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Debate: Should Dermatologists or Rheumatologists Manage Musculoskeletal Symptoms in Patients With Psoriasis?
SEATTLE — That was the subject of a debate between a dermatologist and a rheumatologist at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis.
Fabian Proft, MD, the rheumatologist, spoke first and emphasized the potential that MSK symptoms are a sign of psoriatic arthritis (PsA) and therefore should be managed by a rheumatologist.
“Obviously, the rheumatologist perspective [is that] I should be in the driver’s seat when taking care of patient with psoriasis and MSK symptoms, but I will still need to have a copilot there: [The dermatologist] will have a slot,” said Dr. Proft, who is a rheumatologist at Charité — Universitätsmedizin Berlin.
“It’s so important that we make the correct and early diagnosis of [psoriatic arthritis and psoriasis] symptoms,” said Dr. Proft. He specifically called out cases where patients have symptoms that are difficult to determine, whether the cause is inflammatory, and when experience with imaging can be a key factor in the diagnosis.
It’s important not to overdiagnose or overtreat patients, he said, providing an example of a patient with psoriasis who had been training for a marathon. The MRI image suggested that his Achilles tendonitis pain was related to his athletic training, not PsA-associated inflammation. “So I think this is very important that you have the knowledge to read MRIs, and especially also carefully assessing them so as not to overdiagnose patients,” said Dr. Proft.
Dermatologist Rebuttal
In her rebuttal, Laura Savage, MD, PhD, emphasized the need for more of a coequal partnership between the two specialties because of the ability of dermatologists to intervene early in the treatment and prevention of PsA.
“Traditionally, I agree rheumatologists would solely be responsible for the assessment and the management of psoriatic arthritis, but I think that paradigm has shifted in part due to the increased recognition of the need for earlier intervention to limit disease progression and to reduce or even prevent functional limitation,” said Dr. Savage, who is a consultant dermatologist at Leeds Teaching Hospitals NHS Trust and a senior lecturer at the University of Leeds, Leeds, England.
Ideally, molecular biomarkers would be available to predict the development of PsA, but there aren’t any. Still, “we have a huge biomarker in the form of the skin, and it’s recognized that the majority of patients who will develop psoriatic arthritis will have antecedent psoriasis in about 70% of cases,” Dr. Savage said. “There’s a typical time delay of around 7-12 years between the onset of the skin [disease] and the patients developing psoriatic arthritis, and so many of them are going to be into the care of other healthcare practitioners, and particularly the care of dermatologists.”
Dermatologists may also be able to play a role in the prevention of PsA, according to Dr. Savage. In one retrospective study, treatment of skin lesions with biologics was associated with a reduced frequency of progression to PsA (11.1% vs 16.4%) over 10 years (P = .0006). Studies with tumor necrosis factor inhibitors and other interventions have shown similar results.
Such findings have led to the treat intercept strategy, which targets patients with psoriasis who have risk factors for transition to PsA — such as nail pitting, gluteal cleft disease, scalp disease, type 2 diabetes, obesity, and a first-degree relative with PsA — as well as symptoms of prodromal PSA, such as arthralgia and fatigue.
“I think dermatologists are aware of the need to not leave our patients languishing on these therapies and actually escalating them onto effective treatments that may also be able to treat early psoriatic arthritis. We could be more mindful about our choice of treatments for these patients, going on to thinking about their increased risk of PSA and trying to intercept,” Dr. Savage said. “What we don’t want is our patients to be developing these musculoskeletal symptoms of pain and stiffness and functional limitation and disability. We want to be treating the patients with musculoskeletal symptoms of that earlier prodromal phase when they’re developing arthralgia and fatigue.”
She conceded that more complicated patients are good candidates for care by the rheumatologist. “You can do your fancy imaging, and we’ll leave that to you, and the difficult-to-treat patients to [the rheumatologist], but actually we need to just get on and treat them,” she said. “One could argue as well that as a dermatologist, I’m likely to broaden my horizons in terms of choice of therapy and treat all of the domains of the patient. So I would argue that actually it should be the dermatologist who is in that driving seat, particularly when it comes to the management of early psoriatic arthritis, and actually what we should be doing is driving our patients and steering them to earlier intervention and better control for all domains of disease.”
Collaborative Care
During the follow-up discussion, both Dr. Proft and Dr. Savage agreed that dermatologists and rheumatologists should be working together in managing patients. “What we need to do is steer our patients toward collaborative care with our rheumatologists by trying to minimize delays to treatment, by working together in parallel clinics, combined clinics, and on virtual [multidisciplinary teams],” said Dr. Savage.
Dr. Proft agreed. “We should join forces and make decisions together.”
Dr. Savage and Dr. Proft did not provide any financial disclosures.
A version of this article appeared on Medscape.com.
SEATTLE — That was the subject of a debate between a dermatologist and a rheumatologist at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis.
Fabian Proft, MD, the rheumatologist, spoke first and emphasized the potential that MSK symptoms are a sign of psoriatic arthritis (PsA) and therefore should be managed by a rheumatologist.
“Obviously, the rheumatologist perspective [is that] I should be in the driver’s seat when taking care of patient with psoriasis and MSK symptoms, but I will still need to have a copilot there: [The dermatologist] will have a slot,” said Dr. Proft, who is a rheumatologist at Charité — Universitätsmedizin Berlin.
“It’s so important that we make the correct and early diagnosis of [psoriatic arthritis and psoriasis] symptoms,” said Dr. Proft. He specifically called out cases where patients have symptoms that are difficult to determine, whether the cause is inflammatory, and when experience with imaging can be a key factor in the diagnosis.
It’s important not to overdiagnose or overtreat patients, he said, providing an example of a patient with psoriasis who had been training for a marathon. The MRI image suggested that his Achilles tendonitis pain was related to his athletic training, not PsA-associated inflammation. “So I think this is very important that you have the knowledge to read MRIs, and especially also carefully assessing them so as not to overdiagnose patients,” said Dr. Proft.
Dermatologist Rebuttal
In her rebuttal, Laura Savage, MD, PhD, emphasized the need for more of a coequal partnership between the two specialties because of the ability of dermatologists to intervene early in the treatment and prevention of PsA.
“Traditionally, I agree rheumatologists would solely be responsible for the assessment and the management of psoriatic arthritis, but I think that paradigm has shifted in part due to the increased recognition of the need for earlier intervention to limit disease progression and to reduce or even prevent functional limitation,” said Dr. Savage, who is a consultant dermatologist at Leeds Teaching Hospitals NHS Trust and a senior lecturer at the University of Leeds, Leeds, England.
Ideally, molecular biomarkers would be available to predict the development of PsA, but there aren’t any. Still, “we have a huge biomarker in the form of the skin, and it’s recognized that the majority of patients who will develop psoriatic arthritis will have antecedent psoriasis in about 70% of cases,” Dr. Savage said. “There’s a typical time delay of around 7-12 years between the onset of the skin [disease] and the patients developing psoriatic arthritis, and so many of them are going to be into the care of other healthcare practitioners, and particularly the care of dermatologists.”
Dermatologists may also be able to play a role in the prevention of PsA, according to Dr. Savage. In one retrospective study, treatment of skin lesions with biologics was associated with a reduced frequency of progression to PsA (11.1% vs 16.4%) over 10 years (P = .0006). Studies with tumor necrosis factor inhibitors and other interventions have shown similar results.
Such findings have led to the treat intercept strategy, which targets patients with psoriasis who have risk factors for transition to PsA — such as nail pitting, gluteal cleft disease, scalp disease, type 2 diabetes, obesity, and a first-degree relative with PsA — as well as symptoms of prodromal PSA, such as arthralgia and fatigue.
“I think dermatologists are aware of the need to not leave our patients languishing on these therapies and actually escalating them onto effective treatments that may also be able to treat early psoriatic arthritis. We could be more mindful about our choice of treatments for these patients, going on to thinking about their increased risk of PSA and trying to intercept,” Dr. Savage said. “What we don’t want is our patients to be developing these musculoskeletal symptoms of pain and stiffness and functional limitation and disability. We want to be treating the patients with musculoskeletal symptoms of that earlier prodromal phase when they’re developing arthralgia and fatigue.”
She conceded that more complicated patients are good candidates for care by the rheumatologist. “You can do your fancy imaging, and we’ll leave that to you, and the difficult-to-treat patients to [the rheumatologist], but actually we need to just get on and treat them,” she said. “One could argue as well that as a dermatologist, I’m likely to broaden my horizons in terms of choice of therapy and treat all of the domains of the patient. So I would argue that actually it should be the dermatologist who is in that driving seat, particularly when it comes to the management of early psoriatic arthritis, and actually what we should be doing is driving our patients and steering them to earlier intervention and better control for all domains of disease.”
Collaborative Care
During the follow-up discussion, both Dr. Proft and Dr. Savage agreed that dermatologists and rheumatologists should be working together in managing patients. “What we need to do is steer our patients toward collaborative care with our rheumatologists by trying to minimize delays to treatment, by working together in parallel clinics, combined clinics, and on virtual [multidisciplinary teams],” said Dr. Savage.
Dr. Proft agreed. “We should join forces and make decisions together.”
Dr. Savage and Dr. Proft did not provide any financial disclosures.
A version of this article appeared on Medscape.com.
SEATTLE — That was the subject of a debate between a dermatologist and a rheumatologist at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis.
Fabian Proft, MD, the rheumatologist, spoke first and emphasized the potential that MSK symptoms are a sign of psoriatic arthritis (PsA) and therefore should be managed by a rheumatologist.
“Obviously, the rheumatologist perspective [is that] I should be in the driver’s seat when taking care of patient with psoriasis and MSK symptoms, but I will still need to have a copilot there: [The dermatologist] will have a slot,” said Dr. Proft, who is a rheumatologist at Charité — Universitätsmedizin Berlin.
“It’s so important that we make the correct and early diagnosis of [psoriatic arthritis and psoriasis] symptoms,” said Dr. Proft. He specifically called out cases where patients have symptoms that are difficult to determine, whether the cause is inflammatory, and when experience with imaging can be a key factor in the diagnosis.
It’s important not to overdiagnose or overtreat patients, he said, providing an example of a patient with psoriasis who had been training for a marathon. The MRI image suggested that his Achilles tendonitis pain was related to his athletic training, not PsA-associated inflammation. “So I think this is very important that you have the knowledge to read MRIs, and especially also carefully assessing them so as not to overdiagnose patients,” said Dr. Proft.
Dermatologist Rebuttal
In her rebuttal, Laura Savage, MD, PhD, emphasized the need for more of a coequal partnership between the two specialties because of the ability of dermatologists to intervene early in the treatment and prevention of PsA.
“Traditionally, I agree rheumatologists would solely be responsible for the assessment and the management of psoriatic arthritis, but I think that paradigm has shifted in part due to the increased recognition of the need for earlier intervention to limit disease progression and to reduce or even prevent functional limitation,” said Dr. Savage, who is a consultant dermatologist at Leeds Teaching Hospitals NHS Trust and a senior lecturer at the University of Leeds, Leeds, England.
Ideally, molecular biomarkers would be available to predict the development of PsA, but there aren’t any. Still, “we have a huge biomarker in the form of the skin, and it’s recognized that the majority of patients who will develop psoriatic arthritis will have antecedent psoriasis in about 70% of cases,” Dr. Savage said. “There’s a typical time delay of around 7-12 years between the onset of the skin [disease] and the patients developing psoriatic arthritis, and so many of them are going to be into the care of other healthcare practitioners, and particularly the care of dermatologists.”
Dermatologists may also be able to play a role in the prevention of PsA, according to Dr. Savage. In one retrospective study, treatment of skin lesions with biologics was associated with a reduced frequency of progression to PsA (11.1% vs 16.4%) over 10 years (P = .0006). Studies with tumor necrosis factor inhibitors and other interventions have shown similar results.
Such findings have led to the treat intercept strategy, which targets patients with psoriasis who have risk factors for transition to PsA — such as nail pitting, gluteal cleft disease, scalp disease, type 2 diabetes, obesity, and a first-degree relative with PsA — as well as symptoms of prodromal PSA, such as arthralgia and fatigue.
“I think dermatologists are aware of the need to not leave our patients languishing on these therapies and actually escalating them onto effective treatments that may also be able to treat early psoriatic arthritis. We could be more mindful about our choice of treatments for these patients, going on to thinking about their increased risk of PSA and trying to intercept,” Dr. Savage said. “What we don’t want is our patients to be developing these musculoskeletal symptoms of pain and stiffness and functional limitation and disability. We want to be treating the patients with musculoskeletal symptoms of that earlier prodromal phase when they’re developing arthralgia and fatigue.”
She conceded that more complicated patients are good candidates for care by the rheumatologist. “You can do your fancy imaging, and we’ll leave that to you, and the difficult-to-treat patients to [the rheumatologist], but actually we need to just get on and treat them,” she said. “One could argue as well that as a dermatologist, I’m likely to broaden my horizons in terms of choice of therapy and treat all of the domains of the patient. So I would argue that actually it should be the dermatologist who is in that driving seat, particularly when it comes to the management of early psoriatic arthritis, and actually what we should be doing is driving our patients and steering them to earlier intervention and better control for all domains of disease.”
Collaborative Care
During the follow-up discussion, both Dr. Proft and Dr. Savage agreed that dermatologists and rheumatologists should be working together in managing patients. “What we need to do is steer our patients toward collaborative care with our rheumatologists by trying to minimize delays to treatment, by working together in parallel clinics, combined clinics, and on virtual [multidisciplinary teams],” said Dr. Savage.
Dr. Proft agreed. “We should join forces and make decisions together.”
Dr. Savage and Dr. Proft did not provide any financial disclosures.
A version of this article appeared on Medscape.com.
FROM GRAPPA 2024
Eptinezumab Inhibitor Fails Cluster Headache Test
SAN DIEGO — However, the drug met secondary outcomes of reduction in weekly attacks, mean change in baseline pain, and Patient Global Impression of Change (PGIC) score.
Eptinezumab is the latest of multiple anti–calcitonin gene-related peptide (CGRP) therapies to fail in the clinic against episodic cluster headache, all using weekly attacks as a primary endpoint, though therapies also scored positive results for secondary endpoints, according to Stewart Tepper, MD, who presented the study results at the annual meeting of the American Headache Society
Eptinezumab is already approved for migraine, and is fully bioavailable by the end of an infusion. “That was why we thought this might be a really interesting treatment for prevention of cluster headache,” said Dr. Tepper, who is VP of external research at the New England Institute for Neurology and Headache in Stamford, Connecticut.
Are We Looking at the Wrong Endpoint?
Secondary endpoints offered more encouragement. “For each week, the eptinezumab looked either numerically higher than the placebo or nominal statistical significance was achieved. By week 4, two-thirds of the patients had at least a 50% reduction in their number of weekly cluster attacks. Then the average pain intensity for the day and the patient global impression of change were all in favor of eptinezumab. That made us interested in whether we’re missing something, whether this is maybe not the correct endpoint to be looking at,” said Dr. Tepper.
He suggested that it may be time for the Food and Drug Administration (FDA) to reconsider the endpoints used in clinical trials for cluster headaches.
Study criteria included cluster periods that lasted at least 6 weeks, and at least 1 year since the diagnosis of episodic cluster headache. The study enrolled patients who were out of their cluster period, who underwent a second screening of 7-14 days after they entered a new cycle. After that, they were randomized to an injection of placebo or 400 mg eptinezumab, and followed for 4 weeks. After 4 weeks, all patients received an injection of 400 mg eptinezumab and placebo patients were crossed over to eptinezumab and followed out to 24 weeks.
The study population included 231 patients (78% male; mean age, 44 years), with a mean of 2.7 cluster headache attacks per day an average duration of 62 minutes per attack. The worst pain was reported as excruciating in 59% of participants.
The mean change in number of weekly attacks in weeks 1 and 2, compared with baseline, was not statistically significant (–4.6 with eptinezumab, –4.6 with placebo; P = .5048). More patients in the eptinezumab group had a 50% or greater reduction in attack frequency in weeks 3 (50.9% vs 37.3%; P < .05), week 3 (62.5% vs 43.8%; P < .01), and week 4 (66.7% vs 50.5%; P < .01). The difference in mean change in pain from baseline became statistically significant at week 3 and 4 (P < .01). There were also statistically significant differences in PGIC score at weeks 1, 2, and 4. The frequency of any treatment-emergent adverse event was similar in the eptinezumab and placebo groups (25.0% vs 26.5%), and only one led to treatment withdrawal in the eptinezumab group (0.9%).
