at parity with or higher than office E/M visits, practices can focus primarily on physician and staff education and system implementation of the new codes. However, if telemedicine visit payments are less than in-person E/M office visits, it would have significant implications for practices, providers, and patients. Providers might be discouraged from offering virtual care, leading to a disparity in the availability of telehealth services, with patients in some areas or with certain conditions having limited access. Additionally, not all patients have access to a smartphone or stable internet. Research has shown increased use of audio-only visits among marginalized groups including African Americans, non-English speakers, older patients, those with public insurance as opposed to private insurance and patients living in rural communities and communities with low broadband access. For these patients, audio-only is a lifeline that allows them to access needed care.

Hughes HK, Hasselfeld BW, Greene JA. Health Care Access on the Line - Audio-Only Visits and Digitally Inclusive Care. N Engl J Med. 2022 Nov 17;387(20):1823-1826. doi: 10.1056/NEJMp2118292. Epub 2022 Nov 12. PMID: 36373819.

Chen J, Li KY, Andino J, Hill CE, Ng S, Steppe E, Ellimoottil C. Predictors of Audio-Only Versus Video Telehealth Visits During the COVID-19 Pandemic. J Gen Intern Med. 2022 Apr;37(5):1138-1144. doi: 10.1007/s11606-021-07172-y. Epub 2021 Nov 17. PMID: 34791589; PMCID: PMC8597874.

If payment for audio-only is significantly less than in-person office E/M payments, practices may not offer this option furthering health care inequities.

Beyond the extensive preparation needed and the financial implications, there could be impacts to coverage policies. Currently, telemedicine coverage is triggered by reporting the appropriate office E/M level visit with telemedicine modifier 95. If the new telemedicine codes are no longer tied to the in-person codes, laws requiring payers to provide coverage and parity may need to be adjusted accordingly or they could become less effective. If coverage parity is not maintained, that may lead to changes in practice that could also worsen access and health disparities. Some insurers have already started rolling back coverages. Recently, Aetna decided to stop covering telemedicine visits as of Dec. 1, 2023.

https://apps.availity.com/web/core/vault/vault/v1/files/336562/Kad1BQ9kR/c8ba0f72-6752-461d-a994-03ac8c047f3c?cacheBust=1696965544

Other insurers may follow suit.

As practices prepare for 2024, tracking insurance coverage policies for telemedicine, staying alert for information from the AMA about the new telemedicine CPT codes, and monitoring the proposed payments for telemedicine that CMS will release in late June to early July in the 2025 Medicare Physician Fee Schedule proposed rule will be important. Participation in advocacy efforts will be critical once the full details are released by the AMA and CMS about the new telemedicine codes and their proposed values. The AGA is monitoring this issue and will continue to fight to reduce burden to physicians and practices, which includes fighting for payment parity with in-person office E/M visits and maintaining coverage benefits for patients.

The authors have reported no conflicts of interest.

In a significant move that will fundamentally change the way clinicians bill for telemedicine services, the American Medical Association has unveiled 17 new Evaluation and Management (E/M) Current Procedural Terminology (CPT) codes specifically for telemedicine visits scheduled for release in CPT 2025. The AMA says the new codes are designed to bring the coding system up to date with the changing landscape of health care and reflect the realities of modern medical practice.

The 17 new CPT codes will encompass a variety of telemedicine services. While the official language of the codes has not been released yet, codes for telemedicine visits using a real-time audio-visual platform could be organized similarly to existing office/outpatient E/M visits (99202-99205, 99212-99215). As part of these revisions, the current telephone E/M codes (99441-99443) will be deleted and replaced with new codes for audio-only E/M.

Implementation of so many codes will require health care providers and systems to adapt their documentation and coding practices. Typically, the exact language and code numbers for new and revised codes are not released to the public until fall of the preceding year, leaving only a few months for practices to educate their physicians and coding staff and prepare their internal systems for implementation starting Jan. 1, 2025. However, given the significant education and systems changes that will be necessary to prepare for so many new codes, we will advocate that the AMA release this information in early 2024.

Additionally, the reimbursement for telemedicine services may not ultimately be the same as for in-person E/M office visits. The AMA/Specialty Society RVS Update Committee (RUC) provides recommendations to the Centers for Medicare & Medicaid Services (CMS) for consideration in developing Relative Value Units (RVUs) for new procedures, including the telemedicine codes. The RUC’s recommendations for the telemedicine codes are not yet publicly available. However, it is important to note that regardless of the RUC recommendations, CMS makes all final decisions about Medicare payment. CMS could decide to set the payments for the telemedicine codes at parity with in-person office E/M visits or less than, more than, or some combination at the individual code level.

If payments for telemedicine visits are set at parity with or higher than office E/M visits, practices can focus primarily on physician and staff education and system implementation of the new codes. However, if telemedicine visit payments are less than in-person E/M office visits, it would have significant implications for practices, providers, and patients. Providers might be discouraged from offering virtual care, leading to a disparity in the availability of telehealth services, with patients in some areas or with certain conditions having limited access. Additionally, not all patients have access to a smartphone or stable internet. Research has shown increased use of audio-only visits among marginalized groups including African Americans, non-English speakers, older patients, those with public insurance as opposed to private insurance and patients living in rural communities and communities with low broadband access. For these patients, audio-only is a lifeline that allows them to access needed care.

Hughes HK, Hasselfeld BW, Greene JA. Health Care Access on the Line - Audio-Only Visits and Digitally Inclusive Care. N Engl J Med. 2022 Nov 17;387(20):1823-1826. doi: 10.1056/NEJMp2118292. Epub 2022 Nov 12. PMID: 36373819.

Chen J, Li KY, Andino J, Hill CE, Ng S, Steppe E, Ellimoottil C. Predictors of Audio-Only Versus Video Telehealth Visits During the COVID-19 Pandemic. J Gen Intern Med. 2022 Apr;37(5):1138-1144. doi: 10.1007/s11606-021-07172-y. Epub 2021 Nov 17. PMID: 34791589; PMCID: PMC8597874.

If payment for audio-only is significantly less than in-person office E/M payments, practices may not offer this option furthering health care inequities.

Beyond the extensive preparation needed and the financial implications, there could be impacts to coverage policies. Currently, telemedicine coverage is triggered by reporting the appropriate office E/M level visit with telemedicine modifier 95. If the new telemedicine codes are no longer tied to the in-person codes, laws requiring payers to provide coverage and parity may need to be adjusted accordingly or they could become less effective. If coverage parity is not maintained, that may lead to changes in practice that could also worsen access and health disparities. Some insurers have already started rolling back coverages. Recently, Aetna decided to stop covering telemedicine visits as of Dec. 1, 2023.

https://apps.availity.com/web/core/vault/vault/v1/files/336562/Kad1BQ9kR/c8ba0f72-6752-461d-a994-03ac8c047f3c?cacheBust=1696965544

Other insurers may follow suit.

