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Treatment of relapsing progressive MS may reduce disability progression
Superimposed relapses were associated with a significantly reduced risk of disability progression in a longitudinal, prospective cohort study of 1,419 multiple sclerosis patients (MS) of the progressive-onset type.
To determine the role of inflammatory relapses on disability in the progressive-relapsing phenotype of progressive-onset MS, the researchers collected data from MSBase, an international, observational cohort of MS patients, from January 1995 to February 2017. The study population included 1,419 adults with MS (553 in the relapse subgroup, 866 in a nonrelapse subgroup) from 83 centers in 28 countries; the median prospective follow-up period was 5 years. The patients included in the analysis had adult-onset disease, at least three clinic visits with Expanded Disability Status Scale (EDSS) score recorded, and a time frame of more than 3 months between the second and last visit.
Overall, patients with relapses had significantly less risk of disability progression after adjusting for confounding variables (adjusted hazard ratio, 0.83; 95% confidence interval, 0.74-0.94; P = .003). Disease progression was defined as worsening of the EDSS score.
In addition, the researchers examined the data in a stratified model and found a 4% relative decrease in the hazard of confirmed disability progression events for each 10% increment of follow-up time for receiving disease-modifying therapy (DMT). However, DMT did not reduce disease progression risk in progressive-onset MS patients without relapse.
“This suggests that relapses in progressive-onset MS, as a clinical correlate of episodic inflammatory activity, represent a positive prognostic marker and provide an opportunity to improve disease outcomes through prevention of relapse-related disability accrual,” the researchers wrote.
Interferon-beta was the most common DMT, given to 73% of the relapse patients and 56% of the nonrelapse patients, followed by glatiramer acetate (20% and 13%, respectively), and fingolimod (12% and 16%, respectively).
The study’s main limitation was the use of the EDSS as a measure of disability, as well as the absence of quantifiable disability change to confirm relapse, the researchers noted. However, “these findings provide further evidence for a progressive-onset MS phenotype with acute episodic inflammatory changes, thereby identifying patients who may respond to existing immunotherapies.”
The study was supported by grants from the National Health and Medical Research Council of Australia and the MSBase Foundation, a nonprofit organization that itself receives support from multiple companies, including Merck, Novartis, and Sanofi. Dr. Hughes had no financial conflicts to disclose, but most coauthors disclosed relationships with multiple companies including Merck, Novartis, Sanofi. Genzyme, and Biogen.
SOURCE: Hughes J et al. JAMA Neurol. 2018 Aug 6. doi: 10.1001/jamaneurol.2018.2109.
This study is important because it addresses an area of controversy in management of patients with a progressive multiple sclerosis (MS) phenotype. The role of superimposed relapses in patients with progressive MS has long been debated, with some studies reporting no impact on long-term disability accrual and other reporting a negative impact of relapses. Treatment of progressive MS remains controversial as well, with only one therapy approved by the Food and Drug Administration for any form of progressive MS. There is considerable ongoing debate about whether MS disease-modifying therapies (MSDMT) are effective in progressive forms of MS, and whether clinical or MRI evidence of active inflammation predicts a better chance of response.
This study has several important strengths and limitations. The large sample size allowed statistical power to detect relatively small differences in disability progression risk between progressive MS subtypes. The better prognosis in progressive patients with superimposed relapses contradicts some earlier studies that suggested a worse prognosis or no difference in prognosis between progressive patients with and without relapses. This study also supports a role for MSDMT in progressive MS patients, at least those with clinical evidence of relapses, and possibly MRI evidence of inflammatory disease activity (although this was not specifically addressed in the current study). Limitations of the study include the observational nature of the database, variable periods of follow-up, lack of objective verification of recorded relapses either with EDSS scores or MRI confirmation, and lack of an untreated control group. Therefore, no conclusions can be drawn as to whether MSDMT exposure had a favorable impact on the whole cohort of progressive patients versus no treatment.
Jonathan L. Carter, MD , is an MS specialist at the Mayo Clinic in Scottsdale, Ariz. He had no relevant disclosures to report.
This study is important because it addresses an area of controversy in management of patients with a progressive multiple sclerosis (MS) phenotype. The role of superimposed relapses in patients with progressive MS has long been debated, with some studies reporting no impact on long-term disability accrual and other reporting a negative impact of relapses. Treatment of progressive MS remains controversial as well, with only one therapy approved by the Food and Drug Administration for any form of progressive MS. There is considerable ongoing debate about whether MS disease-modifying therapies (MSDMT) are effective in progressive forms of MS, and whether clinical or MRI evidence of active inflammation predicts a better chance of response.
This study has several important strengths and limitations. The large sample size allowed statistical power to detect relatively small differences in disability progression risk between progressive MS subtypes. The better prognosis in progressive patients with superimposed relapses contradicts some earlier studies that suggested a worse prognosis or no difference in prognosis between progressive patients with and without relapses. This study also supports a role for MSDMT in progressive MS patients, at least those with clinical evidence of relapses, and possibly MRI evidence of inflammatory disease activity (although this was not specifically addressed in the current study). Limitations of the study include the observational nature of the database, variable periods of follow-up, lack of objective verification of recorded relapses either with EDSS scores or MRI confirmation, and lack of an untreated control group. Therefore, no conclusions can be drawn as to whether MSDMT exposure had a favorable impact on the whole cohort of progressive patients versus no treatment.
Jonathan L. Carter, MD , is an MS specialist at the Mayo Clinic in Scottsdale, Ariz. He had no relevant disclosures to report.
This study is important because it addresses an area of controversy in management of patients with a progressive multiple sclerosis (MS) phenotype. The role of superimposed relapses in patients with progressive MS has long been debated, with some studies reporting no impact on long-term disability accrual and other reporting a negative impact of relapses. Treatment of progressive MS remains controversial as well, with only one therapy approved by the Food and Drug Administration for any form of progressive MS. There is considerable ongoing debate about whether MS disease-modifying therapies (MSDMT) are effective in progressive forms of MS, and whether clinical or MRI evidence of active inflammation predicts a better chance of response.
This study has several important strengths and limitations. The large sample size allowed statistical power to detect relatively small differences in disability progression risk between progressive MS subtypes. The better prognosis in progressive patients with superimposed relapses contradicts some earlier studies that suggested a worse prognosis or no difference in prognosis between progressive patients with and without relapses. This study also supports a role for MSDMT in progressive MS patients, at least those with clinical evidence of relapses, and possibly MRI evidence of inflammatory disease activity (although this was not specifically addressed in the current study). Limitations of the study include the observational nature of the database, variable periods of follow-up, lack of objective verification of recorded relapses either with EDSS scores or MRI confirmation, and lack of an untreated control group. Therefore, no conclusions can be drawn as to whether MSDMT exposure had a favorable impact on the whole cohort of progressive patients versus no treatment.
Jonathan L. Carter, MD , is an MS specialist at the Mayo Clinic in Scottsdale, Ariz. He had no relevant disclosures to report.
Superimposed relapses were associated with a significantly reduced risk of disability progression in a longitudinal, prospective cohort study of 1,419 multiple sclerosis patients (MS) of the progressive-onset type.
To determine the role of inflammatory relapses on disability in the progressive-relapsing phenotype of progressive-onset MS, the researchers collected data from MSBase, an international, observational cohort of MS patients, from January 1995 to February 2017. The study population included 1,419 adults with MS (553 in the relapse subgroup, 866 in a nonrelapse subgroup) from 83 centers in 28 countries; the median prospective follow-up period was 5 years. The patients included in the analysis had adult-onset disease, at least three clinic visits with Expanded Disability Status Scale (EDSS) score recorded, and a time frame of more than 3 months between the second and last visit.
Overall, patients with relapses had significantly less risk of disability progression after adjusting for confounding variables (adjusted hazard ratio, 0.83; 95% confidence interval, 0.74-0.94; P = .003). Disease progression was defined as worsening of the EDSS score.
In addition, the researchers examined the data in a stratified model and found a 4% relative decrease in the hazard of confirmed disability progression events for each 10% increment of follow-up time for receiving disease-modifying therapy (DMT). However, DMT did not reduce disease progression risk in progressive-onset MS patients without relapse.
“This suggests that relapses in progressive-onset MS, as a clinical correlate of episodic inflammatory activity, represent a positive prognostic marker and provide an opportunity to improve disease outcomes through prevention of relapse-related disability accrual,” the researchers wrote.
Interferon-beta was the most common DMT, given to 73% of the relapse patients and 56% of the nonrelapse patients, followed by glatiramer acetate (20% and 13%, respectively), and fingolimod (12% and 16%, respectively).
The study’s main limitation was the use of the EDSS as a measure of disability, as well as the absence of quantifiable disability change to confirm relapse, the researchers noted. However, “these findings provide further evidence for a progressive-onset MS phenotype with acute episodic inflammatory changes, thereby identifying patients who may respond to existing immunotherapies.”
The study was supported by grants from the National Health and Medical Research Council of Australia and the MSBase Foundation, a nonprofit organization that itself receives support from multiple companies, including Merck, Novartis, and Sanofi. Dr. Hughes had no financial conflicts to disclose, but most coauthors disclosed relationships with multiple companies including Merck, Novartis, Sanofi. Genzyme, and Biogen.
SOURCE: Hughes J et al. JAMA Neurol. 2018 Aug 6. doi: 10.1001/jamaneurol.2018.2109.
Superimposed relapses were associated with a significantly reduced risk of disability progression in a longitudinal, prospective cohort study of 1,419 multiple sclerosis patients (MS) of the progressive-onset type.
To determine the role of inflammatory relapses on disability in the progressive-relapsing phenotype of progressive-onset MS, the researchers collected data from MSBase, an international, observational cohort of MS patients, from January 1995 to February 2017. The study population included 1,419 adults with MS (553 in the relapse subgroup, 866 in a nonrelapse subgroup) from 83 centers in 28 countries; the median prospective follow-up period was 5 years. The patients included in the analysis had adult-onset disease, at least three clinic visits with Expanded Disability Status Scale (EDSS) score recorded, and a time frame of more than 3 months between the second and last visit.
Overall, patients with relapses had significantly less risk of disability progression after adjusting for confounding variables (adjusted hazard ratio, 0.83; 95% confidence interval, 0.74-0.94; P = .003). Disease progression was defined as worsening of the EDSS score.
In addition, the researchers examined the data in a stratified model and found a 4% relative decrease in the hazard of confirmed disability progression events for each 10% increment of follow-up time for receiving disease-modifying therapy (DMT). However, DMT did not reduce disease progression risk in progressive-onset MS patients without relapse.
“This suggests that relapses in progressive-onset MS, as a clinical correlate of episodic inflammatory activity, represent a positive prognostic marker and provide an opportunity to improve disease outcomes through prevention of relapse-related disability accrual,” the researchers wrote.
Interferon-beta was the most common DMT, given to 73% of the relapse patients and 56% of the nonrelapse patients, followed by glatiramer acetate (20% and 13%, respectively), and fingolimod (12% and 16%, respectively).
The study’s main limitation was the use of the EDSS as a measure of disability, as well as the absence of quantifiable disability change to confirm relapse, the researchers noted. However, “these findings provide further evidence for a progressive-onset MS phenotype with acute episodic inflammatory changes, thereby identifying patients who may respond to existing immunotherapies.”
The study was supported by grants from the National Health and Medical Research Council of Australia and the MSBase Foundation, a nonprofit organization that itself receives support from multiple companies, including Merck, Novartis, and Sanofi. Dr. Hughes had no financial conflicts to disclose, but most coauthors disclosed relationships with multiple companies including Merck, Novartis, Sanofi. Genzyme, and Biogen.
SOURCE: Hughes J et al. JAMA Neurol. 2018 Aug 6. doi: 10.1001/jamaneurol.2018.2109.
FROM JAMA NEUROLOGY
Key clinical point: Disease-modifying therapy was significantly associated with less disability progression in multiple sclerosis patients with superimposed relapses, compared with those without relapses.
Major finding: Progressive-onset multiple sclerosis patients with superimposed relapses were significantly less likely to have confirmed disability progression (adjusted hazard ratio, 0.83).
Study details: The data came from a longitudinal, prospective cohort study of 1,419 adults with progressive-onset multiple sclerosis.
Disclosures: The study was supported by grants from the National Health and Medical Research Council of Australia and the MSBase Foundation, a nonprofit organization that itself receives support from multiple companies, including Merck, Novartis, and Sanofi. Dr. Hughes had no financial conflicts to disclose, but most coauthors disclosed relationships with multiple companies, including Merck, Novartis, Sanofi, Genzyme, and Biogen.
Source: Hughes J et al. JAMA Neurol. 2018 Aug 6. doi: 10.1001/jamaneurol.2018.2109.
Conference News Roundup—European Academy of Neurology
Thrombectomy Is Feasible for the Elderly, but Entails Risks
Mechanical thrombectomy is an increasingly important therapy for acute stroke that can benefit the very old, assuming a careful selection of patients and risk assessment, according to a Portuguese study.
For several years, endovascular thrombectomy has been a way of removing larger vascular obstructions. In this procedure, the thrombus is extracted from the cerebral vessel via a catheter inserted in the groin. Numerous international studies have shown that endovascular treatment is a substantial improvement over purely drug-based therapy. The procedure is especially effective in dealing with extremely long blood clots and large obstructions of the cerebral arteries and often yields positive results. Thanks to this procedure, more than 60% of patients treated survive the stroke with no or minor subsequent impairment.
“More and more study results show the high effectiveness of mechanical removal of blood clots after a stroke. But researchers are still trying to determine the type of patient for whom this relatively new procedure is the best treatment option,” said Ary Lopes de Sousa, MD, a neurology resident at Central Lisbon Hospital Center.
Dr. de Sousa and his colleagues reviewed the treatment success of thrombectomy in more than 200 patients with anterior acute ischemic stroke and no or slight disability prior to this event. The researchers separated patients into two groups: one with individuals younger than 80 and one with individuals age 80 and older.
In the group of patients age 80 and older, hypertension and transient ischemic attacks were more frequent. The treatment did not differ between the two groups (eg, in terms of the time frame of the revascularization). But in the older group, two-thirds of the patients exhibited a poor functional outcome at three months after the treatment (ie, they were moderately or severely limited in their ability to handle their daily tasks). The number of impaired individuals in that group was substantially larger than in the younger group, where 46% faced limitations in their everyday lives. On the other hand, one-third of the patients age 80 and older were able to handle their everyday lives three months after the treatment with no or mild impairments from the stroke. No difference in mortality was observed between the two age groups.
“For patients over 80, thrombectomy appears to be riskier than for younger patients,” said Dr. de Sousa. “But one third of the patients over 80 can be fully functional in their everyday lives after the procedure, so we must identify the factors associated with this favorable outcome. This [step] will support us applying this modern procedure efficiently to those individuals among the very old who can benefit from it.”
Studies Gauge the Cost of Migraine
A pair of studies have evaluated the cost of migraine to individuals, society, and businesses. A French study looked at the socioeconomic impact of the condition. In a survey of more than 7,700 people, a representative sample of the general population, 3.8% indicated that they experienced severe migraines on at least eight days per month. “Two-thirds of those [patients] were women, and the average age of those affected was 41, meaning that migraines significantly affect people at the peak of their careers, and who have families to provide for. These regular attacks represent a serious problem as far as keeping their jobs is concerned,” said Dr. Guillaume Leiba, Pricing and Market Access Manager at Novartis in Paris. In the current study, patients with severe migraine reported missing 33 working days per year because of their condition. This absence translates into a cost to society of approximately EUR 3.8 billion. Migraine also has an impact on patients’ social environment: 14% of respondents indicated that family members had to adjust their working hours because of patients’ migraine headaches. The study also quantified the financial burden placed on migraineurs: 58% reported an average monthly cost of more than EUR 30 per month for nonreimbursed medicines. Approximately 43% spent more than EUR 50 each month on other, nonpharmaceutical therapies. Despite the high level of public and private spending associated with the condition, quality of life for migraineurs remains far from satisfactory. More than three-quarters have sleep disorders and benefit less from their free time than healthy controls.
A Swiss study obtained more detailed results regarding absenteeism in the workplace. A group of 700 working migraineurs reported losing an average of 32 days per year because of migraine. This rate is similar to that reported in the French study. But there were significant differences depending on the specific type of headache, according to study author François Cadiou, CEO of Healint in Singapore. “With an average of more than 56 working days missed per year, patients with chronic migraine had the highest rate of absenteeism. People with episodic migraine were unable to go to work on 33 days of the year, while those with low-frequency episodic migraine took an average of 15 days off because of their condition.” Another finding has implications for preventive measures: the number of sick days was not always constant. In fact, the total steadily increased, and with it the amount of medication taken if patients indicated anxiety or depression as a symptom or trigger at least once within the 28-day observation period. In light of the outcomes presented, experts at the EAN Congress have issued a call for increased investment in migraine research and prevention, citing the advantages to society.
Both studies were funded by Novartis Pharma.
Parkinson’s Disease Progression Varies by Gender
A current study has now furnished the first neurophysiologic evidence that Parkinson’s disease progresses differently in women than in men. “Numerous demographic studies have provided evidence that men contract Parkinson’s disease nearly twice as often as women. What was unclear, however, was whether a gender-specific pathophysiology exists as soon as the first symptoms appear,” said Maja Kojovic, MD, PhD, a consultant neurologist at Ljubljana University Medical Center in Slovenia.
The international research team proceeded from the concept that in early Parkinson’s disease, functional changes can be detected in the primary motor cortex (M1) using transcranial magnetic stimulation (TMS). If pathophysiology differs between genders in Parkinson’s disease, they hypothesized, it will be reflected in differences of M1 TMS measurements.
