Multiple Sclerosis Hub

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].

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].

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.

—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.

—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.

—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.

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.

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.

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.

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.

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, compared with interferon beta-1a.

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, compared with interferon beta-1a.

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, compared with interferon beta-1a.

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—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.

—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.

—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.

—Michele G. Sullivan

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.

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.

NASHVILLE—For patients with multiple sclerosis (MS) and walking impairments, high-intensity interval exercise is as enjoyable as traditional continuous exercise and does not induce sustained, harmful effects on mood, according to research presented at the 2018 CMSC Annual Meeting. This finding could influence evidence-based prescriptions for exercise that are appropriate for improving physiologic conditioning, according to the researchers.

MS often results in walking dysfunction and physiologic deconditioning. High-intensity interval exercise has induced significant improvements in physiologic conditioning in healthy and clinical populations, including patients with MS. Before integrating high-intensity interval exercise into an exercise prescription, and to increase the likelihood that participants will engage in and adhere to this exercise regimen, investigators thought it important to ascertain whether people with MS and mobility disability enjoy the high-intensity interval exercise and experience mood benefits.

Elizabeth Hubbard, PhD, Assistant Professor of Kinesiology at Berry College in Mount Berry, Georgia, conducted a study to examine the effects of single sessions of high-intensity interval exercise and continuous exercise on mood and enjoyment outcomes in persons with MS and mobility disability. In their study, 20 participants (median Expanded Disability Status Scale score, 5.8) underwent counterbalanced presentations of high-intensity interval exercise and continuous exercise bouts using a recumbent stepper. The high-intensity interval exercise bout was 20 minutes long and included 10 cycles of one-minute intervals at a wattage associated with 90% VO2 peak, followed by one-minute recovery intervals at 15 W. The continuous exercise bout lasted for 20 minutes at a wattage associated with 50% to 60% VO2 peak. The researchers administered the Profile of Mood States (POMS) survey before, immediately after, and 30 minutes after exercise. The Physical Activity Enjoyment Scale (PACES) questionnaire was administered immediately after exercise.

NASHVILLE—For patients with multiple sclerosis (MS) and walking impairments, high-intensity interval exercise is as enjoyable as traditional continuous exercise and does not induce sustained, harmful effects on mood, according to research presented at the 2018 CMSC Annual Meeting. This finding could influence evidence-based prescriptions for exercise that are appropriate for improving physiologic conditioning, according to the researchers.

MS often results in walking dysfunction and physiologic deconditioning. High-intensity interval exercise has induced significant improvements in physiologic conditioning in healthy and clinical populations, including patients with MS. Before integrating high-intensity interval exercise into an exercise prescription, and to increase the likelihood that participants will engage in and adhere to this exercise regimen, investigators thought it important to ascertain whether people with MS and mobility disability enjoy the high-intensity interval exercise and experience mood benefits.

Elizabeth Hubbard, PhD, Assistant Professor of Kinesiology at Berry College in Mount Berry, Georgia, conducted a study to examine the effects of single sessions of high-intensity interval exercise and continuous exercise on mood and enjoyment outcomes in persons with MS and mobility disability. In their study, 20 participants (median Expanded Disability Status Scale score, 5.8) underwent counterbalanced presentations of high-intensity interval exercise and continuous exercise bouts using a recumbent stepper. The high-intensity interval exercise bout was 20 minutes long and included 10 cycles of one-minute intervals at a wattage associated with 90% VO2 peak, followed by one-minute recovery intervals at 15 W. The continuous exercise bout lasted for 20 minutes at a wattage associated with 50% to 60% VO2 peak. The researchers administered the Profile of Mood States (POMS) survey before, immediately after, and 30 minutes after exercise. The Physical Activity Enjoyment Scale (PACES) questionnaire was administered immediately after exercise.

NASHVILLE—For patients with multiple sclerosis (MS) and walking impairments, high-intensity interval exercise is as enjoyable as traditional continuous exercise and does not induce sustained, harmful effects on mood, according to research presented at the 2018 CMSC Annual Meeting. This finding could influence evidence-based prescriptions for exercise that are appropriate for improving physiologic conditioning, according to the researchers.