As practices prepare for 2024, tracking insurance coverage policies for telemedicine, staying alert for information from the AMA about the new telemedicine CPT codes, and monitoring the proposed payments for telemedicine that CMS will release in late June to early July in the 2025 Medicare Physician Fee Schedule proposed rule will be important. Participation in advocacy efforts will be critical once the full details are released by the AMA and CMS about the new telemedicine codes and their proposed values. The AGA is monitoring this issue and will continue to fight to reduce burden to physicians and practices, which includes fighting for payment parity with in-person office E/M visits and maintaining coverage benefits for patients.

The authors have reported no conflicts of interest.

In a significant move that will fundamentally change the way clinicians bill for telemedicine services, the American Medical Association has unveiled 17 new Evaluation and Management (E/M) Current Procedural Terminology (CPT) codes specifically for telemedicine visits scheduled for release in CPT 2025. The AMA says the new codes are designed to bring the coding system up to date with the changing landscape of health care and reflect the realities of modern medical practice.

The 17 new CPT codes will encompass a variety of telemedicine services. While the official language of the codes has not been released yet, codes for telemedicine visits using a real-time audio-visual platform could be organized similarly to existing office/outpatient E/M visits (99202-99205, 99212-99215). As part of these revisions, the current telephone E/M codes (99441-99443) will be deleted and replaced with new codes for audio-only E/M.

Implementation of so many codes will require health care providers and systems to adapt their documentation and coding practices. Typically, the exact language and code numbers for new and revised codes are not released to the public until fall of the preceding year, leaving only a few months for practices to educate their physicians and coding staff and prepare their internal systems for implementation starting Jan. 1, 2025. However, given the significant education and systems changes that will be necessary to prepare for so many new codes, we will advocate that the AMA release this information in early 2024.

Additionally, the reimbursement for telemedicine services may not ultimately be the same as for in-person E/M office visits. The AMA/Specialty Society RVS Update Committee (RUC) provides recommendations to the Centers for Medicare & Medicaid Services (CMS) for consideration in developing Relative Value Units (RVUs) for new procedures, including the telemedicine codes. The RUC’s recommendations for the telemedicine codes are not yet publicly available. However, it is important to note that regardless of the RUC recommendations, CMS makes all final decisions about Medicare payment. CMS could decide to set the payments for the telemedicine codes at parity with in-person office E/M visits or less than, more than, or some combination at the individual code level.

If payments for telemedicine visits are set at parity with or higher than office E/M visits, practices can focus primarily on physician and staff education and system implementation of the new codes. However, if telemedicine visit payments are less than in-person E/M office visits, it would have significant implications for practices, providers, and patients. Providers might be discouraged from offering virtual care, leading to a disparity in the availability of telehealth services, with patients in some areas or with certain conditions having limited access. Additionally, not all patients have access to a smartphone or stable internet. Research has shown increased use of audio-only visits among marginalized groups including African Americans, non-English speakers, older patients, those with public insurance as opposed to private insurance and patients living in rural communities and communities with low broadband access. For these patients, audio-only is a lifeline that allows them to access needed care.

Hughes HK, Hasselfeld BW, Greene JA. Health Care Access on the Line - Audio-Only Visits and Digitally Inclusive Care. N Engl J Med. 2022 Nov 17;387(20):1823-1826. doi: 10.1056/NEJMp2118292. Epub 2022 Nov 12. PMID: 36373819.

Chen J, Li KY, Andino J, Hill CE, Ng S, Steppe E, Ellimoottil C. Predictors of Audio-Only Versus Video Telehealth Visits During the COVID-19 Pandemic. J Gen Intern Med. 2022 Apr;37(5):1138-1144. doi: 10.1007/s11606-021-07172-y. Epub 2021 Nov 17. PMID: 34791589; PMCID: PMC8597874.

If payment for audio-only is significantly less than in-person office E/M payments, practices may not offer this option furthering health care inequities.

Beyond the extensive preparation needed and the financial implications, there could be impacts to coverage policies. Currently, telemedicine coverage is triggered by reporting the appropriate office E/M level visit with telemedicine modifier 95. If the new telemedicine codes are no longer tied to the in-person codes, laws requiring payers to provide coverage and parity may need to be adjusted accordingly or they could become less effective. If coverage parity is not maintained, that may lead to changes in practice that could also worsen access and health disparities. Some insurers have already started rolling back coverages. Recently, Aetna decided to stop covering telemedicine visits as of Dec. 1, 2023.

https://apps.availity.com/web/core/vault/vault/v1/files/336562/Kad1BQ9kR/c8ba0f72-6752-461d-a994-03ac8c047f3c?cacheBust=1696965544

Other insurers may follow suit.

As practices prepare for 2024, tracking insurance coverage policies for telemedicine, staying alert for information from the AMA about the new telemedicine CPT codes, and monitoring the proposed payments for telemedicine that CMS will release in late June to early July in the 2025 Medicare Physician Fee Schedule proposed rule will be important. Participation in advocacy efforts will be critical once the full details are released by the AMA and CMS about the new telemedicine codes and their proposed values. The AGA is monitoring this issue and will continue to fight to reduce burden to physicians and practices, which includes fighting for payment parity with in-person office E/M visits and maintaining coverage benefits for patients.

The authors have reported no conflicts of interest.

Could antidepressants hold the key to treating long COVID? University of Pennsylvania researchers have uncovered a link between long COVID and levels of serotonin in the body that may offer a new explanation for the condition. The study even points to a possible treatment.

Serotonin is a neurotransmitter that has many functions in the body and is targeted by the most commonly prescribed antidepressants – the selective serotonin reuptake inhibitors.

Serotonin is widely studied for its effects on the brain – it regulates the messaging between neurons, affecting sleep, mood, and memory. It is present in the gut, is found in cells along the gastrointestinal tract, and is absorbed by blood platelets. Gut serotonin, known as circulating serotonin, is responsible for a host of other functions, including the regulation of blood flow, body temperature, and digestion.

Low levels of serotonin could result in any number of seemingly unrelated symptoms, as in the case of long COVID, experts say. The condition affects about 7% of Americans and is associated with a wide range of health problems, including fatigue, shortness of breath, neurological symptoms, joint pain, blood clots, heart palpitations, and digestive problems.

Long COVID is difficult to treat because researchers haven’t been able to pinpoint the underlying mechanisms that cause prolonged illness after a SARS-CoV-2 infection, said study author Christoph A. Thaiss, PhD, an assistant professor of microbiology at the Perelman School of Medicine at the University of Pennsylvania.

The hope is that this study could have implications for new treatments, he said.

“Long COVID can have manifestations not only in the brain but in many different parts of the body, so it’s possible that serotonin reductions are involved in many different aspects of the disease,” said Dr. Thaiss.