Thoughts on Redesigning Cluster Headache Clinical Trials
During the Q&A session, Andrea Harriott, MD, PhD, a neurologist at Massachusetts General Hospital, Boston, and the session’s moderator, asked Dr. Tepper for his thoughts on how to design a good cluster headache trial. “I think we should go to the regulators and say we’re looking at the wrong outcome measure, and that we should use responder rate as the primary endpoint. That’s my guess. I think after four failed cluster studies for anti-CGRP therapies in terms of primary endpoint, all of which suggest some benefit, I think maybe we are looking at the wrong endpoint,” said Dr. Tepper.
Dr. Tepper was also asked about the potential for comparative efficacy trials testing anti-CGRP versus usual therapy, or usual therapy combined with antibodies against usual therapy. He noted that he had coauthored a recent commentary that responded to International Headache Society 2022 guidelines for randomized, placebo-controlled trials in cluster headache. “We actually did suggest comparative effectiveness [trials], both for recruitment and for compassion, but one of the problems is that verapamil is not even FDA approved for cluster headache in the US, and galcanezumab (Emgality, Eli Lilly) [is not approved] in the EU, so it becomes difficult from a regulatory standpoint to set that up, and you have to have buy in from regulatory authorities,” said Dr. Tepper.
Dr. Tepper has financial relationships with many pharmaceutical companies, including consulting for/advising Lundbeck, which funded the study. Dr. Harriott has served on the scientific advisory board of Theranica and has an authorship agreement with AbbVie.
SAN DIEGO — However, the drug met secondary outcomes of reduction in weekly attacks, mean change in baseline pain, and Patient Global Impression of Change (PGIC) score.
Eptinezumab is the latest of multiple anti–calcitonin gene-related peptide (CGRP) therapies to fail in the clinic against episodic cluster headache, all using weekly attacks as a primary endpoint, though therapies also scored positive results for secondary endpoints, according to Stewart Tepper, MD, who presented the study results at the annual meeting of the American Headache Society
Eptinezumab is already approved for migraine, and is fully bioavailable by the end of an infusion. “That was why we thought this might be a really interesting treatment for prevention of cluster headache,” said Dr. Tepper, who is VP of external research at the New England Institute for Neurology and Headache in Stamford, Connecticut.
Are We Looking at the Wrong Endpoint?
Secondary endpoints offered more encouragement. “For each week, the eptinezumab looked either numerically higher than the placebo or nominal statistical significance was achieved. By week 4, two-thirds of the patients had at least a 50% reduction in their number of weekly cluster attacks. Then the average pain intensity for the day and the patient global impression of change were all in favor of eptinezumab. That made us interested in whether we’re missing something, whether this is maybe not the correct endpoint to be looking at,” said Dr. Tepper.
He suggested that it may be time for the Food and Drug Administration (FDA) to reconsider the endpoints used in clinical trials for cluster headaches.
Study criteria included cluster periods that lasted at least 6 weeks, and at least 1 year since the diagnosis of episodic cluster headache. The study enrolled patients who were out of their cluster period, who underwent a second screening of 7-14 days after they entered a new cycle. After that, they were randomized to an injection of placebo or 400 mg eptinezumab, and followed for 4 weeks. After 4 weeks, all patients received an injection of 400 mg eptinezumab and placebo patients were crossed over to eptinezumab and followed out to 24 weeks.
The study population included 231 patients (78% male; mean age, 44 years), with a mean of 2.7 cluster headache attacks per day an average duration of 62 minutes per attack. The worst pain was reported as excruciating in 59% of participants.
The mean change in number of weekly attacks in weeks 1 and 2, compared with baseline, was not statistically significant (–4.6 with eptinezumab, –4.6 with placebo; P = .5048). More patients in the eptinezumab group had a 50% or greater reduction in attack frequency in weeks 3 (50.9% vs 37.3%; P < .05), week 3 (62.5% vs 43.8%; P < .01), and week 4 (66.7% vs 50.5%; P < .01). The difference in mean change in pain from baseline became statistically significant at week 3 and 4 (P < .01). There were also statistically significant differences in PGIC score at weeks 1, 2, and 4. The frequency of any treatment-emergent adverse event was similar in the eptinezumab and placebo groups (25.0% vs 26.5%), and only one led to treatment withdrawal in the eptinezumab group (0.9%).
Thoughts on Redesigning Cluster Headache Clinical Trials
During the Q&A session, Andrea Harriott, MD, PhD, a neurologist at Massachusetts General Hospital, Boston, and the session’s moderator, asked Dr. Tepper for his thoughts on how to design a good cluster headache trial. “I think we should go to the regulators and say we’re looking at the wrong outcome measure, and that we should use responder rate as the primary endpoint. That’s my guess. I think after four failed cluster studies for anti-CGRP therapies in terms of primary endpoint, all of which suggest some benefit, I think maybe we are looking at the wrong endpoint,” said Dr. Tepper.
Dr. Tepper was also asked about the potential for comparative efficacy trials testing anti-CGRP versus usual therapy, or usual therapy combined with antibodies against usual therapy. He noted that he had coauthored a recent commentary that responded to International Headache Society 2022 guidelines for randomized, placebo-controlled trials in cluster headache. “We actually did suggest comparative effectiveness [trials], both for recruitment and for compassion, but one of the problems is that verapamil is not even FDA approved for cluster headache in the US, and galcanezumab (Emgality, Eli Lilly) [is not approved] in the EU, so it becomes difficult from a regulatory standpoint to set that up, and you have to have buy in from regulatory authorities,” said Dr. Tepper.
Dr. Tepper has financial relationships with many pharmaceutical companies, including consulting for/advising Lundbeck, which funded the study. Dr. Harriott has served on the scientific advisory board of Theranica and has an authorship agreement with AbbVie.
SAN DIEGO — However, the drug met secondary outcomes of reduction in weekly attacks, mean change in baseline pain, and Patient Global Impression of Change (PGIC) score.
Eptinezumab is the latest of multiple anti–calcitonin gene-related peptide (CGRP) therapies to fail in the clinic against episodic cluster headache, all using weekly attacks as a primary endpoint, though therapies also scored positive results for secondary endpoints, according to Stewart Tepper, MD, who presented the study results at the annual meeting of the American Headache Society
Eptinezumab is already approved for migraine, and is fully bioavailable by the end of an infusion. “That was why we thought this might be a really interesting treatment for prevention of cluster headache,” said Dr. Tepper, who is VP of external research at the New England Institute for Neurology and Headache in Stamford, Connecticut.
Are We Looking at the Wrong Endpoint?
Secondary endpoints offered more encouragement. “For each week, the eptinezumab looked either numerically higher than the placebo or nominal statistical significance was achieved. By week 4, two-thirds of the patients had at least a 50% reduction in their number of weekly cluster attacks. Then the average pain intensity for the day and the patient global impression of change were all in favor of eptinezumab. That made us interested in whether we’re missing something, whether this is maybe not the correct endpoint to be looking at,” said Dr. Tepper.
He suggested that it may be time for the Food and Drug Administration (FDA) to reconsider the endpoints used in clinical trials for cluster headaches.
Study criteria included cluster periods that lasted at least 6 weeks, and at least 1 year since the diagnosis of episodic cluster headache. The study enrolled patients who were out of their cluster period, who underwent a second screening of 7-14 days after they entered a new cycle. After that, they were randomized to an injection of placebo or 400 mg eptinezumab, and followed for 4 weeks. After 4 weeks, all patients received an injection of 400 mg eptinezumab and placebo patients were crossed over to eptinezumab and followed out to 24 weeks.
The study population included 231 patients (78% male; mean age, 44 years), with a mean of 2.7 cluster headache attacks per day an average duration of 62 minutes per attack. The worst pain was reported as excruciating in 59% of participants.
The mean change in number of weekly attacks in weeks 1 and 2, compared with baseline, was not statistically significant (–4.6 with eptinezumab, –4.6 with placebo; P = .5048). More patients in the eptinezumab group had a 50% or greater reduction in attack frequency in weeks 3 (50.9% vs 37.3%; P < .05), week 3 (62.5% vs 43.8%; P < .01), and week 4 (66.7% vs 50.5%; P < .01). The difference in mean change in pain from baseline became statistically significant at week 3 and 4 (P < .01). There were also statistically significant differences in PGIC score at weeks 1, 2, and 4. The frequency of any treatment-emergent adverse event was similar in the eptinezumab and placebo groups (25.0% vs 26.5%), and only one led to treatment withdrawal in the eptinezumab group (0.9%).
Thoughts on Redesigning Cluster Headache Clinical Trials
During the Q&A session, Andrea Harriott, MD, PhD, a neurologist at Massachusetts General Hospital, Boston, and the session’s moderator, asked Dr. Tepper for his thoughts on how to design a good cluster headache trial. “I think we should go to the regulators and say we’re looking at the wrong outcome measure, and that we should use responder rate as the primary endpoint. That’s my guess. I think after four failed cluster studies for anti-CGRP therapies in terms of primary endpoint, all of which suggest some benefit, I think maybe we are looking at the wrong endpoint,” said Dr. Tepper.
Dr. Tepper was also asked about the potential for comparative efficacy trials testing anti-CGRP versus usual therapy, or usual therapy combined with antibodies against usual therapy. He noted that he had coauthored a recent commentary that responded to International Headache Society 2022 guidelines for randomized, placebo-controlled trials in cluster headache. “We actually did suggest comparative effectiveness [trials], both for recruitment and for compassion, but one of the problems is that verapamil is not even FDA approved for cluster headache in the US, and galcanezumab (Emgality, Eli Lilly) [is not approved] in the EU, so it becomes difficult from a regulatory standpoint to set that up, and you have to have buy in from regulatory authorities,” said Dr. Tepper.
Dr. Tepper has financial relationships with many pharmaceutical companies, including consulting for/advising Lundbeck, which funded the study. Dr. Harriott has served on the scientific advisory board of Theranica and has an authorship agreement with AbbVie.
FROM AHS 2024
Migraine Linked to Cardiovascular Risk in Veterans Study
SAN DIEGO — , according to results from a retrospective analysis of Veterans Health Administration (VHA) data. Migraine was also linked to greater risk of cardiovascular disease, and the researchers found similar risk among both genders, with the exceptions of a larger stroke risk among women and larger risk of TIA among men.
Gender Matters
The research complements other studies, such as an analysis drawn from the Women’s Health Study, according to Alexandra Schwartz, a doctoral student at Yeshiva University, who presented the research at the annual meeting of the American Headache Society. That study found a 53% increased risk of stroke (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.02-2.31) among 17,531 female subjects between the ages of 25 and 42. Another, smaller study in 1,400 men drawn from the Physicians Health study found an increased risk of major cardiovascular events of 1.24 (P = .008). Previous studies have shown that around two-thirds of VHA patients with migraine are male. “Our population gives us this really unique opportunity to look at men with migraine,” Ms. Schwartz said in an interview.
The differential risk factors among men and women are tantalizing. “Gender likely matters in terms of how migraine and stroke are related, and a number of other cardiovascular diseases,” said Ms. Schwartz.
Migraine has long been considered a disease of women, but 6% of men experience the condition, making it important to understand how migraine might affect cardiovascular result in men. “We would expect that there could be different underlying mechanisms in this kind of relationship ... it is absolutely worth understanding the extent to which this disease might impact their risk of cardiovascular events,” senior author Elizabeth Seng, PhD, said in an interview. She is a professor at Yeshiva University and a research associate at Albert Einstein School of Medicine.
The researchers examined data from 2,006,905 veterans between 2008 and 2021, including 681,784 migraineurs (492,234 men; 189,430 women) and 1,325,121 controls (983,154 men; 341,967 women) that were matched based on age within a 5-year band, gender, race, ethnicity, and VHA site of care.
Among individuals diagnosed with migraine, there was an increased risk of ischemic stroke (odds ratio [OR], 2.7; 95% CI, 2.6-2.7), TIA (OR, 7.3; 95% CI, 6.8-7.7), cardiovascular disease (OR, 3.6; 95% CI, 3.5-3.6), acute myocardial infarction (OR, 1.7; 95% CI, 1.6-1.8), heart failure (OR, 1.3; 95% CI, 1.3-1.4), and unstable angina (OR, 2.7; 95% CI, 2.5-2.8). There was an association between migraine and a lower risk of hemorrhagic stroke (OR, 0.4; 95% CI, 0.4-0.5), but only in men. When the findings were analyzed by gender, the findings were generally similar with the exception of a statistically significant, larger risk of ischemic stroke in women (OR, 3.0 versus 2.6), and a trend toward greater risk of TIA in men (OR, 7.3 versus 6.5).
While the study lends unique insight due to the high proportion of men, it also comes with the limitation that the participants were veterans, and may therefore differ from the general population with respect to general health status and other characteristics, said Ms. Schwartz.
Another Piece of the Puzzle
The large number of men in the study is important, according to session moderator Laine Green, MD, who was asked for comment. “The biggest population that was studied with respect to cardiovascular risk was the Women’s Health Study, which was predominantly White nurses over time, and it is one of our biggest important pieces of information when it comes to cardiovascular risk, specifically looking at those with migraine who seem to have this doubling of their underlying stroke risk. Trying to get the same type of information from different populations is exquisitely helpful, because it’s long been thought that the risk for stroke and cardiovascular events seems to lie with females with aura. Knowing that there may be risk in other groups is important and part of the overall counseling that we do with patients,” said Dr. Green, assistant professor of neurology at Mayo Clinic Arizona.
The findings could hint at causal mechanisms, according to Dr. Seng. Preliminary analyses, not yet reported, suggest that age also plays a role in the relationship between migraine and cardiovascular risks. “I think that it’s important to [determine] to what extent migraine might back up the curve on the age-related timing of these events. Migraine peaks in the 40s, and that’s well before most of these cardiovascular events peak. We want to understand not just the cross-sectional relationships, which were large, but also the extent to which migraine may be having a differential impact on risk in different age bands,” said Dr. Seng.
Ms. Schwartz, Dr. Seng, and Dr. Green have no relevant financial disclosures.
SAN DIEGO — , according to results from a retrospective analysis of Veterans Health Administration (VHA) data. Migraine was also linked to greater risk of cardiovascular disease, and the researchers found similar risk among both genders, with the exceptions of a larger stroke risk among women and larger risk of TIA among men.
Gender Matters
The research complements other studies, such as an analysis drawn from the Women’s Health Study, according to Alexandra Schwartz, a doctoral student at Yeshiva University, who presented the research at the annual meeting of the American Headache Society. That study found a 53% increased risk of stroke (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.02-2.31) among 17,531 female subjects between the ages of 25 and 42. Another, smaller study in 1,400 men drawn from the Physicians Health study found an increased risk of major cardiovascular events of 1.24 (P = .008). Previous studies have shown that around two-thirds of VHA patients with migraine are male. “Our population gives us this really unique opportunity to look at men with migraine,” Ms. Schwartz said in an interview.
The differential risk factors among men and women are tantalizing. “Gender likely matters in terms of how migraine and stroke are related, and a number of other cardiovascular diseases,” said Ms. Schwartz.
Migraine has long been considered a disease of women, but 6% of men experience the condition, making it important to understand how migraine might affect cardiovascular result in men. “We would expect that there could be different underlying mechanisms in this kind of relationship ... it is absolutely worth understanding the extent to which this disease might impact their risk of cardiovascular events,” senior author Elizabeth Seng, PhD, said in an interview. She is a professor at Yeshiva University and a research associate at Albert Einstein School of Medicine.
The researchers examined data from 2,006,905 veterans between 2008 and 2021, including 681,784 migraineurs (492,234 men; 189,430 women) and 1,325,121 controls (983,154 men; 341,967 women) that were matched based on age within a 5-year band, gender, race, ethnicity, and VHA site of care.
Among individuals diagnosed with migraine, there was an increased risk of ischemic stroke (odds ratio [OR], 2.7; 95% CI, 2.6-2.7), TIA (OR, 7.3; 95% CI, 6.8-7.7), cardiovascular disease (OR, 3.6; 95% CI, 3.5-3.6), acute myocardial infarction (OR, 1.7; 95% CI, 1.6-1.8), heart failure (OR, 1.3; 95% CI, 1.3-1.4), and unstable angina (OR, 2.7; 95% CI, 2.5-2.8). There was an association between migraine and a lower risk of hemorrhagic stroke (OR, 0.4; 95% CI, 0.4-0.5), but only in men. When the findings were analyzed by gender, the findings were generally similar with the exception of a statistically significant, larger risk of ischemic stroke in women (OR, 3.0 versus 2.6), and a trend toward greater risk of TIA in men (OR, 7.3 versus 6.5).
