Multiple Sclerosis Hub

BARCELONA—Overall intake of polyunsaturated fatty acids (PUFAs) is associated with a lower risk of multiple sclerosis (MS), according to a prospective study described at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). The association mainly results from the effect of plant-derived PUFAs, especially alpha-linolenic acid. Fish-derived fatty acids appear to have no significant association with MS risk.

“While confirmation from other studies is needed, low PUFA intake may be another modifiable risk factor for MS,” said Kjetil Bjørnevik, MD, a research fellow in the neuroepidemiology group at Harvard T.H. Chan School of Public Health in Boston.

For more than 50 years, investigators have been studying the role that fat intake may play in the development of MS. In a 1952 New England Journal of Medicine article, researchers proposed that differences in the incidence of MS in distinct regions of Norway resulted from differences in diet. Subsequent animal studies suggested that omega-6 PUFAs have disease-modifying effects. A recent Cochrane review of randomized controlled trials concluded that PUFAs play no major role on the clinical outcomes of MS. A recent study, however, found an inverse association between overall omega-3 PUFA intake and MS risk.

Dr. Bjørnevik and colleagues prospectively followed more than 175,000 participants in the Nurses’ Health Studies I and II. Participants received questionnaires every second year, and their diet was assessed every fourth year. Dr. Bjørnevik’s team used food-frequency questionnaires to assess the nurses’ intake of alpha-linolenic acid, linoleic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) at baseline (ie, in 1984 and 1991) and during follow-up. The questionnaires had been specifically validated for the intake of PUFAs. The study’s follow-up time spanned several decades. During follow-up, 479 participants developed MS. Each diagnosis of MS was confirmed by a treating neurologist or by medical records. The researchers used a Cox proportional h<hl name="5"/>azard model to calculate acid ratios in each cohort and adjusted all analyses for age, ethnicity, BMI at age 18, smoking, vitamin D intake from supplements, and total caloric intake.

The investigators found no significant association between overall fat intake and MS risk. Neither saturated fat intake nor monounsaturated fat intake was associated with MS. “This [result] is interesting, as it has been suggested that a diet rich in saturated fat could increase MS risk,” said Dr. Bjørnevik. PUFA intake, however, was significantly associated with lower MS risk. The hazard ratio of MS among participants in the top quintile of PUFA intake was 0.66. The researchers also observed a trend toward lower risk of MS in the other quintiles of PUFA intake. No such association obtained for any other fat studied.

When the group examined the specific types of PUFAs, they found no association between dietary intake of fatty-fish-derived PUFAs, including EPA and DHA, and MS risk. “It is mostly these fatty acids that have been suggested to be beneficial for MS risk,” said Dr. Bjørnevik. Both plant-derived PUFAs (ie, alpha-linolenic acid and linoleic acid), however, were associated with lower MS risk. The hazard ratio of MS for the top quintile of alpha-linolenic acid intake was 0.64.

Finally, Dr. Bjørnevik and colleagues compared the effect estimates for PUFA in the baseline analysis and in the cumulative analysis. The results of both analyses were similar. The overall intake of PUFAs was consistently associated with lower MS risk in both analyses. The fish-derived PUFAs were not significantly associated with MS risk in either analysis, but plant-derived PUFAs were associated with a lower MS risk in both analyses.

—Erik Greb

BARCELONA—Overall intake of polyunsaturated fatty acids (PUFAs) is associated with a lower risk of multiple sclerosis (MS), according to a prospective study described at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). The association mainly results from the effect of plant-derived PUFAs, especially alpha-linolenic acid. Fish-derived fatty acids appear to have no significant association with MS risk.

“While confirmation from other studies is needed, low PUFA intake may be another modifiable risk factor for MS,” said Kjetil Bjørnevik, MD, a research fellow in the neuroepidemiology group at Harvard T.H. Chan School of Public Health in Boston.

For more than 50 years, investigators have been studying the role that fat intake may play in the development of MS. In a 1952 New England Journal of Medicine article, researchers proposed that differences in the incidence of MS in distinct regions of Norway resulted from differences in diet. Subsequent animal studies suggested that omega-6 PUFAs have disease-modifying effects. A recent Cochrane review of randomized controlled trials concluded that PUFAs play no major role on the clinical outcomes of MS. A recent study, however, found an inverse association between overall omega-3 PUFA intake and MS risk.

Dr. Bjørnevik and colleagues prospectively followed more than 175,000 participants in the Nurses’ Health Studies I and II. Participants received questionnaires every second year, and their diet was assessed every fourth year. Dr. Bjørnevik’s team used food-frequency questionnaires to assess the nurses’ intake of alpha-linolenic acid, linoleic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) at baseline (ie, in 1984 and 1991) and during follow-up. The questionnaires had been specifically validated for the intake of PUFAs. The study’s follow-up time spanned several decades. During follow-up, 479 participants developed MS. Each diagnosis of MS was confirmed by a treating neurologist or by medical records. The researchers used a Cox proportional h<hl name="5"/>azard model to calculate acid ratios in each cohort and adjusted all analyses for age, ethnicity, BMI at age 18, smoking, vitamin D intake from supplements, and total caloric intake.

The investigators found no significant association between overall fat intake and MS risk. Neither saturated fat intake nor monounsaturated fat intake was associated with MS. “This [result] is interesting, as it has been suggested that a diet rich in saturated fat could increase MS risk,” said Dr. Bjørnevik. PUFA intake, however, was significantly associated with lower MS risk. The hazard ratio of MS among participants in the top quintile of PUFA intake was 0.66. The researchers also observed a trend toward lower risk of MS in the other quintiles of PUFA intake. No such association obtained for any other fat studied.

When the group examined the specific types of PUFAs, they found no association between dietary intake of fatty-fish-derived PUFAs, including EPA and DHA, and MS risk. “It is mostly these fatty acids that have been suggested to be beneficial for MS risk,” said Dr. Bjørnevik. Both plant-derived PUFAs (ie, alpha-linolenic acid and linoleic acid), however, were associated with lower MS risk. The hazard ratio of MS for the top quintile of alpha-linolenic acid intake was 0.64.

Finally, Dr. Bjørnevik and colleagues compared the effect estimates for PUFA in the baseline analysis and in the cumulative analysis. The results of both analyses were similar. The overall intake of PUFAs was consistently associated with lower MS risk in both analyses. The fish-derived PUFAs were not significantly associated with MS risk in either analysis, but plant-derived PUFAs were associated with a lower MS risk in both analyses.

—Erik Greb

BARCELONA—Overall intake of polyunsaturated fatty acids (PUFAs) is associated with a lower risk of multiple sclerosis (MS), according to a prospective study described at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). The association mainly results from the effect of plant-derived PUFAs, especially alpha-linolenic acid. Fish-derived fatty acids appear to have no significant association with MS risk.

“While confirmation from other studies is needed, low PUFA intake may be another modifiable risk factor for MS,” said Kjetil Bjørnevik, MD, a research fellow in the neuroepidemiology group at Harvard T.H. Chan School of Public Health in Boston.

For more than 50 years, investigators have been studying the role that fat intake may play in the development of MS. In a 1952 New England Journal of Medicine article, researchers proposed that differences in the incidence of MS in distinct regions of Norway resulted from differences in diet. Subsequent animal studies suggested that omega-6 PUFAs have disease-modifying effects. A recent Cochrane review of randomized controlled trials concluded that PUFAs play no major role on the clinical outcomes of MS. A recent study, however, found an inverse association between overall omega-3 PUFA intake and MS risk.

Dr. Bjørnevik and colleagues prospectively followed more than 175,000 participants in the Nurses’ Health Studies I and II. Participants received questionnaires every second year, and their diet was assessed every fourth year. Dr. Bjørnevik’s team used food-frequency questionnaires to assess the nurses’ intake of alpha-linolenic acid, linoleic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) at baseline (ie, in 1984 and 1991) and during follow-up. The questionnaires had been specifically validated for the intake of PUFAs. The study’s follow-up time spanned several decades. During follow-up, 479 participants developed MS. Each diagnosis of MS was confirmed by a treating neurologist or by medical records. The researchers used a Cox proportional h<hl name="5"/>azard model to calculate acid ratios in each cohort and adjusted all analyses for age, ethnicity, BMI at age 18, smoking, vitamin D intake from supplements, and total caloric intake.

The investigators found no significant association between overall fat intake and MS risk. Neither saturated fat intake nor monounsaturated fat intake was associated with MS. “This [result] is interesting, as it has been suggested that a diet rich in saturated fat could increase MS risk,” said Dr. Bjørnevik. PUFA intake, however, was significantly associated with lower MS risk. The hazard ratio of MS among participants in the top quintile of PUFA intake was 0.66. The researchers also observed a trend toward lower risk of MS in the other quintiles of PUFA intake. No such association obtained for any other fat studied.

When the group examined the specific types of PUFAs, they found no association between dietary intake of fatty-fish-derived PUFAs, including EPA and DHA, and MS risk. “It is mostly these fatty acids that have been suggested to be beneficial for MS risk,” said Dr. Bjørnevik. Both plant-derived PUFAs (ie, alpha-linolenic acid and linoleic acid), however, were associated with lower MS risk. The hazard ratio of MS for the top quintile of alpha-linolenic acid intake was 0.64.

Finally, Dr. Bjørnevik and colleagues compared the effect estimates for PUFA in the baseline analysis and in the cumulative analysis. The results of both analyses were similar. The overall intake of PUFAs was consistently associated with lower MS risk in both analyses. The fish-derived PUFAs were not significantly associated with MS risk in either analysis, but plant-derived PUFAs were associated with a lower MS risk in both analyses.

—Erik Greb

BARCELONA—Extended-interval dose therapy with natalizumab may reduce the risk of progressive multifocal leukoencephalopathy (PML), reduce annualized relapse rate, and decrease the likelihood of new T2 lesions in high-risk patients with multiple sclerosis (MS), according to Lana Zhovtis-Ryerson, MD, a neurologist at New York University Langone MS Comprehensive Care Center in New York City.

Previous attempts to mitigate the risk of PML associated with natalizumab by altering the optimal dosing frequency through drug holidays compromised the efficacy of treatment, Dr. Zhovtis-Ryerson explained at the 31st Congress of the European Committee for Treatment and Research in MS (ECTRIMS). “Our hypothesis is that extending the dosing frequency up to eight and a half weeks may be safely enacted without clinical or radiographic worsening, and perhaps reduce PML risk,” she said.

Rebound of MS clinical activity tends to occur at 10 to 12 weeks following natalizumab withdrawal, Dr. Zhovtis-Ryerson said, suggesting that natalizumab-receptor saturation may be more germane to the drug’s disease-modifying effects than serum concentration. “Less frequent natalizumab dosing may result in submaximal receptor saturation, leading to a balance where there is adequate exclusion of white blood cells from the CNS, allowing the drug to be MS-protective,” she reported. At the same time, a PML-protective effect may occur because enough of the cells are entering the CNS to maintain immune surveillance of the John Cunningham virus (JCV) that causes PML.

Dr. Zhovtis-Ryerson and colleagues at nine MS centers in the United States examined 1,093 patients with MS who received standard-interval dose therapy with natalizumab and 905 patients with MS who received extended-interval dose therapy with natalizumab. Patients in the standard-interval dose group received 300-mg infusions of natalizumab every four weeks, while those in the extended-interval dose group waited up to eight weeks and five days between doses.

