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New guidance on neurological complications of long COVID
also known as postacute sequelae of SARS-CoV-2 infection (PASC).
The new recommendations, which were published online in Physical Medicine & Rehabilitation, are the result of a collaboration between experts from a variety of medical specialties at 41 long COVID clinics across the United States.
Because physical medicine specialists treat individuals with disability and functional impairments, the AAPM&R was among the first organizations to initiate guidance for the assessment and treatment of long COVID and issued its first consensus statement that addressed long COVID–related fatigue in 2021.
Even though the number of COVID cases and hospitalizations has declined from the peak, long COVID continues to be a major public health issue, Steven R. Flanagan, MD, AAPM&R president-elect and Howard A. Rusk Professor of Rehabilitation Medicine at NYU Langone Health, New York, told reporters attending a press briefing.
“There is some evidence that some of the antivirals may actually help reduce the incidence but not everybody gets them,” said Dr. Flanagan. “In our own clinic here, we continue to see many, many people with problems associated with long COVID,” he added.
According to the consensus guidelines, about 80% of patients hospitalized with acute COVID-19 have neurological symptoms. But these symptoms are not just limited to people who had severe illness, said Leslie Rydberg, MD, coauthor of the neurology long COVID guidance statement.
“What we know is that many people with mild or moderate COVID infection end up with neurologic sequelae that last longer than 4 weeks,” said Dr. Rydberg, the Henry and Monika Betts Medical Student Education Chair and assistant residency program director at Shirley Ryan AbilityLab, Chicago.
Dr. Rydberg added that patients who have symptoms for longer than a month after the initial infection should be evaluated. Although the definition of what constitutes PASC is evolving, the guidance states that the literature indicates that it should be defined as the persistence of symptoms 4 weeks beyond the initial infection.
The most common neurological symptoms are headache, weakness, muscular pain, nerve pain, tremors, peripheral nerve issues, sleep issues, and cognitive effects, Dr. Rydberg told reporters.
She added that “identifying patients with progressive or ominous ‘red flag’ neurological symptoms is essential for emergent triaging.”
Among the red flags are sudden or progressive weakness or sudden or progressive sensory changes, because those could indicate an acute neurologic condition – either due to long COVID or other illnesses – such as a stroke or a problem with the spinal cord, Guillain-Barré syndrome, or myopathy.
While those signs and symptoms would likely be flagged by most clinicians, some of the emergent or urgent signs – such as upper motor neuron changes on physical exam – are more subtle, said Dr. Rydberg.
The new guidance spells out steps for initial evaluation, including identification of red flag symptoms, and also provides treatment recommendations.
Experts also recommend clinicians do the following:
- Treat underlying medical conditions such as pain, psychiatric, cardiovascular, respiratory, and other conditions that may be contributing to neurologic symptoms.
- Consider polypharmacy reduction, looking especially closely at medications with a known impact on neurologic symptoms.
- Urge patients to get regular physical activity, as tolerated, while avoiding overuse syndrome.
- Work with physical, occupational, and speech therapists to increase function and independence.
- Refer patients to counseling and community resources for risk factor modification.
The treatment recommendations are more in-depth for specific long-COVID conditions including headache, cranial neuropathies, sleep disturbances, and neuropathies.
The guidance includes a special statement on the importance of ensuring equitable access to care. Underserved, marginalized, and socioeconomically disadvantaged communities had notably higher rates of infection, hospitalization, and death with less access to rehabilitation services before the pandemic, said Monica Verduzco-Gutierrez, MD, chair of the department of rehabilitation medicine at Long School of Medicine, UT Health San Antonio, and a guideline coauthor.
“We know that these communities have been historically underserved, that there’s already access issues, and that they’re disproportionately impacted by the pandemic,” said Dr. Verduzco-Gutierrez. “This continues as patients develop PASC, or long COVID,” she said, adding that these individuals are still less likely to receive rehabilitation services. “This can lead to poorer outcomes and widened disparities.”
The AAPM&R PASC Multi-Disciplinary Collaborative has previously issued consensus guidance on fatigue, breathing discomfort and respiratory distress, cognitive symptoms, cardiovascular complications, pediatrics, and autonomic dysfunction, and will be publishing guidance on mental health soon.
The collaborative is also putting together a compilation of all the guidance – “a ‘greatest hits’ if you like,” said Dr. Verduzco-Gutierrez.
For clinicians who are unaccustomed to caring for patients with long COVID, the hope is that this new guidance will help them manage the condition, Dr. Rydberg said.
The guidance was written with the support of the AAPM&R. Dr. Verduzco-Gutierrez and two coauthors have disclosed grants, contracts, or honoraria from various funding sources, some paid to their institutions and some personal reimbursement for activities related to PASC and broader areas of research and expertise. However, none of the authors have any conflicts relative to the work on the guidance.
A version of this article originally appeared on Medscape.com.
also known as postacute sequelae of SARS-CoV-2 infection (PASC).
The new recommendations, which were published online in Physical Medicine & Rehabilitation, are the result of a collaboration between experts from a variety of medical specialties at 41 long COVID clinics across the United States.
Because physical medicine specialists treat individuals with disability and functional impairments, the AAPM&R was among the first organizations to initiate guidance for the assessment and treatment of long COVID and issued its first consensus statement that addressed long COVID–related fatigue in 2021.
Even though the number of COVID cases and hospitalizations has declined from the peak, long COVID continues to be a major public health issue, Steven R. Flanagan, MD, AAPM&R president-elect and Howard A. Rusk Professor of Rehabilitation Medicine at NYU Langone Health, New York, told reporters attending a press briefing.
“There is some evidence that some of the antivirals may actually help reduce the incidence but not everybody gets them,” said Dr. Flanagan. “In our own clinic here, we continue to see many, many people with problems associated with long COVID,” he added.
According to the consensus guidelines, about 80% of patients hospitalized with acute COVID-19 have neurological symptoms. But these symptoms are not just limited to people who had severe illness, said Leslie Rydberg, MD, coauthor of the neurology long COVID guidance statement.
“What we know is that many people with mild or moderate COVID infection end up with neurologic sequelae that last longer than 4 weeks,” said Dr. Rydberg, the Henry and Monika Betts Medical Student Education Chair and assistant residency program director at Shirley Ryan AbilityLab, Chicago.
Dr. Rydberg added that patients who have symptoms for longer than a month after the initial infection should be evaluated. Although the definition of what constitutes PASC is evolving, the guidance states that the literature indicates that it should be defined as the persistence of symptoms 4 weeks beyond the initial infection.
The most common neurological symptoms are headache, weakness, muscular pain, nerve pain, tremors, peripheral nerve issues, sleep issues, and cognitive effects, Dr. Rydberg told reporters.
She added that “identifying patients with progressive or ominous ‘red flag’ neurological symptoms is essential for emergent triaging.”
Among the red flags are sudden or progressive weakness or sudden or progressive sensory changes, because those could indicate an acute neurologic condition – either due to long COVID or other illnesses – such as a stroke or a problem with the spinal cord, Guillain-Barré syndrome, or myopathy.
While those signs and symptoms would likely be flagged by most clinicians, some of the emergent or urgent signs – such as upper motor neuron changes on physical exam – are more subtle, said Dr. Rydberg.
The new guidance spells out steps for initial evaluation, including identification of red flag symptoms, and also provides treatment recommendations.
Experts also recommend clinicians do the following:
- Treat underlying medical conditions such as pain, psychiatric, cardiovascular, respiratory, and other conditions that may be contributing to neurologic symptoms.
- Consider polypharmacy reduction, looking especially closely at medications with a known impact on neurologic symptoms.
- Urge patients to get regular physical activity, as tolerated, while avoiding overuse syndrome.
- Work with physical, occupational, and speech therapists to increase function and independence.
- Refer patients to counseling and community resources for risk factor modification.
The treatment recommendations are more in-depth for specific long-COVID conditions including headache, cranial neuropathies, sleep disturbances, and neuropathies.
The guidance includes a special statement on the importance of ensuring equitable access to care. Underserved, marginalized, and socioeconomically disadvantaged communities had notably higher rates of infection, hospitalization, and death with less access to rehabilitation services before the pandemic, said Monica Verduzco-Gutierrez, MD, chair of the department of rehabilitation medicine at Long School of Medicine, UT Health San Antonio, and a guideline coauthor.
“We know that these communities have been historically underserved, that there’s already access issues, and that they’re disproportionately impacted by the pandemic,” said Dr. Verduzco-Gutierrez. “This continues as patients develop PASC, or long COVID,” she said, adding that these individuals are still less likely to receive rehabilitation services. “This can lead to poorer outcomes and widened disparities.”
The AAPM&R PASC Multi-Disciplinary Collaborative has previously issued consensus guidance on fatigue, breathing discomfort and respiratory distress, cognitive symptoms, cardiovascular complications, pediatrics, and autonomic dysfunction, and will be publishing guidance on mental health soon.
The collaborative is also putting together a compilation of all the guidance – “a ‘greatest hits’ if you like,” said Dr. Verduzco-Gutierrez.
For clinicians who are unaccustomed to caring for patients with long COVID, the hope is that this new guidance will help them manage the condition, Dr. Rydberg said.
The guidance was written with the support of the AAPM&R. Dr. Verduzco-Gutierrez and two coauthors have disclosed grants, contracts, or honoraria from various funding sources, some paid to their institutions and some personal reimbursement for activities related to PASC and broader areas of research and expertise. However, none of the authors have any conflicts relative to the work on the guidance.
A version of this article originally appeared on Medscape.com.
also known as postacute sequelae of SARS-CoV-2 infection (PASC).
The new recommendations, which were published online in Physical Medicine & Rehabilitation, are the result of a collaboration between experts from a variety of medical specialties at 41 long COVID clinics across the United States.
Because physical medicine specialists treat individuals with disability and functional impairments, the AAPM&R was among the first organizations to initiate guidance for the assessment and treatment of long COVID and issued its first consensus statement that addressed long COVID–related fatigue in 2021.
Even though the number of COVID cases and hospitalizations has declined from the peak, long COVID continues to be a major public health issue, Steven R. Flanagan, MD, AAPM&R president-elect and Howard A. Rusk Professor of Rehabilitation Medicine at NYU Langone Health, New York, told reporters attending a press briefing.
“There is some evidence that some of the antivirals may actually help reduce the incidence but not everybody gets them,” said Dr. Flanagan. “In our own clinic here, we continue to see many, many people with problems associated with long COVID,” he added.
According to the consensus guidelines, about 80% of patients hospitalized with acute COVID-19 have neurological symptoms. But these symptoms are not just limited to people who had severe illness, said Leslie Rydberg, MD, coauthor of the neurology long COVID guidance statement.
“What we know is that many people with mild or moderate COVID infection end up with neurologic sequelae that last longer than 4 weeks,” said Dr. Rydberg, the Henry and Monika Betts Medical Student Education Chair and assistant residency program director at Shirley Ryan AbilityLab, Chicago.
Dr. Rydberg added that patients who have symptoms for longer than a month after the initial infection should be evaluated. Although the definition of what constitutes PASC is evolving, the guidance states that the literature indicates that it should be defined as the persistence of symptoms 4 weeks beyond the initial infection.
The most common neurological symptoms are headache, weakness, muscular pain, nerve pain, tremors, peripheral nerve issues, sleep issues, and cognitive effects, Dr. Rydberg told reporters.
She added that “identifying patients with progressive or ominous ‘red flag’ neurological symptoms is essential for emergent triaging.”
Among the red flags are sudden or progressive weakness or sudden or progressive sensory changes, because those could indicate an acute neurologic condition – either due to long COVID or other illnesses – such as a stroke or a problem with the spinal cord, Guillain-Barré syndrome, or myopathy.
While those signs and symptoms would likely be flagged by most clinicians, some of the emergent or urgent signs – such as upper motor neuron changes on physical exam – are more subtle, said Dr. Rydberg.
The new guidance spells out steps for initial evaluation, including identification of red flag symptoms, and also provides treatment recommendations.
Experts also recommend clinicians do the following:
- Treat underlying medical conditions such as pain, psychiatric, cardiovascular, respiratory, and other conditions that may be contributing to neurologic symptoms.
- Consider polypharmacy reduction, looking especially closely at medications with a known impact on neurologic symptoms.
- Urge patients to get regular physical activity, as tolerated, while avoiding overuse syndrome.
- Work with physical, occupational, and speech therapists to increase function and independence.
- Refer patients to counseling and community resources for risk factor modification.
The treatment recommendations are more in-depth for specific long-COVID conditions including headache, cranial neuropathies, sleep disturbances, and neuropathies.
The guidance includes a special statement on the importance of ensuring equitable access to care. Underserved, marginalized, and socioeconomically disadvantaged communities had notably higher rates of infection, hospitalization, and death with less access to rehabilitation services before the pandemic, said Monica Verduzco-Gutierrez, MD, chair of the department of rehabilitation medicine at Long School of Medicine, UT Health San Antonio, and a guideline coauthor.
“We know that these communities have been historically underserved, that there’s already access issues, and that they’re disproportionately impacted by the pandemic,” said Dr. Verduzco-Gutierrez. “This continues as patients develop PASC, or long COVID,” she said, adding that these individuals are still less likely to receive rehabilitation services. “This can lead to poorer outcomes and widened disparities.”
The AAPM&R PASC Multi-Disciplinary Collaborative has previously issued consensus guidance on fatigue, breathing discomfort and respiratory distress, cognitive symptoms, cardiovascular complications, pediatrics, and autonomic dysfunction, and will be publishing guidance on mental health soon.
The collaborative is also putting together a compilation of all the guidance – “a ‘greatest hits’ if you like,” said Dr. Verduzco-Gutierrez.
For clinicians who are unaccustomed to caring for patients with long COVID, the hope is that this new guidance will help them manage the condition, Dr. Rydberg said.
The guidance was written with the support of the AAPM&R. Dr. Verduzco-Gutierrez and two coauthors have disclosed grants, contracts, or honoraria from various funding sources, some paid to their institutions and some personal reimbursement for activities related to PASC and broader areas of research and expertise. However, none of the authors have any conflicts relative to the work on the guidance.
A version of this article originally appeared on Medscape.com.
FROM PHYSICIAN MEDICINE & REHABILITATION
‘Robust evidence’ that exercise cuts Parkinson’s risk in women
Investigators found that among almost 99,000 women participating in the ongoing E3N study, those who exercised the most frequently had up to a 25% lower risk for PD than their less-active counterparts.
The results highlight the importance of exercising early in mid-life to prevent PD later on, study investigator Alexis Elbaz, MD, PhD, research director, French Institute of Health and Medical Research (Inserm), Paris, said in an interview.
This is especially critical since there is no cure nor disease-modifying treatments. The medications that are available are aimed at symptom reduction.
“Finding ways to prevent or delay the onset of Parkinson’s is really important, and physical activity seems to be one of the possible strategies to reduce the risk,” Dr. Elbaz said.
The study was published online in Neurology.
Direct protective effect?
Results from previous research examining the relationship physical activity and PD has been inconsistent. One meta-analysis showed a statistically significant association among men but a nonsignificant link in women.
The investigators noted that some of the findings from previous studies may have been affected by reverse causation. As nonmotor symptoms such as constipation and subtle motor signs such as tremor and balance issues can present years before a PD diagnosis, patients may reduce their physical activity because of such symptoms.
To address this potential confounder, the researchers used “lag” analyses, where data on physical activity levels in the years close to a PD diagnosis are omitted.
The study relied on data from the E3N, an ongoing cohort study of 98,995 women, born between 1925 and 1950 and recruited in 1990, who were affiliated with a French national health insurance plan that primarily covers teachers. Participants completed a questionnaire on lifestyle and medical history at baseline and follow-up questionnaires every 2-3 years.
In six of the questionnaires, participants provided details about various recreational, sports, and household activities – for example, walking, climbing stairs, gardening, and cleaning. The authors attributed metabolic equivalent of task (MET) values to each activity and multiplied METs by their frequency and duration to obtain a physical activity score.
Definite and probable PD cases were determined through self-reported physician diagnoses, anti-parkinsonian drug claims, and medical records, with diagnoses verified by an expert panel.
Researchers investigated the relationship between physical activity and PD onset in a nested-case control study that included 25,075 women (1,196 PD cases and 23,879 controls) with a mean age of 71.9 years. They found physical activity was significantly lower in cases than in controls throughout follow-up.
The difference between cases and controls began to increase at 10 years before diagnosis (P-interaction = .003). “When we looked at the trajectories of physical activity in PD patients and in controls, we saw that in the 10 years before the diagnosis, physical activity declined at a steeper rate in controls. We think this is because those subtle prodromal symptoms cause people to exercise less,” said Dr. Elbaz.
In the main analysis, which had a 10-year lag, 1,074 women developed incident PD during a mean follow-up of 17.2 years. Those in the highest quartile of physical activity had a 25% lower risk for PD vs. those in the lowest quartile (adjusted hazard ratio [HR], 0.75, 95% confidence interval [CI], 0.63-0.89).
The risk for PD decreased with increasing levels of physical activity in a linear fashion, noted Dr. Elbaz. “So doing even a little bit of physical activity is better than doing nothing at all.”
Analyses that included 15-year and 20-year lag times had similar findings.
Sensitivity analyses that adjusted for the Mediterranean diet and caffeine and dairy intake also yielded comparable results. This was also true for analyses that adjusted for comorbidities such as body mass index, hypertension, hypercholesterolemia, diabetes, and cardiovascular disease, all of which can affect PD risk.
“This gives weight to the idea that diabetes or cardiovascular diseases do not explain the relationship between physical activity and PD, which means the most likely hypothesis is that physical activity has a direct protective effect on the brain,” said Dr. Elbaz.
Studies have shown that physical activity affects brain plasticity and can reduce oxidative stress in the brain – a key mechanism involved in PD, he added.
Physical activity is a low-risk, inexpensive, and accessible intervention. But the study was not designed to determine the types of physical activity that are most protective against PD.
The study’s main limitation is that it used self-reported physical activity rather than objective measures such as accelerometers. In addition, the participants were not necessarily representative of the general population.
Robust evidence
In an accompanying editorial, Lana M. Chahine, MD, associate professor in the department of neurology at the University of Pittsburgh, and Sirwan K. L. Darweesh, MD, PhD, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Center of Expertise for Parkinson and Movement Disorders, Nijmegen, the Netherlands, said the study “provides robust evidence” that physical activity reduces risk for PD in women.
