User login
Neurologists Lack Awareness of Steroid Toxicity
SAVANNAH, GEORGIA — , results of a US survey showed.
For both MG and CIDP specialists, uncertainty around corticosteroid dosing, duration, and toxicity underscores the need for more guidance, the investigators noted. Over 85% of respondents indicated that a tool for systematically monitoring corticosteroid toxicity would be valuable.
The results indicate “a lack of knowledge by this pool of neurologists about the guidelines and what they contain,” said study investigator Gil Wolfe, MD, professor of neurology at the Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, in New York.
Clearer guidance on how to administer corticosteroids and manage toxicities in patients with gMG and CIDP “would be welcomed by neurologists and have potential for benefit to patient care,” the team noted.
The findings were presented at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.
Lack of Knowledge
Although guidelines for both CIDP and gMG recommend corticosteroids as first-line treatment and emphasize using the lowest effective dose to control symptoms, they do not include specific recommendations on dosing, duration, or toxicity monitoring, the researchers noted.
Despite this, a large proportion of survey respondents reported using guidelines to make clinical decisions on monitoring toxicity, with up to a third actually endorsing a guideline that doesn’t exist.
The cross-sectional, online survey was deployed in November and December 2023 and included 200 US neurologists. Of these, 99 answered questions on CIDP, and 101 answered similar questions on gMG.
To participate in the survey, respondents had to be board-certified neurologists, practicing for at least 2 years post-residency, and have treated or consulted on at least three patients with CIDP or 10 patients with gMG in the past year who were on a corticosteroid dose of at least 10 mg daily for 1 month or more.
CIDP respondents had been practicing a mean of 18.1 years since residency and were board certified in neuromuscular (20%), electrodiagnostic medicine/clinical neurophysiology (21%), and pediatric neurology (8%). Two thirds of them accepted referrals from other neurologists.
The gMG respondents had been practicing a mean of 20.5 years since residency and were board certified in neuromuscular (45%), electrodiagnostic medicine/clinical neurophysiology (35%), and pediatric neurology (17%). A total of 72% accepted referrals from other neurologists.
Respondents estimated that about 60% of their patients with gMG and 58% of patients with CIDP were being treated with corticosteroids, with gMG and CIDP respondents reporting a mean of 26.4 and 15.6 patients, respectively, meeting the study’s dosing criteria.
Appropriate Dosing
When asked what chronic, long-term (≥ 6 months) corticosteroid dose they considered safe in terms of minimizing adverse events, 43% of CIDP respondents and 51% of gMG respondents considered corticosteroid doses of 10 mg/d or less (prednisone equivalent) well tolerated; additionally, 32% and 31%, respectively, considered 20-40 mg/d well tolerated. Moreover, they said only about half of their patients would be able to taper to less than 10 mg/d in less than 6 months.
“Studies suggest safety is not seen until patients are on doses at 5 mg/d or less,” Wolfe said. “There is not enough appreciation that doses at levels we once considered safe really do pose significant risk,” he added.
“With the increasing number of treatment options in MG and to a lesser extent in CIDP, we need to do all we can to use corticosteroids as judiciously as possible and be aware of side effects our patients may not even report unless we make a pointed effort to ask about them.”
Familiarity with corticosteroid toxicities was more common among gMG respondents, of whom 77% reported being very/extremely familiar, than among 55% of CIDP respondents. Appetite/weight gain was reported among the most common adverse effects (AEs) associated with long-term CS use (reported by 68% of CIDP and 58% of gMG respondents). Other common AEs reported were insulin resistance (53% of CIDP and 50% of gMG respondents), decreased bone density (47% and 48%, respectively), immunosuppression (37% and 45%, respectively). Mood and behavioral change were noted by 56% of CIDP and 37% of gMG respondents, particularly mood swings, irritability, mania, and sleep disorders.
When asked how they balanced the risk for and benefit of corticosteroids, more than 80% of CIDP specialists reported personally monitoring for corticosteroid-related toxicity, and 42% reported they collaborated with the patient’s primary care provider. However, fewer than 10% reported ordering lab tests. Among neurologists treating gMG, 84% said they typically monitor corticosteroid toxicity independently, while 41% reported doing so in collaboration with primary care providers.
Two thirds of CIDP respondents and 53% of gMG respondents reported using guidelines to make clinical decisions on monitoring toxicity, and 34% of gMG respondents actually endorsed using the Guideline for Systematic Surveillance of Steroid Safety, which does not exist.
‘A Big Issue’ in Neurology
Commenting on the results, Said R. Beydoun, MD, professor and division chief, Neuromuscular Medicine, Department of Neurology at Keck Medicine of University of Southern California, Los Angeles, said steroid toxicity is “a big issue” in neurology.
These patients can be on chronic therapy, and they aren’t really monitored for osteoporosis or other complications, he said, adding that neurologists aren’t always taking the necessary precautions to prevent steroid toxicity.
Beydoun estimated that about half of neurologists are not adequately familiar with balancing the efficacy of corticosteroids versus in toxicity.
“Objective improvement, either on the functional scale or the muscle impairment scale — that’s really response treatment. Whereas adverse effects of a treatment are something separate. The patient may be improving but also maybe developing other complications from the treatment,” he said.
Also commenting, Ghazala Hayat, MD, professor of neurology and director of neuromuscular and clinical neurophysiology services at Saint Louis University in St. Louis, said there is a clear need for more education.
“I always say prednisone is our best friend initially, and then it becomes the worst enemy. If you don’t see lots of neuromuscular patients, you might not know even how to recognize toxicity or how to taper. Or the opposite to that, if you taper too quickly, patients relapse.”
The study was funded by argenx. Wolfe reported serving on advisory boards for Alexion, argenx, UCB, and Johnson & Johnson. Neelam Goyal, MD, is a consultant/advisor for Alexion, argenx, Amgen, Janssen, Lycia Therapeutics, and UCB and has received grant support from argenx. Beydoun reported receiving research support and consulting and speaking fees from Healey Center, Amylyx, AB Science, Sanofi, Janssen, Genentech, Regeneron, UCB, Abcuro argenx, Alnylam, AstraZeneca, Amylyx, CSL Behring, Grifols, Takeda, Octapharma, UCB, and Janssen. Hayat reported speaker and advisory roles with argenx, Alexion, and MTPA.
A version of this article appeared on Medscape.com.
SAVANNAH, GEORGIA — , results of a US survey showed.
For both MG and CIDP specialists, uncertainty around corticosteroid dosing, duration, and toxicity underscores the need for more guidance, the investigators noted. Over 85% of respondents indicated that a tool for systematically monitoring corticosteroid toxicity would be valuable.
The results indicate “a lack of knowledge by this pool of neurologists about the guidelines and what they contain,” said study investigator Gil Wolfe, MD, professor of neurology at the Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, in New York.
Clearer guidance on how to administer corticosteroids and manage toxicities in patients with gMG and CIDP “would be welcomed by neurologists and have potential for benefit to patient care,” the team noted.
The findings were presented at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.
Lack of Knowledge
Although guidelines for both CIDP and gMG recommend corticosteroids as first-line treatment and emphasize using the lowest effective dose to control symptoms, they do not include specific recommendations on dosing, duration, or toxicity monitoring, the researchers noted.
Despite this, a large proportion of survey respondents reported using guidelines to make clinical decisions on monitoring toxicity, with up to a third actually endorsing a guideline that doesn’t exist.
The cross-sectional, online survey was deployed in November and December 2023 and included 200 US neurologists. Of these, 99 answered questions on CIDP, and 101 answered similar questions on gMG.
To participate in the survey, respondents had to be board-certified neurologists, practicing for at least 2 years post-residency, and have treated or consulted on at least three patients with CIDP or 10 patients with gMG in the past year who were on a corticosteroid dose of at least 10 mg daily for 1 month or more.
CIDP respondents had been practicing a mean of 18.1 years since residency and were board certified in neuromuscular (20%), electrodiagnostic medicine/clinical neurophysiology (21%), and pediatric neurology (8%). Two thirds of them accepted referrals from other neurologists.
The gMG respondents had been practicing a mean of 20.5 years since residency and were board certified in neuromuscular (45%), electrodiagnostic medicine/clinical neurophysiology (35%), and pediatric neurology (17%). A total of 72% accepted referrals from other neurologists.
Respondents estimated that about 60% of their patients with gMG and 58% of patients with CIDP were being treated with corticosteroids, with gMG and CIDP respondents reporting a mean of 26.4 and 15.6 patients, respectively, meeting the study’s dosing criteria.
Appropriate Dosing
When asked what chronic, long-term (≥ 6 months) corticosteroid dose they considered safe in terms of minimizing adverse events, 43% of CIDP respondents and 51% of gMG respondents considered corticosteroid doses of 10 mg/d or less (prednisone equivalent) well tolerated; additionally, 32% and 31%, respectively, considered 20-40 mg/d well tolerated. Moreover, they said only about half of their patients would be able to taper to less than 10 mg/d in less than 6 months.
“Studies suggest safety is not seen until patients are on doses at 5 mg/d or less,” Wolfe said. “There is not enough appreciation that doses at levels we once considered safe really do pose significant risk,” he added.
“With the increasing number of treatment options in MG and to a lesser extent in CIDP, we need to do all we can to use corticosteroids as judiciously as possible and be aware of side effects our patients may not even report unless we make a pointed effort to ask about them.”
Familiarity with corticosteroid toxicities was more common among gMG respondents, of whom 77% reported being very/extremely familiar, than among 55% of CIDP respondents. Appetite/weight gain was reported among the most common adverse effects (AEs) associated with long-term CS use (reported by 68% of CIDP and 58% of gMG respondents). Other common AEs reported were insulin resistance (53% of CIDP and 50% of gMG respondents), decreased bone density (47% and 48%, respectively), immunosuppression (37% and 45%, respectively). Mood and behavioral change were noted by 56% of CIDP and 37% of gMG respondents, particularly mood swings, irritability, mania, and sleep disorders.
When asked how they balanced the risk for and benefit of corticosteroids, more than 80% of CIDP specialists reported personally monitoring for corticosteroid-related toxicity, and 42% reported they collaborated with the patient’s primary care provider. However, fewer than 10% reported ordering lab tests. Among neurologists treating gMG, 84% said they typically monitor corticosteroid toxicity independently, while 41% reported doing so in collaboration with primary care providers.
Two thirds of CIDP respondents and 53% of gMG respondents reported using guidelines to make clinical decisions on monitoring toxicity, and 34% of gMG respondents actually endorsed using the Guideline for Systematic Surveillance of Steroid Safety, which does not exist.
‘A Big Issue’ in Neurology
Commenting on the results, Said R. Beydoun, MD, professor and division chief, Neuromuscular Medicine, Department of Neurology at Keck Medicine of University of Southern California, Los Angeles, said steroid toxicity is “a big issue” in neurology.
These patients can be on chronic therapy, and they aren’t really monitored for osteoporosis or other complications, he said, adding that neurologists aren’t always taking the necessary precautions to prevent steroid toxicity.
Beydoun estimated that about half of neurologists are not adequately familiar with balancing the efficacy of corticosteroids versus in toxicity.
“Objective improvement, either on the functional scale or the muscle impairment scale — that’s really response treatment. Whereas adverse effects of a treatment are something separate. The patient may be improving but also maybe developing other complications from the treatment,” he said.
Also commenting, Ghazala Hayat, MD, professor of neurology and director of neuromuscular and clinical neurophysiology services at Saint Louis University in St. Louis, said there is a clear need for more education.
“I always say prednisone is our best friend initially, and then it becomes the worst enemy. If you don’t see lots of neuromuscular patients, you might not know even how to recognize toxicity or how to taper. Or the opposite to that, if you taper too quickly, patients relapse.”
The study was funded by argenx. Wolfe reported serving on advisory boards for Alexion, argenx, UCB, and Johnson & Johnson. Neelam Goyal, MD, is a consultant/advisor for Alexion, argenx, Amgen, Janssen, Lycia Therapeutics, and UCB and has received grant support from argenx. Beydoun reported receiving research support and consulting and speaking fees from Healey Center, Amylyx, AB Science, Sanofi, Janssen, Genentech, Regeneron, UCB, Abcuro argenx, Alnylam, AstraZeneca, Amylyx, CSL Behring, Grifols, Takeda, Octapharma, UCB, and Janssen. Hayat reported speaker and advisory roles with argenx, Alexion, and MTPA.
A version of this article appeared on Medscape.com.
SAVANNAH, GEORGIA — , results of a US survey showed.
For both MG and CIDP specialists, uncertainty around corticosteroid dosing, duration, and toxicity underscores the need for more guidance, the investigators noted. Over 85% of respondents indicated that a tool for systematically monitoring corticosteroid toxicity would be valuable.
The results indicate “a lack of knowledge by this pool of neurologists about the guidelines and what they contain,” said study investigator Gil Wolfe, MD, professor of neurology at the Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, in New York.
Clearer guidance on how to administer corticosteroids and manage toxicities in patients with gMG and CIDP “would be welcomed by neurologists and have potential for benefit to patient care,” the team noted.
The findings were presented at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.
Lack of Knowledge
Although guidelines for both CIDP and gMG recommend corticosteroids as first-line treatment and emphasize using the lowest effective dose to control symptoms, they do not include specific recommendations on dosing, duration, or toxicity monitoring, the researchers noted.
Despite this, a large proportion of survey respondents reported using guidelines to make clinical decisions on monitoring toxicity, with up to a third actually endorsing a guideline that doesn’t exist.
The cross-sectional, online survey was deployed in November and December 2023 and included 200 US neurologists. Of these, 99 answered questions on CIDP, and 101 answered similar questions on gMG.
To participate in the survey, respondents had to be board-certified neurologists, practicing for at least 2 years post-residency, and have treated or consulted on at least three patients with CIDP or 10 patients with gMG in the past year who were on a corticosteroid dose of at least 10 mg daily for 1 month or more.
CIDP respondents had been practicing a mean of 18.1 years since residency and were board certified in neuromuscular (20%), electrodiagnostic medicine/clinical neurophysiology (21%), and pediatric neurology (8%). Two thirds of them accepted referrals from other neurologists.
The gMG respondents had been practicing a mean of 20.5 years since residency and were board certified in neuromuscular (45%), electrodiagnostic medicine/clinical neurophysiology (35%), and pediatric neurology (17%). A total of 72% accepted referrals from other neurologists.
Respondents estimated that about 60% of their patients with gMG and 58% of patients with CIDP were being treated with corticosteroids, with gMG and CIDP respondents reporting a mean of 26.4 and 15.6 patients, respectively, meeting the study’s dosing criteria.
Appropriate Dosing
When asked what chronic, long-term (≥ 6 months) corticosteroid dose they considered safe in terms of minimizing adverse events, 43% of CIDP respondents and 51% of gMG respondents considered corticosteroid doses of 10 mg/d or less (prednisone equivalent) well tolerated; additionally, 32% and 31%, respectively, considered 20-40 mg/d well tolerated. Moreover, they said only about half of their patients would be able to taper to less than 10 mg/d in less than 6 months.
“Studies suggest safety is not seen until patients are on doses at 5 mg/d or less,” Wolfe said. “There is not enough appreciation that doses at levels we once considered safe really do pose significant risk,” he added.
“With the increasing number of treatment options in MG and to a lesser extent in CIDP, we need to do all we can to use corticosteroids as judiciously as possible and be aware of side effects our patients may not even report unless we make a pointed effort to ask about them.”
Familiarity with corticosteroid toxicities was more common among gMG respondents, of whom 77% reported being very/extremely familiar, than among 55% of CIDP respondents. Appetite/weight gain was reported among the most common adverse effects (AEs) associated with long-term CS use (reported by 68% of CIDP and 58% of gMG respondents). Other common AEs reported were insulin resistance (53% of CIDP and 50% of gMG respondents), decreased bone density (47% and 48%, respectively), immunosuppression (37% and 45%, respectively). Mood and behavioral change were noted by 56% of CIDP and 37% of gMG respondents, particularly mood swings, irritability, mania, and sleep disorders.
When asked how they balanced the risk for and benefit of corticosteroids, more than 80% of CIDP specialists reported personally monitoring for corticosteroid-related toxicity, and 42% reported they collaborated with the patient’s primary care provider. However, fewer than 10% reported ordering lab tests. Among neurologists treating gMG, 84% said they typically monitor corticosteroid toxicity independently, while 41% reported doing so in collaboration with primary care providers.
Two thirds of CIDP respondents and 53% of gMG respondents reported using guidelines to make clinical decisions on monitoring toxicity, and 34% of gMG respondents actually endorsed using the Guideline for Systematic Surveillance of Steroid Safety, which does not exist.
‘A Big Issue’ in Neurology
Commenting on the results, Said R. Beydoun, MD, professor and division chief, Neuromuscular Medicine, Department of Neurology at Keck Medicine of University of Southern California, Los Angeles, said steroid toxicity is “a big issue” in neurology.
These patients can be on chronic therapy, and they aren’t really monitored for osteoporosis or other complications, he said, adding that neurologists aren’t always taking the necessary precautions to prevent steroid toxicity.
Beydoun estimated that about half of neurologists are not adequately familiar with balancing the efficacy of corticosteroids versus in toxicity.
“Objective improvement, either on the functional scale or the muscle impairment scale — that’s really response treatment. Whereas adverse effects of a treatment are something separate. The patient may be improving but also maybe developing other complications from the treatment,” he said.
Also commenting, Ghazala Hayat, MD, professor of neurology and director of neuromuscular and clinical neurophysiology services at Saint Louis University in St. Louis, said there is a clear need for more education.
“I always say prednisone is our best friend initially, and then it becomes the worst enemy. If you don’t see lots of neuromuscular patients, you might not know even how to recognize toxicity or how to taper. Or the opposite to that, if you taper too quickly, patients relapse.”
The study was funded by argenx. Wolfe reported serving on advisory boards for Alexion, argenx, UCB, and Johnson & Johnson. Neelam Goyal, MD, is a consultant/advisor for Alexion, argenx, Amgen, Janssen, Lycia Therapeutics, and UCB and has received grant support from argenx. Beydoun reported receiving research support and consulting and speaking fees from Healey Center, Amylyx, AB Science, Sanofi, Janssen, Genentech, Regeneron, UCB, Abcuro argenx, Alnylam, AstraZeneca, Amylyx, CSL Behring, Grifols, Takeda, Octapharma, UCB, and Janssen. Hayat reported speaker and advisory roles with argenx, Alexion, and MTPA.
A version of this article appeared on Medscape.com.
FROM AANEM 2024
Veterans Affairs Hailed as a ‘Bright Spot’ in ALS Care
SAVANNAH, GEORGIA — , said one expert.
In a plenary address at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024, Ileana Howard, MD, medical co-director of the ALS Center of Excellence at VA Puget Sound in Seattle, said the recently released National Academies report “Living with ALS” cited the Veterans Administration as “a bright spot in the landscape of ALS care due to its interdisciplinary, holistic, and proactive approach to care.”
Since the early 2000s and the publication of several studies linking active military service with ALS, the US Department of Veterans Affairs (VA) has opened an ALS registry, a tissue and brain biobank, and in 2008, granted 100% presumptive service connection to any individual who served more than 90 days of active duty and was later diagnosed with ALS, she said.
“We now serve approximately 4000 veterans with ALS across the system, and we count 47 full interdisciplinary clinics within VA across the nation, with ALS coordinators designated for all 170 VA facilities, regardless of whether they had an ALS clinic or not, to serve as a navigator for patients and their families, to identify the closest ALS clinic that could meet their needs.”
Multidisciplinary vs Interdisciplinary
Howard emphasized that transdisciplinary collaboration is essential for maintaining an effective system. She pointed out that the term “multidisciplinary” is outdated, referring to teams that work independently but in parallel on the same issue.
In contrast, interdisciplinary teams integrate their assessments into a cohesive plan of care, whereas transdisciplinary teams take it further by combining both their assessments and care plans, allowing for greater intentional overlap.
The VA’s ALS handbook lists approximately 20 essential clinicians for a VA ALS clinic, including recreation therapists, assistive technology specialists, and veteran benefit service officers to assist with disability benefits application, among others, she said.
Essential to this collaboration is “role release,” which deliberately blurs the boundaries between disciplines. “The future of our specialty hinges on effective and selfless collaboration,” she said.