Thirty-nine newly diagnosed and untreated patients with Parkinson’s disease (23 males) were assessed using the Unified Parkinson’s Disease Rating Scale (UPDRS). Then the patients and a group of healthy controls underwent TMS measurements of motor thresholds of the brain, input–output curve, short interval intracortical inhibition, cortical silent period, and intracortical facilitation. Brain plasticity was also measured using paired associative stimulation.
The UPDRS tests did not yield any differences in motor scores between the genders. However, the female patients had a less steep input–output curve than the male patients on the side of the brain more affected by Parkinson’s disease.
The women with Parkinson’s disease also exhibited better preserved short interval intracortical inhibition in both hemispheres, compared with affected men, and tended to have a better response to the paired associative stimulation protocol on the side less affected by symptoms. No gender-specific differences were determined, however, in the motor thresholds, intracortical facilitation, and the cortical silent period. The healthy control group did not show any gender or interhemispheric differences for any of the TMS parameters measured. “The detected gender differences in corticospinal and intracortical excitability in patients with early untreated Parkinson’s disease represent differences in disease pathophysiology. Gender may also prove to be a relevant factor when choosing appropriate treatment,” said Dr. Kojovic.
EAN Develops Guideline on Palliative Care of Patients With Severe MS
A cohort of 934 individuals affected by multiple sclerosis (MS) from seven European countries played an instrumental part in developing the European Academy of Neurology’s (EAN) new guideline on palliative care for people with severe MS. “There were 751 MS patients and 183 caregiver relatives involved,” said Sascha Köpke, PhD, Professor of Nursing Research at the University of Lübeck in Germany.
With the involvement of patients and their families in a new guideline, the EAN is emphasizing shared decision-making as an increasingly important concept that underscores patient autonomy and promotes the individualization of diagnosis and therapy. According to this approach, patients and physicians undergo a detailed consultation and then choose the medical treatment. The EAN has supported this patient-centered approach for a long time, and it is becoming increasingly established in other medical areas as well.
“It was resource- and time-intensive to include consumers in the guideline process, but also highly rewarding,” said Prof. Köpke. “Patients and caregivers really helped us to formulate the guideline in a way that was in line with actual practice and their own needs. We were able to see clearly which of our ideas met with approval or rejection.” The comments were also instructive for the group of EAN experts. They raised new aspects as well as sensitive issues that had been left out of the first draft.
Two approaches were chosen to ensure that consumers would participate. “First, there was an international online survey launched by national MS societies following a trial run involving 20 patients and 18 caregivers. Second, we invited MS patients and caregiver relatives to focus group meetings,” said Prof. Köpke. The majority of participants approved the topics proposed by the EAN group of experts. About 98% agreed to incorporate the subject of multidisciplinary rehabilitation in the guideline. There were 569 free comments, of which 182 (32%) pertained to the specified topics. A further 227 comments (40%) addressed additional topics, of which 16 were pertinent to the guideline. Five of the focus group meetings corroborated the results of the online survey and helped to work out important issues for the individuals affected. “The involvement of patients and caregivers increases the reliability and relevance of the guideline for clinical practice,” said Prof. Köpke.
Thrombectomy Is Feasible for the Elderly, but Entails Risks
Mechanical thrombectomy is an increasingly important therapy for acute stroke that can benefit the very old, assuming a careful selection of patients and risk assessment, according to a Portuguese study.
For several years, endovascular thrombectomy has been a way of removing larger vascular obstructions. In this procedure, the thrombus is extracted from the cerebral vessel via a catheter inserted in the groin. Numerous international studies have shown that endovascular treatment is a substantial improvement over purely drug-based therapy. The procedure is especially effective in dealing with extremely long blood clots and large obstructions of the cerebral arteries and often yields positive results. Thanks to this procedure, more than 60% of patients treated survive the stroke with no or minor subsequent impairment.
“More and more study results show the high effectiveness of mechanical removal of blood clots after a stroke. But researchers are still trying to determine the type of patient for whom this relatively new procedure is the best treatment option,” said Ary Lopes de Sousa, MD, a neurology resident at Central Lisbon Hospital Center.
Dr. de Sousa and his colleagues reviewed the treatment success of thrombectomy in more than 200 patients with anterior acute ischemic stroke and no or slight disability prior to this event. The researchers separated patients into two groups: one with individuals younger than 80 and one with individuals age 80 and older.
In the group of patients age 80 and older, hypertension and transient ischemic attacks were more frequent. The treatment did not differ between the two groups (eg, in terms of the time frame of the revascularization). But in the older group, two-thirds of the patients exhibited a poor functional outcome at three months after the treatment (ie, they were moderately or severely limited in their ability to handle their daily tasks). The number of impaired individuals in that group was substantially larger than in the younger group, where 46% faced limitations in their everyday lives. On the other hand, one-third of the patients age 80 and older were able to handle their everyday lives three months after the treatment with no or mild impairments from the stroke. No difference in mortality was observed between the two age groups.
“For patients over 80, thrombectomy appears to be riskier than for younger patients,” said Dr. de Sousa. “But one third of the patients over 80 can be fully functional in their everyday lives after the procedure, so we must identify the factors associated with this favorable outcome. This [step] will support us applying this modern procedure efficiently to those individuals among the very old who can benefit from it.”
Studies Gauge the Cost of Migraine
A pair of studies have evaluated the cost of migraine to individuals, society, and businesses. A French study looked at the socioeconomic impact of the condition. In a survey of more than 7,700 people, a representative sample of the general population, 3.8% indicated that they experienced severe migraines on at least eight days per month. “Two-thirds of those [patients] were women, and the average age of those affected was 41, meaning that migraines significantly affect people at the peak of their careers, and who have families to provide for. These regular attacks represent a serious problem as far as keeping their jobs is concerned,” said Dr. Guillaume Leiba, Pricing and Market Access Manager at Novartis in Paris. In the current study, patients with severe migraine reported missing 33 working days per year because of their condition. This absence translates into a cost to society of approximately EUR 3.8 billion. Migraine also has an impact on patients’ social environment: 14% of respondents indicated that family members had to adjust their working hours because of patients’ migraine headaches. The study also quantified the financial burden placed on migraineurs: 58% reported an average monthly cost of more than EUR 30 per month for nonreimbursed medicines. Approximately 43% spent more than EUR 50 each month on other, nonpharmaceutical therapies. Despite the high level of public and private spending associated with the condition, quality of life for migraineurs remains far from satisfactory. More than three-quarters have sleep disorders and benefit less from their free time than healthy controls.
A Swiss study obtained more detailed results regarding absenteeism in the workplace. A group of 700 working migraineurs reported losing an average of 32 days per year because of migraine. This rate is similar to that reported in the French study. But there were significant differences depending on the specific type of headache, according to study author François Cadiou, CEO of Healint in Singapore. “With an average of more than 56 working days missed per year, patients with chronic migraine had the highest rate of absenteeism. People with episodic migraine were unable to go to work on 33 days of the year, while those with low-frequency episodic migraine took an average of 15 days off because of their condition.” Another finding has implications for preventive measures: the number of sick days was not always constant. In fact, the total steadily increased, and with it the amount of medication taken if patients indicated anxiety or depression as a symptom or trigger at least once within the 28-day observation period. In light of the outcomes presented, experts at the EAN Congress have issued a call for increased investment in migraine research and prevention, citing the advantages to society.
Both studies were funded by Novartis Pharma.
Parkinson’s Disease Progression Varies by Gender
A current study has now furnished the first neurophysiologic evidence that Parkinson’s disease progresses differently in women than in men. “Numerous demographic studies have provided evidence that men contract Parkinson’s disease nearly twice as often as women. What was unclear, however, was whether a gender-specific pathophysiology exists as soon as the first symptoms appear,” said Maja Kojovic, MD, PhD, a consultant neurologist at Ljubljana University Medical Center in Slovenia.
The international research team proceeded from the concept that in early Parkinson’s disease, functional changes can be detected in the primary motor cortex (M1) using transcranial magnetic stimulation (TMS). If pathophysiology differs between genders in Parkinson’s disease, they hypothesized, it will be reflected in differences of M1 TMS measurements.
Thirty-nine newly diagnosed and untreated patients with Parkinson’s disease (23 males) were assessed using the Unified Parkinson’s Disease Rating Scale (UPDRS). Then the patients and a group of healthy controls underwent TMS measurements of motor thresholds of the brain, input–output curve, short interval intracortical inhibition, cortical silent period, and intracortical facilitation. Brain plasticity was also measured using paired associative stimulation.
The UPDRS tests did not yield any differences in motor scores between the genders. However, the female patients had a less steep input–output curve than the male patients on the side of the brain more affected by Parkinson’s disease.
The women with Parkinson’s disease also exhibited better preserved short interval intracortical inhibition in both hemispheres, compared with affected men, and tended to have a better response to the paired associative stimulation protocol on the side less affected by symptoms. No gender-specific differences were determined, however, in the motor thresholds, intracortical facilitation, and the cortical silent period. The healthy control group did not show any gender or interhemispheric differences for any of the TMS parameters measured. “The detected gender differences in corticospinal and intracortical excitability in patients with early untreated Parkinson’s disease represent differences in disease pathophysiology. Gender may also prove to be a relevant factor when choosing appropriate treatment,” said Dr. Kojovic.
EAN Develops Guideline on Palliative Care of Patients With Severe MS
A cohort of 934 individuals affected by multiple sclerosis (MS) from seven European countries played an instrumental part in developing the European Academy of Neurology’s (EAN) new guideline on palliative care for people with severe MS. “There were 751 MS patients and 183 caregiver relatives involved,” said Sascha Köpke, PhD, Professor of Nursing Research at the University of Lübeck in Germany.
With the involvement of patients and their families in a new guideline, the EAN is emphasizing shared decision-making as an increasingly important concept that underscores patient autonomy and promotes the individualization of diagnosis and therapy. According to this approach, patients and physicians undergo a detailed consultation and then choose the medical treatment. The EAN has supported this patient-centered approach for a long time, and it is becoming increasingly established in other medical areas as well.
“It was resource- and time-intensive to include consumers in the guideline process, but also highly rewarding,” said Prof. Köpke. “Patients and caregivers really helped us to formulate the guideline in a way that was in line with actual practice and their own needs. We were able to see clearly which of our ideas met with approval or rejection.” The comments were also instructive for the group of EAN experts. They raised new aspects as well as sensitive issues that had been left out of the first draft.
Two approaches were chosen to ensure that consumers would participate. “First, there was an international online survey launched by national MS societies following a trial run involving 20 patients and 18 caregivers. Second, we invited MS patients and caregiver relatives to focus group meetings,” said Prof. Köpke. The majority of participants approved the topics proposed by the EAN group of experts. About 98% agreed to incorporate the subject of multidisciplinary rehabilitation in the guideline. There were 569 free comments, of which 182 (32%) pertained to the specified topics. A further 227 comments (40%) addressed additional topics, of which 16 were pertinent to the guideline. Five of the focus group meetings corroborated the results of the online survey and helped to work out important issues for the individuals affected. “The involvement of patients and caregivers increases the reliability and relevance of the guideline for clinical practice,” said Prof. Köpke.
Thrombectomy Is Feasible for the Elderly, but Entails Risks
Mechanical thrombectomy is an increasingly important therapy for acute stroke that can benefit the very old, assuming a careful selection of patients and risk assessment, according to a Portuguese study.
For several years, endovascular thrombectomy has been a way of removing larger vascular obstructions. In this procedure, the thrombus is extracted from the cerebral vessel via a catheter inserted in the groin. Numerous international studies have shown that endovascular treatment is a substantial improvement over purely drug-based therapy. The procedure is especially effective in dealing with extremely long blood clots and large obstructions of the cerebral arteries and often yields positive results. Thanks to this procedure, more than 60% of patients treated survive the stroke with no or minor subsequent impairment.
“More and more study results show the high effectiveness of mechanical removal of blood clots after a stroke. But researchers are still trying to determine the type of patient for whom this relatively new procedure is the best treatment option,” said Ary Lopes de Sousa, MD, a neurology resident at Central Lisbon Hospital Center.
Dr. de Sousa and his colleagues reviewed the treatment success of thrombectomy in more than 200 patients with anterior acute ischemic stroke and no or slight disability prior to this event. The researchers separated patients into two groups: one with individuals younger than 80 and one with individuals age 80 and older.
In the group of patients age 80 and older, hypertension and transient ischemic attacks were more frequent. The treatment did not differ between the two groups (eg, in terms of the time frame of the revascularization). But in the older group, two-thirds of the patients exhibited a poor functional outcome at three months after the treatment (ie, they were moderately or severely limited in their ability to handle their daily tasks). The number of impaired individuals in that group was substantially larger than in the younger group, where 46% faced limitations in their everyday lives. On the other hand, one-third of the patients age 80 and older were able to handle their everyday lives three months after the treatment with no or mild impairments from the stroke. No difference in mortality was observed between the two age groups.
“For patients over 80, thrombectomy appears to be riskier than for younger patients,” said Dr. de Sousa. “But one third of the patients over 80 can be fully functional in their everyday lives after the procedure, so we must identify the factors associated with this favorable outcome. This [step] will support us applying this modern procedure efficiently to those individuals among the very old who can benefit from it.”
Studies Gauge the Cost of Migraine
A pair of studies have evaluated the cost of migraine to individuals, society, and businesses. A French study looked at the socioeconomic impact of the condition. In a survey of more than 7,700 people, a representative sample of the general population, 3.8% indicated that they experienced severe migraines on at least eight days per month. “Two-thirds of those [patients] were women, and the average age of those affected was 41, meaning that migraines significantly affect people at the peak of their careers, and who have families to provide for. These regular attacks represent a serious problem as far as keeping their jobs is concerned,” said Dr. Guillaume Leiba, Pricing and Market Access Manager at Novartis in Paris. In the current study, patients with severe migraine reported missing 33 working days per year because of their condition. This absence translates into a cost to society of approximately EUR 3.8 billion. Migraine also has an impact on patients’ social environment: 14% of respondents indicated that family members had to adjust their working hours because of patients’ migraine headaches. The study also quantified the financial burden placed on migraineurs: 58% reported an average monthly cost of more than EUR 30 per month for nonreimbursed medicines. Approximately 43% spent more than EUR 50 each month on other, nonpharmaceutical therapies. Despite the high level of public and private spending associated with the condition, quality of life for migraineurs remains far from satisfactory. More than three-quarters have sleep disorders and benefit less from their free time than healthy controls.
A Swiss study obtained more detailed results regarding absenteeism in the workplace. A group of 700 working migraineurs reported losing an average of 32 days per year because of migraine. This rate is similar to that reported in the French study. But there were significant differences depending on the specific type of headache, according to study author François Cadiou, CEO of Healint in Singapore. “With an average of more than 56 working days missed per year, patients with chronic migraine had the highest rate of absenteeism. People with episodic migraine were unable to go to work on 33 days of the year, while those with low-frequency episodic migraine took an average of 15 days off because of their condition.” Another finding has implications for preventive measures: the number of sick days was not always constant. In fact, the total steadily increased, and with it the amount of medication taken if patients indicated anxiety or depression as a symptom or trigger at least once within the 28-day observation period. In light of the outcomes presented, experts at the EAN Congress have issued a call for increased investment in migraine research and prevention, citing the advantages to society.
Both studies were funded by Novartis Pharma.
Parkinson’s Disease Progression Varies by Gender
A current study has now furnished the first neurophysiologic evidence that Parkinson’s disease progresses differently in women than in men. “Numerous demographic studies have provided evidence that men contract Parkinson’s disease nearly twice as often as women. What was unclear, however, was whether a gender-specific pathophysiology exists as soon as the first symptoms appear,” said Maja Kojovic, MD, PhD, a consultant neurologist at Ljubljana University Medical Center in Slovenia.
The international research team proceeded from the concept that in early Parkinson’s disease, functional changes can be detected in the primary motor cortex (M1) using transcranial magnetic stimulation (TMS). If pathophysiology differs between genders in Parkinson’s disease, they hypothesized, it will be reflected in differences of M1 TMS measurements.
Thirty-nine newly diagnosed and untreated patients with Parkinson’s disease (23 males) were assessed using the Unified Parkinson’s Disease Rating Scale (UPDRS). Then the patients and a group of healthy controls underwent TMS measurements of motor thresholds of the brain, input–output curve, short interval intracortical inhibition, cortical silent period, and intracortical facilitation. Brain plasticity was also measured using paired associative stimulation.
The UPDRS tests did not yield any differences in motor scores between the genders. However, the female patients had a less steep input–output curve than the male patients on the side of the brain more affected by Parkinson’s disease.
The women with Parkinson’s disease also exhibited better preserved short interval intracortical inhibition in both hemispheres, compared with affected men, and tended to have a better response to the paired associative stimulation protocol on the side less affected by symptoms. No gender-specific differences were determined, however, in the motor thresholds, intracortical facilitation, and the cortical silent period. The healthy control group did not show any gender or interhemispheric differences for any of the TMS parameters measured. “The detected gender differences in corticospinal and intracortical excitability in patients with early untreated Parkinson’s disease represent differences in disease pathophysiology. Gender may also prove to be a relevant factor when choosing appropriate treatment,” said Dr. Kojovic.
EAN Develops Guideline on Palliative Care of Patients With Severe MS
A cohort of 934 individuals affected by multiple sclerosis (MS) from seven European countries played an instrumental part in developing the European Academy of Neurology’s (EAN) new guideline on palliative care for people with severe MS. “There were 751 MS patients and 183 caregiver relatives involved,” said Sascha Köpke, PhD, Professor of Nursing Research at the University of Lübeck in Germany.