Dr. Thaiss’s study, published in the journal Cell, found lower serotonin levels in long COVID patients, compared with patients who were diagnosed with acute COVID-19 but who fully recovered.

His team found that reductions in serotonin were driven by low levels of circulating SARS-CoV-2 virus that caused persistent inflammation as well as an inability of the body to absorb tryptophan, an amino acid that’s a precursor to serotonin. Overactive blood platelets were also shown to play a role; they serve as the primary means of serotonin absorption.

The study doesn’t make any recommendations for treatment, but understanding the role of serotonin in long COVID opens the door to a host of novel ideas that could set the stage for clinical trials and affect care.

“The study gives us a few possible targets that could be used in future clinical studies,” Dr. Thaiss said.

Persistent circulating virus is one of the drivers of low serotonin levels, said study author Michael Peluso, MD, an assistant research professor of infectious medicine at the University of California, San Francisco, School of Medicine. This points to the need to reduce viral load using antiviral medications like nirmatrelvir/ritonavir (Paxlovid), which is approved by the U.S. Food and Drug Administration for the treatment of COVID-19, and VV116, which has not yet been approved for use against COVID.

Research published in the New England Journal of Medicine found that the oral antiviral agent VV116 was as effective as nirmatrelvir/ritonavir in reducing the body’s viral load and aiding recovery from SARS-CoV-2 infection. Paxlovid has also been shown to reduce the likelihood of getting long COVID after an acute SARS-CoV-2 infection.

Researchers are investigating ways to target serotonin levels directly, potentially using SSRIs. But first they need to study whether improvement in serotonin level makes a difference.

“What we need now is a good clinical trial to see whether altering levels of serotonin in people with long COVID will lead to symptom relief,” Dr. Peluso said.

Indeed, the research did show that the SSRI fluoxetine, as well as a glycine-tryptophan supplement, improved cognitive function in SARS-CoV-2-infected rodent models, which were used in a portion of the study.

David F. Putrino, PhD, who runs the long COVID clinic at Mount Sinai Health System in New York City, said the research is helping “to paint a biological picture” that’s in line with other research on the mechanisms that cause long COVID symptoms.

But Dr. Putrino, who was not involved in the study, cautions against treating long COVID patients with SSRIs or any other treatment that increases serotonin before testing patients to determine whether their serotonin levels are actually lower than those of healthy persons.

“We don’t want to assume that every patient with long COVID is going to have lower serotonin levels,” said Dr. Putrino.

What’s more, researchers need to investigate whether SSRIs increase levels of circulating serotonin. It’s important to note that researchers found lower levels of circulating serotonin but that serotonin levels in the brain remained normal.

Traditionally, SSRIs are used clinically for increasing the levels of serotonin in the brain, not the body.

“Whether that’s going to contribute to an increase in systemic levels of serotonin, that’s something that needs to be tested,” said Akiko Iwasaki, PhD, co-lead investigator of the Yale School of Medicine, New Haven, Conn., COVID-19 Recovery Study, who was not involved in the research.

Thus far, investigators have not identified one unifying biomarker that seems to cause long COVID in all patients, said Dr. Iwasaki. Some research has found higher levels of certain immune cells and biomarkers: for example, monocytes and activated B lymphocytes, indicating a stronger and ongoing antibody response to the virus. Other recent research conducted by Dr. Iwasaki, Dr. Putrino, and others, published in the journal Nature, showed that long COVID patients tend to have lower levels of cortisol, which could be a factor in the extreme fatigue experienced by many who suffer from the condition.

The findings in the study in The Cell are promising, but they need to be replicated in more people, said Dr. Iwasaki. And even if they’re replicated in a larger study population, this would still be just one biomarker that is associated with one subtype of the disease. There is a need to better understand which biomarkers go with which symptoms so that the most effective treatments can be identified, she said.

Both Dr. Putrino and Dr. Iwasaki contended that there isn’t a single factor that can explain all of long COVID. It’s a complex disease caused by a host of different mechanisms.

Still, low levels of serotonin could be an important piece of the puzzle. The next step, said Dr. Iwasaki, is to uncover how many of the millions of Americans with long COVID have this biomarker.

“People working in the field of long COVID should now be considering this pathway and thinking of ways to measure serotonin in their patients.”

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

Could antidepressants hold the key to treating long COVID? University of Pennsylvania researchers have uncovered a link between long COVID and levels of serotonin in the body that may offer a new explanation for the condition. The study even points to a possible treatment.

Serotonin is a neurotransmitter that has many functions in the body and is targeted by the most commonly prescribed antidepressants – the selective serotonin reuptake inhibitors.

Serotonin is widely studied for its effects on the brain – it regulates the messaging between neurons, affecting sleep, mood, and memory. It is present in the gut, is found in cells along the gastrointestinal tract, and is absorbed by blood platelets. Gut serotonin, known as circulating serotonin, is responsible for a host of other functions, including the regulation of blood flow, body temperature, and digestion.

Low levels of serotonin could result in any number of seemingly unrelated symptoms, as in the case of long COVID, experts say. The condition affects about 7% of Americans and is associated with a wide range of health problems, including fatigue, shortness of breath, neurological symptoms, joint pain, blood clots, heart palpitations, and digestive problems.

Long COVID is difficult to treat because researchers haven’t been able to pinpoint the underlying mechanisms that cause prolonged illness after a SARS-CoV-2 infection, said study author Christoph A. Thaiss, PhD, an assistant professor of microbiology at the Perelman School of Medicine at the University of Pennsylvania.

The hope is that this study could have implications for new treatments, he said.

“Long COVID can have manifestations not only in the brain but in many different parts of the body, so it’s possible that serotonin reductions are involved in many different aspects of the disease,” said Dr. Thaiss.

Dr. Thaiss’s study, published in the journal Cell, found lower serotonin levels in long COVID patients, compared with patients who were diagnosed with acute COVID-19 but who fully recovered.

His team found that reductions in serotonin were driven by low levels of circulating SARS-CoV-2 virus that caused persistent inflammation as well as an inability of the body to absorb tryptophan, an amino acid that’s a precursor to serotonin. Overactive blood platelets were also shown to play a role; they serve as the primary means of serotonin absorption.

The study doesn’t make any recommendations for treatment, but understanding the role of serotonin in long COVID opens the door to a host of novel ideas that could set the stage for clinical trials and affect care.

“The study gives us a few possible targets that could be used in future clinical studies,” Dr. Thaiss said.

Persistent circulating virus is one of the drivers of low serotonin levels, said study author Michael Peluso, MD, an assistant research professor of infectious medicine at the University of California, San Francisco, School of Medicine. This points to the need to reduce viral load using antiviral medications like nirmatrelvir/ritonavir (Paxlovid), which is approved by the U.S. Food and Drug Administration for the treatment of COVID-19, and VV116, which has not yet been approved for use against COVID.