Howard encouraged ALS healthcare providers to move away from outdated terminology rooted in hierarchical team models and to break down silos that no longer benefit either the patients or the care teams.
She noted that while teamwork can enhance patient outcomes and overall health, it has also been associated with better health among healthcare providers. It’s well-known, she said, that neurologists and physiatrists are among the specialties with the highest burnout rates, and ALS teams, in particular, experience significant stress and burnout.
Better Together
A recent Canadian study on resiliency and burnout in ALS clinics surveyed a wide range of practitioners within ALS centers and found respondents drew resiliency through relationships with patients and colleagues, and that there was a strongly expressed desire for increased resources, team building/debriefing, and formal training in emotional exhaustion and burnout.
“A consistent theme was the lack of adequate allied health support (nursing, social work, occupational therapy) to address the complex needs of patients,” said the report’s senior author Kerri Lynn Schellenberg, MD, medical director of the ALS/Motor Neuron Diseases clinic and associate professor at the University of Saskatchewan College of Medicine in Saskatoon, Saskatchewan, Canada.
“The majority of participants felt they would benefit from more consistent team building exercises and debriefing,” noted the authors.
Schellenberg agreed, emphasizing that care teams perform best when there is mutual appreciation and support among members. By learning from one another and reaching consensus together, the care plan benefits from the collective expertise of the team. “We are stronger together,” she said.
Howard and Schellenberg reported no disclosures.
A version of this article appeared on Medscape.com.
SAVANNAH, GEORGIA — , said one expert.
In a plenary address at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024, Ileana Howard, MD, medical co-director of the ALS Center of Excellence at VA Puget Sound in Seattle, said the recently released National Academies report “Living with ALS” cited the Veterans Administration as “a bright spot in the landscape of ALS care due to its interdisciplinary, holistic, and proactive approach to care.”
Since the early 2000s and the publication of several studies linking active military service with ALS, the US Department of Veterans Affairs (VA) has opened an ALS registry, a tissue and brain biobank, and in 2008, granted 100% presumptive service connection to any individual who served more than 90 days of active duty and was later diagnosed with ALS, she said.
“We now serve approximately 4000 veterans with ALS across the system, and we count 47 full interdisciplinary clinics within VA across the nation, with ALS coordinators designated for all 170 VA facilities, regardless of whether they had an ALS clinic or not, to serve as a navigator for patients and their families, to identify the closest ALS clinic that could meet their needs.”
Multidisciplinary vs Interdisciplinary
Howard emphasized that transdisciplinary collaboration is essential for maintaining an effective system. She pointed out that the term “multidisciplinary” is outdated, referring to teams that work independently but in parallel on the same issue.
In contrast, interdisciplinary teams integrate their assessments into a cohesive plan of care, whereas transdisciplinary teams take it further by combining both their assessments and care plans, allowing for greater intentional overlap.
The VA’s ALS handbook lists approximately 20 essential clinicians for a VA ALS clinic, including recreation therapists, assistive technology specialists, and veteran benefit service officers to assist with disability benefits application, among others, she said.
Essential to this collaboration is “role release,” which deliberately blurs the boundaries between disciplines. “The future of our specialty hinges on effective and selfless collaboration,” she said.
Howard encouraged ALS healthcare providers to move away from outdated terminology rooted in hierarchical team models and to break down silos that no longer benefit either the patients or the care teams.
She noted that while teamwork can enhance patient outcomes and overall health, it has also been associated with better health among healthcare providers. It’s well-known, she said, that neurologists and physiatrists are among the specialties with the highest burnout rates, and ALS teams, in particular, experience significant stress and burnout.
Better Together
A recent Canadian study on resiliency and burnout in ALS clinics surveyed a wide range of practitioners within ALS centers and found respondents drew resiliency through relationships with patients and colleagues, and that there was a strongly expressed desire for increased resources, team building/debriefing, and formal training in emotional exhaustion and burnout.
“A consistent theme was the lack of adequate allied health support (nursing, social work, occupational therapy) to address the complex needs of patients,” said the report’s senior author Kerri Lynn Schellenberg, MD, medical director of the ALS/Motor Neuron Diseases clinic and associate professor at the University of Saskatchewan College of Medicine in Saskatoon, Saskatchewan, Canada.
“The majority of participants felt they would benefit from more consistent team building exercises and debriefing,” noted the authors.
Schellenberg agreed, emphasizing that care teams perform best when there is mutual appreciation and support among members. By learning from one another and reaching consensus together, the care plan benefits from the collective expertise of the team. “We are stronger together,” she said.
Howard and Schellenberg reported no disclosures.
A version of this article appeared on Medscape.com.
SAVANNAH, GEORGIA — , said one expert.
In a plenary address at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024, Ileana Howard, MD, medical co-director of the ALS Center of Excellence at VA Puget Sound in Seattle, said the recently released National Academies report “Living with ALS” cited the Veterans Administration as “a bright spot in the landscape of ALS care due to its interdisciplinary, holistic, and proactive approach to care.”
Since the early 2000s and the publication of several studies linking active military service with ALS, the US Department of Veterans Affairs (VA) has opened an ALS registry, a tissue and brain biobank, and in 2008, granted 100% presumptive service connection to any individual who served more than 90 days of active duty and was later diagnosed with ALS, she said.
“We now serve approximately 4000 veterans with ALS across the system, and we count 47 full interdisciplinary clinics within VA across the nation, with ALS coordinators designated for all 170 VA facilities, regardless of whether they had an ALS clinic or not, to serve as a navigator for patients and their families, to identify the closest ALS clinic that could meet their needs.”
Multidisciplinary vs Interdisciplinary
Howard emphasized that transdisciplinary collaboration is essential for maintaining an effective system. She pointed out that the term “multidisciplinary” is outdated, referring to teams that work independently but in parallel on the same issue.
In contrast, interdisciplinary teams integrate their assessments into a cohesive plan of care, whereas transdisciplinary teams take it further by combining both their assessments and care plans, allowing for greater intentional overlap.
The VA’s ALS handbook lists approximately 20 essential clinicians for a VA ALS clinic, including recreation therapists, assistive technology specialists, and veteran benefit service officers to assist with disability benefits application, among others, she said.
Essential to this collaboration is “role release,” which deliberately blurs the boundaries between disciplines. “The future of our specialty hinges on effective and selfless collaboration,” she said.
Howard encouraged ALS healthcare providers to move away from outdated terminology rooted in hierarchical team models and to break down silos that no longer benefit either the patients or the care teams.
She noted that while teamwork can enhance patient outcomes and overall health, it has also been associated with better health among healthcare providers. It’s well-known, she said, that neurologists and physiatrists are among the specialties with the highest burnout rates, and ALS teams, in particular, experience significant stress and burnout.
Better Together
A recent Canadian study on resiliency and burnout in ALS clinics surveyed a wide range of practitioners within ALS centers and found respondents drew resiliency through relationships with patients and colleagues, and that there was a strongly expressed desire for increased resources, team building/debriefing, and formal training in emotional exhaustion and burnout.
“A consistent theme was the lack of adequate allied health support (nursing, social work, occupational therapy) to address the complex needs of patients,” said the report’s senior author Kerri Lynn Schellenberg, MD, medical director of the ALS/Motor Neuron Diseases clinic and associate professor at the University of Saskatchewan College of Medicine in Saskatoon, Saskatchewan, Canada.
“The majority of participants felt they would benefit from more consistent team building exercises and debriefing,” noted the authors.
Schellenberg agreed, emphasizing that care teams perform best when there is mutual appreciation and support among members. By learning from one another and reaching consensus together, the care plan benefits from the collective expertise of the team. “We are stronger together,” she said.
Howard and Schellenberg reported no disclosures.
A version of this article appeared on Medscape.com.
FROM AANEM 2024
Digital Tool May Help Neurologists Assess Steroid Toxicity
SAVANNAH, GEORGIA —
The Glucocorticoid Toxicity Index-Metabolic Domains (GTI-MD), an abbreviated version of the GTI (Steritas), used weighted, standardized clinical outcome assessments to calculate steroid toxicity using a de-identified electronic health record (EHR) dataset.
“The results of our study indicate that patients with MG who initiated steroids demonstrated evidence of steroid toxicity in as little as 90 days after initial exposure, which was significant for patients with 20+ mg at index with repeated use,” noted study investigators, led by Neelam Goyal, MD, clinical professor of neurology and neurological sciences at Stanford University School of Medicine in Palo Alto, California.
The findings were presented at American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.
Rapid Evidence of Toxicity
The GTI uses nine health domains to calculate steroid toxicity scores, and the GTI-MD, which has been shown to be closely correlated, uses four domains collected routinely in clinical practice: Body mass index (BMI), blood pressure, glucose tolerance, and lipid metabolism.
The study used the Optum EHR dataset to identify 682 adult patients with MG, mean age of 70 years, 38% women, with at least two confirmed diagnoses of MG between 30 and 730 days apart and information on steroid utilization.
Patients were divided into two groups: Steroid initiators (SI; n = 377) were those whose steroid use was already in progress at the index date, whereas steroid-naive (SN) patients (n = 305) began their steroid use at the index date. Among the SI group, 30% were on doses greater than 20 mg/d and 22% were on lower doses. Among the SN group, 22% were on doses greater than 20 mg/d and 26% were on lower doses.
As expected, mean GTI-MD scores measured 90 days after the index date were higher in the SI group than in the SN group, indicating a higher level of steroid toxicity in the SI group. This was measured with two subscores of the GTI-MD: The Cumulative Worsening Score (22.6 vs 18.7; P = .007) and the Aggregate Improvement Score (4.9 vs 1.9; P = .27), the latter incorporating resolved toxicities resulting from the introduction of steroid-sparing agents.
The authors commented that scores were higher in the SN group than expected, “which could be explained by age, previous steroid exposure, comorbidities, and side effects from other medications.” However, they concluded that the findings suggest utility of the tool retrospectively, with EHR data.
Clinical Application
The GTI and related measurements are proprietary tools and therefore not readily available to all clinicians, noted Marie Beaudin, MD, another neurologist at Stanford University School of Medicine, who was not involved in the research.
In a separate, observational, ongoing study, Beaudin and Goyal’s team are examining the use of the tool prospectively for following the steroid toxicity burden in 50 patients with MG and correlating it with MG outcomes measured using the MG-Activities of Daily Living, MG Composite, and MG-Quality of Life 15R validated scales, as well as the adverse event unit.
“The objective of this study is to quantify the burden of toxicity that our patients are having from glucocorticoids, see how sensitive to change the scale is as their dosage of prednisone changes, and explore the correlations between the score and their disease outcome measures,” Beaudin said.
Unlike the abbreviated GTI-MD, the GTI measures nine domains: Bone mineral density, BMI, lipid metabolism, blood pressure, glucose tolerance, myopathy, skin toxicity, neuropsychiatric symptoms, and infections.
The score involves actively prompting and examining the patient, making it quite comprehensive. Beaudin said the study has revealed interesting insights into how patients report their side effects. When asked broadly about steroid-related side effects, many patients mention issues like weight or skin issues.
However, she noted, when prompted specifically about symptoms like insomnia, irritability, depression, or cognitive changes, there was an unexpected increase in positive responses, as patients are often unaware these could be side effects. This suggests the study may capture a greater burden than originally anticipated, said Beaudin.
She added that the long-term utility of the GTI score might be to help clinicians predict steroid toxicity and guide management.
“Then we would get more aggressive in trying to wean or taper patients. But these are often complicated cases because as soon as we taper, the disease flares. It’s a difficult decision whether to reduce the dosage of prednisone because toxicity burden is high, when disease burden is high too, and that’s where other medications can come into play.”
For example, she said, for insurance coverage, a high steroid toxicity score could justify the need to initiate more expensive steroid-sparing agents.
Both studies were funded by argenx. Goyal reported that she has consulted and received grant support from argenx, UCB, Alexion, and Janssen argenx. Beaudin is supported by a McLaughlin Scholarship from Laval University, Quebec, Canada.
A version of this article appeared on Medscape.com.
SAVANNAH, GEORGIA —
The Glucocorticoid Toxicity Index-Metabolic Domains (GTI-MD), an abbreviated version of the GTI (Steritas), used weighted, standardized clinical outcome assessments to calculate steroid toxicity using a de-identified electronic health record (EHR) dataset.
“The results of our study indicate that patients with MG who initiated steroids demonstrated evidence of steroid toxicity in as little as 90 days after initial exposure, which was significant for patients with 20+ mg at index with repeated use,” noted study investigators, led by Neelam Goyal, MD, clinical professor of neurology and neurological sciences at Stanford University School of Medicine in Palo Alto, California.
The findings were presented at American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.
Rapid Evidence of Toxicity
The GTI uses nine health domains to calculate steroid toxicity scores, and the GTI-MD, which has been shown to be closely correlated, uses four domains collected routinely in clinical practice: Body mass index (BMI), blood pressure, glucose tolerance, and lipid metabolism.
The study used the Optum EHR dataset to identify 682 adult patients with MG, mean age of 70 years, 38% women, with at least two confirmed diagnoses of MG between 30 and 730 days apart and information on steroid utilization.
Patients were divided into two groups: Steroid initiators (SI; n = 377) were those whose steroid use was already in progress at the index date, whereas steroid-naive (SN) patients (n = 305) began their steroid use at the index date. Among the SI group, 30% were on doses greater than 20 mg/d and 22% were on lower doses. Among the SN group, 22% were on doses greater than 20 mg/d and 26% were on lower doses.
As expected, mean GTI-MD scores measured 90 days after the index date were higher in the SI group than in the SN group, indicating a higher level of steroid toxicity in the SI group. This was measured with two subscores of the GTI-MD: The Cumulative Worsening Score (22.6 vs 18.7; P = .007) and the Aggregate Improvement Score (4.9 vs 1.9; P = .27), the latter incorporating resolved toxicities resulting from the introduction of steroid-sparing agents.
The authors commented that scores were higher in the SN group than expected, “which could be explained by age, previous steroid exposure, comorbidities, and side effects from other medications.” However, they concluded that the findings suggest utility of the tool retrospectively, with EHR data.
Clinical Application
The GTI and related measurements are proprietary tools and therefore not readily available to all clinicians, noted Marie Beaudin, MD, another neurologist at Stanford University School of Medicine, who was not involved in the research.
In a separate, observational, ongoing study, Beaudin and Goyal’s team are examining the use of the tool prospectively for following the steroid toxicity burden in 50 patients with MG and correlating it with MG outcomes measured using the MG-Activities of Daily Living, MG Composite, and MG-Quality of Life 15R validated scales, as well as the adverse event unit.
“The objective of this study is to quantify the burden of toxicity that our patients are having from glucocorticoids, see how sensitive to change the scale is as their dosage of prednisone changes, and explore the correlations between the score and their disease outcome measures,” Beaudin said.
Unlike the abbreviated GTI-MD, the GTI measures nine domains: Bone mineral density, BMI, lipid metabolism, blood pressure, glucose tolerance, myopathy, skin toxicity, neuropsychiatric symptoms, and infections.
The score involves actively prompting and examining the patient, making it quite comprehensive. Beaudin said the study has revealed interesting insights into how patients report their side effects. When asked broadly about steroid-related side effects, many patients mention issues like weight or skin issues.
However, she noted, when prompted specifically about symptoms like insomnia, irritability, depression, or cognitive changes, there was an unexpected increase in positive responses, as patients are often unaware these could be side effects. This suggests the study may capture a greater burden than originally anticipated, said Beaudin.
She added that the long-term utility of the GTI score might be to help clinicians predict steroid toxicity and guide management.
“Then we would get more aggressive in trying to wean or taper patients. But these are often complicated cases because as soon as we taper, the disease flares. It’s a difficult decision whether to reduce the dosage of prednisone because toxicity burden is high, when disease burden is high too, and that’s where other medications can come into play.”
For example, she said, for insurance coverage, a high steroid toxicity score could justify the need to initiate more expensive steroid-sparing agents.
Both studies were funded by argenx. Goyal reported that she has consulted and received grant support from argenx, UCB, Alexion, and Janssen argenx. Beaudin is supported by a McLaughlin Scholarship from Laval University, Quebec, Canada.
A version of this article appeared on Medscape.com.
SAVANNAH, GEORGIA —
The Glucocorticoid Toxicity Index-Metabolic Domains (GTI-MD), an abbreviated version of the GTI (Steritas), used weighted, standardized clinical outcome assessments to calculate steroid toxicity using a de-identified electronic health record (EHR) dataset.
“The results of our study indicate that patients with MG who initiated steroids demonstrated evidence of steroid toxicity in as little as 90 days after initial exposure, which was significant for patients with 20+ mg at index with repeated use,” noted study investigators, led by Neelam Goyal, MD, clinical professor of neurology and neurological sciences at Stanford University School of Medicine in Palo Alto, California.
The findings were presented at American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.
Rapid Evidence of Toxicity
The GTI uses nine health domains to calculate steroid toxicity scores, and the GTI-MD, which has been shown to be closely correlated, uses four domains collected routinely in clinical practice: Body mass index (BMI), blood pressure, glucose tolerance, and lipid metabolism.
The study used the Optum EHR dataset to identify 682 adult patients with MG, mean age of 70 years, 38% women, with at least two confirmed diagnoses of MG between 30 and 730 days apart and information on steroid utilization.
Patients were divided into two groups: Steroid initiators (SI; n = 377) were those whose steroid use was already in progress at the index date, whereas steroid-naive (SN) patients (n = 305) began their steroid use at the index date. Among the SI group, 30% were on doses greater than 20 mg/d and 22% were on lower doses. Among the SN group, 22% were on doses greater than 20 mg/d and 26% were on lower doses.
As expected, mean GTI-MD scores measured 90 days after the index date were higher in the SI group than in the SN group, indicating a higher level of steroid toxicity in the SI group. This was measured with two subscores of the GTI-MD: The Cumulative Worsening Score (22.6 vs 18.7; P = .007) and the Aggregate Improvement Score (4.9 vs 1.9; P = .27), the latter incorporating resolved toxicities resulting from the introduction of steroid-sparing agents.
The authors commented that scores were higher in the SN group than expected, “which could be explained by age, previous steroid exposure, comorbidities, and side effects from other medications.” However, they concluded that the findings suggest utility of the tool retrospectively, with EHR data.
Clinical Application
The GTI and related measurements are proprietary tools and therefore not readily available to all clinicians, noted Marie Beaudin, MD, another neurologist at Stanford University School of Medicine, who was not involved in the research.
In a separate, observational, ongoing study, Beaudin and Goyal’s team are examining the use of the tool prospectively for following the steroid toxicity burden in 50 patients with MG and correlating it with MG outcomes measured using the MG-Activities of Daily Living, MG Composite, and MG-Quality of Life 15R validated scales, as well as the adverse event unit.
“The objective of this study is to quantify the burden of toxicity that our patients are having from glucocorticoids, see how sensitive to change the scale is as their dosage of prednisone changes, and explore the correlations between the score and their disease outcome measures,” Beaudin said.
Unlike the abbreviated GTI-MD, the GTI measures nine domains: Bone mineral density, BMI, lipid metabolism, blood pressure, glucose tolerance, myopathy, skin toxicity, neuropsychiatric symptoms, and infections.
The score involves actively prompting and examining the patient, making it quite comprehensive. Beaudin said the study has revealed interesting insights into how patients report their side effects. When asked broadly about steroid-related side effects, many patients mention issues like weight or skin issues.
However, she noted, when prompted specifically about symptoms like insomnia, irritability, depression, or cognitive changes, there was an unexpected increase in positive responses, as patients are often unaware these could be side effects. This suggests the study may capture a greater burden than originally anticipated, said Beaudin.
She added that the long-term utility of the GTI score might be to help clinicians predict steroid toxicity and guide management.
“Then we would get more aggressive in trying to wean or taper patients. But these are often complicated cases because as soon as we taper, the disease flares. It’s a difficult decision whether to reduce the dosage of prednisone because toxicity burden is high, when disease burden is high too, and that’s where other medications can come into play.”
For example, she said, for insurance coverage, a high steroid toxicity score could justify the need to initiate more expensive steroid-sparing agents.
Both studies were funded by argenx. Goyal reported that she has consulted and received grant support from argenx, UCB, Alexion, and Janssen argenx. Beaudin is supported by a McLaughlin Scholarship from Laval University, Quebec, Canada.