With the involvement of patients and their families in a new guideline, the EAN is emphasizing shared decision-making as an increasingly important concept that underscores patient autonomy and promotes the individualization of diagnosis and therapy. According to this approach, patients and physicians undergo a detailed consultation and then choose the medical treatment. The EAN has supported this patient-centered approach for a long time, and it is becoming increasingly established in other medical areas as well.
“It was resource- and time-intensive to include consumers in the guideline process, but also highly rewarding,” said Prof. Köpke. “Patients and caregivers really helped us to formulate the guideline in a way that was in line with actual practice and their own needs. We were able to see clearly which of our ideas met with approval or rejection.” The comments were also instructive for the group of EAN experts. They raised new aspects as well as sensitive issues that had been left out of the first draft.
Two approaches were chosen to ensure that consumers would participate. “First, there was an international online survey launched by national MS societies following a trial run involving 20 patients and 18 caregivers. Second, we invited MS patients and caregiver relatives to focus group meetings,” said Prof. Köpke. The majority of participants approved the topics proposed by the EAN group of experts. About 98% agreed to incorporate the subject of multidisciplinary rehabilitation in the guideline. There were 569 free comments, of which 182 (32%) pertained to the specified topics. A further 227 comments (40%) addressed additional topics, of which 16 were pertinent to the guideline. Five of the focus group meetings corroborated the results of the online survey and helped to work out important issues for the individuals affected. “The involvement of patients and caregivers increases the reliability and relevance of the guideline for clinical practice,” said Prof. Köpke.
A Rational Approach to Starting, Stopping, and Switching DMTs
Dr. Patricia Coyle’s Donald Paty Memorial Lecture covered current controversies in DMT use.
NASHVILLE—What guides decisions to start, stop, switch, or restart disease-modifying therapy (DMT) in patients with multiple sclerosis (MS)—particularly in the absence of extensive robust data? Because multiple treatment options exist, there is a higher bar for a DMT to be considered successful. Clinicians need to base individualized decisions on the best available evidence, according to a presentation at the 2018 CMSC Annual Meeting.
“We have practice guidelines, but unfortunately they are almost always out of date,” said Patricia K. Coyle, MD, Professor and Vice Chair of Clinical Affairs and Director of the MS Comprehensive Care Center at Stony Brook University Hospital in New York. “Guidelines have a lot of good things to say and several things that I would not quite agree with, but at least they are a helpful start. In the future, as we use cooperative studies, databases, and meaningful observations on large numbers of patients with MS to maximize our information and data, we will ultimately resolve all of these DMT debates.”
Starting Treatment
Controversies surrounding initiation of DMTs include whether to treat patients with radiologically isolated syndrome, when to start treating relapsing forms of MS that are not active, and, in patients with primary progressive MS, when the monoclonal agent ocrelizumab is appropriate. Current American Academy of Neurology (AAN) practice guidelines recommend both prescribing a DMT to patients with clinically isolated syndrome (CIS), patients with a first attack who have at least two MRI lesions characteristic of MS, and offering DMTs to patients with relapsing forms of MS and recent attacks or MRI activity.
The AAN recommendations stem from the benefits seen with early treatment, Dr. Coyle emphasized. “There may be a critical window of opportunity in treating early,” she said. “If MS involves accumulating permanent damage to the CNS, wouldn’t you want to stop or minimize that as quickly as possible—not wait until there has already been significant injury?” Virtually all studies comparing early versus delayed treatment support early treatment—and “age probably matters.”
In a 2017 meta-analysis of 38 clinical trials that assessed disability worsening and disease progression in a total population of 28,000 subjects with MS, the authors found that DMT efficacy and impact on disability fell with advancing age. The model created from this study predicted that none of the DMTs would be efficacious on disability in patients older than 53. Evidence also suggested that, after patients reached age 40.5, high-efficacy DMTs (eg, ocrelizumab, natalizumab) no longer outperformed lower-efficacy oral agents (fingolimod, teriflunomide, dimethyl fumarate) or injectables (interferon betas and glatiramer acetates).
While skeptical of this latter finding, Dr. Coyle termed it “provocative” because it demonstrates that patients should be treated at a younger age. “When MS declares itself, the disease has probably existed for years, damaging CNS tissue,” she said. Older age at onset probably means that the disease has been present but silent for a long period of time. In addition, CNS and brain reserve become increasingly impaired with age. “The older you are, in theory, the less CNS reserve you have.”
Stopping Treatment
Potential reasons for stopping DMT include relapsing MS or CIS that has been inactive for years; secondary progressive MS that is distant from the relapsing phase and now in a purely neurodegenerative one; age older than 60; and pregnancy.
Citing just a handful of studies in this area, Dr. Coyle pointed to the MSBase Registry of patients with relapsing MS who, on injectables, had no relapse for five years or more. Among 485 patients who stopped DMT versus 854 who continued treatment, time to relapse was similar but time to confirmed disability was shorter in those who stopped treatment. Those who stopped treatment also had an increased risk for entering the progressive stage. In another study of two cohorts who stopped DMT, 11.7% of patients with secondary progressive MS who were stable for two to 20 years, versus 58.8% of patients with relapsing MS, had acute disease within one to two years. The authors noted the secondary progressive MS cohort was older with higher EDSS scores. A retrospective review of patients with MS older than 60 who had been on DMT for more than two years showed that, of the 29.7% who stopped DMT, only one relapsed and just 10.7% reinitiated DMT.
“I would not stop a well-tolerated DMT in relapsing MS,” said Dr. Coyle. “I would continue DMT in CIS if patients were at high risk, even if they had had no disease activity for years. I would discuss stopping therapy in patients with secondary progressive MS who were older than 60, and in very debilitated patients with progressive MS.”
Switching DMTs
In terms of switching, a suboptimal response is likely magnified by delaying therapy, not matching patients well to their initial DMT, and not identifying poor response quickly,” said Dr. Coyle.
Reasons to switch include breakthrough activity—ie, the minimal evidence of disease activity (MEDA) or no evidence of disease activity (NEDA) target not met; MRI activity; poor tolerability; and abnormal laboratory data or clinical complications. Clinicians should consult the AAN practice guidelines for recommendations on when and which DMTs to switch.
Dr. Coyle again cited the MSBase Registry, in which three studies were conducted involving patients with MS who were on interferon beta or glatiramer acetate who had breakthrough attacks or disability. “In one study they switched them to another injectable or fingolimod,” she said. “They did better if they got to fingolimod. Another study involved switching to another injectable or natalizumab. They did better if they were on natalizumab. A third study looked at switching to fingolimod or natalizumab. They did better with natalizumab.”
Dr. Coyle observed that the first one to two years after initiating DMT may be the most important for determining whether a patient is doing well. “A DMT takes a few months to be fully operational,” she said. “If you are switching for breakthrough activity, you need to go to a higher-efficacy DMT. My treat-to target is not NEDA, it is MEDA.”
—Fred Balzac
Suggested Reading
Berkovich R. Clinical and MRI outcomes after stopping or switching disease-modifying therapy in stable MS patients: a case series report. Mult Scler Relat Disord. 2017;17:123-127.
Birnbaum G. Stopping disease-modifying therapy in nonrelapsing multiple sclerosis: experience from a clinical practice. Int J MS Care. 2017;19(1):11-14.
Coyle PK. Switching therapies in multiple sclerosis. CNS Drugs. 2013;27(4):239-247.
Hua LH, Fan TH, Conway D, et al. Discontinuation of disease-modifying therapy in patients with multiple sclerosis over age 60. Mult Scler. 2018 Mar 1 [Epub ahead of print].
Kappos L, Radue EW, Comi G, et al, for the TOFINGO study group. Switching from natalizumab to fingolimod: a randomized, placebo-controlled study in RRMS. Neurology. 2015;85(1):29-39.
Kister I, Spelman T, Alroughani R, et al, for the MSBase Study Group. Discontinuing disease-modifying therapy in MS after a prolonged relapse-free period: a propensity score-matched study. J Neurol Neurosurg Psychiatry. 2016;87(10):1133-1137.
Maillart E, Vidal JS, Brassat D, et al. Natalizumab-PML survivors with subsequent MS treatment: clinico-radiologic outcome. Neurol Neuroimmunol Neuroinflamm. 2017;4(3):e346.
Rae-Grant A, Day GS, Marrie RA, et al. Practice guideline recommendations summary: disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018;90(17):777-788.
Weideman AM, Tapia-Maltos MA, Johnson K, et al. Meta-analysis of the age-dependent efficacy of multiple sclerosis treatments. Front Neurol. 2017;8:577.
Dr. Patricia Coyle’s Donald Paty Memorial Lecture covered current controversies in DMT use.
Dr. Patricia Coyle’s Donald Paty Memorial Lecture covered current controversies in DMT use.
NASHVILLE—What guides decisions to start, stop, switch, or restart disease-modifying therapy (DMT) in patients with multiple sclerosis (MS)—particularly in the absence of extensive robust data? Because multiple treatment options exist, there is a higher bar for a DMT to be considered successful. Clinicians need to base individualized decisions on the best available evidence, according to a presentation at the 2018 CMSC Annual Meeting.
“We have practice guidelines, but unfortunately they are almost always out of date,” said Patricia K. Coyle, MD, Professor and Vice Chair of Clinical Affairs and Director of the MS Comprehensive Care Center at Stony Brook University Hospital in New York. “Guidelines have a lot of good things to say and several things that I would not quite agree with, but at least they are a helpful start. In the future, as we use cooperative studies, databases, and meaningful observations on large numbers of patients with MS to maximize our information and data, we will ultimately resolve all of these DMT debates.”
Starting Treatment
Controversies surrounding initiation of DMTs include whether to treat patients with radiologically isolated syndrome, when to start treating relapsing forms of MS that are not active, and, in patients with primary progressive MS, when the monoclonal agent ocrelizumab is appropriate. Current American Academy of Neurology (AAN) practice guidelines recommend both prescribing a DMT to patients with clinically isolated syndrome (CIS), patients with a first attack who have at least two MRI lesions characteristic of MS, and offering DMTs to patients with relapsing forms of MS and recent attacks or MRI activity.
The AAN recommendations stem from the benefits seen with early treatment, Dr. Coyle emphasized. “There may be a critical window of opportunity in treating early,” she said. “If MS involves accumulating permanent damage to the CNS, wouldn’t you want to stop or minimize that as quickly as possible—not wait until there has already been significant injury?” Virtually all studies comparing early versus delayed treatment support early treatment—and “age probably matters.”
In a 2017 meta-analysis of 38 clinical trials that assessed disability worsening and disease progression in a total population of 28,000 subjects with MS, the authors found that DMT efficacy and impact on disability fell with advancing age. The model created from this study predicted that none of the DMTs would be efficacious on disability in patients older than 53. Evidence also suggested that, after patients reached age 40.5, high-efficacy DMTs (eg, ocrelizumab, natalizumab) no longer outperformed lower-efficacy oral agents (fingolimod, teriflunomide, dimethyl fumarate) or injectables (interferon betas and glatiramer acetates).
While skeptical of this latter finding, Dr. Coyle termed it “provocative” because it demonstrates that patients should be treated at a younger age. “When MS declares itself, the disease has probably existed for years, damaging CNS tissue,” she said. Older age at onset probably means that the disease has been present but silent for a long period of time. In addition, CNS and brain reserve become increasingly impaired with age. “The older you are, in theory, the less CNS reserve you have.”
Stopping Treatment
Potential reasons for stopping DMT include relapsing MS or CIS that has been inactive for years; secondary progressive MS that is distant from the relapsing phase and now in a purely neurodegenerative one; age older than 60; and pregnancy.
Citing just a handful of studies in this area, Dr. Coyle pointed to the MSBase Registry of patients with relapsing MS who, on injectables, had no relapse for five years or more. Among 485 patients who stopped DMT versus 854 who continued treatment, time to relapse was similar but time to confirmed disability was shorter in those who stopped treatment. Those who stopped treatment also had an increased risk for entering the progressive stage. In another study of two cohorts who stopped DMT, 11.7% of patients with secondary progressive MS who were stable for two to 20 years, versus 58.8% of patients with relapsing MS, had acute disease within one to two years. The authors noted the secondary progressive MS cohort was older with higher EDSS scores. A retrospective review of patients with MS older than 60 who had been on DMT for more than two years showed that, of the 29.7% who stopped DMT, only one relapsed and just 10.7% reinitiated DMT.
“I would not stop a well-tolerated DMT in relapsing MS,” said Dr. Coyle. “I would continue DMT in CIS if patients were at high risk, even if they had had no disease activity for years. I would discuss stopping therapy in patients with secondary progressive MS who were older than 60, and in very debilitated patients with progressive MS.”
Switching DMTs
In terms of switching, a suboptimal response is likely magnified by delaying therapy, not matching patients well to their initial DMT, and not identifying poor response quickly,” said Dr. Coyle.
Reasons to switch include breakthrough activity—ie, the minimal evidence of disease activity (MEDA) or no evidence of disease activity (NEDA) target not met; MRI activity; poor tolerability; and abnormal laboratory data or clinical complications. Clinicians should consult the AAN practice guidelines for recommendations on when and which DMTs to switch.
Dr. Coyle again cited the MSBase Registry, in which three studies were conducted involving patients with MS who were on interferon beta or glatiramer acetate who had breakthrough attacks or disability. “In one study they switched them to another injectable or fingolimod,” she said. “They did better if they got to fingolimod. Another study involved switching to another injectable or natalizumab. They did better if they were on natalizumab. A third study looked at switching to fingolimod or natalizumab. They did better with natalizumab.”
Dr. Coyle observed that the first one to two years after initiating DMT may be the most important for determining whether a patient is doing well. “A DMT takes a few months to be fully operational,” she said. “If you are switching for breakthrough activity, you need to go to a higher-efficacy DMT. My treat-to target is not NEDA, it is MEDA.”
—Fred Balzac
Suggested Reading
Berkovich R. Clinical and MRI outcomes after stopping or switching disease-modifying therapy in stable MS patients: a case series report. Mult Scler Relat Disord. 2017;17:123-127.
Birnbaum G. Stopping disease-modifying therapy in nonrelapsing multiple sclerosis: experience from a clinical practice. Int J MS Care. 2017;19(1):11-14.
Coyle PK. Switching therapies in multiple sclerosis. CNS Drugs. 2013;27(4):239-247.
Hua LH, Fan TH, Conway D, et al. Discontinuation of disease-modifying therapy in patients with multiple sclerosis over age 60. Mult Scler. 2018 Mar 1 [Epub ahead of print].
Kappos L, Radue EW, Comi G, et al, for the TOFINGO study group. Switching from natalizumab to fingolimod: a randomized, placebo-controlled study in RRMS. Neurology. 2015;85(1):29-39.
Kister I, Spelman T, Alroughani R, et al, for the MSBase Study Group. Discontinuing disease-modifying therapy in MS after a prolonged relapse-free period: a propensity score-matched study. J Neurol Neurosurg Psychiatry. 2016;87(10):1133-1137.
Maillart E, Vidal JS, Brassat D, et al. Natalizumab-PML survivors with subsequent MS treatment: clinico-radiologic outcome. Neurol Neuroimmunol Neuroinflamm. 2017;4(3):e346.
Rae-Grant A, Day GS, Marrie RA, et al. Practice guideline recommendations summary: disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018;90(17):777-788.
Weideman AM, Tapia-Maltos MA, Johnson K, et al. Meta-analysis of the age-dependent efficacy of multiple sclerosis treatments. Front Neurol. 2017;8:577.
NASHVILLE—What guides decisions to start, stop, switch, or restart disease-modifying therapy (DMT) in patients with multiple sclerosis (MS)—particularly in the absence of extensive robust data? Because multiple treatment options exist, there is a higher bar for a DMT to be considered successful. Clinicians need to base individualized decisions on the best available evidence, according to a presentation at the 2018 CMSC Annual Meeting.
“We have practice guidelines, but unfortunately they are almost always out of date,” said Patricia K. Coyle, MD, Professor and Vice Chair of Clinical Affairs and Director of the MS Comprehensive Care Center at Stony Brook University Hospital in New York. “Guidelines have a lot of good things to say and several things that I would not quite agree with, but at least they are a helpful start. In the future, as we use cooperative studies, databases, and meaningful observations on large numbers of patients with MS to maximize our information and data, we will ultimately resolve all of these DMT debates.”
Starting Treatment
Controversies surrounding initiation of DMTs include whether to treat patients with radiologically isolated syndrome, when to start treating relapsing forms of MS that are not active, and, in patients with primary progressive MS, when the monoclonal agent ocrelizumab is appropriate. Current American Academy of Neurology (AAN) practice guidelines recommend both prescribing a DMT to patients with clinically isolated syndrome (CIS), patients with a first attack who have at least two MRI lesions characteristic of MS, and offering DMTs to patients with relapsing forms of MS and recent attacks or MRI activity.
The AAN recommendations stem from the benefits seen with early treatment, Dr. Coyle emphasized. “There may be a critical window of opportunity in treating early,” she said. “If MS involves accumulating permanent damage to the CNS, wouldn’t you want to stop or minimize that as quickly as possible—not wait until there has already been significant injury?” Virtually all studies comparing early versus delayed treatment support early treatment—and “age probably matters.”
In a 2017 meta-analysis of 38 clinical trials that assessed disability worsening and disease progression in a total population of 28,000 subjects with MS, the authors found that DMT efficacy and impact on disability fell with advancing age. The model created from this study predicted that none of the DMTs would be efficacious on disability in patients older than 53. Evidence also suggested that, after patients reached age 40.5, high-efficacy DMTs (eg, ocrelizumab, natalizumab) no longer outperformed lower-efficacy oral agents (fingolimod, teriflunomide, dimethyl fumarate) or injectables (interferon betas and glatiramer acetates).