None of the patients in the extended-interval dose group developed PML during the study period, compared with four participants who developed PML in the standard-interval dose group. The study population had a total of 1,052 JCV-positive patient years. Post-market algorithms as reported by Biogen show an expected incidence of 2.5 cases of PML per 1,000 patients who are JCV-antibody positive, said Dr. Zhovtis-Ryerson.

The results are not statistically significant, but demonstrate a distinct trend, she added. The extended-dose interval group in this study would be considered to be at theoretically high risk of PML because of a combination of several risk factors, including testing positive for the JC antibody and having a high JCV index, a history of prior immunosuppression, and longer duration of therapy (ie, more than 24 months).

Annualized relapse rates were low in both groups, but “surprisingly,” the number of patients who showed clinical relapses was slightly lower in the extended-interval dose group, Dr. Zhovtis-Ryerson observed. Extended-dose interval schedules may be considered for patients with MS who are treated with natalizumab and are at high risk for PML, she added.

The investigators plan to continue monitoring the current cohort and to add pharmacodynamic studies evaluating CD34 cells and receptor saturation and concentration, Dr. Zhovtis-Ryerson said. A prospective, randomized trial of extended interval dosing with natalizumab is also needed, she concluded.

—Linda Peckel

BARCELONA—Extended-interval dose therapy with natalizumab may reduce the risk of progressive multifocal leukoencephalopathy (PML), reduce annualized relapse rate, and decrease the likelihood of new T2 lesions in high-risk patients with multiple sclerosis (MS), according to Lana Zhovtis-Ryerson, MD, a neurologist at New York University Langone MS Comprehensive Care Center in New York City.

Previous attempts to mitigate the risk of PML associated with natalizumab by altering the optimal dosing frequency through drug holidays compromised the efficacy of treatment, Dr. Zhovtis-Ryerson explained at the 31st Congress of the European Committee for Treatment and Research in MS (ECTRIMS). “Our hypothesis is that extending the dosing frequency up to eight and a half weeks may be safely enacted without clinical or radiographic worsening, and perhaps reduce PML risk,” she said.

Rebound of MS clinical activity tends to occur at 10 to 12 weeks following natalizumab withdrawal, Dr. Zhovtis-Ryerson said, suggesting that natalizumab-receptor saturation may be more germane to the drug’s disease-modifying effects than serum concentration. “Less frequent natalizumab dosing may result in submaximal receptor saturation, leading to a balance where there is adequate exclusion of white blood cells from the CNS, allowing the drug to be MS-protective,” she reported. At the same time, a PML-protective effect may occur because enough of the cells are entering the CNS to maintain immune surveillance of the John Cunningham virus (JCV) that causes PML.

Dr. Zhovtis-Ryerson and colleagues at nine MS centers in the United States examined 1,093 patients with MS who received standard-interval dose therapy with natalizumab and 905 patients with MS who received extended-interval dose therapy with natalizumab. Patients in the standard-interval dose group received 300-mg infusions of natalizumab every four weeks, while those in the extended-interval dose group waited up to eight weeks and five days between doses.

None of the patients in the extended-interval dose group developed PML during the study period, compared with four participants who developed PML in the standard-interval dose group. The study population had a total of 1,052 JCV-positive patient years. Post-market algorithms as reported by Biogen show an expected incidence of 2.5 cases of PML per 1,000 patients who are JCV-antibody positive, said Dr. Zhovtis-Ryerson.

The results are not statistically significant, but demonstrate a distinct trend, she added. The extended-dose interval group in this study would be considered to be at theoretically high risk of PML because of a combination of several risk factors, including testing positive for the JC antibody and having a high JCV index, a history of prior immunosuppression, and longer duration of therapy (ie, more than 24 months).

Annualized relapse rates were low in both groups, but “surprisingly,” the number of patients who showed clinical relapses was slightly lower in the extended-interval dose group, Dr. Zhovtis-Ryerson observed. Extended-dose interval schedules may be considered for patients with MS who are treated with natalizumab and are at high risk for PML, she added.

The investigators plan to continue monitoring the current cohort and to add pharmacodynamic studies evaluating CD34 cells and receptor saturation and concentration, Dr. Zhovtis-Ryerson said. A prospective, randomized trial of extended interval dosing with natalizumab is also needed, she concluded.

—Linda Peckel

BARCELONA—Extended-interval dose therapy with natalizumab may reduce the risk of progressive multifocal leukoencephalopathy (PML), reduce annualized relapse rate, and decrease the likelihood of new T2 lesions in high-risk patients with multiple sclerosis (MS), according to Lana Zhovtis-Ryerson, MD, a neurologist at New York University Langone MS Comprehensive Care Center in New York City.

Previous attempts to mitigate the risk of PML associated with natalizumab by altering the optimal dosing frequency through drug holidays compromised the efficacy of treatment, Dr. Zhovtis-Ryerson explained at the 31st Congress of the European Committee for Treatment and Research in MS (ECTRIMS). “Our hypothesis is that extending the dosing frequency up to eight and a half weeks may be safely enacted without clinical or radiographic worsening, and perhaps reduce PML risk,” she said.

Rebound of MS clinical activity tends to occur at 10 to 12 weeks following natalizumab withdrawal, Dr. Zhovtis-Ryerson said, suggesting that natalizumab-receptor saturation may be more germane to the drug’s disease-modifying effects than serum concentration. “Less frequent natalizumab dosing may result in submaximal receptor saturation, leading to a balance where there is adequate exclusion of white blood cells from the CNS, allowing the drug to be MS-protective,” she reported. At the same time, a PML-protective effect may occur because enough of the cells are entering the CNS to maintain immune surveillance of the John Cunningham virus (JCV) that causes PML.

Dr. Zhovtis-Ryerson and colleagues at nine MS centers in the United States examined 1,093 patients with MS who received standard-interval dose therapy with natalizumab and 905 patients with MS who received extended-interval dose therapy with natalizumab. Patients in the standard-interval dose group received 300-mg infusions of natalizumab every four weeks, while those in the extended-interval dose group waited up to eight weeks and five days between doses.

None of the patients in the extended-interval dose group developed PML during the study period, compared with four participants who developed PML in the standard-interval dose group. The study population had a total of 1,052 JCV-positive patient years. Post-market algorithms as reported by Biogen show an expected incidence of 2.5 cases of PML per 1,000 patients who are JCV-antibody positive, said Dr. Zhovtis-Ryerson.

The results are not statistically significant, but demonstrate a distinct trend, she added. The extended-dose interval group in this study would be considered to be at theoretically high risk of PML because of a combination of several risk factors, including testing positive for the JC antibody and having a high JCV index, a history of prior immunosuppression, and longer duration of therapy (ie, more than 24 months).

Annualized relapse rates were low in both groups, but “surprisingly,” the number of patients who showed clinical relapses was slightly lower in the extended-interval dose group, Dr. Zhovtis-Ryerson observed. Extended-dose interval schedules may be considered for patients with MS who are treated with natalizumab and are at high risk for PML, she added.

The investigators plan to continue monitoring the current cohort and to add pharmacodynamic studies evaluating CD34 cells and receptor saturation and concentration, Dr. Zhovtis-Ryerson said. A prospective, randomized trial of extended interval dosing with natalizumab is also needed, she concluded.

—Linda Peckel

BARCELONA—Neurologists can predict outcomes in patients with relapsing-remitting multiple sclerosis (MS) more accurately by adopting an expanded conception of no evidence of disease activity (NEDA), according to data presented at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). In addition to relapses, disability progression, and MRI activity, NEDA-4 includes change in brain volume over time. A patient’s NEDA-4 status at one year has advantages over the conventional NEDA-3 for predicting subsequent disability and structural damage for as long as seven years. NEDA-3 status at one year, however, is more closely correlated with relapses and new or enlarging T2 lesions than NEDA-4 status is.

Achieving NEDA reduces the probability of subsequent clinical and MRI disease activity. “These findings support the use of NEDA-4 as a more comprehensive and balanced measure for predicting long-term disease evolution in relapsing MS,” said Ludwig Kappos, MD, Chair of Neurology at University Hospital in Basel, Switzerland. “The finding needs further confirmation with longer follow-up and also other groups of patients.”

An Analysis of FREEDOMS Data

Dr. Kappos and colleagues examined data from the FREEDOMS extension studies, which compared fingolimod with placebo, to determine whether adding brain-volume change to NEDA-3 improved the latter’s predictive value. The disease outcomes that the researchers chose to study were confirmed relapse, new or enlarging T2 lesions on MRI, six-month confirmed disability progression, confirmed Expanded Disability Status Scale (EDSS) score of 6 or greater, and mean annual brain volume loss. Dr. Kappos and colleagues examined participants’ NEDA-4 and NEDA-3 statuses after one year of observation and after two years of observation. They analyzed the data with Cox regression analysis and the Akaike information criterion to evaluate the respective predictive values of NEDA-4 and NEDA-3.

The investigators found that NEDA-4 status at one year and NEDA-3 status at one year predicted time to first relapse, although NEDA-3 status was associated with a higher hazard ratio of first relapse than NEDA-4 was. Similarly, NEDA-4 status at one year and NEDA-3 status at one year predicted time to new T2 lesion activity, but NEDA-3 predicted this outcome slightly better than NEDA-4 did. NEDA-3 status was associated with a hazard ratio of 1.4 for six-month confirmed disability progression, and NEDA-4 was associated with a 1.6 hazard ratio for this outcome.

Few participants reached an EDSS of 6 or greater, which was the most stringent and perhaps the most clinically relevant criterion of the study, said Dr. Kappos. Failure to achieve NEDA-3 at one year increased the risk of this outcome by a hazard ratio of 1.6, and failure to achieve NEDA-4 at one year increased the risk of this outcome by a hazard ratio of 2.8. Likewise, failure to achieve NEDA-4 at one year was more closely correlated with continuous brain volume loss over the observation period than failure to achieve NEDA-3 at one year was.

Imaging Affects NEDA’s Predictive Value

The investigators obtained similar results when they examined patients’ NEDA-4 and NEDA-3 status at two years. NEDA-4 status at two years predicted brain volume change and attainment of an EDSS score of 6 or greater with more accuracy than did NEDA-3 status at two years. NEDA-3 status at two years had advantages over NEDA-4 status at two years for predicting new and enhancing lesions and confirmed relapses. Both methods of statistical analysis indicated similar conclusions.

Dr. Kappos acknowledged that MRI in the clinical setting has not been standardized. This lack of uniformity may affect the relative predictive value of new and enlarging T2 lesions, compared with gadolinium enhancement, which is more easily detected in nonstandardized scans, he added. The measurement of brain volume change depends to an even greater extent on a stringent methodology of the assessments and high-quality scans.

—Erik Greb

BARCELONA—Neurologists can predict outcomes in patients with relapsing-remitting multiple sclerosis (MS) more accurately by adopting an expanded conception of no evidence of disease activity (NEDA), according to data presented at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). In addition to relapses, disability progression, and MRI activity, NEDA-4 includes change in brain volume over time. A patient’s NEDA-4 status at one year has advantages over the conventional NEDA-3 for predicting subsequent disability and structural damage for as long as seven years. NEDA-3 status at one year, however, is more closely correlated with relapses and new or enlarging T2 lesions than NEDA-4 status is.