A version of this article appeared on Medscape.com.
FROM AANEM 2024
Remote Assessments: A Win-Win for ALS Patients and Clinics?
SAVANNAH, GEORGIA — , results of a retrospective study showed.
The findings, along with those of another study by the same group, suggest that remote monitoring of patients with ALS is a feasible option for both maximizing quality of life and minimizing cost and disruption.
Both studies were presented at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.
“What we’re trying to do is look for screening tools that we can use when these patients are in the community to see if a specific score transition is associated with a high probability of needing an intervention that would require bringing them in to do gold standard tests,” said study investigator Tefani Perera, MD, a neurology resident at the University of Calgary, in Alberta, Canada.
Optimizing Quality of Life
Tailoring in-person care is particularly important for patients with ALS who often face significant challenges with mobility, Perera said. However, most multidisciplinary ALS clinics schedule in-person follow-ups at regular intervals rather than “as needed.
“These are very long clinic days where they are assessed for one thing after another, even if they don’t need it. So maybe we can actually select for what they need to be assessed for at each specific visit? Life expectancy is not that long for these patients, so we want to make sure their quality of life is optimized.”
For the BiPAP study, the investigators used the Pooled Resource Open-Access ALS Clinical Trials database to identify patients with ALS with two or more respiratory assessments on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R).
The ALSFRS-R is a 12-item questionnaire, which includes three respiratory sub-scores for respiratory insufficiency (RiS), dyspnea (DyS) and orthopnea (OS).
Patients with a baseline RiS sub-score of 4 — meaning no need for BiPAP — were included in the study (n = 3838), with the primary outcome being a drop in RiS sub-score indicating the need for BiPAP.
The median time from baseline to transition to BiPAP was 563 days, with 3.4% of patients reaching this outcome by 3 months.
Results showed the probability of needing BiPAP was significantly associated with baseline DyS and OS scores (P < .0001). Among patients with baseline DyS scores of 3, 2, and 1, the percentages of patients needing BiPAP within 3 months were 5.5%, 8.7%, and 20.1%, respectively. In addition, in patients with baseline OS scores of 3, 2, and 1, the percentages of patients needing BiPAP within 3 months were 9.1%, 12.7%, and 24.2%, respectively.
Regardless of the baseline score, any drop in either of these sub-scores over the study period was also associated with an increased likelihood of requiring BiPAP within 3 months, with a DyS transition from 3 to 2 and an OS transition from 4 to 3 being most notable.
These scores could be used to trigger gold standard assessments for BiPAP, such as nocturnal oximetry, overnight polysomnography, daytime hypercapnia, and forced and slow vital capacities, Perera said. On the other hand, the scores could also help patients and clinicians avoid unnecessary visits.
“When the dyspnea and orthopnea scores are high, they might not need this intervention until 2 years later, so do we even need to bring them in to do these tests or see a respirologist when they don’t actually need it?”
The group’s second study was a systematic review of 26 papers on ALS remote assessment devices and methods, including accelerometers (15.4%), telenursing protocols (3.8%), speech collection apps (26.9%), questionnaires (15.4%), multifactorial sensors (15.4%), and respiratory function monitors (19.2%). Domains of symptoms monitored included speech (12 studies), motor (11 studies), respiratory (11 studies), cardiac (three studies), and bulbar, psychiatric, and autonomic (one study each).
The researchers characterized various remote tools as having potential and concluded that a multidomain approach to symptom monitoring is achievable. They also noted that the majority of studies assessing adherence and patient feedback indicated a favorable response to patient monitoring.
“I work in a resource-rich center, where we have these huge multidisciplinary clinics, and we have the capacity to bring patients back every 3 months, but outside these big centers, in resource-limited settings, to have an ability to track remotely and bring patients in when they really need it is very important,” said Perera.
Best of Both Worlds
Ileana Howard, MD, physiatrist and professor of rehabilitation medicine at the University of Washington and medical co-director of the ALS Center of Excellence at VA Puget Sound in Seattle, agreed.
“One of the biggest challenges in ALS care today is ensuring equitable access to high quality care and supports, and telehealth was adopted by the VA early on as a means of doing that,” she said. “Remote monitoring technology is a really key development to help improve that type of care.”
However, she added that it should not be a question of one type of care versus the other. “The ideal care is when we have access to providing both face-to-face and virtual care for our patients so that we can meet their needs and preferences for care,” she said.
“Sometimes, in my experience, patients don’t understand why it’s important to go to an ALS specialty center. In those cases, I’ve been able to make initial contact with those individuals through telehealth and be able to provide education, which, in turn, often results in them making the decision to come to the specialty center once they understand what resources we have to offer.”
Also commenting on the research, Ghazala Hayat, MD, also endorsed a mixed approach.
“Telehealth is a very good tool that we should use interspersed with in-person visits,” said Hayat, director of the multidisciplinary ALS clinic at St. Louis University School of Medicine, St. Louis, Missouri, and professor of neurology and director of neuromuscular and clinical neurophysiology.
“I think the first few visits should always be in person — you need to connect with the patient,” she said. “But then, once they feel comfortable, remote monitoring is a very good idea, especially later in the disease process, when it becomes really difficult for the family to bring the patient in.”
The authors reported no relevant disclosures. Howard reported no disclosures. Hayat reported serving as a speaker and in advisory roles for argenx, Alexion, and MTPA. The study was funded by Amylyx Pharmaceuticals.
A version of this article appeared on Medscape.com.
SAVANNAH, GEORGIA — , results of a retrospective study showed.
The findings, along with those of another study by the same group, suggest that remote monitoring of patients with ALS is a feasible option for both maximizing quality of life and minimizing cost and disruption.
Both studies were presented at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.
“What we’re trying to do is look for screening tools that we can use when these patients are in the community to see if a specific score transition is associated with a high probability of needing an intervention that would require bringing them in to do gold standard tests,” said study investigator Tefani Perera, MD, a neurology resident at the University of Calgary, in Alberta, Canada.
Optimizing Quality of Life
Tailoring in-person care is particularly important for patients with ALS who often face significant challenges with mobility, Perera said. However, most multidisciplinary ALS clinics schedule in-person follow-ups at regular intervals rather than “as needed.
“These are very long clinic days where they are assessed for one thing after another, even if they don’t need it. So maybe we can actually select for what they need to be assessed for at each specific visit? Life expectancy is not that long for these patients, so we want to make sure their quality of life is optimized.”
For the BiPAP study, the investigators used the Pooled Resource Open-Access ALS Clinical Trials database to identify patients with ALS with two or more respiratory assessments on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R).
The ALSFRS-R is a 12-item questionnaire, which includes three respiratory sub-scores for respiratory insufficiency (RiS), dyspnea (DyS) and orthopnea (OS).
Patients with a baseline RiS sub-score of 4 — meaning no need for BiPAP — were included in the study (n = 3838), with the primary outcome being a drop in RiS sub-score indicating the need for BiPAP.
The median time from baseline to transition to BiPAP was 563 days, with 3.4% of patients reaching this outcome by 3 months.
Results showed the probability of needing BiPAP was significantly associated with baseline DyS and OS scores (P < .0001). Among patients with baseline DyS scores of 3, 2, and 1, the percentages of patients needing BiPAP within 3 months were 5.5%, 8.7%, and 20.1%, respectively. In addition, in patients with baseline OS scores of 3, 2, and 1, the percentages of patients needing BiPAP within 3 months were 9.1%, 12.7%, and 24.2%, respectively.
Regardless of the baseline score, any drop in either of these sub-scores over the study period was also associated with an increased likelihood of requiring BiPAP within 3 months, with a DyS transition from 3 to 2 and an OS transition from 4 to 3 being most notable.
These scores could be used to trigger gold standard assessments for BiPAP, such as nocturnal oximetry, overnight polysomnography, daytime hypercapnia, and forced and slow vital capacities, Perera said. On the other hand, the scores could also help patients and clinicians avoid unnecessary visits.
“When the dyspnea and orthopnea scores are high, they might not need this intervention until 2 years later, so do we even need to bring them in to do these tests or see a respirologist when they don’t actually need it?”
The group’s second study was a systematic review of 26 papers on ALS remote assessment devices and methods, including accelerometers (15.4%), telenursing protocols (3.8%), speech collection apps (26.9%), questionnaires (15.4%), multifactorial sensors (15.4%), and respiratory function monitors (19.2%). Domains of symptoms monitored included speech (12 studies), motor (11 studies), respiratory (11 studies), cardiac (three studies), and bulbar, psychiatric, and autonomic (one study each).
The researchers characterized various remote tools as having potential and concluded that a multidomain approach to symptom monitoring is achievable. They also noted that the majority of studies assessing adherence and patient feedback indicated a favorable response to patient monitoring.
“I work in a resource-rich center, where we have these huge multidisciplinary clinics, and we have the capacity to bring patients back every 3 months, but outside these big centers, in resource-limited settings, to have an ability to track remotely and bring patients in when they really need it is very important,” said Perera.
Best of Both Worlds
Ileana Howard, MD, physiatrist and professor of rehabilitation medicine at the University of Washington and medical co-director of the ALS Center of Excellence at VA Puget Sound in Seattle, agreed.
“One of the biggest challenges in ALS care today is ensuring equitable access to high quality care and supports, and telehealth was adopted by the VA early on as a means of doing that,” she said. “Remote monitoring technology is a really key development to help improve that type of care.”
However, she added that it should not be a question of one type of care versus the other. “The ideal care is when we have access to providing both face-to-face and virtual care for our patients so that we can meet their needs and preferences for care,” she said.
“Sometimes, in my experience, patients don’t understand why it’s important to go to an ALS specialty center. In those cases, I’ve been able to make initial contact with those individuals through telehealth and be able to provide education, which, in turn, often results in them making the decision to come to the specialty center once they understand what resources we have to offer.”
Also commenting on the research, Ghazala Hayat, MD, also endorsed a mixed approach.
“Telehealth is a very good tool that we should use interspersed with in-person visits,” said Hayat, director of the multidisciplinary ALS clinic at St. Louis University School of Medicine, St. Louis, Missouri, and professor of neurology and director of neuromuscular and clinical neurophysiology.
“I think the first few visits should always be in person — you need to connect with the patient,” she said. “But then, once they feel comfortable, remote monitoring is a very good idea, especially later in the disease process, when it becomes really difficult for the family to bring the patient in.”
The authors reported no relevant disclosures. Howard reported no disclosures. Hayat reported serving as a speaker and in advisory roles for argenx, Alexion, and MTPA. The study was funded by Amylyx Pharmaceuticals.
A version of this article appeared on Medscape.com.
SAVANNAH, GEORGIA — , results of a retrospective study showed.
The findings, along with those of another study by the same group, suggest that remote monitoring of patients with ALS is a feasible option for both maximizing quality of life and minimizing cost and disruption.
Both studies were presented at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.
“What we’re trying to do is look for screening tools that we can use when these patients are in the community to see if a specific score transition is associated with a high probability of needing an intervention that would require bringing them in to do gold standard tests,” said study investigator Tefani Perera, MD, a neurology resident at the University of Calgary, in Alberta, Canada.
Optimizing Quality of Life
Tailoring in-person care is particularly important for patients with ALS who often face significant challenges with mobility, Perera said. However, most multidisciplinary ALS clinics schedule in-person follow-ups at regular intervals rather than “as needed.
“These are very long clinic days where they are assessed for one thing after another, even if they don’t need it. So maybe we can actually select for what they need to be assessed for at each specific visit? Life expectancy is not that long for these patients, so we want to make sure their quality of life is optimized.”
For the BiPAP study, the investigators used the Pooled Resource Open-Access ALS Clinical Trials database to identify patients with ALS with two or more respiratory assessments on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R).
The ALSFRS-R is a 12-item questionnaire, which includes three respiratory sub-scores for respiratory insufficiency (RiS), dyspnea (DyS) and orthopnea (OS).
Patients with a baseline RiS sub-score of 4 — meaning no need for BiPAP — were included in the study (n = 3838), with the primary outcome being a drop in RiS sub-score indicating the need for BiPAP.
The median time from baseline to transition to BiPAP was 563 days, with 3.4% of patients reaching this outcome by 3 months.
Results showed the probability of needing BiPAP was significantly associated with baseline DyS and OS scores (P < .0001). Among patients with baseline DyS scores of 3, 2, and 1, the percentages of patients needing BiPAP within 3 months were 5.5%, 8.7%, and 20.1%, respectively. In addition, in patients with baseline OS scores of 3, 2, and 1, the percentages of patients needing BiPAP within 3 months were 9.1%, 12.7%, and 24.2%, respectively.
Regardless of the baseline score, any drop in either of these sub-scores over the study period was also associated with an increased likelihood of requiring BiPAP within 3 months, with a DyS transition from 3 to 2 and an OS transition from 4 to 3 being most notable.
These scores could be used to trigger gold standard assessments for BiPAP, such as nocturnal oximetry, overnight polysomnography, daytime hypercapnia, and forced and slow vital capacities, Perera said. On the other hand, the scores could also help patients and clinicians avoid unnecessary visits.
“When the dyspnea and orthopnea scores are high, they might not need this intervention until 2 years later, so do we even need to bring them in to do these tests or see a respirologist when they don’t actually need it?”
The group’s second study was a systematic review of 26 papers on ALS remote assessment devices and methods, including accelerometers (15.4%), telenursing protocols (3.8%), speech collection apps (26.9%), questionnaires (15.4%), multifactorial sensors (15.4%), and respiratory function monitors (19.2%). Domains of symptoms monitored included speech (12 studies), motor (11 studies), respiratory (11 studies), cardiac (three studies), and bulbar, psychiatric, and autonomic (one study each).
The researchers characterized various remote tools as having potential and concluded that a multidomain approach to symptom monitoring is achievable. They also noted that the majority of studies assessing adherence and patient feedback indicated a favorable response to patient monitoring.
“I work in a resource-rich center, where we have these huge multidisciplinary clinics, and we have the capacity to bring patients back every 3 months, but outside these big centers, in resource-limited settings, to have an ability to track remotely and bring patients in when they really need it is very important,” said Perera.
Best of Both Worlds
Ileana Howard, MD, physiatrist and professor of rehabilitation medicine at the University of Washington and medical co-director of the ALS Center of Excellence at VA Puget Sound in Seattle, agreed.
“One of the biggest challenges in ALS care today is ensuring equitable access to high quality care and supports, and telehealth was adopted by the VA early on as a means of doing that,” she said. “Remote monitoring technology is a really key development to help improve that type of care.”
However, she added that it should not be a question of one type of care versus the other. “The ideal care is when we have access to providing both face-to-face and virtual care for our patients so that we can meet their needs and preferences for care,” she said.
“Sometimes, in my experience, patients don’t understand why it’s important to go to an ALS specialty center. In those cases, I’ve been able to make initial contact with those individuals through telehealth and be able to provide education, which, in turn, often results in them making the decision to come to the specialty center once they understand what resources we have to offer.”
Also commenting on the research, Ghazala Hayat, MD, also endorsed a mixed approach.
“Telehealth is a very good tool that we should use interspersed with in-person visits,” said Hayat, director of the multidisciplinary ALS clinic at St. Louis University School of Medicine, St. Louis, Missouri, and professor of neurology and director of neuromuscular and clinical neurophysiology.
“I think the first few visits should always be in person — you need to connect with the patient,” she said. “But then, once they feel comfortable, remote monitoring is a very good idea, especially later in the disease process, when it becomes really difficult for the family to bring the patient in.”
The authors reported no relevant disclosures. Howard reported no disclosures. Hayat reported serving as a speaker and in advisory roles for argenx, Alexion, and MTPA. The study was funded by Amylyx Pharmaceuticals.
A version of this article appeared on Medscape.com.
FROM AANEM 2024
Sustained Control with Investigational Monoclonal Antibody for Myasthenia Gravis
SAVANNAH, GEORGIA – , according to topline results from the phase 3 VIVACITY-MG3 study.
The VIVACITY-MG3 trial is the first registrational study of a neonatal fragment crystallizable receptor (FcRn) blocker to show sustained efficacy through 6 months of fixed schedule dosing.
Lead investigator Tuan Vu, MD, professor of neurology at the University of South Florida in Tampa, presented the findings at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.
Autoantibody Depletion
FcRN plays a crucial role in the transport of immunoglobulin G. Blocking it can reduce circulating immunoglobulin G antibodies, including pathogenic gMG autoantibodies.
The double-blind, placebo-controlled trial included 196 adults with a broad range of seropositive gMG – who account for approximately 95% of the gMG patient population – and 42 seronegative patients.
The mean age was 52 years, 92% were female, and 63% were White. The mean disease duration was about 8 years. Among seropositive patients, 87.6% were acetylcholine receptor autoantibody-positive (AChR+), 10.5% were muscle-specific kinase autoantibody-positive (MuSK+), and 2% were low-density lipoprotein receptor-related protein 4 antibody positive.
They were randomly assigned 1:1 to receive either nipocalimab IV plus standard of care, or placebo plus standard of care for 24 weeks. A total of 87 patients in the nipocalimab arm and 82 in the placebo arm completed the study.
The primary efficacy endpoint was the Myasthenia Gravis Activities of Daily Living (MG-ADL) score. Participants treated with nipocalimab demonstrated a statistically significant improvement of 4.70 points from baseline, compared to the 3.25-point improvement in those treated with placebo (P =.002).
Clinically Meaningful Changes?
“For someone living with gMG, a 1 to 2-point improvement on MG-ADL may be the difference between normal eating and frequent choking on food, or shortness of breath at rest and being on a ventilator,” the drug’s manufacturer noted in a release.
Secondary endpoints were also better in the nipocalimab group, compared with participants on placebo. Specifically, on the 13-item clinician assessed Quantitative Myasthenia Gravis disease severity score, patients who received nipocalimab had an average reduction of 4.86 points from baseline compared to a reduction of 2.05 points in the placebo arm (P <.001).
Similarly, MG-ADL response (defined as ≥ 2-point improvement from baseline) was significantly greater in the nipocalimab versus placebo arms (68.8% vs 52.6%; P =.021).
Subgroup analysis revealed similar results for the different types of seropositive patients, but there was no statistically significant difference in results for seronegative patients treated with nipocalimab versus placebo.
“The drug was pretty well tolerated and there was little difference, other than more patients with muscle spasm in the nipocalimab group (12.2% vs 3.1%),” said Vu.
In addition, peripheral edema occurred in 11.2% of the nipocalimab group and none of the placebo-treated patients. Cholesterol levels were also higher in the nipocalimab arm, but there were no cardiac side effects, he added.
Encouraging Findings
Commenting on the findings, Neelam Goyal, MD, clinical professor of neurology and neurological sciences at Stanford University School of Medicine in Palo Alto, California, was encouraged.
“It’s a phase 3 trial, it’s positive, which is great, so it’ll be another drug on the market, another option for our patients,” she said. However, she cautioned, “their placebo arm did better than most placebos, so I think the delta is not as robust, but it was still statistically significant.”
Goyal noted that, if approved, nipocalimab will be the third FcRn inhibitor in the MG field, preceded by efgartigimod (Vyvgart), which is approved for AChR antibody-positive disease, and rozanolixizumab-noli (Rystiggo) which is approved for both for AChR and MUSK antibody positive disease.
“Its target of action is similar to the two drugs that are already on the market, but one thing that is unique about nipocalimab is that it is continuous dosing versus the other two medications that are given cyclically,” she said.
“The reason that’s an upside, is that with cyclical dosing, patients have a return of symptoms. We treat, they get better, and then they get worse. That’s very disconcerting to patients. So, they want to be treated continuously.”
Additionally, she said there are some early data suggesting its safety in pregnancy.
Vu disclosed he is the USF Site Principal Investigator for MG clinical trials sponsored by Alexion/ AstraZeneca Rare Disease, Amgen, argenx, Cartesian Therapeutics, COUR Pharmaceuticals, Dianthus Therapeutics, Immunovant, Johnson & Johnson, NMD Pharmaceuticals, Regeneron Pharmaceuticals, and UCB, and has served as a speaker for Alexion/AstraZeneca Rare Disease, argenx, and CSL Behring. He performs consulting work for Alexion/AstraZeneca Rare Disease, argenx, Dianthus Therapeutics, ImmunAbs, and UCB. Goyal disclosed consultant, advisory or grant support from argenx, UCB, Alexion, and Janssen. The study was funded by Janssen.
