ICYMI Multiple Sclerosis

BARCELONA—In people with primary progressive multiple sclerosis (MS), treatment with ocrelizumab may significantly reduce the progression of clinical disability sustained for at least 12 weeks, compared with placebo, according to results from a pivotal phase III study presented at the 31st Congress of ECTRIMS. In the study, which is called ORATORIO, clinical disability was measured by the Expanded Disability Status Scale (EDSS).

Ocrelizumab is an investigational, humanized monoclonal antibody designed to selectively target CD20-positive B cells. CD20-positive B cells are a type of immune cell thought to be a key contributor to myelin damage and axonal damage. Preclinical studies suggest that ocrelizumab binds to CD20 cell-surface proteins expressed on certain B cells, but not on stem cells or plasma cells, thus potentially preserving important functions of the immune system.

The ORATORIO trial was a randomized, double-blind, global multicenter study. Researchers administered placebo or 600 mg of ocrelizumab by IV infusion every six months to 732 people with primary progressive MS. The doses of ocrelizumab were given as two 300-mg infusions two weeks apart. The primary end point of the study was time to onset of confirmed disability progression, defined as an increase in EDSS that is sustained for at least 12 weeks.

Overall, the incidence of adverse events associated with ocrelizumab was similar to that of placebo. The most common adverse events were mild-to-moderate infusion-related reactions. The incidence of serious adverse events associated with ocrelizumab, including serious infections, was also similar to that of placebo.

“People with the primary progressive form of MS typically experience symptoms that continuously worsen after the onset of their disease, and there are no approved treatments for this debilitating condition,” said Sandra Horning, MD, Chief Medical Officer and head of Global Product Development for Genentech, the developer of the therapy. “Ocrelizumab is the first investigational medicine to show a clinically meaningful and statistically significant effect on the progression of disease in primary progressive MS.”

In addition to ORATORIO, the phase III clinical development program for ocrelizumab includes OPERA I and OPERA II, which are randomized, double-blind, double-dummy, global multicenter studies in people with relapsing forms of MS. The results of the studies appear to validate the hypothesis that B cells are central to the underlying biology of MS. Genentech plans to pursue marketing authorization for ocrelizumab in relapsing MS and in primary progressive MS. The company will submit data from the OPERA I and II studies and from the ORATORIO study to the FDA in early 2016.

BARCELONA—In people with primary progressive multiple sclerosis (MS), treatment with ocrelizumab may significantly reduce the progression of clinical disability sustained for at least 12 weeks, compared with placebo, according to results from a pivotal phase III study presented at the 31st Congress of ECTRIMS. In the study, which is called ORATORIO, clinical disability was measured by the Expanded Disability Status Scale (EDSS).

Ocrelizumab is an investigational, humanized monoclonal antibody designed to selectively target CD20-positive B cells. CD20-positive B cells are a type of immune cell thought to be a key contributor to myelin damage and axonal damage. Preclinical studies suggest that ocrelizumab binds to CD20 cell-surface proteins expressed on certain B cells, but not on stem cells or plasma cells, thus potentially preserving important functions of the immune system.

The ORATORIO trial was a randomized, double-blind, global multicenter study. Researchers administered placebo or 600 mg of ocrelizumab by IV infusion every six months to 732 people with primary progressive MS. The doses of ocrelizumab were given as two 300-mg infusions two weeks apart. The primary end point of the study was time to onset of confirmed disability progression, defined as an increase in EDSS that is sustained for at least 12 weeks.

Overall, the incidence of adverse events associated with ocrelizumab was similar to that of placebo. The most common adverse events were mild-to-moderate infusion-related reactions. The incidence of serious adverse events associated with ocrelizumab, including serious infections, was also similar to that of placebo.

“People with the primary progressive form of MS typically experience symptoms that continuously worsen after the onset of their disease, and there are no approved treatments for this debilitating condition,” said Sandra Horning, MD, Chief Medical Officer and head of Global Product Development for Genentech, the developer of the therapy. “Ocrelizumab is the first investigational medicine to show a clinically meaningful and statistically significant effect on the progression of disease in primary progressive MS.”

In addition to ORATORIO, the phase III clinical development program for ocrelizumab includes OPERA I and OPERA II, which are randomized, double-blind, double-dummy, global multicenter studies in people with relapsing forms of MS. The results of the studies appear to validate the hypothesis that B cells are central to the underlying biology of MS. Genentech plans to pursue marketing authorization for ocrelizumab in relapsing MS and in primary progressive MS. The company will submit data from the OPERA I and II studies and from the ORATORIO study to the FDA in early 2016.

BARCELONA—In people with primary progressive multiple sclerosis (MS), treatment with ocrelizumab may significantly reduce the progression of clinical disability sustained for at least 12 weeks, compared with placebo, according to results from a pivotal phase III study presented at the 31st Congress of ECTRIMS. In the study, which is called ORATORIO, clinical disability was measured by the Expanded Disability Status Scale (EDSS).

Ocrelizumab is an investigational, humanized monoclonal antibody designed to selectively target CD20-positive B cells. CD20-positive B cells are a type of immune cell thought to be a key contributor to myelin damage and axonal damage. Preclinical studies suggest that ocrelizumab binds to CD20 cell-surface proteins expressed on certain B cells, but not on stem cells or plasma cells, thus potentially preserving important functions of the immune system.

The ORATORIO trial was a randomized, double-blind, global multicenter study. Researchers administered placebo or 600 mg of ocrelizumab by IV infusion every six months to 732 people with primary progressive MS. The doses of ocrelizumab were given as two 300-mg infusions two weeks apart. The primary end point of the study was time to onset of confirmed disability progression, defined as an increase in EDSS that is sustained for at least 12 weeks.

Overall, the incidence of adverse events associated with ocrelizumab was similar to that of placebo. The most common adverse events were mild-to-moderate infusion-related reactions. The incidence of serious adverse events associated with ocrelizumab, including serious infections, was also similar to that of placebo.

“People with the primary progressive form of MS typically experience symptoms that continuously worsen after the onset of their disease, and there are no approved treatments for this debilitating condition,” said Sandra Horning, MD, Chief Medical Officer and head of Global Product Development for Genentech, the developer of the therapy. “Ocrelizumab is the first investigational medicine to show a clinically meaningful and statistically significant effect on the progression of disease in primary progressive MS.”

In addition to ORATORIO, the phase III clinical development program for ocrelizumab includes OPERA I and OPERA II, which are randomized, double-blind, double-dummy, global multicenter studies in people with relapsing forms of MS. The results of the studies appear to validate the hypothesis that B cells are central to the underlying biology of MS. Genentech plans to pursue marketing authorization for ocrelizumab in relapsing MS and in primary progressive MS. The company will submit data from the OPERA I and II studies and from the ORATORIO study to the FDA in early 2016.

A peptide derived from erythropoietin (EPO) demonstrated potent clinical benefits in animal models of multiple sclerosis (MS) without inducing hematologic side effects, according to research published online ahead of print August 14 in Neurotherapeutics. The peptide, JM-4, reduced disability and protected against demyelination in mice with experimental autoimmune encephalomyelitis (EAE). Unlike full-length EPO, JM-4 did not elevate hematocrit in mice with EAE, said RuiRong Yuan, MD, of the VA Medical Center of East Orange and the Department of Neurology and Neurosciences at Rutgers New Jersey Medical School in Newark.

JM-4 “may hold considerable potential for direct clinical application in the treatment of neuroinflammatory diseases, demyelinating illnesses, CNS trauma, and stroke, as well as in the treatment of inflammatory/immune diseases of non-neural origins,” said Dr. Yuan and her research colleagues.

Dissecting EPO

Prior studies have found that full-length EPO may be tissue-protective in several animal models of neurologic injuries, including traumatic brain injury and stroke, but EPO may induce hazardous increases in red cell mass, which can lead to cardiovascular complications. Dr. Yuan and colleagues hypothesized that the erythropoietic and tissue-protective elements of EPO reside in different domains of the molecule and the tissue-protective domains could be separated from the regions responsible for erythropoiesis.

To test their hypothesis, the researchers generated a set of EPO-derived small peptides that contain one or two cysteines within a 7- to 25-mer peptide. They screened these peptides for biologic activity and stability in vitro. They then studied whether the peptides retained their tissue-protective properties in two mouse models of EAE: C57BL/6 mice with EAE induced by immunization with proteolipid protein (PLP) and SJL/J mice with EAE induced by immunization with myelin oligodendrocyte glycoprotein (MOG).