Achieving NEDA reduces the probability of subsequent clinical and MRI disease activity. “These findings support the use of NEDA-4 as a more comprehensive and balanced measure for predicting long-term disease evolution in relapsing MS,” said Ludwig Kappos, MD, Chair of Neurology at University Hospital in Basel, Switzerland. “The finding needs further confirmation with longer follow-up and also other groups of patients.”

An Analysis of FREEDOMS Data

Dr. Kappos and colleagues examined data from the FREEDOMS extension studies, which compared fingolimod with placebo, to determine whether adding brain-volume change to NEDA-3 improved the latter’s predictive value. The disease outcomes that the researchers chose to study were confirmed relapse, new or enlarging T2 lesions on MRI, six-month confirmed disability progression, confirmed Expanded Disability Status Scale (EDSS) score of 6 or greater, and mean annual brain volume loss. Dr. Kappos and colleagues examined participants’ NEDA-4 and NEDA-3 statuses after one year of observation and after two years of observation. They analyzed the data with Cox regression analysis and the Akaike information criterion to evaluate the respective predictive values of NEDA-4 and NEDA-3.

The investigators found that NEDA-4 status at one year and NEDA-3 status at one year predicted time to first relapse, although NEDA-3 status was associated with a higher hazard ratio of first relapse than NEDA-4 was. Similarly, NEDA-4 status at one year and NEDA-3 status at one year predicted time to new T2 lesion activity, but NEDA-3 predicted this outcome slightly better than NEDA-4 did. NEDA-3 status was associated with a hazard ratio of 1.4 for six-month confirmed disability progression, and NEDA-4 was associated with a 1.6 hazard ratio for this outcome.

Few participants reached an EDSS of 6 or greater, which was the most stringent and perhaps the most clinically relevant criterion of the study, said Dr. Kappos. Failure to achieve NEDA-3 at one year increased the risk of this outcome by a hazard ratio of 1.6, and failure to achieve NEDA-4 at one year increased the risk of this outcome by a hazard ratio of 2.8. Likewise, failure to achieve NEDA-4 at one year was more closely correlated with continuous brain volume loss over the observation period than failure to achieve NEDA-3 at one year was.

Imaging Affects NEDA’s Predictive Value

The investigators obtained similar results when they examined patients’ NEDA-4 and NEDA-3 status at two years. NEDA-4 status at two years predicted brain volume change and attainment of an EDSS score of 6 or greater with more accuracy than did NEDA-3 status at two years. NEDA-3 status at two years had advantages over NEDA-4 status at two years for predicting new and enhancing lesions and confirmed relapses. Both methods of statistical analysis indicated similar conclusions.

Dr. Kappos acknowledged that MRI in the clinical setting has not been standardized. This lack of uniformity may affect the relative predictive value of new and enlarging T2 lesions, compared with gadolinium enhancement, which is more easily detected in nonstandardized scans, he added. The measurement of brain volume change depends to an even greater extent on a stringent methodology of the assessments and high-quality scans.

—Erik Greb

BARCELONA—Neurologists can predict outcomes in patients with relapsing-remitting multiple sclerosis (MS) more accurately by adopting an expanded conception of no evidence of disease activity (NEDA), according to data presented at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). In addition to relapses, disability progression, and MRI activity, NEDA-4 includes change in brain volume over time. A patient’s NEDA-4 status at one year has advantages over the conventional NEDA-3 for predicting subsequent disability and structural damage for as long as seven years. NEDA-3 status at one year, however, is more closely correlated with relapses and new or enlarging T2 lesions than NEDA-4 status is.

Achieving NEDA reduces the probability of subsequent clinical and MRI disease activity. “These findings support the use of NEDA-4 as a more comprehensive and balanced measure for predicting long-term disease evolution in relapsing MS,” said Ludwig Kappos, MD, Chair of Neurology at University Hospital in Basel, Switzerland. “The finding needs further confirmation with longer follow-up and also other groups of patients.”

An Analysis of FREEDOMS Data

Dr. Kappos and colleagues examined data from the FREEDOMS extension studies, which compared fingolimod with placebo, to determine whether adding brain-volume change to NEDA-3 improved the latter’s predictive value. The disease outcomes that the researchers chose to study were confirmed relapse, new or enlarging T2 lesions on MRI, six-month confirmed disability progression, confirmed Expanded Disability Status Scale (EDSS) score of 6 or greater, and mean annual brain volume loss. Dr. Kappos and colleagues examined participants’ NEDA-4 and NEDA-3 statuses after one year of observation and after two years of observation. They analyzed the data with Cox regression analysis and the Akaike information criterion to evaluate the respective predictive values of NEDA-4 and NEDA-3.

The investigators found that NEDA-4 status at one year and NEDA-3 status at one year predicted time to first relapse, although NEDA-3 status was associated with a higher hazard ratio of first relapse than NEDA-4 was. Similarly, NEDA-4 status at one year and NEDA-3 status at one year predicted time to new T2 lesion activity, but NEDA-3 predicted this outcome slightly better than NEDA-4 did. NEDA-3 status was associated with a hazard ratio of 1.4 for six-month confirmed disability progression, and NEDA-4 was associated with a 1.6 hazard ratio for this outcome.

Few participants reached an EDSS of 6 or greater, which was the most stringent and perhaps the most clinically relevant criterion of the study, said Dr. Kappos. Failure to achieve NEDA-3 at one year increased the risk of this outcome by a hazard ratio of 1.6, and failure to achieve NEDA-4 at one year increased the risk of this outcome by a hazard ratio of 2.8. Likewise, failure to achieve NEDA-4 at one year was more closely correlated with continuous brain volume loss over the observation period than failure to achieve NEDA-3 at one year was.

Imaging Affects NEDA’s Predictive Value

The investigators obtained similar results when they examined patients’ NEDA-4 and NEDA-3 status at two years. NEDA-4 status at two years predicted brain volume change and attainment of an EDSS score of 6 or greater with more accuracy than did NEDA-3 status at two years. NEDA-3 status at two years had advantages over NEDA-4 status at two years for predicting new and enhancing lesions and confirmed relapses. Both methods of statistical analysis indicated similar conclusions.

Dr. Kappos acknowledged that MRI in the clinical setting has not been standardized. This lack of uniformity may affect the relative predictive value of new and enlarging T2 lesions, compared with gadolinium enhancement, which is more easily detected in nonstandardized scans, he added. The measurement of brain volume change depends to an even greater extent on a stringent methodology of the assessments and high-quality scans.

—Erik Greb

BARCELONA—Monitoring for relapses and MRI activity is the best means of predicting treatment response in patients with multiple sclerosis (MS), according to research presented at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Relapses are less frequent than MRI activity, however, especially among newly diagnosed patients.

Isolated MRI activity may help assess treatment response, but technical issues such as variability in image acquisition and scan comparison may make this approach difficult. “There is not a magic threshold for the number of new T2 lesions to be tolerated,” said Luca Prosperini, MD, PhD, Researcher in the Department of Neurology and Psychiatry at Sapienza University in Rome. The location of the lesions may be more relevant for defining treatment response than their number, he added.

Soon after disease onset, neurologists should monitor the patient for signs of aggressive disease, although this MS phenotype is less frequent. Characterizing clinical and MRI features is important because patients with aggressive disease may require aggressive treatment such as the induction approach, said Dr. Prosperini.

Examining MRI Activity

“MRI activity is probably the most sensitive tool to detect biological disease activity, even a few months after the treatment starts,” said Dr. Prosperini. Various published studies, in which patients underwent MRI at six to 12 months after treatment initiation, support early on-treatment MRI assessment as a way to predict future response to treatment, future relapses, and future disability in the medium and long terms.

In a 2004 post hoc analysis of the pivotal trial of interferon beta-1a, the investigators found that on-treatment MRI activity, especially new T2 lesions, was associated with increased disability and increased brain atrophy at the end of the two-year follow-up in the active group, but not in the placebo group. In a 2013 post hoc analysis that included data from the pivotal trial’s extension phase, patients who accumulated the highest level of disability at 15 years after treatment initiation had had gadolinium-enhancing lesions after one year of treatment.

In a 2009 study of 394 patients with relapsing-remitting MS who started different formulations of interferon beta and were reassessed after one year, Dr. Prosperini and colleagues found a clear dose-effect relationship between new T2 lesions and the risk of future disability. “The greater the number of new T2 lesions, the higher the risk of disability progression over a follow-up time of four or five years,” said Dr. Prosperini. “It’s even more relevant that this statistical figure can be replicated even after removing patients who relapsed in the first year. In other words, the dose-effect phenomenon of new T2 lesions assessed at one year is independent of early clinical disease activity.”

In 2013, Dr. Prosperini and colleagues compared two criteria for assessing nonresponse to treatment. They used the European Medicines Agency criteria for escalating to a second-line therapy, as well as the isolated MRI activity criteria (ie, patients with one or more gadolinium-enhancing lesion or two or more T2 lesions). Both sets of criteria predicted patients’ risk of future disability worsening with similarly high accuracy.

Monitoring Clinical and MRI Activity

In 2015, Boster et al presented a post hoc analysis of data from the FREEDOMS I and II trials, which followed 1,693 patients with relapsing-remitting MS who received fingolimod. The study’s follow-up lasted four years. On-treatment relapses, MRI activity, and a combination of both factors effectively predicted future relapses and future disability. In addition, focal MRI activity, defined as one or more gadolinium-enhancing lesion or two or more new T2 lesions, was the strongest predictor of failure to achieve no evidence of disease activity.

Some neurologists believe that isolated MRI activity is insufficient reason to change treatment, and a 2011 post hoc analysis by Sormani et al supports this idea. The researchers examined 560 patients with relapsing-remitting MS in the PRISMS trial of interferon beta-1a. The combination of relapses and new T2 lesions fully estimated the treatment effect at the end of two years, but each of these measures alone estimated only about 63% of the treatment effect.

Next, Sormani and colleagues developed a statistically optimized version of the Rio score in 2013 and analyzed how accurately it could classify patients’ risk of disability worsening after one year of treatment with interferon beta. Their data indicated that patients with a modified Rio score of 2 or greater have a high risk (ie, 50%) of disability worsening. A score of 2 corresponds to having at least two relapses in the first year or one relapse and at least five new T2 lesions, said Dr. Prosperini. Because patients at medium risk (ie, those with a modified Rio score of 1) are the most difficult to classify, in terms of treatment response, Sormani suggested that they be reassessed at 18 months of treatment. If these patients have one or more relapse, or two or more new T2 lesions, they should be considered nonresponders, the researchers concluded.

The amount of MRI activity to be tolerated remains a matter of debate. To investigate this question, Sormani and colleagues examined a large amount of data from the MRI in MS network about patients treated with interferon beta. The investigators determined that patients with two or more relapses or one relapse and three or more new T2 lesions were at highest risk of disability worsening. The investigators initially classified 130 patients as being at high risk, but the final number of patients who had sustained disability worsening was more than 300. “So, this score suffered from a low sensitivity,” said Dr. Prosperini.

Lesion Location May Predict Outcomes

“Another important question is the topography of the new lesions,” he continued. Galassi et al presented a study at ECTRIMS of 390 patients with relapsing-remitting MS who initiated treatment with interferon beta and were assessed at one year. Follow-up lasted for four years. When the researchers chose disability worsening as their final outcome and performed multivariable Cox regression analysis, they found that new infratentorial lesions and new spinal cord lesions were independent predictors of disability worsening. Lesion count, however, did not contribute to model fit.