A version of this article appeared on Medscape.com.
SAVANNAH, GEORGIA – , according to topline results from the phase 3 VIVACITY-MG3 study.
The VIVACITY-MG3 trial is the first registrational study of a neonatal fragment crystallizable receptor (FcRn) blocker to show sustained efficacy through 6 months of fixed schedule dosing.
Lead investigator Tuan Vu, MD, professor of neurology at the University of South Florida in Tampa, presented the findings at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.
Autoantibody Depletion
FcRN plays a crucial role in the transport of immunoglobulin G. Blocking it can reduce circulating immunoglobulin G antibodies, including pathogenic gMG autoantibodies.
The double-blind, placebo-controlled trial included 196 adults with a broad range of seropositive gMG – who account for approximately 95% of the gMG patient population – and 42 seronegative patients.
The mean age was 52 years, 92% were female, and 63% were White. The mean disease duration was about 8 years. Among seropositive patients, 87.6% were acetylcholine receptor autoantibody-positive (AChR+), 10.5% were muscle-specific kinase autoantibody-positive (MuSK+), and 2% were low-density lipoprotein receptor-related protein 4 antibody positive.
They were randomly assigned 1:1 to receive either nipocalimab IV plus standard of care, or placebo plus standard of care for 24 weeks. A total of 87 patients in the nipocalimab arm and 82 in the placebo arm completed the study.
The primary efficacy endpoint was the Myasthenia Gravis Activities of Daily Living (MG-ADL) score. Participants treated with nipocalimab demonstrated a statistically significant improvement of 4.70 points from baseline, compared to the 3.25-point improvement in those treated with placebo (P =.002).
Clinically Meaningful Changes?
“For someone living with gMG, a 1 to 2-point improvement on MG-ADL may be the difference between normal eating and frequent choking on food, or shortness of breath at rest and being on a ventilator,” the drug’s manufacturer noted in a release.
Secondary endpoints were also better in the nipocalimab group, compared with participants on placebo. Specifically, on the 13-item clinician assessed Quantitative Myasthenia Gravis disease severity score, patients who received nipocalimab had an average reduction of 4.86 points from baseline compared to a reduction of 2.05 points in the placebo arm (P <.001).
Similarly, MG-ADL response (defined as ≥ 2-point improvement from baseline) was significantly greater in the nipocalimab versus placebo arms (68.8% vs 52.6%; P =.021).
Subgroup analysis revealed similar results for the different types of seropositive patients, but there was no statistically significant difference in results for seronegative patients treated with nipocalimab versus placebo.
“The drug was pretty well tolerated and there was little difference, other than more patients with muscle spasm in the nipocalimab group (12.2% vs 3.1%),” said Vu.
In addition, peripheral edema occurred in 11.2% of the nipocalimab group and none of the placebo-treated patients. Cholesterol levels were also higher in the nipocalimab arm, but there were no cardiac side effects, he added.
Encouraging Findings
Commenting on the findings, Neelam Goyal, MD, clinical professor of neurology and neurological sciences at Stanford University School of Medicine in Palo Alto, California, was encouraged.
“It’s a phase 3 trial, it’s positive, which is great, so it’ll be another drug on the market, another option for our patients,” she said. However, she cautioned, “their placebo arm did better than most placebos, so I think the delta is not as robust, but it was still statistically significant.”
Goyal noted that, if approved, nipocalimab will be the third FcRn inhibitor in the MG field, preceded by efgartigimod (Vyvgart), which is approved for AChR antibody-positive disease, and rozanolixizumab-noli (Rystiggo) which is approved for both for AChR and MUSK antibody positive disease.
“Its target of action is similar to the two drugs that are already on the market, but one thing that is unique about nipocalimab is that it is continuous dosing versus the other two medications that are given cyclically,” she said.
“The reason that’s an upside, is that with cyclical dosing, patients have a return of symptoms. We treat, they get better, and then they get worse. That’s very disconcerting to patients. So, they want to be treated continuously.”
Additionally, she said there are some early data suggesting its safety in pregnancy.
Vu disclosed he is the USF Site Principal Investigator for MG clinical trials sponsored by Alexion/ AstraZeneca Rare Disease, Amgen, argenx, Cartesian Therapeutics, COUR Pharmaceuticals, Dianthus Therapeutics, Immunovant, Johnson & Johnson, NMD Pharmaceuticals, Regeneron Pharmaceuticals, and UCB, and has served as a speaker for Alexion/AstraZeneca Rare Disease, argenx, and CSL Behring. He performs consulting work for Alexion/AstraZeneca Rare Disease, argenx, Dianthus Therapeutics, ImmunAbs, and UCB. Goyal disclosed consultant, advisory or grant support from argenx, UCB, Alexion, and Janssen. The study was funded by Janssen.
A version of this article appeared on Medscape.com.
SAVANNAH, GEORGIA – , according to topline results from the phase 3 VIVACITY-MG3 study.
The VIVACITY-MG3 trial is the first registrational study of a neonatal fragment crystallizable receptor (FcRn) blocker to show sustained efficacy through 6 months of fixed schedule dosing.
Lead investigator Tuan Vu, MD, professor of neurology at the University of South Florida in Tampa, presented the findings at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.
Autoantibody Depletion
FcRN plays a crucial role in the transport of immunoglobulin G. Blocking it can reduce circulating immunoglobulin G antibodies, including pathogenic gMG autoantibodies.
The double-blind, placebo-controlled trial included 196 adults with a broad range of seropositive gMG – who account for approximately 95% of the gMG patient population – and 42 seronegative patients.
The mean age was 52 years, 92% were female, and 63% were White. The mean disease duration was about 8 years. Among seropositive patients, 87.6% were acetylcholine receptor autoantibody-positive (AChR+), 10.5% were muscle-specific kinase autoantibody-positive (MuSK+), and 2% were low-density lipoprotein receptor-related protein 4 antibody positive.
They were randomly assigned 1:1 to receive either nipocalimab IV plus standard of care, or placebo plus standard of care for 24 weeks. A total of 87 patients in the nipocalimab arm and 82 in the placebo arm completed the study.
The primary efficacy endpoint was the Myasthenia Gravis Activities of Daily Living (MG-ADL) score. Participants treated with nipocalimab demonstrated a statistically significant improvement of 4.70 points from baseline, compared to the 3.25-point improvement in those treated with placebo (P =.002).
Clinically Meaningful Changes?
“For someone living with gMG, a 1 to 2-point improvement on MG-ADL may be the difference between normal eating and frequent choking on food, or shortness of breath at rest and being on a ventilator,” the drug’s manufacturer noted in a release.
Secondary endpoints were also better in the nipocalimab group, compared with participants on placebo. Specifically, on the 13-item clinician assessed Quantitative Myasthenia Gravis disease severity score, patients who received nipocalimab had an average reduction of 4.86 points from baseline compared to a reduction of 2.05 points in the placebo arm (P <.001).
Similarly, MG-ADL response (defined as ≥ 2-point improvement from baseline) was significantly greater in the nipocalimab versus placebo arms (68.8% vs 52.6%; P =.021).
Subgroup analysis revealed similar results for the different types of seropositive patients, but there was no statistically significant difference in results for seronegative patients treated with nipocalimab versus placebo.
“The drug was pretty well tolerated and there was little difference, other than more patients with muscle spasm in the nipocalimab group (12.2% vs 3.1%),” said Vu.
In addition, peripheral edema occurred in 11.2% of the nipocalimab group and none of the placebo-treated patients. Cholesterol levels were also higher in the nipocalimab arm, but there were no cardiac side effects, he added.
Encouraging Findings
Commenting on the findings, Neelam Goyal, MD, clinical professor of neurology and neurological sciences at Stanford University School of Medicine in Palo Alto, California, was encouraged.
“It’s a phase 3 trial, it’s positive, which is great, so it’ll be another drug on the market, another option for our patients,” she said. However, she cautioned, “their placebo arm did better than most placebos, so I think the delta is not as robust, but it was still statistically significant.”
Goyal noted that, if approved, nipocalimab will be the third FcRn inhibitor in the MG field, preceded by efgartigimod (Vyvgart), which is approved for AChR antibody-positive disease, and rozanolixizumab-noli (Rystiggo) which is approved for both for AChR and MUSK antibody positive disease.
“Its target of action is similar to the two drugs that are already on the market, but one thing that is unique about nipocalimab is that it is continuous dosing versus the other two medications that are given cyclically,” she said.
“The reason that’s an upside, is that with cyclical dosing, patients have a return of symptoms. We treat, they get better, and then they get worse. That’s very disconcerting to patients. So, they want to be treated continuously.”
Additionally, she said there are some early data suggesting its safety in pregnancy.
Vu disclosed he is the USF Site Principal Investigator for MG clinical trials sponsored by Alexion/ AstraZeneca Rare Disease, Amgen, argenx, Cartesian Therapeutics, COUR Pharmaceuticals, Dianthus Therapeutics, Immunovant, Johnson & Johnson, NMD Pharmaceuticals, Regeneron Pharmaceuticals, and UCB, and has served as a speaker for Alexion/AstraZeneca Rare Disease, argenx, and CSL Behring. He performs consulting work for Alexion/AstraZeneca Rare Disease, argenx, Dianthus Therapeutics, ImmunAbs, and UCB. Goyal disclosed consultant, advisory or grant support from argenx, UCB, Alexion, and Janssen. The study was funded by Janssen.
A version of this article appeared on Medscape.com.
FROM AANEM 2024
First-in-Class B-Cell Depleting Agent Promising for Myasthenia Gravis
SAVANNAH, GEORGIA — , new phase 3 data showed.
“Based on these results, we have demonstrated that targeting B cells, including the antibody-secreting cells, is beneficial, and there is likely a role for this kind of therapeutic strategy for patients with myasthenia gravis,” said senior investigator Richard Nowak, MD.
The findings were published and presented at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.
Largest Cohort of Muscle-Specific Kinase (MuSK) Antibody–Positive Disease
The Myasthenia Gravis INebilizumab Trial study enrolled 238 participants, 60.8% women, mean age 47.5 years, from 79 sites in 18 countries. The participants were divided into two cohorts: 190 acetylcholine receptor (AChR) autoantibody–positive patients and 48 MuSK autoantibody–positive patients.
“This is the largest enrolled cohort of MuSK antibody–positive disease in a placebo-controlled trial to date,” said Nowak, director of the Yale Myasthenia Gravis Clinic and associate professor of neurology at Yale School of Medicine, in New Haven, Connecticut.
Both groups had similar gMG duration (mean 6.7 and 5.2 years for AChR+ and MuSK+ patients, respectively) and disease severity based on Myasthenia Gravis Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) baseline score. In addition, more than 80% of participants were on a prednisone equivalent dose greater than 5 mg daily at study entry.
Participants were randomly assigned to receive intravenous (IV) inebilizumab or IV placebo for 52 weeks (AChR+ group) or 26 weeks (MuSK+ group). In addition, study participants who were taking corticosteroids were tapered down starting at week 4 to prednisone 5 mg per day by week 24.
The trial met its primary endpoint, with a statistically significant change from baseline in MG-ADL and with a reduction of 4.2 points for inebilizumab versus 2.2 for placebo (P < .0001) at week 26 for the combined study population.
“You can see that the trend is actually going toward separation of the two groups after week 8 in the combined population,” said Nowak. Key secondary endpoints also showed statistically significant and clinically meaningful change from baseline compared with placebo.
This included a statistically significant change in QMG score inebilizumab compared with placebo for the combined population, a reduction of 4.8 versus 2.3 points, respectively, at week 26 (P = .0002).
In addition, both MG-ADL and QMG scores in the AChR+ subgroup were superior for inebilizumab versus placebo at week 26, with reductions of 4.2 versus 2.4, and 4.4 versus 2.0; P = .0015 and P = .0011, respectively.
In the MuSK+ subgroup, inebilizumab-treated patients had better MG-ADL scores than placebo-treated patients, with reductions of 3.9 versus 1.7 points, respectively, at week 26, although this difference did not meet statistical significance.
“There were no increased safety incidents in the inebilizumab-treated patients versus placebo, and a similar percentage of safety incidents in the AChR–positive and MuSK–positive groups. There were three deaths reported, all likely related to myasthenic crisis,” he said.
Nowak said that inebilizumab is “unique from the other currently FDA-approved medications for myasthenia gravis in that it’s targeting the upstream immunopathogenic mechanism of disease, specifically B cells — and B cells that are actually antibody-secreting cells.”
“It is targeting the factories of autoantibody production, whereas an FcRn antagonist, for example, is not targeting those factories but rather targeting what’s being produced — the immunoglobulins, IgGs in general,” he added.
Nowak said that what is particularly exciting about the drug is that the schedule is not very frequent. It begins with an initial IV infusion, followed by a second infusion 2 weeks later and a third infusion 6 months after that, so that patients are treated approximately every 6 months. This is in contrast to some other targeted therapies, where failing to address the underlying factors driving immunopathogenesis necessitates more regular and frequent medication administration.
New, Novel, Exciting
Commenting on the research, Neelam Goyal, MD, who chaired the session, said, “It’s definitely new, novel, interesting, exciting.”
Goyal, clinical professor of neurology and neurological sciences at Stanford University School of Medicine in Palo Alto, California, also noted that while B-cell depletion has shown some previous success in MG, it was with rituximab, a CD20 B-cell depleting agent.
She noted that unlike rituximab, which targets CD20, inebilizumab targets CD19, although both medications lead to B-cell depletion. Rituximab has proven effective for MUSK–positive MG, which accounts for approximately 5% of cases.
However, Goyal noted that the results for AChR–positive MG have been mixed — “the BeatMG trial was negative and the RINOMAX trial was positive. So, I think this is really interesting. It is exciting, and this drug is already on the market.”
She added that although inebilizumab is already US Food and Drug Administration–approved for the treatment of neuromyelitis optica, it still faces approval and indication hurdles for MG.
The future of this drug in the management algorithm for MG remains uncertain. Goyal noted that it’s “quite costly,” and although its benefits are evident — particularly for FcRn and complement inhibitors — some early data from chimeric antigen receptor T-cell therapy studies appear significantly more impressive.
Nowak disclosed research support from the National Institutes of Health, Genentech, Alexion Pharmaceuticals, argenx, Annexon Biosciences, Ra Pharmaceuticals (now UCB S.A.), the Myasthenia Gravis Foundation of America, Momenta Pharmaceuticals (now Janssen), Immunovant, Grifols, S.A., and Viela Bio, Horizon Therapeutics (now Amgen). Served as a consultant and advisor for Alexion Pharmaceuticals, argenx, Cabaletta Bio, Cour Pharmaceuticals, Ra Pharmaceuticals (now UCB S.A.), Immunovant, Momenta Pharmaceuticals (now Janssen), and Viela Bio (Horizon Therapeutics, now Amgen).
Goyal disclosed consultant, advisory, or grant support from argenx, UCB, Alexion, and Janssen. The study was funded by Amgen.
A version of this article appeared on Medscape.com.
SAVANNAH, GEORGIA — , new phase 3 data showed.
“Based on these results, we have demonstrated that targeting B cells, including the antibody-secreting cells, is beneficial, and there is likely a role for this kind of therapeutic strategy for patients with myasthenia gravis,” said senior investigator Richard Nowak, MD.
The findings were published and presented at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.
Largest Cohort of Muscle-Specific Kinase (MuSK) Antibody–Positive Disease
The Myasthenia Gravis INebilizumab Trial study enrolled 238 participants, 60.8% women, mean age 47.5 years, from 79 sites in 18 countries. The participants were divided into two cohorts: 190 acetylcholine receptor (AChR) autoantibody–positive patients and 48 MuSK autoantibody–positive patients.
“This is the largest enrolled cohort of MuSK antibody–positive disease in a placebo-controlled trial to date,” said Nowak, director of the Yale Myasthenia Gravis Clinic and associate professor of neurology at Yale School of Medicine, in New Haven, Connecticut.
Both groups had similar gMG duration (mean 6.7 and 5.2 years for AChR+ and MuSK+ patients, respectively) and disease severity based on Myasthenia Gravis Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) baseline score. In addition, more than 80% of participants were on a prednisone equivalent dose greater than 5 mg daily at study entry.
Participants were randomly assigned to receive intravenous (IV) inebilizumab or IV placebo for 52 weeks (AChR+ group) or 26 weeks (MuSK+ group). In addition, study participants who were taking corticosteroids were tapered down starting at week 4 to prednisone 5 mg per day by week 24.
The trial met its primary endpoint, with a statistically significant change from baseline in MG-ADL and with a reduction of 4.2 points for inebilizumab versus 2.2 for placebo (P < .0001) at week 26 for the combined study population.
“You can see that the trend is actually going toward separation of the two groups after week 8 in the combined population,” said Nowak. Key secondary endpoints also showed statistically significant and clinically meaningful change from baseline compared with placebo.
This included a statistically significant change in QMG score inebilizumab compared with placebo for the combined population, a reduction of 4.8 versus 2.3 points, respectively, at week 26 (P = .0002).
In addition, both MG-ADL and QMG scores in the AChR+ subgroup were superior for inebilizumab versus placebo at week 26, with reductions of 4.2 versus 2.4, and 4.4 versus 2.0; P = .0015 and P = .0011, respectively.
In the MuSK+ subgroup, inebilizumab-treated patients had better MG-ADL scores than placebo-treated patients, with reductions of 3.9 versus 1.7 points, respectively, at week 26, although this difference did not meet statistical significance.
“There were no increased safety incidents in the inebilizumab-treated patients versus placebo, and a similar percentage of safety incidents in the AChR–positive and MuSK–positive groups. There were three deaths reported, all likely related to myasthenic crisis,” he said.
Nowak said that inebilizumab is “unique from the other currently FDA-approved medications for myasthenia gravis in that it’s targeting the upstream immunopathogenic mechanism of disease, specifically B cells — and B cells that are actually antibody-secreting cells.”
“It is targeting the factories of autoantibody production, whereas an FcRn antagonist, for example, is not targeting those factories but rather targeting what’s being produced — the immunoglobulins, IgGs in general,” he added.
Nowak said that what is particularly exciting about the drug is that the schedule is not very frequent. It begins with an initial IV infusion, followed by a second infusion 2 weeks later and a third infusion 6 months after that, so that patients are treated approximately every 6 months. This is in contrast to some other targeted therapies, where failing to address the underlying factors driving immunopathogenesis necessitates more regular and frequent medication administration.
New, Novel, Exciting
Commenting on the research, Neelam Goyal, MD, who chaired the session, said, “It’s definitely new, novel, interesting, exciting.”
Goyal, clinical professor of neurology and neurological sciences at Stanford University School of Medicine in Palo Alto, California, also noted that while B-cell depletion has shown some previous success in MG, it was with rituximab, a CD20 B-cell depleting agent.
She noted that unlike rituximab, which targets CD20, inebilizumab targets CD19, although both medications lead to B-cell depletion. Rituximab has proven effective for MUSK–positive MG, which accounts for approximately 5% of cases.
However, Goyal noted that the results for AChR–positive MG have been mixed — “the BeatMG trial was negative and the RINOMAX trial was positive. So, I think this is really interesting. It is exciting, and this drug is already on the market.”
She added that although inebilizumab is already US Food and Drug Administration–approved for the treatment of neuromyelitis optica, it still faces approval and indication hurdles for MG.
The future of this drug in the management algorithm for MG remains uncertain. Goyal noted that it’s “quite costly,” and although its benefits are evident — particularly for FcRn and complement inhibitors — some early data from chimeric antigen receptor T-cell therapy studies appear significantly more impressive.
Nowak disclosed research support from the National Institutes of Health, Genentech, Alexion Pharmaceuticals, argenx, Annexon Biosciences, Ra Pharmaceuticals (now UCB S.A.), the Myasthenia Gravis Foundation of America, Momenta Pharmaceuticals (now Janssen), Immunovant, Grifols, S.A., and Viela Bio, Horizon Therapeutics (now Amgen). Served as a consultant and advisor for Alexion Pharmaceuticals, argenx, Cabaletta Bio, Cour Pharmaceuticals, Ra Pharmaceuticals (now UCB S.A.), Immunovant, Momenta Pharmaceuticals (now Janssen), and Viela Bio (Horizon Therapeutics, now Amgen).