Research published in the New England Journal of Medicine found that the oral antiviral agent VV116 was as effective as nirmatrelvir/ritonavir in reducing the body’s viral load and aiding recovery from SARS-CoV-2 infection. Paxlovid has also been shown to reduce the likelihood of getting long COVID after an acute SARS-CoV-2 infection.

Researchers are investigating ways to target serotonin levels directly, potentially using SSRIs. But first they need to study whether improvement in serotonin level makes a difference.

“What we need now is a good clinical trial to see whether altering levels of serotonin in people with long COVID will lead to symptom relief,” Dr. Peluso said.

Indeed, the research did show that the SSRI fluoxetine, as well as a glycine-tryptophan supplement, improved cognitive function in SARS-CoV-2-infected rodent models, which were used in a portion of the study.

David F. Putrino, PhD, who runs the long COVID clinic at Mount Sinai Health System in New York City, said the research is helping “to paint a biological picture” that’s in line with other research on the mechanisms that cause long COVID symptoms.

But Dr. Putrino, who was not involved in the study, cautions against treating long COVID patients with SSRIs or any other treatment that increases serotonin before testing patients to determine whether their serotonin levels are actually lower than those of healthy persons.

“We don’t want to assume that every patient with long COVID is going to have lower serotonin levels,” said Dr. Putrino.

What’s more, researchers need to investigate whether SSRIs increase levels of circulating serotonin. It’s important to note that researchers found lower levels of circulating serotonin but that serotonin levels in the brain remained normal.

Traditionally, SSRIs are used clinically for increasing the levels of serotonin in the brain, not the body.

“Whether that’s going to contribute to an increase in systemic levels of serotonin, that’s something that needs to be tested,” said Akiko Iwasaki, PhD, co-lead investigator of the Yale School of Medicine, New Haven, Conn., COVID-19 Recovery Study, who was not involved in the research.

Thus far, investigators have not identified one unifying biomarker that seems to cause long COVID in all patients, said Dr. Iwasaki. Some research has found higher levels of certain immune cells and biomarkers: for example, monocytes and activated B lymphocytes, indicating a stronger and ongoing antibody response to the virus. Other recent research conducted by Dr. Iwasaki, Dr. Putrino, and others, published in the journal Nature, showed that long COVID patients tend to have lower levels of cortisol, which could be a factor in the extreme fatigue experienced by many who suffer from the condition.

The findings in the study in The Cell are promising, but they need to be replicated in more people, said Dr. Iwasaki. And even if they’re replicated in a larger study population, this would still be just one biomarker that is associated with one subtype of the disease. There is a need to better understand which biomarkers go with which symptoms so that the most effective treatments can be identified, she said.

Both Dr. Putrino and Dr. Iwasaki contended that there isn’t a single factor that can explain all of long COVID. It’s a complex disease caused by a host of different mechanisms.

Still, low levels of serotonin could be an important piece of the puzzle. The next step, said Dr. Iwasaki, is to uncover how many of the millions of Americans with long COVID have this biomarker.

“People working in the field of long COVID should now be considering this pathway and thinking of ways to measure serotonin in their patients.”

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

Could antidepressants hold the key to treating long COVID? University of Pennsylvania researchers have uncovered a link between long COVID and levels of serotonin in the body that may offer a new explanation for the condition. The study even points to a possible treatment.

Serotonin is a neurotransmitter that has many functions in the body and is targeted by the most commonly prescribed antidepressants – the selective serotonin reuptake inhibitors.

Serotonin is widely studied for its effects on the brain – it regulates the messaging between neurons, affecting sleep, mood, and memory. It is present in the gut, is found in cells along the gastrointestinal tract, and is absorbed by blood platelets. Gut serotonin, known as circulating serotonin, is responsible for a host of other functions, including the regulation of blood flow, body temperature, and digestion.

Low levels of serotonin could result in any number of seemingly unrelated symptoms, as in the case of long COVID, experts say. The condition affects about 7% of Americans and is associated with a wide range of health problems, including fatigue, shortness of breath, neurological symptoms, joint pain, blood clots, heart palpitations, and digestive problems.

Long COVID is difficult to treat because researchers haven’t been able to pinpoint the underlying mechanisms that cause prolonged illness after a SARS-CoV-2 infection, said study author Christoph A. Thaiss, PhD, an assistant professor of microbiology at the Perelman School of Medicine at the University of Pennsylvania.

The hope is that this study could have implications for new treatments, he said.

“Long COVID can have manifestations not only in the brain but in many different parts of the body, so it’s possible that serotonin reductions are involved in many different aspects of the disease,” said Dr. Thaiss.

Dr. Thaiss’s study, published in the journal Cell, found lower serotonin levels in long COVID patients, compared with patients who were diagnosed with acute COVID-19 but who fully recovered.

His team found that reductions in serotonin were driven by low levels of circulating SARS-CoV-2 virus that caused persistent inflammation as well as an inability of the body to absorb tryptophan, an amino acid that’s a precursor to serotonin. Overactive blood platelets were also shown to play a role; they serve as the primary means of serotonin absorption.

The study doesn’t make any recommendations for treatment, but understanding the role of serotonin in long COVID opens the door to a host of novel ideas that could set the stage for clinical trials and affect care.

“The study gives us a few possible targets that could be used in future clinical studies,” Dr. Thaiss said.

Persistent circulating virus is one of the drivers of low serotonin levels, said study author Michael Peluso, MD, an assistant research professor of infectious medicine at the University of California, San Francisco, School of Medicine. This points to the need to reduce viral load using antiviral medications like nirmatrelvir/ritonavir (Paxlovid), which is approved by the U.S. Food and Drug Administration for the treatment of COVID-19, and VV116, which has not yet been approved for use against COVID.

Research published in the New England Journal of Medicine found that the oral antiviral agent VV116 was as effective as nirmatrelvir/ritonavir in reducing the body’s viral load and aiding recovery from SARS-CoV-2 infection. Paxlovid has also been shown to reduce the likelihood of getting long COVID after an acute SARS-CoV-2 infection.

Researchers are investigating ways to target serotonin levels directly, potentially using SSRIs. But first they need to study whether improvement in serotonin level makes a difference.

“What we need now is a good clinical trial to see whether altering levels of serotonin in people with long COVID will lead to symptom relief,” Dr. Peluso said.

Indeed, the research did show that the SSRI fluoxetine, as well as a glycine-tryptophan supplement, improved cognitive function in SARS-CoV-2-infected rodent models, which were used in a portion of the study.

David F. Putrino, PhD, who runs the long COVID clinic at Mount Sinai Health System in New York City, said the research is helping “to paint a biological picture” that’s in line with other research on the mechanisms that cause long COVID symptoms.