While the study lends unique insight due to the high proportion of men, it also comes with the limitation that the participants were veterans, and may therefore differ from the general population with respect to general health status and other characteristics, said Ms. Schwartz.
Another Piece of the Puzzle
The large number of men in the study is important, according to session moderator Laine Green, MD, who was asked for comment. “The biggest population that was studied with respect to cardiovascular risk was the Women’s Health Study, which was predominantly White nurses over time, and it is one of our biggest important pieces of information when it comes to cardiovascular risk, specifically looking at those with migraine who seem to have this doubling of their underlying stroke risk. Trying to get the same type of information from different populations is exquisitely helpful, because it’s long been thought that the risk for stroke and cardiovascular events seems to lie with females with aura. Knowing that there may be risk in other groups is important and part of the overall counseling that we do with patients,” said Dr. Green, assistant professor of neurology at Mayo Clinic Arizona.
The findings could hint at causal mechanisms, according to Dr. Seng. Preliminary analyses, not yet reported, suggest that age also plays a role in the relationship between migraine and cardiovascular risks. “I think that it’s important to [determine] to what extent migraine might back up the curve on the age-related timing of these events. Migraine peaks in the 40s, and that’s well before most of these cardiovascular events peak. We want to understand not just the cross-sectional relationships, which were large, but also the extent to which migraine may be having a differential impact on risk in different age bands,” said Dr. Seng.
Ms. Schwartz, Dr. Seng, and Dr. Green have no relevant financial disclosures.
SAN DIEGO — , according to results from a retrospective analysis of Veterans Health Administration (VHA) data. Migraine was also linked to greater risk of cardiovascular disease, and the researchers found similar risk among both genders, with the exceptions of a larger stroke risk among women and larger risk of TIA among men.
Gender Matters
The research complements other studies, such as an analysis drawn from the Women’s Health Study, according to Alexandra Schwartz, a doctoral student at Yeshiva University, who presented the research at the annual meeting of the American Headache Society. That study found a 53% increased risk of stroke (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.02-2.31) among 17,531 female subjects between the ages of 25 and 42. Another, smaller study in 1,400 men drawn from the Physicians Health study found an increased risk of major cardiovascular events of 1.24 (P = .008). Previous studies have shown that around two-thirds of VHA patients with migraine are male. “Our population gives us this really unique opportunity to look at men with migraine,” Ms. Schwartz said in an interview.
The differential risk factors among men and women are tantalizing. “Gender likely matters in terms of how migraine and stroke are related, and a number of other cardiovascular diseases,” said Ms. Schwartz.
Migraine has long been considered a disease of women, but 6% of men experience the condition, making it important to understand how migraine might affect cardiovascular result in men. “We would expect that there could be different underlying mechanisms in this kind of relationship ... it is absolutely worth understanding the extent to which this disease might impact their risk of cardiovascular events,” senior author Elizabeth Seng, PhD, said in an interview. She is a professor at Yeshiva University and a research associate at Albert Einstein School of Medicine.
The researchers examined data from 2,006,905 veterans between 2008 and 2021, including 681,784 migraineurs (492,234 men; 189,430 women) and 1,325,121 controls (983,154 men; 341,967 women) that were matched based on age within a 5-year band, gender, race, ethnicity, and VHA site of care.
Among individuals diagnosed with migraine, there was an increased risk of ischemic stroke (odds ratio [OR], 2.7; 95% CI, 2.6-2.7), TIA (OR, 7.3; 95% CI, 6.8-7.7), cardiovascular disease (OR, 3.6; 95% CI, 3.5-3.6), acute myocardial infarction (OR, 1.7; 95% CI, 1.6-1.8), heart failure (OR, 1.3; 95% CI, 1.3-1.4), and unstable angina (OR, 2.7; 95% CI, 2.5-2.8). There was an association between migraine and a lower risk of hemorrhagic stroke (OR, 0.4; 95% CI, 0.4-0.5), but only in men. When the findings were analyzed by gender, the findings were generally similar with the exception of a statistically significant, larger risk of ischemic stroke in women (OR, 3.0 versus 2.6), and a trend toward greater risk of TIA in men (OR, 7.3 versus 6.5).
While the study lends unique insight due to the high proportion of men, it also comes with the limitation that the participants were veterans, and may therefore differ from the general population with respect to general health status and other characteristics, said Ms. Schwartz.
Another Piece of the Puzzle
The large number of men in the study is important, according to session moderator Laine Green, MD, who was asked for comment. “The biggest population that was studied with respect to cardiovascular risk was the Women’s Health Study, which was predominantly White nurses over time, and it is one of our biggest important pieces of information when it comes to cardiovascular risk, specifically looking at those with migraine who seem to have this doubling of their underlying stroke risk. Trying to get the same type of information from different populations is exquisitely helpful, because it’s long been thought that the risk for stroke and cardiovascular events seems to lie with females with aura. Knowing that there may be risk in other groups is important and part of the overall counseling that we do with patients,” said Dr. Green, assistant professor of neurology at Mayo Clinic Arizona.
The findings could hint at causal mechanisms, according to Dr. Seng. Preliminary analyses, not yet reported, suggest that age also plays a role in the relationship between migraine and cardiovascular risks. “I think that it’s important to [determine] to what extent migraine might back up the curve on the age-related timing of these events. Migraine peaks in the 40s, and that’s well before most of these cardiovascular events peak. We want to understand not just the cross-sectional relationships, which were large, but also the extent to which migraine may be having a differential impact on risk in different age bands,” said Dr. Seng.
Ms. Schwartz, Dr. Seng, and Dr. Green have no relevant financial disclosures.
FROM AHS 2024
New Survey Explores New Daily Persistent Headache
SAN DIEGO —
“There’s just not a lot [of information] about these patients,” Mark Burish, MD, PhD, associate professor of neurology at UT Houston, said in an interview. He presented the results of the survey at the annual meeting of the American Headache Society.
There have been some retrospective analyses of patient data, but that has a lot of potential for bias. “It’s only the patients who can afford to be there, and who needed those treatments, and so we want to do more of a general survey,” said Dr. Burish.
The results weren’t particularly surprising, and tended to reaffirm what was known anecdotally, including symptoms similar to those of migraine, but it gave some insight into treatments. “Some of the CGRP inhibitors and the onabotulinum toxin seem to be some of the more effective treatments, according to our survey, so those are probably worth looking into for these patients if you can get them approved by insurance, and if you can get patients to accept the idea they might have to give themselves an injection of some sort,” said Dr. Burish.
Despite having some promise, there was variation among CGRP inhibitors. Eptinezumab, rimegepant, and atogepant were commonly reported as effective, but others, such as erenumab and galcanezumab, were less often reported. “None of them were incredibly effective. These were just the best things we have at this time,” said Dr. Burish.
Additional Information on a Rare, Hard-to-Treat Condition
Jason Sico, MD, who moderated the session, was asked for comment. “I’m so appreciative that the team has looked at a new daily persistent headache. It’s a rare type of headache disorder. It’s also one that is notoriously difficult to treat and something that we that we really need to know more about. It is difficult to really get good, robust in-depth information on these patients, and the team did a really nice job with that,” said Dr. Sico, associate professor of neurology and internal medicine at Yale School of Medicine and national director of the Headache Centers of Excellence Program within the Veterans Health Administration.
He noted that the researchers found that opioids were the most commonly used acute treatment. That’s not surprising, but “it would be interesting to see what was tried before someone had gotten to opioids,” he said.
The findings also gave some unexpected insight into the condition. “I really found it striking that an overwhelming majority of patients reported brain fog. Given the context that it is daily persistent headache, one could surmise that they have brain fog a lot of the time,” said Dr. Sico.
‘A Good Data Set’
The researchers analyzed data from 337 international patients who responded to a survey. They also randomly selected 34 patients for an interview, and 32 of those were deemed likely to have NDPH. “So we really spent some effort making sure this was a good data set,” said Dr. Burish. The participant population was 72% female, 83.7% White, and 70.7% were based in the United States, though other countries included Canada, the United Kingdom, Australia, Ireland, Germany, Sweden, and Switzerland. The mean age was 41.2 years. The peak ages of onset were between 11 and 40 years, though there were a few cases in the 0-5 age range and over 70. Possible triggers that occurred in the 3 months before onset included psychological stressors (34%), infection or inflammation (32%, COVID infection (5%), injury or surgery (8%), or a change in medications (4%). No clear trigger was identified by 22% of respondents.
The survey included information on associated features, and frequently reported issues included brain fog (approximate 75%), sound sensitivity (about 62%), light sensitivity (57%), nausea (39%), smell sensitivity (32%), visual disturbances (28%), vomiting (13%), and chills (9%).
Insights Into Treatment Efficacy
Dr. Burish showed a slide of responses to questions about acute treatments that respondents had tried at least once and viewed as ‘completely effective,’ ‘mostly effective,’ or ‘somewhat effective.’
“No medicine was completely effective, which I think a lot of people know from NDPH. It is notoriously difficult to treat. The things on the top of the list are mostly opioids. There’s one (non-opioid), the DHE (dihydroergotamine) injection. All the way on the other side, you have diphenhydramine. The NSAIDs and triptans are mostly in the middle. We did ask about some of the wearable devices, and we had extra questions about, are you using it appropriately? Those are kind of in the middle or towards the bottom [in frequency],” said Dr. Burish.
There was a similar question regarding effective preventive medications that had been tried for at least 2 months or 3 months in the cause of onabotulinum toxin or CGRP medications. “This one had a little bit more of a pattern to it: A lot of the CGRP medications are up toward the top. It’s not perfect. Erenumab and galcanezumab are closer to the bottom, but it was interesting that a lot of the CGRP medicines were toward the top. Onabotulinum toxin was also somewhat toward the top. We looked at a few different anti-inflammatories. Methylprednisolone is kind of toward the upper half at least, whereas prednisone and montelukast are at the absolute bottom. And the prednisone is a pretty good dose, 50 milligrams or higher. There are some people thinking that this is an inflammation or infectious etiology, (but) it wasn’t that all of the anti-inflammatories were necessarily toward the top of the list,” said Dr. Burish.
Dr. Burish has received funding from Lundbeck. Dr. Sico has no relevant financial disclosures.
SAN DIEGO —
“There’s just not a lot [of information] about these patients,” Mark Burish, MD, PhD, associate professor of neurology at UT Houston, said in an interview. He presented the results of the survey at the annual meeting of the American Headache Society.
There have been some retrospective analyses of patient data, but that has a lot of potential for bias. “It’s only the patients who can afford to be there, and who needed those treatments, and so we want to do more of a general survey,” said Dr. Burish.
The results weren’t particularly surprising, and tended to reaffirm what was known anecdotally, including symptoms similar to those of migraine, but it gave some insight into treatments. “Some of the CGRP inhibitors and the onabotulinum toxin seem to be some of the more effective treatments, according to our survey, so those are probably worth looking into for these patients if you can get them approved by insurance, and if you can get patients to accept the idea they might have to give themselves an injection of some sort,” said Dr. Burish.
Despite having some promise, there was variation among CGRP inhibitors. Eptinezumab, rimegepant, and atogepant were commonly reported as effective, but others, such as erenumab and galcanezumab, were less often reported. “None of them were incredibly effective. These were just the best things we have at this time,” said Dr. Burish.
Additional Information on a Rare, Hard-to-Treat Condition
Jason Sico, MD, who moderated the session, was asked for comment. “I’m so appreciative that the team has looked at a new daily persistent headache. It’s a rare type of headache disorder. It’s also one that is notoriously difficult to treat and something that we that we really need to know more about. It is difficult to really get good, robust in-depth information on these patients, and the team did a really nice job with that,” said Dr. Sico, associate professor of neurology and internal medicine at Yale School of Medicine and national director of the Headache Centers of Excellence Program within the Veterans Health Administration.
He noted that the researchers found that opioids were the most commonly used acute treatment. That’s not surprising, but “it would be interesting to see what was tried before someone had gotten to opioids,” he said.
The findings also gave some unexpected insight into the condition. “I really found it striking that an overwhelming majority of patients reported brain fog. Given the context that it is daily persistent headache, one could surmise that they have brain fog a lot of the time,” said Dr. Sico.
‘A Good Data Set’
The researchers analyzed data from 337 international patients who responded to a survey. They also randomly selected 34 patients for an interview, and 32 of those were deemed likely to have NDPH. “So we really spent some effort making sure this was a good data set,” said Dr. Burish. The participant population was 72% female, 83.7% White, and 70.7% were based in the United States, though other countries included Canada, the United Kingdom, Australia, Ireland, Germany, Sweden, and Switzerland. The mean age was 41.2 years. The peak ages of onset were between 11 and 40 years, though there were a few cases in the 0-5 age range and over 70. Possible triggers that occurred in the 3 months before onset included psychological stressors (34%), infection or inflammation (32%, COVID infection (5%), injury or surgery (8%), or a change in medications (4%). No clear trigger was identified by 22% of respondents.
The survey included information on associated features, and frequently reported issues included brain fog (approximate 75%), sound sensitivity (about 62%), light sensitivity (57%), nausea (39%), smell sensitivity (32%), visual disturbances (28%), vomiting (13%), and chills (9%).
Insights Into Treatment Efficacy
Dr. Burish showed a slide of responses to questions about acute treatments that respondents had tried at least once and viewed as ‘completely effective,’ ‘mostly effective,’ or ‘somewhat effective.’
“No medicine was completely effective, which I think a lot of people know from NDPH. It is notoriously difficult to treat. The things on the top of the list are mostly opioids. There’s one (non-opioid), the DHE (dihydroergotamine) injection. All the way on the other side, you have diphenhydramine. The NSAIDs and triptans are mostly in the middle. We did ask about some of the wearable devices, and we had extra questions about, are you using it appropriately? Those are kind of in the middle or towards the bottom [in frequency],” said Dr. Burish.
There was a similar question regarding effective preventive medications that had been tried for at least 2 months or 3 months in the cause of onabotulinum toxin or CGRP medications. “This one had a little bit more of a pattern to it: A lot of the CGRP medications are up toward the top. It’s not perfect. Erenumab and galcanezumab are closer to the bottom, but it was interesting that a lot of the CGRP medicines were toward the top. Onabotulinum toxin was also somewhat toward the top. We looked at a few different anti-inflammatories. Methylprednisolone is kind of toward the upper half at least, whereas prednisone and montelukast are at the absolute bottom. And the prednisone is a pretty good dose, 50 milligrams or higher. There are some people thinking that this is an inflammation or infectious etiology, (but) it wasn’t that all of the anti-inflammatories were necessarily toward the top of the list,” said Dr. Burish.
Dr. Burish has received funding from Lundbeck. Dr. Sico has no relevant financial disclosures.
SAN DIEGO —
“There’s just not a lot [of information] about these patients,” Mark Burish, MD, PhD, associate professor of neurology at UT Houston, said in an interview. He presented the results of the survey at the annual meeting of the American Headache Society.
There have been some retrospective analyses of patient data, but that has a lot of potential for bias. “It’s only the patients who can afford to be there, and who needed those treatments, and so we want to do more of a general survey,” said Dr. Burish.
The results weren’t particularly surprising, and tended to reaffirm what was known anecdotally, including symptoms similar to those of migraine, but it gave some insight into treatments. “Some of the CGRP inhibitors and the onabotulinum toxin seem to be some of the more effective treatments, according to our survey, so those are probably worth looking into for these patients if you can get them approved by insurance, and if you can get patients to accept the idea they might have to give themselves an injection of some sort,” said Dr. Burish.
Despite having some promise, there was variation among CGRP inhibitors. Eptinezumab, rimegepant, and atogepant were commonly reported as effective, but others, such as erenumab and galcanezumab, were less often reported. “None of them were incredibly effective. These were just the best things we have at this time,” said Dr. Burish.
Additional Information on a Rare, Hard-to-Treat Condition
Jason Sico, MD, who moderated the session, was asked for comment. “I’m so appreciative that the team has looked at a new daily persistent headache. It’s a rare type of headache disorder. It’s also one that is notoriously difficult to treat and something that we that we really need to know more about. It is difficult to really get good, robust in-depth information on these patients, and the team did a really nice job with that,” said Dr. Sico, associate professor of neurology and internal medicine at Yale School of Medicine and national director of the Headache Centers of Excellence Program within the Veterans Health Administration.
He noted that the researchers found that opioids were the most commonly used acute treatment. That’s not surprising, but “it would be interesting to see what was tried before someone had gotten to opioids,” he said.