Goyal disclosed consultant, advisory, or grant support from argenx, UCB, Alexion, and Janssen. The study was funded by Amgen.
A version of this article appeared on Medscape.com.
SAVANNAH, GEORGIA — , new phase 3 data showed.
“Based on these results, we have demonstrated that targeting B cells, including the antibody-secreting cells, is beneficial, and there is likely a role for this kind of therapeutic strategy for patients with myasthenia gravis,” said senior investigator Richard Nowak, MD.
The findings were published and presented at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.
Largest Cohort of Muscle-Specific Kinase (MuSK) Antibody–Positive Disease
The Myasthenia Gravis INebilizumab Trial study enrolled 238 participants, 60.8% women, mean age 47.5 years, from 79 sites in 18 countries. The participants were divided into two cohorts: 190 acetylcholine receptor (AChR) autoantibody–positive patients and 48 MuSK autoantibody–positive patients.
“This is the largest enrolled cohort of MuSK antibody–positive disease in a placebo-controlled trial to date,” said Nowak, director of the Yale Myasthenia Gravis Clinic and associate professor of neurology at Yale School of Medicine, in New Haven, Connecticut.
Both groups had similar gMG duration (mean 6.7 and 5.2 years for AChR+ and MuSK+ patients, respectively) and disease severity based on Myasthenia Gravis Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) baseline score. In addition, more than 80% of participants were on a prednisone equivalent dose greater than 5 mg daily at study entry.
Participants were randomly assigned to receive intravenous (IV) inebilizumab or IV placebo for 52 weeks (AChR+ group) or 26 weeks (MuSK+ group). In addition, study participants who were taking corticosteroids were tapered down starting at week 4 to prednisone 5 mg per day by week 24.
The trial met its primary endpoint, with a statistically significant change from baseline in MG-ADL and with a reduction of 4.2 points for inebilizumab versus 2.2 for placebo (P < .0001) at week 26 for the combined study population.
“You can see that the trend is actually going toward separation of the two groups after week 8 in the combined population,” said Nowak. Key secondary endpoints also showed statistically significant and clinically meaningful change from baseline compared with placebo.
This included a statistically significant change in QMG score inebilizumab compared with placebo for the combined population, a reduction of 4.8 versus 2.3 points, respectively, at week 26 (P = .0002).
In addition, both MG-ADL and QMG scores in the AChR+ subgroup were superior for inebilizumab versus placebo at week 26, with reductions of 4.2 versus 2.4, and 4.4 versus 2.0; P = .0015 and P = .0011, respectively.
In the MuSK+ subgroup, inebilizumab-treated patients had better MG-ADL scores than placebo-treated patients, with reductions of 3.9 versus 1.7 points, respectively, at week 26, although this difference did not meet statistical significance.
“There were no increased safety incidents in the inebilizumab-treated patients versus placebo, and a similar percentage of safety incidents in the AChR–positive and MuSK–positive groups. There were three deaths reported, all likely related to myasthenic crisis,” he said.
Nowak said that inebilizumab is “unique from the other currently FDA-approved medications for myasthenia gravis in that it’s targeting the upstream immunopathogenic mechanism of disease, specifically B cells — and B cells that are actually antibody-secreting cells.”
“It is targeting the factories of autoantibody production, whereas an FcRn antagonist, for example, is not targeting those factories but rather targeting what’s being produced — the immunoglobulins, IgGs in general,” he added.
Nowak said that what is particularly exciting about the drug is that the schedule is not very frequent. It begins with an initial IV infusion, followed by a second infusion 2 weeks later and a third infusion 6 months after that, so that patients are treated approximately every 6 months. This is in contrast to some other targeted therapies, where failing to address the underlying factors driving immunopathogenesis necessitates more regular and frequent medication administration.
New, Novel, Exciting
Commenting on the research, Neelam Goyal, MD, who chaired the session, said, “It’s definitely new, novel, interesting, exciting.”
Goyal, clinical professor of neurology and neurological sciences at Stanford University School of Medicine in Palo Alto, California, also noted that while B-cell depletion has shown some previous success in MG, it was with rituximab, a CD20 B-cell depleting agent.
She noted that unlike rituximab, which targets CD20, inebilizumab targets CD19, although both medications lead to B-cell depletion. Rituximab has proven effective for MUSK–positive MG, which accounts for approximately 5% of cases.
However, Goyal noted that the results for AChR–positive MG have been mixed — “the BeatMG trial was negative and the RINOMAX trial was positive. So, I think this is really interesting. It is exciting, and this drug is already on the market.”
She added that although inebilizumab is already US Food and Drug Administration–approved for the treatment of neuromyelitis optica, it still faces approval and indication hurdles for MG.
The future of this drug in the management algorithm for MG remains uncertain. Goyal noted that it’s “quite costly,” and although its benefits are evident — particularly for FcRn and complement inhibitors — some early data from chimeric antigen receptor T-cell therapy studies appear significantly more impressive.
Nowak disclosed research support from the National Institutes of Health, Genentech, Alexion Pharmaceuticals, argenx, Annexon Biosciences, Ra Pharmaceuticals (now UCB S.A.), the Myasthenia Gravis Foundation of America, Momenta Pharmaceuticals (now Janssen), Immunovant, Grifols, S.A., and Viela Bio, Horizon Therapeutics (now Amgen). Served as a consultant and advisor for Alexion Pharmaceuticals, argenx, Cabaletta Bio, Cour Pharmaceuticals, Ra Pharmaceuticals (now UCB S.A.), Immunovant, Momenta Pharmaceuticals (now Janssen), and Viela Bio (Horizon Therapeutics, now Amgen).
Goyal disclosed consultant, advisory, or grant support from argenx, UCB, Alexion, and Janssen. The study was funded by Amgen.
A version of this article appeared on Medscape.com.
FROM AANEM 2024
Antidepressants Linked to Improved Verbal Memory
MILAN — , a clinical effect linked to changes in serotonin 4 (5-HT4) receptor levels in the brain, as shown on PET.
These findings suggested there is a role for specifically targeting the 5-HT4 receptor to improve verbal memory in depression, said investigator Vibeke H. Dam, PhD, from Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
“Verbal memory is often impaired in depression, and this has a lot of impact on patients’ ability to work and have a normal life. That’s why we’re so excited about this receptor in particular,” Dr. Dam said.
“If we can find a way to activate it more directly, we’re thinking this could be a way to treat this memory symptom that a lot of patients have and that currently we don’t really have a treatment for,” she added.
The findings were presented at the 37th European College of Neuropsychopharmacology (ECNP) Congress and recently published in Biological Psychiatry .
Largest Trial of Its Kind
The study is the largest single-site PET trial investigating serotonergic neurotransmission in major depressive disorder over the course of antidepressant treatment to date. It included 90 patients with moderate to severe depression who underwent baseline cognitive tests and brain scans to measure 5-HT4 receptor levels before starting their treatment with the selective serotonin reuptake inhibitor escitalopram.
Patients who showed no improvement in depressive symptoms after 4 weeks (n = 14), as assessed by the Hamilton Depression Rating Scale 6 (HAMD6), were switched to the serotonin-norepinephrine reuptake inhibitor duloxetine.
Both escitalopram and duloxetine inhibit the reuptake of 5-HT4, enhancing neurotransmitter activity; escitalopram primarily increases serotonin levels, while duloxetine increases both serotonin and norepinephrine levels.
The primary cognitive outcome measure was change in the Verbal Affective Memory Task 26. Secondary cognitive outcomes were change in working memory, reaction time, emotion recognition bias, and negative social emotion.
After 8 weeks of treatment, a subset of 40 patients repeated PET scans, and at 12 weeks, all patients repeated cognitive testing.
Matching neuroimaging and cognitive data were available for 88 patients at baseline and for 39 patients with rescan.
As expected, the study showed that antidepressant treatment resulted in the downregulation of 5-HT4 receptor levels. “One hypothesis is that if we increase the availability of serotonin [with treatment], downregulation of the receptors might be a response,” said Dr. Dam.
“What was interesting was that this was the effect across all patients, whether they [clinically] responded or not. So we see the medication does what it’s supposed to do in the brain.” But, she said, there was no association between 5-HT4 receptor levels and HAMD6 scores.
Gains in Verbal Memory
Although the downregulation of 5-HT4 did not correlate with somatic or mood symptoms, it did correlate with cognitive symptoms.
Interestingly, while most patients showed improvement in depressive symptoms — many reaching remission or recovery — they also experienced gains in verbal memory. However, these improvements were not correlated. It was possible for one to improve more than the other, with no apparent link between the two, said Dr. Dam.
“What was linked was how the brain responded to the medication for this particular receptor. So even though there is this downregulation of the receptor, there’s still a lot of activation of it, and our thinking is that it’s activation of the receptor that is the important bit.”
Work by other groups has shown that another medication, prucalopride, which is used to treat gastroparesis, can more directly activate the 5-HT4 receptor, and that the treatment of healthy volunteers with this medication can boost memory and learning, said Dr. Dam.
“We could repurpose this drug, and we’re currently looking for funding to test this in a wide variety of different groups such as concussion, diabetes, and depression.”
The study’s coinvestigator, Vibe G. Frokjaer, MD, said more research is required to understand the potential implications of the findings.
“Poor cognitive function is very hard to treat efficiently and may require extra treatment. This work points to the possibility of stimulating this specific receptor so that we can treat cognitive problems, even aside from whether or not the patient has overcome the core symptoms of depression,” she said in a release.
Commenting on the research, Philip Cowen, MD, professor of psychopharmacology at the University of Oxford, England, said in a release that in light of “recent controversies about the role of brain serotonin in clinical depression, it is noteworthy that the PET studies of the Copenhagen Group provide unequivocal evidence that brain 5-HT4 receptors are decreased in unmedicated depressed patients.
“Their work also demonstrates the intimate role of brain 5-HT4 receptors in cognitive function,” he added. “This confirms recent work from Oxford, showing that the 5-HT4 receptor stimulant, prucalopride — a drug licensed for the treatment of constipation — improves memory in both healthy participants and people at risk of depression,” he added.
The study was funded by the Innovation Fund Denmark, Research Fund of the Mental Health Services – Capital Region of Denmark, Independent Research Fund Denmark, Global Justice Foundation, Research Council of Rigshospitalet, Augustinus Foundation, Savværksejer Jeppe Juhl og hustru Ovita Juhls Mindelegat, Lundbeck Foundation, and H. Lundbeck A/S.
Dr. Dam reported serving as a speaker for H. Lundbeck. Frokjaer reported serving as a consultant for Sage Therapeutics and lecturer for H. Lundbeck, Janssen-Cilag, and Gedeon Richter. Study investigator Martin B. Jørgensen has given talks sponsored by Boehringer Ingelheim and Lundbeck Pharma. All other investigators reported no relevant disclosures.
A version of this article appeared on Medscape.com.
MILAN — , a clinical effect linked to changes in serotonin 4 (5-HT4) receptor levels in the brain, as shown on PET.
These findings suggested there is a role for specifically targeting the 5-HT4 receptor to improve verbal memory in depression, said investigator Vibeke H. Dam, PhD, from Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
“Verbal memory is often impaired in depression, and this has a lot of impact on patients’ ability to work and have a normal life. That’s why we’re so excited about this receptor in particular,” Dr. Dam said.
“If we can find a way to activate it more directly, we’re thinking this could be a way to treat this memory symptom that a lot of patients have and that currently we don’t really have a treatment for,” she added.
The findings were presented at the 37th European College of Neuropsychopharmacology (ECNP) Congress and recently published in Biological Psychiatry .
Largest Trial of Its Kind
The study is the largest single-site PET trial investigating serotonergic neurotransmission in major depressive disorder over the course of antidepressant treatment to date. It included 90 patients with moderate to severe depression who underwent baseline cognitive tests and brain scans to measure 5-HT4 receptor levels before starting their treatment with the selective serotonin reuptake inhibitor escitalopram.
Patients who showed no improvement in depressive symptoms after 4 weeks (n = 14), as assessed by the Hamilton Depression Rating Scale 6 (HAMD6), were switched to the serotonin-norepinephrine reuptake inhibitor duloxetine.
Both escitalopram and duloxetine inhibit the reuptake of 5-HT4, enhancing neurotransmitter activity; escitalopram primarily increases serotonin levels, while duloxetine increases both serotonin and norepinephrine levels.
The primary cognitive outcome measure was change in the Verbal Affective Memory Task 26. Secondary cognitive outcomes were change in working memory, reaction time, emotion recognition bias, and negative social emotion.
After 8 weeks of treatment, a subset of 40 patients repeated PET scans, and at 12 weeks, all patients repeated cognitive testing.
Matching neuroimaging and cognitive data were available for 88 patients at baseline and for 39 patients with rescan.
As expected, the study showed that antidepressant treatment resulted in the downregulation of 5-HT4 receptor levels. “One hypothesis is that if we increase the availability of serotonin [with treatment], downregulation of the receptors might be a response,” said Dr. Dam.
“What was interesting was that this was the effect across all patients, whether they [clinically] responded or not. So we see the medication does what it’s supposed to do in the brain.” But, she said, there was no association between 5-HT4 receptor levels and HAMD6 scores.
Gains in Verbal Memory
Although the downregulation of 5-HT4 did not correlate with somatic or mood symptoms, it did correlate with cognitive symptoms.
Interestingly, while most patients showed improvement in depressive symptoms — many reaching remission or recovery — they also experienced gains in verbal memory. However, these improvements were not correlated. It was possible for one to improve more than the other, with no apparent link between the two, said Dr. Dam.
“What was linked was how the brain responded to the medication for this particular receptor. So even though there is this downregulation of the receptor, there’s still a lot of activation of it, and our thinking is that it’s activation of the receptor that is the important bit.”
Work by other groups has shown that another medication, prucalopride, which is used to treat gastroparesis, can more directly activate the 5-HT4 receptor, and that the treatment of healthy volunteers with this medication can boost memory and learning, said Dr. Dam.
“We could repurpose this drug, and we’re currently looking for funding to test this in a wide variety of different groups such as concussion, diabetes, and depression.”
The study’s coinvestigator, Vibe G. Frokjaer, MD, said more research is required to understand the potential implications of the findings.
“Poor cognitive function is very hard to treat efficiently and may require extra treatment. This work points to the possibility of stimulating this specific receptor so that we can treat cognitive problems, even aside from whether or not the patient has overcome the core symptoms of depression,” she said in a release.
Commenting on the research, Philip Cowen, MD, professor of psychopharmacology at the University of Oxford, England, said in a release that in light of “recent controversies about the role of brain serotonin in clinical depression, it is noteworthy that the PET studies of the Copenhagen Group provide unequivocal evidence that brain 5-HT4 receptors are decreased in unmedicated depressed patients.
“Their work also demonstrates the intimate role of brain 5-HT4 receptors in cognitive function,” he added. “This confirms recent work from Oxford, showing that the 5-HT4 receptor stimulant, prucalopride — a drug licensed for the treatment of constipation — improves memory in both healthy participants and people at risk of depression,” he added.
The study was funded by the Innovation Fund Denmark, Research Fund of the Mental Health Services – Capital Region of Denmark, Independent Research Fund Denmark, Global Justice Foundation, Research Council of Rigshospitalet, Augustinus Foundation, Savværksejer Jeppe Juhl og hustru Ovita Juhls Mindelegat, Lundbeck Foundation, and H. Lundbeck A/S.
Dr. Dam reported serving as a speaker for H. Lundbeck. Frokjaer reported serving as a consultant for Sage Therapeutics and lecturer for H. Lundbeck, Janssen-Cilag, and Gedeon Richter. Study investigator Martin B. Jørgensen has given talks sponsored by Boehringer Ingelheim and Lundbeck Pharma. All other investigators reported no relevant disclosures.
A version of this article appeared on Medscape.com.
MILAN — , a clinical effect linked to changes in serotonin 4 (5-HT4) receptor levels in the brain, as shown on PET.
These findings suggested there is a role for specifically targeting the 5-HT4 receptor to improve verbal memory in depression, said investigator Vibeke H. Dam, PhD, from Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
“Verbal memory is often impaired in depression, and this has a lot of impact on patients’ ability to work and have a normal life. That’s why we’re so excited about this receptor in particular,” Dr. Dam said.
“If we can find a way to activate it more directly, we’re thinking this could be a way to treat this memory symptom that a lot of patients have and that currently we don’t really have a treatment for,” she added.
The findings were presented at the 37th European College of Neuropsychopharmacology (ECNP) Congress and recently published in Biological Psychiatry .
Largest Trial of Its Kind
The study is the largest single-site PET trial investigating serotonergic neurotransmission in major depressive disorder over the course of antidepressant treatment to date. It included 90 patients with moderate to severe depression who underwent baseline cognitive tests and brain scans to measure 5-HT4 receptor levels before starting their treatment with the selective serotonin reuptake inhibitor escitalopram.
Patients who showed no improvement in depressive symptoms after 4 weeks (n = 14), as assessed by the Hamilton Depression Rating Scale 6 (HAMD6), were switched to the serotonin-norepinephrine reuptake inhibitor duloxetine.
Both escitalopram and duloxetine inhibit the reuptake of 5-HT4, enhancing neurotransmitter activity; escitalopram primarily increases serotonin levels, while duloxetine increases both serotonin and norepinephrine levels.
The primary cognitive outcome measure was change in the Verbal Affective Memory Task 26. Secondary cognitive outcomes were change in working memory, reaction time, emotion recognition bias, and negative social emotion.
After 8 weeks of treatment, a subset of 40 patients repeated PET scans, and at 12 weeks, all patients repeated cognitive testing.
Matching neuroimaging and cognitive data were available for 88 patients at baseline and for 39 patients with rescan.
As expected, the study showed that antidepressant treatment resulted in the downregulation of 5-HT4 receptor levels. “One hypothesis is that if we increase the availability of serotonin [with treatment], downregulation of the receptors might be a response,” said Dr. Dam.
“What was interesting was that this was the effect across all patients, whether they [clinically] responded or not. So we see the medication does what it’s supposed to do in the brain.” But, she said, there was no association between 5-HT4 receptor levels and HAMD6 scores.
Gains in Verbal Memory
Although the downregulation of 5-HT4 did not correlate with somatic or mood symptoms, it did correlate with cognitive symptoms.
Interestingly, while most patients showed improvement in depressive symptoms — many reaching remission or recovery — they also experienced gains in verbal memory. However, these improvements were not correlated. It was possible for one to improve more than the other, with no apparent link between the two, said Dr. Dam.
“What was linked was how the brain responded to the medication for this particular receptor. So even though there is this downregulation of the receptor, there’s still a lot of activation of it, and our thinking is that it’s activation of the receptor that is the important bit.”
Work by other groups has shown that another medication, prucalopride, which is used to treat gastroparesis, can more directly activate the 5-HT4 receptor, and that the treatment of healthy volunteers with this medication can boost memory and learning, said Dr. Dam.
“We could repurpose this drug, and we’re currently looking for funding to test this in a wide variety of different groups such as concussion, diabetes, and depression.”
The study’s coinvestigator, Vibe G. Frokjaer, MD, said more research is required to understand the potential implications of the findings.
“Poor cognitive function is very hard to treat efficiently and may require extra treatment. This work points to the possibility of stimulating this specific receptor so that we can treat cognitive problems, even aside from whether or not the patient has overcome the core symptoms of depression,” she said in a release.
Commenting on the research, Philip Cowen, MD, professor of psychopharmacology at the University of Oxford, England, said in a release that in light of “recent controversies about the role of brain serotonin in clinical depression, it is noteworthy that the PET studies of the Copenhagen Group provide unequivocal evidence that brain 5-HT4 receptors are decreased in unmedicated depressed patients.
“Their work also demonstrates the intimate role of brain 5-HT4 receptors in cognitive function,” he added. “This confirms recent work from Oxford, showing that the 5-HT4 receptor stimulant, prucalopride — a drug licensed for the treatment of constipation — improves memory in both healthy participants and people at risk of depression,” he added.
The study was funded by the Innovation Fund Denmark, Research Fund of the Mental Health Services – Capital Region of Denmark, Independent Research Fund Denmark, Global Justice Foundation, Research Council of Rigshospitalet, Augustinus Foundation, Savværksejer Jeppe Juhl og hustru Ovita Juhls Mindelegat, Lundbeck Foundation, and H. Lundbeck A/S.