While skeptical of this latter finding, Dr. Coyle termed it “provocative” because it demonstrates that patients should be treated at a younger age. “When MS declares itself, the disease has probably existed for years, damaging CNS tissue,” she said. Older age at onset probably means that the disease has been present but silent for a long period of time. In addition, CNS and brain reserve become increasingly impaired with age. “The older you are, in theory, the less CNS reserve you have.”
Stopping Treatment
Potential reasons for stopping DMT include relapsing MS or CIS that has been inactive for years; secondary progressive MS that is distant from the relapsing phase and now in a purely neurodegenerative one; age older than 60; and pregnancy.
Citing just a handful of studies in this area, Dr. Coyle pointed to the MSBase Registry of patients with relapsing MS who, on injectables, had no relapse for five years or more. Among 485 patients who stopped DMT versus 854 who continued treatment, time to relapse was similar but time to confirmed disability was shorter in those who stopped treatment. Those who stopped treatment also had an increased risk for entering the progressive stage. In another study of two cohorts who stopped DMT, 11.7% of patients with secondary progressive MS who were stable for two to 20 years, versus 58.8% of patients with relapsing MS, had acute disease within one to two years. The authors noted the secondary progressive MS cohort was older with higher EDSS scores. A retrospective review of patients with MS older than 60 who had been on DMT for more than two years showed that, of the 29.7% who stopped DMT, only one relapsed and just 10.7% reinitiated DMT.
“I would not stop a well-tolerated DMT in relapsing MS,” said Dr. Coyle. “I would continue DMT in CIS if patients were at high risk, even if they had had no disease activity for years. I would discuss stopping therapy in patients with secondary progressive MS who were older than 60, and in very debilitated patients with progressive MS.”
Switching DMTs
In terms of switching, a suboptimal response is likely magnified by delaying therapy, not matching patients well to their initial DMT, and not identifying poor response quickly,” said Dr. Coyle.
Reasons to switch include breakthrough activity—ie, the minimal evidence of disease activity (MEDA) or no evidence of disease activity (NEDA) target not met; MRI activity; poor tolerability; and abnormal laboratory data or clinical complications. Clinicians should consult the AAN practice guidelines for recommendations on when and which DMTs to switch.
Dr. Coyle again cited the MSBase Registry, in which three studies were conducted involving patients with MS who were on interferon beta or glatiramer acetate who had breakthrough attacks or disability. “In one study they switched them to another injectable or fingolimod,” she said. “They did better if they got to fingolimod. Another study involved switching to another injectable or natalizumab. They did better if they were on natalizumab. A third study looked at switching to fingolimod or natalizumab. They did better with natalizumab.”
Dr. Coyle observed that the first one to two years after initiating DMT may be the most important for determining whether a patient is doing well. “A DMT takes a few months to be fully operational,” she said. “If you are switching for breakthrough activity, you need to go to a higher-efficacy DMT. My treat-to target is not NEDA, it is MEDA.”
—Fred Balzac
Suggested Reading
Berkovich R. Clinical and MRI outcomes after stopping or switching disease-modifying therapy in stable MS patients: a case series report. Mult Scler Relat Disord. 2017;17:123-127.
Birnbaum G. Stopping disease-modifying therapy in nonrelapsing multiple sclerosis: experience from a clinical practice. Int J MS Care. 2017;19(1):11-14.
Coyle PK. Switching therapies in multiple sclerosis. CNS Drugs. 2013;27(4):239-247.
Hua LH, Fan TH, Conway D, et al. Discontinuation of disease-modifying therapy in patients with multiple sclerosis over age 60. Mult Scler. 2018 Mar 1 [Epub ahead of print].
Kappos L, Radue EW, Comi G, et al, for the TOFINGO study group. Switching from natalizumab to fingolimod: a randomized, placebo-controlled study in RRMS. Neurology. 2015;85(1):29-39.
Kister I, Spelman T, Alroughani R, et al, for the MSBase Study Group. Discontinuing disease-modifying therapy in MS after a prolonged relapse-free period: a propensity score-matched study. J Neurol Neurosurg Psychiatry. 2016;87(10):1133-1137.
Maillart E, Vidal JS, Brassat D, et al. Natalizumab-PML survivors with subsequent MS treatment: clinico-radiologic outcome. Neurol Neuroimmunol Neuroinflamm. 2017;4(3):e346.
Rae-Grant A, Day GS, Marrie RA, et al. Practice guideline recommendations summary: disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018;90(17):777-788.
Weideman AM, Tapia-Maltos MA, Johnson K, et al. Meta-analysis of the age-dependent efficacy of multiple sclerosis treatments. Front Neurol. 2017;8:577.
Fitbit Flex is feasible, provides nuanced step count data in MS patients
LOS ANGELES – The commercially available Fitbit Flex accelerometer proved useful and feasible for longitudinal measurement of average daily steps in a prospective, 1-year study of patients with multiple sclerosis.
The wrist-worn device was well received, with 79 of 96 participants (82%) completing follow-up, and it revealed changes in daily functioning that were not captured using more traditional disability metrics, Valerie J. Block, DPTSc, reported at the annual meeting of the American Academy of Neurology.
The study involved 61 adults with relapsing multiple sclerosis (MS) and 35 with progressive MS who were recruited into the University of California, San Francisco (UCSF) FITriMS cohort. All were able to walk at least 2 minutes at baseline, and their daily physical activity was recorded continuously by the device over 1 year. Performance-based measures, including the Expanded Disability Status Scale (EDSS) and timed 25-foot walk test, were evaluated at baseline and at 1 year, and patient-reported outcomes such as the 12-item MS walking scale were completed at baseline and at 1.5, 3, 6, 9, and 12 months. Nine patients withdrew, and eight were lost to follow-up.
“This was a fairly stable, actively treated cohort, and overall, there was no significant change in average daily steps (STEPS) over 1 year. However, there was a trend toward a decrease (–315 steps/day; P = .117), and 53% of patients had a decrease of more than 800 steps per day, which is a proposed minimal clinically important difference threshold,” Dr. Block, a postdoctoral scholar at UCSF, said in an interview.
Despite the modest, gradual reduction in STEPS over the year, most participants were able to complete the study, providing at least 1 valid week of STEPS data per month throughout the year, she said, noting that there was no difference in device use between relapsing MS and progressive MS participants.
A significant association between decreasing STEPS and worsening of clinic-based and patient-reported outcomes was demonstrated, but declining STEPS occurred even when disability levels, as measured by the EDSS, remained stable.
“Participants who started off the study with lower STEPS, below the cohort median of 4,766 STEPS, had fourfold higher odds of clinically-meaningful disability worsening at 1 year after adjusting for age, sex, and disease duration,” she said.
Further, earlier data published by Dr. Block and her colleagues showed there is wide variability in the change in steps over 1 year. In that study, the change in step count in patients whose EDSS score remained unchanged ranged from +814 to –3,718, suggesting that popular mainstream wearable technology is not only feasible but also can provide a more detailed and nuanced measure of how patients are functioning in their daily lives, she said.
Together, these findings suggest that remote accelerometry provides useful continuous information about physical activity in real-world setting, she said, concluding that “these results support the possibility of using STEPS as a more sensitive and granular outcome measure in clinical trials and for targeted interventions in clinical care.”
This study was supported by the National Center for Advancing Translational Sciences. Dr. Block reported having no disclosures.
SOURCE: Block VJ et al. Neurology. 2018 Apr 10;90(15 Suppl):N5.001.
LOS ANGELES – The commercially available Fitbit Flex accelerometer proved useful and feasible for longitudinal measurement of average daily steps in a prospective, 1-year study of patients with multiple sclerosis.
The wrist-worn device was well received, with 79 of 96 participants (82%) completing follow-up, and it revealed changes in daily functioning that were not captured using more traditional disability metrics, Valerie J. Block, DPTSc, reported at the annual meeting of the American Academy of Neurology.
The study involved 61 adults with relapsing multiple sclerosis (MS) and 35 with progressive MS who were recruited into the University of California, San Francisco (UCSF) FITriMS cohort. All were able to walk at least 2 minutes at baseline, and their daily physical activity was recorded continuously by the device over 1 year. Performance-based measures, including the Expanded Disability Status Scale (EDSS) and timed 25-foot walk test, were evaluated at baseline and at 1 year, and patient-reported outcomes such as the 12-item MS walking scale were completed at baseline and at 1.5, 3, 6, 9, and 12 months. Nine patients withdrew, and eight were lost to follow-up.
“This was a fairly stable, actively treated cohort, and overall, there was no significant change in average daily steps (STEPS) over 1 year. However, there was a trend toward a decrease (–315 steps/day; P = .117), and 53% of patients had a decrease of more than 800 steps per day, which is a proposed minimal clinically important difference threshold,” Dr. Block, a postdoctoral scholar at UCSF, said in an interview.
Despite the modest, gradual reduction in STEPS over the year, most participants were able to complete the study, providing at least 1 valid week of STEPS data per month throughout the year, she said, noting that there was no difference in device use between relapsing MS and progressive MS participants.
A significant association between decreasing STEPS and worsening of clinic-based and patient-reported outcomes was demonstrated, but declining STEPS occurred even when disability levels, as measured by the EDSS, remained stable.
“Participants who started off the study with lower STEPS, below the cohort median of 4,766 STEPS, had fourfold higher odds of clinically-meaningful disability worsening at 1 year after adjusting for age, sex, and disease duration,” she said.
Further, earlier data published by Dr. Block and her colleagues showed there is wide variability in the change in steps over 1 year. In that study, the change in step count in patients whose EDSS score remained unchanged ranged from +814 to –3,718, suggesting that popular mainstream wearable technology is not only feasible but also can provide a more detailed and nuanced measure of how patients are functioning in their daily lives, she said.
Together, these findings suggest that remote accelerometry provides useful continuous information about physical activity in real-world setting, she said, concluding that “these results support the possibility of using STEPS as a more sensitive and granular outcome measure in clinical trials and for targeted interventions in clinical care.”
This study was supported by the National Center for Advancing Translational Sciences. Dr. Block reported having no disclosures.
SOURCE: Block VJ et al. Neurology. 2018 Apr 10;90(15 Suppl):N5.001.
LOS ANGELES – The commercially available Fitbit Flex accelerometer proved useful and feasible for longitudinal measurement of average daily steps in a prospective, 1-year study of patients with multiple sclerosis.
The wrist-worn device was well received, with 79 of 96 participants (82%) completing follow-up, and it revealed changes in daily functioning that were not captured using more traditional disability metrics, Valerie J. Block, DPTSc, reported at the annual meeting of the American Academy of Neurology.
The study involved 61 adults with relapsing multiple sclerosis (MS) and 35 with progressive MS who were recruited into the University of California, San Francisco (UCSF) FITriMS cohort. All were able to walk at least 2 minutes at baseline, and their daily physical activity was recorded continuously by the device over 1 year. Performance-based measures, including the Expanded Disability Status Scale (EDSS) and timed 25-foot walk test, were evaluated at baseline and at 1 year, and patient-reported outcomes such as the 12-item MS walking scale were completed at baseline and at 1.5, 3, 6, 9, and 12 months. Nine patients withdrew, and eight were lost to follow-up.
“This was a fairly stable, actively treated cohort, and overall, there was no significant change in average daily steps (STEPS) over 1 year. However, there was a trend toward a decrease (–315 steps/day; P = .117), and 53% of patients had a decrease of more than 800 steps per day, which is a proposed minimal clinically important difference threshold,” Dr. Block, a postdoctoral scholar at UCSF, said in an interview.
Despite the modest, gradual reduction in STEPS over the year, most participants were able to complete the study, providing at least 1 valid week of STEPS data per month throughout the year, she said, noting that there was no difference in device use between relapsing MS and progressive MS participants.
A significant association between decreasing STEPS and worsening of clinic-based and patient-reported outcomes was demonstrated, but declining STEPS occurred even when disability levels, as measured by the EDSS, remained stable.
“Participants who started off the study with lower STEPS, below the cohort median of 4,766 STEPS, had fourfold higher odds of clinically-meaningful disability worsening at 1 year after adjusting for age, sex, and disease duration,” she said.
Further, earlier data published by Dr. Block and her colleagues showed there is wide variability in the change in steps over 1 year. In that study, the change in step count in patients whose EDSS score remained unchanged ranged from +814 to –3,718, suggesting that popular mainstream wearable technology is not only feasible but also can provide a more detailed and nuanced measure of how patients are functioning in their daily lives, she said.
Together, these findings suggest that remote accelerometry provides useful continuous information about physical activity in real-world setting, she said, concluding that “these results support the possibility of using STEPS as a more sensitive and granular outcome measure in clinical trials and for targeted interventions in clinical care.”
This study was supported by the National Center for Advancing Translational Sciences. Dr. Block reported having no disclosures.
SOURCE: Block VJ et al. Neurology. 2018 Apr 10;90(15 Suppl):N5.001.
REPORTING FROM AAN 2018
Key clinical point: Wearable accelerometers like the Fitbit Flex are feasible and useful for daily step counts in MS patients.
Major finding: 79 of 96 participants (82%) completed follow-up,
Study details: A prospective, 1-year study of 96 patients with MS
Disclosures: This study was supported by the National Center for Advancing Translational Sciences. Dr. Block reported having no disclosures.
Source: Block VJ et al. Neurology. 2018 Apr 10;90(15 Suppl):N5.001.
Investigators Describe the MS Prodrome
Patients who later develop MS are more likely than others to consult physicians for nervous system and genitourinary symptoms.
The prodrome of multiple sclerosis (MS) may include an increased risk of nervous system, sensory, and musculoskeletal disorders, according to research published online ahead of print July 1 in Multiple Sclerosis Journal. Patients who later develop MS also may be more likely to have genitourinary and psychiatric symptoms in the five years before diagnosis.
“The existence of such warning signs is well-accepted for Alzheimer’s disease and Parkinson’s disease, but there has been little investigation into a similar pattern for MS,” said Helen Tremlett, PhD, Professor in the Division of Neurology at the University of British Columbia in Canada. “We now need to delve deeper into this phenomenon, perhaps using data-mining techniques. We want to see if there are discernible patterns related to sex, age, or the type of MS they eventually develop.”
Clinical and Administrative Matched Cohorts
Dr. Tremlett and colleagues analyzed data from a matched-cohort record-linkage study to examine the MS prodrome. The investigators used population-based health administrative data and clinical data from the Canadian provinces of British Columbia, Saskatchewan, Manitoba, and Nova Scotia. The information included demographics, hospital visits, physician encounters, and prescriptions filled. Clinical data were for patients diagnosed by a neurologist at an MS clinic and included first clinical visit (or date of diagnosis) and date of symptom onset. Data were collected from April 1984 to April 2014.
Using the data, Dr. Tremlett and colleagues created a health-administrative cohort and a clinical cohort. The clinical cohort did not include data from Saskatchewan. To create the cohorts, the investigators identified patients with MS and matched them by sex, year of birth, and postal code with as many as five controls. The index date was the earliest recorded claim for a demyelinating disease for the health-administrative cohort and the date of MS symptom onset for the clinical cohort. Study outcomes were the number of physician and hospital encounters per ICD-10 chapter, the number of physician encounters per physician specialty, and the percentage of people with one or more prescriptions per drug class in the five years before the index date.
Clinical Cohort Results May Be More Accurate
The administrative cohort included 13,951 cases and 66,940 controls. The clinical cohort included 3,202 cases and 16,006 controls. Compared with controls, people with MS had more physician and hospital encounters for the nervous (rate ratio [RR], 2.31 to 4.75), sensory (RR, 1.40 to 2.28), musculoskeletal (RR, 1.19 to 1.70), and genitourinary systems (RR, 1.17 to 1.59) in the five years before the first demyelinating claim or symptom onset. Cases had more visits with psychiatrists and urologists (RR, 1.48 to 1.80) and higher proportions of musculoskeletal, genitourinary, or hormonal-related prescriptions (1.1–1.5 times higher), compared with controls. People with MS had fewer pregnancy-related encounters than controls, however (RR, 0.78 to 0.88).
The “more conservative” results for the clinical cohort are more likely to reflect the MS prodrome accurately because they are “unlikely to be influenced by a physician’s suspicion or consideration of MS,” said Dr. Tremlett and colleagues. “Although not all individuals with MS attend an MS specialty clinic, the clinical cohort represents a subgroup of the population that may differ with respect to demographic and clinical characteristics from nonclinic attendees (eg, have fewer comorbidities),” they added. NR
—Erik Greb
Suggested Reading
Wijnands JM, Zhu F, Kingwell E, et al. Five years before multiple sclerosis onset: Phenotyping the prodrome. Mult Scler. 2018 Jul 1 [Epub ahead of print].
Patients who later develop MS are more likely than others to consult physicians for nervous system and genitourinary symptoms.
Patients who later develop MS are more likely than others to consult physicians for nervous system and genitourinary symptoms.
The prodrome of multiple sclerosis (MS) may include an increased risk of nervous system, sensory, and musculoskeletal disorders, according to research published online ahead of print July 1 in Multiple Sclerosis Journal. Patients who later develop MS also may be more likely to have genitourinary and psychiatric symptoms in the five years before diagnosis.
“The existence of such warning signs is well-accepted for Alzheimer’s disease and Parkinson’s disease, but there has been little investigation into a similar pattern for MS,” said Helen Tremlett, PhD, Professor in the Division of Neurology at the University of British Columbia in Canada. “We now need to delve deeper into this phenomenon, perhaps using data-mining techniques. We want to see if there are discernible patterns related to sex, age, or the type of MS they eventually develop.”