MS often results in walking dysfunction and physiologic deconditioning. High-intensity interval exercise has induced significant improvements in physiologic conditioning in healthy and clinical populations, including patients with MS. Before integrating high-intensity interval exercise into an exercise prescription, and to increase the likelihood that participants will engage in and adhere to this exercise regimen, investigators thought it important to ascertain whether people with MS and mobility disability enjoy the high-intensity interval exercise and experience mood benefits.

Elizabeth Hubbard, PhD, Assistant Professor of Kinesiology at Berry College in Mount Berry, Georgia, conducted a study to examine the effects of single sessions of high-intensity interval exercise and continuous exercise on mood and enjoyment outcomes in persons with MS and mobility disability. In their study, 20 participants (median Expanded Disability Status Scale score, 5.8) underwent counterbalanced presentations of high-intensity interval exercise and continuous exercise bouts using a recumbent stepper. The high-intensity interval exercise bout was 20 minutes long and included 10 cycles of one-minute intervals at a wattage associated with 90% VO2 peak, followed by one-minute recovery intervals at 15 W. The continuous exercise bout lasted for 20 minutes at a wattage associated with 50% to 60% VO2 peak. The researchers administered the Profile of Mood States (POMS) survey before, immediately after, and 30 minutes after exercise. The Physical Activity Enjoyment Scale (PACES) questionnaire was administered immediately after exercise.

NASHVILLE—For patients with multiple sclerosis (MS) who receive treatment with natalizumab, progressive multifocal leukoencephalopathy (PML) can be avoided, according to research presented at the 2018 CMSC Annual Meeting. “You can actually prevent this disease from occurring because we have risk-limiting strategies in many circumstances,” said Joseph R. Berger, MD, Professor of Neurology at the Hospital of the University of Pennsylvania in Philadelphia.

Long-Term Use of Natalizumab Is Associated With Increased PML Risk

Unlike other conditions such as HIV, MS itself is not linked to a higher risk of PML, said Dr. Berger. Instead, it is the medications that introduce the risk, he said, with at least three, and possibly four, drugs posing a risk to patients.

“We know that the risk with natalizumab is incredibly high in the context of John Cunningham virus [JCV] antibody positivity and prolonged therapy,” Dr. Berger said. “You can safely give natalizumab for a short period of time when treating patients with aggressive MS. I will frequently employ that strategy even in the context of JCV antibody positivity.” There is no risk of PML when natalizumab is used for under eight months, Dr. Berger said.“If you leave people on the drug indefinitely, there is a substantial risk of developing PML,” said Dr. Berger. “Individuals who have been on the drug for two years, who have seen prior immunosuppressant therapy, who are JCV antibody positive—that group of individuals develops PML at rates of one in 50 to one in 100.” These levels are “even higher than those in the HIV population before the rise of antiretroviral medications,” he added.

As of November 30, 2017, 177,800 patients have received natalizumab in the postmarketing setting, and 756 cases of PML have been reported as of December 7, 2017. All but three of those cases were in patients with MS, and the overall incidence was 4.19 out of 1,000.

Dr. Berger recommended regular screening MRIs for PML in patients taking natalizumab and advised physicians to be on alert for the appearance of new neurologic symptoms or a new or increasing JCV antibody index.

Drugs With Low and Unknown Risks

Two other MS drugs, fingolimod and dimethyl fumarate, entail a low risk of PML. The numbers of PML cases reported for these drugs are 19 and five, respectively, as of February 2018, said Dr. Berger. Two of the patients receiving fingolimod who developed PML had had earlier exposure to natalizumab.

For JC antibody positive patients receiving dimethyl fumarate, the risk of PML may be eliminated when the treatment is discontinued and their lymphocyte count decreases to a level below 500 per µL Dr. Berger said.

“Unfortunately for fingolimod, we do not have a defined risk-mitigation strategy,” he said. However, researchers have noticed that PML has occurred more often in older people on fingolimod, possibly because of the aging of the immune system.

Alemtuzumab, ocrelizumab (with rituximab as proxy), and teriflunomide (with leflunomide as proxy), entail an unknown risk of PML, according to Dr. Berger. There have been three cases of PML associated with ocrelizumab and one associated with teriflunomide, but all were carry-overs from natalizumab or fingolimod exposure or occurred after natalizumab exposure.