Peptides Did Not Elevate Hematocrit

The investigators previously reported that full-length EPO demonstrated beneficial effects in EAE C57BL/6 mice without significantly altering hematocrit. In EAE SJL/J mice, however, half of the animals rapidly developed clinical symptoms related to erythrocytosis and died after less than seven days of EPO therapy.

In studying the EPO-derived peptides, researchers compared SJL/J mice that were treated with full-length EPO or EPO-derived peptides, and a control group that received phosphate-buffered saline (PBS) as a sham treatment. Hematocrit increased dramatically after whole EPO treatment for seven days, rising to approximately 75% by day 14, said Dr. Yuan. In contrast, hematocrit levels in groups treated with PBS or the peptides, including JM-4, remained unchanged at approximately 51% over the five-week follow-up period.

JM-4 Reduced Disability

The investigators found that the 19-mer JM-4 peptide possessed more consistent beneficial effects than all of the other EPO-derived peptides in their set. To determine if JM-4 could prevent disease exacerbation, SJL/J mice were first immunized with a suboptimal dose of PLP, which induced significant neurologic disability by day 10. Symptomatic mice were then treated with IV JM-4 at 250 μg/kg/day in 200 μL of PBS, or sham-treated with PBS for seven days. Early sustained clinical improvement occurred in the JM-4 treated group compared with the group receiving sham treatment.

Similar results were observed in experiments using the monophasic C57BL/6 EAE disease model. Significant clinical improvement was observed in both the EPO- and JM-4-treated groups, compared with the control group.

Modifying Flare-Ups

To see if JM-4 could modify recurrent disease flare-ups and if symptom improvement could be sustained after termination of therapy, the researchers employed a relapsing-remitting model of EAE. The investigators immunized SJL/J mice with a suboptimal dose of PLP and allowed the animals to recover without intervention. The recovered mice were then separated into two groups that received treatment with JM-4 or PBS for seven days before being challenged with a second immunization containing the same amount of PLP antigen. Previous JM-4 therapy delayed the onset of disease and significantly reduced EAE-induced motor dysfunction compared with the sham-treated mice. Over the following five weeks, the sham-treated group continued to exhibit protracted relapses and more pronounced neurologic deficit, while the JM-4-treated mice had mild disease with little or no hindlimb impairment.

Further examination revealed that JM-4 treatment protected against demyelination and axonal damage in the acute EAE spinal cord, compared with sham treatment. JM-4 treatment also modulated inflammatory and immune reaction within the peripheral lymphatic tissue. In addition, the peptide suppressed proinflammatory cytokine production in MOG peptide enriched T cells and provided neuroprotection against cytotoxic insult, said the researchers.

Potential in a Range of Diseases?

It was important that JM-4 demonstrated therapeutic effect during early neurologic presentation in the EAE animal models because that time point more accurately reflects the human clinical situation.

“Therapies that are effective at symptom onset and provoke long-term resolution of subsequent relapses would be desirable for MS treatment,” Dr. Yuan and colleagues said. “In the preclinical animal model data presented here, our agents have performed satisfactorily in this regard.” The JM-4 peptide “shows promise for treatment of a broad spectrum of neural and non-neural conditions associated with inflammation,” concluded the researchers.

—Jake Remaly

A peptide derived from erythropoietin (EPO) demonstrated potent clinical benefits in animal models of multiple sclerosis (MS) without inducing hematologic side effects, according to research published online ahead of print August 14 in Neurotherapeutics. The peptide, JM-4, reduced disability and protected against demyelination in mice with experimental autoimmune encephalomyelitis (EAE). Unlike full-length EPO, JM-4 did not elevate hematocrit in mice with EAE, said RuiRong Yuan, MD, of the VA Medical Center of East Orange and the Department of Neurology and Neurosciences at Rutgers New Jersey Medical School in Newark.

JM-4 “may hold considerable potential for direct clinical application in the treatment of neuroinflammatory diseases, demyelinating illnesses, CNS trauma, and stroke, as well as in the treatment of inflammatory/immune diseases of non-neural origins,” said Dr. Yuan and her research colleagues.

Dissecting EPO

Prior studies have found that full-length EPO may be tissue-protective in several animal models of neurologic injuries, including traumatic brain injury and stroke, but EPO may induce hazardous increases in red cell mass, which can lead to cardiovascular complications. Dr. Yuan and colleagues hypothesized that the erythropoietic and tissue-protective elements of EPO reside in different domains of the molecule and the tissue-protective domains could be separated from the regions responsible for erythropoiesis.

To test their hypothesis, the researchers generated a set of EPO-derived small peptides that contain one or two cysteines within a 7- to 25-mer peptide. They screened these peptides for biologic activity and stability in vitro. They then studied whether the peptides retained their tissue-protective properties in two mouse models of EAE: C57BL/6 mice with EAE induced by immunization with proteolipid protein (PLP) and SJL/J mice with EAE induced by immunization with myelin oligodendrocyte glycoprotein (MOG).

Peptides Did Not Elevate Hematocrit

The investigators previously reported that full-length EPO demonstrated beneficial effects in EAE C57BL/6 mice without significantly altering hematocrit. In EAE SJL/J mice, however, half of the animals rapidly developed clinical symptoms related to erythrocytosis and died after less than seven days of EPO therapy.

In studying the EPO-derived peptides, researchers compared SJL/J mice that were treated with full-length EPO or EPO-derived peptides, and a control group that received phosphate-buffered saline (PBS) as a sham treatment. Hematocrit increased dramatically after whole EPO treatment for seven days, rising to approximately 75% by day 14, said Dr. Yuan. In contrast, hematocrit levels in groups treated with PBS or the peptides, including JM-4, remained unchanged at approximately 51% over the five-week follow-up period.

JM-4 Reduced Disability

The investigators found that the 19-mer JM-4 peptide possessed more consistent beneficial effects than all of the other EPO-derived peptides in their set. To determine if JM-4 could prevent disease exacerbation, SJL/J mice were first immunized with a suboptimal dose of PLP, which induced significant neurologic disability by day 10. Symptomatic mice were then treated with IV JM-4 at 250 μg/kg/day in 200 μL of PBS, or sham-treated with PBS for seven days. Early sustained clinical improvement occurred in the JM-4 treated group compared with the group receiving sham treatment.

Similar results were observed in experiments using the monophasic C57BL/6 EAE disease model. Significant clinical improvement was observed in both the EPO- and JM-4-treated groups, compared with the control group.

Modifying Flare-Ups

To see if JM-4 could modify recurrent disease flare-ups and if symptom improvement could be sustained after termination of therapy, the researchers employed a relapsing-remitting model of EAE. The investigators immunized SJL/J mice with a suboptimal dose of PLP and allowed the animals to recover without intervention. The recovered mice were then separated into two groups that received treatment with JM-4 or PBS for seven days before being challenged with a second immunization containing the same amount of PLP antigen. Previous JM-4 therapy delayed the onset of disease and significantly reduced EAE-induced motor dysfunction compared with the sham-treated mice. Over the following five weeks, the sham-treated group continued to exhibit protracted relapses and more pronounced neurologic deficit, while the JM-4-treated mice had mild disease with little or no hindlimb impairment.

Further examination revealed that JM-4 treatment protected against demyelination and axonal damage in the acute EAE spinal cord, compared with sham treatment. JM-4 treatment also modulated inflammatory and immune reaction within the peripheral lymphatic tissue. In addition, the peptide suppressed proinflammatory cytokine production in MOG peptide enriched T cells and provided neuroprotection against cytotoxic insult, said the researchers.

Potential in a Range of Diseases?

It was important that JM-4 demonstrated therapeutic effect during early neurologic presentation in the EAE animal models because that time point more accurately reflects the human clinical situation.

“Therapies that are effective at symptom onset and provoke long-term resolution of subsequent relapses would be desirable for MS treatment,” Dr. Yuan and colleagues said. “In the preclinical animal model data presented here, our agents have performed satisfactorily in this regard.” The JM-4 peptide “shows promise for treatment of a broad spectrum of neural and non-neural conditions associated with inflammation,” concluded the researchers.

—Jake Remaly

A peptide derived from erythropoietin (EPO) demonstrated potent clinical benefits in animal models of multiple sclerosis (MS) without inducing hematologic side effects, according to research published online ahead of print August 14 in Neurotherapeutics. The peptide, JM-4, reduced disability and protected against demyelination in mice with experimental autoimmune encephalomyelitis (EAE). Unlike full-length EPO, JM-4 did not elevate hematocrit in mice with EAE, said RuiRong Yuan, MD, of the VA Medical Center of East Orange and the Department of Neurology and Neurosciences at Rutgers New Jersey Medical School in Newark.