“These results show that the field is moving in the right direction and provide a clear rationale for exercise trials to prevent or delay the onset of manifest PD in at-risk individuals” they wrote.
The study highlights “gaps” in knowledge that merit closer attention and that “further insight is warranted on how much the effects on PD vary by type, intensity, frequency, and duration of physical activity,” the editorialists noted.
Another gap is how the accuracy of assessment of physical activity can be improved beyond self-report. “Wearable sensor technology now offers the potential to assess physical activity remotely and objectively in prevention trials,” they added.
Other areas that need exploring relate to mechanisms by which physical activity reduces PD risk, and to what extent effects of physical activity vary between individuals, Dr. Chahine and Dr. Darweesh noted.
Commenting for this article, Michael S. Okun, MD, executive director of the Fixel Institute for Neurological Diseases at University of Florida Health, and medical adviser for the Parkinson’s Foundation, said the findings are “significant and important.”
Based on only a handful of previous studies, it was assumed that physical activity was associated with reduced Parkinson’s diagnosis only in men, said Dr. Okun. “The current dataset was larger and included longer-term outcomes, and it informs the field that exercise may be important for reducing the risk of Parkinson’s disease in men as well as in women.”
The investigators, the editorialists, and Dr. Okun reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Investigators found that among almost 99,000 women participating in the ongoing E3N study, those who exercised the most frequently had up to a 25% lower risk for PD than their less-active counterparts.
The results highlight the importance of exercising early in mid-life to prevent PD later on, study investigator Alexis Elbaz, MD, PhD, research director, French Institute of Health and Medical Research (Inserm), Paris, said in an interview.
This is especially critical since there is no cure nor disease-modifying treatments. The medications that are available are aimed at symptom reduction.
“Finding ways to prevent or delay the onset of Parkinson’s is really important, and physical activity seems to be one of the possible strategies to reduce the risk,” Dr. Elbaz said.
The study was published online in Neurology.
Direct protective effect?
Results from previous research examining the relationship physical activity and PD has been inconsistent. One meta-analysis showed a statistically significant association among men but a nonsignificant link in women.
The investigators noted that some of the findings from previous studies may have been affected by reverse causation. As nonmotor symptoms such as constipation and subtle motor signs such as tremor and balance issues can present years before a PD diagnosis, patients may reduce their physical activity because of such symptoms.
To address this potential confounder, the researchers used “lag” analyses, where data on physical activity levels in the years close to a PD diagnosis are omitted.
The study relied on data from the E3N, an ongoing cohort study of 98,995 women, born between 1925 and 1950 and recruited in 1990, who were affiliated with a French national health insurance plan that primarily covers teachers. Participants completed a questionnaire on lifestyle and medical history at baseline and follow-up questionnaires every 2-3 years.
In six of the questionnaires, participants provided details about various recreational, sports, and household activities – for example, walking, climbing stairs, gardening, and cleaning. The authors attributed metabolic equivalent of task (MET) values to each activity and multiplied METs by their frequency and duration to obtain a physical activity score.
Definite and probable PD cases were determined through self-reported physician diagnoses, anti-parkinsonian drug claims, and medical records, with diagnoses verified by an expert panel.
Researchers investigated the relationship between physical activity and PD onset in a nested-case control study that included 25,075 women (1,196 PD cases and 23,879 controls) with a mean age of 71.9 years. They found physical activity was significantly lower in cases than in controls throughout follow-up.
The difference between cases and controls began to increase at 10 years before diagnosis (P-interaction = .003). “When we looked at the trajectories of physical activity in PD patients and in controls, we saw that in the 10 years before the diagnosis, physical activity declined at a steeper rate in controls. We think this is because those subtle prodromal symptoms cause people to exercise less,” said Dr. Elbaz.
In the main analysis, which had a 10-year lag, 1,074 women developed incident PD during a mean follow-up of 17.2 years. Those in the highest quartile of physical activity had a 25% lower risk for PD vs. those in the lowest quartile (adjusted hazard ratio [HR], 0.75, 95% confidence interval [CI], 0.63-0.89).
The risk for PD decreased with increasing levels of physical activity in a linear fashion, noted Dr. Elbaz. “So doing even a little bit of physical activity is better than doing nothing at all.”
Analyses that included 15-year and 20-year lag times had similar findings.
Sensitivity analyses that adjusted for the Mediterranean diet and caffeine and dairy intake also yielded comparable results. This was also true for analyses that adjusted for comorbidities such as body mass index, hypertension, hypercholesterolemia, diabetes, and cardiovascular disease, all of which can affect PD risk.
“This gives weight to the idea that diabetes or cardiovascular diseases do not explain the relationship between physical activity and PD, which means the most likely hypothesis is that physical activity has a direct protective effect on the brain,” said Dr. Elbaz.
Studies have shown that physical activity affects brain plasticity and can reduce oxidative stress in the brain – a key mechanism involved in PD, he added.
Physical activity is a low-risk, inexpensive, and accessible intervention. But the study was not designed to determine the types of physical activity that are most protective against PD.
The study’s main limitation is that it used self-reported physical activity rather than objective measures such as accelerometers. In addition, the participants were not necessarily representative of the general population.
Robust evidence
In an accompanying editorial, Lana M. Chahine, MD, associate professor in the department of neurology at the University of Pittsburgh, and Sirwan K. L. Darweesh, MD, PhD, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Center of Expertise for Parkinson and Movement Disorders, Nijmegen, the Netherlands, said the study “provides robust evidence” that physical activity reduces risk for PD in women.
“These results show that the field is moving in the right direction and provide a clear rationale for exercise trials to prevent or delay the onset of manifest PD in at-risk individuals” they wrote.
The study highlights “gaps” in knowledge that merit closer attention and that “further insight is warranted on how much the effects on PD vary by type, intensity, frequency, and duration of physical activity,” the editorialists noted.
Another gap is how the accuracy of assessment of physical activity can be improved beyond self-report. “Wearable sensor technology now offers the potential to assess physical activity remotely and objectively in prevention trials,” they added.
Other areas that need exploring relate to mechanisms by which physical activity reduces PD risk, and to what extent effects of physical activity vary between individuals, Dr. Chahine and Dr. Darweesh noted.
Commenting for this article, Michael S. Okun, MD, executive director of the Fixel Institute for Neurological Diseases at University of Florida Health, and medical adviser for the Parkinson’s Foundation, said the findings are “significant and important.”
Based on only a handful of previous studies, it was assumed that physical activity was associated with reduced Parkinson’s diagnosis only in men, said Dr. Okun. “The current dataset was larger and included longer-term outcomes, and it informs the field that exercise may be important for reducing the risk of Parkinson’s disease in men as well as in women.”
The investigators, the editorialists, and Dr. Okun reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Investigators found that among almost 99,000 women participating in the ongoing E3N study, those who exercised the most frequently had up to a 25% lower risk for PD than their less-active counterparts.
The results highlight the importance of exercising early in mid-life to prevent PD later on, study investigator Alexis Elbaz, MD, PhD, research director, French Institute of Health and Medical Research (Inserm), Paris, said in an interview.
This is especially critical since there is no cure nor disease-modifying treatments. The medications that are available are aimed at symptom reduction.
“Finding ways to prevent or delay the onset of Parkinson’s is really important, and physical activity seems to be one of the possible strategies to reduce the risk,” Dr. Elbaz said.
The study was published online in Neurology.
Direct protective effect?
Results from previous research examining the relationship physical activity and PD has been inconsistent. One meta-analysis showed a statistically significant association among men but a nonsignificant link in women.
The investigators noted that some of the findings from previous studies may have been affected by reverse causation. As nonmotor symptoms such as constipation and subtle motor signs such as tremor and balance issues can present years before a PD diagnosis, patients may reduce their physical activity because of such symptoms.
To address this potential confounder, the researchers used “lag” analyses, where data on physical activity levels in the years close to a PD diagnosis are omitted.
The study relied on data from the E3N, an ongoing cohort study of 98,995 women, born between 1925 and 1950 and recruited in 1990, who were affiliated with a French national health insurance plan that primarily covers teachers. Participants completed a questionnaire on lifestyle and medical history at baseline and follow-up questionnaires every 2-3 years.
In six of the questionnaires, participants provided details about various recreational, sports, and household activities – for example, walking, climbing stairs, gardening, and cleaning. The authors attributed metabolic equivalent of task (MET) values to each activity and multiplied METs by their frequency and duration to obtain a physical activity score.
Definite and probable PD cases were determined through self-reported physician diagnoses, anti-parkinsonian drug claims, and medical records, with diagnoses verified by an expert panel.
Researchers investigated the relationship between physical activity and PD onset in a nested-case control study that included 25,075 women (1,196 PD cases and 23,879 controls) with a mean age of 71.9 years. They found physical activity was significantly lower in cases than in controls throughout follow-up.
The difference between cases and controls began to increase at 10 years before diagnosis (P-interaction = .003). “When we looked at the trajectories of physical activity in PD patients and in controls, we saw that in the 10 years before the diagnosis, physical activity declined at a steeper rate in controls. We think this is because those subtle prodromal symptoms cause people to exercise less,” said Dr. Elbaz.
In the main analysis, which had a 10-year lag, 1,074 women developed incident PD during a mean follow-up of 17.2 years. Those in the highest quartile of physical activity had a 25% lower risk for PD vs. those in the lowest quartile (adjusted hazard ratio [HR], 0.75, 95% confidence interval [CI], 0.63-0.89).
The risk for PD decreased with increasing levels of physical activity in a linear fashion, noted Dr. Elbaz. “So doing even a little bit of physical activity is better than doing nothing at all.”
Analyses that included 15-year and 20-year lag times had similar findings.
Sensitivity analyses that adjusted for the Mediterranean diet and caffeine and dairy intake also yielded comparable results. This was also true for analyses that adjusted for comorbidities such as body mass index, hypertension, hypercholesterolemia, diabetes, and cardiovascular disease, all of which can affect PD risk.
“This gives weight to the idea that diabetes or cardiovascular diseases do not explain the relationship between physical activity and PD, which means the most likely hypothesis is that physical activity has a direct protective effect on the brain,” said Dr. Elbaz.
Studies have shown that physical activity affects brain plasticity and can reduce oxidative stress in the brain – a key mechanism involved in PD, he added.
Physical activity is a low-risk, inexpensive, and accessible intervention. But the study was not designed to determine the types of physical activity that are most protective against PD.
The study’s main limitation is that it used self-reported physical activity rather than objective measures such as accelerometers. In addition, the participants were not necessarily representative of the general population.
Robust evidence
In an accompanying editorial, Lana M. Chahine, MD, associate professor in the department of neurology at the University of Pittsburgh, and Sirwan K. L. Darweesh, MD, PhD, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Center of Expertise for Parkinson and Movement Disorders, Nijmegen, the Netherlands, said the study “provides robust evidence” that physical activity reduces risk for PD in women.
“These results show that the field is moving in the right direction and provide a clear rationale for exercise trials to prevent or delay the onset of manifest PD in at-risk individuals” they wrote.
The study highlights “gaps” in knowledge that merit closer attention and that “further insight is warranted on how much the effects on PD vary by type, intensity, frequency, and duration of physical activity,” the editorialists noted.
Another gap is how the accuracy of assessment of physical activity can be improved beyond self-report. “Wearable sensor technology now offers the potential to assess physical activity remotely and objectively in prevention trials,” they added.
Other areas that need exploring relate to mechanisms by which physical activity reduces PD risk, and to what extent effects of physical activity vary between individuals, Dr. Chahine and Dr. Darweesh noted.
Commenting for this article, Michael S. Okun, MD, executive director of the Fixel Institute for Neurological Diseases at University of Florida Health, and medical adviser for the Parkinson’s Foundation, said the findings are “significant and important.”
Based on only a handful of previous studies, it was assumed that physical activity was associated with reduced Parkinson’s diagnosis only in men, said Dr. Okun. “The current dataset was larger and included longer-term outcomes, and it informs the field that exercise may be important for reducing the risk of Parkinson’s disease in men as well as in women.”
The investigators, the editorialists, and Dr. Okun reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
FROM NEUROLOGY
Overdose deaths mark another record year, but experts hopeful
, according to newly released figures from the Centers for Disease Control and Prevention.
Overdose deaths in 2022 totaled an estimated 109,680 people, which is 2% more than the 107,573 deaths in 2021, according to the figures. But the 2022 total is still a record for the third straight year.
Public health officials are now in a hopeful position. If the 2022 data represents a peak, then the country will see deaths decline toward pre-pandemic levels. If overdose deaths instead have reached a plateau, it means that the United States will sustain the nearly 20% leap that came amid a deadly increase in drug use in 2020 and 2021.
“The fact that it does seem to be flattening out, at least at a national level, is encouraging,” Columbia University epidemiologist Katherine Keyes, PhD, MPH, told The Associated Press. “But these numbers are still extraordinarily high. We shouldn’t suggest the crisis is in any way over.”
The newly released figures from the CDC are considered estimates because some states may still send updated 2022 information later this year.
Although the number of deaths from 2021 to 2022 was stable on a national level, the picture varied more widely at the state level. More than half of U.S. states saw increases, while deaths in 23 states decreased, and just one – Iowa – had the same number of overdose deaths in 2021 and 2022.
The states with the highest counts in 2022 were:
- California: 11,978 deaths
- Florida: 8,032 deaths
- Texas: 5,607 deaths
- Pennsylvania: 5,222 deaths
- Ohio: 5,103 deaths
Synthetic opioids, such as fentanyl and tramadol, account for most drug overdose deaths, according to a December 2022 report from the CDC.
State officials told The AP that they believe the plateau in overdose deaths is in part due to educational campaigns to warn the public about the dangers of drug use, as well as from expanded addiction treatment and increased access to the overdose-reversal medicine naloxone.
A version of this article originally appeared on WebMD.com.
, according to newly released figures from the Centers for Disease Control and Prevention.
Overdose deaths in 2022 totaled an estimated 109,680 people, which is 2% more than the 107,573 deaths in 2021, according to the figures. But the 2022 total is still a record for the third straight year.
Public health officials are now in a hopeful position. If the 2022 data represents a peak, then the country will see deaths decline toward pre-pandemic levels. If overdose deaths instead have reached a plateau, it means that the United States will sustain the nearly 20% leap that came amid a deadly increase in drug use in 2020 and 2021.
“The fact that it does seem to be flattening out, at least at a national level, is encouraging,” Columbia University epidemiologist Katherine Keyes, PhD, MPH, told The Associated Press. “But these numbers are still extraordinarily high. We shouldn’t suggest the crisis is in any way over.”
The newly released figures from the CDC are considered estimates because some states may still send updated 2022 information later this year.
Although the number of deaths from 2021 to 2022 was stable on a national level, the picture varied more widely at the state level. More than half of U.S. states saw increases, while deaths in 23 states decreased, and just one – Iowa – had the same number of overdose deaths in 2021 and 2022.
The states with the highest counts in 2022 were:
- California: 11,978 deaths
- Florida: 8,032 deaths
- Texas: 5,607 deaths
- Pennsylvania: 5,222 deaths
- Ohio: 5,103 deaths
Synthetic opioids, such as fentanyl and tramadol, account for most drug overdose deaths, according to a December 2022 report from the CDC.
State officials told The AP that they believe the plateau in overdose deaths is in part due to educational campaigns to warn the public about the dangers of drug use, as well as from expanded addiction treatment and increased access to the overdose-reversal medicine naloxone.
A version of this article originally appeared on WebMD.com.
, according to newly released figures from the Centers for Disease Control and Prevention.
Overdose deaths in 2022 totaled an estimated 109,680 people, which is 2% more than the 107,573 deaths in 2021, according to the figures. But the 2022 total is still a record for the third straight year.
Public health officials are now in a hopeful position. If the 2022 data represents a peak, then the country will see deaths decline toward pre-pandemic levels. If overdose deaths instead have reached a plateau, it means that the United States will sustain the nearly 20% leap that came amid a deadly increase in drug use in 2020 and 2021.
“The fact that it does seem to be flattening out, at least at a national level, is encouraging,” Columbia University epidemiologist Katherine Keyes, PhD, MPH, told The Associated Press. “But these numbers are still extraordinarily high. We shouldn’t suggest the crisis is in any way over.”
The newly released figures from the CDC are considered estimates because some states may still send updated 2022 information later this year.
Although the number of deaths from 2021 to 2022 was stable on a national level, the picture varied more widely at the state level. More than half of U.S. states saw increases, while deaths in 23 states decreased, and just one – Iowa – had the same number of overdose deaths in 2021 and 2022.
The states with the highest counts in 2022 were:
- California: 11,978 deaths
- Florida: 8,032 deaths
- Texas: 5,607 deaths
- Pennsylvania: 5,222 deaths
- Ohio: 5,103 deaths
Synthetic opioids, such as fentanyl and tramadol, account for most drug overdose deaths, according to a December 2022 report from the CDC.
State officials told The AP that they believe the plateau in overdose deaths is in part due to educational campaigns to warn the public about the dangers of drug use, as well as from expanded addiction treatment and increased access to the overdose-reversal medicine naloxone.
A version of this article originally appeared on WebMD.com.
Choosing our terms: The diagnostic words we use can be harmful
We are living in an era of increasing sensitivity to our diversity and the ways we interact, but also an era of growing resistance to change and accommodation. As clinicians, we hope to be among the sensitive and the progressive, open to improving our views and interactions. And as part of our respect for those we treat, we seek to speak clearly with them about our assessment of what is disrupting their lives and about their options.
Using the right words is crucial in that work. Well-chosen words can be heard and understood. Poorly chosen words can be confusing or off-putting; they may miscommunicate or be offensive. Careful choice of words is also important among colleagues, who may not always mean the same things when using the same words.
In psychiatry, consumer knowledge and access are growing. There are effective standard treatments and promising new ones. But our terminology is often antique and obscure. This is so despite a recognition that some terms we use may communicate poorly and some are deprecating.
A notable example is “schizophrenia.” Originally referring to cognitive phenomena that were not adequately coherent with reality or one another, it has gone through periods of describing most psychosis to particular subsets of psychoses. Debates persist on specific criteria for key symptoms and typical course. Even two clinicians trained in the same site may not agree on the defining criteria, and the public, mostly informed by books, movies, and newspapers, is even more confused, often believing schizophrenia is multiple-personality disorder. In addition, the press and public often associate schizophrenia with violent behavior and uniformly bad outcomes, and for those reasons, a diagnosis is not only frightening but also stigmatizing.1
Many papers have presented the case for retiring “schizophrenia.”2 And practical efforts to rename schizophrenia have been made. These efforts have occurred in countries in which English is not the primary language.3 In Japan, schizophrenia was replaced by “integration disorder.” In Hong Kong, “disorder of thought and perception” was implemented. Korea chose “attunement disorder.” A recent large survey of stakeholders, including clinicians, researchers, and consumers in the United States, explored alternatives in English.4 Terms receiving approval included: “psychosis spectrum syndrome,” “altered perception syndrome,” and “neuro-emotional integration disorder.”