Clinical and Administrative Matched Cohorts
Dr. Tremlett and colleagues analyzed data from a matched-cohort record-linkage study to examine the MS prodrome. The investigators used population-based health administrative data and clinical data from the Canadian provinces of British Columbia, Saskatchewan, Manitoba, and Nova Scotia. The information included demographics, hospital visits, physician encounters, and prescriptions filled. Clinical data were for patients diagnosed by a neurologist at an MS clinic and included first clinical visit (or date of diagnosis) and date of symptom onset. Data were collected from April 1984 to April 2014.
Using the data, Dr. Tremlett and colleagues created a health-administrative cohort and a clinical cohort. The clinical cohort did not include data from Saskatchewan. To create the cohorts, the investigators identified patients with MS and matched them by sex, year of birth, and postal code with as many as five controls. The index date was the earliest recorded claim for a demyelinating disease for the health-administrative cohort and the date of MS symptom onset for the clinical cohort. Study outcomes were the number of physician and hospital encounters per ICD-10 chapter, the number of physician encounters per physician specialty, and the percentage of people with one or more prescriptions per drug class in the five years before the index date.
Clinical Cohort Results May Be More Accurate
The administrative cohort included 13,951 cases and 66,940 controls. The clinical cohort included 3,202 cases and 16,006 controls. Compared with controls, people with MS had more physician and hospital encounters for the nervous (rate ratio [RR], 2.31 to 4.75), sensory (RR, 1.40 to 2.28), musculoskeletal (RR, 1.19 to 1.70), and genitourinary systems (RR, 1.17 to 1.59) in the five years before the first demyelinating claim or symptom onset. Cases had more visits with psychiatrists and urologists (RR, 1.48 to 1.80) and higher proportions of musculoskeletal, genitourinary, or hormonal-related prescriptions (1.1–1.5 times higher), compared with controls. People with MS had fewer pregnancy-related encounters than controls, however (RR, 0.78 to 0.88).
The “more conservative” results for the clinical cohort are more likely to reflect the MS prodrome accurately because they are “unlikely to be influenced by a physician’s suspicion or consideration of MS,” said Dr. Tremlett and colleagues. “Although not all individuals with MS attend an MS specialty clinic, the clinical cohort represents a subgroup of the population that may differ with respect to demographic and clinical characteristics from nonclinic attendees (eg, have fewer comorbidities),” they added. NR
—Erik Greb
Suggested Reading
Wijnands JM, Zhu F, Kingwell E, et al. Five years before multiple sclerosis onset: Phenotyping the prodrome. Mult Scler. 2018 Jul 1 [Epub ahead of print].
The prodrome of multiple sclerosis (MS) may include an increased risk of nervous system, sensory, and musculoskeletal disorders, according to research published online ahead of print July 1 in Multiple Sclerosis Journal. Patients who later develop MS also may be more likely to have genitourinary and psychiatric symptoms in the five years before diagnosis.
“The existence of such warning signs is well-accepted for Alzheimer’s disease and Parkinson’s disease, but there has been little investigation into a similar pattern for MS,” said Helen Tremlett, PhD, Professor in the Division of Neurology at the University of British Columbia in Canada. “We now need to delve deeper into this phenomenon, perhaps using data-mining techniques. We want to see if there are discernible patterns related to sex, age, or the type of MS they eventually develop.”
Clinical and Administrative Matched Cohorts
Dr. Tremlett and colleagues analyzed data from a matched-cohort record-linkage study to examine the MS prodrome. The investigators used population-based health administrative data and clinical data from the Canadian provinces of British Columbia, Saskatchewan, Manitoba, and Nova Scotia. The information included demographics, hospital visits, physician encounters, and prescriptions filled. Clinical data were for patients diagnosed by a neurologist at an MS clinic and included first clinical visit (or date of diagnosis) and date of symptom onset. Data were collected from April 1984 to April 2014.
Using the data, Dr. Tremlett and colleagues created a health-administrative cohort and a clinical cohort. The clinical cohort did not include data from Saskatchewan. To create the cohorts, the investigators identified patients with MS and matched them by sex, year of birth, and postal code with as many as five controls. The index date was the earliest recorded claim for a demyelinating disease for the health-administrative cohort and the date of MS symptom onset for the clinical cohort. Study outcomes were the number of physician and hospital encounters per ICD-10 chapter, the number of physician encounters per physician specialty, and the percentage of people with one or more prescriptions per drug class in the five years before the index date.
Clinical Cohort Results May Be More Accurate
The administrative cohort included 13,951 cases and 66,940 controls. The clinical cohort included 3,202 cases and 16,006 controls. Compared with controls, people with MS had more physician and hospital encounters for the nervous (rate ratio [RR], 2.31 to 4.75), sensory (RR, 1.40 to 2.28), musculoskeletal (RR, 1.19 to 1.70), and genitourinary systems (RR, 1.17 to 1.59) in the five years before the first demyelinating claim or symptom onset. Cases had more visits with psychiatrists and urologists (RR, 1.48 to 1.80) and higher proportions of musculoskeletal, genitourinary, or hormonal-related prescriptions (1.1–1.5 times higher), compared with controls. People with MS had fewer pregnancy-related encounters than controls, however (RR, 0.78 to 0.88).
The “more conservative” results for the clinical cohort are more likely to reflect the MS prodrome accurately because they are “unlikely to be influenced by a physician’s suspicion or consideration of MS,” said Dr. Tremlett and colleagues. “Although not all individuals with MS attend an MS specialty clinic, the clinical cohort represents a subgroup of the population that may differ with respect to demographic and clinical characteristics from nonclinic attendees (eg, have fewer comorbidities),” they added. NR
—Erik Greb
Suggested Reading
Wijnands JM, Zhu F, Kingwell E, et al. Five years before multiple sclerosis onset: Phenotyping the prodrome. Mult Scler. 2018 Jul 1 [Epub ahead of print].
Lipid Metabolism May Be a Therapeutic Target in MS
NASHVILLE—Multiple sclerosis (MS) traditionally has been considered a chronic inflammatory autoimmune disease, but inflammation decreases as the disease progresses. Many other biologic processes are dysregulated in MS, such as myelin signal transport, mitochondrial function, and iron metabolism. Lipid metabolism affects all of these processes, including inflammation, and thus could be a valuable therapeutic target, according to research presented at the 2018 CMSC Annual Meeting.
“MS is not an inflammatory disease,” said John D. Nieland, PhD, Associate Professor of Health Science and Technology at Aalborg University in Denmark. “The inflammatory response is important, but it is not the only component. If you do not focus on the other components, you will never be able to treat the disease.”
The Role of Lipids in the CNS
Healthy brains have a high amount of glucose metabolism, but glucose metabolism is reduced in MS and other neurologic disorders such as Parkinson’s disease and Alzheimer’s disease. “If glucose metabolism is downregulated, something else has to be taking over,” said Dr. Nieland. He and his colleagues hypothesize that lipid metabolism replaces glucose metabolism in MS. They further hypothesize that MS fundamentally is a dysfunction of lipid metabolism.
Lipids have an essential role in the CNS. Proper signal transduction requires lipids to be bound to the myelin sheath. The proteins that compose myelin sheaths are highly immunogenic, and lipids shield them from exposure to the immune system. The half-life of lipids attached to the myelin sheath is three days, so these lipids must be replaced constantly. In addition, lipids are essential for the function of glutamate, cannabinoid, and insulin receptors.
An increase in lipid metabolism decreases glucose metabolism and induces the production of prostaglandin E2, which is a key molecule in the inflammatory response. In the early stages of MS, inflammation attacks the myelin sheath and other brain proteins. Increased lipid metabolism decreases lipid concentrations in the CNS, including around myelin. When lipids are removed from the myelin sheath, they expose the immunogenic proteins that compose it, thus provoking an immune response. Dysregulated lipid metabolism also contributes to oxidative stress, mitochondrial dysfunction, demyelination, and neuronal loss.
Chemical Inhibition of Lipid Metabolism
Dr. Nieland and colleagues hypothesized that blocking lipid metabolism would reverse the inflammatory response and other harmful processes that occur in MS. Previous research by Shriver and colleagues indicated that inhibition of carnitine palmitoyltransferase 1 (CPT1), a molecule essential to lipid metabolism, in encephalitogenic T cells increases apoptosis and reduces the production of inflammatory cytokines. Two of the molecule’s three isoforms, CPT1A and CPT1C, are upregulated in MS. Stress prompts an increase in CPT1 expression, which spurs a shift to lipid metabolism. “If you block CPT1, you jam lipid metabolism,” Dr. Nieland said. “There is no way around it.” Dr. Nieland’s group thus chose CPT1 as its target.
The investigators first conducted studies using etomoxir, which inhibits CPT1 and blocks long-chain fatty acids from entering the mitochondria for beta oxidation. Through these effects, etomoxir causes cells to shift to glucose metabolism.
The researchers immunized 42 mice with myelin oligodendrocyte glycoprotein (MOG35–55) to induce experimental autoimmune encephalopathy (EAE). When the animals first exhibited symptoms at Day 10, they were randomized to receive subcutaneous etomoxir or placebo daily. Disease score decreased significantly in the treated animals, compared with the control animals. On Day 24, more than 50% of the treated mice exhibited normal behavior, compared with approximately 20% of control mice.
In another study, the investigators immunized 47 rats with myelin basic protein to induce EAE. The animals began having symptoms at Day 7, and the investigators randomized them to daily treatment with subcutaneous etomoxir or placebo. At Day 11, disease score was significantly lower among treated animals, compared with control animals. Body weight was significantly higher among rats that received etomoxir, compared with controls, at that time point. Also, 25% of treated animals exhibited normal behavior, but no controls did.
In a third study, the investigators compared etomoxir, interferon beta, and placebo in a rat model of EAE. Each treatment group included 10 rats, and etomoxir had superior effects on disease score and body weight, compared with interferon beta and placebo. When the investigators examined the rats’ serum, they found that levels of antibodies against brain antigens common in EAE were lower in rats treated with etomoxir, compared with those treated with interferon beta or placebo.
Biologic Inhibition of Lipid Metabolism
In addition to pharmacologic treatment, genetic mutations affect CPT1 function. The Hutterites, an ethnoreligious group in Canada, have a mutation in CPT1A that almost completely blocks the molecule’s activity. Similarly, the Inuit have a mutation in CPT1A that reduces its activity to approximately 22%. The prevalence of MS is one in 1,100 among the Hutterites and one in 50,000 among the Inuit, compared with one in 350 in the Canadian population. These observations suggest that gene therapy could be another way to block CPT1.
Dr. Nieland’s group collaborated with the Netherlands Cancer Institute to develop mouse strains with two distinct mutations in CPT1A. The first mutation mimics that found among the Hutterites, and the other mimics that found among the Inuit. In a preliminary study, the investigators induced EAE in three wild-type mice and two mice with the CPT1A mutation similar to that of the Inuit. The mice were 10 weeks old at the time of immunization.
At 24 days, disease score was lower in the CPT1A mutant mice, compared with the wild-type mice. Furthermore, body weight was higher in the mutant mice, compared with the wild-type mice. The investigators also measured the mice’s grip strength at Day 2 and Day 24. Grip strength decreased in the wild-type mice but remained the same in the mutant mice. At Day 24, grip strength was significantly higher among mutant mice than among wild-type mice.
“These results indicate an interaction of the lipid metabolism in the brain and in the immune system, which supports our hypothesis regarding MS pathology,” said Anne Skøttrup Mørkholt, a doctoral student at Aalborg University, who collaborated with Dr. Nieland on these animal studies. “MS is not a disease of the immune system, but a systemic disease with dysregulation of multiple components.”
Lipid Metabolism in Other Neurologic Diseases
Data suggest that lipid metabolism may contribute to other neurologic diseases such as amyotrophic lateral sclerosis (ALS) as well. Huang et al found a correlation between serum triglyceride levels and the development of ALS. Dupuis et al observed upregulated lipid metabolism and downregulated glucose metabolism in SOD1 mouse models of the disease, as did subsequent researchers. In addition, a 2015 study by Palamiuc et al found that CPT1B was significantly increased in the muscle tissue of SOD1 mice.
To investigate whether suppressing lipid metabolism affected ALS, Dr. Nieland’s group examined a SOD1 mouse model of the disease. The mice developed symptoms at Day 70 and were randomized at Day 100 to etomoxir or placebo. Etomoxir was associated with less weight loss and better neurologic score, compared with placebo. Etomoxir also was associated with better performance on the wire hanging and rotarod tests, compared with placebo. “It seems like etomoxir was able to slow down the disease progression,” said Michael Sloth Trabjerg, MD, a doctoral student at Aalborg University.
Because research has found increased beta oxidation and decreased glucose metabolism in Parkinson’s disease, Dr. Nieland’s group studied the effect of CPT1 inhibition in a rotenone mouse model of the disease. They induced the disease in the mice for 32 days before randomizing them to placebo or etomoxir. For all mice, treatment alternated between rotenone on one day and placebo or etomoxir on the next day. The investigators observed significantly better sensorimotor performance among treated mice, compared with controls, on Day 47 and Day 56. At Day 60, mice who received etomoxir had significantly more muscle strength and longer latency to fall on the rotarod test, compared with mice that received placebo. These data are being prepared for publication.
The data suggest that dysregulated glucose metabolism and increased lipid metabolism play a role in ALS and Parkinson’s disease. “CPT1 seems to be a prominent target for moderating these diseases,” said Dr. Trabjerg.
—Erik Greb
Suggested Reading
Dodge JC, Treleaven CM, Fidler JA, et al. Metabolic signatures of amyotrophic lateral sclerosis reveal insights into disease pathogenesis. Proc Natl Acad Sci U S A. 2013;110(26):10812-10817.
Dupuis L, Oudart H, René F, et al. Evidence for defective energy homeostasis in amyotrophic lateral sclerosis: benefit of a high-energy diet in a transgenic mouse model. Proc Natl Acad Sci U S A. 2004;101(30):11159-11164.
Huang R, Guo X, Chen X, et al. The serum lipid profiles of amyotrophic lateral sclerosis patients: A study from south-west China and a meta-analysis. Amyotroph Lateral Scler Frontotemporal Degener. 2015;16(5-6):359-365.
Kim SM, Kim H, Kim JE, et al. Amyotrophic lateral sclerosis is associated with hypolipidemia at the presymptomatic stage in mice. PLoS One. 2011;6(3):e17985.
Lieury A, Chanal M, Androdias G, et al. Tissue remodeling in periplaque regions of multiple sclerosis spinal cord lesions. Glia. 2014;62(10):1645-1658.
Mørkholt AS, Kastaniegaard K, Trabjerg MS, et al. Identification of brain antigens recognized by autoantibodies in experimental autoimmune encephalomyelitis-induced animals treated with etomoxir or interferon-β. Sci Rep. 2018;8(1):7092.
Palamiuc L, Schlagowski A, Ngo ST, et al. A metabolic switch toward lipid use in glycolytic muscle is an early pathologic event in a mouse model of amyotrophic lateral sclerosis. EMBO Mol Med. 2015;7(5):526-546.
Shriver LP, Manchester M. Inhibition of fatty acid metabolism ameliorates disease activity in an animal model of multiple sclerosis. Sci Rep. 2011;1:79.
van der Windt GJ, Everts B, Chang CH, et al. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity. 2012;36(1):68-78.
NASHVILLE—Multiple sclerosis (MS) traditionally has been considered a chronic inflammatory autoimmune disease, but inflammation decreases as the disease progresses. Many other biologic processes are dysregulated in MS, such as myelin signal transport, mitochondrial function, and iron metabolism. Lipid metabolism affects all of these processes, including inflammation, and thus could be a valuable therapeutic target, according to research presented at the 2018 CMSC Annual Meeting.
“MS is not an inflammatory disease,” said John D. Nieland, PhD, Associate Professor of Health Science and Technology at Aalborg University in Denmark. “The inflammatory response is important, but it is not the only component. If you do not focus on the other components, you will never be able to treat the disease.”
The Role of Lipids in the CNS
Healthy brains have a high amount of glucose metabolism, but glucose metabolism is reduced in MS and other neurologic disorders such as Parkinson’s disease and Alzheimer’s disease. “If glucose metabolism is downregulated, something else has to be taking over,” said Dr. Nieland. He and his colleagues hypothesize that lipid metabolism replaces glucose metabolism in MS. They further hypothesize that MS fundamentally is a dysfunction of lipid metabolism.
Lipids have an essential role in the CNS. Proper signal transduction requires lipids to be bound to the myelin sheath. The proteins that compose myelin sheaths are highly immunogenic, and lipids shield them from exposure to the immune system. The half-life of lipids attached to the myelin sheath is three days, so these lipids must be replaced constantly. In addition, lipids are essential for the function of glutamate, cannabinoid, and insulin receptors.
An increase in lipid metabolism decreases glucose metabolism and induces the production of prostaglandin E2, which is a key molecule in the inflammatory response. In the early stages of MS, inflammation attacks the myelin sheath and other brain proteins. Increased lipid metabolism decreases lipid concentrations in the CNS, including around myelin. When lipids are removed from the myelin sheath, they expose the immunogenic proteins that compose it, thus provoking an immune response. Dysregulated lipid metabolism also contributes to oxidative stress, mitochondrial dysfunction, demyelination, and neuronal loss.
Chemical Inhibition of Lipid Metabolism
Dr. Nieland and colleagues hypothesized that blocking lipid metabolism would reverse the inflammatory response and other harmful processes that occur in MS. Previous research by Shriver and colleagues indicated that inhibition of carnitine palmitoyltransferase 1 (CPT1), a molecule essential to lipid metabolism, in encephalitogenic T cells increases apoptosis and reduces the production of inflammatory cytokines. Two of the molecule’s three isoforms, CPT1A and CPT1C, are upregulated in MS. Stress prompts an increase in CPT1 expression, which spurs a shift to lipid metabolism. “If you block CPT1, you jam lipid metabolism,” Dr. Nieland said. “There is no way around it.” Dr. Nieland’s group thus chose CPT1 as its target.