What should a physician do if a patient develops PML? Stopping the drug and restoring the immune system are crucial steps, Dr. Berger said. Although evidence indicates that plasma exchange clears natalizumab, “there is no study that demonstrates that it is in the patient’s best interest,” said Dr. Berger. A retrospective study found no improvement in morbidity or mortality after plasma exchange.

Multiple strategies to treat PML, including immunizations and inhibitors of DNA replication, have failed to make an impact so far, said Dr. Berger. These strategies did not show benefits in clinical trials, and evidence does not support them.

—Randy Dotinga

Suggested Reading

Berger JR. Classifying PML risk with disease modifying therapies. Mult Scler Relat Disord. 2017;12:59-63.

Khatri BO, Man S, Giovannoni G, et al. Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function. Neurology. 2009;72(5):402-409.

Landi D, De Rossi N, Zagaglia S, et al. No evidence of beneficial effects of plasmapheresis in natalizumab-associated PML. Neurology. 2017;88(12):1144-1152.

NASHVILLE—For patients with multiple sclerosis (MS) who receive treatment with natalizumab, progressive multifocal leukoencephalopathy (PML) can be avoided, according to research presented at the 2018 CMSC Annual Meeting. “You can actually prevent this disease from occurring because we have risk-limiting strategies in many circumstances,” said Joseph R. Berger, MD, Professor of Neurology at the Hospital of the University of Pennsylvania in Philadelphia.

Long-Term Use of Natalizumab Is Associated With Increased PML Risk

Unlike other conditions such as HIV, MS itself is not linked to a higher risk of PML, said Dr. Berger. Instead, it is the medications that introduce the risk, he said, with at least three, and possibly four, drugs posing a risk to patients.

“We know that the risk with natalizumab is incredibly high in the context of John Cunningham virus [JCV] antibody positivity and prolonged therapy,” Dr. Berger said. “You can safely give natalizumab for a short period of time when treating patients with aggressive MS. I will frequently employ that strategy even in the context of JCV antibody positivity.” There is no risk of PML when natalizumab is used for under eight months, Dr. Berger said.“If you leave people on the drug indefinitely, there is a substantial risk of developing PML,” said Dr. Berger. “Individuals who have been on the drug for two years, who have seen prior immunosuppressant therapy, who are JCV antibody positive—that group of individuals develops PML at rates of one in 50 to one in 100.” These levels are “even higher than those in the HIV population before the rise of antiretroviral medications,” he added.

As of November 30, 2017, 177,800 patients have received natalizumab in the postmarketing setting, and 756 cases of PML have been reported as of December 7, 2017. All but three of those cases were in patients with MS, and the overall incidence was 4.19 out of 1,000.

Dr. Berger recommended regular screening MRIs for PML in patients taking natalizumab and advised physicians to be on alert for the appearance of new neurologic symptoms or a new or increasing JCV antibody index.

Drugs With Low and Unknown Risks

Two other MS drugs, fingolimod and dimethyl fumarate, entail a low risk of PML. The numbers of PML cases reported for these drugs are 19 and five, respectively, as of February 2018, said Dr. Berger. Two of the patients receiving fingolimod who developed PML had had earlier exposure to natalizumab.

For JC antibody positive patients receiving dimethyl fumarate, the risk of PML may be eliminated when the treatment is discontinued and their lymphocyte count decreases to a level below 500 per µL Dr. Berger said.

“Unfortunately for fingolimod, we do not have a defined risk-mitigation strategy,” he said. However, researchers have noticed that PML has occurred more often in older people on fingolimod, possibly because of the aging of the immune system.

Alemtuzumab, ocrelizumab (with rituximab as proxy), and teriflunomide (with leflunomide as proxy), entail an unknown risk of PML, according to Dr. Berger. There have been three cases of PML associated with ocrelizumab and one associated with teriflunomide, but all were carry-overs from natalizumab or fingolimod exposure or occurred after natalizumab exposure.

What should a physician do if a patient develops PML? Stopping the drug and restoring the immune system are crucial steps, Dr. Berger said. Although evidence indicates that plasma exchange clears natalizumab, “there is no study that demonstrates that it is in the patient’s best interest,” said Dr. Berger. A retrospective study found no improvement in morbidity or mortality after plasma exchange.