Despite these recommendations, the standard manuals of diagnosis, the ICD and DSM, have maintained the century-old term “schizophrenia” in their most recent editions, released in 2022. Aside from the inertia commonly associated with long-standing practices, it has been noted that many of the alternatives suggested or, in some places, implemented, are complex, somewhat vague, or too inclusive to distinguish different clinical presentations requiring different treatment approaches. They might not be compelling for use or optimal to guide caregiving.
Perhaps more concerning than “schizophrenia” are terms used to describe personality disorders.5 “Personality disorder” itself is problematic, implying a core and possibly unalterable fault in an individual. And among the personality disorders, words for the related group of disorders called “Cluster B” in the DSM raise issues. This includes the terms narcissistic, antisocial, histrionic, and borderline in DSM-5-TR. The first three terms are clearly pejorative. The last is unclear: What is the border between? Originally, it was bordering on psychosis, but as explained in DSM and ICD, borderline disorder is much more closely related to other personality disorders.
Notably, the “Cluster B” disorders run together in families, but men are more likely to be called antisocial and women borderline, even though the overlap in signs and symptoms is profound, suggesting marginally different manifestations of the same condition. The ICD has made changes to address the problems associated with some of these terms. ICD proposes personality “difficulty” to replace personality “disorder”; a modest change but less offensive. And it proposes seeing all, or at least most, personality disorders as being related to one another. Most share features of disturbances in sense-of-self and relationships with others. As descriptors, ICD kept “borderline pattern,” but replaced “antisocial” with “dissocial,” in an effort to be accurate but less demeaning. Other descriptors it proposes are negative affectivity, detachment, disinhibition, and anankastia, the last referring to compulsions.
These are notable advances. Can the field find even better terms to communicate hard to hear information, with words that are less problematic? In search of options, we surveyed clinicians at academic centers about the terms they preferred to avoid and the ones they prefer to use in talking with patients.6 Their practices may be informative.
Briefly summarized, these clinicians preferred not to use “schizophrenia” and very few used “antisocial,” “histrionic,” or “narcissistic.” Most avoided using “borderline” as well. Instead, they recommended discussing specific symptoms and manifestations of illness or dysfunctional behavior and relationships with their patients. They employed terms including “psychosis,” “hallucination,” “delusion,” “thinking disorder,” and “mood disorder.” They explained these terms, as needed, and found that patients understood them.
For Cluster B personality disorders, they spoke of personality traits and styles and specifically about “conduct,” “rule breaking,” “coping,” “self-focus,” “emotionality,” and “reactivity.” Those choices are not perfect, of course. Medical terms are often not standard words used in a conversational way. But the words chosen by these clinicians are generally straightforward and may communicate in a clear and acceptable fashion. It is also notable that the terms match how the clinicians assess and treat their patients, as observed in a separate study of their practices.7 That is, the clinicians advised that they look for and suggest treatments for the specific symptoms they see that most disrupt an individual’s life, such as delusions or mood instability. They are not much guided by diagnoses, like schizophrenia or borderline disorder. That makes the chosen terms not only less confusing or off-putting but also more practical.
Changing terminology in any field is difficult. We are trained to use standard terms. Clearly, however, many clinicians avoid some terms and use alternatives in their work. Asked why, they responded that they did so precisely to communicate more effectively and more respectfully. That is key to their treatment goals. Perhaps others will consider these choices useful in their work. And perhaps both the DSM and the ICD will not only continue to consider but will decide to implement alternatives for problematic terms in the years ahead, as they discuss their next revisions.
Dr. Cohen is director of the Program for Neuropsychiatric Research at McLean Hospital, Belmont, Mass., and Robertson-Steele Professor of Psychiatry at Harvard Medical School, Boston.
References
1. Lasalvia A et al. Renaming schizophrenia? A survey among psychiatrists, mental health service users and family members in Italy. Schizophr Res. 2021;228:502-9.
2. Gülöksüz S et al. Renaming schizophrenia: 5 x 5. Epidemiol Psychiatr Sci. 2019;28(3):254-7.
3. Sartorius N et al. Name change for schizophrenia. Schizophr Bull. 2014;40(2):255-8.
4. Mesholam-Gately RI et al. Are we ready for a name change for schizophrenia? A survey of multiple stakeholders. Schizophr Res. 2021;238:152-60.
5. Mulder R. The evolving nosology of personality disorder and its clinical utility. World Psychiatry. 2021 Oct;20(3):361-2.
6. Cohen BM et al. Diagnostic terms psychiatrists prefer to use for common psychotic and personality disorders. J Psychiatr Res. 2022 Sep 5;155:226-31.
7. Cohen BM, et al. Use of DSM-5 diagnoses vs. other clinical information by US academic-affiliated psychiatrists in assessing and treating psychotic disorders. World Psychiatry. 2021 Oct;20(3):447-8.
We are living in an era of increasing sensitivity to our diversity and the ways we interact, but also an era of growing resistance to change and accommodation. As clinicians, we hope to be among the sensitive and the progressive, open to improving our views and interactions. And as part of our respect for those we treat, we seek to speak clearly with them about our assessment of what is disrupting their lives and about their options.
Using the right words is crucial in that work. Well-chosen words can be heard and understood. Poorly chosen words can be confusing or off-putting; they may miscommunicate or be offensive. Careful choice of words is also important among colleagues, who may not always mean the same things when using the same words.
In psychiatry, consumer knowledge and access are growing. There are effective standard treatments and promising new ones. But our terminology is often antique and obscure. This is so despite a recognition that some terms we use may communicate poorly and some are deprecating.
A notable example is “schizophrenia.” Originally referring to cognitive phenomena that were not adequately coherent with reality or one another, it has gone through periods of describing most psychosis to particular subsets of psychoses. Debates persist on specific criteria for key symptoms and typical course. Even two clinicians trained in the same site may not agree on the defining criteria, and the public, mostly informed by books, movies, and newspapers, is even more confused, often believing schizophrenia is multiple-personality disorder. In addition, the press and public often associate schizophrenia with violent behavior and uniformly bad outcomes, and for those reasons, a diagnosis is not only frightening but also stigmatizing.1
Many papers have presented the case for retiring “schizophrenia.”2 And practical efforts to rename schizophrenia have been made. These efforts have occurred in countries in which English is not the primary language.3 In Japan, schizophrenia was replaced by “integration disorder.” In Hong Kong, “disorder of thought and perception” was implemented. Korea chose “attunement disorder.” A recent large survey of stakeholders, including clinicians, researchers, and consumers in the United States, explored alternatives in English.4 Terms receiving approval included: “psychosis spectrum syndrome,” “altered perception syndrome,” and “neuro-emotional integration disorder.”
Despite these recommendations, the standard manuals of diagnosis, the ICD and DSM, have maintained the century-old term “schizophrenia” in their most recent editions, released in 2022. Aside from the inertia commonly associated with long-standing practices, it has been noted that many of the alternatives suggested or, in some places, implemented, are complex, somewhat vague, or too inclusive to distinguish different clinical presentations requiring different treatment approaches. They might not be compelling for use or optimal to guide caregiving.
Perhaps more concerning than “schizophrenia” are terms used to describe personality disorders.5 “Personality disorder” itself is problematic, implying a core and possibly unalterable fault in an individual. And among the personality disorders, words for the related group of disorders called “Cluster B” in the DSM raise issues. This includes the terms narcissistic, antisocial, histrionic, and borderline in DSM-5-TR. The first three terms are clearly pejorative. The last is unclear: What is the border between? Originally, it was bordering on psychosis, but as explained in DSM and ICD, borderline disorder is much more closely related to other personality disorders.
Notably, the “Cluster B” disorders run together in families, but men are more likely to be called antisocial and women borderline, even though the overlap in signs and symptoms is profound, suggesting marginally different manifestations of the same condition. The ICD has made changes to address the problems associated with some of these terms. ICD proposes personality “difficulty” to replace personality “disorder”; a modest change but less offensive. And it proposes seeing all, or at least most, personality disorders as being related to one another. Most share features of disturbances in sense-of-self and relationships with others. As descriptors, ICD kept “borderline pattern,” but replaced “antisocial” with “dissocial,” in an effort to be accurate but less demeaning. Other descriptors it proposes are negative affectivity, detachment, disinhibition, and anankastia, the last referring to compulsions.
These are notable advances. Can the field find even better terms to communicate hard to hear information, with words that are less problematic? In search of options, we surveyed clinicians at academic centers about the terms they preferred to avoid and the ones they prefer to use in talking with patients.6 Their practices may be informative.
Briefly summarized, these clinicians preferred not to use “schizophrenia” and very few used “antisocial,” “histrionic,” or “narcissistic.” Most avoided using “borderline” as well. Instead, they recommended discussing specific symptoms and manifestations of illness or dysfunctional behavior and relationships with their patients. They employed terms including “psychosis,” “hallucination,” “delusion,” “thinking disorder,” and “mood disorder.” They explained these terms, as needed, and found that patients understood them.
For Cluster B personality disorders, they spoke of personality traits and styles and specifically about “conduct,” “rule breaking,” “coping,” “self-focus,” “emotionality,” and “reactivity.” Those choices are not perfect, of course. Medical terms are often not standard words used in a conversational way. But the words chosen by these clinicians are generally straightforward and may communicate in a clear and acceptable fashion. It is also notable that the terms match how the clinicians assess and treat their patients, as observed in a separate study of their practices.7 That is, the clinicians advised that they look for and suggest treatments for the specific symptoms they see that most disrupt an individual’s life, such as delusions or mood instability. They are not much guided by diagnoses, like schizophrenia or borderline disorder. That makes the chosen terms not only less confusing or off-putting but also more practical.
Changing terminology in any field is difficult. We are trained to use standard terms. Clearly, however, many clinicians avoid some terms and use alternatives in their work. Asked why, they responded that they did so precisely to communicate more effectively and more respectfully. That is key to their treatment goals. Perhaps others will consider these choices useful in their work. And perhaps both the DSM and the ICD will not only continue to consider but will decide to implement alternatives for problematic terms in the years ahead, as they discuss their next revisions.
Dr. Cohen is director of the Program for Neuropsychiatric Research at McLean Hospital, Belmont, Mass., and Robertson-Steele Professor of Psychiatry at Harvard Medical School, Boston.
References
1. Lasalvia A et al. Renaming schizophrenia? A survey among psychiatrists, mental health service users and family members in Italy. Schizophr Res. 2021;228:502-9.
2. Gülöksüz S et al. Renaming schizophrenia: 5 x 5. Epidemiol Psychiatr Sci. 2019;28(3):254-7.
3. Sartorius N et al. Name change for schizophrenia. Schizophr Bull. 2014;40(2):255-8.
4. Mesholam-Gately RI et al. Are we ready for a name change for schizophrenia? A survey of multiple stakeholders. Schizophr Res. 2021;238:152-60.
5. Mulder R. The evolving nosology of personality disorder and its clinical utility. World Psychiatry. 2021 Oct;20(3):361-2.
6. Cohen BM et al. Diagnostic terms psychiatrists prefer to use for common psychotic and personality disorders. J Psychiatr Res. 2022 Sep 5;155:226-31.
7. Cohen BM, et al. Use of DSM-5 diagnoses vs. other clinical information by US academic-affiliated psychiatrists in assessing and treating psychotic disorders. World Psychiatry. 2021 Oct;20(3):447-8.
We are living in an era of increasing sensitivity to our diversity and the ways we interact, but also an era of growing resistance to change and accommodation. As clinicians, we hope to be among the sensitive and the progressive, open to improving our views and interactions. And as part of our respect for those we treat, we seek to speak clearly with them about our assessment of what is disrupting their lives and about their options.
Using the right words is crucial in that work. Well-chosen words can be heard and understood. Poorly chosen words can be confusing or off-putting; they may miscommunicate or be offensive. Careful choice of words is also important among colleagues, who may not always mean the same things when using the same words.
In psychiatry, consumer knowledge and access are growing. There are effective standard treatments and promising new ones. But our terminology is often antique and obscure. This is so despite a recognition that some terms we use may communicate poorly and some are deprecating.
A notable example is “schizophrenia.” Originally referring to cognitive phenomena that were not adequately coherent with reality or one another, it has gone through periods of describing most psychosis to particular subsets of psychoses. Debates persist on specific criteria for key symptoms and typical course. Even two clinicians trained in the same site may not agree on the defining criteria, and the public, mostly informed by books, movies, and newspapers, is even more confused, often believing schizophrenia is multiple-personality disorder. In addition, the press and public often associate schizophrenia with violent behavior and uniformly bad outcomes, and for those reasons, a diagnosis is not only frightening but also stigmatizing.1
Many papers have presented the case for retiring “schizophrenia.”2 And practical efforts to rename schizophrenia have been made. These efforts have occurred in countries in which English is not the primary language.3 In Japan, schizophrenia was replaced by “integration disorder.” In Hong Kong, “disorder of thought and perception” was implemented. Korea chose “attunement disorder.” A recent large survey of stakeholders, including clinicians, researchers, and consumers in the United States, explored alternatives in English.4 Terms receiving approval included: “psychosis spectrum syndrome,” “altered perception syndrome,” and “neuro-emotional integration disorder.”
Despite these recommendations, the standard manuals of diagnosis, the ICD and DSM, have maintained the century-old term “schizophrenia” in their most recent editions, released in 2022. Aside from the inertia commonly associated with long-standing practices, it has been noted that many of the alternatives suggested or, in some places, implemented, are complex, somewhat vague, or too inclusive to distinguish different clinical presentations requiring different treatment approaches. They might not be compelling for use or optimal to guide caregiving.
Perhaps more concerning than “schizophrenia” are terms used to describe personality disorders.5 “Personality disorder” itself is problematic, implying a core and possibly unalterable fault in an individual. And among the personality disorders, words for the related group of disorders called “Cluster B” in the DSM raise issues. This includes the terms narcissistic, antisocial, histrionic, and borderline in DSM-5-TR. The first three terms are clearly pejorative. The last is unclear: What is the border between? Originally, it was bordering on psychosis, but as explained in DSM and ICD, borderline disorder is much more closely related to other personality disorders.
Notably, the “Cluster B” disorders run together in families, but men are more likely to be called antisocial and women borderline, even though the overlap in signs and symptoms is profound, suggesting marginally different manifestations of the same condition. The ICD has made changes to address the problems associated with some of these terms. ICD proposes personality “difficulty” to replace personality “disorder”; a modest change but less offensive. And it proposes seeing all, or at least most, personality disorders as being related to one another. Most share features of disturbances in sense-of-self and relationships with others. As descriptors, ICD kept “borderline pattern,” but replaced “antisocial” with “dissocial,” in an effort to be accurate but less demeaning. Other descriptors it proposes are negative affectivity, detachment, disinhibition, and anankastia, the last referring to compulsions.
These are notable advances. Can the field find even better terms to communicate hard to hear information, with words that are less problematic? In search of options, we surveyed clinicians at academic centers about the terms they preferred to avoid and the ones they prefer to use in talking with patients.6 Their practices may be informative.
Briefly summarized, these clinicians preferred not to use “schizophrenia” and very few used “antisocial,” “histrionic,” or “narcissistic.” Most avoided using “borderline” as well. Instead, they recommended discussing specific symptoms and manifestations of illness or dysfunctional behavior and relationships with their patients. They employed terms including “psychosis,” “hallucination,” “delusion,” “thinking disorder,” and “mood disorder.” They explained these terms, as needed, and found that patients understood them.
For Cluster B personality disorders, they spoke of personality traits and styles and specifically about “conduct,” “rule breaking,” “coping,” “self-focus,” “emotionality,” and “reactivity.” Those choices are not perfect, of course. Medical terms are often not standard words used in a conversational way. But the words chosen by these clinicians are generally straightforward and may communicate in a clear and acceptable fashion. It is also notable that the terms match how the clinicians assess and treat their patients, as observed in a separate study of their practices.7 That is, the clinicians advised that they look for and suggest treatments for the specific symptoms they see that most disrupt an individual’s life, such as delusions or mood instability. They are not much guided by diagnoses, like schizophrenia or borderline disorder. That makes the chosen terms not only less confusing or off-putting but also more practical.
Changing terminology in any field is difficult. We are trained to use standard terms. Clearly, however, many clinicians avoid some terms and use alternatives in their work. Asked why, they responded that they did so precisely to communicate more effectively and more respectfully. That is key to their treatment goals. Perhaps others will consider these choices useful in their work. And perhaps both the DSM and the ICD will not only continue to consider but will decide to implement alternatives for problematic terms in the years ahead, as they discuss their next revisions.
Dr. Cohen is director of the Program for Neuropsychiatric Research at McLean Hospital, Belmont, Mass., and Robertson-Steele Professor of Psychiatry at Harvard Medical School, Boston.
References
1. Lasalvia A et al. Renaming schizophrenia? A survey among psychiatrists, mental health service users and family members in Italy. Schizophr Res. 2021;228:502-9.
2. Gülöksüz S et al. Renaming schizophrenia: 5 x 5. Epidemiol Psychiatr Sci. 2019;28(3):254-7.
3. Sartorius N et al. Name change for schizophrenia. Schizophr Bull. 2014;40(2):255-8.
4. Mesholam-Gately RI et al. Are we ready for a name change for schizophrenia? A survey of multiple stakeholders. Schizophr Res. 2021;238:152-60.
5. Mulder R. The evolving nosology of personality disorder and its clinical utility. World Psychiatry. 2021 Oct;20(3):361-2.
6. Cohen BM et al. Diagnostic terms psychiatrists prefer to use for common psychotic and personality disorders. J Psychiatr Res. 2022 Sep 5;155:226-31.
7. Cohen BM, et al. Use of DSM-5 diagnoses vs. other clinical information by US academic-affiliated psychiatrists in assessing and treating psychotic disorders. World Psychiatry. 2021 Oct;20(3):447-8.
Age-specific cut-offs needed for cardiac troponin tests?