The findings also gave some unexpected insight into the condition. “I really found it striking that an overwhelming majority of patients reported brain fog. Given the context that it is daily persistent headache, one could surmise that they have brain fog a lot of the time,” said Dr. Sico.
‘A Good Data Set’
The researchers analyzed data from 337 international patients who responded to a survey. They also randomly selected 34 patients for an interview, and 32 of those were deemed likely to have NDPH. “So we really spent some effort making sure this was a good data set,” said Dr. Burish. The participant population was 72% female, 83.7% White, and 70.7% were based in the United States, though other countries included Canada, the United Kingdom, Australia, Ireland, Germany, Sweden, and Switzerland. The mean age was 41.2 years. The peak ages of onset were between 11 and 40 years, though there were a few cases in the 0-5 age range and over 70. Possible triggers that occurred in the 3 months before onset included psychological stressors (34%), infection or inflammation (32%, COVID infection (5%), injury or surgery (8%), or a change in medications (4%). No clear trigger was identified by 22% of respondents.
The survey included information on associated features, and frequently reported issues included brain fog (approximate 75%), sound sensitivity (about 62%), light sensitivity (57%), nausea (39%), smell sensitivity (32%), visual disturbances (28%), vomiting (13%), and chills (9%).
Insights Into Treatment Efficacy
Dr. Burish showed a slide of responses to questions about acute treatments that respondents had tried at least once and viewed as ‘completely effective,’ ‘mostly effective,’ or ‘somewhat effective.’
“No medicine was completely effective, which I think a lot of people know from NDPH. It is notoriously difficult to treat. The things on the top of the list are mostly opioids. There’s one (non-opioid), the DHE (dihydroergotamine) injection. All the way on the other side, you have diphenhydramine. The NSAIDs and triptans are mostly in the middle. We did ask about some of the wearable devices, and we had extra questions about, are you using it appropriately? Those are kind of in the middle or towards the bottom [in frequency],” said Dr. Burish.
There was a similar question regarding effective preventive medications that had been tried for at least 2 months or 3 months in the cause of onabotulinum toxin or CGRP medications. “This one had a little bit more of a pattern to it: A lot of the CGRP medications are up toward the top. It’s not perfect. Erenumab and galcanezumab are closer to the bottom, but it was interesting that a lot of the CGRP medicines were toward the top. Onabotulinum toxin was also somewhat toward the top. We looked at a few different anti-inflammatories. Methylprednisolone is kind of toward the upper half at least, whereas prednisone and montelukast are at the absolute bottom. And the prednisone is a pretty good dose, 50 milligrams or higher. There are some people thinking that this is an inflammation or infectious etiology, (but) it wasn’t that all of the anti-inflammatories were necessarily toward the top of the list,” said Dr. Burish.
Dr. Burish has received funding from Lundbeck. Dr. Sico has no relevant financial disclosures.
FROM AHS 2024
Lidocaine Effective Against Pediatric Migraine
SAN DIEGO — The treatment has long been used in adults, and frequently in children on the strength of observational evidence.
Prior Research
Most of the studies have been conducted in adults, and these were often in specific settings like the emergency department for status migrainosus, while outpatient studies were generally conducted in chronic migraine, according to presenting author Christina Szperka, MD. “The assumptions were a little bit different,” Dr. Szperka, director of the pediatric headache program at Children’s Hospital of Philadelphia, said in an interview.
Retrospective studies are also fraught with bias. “We’ve tried to look at retrospective data. People don’t necessarily report how they’re doing unless they come back, and so you lose a huge portion of kids,” said Dr. Szperka, who presented the research at the annual meeting of the American Headache Society.
“From a clinical perspective, I think it gives us additional evidence that what we’re doing makes a difference, and I think that will help us in terms of insurance coverage, because that’s really been a major barrier,” said Dr. Szperka.
The study also opens other avenues for research. “Just doing the greater occipital nerves only reduces the pain so much. So what’s the next step? Do I study additional injections? Do I do a study where I compare different medications?”
She previously conducted a study of how providers were using lidocaine injections, and “there was a large amount of variability, both in terms of what nerves are being injected, what medications they were using, the patient population, et cetera,” said Dr. Szperka. Previous observational studies have suggested efficacy in pediatric populations for transition and prevention of migraine, new daily persistent headache, posttraumatic headache, and post-shunt occipital neuralgia.
A Randomized, Controlled Trial
In the new study, 58 adolescents aged 7 to 21 (mean age, 16.0 years; 44 female) were initially treated with lidocaine cream. The patients were “relatively refractory,” said Dr. Szperka, with 25 having received intravenous medications and 6 having been inpatients. After 30 minutes, if they still had pain and consented to further treatment, Dr. Szperka performed bilateral greater occipital nerve injections with lidocaine or a saline placebo, and did additional injections after 30 minutes if there wasn’t sufficient improvement.
There was no significant change in pain after the lidocaine cream treatment, and all patients proceeded to be randomized to lidocaine or placebo injections. The primary outcome of 30-minute reduction in pain score ranked 0-10 favored the lidocaine group (2.3 vs 1.1; P = .013). There was a 2-point reduction in pain scores in 69% of the lidocaine group and 34% of the saline group (P = .009) and a higher frequency of pain relief from moderate/severe to no pain or mild (52% versus 24%; P = .03). There was no significant difference in pain freedom.
After 24 hours, the treatment group was more likely to experience pain relief from moderate/severe to no pain or mild (24% vs 3%; P = .05) and to be free from associated symptoms (48% vs 21%; P = .027). Pain at the injection site was significantly higher in the placebo group (5.4 vs 3.2), prompting a change in plans for future trials. “I don’t think I would do saline again, because I think it hurt them, and I don’t want to cause them harm,” said Dr. Szperka.
Adverse events were common, with all but one patient in the study experiencing at least one. “I think this is a couple of things: One, kids don’t like needles in their head. Nerve blocks hurt. And so it was not surprising in some ways that we had a very high rate of adverse events. We also consented them, and that had a long wait period, and there’s a lot of anxiety in the room. However, most of the adverse events were mild,” said Dr. Szperka.
Important Research in an Understudied Population
Laine Greene, MD, who moderated the session, was asked for comment. “I think it’s an important study. Occipital nerve blocks have been used for a long period of time in management of migraine and other headache disorders. The quality of the evidence has always been brought into question, especially from payers, but also a very important aspect to this is that a lot of clinical trials over time have not specifically been done in children or adolescents, so any work that is done in that age category is significantly helpful to advancing therapeutics,” said Dr. Greene, associate professor of neurology at Mayo Clinic Arizona.
Dr. Szperka has consulted for AbbVie and Teva, and serves on data safety and monitoring boards for Eli Lilly and Upsher-Smith. She has been a principal investigator in trials sponsored by Abbvie, Amgen, Biohaven/Pfizer, Teva, and Theranica. Dr. Greene has no relevant financial disclosures.
SAN DIEGO — The treatment has long been used in adults, and frequently in children on the strength of observational evidence.
Prior Research
Most of the studies have been conducted in adults, and these were often in specific settings like the emergency department for status migrainosus, while outpatient studies were generally conducted in chronic migraine, according to presenting author Christina Szperka, MD. “The assumptions were a little bit different,” Dr. Szperka, director of the pediatric headache program at Children’s Hospital of Philadelphia, said in an interview.
Retrospective studies are also fraught with bias. “We’ve tried to look at retrospective data. People don’t necessarily report how they’re doing unless they come back, and so you lose a huge portion of kids,” said Dr. Szperka, who presented the research at the annual meeting of the American Headache Society.
“From a clinical perspective, I think it gives us additional evidence that what we’re doing makes a difference, and I think that will help us in terms of insurance coverage, because that’s really been a major barrier,” said Dr. Szperka.
The study also opens other avenues for research. “Just doing the greater occipital nerves only reduces the pain so much. So what’s the next step? Do I study additional injections? Do I do a study where I compare different medications?”
She previously conducted a study of how providers were using lidocaine injections, and “there was a large amount of variability, both in terms of what nerves are being injected, what medications they were using, the patient population, et cetera,” said Dr. Szperka. Previous observational studies have suggested efficacy in pediatric populations for transition and prevention of migraine, new daily persistent headache, posttraumatic headache, and post-shunt occipital neuralgia.
A Randomized, Controlled Trial
In the new study, 58 adolescents aged 7 to 21 (mean age, 16.0 years; 44 female) were initially treated with lidocaine cream. The patients were “relatively refractory,” said Dr. Szperka, with 25 having received intravenous medications and 6 having been inpatients. After 30 minutes, if they still had pain and consented to further treatment, Dr. Szperka performed bilateral greater occipital nerve injections with lidocaine or a saline placebo, and did additional injections after 30 minutes if there wasn’t sufficient improvement.
There was no significant change in pain after the lidocaine cream treatment, and all patients proceeded to be randomized to lidocaine or placebo injections. The primary outcome of 30-minute reduction in pain score ranked 0-10 favored the lidocaine group (2.3 vs 1.1; P = .013). There was a 2-point reduction in pain scores in 69% of the lidocaine group and 34% of the saline group (P = .009) and a higher frequency of pain relief from moderate/severe to no pain or mild (52% versus 24%; P = .03). There was no significant difference in pain freedom.
After 24 hours, the treatment group was more likely to experience pain relief from moderate/severe to no pain or mild (24% vs 3%; P = .05) and to be free from associated symptoms (48% vs 21%; P = .027). Pain at the injection site was significantly higher in the placebo group (5.4 vs 3.2), prompting a change in plans for future trials. “I don’t think I would do saline again, because I think it hurt them, and I don’t want to cause them harm,” said Dr. Szperka.
Adverse events were common, with all but one patient in the study experiencing at least one. “I think this is a couple of things: One, kids don’t like needles in their head. Nerve blocks hurt. And so it was not surprising in some ways that we had a very high rate of adverse events. We also consented them, and that had a long wait period, and there’s a lot of anxiety in the room. However, most of the adverse events were mild,” said Dr. Szperka.
Important Research in an Understudied Population
Laine Greene, MD, who moderated the session, was asked for comment. “I think it’s an important study. Occipital nerve blocks have been used for a long period of time in management of migraine and other headache disorders. The quality of the evidence has always been brought into question, especially from payers, but also a very important aspect to this is that a lot of clinical trials over time have not specifically been done in children or adolescents, so any work that is done in that age category is significantly helpful to advancing therapeutics,” said Dr. Greene, associate professor of neurology at Mayo Clinic Arizona.
Dr. Szperka has consulted for AbbVie and Teva, and serves on data safety and monitoring boards for Eli Lilly and Upsher-Smith. She has been a principal investigator in trials sponsored by Abbvie, Amgen, Biohaven/Pfizer, Teva, and Theranica. Dr. Greene has no relevant financial disclosures.
SAN DIEGO — The treatment has long been used in adults, and frequently in children on the strength of observational evidence.
Prior Research
Most of the studies have been conducted in adults, and these were often in specific settings like the emergency department for status migrainosus, while outpatient studies were generally conducted in chronic migraine, according to presenting author Christina Szperka, MD. “The assumptions were a little bit different,” Dr. Szperka, director of the pediatric headache program at Children’s Hospital of Philadelphia, said in an interview.
Retrospective studies are also fraught with bias. “We’ve tried to look at retrospective data. People don’t necessarily report how they’re doing unless they come back, and so you lose a huge portion of kids,” said Dr. Szperka, who presented the research at the annual meeting of the American Headache Society.
“From a clinical perspective, I think it gives us additional evidence that what we’re doing makes a difference, and I think that will help us in terms of insurance coverage, because that’s really been a major barrier,” said Dr. Szperka.
The study also opens other avenues for research. “Just doing the greater occipital nerves only reduces the pain so much. So what’s the next step? Do I study additional injections? Do I do a study where I compare different medications?”
She previously conducted a study of how providers were using lidocaine injections, and “there was a large amount of variability, both in terms of what nerves are being injected, what medications they were using, the patient population, et cetera,” said Dr. Szperka. Previous observational studies have suggested efficacy in pediatric populations for transition and prevention of migraine, new daily persistent headache, posttraumatic headache, and post-shunt occipital neuralgia.
A Randomized, Controlled Trial
In the new study, 58 adolescents aged 7 to 21 (mean age, 16.0 years; 44 female) were initially treated with lidocaine cream. The patients were “relatively refractory,” said Dr. Szperka, with 25 having received intravenous medications and 6 having been inpatients. After 30 minutes, if they still had pain and consented to further treatment, Dr. Szperka performed bilateral greater occipital nerve injections with lidocaine or a saline placebo, and did additional injections after 30 minutes if there wasn’t sufficient improvement.
There was no significant change in pain after the lidocaine cream treatment, and all patients proceeded to be randomized to lidocaine or placebo injections. The primary outcome of 30-minute reduction in pain score ranked 0-10 favored the lidocaine group (2.3 vs 1.1; P = .013). There was a 2-point reduction in pain scores in 69% of the lidocaine group and 34% of the saline group (P = .009) and a higher frequency of pain relief from moderate/severe to no pain or mild (52% versus 24%; P = .03). There was no significant difference in pain freedom.
After 24 hours, the treatment group was more likely to experience pain relief from moderate/severe to no pain or mild (24% vs 3%; P = .05) and to be free from associated symptoms (48% vs 21%; P = .027). Pain at the injection site was significantly higher in the placebo group (5.4 vs 3.2), prompting a change in plans for future trials. “I don’t think I would do saline again, because I think it hurt them, and I don’t want to cause them harm,” said Dr. Szperka.
Adverse events were common, with all but one patient in the study experiencing at least one. “I think this is a couple of things: One, kids don’t like needles in their head. Nerve blocks hurt. And so it was not surprising in some ways that we had a very high rate of adverse events. We also consented them, and that had a long wait period, and there’s a lot of anxiety in the room. However, most of the adverse events were mild,” said Dr. Szperka.
Important Research in an Understudied Population
Laine Greene, MD, who moderated the session, was asked for comment. “I think it’s an important study. Occipital nerve blocks have been used for a long period of time in management of migraine and other headache disorders. The quality of the evidence has always been brought into question, especially from payers, but also a very important aspect to this is that a lot of clinical trials over time have not specifically been done in children or adolescents, so any work that is done in that age category is significantly helpful to advancing therapeutics,” said Dr. Greene, associate professor of neurology at Mayo Clinic Arizona.
Dr. Szperka has consulted for AbbVie and Teva, and serves on data safety and monitoring boards for Eli Lilly and Upsher-Smith. She has been a principal investigator in trials sponsored by Abbvie, Amgen, Biohaven/Pfizer, Teva, and Theranica. Dr. Greene has no relevant financial disclosures.
FROM AHS 2024
Potential Genes Identified for Post-Traumatic Headache
SAN DIEGO — , according to results from a preliminary study.
Post-traumatic headache is a common symptom of traumatic brain injury (TBI).
There is evidence that genetic mutations could play a role in both TBI development and response. In particular, the S213L mutation for familial hemiplegic migraine-1 (FHM1), found in the CACNA1A gene, can cause individuals carrying it to be highly sensitive to otherwise trivial head impacts, according to Lyn Griffiths, PhD.
The consequences can be post-traumatic headache, but also seizures, cerebral edema, coma, or worse. Another form of FHM is associated with mutations in ATP1A2.
“This stimulated our interest in looking at genes that relate to TBI with a particular focus on ion channel genes,” said Dr. Griffiths, during a presentation of the study at the annual meeting of the American Headache Society.
The researchers analyzed data from 117 participants who had at least one concussion with a post-traumatic headache, and recruited family members when possible. There were 15 participants who developed severe reactions to trivial head trauma, 13 who had been diagnosed with concussion and underwent imaging related to TBI-associated symptoms, 54 who had been recruited through local sporting groups campuses, and 35 recruited through a medical research foundation. Blood or saliva samples were used to perform whole exome sequencing.
The researchers looked for gene candidates within different tiers. Tier 1 included genes that had already been implicated in severe migraine. The second tier included 353 ion channel and iron transporter genes. Tier 3 comprised neurotransmission-related genes.
After sequencing, the researchers filtered genetic mutations to include only those that affected amino acid composition of the protein, were predicted by two or more in silico analysis tools to be damaging, and were identified in multiple, unrelated patients.
In tier 2, the greatest number of potential damaging variants were found in the SCN9A gene, which is involved in pain perception and processing. There were six variants found in eight cases. Of these eight individuals, three had suffered severe reactions to relatively minor head trauma.
In tier 3, the researchers identified mutations in eight neurotransmitter-related genes.
Through comparison with a general population control group, the researchers identified 43 different rare, amino acid–changing variants that occurred within 16 ion channel and ion channel transporter genes. These mutations were found in 53 individuals, at an approximately fivefold higher frequency than the control group (odds ratio, 5.6; P < .0001).