But Dr. Putrino, who was not involved in the study, cautions against treating long COVID patients with SSRIs or any other treatment that increases serotonin before testing patients to determine whether their serotonin levels are actually lower than those of healthy persons.

“We don’t want to assume that every patient with long COVID is going to have lower serotonin levels,” said Dr. Putrino.

What’s more, researchers need to investigate whether SSRIs increase levels of circulating serotonin. It’s important to note that researchers found lower levels of circulating serotonin but that serotonin levels in the brain remained normal.

Traditionally, SSRIs are used clinically for increasing the levels of serotonin in the brain, not the body.

“Whether that’s going to contribute to an increase in systemic levels of serotonin, that’s something that needs to be tested,” said Akiko Iwasaki, PhD, co-lead investigator of the Yale School of Medicine, New Haven, Conn., COVID-19 Recovery Study, who was not involved in the research.

Thus far, investigators have not identified one unifying biomarker that seems to cause long COVID in all patients, said Dr. Iwasaki. Some research has found higher levels of certain immune cells and biomarkers: for example, monocytes and activated B lymphocytes, indicating a stronger and ongoing antibody response to the virus. Other recent research conducted by Dr. Iwasaki, Dr. Putrino, and others, published in the journal Nature, showed that long COVID patients tend to have lower levels of cortisol, which could be a factor in the extreme fatigue experienced by many who suffer from the condition.

The findings in the study in The Cell are promising, but they need to be replicated in more people, said Dr. Iwasaki. And even if they’re replicated in a larger study population, this would still be just one biomarker that is associated with one subtype of the disease. There is a need to better understand which biomarkers go with which symptoms so that the most effective treatments can be identified, she said.

Both Dr. Putrino and Dr. Iwasaki contended that there isn’t a single factor that can explain all of long COVID. It’s a complex disease caused by a host of different mechanisms.

Still, low levels of serotonin could be an important piece of the puzzle. The next step, said Dr. Iwasaki, is to uncover how many of the millions of Americans with long COVID have this biomarker.

“People working in the field of long COVID should now be considering this pathway and thinking of ways to measure serotonin in their patients.”

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

Clinicians are well aware of the benefits of physical activity and the consequences of inactivity. 

Managing the diseases associated with inactivity – heart disease, type 2 diabetes, hypertension – falls to physicians. So one might assume they routinely prescribe exercise to their patients, just as they would statins, insulin, or beta-blockers. 

But evidence indicates that doctors don’t routinely have those conversations. They may lack confidence in their ability to give effective advice, fear offending patients, or simply not know what to say.

That’s understandable. Many doctors receive little training on how to counsel patients to exercise, according to research over the past decade. Despite efforts to improve this, many medical students still feel unprepared to prescribe physical activity to patients.

But here’s the thing: Doctors are in a unique position to change things.

Only 28% of Americans meet physical activity guidelines, according to the U.S. Centers for Disease Control and Prevention. At the same time, other research suggests that patients want to be more active and would like help from their doctor.

“Patients are motivated to hear about physical activity from physicians and try to make a change,” says Jane Thornton, MD, PhD, an assistant professor in family medicine at Western University, Ont. “Just saying something, even if you don’t have specialized knowledge, makes a difference because of the credibility we have as physicians.”

Conveniently, just like exercise, the best way to get started is to ... get started.

Here’s how to break down the process into steps.
 

1. Ask patients about their physical activity

Think of this as taking any kind of patient history, only for physical activity.

Do they have a regular exercise routine? For how many minutes a day are they active? How many days a week?

“It takes less than a minute to ask and record,” Dr. Thornton says. Once you put it into the patient’s electronic record, you have something you can track.
 

2. Write an actual prescription

By giving the patient a written, printed prescription when they leave your office, “you’re showing it’s an important part of treatment or prevention,” Dr. Thornton explains. It puts physical activity on the level of a vital sign.

Include frequency, intensity, time, and type of exercise. The American College of Sports Medicine’s Exercise is Medicine initiative provides a prescription template you can use.
 

3. Measure what they do

Measurement helps the patient adopt the new behavior, and it helps the physician provide tailored advice going forward, Dr. Thornton says.

With the rise of health-monitoring wearables, tracking activity has never been easier. Of course, not everyone wants to (or can afford to) use a smartwatch or fitness tracker.

For tech-averse patients, ask if they’re willing to write something down, like how many minutes they spent walking, or how many yoga classes they attended. You may never get this from some patients, but it never hurts to ask.
 

4. Refer out when necessary

This brings us to a sticky issue for many physicians: lack of confidence in their ability to speak authoritatively about physical activity. “In most cases, you can absolutely say, ‘Start slow, go gradually,’ that kind of thing,” Dr. Thornton says. “As with anything, confidence will come with practice.”

For specific prescriptive advice, check out the Exercise is Medicine website, which also has handouts you can share with patients and information for specific conditions. If your patient has prediabetes, you can also point them toward the CDC’s diabetes prevention program, which is available in-person or online and may be free or covered by insurance.

If a patient has contraindications, refer out. If you don’t have exercise or rehab professionals in your network, Dr. Thornton recommends reaching out to your regional or national association of sports-medicine professionals. You should be able to find it with a quick Google search.
 

5. Follow up

Ask about physical activity during every contact, either in person or online. 

Dr. Thornton says the second and fifth steps matter most to patients, especially when the prescription and follow-up come from their primary care physician, rather than a nurse or physician assistant to whom you’ve delegated the task.

“The value comes in having a physician emphasize the importance,” Dr. Thornton says. The more time you spend on it, the more that value comes through.
 

What NOT to say to patients about exercise

This might surprise you: 

“I definitely don’t think telling people the official recommendations for physical activity is useful,” says Yoni Freedhoff, MD, an associate professor of family medicine at the University of Ottawa and medical director of the Bariatric Medical Institute. “If anything, I’d venture it’s counterproductive.”

It’s not that there’s anything wrong with the recommended minimum – 150 minutes of moderate-to-vigorous-intensity physical activity per week. The problem is what it says to a patient who doesn’t come close to those standards. 

“Few real-world people have the interest, time, energy, or privilege to achieve them,” Dr. Freedhoff says. “Many will recognize that instantly and consequently feel [that] less than that is pointless.”

And that, Dr. Thornton says, is categorically not true. “Even minimal physical activity, in some cases, is beneficial.”

You also want to avoid any explicit connection between exercise and weight loss, Dr. Thornton says.

Though many people do connect the two, the link is often negative, notes a 2019 study from the University of Toronto., triggering painful memories that might go all the way back to gym class. 

Try this pivot from Dr. Freedhoff: “Focus on the role of exercise in mitigating the risks of weight,” he says – like decreasing pain, increasing energy, and improving sleep.
 