The study shows that the 99th percentile for the upper reference limit (used to define myocardial injury) for high-sensitivity (hs)–troponin T in the new analysis matched those reported by manufacturers. However, the same threshold for hs–troponin I was lower than was manufacturer-reported levels when considering the whole population.
And for both hs–troponin T and hs–troponin I, there were significant differences in 99th percentile levels by age.
“Our data suggest that some cases of myocardial injury may be missed in the whole population by using current non–age specific thresholds of troponin I,” lead author, John McEvoy, MB, University of Galway (Ireland), said in an interview. “If the non–age specific threshold was lowered to that in our cohort, then we would pick up more people with myocardial injury.”
“However,” Dr. McEvoy added, “if age-specific thresholds were deployed, then our data suggest that thresholds used to diagnose myocardial injury would need to be higher in older adults, somewhat lower in middle-aged individuals and much lower in younger people.”
The study was published online in the Journal of the American College of Cardiology.
The authors explain that the 99th percentile upper–reference limit threshold is the common benchmark of abnormality for all troponin assays. Five high-sensitivity cardiac troponin assays have been cleared by the Food and Drug Administration for clinical use and allow for earlier diagnosis of MI.
However, there has been variability in the approach used to define the 99th percentile upper reference limits for these assays, with definitions of healthy reference populations differing and the various assays available are not standardized or harmonized. So troponin concentrations at 99th percentiles do not align across assays, and the generalizability of manufacturer-reported reference upper reference limits for hs-troponin assays to the U.S. adult population is unknown.
They note that though sex-specific 99th percentile upper reference limits for hs-troponin have been recommended since 2018, age-specific thresholds are not yet endorsed, and whether thresholds differ by race or ethnicity is also controversial.
They aimed to investigate these issues using stored serum samples from adults aged 18 or older who participated in the 1999-2004 National Health and Nutrition Examination Survey (NHANES).
Dr. McEvoy described the NHANES database as “the gold standard cohort for representation of the U.S. adult population,” noting that other studies conducted by the manufacturers of the troponin tests have often used convenience samples from patients attending hospital clinics and blood donors, which he said were not representative of the whole population.
For the study, the researchers estimated that the 99th percentile upper reference limit for four hs-troponin assays (one troponin T and three troponin I) in a strictly defined healthy reference subgroup of 2,746 individuals from the NHANES cohort.
Results showed that the NHANES 99th percentile upper reference limit for hs–troponin T (19 ng/L) matched the manufacturer-reported level (19 ng/L). But, the NHANES upper reference levels for three troponin I assays were lower than were levels stated by the manufacturers.
The NHANES levels were 13 ng/L for the Abbott hs–troponin I assay (manufacturer: 28 ng/L); 5 ng/L for the Ortho hs–troponin I assay (manufacturer: 11 ng/L); and 37 ng/L for the Siemens hs–troponin I assay (manufacturer: 46.5 ng/L).
Furthermore, the 99th percentile upper reference limits for all four hs-troponin assays were statistically significantly lower in healthy adults younger than 40 years, compared with healthy adults older than 60 years.
There were also significant differences in upper reference limits by sex, but none by race/ethnicity.
Dr. McEvoy explained that NHANES is a very well phenotyped database with information on individuals’ health, body mass index, and other biomarkers. “This allows us to define a completely healthy subgroup of people, which could explain why the 99th percentile threshold for hs–troponin I was lower than previously reported from other cohorts,” he added.
Though there may be concern that such a healthy subgroup would mean the sample is enriched with younger people, whereas the typical person having their troponin measured would be older, Dr. McEvoy pointed out that there were more than 400 people older than 60 years in the healthy group. “This is probably the biggest cohort of super healthy older U.S. adults ever sampled in this regard,” he commented.
Dr. McEvoy said that the overall results from the study suggested that different thresholds might need to be considered for troponin I. “This could lead to threshold levels used to diagnose myocardial injury being cut in the population as a whole.”
But, he said a more important message was the need for age-specific thresholds.
“We found that troponin levels track with age. Even in individuals who age in a very healthy way, their troponin levels are greater than in younger people. This is the first time this has been shown with such clear statistical significance,” Dr. McEvoy said. “We think this data provides a compelling case for the use of age-specific cut-offs.”
He explained that, if age-specific thresholds were used to diagnose myocardial injury, the cut point from the current data would be higher than it would be from current manufacturers’ recommendations in those older than 60 years, so fewer people in this age group would be labeled as having myocardial injury.
“Our results suggest that, at present, we are seeing more false positives in older people leading to more unnecessary tests.” Using age-specific cut off points will reduce the number of false positives in older people. Dr. McEvoy noted a similar change in the way D-Dimer blood tests have been used to diagnose pulmonary embolism in recent years.
Using age-specific cut-offs for hs-troponin would also reduce the number of false negatives in younger people, Dr. McEvoy added.
Further studies needed?
In an accompanying editorial, Cian McCarthy, MB, Austin Vyas, and James Januzzi, MD, of Massachusetts General Hospital, Boston, note that though there are substantial shortcomings to using the 99th percentile upper reference limit of troponins for the diagnosis of cardiac injury, they believe this measurement should persist as a central component of the MI diagnostic criteria, with the caveat that this is only one component of the definition of MI and does not alone define it.
“Cardiac troponin measurement is one of the most commonly utilized blood tests in hospital-based settings, and yet important questions remain about what exactly is a normal value for this test,” the editorialists comment.
They say this new study emphasizes the importance of age and sex in interpretation of troponin levels.
“Although the use of such cut-offs may further complicate MI diagnostic criteria, this is superseded by the benefits of improved diagnostic accuracy in younger and female patients (a critical health equity step) while reducing MI overdiagnosis in the elderly, with the resultant harms that might follow, adverse psychosocial patient impact, and unnecessary health care expenditure from cascade testing,” they write.
They conclude that further large studies derived from healthy cohorts should be conducted to answer this question in a definitive fashion.
A version of this article first appeared on Medscape.com.
The study shows that the 99th percentile for the upper reference limit (used to define myocardial injury) for high-sensitivity (hs)–troponin T in the new analysis matched those reported by manufacturers. However, the same threshold for hs–troponin I was lower than was manufacturer-reported levels when considering the whole population.
And for both hs–troponin T and hs–troponin I, there were significant differences in 99th percentile levels by age.
“Our data suggest that some cases of myocardial injury may be missed in the whole population by using current non–age specific thresholds of troponin I,” lead author, John McEvoy, MB, University of Galway (Ireland), said in an interview. “If the non–age specific threshold was lowered to that in our cohort, then we would pick up more people with myocardial injury.”
“However,” Dr. McEvoy added, “if age-specific thresholds were deployed, then our data suggest that thresholds used to diagnose myocardial injury would need to be higher in older adults, somewhat lower in middle-aged individuals and much lower in younger people.”
The study was published online in the Journal of the American College of Cardiology.
The authors explain that the 99th percentile upper–reference limit threshold is the common benchmark of abnormality for all troponin assays. Five high-sensitivity cardiac troponin assays have been cleared by the Food and Drug Administration for clinical use and allow for earlier diagnosis of MI.
However, there has been variability in the approach used to define the 99th percentile upper reference limits for these assays, with definitions of healthy reference populations differing and the various assays available are not standardized or harmonized. So troponin concentrations at 99th percentiles do not align across assays, and the generalizability of manufacturer-reported reference upper reference limits for hs-troponin assays to the U.S. adult population is unknown.
They note that though sex-specific 99th percentile upper reference limits for hs-troponin have been recommended since 2018, age-specific thresholds are not yet endorsed, and whether thresholds differ by race or ethnicity is also controversial.
They aimed to investigate these issues using stored serum samples from adults aged 18 or older who participated in the 1999-2004 National Health and Nutrition Examination Survey (NHANES).
Dr. McEvoy described the NHANES database as “the gold standard cohort for representation of the U.S. adult population,” noting that other studies conducted by the manufacturers of the troponin tests have often used convenience samples from patients attending hospital clinics and blood donors, which he said were not representative of the whole population.
For the study, the researchers estimated that the 99th percentile upper reference limit for four hs-troponin assays (one troponin T and three troponin I) in a strictly defined healthy reference subgroup of 2,746 individuals from the NHANES cohort.
Results showed that the NHANES 99th percentile upper reference limit for hs–troponin T (19 ng/L) matched the manufacturer-reported level (19 ng/L). But, the NHANES upper reference levels for three troponin I assays were lower than were levels stated by the manufacturers.
The NHANES levels were 13 ng/L for the Abbott hs–troponin I assay (manufacturer: 28 ng/L); 5 ng/L for the Ortho hs–troponin I assay (manufacturer: 11 ng/L); and 37 ng/L for the Siemens hs–troponin I assay (manufacturer: 46.5 ng/L).
Furthermore, the 99th percentile upper reference limits for all four hs-troponin assays were statistically significantly lower in healthy adults younger than 40 years, compared with healthy adults older than 60 years.
There were also significant differences in upper reference limits by sex, but none by race/ethnicity.
Dr. McEvoy explained that NHANES is a very well phenotyped database with information on individuals’ health, body mass index, and other biomarkers. “This allows us to define a completely healthy subgroup of people, which could explain why the 99th percentile threshold for hs–troponin I was lower than previously reported from other cohorts,” he added.
Though there may be concern that such a healthy subgroup would mean the sample is enriched with younger people, whereas the typical person having their troponin measured would be older, Dr. McEvoy pointed out that there were more than 400 people older than 60 years in the healthy group. “This is probably the biggest cohort of super healthy older U.S. adults ever sampled in this regard,” he commented.
Dr. McEvoy said that the overall results from the study suggested that different thresholds might need to be considered for troponin I. “This could lead to threshold levels used to diagnose myocardial injury being cut in the population as a whole.”
But, he said a more important message was the need for age-specific thresholds.
“We found that troponin levels track with age. Even in individuals who age in a very healthy way, their troponin levels are greater than in younger people. This is the first time this has been shown with such clear statistical significance,” Dr. McEvoy said. “We think this data provides a compelling case for the use of age-specific cut-offs.”
He explained that, if age-specific thresholds were used to diagnose myocardial injury, the cut point from the current data would be higher than it would be from current manufacturers’ recommendations in those older than 60 years, so fewer people in this age group would be labeled as having myocardial injury.
“Our results suggest that, at present, we are seeing more false positives in older people leading to more unnecessary tests.” Using age-specific cut off points will reduce the number of false positives in older people. Dr. McEvoy noted a similar change in the way D-Dimer blood tests have been used to diagnose pulmonary embolism in recent years.
Using age-specific cut-offs for hs-troponin would also reduce the number of false negatives in younger people, Dr. McEvoy added.
Further studies needed?
In an accompanying editorial, Cian McCarthy, MB, Austin Vyas, and James Januzzi, MD, of Massachusetts General Hospital, Boston, note that though there are substantial shortcomings to using the 99th percentile upper reference limit of troponins for the diagnosis of cardiac injury, they believe this measurement should persist as a central component of the MI diagnostic criteria, with the caveat that this is only one component of the definition of MI and does not alone define it.
“Cardiac troponin measurement is one of the most commonly utilized blood tests in hospital-based settings, and yet important questions remain about what exactly is a normal value for this test,” the editorialists comment.
They say this new study emphasizes the importance of age and sex in interpretation of troponin levels.
“Although the use of such cut-offs may further complicate MI diagnostic criteria, this is superseded by the benefits of improved diagnostic accuracy in younger and female patients (a critical health equity step) while reducing MI overdiagnosis in the elderly, with the resultant harms that might follow, adverse psychosocial patient impact, and unnecessary health care expenditure from cascade testing,” they write.
They conclude that further large studies derived from healthy cohorts should be conducted to answer this question in a definitive fashion.
A version of this article first appeared on Medscape.com.
The study shows that the 99th percentile for the upper reference limit (used to define myocardial injury) for high-sensitivity (hs)–troponin T in the new analysis matched those reported by manufacturers. However, the same threshold for hs–troponin I was lower than was manufacturer-reported levels when considering the whole population.
And for both hs–troponin T and hs–troponin I, there were significant differences in 99th percentile levels by age.
“Our data suggest that some cases of myocardial injury may be missed in the whole population by using current non–age specific thresholds of troponin I,” lead author, John McEvoy, MB, University of Galway (Ireland), said in an interview. “If the non–age specific threshold was lowered to that in our cohort, then we would pick up more people with myocardial injury.”
“However,” Dr. McEvoy added, “if age-specific thresholds were deployed, then our data suggest that thresholds used to diagnose myocardial injury would need to be higher in older adults, somewhat lower in middle-aged individuals and much lower in younger people.”
The study was published online in the Journal of the American College of Cardiology.
The authors explain that the 99th percentile upper–reference limit threshold is the common benchmark of abnormality for all troponin assays. Five high-sensitivity cardiac troponin assays have been cleared by the Food and Drug Administration for clinical use and allow for earlier diagnosis of MI.
However, there has been variability in the approach used to define the 99th percentile upper reference limits for these assays, with definitions of healthy reference populations differing and the various assays available are not standardized or harmonized. So troponin concentrations at 99th percentiles do not align across assays, and the generalizability of manufacturer-reported reference upper reference limits for hs-troponin assays to the U.S. adult population is unknown.
They note that though sex-specific 99th percentile upper reference limits for hs-troponin have been recommended since 2018, age-specific thresholds are not yet endorsed, and whether thresholds differ by race or ethnicity is also controversial.
They aimed to investigate these issues using stored serum samples from adults aged 18 or older who participated in the 1999-2004 National Health and Nutrition Examination Survey (NHANES).
Dr. McEvoy described the NHANES database as “the gold standard cohort for representation of the U.S. adult population,” noting that other studies conducted by the manufacturers of the troponin tests have often used convenience samples from patients attending hospital clinics and blood donors, which he said were not representative of the whole population.
For the study, the researchers estimated that the 99th percentile upper reference limit for four hs-troponin assays (one troponin T and three troponin I) in a strictly defined healthy reference subgroup of 2,746 individuals from the NHANES cohort.
Results showed that the NHANES 99th percentile upper reference limit for hs–troponin T (19 ng/L) matched the manufacturer-reported level (19 ng/L). But, the NHANES upper reference levels for three troponin I assays were lower than were levels stated by the manufacturers.
The NHANES levels were 13 ng/L for the Abbott hs–troponin I assay (manufacturer: 28 ng/L); 5 ng/L for the Ortho hs–troponin I assay (manufacturer: 11 ng/L); and 37 ng/L for the Siemens hs–troponin I assay (manufacturer: 46.5 ng/L).
Furthermore, the 99th percentile upper reference limits for all four hs-troponin assays were statistically significantly lower in healthy adults younger than 40 years, compared with healthy adults older than 60 years.
There were also significant differences in upper reference limits by sex, but none by race/ethnicity.
Dr. McEvoy explained that NHANES is a very well phenotyped database with information on individuals’ health, body mass index, and other biomarkers. “This allows us to define a completely healthy subgroup of people, which could explain why the 99th percentile threshold for hs–troponin I was lower than previously reported from other cohorts,” he added.
Though there may be concern that such a healthy subgroup would mean the sample is enriched with younger people, whereas the typical person having their troponin measured would be older, Dr. McEvoy pointed out that there were more than 400 people older than 60 years in the healthy group. “This is probably the biggest cohort of super healthy older U.S. adults ever sampled in this regard,” he commented.
Dr. McEvoy said that the overall results from the study suggested that different thresholds might need to be considered for troponin I. “This could lead to threshold levels used to diagnose myocardial injury being cut in the population as a whole.”
But, he said a more important message was the need for age-specific thresholds.
“We found that troponin levels track with age. Even in individuals who age in a very healthy way, their troponin levels are greater than in younger people. This is the first time this has been shown with such clear statistical significance,” Dr. McEvoy said. “We think this data provides a compelling case for the use of age-specific cut-offs.”
He explained that, if age-specific thresholds were used to diagnose myocardial injury, the cut point from the current data would be higher than it would be from current manufacturers’ recommendations in those older than 60 years, so fewer people in this age group would be labeled as having myocardial injury.
“Our results suggest that, at present, we are seeing more false positives in older people leading to more unnecessary tests.” Using age-specific cut off points will reduce the number of false positives in older people. Dr. McEvoy noted a similar change in the way D-Dimer blood tests have been used to diagnose pulmonary embolism in recent years.
Using age-specific cut-offs for hs-troponin would also reduce the number of false negatives in younger people, Dr. McEvoy added.
Further studies needed?
In an accompanying editorial, Cian McCarthy, MB, Austin Vyas, and James Januzzi, MD, of Massachusetts General Hospital, Boston, note that though there are substantial shortcomings to using the 99th percentile upper reference limit of troponins for the diagnosis of cardiac injury, they believe this measurement should persist as a central component of the MI diagnostic criteria, with the caveat that this is only one component of the definition of MI and does not alone define it.
“Cardiac troponin measurement is one of the most commonly utilized blood tests in hospital-based settings, and yet important questions remain about what exactly is a normal value for this test,” the editorialists comment.
They say this new study emphasizes the importance of age and sex in interpretation of troponin levels.
“Although the use of such cut-offs may further complicate MI diagnostic criteria, this is superseded by the benefits of improved diagnostic accuracy in younger and female patients (a critical health equity step) while reducing MI overdiagnosis in the elderly, with the resultant harms that might follow, adverse psychosocial patient impact, and unnecessary health care expenditure from cascade testing,” they write.
They conclude that further large studies derived from healthy cohorts should be conducted to answer this question in a definitive fashion.
A version of this article first appeared on Medscape.com.
FROM JACC
Breast cancer survivors need a comprehensive care plan, says doctor
said Patricia A. Ganz, MD, during a presentation at the European Society for Medical Oncology Breast Cancer annual congress.
Several studies suggest that many breast cancer patients are not well prepared to move forward after a breast cancer diagnosis and subsequent treatments, continued Dr. Ganz, who works at the UCLA Jonsson Comprehensive Cancer Center, Los Angeles.
Meeting the survivorship needs of breast cancer patients requires addressing both their physical and psychosocial needs, Dr. Ganz said. She explained how to achieve that, but first pointed to research elaborating on what's missing from some breast cancer survivors' care and barriers to these patients having their variety of health-related needs met.
In a 2021 study published in the Journal of Cancer Survivorship, Dr. Ganz and colleagues conducted a survey of approximately 200 medical oncologists in the United States. They determined that less than 50% provide survivorship care plans to patients at the end of treatment or communicate with patients’ other physicians about follow-up care.