Dr. Dam reported serving as a speaker for H. Lundbeck. Frokjaer reported serving as a consultant for Sage Therapeutics and lecturer for H. Lundbeck, Janssen-Cilag, and Gedeon Richter. Study investigator Martin B. Jørgensen has given talks sponsored by Boehringer Ingelheim and Lundbeck Pharma. All other investigators reported no relevant disclosures.
A version of this article appeared on Medscape.com.
FROM ECNP 2024
Heightened Amygdala Activity Tied to Postpartum Depression
MILAN, ITALY — Pregnant women with heightened amygdala activity have a reduced capacity to regulate emotions and report more symptoms of depression than those with lower activity in this brain region, a new imaging study suggested.
If validated, these findings could pave the way for identifying women at higher risk for postpartum depression, said lead researcher Franziska Weinmar, MSc, from the University of Tübingen in Germany.
The study was presented at the 37th European College of Neuropsychopharmacology Congress.
Differences in Brain Activity
During pregnancy and the peripartum period, rising hormone levels create a “psychoneuroendocrinological window of vulnerability” for mental health in which 80% of women can develop transitory “baby blues,” and about one in seven develop more serious postpartum depression, Ms. Weinmar told this news organization.
The study included 47 women — 15 pregnant women and 32 nonpregnant controls. The nonpregnant women had normal menstrual cycles; 16 were in the early follicular phase with low estradiol levels (231.7 pmol/L), and 16 had high estradiol levels (516.6 pmol/L) after administration of estradiol.
To examine brain activity, participants were asked to view negative emotional images while undergoing functional MRI. They were then asked to use cognitive reappraisal to regulate their emotional response to the images.
The findings showed that both pregnant and nonpregnant women were equally successful at emotional regulation, but this process involved different brain activity in pregnant vs their nonpregnant counterpart.
All women had increased left middle frontal gyrus activity when regulating their emotions, but there was a difference in the amygdala between the pregnancy group and controls, Ms. Weinmar noted.
This suggests that pregnant women may have to exert more neural effort in emotional regulation, she said. “And pregnant women with higher amygdala activity were less able to regulate their emotions successfully compared to those with less amygdala activity.”
Linear regression analyses were performed to assess the relation of brain activity during down-regulation, regulation success, and self-reported depression scores, and this showed that higher amygdala activity was also associated with higher depression scores.
“We need to be cautious in interpreting this,” said Ms. Weinmar. “This is a small sample, and we are the first to undertake this work.”
Nonetheless, she said that if the findings are confirmed by larger studies, pregnant women could be assessed “in the waiting room” using existing questionnaires that evaluate emotional regulation.
If a woman has difficulties with emotion regulation, “there are adaptive strategies, like cognitive reappraisal that a counseling psychotherapist can help with,” said Ms. Weinmar.
“I could also imagine group sessions, for example, or online courses,” she said, adding that obstetricians could also be trained to identify these women.
Commenting on the findings in a press release, Susana Carmona, PhD, from Gregorio Marañón Hospital in Madrid, Spain, said research like this is crucial for gaining insight into one of the most intense physiological processes a human can undergo: pregnancy. It’s remarkable how much remains unknown.
“Recently, the FDA [Food and Drug Administration] approved the first treatment for postpartum depression. However, we still have a long way to go in characterizing what happens in the brain during pregnancy, identifying biomarkers that can indicate the risk of developing perinatal mental disorders, and designing strategies to prevent mother and infant suffering during the delicate and critical peripartum period,” Dr. Carmona added.
The study was supported by the Center for Integrative Neuroscience in Tübingen, Germany, and the International Research Training Group “Women’s Mental Health Across the Reproductive Years” (IRTG 2804). Ms. Weinmar and Dr. Carmona reported no relevant disclosures.
A version of this article appeared on Medscape.com.
MILAN, ITALY — Pregnant women with heightened amygdala activity have a reduced capacity to regulate emotions and report more symptoms of depression than those with lower activity in this brain region, a new imaging study suggested.
If validated, these findings could pave the way for identifying women at higher risk for postpartum depression, said lead researcher Franziska Weinmar, MSc, from the University of Tübingen in Germany.
The study was presented at the 37th European College of Neuropsychopharmacology Congress.
Differences in Brain Activity
During pregnancy and the peripartum period, rising hormone levels create a “psychoneuroendocrinological window of vulnerability” for mental health in which 80% of women can develop transitory “baby blues,” and about one in seven develop more serious postpartum depression, Ms. Weinmar told this news organization.
The study included 47 women — 15 pregnant women and 32 nonpregnant controls. The nonpregnant women had normal menstrual cycles; 16 were in the early follicular phase with low estradiol levels (231.7 pmol/L), and 16 had high estradiol levels (516.6 pmol/L) after administration of estradiol.
To examine brain activity, participants were asked to view negative emotional images while undergoing functional MRI. They were then asked to use cognitive reappraisal to regulate their emotional response to the images.
The findings showed that both pregnant and nonpregnant women were equally successful at emotional regulation, but this process involved different brain activity in pregnant vs their nonpregnant counterpart.
All women had increased left middle frontal gyrus activity when regulating their emotions, but there was a difference in the amygdala between the pregnancy group and controls, Ms. Weinmar noted.
This suggests that pregnant women may have to exert more neural effort in emotional regulation, she said. “And pregnant women with higher amygdala activity were less able to regulate their emotions successfully compared to those with less amygdala activity.”
Linear regression analyses were performed to assess the relation of brain activity during down-regulation, regulation success, and self-reported depression scores, and this showed that higher amygdala activity was also associated with higher depression scores.
“We need to be cautious in interpreting this,” said Ms. Weinmar. “This is a small sample, and we are the first to undertake this work.”
Nonetheless, she said that if the findings are confirmed by larger studies, pregnant women could be assessed “in the waiting room” using existing questionnaires that evaluate emotional regulation.
If a woman has difficulties with emotion regulation, “there are adaptive strategies, like cognitive reappraisal that a counseling psychotherapist can help with,” said Ms. Weinmar.
“I could also imagine group sessions, for example, or online courses,” she said, adding that obstetricians could also be trained to identify these women.
Commenting on the findings in a press release, Susana Carmona, PhD, from Gregorio Marañón Hospital in Madrid, Spain, said research like this is crucial for gaining insight into one of the most intense physiological processes a human can undergo: pregnancy. It’s remarkable how much remains unknown.
“Recently, the FDA [Food and Drug Administration] approved the first treatment for postpartum depression. However, we still have a long way to go in characterizing what happens in the brain during pregnancy, identifying biomarkers that can indicate the risk of developing perinatal mental disorders, and designing strategies to prevent mother and infant suffering during the delicate and critical peripartum period,” Dr. Carmona added.
The study was supported by the Center for Integrative Neuroscience in Tübingen, Germany, and the International Research Training Group “Women’s Mental Health Across the Reproductive Years” (IRTG 2804). Ms. Weinmar and Dr. Carmona reported no relevant disclosures.
A version of this article appeared on Medscape.com.
MILAN, ITALY — Pregnant women with heightened amygdala activity have a reduced capacity to regulate emotions and report more symptoms of depression than those with lower activity in this brain region, a new imaging study suggested.
If validated, these findings could pave the way for identifying women at higher risk for postpartum depression, said lead researcher Franziska Weinmar, MSc, from the University of Tübingen in Germany.
The study was presented at the 37th European College of Neuropsychopharmacology Congress.
Differences in Brain Activity
During pregnancy and the peripartum period, rising hormone levels create a “psychoneuroendocrinological window of vulnerability” for mental health in which 80% of women can develop transitory “baby blues,” and about one in seven develop more serious postpartum depression, Ms. Weinmar told this news organization.
The study included 47 women — 15 pregnant women and 32 nonpregnant controls. The nonpregnant women had normal menstrual cycles; 16 were in the early follicular phase with low estradiol levels (231.7 pmol/L), and 16 had high estradiol levels (516.6 pmol/L) after administration of estradiol.
To examine brain activity, participants were asked to view negative emotional images while undergoing functional MRI. They were then asked to use cognitive reappraisal to regulate their emotional response to the images.
The findings showed that both pregnant and nonpregnant women were equally successful at emotional regulation, but this process involved different brain activity in pregnant vs their nonpregnant counterpart.
All women had increased left middle frontal gyrus activity when regulating their emotions, but there was a difference in the amygdala between the pregnancy group and controls, Ms. Weinmar noted.
This suggests that pregnant women may have to exert more neural effort in emotional regulation, she said. “And pregnant women with higher amygdala activity were less able to regulate their emotions successfully compared to those with less amygdala activity.”
Linear regression analyses were performed to assess the relation of brain activity during down-regulation, regulation success, and self-reported depression scores, and this showed that higher amygdala activity was also associated with higher depression scores.
“We need to be cautious in interpreting this,” said Ms. Weinmar. “This is a small sample, and we are the first to undertake this work.”
Nonetheless, she said that if the findings are confirmed by larger studies, pregnant women could be assessed “in the waiting room” using existing questionnaires that evaluate emotional regulation.
If a woman has difficulties with emotion regulation, “there are adaptive strategies, like cognitive reappraisal that a counseling psychotherapist can help with,” said Ms. Weinmar.
“I could also imagine group sessions, for example, or online courses,” she said, adding that obstetricians could also be trained to identify these women.
Commenting on the findings in a press release, Susana Carmona, PhD, from Gregorio Marañón Hospital in Madrid, Spain, said research like this is crucial for gaining insight into one of the most intense physiological processes a human can undergo: pregnancy. It’s remarkable how much remains unknown.
“Recently, the FDA [Food and Drug Administration] approved the first treatment for postpartum depression. However, we still have a long way to go in characterizing what happens in the brain during pregnancy, identifying biomarkers that can indicate the risk of developing perinatal mental disorders, and designing strategies to prevent mother and infant suffering during the delicate and critical peripartum period,” Dr. Carmona added.
The study was supported by the Center for Integrative Neuroscience in Tübingen, Germany, and the International Research Training Group “Women’s Mental Health Across the Reproductive Years” (IRTG 2804). Ms. Weinmar and Dr. Carmona reported no relevant disclosures.
A version of this article appeared on Medscape.com.
FROM ECNP 2024
Neuromyelitis Optica: Historically Misdiagnosed — Now Demands Prompt Treatment
Urgency of treatment is something that many physicians may not fully appreciate when it comes to neuromyelitis optica (NMO), according to experts on this rare autoimmune demyelinating disorder. This may be partly due to its similar presentation to multiple sclerosis (MS), said Michael Levy, MD, PhD, associate professor, Harvard Medical School, research director, Division of Neuroimmunology & Neuroinfectious Disease, and director, Neuroimmunology Clinic and Research Laboratory, at Massachusetts General Hospital in Boston. But while the two conditions share many clinical characteristics, “immunologically, they are about as different as can be,” he warned.
The urgency of distinction is important because where MS is known to have a relatively gradual progression, NMO is now red-flagged to potentially cause rapid and irreversible damage. While the course of MS might be described as a slow burn, NMO should be treated like a wildfire.
“That message has gotten muddled, particularly because acute treatment in MS has never been shown to affect outcome,” said Jeffrey Bennett, MD, PhD, professor of neurology and ophthalmology at the University of Colorado School of Medicine, Aurora. In contrast, rapid diagnosis and treatment of NMO “means potentially preventing future devastating neurologic injury,” he said.
First described by Dr. Eugène Devic in 1894, and sometimes known as Devic’s disease, NMO is believed to have a prevalence that varies widely depending on ethnicity and gender. A recent report suggests a prevalence of approximately1/100,000 population among Whites with an annual incidence of less than 1/million in this population, while the prevalence is higher among East Asians (approximately 3.5/100,000), and may reach as high as 10/100,000 in Blacks.1 It has a high female-to-male ratio (up to 9:1) with a mean age of onset of about 40 years, although pediatric cases are described.
It has long been recognized that NMO lacks the “neurocerebritis” of MS, with inflammation predominant in the optic and spinal nerves, but it was not until 2004 that researchers at the Mayo Clinic identified serum aquaporin-4 immunoglobulin G antibodies (AQP4-IgG) that could reliably distinguish NMO from MS. In 2015, the international consensus diagnostic criteria for neuromyelitis optica2 cited core clinical characteristics required for patients with AQP4-IgG-positive NMO spectrum disorder (NMOSD) “including clinical syndromes or MRI findings related to optic nerve, spinal cord, area postrema, other brainstem, diencephalic, or cerebral presentations.” Rarely, NMO patients can be seronegative for AQP4-IgG, but are still considered to have NMOSD for which non-opticospinal clinical and MRI characteristics findings are described. MS patients testing negative for AQP4-IgG should also be tested for the related myelin oligodendrocyte glycoprotein antibody disease (MOGAD), which has a prevalence about four to five times greater than NMO, Dr. Bennett said.
Testing
Because both NMO and MOGAD can be identified by antibodies, they are less commonly misdiagnosed as MS compared to previously. But, prior to the identification of the AQP4-IgG antibody in 2004, the misdiagnosis rate of NMO was probably about 95% said Dr. Levy.
“Of course, before we had the antibody test or clinical criteria, we couldn’t confirm a diagnosis of NMO, so basically everyone had a diagnosis of MS, and after the antibody test became commercially available in 2005/2006, we could confirm the diagnosis, with our study in 2012 showing a much lower misdiagnosis rate of 30%.”3 More recently, the misdiagnosis rates are even lower, he added. A recent study out of Argentina found a rate of only 12%.4
The specificity and sensitivity of cell binding assay serum AQP4-IgG testing is roughly 99% and 90%, respectively, better than ELIZA testing (which has a sensitivity in the 60-65% range), said Dr. Bennett. “That’s why we highly emphasize to physicians, that if you have a suspicion for NMOSD you go to a cell binding assay, and make sure that where you’re sending the serum, the lab can do that procedure.” Still, because of the risk of false positives, he urges restraint in testing for the disorder in the absence of a high suspicion for it. “If you test a lot of people indiscriminately for a rare disorder, you get a lot of false positives because the actual true positives are a very small fraction of that group. So, even with a specificity of around 99% that means 1% of the people you test are falsely positive. And if you’re testing a group of people indiscriminately, then your true positives are less than 1% by far, so then most of the people that you pick up are not truly with disease.”
Acute Treatment
While misdiagnosis of NMO as MS is less common than previously, it is still a concern, not only because of the irreversible risks associated with delayed acute treatment, but also the risks of inappropriate preventive MS therapy, which could be harmful to patients with NMO.
Acute flare-ups of NMO and MOGAD are currently all treated with the same decades-old mainstays for acute MS — intravenous steroids and plasma exchange — but the approach is more aggressive. Retrospective studies have shown that, for NMO, plasma exchange has shown an increased likelihood of improvement versus steroids alone, said Dr. Bennett, but since time is of the essence, treatment should begin before a definitive diagnosis is confirmed.
“What’s limiting our patients is, number one, recognizing NMOSD when the attack is happening in your face. You’ve got to know, hey, this is NMOSD or I’m suspicious of NMOSD and hence, I need to treat it urgently because the outcome has a high probability of not being good. You’ve got to realize that this is NMOSD before the test comes back, because by the time it comes back positive in several days, you’re probably missing the optimal window to treat. The point is to know that the presentation in front of you, the MRI pictures in front of you, the laboratory tests that you might have done in terms of spinal fluid analysis, all highly suggest NMOSD. And so hence, I’m going to take the chance that I might be wrong, but I’m going to treat as if it is and wait for the test to come back.”
Realistically, the risks associated with this approach are minor compared with the potential benefit, Dr. Bennett said. “For plasma exchange, there’s the placement of the central line, and the complications that could happen from that. Plasma exchange can lead to metabolic ionic changes in the blood, fluid shifts that might have to be watched in the hospital setting.”
While waiting for diagnostic results, one clue that may emerge from acute treatment is recovery time. “The recovery from MOGAD attacks is really distinct,” said Dr. Levy. “They get better a lot faster. So, if they’re blind in the hospital, and 3 months later they can see again with treatment, that’s MOGAD.” On the other hand, comorbidities such as lupus strongly favor NMO, he added. And another underrecognized, unique symptom of NMO is that about 10% of people may present with protracted episodes of nausea, vomiting, or hiccups, added Dr. Bennett. “What’s important is not that the neurologist recognize this per se in the emergency department, because they’re not going to be called for that patient — the GI doctors will be called for that patient. But when you’re seeing a patient who may have another presentation: a spinal cord attack, a vision attack with optic neuritis, and you ask them simply ‘have you ever had an episode of protracted nausea, vomiting, or hiccups?’ — I can’t tell you how many times I can have someone say ‘that’s weird I was just in the ED 3 months ago for that.’ And then, I know exactly what’s going on.”
Prevention of Relapse
Treatment of NMO presents some particular challenges for clinicians because the old treatment, rituximab, an anti-CD20 monoclonal antibody which has been used since 2005, has been so affordable and successful. “It’s hard to get people off,” said Dr. Levy. “It’s still the most commonly used drug for NMO in the US, even though it’s not approved. It’s cheap enough, and so people get started on that as a treatment, and then they just continue it, even as an outpatient.”
But since 2019, four new FDA-approved therapies have entered the scene with even better efficacy: the anti-CD-19 targeted medication inebilizumab (Uplizna, Viela Bio, approved in 2020), which requires two 90-minute infusions per year; the interleukin-6 (IL-6) receptor inhibitor satralizumab (Enspryng, Roche, approved in 2020), which is administered subcutaneously once monthly; and the anti-complement C5 inhibitors eculizumab (Soliris, Alexion Pharmaceuticals, approved in 2019), and ravulizumab (Ultomiris, Alexion Pharmaceuticals, approved in 2024), which require infusions every 2 weeks or every 2 months, respectively.
Both experts point to compelling clinical evidence to prescribe the Food and Drug Administration–approved drugs for newly diagnosed NMO, and to switch existing patients from rituximab to the new drugs. “The data is pretty clear that there’s about a 35% failure rate with rituximab, as opposed to less than 5% with the new drugs,” explained Dr. Levy. But ironically, where insurance companies used to balk at covering rituximab because it was not FDA approved for NMO, they are now balking at the FDA-approved options because of the cost. “Even in an academic center, where we get a discount on the drugs, the biosimilar generic of rituximab costs about $890 per dose,” he said. “So overall, it’s less than $4,000 a year for rituximab. Compare that with the most expensive FDA-approved option, which is eculizumab. That’s $715,000 per year. And then the other three drugs are below that, but none are less than about $290,000 a year.”
Patients are also hesitant to switch from rituximab if they’ve been well-controlled on it. “There’s a process to it, and I always talk my patients through it, but I would say less than half make the switch,” said Dr. Levy. “Most people want to stay. It’s a whole different schedule, and mixing two drugs. Are you going to overlap and overly immune suppress? Is the insurance going to approve it? It becomes more complicated.”
“Insurance companies are sometimes inappropriately pushing physicians, asking for patients to fail rituximab before they’ll approve an FDA-approved drug, which is like playing doctor when they’re not a licensed physician,” added Dr. Bennett. “And I think that is absolutely inappropriate, especially in light of the fact that before there were approved drugs, insurance companies used to deny rituximab because it was ‘experimental’ and ‘too expensive’ — and now it’s a cheaper alternative.”
Requiring failure on rituximab is also unethical, given the potential for irreversible damage, Dr. Levy pointed out. “With NMO we don’t tolerate a failure. That’s also how the trials of the new drugs were done. It was considered unethical to have an outcome of annualized relapse rate, like we used to in MS, where we say, OK if you have two attacks a year, then the drug has failed. With NMO, one failure, one breakthrough, and that drug is worthless. We switch.”
A Wealth of Treatment Choices
Patients opting for an FDA-approved treatment now have a “wildly effective” array of new drugs, said Dr. Levy, but choosing can be difficult when each has its own set of advantages and disadvantages. “I have equal numbers of patients on all the drugs, and I show all the data to my patients: efficacy, safety, logistics, cost, and then I ask ‘What are your priorities? Which of these things that I say really rings with you? Is it the infusion schedule? Is it the efficacy? Is it the safety concern? Is it the cost? What are you most concerned about?’ And then we start to have the conversation that way. It’s a shared decision-making process.”