JM-4 “may hold considerable potential for direct clinical application in the treatment of neuroinflammatory diseases, demyelinating illnesses, CNS trauma, and stroke, as well as in the treatment of inflammatory/immune diseases of non-neural origins,” said Dr. Yuan and her research colleagues.

Dissecting EPO

Prior studies have found that full-length EPO may be tissue-protective in several animal models of neurologic injuries, including traumatic brain injury and stroke, but EPO may induce hazardous increases in red cell mass, which can lead to cardiovascular complications. Dr. Yuan and colleagues hypothesized that the erythropoietic and tissue-protective elements of EPO reside in different domains of the molecule and the tissue-protective domains could be separated from the regions responsible for erythropoiesis.

To test their hypothesis, the researchers generated a set of EPO-derived small peptides that contain one or two cysteines within a 7- to 25-mer peptide. They screened these peptides for biologic activity and stability in vitro. They then studied whether the peptides retained their tissue-protective properties in two mouse models of EAE: C57BL/6 mice with EAE induced by immunization with proteolipid protein (PLP) and SJL/J mice with EAE induced by immunization with myelin oligodendrocyte glycoprotein (MOG).

Peptides Did Not Elevate Hematocrit

The investigators previously reported that full-length EPO demonstrated beneficial effects in EAE C57BL/6 mice without significantly altering hematocrit. In EAE SJL/J mice, however, half of the animals rapidly developed clinical symptoms related to erythrocytosis and died after less than seven days of EPO therapy.

In studying the EPO-derived peptides, researchers compared SJL/J mice that were treated with full-length EPO or EPO-derived peptides, and a control group that received phosphate-buffered saline (PBS) as a sham treatment. Hematocrit increased dramatically after whole EPO treatment for seven days, rising to approximately 75% by day 14, said Dr. Yuan. In contrast, hematocrit levels in groups treated with PBS or the peptides, including JM-4, remained unchanged at approximately 51% over the five-week follow-up period.

JM-4 Reduced Disability

The investigators found that the 19-mer JM-4 peptide possessed more consistent beneficial effects than all of the other EPO-derived peptides in their set. To determine if JM-4 could prevent disease exacerbation, SJL/J mice were first immunized with a suboptimal dose of PLP, which induced significant neurologic disability by day 10. Symptomatic mice were then treated with IV JM-4 at 250 μg/kg/day in 200 μL of PBS, or sham-treated with PBS for seven days. Early sustained clinical improvement occurred in the JM-4 treated group compared with the group receiving sham treatment.

Similar results were observed in experiments using the monophasic C57BL/6 EAE disease model. Significant clinical improvement was observed in both the EPO- and JM-4-treated groups, compared with the control group.

Modifying Flare-Ups

To see if JM-4 could modify recurrent disease flare-ups and if symptom improvement could be sustained after termination of therapy, the researchers employed a relapsing-remitting model of EAE. The investigators immunized SJL/J mice with a suboptimal dose of PLP and allowed the animals to recover without intervention. The recovered mice were then separated into two groups that received treatment with JM-4 or PBS for seven days before being challenged with a second immunization containing the same amount of PLP antigen. Previous JM-4 therapy delayed the onset of disease and significantly reduced EAE-induced motor dysfunction compared with the sham-treated mice. Over the following five weeks, the sham-treated group continued to exhibit protracted relapses and more pronounced neurologic deficit, while the JM-4-treated mice had mild disease with little or no hindlimb impairment.

Further examination revealed that JM-4 treatment protected against demyelination and axonal damage in the acute EAE spinal cord, compared with sham treatment. JM-4 treatment also modulated inflammatory and immune reaction within the peripheral lymphatic tissue. In addition, the peptide suppressed proinflammatory cytokine production in MOG peptide enriched T cells and provided neuroprotection against cytotoxic insult, said the researchers.

Potential in a Range of Diseases?

It was important that JM-4 demonstrated therapeutic effect during early neurologic presentation in the EAE animal models because that time point more accurately reflects the human clinical situation.

“Therapies that are effective at symptom onset and provoke long-term resolution of subsequent relapses would be desirable for MS treatment,” Dr. Yuan and colleagues said. “In the preclinical animal model data presented here, our agents have performed satisfactorily in this regard.” The JM-4 peptide “shows promise for treatment of a broad spectrum of neural and non-neural conditions associated with inflammation,” concluded the researchers.

—Jake Remaly

Patients who continue smoking after they have been diagnosed with multiple sclerosis (MS) may progress to secondary progressive MS earlier than patients who quit smoking, according to research published online ahead of print September 8 in JAMA Neurology. The findings suggest that physicians should advise patients to stop smoking to avoid aggravating MS-related disability, said Jan Hillert, MD, PhD, of the Karolinska Institutet at Karolinska University Hospital Solna in Stockholm.

“Evidence clearly supports advising patients with MS who smoke to quit,” said Dr. Hillert and colleagues. “Health care services for patients with MS should be organized to support such a lifestyle change.”

A Cross-Sectional Analysis

Cigarette smoking is a known risk factor for MS, with an odds ratio between 1.2 and 1.5, but investigators had not assessed whether quitting smoking after diagnosis affects the course of the disease. To clarify the impact of smoking continuation and cessation on time to conversion from relapsing-remitting MS to secondary progressive MS, Dr. Hillert and colleagues performed a cross-sectional study of patients in the Genes and Environment in Multiple Sclerosis (GEMS) Study in Sweden, a population-based case–control study that includes patients with prevalent MS from the Swedish National MS Registry. Researchers included in their main analysis 728 patients who smoked at diagnosis and who completed questionnaires from November 2009 to March 2011 about their smoking habits.

Researchers categorized 332 of these patients as continuous smokers (ie, they averaged at least one cigarette per day every year from the year after diagnosis) and 118 as quitters. Intermittent smokers were not considered in the primary outcome. An optimized accelerated failure time survival model showed that each additional year of smoking after diagnosis accelerated the time to conversion to secondary progressive MS by 4.7%. Uncorrected Kaplan–Meier plots showed that those who continued to smoke each year after diagnosis converted to secondary progressive MS at a median age of 48, compared with a median age of 56 for those who quit smoking, said the researchers. Smoking measured by pack-years had similar associations with time to conversion as years of active smoking, suggesting that these measures may be approximate proxies of each other.

Potential Confounder

Confounders can exist in any association study, and there might be variables associated with smoking that were not captured in this study, the researchers said.

While the groups were well balanced across most measures, those who quit smoking had shorter time to MS treatment than those who continued smoking, which is a potential confounder in the difference in time of secondary progressive MS onset, said Myla D. Goldman, MD, of the University of Virginia in Charlottesville, and Olaf Stüve, MD, PhD, of the University of Texas Southwestern Medical Center at Dallas, in an editorial commentary published with the study.

In addition, the broad categories of patient smoking levels “unfortunately prohibited any granularity about any dose effect of smoking on progression,” Drs. Goldman and Stüve said. “Thus, it remains unclear whether simply cutting back on the amount one is smoking could provide any benefit.”

A Risk Factor Worth Modifying

About 60% of Swedish patients with MS are smokers, reflecting a potentially large overall health benefit to smoking cessation efforts, Dr. Hillert and colleagues said.

“Most importantly, [this study] provides the first evidence, to our knowledge, that quitting smoking appears to delay onset of secondary progressive MS and provide protective benefit,” said Drs. Goldman and Stüve. “Therefore, even after MS diagnosis, smoking is a risk factor worth modifying.”

—Jake Remaly

Patients who continue smoking after they have been diagnosed with multiple sclerosis (MS) may progress to secondary progressive MS earlier than patients who quit smoking, according to research published online ahead of print September 8 in JAMA Neurology. The findings suggest that physicians should advise patients to stop smoking to avoid aggravating MS-related disability, said Jan Hillert, MD, PhD, of the Karolinska Institutet at Karolinska University Hospital Solna in Stockholm.

“Evidence clearly supports advising patients with MS who smoke to quit,” said Dr. Hillert and colleagues. “Health care services for patients with MS should be organized to support such a lifestyle change.”