In a secondary analysis of data from the same survey published in 2022 in Breast Cancer Research and Treatment, Dr. Ganz and colleagues examined medical oncologists’ perceived barriers to addressing both physical and psychosocial long-term effects in breast cancer survivors. For both, lack of time was the greatest perceived barrier, cited by nearly two-thirds of oncologists. Other barriers to addressing physical effects included lack of evidence-based, effective interventions, lack of clinical algorithms to guide care, and ambiguity regarding professional responsibility at the end of treatment. Other top barriers to addressing psychosocial issues included lack of mental health providers, lack of psychosocial resources, and lack of clinician knowledge and skills.
Data from additional studies suggest that, overall, cancer patients with greater physical burdens, such as more complex and lengthy treatment regimens, also have greater psychosocial needs, Dr. Ganz noted. Plus, approximately 15%-20% of cancer survivors have ongoing anxiety and depressive symptoms.
Shift to primary care
As more breast cancer and other cancer patients survive for longer periods, more care will likely occur in general medical settings, Dr. Ganz said. Issues to be addressed will include the potential increased risk of comorbid conditions for these survivors, and whether survivorship interventions earlier in the disease trajectory will impact survivorship. For cancer patients who achieve remission after treatment, the first 5 years after a diagnosis involves treatment and short-term surveillance for late effects. Beyond 5 years, care for cancer survivors mainly involves primary care and management of any comorbid conditions, as well as surveillance for late effects and recurrences, and awareness of new research.
A patient consultation early in the process after diagnosis is the start of a continuum of care, Dr. Ganz said. A patient consultation should address symptoms related to initial treatments, such as neuropathy, pain, fatigue, and insomnia, as well as the psychological symptoms of anxiety and depression. An early consultation also should evaluate adherence to endocrine therapy and management of symptoms, if needed, with the larger goal of preparing patients for recovery and the transition to survivorship, and what to expect for long-term follow-up.
Delivering the three P’s
The “Three P’s” of survivor care for breast cancer patients are palliation, prevention, and promotion of health, according to Dr. Ganz .
The first “P,” for palliative, is a key part of survivorship care, said Dr. Ganz. Palliative care is defined as care that focuses on reducing symptom severity and improving quality of life. The biological effects of cancer treatment can be associated with physical effects, such as functional limitations and frailty, and behavioral/cognitive effects such as depression, fatigue, and cognitive deficits, she said. To manage these effects and provide palliative care, consultation is needed with specialists in relevant areas including mental health, pain management, physical medicine/rehabilitation, endocrinology, cardiology, and neurology.
The second “P,” which is for prevention in survivorship care, refers to ongoing follow-up screening to identify any potentially serious late-onset complications such as osteoporosis or cardiac disease so they can be addressed, said Dr. Ganz. Other considerations include chemoprevention if available and genetic counseling for patients with hereditary cancers. Prevention also includes counseling patients about lifestyle modifications to help prevent additional cancer.
The goal of the third “P,” which is for health promotion, is to promote risk reduction for the health problems associated with accelerated aging that may arise in cancer survivors, said Dr. Ganz.
Health promotion strategies include maintaining a healthy weight, increasing physical activity, and avoiding harmful exposures, she said. Healthy lifestyle interventions can also reduce the risk of other chronic diseases such as diabetes and heart disease.
To that end, Dr. Ganz outlined several behavioral interventions that may mitigate the effects of cancer treatment on the accelerated aging process, including stress reduction in the form of meditation or yoga, cognitive behavioral therapy, improving sleep, increasing physical activity, reducing obesity, and decreasing tobacco and alcohol use. These interventions may help reduce inflammation and promote tissue repair and healing.
For cancer survivors, the life span may be longer than the health span, and these patients may benefit from an integrated model of care, with systematic screening and consolidated appointments, rather than a fragmented model in which departments and referrals are siloed, which may result in conflicting advice or redundancy, said Dr. Ganz.
Looking ahead, more research is needed to explore models of care delivery, as requirements for survivor care will vary among patients and care settings, Dr. Ganz said.
However, regardless of setting, treatment plans and shared decision-making can help reduce potential long-term or late-emerging effects, she said. Developing a survivorship care plan can help patients learn how to enhance their recovery.
During a question and answer session, Dr. Ganz was asked about whether hormone therapy could be used for patients with hormone negative breast cancer. “I think vaginal estrogen can be used if someone is on tamoxifen,” she said. However, “we need to be cautious” in case there are remaining estrogen positive cells, in order to avoid potential metastases, and use of hormone therapy in breast cancer survivors is an individualized decision based in part on quality of life.
Engaging a patient’s partner early can be helpful
If possible, engage the patient’s partner in survivorship discussions, said Luzia Travado, PhD, head of psycho-oncology at the Champalimaud Foundation, Lisbon, who presented on the topic of sexuality and commented on survivorship during the discussion. For those women with partners, engaging the partner early in treatment often means they are more likely to play a larger role in the post treatment and long term by providing stability and emotional support.
“Make sure partners are engaged and understand that they have a role, and that this role is valued,” she said. Unfortunately, there are a lot of divorced women with breast cancer, as the disease can take a toll on relationships. However, remember “sexuality is not just sex; it is caring, loving, and intimacy.”
“To end on a positive note, it is important to empower patients, and to give them self-management skills so they can make things even better in their survivorship,” said Dr. Ganz. In spite of discussing difficulties and challenges, one of the goals of the session was to offer potential solutions and answers.
Dr. Ganz disclosed serving as editor of the cancer survivorship section on Up-to-Date, and serving as a consultant for Blue Note Therapeutics, GRAIL, InformedDNA, and Roche-Genentech. Dr. Travado had no relevant financial conflicts to disclose.
said Patricia A. Ganz, MD, during a presentation at the European Society for Medical Oncology Breast Cancer annual congress.
Several studies suggest that many breast cancer patients are not well prepared to move forward after a breast cancer diagnosis and subsequent treatments, continued Dr. Ganz, who works at the UCLA Jonsson Comprehensive Cancer Center, Los Angeles.
Meeting the survivorship needs of breast cancer patients requires addressing both their physical and psychosocial needs, Dr. Ganz said. She explained how to achieve that, but first pointed to research elaborating on what's missing from some breast cancer survivors' care and barriers to these patients having their variety of health-related needs met.
In a 2021 study published in the Journal of Cancer Survivorship, Dr. Ganz and colleagues conducted a survey of approximately 200 medical oncologists in the United States. They determined that less than 50% provide survivorship care plans to patients at the end of treatment or communicate with patients’ other physicians about follow-up care.
In a secondary analysis of data from the same survey published in 2022 in Breast Cancer Research and Treatment, Dr. Ganz and colleagues examined medical oncologists’ perceived barriers to addressing both physical and psychosocial long-term effects in breast cancer survivors. For both, lack of time was the greatest perceived barrier, cited by nearly two-thirds of oncologists. Other barriers to addressing physical effects included lack of evidence-based, effective interventions, lack of clinical algorithms to guide care, and ambiguity regarding professional responsibility at the end of treatment. Other top barriers to addressing psychosocial issues included lack of mental health providers, lack of psychosocial resources, and lack of clinician knowledge and skills.
Data from additional studies suggest that, overall, cancer patients with greater physical burdens, such as more complex and lengthy treatment regimens, also have greater psychosocial needs, Dr. Ganz noted. Plus, approximately 15%-20% of cancer survivors have ongoing anxiety and depressive symptoms.
Shift to primary care
As more breast cancer and other cancer patients survive for longer periods, more care will likely occur in general medical settings, Dr. Ganz said. Issues to be addressed will include the potential increased risk of comorbid conditions for these survivors, and whether survivorship interventions earlier in the disease trajectory will impact survivorship. For cancer patients who achieve remission after treatment, the first 5 years after a diagnosis involves treatment and short-term surveillance for late effects. Beyond 5 years, care for cancer survivors mainly involves primary care and management of any comorbid conditions, as well as surveillance for late effects and recurrences, and awareness of new research.
A patient consultation early in the process after diagnosis is the start of a continuum of care, Dr. Ganz said. A patient consultation should address symptoms related to initial treatments, such as neuropathy, pain, fatigue, and insomnia, as well as the psychological symptoms of anxiety and depression. An early consultation also should evaluate adherence to endocrine therapy and management of symptoms, if needed, with the larger goal of preparing patients for recovery and the transition to survivorship, and what to expect for long-term follow-up.
Delivering the three P’s
The “Three P’s” of survivor care for breast cancer patients are palliation, prevention, and promotion of health, according to Dr. Ganz .
The first “P,” for palliative, is a key part of survivorship care, said Dr. Ganz. Palliative care is defined as care that focuses on reducing symptom severity and improving quality of life. The biological effects of cancer treatment can be associated with physical effects, such as functional limitations and frailty, and behavioral/cognitive effects such as depression, fatigue, and cognitive deficits, she said. To manage these effects and provide palliative care, consultation is needed with specialists in relevant areas including mental health, pain management, physical medicine/rehabilitation, endocrinology, cardiology, and neurology.
The second “P,” which is for prevention in survivorship care, refers to ongoing follow-up screening to identify any potentially serious late-onset complications such as osteoporosis or cardiac disease so they can be addressed, said Dr. Ganz. Other considerations include chemoprevention if available and genetic counseling for patients with hereditary cancers. Prevention also includes counseling patients about lifestyle modifications to help prevent additional cancer.
The goal of the third “P,” which is for health promotion, is to promote risk reduction for the health problems associated with accelerated aging that may arise in cancer survivors, said Dr. Ganz.
Health promotion strategies include maintaining a healthy weight, increasing physical activity, and avoiding harmful exposures, she said. Healthy lifestyle interventions can also reduce the risk of other chronic diseases such as diabetes and heart disease.
To that end, Dr. Ganz outlined several behavioral interventions that may mitigate the effects of cancer treatment on the accelerated aging process, including stress reduction in the form of meditation or yoga, cognitive behavioral therapy, improving sleep, increasing physical activity, reducing obesity, and decreasing tobacco and alcohol use. These interventions may help reduce inflammation and promote tissue repair and healing.
For cancer survivors, the life span may be longer than the health span, and these patients may benefit from an integrated model of care, with systematic screening and consolidated appointments, rather than a fragmented model in which departments and referrals are siloed, which may result in conflicting advice or redundancy, said Dr. Ganz.
Looking ahead, more research is needed to explore models of care delivery, as requirements for survivor care will vary among patients and care settings, Dr. Ganz said.
However, regardless of setting, treatment plans and shared decision-making can help reduce potential long-term or late-emerging effects, she said. Developing a survivorship care plan can help patients learn how to enhance their recovery.
During a question and answer session, Dr. Ganz was asked about whether hormone therapy could be used for patients with hormone negative breast cancer. “I think vaginal estrogen can be used if someone is on tamoxifen,” she said. However, “we need to be cautious” in case there are remaining estrogen positive cells, in order to avoid potential metastases, and use of hormone therapy in breast cancer survivors is an individualized decision based in part on quality of life.
Engaging a patient’s partner early can be helpful
If possible, engage the patient’s partner in survivorship discussions, said Luzia Travado, PhD, head of psycho-oncology at the Champalimaud Foundation, Lisbon, who presented on the topic of sexuality and commented on survivorship during the discussion. For those women with partners, engaging the partner early in treatment often means they are more likely to play a larger role in the post treatment and long term by providing stability and emotional support.
“Make sure partners are engaged and understand that they have a role, and that this role is valued,” she said. Unfortunately, there are a lot of divorced women with breast cancer, as the disease can take a toll on relationships. However, remember “sexuality is not just sex; it is caring, loving, and intimacy.”
“To end on a positive note, it is important to empower patients, and to give them self-management skills so they can make things even better in their survivorship,” said Dr. Ganz. In spite of discussing difficulties and challenges, one of the goals of the session was to offer potential solutions and answers.
Dr. Ganz disclosed serving as editor of the cancer survivorship section on Up-to-Date, and serving as a consultant for Blue Note Therapeutics, GRAIL, InformedDNA, and Roche-Genentech. Dr. Travado had no relevant financial conflicts to disclose.
said Patricia A. Ganz, MD, during a presentation at the European Society for Medical Oncology Breast Cancer annual congress.
Several studies suggest that many breast cancer patients are not well prepared to move forward after a breast cancer diagnosis and subsequent treatments, continued Dr. Ganz, who works at the UCLA Jonsson Comprehensive Cancer Center, Los Angeles.
Meeting the survivorship needs of breast cancer patients requires addressing both their physical and psychosocial needs, Dr. Ganz said. She explained how to achieve that, but first pointed to research elaborating on what's missing from some breast cancer survivors' care and barriers to these patients having their variety of health-related needs met.
In a 2021 study published in the Journal of Cancer Survivorship, Dr. Ganz and colleagues conducted a survey of approximately 200 medical oncologists in the United States. They determined that less than 50% provide survivorship care plans to patients at the end of treatment or communicate with patients’ other physicians about follow-up care.
In a secondary analysis of data from the same survey published in 2022 in Breast Cancer Research and Treatment, Dr. Ganz and colleagues examined medical oncologists’ perceived barriers to addressing both physical and psychosocial long-term effects in breast cancer survivors. For both, lack of time was the greatest perceived barrier, cited by nearly two-thirds of oncologists. Other barriers to addressing physical effects included lack of evidence-based, effective interventions, lack of clinical algorithms to guide care, and ambiguity regarding professional responsibility at the end of treatment. Other top barriers to addressing psychosocial issues included lack of mental health providers, lack of psychosocial resources, and lack of clinician knowledge and skills.
Data from additional studies suggest that, overall, cancer patients with greater physical burdens, such as more complex and lengthy treatment regimens, also have greater psychosocial needs, Dr. Ganz noted. Plus, approximately 15%-20% of cancer survivors have ongoing anxiety and depressive symptoms.
Shift to primary care
As more breast cancer and other cancer patients survive for longer periods, more care will likely occur in general medical settings, Dr. Ganz said. Issues to be addressed will include the potential increased risk of comorbid conditions for these survivors, and whether survivorship interventions earlier in the disease trajectory will impact survivorship. For cancer patients who achieve remission after treatment, the first 5 years after a diagnosis involves treatment and short-term surveillance for late effects. Beyond 5 years, care for cancer survivors mainly involves primary care and management of any comorbid conditions, as well as surveillance for late effects and recurrences, and awareness of new research.
A patient consultation early in the process after diagnosis is the start of a continuum of care, Dr. Ganz said. A patient consultation should address symptoms related to initial treatments, such as neuropathy, pain, fatigue, and insomnia, as well as the psychological symptoms of anxiety and depression. An early consultation also should evaluate adherence to endocrine therapy and management of symptoms, if needed, with the larger goal of preparing patients for recovery and the transition to survivorship, and what to expect for long-term follow-up.
Delivering the three P’s
The “Three P’s” of survivor care for breast cancer patients are palliation, prevention, and promotion of health, according to Dr. Ganz .
The first “P,” for palliative, is a key part of survivorship care, said Dr. Ganz. Palliative care is defined as care that focuses on reducing symptom severity and improving quality of life. The biological effects of cancer treatment can be associated with physical effects, such as functional limitations and frailty, and behavioral/cognitive effects such as depression, fatigue, and cognitive deficits, she said. To manage these effects and provide palliative care, consultation is needed with specialists in relevant areas including mental health, pain management, physical medicine/rehabilitation, endocrinology, cardiology, and neurology.
The second “P,” which is for prevention in survivorship care, refers to ongoing follow-up screening to identify any potentially serious late-onset complications such as osteoporosis or cardiac disease so they can be addressed, said Dr. Ganz. Other considerations include chemoprevention if available and genetic counseling for patients with hereditary cancers. Prevention also includes counseling patients about lifestyle modifications to help prevent additional cancer.
The goal of the third “P,” which is for health promotion, is to promote risk reduction for the health problems associated with accelerated aging that may arise in cancer survivors, said Dr. Ganz.
Health promotion strategies include maintaining a healthy weight, increasing physical activity, and avoiding harmful exposures, she said. Healthy lifestyle interventions can also reduce the risk of other chronic diseases such as diabetes and heart disease.
To that end, Dr. Ganz outlined several behavioral interventions that may mitigate the effects of cancer treatment on the accelerated aging process, including stress reduction in the form of meditation or yoga, cognitive behavioral therapy, improving sleep, increasing physical activity, reducing obesity, and decreasing tobacco and alcohol use. These interventions may help reduce inflammation and promote tissue repair and healing.
For cancer survivors, the life span may be longer than the health span, and these patients may benefit from an integrated model of care, with systematic screening and consolidated appointments, rather than a fragmented model in which departments and referrals are siloed, which may result in conflicting advice or redundancy, said Dr. Ganz.
Looking ahead, more research is needed to explore models of care delivery, as requirements for survivor care will vary among patients and care settings, Dr. Ganz said.
However, regardless of setting, treatment plans and shared decision-making can help reduce potential long-term or late-emerging effects, she said. Developing a survivorship care plan can help patients learn how to enhance their recovery.
During a question and answer session, Dr. Ganz was asked about whether hormone therapy could be used for patients with hormone negative breast cancer. “I think vaginal estrogen can be used if someone is on tamoxifen,” she said. However, “we need to be cautious” in case there are remaining estrogen positive cells, in order to avoid potential metastases, and use of hormone therapy in breast cancer survivors is an individualized decision based in part on quality of life.
Engaging a patient’s partner early can be helpful
If possible, engage the patient’s partner in survivorship discussions, said Luzia Travado, PhD, head of psycho-oncology at the Champalimaud Foundation, Lisbon, who presented on the topic of sexuality and commented on survivorship during the discussion. For those women with partners, engaging the partner early in treatment often means they are more likely to play a larger role in the post treatment and long term by providing stability and emotional support.
“Make sure partners are engaged and understand that they have a role, and that this role is valued,” she said. Unfortunately, there are a lot of divorced women with breast cancer, as the disease can take a toll on relationships. However, remember “sexuality is not just sex; it is caring, loving, and intimacy.”
“To end on a positive note, it is important to empower patients, and to give them self-management skills so they can make things even better in their survivorship,” said Dr. Ganz. In spite of discussing difficulties and challenges, one of the goals of the session was to offer potential solutions and answers.
Dr. Ganz disclosed serving as editor of the cancer survivorship section on Up-to-Date, and serving as a consultant for Blue Note Therapeutics, GRAIL, InformedDNA, and Roche-Genentech. Dr. Travado had no relevant financial conflicts to disclose.