Multiple strategies to treat PML, including immunizations and inhibitors of DNA replication, have failed to make an impact so far, said Dr. Berger. These strategies did not show benefits in clinical trials, and evidence does not support them.

—Randy Dotinga

Suggested Reading

Berger JR. Classifying PML risk with disease modifying therapies. Mult Scler Relat Disord. 2017;12:59-63.

Khatri BO, Man S, Giovannoni G, et al. Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function. Neurology. 2009;72(5):402-409.

Landi D, De Rossi N, Zagaglia S, et al. No evidence of beneficial effects of plasmapheresis in natalizumab-associated PML. Neurology. 2017;88(12):1144-1152.

NASHVILLE—For patients with multiple sclerosis (MS) who receive treatment with natalizumab, progressive multifocal leukoencephalopathy (PML) can be avoided, according to research presented at the 2018 CMSC Annual Meeting. “You can actually prevent this disease from occurring because we have risk-limiting strategies in many circumstances,” said Joseph R. Berger, MD, Professor of Neurology at the Hospital of the University of Pennsylvania in Philadelphia.

Long-Term Use of Natalizumab Is Associated With Increased PML Risk

Unlike other conditions such as HIV, MS itself is not linked to a higher risk of PML, said Dr. Berger. Instead, it is the medications that introduce the risk, he said, with at least three, and possibly four, drugs posing a risk to patients.

“We know that the risk with natalizumab is incredibly high in the context of John Cunningham virus [JCV] antibody positivity and prolonged therapy,” Dr. Berger said. “You can safely give natalizumab for a short period of time when treating patients with aggressive MS. I will frequently employ that strategy even in the context of JCV antibody positivity.” There is no risk of PML when natalizumab is used for under eight months, Dr. Berger said.“If you leave people on the drug indefinitely, there is a substantial risk of developing PML,” said Dr. Berger. “Individuals who have been on the drug for two years, who have seen prior immunosuppressant therapy, who are JCV antibody positive—that group of individuals develops PML at rates of one in 50 to one in 100.” These levels are “even higher than those in the HIV population before the rise of antiretroviral medications,” he added.

As of November 30, 2017, 177,800 patients have received natalizumab in the postmarketing setting, and 756 cases of PML have been reported as of December 7, 2017. All but three of those cases were in patients with MS, and the overall incidence was 4.19 out of 1,000.

Dr. Berger recommended regular screening MRIs for PML in patients taking natalizumab and advised physicians to be on alert for the appearance of new neurologic symptoms or a new or increasing JCV antibody index.

Drugs With Low and Unknown Risks

Two other MS drugs, fingolimod and dimethyl fumarate, entail a low risk of PML. The numbers of PML cases reported for these drugs are 19 and five, respectively, as of February 2018, said Dr. Berger. Two of the patients receiving fingolimod who developed PML had had earlier exposure to natalizumab.

For JC antibody positive patients receiving dimethyl fumarate, the risk of PML may be eliminated when the treatment is discontinued and their lymphocyte count decreases to a level below 500 per µL Dr. Berger said.

“Unfortunately for fingolimod, we do not have a defined risk-mitigation strategy,” he said. However, researchers have noticed that PML has occurred more often in older people on fingolimod, possibly because of the aging of the immune system.

Alemtuzumab, ocrelizumab (with rituximab as proxy), and teriflunomide (with leflunomide as proxy), entail an unknown risk of PML, according to Dr. Berger. There have been three cases of PML associated with ocrelizumab and one associated with teriflunomide, but all were carry-overs from natalizumab or fingolimod exposure or occurred after natalizumab exposure.

What should a physician do if a patient develops PML? Stopping the drug and restoring the immune system are crucial steps, Dr. Berger said. Although evidence indicates that plasma exchange clears natalizumab, “there is no study that demonstrates that it is in the patient’s best interest,” said Dr. Berger. A retrospective study found no improvement in morbidity or mortality after plasma exchange.

Multiple strategies to treat PML, including immunizations and inhibitors of DNA replication, have failed to make an impact so far, said Dr. Berger. These strategies did not show benefits in clinical trials, and evidence does not support them.

—Randy Dotinga

Suggested Reading

Berger JR. Classifying PML risk with disease modifying therapies. Mult Scler Relat Disord. 2017;12:59-63.