How to motivate patients to move

New research backs up this more positive approach. In a study published in Annals of Internal Medicine, doctors in the United Kingdom who emphasized benefits and minimized health harms convinced more patients to join a weight management program than negative or neutral docs did. These doctors conveyed optimism and excitement, smiling and avoiding any mention of obesity or body mass index.

Exactly what benefits inspire change will be different for each patient. But in general, the more immediate the benefit, the more motivating it will be. 

As the University of Toronto study noted, patients weren’t motivated by vague, distant goals like “increasing life expectancy or avoiding health problems many years in the future.”

They’re much more likely to take action to avoid surgery, reduce medications, or minimize the risk of falling. 

For an older patient, Dr. Freedhoff says, “focusing on the preservation of functional independence can be extremely motivating.” That’s especially true if the patient has vivid memories of seeing a sedentary loved one decline late in life. 

For patients who may be more focused on appearance, they could respond to the idea of improving their body composition. For that, “we talk about the quality of weight loss,” says Spencer Nadolsky, DO, an obesity and lipid specialist and medical director of WeightWatchers. “Ultimately, exercise helps shape the body instead of just changing the number on the scale.”
 

Reducing resistance to resistance training

A conversation about reshaping the body or avoiding age-related disabilities leads naturally to resistance training.  

“I always frame resistance training as the single most valuable thing a person might do to try to preserve their functional independence,” Dr. Freedhoff says. If the patient is over 65, he won’t wait for them to show an interest. “I’ll absolutely bring it up with them directly.”

Dr. Freedhoff has an on-site training facility where trainers show patients how to work out at home with minimal equipment, like dumbbells and resistance bands. 

Most doctors, however, don’t have those options. That can lead to a tricky conversation. Participants in the University of Toronto study told the authors they disliked the gym, finding it “boring, intimidating, or discouraging.” 

And yet, “a common suggestion ... from health care providers was to join a gym.”

Many patients, Spencer Nadolsky, MD, says, associate strength training with “grunting, groaning, or getting ‘bulky’ vs. ‘toned.’ ” Memories of soreness from overzealous workouts are another barrier.

He recommends “starting small and slow,” with one or two full-body workouts a week. Those initial workouts might include just one to two sets of four to five exercises. “Consider if someone is exercising at home or in a gym to build a routine around equipment that’s available to them,” Dr. Nadolsky says.

Once you determine what you have to work with, help the patient choose exercises that fit their needs, goals, preferences, limitations, and prior injuries.

One more consideration: While Dr. Nadolsky tries to “stay away from telling a patient they need to do specific types of exercise to be successful,” he makes an exception for patients who’re taking a GLP-1 agonist. “There is a concern for muscle mass loss along with fat loss.”
 

Practicing, preaching, and checking privilege

When Dr. Thornton, Dr. Freedhoff, and Dr. Nadolsky discuss exercise, their patients know they practice what they preach. 

Dr. Nadolsky, who was a nationally ranked wrestler at the University of North Carolina, hosts the Docs Who Lift podcast with his brother, Karl Nadolsky, MD. 

Dr. Freedhoff is also a lifter and fitness enthusiast, and Dr. Thornton was a world-class rower whose team came within 0.8 seconds of a silver medal at the Beijing Olympics. (They finished fourth.)

But not all physicians follow their own lifestyle advice, Dr. Freedhoff says. That doesn’t make them bad doctors – it makes them human.

“I’ve done 300 minutes a week of exercise” – the recommended amount for weight maintenance – “to see what’s involved,” Dr. Freedhoff says. “That’s far, far, far from a trivial amount.”

That leads to this advice for his fellow physicians:

“The most important thing to know about exercise is that finding the time and having the health to do so is a privilege,” he says. 

Understanding that is crucial for assessing your patient’s needs and providing the right help.

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

Clinicians are well aware of the benefits of physical activity and the consequences of inactivity. 

Managing the diseases associated with inactivity – heart disease, type 2 diabetes, hypertension – falls to physicians. So one might assume they routinely prescribe exercise to their patients, just as they would statins, insulin, or beta-blockers. 

But evidence indicates that doctors don’t routinely have those conversations. They may lack confidence in their ability to give effective advice, fear offending patients, or simply not know what to say.

That’s understandable. Many doctors receive little training on how to counsel patients to exercise, according to research over the past decade. Despite efforts to improve this, many medical students still feel unprepared to prescribe physical activity to patients.

But here’s the thing: Doctors are in a unique position to change things.

Only 28% of Americans meet physical activity guidelines, according to the U.S. Centers for Disease Control and Prevention. At the same time, other research suggests that patients want to be more active and would like help from their doctor.

“Patients are motivated to hear about physical activity from physicians and try to make a change,” says Jane Thornton, MD, PhD, an assistant professor in family medicine at Western University, Ont. “Just saying something, even if you don’t have specialized knowledge, makes a difference because of the credibility we have as physicians.”

Conveniently, just like exercise, the best way to get started is to ... get started.

Here’s how to break down the process into steps.
 

1. Ask patients about their physical activity

Think of this as taking any kind of patient history, only for physical activity.

Do they have a regular exercise routine? For how many minutes a day are they active? How many days a week?

“It takes less than a minute to ask and record,” Dr. Thornton says. Once you put it into the patient’s electronic record, you have something you can track.
 

2. Write an actual prescription

By giving the patient a written, printed prescription when they leave your office, “you’re showing it’s an important part of treatment or prevention,” Dr. Thornton explains. It puts physical activity on the level of a vital sign.

Include frequency, intensity, time, and type of exercise. The American College of Sports Medicine’s Exercise is Medicine initiative provides a prescription template you can use.
 

3. Measure what they do

Measurement helps the patient adopt the new behavior, and it helps the physician provide tailored advice going forward, Dr. Thornton says.

With the rise of health-monitoring wearables, tracking activity has never been easier. Of course, not everyone wants to (or can afford to) use a smartwatch or fitness tracker.

For tech-averse patients, ask if they’re willing to write something down, like how many minutes they spent walking, or how many yoga classes they attended. You may never get this from some patients, but it never hurts to ask.
 

4. Refer out when necessary

This brings us to a sticky issue for many physicians: lack of confidence in their ability to speak authoritatively about physical activity. “In most cases, you can absolutely say, ‘Start slow, go gradually,’ that kind of thing,” Dr. Thornton says. “As with anything, confidence will come with practice.”

For specific prescriptive advice, check out the Exercise is Medicine website, which also has handouts you can share with patients and information for specific conditions. If your patient has prediabetes, you can also point them toward the CDC’s diabetes prevention program, which is available in-person or online and may be free or covered by insurance.

If a patient has contraindications, refer out. If you don’t have exercise or rehab professionals in your network, Dr. Thornton recommends reaching out to your regional or national association of sports-medicine professionals. You should be able to find it with a quick Google search.
 

5. Follow up

Ask about physical activity during every contact, either in person or online. 