There is definitely an art to finding the best fit for each patient, agreed Dr. Bennett, “both with the urgency of controlling the disease, the particular patient in front of you, their ability to adhere to certain therapies, their ability to have access to infusions, or to self-inject, or to get transported to an infusion center or have access to home infusion.”
Patient empowerment in the decision is very important, added Dr. Levy. “When people make the decision on their own, they’re much more likely to be compliant, rather than me telling them they have to do this. And that’s why I think we haven’t had a single relapse on the new drugs. There have been switches because of intolerance, and cost, and all those issues, but not because of a breakthrough attack.”
Future
Looking ahead in the field, Dr. Bennett sees the biggest potential for improvement is in the management of acute attacks, which he describes as “a major treatment gap.” Although plasma exchange is immediately effective in limiting the amount of circulating pathogenic AQP4-IgG “there are other approaches that could be even more beneficial,” he said. “A promising strategy is to use drugs that act immediately on arms of the immune response that are directly injuring brain tissue. These include serum complement and cells such as neutrophils and natural killer cells that release destructive enzymes and inflammatory mediators,” he explained. “Complement inhibitors, such as the C5 inhibitors eculizumab and ravulizumab, currently approved for NMOSD relapse prevention, act immediately to inhibit complement-mediated tissue injury. Similarly, high doses of antihistamines could be used to rapidly stop the release of the destructive enzyme elastase from neutrophils and natural killer cells, while elastase inhibitors could be given to minimize cell injury. Direct clinical studies are needed to find both the optimal treatment window and regimen.”
References
1. Hor JY et al. Epidemiology of Neuromyelitis Optica Spectrum Disorder and Its Prevalence and Incidence Worldwide. Front Neurol. 2020 Jun 26:11:501. doi: 10.3389/fneur.2020.00501.
2. Wingerchuk DM et al. International Consensus Diagnostic Criteria for Neuromyelitis Optica Spectrum Disorders. Neurology. 2015 Jul 14;85(2):177-89. doi: 10.1212/WNL.0000000000001729.
3. Mealy MA et al. Epidemiology of Neuromyelitis Optica in the United States: A Multicenter Analysis. Arch Neurol. 2012 Sep;69(9):1176-80. doi: 10.1001/archneurol.2012.314.
4. Contentti EC et al. Frequency of NMOSD Misdiagnosis in a Cohort From Latin America: Impact and Evaluation of Different Contributors. Mult Scler. 2023 Feb;29(2):277-286. doi: 10.1177/13524585221136259.
Urgency of treatment is something that many physicians may not fully appreciate when it comes to neuromyelitis optica (NMO), according to experts on this rare autoimmune demyelinating disorder. This may be partly due to its similar presentation to multiple sclerosis (MS), said Michael Levy, MD, PhD, associate professor, Harvard Medical School, research director, Division of Neuroimmunology & Neuroinfectious Disease, and director, Neuroimmunology Clinic and Research Laboratory, at Massachusetts General Hospital in Boston. But while the two conditions share many clinical characteristics, “immunologically, they are about as different as can be,” he warned.
The urgency of distinction is important because where MS is known to have a relatively gradual progression, NMO is now red-flagged to potentially cause rapid and irreversible damage. While the course of MS might be described as a slow burn, NMO should be treated like a wildfire.
“That message has gotten muddled, particularly because acute treatment in MS has never been shown to affect outcome,” said Jeffrey Bennett, MD, PhD, professor of neurology and ophthalmology at the University of Colorado School of Medicine, Aurora. In contrast, rapid diagnosis and treatment of NMO “means potentially preventing future devastating neurologic injury,” he said.
First described by Dr. Eugène Devic in 1894, and sometimes known as Devic’s disease, NMO is believed to have a prevalence that varies widely depending on ethnicity and gender. A recent report suggests a prevalence of approximately1/100,000 population among Whites with an annual incidence of less than 1/million in this population, while the prevalence is higher among East Asians (approximately 3.5/100,000), and may reach as high as 10/100,000 in Blacks.1 It has a high female-to-male ratio (up to 9:1) with a mean age of onset of about 40 years, although pediatric cases are described.
It has long been recognized that NMO lacks the “neurocerebritis” of MS, with inflammation predominant in the optic and spinal nerves, but it was not until 2004 that researchers at the Mayo Clinic identified serum aquaporin-4 immunoglobulin G antibodies (AQP4-IgG) that could reliably distinguish NMO from MS. In 2015, the international consensus diagnostic criteria for neuromyelitis optica2 cited core clinical characteristics required for patients with AQP4-IgG-positive NMO spectrum disorder (NMOSD) “including clinical syndromes or MRI findings related to optic nerve, spinal cord, area postrema, other brainstem, diencephalic, or cerebral presentations.” Rarely, NMO patients can be seronegative for AQP4-IgG, but are still considered to have NMOSD for which non-opticospinal clinical and MRI characteristics findings are described. MS patients testing negative for AQP4-IgG should also be tested for the related myelin oligodendrocyte glycoprotein antibody disease (MOGAD), which has a prevalence about four to five times greater than NMO, Dr. Bennett said.
Testing
Because both NMO and MOGAD can be identified by antibodies, they are less commonly misdiagnosed as MS compared to previously. But, prior to the identification of the AQP4-IgG antibody in 2004, the misdiagnosis rate of NMO was probably about 95% said Dr. Levy.
“Of course, before we had the antibody test or clinical criteria, we couldn’t confirm a diagnosis of NMO, so basically everyone had a diagnosis of MS, and after the antibody test became commercially available in 2005/2006, we could confirm the diagnosis, with our study in 2012 showing a much lower misdiagnosis rate of 30%.”3 More recently, the misdiagnosis rates are even lower, he added. A recent study out of Argentina found a rate of only 12%.4
The specificity and sensitivity of cell binding assay serum AQP4-IgG testing is roughly 99% and 90%, respectively, better than ELIZA testing (which has a sensitivity in the 60-65% range), said Dr. Bennett. “That’s why we highly emphasize to physicians, that if you have a suspicion for NMOSD you go to a cell binding assay, and make sure that where you’re sending the serum, the lab can do that procedure.” Still, because of the risk of false positives, he urges restraint in testing for the disorder in the absence of a high suspicion for it. “If you test a lot of people indiscriminately for a rare disorder, you get a lot of false positives because the actual true positives are a very small fraction of that group. So, even with a specificity of around 99% that means 1% of the people you test are falsely positive. And if you’re testing a group of people indiscriminately, then your true positives are less than 1% by far, so then most of the people that you pick up are not truly with disease.”
Acute Treatment
While misdiagnosis of NMO as MS is less common than previously, it is still a concern, not only because of the irreversible risks associated with delayed acute treatment, but also the risks of inappropriate preventive MS therapy, which could be harmful to patients with NMO.
Acute flare-ups of NMO and MOGAD are currently all treated with the same decades-old mainstays for acute MS — intravenous steroids and plasma exchange — but the approach is more aggressive. Retrospective studies have shown that, for NMO, plasma exchange has shown an increased likelihood of improvement versus steroids alone, said Dr. Bennett, but since time is of the essence, treatment should begin before a definitive diagnosis is confirmed.
“What’s limiting our patients is, number one, recognizing NMOSD when the attack is happening in your face. You’ve got to know, hey, this is NMOSD or I’m suspicious of NMOSD and hence, I need to treat it urgently because the outcome has a high probability of not being good. You’ve got to realize that this is NMOSD before the test comes back, because by the time it comes back positive in several days, you’re probably missing the optimal window to treat. The point is to know that the presentation in front of you, the MRI pictures in front of you, the laboratory tests that you might have done in terms of spinal fluid analysis, all highly suggest NMOSD. And so hence, I’m going to take the chance that I might be wrong, but I’m going to treat as if it is and wait for the test to come back.”
Realistically, the risks associated with this approach are minor compared with the potential benefit, Dr. Bennett said. “For plasma exchange, there’s the placement of the central line, and the complications that could happen from that. Plasma exchange can lead to metabolic ionic changes in the blood, fluid shifts that might have to be watched in the hospital setting.”
While waiting for diagnostic results, one clue that may emerge from acute treatment is recovery time. “The recovery from MOGAD attacks is really distinct,” said Dr. Levy. “They get better a lot faster. So, if they’re blind in the hospital, and 3 months later they can see again with treatment, that’s MOGAD.” On the other hand, comorbidities such as lupus strongly favor NMO, he added. And another underrecognized, unique symptom of NMO is that about 10% of people may present with protracted episodes of nausea, vomiting, or hiccups, added Dr. Bennett. “What’s important is not that the neurologist recognize this per se in the emergency department, because they’re not going to be called for that patient — the GI doctors will be called for that patient. But when you’re seeing a patient who may have another presentation: a spinal cord attack, a vision attack with optic neuritis, and you ask them simply ‘have you ever had an episode of protracted nausea, vomiting, or hiccups?’ — I can’t tell you how many times I can have someone say ‘that’s weird I was just in the ED 3 months ago for that.’ And then, I know exactly what’s going on.”
Prevention of Relapse
Treatment of NMO presents some particular challenges for clinicians because the old treatment, rituximab, an anti-CD20 monoclonal antibody which has been used since 2005, has been so affordable and successful. “It’s hard to get people off,” said Dr. Levy. “It’s still the most commonly used drug for NMO in the US, even though it’s not approved. It’s cheap enough, and so people get started on that as a treatment, and then they just continue it, even as an outpatient.”
But since 2019, four new FDA-approved therapies have entered the scene with even better efficacy: the anti-CD-19 targeted medication inebilizumab (Uplizna, Viela Bio, approved in 2020), which requires two 90-minute infusions per year; the interleukin-6 (IL-6) receptor inhibitor satralizumab (Enspryng, Roche, approved in 2020), which is administered subcutaneously once monthly; and the anti-complement C5 inhibitors eculizumab (Soliris, Alexion Pharmaceuticals, approved in 2019), and ravulizumab (Ultomiris, Alexion Pharmaceuticals, approved in 2024), which require infusions every 2 weeks or every 2 months, respectively.
Both experts point to compelling clinical evidence to prescribe the Food and Drug Administration–approved drugs for newly diagnosed NMO, and to switch existing patients from rituximab to the new drugs. “The data is pretty clear that there’s about a 35% failure rate with rituximab, as opposed to less than 5% with the new drugs,” explained Dr. Levy. But ironically, where insurance companies used to balk at covering rituximab because it was not FDA approved for NMO, they are now balking at the FDA-approved options because of the cost. “Even in an academic center, where we get a discount on the drugs, the biosimilar generic of rituximab costs about $890 per dose,” he said. “So overall, it’s less than $4,000 a year for rituximab. Compare that with the most expensive FDA-approved option, which is eculizumab. That’s $715,000 per year. And then the other three drugs are below that, but none are less than about $290,000 a year.”
Patients are also hesitant to switch from rituximab if they’ve been well-controlled on it. “There’s a process to it, and I always talk my patients through it, but I would say less than half make the switch,” said Dr. Levy. “Most people want to stay. It’s a whole different schedule, and mixing two drugs. Are you going to overlap and overly immune suppress? Is the insurance going to approve it? It becomes more complicated.”
“Insurance companies are sometimes inappropriately pushing physicians, asking for patients to fail rituximab before they’ll approve an FDA-approved drug, which is like playing doctor when they’re not a licensed physician,” added Dr. Bennett. “And I think that is absolutely inappropriate, especially in light of the fact that before there were approved drugs, insurance companies used to deny rituximab because it was ‘experimental’ and ‘too expensive’ — and now it’s a cheaper alternative.”
Requiring failure on rituximab is also unethical, given the potential for irreversible damage, Dr. Levy pointed out. “With NMO we don’t tolerate a failure. That’s also how the trials of the new drugs were done. It was considered unethical to have an outcome of annualized relapse rate, like we used to in MS, where we say, OK if you have two attacks a year, then the drug has failed. With NMO, one failure, one breakthrough, and that drug is worthless. We switch.”
A Wealth of Treatment Choices
Patients opting for an FDA-approved treatment now have a “wildly effective” array of new drugs, said Dr. Levy, but choosing can be difficult when each has its own set of advantages and disadvantages. “I have equal numbers of patients on all the drugs, and I show all the data to my patients: efficacy, safety, logistics, cost, and then I ask ‘What are your priorities? Which of these things that I say really rings with you? Is it the infusion schedule? Is it the efficacy? Is it the safety concern? Is it the cost? What are you most concerned about?’ And then we start to have the conversation that way. It’s a shared decision-making process.”
There is definitely an art to finding the best fit for each patient, agreed Dr. Bennett, “both with the urgency of controlling the disease, the particular patient in front of you, their ability to adhere to certain therapies, their ability to have access to infusions, or to self-inject, or to get transported to an infusion center or have access to home infusion.”
Patient empowerment in the decision is very important, added Dr. Levy. “When people make the decision on their own, they’re much more likely to be compliant, rather than me telling them they have to do this. And that’s why I think we haven’t had a single relapse on the new drugs. There have been switches because of intolerance, and cost, and all those issues, but not because of a breakthrough attack.”
Future
Looking ahead in the field, Dr. Bennett sees the biggest potential for improvement is in the management of acute attacks, which he describes as “a major treatment gap.” Although plasma exchange is immediately effective in limiting the amount of circulating pathogenic AQP4-IgG “there are other approaches that could be even more beneficial,” he said. “A promising strategy is to use drugs that act immediately on arms of the immune response that are directly injuring brain tissue. These include serum complement and cells such as neutrophils and natural killer cells that release destructive enzymes and inflammatory mediators,” he explained. “Complement inhibitors, such as the C5 inhibitors eculizumab and ravulizumab, currently approved for NMOSD relapse prevention, act immediately to inhibit complement-mediated tissue injury. Similarly, high doses of antihistamines could be used to rapidly stop the release of the destructive enzyme elastase from neutrophils and natural killer cells, while elastase inhibitors could be given to minimize cell injury. Direct clinical studies are needed to find both the optimal treatment window and regimen.”
References
1. Hor JY et al. Epidemiology of Neuromyelitis Optica Spectrum Disorder and Its Prevalence and Incidence Worldwide. Front Neurol. 2020 Jun 26:11:501. doi: 10.3389/fneur.2020.00501.
2. Wingerchuk DM et al. International Consensus Diagnostic Criteria for Neuromyelitis Optica Spectrum Disorders. Neurology. 2015 Jul 14;85(2):177-89. doi: 10.1212/WNL.0000000000001729.
3. Mealy MA et al. Epidemiology of Neuromyelitis Optica in the United States: A Multicenter Analysis. Arch Neurol. 2012 Sep;69(9):1176-80. doi: 10.1001/archneurol.2012.314.
4. Contentti EC et al. Frequency of NMOSD Misdiagnosis in a Cohort From Latin America: Impact and Evaluation of Different Contributors. Mult Scler. 2023 Feb;29(2):277-286. doi: 10.1177/13524585221136259.
Urgency of treatment is something that many physicians may not fully appreciate when it comes to neuromyelitis optica (NMO), according to experts on this rare autoimmune demyelinating disorder. This may be partly due to its similar presentation to multiple sclerosis (MS), said Michael Levy, MD, PhD, associate professor, Harvard Medical School, research director, Division of Neuroimmunology & Neuroinfectious Disease, and director, Neuroimmunology Clinic and Research Laboratory, at Massachusetts General Hospital in Boston. But while the two conditions share many clinical characteristics, “immunologically, they are about as different as can be,” he warned.
The urgency of distinction is important because where MS is known to have a relatively gradual progression, NMO is now red-flagged to potentially cause rapid and irreversible damage. While the course of MS might be described as a slow burn, NMO should be treated like a wildfire.
“That message has gotten muddled, particularly because acute treatment in MS has never been shown to affect outcome,” said Jeffrey Bennett, MD, PhD, professor of neurology and ophthalmology at the University of Colorado School of Medicine, Aurora. In contrast, rapid diagnosis and treatment of NMO “means potentially preventing future devastating neurologic injury,” he said.
First described by Dr. Eugène Devic in 1894, and sometimes known as Devic’s disease, NMO is believed to have a prevalence that varies widely depending on ethnicity and gender. A recent report suggests a prevalence of approximately1/100,000 population among Whites with an annual incidence of less than 1/million in this population, while the prevalence is higher among East Asians (approximately 3.5/100,000), and may reach as high as 10/100,000 in Blacks.1 It has a high female-to-male ratio (up to 9:1) with a mean age of onset of about 40 years, although pediatric cases are described.
It has long been recognized that NMO lacks the “neurocerebritis” of MS, with inflammation predominant in the optic and spinal nerves, but it was not until 2004 that researchers at the Mayo Clinic identified serum aquaporin-4 immunoglobulin G antibodies (AQP4-IgG) that could reliably distinguish NMO from MS. In 2015, the international consensus diagnostic criteria for neuromyelitis optica2 cited core clinical characteristics required for patients with AQP4-IgG-positive NMO spectrum disorder (NMOSD) “including clinical syndromes or MRI findings related to optic nerve, spinal cord, area postrema, other brainstem, diencephalic, or cerebral presentations.” Rarely, NMO patients can be seronegative for AQP4-IgG, but are still considered to have NMOSD for which non-opticospinal clinical and MRI characteristics findings are described. MS patients testing negative for AQP4-IgG should also be tested for the related myelin oligodendrocyte glycoprotein antibody disease (MOGAD), which has a prevalence about four to five times greater than NMO, Dr. Bennett said.
Testing
Because both NMO and MOGAD can be identified by antibodies, they are less commonly misdiagnosed as MS compared to previously. But, prior to the identification of the AQP4-IgG antibody in 2004, the misdiagnosis rate of NMO was probably about 95% said Dr. Levy.
“Of course, before we had the antibody test or clinical criteria, we couldn’t confirm a diagnosis of NMO, so basically everyone had a diagnosis of MS, and after the antibody test became commercially available in 2005/2006, we could confirm the diagnosis, with our study in 2012 showing a much lower misdiagnosis rate of 30%.”3 More recently, the misdiagnosis rates are even lower, he added. A recent study out of Argentina found a rate of only 12%.4
The specificity and sensitivity of cell binding assay serum AQP4-IgG testing is roughly 99% and 90%, respectively, better than ELIZA testing (which has a sensitivity in the 60-65% range), said Dr. Bennett. “That’s why we highly emphasize to physicians, that if you have a suspicion for NMOSD you go to a cell binding assay, and make sure that where you’re sending the serum, the lab can do that procedure.” Still, because of the risk of false positives, he urges restraint in testing for the disorder in the absence of a high suspicion for it. “If you test a lot of people indiscriminately for a rare disorder, you get a lot of false positives because the actual true positives are a very small fraction of that group. So, even with a specificity of around 99% that means 1% of the people you test are falsely positive. And if you’re testing a group of people indiscriminately, then your true positives are less than 1% by far, so then most of the people that you pick up are not truly with disease.”
Acute Treatment
While misdiagnosis of NMO as MS is less common than previously, it is still a concern, not only because of the irreversible risks associated with delayed acute treatment, but also the risks of inappropriate preventive MS therapy, which could be harmful to patients with NMO.
Acute flare-ups of NMO and MOGAD are currently all treated with the same decades-old mainstays for acute MS — intravenous steroids and plasma exchange — but the approach is more aggressive. Retrospective studies have shown that, for NMO, plasma exchange has shown an increased likelihood of improvement versus steroids alone, said Dr. Bennett, but since time is of the essence, treatment should begin before a definitive diagnosis is confirmed.
“What’s limiting our patients is, number one, recognizing NMOSD when the attack is happening in your face. You’ve got to know, hey, this is NMOSD or I’m suspicious of NMOSD and hence, I need to treat it urgently because the outcome has a high probability of not being good. You’ve got to realize that this is NMOSD before the test comes back, because by the time it comes back positive in several days, you’re probably missing the optimal window to treat. The point is to know that the presentation in front of you, the MRI pictures in front of you, the laboratory tests that you might have done in terms of spinal fluid analysis, all highly suggest NMOSD. And so hence, I’m going to take the chance that I might be wrong, but I’m going to treat as if it is and wait for the test to come back.”