For patients with a good prognosis, early and safe treatment should be the goals, said Dr. Prosperini. Early and effective treatment should be the goals for patients with a bad prognosis, he added. “Consider induction strategy in aggressive MS, even if it’s the less frequent phenotype. After treatment starts, we should assess patients correctly and regularly.”

—Erik Greb

BARCELONA—Monitoring for relapses and MRI activity is the best means of predicting treatment response in patients with multiple sclerosis (MS), according to research presented at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Relapses are less frequent than MRI activity, however, especially among newly diagnosed patients.

Isolated MRI activity may help assess treatment response, but technical issues such as variability in image acquisition and scan comparison may make this approach difficult. “There is not a magic threshold for the number of new T2 lesions to be tolerated,” said Luca Prosperini, MD, PhD, Researcher in the Department of Neurology and Psychiatry at Sapienza University in Rome. The location of the lesions may be more relevant for defining treatment response than their number, he added.

Soon after disease onset, neurologists should monitor the patient for signs of aggressive disease, although this MS phenotype is less frequent. Characterizing clinical and MRI features is important because patients with aggressive disease may require aggressive treatment such as the induction approach, said Dr. Prosperini.

Examining MRI Activity

“MRI activity is probably the most sensitive tool to detect biological disease activity, even a few months after the treatment starts,” said Dr. Prosperini. Various published studies, in which patients underwent MRI at six to 12 months after treatment initiation, support early on-treatment MRI assessment as a way to predict future response to treatment, future relapses, and future disability in the medium and long terms.

In a 2004 post hoc analysis of the pivotal trial of interferon beta-1a, the investigators found that on-treatment MRI activity, especially new T2 lesions, was associated with increased disability and increased brain atrophy at the end of the two-year follow-up in the active group, but not in the placebo group. In a 2013 post hoc analysis that included data from the pivotal trial’s extension phase, patients who accumulated the highest level of disability at 15 years after treatment initiation had had gadolinium-enhancing lesions after one year of treatment.

In a 2009 study of 394 patients with relapsing-remitting MS who started different formulations of interferon beta and were reassessed after one year, Dr. Prosperini and colleagues found a clear dose-effect relationship between new T2 lesions and the risk of future disability. “The greater the number of new T2 lesions, the higher the risk of disability progression over a follow-up time of four or five years,” said Dr. Prosperini. “It’s even more relevant that this statistical figure can be replicated even after removing patients who relapsed in the first year. In other words, the dose-effect phenomenon of new T2 lesions assessed at one year is independent of early clinical disease activity.”

In 2013, Dr. Prosperini and colleagues compared two criteria for assessing nonresponse to treatment. They used the European Medicines Agency criteria for escalating to a second-line therapy, as well as the isolated MRI activity criteria (ie, patients with one or more gadolinium-enhancing lesion or two or more T2 lesions). Both sets of criteria predicted patients’ risk of future disability worsening with similarly high accuracy.

Monitoring Clinical and MRI Activity

In 2015, Boster et al presented a post hoc analysis of data from the FREEDOMS I and II trials, which followed 1,693 patients with relapsing-remitting MS who received fingolimod. The study’s follow-up lasted four years. On-treatment relapses, MRI activity, and a combination of both factors effectively predicted future relapses and future disability. In addition, focal MRI activity, defined as one or more gadolinium-enhancing lesion or two or more new T2 lesions, was the strongest predictor of failure to achieve no evidence of disease activity.

Some neurologists believe that isolated MRI activity is insufficient reason to change treatment, and a 2011 post hoc analysis by Sormani et al supports this idea. The researchers examined 560 patients with relapsing-remitting MS in the PRISMS trial of interferon beta-1a. The combination of relapses and new T2 lesions fully estimated the treatment effect at the end of two years, but each of these measures alone estimated only about 63% of the treatment effect.

Next, Sormani and colleagues developed a statistically optimized version of the Rio score in 2013 and analyzed how accurately it could classify patients’ risk of disability worsening after one year of treatment with interferon beta. Their data indicated that patients with a modified Rio score of 2 or greater have a high risk (ie, 50%) of disability worsening. A score of 2 corresponds to having at least two relapses in the first year or one relapse and at least five new T2 lesions, said Dr. Prosperini. Because patients at medium risk (ie, those with a modified Rio score of 1) are the most difficult to classify, in terms of treatment response, Sormani suggested that they be reassessed at 18 months of treatment. If these patients have one or more relapse, or two or more new T2 lesions, they should be considered nonresponders, the researchers concluded.

The amount of MRI activity to be tolerated remains a matter of debate. To investigate this question, Sormani and colleagues examined a large amount of data from the MRI in MS network about patients treated with interferon beta. The investigators determined that patients with two or more relapses or one relapse and three or more new T2 lesions were at highest risk of disability worsening. The investigators initially classified 130 patients as being at high risk, but the final number of patients who had sustained disability worsening was more than 300. “So, this score suffered from a low sensitivity,” said Dr. Prosperini.

Lesion Location May Predict Outcomes

“Another important question is the topography of the new lesions,” he continued. Galassi et al presented a study at ECTRIMS of 390 patients with relapsing-remitting MS who initiated treatment with interferon beta and were assessed at one year. Follow-up lasted for four years. When the researchers chose disability worsening as their final outcome and performed multivariable Cox regression analysis, they found that new infratentorial lesions and new spinal cord lesions were independent predictors of disability worsening. Lesion count, however, did not contribute to model fit.

For patients with a good prognosis, early and safe treatment should be the goals, said Dr. Prosperini. Early and effective treatment should be the goals for patients with a bad prognosis, he added. “Consider induction strategy in aggressive MS, even if it’s the less frequent phenotype. After treatment starts, we should assess patients correctly and regularly.”

—Erik Greb

BARCELONA—Monitoring for relapses and MRI activity is the best means of predicting treatment response in patients with multiple sclerosis (MS), according to research presented at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Relapses are less frequent than MRI activity, however, especially among newly diagnosed patients.

Isolated MRI activity may help assess treatment response, but technical issues such as variability in image acquisition and scan comparison may make this approach difficult. “There is not a magic threshold for the number of new T2 lesions to be tolerated,” said Luca Prosperini, MD, PhD, Researcher in the Department of Neurology and Psychiatry at Sapienza University in Rome. The location of the lesions may be more relevant for defining treatment response than their number, he added.

Soon after disease onset, neurologists should monitor the patient for signs of aggressive disease, although this MS phenotype is less frequent. Characterizing clinical and MRI features is important because patients with aggressive disease may require aggressive treatment such as the induction approach, said Dr. Prosperini.

Examining MRI Activity

“MRI activity is probably the most sensitive tool to detect biological disease activity, even a few months after the treatment starts,” said Dr. Prosperini. Various published studies, in which patients underwent MRI at six to 12 months after treatment initiation, support early on-treatment MRI assessment as a way to predict future response to treatment, future relapses, and future disability in the medium and long terms.

In a 2004 post hoc analysis of the pivotal trial of interferon beta-1a, the investigators found that on-treatment MRI activity, especially new T2 lesions, was associated with increased disability and increased brain atrophy at the end of the two-year follow-up in the active group, but not in the placebo group. In a 2013 post hoc analysis that included data from the pivotal trial’s extension phase, patients who accumulated the highest level of disability at 15 years after treatment initiation had had gadolinium-enhancing lesions after one year of treatment.

In a 2009 study of 394 patients with relapsing-remitting MS who started different formulations of interferon beta and were reassessed after one year, Dr. Prosperini and colleagues found a clear dose-effect relationship between new T2 lesions and the risk of future disability. “The greater the number of new T2 lesions, the higher the risk of disability progression over a follow-up time of four or five years,” said Dr. Prosperini. “It’s even more relevant that this statistical figure can be replicated even after removing patients who relapsed in the first year. In other words, the dose-effect phenomenon of new T2 lesions assessed at one year is independent of early clinical disease activity.”

In 2013, Dr. Prosperini and colleagues compared two criteria for assessing nonresponse to treatment. They used the European Medicines Agency criteria for escalating to a second-line therapy, as well as the isolated MRI activity criteria (ie, patients with one or more gadolinium-enhancing lesion or two or more T2 lesions). Both sets of criteria predicted patients’ risk of future disability worsening with similarly high accuracy.

Monitoring Clinical and MRI Activity

In 2015, Boster et al presented a post hoc analysis of data from the FREEDOMS I and II trials, which followed 1,693 patients with relapsing-remitting MS who received fingolimod. The study’s follow-up lasted four years. On-treatment relapses, MRI activity, and a combination of both factors effectively predicted future relapses and future disability. In addition, focal MRI activity, defined as one or more gadolinium-enhancing lesion or two or more new T2 lesions, was the strongest predictor of failure to achieve no evidence of disease activity.

Some neurologists believe that isolated MRI activity is insufficient reason to change treatment, and a 2011 post hoc analysis by Sormani et al supports this idea. The researchers examined 560 patients with relapsing-remitting MS in the PRISMS trial of interferon beta-1a. The combination of relapses and new T2 lesions fully estimated the treatment effect at the end of two years, but each of these measures alone estimated only about 63% of the treatment effect.

Next, Sormani and colleagues developed a statistically optimized version of the Rio score in 2013 and analyzed how accurately it could classify patients’ risk of disability worsening after one year of treatment with interferon beta. Their data indicated that patients with a modified Rio score of 2 or greater have a high risk (ie, 50%) of disability worsening. A score of 2 corresponds to having at least two relapses in the first year or one relapse and at least five new T2 lesions, said Dr. Prosperini. Because patients at medium risk (ie, those with a modified Rio score of 1) are the most difficult to classify, in terms of treatment response, Sormani suggested that they be reassessed at 18 months of treatment. If these patients have one or more relapse, or two or more new T2 lesions, they should be considered nonresponders, the researchers concluded.

The amount of MRI activity to be tolerated remains a matter of debate. To investigate this question, Sormani and colleagues examined a large amount of data from the MRI in MS network about patients treated with interferon beta. The investigators determined that patients with two or more relapses or one relapse and three or more new T2 lesions were at highest risk of disability worsening. The investigators initially classified 130 patients as being at high risk, but the final number of patients who had sustained disability worsening was more than 300. “So, this score suffered from a low sensitivity,” said Dr. Prosperini.

Lesion Location May Predict Outcomes

“Another important question is the topography of the new lesions,” he continued. Galassi et al presented a study at ECTRIMS of 390 patients with relapsing-remitting MS who initiated treatment with interferon beta and were assessed at one year. Follow-up lasted for four years. When the researchers chose disability worsening as their final outcome and performed multivariable Cox regression analysis, they found that new infratentorial lesions and new spinal cord lesions were independent predictors of disability worsening. Lesion count, however, did not contribute to model fit.

For patients with a good prognosis, early and safe treatment should be the goals, said Dr. Prosperini. Early and effective treatment should be the goals for patients with a bad prognosis, he added. “Consider induction strategy in aggressive MS, even if it’s the less frequent phenotype. After treatment starts, we should assess patients correctly and regularly.”

—Erik Greb

BARCELONA—Researchers are actively seeking means of promoting myelin repair in patients with multiple sclerosis (MS), and some drugs have advanced from the preclinical to the clinical phase, according to an overview presented at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). The therapy furthest along in development is the anti-LINGO1 monoclonal antibody, which promotes endogenous remyelination. Exogenous strategies for myelin repair are still in preclinical stages, and perhaps the most promising of these methods relies on induced pluripotent stem cells.