The investigators first conducted studies using etomoxir, which inhibits CPT1 and blocks long-chain fatty acids from entering the mitochondria for beta oxidation. Through these effects, etomoxir causes cells to shift to glucose metabolism.
The researchers immunized 42 mice with myelin oligodendrocyte glycoprotein (MOG35–55) to induce experimental autoimmune encephalopathy (EAE). When the animals first exhibited symptoms at Day 10, they were randomized to receive subcutaneous etomoxir or placebo daily. Disease score decreased significantly in the treated animals, compared with the control animals. On Day 24, more than 50% of the treated mice exhibited normal behavior, compared with approximately 20% of control mice.
In another study, the investigators immunized 47 rats with myelin basic protein to induce EAE. The animals began having symptoms at Day 7, and the investigators randomized them to daily treatment with subcutaneous etomoxir or placebo. At Day 11, disease score was significantly lower among treated animals, compared with control animals. Body weight was significantly higher among rats that received etomoxir, compared with controls, at that time point. Also, 25% of treated animals exhibited normal behavior, but no controls did.
In a third study, the investigators compared etomoxir, interferon beta, and placebo in a rat model of EAE. Each treatment group included 10 rats, and etomoxir had superior effects on disease score and body weight, compared with interferon beta and placebo. When the investigators examined the rats’ serum, they found that levels of antibodies against brain antigens common in EAE were lower in rats treated with etomoxir, compared with those treated with interferon beta or placebo.
Biologic Inhibition of Lipid Metabolism
In addition to pharmacologic treatment, genetic mutations affect CPT1 function. The Hutterites, an ethnoreligious group in Canada, have a mutation in CPT1A that almost completely blocks the molecule’s activity. Similarly, the Inuit have a mutation in CPT1A that reduces its activity to approximately 22%. The prevalence of MS is one in 1,100 among the Hutterites and one in 50,000 among the Inuit, compared with one in 350 in the Canadian population. These observations suggest that gene therapy could be another way to block CPT1.
Dr. Nieland’s group collaborated with the Netherlands Cancer Institute to develop mouse strains with two distinct mutations in CPT1A. The first mutation mimics that found among the Hutterites, and the other mimics that found among the Inuit. In a preliminary study, the investigators induced EAE in three wild-type mice and two mice with the CPT1A mutation similar to that of the Inuit. The mice were 10 weeks old at the time of immunization.
At 24 days, disease score was lower in the CPT1A mutant mice, compared with the wild-type mice. Furthermore, body weight was higher in the mutant mice, compared with the wild-type mice. The investigators also measured the mice’s grip strength at Day 2 and Day 24. Grip strength decreased in the wild-type mice but remained the same in the mutant mice. At Day 24, grip strength was significantly higher among mutant mice than among wild-type mice.
“These results indicate an interaction of the lipid metabolism in the brain and in the immune system, which supports our hypothesis regarding MS pathology,” said Anne Skøttrup Mørkholt, a doctoral student at Aalborg University, who collaborated with Dr. Nieland on these animal studies. “MS is not a disease of the immune system, but a systemic disease with dysregulation of multiple components.”
Lipid Metabolism in Other Neurologic Diseases
Data suggest that lipid metabolism may contribute to other neurologic diseases such as amyotrophic lateral sclerosis (ALS) as well. Huang et al found a correlation between serum triglyceride levels and the development of ALS. Dupuis et al observed upregulated lipid metabolism and downregulated glucose metabolism in SOD1 mouse models of the disease, as did subsequent researchers. In addition, a 2015 study by Palamiuc et al found that CPT1B was significantly increased in the muscle tissue of SOD1 mice.
To investigate whether suppressing lipid metabolism affected ALS, Dr. Nieland’s group examined a SOD1 mouse model of the disease. The mice developed symptoms at Day 70 and were randomized at Day 100 to etomoxir or placebo. Etomoxir was associated with less weight loss and better neurologic score, compared with placebo. Etomoxir also was associated with better performance on the wire hanging and rotarod tests, compared with placebo. “It seems like etomoxir was able to slow down the disease progression,” said Michael Sloth Trabjerg, MD, a doctoral student at Aalborg University.
Because research has found increased beta oxidation and decreased glucose metabolism in Parkinson’s disease, Dr. Nieland’s group studied the effect of CPT1 inhibition in a rotenone mouse model of the disease. They induced the disease in the mice for 32 days before randomizing them to placebo or etomoxir. For all mice, treatment alternated between rotenone on one day and placebo or etomoxir on the next day. The investigators observed significantly better sensorimotor performance among treated mice, compared with controls, on Day 47 and Day 56. At Day 60, mice who received etomoxir had significantly more muscle strength and longer latency to fall on the rotarod test, compared with mice that received placebo. These data are being prepared for publication.
The data suggest that dysregulated glucose metabolism and increased lipid metabolism play a role in ALS and Parkinson’s disease. “CPT1 seems to be a prominent target for moderating these diseases,” said Dr. Trabjerg.
—Erik Greb
Suggested Reading
Dodge JC, Treleaven CM, Fidler JA, et al. Metabolic signatures of amyotrophic lateral sclerosis reveal insights into disease pathogenesis. Proc Natl Acad Sci U S A. 2013;110(26):10812-10817.
Dupuis L, Oudart H, René F, et al. Evidence for defective energy homeostasis in amyotrophic lateral sclerosis: benefit of a high-energy diet in a transgenic mouse model. Proc Natl Acad Sci U S A. 2004;101(30):11159-11164.
Huang R, Guo X, Chen X, et al. The serum lipid profiles of amyotrophic lateral sclerosis patients: A study from south-west China and a meta-analysis. Amyotroph Lateral Scler Frontotemporal Degener. 2015;16(5-6):359-365.
Kim SM, Kim H, Kim JE, et al. Amyotrophic lateral sclerosis is associated with hypolipidemia at the presymptomatic stage in mice. PLoS One. 2011;6(3):e17985.
Lieury A, Chanal M, Androdias G, et al. Tissue remodeling in periplaque regions of multiple sclerosis spinal cord lesions. Glia. 2014;62(10):1645-1658.
Mørkholt AS, Kastaniegaard K, Trabjerg MS, et al. Identification of brain antigens recognized by autoantibodies in experimental autoimmune encephalomyelitis-induced animals treated with etomoxir or interferon-β. Sci Rep. 2018;8(1):7092.
Palamiuc L, Schlagowski A, Ngo ST, et al. A metabolic switch toward lipid use in glycolytic muscle is an early pathologic event in a mouse model of amyotrophic lateral sclerosis. EMBO Mol Med. 2015;7(5):526-546.
Shriver LP, Manchester M. Inhibition of fatty acid metabolism ameliorates disease activity in an animal model of multiple sclerosis. Sci Rep. 2011;1:79.
van der Windt GJ, Everts B, Chang CH, et al. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity. 2012;36(1):68-78.
NASHVILLE—Multiple sclerosis (MS) traditionally has been considered a chronic inflammatory autoimmune disease, but inflammation decreases as the disease progresses. Many other biologic processes are dysregulated in MS, such as myelin signal transport, mitochondrial function, and iron metabolism. Lipid metabolism affects all of these processes, including inflammation, and thus could be a valuable therapeutic target, according to research presented at the 2018 CMSC Annual Meeting.
“MS is not an inflammatory disease,” said John D. Nieland, PhD, Associate Professor of Health Science and Technology at Aalborg University in Denmark. “The inflammatory response is important, but it is not the only component. If you do not focus on the other components, you will never be able to treat the disease.”
The Role of Lipids in the CNS
Healthy brains have a high amount of glucose metabolism, but glucose metabolism is reduced in MS and other neurologic disorders such as Parkinson’s disease and Alzheimer’s disease. “If glucose metabolism is downregulated, something else has to be taking over,” said Dr. Nieland. He and his colleagues hypothesize that lipid metabolism replaces glucose metabolism in MS. They further hypothesize that MS fundamentally is a dysfunction of lipid metabolism.
Lipids have an essential role in the CNS. Proper signal transduction requires lipids to be bound to the myelin sheath. The proteins that compose myelin sheaths are highly immunogenic, and lipids shield them from exposure to the immune system. The half-life of lipids attached to the myelin sheath is three days, so these lipids must be replaced constantly. In addition, lipids are essential for the function of glutamate, cannabinoid, and insulin receptors.
An increase in lipid metabolism decreases glucose metabolism and induces the production of prostaglandin E2, which is a key molecule in the inflammatory response. In the early stages of MS, inflammation attacks the myelin sheath and other brain proteins. Increased lipid metabolism decreases lipid concentrations in the CNS, including around myelin. When lipids are removed from the myelin sheath, they expose the immunogenic proteins that compose it, thus provoking an immune response. Dysregulated lipid metabolism also contributes to oxidative stress, mitochondrial dysfunction, demyelination, and neuronal loss.
Chemical Inhibition of Lipid Metabolism
Dr. Nieland and colleagues hypothesized that blocking lipid metabolism would reverse the inflammatory response and other harmful processes that occur in MS. Previous research by Shriver and colleagues indicated that inhibition of carnitine palmitoyltransferase 1 (CPT1), a molecule essential to lipid metabolism, in encephalitogenic T cells increases apoptosis and reduces the production of inflammatory cytokines. Two of the molecule’s three isoforms, CPT1A and CPT1C, are upregulated in MS. Stress prompts an increase in CPT1 expression, which spurs a shift to lipid metabolism. “If you block CPT1, you jam lipid metabolism,” Dr. Nieland said. “There is no way around it.” Dr. Nieland’s group thus chose CPT1 as its target.
The investigators first conducted studies using etomoxir, which inhibits CPT1 and blocks long-chain fatty acids from entering the mitochondria for beta oxidation. Through these effects, etomoxir causes cells to shift to glucose metabolism.
The researchers immunized 42 mice with myelin oligodendrocyte glycoprotein (MOG35–55) to induce experimental autoimmune encephalopathy (EAE). When the animals first exhibited symptoms at Day 10, they were randomized to receive subcutaneous etomoxir or placebo daily. Disease score decreased significantly in the treated animals, compared with the control animals. On Day 24, more than 50% of the treated mice exhibited normal behavior, compared with approximately 20% of control mice.
In another study, the investigators immunized 47 rats with myelin basic protein to induce EAE. The animals began having symptoms at Day 7, and the investigators randomized them to daily treatment with subcutaneous etomoxir or placebo. At Day 11, disease score was significantly lower among treated animals, compared with control animals. Body weight was significantly higher among rats that received etomoxir, compared with controls, at that time point. Also, 25% of treated animals exhibited normal behavior, but no controls did.
In a third study, the investigators compared etomoxir, interferon beta, and placebo in a rat model of EAE. Each treatment group included 10 rats, and etomoxir had superior effects on disease score and body weight, compared with interferon beta and placebo. When the investigators examined the rats’ serum, they found that levels of antibodies against brain antigens common in EAE were lower in rats treated with etomoxir, compared with those treated with interferon beta or placebo.
Biologic Inhibition of Lipid Metabolism
In addition to pharmacologic treatment, genetic mutations affect CPT1 function. The Hutterites, an ethnoreligious group in Canada, have a mutation in CPT1A that almost completely blocks the molecule’s activity. Similarly, the Inuit have a mutation in CPT1A that reduces its activity to approximately 22%. The prevalence of MS is one in 1,100 among the Hutterites and one in 50,000 among the Inuit, compared with one in 350 in the Canadian population. These observations suggest that gene therapy could be another way to block CPT1.
Dr. Nieland’s group collaborated with the Netherlands Cancer Institute to develop mouse strains with two distinct mutations in CPT1A. The first mutation mimics that found among the Hutterites, and the other mimics that found among the Inuit. In a preliminary study, the investigators induced EAE in three wild-type mice and two mice with the CPT1A mutation similar to that of the Inuit. The mice were 10 weeks old at the time of immunization.
At 24 days, disease score was lower in the CPT1A mutant mice, compared with the wild-type mice. Furthermore, body weight was higher in the mutant mice, compared with the wild-type mice. The investigators also measured the mice’s grip strength at Day 2 and Day 24. Grip strength decreased in the wild-type mice but remained the same in the mutant mice. At Day 24, grip strength was significantly higher among mutant mice than among wild-type mice.
“These results indicate an interaction of the lipid metabolism in the brain and in the immune system, which supports our hypothesis regarding MS pathology,” said Anne Skøttrup Mørkholt, a doctoral student at Aalborg University, who collaborated with Dr. Nieland on these animal studies. “MS is not a disease of the immune system, but a systemic disease with dysregulation of multiple components.”
Lipid Metabolism in Other Neurologic Diseases
Data suggest that lipid metabolism may contribute to other neurologic diseases such as amyotrophic lateral sclerosis (ALS) as well. Huang et al found a correlation between serum triglyceride levels and the development of ALS. Dupuis et al observed upregulated lipid metabolism and downregulated glucose metabolism in SOD1 mouse models of the disease, as did subsequent researchers. In addition, a 2015 study by Palamiuc et al found that CPT1B was significantly increased in the muscle tissue of SOD1 mice.
To investigate whether suppressing lipid metabolism affected ALS, Dr. Nieland’s group examined a SOD1 mouse model of the disease. The mice developed symptoms at Day 70 and were randomized at Day 100 to etomoxir or placebo. Etomoxir was associated with less weight loss and better neurologic score, compared with placebo. Etomoxir also was associated with better performance on the wire hanging and rotarod tests, compared with placebo. “It seems like etomoxir was able to slow down the disease progression,” said Michael Sloth Trabjerg, MD, a doctoral student at Aalborg University.
Because research has found increased beta oxidation and decreased glucose metabolism in Parkinson’s disease, Dr. Nieland’s group studied the effect of CPT1 inhibition in a rotenone mouse model of the disease. They induced the disease in the mice for 32 days before randomizing them to placebo or etomoxir. For all mice, treatment alternated between rotenone on one day and placebo or etomoxir on the next day. The investigators observed significantly better sensorimotor performance among treated mice, compared with controls, on Day 47 and Day 56. At Day 60, mice who received etomoxir had significantly more muscle strength and longer latency to fall on the rotarod test, compared with mice that received placebo. These data are being prepared for publication.
The data suggest that dysregulated glucose metabolism and increased lipid metabolism play a role in ALS and Parkinson’s disease. “CPT1 seems to be a prominent target for moderating these diseases,” said Dr. Trabjerg.
—Erik Greb
Suggested Reading
Dodge JC, Treleaven CM, Fidler JA, et al. Metabolic signatures of amyotrophic lateral sclerosis reveal insights into disease pathogenesis. Proc Natl Acad Sci U S A. 2013;110(26):10812-10817.
Dupuis L, Oudart H, René F, et al. Evidence for defective energy homeostasis in amyotrophic lateral sclerosis: benefit of a high-energy diet in a transgenic mouse model. Proc Natl Acad Sci U S A. 2004;101(30):11159-11164.
Huang R, Guo X, Chen X, et al. The serum lipid profiles of amyotrophic lateral sclerosis patients: A study from south-west China and a meta-analysis. Amyotroph Lateral Scler Frontotemporal Degener. 2015;16(5-6):359-365.
Kim SM, Kim H, Kim JE, et al. Amyotrophic lateral sclerosis is associated with hypolipidemia at the presymptomatic stage in mice. PLoS One. 2011;6(3):e17985.
Lieury A, Chanal M, Androdias G, et al. Tissue remodeling in periplaque regions of multiple sclerosis spinal cord lesions. Glia. 2014;62(10):1645-1658.
Mørkholt AS, Kastaniegaard K, Trabjerg MS, et al. Identification of brain antigens recognized by autoantibodies in experimental autoimmune encephalomyelitis-induced animals treated with etomoxir or interferon-β. Sci Rep. 2018;8(1):7092.
Palamiuc L, Schlagowski A, Ngo ST, et al. A metabolic switch toward lipid use in glycolytic muscle is an early pathologic event in a mouse model of amyotrophic lateral sclerosis. EMBO Mol Med. 2015;7(5):526-546.
Shriver LP, Manchester M. Inhibition of fatty acid metabolism ameliorates disease activity in an animal model of multiple sclerosis. Sci Rep. 2011;1:79.
van der Windt GJ, Everts B, Chang CH, et al. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity. 2012;36(1):68-78.
Research supports cannabis in MS, but legal, clinical pictures are murky
The medical marijuana landscape is changing so fast that Colorado Neurological Institute neurologist Allen C. Bowling, MD, PhD, already needs to update a presentation he gave about cannabis in multiple sclerosis in late May.
Since then, both those facts became history over a span of 2 days.
First, on June 25, the FDA announced its approval of Epidiolex (cannabidiol) for the treatment of seizures in two rare forms of epilepsy, Lennox-Gastaut syndrome and Dravet syndrome. It’s the first time the FDA has approved a drug with a purified ingredient – cannabidiol, a nonpsychoactive substance – that’s derived from marijuana.
Then, on June 26, voters in Oklahoma approved a ballot measure that allows the possession of marijuana for medical use; users must register with the state. Thirty states and the District of Columbia have made medical marijuana legal, according to the procon.org website, although the two newest ones (Oklahoma and West Virginia) are still developing procedures.
The laws vary widely. Some states don’t allow patients to smoke medical marijuana, and some don’t allow visitors to use out-of-state registry ID cards. And certain states limit the use of medical marijuana to specific conditions. Medical marijuana use by patients with MS is specifically allowed in many states, including Alaska, Arizona, Florida, Minnesota, and several others.