A Cross-Sectional Analysis

Cigarette smoking is a known risk factor for MS, with an odds ratio between 1.2 and 1.5, but investigators had not assessed whether quitting smoking after diagnosis affects the course of the disease. To clarify the impact of smoking continuation and cessation on time to conversion from relapsing-remitting MS to secondary progressive MS, Dr. Hillert and colleagues performed a cross-sectional study of patients in the Genes and Environment in Multiple Sclerosis (GEMS) Study in Sweden, a population-based case–control study that includes patients with prevalent MS from the Swedish National MS Registry. Researchers included in their main analysis 728 patients who smoked at diagnosis and who completed questionnaires from November 2009 to March 2011 about their smoking habits.

Researchers categorized 332 of these patients as continuous smokers (ie, they averaged at least one cigarette per day every year from the year after diagnosis) and 118 as quitters. Intermittent smokers were not considered in the primary outcome. An optimized accelerated failure time survival model showed that each additional year of smoking after diagnosis accelerated the time to conversion to secondary progressive MS by 4.7%. Uncorrected Kaplan–Meier plots showed that those who continued to smoke each year after diagnosis converted to secondary progressive MS at a median age of 48, compared with a median age of 56 for those who quit smoking, said the researchers. Smoking measured by pack-years had similar associations with time to conversion as years of active smoking, suggesting that these measures may be approximate proxies of each other.

Potential Confounder

Confounders can exist in any association study, and there might be variables associated with smoking that were not captured in this study, the researchers said.

While the groups were well balanced across most measures, those who quit smoking had shorter time to MS treatment than those who continued smoking, which is a potential confounder in the difference in time of secondary progressive MS onset, said Myla D. Goldman, MD, of the University of Virginia in Charlottesville, and Olaf Stüve, MD, PhD, of the University of Texas Southwestern Medical Center at Dallas, in an editorial commentary published with the study.

In addition, the broad categories of patient smoking levels “unfortunately prohibited any granularity about any dose effect of smoking on progression,” Drs. Goldman and Stüve said. “Thus, it remains unclear whether simply cutting back on the amount one is smoking could provide any benefit.”

A Risk Factor Worth Modifying

About 60% of Swedish patients with MS are smokers, reflecting a potentially large overall health benefit to smoking cessation efforts, Dr. Hillert and colleagues said.

“Most importantly, [this study] provides the first evidence, to our knowledge, that quitting smoking appears to delay onset of secondary progressive MS and provide protective benefit,” said Drs. Goldman and Stüve. “Therefore, even after MS diagnosis, smoking is a risk factor worth modifying.”

—Jake Remaly

Patients who continue smoking after they have been diagnosed with multiple sclerosis (MS) may progress to secondary progressive MS earlier than patients who quit smoking, according to research published online ahead of print September 8 in JAMA Neurology. The findings suggest that physicians should advise patients to stop smoking to avoid aggravating MS-related disability, said Jan Hillert, MD, PhD, of the Karolinska Institutet at Karolinska University Hospital Solna in Stockholm.

“Evidence clearly supports advising patients with MS who smoke to quit,” said Dr. Hillert and colleagues. “Health care services for patients with MS should be organized to support such a lifestyle change.”

A Cross-Sectional Analysis

Cigarette smoking is a known risk factor for MS, with an odds ratio between 1.2 and 1.5, but investigators had not assessed whether quitting smoking after diagnosis affects the course of the disease. To clarify the impact of smoking continuation and cessation on time to conversion from relapsing-remitting MS to secondary progressive MS, Dr. Hillert and colleagues performed a cross-sectional study of patients in the Genes and Environment in Multiple Sclerosis (GEMS) Study in Sweden, a population-based case–control study that includes patients with prevalent MS from the Swedish National MS Registry. Researchers included in their main analysis 728 patients who smoked at diagnosis and who completed questionnaires from November 2009 to March 2011 about their smoking habits.

Researchers categorized 332 of these patients as continuous smokers (ie, they averaged at least one cigarette per day every year from the year after diagnosis) and 118 as quitters. Intermittent smokers were not considered in the primary outcome. An optimized accelerated failure time survival model showed that each additional year of smoking after diagnosis accelerated the time to conversion to secondary progressive MS by 4.7%. Uncorrected Kaplan–Meier plots showed that those who continued to smoke each year after diagnosis converted to secondary progressive MS at a median age of 48, compared with a median age of 56 for those who quit smoking, said the researchers. Smoking measured by pack-years had similar associations with time to conversion as years of active smoking, suggesting that these measures may be approximate proxies of each other.

Potential Confounder

Confounders can exist in any association study, and there might be variables associated with smoking that were not captured in this study, the researchers said.

While the groups were well balanced across most measures, those who quit smoking had shorter time to MS treatment than those who continued smoking, which is a potential confounder in the difference in time of secondary progressive MS onset, said Myla D. Goldman, MD, of the University of Virginia in Charlottesville, and Olaf Stüve, MD, PhD, of the University of Texas Southwestern Medical Center at Dallas, in an editorial commentary published with the study.

In addition, the broad categories of patient smoking levels “unfortunately prohibited any granularity about any dose effect of smoking on progression,” Drs. Goldman and Stüve said. “Thus, it remains unclear whether simply cutting back on the amount one is smoking could provide any benefit.”

A Risk Factor Worth Modifying

About 60% of Swedish patients with MS are smokers, reflecting a potentially large overall health benefit to smoking cessation efforts, Dr. Hillert and colleagues said.

“Most importantly, [this study] provides the first evidence, to our knowledge, that quitting smoking appears to delay onset of secondary progressive MS and provide protective benefit,” said Drs. Goldman and Stüve. “Therefore, even after MS diagnosis, smoking is a risk factor worth modifying.”

—Jake Remaly

Disease duration, clinical course, age, and gender contribute to the dynamic nature of white matter MS pathology, according to an analysis of 1,220 tissue blocks from 120 patients with MS. Researchers found:

• Active plaques were most often found in early disease.

• In later stages, smoldering, inactive, and shadow plaques predominated.

• Early active plaques rapidly declined with disease duration.

• Plaque type distribution differed significantly by clinical course.

• The majority of plaques in acute monophasic  and relapsing-remitting MS were active.

• In secondary progressive MS (SPMS) with attacks, all plaque types could be distinguished.

• In SPMS without attacks, inactive plaques predominated.

• Smoldering plaques were found almost exclusively in progressive MS.

• At 47 years of age, equilibrium was seen between active and inactive plaques and smoldering plaques began to peak.

• Men displayed a higher proportion of smoldering plaques.

Citation: Frischer JM, Weigand SD, Guo Y, et al. Clinical and pathological insights into the dynamic nature of the white matter multiple sclerosis plaque. [Published online ahead of print August 3, 2015]. Ann Neurol. doi: 10.1002/ana.24497.

Disease duration, clinical course, age, and gender contribute to the dynamic nature of white matter MS pathology, according to an analysis of 1,220 tissue blocks from 120 patients with MS. Researchers found:

• Active plaques were most often found in early disease.

• In later stages, smoldering, inactive, and shadow plaques predominated.

• Early active plaques rapidly declined with disease duration.

• Plaque type distribution differed significantly by clinical course.

• The majority of plaques in acute monophasic  and relapsing-remitting MS were active.

• In secondary progressive MS (SPMS) with attacks, all plaque types could be distinguished.

• In SPMS without attacks, inactive plaques predominated.

• Smoldering plaques were found almost exclusively in progressive MS.

• At 47 years of age, equilibrium was seen between active and inactive plaques and smoldering plaques began to peak.

• Men displayed a higher proportion of smoldering plaques.

Citation: Frischer JM, Weigand SD, Guo Y, et al. Clinical and pathological insights into the dynamic nature of the white matter multiple sclerosis plaque. [Published online ahead of print August 3, 2015]. Ann Neurol. doi: 10.1002/ana.24497.

Disease duration, clinical course, age, and gender contribute to the dynamic nature of white matter MS pathology, according to an analysis of 1,220 tissue blocks from 120 patients with MS. Researchers found:

• Active plaques were most often found in early disease.

• In later stages, smoldering, inactive, and shadow plaques predominated.

• Early active plaques rapidly declined with disease duration.

• Plaque type distribution differed significantly by clinical course.

• The majority of plaques in acute monophasic  and relapsing-remitting MS were active.

• In secondary progressive MS (SPMS) with attacks, all plaque types could be distinguished.

• In SPMS without attacks, inactive plaques predominated.

• Smoldering plaques were found almost exclusively in progressive MS.