“There is still a crucial need of markers: clinical markers of repair, biomarkers of repair, [and] imaging markers of repair,” said Catherine Lubetzki, MD, PhD, Professor of Neurology at Pierre and Marie Curie University in Paris. Trial designs for remyelinating strategies also need to be optimized, she added.

Exogenous Strategies

Exogenous strategies introduce myelinating cells into the patient. Oligodendrocyte progenitor cells (OPCs), Schwann cells, and neuronal stem cells are under investigation as potential exogenous methods of remyelination.

Induced pluripotent stem cells have been the major advance in this area in the past several years, said Dr. Lubetzki. Investigators use a mixture of transcription factors to induce skin fibroblasts to become stem cells, and then reprogram them into an oligodendrocyte cell phase. This method can enable autologous grafts. Goldman and colleagues transplanted OPCs generated from human fibroblasts into the brains of dysmyelinating mutant mice. The OPCs promoted extensive remyelination and improved the mice’s survival.

Selecting Candidates Based on Their Mechanisms

One method of selecting drug candidates that could promote endogenous remyelination is based on the molecules’ mechanisms of action. Dr. Lubetzki and colleagues studied eliprodil because of its known neuroprotective properties. In 1999, they demonstrated that eliprodil strongly stimulated CNS myelination in an in vitro system of myelination.

More recently, Dr. Lubetzki and colleagues have been investigating molecules that guide OPCs to demyelinated areas. In a proof-of-concept study, the investigators found that semaphorin 3F performs such a function. They also concluded that speeding the recruitment of OPCs to demyelinated plaques results in accelerated remyelination. Approximately one year ago, the team began an ongoing preclinical study in which they are overexpressing semaphorin 3F at lesion sites to speed the recruitment of OPCs and accelerate the remyelination process. The goal is to stimulate remyelination during the window of time when axonal damage is reversible, said Dr. Lubetzki.

Perhaps the best-known investigational strategy for promoting endogenous repair involves the protein LINGO1. Researchers at Biogen found that when LINGO1 is expressed at the surface of immature oligodendrocytes, the protein blocks their maturation and prevents myelination. They developed a monoclonal antibody to suppress the expression of LINGO1, thus allowing oligodendrocytes’ maturation to proceed and improving myelination and remyelination.

The anti-LINGO1 monoclonal anti­body yielded positive results in experimental models, and investigators subsequently began two phase II studies of the treatment in humans. Results of the first study were reported at ECTRIMS; the monoclonal antibody improved full-field visual evoked potential latency in patients with acute optic neuritis, and this result was consistent with improved remyelination. The other phase II study includes 419 patients with relapsing-remitting MS and is ongoing.

Screening Banks of Molecules

The other main approach to selecting drug candidates that could promote endogenous remyelination is to screen a large bank of molecules. This approach “will lead to an increasing number of candidates and new screening tools,” said Dr. Lubetzki.

Several years ago, Tesar and colleagues developed a method of deriving OPCs from epiblast stem cells. The investigators recently used this cellular model to perform high-throughput screening of a large library of bioactive small molecules. They identified seven compounds that, at low concentrations, enhanced the generation of mature oligodendrocytes from OPCs. After they validated this method in various models, Tesar and colleagues identified two drug candidates: miconazole, an antifungal drug, and clobetasol, an immunosuppressant. The researchers now have “a strong rationale for translation into human subjects with MS,” said Dr. Lubetzki.

In 2014, Chan et al developed a micropillar array system for screening molecules. Oligodendrocytes placed in the array are able to wrap membrane around the micropillars, and investigators can measure the thickness of the membrane. The method thus is a binary indicant of the presence or absence of myelination. When Chan and colleagues used the micropillar array model to perform high-throughput screening, they identified a cluster of antimuscarinic compounds that enhanced oligodendrocyte differentiation. One of these drugs was clemastine, an antihistaminic compound that promotes myelination. Researchers are studying clemastine as a remyelinating agent in an ongoing phase II study of 50 patients with relapsing-remitting MS.

Finally, Zalc and colleagues developed a method of medium-throughput screening based on a transgenic tadpole model. Adding metronidazole to the water bath in which the tadpole swims causes a drastic reduction in the number of oligodendrocytes within the tadpole’s optic nerve. When researchers remove the metronidazole from the bath, new oligodendrocytes form within the optic nerve. Zalc and colleagues have used the model to analyze drugs that appear to promote remyelination, such as clemastine, benztropine, and retinoic acid.

One question that researchers have not resolved yet is whether newly formed myelin, which is thinner than normal myelin, is as durable as myelin formed in the normal way. “Twenty years after remyelination, will this myelin be as resistant as the normally made myelin? We don’t know. But at least for the short term or the medium term, this newly formed myelin seems to be as efficient as the usually formed myelin,” concluded Dr. Lubetzki.

—Erik Greb

BARCELONA—Researchers are actively seeking means of promoting myelin repair in patients with multiple sclerosis (MS), and some drugs have advanced from the preclinical to the clinical phase, according to an overview presented at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). The therapy furthest along in development is the anti-LINGO1 monoclonal antibody, which promotes endogenous remyelination. Exogenous strategies for myelin repair are still in preclinical stages, and perhaps the most promising of these methods relies on induced pluripotent stem cells.

“There is still a crucial need of markers: clinical markers of repair, biomarkers of repair, [and] imaging markers of repair,” said Catherine Lubetzki, MD, PhD, Professor of Neurology at Pierre and Marie Curie University in Paris. Trial designs for remyelinating strategies also need to be optimized, she added.

Exogenous Strategies

Exogenous strategies introduce myelinating cells into the patient. Oligodendrocyte progenitor cells (OPCs), Schwann cells, and neuronal stem cells are under investigation as potential exogenous methods of remyelination.

Induced pluripotent stem cells have been the major advance in this area in the past several years, said Dr. Lubetzki. Investigators use a mixture of transcription factors to induce skin fibroblasts to become stem cells, and then reprogram them into an oligodendrocyte cell phase. This method can enable autologous grafts. Goldman and colleagues transplanted OPCs generated from human fibroblasts into the brains of dysmyelinating mutant mice. The OPCs promoted extensive remyelination and improved the mice’s survival.

Selecting Candidates Based on Their Mechanisms

One method of selecting drug candidates that could promote endogenous remyelination is based on the molecules’ mechanisms of action. Dr. Lubetzki and colleagues studied eliprodil because of its known neuroprotective properties. In 1999, they demonstrated that eliprodil strongly stimulated CNS myelination in an in vitro system of myelination.

More recently, Dr. Lubetzki and colleagues have been investigating molecules that guide OPCs to demyelinated areas. In a proof-of-concept study, the investigators found that semaphorin 3F performs such a function. They also concluded that speeding the recruitment of OPCs to demyelinated plaques results in accelerated remyelination. Approximately one year ago, the team began an ongoing preclinical study in which they are overexpressing semaphorin 3F at lesion sites to speed the recruitment of OPCs and accelerate the remyelination process. The goal is to stimulate remyelination during the window of time when axonal damage is reversible, said Dr. Lubetzki.

Perhaps the best-known investigational strategy for promoting endogenous repair involves the protein LINGO1. Researchers at Biogen found that when LINGO1 is expressed at the surface of immature oligodendrocytes, the protein blocks their maturation and prevents myelination. They developed a monoclonal antibody to suppress the expression of LINGO1, thus allowing oligodendrocytes’ maturation to proceed and improving myelination and remyelination.

The anti-LINGO1 monoclonal anti­body yielded positive results in experimental models, and investigators subsequently began two phase II studies of the treatment in humans. Results of the first study were reported at ECTRIMS; the monoclonal antibody improved full-field visual evoked potential latency in patients with acute optic neuritis, and this result was consistent with improved remyelination. The other phase II study includes 419 patients with relapsing-remitting MS and is ongoing.

Screening Banks of Molecules

The other main approach to selecting drug candidates that could promote endogenous remyelination is to screen a large bank of molecules. This approach “will lead to an increasing number of candidates and new screening tools,” said Dr. Lubetzki.

Several years ago, Tesar and colleagues developed a method of deriving OPCs from epiblast stem cells. The investigators recently used this cellular model to perform high-throughput screening of a large library of bioactive small molecules. They identified seven compounds that, at low concentrations, enhanced the generation of mature oligodendrocytes from OPCs. After they validated this method in various models, Tesar and colleagues identified two drug candidates: miconazole, an antifungal drug, and clobetasol, an immunosuppressant. The researchers now have “a strong rationale for translation into human subjects with MS,” said Dr. Lubetzki.

In 2014, Chan et al developed a micropillar array system for screening molecules. Oligodendrocytes placed in the array are able to wrap membrane around the micropillars, and investigators can measure the thickness of the membrane. The method thus is a binary indicant of the presence or absence of myelination. When Chan and colleagues used the micropillar array model to perform high-throughput screening, they identified a cluster of antimuscarinic compounds that enhanced oligodendrocyte differentiation. One of these drugs was clemastine, an antihistaminic compound that promotes myelination. Researchers are studying clemastine as a remyelinating agent in an ongoing phase II study of 50 patients with relapsing-remitting MS.

Finally, Zalc and colleagues developed a method of medium-throughput screening based on a transgenic tadpole model. Adding metronidazole to the water bath in which the tadpole swims causes a drastic reduction in the number of oligodendrocytes within the tadpole’s optic nerve. When researchers remove the metronidazole from the bath, new oligodendrocytes form within the optic nerve. Zalc and colleagues have used the model to analyze drugs that appear to promote remyelination, such as clemastine, benztropine, and retinoic acid.

One question that researchers have not resolved yet is whether newly formed myelin, which is thinner than normal myelin, is as durable as myelin formed in the normal way. “Twenty years after remyelination, will this myelin be as resistant as the normally made myelin? We don’t know. But at least for the short term or the medium term, this newly formed myelin seems to be as efficient as the usually formed myelin,” concluded Dr. Lubetzki.

—Erik Greb

BARCELONA—Researchers are actively seeking means of promoting myelin repair in patients with multiple sclerosis (MS), and some drugs have advanced from the preclinical to the clinical phase, according to an overview presented at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). The therapy furthest along in development is the anti-LINGO1 monoclonal antibody, which promotes endogenous remyelination. Exogenous strategies for myelin repair are still in preclinical stages, and perhaps the most promising of these methods relies on induced pluripotent stem cells.

“There is still a crucial need of markers: clinical markers of repair, biomarkers of repair, [and] imaging markers of repair,” said Catherine Lubetzki, MD, PhD, Professor of Neurology at Pierre and Marie Curie University in Paris. Trial designs for remyelinating strategies also need to be optimized, she added.

Exogenous Strategies

Exogenous strategies introduce myelinating cells into the patient. Oligodendrocyte progenitor cells (OPCs), Schwann cells, and neuronal stem cells are under investigation as potential exogenous methods of remyelination.

Induced pluripotent stem cells have been the major advance in this area in the past several years, said Dr. Lubetzki. Investigators use a mixture of transcription factors to induce skin fibroblasts to become stem cells, and then reprogram them into an oligodendrocyte cell phase. This method can enable autologous grafts. Goldman and colleagues transplanted OPCs generated from human fibroblasts into the brains of dysmyelinating mutant mice. The OPCs promoted extensive remyelination and improved the mice’s survival.