FROM ESMO BREAST CANCER 2023
Update on Migraine Prevention 2023
What is your experience with prescribing preventive medication for your patients with migraine?
Roughly 40% of patients living with migraine should be on preventive medication or other treatment, but probably fewer than 15% of patients with migraine are currently receiving therapy. There are several reasons for this: General physicians rarely put patients on preventive medication unless they are interested in or knowledgeable about headache, and the older preventive medicines that neurologists and headache specialists have used for many years have a lot of potential side effects and do not begin to work quickly.
It takes approximately 2 to 3 months for preventive medication to become effective, and many patients need to be slowly titrated up to an effective dose. By the time patients reach a steady state over a few weeks, if it is still not working well, they must slowly taper it and try something else. This is what often occurs with older preventive migraine medications—especially one of the most commonly used preventives, topiramate (Topamax). This drug was first indicated for epilepsy and then later for mood stabilization. Though it has good efficacy in reducing migraine attacks, it has many possible side effects, some of them troublesome. I often had multiple calls from patients in their first month of taking it complain of memory or word-finding issues and tingling in the extremities. More serious adverse events can be increased pressure in the eyes, such as glaucoma, and kidney stones. I often get referrals from other neurologists and headache specialists regarding patients who have failed multiple preventive medicines; 90% percent of these referrals need to be switched to the newer, more costly calcitonin gene-related peptide (CGRP)-blocking preventative medications, if insurance companies will cover them.
What categories of migraine preventive drugs do you generally prescribe your patients?
Of the older medications, most are epilepsy medicines, beta blockers, antidepressants, or cardiac medications such as angiotensin receptor blockers (candesartan). Of the newer medications, I use 1 of the 4 injectable monoclonal antibodies (mAbs), or 1 of the 2 gepants.
Older migraine preventive medication
Anticonvulsants (epilepsy medications)
Anticonvulsants are used for the treatment of several conditions, including epilepsy and pain control, but some can help reduce migraine attacks. These medicines, like all drugs, have the potential to cause side effects, especially topiramate; this medicine often causes paresthesia or tingling in the extremities as well as trouble with speech and memory, kidney stones, pancreatitis, and weight loss. The weight loss side effect of this drug has made it more appealing for some patients who had previously gained 10 to 15 pounds taking antidepressant medication to treat their migraine. I personally thought it was the most effective of all the preventive migraine medications if the patient could tolerate it.
Beta Blockers
Beta blockers cause the heart rate to decrease and also lower blood pressure. Most of my migraine patients are healthy females in their 20s and 30s and, when taking a beta blocker, can get short of breath when they exercise. These medications can also cause some depression and gastrointestinal issues and raise cholesterol levels.
Antidepressants
The type of antidepressants that I normally prescribe for migraine prevention are the tricyclic antidepressants. The one that has the best data in the literature and is often prescribed is amitriptyline (Elavil); I prefer a cousin to this medicine, nortriptyline. I prescribe tricyclics because many of my migraine patients have 2 other comorbid problems: depression and trouble staying asleep at night. Amitriptyline tends to cause drowsiness and can help patients sleep. It can also cause dry mouth, trouble urinating (especially in men), constipation, weight gain, and can slow patients down mentally, so it should not be prescribed to elderly patients. These antidepressants should be prescribed in very low doses and taken an hour before bedtime. The dose should be increased gradually over several weeks to help reduce adverse events. The best dose for migraine is often lower than the antidepressant dose, so sometimes a depressed patient needs 2 types of antidepressants. The typical dose for migraine prevention is about 50 to 75 mg. For depression, it is about 150 mg.
The patient would then need to increase their dose gradually for a month and remain on the target dose for at least another month. At the end of 2 months, they would have some idea whether it was working for them. If it was not, I might increase the dose even further. It is important to set expectations with patients at the beginning of treatment and tell them it is going to take 2 to 3 months to see if it works. If it does not work, I tell them, we will have to try another one, and that is going to take 2 or 3 months as well, until we can switch to the newer medications, which start to work in the first month, often in the first few days.
Why wouldn’t we just start with the newer preventives? Insurance companies require patients to fail, on average, 2 categories of the older medications before they will pay for the newer ones. Medicare usually only covers the older generic medications.
New migraine preventive medications
Monoclonal Antibodies
mAbs that block CGRP for the prevention of migraine, such as erenumab, fremanezumab, galcanezumab, and eptinezumab, target either the CGRP ligand itself or block the receptor to CGRP. This class of medication became available about 5 years ago. The first one approved was erenumab (Aimovig). It was tried by a lot of headache specialists, many neurologists, and then some general physicians once it came to market. It is the only one in its class that grabs the ligand CGRP and prevents it from docking on its receptor. Recently, 5-year safety data indicated it is extremely safe with only a few side effects, (it has been shown to cause some constipation and hypertension). It does, however, tend to lower the number of migraine days per month by about 40% to 50%. At the beginning of erenumab’s availability, researchers took patients that had 8 to 22 days of migraine per month and put them in double-blind, placebo-controlled, randomized trials. They found that some patients' migraine days went down gradually to 10 to 12 days from 20 migraine days per month. Erenumab works quickly, and most patients improve within 2 weeks.
Fremanezumab (AJOVY™) was the second mAb approved, followed pretty quickly by the third, galcanezumab (Emgality™). All 3 of these mAbs are administered once a month by a subcutaneous injection from an autoinjector. If a patient takes 3 fremanezumab injections in 1 day, they do not have to repeat that dose for 3 months. The upside of these 3 treatments is that the patient can self-administer the medication at home with few, if any, adverse events; the downside is they are expensive medications, costing about $600 per month.
Shortly thereafter, a fourth mAb, eptinezumab (VYEPTI™), was brought to market. Unlike the other 3 mAbs, it is administered as an intravenous infusion. The patient must come to an office or infusion center for a 30-minute intravenous infusion, which is not as convenient as treating themselves with an autoinjector at home. Eptinezumab is a strong medication that is often prescribed when other treatments are not effective. Each of the 4 mAbs has its own possible adverse events, but these are few and usually mild. The mAbs have a half-life of about 28 to 32 days; it takes 5 to 6 months after an injection for these mAbs to be metabolized by the reticuloendothelial system.
Gepants
The gepants are small molecule CGRP receptor blockers with much shorter half-lives than mAbs. They work by blocking the CGRP receptor so the CGRP ligand cannot dock there and cause vasodilation and increased pain transmission. Gepants have half-lives of 6 to 12 hours and can be used to treat a migraine acutely. Several drug companies studied the effects of taking a gepant every day or every other day, showing it can also be used as a migraine preventive medication. Ubrogepant (Ubrelvy®) was the first gepant to receive approval from the US Food and Drug Administration (FDA), but it was authorized only for acute care. Rimegepant (Nurtec®) was the second gepant approved, initially for acute treatment and later becoming the first gepant approved for migraine prevention. The same tablet can be used for acute care or for prevention. Preventive treatment consists of one 75 mg oral disintegrating tablet taken every second day. It works quite well as a preventive and has very few side effects. Nausea and abdominal discomfort occur in < 3% of patients. Some patients prefer to take a pill every other day over having an injection once per month or once every 3 months. It makes more sense for a woman of childbearing potential to take a drug with very short half-life vs one that lasts for 5 to 6 months in case she decides to become pregnant (or unexpectedly becomes pregnant).
A third gepant, atogepant (Qulipta™), was later approved, but only for prevention. It is available in 3 different strengths: 10 mg, 30 mg, and 60 mg. I tend to prescribe the 60-mg strength, and the dose is 1 pill every day.
If you compare rimegepant, which is taken once every other day, and atogepant, taken once daily, the latter tends to have slightly more side effects of nausea, drowsiness, and constipation, whereas rimegepant has been shown to have fewer side effects in double-blind, randomized studies. Like all gepants, it is quite effective and fast acting.
The goal of preventive medications is to decrease the frequency, severity, and duration of migraine attacks. Effective treatment can increase responsiveness to acute migraine therapy and improve the quality of life in patients suffering from migraine. Every patient is different and thus the side effects they experience vary. With time and patience, most patients find the relief from migraine they have been desperately seeking through the preventive medicines discussed above. This is a good time to have migraine, if you can get in to see a knowledgeable doctor and your insurance company cooperates. When I started my neurology practice 51 years ago, we had few preventives, and none approved by the FDA. Now we have several older, approved preventives—4 newer mAbs, and 2 newer gepants—as well as several devices, which we will discuss in the future.
What is your experience with prescribing preventive medication for your patients with migraine?
Roughly 40% of patients living with migraine should be on preventive medication or other treatment, but probably fewer than 15% of patients with migraine are currently receiving therapy. There are several reasons for this: General physicians rarely put patients on preventive medication unless they are interested in or knowledgeable about headache, and the older preventive medicines that neurologists and headache specialists have used for many years have a lot of potential side effects and do not begin to work quickly.
It takes approximately 2 to 3 months for preventive medication to become effective, and many patients need to be slowly titrated up to an effective dose. By the time patients reach a steady state over a few weeks, if it is still not working well, they must slowly taper it and try something else. This is what often occurs with older preventive migraine medications—especially one of the most commonly used preventives, topiramate (Topamax). This drug was first indicated for epilepsy and then later for mood stabilization. Though it has good efficacy in reducing migraine attacks, it has many possible side effects, some of them troublesome. I often had multiple calls from patients in their first month of taking it complain of memory or word-finding issues and tingling in the extremities. More serious adverse events can be increased pressure in the eyes, such as glaucoma, and kidney stones. I often get referrals from other neurologists and headache specialists regarding patients who have failed multiple preventive medicines; 90% percent of these referrals need to be switched to the newer, more costly calcitonin gene-related peptide (CGRP)-blocking preventative medications, if insurance companies will cover them.
What categories of migraine preventive drugs do you generally prescribe your patients?
Of the older medications, most are epilepsy medicines, beta blockers, antidepressants, or cardiac medications such as angiotensin receptor blockers (candesartan). Of the newer medications, I use 1 of the 4 injectable monoclonal antibodies (mAbs), or 1 of the 2 gepants.
Older migraine preventive medication
Anticonvulsants (epilepsy medications)
Anticonvulsants are used for the treatment of several conditions, including epilepsy and pain control, but some can help reduce migraine attacks. These medicines, like all drugs, have the potential to cause side effects, especially topiramate; this medicine often causes paresthesia or tingling in the extremities as well as trouble with speech and memory, kidney stones, pancreatitis, and weight loss. The weight loss side effect of this drug has made it more appealing for some patients who had previously gained 10 to 15 pounds taking antidepressant medication to treat their migraine. I personally thought it was the most effective of all the preventive migraine medications if the patient could tolerate it.
Beta Blockers
Beta blockers cause the heart rate to decrease and also lower blood pressure. Most of my migraine patients are healthy females in their 20s and 30s and, when taking a beta blocker, can get short of breath when they exercise. These medications can also cause some depression and gastrointestinal issues and raise cholesterol levels.
Antidepressants
The type of antidepressants that I normally prescribe for migraine prevention are the tricyclic antidepressants. The one that has the best data in the literature and is often prescribed is amitriptyline (Elavil); I prefer a cousin to this medicine, nortriptyline. I prescribe tricyclics because many of my migraine patients have 2 other comorbid problems: depression and trouble staying asleep at night. Amitriptyline tends to cause drowsiness and can help patients sleep. It can also cause dry mouth, trouble urinating (especially in men), constipation, weight gain, and can slow patients down mentally, so it should not be prescribed to elderly patients. These antidepressants should be prescribed in very low doses and taken an hour before bedtime. The dose should be increased gradually over several weeks to help reduce adverse events. The best dose for migraine is often lower than the antidepressant dose, so sometimes a depressed patient needs 2 types of antidepressants. The typical dose for migraine prevention is about 50 to 75 mg. For depression, it is about 150 mg.
The patient would then need to increase their dose gradually for a month and remain on the target dose for at least another month. At the end of 2 months, they would have some idea whether it was working for them. If it was not, I might increase the dose even further. It is important to set expectations with patients at the beginning of treatment and tell them it is going to take 2 to 3 months to see if it works. If it does not work, I tell them, we will have to try another one, and that is going to take 2 or 3 months as well, until we can switch to the newer medications, which start to work in the first month, often in the first few days.
Why wouldn’t we just start with the newer preventives? Insurance companies require patients to fail, on average, 2 categories of the older medications before they will pay for the newer ones. Medicare usually only covers the older generic medications.
New migraine preventive medications
Monoclonal Antibodies
mAbs that block CGRP for the prevention of migraine, such as erenumab, fremanezumab, galcanezumab, and eptinezumab, target either the CGRP ligand itself or block the receptor to CGRP. This class of medication became available about 5 years ago. The first one approved was erenumab (Aimovig). It was tried by a lot of headache specialists, many neurologists, and then some general physicians once it came to market. It is the only one in its class that grabs the ligand CGRP and prevents it from docking on its receptor. Recently, 5-year safety data indicated it is extremely safe with only a few side effects, (it has been shown to cause some constipation and hypertension). It does, however, tend to lower the number of migraine days per month by about 40% to 50%. At the beginning of erenumab’s availability, researchers took patients that had 8 to 22 days of migraine per month and put them in double-blind, placebo-controlled, randomized trials. They found that some patients' migraine days went down gradually to 10 to 12 days from 20 migraine days per month. Erenumab works quickly, and most patients improve within 2 weeks.
Fremanezumab (AJOVY™) was the second mAb approved, followed pretty quickly by the third, galcanezumab (Emgality™). All 3 of these mAbs are administered once a month by a subcutaneous injection from an autoinjector. If a patient takes 3 fremanezumab injections in 1 day, they do not have to repeat that dose for 3 months. The upside of these 3 treatments is that the patient can self-administer the medication at home with few, if any, adverse events; the downside is they are expensive medications, costing about $600 per month.
Shortly thereafter, a fourth mAb, eptinezumab (VYEPTI™), was brought to market. Unlike the other 3 mAbs, it is administered as an intravenous infusion. The patient must come to an office or infusion center for a 30-minute intravenous infusion, which is not as convenient as treating themselves with an autoinjector at home. Eptinezumab is a strong medication that is often prescribed when other treatments are not effective. Each of the 4 mAbs has its own possible adverse events, but these are few and usually mild. The mAbs have a half-life of about 28 to 32 days; it takes 5 to 6 months after an injection for these mAbs to be metabolized by the reticuloendothelial system.
Gepants
The gepants are small molecule CGRP receptor blockers with much shorter half-lives than mAbs. They work by blocking the CGRP receptor so the CGRP ligand cannot dock there and cause vasodilation and increased pain transmission. Gepants have half-lives of 6 to 12 hours and can be used to treat a migraine acutely. Several drug companies studied the effects of taking a gepant every day or every other day, showing it can also be used as a migraine preventive medication. Ubrogepant (Ubrelvy®) was the first gepant to receive approval from the US Food and Drug Administration (FDA), but it was authorized only for acute care. Rimegepant (Nurtec®) was the second gepant approved, initially for acute treatment and later becoming the first gepant approved for migraine prevention. The same tablet can be used for acute care or for prevention. Preventive treatment consists of one 75 mg oral disintegrating tablet taken every second day. It works quite well as a preventive and has very few side effects. Nausea and abdominal discomfort occur in < 3% of patients. Some patients prefer to take a pill every other day over having an injection once per month or once every 3 months. It makes more sense for a woman of childbearing potential to take a drug with very short half-life vs one that lasts for 5 to 6 months in case she decides to become pregnant (or unexpectedly becomes pregnant).
A third gepant, atogepant (Qulipta™), was later approved, but only for prevention. It is available in 3 different strengths: 10 mg, 30 mg, and 60 mg. I tend to prescribe the 60-mg strength, and the dose is 1 pill every day.
If you compare rimegepant, which is taken once every other day, and atogepant, taken once daily, the latter tends to have slightly more side effects of nausea, drowsiness, and constipation, whereas rimegepant has been shown to have fewer side effects in double-blind, randomized studies. Like all gepants, it is quite effective and fast acting.
The goal of preventive medications is to decrease the frequency, severity, and duration of migraine attacks. Effective treatment can increase responsiveness to acute migraine therapy and improve the quality of life in patients suffering from migraine. Every patient is different and thus the side effects they experience vary. With time and patience, most patients find the relief from migraine they have been desperately seeking through the preventive medicines discussed above. This is a good time to have migraine, if you can get in to see a knowledgeable doctor and your insurance company cooperates. When I started my neurology practice 51 years ago, we had few preventives, and none approved by the FDA. Now we have several older, approved preventives—4 newer mAbs, and 2 newer gepants—as well as several devices, which we will discuss in the future.
What is your experience with prescribing preventive medication for your patients with migraine?
Roughly 40% of patients living with migraine should be on preventive medication or other treatment, but probably fewer than 15% of patients with migraine are currently receiving therapy. There are several reasons for this: General physicians rarely put patients on preventive medication unless they are interested in or knowledgeable about headache, and the older preventive medicines that neurologists and headache specialists have used for many years have a lot of potential side effects and do not begin to work quickly.
It takes approximately 2 to 3 months for preventive medication to become effective, and many patients need to be slowly titrated up to an effective dose. By the time patients reach a steady state over a few weeks, if it is still not working well, they must slowly taper it and try something else. This is what often occurs with older preventive migraine medications—especially one of the most commonly used preventives, topiramate (Topamax). This drug was first indicated for epilepsy and then later for mood stabilization. Though it has good efficacy in reducing migraine attacks, it has many possible side effects, some of them troublesome. I often had multiple calls from patients in their first month of taking it complain of memory or word-finding issues and tingling in the extremities. More serious adverse events can be increased pressure in the eyes, such as glaucoma, and kidney stones. I often get referrals from other neurologists and headache specialists regarding patients who have failed multiple preventive medicines; 90% percent of these referrals need to be switched to the newer, more costly calcitonin gene-related peptide (CGRP)-blocking preventative medications, if insurance companies will cover them.
What categories of migraine preventive drugs do you generally prescribe your patients?
Of the older medications, most are epilepsy medicines, beta blockers, antidepressants, or cardiac medications such as angiotensin receptor blockers (candesartan). Of the newer medications, I use 1 of the 4 injectable monoclonal antibodies (mAbs), or 1 of the 2 gepants.