• At 47 years of age, equilibrium was seen between active and inactive plaques and smoldering plaques began to peak.

• Men displayed a higher proportion of smoldering plaques.

Citation: Frischer JM, Weigand SD, Guo Y, et al. Clinical and pathological insights into the dynamic nature of the white matter multiple sclerosis plaque. [Published online ahead of print August 3, 2015]. Ann Neurol. doi: 10.1002/ana.24497.

Dyschromatopsia in the non-optic neuritis eyes (NON-eyes) of MS patients is due to damage of retinal ganglion cells (RGC), according to a study of 106 patients with MS. Researchers found:

• There were moderate, significant correlations between color vision and macular retinal nerve fiber layer, ganglion cell complex (GCC), thalamus, and lesion volume within the optic radiations.

• Only GCC remained significant in a logistic regression model.

• In the final model including lesion load, and normalized brain parenchymal volume (NBPV) as markers of diffuse neuroaxonal damage, GCC remained associated with dyschromatopsia, an association that remained significant when sex, age, and disease duration were added as covariates.

Citation: Lampert EJ, Andorra M, Torres-Torres R, et al. Color vision impairment in multiple sclerosis points to retinal ganglion cell damage. [Published online ahead of print August 11, 2015]. J Neurol. doi: 10.1007/s00415-015-7876-3.

Dyschromatopsia in the non-optic neuritis eyes (NON-eyes) of MS patients is due to damage of retinal ganglion cells (RGC), according to a study of 106 patients with MS. Researchers found:

• There were moderate, significant correlations between color vision and macular retinal nerve fiber layer, ganglion cell complex (GCC), thalamus, and lesion volume within the optic radiations.

• Only GCC remained significant in a logistic regression model.

• In the final model including lesion load, and normalized brain parenchymal volume (NBPV) as markers of diffuse neuroaxonal damage, GCC remained associated with dyschromatopsia, an association that remained significant when sex, age, and disease duration were added as covariates.

Citation: Lampert EJ, Andorra M, Torres-Torres R, et al. Color vision impairment in multiple sclerosis points to retinal ganglion cell damage. [Published online ahead of print August 11, 2015]. J Neurol. doi: 10.1007/s00415-015-7876-3.

Dyschromatopsia in the non-optic neuritis eyes (NON-eyes) of MS patients is due to damage of retinal ganglion cells (RGC), according to a study of 106 patients with MS. Researchers found:

• There were moderate, significant correlations between color vision and macular retinal nerve fiber layer, ganglion cell complex (GCC), thalamus, and lesion volume within the optic radiations.

• Only GCC remained significant in a logistic regression model.

• In the final model including lesion load, and normalized brain parenchymal volume (NBPV) as markers of diffuse neuroaxonal damage, GCC remained associated with dyschromatopsia, an association that remained significant when sex, age, and disease duration were added as covariates.

Citation: Lampert EJ, Andorra M, Torres-Torres R, et al. Color vision impairment in multiple sclerosis points to retinal ganglion cell damage. [Published online ahead of print August 11, 2015]. J Neurol. doi: 10.1007/s00415-015-7876-3.

Mixed amphetamine salts, extended release (MAS-XR) may be a potential treatment for MS patients with demonstrated processing speed (PS) impairment, according to a study of 52 patients randomized to MAS-XR 5 mg, MAS-XR 10 mg, or placebo. Researchers found:

• At baseline, mean score on the symbol digit modalities test (SDMT) was 43.3 and mean score on the paced auditory serial addition test (PASAT) was 34.8.

• 48.1% of patients were classified as impaired at baseline.

• After treatment, the MAS-XR 10 mg group showed significant improvement on SDMT score, improving 5.2 points vs 0.6 point improvement in the placebo group.

• Change on the PASAT was not significantly different in either treatment group.

Citation: Morrow SA, Rosehart H. Effects of single dose mixed amphetamine salts - extended release on processing speed in multiple sclerosis: a double blind placebo controlled study. [Published online ahead of print August 21, 2015]. Psychopharmacology. doi: 10.1007/s00213-015-4051-6.

Mixed amphetamine salts, extended release (MAS-XR) may be a potential treatment for MS patients with demonstrated processing speed (PS) impairment, according to a study of 52 patients randomized to MAS-XR 5 mg, MAS-XR 10 mg, or placebo. Researchers found:

• At baseline, mean score on the symbol digit modalities test (SDMT) was 43.3 and mean score on the paced auditory serial addition test (PASAT) was 34.8.

• 48.1% of patients were classified as impaired at baseline.

• After treatment, the MAS-XR 10 mg group showed significant improvement on SDMT score, improving 5.2 points vs 0.6 point improvement in the placebo group.

• Change on the PASAT was not significantly different in either treatment group.

Citation: Morrow SA, Rosehart H. Effects of single dose mixed amphetamine salts - extended release on processing speed in multiple sclerosis: a double blind placebo controlled study. [Published online ahead of print August 21, 2015]. Psychopharmacology. doi: 10.1007/s00213-015-4051-6.

Mixed amphetamine salts, extended release (MAS-XR) may be a potential treatment for MS patients with demonstrated processing speed (PS) impairment, according to a study of 52 patients randomized to MAS-XR 5 mg, MAS-XR 10 mg, or placebo. Researchers found:

• At baseline, mean score on the symbol digit modalities test (SDMT) was 43.3 and mean score on the paced auditory serial addition test (PASAT) was 34.8.

• 48.1% of patients were classified as impaired at baseline.

• After treatment, the MAS-XR 10 mg group showed significant improvement on SDMT score, improving 5.2 points vs 0.6 point improvement in the placebo group.

• Change on the PASAT was not significantly different in either treatment group.

Citation: Morrow SA, Rosehart H. Effects of single dose mixed amphetamine salts - extended release on processing speed in multiple sclerosis: a double blind placebo controlled study. [Published online ahead of print August 21, 2015]. Psychopharmacology. doi: 10.1007/s00213-015-4051-6.

Patients with MS have a lower increase in serum 25-hyroxyvitamin D (25(OH)D) levels with supplementation, even after accounting for putative confounders, according to a study of 27 female relapsing-remitting MS patients aged 18 to 60 years and 30 healthy controls. Researchers found:

• At baseline, there were no significant differences in 25(OH)D levels or demographics, except a higher body mass index (BMI) in the MS group.

• In a multivariate model accounting for BMI, medication adherence, and oral contraceptive use, MS patients had a 16.7 nmol/l lower increase in 25(OH)D levels compared with controls.

Citation: Bhargava P, Steele SU, Waubant E, et al. Multiple sclerosis patients have a diminished serologic response to vitamin D supplementation compared to healthy controls. [Published online ahead of print August 18, 2015]. Mult Scler. doi:10.1177/1352458515600248.

Patients with MS have a lower increase in serum 25-hyroxyvitamin D (25(OH)D) levels with supplementation, even after accounting for putative confounders, according to a study of 27 female relapsing-remitting MS patients aged 18 to 60 years and 30 healthy controls. Researchers found:

• At baseline, there were no significant differences in 25(OH)D levels or demographics, except a higher body mass index (BMI) in the MS group.

• In a multivariate model accounting for BMI, medication adherence, and oral contraceptive use, MS patients had a 16.7 nmol/l lower increase in 25(OH)D levels compared with controls.

Citation: Bhargava P, Steele SU, Waubant E, et al. Multiple sclerosis patients have a diminished serologic response to vitamin D supplementation compared to healthy controls. [Published online ahead of print August 18, 2015]. Mult Scler. doi:10.1177/1352458515600248.

Patients with MS have a lower increase in serum 25-hyroxyvitamin D (25(OH)D) levels with supplementation, even after accounting for putative confounders, according to a study of 27 female relapsing-remitting MS patients aged 18 to 60 years and 30 healthy controls. Researchers found:

• At baseline, there were no significant differences in 25(OH)D levels or demographics, except a higher body mass index (BMI) in the MS group.

• In a multivariate model accounting for BMI, medication adherence, and oral contraceptive use, MS patients had a 16.7 nmol/l lower increase in 25(OH)D levels compared with controls.

Citation: Bhargava P, Steele SU, Waubant E, et al. Multiple sclerosis patients have a diminished serologic response to vitamin D supplementation compared to healthy controls. [Published online ahead of print August 18, 2015]. Mult Scler. doi:10.1177/1352458515600248.