Realistically, the risks associated with this approach are minor compared with the potential benefit, Dr. Bennett said. “For plasma exchange, there’s the placement of the central line, and the complications that could happen from that. Plasma exchange can lead to metabolic ionic changes in the blood, fluid shifts that might have to be watched in the hospital setting.”
While waiting for diagnostic results, one clue that may emerge from acute treatment is recovery time. “The recovery from MOGAD attacks is really distinct,” said Dr. Levy. “They get better a lot faster. So, if they’re blind in the hospital, and 3 months later they can see again with treatment, that’s MOGAD.” On the other hand, comorbidities such as lupus strongly favor NMO, he added. And another underrecognized, unique symptom of NMO is that about 10% of people may present with protracted episodes of nausea, vomiting, or hiccups, added Dr. Bennett. “What’s important is not that the neurologist recognize this per se in the emergency department, because they’re not going to be called for that patient — the GI doctors will be called for that patient. But when you’re seeing a patient who may have another presentation: a spinal cord attack, a vision attack with optic neuritis, and you ask them simply ‘have you ever had an episode of protracted nausea, vomiting, or hiccups?’ — I can’t tell you how many times I can have someone say ‘that’s weird I was just in the ED 3 months ago for that.’ And then, I know exactly what’s going on.”
Prevention of Relapse
Treatment of NMO presents some particular challenges for clinicians because the old treatment, rituximab, an anti-CD20 monoclonal antibody which has been used since 2005, has been so affordable and successful. “It’s hard to get people off,” said Dr. Levy. “It’s still the most commonly used drug for NMO in the US, even though it’s not approved. It’s cheap enough, and so people get started on that as a treatment, and then they just continue it, even as an outpatient.”
But since 2019, four new FDA-approved therapies have entered the scene with even better efficacy: the anti-CD-19 targeted medication inebilizumab (Uplizna, Viela Bio, approved in 2020), which requires two 90-minute infusions per year; the interleukin-6 (IL-6) receptor inhibitor satralizumab (Enspryng, Roche, approved in 2020), which is administered subcutaneously once monthly; and the anti-complement C5 inhibitors eculizumab (Soliris, Alexion Pharmaceuticals, approved in 2019), and ravulizumab (Ultomiris, Alexion Pharmaceuticals, approved in 2024), which require infusions every 2 weeks or every 2 months, respectively.
Both experts point to compelling clinical evidence to prescribe the Food and Drug Administration–approved drugs for newly diagnosed NMO, and to switch existing patients from rituximab to the new drugs. “The data is pretty clear that there’s about a 35% failure rate with rituximab, as opposed to less than 5% with the new drugs,” explained Dr. Levy. But ironically, where insurance companies used to balk at covering rituximab because it was not FDA approved for NMO, they are now balking at the FDA-approved options because of the cost. “Even in an academic center, where we get a discount on the drugs, the biosimilar generic of rituximab costs about $890 per dose,” he said. “So overall, it’s less than $4,000 a year for rituximab. Compare that with the most expensive FDA-approved option, which is eculizumab. That’s $715,000 per year. And then the other three drugs are below that, but none are less than about $290,000 a year.”
Patients are also hesitant to switch from rituximab if they’ve been well-controlled on it. “There’s a process to it, and I always talk my patients through it, but I would say less than half make the switch,” said Dr. Levy. “Most people want to stay. It’s a whole different schedule, and mixing two drugs. Are you going to overlap and overly immune suppress? Is the insurance going to approve it? It becomes more complicated.”
“Insurance companies are sometimes inappropriately pushing physicians, asking for patients to fail rituximab before they’ll approve an FDA-approved drug, which is like playing doctor when they’re not a licensed physician,” added Dr. Bennett. “And I think that is absolutely inappropriate, especially in light of the fact that before there were approved drugs, insurance companies used to deny rituximab because it was ‘experimental’ and ‘too expensive’ — and now it’s a cheaper alternative.”
Requiring failure on rituximab is also unethical, given the potential for irreversible damage, Dr. Levy pointed out. “With NMO we don’t tolerate a failure. That’s also how the trials of the new drugs were done. It was considered unethical to have an outcome of annualized relapse rate, like we used to in MS, where we say, OK if you have two attacks a year, then the drug has failed. With NMO, one failure, one breakthrough, and that drug is worthless. We switch.”
A Wealth of Treatment Choices
Patients opting for an FDA-approved treatment now have a “wildly effective” array of new drugs, said Dr. Levy, but choosing can be difficult when each has its own set of advantages and disadvantages. “I have equal numbers of patients on all the drugs, and I show all the data to my patients: efficacy, safety, logistics, cost, and then I ask ‘What are your priorities? Which of these things that I say really rings with you? Is it the infusion schedule? Is it the efficacy? Is it the safety concern? Is it the cost? What are you most concerned about?’ And then we start to have the conversation that way. It’s a shared decision-making process.”
There is definitely an art to finding the best fit for each patient, agreed Dr. Bennett, “both with the urgency of controlling the disease, the particular patient in front of you, their ability to adhere to certain therapies, their ability to have access to infusions, or to self-inject, or to get transported to an infusion center or have access to home infusion.”
Patient empowerment in the decision is very important, added Dr. Levy. “When people make the decision on their own, they’re much more likely to be compliant, rather than me telling them they have to do this. And that’s why I think we haven’t had a single relapse on the new drugs. There have been switches because of intolerance, and cost, and all those issues, but not because of a breakthrough attack.”
Future
Looking ahead in the field, Dr. Bennett sees the biggest potential for improvement is in the management of acute attacks, which he describes as “a major treatment gap.” Although plasma exchange is immediately effective in limiting the amount of circulating pathogenic AQP4-IgG “there are other approaches that could be even more beneficial,” he said. “A promising strategy is to use drugs that act immediately on arms of the immune response that are directly injuring brain tissue. These include serum complement and cells such as neutrophils and natural killer cells that release destructive enzymes and inflammatory mediators,” he explained. “Complement inhibitors, such as the C5 inhibitors eculizumab and ravulizumab, currently approved for NMOSD relapse prevention, act immediately to inhibit complement-mediated tissue injury. Similarly, high doses of antihistamines could be used to rapidly stop the release of the destructive enzyme elastase from neutrophils and natural killer cells, while elastase inhibitors could be given to minimize cell injury. Direct clinical studies are needed to find both the optimal treatment window and regimen.”
References
1. Hor JY et al. Epidemiology of Neuromyelitis Optica Spectrum Disorder and Its Prevalence and Incidence Worldwide. Front Neurol. 2020 Jun 26:11:501. doi: 10.3389/fneur.2020.00501.
2. Wingerchuk DM et al. International Consensus Diagnostic Criteria for Neuromyelitis Optica Spectrum Disorders. Neurology. 2015 Jul 14;85(2):177-89. doi: 10.1212/WNL.0000000000001729.
3. Mealy MA et al. Epidemiology of Neuromyelitis Optica in the United States: A Multicenter Analysis. Arch Neurol. 2012 Sep;69(9):1176-80. doi: 10.1001/archneurol.2012.314.
4. Contentti EC et al. Frequency of NMOSD Misdiagnosis in a Cohort From Latin America: Impact and Evaluation of Different Contributors. Mult Scler. 2023 Feb;29(2):277-286. doi: 10.1177/13524585221136259.
Can Hormones Guide Sex-Specific Treatments for Alcohol Use Disorder?
MILAN — Specific combinations of hormonal and biochemical factors were associated with different clinical characteristics and treatment outcomes of alcohol use disorder (AUD) between men and women.
“These hormones and proteins are known to have an influence on behavior, and indeed we see an association between different levels of these compounds and different behavioral aspects of [AUD], although we can’t for sure say that one directly causes another,” said lead researcher Victor M. Karpyak, MD, PhD, professor of psychiatry at the Mayo Clinic, in a release.
The findings were presented at the 37th European College of Neuropsychopharmacology (ECNP) Congress.
Sex Hormone Signatures
Previous research has highlighted differences in symptoms including cravings, withdrawal, consumption patterns, depression, and anxiety between men and women with AUD, said Dr. Karpyak. Differences in hormones and biochemicals have also been observed between individuals with and without AUD.
However, specific biochemical and hormonal “signatures” associated with male and female responses to treatment have thus far not been explored, he told this news organization.
The study included 400 treatment-seeking individuals (132 women and 268 men; mean age, 41.8 years; 93% White) who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for AUD and were enrolled in a clinical trial of acamprosate.
Baseline assessment included psychiatric comorbidities and substance use with the Psychiatric Research Interview for Substance and Mental Disorders, alcohol consumption pattern over the past 90 days by Timeline Follow-Back calendar, recent craving on the Penn Alcohol Craving Scale (PACS), situations at the risk of drinking on the Inventory of Drug-Taking Situation, recent depression severity on the Patient Health Questionnaire 9 (PHQ-9), and recent anxiety severity on the Generalized Anxiety Disorder 7 scale.
Plasma sex-related hormone and protein measurements were taken at baseline — after detoxification but before treatment. These included total testosterone, estradiol, estrone, progesterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), sex hormone–binding globulin (SHBG), and albumin.
“The important thing is that these measurements were taken during sobriety,” said Dr. Karpyak. Study participants were already in residential treatment programs, and the average time since their last drink was approximately 3 weeks. Relapse was defined as any alcohol consumption during the first 3 months.
What Works for Men May Not Work for Women
Results showed that men with symptoms of depression and a higher craving for alcohol, as shown on baseline PHQ-9 and PACS scores, had lower baseline levels of testosterone, estrone, estradiol, and SHBG than those without these symptoms (P = .0102 and P = .0014, respectively).
In addition, a combination of higher progesterone and lower albumin was associated with a lower risk for relapse during the first 3 months (odds ratio [OR], 0.518; P = .0079).
In women, a combination of lower estrone and estradiol and higher FSH and LH levels was associated with higher maximum number of drinks per day (P = .035).
In addition, women who were more likely to relapse during the first 3 months of treatment had higher baseline levels of testosterone, SHBG, and albumin than those at lower relapse risk (OR, 4.536; P = .0057).
Dr. Karpyak noted that these “hormone signatures” were associative and not predictive.
What this means, he said, “is that if you are treating a man and a woman for alcoholism, you are dealing with different biochemical and psychological starting points. This implies that what works for a man may not work for a woman, and vice versa.”
Toward Gender Equity
The findings may eventually lead to a way to predict treatment responses in patients with AUD, Dr. Karpyak added, but cautioned that despite statistical significance, these are preliminary findings.
Before these results can be integrated into clinical practice, they need to be replicated. Dr. Karpyak emphasized the need for follow-up research that builds on these findings, using them as preliminary data to determine whether prediction holds real significance.
“Given that many of these differences are related to sex hormones, we particularly want to see how the dramatic hormonal change women experience during the menstrual cycle and at menopause may affect the biochemistry of alcoholism and guide treatment efforts,” he said.
In a statement, Erika Comasco, PhD, associate professor in molecular psychiatry, Uppsala University, Sweden, said the research “is an important step forward to gender equity in medicine.”
“The findings provide an important first insight into the relationship between sex hormones and alcohol use disorder treatment,” she explained. “While sex differences in the way the disorder manifests itself are known, these results suggest that sex hormones may modulate treatment response, potentially supporting sex-specific pharmacological intervention.”
Dr. Comasco shares Dr. Karpyak’s view that hormonal fluctuations linked to the menstrual cycle may influence alcohol misuse and believes more research is needed to explore their impact on treatment and relapse outcomes in female patients.
This study was funded by the National Institute on Alcohol Abuse and Alcoholism (National Institutes of Health) and the Samuel C. Johnson Genomics of Addiction Program at Mayo Clinic. Dr. Karpyak and Dr. Comasco reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
MILAN — Specific combinations of hormonal and biochemical factors were associated with different clinical characteristics and treatment outcomes of alcohol use disorder (AUD) between men and women.
“These hormones and proteins are known to have an influence on behavior, and indeed we see an association between different levels of these compounds and different behavioral aspects of [AUD], although we can’t for sure say that one directly causes another,” said lead researcher Victor M. Karpyak, MD, PhD, professor of psychiatry at the Mayo Clinic, in a release.
The findings were presented at the 37th European College of Neuropsychopharmacology (ECNP) Congress.
Sex Hormone Signatures
Previous research has highlighted differences in symptoms including cravings, withdrawal, consumption patterns, depression, and anxiety between men and women with AUD, said Dr. Karpyak. Differences in hormones and biochemicals have also been observed between individuals with and without AUD.
However, specific biochemical and hormonal “signatures” associated with male and female responses to treatment have thus far not been explored, he told this news organization.
The study included 400 treatment-seeking individuals (132 women and 268 men; mean age, 41.8 years; 93% White) who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for AUD and were enrolled in a clinical trial of acamprosate.
Baseline assessment included psychiatric comorbidities and substance use with the Psychiatric Research Interview for Substance and Mental Disorders, alcohol consumption pattern over the past 90 days by Timeline Follow-Back calendar, recent craving on the Penn Alcohol Craving Scale (PACS), situations at the risk of drinking on the Inventory of Drug-Taking Situation, recent depression severity on the Patient Health Questionnaire 9 (PHQ-9), and recent anxiety severity on the Generalized Anxiety Disorder 7 scale.
Plasma sex-related hormone and protein measurements were taken at baseline — after detoxification but before treatment. These included total testosterone, estradiol, estrone, progesterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), sex hormone–binding globulin (SHBG), and albumin.
“The important thing is that these measurements were taken during sobriety,” said Dr. Karpyak. Study participants were already in residential treatment programs, and the average time since their last drink was approximately 3 weeks. Relapse was defined as any alcohol consumption during the first 3 months.
What Works for Men May Not Work for Women
Results showed that men with symptoms of depression and a higher craving for alcohol, as shown on baseline PHQ-9 and PACS scores, had lower baseline levels of testosterone, estrone, estradiol, and SHBG than those without these symptoms (P = .0102 and P = .0014, respectively).
In addition, a combination of higher progesterone and lower albumin was associated with a lower risk for relapse during the first 3 months (odds ratio [OR], 0.518; P = .0079).
In women, a combination of lower estrone and estradiol and higher FSH and LH levels was associated with higher maximum number of drinks per day (P = .035).
In addition, women who were more likely to relapse during the first 3 months of treatment had higher baseline levels of testosterone, SHBG, and albumin than those at lower relapse risk (OR, 4.536; P = .0057).
Dr. Karpyak noted that these “hormone signatures” were associative and not predictive.
What this means, he said, “is that if you are treating a man and a woman for alcoholism, you are dealing with different biochemical and psychological starting points. This implies that what works for a man may not work for a woman, and vice versa.”
Toward Gender Equity
The findings may eventually lead to a way to predict treatment responses in patients with AUD, Dr. Karpyak added, but cautioned that despite statistical significance, these are preliminary findings.
Before these results can be integrated into clinical practice, they need to be replicated. Dr. Karpyak emphasized the need for follow-up research that builds on these findings, using them as preliminary data to determine whether prediction holds real significance.
“Given that many of these differences are related to sex hormones, we particularly want to see how the dramatic hormonal change women experience during the menstrual cycle and at menopause may affect the biochemistry of alcoholism and guide treatment efforts,” he said.
In a statement, Erika Comasco, PhD, associate professor in molecular psychiatry, Uppsala University, Sweden, said the research “is an important step forward to gender equity in medicine.”
“The findings provide an important first insight into the relationship between sex hormones and alcohol use disorder treatment,” she explained. “While sex differences in the way the disorder manifests itself are known, these results suggest that sex hormones may modulate treatment response, potentially supporting sex-specific pharmacological intervention.”
Dr. Comasco shares Dr. Karpyak’s view that hormonal fluctuations linked to the menstrual cycle may influence alcohol misuse and believes more research is needed to explore their impact on treatment and relapse outcomes in female patients.
This study was funded by the National Institute on Alcohol Abuse and Alcoholism (National Institutes of Health) and the Samuel C. Johnson Genomics of Addiction Program at Mayo Clinic. Dr. Karpyak and Dr. Comasco reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
MILAN — Specific combinations of hormonal and biochemical factors were associated with different clinical characteristics and treatment outcomes of alcohol use disorder (AUD) between men and women.
“These hormones and proteins are known to have an influence on behavior, and indeed we see an association between different levels of these compounds and different behavioral aspects of [AUD], although we can’t for sure say that one directly causes another,” said lead researcher Victor M. Karpyak, MD, PhD, professor of psychiatry at the Mayo Clinic, in a release.
The findings were presented at the 37th European College of Neuropsychopharmacology (ECNP) Congress.
Sex Hormone Signatures
Previous research has highlighted differences in symptoms including cravings, withdrawal, consumption patterns, depression, and anxiety between men and women with AUD, said Dr. Karpyak. Differences in hormones and biochemicals have also been observed between individuals with and without AUD.
However, specific biochemical and hormonal “signatures” associated with male and female responses to treatment have thus far not been explored, he told this news organization.
The study included 400 treatment-seeking individuals (132 women and 268 men; mean age, 41.8 years; 93% White) who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for AUD and were enrolled in a clinical trial of acamprosate.
Baseline assessment included psychiatric comorbidities and substance use with the Psychiatric Research Interview for Substance and Mental Disorders, alcohol consumption pattern over the past 90 days by Timeline Follow-Back calendar, recent craving on the Penn Alcohol Craving Scale (PACS), situations at the risk of drinking on the Inventory of Drug-Taking Situation, recent depression severity on the Patient Health Questionnaire 9 (PHQ-9), and recent anxiety severity on the Generalized Anxiety Disorder 7 scale.
Plasma sex-related hormone and protein measurements were taken at baseline — after detoxification but before treatment. These included total testosterone, estradiol, estrone, progesterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), sex hormone–binding globulin (SHBG), and albumin.
“The important thing is that these measurements were taken during sobriety,” said Dr. Karpyak. Study participants were already in residential treatment programs, and the average time since their last drink was approximately 3 weeks. Relapse was defined as any alcohol consumption during the first 3 months.
What Works for Men May Not Work for Women
Results showed that men with symptoms of depression and a higher craving for alcohol, as shown on baseline PHQ-9 and PACS scores, had lower baseline levels of testosterone, estrone, estradiol, and SHBG than those without these symptoms (P = .0102 and P = .0014, respectively).
In addition, a combination of higher progesterone and lower albumin was associated with a lower risk for relapse during the first 3 months (odds ratio [OR], 0.518; P = .0079).
In women, a combination of lower estrone and estradiol and higher FSH and LH levels was associated with higher maximum number of drinks per day (P = .035).
In addition, women who were more likely to relapse during the first 3 months of treatment had higher baseline levels of testosterone, SHBG, and albumin than those at lower relapse risk (OR, 4.536; P = .0057).
Dr. Karpyak noted that these “hormone signatures” were associative and not predictive.
What this means, he said, “is that if you are treating a man and a woman for alcoholism, you are dealing with different biochemical and psychological starting points. This implies that what works for a man may not work for a woman, and vice versa.”
Toward Gender Equity
The findings may eventually lead to a way to predict treatment responses in patients with AUD, Dr. Karpyak added, but cautioned that despite statistical significance, these are preliminary findings.
Before these results can be integrated into clinical practice, they need to be replicated. Dr. Karpyak emphasized the need for follow-up research that builds on these findings, using them as preliminary data to determine whether prediction holds real significance.
“Given that many of these differences are related to sex hormones, we particularly want to see how the dramatic hormonal change women experience during the menstrual cycle and at menopause may affect the biochemistry of alcoholism and guide treatment efforts,” he said.
In a statement, Erika Comasco, PhD, associate professor in molecular psychiatry, Uppsala University, Sweden, said the research “is an important step forward to gender equity in medicine.”
“The findings provide an important first insight into the relationship between sex hormones and alcohol use disorder treatment,” she explained. “While sex differences in the way the disorder manifests itself are known, these results suggest that sex hormones may modulate treatment response, potentially supporting sex-specific pharmacological intervention.”
Dr. Comasco shares Dr. Karpyak’s view that hormonal fluctuations linked to the menstrual cycle may influence alcohol misuse and believes more research is needed to explore their impact on treatment and relapse outcomes in female patients.
This study was funded by the National Institute on Alcohol Abuse and Alcoholism (National Institutes of Health) and the Samuel C. Johnson Genomics of Addiction Program at Mayo Clinic. Dr. Karpyak and Dr. Comasco reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
FROM ECNP 2024