Khatri BO, Man S, Giovannoni G, et al. Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function. Neurology. 2009;72(5):402-409.

Landi D, De Rossi N, Zagaglia S, et al. No evidence of beneficial effects of plasmapheresis in natalizumab-associated PML. Neurology. 2017;88(12):1144-1152.

NASHVILLE—Among veterans with multiple sclerosis (MS), excess MS-related mortality is mainly influenced by initial presentation with progressive MS, sensory and cerebellar complaints, and higher levels of disability. Excess mortality also may be influenced by motor complaints and low BMI, according to research presented at the 2018 CMSC Annual Meeting. Main causes of death include MS itself, infection, respiratory disease, and cancer.

These findings suggest a need to pay more attention “to preventive strategies such as yearly influenza immunization, aggressively treating MS-related complications, and comorbidities, especially vascular risk factors,” said the researchers.

Studying mortality in chronic neurologic diseases may help identify treatable risk factors, and population-based studies of English death records have found that about 64% of patients with MS have a neurologic cause of death.

To identify the predictors of mortality in veterans with MS attending outpatient clinics, Meheroz H. Rabadi, MD, Clinical Professor of Neurology at the University of Oklahoma College of Medicine and Medical Director of the Oklahoma City Veterans Affairs Medical Center MS Program, and Christopher E. Aston, PhD, Associate Research Professor of Pediatrics and a biostatistician at the University of Oklahoma Sciences Center, conducted a retrospective study.

Data From a Veterans Affairs Medical Center

The researchers conducted a retrospective electronic chart review of data from 229 veterans with MS diagnosed based on the McDonald criteria who were registered in the MS program at the Oklahoma City Veterans Affairs Medical Center between January 1, 2000, and December 31, 2014. Participants were followed up every four months in the clinic.

Data included age at initial clinic visit, gender, ethnicity and race, age at MS diagnosis, clinical MS subtype (ie, relapsing-remitting, secondary progressive, primary progressive, clinically isolated syndrome, or radiologically isolated syndrome), and initial presenting features (eg, visual complaints, motor weakness, balance disorder, and sensory complaints).

Drs. Rabadi and Aston determined an impairment index based on the presence or absence of motor and nonmotor signs on initial examination. MS severity was measured by initial Expanded Disability Status Scale and total Functional Independence Measure scores.

The researchers recorded the presence of pre-existing and new-onset comorbidities that are commonly encountered in veterans and are the most common causes of disability and death in the United States, such as hypertension, hyperlipidemia, diabetes mellitus, BMI, and history of smoking. They also recorded the presence of MS-related complications such as pressure ulcers, neurogenic bowel, and neurogenic bladder.

Main Causes of Death

A total of 226 participants were included in the analysis; 17% were female. Most participants were white (81%), 13% were black, 1% were Hispanic, and 2% were Native American. The mean age of MS diagnosis was 36, and the mean age of study entry was 49. The mean duration of MS was 21 years, and the mean duration of follow-up was 12 years. In all, 45 (20%) participants had primary progressive MS, 54 (24%) had secondary progressive MS, 96 (43%) had relapsing-remitting MS, and 31 (14%) had another or unknown MS type.

The mortality rate at the end of the 15-year study period was 14%. Among the 33 patients who died, the main causes of death documented were MS disease itself (57% of cases), infection (43%), cancer (18%), and respiratory failure (18%). Cox regression analysis using the whole cohort found that significant predictors of mortality were progressive MS type; older age at entry into the study; the presence of sensory, cerebellar, or motor complaints on presentation; more disability on presentation; lower BMI; diabetes; not having been on disease-modifying therapy; and the presence of pressure ulcers or neurogenic bladder.

Among patients who died during follow up, 36% had primary progressive MS, compared with 17% of patients who were alive; 42% of patients who died had secondary progressive MS, compared with 21% of those who were alive.

In addition, patients who died had an average age of 56 at study entry, compared with an average age of 48 among those who were alive. BMI among those who died was 23.7, compared with 28 among patients who were alive. Thirty-nine percent of patients who died were never on a disease-modifying therapy, compared with 22% of patients who were alive. Thirty-three percent of patients who died had diabetes mellitus, compared with 16% of those who were alive. Finally, 12% of patients who died had pressure ulcers, compared with 2% of patients who were alive, and 82% of patients who died had neurogenic bladder, compared with 53% of patients who were alive.