There’s another complexity: According to procon.org, 17 states have laws about the use of cannabidiol. In Georgia, for instance, the use of some cannabis oil is allowed for the treatment of MS and other conditions.
In the wake of the FDA ruling, Dr. Bowling spoke in an interview about cannabis, MS, and the questions that neurologists should be asking themselves.
Q: What are studies telling us about cannabis and MS?
A: There are lots of clinical studies – 19 randomized controlled trials. A consistent finding is that there’s benefit in terms of pain and people’s subjective sense of spasticity (Neurology. 2014 Apr 29;82(17):1556-63).
Q: During your CMSC presentation, you talked about how “fidelity” has been a problem in cannabis research. Could you elaborate on what you mean?
A: The products used in these studies are generally standardized, research-grade products that you can’t buy in any U.S. dispensary.
Cannabis is complex and contains more than 100 different potentially pharmacologically active molecules. You can’t conclude that if you see a product in clinical trials, you’ll then be able to walk into a dispensary for recreational or medical cannabis and get a product that produces the same effect.
Q: What have you seen in your own patient population in terms of cannabis use?
A: I find what’s been found with the studies: It helps with pain and people’s sense of muscle stiffness.
It’s especially helpful in people with pain and spasticity that breaks through in the late afternoon or at night when they’re trying to go to sleep. Just a little bit of cannabis can get them through those difficult times and improve their quality of life.
Q: What choices do patients make regarding whether to get high from the cannabis they use?
A: Some have absolutely zero interest in getting high, and they try to avoid the THC-containing products. Other like getting high in addition to getting help with pain and spasticity.
Q: Who should not use medical marijuana in the MS community?
A: Patients who don’t have symptoms that could respond.
I’m also very concerned about patients who are 25 years and younger because of the effects that cannabis can have on brain development out to age 25 and the higher risk of addiction in people who are younger.
Q: What do you think the future will hold on the cannabis front?
A: Now that it’s less of a taboo topic, there’s an ever-growing number of trials each year, including very high-quality studies.
Pharmaceutically produced, cannabis-based medicines will be a growing area. Epidiolex is a perfect example of that.
It’s important for physicians to know that the way cannabis-based medicine is produced by a pharmaceutical company is different in so many levels than the cannabis in states with recreational and medical marijuana.
Q: What are some ways that the pharmaceutical products are different?
A: The rigor of the production process, the standardization, the purity, the correct labeling and expiration dates. Plus, the lack of the use of pesticides and other contaminants. And they’re distributed by pharmacists.
Q: What should neurologists be thinking if they’re considering whether to recommend cannabis to their patients?
A: This is a very complex topic, and it’s not something that most of us have training in. You can’t sit down for 1 or 2 hours, get up to speed, and have your own well-informed opinion on it. You really need to put more time and effort.
Q: What are some issues that neurologists should consider?
A: You really need to find out what your state is doing about it and see how you feel about that.
How is your state administering medical and/or recreational marijuana? The administration of these programs is extremely different from state to state. Do these details satisfy you, and are you content having your patients interface with these programs?
Dr. Bowling reports no relevant disclosures.
The medical marijuana landscape is changing so fast that Colorado Neurological Institute neurologist Allen C. Bowling, MD, PhD, already needs to update a presentation he gave about cannabis in multiple sclerosis in late May.
Since then, both those facts became history over a span of 2 days.
First, on June 25, the FDA announced its approval of Epidiolex (cannabidiol) for the treatment of seizures in two rare forms of epilepsy, Lennox-Gastaut syndrome and Dravet syndrome. It’s the first time the FDA has approved a drug with a purified ingredient – cannabidiol, a nonpsychoactive substance – that’s derived from marijuana.
Then, on June 26, voters in Oklahoma approved a ballot measure that allows the possession of marijuana for medical use; users must register with the state. Thirty states and the District of Columbia have made medical marijuana legal, according to the procon.org website, although the two newest ones (Oklahoma and West Virginia) are still developing procedures.
The laws vary widely. Some states don’t allow patients to smoke medical marijuana, and some don’t allow visitors to use out-of-state registry ID cards. And certain states limit the use of medical marijuana to specific conditions. Medical marijuana use by patients with MS is specifically allowed in many states, including Alaska, Arizona, Florida, Minnesota, and several others.
There’s another complexity: According to procon.org, 17 states have laws about the use of cannabidiol. In Georgia, for instance, the use of some cannabis oil is allowed for the treatment of MS and other conditions.
In the wake of the FDA ruling, Dr. Bowling spoke in an interview about cannabis, MS, and the questions that neurologists should be asking themselves.
Q: What are studies telling us about cannabis and MS?
A: There are lots of clinical studies – 19 randomized controlled trials. A consistent finding is that there’s benefit in terms of pain and people’s subjective sense of spasticity (Neurology. 2014 Apr 29;82(17):1556-63).
Q: During your CMSC presentation, you talked about how “fidelity” has been a problem in cannabis research. Could you elaborate on what you mean?
A: The products used in these studies are generally standardized, research-grade products that you can’t buy in any U.S. dispensary.
Cannabis is complex and contains more than 100 different potentially pharmacologically active molecules. You can’t conclude that if you see a product in clinical trials, you’ll then be able to walk into a dispensary for recreational or medical cannabis and get a product that produces the same effect.
Q: What have you seen in your own patient population in terms of cannabis use?
A: I find what’s been found with the studies: It helps with pain and people’s sense of muscle stiffness.
It’s especially helpful in people with pain and spasticity that breaks through in the late afternoon or at night when they’re trying to go to sleep. Just a little bit of cannabis can get them through those difficult times and improve their quality of life.
Q: What choices do patients make regarding whether to get high from the cannabis they use?
A: Some have absolutely zero interest in getting high, and they try to avoid the THC-containing products. Other like getting high in addition to getting help with pain and spasticity.
Q: Who should not use medical marijuana in the MS community?
A: Patients who don’t have symptoms that could respond.
I’m also very concerned about patients who are 25 years and younger because of the effects that cannabis can have on brain development out to age 25 and the higher risk of addiction in people who are younger.
Q: What do you think the future will hold on the cannabis front?
A: Now that it’s less of a taboo topic, there’s an ever-growing number of trials each year, including very high-quality studies.
Pharmaceutically produced, cannabis-based medicines will be a growing area. Epidiolex is a perfect example of that.
It’s important for physicians to know that the way cannabis-based medicine is produced by a pharmaceutical company is different in so many levels than the cannabis in states with recreational and medical marijuana.
Q: What are some ways that the pharmaceutical products are different?
A: The rigor of the production process, the standardization, the purity, the correct labeling and expiration dates. Plus, the lack of the use of pesticides and other contaminants. And they’re distributed by pharmacists.
Q: What should neurologists be thinking if they’re considering whether to recommend cannabis to their patients?
A: This is a very complex topic, and it’s not something that most of us have training in. You can’t sit down for 1 or 2 hours, get up to speed, and have your own well-informed opinion on it. You really need to put more time and effort.
Q: What are some issues that neurologists should consider?
A: You really need to find out what your state is doing about it and see how you feel about that.
How is your state administering medical and/or recreational marijuana? The administration of these programs is extremely different from state to state. Do these details satisfy you, and are you content having your patients interface with these programs?
Dr. Bowling reports no relevant disclosures.
The medical marijuana landscape is changing so fast that Colorado Neurological Institute neurologist Allen C. Bowling, MD, PhD, already needs to update a presentation he gave about cannabis in multiple sclerosis in late May.
Since then, both those facts became history over a span of 2 days.
First, on June 25, the FDA announced its approval of Epidiolex (cannabidiol) for the treatment of seizures in two rare forms of epilepsy, Lennox-Gastaut syndrome and Dravet syndrome. It’s the first time the FDA has approved a drug with a purified ingredient – cannabidiol, a nonpsychoactive substance – that’s derived from marijuana.
Then, on June 26, voters in Oklahoma approved a ballot measure that allows the possession of marijuana for medical use; users must register with the state. Thirty states and the District of Columbia have made medical marijuana legal, according to the procon.org website, although the two newest ones (Oklahoma and West Virginia) are still developing procedures.
The laws vary widely. Some states don’t allow patients to smoke medical marijuana, and some don’t allow visitors to use out-of-state registry ID cards. And certain states limit the use of medical marijuana to specific conditions. Medical marijuana use by patients with MS is specifically allowed in many states, including Alaska, Arizona, Florida, Minnesota, and several others.
There’s another complexity: According to procon.org, 17 states have laws about the use of cannabidiol. In Georgia, for instance, the use of some cannabis oil is allowed for the treatment of MS and other conditions.
In the wake of the FDA ruling, Dr. Bowling spoke in an interview about cannabis, MS, and the questions that neurologists should be asking themselves.
Q: What are studies telling us about cannabis and MS?
A: There are lots of clinical studies – 19 randomized controlled trials. A consistent finding is that there’s benefit in terms of pain and people’s subjective sense of spasticity (Neurology. 2014 Apr 29;82(17):1556-63).
Q: During your CMSC presentation, you talked about how “fidelity” has been a problem in cannabis research. Could you elaborate on what you mean?
A: The products used in these studies are generally standardized, research-grade products that you can’t buy in any U.S. dispensary.
Cannabis is complex and contains more than 100 different potentially pharmacologically active molecules. You can’t conclude that if you see a product in clinical trials, you’ll then be able to walk into a dispensary for recreational or medical cannabis and get a product that produces the same effect.
Q: What have you seen in your own patient population in terms of cannabis use?
A: I find what’s been found with the studies: It helps with pain and people’s sense of muscle stiffness.
It’s especially helpful in people with pain and spasticity that breaks through in the late afternoon or at night when they’re trying to go to sleep. Just a little bit of cannabis can get them through those difficult times and improve their quality of life.
Q: What choices do patients make regarding whether to get high from the cannabis they use?
A: Some have absolutely zero interest in getting high, and they try to avoid the THC-containing products. Other like getting high in addition to getting help with pain and spasticity.
Q: Who should not use medical marijuana in the MS community?
A: Patients who don’t have symptoms that could respond.
I’m also very concerned about patients who are 25 years and younger because of the effects that cannabis can have on brain development out to age 25 and the higher risk of addiction in people who are younger.
Q: What do you think the future will hold on the cannabis front?
A: Now that it’s less of a taboo topic, there’s an ever-growing number of trials each year, including very high-quality studies.
Pharmaceutically produced, cannabis-based medicines will be a growing area. Epidiolex is a perfect example of that.
It’s important for physicians to know that the way cannabis-based medicine is produced by a pharmaceutical company is different in so many levels than the cannabis in states with recreational and medical marijuana.
Q: What are some ways that the pharmaceutical products are different?
A: The rigor of the production process, the standardization, the purity, the correct labeling and expiration dates. Plus, the lack of the use of pesticides and other contaminants. And they’re distributed by pharmacists.
Q: What should neurologists be thinking if they’re considering whether to recommend cannabis to their patients?
A: This is a very complex topic, and it’s not something that most of us have training in. You can’t sit down for 1 or 2 hours, get up to speed, and have your own well-informed opinion on it. You really need to put more time and effort.
Q: What are some issues that neurologists should consider?
A: You really need to find out what your state is doing about it and see how you feel about that.
How is your state administering medical and/or recreational marijuana? The administration of these programs is extremely different from state to state. Do these details satisfy you, and are you content having your patients interface with these programs?
Dr. Bowling reports no relevant disclosures.
Ozanimod May Provide Better MS Outcomes Than Interferon Beta
NASHVILLE—Two doses of ozanimod provide greater benefits on annualized relapse rate and MRI end points than interferon beta-1a does, according to research described at the 2018 CMSC Annual Meeting. Together with safety and tolerability results, the data indicate that oral ozanimod has a favorable risk–benefit profile in patients with relapsing-remitting multiple sclerosis (MS), said the investigators.
Ozanimod is an oral immunomodulator that selectively targets sphingosine 1-phosphate receptors 1 and 5. The drug is administered once daily. Bruce A. C. Cree, MD, PhD, Associate Professor of Neurology at the University of California, San Francisco, and colleagues examined data for patients with relapsing-remitting MS in the SUNBEAM and RADIANCE Part B trials to compare the efficacy and safety of ozanimod with those of interferon beta-1a. Patients received 1 mg or 0.5 mg of ozanimod HCl (with a seven-day dose escalation) or 30 μg of interferon beta-1a.
Ozanimod Decreased Annualized Relapse Rate
Dr. Cree and colleagues analyzed 12-month efficacy data from SUNBEAM, 24-month efficacy data from RADIANCE, and pooled safety data.
In all, 1,346 patients were treated in SUNBEAM, and 1,313 patients were treated in RADIANCE. Ozanimod 1 mg and 0.5 mg reduced participants’ adjusted annualized relapse rate by 48% (0.181) and 31% (0.241), respectively, versus interferon beta-1a (0.350) in SUNBEAM, and by 38% (0.172) and 21% (0.218), respectively, versus interferon beta-1a (0.276) in RADIANCE.
The adjusted mean number of new or enlarging T2 lesions was reduced by 48% and 25% versus interferon beta-1a for ozanimod 1 mg and 0.5 mg, respectively, in SUNBEAM, and by 42% and 34%, respectively, in RADIANCE. The adjusted mean number of gadolinium-enhancing lesions was reduced by 63% for the 1-mg dose of ozanimod and by 34% for the 0.5-mg dose of ozanimod versus interferon beta-1a in SUNBEAM. In RADIANCE, ozanimod 1 mg reduced this outcome by 53% and ozanimod 0.5 mg reduced this outcome by 47%, compared with interferon beta-1a.
Fewer Adverse Events With Ozanimod
Confirmed three-month pooled disability progression was low in the ozanimod 1 mg (0.102), ozanimod 0.5 mg (0.080), and interferon beta-1a (0.099) groups. In SUNBEAM, whole brain volume loss was 33% lower with ozanimod 1 mg and 12% lower with ozanimod 0.5 mg, compared with interferon beta-1a. In RADIANCE, whole brain volume loss was 27% lower with ozanimod 1 mg and 25% lower with ozanimod 0.5 mg, compared with interferon beta-1a. Ozanimod was associated with greater slowing of cortical gray matter and thalamic volume loss in both studies, c
Compared with interferon beta-1a, ozanimod-treated patients had fewer adverse events (ozanimod 1 mg, 67.1%; ozanimod 0.5 mg, 65.6%; interferon beta-1a, 79.2%) and adverse events leading to study drug discontinuation (ozanimod 1 mg, 2.9%; ozanimod 0.5 mg, 2.4%; interferon beta-1a, 3.8%). Serious adverse events, including infections, were balanced and infrequent across groups (ozanimod 1 mg, 4.6%; ozanimod 0.5 mg, 5.3%; interferon beta-1a, 4.4%); no serious opportunistic infections were reported.
No second degree or higher atrioventricular block was observed. Researchers observed one death due to drowning (ozanimod 0.5 mg) deemed unrelated to the study drug.
NASHVILLE—Two doses of ozanimod provide greater benefits on annualized relapse rate and MRI end points than interferon beta-1a does, according to research described at the 2018 CMSC Annual Meeting. Together with safety and tolerability results, the data indicate that oral ozanimod has a favorable risk–benefit profile in patients with relapsing-remitting multiple sclerosis (MS), said the investigators.
Ozanimod is an oral immunomodulator that selectively targets sphingosine 1-phosphate receptors 1 and 5. The drug is administered once daily. Bruce A. C. Cree, MD, PhD, Associate Professor of Neurology at the University of California, San Francisco, and colleagues examined data for patients with relapsing-remitting MS in the SUNBEAM and RADIANCE Part B trials to compare the efficacy and safety of ozanimod with those of interferon beta-1a. Patients received 1 mg or 0.5 mg of ozanimod HCl (with a seven-day dose escalation) or 30 μg of interferon beta-1a.
Ozanimod Decreased Annualized Relapse Rate
Dr. Cree and colleagues analyzed 12-month efficacy data from SUNBEAM, 24-month efficacy data from RADIANCE, and pooled safety data.
In all, 1,346 patients were treated in SUNBEAM, and 1,313 patients were treated in RADIANCE. Ozanimod 1 mg and 0.5 mg reduced participants’ adjusted annualized relapse rate by 48% (0.181) and 31% (0.241), respectively, versus interferon beta-1a (0.350) in SUNBEAM, and by 38% (0.172) and 21% (0.218), respectively, versus interferon beta-1a (0.276) in RADIANCE.
The adjusted mean number of new or enlarging T2 lesions was reduced by 48% and 25% versus interferon beta-1a for ozanimod 1 mg and 0.5 mg, respectively, in SUNBEAM, and by 42% and 34%, respectively, in RADIANCE. The adjusted mean number of gadolinium-enhancing lesions was reduced by 63% for the 1-mg dose of ozanimod and by 34% for the 0.5-mg dose of ozanimod versus interferon beta-1a in SUNBEAM. In RADIANCE, ozanimod 1 mg reduced this outcome by 53% and ozanimod 0.5 mg reduced this outcome by 47%, compared with interferon beta-1a.
Fewer Adverse Events With Ozanimod
Confirmed three-month pooled disability progression was low in the ozanimod 1 mg (0.102), ozanimod 0.5 mg (0.080), and interferon beta-1a (0.099) groups. In SUNBEAM, whole brain volume loss was 33% lower with ozanimod 1 mg and 12% lower with ozanimod 0.5 mg, compared with interferon beta-1a. In RADIANCE, whole brain volume loss was 27% lower with ozanimod 1 mg and 25% lower with ozanimod 0.5 mg, compared with interferon beta-1a. Ozanimod was associated with greater slowing of cortical gray matter and thalamic volume loss in both studies, c
Compared with interferon beta-1a, ozanimod-treated patients had fewer adverse events (ozanimod 1 mg, 67.1%; ozanimod 0.5 mg, 65.6%; interferon beta-1a, 79.2%) and adverse events leading to study drug discontinuation (ozanimod 1 mg, 2.9%; ozanimod 0.5 mg, 2.4%; interferon beta-1a, 3.8%). Serious adverse events, including infections, were balanced and infrequent across groups (ozanimod 1 mg, 4.6%; ozanimod 0.5 mg, 5.3%; interferon beta-1a, 4.4%); no serious opportunistic infections were reported.