Older migraine preventive medication
Anticonvulsants (epilepsy medications)
Anticonvulsants are used for the treatment of several conditions, including epilepsy and pain control, but some can help reduce migraine attacks. These medicines, like all drugs, have the potential to cause side effects, especially topiramate; this medicine often causes paresthesia or tingling in the extremities as well as trouble with speech and memory, kidney stones, pancreatitis, and weight loss. The weight loss side effect of this drug has made it more appealing for some patients who had previously gained 10 to 15 pounds taking antidepressant medication to treat their migraine. I personally thought it was the most effective of all the preventive migraine medications if the patient could tolerate it.
Beta Blockers
Beta blockers cause the heart rate to decrease and also lower blood pressure. Most of my migraine patients are healthy females in their 20s and 30s and, when taking a beta blocker, can get short of breath when they exercise. These medications can also cause some depression and gastrointestinal issues and raise cholesterol levels.
Antidepressants
The type of antidepressants that I normally prescribe for migraine prevention are the tricyclic antidepressants. The one that has the best data in the literature and is often prescribed is amitriptyline (Elavil); I prefer a cousin to this medicine, nortriptyline. I prescribe tricyclics because many of my migraine patients have 2 other comorbid problems: depression and trouble staying asleep at night. Amitriptyline tends to cause drowsiness and can help patients sleep. It can also cause dry mouth, trouble urinating (especially in men), constipation, weight gain, and can slow patients down mentally, so it should not be prescribed to elderly patients. These antidepressants should be prescribed in very low doses and taken an hour before bedtime. The dose should be increased gradually over several weeks to help reduce adverse events. The best dose for migraine is often lower than the antidepressant dose, so sometimes a depressed patient needs 2 types of antidepressants. The typical dose for migraine prevention is about 50 to 75 mg. For depression, it is about 150 mg.
The patient would then need to increase their dose gradually for a month and remain on the target dose for at least another month. At the end of 2 months, they would have some idea whether it was working for them. If it was not, I might increase the dose even further. It is important to set expectations with patients at the beginning of treatment and tell them it is going to take 2 to 3 months to see if it works. If it does not work, I tell them, we will have to try another one, and that is going to take 2 or 3 months as well, until we can switch to the newer medications, which start to work in the first month, often in the first few days.
Why wouldn’t we just start with the newer preventives? Insurance companies require patients to fail, on average, 2 categories of the older medications before they will pay for the newer ones. Medicare usually only covers the older generic medications.
New migraine preventive medications
Monoclonal Antibodies
mAbs that block CGRP for the prevention of migraine, such as erenumab, fremanezumab, galcanezumab, and eptinezumab, target either the CGRP ligand itself or block the receptor to CGRP. This class of medication became available about 5 years ago. The first one approved was erenumab (Aimovig). It was tried by a lot of headache specialists, many neurologists, and then some general physicians once it came to market. It is the only one in its class that grabs the ligand CGRP and prevents it from docking on its receptor. Recently, 5-year safety data indicated it is extremely safe with only a few side effects, (it has been shown to cause some constipation and hypertension). It does, however, tend to lower the number of migraine days per month by about 40% to 50%. At the beginning of erenumab’s availability, researchers took patients that had 8 to 22 days of migraine per month and put them in double-blind, placebo-controlled, randomized trials. They found that some patients' migraine days went down gradually to 10 to 12 days from 20 migraine days per month. Erenumab works quickly, and most patients improve within 2 weeks.
Fremanezumab (AJOVY™) was the second mAb approved, followed pretty quickly by the third, galcanezumab (Emgality™). All 3 of these mAbs are administered once a month by a subcutaneous injection from an autoinjector. If a patient takes 3 fremanezumab injections in 1 day, they do not have to repeat that dose for 3 months. The upside of these 3 treatments is that the patient can self-administer the medication at home with few, if any, adverse events; the downside is they are expensive medications, costing about $600 per month.
Shortly thereafter, a fourth mAb, eptinezumab (VYEPTI™), was brought to market. Unlike the other 3 mAbs, it is administered as an intravenous infusion. The patient must come to an office or infusion center for a 30-minute intravenous infusion, which is not as convenient as treating themselves with an autoinjector at home. Eptinezumab is a strong medication that is often prescribed when other treatments are not effective. Each of the 4 mAbs has its own possible adverse events, but these are few and usually mild. The mAbs have a half-life of about 28 to 32 days; it takes 5 to 6 months after an injection for these mAbs to be metabolized by the reticuloendothelial system.
Gepants
The gepants are small molecule CGRP receptor blockers with much shorter half-lives than mAbs. They work by blocking the CGRP receptor so the CGRP ligand cannot dock there and cause vasodilation and increased pain transmission. Gepants have half-lives of 6 to 12 hours and can be used to treat a migraine acutely. Several drug companies studied the effects of taking a gepant every day or every other day, showing it can also be used as a migraine preventive medication. Ubrogepant (Ubrelvy®) was the first gepant to receive approval from the US Food and Drug Administration (FDA), but it was authorized only for acute care. Rimegepant (Nurtec®) was the second gepant approved, initially for acute treatment and later becoming the first gepant approved for migraine prevention. The same tablet can be used for acute care or for prevention. Preventive treatment consists of one 75 mg oral disintegrating tablet taken every second day. It works quite well as a preventive and has very few side effects. Nausea and abdominal discomfort occur in < 3% of patients. Some patients prefer to take a pill every other day over having an injection once per month or once every 3 months. It makes more sense for a woman of childbearing potential to take a drug with very short half-life vs one that lasts for 5 to 6 months in case she decides to become pregnant (or unexpectedly becomes pregnant).
A third gepant, atogepant (Qulipta™), was later approved, but only for prevention. It is available in 3 different strengths: 10 mg, 30 mg, and 60 mg. I tend to prescribe the 60-mg strength, and the dose is 1 pill every day.
If you compare rimegepant, which is taken once every other day, and atogepant, taken once daily, the latter tends to have slightly more side effects of nausea, drowsiness, and constipation, whereas rimegepant has been shown to have fewer side effects in double-blind, randomized studies. Like all gepants, it is quite effective and fast acting.
The goal of preventive medications is to decrease the frequency, severity, and duration of migraine attacks. Effective treatment can increase responsiveness to acute migraine therapy and improve the quality of life in patients suffering from migraine. Every patient is different and thus the side effects they experience vary. With time and patience, most patients find the relief from migraine they have been desperately seeking through the preventive medicines discussed above. This is a good time to have migraine, if you can get in to see a knowledgeable doctor and your insurance company cooperates. When I started my neurology practice 51 years ago, we had few preventives, and none approved by the FDA. Now we have several older, approved preventives—4 newer mAbs, and 2 newer gepants—as well as several devices, which we will discuss in the future.
The Current and Future Role of JAK Inhibitors for Psoriatic Arthritis
Introduction
The first Janus kinase (JAK) inhibitor received regulatory approval for the treatment of psoriatic arthritis (PsA) more than 5 years ago. Although there are limited comparative data between this and other JAK inhibitors approved or in development for the treatment of PsA, it is reasonable to anticipate variability in therapeutic effect and the risk of adverse events between different JAK inhibitors. So far, there have been considerable differences in the relative selectivity of each agent on the 4 JAK isoform enzymes, JAK1, JAK2, JAK3, and TYK2. This selectivity determines the downstream signal transducers and activators of transcription proteins (JAK-STAT [signal transducer and activator of transcription] pathway) that ultimately mediate both anti-inflammatory and off-target effects. In this review of JAK inhibitors in PsA, differences between JAK inhibitors will be explored for their potential impact on benefit-to-risk ratio while treating PsA.
Background
Data from the National Psoriasis Foundation (NPF) estimates that 8 million individuals in the United States have psoriasis.1 PsA, an inflammatory spondyloarthritis associated with psoriasis, develops in about 30% of these individuals, but precise epidemiology on this subset of psoriasis patients is complicated by missed and delayed diagnoses. Of patients with psoriasis, only about 15% of patients with PsA have joint inflammation at the time or in advance of skin lesions.2 This might explain delays in diagnosis. In one study, 15% of patients treated for psoriasis were found to have concomitant but unrecognized PsA.3
PsA was first classified as a distinct pathologic condition only about 50 years ago, even though skeletal remains indicate that this disease existed in early civilizations.2 Based on consensus that PsA deserved definition as a distinct entity, the Classification Criteria for Psoriatic Arthritis (CASPAR) were published in 2006.4 By these criteria, cumulative points are allotted for clinical signs of skin, nail, and joint involvement, as well as radiographic signs in patients judged to have inflammatory disease in the joints, spine, or entheses to classify them as having PsA.
There are numerous recommendations for the treatment of PsA, including those issued by the American College of Rheumatology (ACR),5 the European Alliance of Associations for Rheumatology (EULAR),6 and the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA).7 Although generally compatible with the others, the GRAPPA recommendations, which are the most recent, have addressed the heterogeneity of PsA by recommending therapies for specific disease domains, such as the skin, nail, and joint manifestations.
For treatment of PsA, the available drug classes for moderate-to-severe disease include immunomodulators, such as methotrexate, biologics that inhibit cytokines, such as tumor necrosis factor (TNF) and the interleukin (IL) cytokines IL-17, 1L-23, and IL12/IL-23, phosphodiesterase-4 (PDE4) inhibitors, and JAK inhibitors. In the GRAPPA recommendations, JAK inhibitors are listed along with other targeted therapies as first-line choices for peripheral arthritis, axial disease, enthesitis, dactylitis, and plaque psoriasis.
JAK Inhibitors and PsA
There are multiple ways to classify JAK inhibitors. Tofacitinib, the first JAK inhibitor approved for PsA, is labeled a first-generation agent because it is relatively nonselective for the 4 JAK isoforms.8 Second-generation agents, such as upadacitinib, have been distinguished from tofacitinib, baricitinib, and other first-generation drugs by greater relative selectivity on the JAK1 enzyme. Other drugs in development for PsA target different JAK isoforms. Deucravacitinib, for example, which was approved for psoriasis after a favorable phase 3 trial9 and has shown promise for PsA in a phase 2 trial, is selective for the TYK2 isoform.10 A rapidly growing list of JAK inhibitors with different selectivity profiles, including dual JAK inhibitory effects, are being explored in a host of inflammatory diseases.
The relationship between selectivity on specific JAK isoforms, anti-inflammatory effects, and off-target effects is not fully understood.8 In addition, characteristics beyond JAK selectivity have potential pharmacologic importance. For example, JAK inhibitors can be classified as ATP competitive inhibitors and allosteric inhibitors, both of which are reversible binding modes.8 Within each of these subcategories, the site of kinase binding has the potential to influence clinical activity.8
JAK Inhibitors: Clinical Experience in PsA
Tofacitinib, a first-generation JAK inhibitor, initially licensed for use in the treatment of rheumatoid arthritis (RA), received regulatory approval for PsA on the basis of the OPAL Beyond trial.11 Approval of upadacitinib for PsA followed about 4 years later on the basis of the SELECT PsA-1 trial.12 The primary endpoint in both of these studies was proportion of patients with an ACR response, signifying degree of improvement from baseline, of ≥20%. For the JAK inhibitors, the ACR20 rates were about 50% and 70% in the tofacitinib and upadacitinib phase 3 trials, respectively. Other JAK inhibitors have been evaluated in PsA but none so far are approved in the United States.
Despite experimental evidence supporting the hypothesis that JAK1 selectivity is clinically relevant to the treatment of PsA and other spondyloarthritides,13 there is no level 1 evidence of an efficacy or safety advantage for second- relative to first-generation JAK inhibitors. A small number of indirect comparisons, such as one employing a network Bayesian analysis to compare these drugs for the treatment of RA,14 have supported a clinical advantage for JAK1 selectivity, but head-to-head comparisons are needed to confirm differences.
Prescribing information for both tofacitinib and upadacitinib in PsA and other indications include a black box warning for risk of serious adverse events, including major adverse cardiac events (MACE) and thromboembolism. The warning is based on the placebo-controlled ORAL trial with tofacitinib in RA.15 The study population was enhanced for risk with eligibility that required older age and the presence of cardiovascular risk factors. In this high-risk RA population, tofacitinib was associated with modest increases in serious adverse events, including MACE and thromboembolism, relative to placebo over several years of follow-up. A similar trial has not been conducted with upadacitinib or in patients with PsA.
In a phase 3 trial with the TYK2-selective deucravacitinib in psoriasis, there was no increase in the rate of MACE or thromboembolism.9 When granted regulatory approval for psoriasis, the product information did not include a black box warning, differentiating it from other currently available JAK inhibitors. It has not yet been proven whether the absence of serious adverse events in the phase 3 psoriasis and phase 2 PsA trials with deucravacitinib are related to TYK2 JAK enzyme selectivity.
Although TYK2 is closely associated with upregulation of IL-23 and other inflammatory cytokines implicated in the pathophysiology of PSA, the JAK-STAT signaling pathway is incompletely understood.8 Moreover, all of the JAK inhibitors synthesized so far have relative rather than absolute selectivity for any specific JAK isoform. This complicates the ability to attribute benefits and risks to the inhibition of any single JAK enzyme isoform and amplifies the need for comparative studies.
While other JAK inhibitors have reached late stages of development for the treatment of PsA, such as filgotinib (a JAK1 selective drug) and brepocitinib (which is selective for both JAK1 and TYK2),16,17 it is appropriate to emphasize that currently available JAK inhibitors are effective and acceptably safe for PsA. The goal of continued drug development is the potential to develop agents with even greater efficacy but with a lower risk of off-target effects. Currently, the black box warnings included in the labeling of tofacitinib and upadacitinib give pause, leading many clinicians to move to these agents after an inadequate response to biologics. Newer therapies in the JAK inhibitor class free of serious adverse effects might reverse the order, given the preference of many patients for oral agents.
The JAK inhibitor development program is rich not just for inflammatory diseases and autoimmune diseases, but for myeloproliferative diseases and neoplasms. JAK inhibitors are already identified in the GRAPPA recommendations as appropriate first-line options for most manifestations of PsA, including joint and skin involvement, but newer drugs with a more favorable JAK selectivity or other pharmacologic characteristics and decreased adverse risks might make these a more dominant treatment choice.
Summary
Relative selectivity for JAK isoforms promises therapies that are both more effective and safer for PsA as well as other inflammatory diseases. This promise is now being explored in experimental trials testing therapies with variable degrees of selectivity in the context of other characteristics, such as kinase binding, with the potential to influence clinical effects. However, the promise will not be fulfilled until large clinical trials, particularly comparative trials, can confirm the importance of JAK isoform selectivity. If specific types of selectivity prove relevant to the benefit-to-risk ratio of JAK inhibitors in PsA, it may alter the current order of treatment preferences for this disease.
Introduction
The first Janus kinase (JAK) inhibitor received regulatory approval for the treatment of psoriatic arthritis (PsA) more than 5 years ago. Although there are limited comparative data between this and other JAK inhibitors approved or in development for the treatment of PsA, it is reasonable to anticipate variability in therapeutic effect and the risk of adverse events between different JAK inhibitors. So far, there have been considerable differences in the relative selectivity of each agent on the 4 JAK isoform enzymes, JAK1, JAK2, JAK3, and TYK2. This selectivity determines the downstream signal transducers and activators of transcription proteins (JAK-STAT [signal transducer and activator of transcription] pathway) that ultimately mediate both anti-inflammatory and off-target effects. In this review of JAK inhibitors in PsA, differences between JAK inhibitors will be explored for their potential impact on benefit-to-risk ratio while treating PsA.
Background
Data from the National Psoriasis Foundation (NPF) estimates that 8 million individuals in the United States have psoriasis.1 PsA, an inflammatory spondyloarthritis associated with psoriasis, develops in about 30% of these individuals, but precise epidemiology on this subset of psoriasis patients is complicated by missed and delayed diagnoses. Of patients with psoriasis, only about 15% of patients with PsA have joint inflammation at the time or in advance of skin lesions.2 This might explain delays in diagnosis. In one study, 15% of patients treated for psoriasis were found to have concomitant but unrecognized PsA.3
PsA was first classified as a distinct pathologic condition only about 50 years ago, even though skeletal remains indicate that this disease existed in early civilizations.2 Based on consensus that PsA deserved definition as a distinct entity, the Classification Criteria for Psoriatic Arthritis (CASPAR) were published in 2006.4 By these criteria, cumulative points are allotted for clinical signs of skin, nail, and joint involvement, as well as radiographic signs in patients judged to have inflammatory disease in the joints, spine, or entheses to classify them as having PsA.
There are numerous recommendations for the treatment of PsA, including those issued by the American College of Rheumatology (ACR),5 the European Alliance of Associations for Rheumatology (EULAR),6 and the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA).7 Although generally compatible with the others, the GRAPPA recommendations, which are the most recent, have addressed the heterogeneity of PsA by recommending therapies for specific disease domains, such as the skin, nail, and joint manifestations.
For treatment of PsA, the available drug classes for moderate-to-severe disease include immunomodulators, such as methotrexate, biologics that inhibit cytokines, such as tumor necrosis factor (TNF) and the interleukin (IL) cytokines IL-17, 1L-23, and IL12/IL-23, phosphodiesterase-4 (PDE4) inhibitors, and JAK inhibitors. In the GRAPPA recommendations, JAK inhibitors are listed along with other targeted therapies as first-line choices for peripheral arthritis, axial disease, enthesitis, dactylitis, and plaque psoriasis.
JAK Inhibitors and PsA
There are multiple ways to classify JAK inhibitors. Tofacitinib, the first JAK inhibitor approved for PsA, is labeled a first-generation agent because it is relatively nonselective for the 4 JAK isoforms.8 Second-generation agents, such as upadacitinib, have been distinguished from tofacitinib, baricitinib, and other first-generation drugs by greater relative selectivity on the JAK1 enzyme. Other drugs in development for PsA target different JAK isoforms. Deucravacitinib, for example, which was approved for psoriasis after a favorable phase 3 trial9 and has shown promise for PsA in a phase 2 trial, is selective for the TYK2 isoform.10 A rapidly growing list of JAK inhibitors with different selectivity profiles, including dual JAK inhibitory effects, are being explored in a host of inflammatory diseases.