—Erica Tricarico

NASHVILLE—Among veterans with multiple sclerosis (MS), excess MS-related mortality is mainly influenced by initial presentation with progressive MS, sensory and cerebellar complaints, and higher levels of disability. Excess mortality also may be influenced by motor complaints and low BMI, according to research presented at the 2018 CMSC Annual Meeting. Main causes of death include MS itself, infection, respiratory disease, and cancer.

These findings suggest a need to pay more attention “to preventive strategies such as yearly influenza immunization, aggressively treating MS-related complications, and comorbidities, especially vascular risk factors,” said the researchers.

Studying mortality in chronic neurologic diseases may help identify treatable risk factors, and population-based studies of English death records have found that about 64% of patients with MS have a neurologic cause of death.

To identify the predictors of mortality in veterans with MS attending outpatient clinics, Meheroz H. Rabadi, MD, Clinical Professor of Neurology at the University of Oklahoma College of Medicine and Medical Director of the Oklahoma City Veterans Affairs Medical Center MS Program, and Christopher E. Aston, PhD, Associate Research Professor of Pediatrics and a biostatistician at the University of Oklahoma Sciences Center, conducted a retrospective study.

Data From a Veterans Affairs Medical Center

The researchers conducted a retrospective electronic chart review of data from 229 veterans with MS diagnosed based on the McDonald criteria who were registered in the MS program at the Oklahoma City Veterans Affairs Medical Center between January 1, 2000, and December 31, 2014. Participants were followed up every four months in the clinic.

Data included age at initial clinic visit, gender, ethnicity and race, age at MS diagnosis, clinical MS subtype (ie, relapsing-remitting, secondary progressive, primary progressive, clinically isolated syndrome, or radiologically isolated syndrome), and initial presenting features (eg, visual complaints, motor weakness, balance disorder, and sensory complaints).

Drs. Rabadi and Aston determined an impairment index based on the presence or absence of motor and nonmotor signs on initial examination. MS severity was measured by initial Expanded Disability Status Scale and total Functional Independence Measure scores.

The researchers recorded the presence of pre-existing and new-onset comorbidities that are commonly encountered in veterans and are the most common causes of disability and death in the United States, such as hypertension, hyperlipidemia, diabetes mellitus, BMI, and history of smoking. They also recorded the presence of MS-related complications such as pressure ulcers, neurogenic bowel, and neurogenic bladder.

Main Causes of Death

A total of 226 participants were included in the analysis; 17% were female. Most participants were white (81%), 13% were black, 1% were Hispanic, and 2% were Native American. The mean age of MS diagnosis was 36, and the mean age of study entry was 49. The mean duration of MS was 21 years, and the mean duration of follow-up was 12 years. In all, 45 (20%) participants had primary progressive MS, 54 (24%) had secondary progressive MS, 96 (43%) had relapsing-remitting MS, and 31 (14%) had another or unknown MS type.

The mortality rate at the end of the 15-year study period was 14%. Among the 33 patients who died, the main causes of death documented were MS disease itself (57% of cases), infection (43%), cancer (18%), and respiratory failure (18%). Cox regression analysis using the whole cohort found that significant predictors of mortality were progressive MS type; older age at entry into the study; the presence of sensory, cerebellar, or motor complaints on presentation; more disability on presentation; lower BMI; diabetes; not having been on disease-modifying therapy; and the presence of pressure ulcers or neurogenic bladder.

Among patients who died during follow up, 36% had primary progressive MS, compared with 17% of patients who were alive; 42% of patients who died had secondary progressive MS, compared with 21% of those who were alive.

In addition, patients who died had an average age of 56 at study entry, compared with an average age of 48 among those who were alive. BMI among those who died was 23.7, compared with 28 among patients who were alive. Thirty-nine percent of patients who died were never on a disease-modifying therapy, compared with 22% of patients who were alive. Thirty-three percent of patients who died had diabetes mellitus, compared with 16% of those who were alive. Finally, 12% of patients who died had pressure ulcers, compared with 2% of patients who were alive, and 82% of patients who died had neurogenic bladder, compared with 53% of patients who were alive.