Selecting Candidates Based on Their Mechanisms

One method of selecting drug candidates that could promote endogenous remyelination is based on the molecules’ mechanisms of action. Dr. Lubetzki and colleagues studied eliprodil because of its known neuroprotective properties. In 1999, they demonstrated that eliprodil strongly stimulated CNS myelination in an in vitro system of myelination.

More recently, Dr. Lubetzki and colleagues have been investigating molecules that guide OPCs to demyelinated areas. In a proof-of-concept study, the investigators found that semaphorin 3F performs such a function. They also concluded that speeding the recruitment of OPCs to demyelinated plaques results in accelerated remyelination. Approximately one year ago, the team began an ongoing preclinical study in which they are overexpressing semaphorin 3F at lesion sites to speed the recruitment of OPCs and accelerate the remyelination process. The goal is to stimulate remyelination during the window of time when axonal damage is reversible, said Dr. Lubetzki.

Perhaps the best-known investigational strategy for promoting endogenous repair involves the protein LINGO1. Researchers at Biogen found that when LINGO1 is expressed at the surface of immature oligodendrocytes, the protein blocks their maturation and prevents myelination. They developed a monoclonal antibody to suppress the expression of LINGO1, thus allowing oligodendrocytes’ maturation to proceed and improving myelination and remyelination.

The anti-LINGO1 monoclonal anti­body yielded positive results in experimental models, and investigators subsequently began two phase II studies of the treatment in humans. Results of the first study were reported at ECTRIMS; the monoclonal antibody improved full-field visual evoked potential latency in patients with acute optic neuritis, and this result was consistent with improved remyelination. The other phase II study includes 419 patients with relapsing-remitting MS and is ongoing.

Screening Banks of Molecules

The other main approach to selecting drug candidates that could promote endogenous remyelination is to screen a large bank of molecules. This approach “will lead to an increasing number of candidates and new screening tools,” said Dr. Lubetzki.

Several years ago, Tesar and colleagues developed a method of deriving OPCs from epiblast stem cells. The investigators recently used this cellular model to perform high-throughput screening of a large library of bioactive small molecules. They identified seven compounds that, at low concentrations, enhanced the generation of mature oligodendrocytes from OPCs. After they validated this method in various models, Tesar and colleagues identified two drug candidates: miconazole, an antifungal drug, and clobetasol, an immunosuppressant. The researchers now have “a strong rationale for translation into human subjects with MS,” said Dr. Lubetzki.

In 2014, Chan et al developed a micropillar array system for screening molecules. Oligodendrocytes placed in the array are able to wrap membrane around the micropillars, and investigators can measure the thickness of the membrane. The method thus is a binary indicant of the presence or absence of myelination. When Chan and colleagues used the micropillar array model to perform high-throughput screening, they identified a cluster of antimuscarinic compounds that enhanced oligodendrocyte differentiation. One of these drugs was clemastine, an antihistaminic compound that promotes myelination. Researchers are studying clemastine as a remyelinating agent in an ongoing phase II study of 50 patients with relapsing-remitting MS.

Finally, Zalc and colleagues developed a method of medium-throughput screening based on a transgenic tadpole model. Adding metronidazole to the water bath in which the tadpole swims causes a drastic reduction in the number of oligodendrocytes within the tadpole’s optic nerve. When researchers remove the metronidazole from the bath, new oligodendrocytes form within the optic nerve. Zalc and colleagues have used the model to analyze drugs that appear to promote remyelination, such as clemastine, benztropine, and retinoic acid.

One question that researchers have not resolved yet is whether newly formed myelin, which is thinner than normal myelin, is as durable as myelin formed in the normal way. “Twenty years after remyelination, will this myelin be as resistant as the normally made myelin? We don’t know. But at least for the short term or the medium term, this newly formed myelin seems to be as efficient as the usually formed myelin,” concluded Dr. Lubetzki.

—Erik Greb

BARCELONA—In the months following a first clinical event suggestive of multiple sclerosis (MS), MRI findings and Expanded Disability Status Scale (EDSS) score can help predict which patients will have sustained disability progression, according to the results of a longitudinal study presented at the 31st Congress of the European Committee for Treatment and Research in MS (ECTRIMS). The significance of these findings lies in the fact that MS is a heterogeneous disease with a broad spectrum of phenotypes, which makes it difficult to predict disease course, said Tomas Uher, MD, a neurologist at Charles University in Prague. Thus, early identification of patients with MS who are at the highest risk of disease progression may help guide therapeutic decision making.

Testing MRI and Clinical Indicators

The current investigation was a substudy of the Study of Early Interferon β1-a Treatment in High Risk Subjects after Clinically Isolated Syndrome (SET). The primary outcome was sustained disability progression, defined as a 1.0-point increase in the EDSS confirmed after 12 months or, if the EDSS score was 0 at baseline, an increase of 1.5 points.

A total of 210 patients who had had a first clinical event suggestive of MS within the previous four months were included in the analysis. Subjects had a baseline EDSS score of 3.5 or lower, at least two T2 lesions as seen on brain MRI, and at least two CSF-restricted oligoclonal bands. In addition to MRI assessment at baseline, six months, and 12 months, patients underwent clinical visits every three months and were followed for a minimum of four years, with an average follow-up duration of six years. Sixty-six percent of participants were women, and the population’s mean age was 29.

A total of 42 clinical and MRI predictors were analyzed, including the MS Functional Composite and gray matter and white matter volume change. Results were adjusted for age, sex, and disease duration.

Significantly Increased Risks

By study’s end, 61% of subjects had experienced a new relapse, and 20% had experienced sustained disability progression. Statistically significant factors shown to be the best predictors of disease progression were any new relapse, any change in EDSS score, and T1 lesion volume greater than 1.25 mL at six months or at 12 months; a decrease in corpus callosum volume greater than 0.5% and whole-brain volume change greater than 0.4% at six months; and corpus callosum change greater than 0.7% at 12 months.

“When we looked at individual predictors, we found that patients had a twofold to as much as a fivefold greater risk of disability progression, compared with patients who didn’t fulfill the criteria,” Dr. Uher noted. For example, the hazard ratio for sustained disease progression was 2.2 for new relapse at six months, 3.3 for corpus callosum volume decrease at six months, and 4.9 for EDSS change at 12 months.

Further studies are needed to confirm these results, as well as to determine which disease-modifying therapies would prevent disability progression in patients at highest risk. Additional studies also are needed to evaluate the feasibility of MRI volumetry in clinical practice, Dr. Uher concluded.

—Adriene Marshall

BARCELONA—In the months following a first clinical event suggestive of multiple sclerosis (MS), MRI findings and Expanded Disability Status Scale (EDSS) score can help predict which patients will have sustained disability progression, according to the results of a longitudinal study presented at the 31st Congress of the European Committee for Treatment and Research in MS (ECTRIMS). The significance of these findings lies in the fact that MS is a heterogeneous disease with a broad spectrum of phenotypes, which makes it difficult to predict disease course, said Tomas Uher, MD, a neurologist at Charles University in Prague. Thus, early identification of patients with MS who are at the highest risk of disease progression may help guide therapeutic decision making.

Testing MRI and Clinical Indicators

The current investigation was a substudy of the Study of Early Interferon β1-a Treatment in High Risk Subjects after Clinically Isolated Syndrome (SET). The primary outcome was sustained disability progression, defined as a 1.0-point increase in the EDSS confirmed after 12 months or, if the EDSS score was 0 at baseline, an increase of 1.5 points.

A total of 210 patients who had had a first clinical event suggestive of MS within the previous four months were included in the analysis. Subjects had a baseline EDSS score of 3.5 or lower, at least two T2 lesions as seen on brain MRI, and at least two CSF-restricted oligoclonal bands. In addition to MRI assessment at baseline, six months, and 12 months, patients underwent clinical visits every three months and were followed for a minimum of four years, with an average follow-up duration of six years. Sixty-six percent of participants were women, and the population’s mean age was 29.

A total of 42 clinical and MRI predictors were analyzed, including the MS Functional Composite and gray matter and white matter volume change. Results were adjusted for age, sex, and disease duration.

Significantly Increased Risks

By study’s end, 61% of subjects had experienced a new relapse, and 20% had experienced sustained disability progression. Statistically significant factors shown to be the best predictors of disease progression were any new relapse, any change in EDSS score, and T1 lesion volume greater than 1.25 mL at six months or at 12 months; a decrease in corpus callosum volume greater than 0.5% and whole-brain volume change greater than 0.4% at six months; and corpus callosum change greater than 0.7% at 12 months.

“When we looked at individual predictors, we found that patients had a twofold to as much as a fivefold greater risk of disability progression, compared with patients who didn’t fulfill the criteria,” Dr. Uher noted. For example, the hazard ratio for sustained disease progression was 2.2 for new relapse at six months, 3.3 for corpus callosum volume decrease at six months, and 4.9 for EDSS change at 12 months.

Further studies are needed to confirm these results, as well as to determine which disease-modifying therapies would prevent disability progression in patients at highest risk. Additional studies also are needed to evaluate the feasibility of MRI volumetry in clinical practice, Dr. Uher concluded.

—Adriene Marshall

BARCELONA—In the months following a first clinical event suggestive of multiple sclerosis (MS), MRI findings and Expanded Disability Status Scale (EDSS) score can help predict which patients will have sustained disability progression, according to the results of a longitudinal study presented at the 31st Congress of the European Committee for Treatment and Research in MS (ECTRIMS). The significance of these findings lies in the fact that MS is a heterogeneous disease with a broad spectrum of phenotypes, which makes it difficult to predict disease course, said Tomas Uher, MD, a neurologist at Charles University in Prague. Thus, early identification of patients with MS who are at the highest risk of disease progression may help guide therapeutic decision making.

Testing MRI and Clinical Indicators

The current investigation was a substudy of the Study of Early Interferon β1-a Treatment in High Risk Subjects after Clinically Isolated Syndrome (SET). The primary outcome was sustained disability progression, defined as a 1.0-point increase in the EDSS confirmed after 12 months or, if the EDSS score was 0 at baseline, an increase of 1.5 points.

A total of 210 patients who had had a first clinical event suggestive of MS within the previous four months were included in the analysis. Subjects had a baseline EDSS score of 3.5 or lower, at least two T2 lesions as seen on brain MRI, and at least two CSF-restricted oligoclonal bands. In addition to MRI assessment at baseline, six months, and 12 months, patients underwent clinical visits every three months and were followed for a minimum of four years, with an average follow-up duration of six years. Sixty-six percent of participants were women, and the population’s mean age was 29.

A total of 42 clinical and MRI predictors were analyzed, including the MS Functional Composite and gray matter and white matter volume change. Results were adjusted for age, sex, and disease duration.

Significantly Increased Risks

By study’s end, 61% of subjects had experienced a new relapse, and 20% had experienced sustained disability progression. Statistically significant factors shown to be the best predictors of disease progression were any new relapse, any change in EDSS score, and T1 lesion volume greater than 1.25 mL at six months or at 12 months; a decrease in corpus callosum volume greater than 0.5% and whole-brain volume change greater than 0.4% at six months; and corpus callosum change greater than 0.7% at 12 months.

“When we looked at individual predictors, we found that patients had a twofold to as much as a fivefold greater risk of disability progression, compared with patients who didn’t fulfill the criteria,” Dr. Uher noted. For example, the hazard ratio for sustained disease progression was 2.2 for new relapse at six months, 3.3 for corpus callosum volume decrease at six months, and 4.9 for EDSS change at 12 months.