Rates of mortality and several comorbidities are higher in an MS versus non-MS cohort, according to a study of 15, 864 patients with MS and 78,420 people without MS. Researchers found that in the MS cohort compared with the non-MS cohort:

• All-causes mortality was 2.9 times higher.

• Relative risks of mortality were: infectious disease (6.2), diseases of the nervous system (5.8), respiratory system (5.0), circulatory system (2.1), and suicide (2.6).

• Relative risks of comorbidities were: sepsis (5.7), ischemic stroke (3.8), attempted suicide (2.4), and ulcerative colitis (2.0).

• The rate of cancers was higher: lymphoproliferative disorders (2.2) and melanoma (1.7). 

Citation: Capkur G, Dahlke F, Lahoz R, et al. Mortality and comorbidities in patients with multiple sclerosis compared with a population without multiple sclerosis: An observational study using the US department of defense administrative claims database. [Published online ahead of print August 18, 2015]. Mul Scler Rel Dis. doi: http://dx.doi.org/10.1016/j.msard.2015.08.005.

Comment: Multiple sclerosis (MS) is not a benign disease; people with MS die at a rate higher than those without MS. This study reinforces the importance of early effective treatment to reduce disease burden and treat symptomatic problems in people who have MS. It is also just as important to identify and treat other significant comorbidities in those we treat for MS.—Mark Gudesblatt, MD, Medical Director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Islip, NY

Rates of mortality and several comorbidities are higher in an MS versus non-MS cohort, according to a study of 15, 864 patients with MS and 78,420 people without MS. Researchers found that in the MS cohort compared with the non-MS cohort:

• All-causes mortality was 2.9 times higher.

• Relative risks of mortality were: infectious disease (6.2), diseases of the nervous system (5.8), respiratory system (5.0), circulatory system (2.1), and suicide (2.6).

• Relative risks of comorbidities were: sepsis (5.7), ischemic stroke (3.8), attempted suicide (2.4), and ulcerative colitis (2.0).

• The rate of cancers was higher: lymphoproliferative disorders (2.2) and melanoma (1.7). 

Citation: Capkur G, Dahlke F, Lahoz R, et al. Mortality and comorbidities in patients with multiple sclerosis compared with a population without multiple sclerosis: An observational study using the US department of defense administrative claims database. [Published online ahead of print August 18, 2015]. Mul Scler Rel Dis. doi: http://dx.doi.org/10.1016/j.msard.2015.08.005.

Comment: Multiple sclerosis (MS) is not a benign disease; people with MS die at a rate higher than those without MS. This study reinforces the importance of early effective treatment to reduce disease burden and treat symptomatic problems in people who have MS. It is also just as important to identify and treat other significant comorbidities in those we treat for MS.—Mark Gudesblatt, MD, Medical Director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Islip, NY

Rates of mortality and several comorbidities are higher in an MS versus non-MS cohort, according to a study of 15, 864 patients with MS and 78,420 people without MS. Researchers found that in the MS cohort compared with the non-MS cohort:

• All-causes mortality was 2.9 times higher.

• Relative risks of mortality were: infectious disease (6.2), diseases of the nervous system (5.8), respiratory system (5.0), circulatory system (2.1), and suicide (2.6).

• Relative risks of comorbidities were: sepsis (5.7), ischemic stroke (3.8), attempted suicide (2.4), and ulcerative colitis (2.0).

• The rate of cancers was higher: lymphoproliferative disorders (2.2) and melanoma (1.7). 

Citation: Capkur G, Dahlke F, Lahoz R, et al. Mortality and comorbidities in patients with multiple sclerosis compared with a population without multiple sclerosis: An observational study using the US department of defense administrative claims database. [Published online ahead of print August 18, 2015]. Mul Scler Rel Dis. doi: http://dx.doi.org/10.1016/j.msard.2015.08.005.

Comment: Multiple sclerosis (MS) is not a benign disease; people with MS die at a rate higher than those without MS. This study reinforces the importance of early effective treatment to reduce disease burden and treat symptomatic problems in people who have MS. It is also just as important to identify and treat other significant comorbidities in those we treat for MS.—Mark Gudesblatt, MD, Medical Director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Islip, NY

For the first time, progressive multifocal leukoencephalopathy (PML) has been reported in patients with multiple sclerosis (MS) treated with fingolimod who had not previously been treated with an immunosuppressant, according to an FDA warning issued on August 4.

The FDA described two cases of PML—one is considered definite and the second is considered probable—in patients who had not received prior treatment with an immunosupressant drug for MS or any other medical condition. Prior cases of PML in patients taking fingolimod, including a case in a European patient in 2013, were confounded by immunosuppressant use before or concurrent with the drug.

In addition, Novartis, the manufacturer of the drug, reported on August 17 that it had been informed of another case of PML in a patient who did not have prior exposure to natalizumab. This patient has a history of colorectal cancer that was treated with chemotherapy and radiation treatment, and Crohn’s disease.

Clinicians who suspect that a patient on fingolimod may have PML should stop treatment and evaluate the patient for a diagnosis of PML, according to the FDA. People on fingolimod should contact their health care professionals immediately “if they experience symptoms such as new or worsening weakness; increased trouble using their arms or legs; or changes in thinking, eyesight, strength, or balance,” said the agency.

Symptoms in the patient with definite PML, a 54-year-old who had had MS for about 14 years and had been treated with fingolimod for about 2.5 years, included instability while walking, clumsiness, inattention, somnolence, and mental sluggishness. John Cunningham virus (JCV) DNA was present in the patient’s CSF, and MRI findings were characteristic of PML. The probable case was in a 49-year-old who had been treated with fingolimod for about four years and had no symptoms, but had new MRI lesions consistent with PML and a CSF test that was positive for JCV DNA.

Fingolimod, taken once per day by mouth, is a sphingosine 1-phosphate receptor modulator marketed by Novartis as Gilenya. It was approved in 2010 and is indicated for treating relapsing forms of MS to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability. The fingolimod prescribing information and Medication Guide are being updated to include information about cases of PML. Possible cases of PML associated with fingolimod should be reported to the FDA’s MedWatch program website or by calling 1-800-332-1088.

—Elizabeth Mechcatie

For the first time, progressive multifocal leukoencephalopathy (PML) has been reported in patients with multiple sclerosis (MS) treated with fingolimod who had not previously been treated with an immunosuppressant, according to an FDA warning issued on August 4.

The FDA described two cases of PML—one is considered definite and the second is considered probable—in patients who had not received prior treatment with an immunosupressant drug for MS or any other medical condition. Prior cases of PML in patients taking fingolimod, including a case in a European patient in 2013, were confounded by immunosuppressant use before or concurrent with the drug.

In addition, Novartis, the manufacturer of the drug, reported on August 17 that it had been informed of another case of PML in a patient who did not have prior exposure to natalizumab. This patient has a history of colorectal cancer that was treated with chemotherapy and radiation treatment, and Crohn’s disease.

Clinicians who suspect that a patient on fingolimod may have PML should stop treatment and evaluate the patient for a diagnosis of PML, according to the FDA. People on fingolimod should contact their health care professionals immediately “if they experience symptoms such as new or worsening weakness; increased trouble using their arms or legs; or changes in thinking, eyesight, strength, or balance,” said the agency.

Symptoms in the patient with definite PML, a 54-year-old who had had MS for about 14 years and had been treated with fingolimod for about 2.5 years, included instability while walking, clumsiness, inattention, somnolence, and mental sluggishness. John Cunningham virus (JCV) DNA was present in the patient’s CSF, and MRI findings were characteristic of PML. The probable case was in a 49-year-old who had been treated with fingolimod for about four years and had no symptoms, but had new MRI lesions consistent with PML and a CSF test that was positive for JCV DNA.

Fingolimod, taken once per day by mouth, is a sphingosine 1-phosphate receptor modulator marketed by Novartis as Gilenya. It was approved in 2010 and is indicated for treating relapsing forms of MS to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability. The fingolimod prescribing information and Medication Guide are being updated to include information about cases of PML. Possible cases of PML associated with fingolimod should be reported to the FDA’s MedWatch program website or by calling 1-800-332-1088.

—Elizabeth Mechcatie

For the first time, progressive multifocal leukoencephalopathy (PML) has been reported in patients with multiple sclerosis (MS) treated with fingolimod who had not previously been treated with an immunosuppressant, according to an FDA warning issued on August 4.

The FDA described two cases of PML—one is considered definite and the second is considered probable—in patients who had not received prior treatment with an immunosupressant drug for MS or any other medical condition. Prior cases of PML in patients taking fingolimod, including a case in a European patient in 2013, were confounded by immunosuppressant use before or concurrent with the drug.