Dr. Thornton says the second and fifth steps matter most to patients, especially when the prescription and follow-up come from their primary care physician, rather than a nurse or physician assistant to whom you’ve delegated the task.

“The value comes in having a physician emphasize the importance,” Dr. Thornton says. The more time you spend on it, the more that value comes through.
 

What NOT to say to patients about exercise

This might surprise you: 

“I definitely don’t think telling people the official recommendations for physical activity is useful,” says Yoni Freedhoff, MD, an associate professor of family medicine at the University of Ottawa and medical director of the Bariatric Medical Institute. “If anything, I’d venture it’s counterproductive.”

It’s not that there’s anything wrong with the recommended minimum – 150 minutes of moderate-to-vigorous-intensity physical activity per week. The problem is what it says to a patient who doesn’t come close to those standards. 

“Few real-world people have the interest, time, energy, or privilege to achieve them,” Dr. Freedhoff says. “Many will recognize that instantly and consequently feel [that] less than that is pointless.”

And that, Dr. Thornton says, is categorically not true. “Even minimal physical activity, in some cases, is beneficial.”

You also want to avoid any explicit connection between exercise and weight loss, Dr. Thornton says.

Though many people do connect the two, the link is often negative, notes a 2019 study from the University of Toronto., triggering painful memories that might go all the way back to gym class. 

Try this pivot from Dr. Freedhoff: “Focus on the role of exercise in mitigating the risks of weight,” he says – like decreasing pain, increasing energy, and improving sleep.
 

How to motivate patients to move

New research backs up this more positive approach. In a study published in Annals of Internal Medicine, doctors in the United Kingdom who emphasized benefits and minimized health harms convinced more patients to join a weight management program than negative or neutral docs did. These doctors conveyed optimism and excitement, smiling and avoiding any mention of obesity or body mass index.

Exactly what benefits inspire change will be different for each patient. But in general, the more immediate the benefit, the more motivating it will be. 

As the University of Toronto study noted, patients weren’t motivated by vague, distant goals like “increasing life expectancy or avoiding health problems many years in the future.”

They’re much more likely to take action to avoid surgery, reduce medications, or minimize the risk of falling. 

For an older patient, Dr. Freedhoff says, “focusing on the preservation of functional independence can be extremely motivating.” That’s especially true if the patient has vivid memories of seeing a sedentary loved one decline late in life. 

For patients who may be more focused on appearance, they could respond to the idea of improving their body composition. For that, “we talk about the quality of weight loss,” says Spencer Nadolsky, DO, an obesity and lipid specialist and medical director of WeightWatchers. “Ultimately, exercise helps shape the body instead of just changing the number on the scale.”
 

Reducing resistance to resistance training

A conversation about reshaping the body or avoiding age-related disabilities leads naturally to resistance training.  

“I always frame resistance training as the single most valuable thing a person might do to try to preserve their functional independence,” Dr. Freedhoff says. If the patient is over 65, he won’t wait for them to show an interest. “I’ll absolutely bring it up with them directly.”

Dr. Freedhoff has an on-site training facility where trainers show patients how to work out at home with minimal equipment, like dumbbells and resistance bands. 

Most doctors, however, don’t have those options. That can lead to a tricky conversation. Participants in the University of Toronto study told the authors they disliked the gym, finding it “boring, intimidating, or discouraging.” 

And yet, “a common suggestion ... from health care providers was to join a gym.”

Many patients, Spencer Nadolsky, MD, says, associate strength training with “grunting, groaning, or getting ‘bulky’ vs. ‘toned.’ ” Memories of soreness from overzealous workouts are another barrier.

He recommends “starting small and slow,” with one or two full-body workouts a week. Those initial workouts might include just one to two sets of four to five exercises. “Consider if someone is exercising at home or in a gym to build a routine around equipment that’s available to them,” Dr. Nadolsky says.

Once you determine what you have to work with, help the patient choose exercises that fit their needs, goals, preferences, limitations, and prior injuries.

One more consideration: While Dr. Nadolsky tries to “stay away from telling a patient they need to do specific types of exercise to be successful,” he makes an exception for patients who’re taking a GLP-1 agonist. “There is a concern for muscle mass loss along with fat loss.”
 

Practicing, preaching, and checking privilege

When Dr. Thornton, Dr. Freedhoff, and Dr. Nadolsky discuss exercise, their patients know they practice what they preach. 

Dr. Nadolsky, who was a nationally ranked wrestler at the University of North Carolina, hosts the Docs Who Lift podcast with his brother, Karl Nadolsky, MD. 

Dr. Freedhoff is also a lifter and fitness enthusiast, and Dr. Thornton was a world-class rower whose team came within 0.8 seconds of a silver medal at the Beijing Olympics. (They finished fourth.)

But not all physicians follow their own lifestyle advice, Dr. Freedhoff says. That doesn’t make them bad doctors – it makes them human.

“I’ve done 300 minutes a week of exercise” – the recommended amount for weight maintenance – “to see what’s involved,” Dr. Freedhoff says. “That’s far, far, far from a trivial amount.”

That leads to this advice for his fellow physicians:

“The most important thing to know about exercise is that finding the time and having the health to do so is a privilege,” he says. 

Understanding that is crucial for assessing your patient’s needs and providing the right help.

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

Clinicians are well aware of the benefits of physical activity and the consequences of inactivity. 

Managing the diseases associated with inactivity – heart disease, type 2 diabetes, hypertension – falls to physicians. So one might assume they routinely prescribe exercise to their patients, just as they would statins, insulin, or beta-blockers. 

But evidence indicates that doctors don’t routinely have those conversations. They may lack confidence in their ability to give effective advice, fear offending patients, or simply not know what to say.

That’s understandable. Many doctors receive little training on how to counsel patients to exercise, according to research over the past decade. Despite efforts to improve this, many medical students still feel unprepared to prescribe physical activity to patients.

But here’s the thing: Doctors are in a unique position to change things.

Only 28% of Americans meet physical activity guidelines, according to the U.S. Centers for Disease Control and Prevention. At the same time, other research suggests that patients want to be more active and would like help from their doctor.

“Patients are motivated to hear about physical activity from physicians and try to make a change,” says Jane Thornton, MD, PhD, an assistant professor in family medicine at Western University, Ont. “Just saying something, even if you don’t have specialized knowledge, makes a difference because of the credibility we have as physicians.”

Conveniently, just like exercise, the best way to get started is to ... get started.

Here’s how to break down the process into steps.
 

1. Ask patients about their physical activity

Think of this as taking any kind of patient history, only for physical activity.

Do they have a regular exercise routine? For how many minutes a day are they active? How many days a week?

“It takes less than a minute to ask and record,” Dr. Thornton says. Once you put it into the patient’s electronic record, you have something you can track.
 