“We identified a number of rare genetic variants implicated in migraine — ion channel and other neurologically associated genes — in those suffering from post-traumatic headache,” said Dr. Griffiths. She also noted that the whole genomes they collected will allow for further analysis of other gene candidates in the future.
During the Q&A period, Dr. Griffiths was asked if the research group tracked the severity of the TBIs suffered by participants. She responded that they had not, and this was a limitation of the study.
Another questioner asked if parents should consider genetic testing for susceptibility mutations when considering whether to allow a child to participate in sports or activities with elevated risk of TBI. “I don’t necessarily think this is a bad thing,” she said, though she conceded that the work is still immature. “It’s probably a bit early because we haven’t identified all the genes that are involved or all the specific mutations ... but I think down the track, that makes perfect sense. Why would you not do some sensible preventive screening to aid with things like maybe you wear more headgear or you consider what’s the appropriate sport for that person?”
Laine Green, MD, assistant professor of neurology at Mayo Clinic Arizona, Phoenix, who moderated the session, was asked for comment. “I think the idea of potentially identifying people that have more genetic susceptibility to injuries is very intriguing, because post-traumatic headache and symptoms is always a difficult area to treat, potentially identifying those that with more genetic susceptibility might be helpful. It may also potentially allow us to target specific treatments, especially in this case, looking at different ion channels. There are medications that may work better at ion channel targets than other targets,” said Dr. Green.
He also endorsed the potential value of screening. “Speaking as a parent, I might like to know my child is at higher risk if they’re going to participate in contact sports or other high risk activities,” he said.
Dr. Griffiths and Dr. Green have no relevant financial disclosures.
SAN DIEGO — , according to results from a preliminary study.
Post-traumatic headache is a common symptom of traumatic brain injury (TBI).
There is evidence that genetic mutations could play a role in both TBI development and response. In particular, the S213L mutation for familial hemiplegic migraine-1 (FHM1), found in the CACNA1A gene, can cause individuals carrying it to be highly sensitive to otherwise trivial head impacts, according to Lyn Griffiths, PhD.
The consequences can be post-traumatic headache, but also seizures, cerebral edema, coma, or worse. Another form of FHM is associated with mutations in ATP1A2.
“This stimulated our interest in looking at genes that relate to TBI with a particular focus on ion channel genes,” said Dr. Griffiths, during a presentation of the study at the annual meeting of the American Headache Society.
The researchers analyzed data from 117 participants who had at least one concussion with a post-traumatic headache, and recruited family members when possible. There were 15 participants who developed severe reactions to trivial head trauma, 13 who had been diagnosed with concussion and underwent imaging related to TBI-associated symptoms, 54 who had been recruited through local sporting groups campuses, and 35 recruited through a medical research foundation. Blood or saliva samples were used to perform whole exome sequencing.
The researchers looked for gene candidates within different tiers. Tier 1 included genes that had already been implicated in severe migraine. The second tier included 353 ion channel and iron transporter genes. Tier 3 comprised neurotransmission-related genes.
After sequencing, the researchers filtered genetic mutations to include only those that affected amino acid composition of the protein, were predicted by two or more in silico analysis tools to be damaging, and were identified in multiple, unrelated patients.
In tier 2, the greatest number of potential damaging variants were found in the SCN9A gene, which is involved in pain perception and processing. There were six variants found in eight cases. Of these eight individuals, three had suffered severe reactions to relatively minor head trauma.
In tier 3, the researchers identified mutations in eight neurotransmitter-related genes.
Through comparison with a general population control group, the researchers identified 43 different rare, amino acid–changing variants that occurred within 16 ion channel and ion channel transporter genes. These mutations were found in 53 individuals, at an approximately fivefold higher frequency than the control group (odds ratio, 5.6; P < .0001).
“We identified a number of rare genetic variants implicated in migraine — ion channel and other neurologically associated genes — in those suffering from post-traumatic headache,” said Dr. Griffiths. She also noted that the whole genomes they collected will allow for further analysis of other gene candidates in the future.
During the Q&A period, Dr. Griffiths was asked if the research group tracked the severity of the TBIs suffered by participants. She responded that they had not, and this was a limitation of the study.
Another questioner asked if parents should consider genetic testing for susceptibility mutations when considering whether to allow a child to participate in sports or activities with elevated risk of TBI. “I don’t necessarily think this is a bad thing,” she said, though she conceded that the work is still immature. “It’s probably a bit early because we haven’t identified all the genes that are involved or all the specific mutations ... but I think down the track, that makes perfect sense. Why would you not do some sensible preventive screening to aid with things like maybe you wear more headgear or you consider what’s the appropriate sport for that person?”
Laine Green, MD, assistant professor of neurology at Mayo Clinic Arizona, Phoenix, who moderated the session, was asked for comment. “I think the idea of potentially identifying people that have more genetic susceptibility to injuries is very intriguing, because post-traumatic headache and symptoms is always a difficult area to treat, potentially identifying those that with more genetic susceptibility might be helpful. It may also potentially allow us to target specific treatments, especially in this case, looking at different ion channels. There are medications that may work better at ion channel targets than other targets,” said Dr. Green.
He also endorsed the potential value of screening. “Speaking as a parent, I might like to know my child is at higher risk if they’re going to participate in contact sports or other high risk activities,” he said.
Dr. Griffiths and Dr. Green have no relevant financial disclosures.
SAN DIEGO — , according to results from a preliminary study.
Post-traumatic headache is a common symptom of traumatic brain injury (TBI).
There is evidence that genetic mutations could play a role in both TBI development and response. In particular, the S213L mutation for familial hemiplegic migraine-1 (FHM1), found in the CACNA1A gene, can cause individuals carrying it to be highly sensitive to otherwise trivial head impacts, according to Lyn Griffiths, PhD.
The consequences can be post-traumatic headache, but also seizures, cerebral edema, coma, or worse. Another form of FHM is associated with mutations in ATP1A2.
“This stimulated our interest in looking at genes that relate to TBI with a particular focus on ion channel genes,” said Dr. Griffiths, during a presentation of the study at the annual meeting of the American Headache Society.
The researchers analyzed data from 117 participants who had at least one concussion with a post-traumatic headache, and recruited family members when possible. There were 15 participants who developed severe reactions to trivial head trauma, 13 who had been diagnosed with concussion and underwent imaging related to TBI-associated symptoms, 54 who had been recruited through local sporting groups campuses, and 35 recruited through a medical research foundation. Blood or saliva samples were used to perform whole exome sequencing.
The researchers looked for gene candidates within different tiers. Tier 1 included genes that had already been implicated in severe migraine. The second tier included 353 ion channel and iron transporter genes. Tier 3 comprised neurotransmission-related genes.
After sequencing, the researchers filtered genetic mutations to include only those that affected amino acid composition of the protein, were predicted by two or more in silico analysis tools to be damaging, and were identified in multiple, unrelated patients.
In tier 2, the greatest number of potential damaging variants were found in the SCN9A gene, which is involved in pain perception and processing. There were six variants found in eight cases. Of these eight individuals, three had suffered severe reactions to relatively minor head trauma.
In tier 3, the researchers identified mutations in eight neurotransmitter-related genes.
Through comparison with a general population control group, the researchers identified 43 different rare, amino acid–changing variants that occurred within 16 ion channel and ion channel transporter genes. These mutations were found in 53 individuals, at an approximately fivefold higher frequency than the control group (odds ratio, 5.6; P < .0001).
“We identified a number of rare genetic variants implicated in migraine — ion channel and other neurologically associated genes — in those suffering from post-traumatic headache,” said Dr. Griffiths. She also noted that the whole genomes they collected will allow for further analysis of other gene candidates in the future.
During the Q&A period, Dr. Griffiths was asked if the research group tracked the severity of the TBIs suffered by participants. She responded that they had not, and this was a limitation of the study.
Another questioner asked if parents should consider genetic testing for susceptibility mutations when considering whether to allow a child to participate in sports or activities with elevated risk of TBI. “I don’t necessarily think this is a bad thing,” she said, though she conceded that the work is still immature. “It’s probably a bit early because we haven’t identified all the genes that are involved or all the specific mutations ... but I think down the track, that makes perfect sense. Why would you not do some sensible preventive screening to aid with things like maybe you wear more headgear or you consider what’s the appropriate sport for that person?”
Laine Green, MD, assistant professor of neurology at Mayo Clinic Arizona, Phoenix, who moderated the session, was asked for comment. “I think the idea of potentially identifying people that have more genetic susceptibility to injuries is very intriguing, because post-traumatic headache and symptoms is always a difficult area to treat, potentially identifying those that with more genetic susceptibility might be helpful. It may also potentially allow us to target specific treatments, especially in this case, looking at different ion channels. There are medications that may work better at ion channel targets than other targets,” said Dr. Green.
He also endorsed the potential value of screening. “Speaking as a parent, I might like to know my child is at higher risk if they’re going to participate in contact sports or other high risk activities,” he said.
Dr. Griffiths and Dr. Green have no relevant financial disclosures.
FROM AHS 2024
Measuring Cognition in Migraine, One Patient at a Time
SAN DIEGO —
In fact, these effects may appear in the prodromal phase and carry through the headache and into the post-headache period, according to Richard Lipton, MD, who spoke about cognition and migraine at the annual meeting of the American Headache Society.
He pointed out existing evidence that migraine patients have cognitive impairment relative to the general population even during the interictal period. Such studies suggest that migraine, especially with aura, could be a risk factor for later dementia.
One important limitation of studies that compare people with migraines with controls is that a range of factors could explain an association between lower cognitive function and migraines, including socioeconomic factors, education, severe headaches requiring specialty care, and comorbidities, among others. Acute and preventative treatments could also affect cognition.
However, longitudinal studies of cognitive function in individual patients have been sparse. Questions remain, like whether cognitive performance differs between the headache period and the interictal period, as well as similar questions about the premonitory and post-drome phases. “And then there’s a long-term question: Do people with migraine show more interictal or ictal decline in cognitive performance relative to migraine-free controls?” said Dr. Lipton, professor of neurology at Albert Einstein College of Medicine in the Bronx, New York.
He showed evidence from a retrospective study by Lundbeck conducted at four sites that asked patients with chronic migraine about bothersome symptoms both before and after treatment. More than three-fourths (77.7%) rated “difficulty concentrating or thinking clearly” as a bothersome symptom.
Following treatment, 5.0% said their cognitive issues had completely improved, 32.0% that they were “very much” improved, 26.0% moderately improved, 23.0% slightly improved, and 14.0% not at all improved.
“I am not saying this is a rigorous study, but I am saying that it illustrates two points that are important for us today: One is that brain fog is very common in a subspecialty care sample of headache patients like the ones many of us treat, and it also suggests that there’s hope that treatment can improve cognitive impairment as migraine gets better,” said Dr. Lipton.
Cognition has received less attention than other migraine symptoms, and treatment can be a two-edged sword: “There’s some evidence that some treatments can reduce cognitive impairment, and obvious evidence that some treatments, topiramate and tricyclics, can induce cognitive impairment,” said Dr. Lipton.
Studies that compare cognition within the same patient at different time periods can get around some of the limitations of comparisons between populations, but face their own challenges. “Single shot” cognitive measures may not be reliably repeatable and differences seen on “good” versus “bad” days or proximity to recent headaches.
The solution, Dr. Lipton believes, is intensive repeated measures that avoid the practice effect, in which a participant improves at a test due to repetition.
He summarized a study that was presented later in the day at a poster session, which used smartphones or other devices to test 19 participants five times per day, over 5 days, in natural environments. Devices gathered both subjective and objective assessments of cognition, along with information on mood, stress, and status and fluctuations in pain, and have the potential to go further by measuring things like physical exertion, heart rate, pollution levels, and other variables.
“It clearly improves the reliability and the validity of cognitive assessment and makes it possible to link cognition to the stage of the headache cycle,” said Dr. Lipton.
The researchers found worse cognitive performance during the headache phase as compared with the interictal phase. “Objective cognitive performance measurably declines during the headache phase, and the next step is to fully control for acute medications that people may take during the headache phase,” said Dr. Lipton.
He expressed hope that improved measurements can improve outcomes, if it’s possible to identify therapies that don’t impact cognition. “We think it’s very likely that certain classes of acute and preventive medications may not cause cognitive impairment, and there is a strong hope that they may actually reduce the cognitive burden of disease and potentially even reduce cognitive decline. Those are areas that I’m very excited to explore in the future,” said Dr. Lipton.
The results emphasize the need to treat patients early, according to Nada Hindiyeh, MD, who attended the session and was asked for comment. “Generally, patients are going to come to you with episodic migraines. When migraines start to increase in frequency and severity, that means all of these other symptoms are going to come along with it and be increased in frequency and severity, so it’s important to recognize this early so you can get patients on the right treatments and preventives to really prevent these episodes from happening and prevent that cognitive decline,” said Dr. Hindiyeh, director of headache neurology at Metrodora Institute, West Valley City, Utah.
Dr. Lipton has financial relationships with Aeon, AbbVie/Allergan, Amgen, Biohaven, Dr. Reddy’s Laboratories, electroCore, Eli Lilly, GlaxoSmithKline, Lundbeck, Merck, Novartis, Pfizer, Teva, Axon, CoolTech, and Manistee. Dr. Hindiyeh has no relevant financial disclosures.
SAN DIEGO —
In fact, these effects may appear in the prodromal phase and carry through the headache and into the post-headache period, according to Richard Lipton, MD, who spoke about cognition and migraine at the annual meeting of the American Headache Society.
He pointed out existing evidence that migraine patients have cognitive impairment relative to the general population even during the interictal period. Such studies suggest that migraine, especially with aura, could be a risk factor for later dementia.
One important limitation of studies that compare people with migraines with controls is that a range of factors could explain an association between lower cognitive function and migraines, including socioeconomic factors, education, severe headaches requiring specialty care, and comorbidities, among others. Acute and preventative treatments could also affect cognition.
However, longitudinal studies of cognitive function in individual patients have been sparse. Questions remain, like whether cognitive performance differs between the headache period and the interictal period, as well as similar questions about the premonitory and post-drome phases. “And then there’s a long-term question: Do people with migraine show more interictal or ictal decline in cognitive performance relative to migraine-free controls?” said Dr. Lipton, professor of neurology at Albert Einstein College of Medicine in the Bronx, New York.
He showed evidence from a retrospective study by Lundbeck conducted at four sites that asked patients with chronic migraine about bothersome symptoms both before and after treatment. More than three-fourths (77.7%) rated “difficulty concentrating or thinking clearly” as a bothersome symptom.
Following treatment, 5.0% said their cognitive issues had completely improved, 32.0% that they were “very much” improved, 26.0% moderately improved, 23.0% slightly improved, and 14.0% not at all improved.
“I am not saying this is a rigorous study, but I am saying that it illustrates two points that are important for us today: One is that brain fog is very common in a subspecialty care sample of headache patients like the ones many of us treat, and it also suggests that there’s hope that treatment can improve cognitive impairment as migraine gets better,” said Dr. Lipton.
Cognition has received less attention than other migraine symptoms, and treatment can be a two-edged sword: “There’s some evidence that some treatments can reduce cognitive impairment, and obvious evidence that some treatments, topiramate and tricyclics, can induce cognitive impairment,” said Dr. Lipton.
Studies that compare cognition within the same patient at different time periods can get around some of the limitations of comparisons between populations, but face their own challenges. “Single shot” cognitive measures may not be reliably repeatable and differences seen on “good” versus “bad” days or proximity to recent headaches.
The solution, Dr. Lipton believes, is intensive repeated measures that avoid the practice effect, in which a participant improves at a test due to repetition.
He summarized a study that was presented later in the day at a poster session, which used smartphones or other devices to test 19 participants five times per day, over 5 days, in natural environments. Devices gathered both subjective and objective assessments of cognition, along with information on mood, stress, and status and fluctuations in pain, and have the potential to go further by measuring things like physical exertion, heart rate, pollution levels, and other variables.
“It clearly improves the reliability and the validity of cognitive assessment and makes it possible to link cognition to the stage of the headache cycle,” said Dr. Lipton.
The researchers found worse cognitive performance during the headache phase as compared with the interictal phase. “Objective cognitive performance measurably declines during the headache phase, and the next step is to fully control for acute medications that people may take during the headache phase,” said Dr. Lipton.