In addition, Novartis, the manufacturer of the drug, reported on August 17 that it had been informed of another case of PML in a patient who did not have prior exposure to natalizumab. This patient has a history of colorectal cancer that was treated with chemotherapy and radiation treatment, and Crohn’s disease.

Clinicians who suspect that a patient on fingolimod may have PML should stop treatment and evaluate the patient for a diagnosis of PML, according to the FDA. People on fingolimod should contact their health care professionals immediately “if they experience symptoms such as new or worsening weakness; increased trouble using their arms or legs; or changes in thinking, eyesight, strength, or balance,” said the agency.

Symptoms in the patient with definite PML, a 54-year-old who had had MS for about 14 years and had been treated with fingolimod for about 2.5 years, included instability while walking, clumsiness, inattention, somnolence, and mental sluggishness. John Cunningham virus (JCV) DNA was present in the patient’s CSF, and MRI findings were characteristic of PML. The probable case was in a 49-year-old who had been treated with fingolimod for about four years and had no symptoms, but had new MRI lesions consistent with PML and a CSF test that was positive for JCV DNA.

Fingolimod, taken once per day by mouth, is a sphingosine 1-phosphate receptor modulator marketed by Novartis as Gilenya. It was approved in 2010 and is indicated for treating relapsing forms of MS to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability. The fingolimod prescribing information and Medication Guide are being updated to include information about cases of PML. Possible cases of PML associated with fingolimod should be reported to the FDA’s MedWatch program website or by calling 1-800-332-1088.

—Elizabeth Mechcatie

INDIANAPOLIS—Although many drugs have failed in clinical trials to provide benefits to patients with progressive multiple sclerosis (MS), neurologists have reason to be optimistic about the quest for effective therapies, according to an overview presented at the 2015 CMSC Annual Meeting. Ongoing studies are investigating agents that appear to offer neuroprotection. An international collaboration is helping to advance research into mesenchymal stem cells (MSCs), which may promote remyelination. “There are lots of things we can look at when we think about how we would approach progressive MS,” said Alan J. Thompson, MD, consultant neurologist at the National Hospital for Neurology and Neurosurgery in London.

Agents That May Offer Neuroprotection
One approach to providing neuroprotection is to block sodium channels on the axon and on the microglia. This technique has proven effective in animal models, but human trials have yielded mixed results. In 2010, Kapoor et al randomized 120 patients with secondary progressive MS to 400 mg of lamotrigine, a sodium-channel blocker, or placebo. At two years, participants who received lamotrigine had greater cerebral volume loss than controls. Brain volume partly recovered when treatment was stopped, however.

When the researchers performed a post hoc analysis of their data, they made two observations that supported a benefit of lamotrigine. The first was that lamotrigine was associated with improvements on the timed 25-foot walk. The other observation was that when patients who stopped taking lamotrigine were excluded from the analysis, lamotrigine reduced serum neurofilament levels, compared with placebo. Serum neurofilament levels were correlated with disability, and the researchers concluded that lamotrigine might protect axons against degeneration. “There’s some indication that this [drug] needs to be pursued a little bit further,” said Dr. Thompson.

Kapoor et al later studied phenytoin, a neuroprotective agent with mechanism of action similar to that of lamotrigine, in a phase II randomized controlled trial of 86 patients with acute optic neuritis. The trial’s primary end point was retinal nerve fiber layer thickness. After six months, participants who received phenytoin had a 30% reduction in atrophy, compared with controls.

Biotin, a coenzyme involved in fatty acid synthesis and energy production, also has shown potential as a neuroprotective agent. In a phase III study of 154 patients with primary and secondary progressive MS, biotin met the primary end point of improvement on EDSS or timed 25-foot walk at nine months that was confirmed at 12 months. The drug’s effect on EDSS score was the greater contributor to the positive result. The data are “exciting,” but should be interpreted cautiously because of the study’s relatively small number of patients, according to Dr. Thompson. The results of a trial of biotin in patients with optic neuritis will be reported later this year, he added.

Ongoing Trials of Neuroprotective Agents
Research into agents that may provide neuroprotection is ongoing. One study, the MS-Secondary Progressive Multi-Arm Randomization Trial (MS-SMART), uses an adaptive trial design that will allow investigators to compare several agents at the same time. In MS-SMART, equal numbers of participants will receive amiloride (5 mg bid), riluzole (50 mg bid), fluoxetine (20 mg bid), or placebo.

Amiloride blocks the neuronal proton-gated acid-sensing ion channel, which is increased within axons and oligodendrocytes in MS lesions. Researchers at the University of Oxford in the United Kingdom found that the drug reduced the rates of atrophy and white and gray matter damage in people with primary progressive MS.

Riluzole is a treatment for motor neuron disease. A Dutch pilot study in 2005 suggested that riluzole reduced the rate of cervical cord atrophy and decreased the development of new T1 hypointense lesions on MRI.

Fluoxetine, a selective serotonin reuptake inhibitor, is an antidepressant. The drug might protect against axonal loss because it stimulates glycogenolysis, which is a necessary energy source for axons, and enhances the production of brain-derived neurotrophic factor in rodent astrocyte cultures. Recruitment into MS-SMART will continue through 2015.

In addition, the Secondary and Primary Progressive Ibudilast NeuroNEXT Trial in MS (SPRINT-MS) will examine the potential neuroprotective effects of ibudilast. The randomized, placebo-controlled study will last for 96 weeks and focus on ibudilast’s effect on whole-brain atrophy. Secondary end points will include diffusion tensor imaging of descending pyramidal tracts, magnetization transfer ratio of the whole brain, and optical coherence tomography of the retinal nerve fiber layer.

Stem Cells Could Promote Remyelination
Neurologists will continue to seek therapies that can stimulate remyelination in patients with progressive MS. Various studies since 2009 have suggested that MSCs could produce this outcome. Despite their small patient populations, these trials can produce meaningful results, said Dr. Thompson.

He and his colleagues published a proof-of-concept study of autologous MSCs for the treatment of MS in Lancet Neurology in 2012. They examined 10 patients with secondary progressive MS and previous optic neuritis before and after the latter received MSCs. The treatment significantly improved visual acuity, and the researchers found evidence that it might promote remyelination.

Organizations including the Consortium of MS Centers have supported the International MSC Transplantation Study Group, which will guide future research into MSCs. The study group published a consensus paper on MSCs in Multiple Sclerosis in 2010. The consensus paper drew on the current literature to set guidelines for phase I and phase II clinical trials of MSCs in patients with MS. “Useful collaborative work going on in this area [provides] a lot of cause for optimism,” said Dr. Thompson.

—Erik Greb

INDIANAPOLIS—Although many drugs have failed in clinical trials to provide benefits to patients with progressive multiple sclerosis (MS), neurologists have reason to be optimistic about the quest for effective therapies, according to an overview presented at the 2015 CMSC Annual Meeting. Ongoing studies are investigating agents that appear to offer neuroprotection. An international collaboration is helping to advance research into mesenchymal stem cells (MSCs), which may promote remyelination. “There are lots of things we can look at when we think about how we would approach progressive MS,” said Alan J. Thompson, MD, consultant neurologist at the National Hospital for Neurology and Neurosurgery in London.

Agents That May Offer Neuroprotection
One approach to providing neuroprotection is to block sodium channels on the axon and on the microglia. This technique has proven effective in animal models, but human trials have yielded mixed results. In 2010, Kapoor et al randomized 120 patients with secondary progressive MS to 400 mg of lamotrigine, a sodium-channel blocker, or placebo. At two years, participants who received lamotrigine had greater cerebral volume loss than controls. Brain volume partly recovered when treatment was stopped, however.

When the researchers performed a post hoc analysis of their data, they made two observations that supported a benefit of lamotrigine. The first was that lamotrigine was associated with improvements on the timed 25-foot walk. The other observation was that when patients who stopped taking lamotrigine were excluded from the analysis, lamotrigine reduced serum neurofilament levels, compared with placebo. Serum neurofilament levels were correlated with disability, and the researchers concluded that lamotrigine might protect axons against degeneration. “There’s some indication that this [drug] needs to be pursued a little bit further,” said Dr. Thompson.