2. Write an actual prescription

By giving the patient a written, printed prescription when they leave your office, “you’re showing it’s an important part of treatment or prevention,” Dr. Thornton explains. It puts physical activity on the level of a vital sign.

Include frequency, intensity, time, and type of exercise. The American College of Sports Medicine’s Exercise is Medicine initiative provides a prescription template you can use.
 

3. Measure what they do

Measurement helps the patient adopt the new behavior, and it helps the physician provide tailored advice going forward, Dr. Thornton says.

With the rise of health-monitoring wearables, tracking activity has never been easier. Of course, not everyone wants to (or can afford to) use a smartwatch or fitness tracker.

For tech-averse patients, ask if they’re willing to write something down, like how many minutes they spent walking, or how many yoga classes they attended. You may never get this from some patients, but it never hurts to ask.
 

4. Refer out when necessary

This brings us to a sticky issue for many physicians: lack of confidence in their ability to speak authoritatively about physical activity. “In most cases, you can absolutely say, ‘Start slow, go gradually,’ that kind of thing,” Dr. Thornton says. “As with anything, confidence will come with practice.”

For specific prescriptive advice, check out the Exercise is Medicine website, which also has handouts you can share with patients and information for specific conditions. If your patient has prediabetes, you can also point them toward the CDC’s diabetes prevention program, which is available in-person or online and may be free or covered by insurance.

If a patient has contraindications, refer out. If you don’t have exercise or rehab professionals in your network, Dr. Thornton recommends reaching out to your regional or national association of sports-medicine professionals. You should be able to find it with a quick Google search.
 

5. Follow up

Ask about physical activity during every contact, either in person or online. 

Dr. Thornton says the second and fifth steps matter most to patients, especially when the prescription and follow-up come from their primary care physician, rather than a nurse or physician assistant to whom you’ve delegated the task.

“The value comes in having a physician emphasize the importance,” Dr. Thornton says. The more time you spend on it, the more that value comes through.
 

What NOT to say to patients about exercise

This might surprise you: 

“I definitely don’t think telling people the official recommendations for physical activity is useful,” says Yoni Freedhoff, MD, an associate professor of family medicine at the University of Ottawa and medical director of the Bariatric Medical Institute. “If anything, I’d venture it’s counterproductive.”

It’s not that there’s anything wrong with the recommended minimum – 150 minutes of moderate-to-vigorous-intensity physical activity per week. The problem is what it says to a patient who doesn’t come close to those standards. 

“Few real-world people have the interest, time, energy, or privilege to achieve them,” Dr. Freedhoff says. “Many will recognize that instantly and consequently feel [that] less than that is pointless.”

And that, Dr. Thornton says, is categorically not true. “Even minimal physical activity, in some cases, is beneficial.”

You also want to avoid any explicit connection between exercise and weight loss, Dr. Thornton says.

Though many people do connect the two, the link is often negative, notes a 2019 study from the University of Toronto., triggering painful memories that might go all the way back to gym class. 

Try this pivot from Dr. Freedhoff: “Focus on the role of exercise in mitigating the risks of weight,” he says – like decreasing pain, increasing energy, and improving sleep.
 

How to motivate patients to move

New research backs up this more positive approach. In a study published in Annals of Internal Medicine, doctors in the United Kingdom who emphasized benefits and minimized health harms convinced more patients to join a weight management program than negative or neutral docs did. These doctors conveyed optimism and excitement, smiling and avoiding any mention of obesity or body mass index.

Exactly what benefits inspire change will be different for each patient. But in general, the more immediate the benefit, the more motivating it will be. 

As the University of Toronto study noted, patients weren’t motivated by vague, distant goals like “increasing life expectancy or avoiding health problems many years in the future.”

They’re much more likely to take action to avoid surgery, reduce medications, or minimize the risk of falling. 

For an older patient, Dr. Freedhoff says, “focusing on the preservation of functional independence can be extremely motivating.” That’s especially true if the patient has vivid memories of seeing a sedentary loved one decline late in life. 

For patients who may be more focused on appearance, they could respond to the idea of improving their body composition. For that, “we talk about the quality of weight loss,” says Spencer Nadolsky, DO, an obesity and lipid specialist and medical director of WeightWatchers. “Ultimately, exercise helps shape the body instead of just changing the number on the scale.”
 

Reducing resistance to resistance training

A conversation about reshaping the body or avoiding age-related disabilities leads naturally to resistance training.  

“I always frame resistance training as the single most valuable thing a person might do to try to preserve their functional independence,” Dr. Freedhoff says. If the patient is over 65, he won’t wait for them to show an interest. “I’ll absolutely bring it up with them directly.”

Dr. Freedhoff has an on-site training facility where trainers show patients how to work out at home with minimal equipment, like dumbbells and resistance bands. 

Most doctors, however, don’t have those options. That can lead to a tricky conversation. Participants in the University of Toronto study told the authors they disliked the gym, finding it “boring, intimidating, or discouraging.” 

And yet, “a common suggestion ... from health care providers was to join a gym.”

Many patients, Spencer Nadolsky, MD, says, associate strength training with “grunting, groaning, or getting ‘bulky’ vs. ‘toned.’ ” Memories of soreness from overzealous workouts are another barrier.

He recommends “starting small and slow,” with one or two full-body workouts a week. Those initial workouts might include just one to two sets of four to five exercises. “Consider if someone is exercising at home or in a gym to build a routine around equipment that’s available to them,” Dr. Nadolsky says.

Once you determine what you have to work with, help the patient choose exercises that fit their needs, goals, preferences, limitations, and prior injuries.

One more consideration: While Dr. Nadolsky tries to “stay away from telling a patient they need to do specific types of exercise to be successful,” he makes an exception for patients who’re taking a GLP-1 agonist. “There is a concern for muscle mass loss along with fat loss.”
 

Practicing, preaching, and checking privilege

When Dr. Thornton, Dr. Freedhoff, and Dr. Nadolsky discuss exercise, their patients know they practice what they preach. 

Dr. Nadolsky, who was a nationally ranked wrestler at the University of North Carolina, hosts the Docs Who Lift podcast with his brother, Karl Nadolsky, MD. 

Dr. Freedhoff is also a lifter and fitness enthusiast, and Dr. Thornton was a world-class rower whose team came within 0.8 seconds of a silver medal at the Beijing Olympics. (They finished fourth.)

But not all physicians follow their own lifestyle advice, Dr. Freedhoff says. That doesn’t make them bad doctors – it makes them human.

“I’ve done 300 minutes a week of exercise” – the recommended amount for weight maintenance – “to see what’s involved,” Dr. Freedhoff says. “That’s far, far, far from a trivial amount.”

That leads to this advice for his fellow physicians:

“The most important thing to know about exercise is that finding the time and having the health to do so is a privilege,” he says. 

Understanding that is crucial for assessing your patient’s needs and providing the right help.

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