—Erica Tricarico

NASHVILLE—Among veterans with multiple sclerosis (MS), excess MS-related mortality is mainly influenced by initial presentation with progressive MS, sensory and cerebellar complaints, and higher levels of disability. Excess mortality also may be influenced by motor complaints and low BMI, according to research presented at the 2018 CMSC Annual Meeting. Main causes of death include MS itself, infection, respiratory disease, and cancer.

These findings suggest a need to pay more attention “to preventive strategies such as yearly influenza immunization, aggressively treating MS-related complications, and comorbidities, especially vascular risk factors,” said the researchers.

Studying mortality in chronic neurologic diseases may help identify treatable risk factors, and population-based studies of English death records have found that about 64% of patients with MS have a neurologic cause of death.

To identify the predictors of mortality in veterans with MS attending outpatient clinics, Meheroz H. Rabadi, MD, Clinical Professor of Neurology at the University of Oklahoma College of Medicine and Medical Director of the Oklahoma City Veterans Affairs Medical Center MS Program, and Christopher E. Aston, PhD, Associate Research Professor of Pediatrics and a biostatistician at the University of Oklahoma Sciences Center, conducted a retrospective study.

Data From a Veterans Affairs Medical Center

The researchers conducted a retrospective electronic chart review of data from 229 veterans with MS diagnosed based on the McDonald criteria who were registered in the MS program at the Oklahoma City Veterans Affairs Medical Center between January 1, 2000, and December 31, 2014. Participants were followed up every four months in the clinic.

Data included age at initial clinic visit, gender, ethnicity and race, age at MS diagnosis, clinical MS subtype (ie, relapsing-remitting, secondary progressive, primary progressive, clinically isolated syndrome, or radiologically isolated syndrome), and initial presenting features (eg, visual complaints, motor weakness, balance disorder, and sensory complaints).

Drs. Rabadi and Aston determined an impairment index based on the presence or absence of motor and nonmotor signs on initial examination. MS severity was measured by initial Expanded Disability Status Scale and total Functional Independence Measure scores.

The researchers recorded the presence of pre-existing and new-onset comorbidities that are commonly encountered in veterans and are the most common causes of disability and death in the United States, such as hypertension, hyperlipidemia, diabetes mellitus, BMI, and history of smoking. They also recorded the presence of MS-related complications such as pressure ulcers, neurogenic bowel, and neurogenic bladder.

Main Causes of Death

A total of 226 participants were included in the analysis; 17% were female. Most participants were white (81%), 13% were black, 1% were Hispanic, and 2% were Native American. The mean age of MS diagnosis was 36, and the mean age of study entry was 49. The mean duration of MS was 21 years, and the mean duration of follow-up was 12 years. In all, 45 (20%) participants had primary progressive MS, 54 (24%) had secondary progressive MS, 96 (43%) had relapsing-remitting MS, and 31 (14%) had another or unknown MS type.

The mortality rate at the end of the 15-year study period was 14%. Among the 33 patients who died, the main causes of death documented were MS disease itself (57% of cases), infection (43%), cancer (18%), and respiratory failure (18%). Cox regression analysis using the whole cohort found that significant predictors of mortality were progressive MS type; older age at entry into the study; the presence of sensory, cerebellar, or motor complaints on presentation; more disability on presentation; lower BMI; diabetes; not having been on disease-modifying therapy; and the presence of pressure ulcers or neurogenic bladder.

Among patients who died during follow up, 36% had primary progressive MS, compared with 17% of patients who were alive; 42% of patients who died had secondary progressive MS, compared with 21% of those who were alive.

In addition, patients who died had an average age of 56 at study entry, compared with an average age of 48 among those who were alive. BMI among those who died was 23.7, compared with 28 among patients who were alive. Thirty-nine percent of patients who died were never on a disease-modifying therapy, compared with 22% of patients who were alive. Thirty-three percent of patients who died had diabetes mellitus, compared with 16% of those who were alive. Finally, 12% of patients who died had pressure ulcers, compared with 2% of patients who were alive, and 82% of patients who died had neurogenic bladder, compared with 53% of patients who were alive.

—Erica Tricarico