He expressed hope that improved measurements can improve outcomes, if it’s possible to identify therapies that don’t impact cognition. “We think it’s very likely that certain classes of acute and preventive medications may not cause cognitive impairment, and there is a strong hope that they may actually reduce the cognitive burden of disease and potentially even reduce cognitive decline. Those are areas that I’m very excited to explore in the future,” said Dr. Lipton.
The results emphasize the need to treat patients early, according to Nada Hindiyeh, MD, who attended the session and was asked for comment. “Generally, patients are going to come to you with episodic migraines. When migraines start to increase in frequency and severity, that means all of these other symptoms are going to come along with it and be increased in frequency and severity, so it’s important to recognize this early so you can get patients on the right treatments and preventives to really prevent these episodes from happening and prevent that cognitive decline,” said Dr. Hindiyeh, director of headache neurology at Metrodora Institute, West Valley City, Utah.
Dr. Lipton has financial relationships with Aeon, AbbVie/Allergan, Amgen, Biohaven, Dr. Reddy’s Laboratories, electroCore, Eli Lilly, GlaxoSmithKline, Lundbeck, Merck, Novartis, Pfizer, Teva, Axon, CoolTech, and Manistee. Dr. Hindiyeh has no relevant financial disclosures.
SAN DIEGO —
In fact, these effects may appear in the prodromal phase and carry through the headache and into the post-headache period, according to Richard Lipton, MD, who spoke about cognition and migraine at the annual meeting of the American Headache Society.
He pointed out existing evidence that migraine patients have cognitive impairment relative to the general population even during the interictal period. Such studies suggest that migraine, especially with aura, could be a risk factor for later dementia.
One important limitation of studies that compare people with migraines with controls is that a range of factors could explain an association between lower cognitive function and migraines, including socioeconomic factors, education, severe headaches requiring specialty care, and comorbidities, among others. Acute and preventative treatments could also affect cognition.
However, longitudinal studies of cognitive function in individual patients have been sparse. Questions remain, like whether cognitive performance differs between the headache period and the interictal period, as well as similar questions about the premonitory and post-drome phases. “And then there’s a long-term question: Do people with migraine show more interictal or ictal decline in cognitive performance relative to migraine-free controls?” said Dr. Lipton, professor of neurology at Albert Einstein College of Medicine in the Bronx, New York.
He showed evidence from a retrospective study by Lundbeck conducted at four sites that asked patients with chronic migraine about bothersome symptoms both before and after treatment. More than three-fourths (77.7%) rated “difficulty concentrating or thinking clearly” as a bothersome symptom.
Following treatment, 5.0% said their cognitive issues had completely improved, 32.0% that they were “very much” improved, 26.0% moderately improved, 23.0% slightly improved, and 14.0% not at all improved.
“I am not saying this is a rigorous study, but I am saying that it illustrates two points that are important for us today: One is that brain fog is very common in a subspecialty care sample of headache patients like the ones many of us treat, and it also suggests that there’s hope that treatment can improve cognitive impairment as migraine gets better,” said Dr. Lipton.
Cognition has received less attention than other migraine symptoms, and treatment can be a two-edged sword: “There’s some evidence that some treatments can reduce cognitive impairment, and obvious evidence that some treatments, topiramate and tricyclics, can induce cognitive impairment,” said Dr. Lipton.
Studies that compare cognition within the same patient at different time periods can get around some of the limitations of comparisons between populations, but face their own challenges. “Single shot” cognitive measures may not be reliably repeatable and differences seen on “good” versus “bad” days or proximity to recent headaches.
The solution, Dr. Lipton believes, is intensive repeated measures that avoid the practice effect, in which a participant improves at a test due to repetition.
He summarized a study that was presented later in the day at a poster session, which used smartphones or other devices to test 19 participants five times per day, over 5 days, in natural environments. Devices gathered both subjective and objective assessments of cognition, along with information on mood, stress, and status and fluctuations in pain, and have the potential to go further by measuring things like physical exertion, heart rate, pollution levels, and other variables.
“It clearly improves the reliability and the validity of cognitive assessment and makes it possible to link cognition to the stage of the headache cycle,” said Dr. Lipton.
The researchers found worse cognitive performance during the headache phase as compared with the interictal phase. “Objective cognitive performance measurably declines during the headache phase, and the next step is to fully control for acute medications that people may take during the headache phase,” said Dr. Lipton.
He expressed hope that improved measurements can improve outcomes, if it’s possible to identify therapies that don’t impact cognition. “We think it’s very likely that certain classes of acute and preventive medications may not cause cognitive impairment, and there is a strong hope that they may actually reduce the cognitive burden of disease and potentially even reduce cognitive decline. Those are areas that I’m very excited to explore in the future,” said Dr. Lipton.
The results emphasize the need to treat patients early, according to Nada Hindiyeh, MD, who attended the session and was asked for comment. “Generally, patients are going to come to you with episodic migraines. When migraines start to increase in frequency and severity, that means all of these other symptoms are going to come along with it and be increased in frequency and severity, so it’s important to recognize this early so you can get patients on the right treatments and preventives to really prevent these episodes from happening and prevent that cognitive decline,” said Dr. Hindiyeh, director of headache neurology at Metrodora Institute, West Valley City, Utah.
Dr. Lipton has financial relationships with Aeon, AbbVie/Allergan, Amgen, Biohaven, Dr. Reddy’s Laboratories, electroCore, Eli Lilly, GlaxoSmithKline, Lundbeck, Merck, Novartis, Pfizer, Teva, Axon, CoolTech, and Manistee. Dr. Hindiyeh has no relevant financial disclosures.
FROM AHS 2024
Prospective MS Trial Proves Ocrelizumab Efficacy in Under-Represented Populations
NASHVILLE, Tennessee — , according to the results of a 1-year analysis of the CHIMES trial. The study is the first-ever prospective study of an MS disease-modifying therapy (DMT) exclusively performed in under-represented populations, and offers lessons to researchers aiming to design more inclusive clinical trials to bolster participation by under-represented populations.
“The goal was to better understand efficacy of therapy in under-represented populations because we typically have very low numbers of these patients in our clinical trials, although there are multiple studies over the past decades suggesting that there may be poorer outcomes in Black and Hispanic individuals, particularly in the United States, and that there also may be more aggressive disease,” said Mitzi Williams, MD, who presented the study in a poster session at the annual meeting of the Consortium of Multiple Sclerosis Centers.
The team recruited 113 Black participants and 69 Hispanic participants, and, in fact, over-recruited the target number by 25%, and did so 2 months before the launch of the study in July 2020, which just happened to be in the midst of a global pandemic.
After 48 weeks of ocrelizumab treatment, 46.0% of Black participants and 58.0% of Hispanic participants achieved no evidence of disease activity in three components (NEDA-3), while 94.7% and 95.7% were free from relapses, respectively, and 94.7% and 94.2% were free from disease worsening. Serious adverse events occurred in 6.2% and 4.3% of each group, respectively, and there were no new safety signals in either group.
“The good news is that the efficacy and safety was very similar to what we saw in other clinical trials. I don’t think we really expected it to be much different, because when we think about race, it’s a social construct, not a biologic construct. What we do hope to find out is more about some of the interplay of social determinants of health, and how getting on high efficacy treatment can improve and increase productivity and outcomes in the long term,” said Dr. Williams, who is medical director of Joi Life Wellness Group, Smyrna, Georgia.
The researchers succeeded by involving patient advocates and advocacy organizations at the very earliest stages of the trial design. “We were very intentional about looking at things like social determinants of health, childcare, transportation, and things like that to ease some of the burden of participating in the trial, obviously in a legal and compliant way,” said Dr. Williams. The team also ensured complete and accurate translation of patient materials into Spanish.
The study was also a phase 4 trial, which may have simplified recruitment. “So it’s a therapy that’s already approved, which may make people feel more comfortable, but obviously the goal is for our phase 3 trials to make sure that we are recruiting represented populations. We’re taking these learnings and applying them to the broader clinical trial population so that hopefully we won’t have to come back and do phase 4 studies like this,” said Dr. Williams.
She noted that the results of more inclusive studies don’t just benefit underserved populations. “You have groups of people that are suffering and having more disability from a condition, and you need to understand why. When we broaden the population to understand those that are most vulnerable and underserved and [having the worst outcomes], it really helps us to better treat everybody. Because if we can get a hold of those factors that make us do the worst, then we can also better understand the factors that make us do the best,” said Dr. Williams.
Inclusive Recruitment in Clinical Trials
Asked for comment, Ahmed Obeidat, MD, PhD, highlighted the importance of inclusive recruitment. “The study is very important because historically and even in most recent clinical trials, these groups were markedly under-represented and most completed clinical trials derive conclusions based on the study of a nondiverse, White-non-Hispanic predominant population,” said Dr. Obeidat, who is an associate professor at the Medical College of Wisconsin, Milwaukee. He pointed to a systematic review showing that the median percentage of White participants in MS clinical trials was 93% and ranged from 86% to 98%.
“Several factors may contribute to the disparity in clinical trial participation, and solutions must be explored and developed. CHIMES is a first step in this direction where the study itself is designed to address disparity in MS clinical trial participation,” said Dr. Obeidat.
Dr. Obeidat also pointed to the need to consider other forms of diversity in clinical trials, such as older patients and those with advanced disability. “Investigators, coordinators, and other staff should all strive to be as inclusive as possible in clinical trials,” he said.
Dr. Williams has received consulting fees from Alexion, Biogen, Bristol Myers Squibb, EMD Serono, Genentech Inc., Janssen, Novartis, Sanofi, and TG Therapeutics, and serves on speakers bureaus for Biogen, Bristol Myers Squibb, EMD Serono, Janssen, Genentech, and TG Therapeutics. Dr. Ahmed Z. Obeidat has financial relationships with Alexion Pharmaceuticals, Banner Life Sciences, BD Biosciences, Biogen, Biologix Solutions, Bristol Myers Squibb, Celgene, EMD Serono, Genentech, GW Pharmaceuticals, Horizon Therapeutics, Jazz Pharmaceuticals, Novartis, Sandoz, Sanofi Genzyme, TG Therapeutics, and Viela Bio.
NASHVILLE, Tennessee — , according to the results of a 1-year analysis of the CHIMES trial. The study is the first-ever prospective study of an MS disease-modifying therapy (DMT) exclusively performed in under-represented populations, and offers lessons to researchers aiming to design more inclusive clinical trials to bolster participation by under-represented populations.
“The goal was to better understand efficacy of therapy in under-represented populations because we typically have very low numbers of these patients in our clinical trials, although there are multiple studies over the past decades suggesting that there may be poorer outcomes in Black and Hispanic individuals, particularly in the United States, and that there also may be more aggressive disease,” said Mitzi Williams, MD, who presented the study in a poster session at the annual meeting of the Consortium of Multiple Sclerosis Centers.
The team recruited 113 Black participants and 69 Hispanic participants, and, in fact, over-recruited the target number by 25%, and did so 2 months before the launch of the study in July 2020, which just happened to be in the midst of a global pandemic.
After 48 weeks of ocrelizumab treatment, 46.0% of Black participants and 58.0% of Hispanic participants achieved no evidence of disease activity in three components (NEDA-3), while 94.7% and 95.7% were free from relapses, respectively, and 94.7% and 94.2% were free from disease worsening. Serious adverse events occurred in 6.2% and 4.3% of each group, respectively, and there were no new safety signals in either group.
“The good news is that the efficacy and safety was very similar to what we saw in other clinical trials. I don’t think we really expected it to be much different, because when we think about race, it’s a social construct, not a biologic construct. What we do hope to find out is more about some of the interplay of social determinants of health, and how getting on high efficacy treatment can improve and increase productivity and outcomes in the long term,” said Dr. Williams, who is medical director of Joi Life Wellness Group, Smyrna, Georgia.
The researchers succeeded by involving patient advocates and advocacy organizations at the very earliest stages of the trial design. “We were very intentional about looking at things like social determinants of health, childcare, transportation, and things like that to ease some of the burden of participating in the trial, obviously in a legal and compliant way,” said Dr. Williams. The team also ensured complete and accurate translation of patient materials into Spanish.
The study was also a phase 4 trial, which may have simplified recruitment. “So it’s a therapy that’s already approved, which may make people feel more comfortable, but obviously the goal is for our phase 3 trials to make sure that we are recruiting represented populations. We’re taking these learnings and applying them to the broader clinical trial population so that hopefully we won’t have to come back and do phase 4 studies like this,” said Dr. Williams.
She noted that the results of more inclusive studies don’t just benefit underserved populations. “You have groups of people that are suffering and having more disability from a condition, and you need to understand why. When we broaden the population to understand those that are most vulnerable and underserved and [having the worst outcomes], it really helps us to better treat everybody. Because if we can get a hold of those factors that make us do the worst, then we can also better understand the factors that make us do the best,” said Dr. Williams.
Inclusive Recruitment in Clinical Trials
Asked for comment, Ahmed Obeidat, MD, PhD, highlighted the importance of inclusive recruitment. “The study is very important because historically and even in most recent clinical trials, these groups were markedly under-represented and most completed clinical trials derive conclusions based on the study of a nondiverse, White-non-Hispanic predominant population,” said Dr. Obeidat, who is an associate professor at the Medical College of Wisconsin, Milwaukee. He pointed to a systematic review showing that the median percentage of White participants in MS clinical trials was 93% and ranged from 86% to 98%.
“Several factors may contribute to the disparity in clinical trial participation, and solutions must be explored and developed. CHIMES is a first step in this direction where the study itself is designed to address disparity in MS clinical trial participation,” said Dr. Obeidat.
Dr. Obeidat also pointed to the need to consider other forms of diversity in clinical trials, such as older patients and those with advanced disability. “Investigators, coordinators, and other staff should all strive to be as inclusive as possible in clinical trials,” he said.
Dr. Williams has received consulting fees from Alexion, Biogen, Bristol Myers Squibb, EMD Serono, Genentech Inc., Janssen, Novartis, Sanofi, and TG Therapeutics, and serves on speakers bureaus for Biogen, Bristol Myers Squibb, EMD Serono, Janssen, Genentech, and TG Therapeutics. Dr. Ahmed Z. Obeidat has financial relationships with Alexion Pharmaceuticals, Banner Life Sciences, BD Biosciences, Biogen, Biologix Solutions, Bristol Myers Squibb, Celgene, EMD Serono, Genentech, GW Pharmaceuticals, Horizon Therapeutics, Jazz Pharmaceuticals, Novartis, Sandoz, Sanofi Genzyme, TG Therapeutics, and Viela Bio.
NASHVILLE, Tennessee — , according to the results of a 1-year analysis of the CHIMES trial. The study is the first-ever prospective study of an MS disease-modifying therapy (DMT) exclusively performed in under-represented populations, and offers lessons to researchers aiming to design more inclusive clinical trials to bolster participation by under-represented populations.
“The goal was to better understand efficacy of therapy in under-represented populations because we typically have very low numbers of these patients in our clinical trials, although there are multiple studies over the past decades suggesting that there may be poorer outcomes in Black and Hispanic individuals, particularly in the United States, and that there also may be more aggressive disease,” said Mitzi Williams, MD, who presented the study in a poster session at the annual meeting of the Consortium of Multiple Sclerosis Centers.
The team recruited 113 Black participants and 69 Hispanic participants, and, in fact, over-recruited the target number by 25%, and did so 2 months before the launch of the study in July 2020, which just happened to be in the midst of a global pandemic.
After 48 weeks of ocrelizumab treatment, 46.0% of Black participants and 58.0% of Hispanic participants achieved no evidence of disease activity in three components (NEDA-3), while 94.7% and 95.7% were free from relapses, respectively, and 94.7% and 94.2% were free from disease worsening. Serious adverse events occurred in 6.2% and 4.3% of each group, respectively, and there were no new safety signals in either group.
“The good news is that the efficacy and safety was very similar to what we saw in other clinical trials. I don’t think we really expected it to be much different, because when we think about race, it’s a social construct, not a biologic construct. What we do hope to find out is more about some of the interplay of social determinants of health, and how getting on high efficacy treatment can improve and increase productivity and outcomes in the long term,” said Dr. Williams, who is medical director of Joi Life Wellness Group, Smyrna, Georgia.
The researchers succeeded by involving patient advocates and advocacy organizations at the very earliest stages of the trial design. “We were very intentional about looking at things like social determinants of health, childcare, transportation, and things like that to ease some of the burden of participating in the trial, obviously in a legal and compliant way,” said Dr. Williams. The team also ensured complete and accurate translation of patient materials into Spanish.
The study was also a phase 4 trial, which may have simplified recruitment. “So it’s a therapy that’s already approved, which may make people feel more comfortable, but obviously the goal is for our phase 3 trials to make sure that we are recruiting represented populations. We’re taking these learnings and applying them to the broader clinical trial population so that hopefully we won’t have to come back and do phase 4 studies like this,” said Dr. Williams.