Kapoor et al later studied phenytoin, a neuroprotective agent with mechanism of action similar to that of lamotrigine, in a phase II randomized controlled trial of 86 patients with acute optic neuritis. The trial’s primary end point was retinal nerve fiber layer thickness. After six months, participants who received phenytoin had a 30% reduction in atrophy, compared with controls.

Biotin, a coenzyme involved in fatty acid synthesis and energy production, also has shown potential as a neuroprotective agent. In a phase III study of 154 patients with primary and secondary progressive MS, biotin met the primary end point of improvement on EDSS or timed 25-foot walk at nine months that was confirmed at 12 months. The drug’s effect on EDSS score was the greater contributor to the positive result. The data are “exciting,” but should be interpreted cautiously because of the study’s relatively small number of patients, according to Dr. Thompson. The results of a trial of biotin in patients with optic neuritis will be reported later this year, he added.

Ongoing Trials of Neuroprotective Agents
Research into agents that may provide neuroprotection is ongoing. One study, the MS-Secondary Progressive Multi-Arm Randomization Trial (MS-SMART), uses an adaptive trial design that will allow investigators to compare several agents at the same time. In MS-SMART, equal numbers of participants will receive amiloride (5 mg bid), riluzole (50 mg bid), fluoxetine (20 mg bid), or placebo.

Amiloride blocks the neuronal proton-gated acid-sensing ion channel, which is increased within axons and oligodendrocytes in MS lesions. Researchers at the University of Oxford in the United Kingdom found that the drug reduced the rates of atrophy and white and gray matter damage in people with primary progressive MS.

Riluzole is a treatment for motor neuron disease. A Dutch pilot study in 2005 suggested that riluzole reduced the rate of cervical cord atrophy and decreased the development of new T1 hypointense lesions on MRI.

Fluoxetine, a selective serotonin reuptake inhibitor, is an antidepressant. The drug might protect against axonal loss because it stimulates glycogenolysis, which is a necessary energy source for axons, and enhances the production of brain-derived neurotrophic factor in rodent astrocyte cultures. Recruitment into MS-SMART will continue through 2015.

In addition, the Secondary and Primary Progressive Ibudilast NeuroNEXT Trial in MS (SPRINT-MS) will examine the potential neuroprotective effects of ibudilast. The randomized, placebo-controlled study will last for 96 weeks and focus on ibudilast’s effect on whole-brain atrophy. Secondary end points will include diffusion tensor imaging of descending pyramidal tracts, magnetization transfer ratio of the whole brain, and optical coherence tomography of the retinal nerve fiber layer.

Stem Cells Could Promote Remyelination
Neurologists will continue to seek therapies that can stimulate remyelination in patients with progressive MS. Various studies since 2009 have suggested that MSCs could produce this outcome. Despite their small patient populations, these trials can produce meaningful results, said Dr. Thompson.

He and his colleagues published a proof-of-concept study of autologous MSCs for the treatment of MS in Lancet Neurology in 2012. They examined 10 patients with secondary progressive MS and previous optic neuritis before and after the latter received MSCs. The treatment significantly improved visual acuity, and the researchers found evidence that it might promote remyelination.

Organizations including the Consortium of MS Centers have supported the International MSC Transplantation Study Group, which will guide future research into MSCs. The study group published a consensus paper on MSCs in Multiple Sclerosis in 2010. The consensus paper drew on the current literature to set guidelines for phase I and phase II clinical trials of MSCs in patients with MS. “Useful collaborative work going on in this area [provides] a lot of cause for optimism,” said Dr. Thompson.

—Erik Greb

INDIANAPOLIS—Although many drugs have failed in clinical trials to provide benefits to patients with progressive multiple sclerosis (MS), neurologists have reason to be optimistic about the quest for effective therapies, according to an overview presented at the 2015 CMSC Annual Meeting. Ongoing studies are investigating agents that appear to offer neuroprotection. An international collaboration is helping to advance research into mesenchymal stem cells (MSCs), which may promote remyelination. “There are lots of things we can look at when we think about how we would approach progressive MS,” said Alan J. Thompson, MD, consultant neurologist at the National Hospital for Neurology and Neurosurgery in London.

Agents That May Offer Neuroprotection
One approach to providing neuroprotection is to block sodium channels on the axon and on the microglia. This technique has proven effective in animal models, but human trials have yielded mixed results. In 2010, Kapoor et al randomized 120 patients with secondary progressive MS to 400 mg of lamotrigine, a sodium-channel blocker, or placebo. At two years, participants who received lamotrigine had greater cerebral volume loss than controls. Brain volume partly recovered when treatment was stopped, however.

When the researchers performed a post hoc analysis of their data, they made two observations that supported a benefit of lamotrigine. The first was that lamotrigine was associated with improvements on the timed 25-foot walk. The other observation was that when patients who stopped taking lamotrigine were excluded from the analysis, lamotrigine reduced serum neurofilament levels, compared with placebo. Serum neurofilament levels were correlated with disability, and the researchers concluded that lamotrigine might protect axons against degeneration. “There’s some indication that this [drug] needs to be pursued a little bit further,” said Dr. Thompson.

Kapoor et al later studied phenytoin, a neuroprotective agent with mechanism of action similar to that of lamotrigine, in a phase II randomized controlled trial of 86 patients with acute optic neuritis. The trial’s primary end point was retinal nerve fiber layer thickness. After six months, participants who received phenytoin had a 30% reduction in atrophy, compared with controls.

Biotin, a coenzyme involved in fatty acid synthesis and energy production, also has shown potential as a neuroprotective agent. In a phase III study of 154 patients with primary and secondary progressive MS, biotin met the primary end point of improvement on EDSS or timed 25-foot walk at nine months that was confirmed at 12 months. The drug’s effect on EDSS score was the greater contributor to the positive result. The data are “exciting,” but should be interpreted cautiously because of the study’s relatively small number of patients, according to Dr. Thompson. The results of a trial of biotin in patients with optic neuritis will be reported later this year, he added.

Ongoing Trials of Neuroprotective Agents
Research into agents that may provide neuroprotection is ongoing. One study, the MS-Secondary Progressive Multi-Arm Randomization Trial (MS-SMART), uses an adaptive trial design that will allow investigators to compare several agents at the same time. In MS-SMART, equal numbers of participants will receive amiloride (5 mg bid), riluzole (50 mg bid), fluoxetine (20 mg bid), or placebo.

Amiloride blocks the neuronal proton-gated acid-sensing ion channel, which is increased within axons and oligodendrocytes in MS lesions. Researchers at the University of Oxford in the United Kingdom found that the drug reduced the rates of atrophy and white and gray matter damage in people with primary progressive MS.

Riluzole is a treatment for motor neuron disease. A Dutch pilot study in 2005 suggested that riluzole reduced the rate of cervical cord atrophy and decreased the development of new T1 hypointense lesions on MRI.

Fluoxetine, a selective serotonin reuptake inhibitor, is an antidepressant. The drug might protect against axonal loss because it stimulates glycogenolysis, which is a necessary energy source for axons, and enhances the production of brain-derived neurotrophic factor in rodent astrocyte cultures. Recruitment into MS-SMART will continue through 2015.

In addition, the Secondary and Primary Progressive Ibudilast NeuroNEXT Trial in MS (SPRINT-MS) will examine the potential neuroprotective effects of ibudilast. The randomized, placebo-controlled study will last for 96 weeks and focus on ibudilast’s effect on whole-brain atrophy. Secondary end points will include diffusion tensor imaging of descending pyramidal tracts, magnetization transfer ratio of the whole brain, and optical coherence tomography of the retinal nerve fiber layer.

Stem Cells Could Promote Remyelination
Neurologists will continue to seek therapies that can stimulate remyelination in patients with progressive MS. Various studies since 2009 have suggested that MSCs could produce this outcome. Despite their small patient populations, these trials can produce meaningful results, said Dr. Thompson.

He and his colleagues published a proof-of-concept study of autologous MSCs for the treatment of MS in Lancet Neurology in 2012. They examined 10 patients with secondary progressive MS and previous optic neuritis before and after the latter received MSCs. The treatment significantly improved visual acuity, and the researchers found evidence that it might promote remyelination.

Organizations including the Consortium of MS Centers have supported the International MSC Transplantation Study Group, which will guide future research into MSCs. The study group published a consensus paper on MSCs in Multiple Sclerosis in 2010. The consensus paper drew on the current literature to set guidelines for phase I and phase II clinical trials of MSCs in patients with MS. “Useful collaborative work going on in this area [provides] a lot of cause for optimism,” said Dr. Thompson.

—Erik Greb