Further studies are needed to confirm these results, as well as to determine which disease-modifying therapies would prevent disability progression in patients at highest risk. Additional studies also are needed to evaluate the feasibility of MRI volumetry in clinical practice, Dr. Uher concluded.

—Adriene Marshall

There may be a benefit to exclusive breastfeeding for women with multiple sclerosis (MS). Women with MS who breastfed their infants exclusively for two months had a lower risk of relapse during the first six months after giving birth, compared with women who did not breastfeed exclusively, according to an article published online ahead of print August 31 in JAMA Neurology.

Previous investigations found that about 20% to 30% of women with MS experience a relapse within three to four months post partum. Currently, there are no therapies or interventions to prevent a relapse, and data on the effect of breastfeeding on postpartum MS relapse are conflicting.

Kerstin Hellwig, MD, a neurologist at St. Josef-Hospital at Ruhr-University Bochum in Germany, and colleagues collected data from 201 pregnant women with relapsing-remitting MS. Each woman was monitored for any relapse for as long as one year after birth. Of these participants, 120 (59.7%) chose to breastfeed exclusively for at least two months, while 42 (20.9%) opted for a combined breastfeeding–supplemental regimen, and 39 (19.4%) did not intend to breastfeed at all. Most of the women (88.6%) in the study cohort had used disease-modifying therapies (DMTs) before pregnancy.

Of the women who breastfed exclusively, 29 (24.2%) experienced a relapse within six months post partum, compared with 31 (38.3%) of those who did not breastfeed exclusively. The effect of exclusive breastfeeding “seems to be plausible,” Dr. Hellwig and coauthors said, since disease activity returned in the second half of the postpartum year in exclusively breastfeeding women, corresponding to the introduction of supplemental feedings and the return of menses.

Dr. Hellwig and colleagues also reported that, compared with women who breastfed exclusively, those who resumed DMTs early had a higher risk of postpartum relapse.

“Relapse in the first six months post partum may be diminished by exclusive breastfeeding, but once regular feedings are introduced, disease activity is likely to return,” Dr. Hellwig and colleagues said. “Taken together, our findings suggest that exclusive breastfeeding acts like a modestly effective treatment with a natural end date.” The researchers concluded that “Women with MS should be supported if they choose to breastfeed exclusively, since it clearly does not increase the risk of postpartum relapse.”

—Ashley Payton

There may be a benefit to exclusive breastfeeding for women with multiple sclerosis (MS). Women with MS who breastfed their infants exclusively for two months had a lower risk of relapse during the first six months after giving birth, compared with women who did not breastfeed exclusively, according to an article published online ahead of print August 31 in JAMA Neurology.

Previous investigations found that about 20% to 30% of women with MS experience a relapse within three to four months post partum. Currently, there are no therapies or interventions to prevent a relapse, and data on the effect of breastfeeding on postpartum MS relapse are conflicting.

Kerstin Hellwig, MD, a neurologist at St. Josef-Hospital at Ruhr-University Bochum in Germany, and colleagues collected data from 201 pregnant women with relapsing-remitting MS. Each woman was monitored for any relapse for as long as one year after birth. Of these participants, 120 (59.7%) chose to breastfeed exclusively for at least two months, while 42 (20.9%) opted for a combined breastfeeding–supplemental regimen, and 39 (19.4%) did not intend to breastfeed at all. Most of the women (88.6%) in the study cohort had used disease-modifying therapies (DMTs) before pregnancy.

Of the women who breastfed exclusively, 29 (24.2%) experienced a relapse within six months post partum, compared with 31 (38.3%) of those who did not breastfeed exclusively. The effect of exclusive breastfeeding “seems to be plausible,” Dr. Hellwig and coauthors said, since disease activity returned in the second half of the postpartum year in exclusively breastfeeding women, corresponding to the introduction of supplemental feedings and the return of menses.

Dr. Hellwig and colleagues also reported that, compared with women who breastfed exclusively, those who resumed DMTs early had a higher risk of postpartum relapse.

“Relapse in the first six months post partum may be diminished by exclusive breastfeeding, but once regular feedings are introduced, disease activity is likely to return,” Dr. Hellwig and colleagues said. “Taken together, our findings suggest that exclusive breastfeeding acts like a modestly effective treatment with a natural end date.” The researchers concluded that “Women with MS should be supported if they choose to breastfeed exclusively, since it clearly does not increase the risk of postpartum relapse.”

—Ashley Payton

There may be a benefit to exclusive breastfeeding for women with multiple sclerosis (MS). Women with MS who breastfed their infants exclusively for two months had a lower risk of relapse during the first six months after giving birth, compared with women who did not breastfeed exclusively, according to an article published online ahead of print August 31 in JAMA Neurology.

Previous investigations found that about 20% to 30% of women with MS experience a relapse within three to four months post partum. Currently, there are no therapies or interventions to prevent a relapse, and data on the effect of breastfeeding on postpartum MS relapse are conflicting.

Kerstin Hellwig, MD, a neurologist at St. Josef-Hospital at Ruhr-University Bochum in Germany, and colleagues collected data from 201 pregnant women with relapsing-remitting MS. Each woman was monitored for any relapse for as long as one year after birth. Of these participants, 120 (59.7%) chose to breastfeed exclusively for at least two months, while 42 (20.9%) opted for a combined breastfeeding–supplemental regimen, and 39 (19.4%) did not intend to breastfeed at all. Most of the women (88.6%) in the study cohort had used disease-modifying therapies (DMTs) before pregnancy.

Of the women who breastfed exclusively, 29 (24.2%) experienced a relapse within six months post partum, compared with 31 (38.3%) of those who did not breastfeed exclusively. The effect of exclusive breastfeeding “seems to be plausible,” Dr. Hellwig and coauthors said, since disease activity returned in the second half of the postpartum year in exclusively breastfeeding women, corresponding to the introduction of supplemental feedings and the return of menses.

Dr. Hellwig and colleagues also reported that, compared with women who breastfed exclusively, those who resumed DMTs early had a higher risk of postpartum relapse.

“Relapse in the first six months post partum may be diminished by exclusive breastfeeding, but once regular feedings are introduced, disease activity is likely to return,” Dr. Hellwig and colleagues said. “Taken together, our findings suggest that exclusive breastfeeding acts like a modestly effective treatment with a natural end date.” The researchers concluded that “Women with MS should be supported if they choose to breastfeed exclusively, since it clearly does not increase the risk of postpartum relapse.”

—Ashley Payton

CHICAGO—Transcranial direct-current stimulation (tDCS) reduces fatigue and improves aspects of verbal memory in patients with multiple sclerosis (MS), according to data from a pilot study presented at the 140th Annual Meeting of the American Neurological Association. The stimulation may not consistently improve working memory, however, contrary to the researchers’ expectations.

Cognitive dysfunction, including working memory deficits, and fatigue are common and debilitating symptoms of MS, said Tracy D. Vannorsdall, PhD, Assistant Professor of Neurology and Psychiatry and Behavioral Sciences at Johns Hopkins University School of Medicine in Baltimore. Prior studies have shown that tDCS enhances working memory in healthy adults. To see if tDCS might improve working memory in patients with MS, Dr. Vannorsdall and her research colleagues conducted a sham-controlled, single-blind crossover study.

A Sham Stimulation Control

The investigators recruited five patients with secondary progressive MS from the Johns Hopkins MS Center. All participants were right-handed native English speakers, and three of the participants were women. Participants were between the ages of 42 and 57, with an average age of 50. They had a mean estimated IQ of 119 and a mean 18.4 years of schooling.

Participants completed cognitive testing before and after receiving 2 mA of anodal or sham stimulation to the left dorsolateral prefrontal cortex for 30 minutes once per day for five consecutive days. Investigators administered the current using a NeuroConn Stimulator Plus. For the sham stimulation, researchers increased the anodal current to 2 mA and decreased it to 0 mA over 30 seconds. After a four-week washout period, participants repeated the study procedures under the stimulation condition to which they had not been assigned originally.

Evaluating Cognition

Participants completed the Minimal Assessment of Cognitive Functioning in MS, a seven-subtest battery that assesses verbal learning and memory, visuospatial learning and memory, working memory, processing speed, verbal fluency, executive functioning, and perceptual accuracy. Participants also completed self-report measures of mood and fatigue and responded to a mental and physical side effects questionnaire. The researchers performed two-tailed paired-samples t-tests to compare changes in scores across anodal and sham conditions.

No adverse events occurred. Depression scale ratings did not significantly change during tDCS, compared with sham stimulation.

Fatigue Severity Scale

Participants’ scores on the Fatigue Severity Scale increased by 7 points over the course of five days of sham stimulation, compared with a decrease of 4.6 points over the course of anodal stimulation.

In addition, researchers observed a trend toward improved verbal immediate recall under the anodal condition, compared with sham stimulation. Anodal stimulation also was associated with better performance across most cognitive tests, but the differences were not significant. The study was underpowered to detect whether reduced fatigue contributed to the improvements in cognition. “These preliminary findings suggest that tDCS may ameliorate fatigue and cognitive dysfunction in secondary progressive MS,” concluded the researchers. Future studies will investigate the mechanism of these effects.

—Jake Remaly

CHICAGO—Transcranial direct-current stimulation (tDCS) reduces fatigue and improves aspects of verbal memory in patients with multiple sclerosis (MS), according to data from a pilot study presented at the 140th Annual Meeting of the American Neurological Association. The stimulation may not consistently improve working memory, however, contrary to the researchers’ expectations.

Cognitive dysfunction, including working memory deficits, and fatigue are common and debilitating symptoms of MS, said Tracy D. Vannorsdall, PhD, Assistant Professor of Neurology and Psychiatry and Behavioral Sciences at Johns Hopkins University School of Medicine in Baltimore. Prior studies have shown that tDCS enhances working memory in healthy adults. To see if tDCS might improve working memory in patients with MS, Dr. Vannorsdall and her research colleagues conducted a sham-controlled, single-blind crossover study.

A Sham Stimulation Control

The investigators recruited five patients with secondary progressive MS from the Johns Hopkins MS Center. All participants were right-handed native English speakers, and three of the participants were women. Participants were between the ages of 42 and 57, with an average age of 50. They had a mean estimated IQ of 119 and a mean 18.4 years of schooling.

Participants completed cognitive testing before and after receiving 2 mA of anodal or sham stimulation to the left dorsolateral prefrontal cortex for 30 minutes once per day for five consecutive days. Investigators administered the current using a NeuroConn Stimulator Plus. For the sham stimulation, researchers increased the anodal current to 2 mA and decreased it to 0 mA over 30 seconds. After a four-week washout period, participants repeated the study procedures under the stimulation condition to which they had not been assigned originally.

Evaluating Cognition

Participants completed the Minimal Assessment of Cognitive Functioning in MS, a seven-subtest battery that assesses verbal learning and memory, visuospatial learning and memory, working memory, processing speed, verbal fluency, executive functioning, and perceptual accuracy. Participants also completed self-report measures of mood and fatigue and responded to a mental and physical side effects questionnaire. The researchers performed two-tailed paired-samples t-tests to compare changes in scores across anodal and sham conditions.

No adverse events occurred. Depression scale ratings did not significantly change during tDCS, compared with sham stimulation.

Fatigue Severity Scale

Participants’ scores on the Fatigue Severity Scale increased by 7 points over the course of five days of sham stimulation, compared with a decrease of 4.6 points over the course of anodal stimulation.