She noted that the results of more inclusive studies don’t just benefit underserved populations. “You have groups of people that are suffering and having more disability from a condition, and you need to understand why. When we broaden the population to understand those that are most vulnerable and underserved and [having the worst outcomes], it really helps us to better treat everybody. Because if we can get a hold of those factors that make us do the worst, then we can also better understand the factors that make us do the best,” said Dr. Williams.
Inclusive Recruitment in Clinical Trials
Asked for comment, Ahmed Obeidat, MD, PhD, highlighted the importance of inclusive recruitment. “The study is very important because historically and even in most recent clinical trials, these groups were markedly under-represented and most completed clinical trials derive conclusions based on the study of a nondiverse, White-non-Hispanic predominant population,” said Dr. Obeidat, who is an associate professor at the Medical College of Wisconsin, Milwaukee. He pointed to a systematic review showing that the median percentage of White participants in MS clinical trials was 93% and ranged from 86% to 98%.
“Several factors may contribute to the disparity in clinical trial participation, and solutions must be explored and developed. CHIMES is a first step in this direction where the study itself is designed to address disparity in MS clinical trial participation,” said Dr. Obeidat.
Dr. Obeidat also pointed to the need to consider other forms of diversity in clinical trials, such as older patients and those with advanced disability. “Investigators, coordinators, and other staff should all strive to be as inclusive as possible in clinical trials,” he said.
Dr. Williams has received consulting fees from Alexion, Biogen, Bristol Myers Squibb, EMD Serono, Genentech Inc., Janssen, Novartis, Sanofi, and TG Therapeutics, and serves on speakers bureaus for Biogen, Bristol Myers Squibb, EMD Serono, Janssen, Genentech, and TG Therapeutics. Dr. Ahmed Z. Obeidat has financial relationships with Alexion Pharmaceuticals, Banner Life Sciences, BD Biosciences, Biogen, Biologix Solutions, Bristol Myers Squibb, Celgene, EMD Serono, Genentech, GW Pharmaceuticals, Horizon Therapeutics, Jazz Pharmaceuticals, Novartis, Sandoz, Sanofi Genzyme, TG Therapeutics, and Viela Bio.
FROM CMSC 2024
Pediatric Ocrelizumab Dose Established for MS
NASHVILLE, Tennessee — , according to pharmacokinetic/pharmacodynamic (PK/PD) data from the OPERETTA 1 phase 2 clinical trial. The safety profile was similar to adult patients.
“While we believe the disease to be the same in children and adolescents, [MS] is distinguished by its very inflammatory nature, oftentimes causing two to three times the number of relapses per year as their adult-onset colleagues,” said Teri Schreiner, MD, during a presentation of the results at the annual meeting of the Consortium of Multiple Sclerosis Centers.
Approved therapies for pediatric MS include fingolimod in the United States and Europe, as well as dimethyl fumarate in Europe. “There’s a real need for high-efficacy treatment [in pediatric patients], again referring back to this disease being very inflammatory in children and adolescents. We oftentimes will use medications off label but this is clearly suboptimal as we lack safety data, and oftentimes run into difficulty with insurance approval of off-label use of medicine,” said Dr. Schreiner, who is an associate professor of neurology at University of Colorado School of Medicine, Aurora.
To determine the dose in pediatric patients that would produce comparable PK and PD to adults, the researchers dosed six patients aged 10-18 with 300 mg ocrelizumab, and 17 such patients with 600 mg ocrelizumab during a 24-week dose-exploration period, followed by a 264-week optional extension period. The cohorts were separated based on weight of less than or more than 40 kg. The mean ages were 11.2 years (mean weight, 34.9 kg) and 15.3 years (mean weight, 62.3 kg), respectively.
During the dose-exploration period, seven blood draws were performed to characterize PK. “When the PK data was analyzed, we saw that the proper cut-off point was 35 kilos. At less than 35 kilos, the appropriate dose was half of that adult dose, so 300 milligrams every 6 months, whereas above 35 kilos, the proper dose was actually 600, or the adult dose. Given the rarity of pediatric-onset MS patients less than 35 kilos, most patients will benefit from the adult dose of 600 milligrams twice yearly,” said Dr. Schreiner.
PD data were also encouraging. “The primary PD was the absence of CD-19 B cells, and that was tracked over time. While there were a few patients in both cohorts that had modest reconstitution, there was no patient in our study that crossed the retreatment threshold, and all blood samples were negative for anti-drug antibodies,” said Dr. Schreiner.
Adverse events occurred in five of six patients in the 300 mg group (83%; 4 grade 2, 1 grade 3) and 100% of patients in the 600 mg group (1 grade 1, 9 grade 2, 6 grade 3, 1 grade 4). There was one serious adverse event in the 300 mg group (16.7%) and four serious adverse events in the 600 mg group (23.5%). None led to treatment discontinuation. “This is largely consistent with what was seen in the adult studies of ocrelizumab,” said Dr. Schreiner.
Roche is now recruiting for the phase 3 OPERETTA 2 trial, which will use the 600 mg dose and compare outcomes to a fingolimod arm.
Establishing Safety in the Pediatric Population
“In [pediatric onset MS] it’s an important piece of information to design OPERETTA 2 and to dose ocrelizumab in pediatric-onset MS in general,” said Jeffrey A Cohen, MD, professor of neurology at the Cleveland Clinic, who was asked for comment.
During the Q&A period, Dr. Schreiner was asked whether it is possible to extrapolate experience from rituximab to the pediatric population. “They’re very similar molecules, and we know the mechanisms of action, but I think part of the importance of doing these studies is to get the safety data so that we actually can say with certainty, we are giving you a drug that has this list of side effects and we know about them definitively. We all use other high-efficacy medications, but I don’t think we can exactly extrapolate,” said Dr. Schreiner.
Session moderator Amy Perrin Ross, APN, noted the lack of approved pediatric therapies for MS. “This is an extremely important study, because we at least in the lower 48 are quite limited in our resources for approved pediatric cases. Information like this will make it easier for a potential pediatric indication, which would then make it easier on us to go after [treatment of the disease in this population]. The weight-based dosing, I think, is really a good thing. Patients have been asking for weight-based dosing on everything for many years,” she said.
Ahmed Obeidat, MD, PhD, associate professor at the Medical College of Wisconsin, also praised the study. “While pediatric MS is rare, it is an area of unmet need when it comes to disease-modifying therapies as only fingolimod is FDA-approved, and many use B cell–depleting therapy, such as rituximab, off label to treat children with MS with good outcomes. The need for guidance on the dosing of B cell–depleting therapy is a main priority for research in pediatric MS,” he said.
The study was funded by Roche. Dr. Schreiner has consulted for Roche and Cycle Pharmaceuticals. Dr. Cohen has consulted for Astoria, Bristol Myers Squibb, Convelo, EMD Serono Inc, FiND, INMune, and Sandoz. Dr. Obeidat has financial relationships with Alexion Pharmaceuticals, Banner Life Sciences, BD Biosciences, Biogen, Biologix Solutions, Bristol Myers Squibb, Celgene, EMD Serono, Genentech, GW Pharmaceuticals, Horizon Therapeutics, Jazz Pharmaceuticals, Novartis, Sandoz, Sanofi Genzyme, TG Therapeutics, and Viela Bio. Ms. Ross has consulted for EMD Serono, BMS, Horizon, Alexion, TG Therapeutics, Novartis, Roche, and Sanofi.
NASHVILLE, Tennessee — , according to pharmacokinetic/pharmacodynamic (PK/PD) data from the OPERETTA 1 phase 2 clinical trial. The safety profile was similar to adult patients.
“While we believe the disease to be the same in children and adolescents, [MS] is distinguished by its very inflammatory nature, oftentimes causing two to three times the number of relapses per year as their adult-onset colleagues,” said Teri Schreiner, MD, during a presentation of the results at the annual meeting of the Consortium of Multiple Sclerosis Centers.
Approved therapies for pediatric MS include fingolimod in the United States and Europe, as well as dimethyl fumarate in Europe. “There’s a real need for high-efficacy treatment [in pediatric patients], again referring back to this disease being very inflammatory in children and adolescents. We oftentimes will use medications off label but this is clearly suboptimal as we lack safety data, and oftentimes run into difficulty with insurance approval of off-label use of medicine,” said Dr. Schreiner, who is an associate professor of neurology at University of Colorado School of Medicine, Aurora.
To determine the dose in pediatric patients that would produce comparable PK and PD to adults, the researchers dosed six patients aged 10-18 with 300 mg ocrelizumab, and 17 such patients with 600 mg ocrelizumab during a 24-week dose-exploration period, followed by a 264-week optional extension period. The cohorts were separated based on weight of less than or more than 40 kg. The mean ages were 11.2 years (mean weight, 34.9 kg) and 15.3 years (mean weight, 62.3 kg), respectively.
During the dose-exploration period, seven blood draws were performed to characterize PK. “When the PK data was analyzed, we saw that the proper cut-off point was 35 kilos. At less than 35 kilos, the appropriate dose was half of that adult dose, so 300 milligrams every 6 months, whereas above 35 kilos, the proper dose was actually 600, or the adult dose. Given the rarity of pediatric-onset MS patients less than 35 kilos, most patients will benefit from the adult dose of 600 milligrams twice yearly,” said Dr. Schreiner.
PD data were also encouraging. “The primary PD was the absence of CD-19 B cells, and that was tracked over time. While there were a few patients in both cohorts that had modest reconstitution, there was no patient in our study that crossed the retreatment threshold, and all blood samples were negative for anti-drug antibodies,” said Dr. Schreiner.
Adverse events occurred in five of six patients in the 300 mg group (83%; 4 grade 2, 1 grade 3) and 100% of patients in the 600 mg group (1 grade 1, 9 grade 2, 6 grade 3, 1 grade 4). There was one serious adverse event in the 300 mg group (16.7%) and four serious adverse events in the 600 mg group (23.5%). None led to treatment discontinuation. “This is largely consistent with what was seen in the adult studies of ocrelizumab,” said Dr. Schreiner.
Roche is now recruiting for the phase 3 OPERETTA 2 trial, which will use the 600 mg dose and compare outcomes to a fingolimod arm.
Establishing Safety in the Pediatric Population
“In [pediatric onset MS] it’s an important piece of information to design OPERETTA 2 and to dose ocrelizumab in pediatric-onset MS in general,” said Jeffrey A Cohen, MD, professor of neurology at the Cleveland Clinic, who was asked for comment.
During the Q&A period, Dr. Schreiner was asked whether it is possible to extrapolate experience from rituximab to the pediatric population. “They’re very similar molecules, and we know the mechanisms of action, but I think part of the importance of doing these studies is to get the safety data so that we actually can say with certainty, we are giving you a drug that has this list of side effects and we know about them definitively. We all use other high-efficacy medications, but I don’t think we can exactly extrapolate,” said Dr. Schreiner.
Session moderator Amy Perrin Ross, APN, noted the lack of approved pediatric therapies for MS. “This is an extremely important study, because we at least in the lower 48 are quite limited in our resources for approved pediatric cases. Information like this will make it easier for a potential pediatric indication, which would then make it easier on us to go after [treatment of the disease in this population]. The weight-based dosing, I think, is really a good thing. Patients have been asking for weight-based dosing on everything for many years,” she said.
Ahmed Obeidat, MD, PhD, associate professor at the Medical College of Wisconsin, also praised the study. “While pediatric MS is rare, it is an area of unmet need when it comes to disease-modifying therapies as only fingolimod is FDA-approved, and many use B cell–depleting therapy, such as rituximab, off label to treat children with MS with good outcomes. The need for guidance on the dosing of B cell–depleting therapy is a main priority for research in pediatric MS,” he said.
The study was funded by Roche. Dr. Schreiner has consulted for Roche and Cycle Pharmaceuticals. Dr. Cohen has consulted for Astoria, Bristol Myers Squibb, Convelo, EMD Serono Inc, FiND, INMune, and Sandoz. Dr. Obeidat has financial relationships with Alexion Pharmaceuticals, Banner Life Sciences, BD Biosciences, Biogen, Biologix Solutions, Bristol Myers Squibb, Celgene, EMD Serono, Genentech, GW Pharmaceuticals, Horizon Therapeutics, Jazz Pharmaceuticals, Novartis, Sandoz, Sanofi Genzyme, TG Therapeutics, and Viela Bio. Ms. Ross has consulted for EMD Serono, BMS, Horizon, Alexion, TG Therapeutics, Novartis, Roche, and Sanofi.
NASHVILLE, Tennessee — , according to pharmacokinetic/pharmacodynamic (PK/PD) data from the OPERETTA 1 phase 2 clinical trial. The safety profile was similar to adult patients.
“While we believe the disease to be the same in children and adolescents, [MS] is distinguished by its very inflammatory nature, oftentimes causing two to three times the number of relapses per year as their adult-onset colleagues,” said Teri Schreiner, MD, during a presentation of the results at the annual meeting of the Consortium of Multiple Sclerosis Centers.
Approved therapies for pediatric MS include fingolimod in the United States and Europe, as well as dimethyl fumarate in Europe. “There’s a real need for high-efficacy treatment [in pediatric patients], again referring back to this disease being very inflammatory in children and adolescents. We oftentimes will use medications off label but this is clearly suboptimal as we lack safety data, and oftentimes run into difficulty with insurance approval of off-label use of medicine,” said Dr. Schreiner, who is an associate professor of neurology at University of Colorado School of Medicine, Aurora.
To determine the dose in pediatric patients that would produce comparable PK and PD to adults, the researchers dosed six patients aged 10-18 with 300 mg ocrelizumab, and 17 such patients with 600 mg ocrelizumab during a 24-week dose-exploration period, followed by a 264-week optional extension period. The cohorts were separated based on weight of less than or more than 40 kg. The mean ages were 11.2 years (mean weight, 34.9 kg) and 15.3 years (mean weight, 62.3 kg), respectively.
During the dose-exploration period, seven blood draws were performed to characterize PK. “When the PK data was analyzed, we saw that the proper cut-off point was 35 kilos. At less than 35 kilos, the appropriate dose was half of that adult dose, so 300 milligrams every 6 months, whereas above 35 kilos, the proper dose was actually 600, or the adult dose. Given the rarity of pediatric-onset MS patients less than 35 kilos, most patients will benefit from the adult dose of 600 milligrams twice yearly,” said Dr. Schreiner.
PD data were also encouraging. “The primary PD was the absence of CD-19 B cells, and that was tracked over time. While there were a few patients in both cohorts that had modest reconstitution, there was no patient in our study that crossed the retreatment threshold, and all blood samples were negative for anti-drug antibodies,” said Dr. Schreiner.
Adverse events occurred in five of six patients in the 300 mg group (83%; 4 grade 2, 1 grade 3) and 100% of patients in the 600 mg group (1 grade 1, 9 grade 2, 6 grade 3, 1 grade 4). There was one serious adverse event in the 300 mg group (16.7%) and four serious adverse events in the 600 mg group (23.5%). None led to treatment discontinuation. “This is largely consistent with what was seen in the adult studies of ocrelizumab,” said Dr. Schreiner.
Roche is now recruiting for the phase 3 OPERETTA 2 trial, which will use the 600 mg dose and compare outcomes to a fingolimod arm.
Establishing Safety in the Pediatric Population
“In [pediatric onset MS] it’s an important piece of information to design OPERETTA 2 and to dose ocrelizumab in pediatric-onset MS in general,” said Jeffrey A Cohen, MD, professor of neurology at the Cleveland Clinic, who was asked for comment.
During the Q&A period, Dr. Schreiner was asked whether it is possible to extrapolate experience from rituximab to the pediatric population. “They’re very similar molecules, and we know the mechanisms of action, but I think part of the importance of doing these studies is to get the safety data so that we actually can say with certainty, we are giving you a drug that has this list of side effects and we know about them definitively. We all use other high-efficacy medications, but I don’t think we can exactly extrapolate,” said Dr. Schreiner.
Session moderator Amy Perrin Ross, APN, noted the lack of approved pediatric therapies for MS. “This is an extremely important study, because we at least in the lower 48 are quite limited in our resources for approved pediatric cases. Information like this will make it easier for a potential pediatric indication, which would then make it easier on us to go after [treatment of the disease in this population]. The weight-based dosing, I think, is really a good thing. Patients have been asking for weight-based dosing on everything for many years,” she said.