The relationship between selectivity on specific JAK isoforms, anti-inflammatory effects, and off-target effects is not fully understood.8 In addition, characteristics beyond JAK selectivity have potential pharmacologic importance. For example, JAK inhibitors can be classified as ATP competitive inhibitors and allosteric inhibitors, both of which are reversible binding modes.8 Within each of these subcategories, the site of kinase binding has the potential to influence clinical activity.8
JAK Inhibitors: Clinical Experience in PsA
Tofacitinib, a first-generation JAK inhibitor, initially licensed for use in the treatment of rheumatoid arthritis (RA), received regulatory approval for PsA on the basis of the OPAL Beyond trial.11 Approval of upadacitinib for PsA followed about 4 years later on the basis of the SELECT PsA-1 trial.12 The primary endpoint in both of these studies was proportion of patients with an ACR response, signifying degree of improvement from baseline, of ≥20%. For the JAK inhibitors, the ACR20 rates were about 50% and 70% in the tofacitinib and upadacitinib phase 3 trials, respectively. Other JAK inhibitors have been evaluated in PsA but none so far are approved in the United States.
Despite experimental evidence supporting the hypothesis that JAK1 selectivity is clinically relevant to the treatment of PsA and other spondyloarthritides,13 there is no level 1 evidence of an efficacy or safety advantage for second- relative to first-generation JAK inhibitors. A small number of indirect comparisons, such as one employing a network Bayesian analysis to compare these drugs for the treatment of RA,14 have supported a clinical advantage for JAK1 selectivity, but head-to-head comparisons are needed to confirm differences.
Prescribing information for both tofacitinib and upadacitinib in PsA and other indications include a black box warning for risk of serious adverse events, including major adverse cardiac events (MACE) and thromboembolism. The warning is based on the placebo-controlled ORAL trial with tofacitinib in RA.15 The study population was enhanced for risk with eligibility that required older age and the presence of cardiovascular risk factors. In this high-risk RA population, tofacitinib was associated with modest increases in serious adverse events, including MACE and thromboembolism, relative to placebo over several years of follow-up. A similar trial has not been conducted with upadacitinib or in patients with PsA.
In a phase 3 trial with the TYK2-selective deucravacitinib in psoriasis, there was no increase in the rate of MACE or thromboembolism.9 When granted regulatory approval for psoriasis, the product information did not include a black box warning, differentiating it from other currently available JAK inhibitors. It has not yet been proven whether the absence of serious adverse events in the phase 3 psoriasis and phase 2 PsA trials with deucravacitinib are related to TYK2 JAK enzyme selectivity.
Although TYK2 is closely associated with upregulation of IL-23 and other inflammatory cytokines implicated in the pathophysiology of PSA, the JAK-STAT signaling pathway is incompletely understood.8 Moreover, all of the JAK inhibitors synthesized so far have relative rather than absolute selectivity for any specific JAK isoform. This complicates the ability to attribute benefits and risks to the inhibition of any single JAK enzyme isoform and amplifies the need for comparative studies.
While other JAK inhibitors have reached late stages of development for the treatment of PsA, such as filgotinib (a JAK1 selective drug) and brepocitinib (which is selective for both JAK1 and TYK2),16,17 it is appropriate to emphasize that currently available JAK inhibitors are effective and acceptably safe for PsA. The goal of continued drug development is the potential to develop agents with even greater efficacy but with a lower risk of off-target effects. Currently, the black box warnings included in the labeling of tofacitinib and upadacitinib give pause, leading many clinicians to move to these agents after an inadequate response to biologics. Newer therapies in the JAK inhibitor class free of serious adverse effects might reverse the order, given the preference of many patients for oral agents.
The JAK inhibitor development program is rich not just for inflammatory diseases and autoimmune diseases, but for myeloproliferative diseases and neoplasms. JAK inhibitors are already identified in the GRAPPA recommendations as appropriate first-line options for most manifestations of PsA, including joint and skin involvement, but newer drugs with a more favorable JAK selectivity or other pharmacologic characteristics and decreased adverse risks might make these a more dominant treatment choice.
Summary
Relative selectivity for JAK isoforms promises therapies that are both more effective and safer for PsA as well as other inflammatory diseases. This promise is now being explored in experimental trials testing therapies with variable degrees of selectivity in the context of other characteristics, such as kinase binding, with the potential to influence clinical effects. However, the promise will not be fulfilled until large clinical trials, particularly comparative trials, can confirm the importance of JAK isoform selectivity. If specific types of selectivity prove relevant to the benefit-to-risk ratio of JAK inhibitors in PsA, it may alter the current order of treatment preferences for this disease.
Introduction
The first Janus kinase (JAK) inhibitor received regulatory approval for the treatment of psoriatic arthritis (PsA) more than 5 years ago. Although there are limited comparative data between this and other JAK inhibitors approved or in development for the treatment of PsA, it is reasonable to anticipate variability in therapeutic effect and the risk of adverse events between different JAK inhibitors. So far, there have been considerable differences in the relative selectivity of each agent on the 4 JAK isoform enzymes, JAK1, JAK2, JAK3, and TYK2. This selectivity determines the downstream signal transducers and activators of transcription proteins (JAK-STAT [signal transducer and activator of transcription] pathway) that ultimately mediate both anti-inflammatory and off-target effects. In this review of JAK inhibitors in PsA, differences between JAK inhibitors will be explored for their potential impact on benefit-to-risk ratio while treating PsA.
Background
Data from the National Psoriasis Foundation (NPF) estimates that 8 million individuals in the United States have psoriasis.1 PsA, an inflammatory spondyloarthritis associated with psoriasis, develops in about 30% of these individuals, but precise epidemiology on this subset of psoriasis patients is complicated by missed and delayed diagnoses. Of patients with psoriasis, only about 15% of patients with PsA have joint inflammation at the time or in advance of skin lesions.2 This might explain delays in diagnosis. In one study, 15% of patients treated for psoriasis were found to have concomitant but unrecognized PsA.3
PsA was first classified as a distinct pathologic condition only about 50 years ago, even though skeletal remains indicate that this disease existed in early civilizations.2 Based on consensus that PsA deserved definition as a distinct entity, the Classification Criteria for Psoriatic Arthritis (CASPAR) were published in 2006.4 By these criteria, cumulative points are allotted for clinical signs of skin, nail, and joint involvement, as well as radiographic signs in patients judged to have inflammatory disease in the joints, spine, or entheses to classify them as having PsA.
There are numerous recommendations for the treatment of PsA, including those issued by the American College of Rheumatology (ACR),5 the European Alliance of Associations for Rheumatology (EULAR),6 and the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA).7 Although generally compatible with the others, the GRAPPA recommendations, which are the most recent, have addressed the heterogeneity of PsA by recommending therapies for specific disease domains, such as the skin, nail, and joint manifestations.
For treatment of PsA, the available drug classes for moderate-to-severe disease include immunomodulators, such as methotrexate, biologics that inhibit cytokines, such as tumor necrosis factor (TNF) and the interleukin (IL) cytokines IL-17, 1L-23, and IL12/IL-23, phosphodiesterase-4 (PDE4) inhibitors, and JAK inhibitors. In the GRAPPA recommendations, JAK inhibitors are listed along with other targeted therapies as first-line choices for peripheral arthritis, axial disease, enthesitis, dactylitis, and plaque psoriasis.
JAK Inhibitors and PsA
There are multiple ways to classify JAK inhibitors. Tofacitinib, the first JAK inhibitor approved for PsA, is labeled a first-generation agent because it is relatively nonselective for the 4 JAK isoforms.8 Second-generation agents, such as upadacitinib, have been distinguished from tofacitinib, baricitinib, and other first-generation drugs by greater relative selectivity on the JAK1 enzyme. Other drugs in development for PsA target different JAK isoforms. Deucravacitinib, for example, which was approved for psoriasis after a favorable phase 3 trial9 and has shown promise for PsA in a phase 2 trial, is selective for the TYK2 isoform.10 A rapidly growing list of JAK inhibitors with different selectivity profiles, including dual JAK inhibitory effects, are being explored in a host of inflammatory diseases.
The relationship between selectivity on specific JAK isoforms, anti-inflammatory effects, and off-target effects is not fully understood.8 In addition, characteristics beyond JAK selectivity have potential pharmacologic importance. For example, JAK inhibitors can be classified as ATP competitive inhibitors and allosteric inhibitors, both of which are reversible binding modes.8 Within each of these subcategories, the site of kinase binding has the potential to influence clinical activity.8
JAK Inhibitors: Clinical Experience in PsA
Tofacitinib, a first-generation JAK inhibitor, initially licensed for use in the treatment of rheumatoid arthritis (RA), received regulatory approval for PsA on the basis of the OPAL Beyond trial.11 Approval of upadacitinib for PsA followed about 4 years later on the basis of the SELECT PsA-1 trial.12 The primary endpoint in both of these studies was proportion of patients with an ACR response, signifying degree of improvement from baseline, of ≥20%. For the JAK inhibitors, the ACR20 rates were about 50% and 70% in the tofacitinib and upadacitinib phase 3 trials, respectively. Other JAK inhibitors have been evaluated in PsA but none so far are approved in the United States.
Despite experimental evidence supporting the hypothesis that JAK1 selectivity is clinically relevant to the treatment of PsA and other spondyloarthritides,13 there is no level 1 evidence of an efficacy or safety advantage for second- relative to first-generation JAK inhibitors. A small number of indirect comparisons, such as one employing a network Bayesian analysis to compare these drugs for the treatment of RA,14 have supported a clinical advantage for JAK1 selectivity, but head-to-head comparisons are needed to confirm differences.
Prescribing information for both tofacitinib and upadacitinib in PsA and other indications include a black box warning for risk of serious adverse events, including major adverse cardiac events (MACE) and thromboembolism. The warning is based on the placebo-controlled ORAL trial with tofacitinib in RA.15 The study population was enhanced for risk with eligibility that required older age and the presence of cardiovascular risk factors. In this high-risk RA population, tofacitinib was associated with modest increases in serious adverse events, including MACE and thromboembolism, relative to placebo over several years of follow-up. A similar trial has not been conducted with upadacitinib or in patients with PsA.
In a phase 3 trial with the TYK2-selective deucravacitinib in psoriasis, there was no increase in the rate of MACE or thromboembolism.9 When granted regulatory approval for psoriasis, the product information did not include a black box warning, differentiating it from other currently available JAK inhibitors. It has not yet been proven whether the absence of serious adverse events in the phase 3 psoriasis and phase 2 PsA trials with deucravacitinib are related to TYK2 JAK enzyme selectivity.
Although TYK2 is closely associated with upregulation of IL-23 and other inflammatory cytokines implicated in the pathophysiology of PSA, the JAK-STAT signaling pathway is incompletely understood.8 Moreover, all of the JAK inhibitors synthesized so far have relative rather than absolute selectivity for any specific JAK isoform. This complicates the ability to attribute benefits and risks to the inhibition of any single JAK enzyme isoform and amplifies the need for comparative studies.
While other JAK inhibitors have reached late stages of development for the treatment of PsA, such as filgotinib (a JAK1 selective drug) and brepocitinib (which is selective for both JAK1 and TYK2),16,17 it is appropriate to emphasize that currently available JAK inhibitors are effective and acceptably safe for PsA. The goal of continued drug development is the potential to develop agents with even greater efficacy but with a lower risk of off-target effects. Currently, the black box warnings included in the labeling of tofacitinib and upadacitinib give pause, leading many clinicians to move to these agents after an inadequate response to biologics. Newer therapies in the JAK inhibitor class free of serious adverse effects might reverse the order, given the preference of many patients for oral agents.
The JAK inhibitor development program is rich not just for inflammatory diseases and autoimmune diseases, but for myeloproliferative diseases and neoplasms. JAK inhibitors are already identified in the GRAPPA recommendations as appropriate first-line options for most manifestations of PsA, including joint and skin involvement, but newer drugs with a more favorable JAK selectivity or other pharmacologic characteristics and decreased adverse risks might make these a more dominant treatment choice.
Summary
Relative selectivity for JAK isoforms promises therapies that are both more effective and safer for PsA as well as other inflammatory diseases. This promise is now being explored in experimental trials testing therapies with variable degrees of selectivity in the context of other characteristics, such as kinase binding, with the potential to influence clinical effects. However, the promise will not be fulfilled until large clinical trials, particularly comparative trials, can confirm the importance of JAK isoform selectivity. If specific types of selectivity prove relevant to the benefit-to-risk ratio of JAK inhibitors in PsA, it may alter the current order of treatment preferences for this disease.
Omega-3 supplementation may improve inflammatory markers in episodic migraine
Key clinical point: Two months of supplementation with omega-3 fatty acids had favorable effects on inflammatory and anti-inflammatory markers in patients with episodic migraine.
Major finding: After 2 months of treatment, the serum concentration of anti-inflammatory interleukin-4 (IL-4) was significantly increased (P = .010) whereas that of proinflammatory interferon gamma was significantly decreased (P = .001) in the omega-3 supplementation vs placebo group. The serum concentration of transforming growth factor beta or IL-17 was not significantly different between the groups.
Study details: The data come from a randomized controlled trial including 40 patients with episodic migraine who were randomly assigned to receive omega-3 supplementation (2 capsules/day; each capsule containing 600 mg eicosapentaenoic acid and 300 mg docosahexaenoic acid; n = 20) or placebo (paraffin oil capsules; n = 20) for 2 months.
Disclosures: This study did not receive any funding. The authors declared no potential conflicts of interest.
Source: Djalali M et al. The effect of omega-3 fatty acids supplementation on inflammatory biomarkers in subjects with migraine: A randomized, double-blind, placebo-controlled trial. Immunopharmacol Immunotoxicol. 2023 (Apr 26). doi: 10.1080/08923973.2023.2196600
Key clinical point: Two months of supplementation with omega-3 fatty acids had favorable effects on inflammatory and anti-inflammatory markers in patients with episodic migraine.
Major finding: After 2 months of treatment, the serum concentration of anti-inflammatory interleukin-4 (IL-4) was significantly increased (P = .010) whereas that of proinflammatory interferon gamma was significantly decreased (P = .001) in the omega-3 supplementation vs placebo group. The serum concentration of transforming growth factor beta or IL-17 was not significantly different between the groups.
Study details: The data come from a randomized controlled trial including 40 patients with episodic migraine who were randomly assigned to receive omega-3 supplementation (2 capsules/day; each capsule containing 600 mg eicosapentaenoic acid and 300 mg docosahexaenoic acid; n = 20) or placebo (paraffin oil capsules; n = 20) for 2 months.
Disclosures: This study did not receive any funding. The authors declared no potential conflicts of interest.
Source: Djalali M et al. The effect of omega-3 fatty acids supplementation on inflammatory biomarkers in subjects with migraine: A randomized, double-blind, placebo-controlled trial. Immunopharmacol Immunotoxicol. 2023 (Apr 26). doi: 10.1080/08923973.2023.2196600
Key clinical point: Two months of supplementation with omega-3 fatty acids had favorable effects on inflammatory and anti-inflammatory markers in patients with episodic migraine.
Major finding: After 2 months of treatment, the serum concentration of anti-inflammatory interleukin-4 (IL-4) was significantly increased (P = .010) whereas that of proinflammatory interferon gamma was significantly decreased (P = .001) in the omega-3 supplementation vs placebo group. The serum concentration of transforming growth factor beta or IL-17 was not significantly different between the groups.
Study details: The data come from a randomized controlled trial including 40 patients with episodic migraine who were randomly assigned to receive omega-3 supplementation (2 capsules/day; each capsule containing 600 mg eicosapentaenoic acid and 300 mg docosahexaenoic acid; n = 20) or placebo (paraffin oil capsules; n = 20) for 2 months.
Disclosures: This study did not receive any funding. The authors declared no potential conflicts of interest.
Source: Djalali M et al. The effect of omega-3 fatty acids supplementation on inflammatory biomarkers in subjects with migraine: A randomized, double-blind, placebo-controlled trial. Immunopharmacol Immunotoxicol. 2023 (Apr 26). doi: 10.1080/08923973.2023.2196600
Maternal migraine raises risk for childhood cancers in offspring
Key clinical point: Maternal migraine diagnosis is associated with a higher risk for several childhood cancers in offspring.
Major finding: A significant positive association was observed between maternal migraine and the risk for non-Hodgkin lymphoma (odds ratio [OR] 1.70; 95% CI 1.01-2.86), central nervous system tumors (OR 1.31; 95% CI 1.02-1.68; particularly glioma: OR 1.64; 95% CI 1.12-2.40), neuroblastoma (OR 1.75; 95% CI 1.00-3.08), and osteosarcoma (OR 2.60; 95% CI 1.18-5.76).
Study details: This study included children age < 20 years with cancers (cases) and birth year- and sex-matched (25:1) children without cancers (control individuals).
Disclosures: This study was supported by the US National Institutes of Health. The authors declared no conflicts of interest.
Source: Orimoloye HT et al. Maternal migraine and risk of pediatric cancers. Pediatr Blood Cancer. 2023 (Apr 26). doi: 10.1002/pbc.30385
Key clinical point: Maternal migraine diagnosis is associated with a higher risk for several childhood cancers in offspring.
Major finding: A significant positive association was observed between maternal migraine and the risk for non-Hodgkin lymphoma (odds ratio [OR] 1.70; 95% CI 1.01-2.86), central nervous system tumors (OR 1.31; 95% CI 1.02-1.68; particularly glioma: OR 1.64; 95% CI 1.12-2.40), neuroblastoma (OR 1.75; 95% CI 1.00-3.08), and osteosarcoma (OR 2.60; 95% CI 1.18-5.76).
Study details: This study included children age < 20 years with cancers (cases) and birth year- and sex-matched (25:1) children without cancers (control individuals).
Disclosures: This study was supported by the US National Institutes of Health. The authors declared no conflicts of interest.
Source: Orimoloye HT et al. Maternal migraine and risk of pediatric cancers. Pediatr Blood Cancer. 2023 (Apr 26). doi: 10.1002/pbc.30385
Key clinical point: Maternal migraine diagnosis is associated with a higher risk for several childhood cancers in offspring.
Major finding: A significant positive association was observed between maternal migraine and the risk for non-Hodgkin lymphoma (odds ratio [OR] 1.70; 95% CI 1.01-2.86), central nervous system tumors (OR 1.31; 95% CI 1.02-1.68; particularly glioma: OR 1.64; 95% CI 1.12-2.40), neuroblastoma (OR 1.75; 95% CI 1.00-3.08), and osteosarcoma (OR 2.60; 95% CI 1.18-5.76).
Study details: This study included children age < 20 years with cancers (cases) and birth year- and sex-matched (25:1) children without cancers (control individuals).
Disclosures: This study was supported by the US National Institutes of Health. The authors declared no conflicts of interest.
Source: Orimoloye HT et al. Maternal migraine and risk of pediatric cancers. Pediatr Blood Cancer. 2023 (Apr 26). doi: 10.1002/pbc.30385