In addition, researchers observed a trend toward improved verbal immediate recall under the anodal condition, compared with sham stimulation. Anodal stimulation also was associated with better performance across most cognitive tests, but the differences were not significant. The study was underpowered to detect whether reduced fatigue contributed to the improvements in cognition. “These preliminary findings suggest that tDCS may ameliorate fatigue and cognitive dysfunction in secondary progressive MS,” concluded the researchers. Future studies will investigate the mechanism of these effects.

—Jake Remaly

CHICAGO—Transcranial direct-current stimulation (tDCS) reduces fatigue and improves aspects of verbal memory in patients with multiple sclerosis (MS), according to data from a pilot study presented at the 140th Annual Meeting of the American Neurological Association. The stimulation may not consistently improve working memory, however, contrary to the researchers’ expectations.

Cognitive dysfunction, including working memory deficits, and fatigue are common and debilitating symptoms of MS, said Tracy D. Vannorsdall, PhD, Assistant Professor of Neurology and Psychiatry and Behavioral Sciences at Johns Hopkins University School of Medicine in Baltimore. Prior studies have shown that tDCS enhances working memory in healthy adults. To see if tDCS might improve working memory in patients with MS, Dr. Vannorsdall and her research colleagues conducted a sham-controlled, single-blind crossover study.

A Sham Stimulation Control

The investigators recruited five patients with secondary progressive MS from the Johns Hopkins MS Center. All participants were right-handed native English speakers, and three of the participants were women. Participants were between the ages of 42 and 57, with an average age of 50. They had a mean estimated IQ of 119 and a mean 18.4 years of schooling.

Participants completed cognitive testing before and after receiving 2 mA of anodal or sham stimulation to the left dorsolateral prefrontal cortex for 30 minutes once per day for five consecutive days. Investigators administered the current using a NeuroConn Stimulator Plus. For the sham stimulation, researchers increased the anodal current to 2 mA and decreased it to 0 mA over 30 seconds. After a four-week washout period, participants repeated the study procedures under the stimulation condition to which they had not been assigned originally.

Evaluating Cognition

Participants completed the Minimal Assessment of Cognitive Functioning in MS, a seven-subtest battery that assesses verbal learning and memory, visuospatial learning and memory, working memory, processing speed, verbal fluency, executive functioning, and perceptual accuracy. Participants also completed self-report measures of mood and fatigue and responded to a mental and physical side effects questionnaire. The researchers performed two-tailed paired-samples t-tests to compare changes in scores across anodal and sham conditions.

No adverse events occurred. Depression scale ratings did not significantly change during tDCS, compared with sham stimulation.

Fatigue Severity Scale

Participants’ scores on the Fatigue Severity Scale increased by 7 points over the course of five days of sham stimulation, compared with a decrease of 4.6 points over the course of anodal stimulation.

In addition, researchers observed a trend toward improved verbal immediate recall under the anodal condition, compared with sham stimulation. Anodal stimulation also was associated with better performance across most cognitive tests, but the differences were not significant. The study was underpowered to detect whether reduced fatigue contributed to the improvements in cognition. “These preliminary findings suggest that tDCS may ameliorate fatigue and cognitive dysfunction in secondary progressive MS,” concluded the researchers. Future studies will investigate the mechanism of these effects.

—Jake Remaly

Anti-tumor necrosis factor (TNF) therapy for inflammatory bowel disease appears to double the relative risk of developing central demyelinating disease, though the absolute risk remains small, according to a preliminary report published online ahead of print October 5 in JAMA Internal Medicine.

Previous case reports have suggested a possible association between anti-TNF agents taken for inflammatory bowel disease and later development of demyelinating diseases, but a definitive link has been difficult to establish because of the rarity of these disorders and the suspicion that there already may be an underlying association between inflammatory bowel disease and demyelinating disease.

Researchers examined the issue by analyzing data from nationwide Danish health registries for patients with inflammatory bowel disease and medication exposure. They identified 4,504 patients treated during a 14-year period who had inflammatory bowel disease and took anti-TNF agents, and 16,429 patients with inflammatory bowel disease matched for sex, age, and disease duration who did not take the medications, according to Nynne Nyboe Andersen, MD, a doctoral student in the Department of Epidemiology Research at Statens Serum Institut in Copenhagen, and her associates.

Eleven patients in the group exposed to medication had central demyelinating events. Two patients had multiple sclerosis, five patients had optic neuritis, and four patients had other central demyelinating disease. Medication-exposed patients had 7.5 events per 10,000 person-years.

In comparison, 17 patients in the unexposed group had central demyelinating events. Five patients had multiple sclerosis, six patients had optic neuritis, one patient had transverse myelitis, and five patients had other central demyelinating disease. The unexposed group had 3.3 events per 10,000 person-years.

The hazard ratio for developing central demyelinating disease after exposure to anti-TNF agents was 2.19, according to the investigators. These preliminary findings represent the first report of this association and must be confirmed in future studies, according to the researchers. “If true, the observed association could either be attributed to the unmasking of a latent demyelinating disease or to the emergence of a de novo demyelinating disease,” said Dr. Nyboe Andersen.

—Mary Ann Moon

Anti-tumor necrosis factor (TNF) therapy for inflammatory bowel disease appears to double the relative risk of developing central demyelinating disease, though the absolute risk remains small, according to a preliminary report published online ahead of print October 5 in JAMA Internal Medicine.

Previous case reports have suggested a possible association between anti-TNF agents taken for inflammatory bowel disease and later development of demyelinating diseases, but a definitive link has been difficult to establish because of the rarity of these disorders and the suspicion that there already may be an underlying association between inflammatory bowel disease and demyelinating disease.

Researchers examined the issue by analyzing data from nationwide Danish health registries for patients with inflammatory bowel disease and medication exposure. They identified 4,504 patients treated during a 14-year period who had inflammatory bowel disease and took anti-TNF agents, and 16,429 patients with inflammatory bowel disease matched for sex, age, and disease duration who did not take the medications, according to Nynne Nyboe Andersen, MD, a doctoral student in the Department of Epidemiology Research at Statens Serum Institut in Copenhagen, and her associates.

Eleven patients in the group exposed to medication had central demyelinating events. Two patients had multiple sclerosis, five patients had optic neuritis, and four patients had other central demyelinating disease. Medication-exposed patients had 7.5 events per 10,000 person-years.

In comparison, 17 patients in the unexposed group had central demyelinating events. Five patients had multiple sclerosis, six patients had optic neuritis, one patient had transverse myelitis, and five patients had other central demyelinating disease. The unexposed group had 3.3 events per 10,000 person-years.

The hazard ratio for developing central demyelinating disease after exposure to anti-TNF agents was 2.19, according to the investigators. These preliminary findings represent the first report of this association and must be confirmed in future studies, according to the researchers. “If true, the observed association could either be attributed to the unmasking of a latent demyelinating disease or to the emergence of a de novo demyelinating disease,” said Dr. Nyboe Andersen.

—Mary Ann Moon

Anti-tumor necrosis factor (TNF) therapy for inflammatory bowel disease appears to double the relative risk of developing central demyelinating disease, though the absolute risk remains small, according to a preliminary report published online ahead of print October 5 in JAMA Internal Medicine.

Previous case reports have suggested a possible association between anti-TNF agents taken for inflammatory bowel disease and later development of demyelinating diseases, but a definitive link has been difficult to establish because of the rarity of these disorders and the suspicion that there already may be an underlying association between inflammatory bowel disease and demyelinating disease.

Researchers examined the issue by analyzing data from nationwide Danish health registries for patients with inflammatory bowel disease and medication exposure. They identified 4,504 patients treated during a 14-year period who had inflammatory bowel disease and took anti-TNF agents, and 16,429 patients with inflammatory bowel disease matched for sex, age, and disease duration who did not take the medications, according to Nynne Nyboe Andersen, MD, a doctoral student in the Department of Epidemiology Research at Statens Serum Institut in Copenhagen, and her associates.

Eleven patients in the group exposed to medication had central demyelinating events. Two patients had multiple sclerosis, five patients had optic neuritis, and four patients had other central demyelinating disease. Medication-exposed patients had 7.5 events per 10,000 person-years.

In comparison, 17 patients in the unexposed group had central demyelinating events. Five patients had multiple sclerosis, six patients had optic neuritis, one patient had transverse myelitis, and five patients had other central demyelinating disease. The unexposed group had 3.3 events per 10,000 person-years.

The hazard ratio for developing central demyelinating disease after exposure to anti-TNF agents was 2.19, according to the investigators. These preliminary findings represent the first report of this association and must be confirmed in future studies, according to the researchers. “If true, the observed association could either be attributed to the unmasking of a latent demyelinating disease or to the emergence of a de novo demyelinating disease,” said Dr. Nyboe Andersen.

—Mary Ann Moon

As treatment for relapsing-remitting multiple sclerosis, glatiramer acetate generic drug and brand drug had equivalent efficacy, safety, and tolerability, according to a study of 794 patients with relapsing-remitting multiple sclerosis aged 18 to 55 years. Researchers found:

• Estimated mean numbers of gadolinium-enhancing lesions with generic drug and brand drug were lower than with placebo, confirming study sensitivity.

• For gadolinium-enhancing, the estimated ratio of generic drug to brand drug was within the predefined equivalence margin.

• The incidence, spectrum, and severity of reported adverse events, including injection site reactions, were similar in the generic drug and brand drug groups.

Citation: Cohen J, Belova A, Selmaj K, et al. Equivalence of generic glatiramer acetate in multiple sclerosis. [Published online ahead of print October 12, 2015]. JAMA Neurol. doi: 10.1001/jamaneurol.2015.2154.

As treatment for relapsing-remitting multiple sclerosis, glatiramer acetate generic drug and brand drug had equivalent efficacy, safety, and tolerability, according to a study of 794 patients with relapsing-remitting multiple sclerosis aged 18 to 55 years. Researchers found:

• Estimated mean numbers of gadolinium-enhancing lesions with generic drug and brand drug were lower than with placebo, confirming study sensitivity.

• For gadolinium-enhancing, the estimated ratio of generic drug to brand drug was within the predefined equivalence margin.

• The incidence, spectrum, and severity of reported adverse events, including injection site reactions, were similar in the generic drug and brand drug groups.

Citation: Cohen J, Belova A, Selmaj K, et al. Equivalence of generic glatiramer acetate in multiple sclerosis. [Published online ahead of print October 12, 2015]. JAMA Neurol. doi: 10.1001/jamaneurol.2015.2154.

As treatment for relapsing-remitting multiple sclerosis, glatiramer acetate generic drug and brand drug had equivalent efficacy, safety, and tolerability, according to a study of 794 patients with relapsing-remitting multiple sclerosis aged 18 to 55 years. Researchers found:

• Estimated mean numbers of gadolinium-enhancing lesions with generic drug and brand drug were lower than with placebo, confirming study sensitivity.

• For gadolinium-enhancing, the estimated ratio of generic drug to brand drug was within the predefined equivalence margin.

• The incidence, spectrum, and severity of reported adverse events, including injection site reactions, were similar in the generic drug and brand drug groups.

Citation: Cohen J, Belova A, Selmaj K, et al. Equivalence of generic glatiramer acetate in multiple sclerosis. [Published online ahead of print October 12, 2015]. JAMA Neurol. doi: 10.1001/jamaneurol.2015.2154.