Ahmed Obeidat, MD, PhD, associate professor at the Medical College of Wisconsin, also praised the study. “While pediatric MS is rare, it is an area of unmet need when it comes to disease-modifying therapies as only fingolimod is FDA-approved, and many use B cell–depleting therapy, such as rituximab, off label to treat children with MS with good outcomes. The need for guidance on the dosing of B cell–depleting therapy is a main priority for research in pediatric MS,” he said.
The study was funded by Roche. Dr. Schreiner has consulted for Roche and Cycle Pharmaceuticals. Dr. Cohen has consulted for Astoria, Bristol Myers Squibb, Convelo, EMD Serono Inc, FiND, INMune, and Sandoz. Dr. Obeidat has financial relationships with Alexion Pharmaceuticals, Banner Life Sciences, BD Biosciences, Biogen, Biologix Solutions, Bristol Myers Squibb, Celgene, EMD Serono, Genentech, GW Pharmaceuticals, Horizon Therapeutics, Jazz Pharmaceuticals, Novartis, Sandoz, Sanofi Genzyme, TG Therapeutics, and Viela Bio. Ms. Ross has consulted for EMD Serono, BMS, Horizon, Alexion, TG Therapeutics, Novartis, Roche, and Sanofi.
FROM CMSC 2024
The Positive Effects of Exercise in MS
NASHVILLE, TENNESSEE — Exercise has a long history in multiple sclerosis (MS). In 1838, the Scottish physician John Abercrombie reported that a patient with “a diminution of muscular power,” who could walk but only unsteadily, decided after various failed treatments like “evacuations and spare diet” to try “violent exercise.” He walked 5-6 miles on a warm evening, as quickly as he was able, and returned home “much fatigued, and considerably heated. Next morning he had severe pains in the calves of his legs, but his other complaints were much diminished, and in a few days disappeared. He has ever since enjoyed good health,” Dr. Abercrombie was quoted in Multiple Sclerosis: The History of a Disease by T. Jock Murray.
The first randomized, controlled trial of an exercise intervention for MS didn’t appear in the literature until 1988, but more than 200 have been published in the years since, according to Robert Motl, PhD, who spoke about exercise interventions for MS at the annual meeting of the Consortium of Multiple Sclerosis Centers.
In fact, the evidence shows that exercise can improve walking performance and quality of life. “When we look at what we might call the unseen symptoms, we can see the exercise training is very effective at reducing fatigue in people with MS. It’s very effective at reducing depressive mood in individuals living with MS. There is moderate evidence that it can improve mobility, particularly lower extremity mobility and walking performance in individuals living with multiple sclerosis, as well as balance. And lastly, we see consistent evidence that exercise training can improve quality of life,” said Dr. Motl, who is a professor of kinesiology and nutrition at University of Illinois, Chicago.
There is less evidence that exercise training helps mobility, anxiety, pain, and participation, he said.
Dr. Motl showed the results of various meta-analyses that he co-authored of randomized, controlled trials (RCTs) of exercise training. One meta-analysis of 20 trials that examined the effect on fitness found an effect size of 0.47, which was about one-half of a standard deviation, and is considered to be a clinically meaningful effect. There was also about a 20% improvement in aerobic capacity, and this improves the capacity for maintaining independence, according to Dr. Motl. “That’s huge as individuals who are living with MS over a long-term period of time are aging with this chronic disease and independence does become an issue later in life. We maybe can forestall some of that,” he said.
Another meta-analysis of 17 RCTs examining exercise training and fatigue found a similar effect size of 0.452. When the authors limited the analysis to studies that used the Fatigue Severity Score and its benchmark of clinically significant fatigue of 4.0, “they were able to reduce the mean fatigue severity score below 4.0, meaning you’re taking individuals who have severe fatigue and reducing their fatigue below a threshold of severity that impacts everyday life. So this is something that is clinically meaningful and relevant to the lives of individuals with MS,” he said.
With respect to depression, a meta-analysis of 14 randomized, controlled trials found an effect size of 0.55 standard deviations. The researchers found that the effect size was associated with the number of days per week: The effect was size was doubled among individuals who exercised 3 or more times per week. Another meta-analysis of walking found an average 2-second improvement in walking speed and about a 40-meter improvement in walking endurance. “I believe that’s pretty comparable to what you see with Ampyra (dalfampridine) and its effects on walking speeds, so we’re seeing something that’s as good as a pharmacological agent for managing walking in MS,” said Dr. Motl.
Another meta-analysis of health-related quality of life found that the effect on the physical domain was about twice as large as the effect on mental health–related quality of life. “I think that makes sense because when you are engaging in exercise, it’s a physically invoking stimulus. As you see adaptations, your perceptions of your physical health improve,” said Dr. Motl.
Dr. Motl also addressed safety. There have been some concerns that exercise could lead to temporary worsening of symptoms, “but it was blown up into a major, major problem when it is only 5% of individuals who have these sorts of severe problems,” said Dr. Motl. A systematic review in 2023 found an adverse event rate of 1.2% in the control groups and 2.0% in the exercise groups. This was about the same rates that are seen in the general population, according to Dr. Motl. A consistent adverse event was lower back pain, but further analysis showed it was only reported with resistance training. “The beauty of that is that we have incredible people in the field of MS, who know how to deliver resistance training more safely. And if we do that more effectively, we can avoid this very common injury with exercise training,” said Dr. Motl.
The review also found a 25% reduction in relapses. “It was very interesting. I don’t know if we want to say exercise is a disease-modifying behavior yet, but that effect at the time that these studies were done was about the same as some of the early disease-modifying therapies, showing the same degree of reduction of relapse rate,” said Dr. Motl.
Dr. Motl also discussed updated guidelines for exercise in patients with mild to moderate MS, as well as Parkinson’s disease and stroke survivors. The general advice is for 2-3 days of moderate aerobic exercise per week, beginning at 10 minutes and gradually increasing to 30 minutes per session. The newer guidelines added an option for advanced aerobic exercise, which can be up to 5 times per week and up to 40 minutes per session. Activities include ergometry, walking, aquatics, and elliptical machines for general aerobic exercise, while advanced exercise can also include running or road cycling. Resistance exercise can be done 2-3 times per week with 1-3 sets of 8-15 repetitions, with a total of 5-10 exercises. The authors recommend weight machines, free weights, or resistance bands.
Dr. Motl has received funding from the Department of Defense, National Institutes of Health, Patient-Centered Outcomes Research Institute, National Multiple Sclerosis Society, and Bristol Myers Squibb Foundation.
NASHVILLE, TENNESSEE — Exercise has a long history in multiple sclerosis (MS). In 1838, the Scottish physician John Abercrombie reported that a patient with “a diminution of muscular power,” who could walk but only unsteadily, decided after various failed treatments like “evacuations and spare diet” to try “violent exercise.” He walked 5-6 miles on a warm evening, as quickly as he was able, and returned home “much fatigued, and considerably heated. Next morning he had severe pains in the calves of his legs, but his other complaints were much diminished, and in a few days disappeared. He has ever since enjoyed good health,” Dr. Abercrombie was quoted in Multiple Sclerosis: The History of a Disease by T. Jock Murray.
The first randomized, controlled trial of an exercise intervention for MS didn’t appear in the literature until 1988, but more than 200 have been published in the years since, according to Robert Motl, PhD, who spoke about exercise interventions for MS at the annual meeting of the Consortium of Multiple Sclerosis Centers.
In fact, the evidence shows that exercise can improve walking performance and quality of life. “When we look at what we might call the unseen symptoms, we can see the exercise training is very effective at reducing fatigue in people with MS. It’s very effective at reducing depressive mood in individuals living with MS. There is moderate evidence that it can improve mobility, particularly lower extremity mobility and walking performance in individuals living with multiple sclerosis, as well as balance. And lastly, we see consistent evidence that exercise training can improve quality of life,” said Dr. Motl, who is a professor of kinesiology and nutrition at University of Illinois, Chicago.
There is less evidence that exercise training helps mobility, anxiety, pain, and participation, he said.
Dr. Motl showed the results of various meta-analyses that he co-authored of randomized, controlled trials (RCTs) of exercise training. One meta-analysis of 20 trials that examined the effect on fitness found an effect size of 0.47, which was about one-half of a standard deviation, and is considered to be a clinically meaningful effect. There was also about a 20% improvement in aerobic capacity, and this improves the capacity for maintaining independence, according to Dr. Motl. “That’s huge as individuals who are living with MS over a long-term period of time are aging with this chronic disease and independence does become an issue later in life. We maybe can forestall some of that,” he said.
Another meta-analysis of 17 RCTs examining exercise training and fatigue found a similar effect size of 0.452. When the authors limited the analysis to studies that used the Fatigue Severity Score and its benchmark of clinically significant fatigue of 4.0, “they were able to reduce the mean fatigue severity score below 4.0, meaning you’re taking individuals who have severe fatigue and reducing their fatigue below a threshold of severity that impacts everyday life. So this is something that is clinically meaningful and relevant to the lives of individuals with MS,” he said.
With respect to depression, a meta-analysis of 14 randomized, controlled trials found an effect size of 0.55 standard deviations. The researchers found that the effect size was associated with the number of days per week: The effect was size was doubled among individuals who exercised 3 or more times per week. Another meta-analysis of walking found an average 2-second improvement in walking speed and about a 40-meter improvement in walking endurance. “I believe that’s pretty comparable to what you see with Ampyra (dalfampridine) and its effects on walking speeds, so we’re seeing something that’s as good as a pharmacological agent for managing walking in MS,” said Dr. Motl.
Another meta-analysis of health-related quality of life found that the effect on the physical domain was about twice as large as the effect on mental health–related quality of life. “I think that makes sense because when you are engaging in exercise, it’s a physically invoking stimulus. As you see adaptations, your perceptions of your physical health improve,” said Dr. Motl.
Dr. Motl also addressed safety. There have been some concerns that exercise could lead to temporary worsening of symptoms, “but it was blown up into a major, major problem when it is only 5% of individuals who have these sorts of severe problems,” said Dr. Motl. A systematic review in 2023 found an adverse event rate of 1.2% in the control groups and 2.0% in the exercise groups. This was about the same rates that are seen in the general population, according to Dr. Motl. A consistent adverse event was lower back pain, but further analysis showed it was only reported with resistance training. “The beauty of that is that we have incredible people in the field of MS, who know how to deliver resistance training more safely. And if we do that more effectively, we can avoid this very common injury with exercise training,” said Dr. Motl.
The review also found a 25% reduction in relapses. “It was very interesting. I don’t know if we want to say exercise is a disease-modifying behavior yet, but that effect at the time that these studies were done was about the same as some of the early disease-modifying therapies, showing the same degree of reduction of relapse rate,” said Dr. Motl.
Dr. Motl also discussed updated guidelines for exercise in patients with mild to moderate MS, as well as Parkinson’s disease and stroke survivors. The general advice is for 2-3 days of moderate aerobic exercise per week, beginning at 10 minutes and gradually increasing to 30 minutes per session. The newer guidelines added an option for advanced aerobic exercise, which can be up to 5 times per week and up to 40 minutes per session. Activities include ergometry, walking, aquatics, and elliptical machines for general aerobic exercise, while advanced exercise can also include running or road cycling. Resistance exercise can be done 2-3 times per week with 1-3 sets of 8-15 repetitions, with a total of 5-10 exercises. The authors recommend weight machines, free weights, or resistance bands.
Dr. Motl has received funding from the Department of Defense, National Institutes of Health, Patient-Centered Outcomes Research Institute, National Multiple Sclerosis Society, and Bristol Myers Squibb Foundation.
NASHVILLE, TENNESSEE — Exercise has a long history in multiple sclerosis (MS). In 1838, the Scottish physician John Abercrombie reported that a patient with “a diminution of muscular power,” who could walk but only unsteadily, decided after various failed treatments like “evacuations and spare diet” to try “violent exercise.” He walked 5-6 miles on a warm evening, as quickly as he was able, and returned home “much fatigued, and considerably heated. Next morning he had severe pains in the calves of his legs, but his other complaints were much diminished, and in a few days disappeared. He has ever since enjoyed good health,” Dr. Abercrombie was quoted in Multiple Sclerosis: The History of a Disease by T. Jock Murray.
The first randomized, controlled trial of an exercise intervention for MS didn’t appear in the literature until 1988, but more than 200 have been published in the years since, according to Robert Motl, PhD, who spoke about exercise interventions for MS at the annual meeting of the Consortium of Multiple Sclerosis Centers.
In fact, the evidence shows that exercise can improve walking performance and quality of life. “When we look at what we might call the unseen symptoms, we can see the exercise training is very effective at reducing fatigue in people with MS. It’s very effective at reducing depressive mood in individuals living with MS. There is moderate evidence that it can improve mobility, particularly lower extremity mobility and walking performance in individuals living with multiple sclerosis, as well as balance. And lastly, we see consistent evidence that exercise training can improve quality of life,” said Dr. Motl, who is a professor of kinesiology and nutrition at University of Illinois, Chicago.
There is less evidence that exercise training helps mobility, anxiety, pain, and participation, he said.
Dr. Motl showed the results of various meta-analyses that he co-authored of randomized, controlled trials (RCTs) of exercise training. One meta-analysis of 20 trials that examined the effect on fitness found an effect size of 0.47, which was about one-half of a standard deviation, and is considered to be a clinically meaningful effect. There was also about a 20% improvement in aerobic capacity, and this improves the capacity for maintaining independence, according to Dr. Motl. “That’s huge as individuals who are living with MS over a long-term period of time are aging with this chronic disease and independence does become an issue later in life. We maybe can forestall some of that,” he said.
Another meta-analysis of 17 RCTs examining exercise training and fatigue found a similar effect size of 0.452. When the authors limited the analysis to studies that used the Fatigue Severity Score and its benchmark of clinically significant fatigue of 4.0, “they were able to reduce the mean fatigue severity score below 4.0, meaning you’re taking individuals who have severe fatigue and reducing their fatigue below a threshold of severity that impacts everyday life. So this is something that is clinically meaningful and relevant to the lives of individuals with MS,” he said.
With respect to depression, a meta-analysis of 14 randomized, controlled trials found an effect size of 0.55 standard deviations. The researchers found that the effect size was associated with the number of days per week: The effect was size was doubled among individuals who exercised 3 or more times per week. Another meta-analysis of walking found an average 2-second improvement in walking speed and about a 40-meter improvement in walking endurance. “I believe that’s pretty comparable to what you see with Ampyra (dalfampridine) and its effects on walking speeds, so we’re seeing something that’s as good as a pharmacological agent for managing walking in MS,” said Dr. Motl.
Another meta-analysis of health-related quality of life found that the effect on the physical domain was about twice as large as the effect on mental health–related quality of life. “I think that makes sense because when you are engaging in exercise, it’s a physically invoking stimulus. As you see adaptations, your perceptions of your physical health improve,” said Dr. Motl.
Dr. Motl also addressed safety. There have been some concerns that exercise could lead to temporary worsening of symptoms, “but it was blown up into a major, major problem when it is only 5% of individuals who have these sorts of severe problems,” said Dr. Motl. A systematic review in 2023 found an adverse event rate of 1.2% in the control groups and 2.0% in the exercise groups. This was about the same rates that are seen in the general population, according to Dr. Motl. A consistent adverse event was lower back pain, but further analysis showed it was only reported with resistance training. “The beauty of that is that we have incredible people in the field of MS, who know how to deliver resistance training more safely. And if we do that more effectively, we can avoid this very common injury with exercise training,” said Dr. Motl.
The review also found a 25% reduction in relapses. “It was very interesting. I don’t know if we want to say exercise is a disease-modifying behavior yet, but that effect at the time that these studies were done was about the same as some of the early disease-modifying therapies, showing the same degree of reduction of relapse rate,” said Dr. Motl.
Dr. Motl also discussed updated guidelines for exercise in patients with mild to moderate MS, as well as Parkinson’s disease and stroke survivors. The general advice is for 2-3 days of moderate aerobic exercise per week, beginning at 10 minutes and gradually increasing to 30 minutes per session. The newer guidelines added an option for advanced aerobic exercise, which can be up to 5 times per week and up to 40 minutes per session. Activities include ergometry, walking, aquatics, and elliptical machines for general aerobic exercise, while advanced exercise can also include running or road cycling. Resistance exercise can be done 2-3 times per week with 1-3 sets of 8-15 repetitions, with a total of 5-10 exercises. The authors recommend weight machines, free weights, or resistance bands.
Dr. Motl has received funding from the Department of Defense, National Institutes of Health, Patient-Centered Outcomes Research Institute, National Multiple Sclerosis Society, and Bristol Myers Squibb Foundation.
FROM CMSC 2024