No second degree or higher atrioventricular block was observed. Researchers observed one death due to drowning (ozanimod 0.5 mg) deemed unrelated to the study drug.
NASHVILLE—Two doses of ozanimod provide greater benefits on annualized relapse rate and MRI end points than interferon beta-1a does, according to research described at the 2018 CMSC Annual Meeting. Together with safety and tolerability results, the data indicate that oral ozanimod has a favorable risk–benefit profile in patients with relapsing-remitting multiple sclerosis (MS), said the investigators.
Ozanimod is an oral immunomodulator that selectively targets sphingosine 1-phosphate receptors 1 and 5. The drug is administered once daily. Bruce A. C. Cree, MD, PhD, Associate Professor of Neurology at the University of California, San Francisco, and colleagues examined data for patients with relapsing-remitting MS in the SUNBEAM and RADIANCE Part B trials to compare the efficacy and safety of ozanimod with those of interferon beta-1a. Patients received 1 mg or 0.5 mg of ozanimod HCl (with a seven-day dose escalation) or 30 μg of interferon beta-1a.
Ozanimod Decreased Annualized Relapse Rate
Dr. Cree and colleagues analyzed 12-month efficacy data from SUNBEAM, 24-month efficacy data from RADIANCE, and pooled safety data.
In all, 1,346 patients were treated in SUNBEAM, and 1,313 patients were treated in RADIANCE. Ozanimod 1 mg and 0.5 mg reduced participants’ adjusted annualized relapse rate by 48% (0.181) and 31% (0.241), respectively, versus interferon beta-1a (0.350) in SUNBEAM, and by 38% (0.172) and 21% (0.218), respectively, versus interferon beta-1a (0.276) in RADIANCE.
The adjusted mean number of new or enlarging T2 lesions was reduced by 48% and 25% versus interferon beta-1a for ozanimod 1 mg and 0.5 mg, respectively, in SUNBEAM, and by 42% and 34%, respectively, in RADIANCE. The adjusted mean number of gadolinium-enhancing lesions was reduced by 63% for the 1-mg dose of ozanimod and by 34% for the 0.5-mg dose of ozanimod versus interferon beta-1a in SUNBEAM. In RADIANCE, ozanimod 1 mg reduced this outcome by 53% and ozanimod 0.5 mg reduced this outcome by 47%, compared with interferon beta-1a.
Fewer Adverse Events With Ozanimod
Confirmed three-month pooled disability progression was low in the ozanimod 1 mg (0.102), ozanimod 0.5 mg (0.080), and interferon beta-1a (0.099) groups. In SUNBEAM, whole brain volume loss was 33% lower with ozanimod 1 mg and 12% lower with ozanimod 0.5 mg, compared with interferon beta-1a. In RADIANCE, whole brain volume loss was 27% lower with ozanimod 1 mg and 25% lower with ozanimod 0.5 mg, compared with interferon beta-1a. Ozanimod was associated with greater slowing of cortical gray matter and thalamic volume loss in both studies, c
Compared with interferon beta-1a, ozanimod-treated patients had fewer adverse events (ozanimod 1 mg, 67.1%; ozanimod 0.5 mg, 65.6%; interferon beta-1a, 79.2%) and adverse events leading to study drug discontinuation (ozanimod 1 mg, 2.9%; ozanimod 0.5 mg, 2.4%; interferon beta-1a, 3.8%). Serious adverse events, including infections, were balanced and infrequent across groups (ozanimod 1 mg, 4.6%; ozanimod 0.5 mg, 5.3%; interferon beta-1a, 4.4%); no serious opportunistic infections were reported.
No second degree or higher atrioventricular block was observed. Researchers observed one death due to drowning (ozanimod 0.5 mg) deemed unrelated to the study drug.
CMSC Guideline Re-Examines Use of Gadolinium-Based Contrast Agents
Standard high-quality MRI without contrast can adequately identify the majority of MS lesions over time, say the authors.
NASHVILLE—Gadolinium-based contrast agents (GBCAs) are necessary for the accurate initial diagnosis of patients experiencing a first clinical attack of symptoms consistent with multiple sclerosis (MS) and for following patients with highly active disease or sudden, unexpected declines, according to a guideline issued by the Consortium of MS Centers (CMSC).
GBCAs are optional, although helpful, in many other clinical scenarios, especially when noncontrast MRI can provide answers.
“The key is that there is an optional role for gadolinium,” said David Li, MD, Professor of Radiology and Associate Member in Neurology at the University of British Columbia in Vancouver, at the 2018 CMSC Annual Meeting.
Although a GBCA is still “essential” for some clinical scenarios in clinically isolated syndrome and MS, standard, high-quality MRI without contrast can adequately identify the majority of new MS lesions over time, the new guideline suggests. If a neurologist needs to monitor ongoing, current activity in settings of acute change, then gadolinium is still necessary, said Dr. Li.
The guideline, which was described at the meeting, is an update of the CMSC’s 2015 document, which endorsed a more liberal use of GBCAs. This more conservative stance reflects new research on the agents and an update in 2017 from the FDA that required a class-wide warning about gadolinium retention.
The agency began investigating gadolinium in 2015. In May 2017, it issued a statement confirming that gadolinium accumulates in neural tissue and can be retained for an extended period. In reviewing the evidence, however, the FDA found no concerning safety signals. Despite the presumed lack of toxicity, the agency issued the warning and recommended limiting the contrast agents’ use. The CMSC’s new MRI protocol guideline reflects these regulatory actions.
“While there is no known CNS toxicity, these agents should be used judiciously, recognizing that gadolinium continues to play an invaluable role in specific circumstances related to the diagnosis and follow-up of individuals with MS,” the document noted.
“It remains indispensable in patients presenting with their first clinical attack, as [its] use allows for an earlier diagnosis by demonstrating lesion dissemination in time in addition to lesion dissemination in space, which are the hallmarks of the diagnosis of MS. Early diagnosis leads to early treatment, which may help in preventing disease progression and improve long-term prognosis,” said Dr. Li. He had no disclosures relevant to gadolinium.
—Michele G. Sullivan
Standard high-quality MRI without contrast can adequately identify the majority of MS lesions over time, say the authors.
Standard high-quality MRI without contrast can adequately identify the majority of MS lesions over time, say the authors.
NASHVILLE—Gadolinium-based contrast agents (GBCAs) are necessary for the accurate initial diagnosis of patients experiencing a first clinical attack of symptoms consistent with multiple sclerosis (MS) and for following patients with highly active disease or sudden, unexpected declines, according to a guideline issued by the Consortium of MS Centers (CMSC).
GBCAs are optional, although helpful, in many other clinical scenarios, especially when noncontrast MRI can provide answers.
“The key is that there is an optional role for gadolinium,” said David Li, MD, Professor of Radiology and Associate Member in Neurology at the University of British Columbia in Vancouver, at the 2018 CMSC Annual Meeting.
Although a GBCA is still “essential” for some clinical scenarios in clinically isolated syndrome and MS, standard, high-quality MRI without contrast can adequately identify the majority of new MS lesions over time, the new guideline suggests. If a neurologist needs to monitor ongoing, current activity in settings of acute change, then gadolinium is still necessary, said Dr. Li.
The guideline, which was described at the meeting, is an update of the CMSC’s 2015 document, which endorsed a more liberal use of GBCAs. This more conservative stance reflects new research on the agents and an update in 2017 from the FDA that required a class-wide warning about gadolinium retention.
The agency began investigating gadolinium in 2015. In May 2017, it issued a statement confirming that gadolinium accumulates in neural tissue and can be retained for an extended period. In reviewing the evidence, however, the FDA found no concerning safety signals. Despite the presumed lack of toxicity, the agency issued the warning and recommended limiting the contrast agents’ use. The CMSC’s new MRI protocol guideline reflects these regulatory actions.
“While there is no known CNS toxicity, these agents should be used judiciously, recognizing that gadolinium continues to play an invaluable role in specific circumstances related to the diagnosis and follow-up of individuals with MS,” the document noted.
“It remains indispensable in patients presenting with their first clinical attack, as [its] use allows for an earlier diagnosis by demonstrating lesion dissemination in time in addition to lesion dissemination in space, which are the hallmarks of the diagnosis of MS. Early diagnosis leads to early treatment, which may help in preventing disease progression and improve long-term prognosis,” said Dr. Li. He had no disclosures relevant to gadolinium.
—Michele G. Sullivan
NASHVILLE—Gadolinium-based contrast agents (GBCAs) are necessary for the accurate initial diagnosis of patients experiencing a first clinical attack of symptoms consistent with multiple sclerosis (MS) and for following patients with highly active disease or sudden, unexpected declines, according to a guideline issued by the Consortium of MS Centers (CMSC).
GBCAs are optional, although helpful, in many other clinical scenarios, especially when noncontrast MRI can provide answers.
“The key is that there is an optional role for gadolinium,” said David Li, MD, Professor of Radiology and Associate Member in Neurology at the University of British Columbia in Vancouver, at the 2018 CMSC Annual Meeting.
Although a GBCA is still “essential” for some clinical scenarios in clinically isolated syndrome and MS, standard, high-quality MRI without contrast can adequately identify the majority of new MS lesions over time, the new guideline suggests. If a neurologist needs to monitor ongoing, current activity in settings of acute change, then gadolinium is still necessary, said Dr. Li.
The guideline, which was described at the meeting, is an update of the CMSC’s 2015 document, which endorsed a more liberal use of GBCAs. This more conservative stance reflects new research on the agents and an update in 2017 from the FDA that required a class-wide warning about gadolinium retention.
The agency began investigating gadolinium in 2015. In May 2017, it issued a statement confirming that gadolinium accumulates in neural tissue and can be retained for an extended period. In reviewing the evidence, however, the FDA found no concerning safety signals. Despite the presumed lack of toxicity, the agency issued the warning and recommended limiting the contrast agents’ use. The CMSC’s new MRI protocol guideline reflects these regulatory actions.
“While there is no known CNS toxicity, these agents should be used judiciously, recognizing that gadolinium continues to play an invaluable role in specific circumstances related to the diagnosis and follow-up of individuals with MS,” the document noted.
“It remains indispensable in patients presenting with their first clinical attack, as [its] use allows for an earlier diagnosis by demonstrating lesion dissemination in time in addition to lesion dissemination in space, which are the hallmarks of the diagnosis of MS. Early diagnosis leads to early treatment, which may help in preventing disease progression and improve long-term prognosis,” said Dr. Li. He had no disclosures relevant to gadolinium.
—Michele G. Sullivan
Eating Fish May Be Associated With a Reduced Risk of MS
Omega-3 fatty acids, combined with a specific genetic profile, may modulate MS risk.
LOS ANGELES—Eating fish at least once per week or eating fish one to three times per month, in addition to taking daily fish oil supplements, may be associated with a reduced risk of multiple sclerosis (MS), according to a preliminary study presented at the American Academy of Neurology’s 70th Annual Meeting. These findings suggest that the omega-3 fatty acids found in fish may be associated with lowering the risk of developing MS.
“Consuming fish that contain omega-3 fatty acids has been shown to have a variety of health benefits, so we wanted to see if this simple lifestyle modification, regularly eating fish and taking fish oil supplements, could reduce the risk of MS,” said lead study author, Regional Lead for Clinical and Translational Neuroscience for the Southern California Permanente Medical Group in Pasadena, and Clinical Assistant Professor at the Keck School of Medicine of the University of Southern California in Los Angeles.
For this study, researchers examined the diets of 1,153 people (average, age 36) from the MS Sunshine Study, a multiethnic matched case–control study of incident MS or clinically isolated syndrome (CIS), recruited from Kaiser Permanente Southern California.
Researchers queried participants about how much fish they consumed regularly. Investigators also examined 13 single nucleotide polymorphisms (SNPs) in FADS1, FADS2, and ELOV2, which regulate fatty acid biosynthesis.
High fish intake was defined as either eating one serving of fish per week or eating one to three servings per month in addition to taking daily fish oil supplements. Low intake was defined as less than one serving of fish per month and no fish oil supplements.
High fish intake was associated with a 45% reduced risk of MS or CIS, when compared with those who ate fish less than once a month and did not take fish oil supplements. A total of 180 of participants with MS had high fish intake, compared with 251 of the healthy controls.
In addition, two SNPs, rs174611 and rs174618, in FADS2 were independently associated with a lower risk of MS, even after accounting for high fish intake. This result suggests that some people may have a genetic advantage when it comes to regulating fatty acid levels, the researchers noted.
The study suggests that omega-3 fatty acids and how they are processed by the body may play an important role in reducing MS risk. Dr. Langer-Gould and colleagues emphasized that their findings show an association, and not cause and effect. More research is needed to confirm the findings and to examine how omega-3 fatty acids may affect inflammation, metabolism, and nerve function.
Omega-3 fatty acids, combined with a specific genetic profile, may modulate MS risk.
Omega-3 fatty acids, combined with a specific genetic profile, may modulate MS risk.
LOS ANGELES—Eating fish at least once per week or eating fish one to three times per month, in addition to taking daily fish oil supplements, may be associated with a reduced risk of multiple sclerosis (MS), according to a preliminary study presented at the American Academy of Neurology’s 70th Annual Meeting. These findings suggest that the omega-3 fatty acids found in fish may be associated with lowering the risk of developing MS.
“Consuming fish that contain omega-3 fatty acids has been shown to have a variety of health benefits, so we wanted to see if this simple lifestyle modification, regularly eating fish and taking fish oil supplements, could reduce the risk of MS,” said lead study author, Regional Lead for Clinical and Translational Neuroscience for the Southern California Permanente Medical Group in Pasadena, and Clinical Assistant Professor at the Keck School of Medicine of the University of Southern California in Los Angeles.
For this study, researchers examined the diets of 1,153 people (average, age 36) from the MS Sunshine Study, a multiethnic matched case–control study of incident MS or clinically isolated syndrome (CIS), recruited from Kaiser Permanente Southern California.
Researchers queried participants about how much fish they consumed regularly. Investigators also examined 13 single nucleotide polymorphisms (SNPs) in FADS1, FADS2, and ELOV2, which regulate fatty acid biosynthesis.
High fish intake was defined as either eating one serving of fish per week or eating one to three servings per month in addition to taking daily fish oil supplements. Low intake was defined as less than one serving of fish per month and no fish oil supplements.
High fish intake was associated with a 45% reduced risk of MS or CIS, when compared with those who ate fish less than once a month and did not take fish oil supplements. A total of 180 of participants with MS had high fish intake, compared with 251 of the healthy controls.
In addition, two SNPs, rs174611 and rs174618, in FADS2 were independently associated with a lower risk of MS, even after accounting for high fish intake. This result suggests that some people may have a genetic advantage when it comes to regulating fatty acid levels, the researchers noted.
The study suggests that omega-3 fatty acids and how they are processed by the body may play an important role in reducing MS risk. Dr. Langer-Gould and colleagues emphasized that their findings show an association, and not cause and effect. More research is needed to confirm the findings and to examine how omega-3 fatty acids may affect inflammation, metabolism, and nerve function.
LOS ANGELES—Eating fish at least once per week or eating fish one to three times per month, in addition to taking daily fish oil supplements, may be associated with a reduced risk of multiple sclerosis (MS), according to a preliminary study presented at the American Academy of Neurology’s 70th Annual Meeting. These findings suggest that the omega-3 fatty acids found in fish may be associated with lowering the risk of developing MS.
“Consuming fish that contain omega-3 fatty acids has been shown to have a variety of health benefits, so we wanted to see if this simple lifestyle modification, regularly eating fish and taking fish oil supplements, could reduce the risk of MS,” said lead study author, Regional Lead for Clinical and Translational Neuroscience for the Southern California Permanente Medical Group in Pasadena, and Clinical Assistant Professor at the Keck School of Medicine of the University of Southern California in Los Angeles.
For this study, researchers examined the diets of 1,153 people (average, age 36) from the MS Sunshine Study, a multiethnic matched case–control study of incident MS or clinically isolated syndrome (CIS), recruited from Kaiser Permanente Southern California.
Researchers queried participants about how much fish they consumed regularly. Investigators also examined 13 single nucleotide polymorphisms (SNPs) in FADS1, FADS2, and ELOV2, which regulate fatty acid biosynthesis.
High fish intake was defined as either eating one serving of fish per week or eating one to three servings per month in addition to taking daily fish oil supplements. Low intake was defined as less than one serving of fish per month and no fish oil supplements.
High fish intake was associated with a 45% reduced risk of MS or CIS, when compared with those who ate fish less than once a month and did not take fish oil supplements. A total of 180 of participants with MS had high fish intake, compared with 251 of the healthy controls.
In addition, two SNPs, rs174611 and rs174618, in FADS2 were independently associated with a lower risk of MS, even after accounting for high fish intake. This result suggests that some people may have a genetic advantage when it comes to regulating fatty acid levels, the researchers noted.
The study suggests that omega-3 fatty acids and how they are processed by the body may play an important role in reducing MS risk. Dr. Langer-Gould and colleagues emphasized that their findings show an association, and not cause and effect. More research is needed to confirm the findings and to examine how omega-3 fatty acids may affect inflammation, metabolism, and nerve function.